34
C H A P T E R
Drugs Used in Disorders
of Coagulation
James L. Zehnder, MD
C ASE STUDY
A 25-year-old woman presents to the emergency depart-
ment complaining of acute onset of shortness of breath and
pleuritic pain. She had been in her usual state of health until
2 days prior when she noted that her left leg was swollen and
red. Her only medication was oral contraceptives. Family
history was significant for a history of “blood clots” in mul-
tiple members of the maternal side of her family. Physical
examination demonstrates an anxious woman with stable
vital signs. The left lower extremity demonstrates erythema
Hemostasis refers to the finely regulated dynamic process of main-
taining fluidity of the blood, repairing vascular injury, and limit-
ing blood loss while avoiding vessel occlusion (thrombosis) and
inadequate perfusion of vital organs. Either extreme—excessive
bleeding or thrombosis—represents a breakdown of the hemo-
static mechanism. Common causes of dysregulated hemostasis
include hereditary or acquired defects in the clotting mechanism
and secondary effects of infection or cancer. Atrial fibrillation is
associated with stasis of blood in the atria, formation of clots, and
increased risk of occlusive stroke. Because of the high prevalence
of chronic atrial fibrillation, especially in the older population,
use of anticoagulants is common. Guidelines for the use of oral
anticoagulants (CHA2DS2-VASC score, see January C et al refer-
ence) are based on various risk factors (congestive heart failure,
hypertension, age, diabetes, history of stroke, vascular disease,
and sex). The drugs used to inhibit thrombosis and to limit abnor-
mal bleeding are the subjects of this chapter.
608
and edema and is tender to touch. Oxygen saturation by
fingertip pulse oximeter while breathing room air is 87%
(normal > 90%). Ultrasound reveals a deep vein thrombosis
in the left lower extremity; chest computed tomography scan
confirms the presence of pulmonary emboli. Laboratory
blood tests indicate elevated d-dimer levels. What therapy
is indicated acutely? What are the long-term therapy
options? How long should she be treated? Should this indi-
vidual use oral contraceptives?
MECHANISMS OF BLOOD
COAGULATION
The vascular endothelial cell layer lining blood vessels has an
anticoagulant phenotype, and circulating blood platelets and
clotting factors do not normally adhere to it to an appreciable
extent. In the setting of vascular injury, the endothelial cell layer
rapidly undergoes a series of changes resulting in a more proco-
agulant phenotype. Injury exposes reactive subendothelial matrix
proteins such as collagen and von Willebrand factor, which
results in platelet adherence and activation, and secretion and
synthesis of vasoconstrictors and platelet-recruiting and activating
molecules. Thus, thromboxane A2 (TXA2) is synthesized from
arachidonic acid within platelets and is a platelet activator and
potent vasoconstrictor. Products secreted from platelet granules
include adenosine diphosphate (ADP), a powerful inducer of
platelet aggregation, and serotonin (5-HT), which stimulates
 CHAPTER 34  Drugs Used in Disorders of Coagulation     609

Wall defect

C vWF EC

GP Ib
Ia
ADP GP
PGI2
TXA2
5-HT –
GP Intrinsic Extrinsic
IIb/IIIa

Platelets Xa
Degranulation
+ GP + +
+ IIb/IIIa Activation
+
GP +
IIb/IIIa
Fibrin
Thrombin Prothrombin
+

Fibrinogen

FIGURE 34–1  Thrombus formation at the site of the damaged vascular wall (EC, endothelial cell) and the role of platelets and clotting fac-
tors. Platelet membrane receptors include the glycoprotein (GP) Ia receptor, binding to collagen (C); GP Ib receptor, binding von Willebrand fac-
tor (vWF); and GP IIb/IIIa, which binds fibrinogen and other macromolecules. Antiplatelet prostacyclin (PGI2) is released from the endothelium.
Aggregating substances released from the degranulating platelet include adenosine diphosphate (ADP), thromboxane A2 (TXA2), and serotonin
(5-HT). Production of factor Xa by intrinsic and extrinsic pathways is detailed in Figure 34–2. (Redrawn and reproduced, with permission, from Simoons ML,
Decker JW: New directions in anticoagulant and antiplatelet treatment. [Editorial.] Br Heart J 1995;74:337.)

aggregation and vasoconstriction. Activation of platelets results in
a conformational change in the αIIbβIII integrin (IIb/IIIa) recep-
tor, enabling it to bind fibrinogen, which cross-links adjacent
platelets, resulting in aggregation and formation of a platelet plug
(Figure 34–1). Simultaneously, the coagulation system cascade
is activated, resulting in thrombin generation and a fibrin clot,
which stabilizes the platelet plug (see below). Knowledge of the
hemostatic mechanism is important for diagnosis of bleeding
disorders. Patients with defects in the formation of the primary
platelet plug (defects in primary hemostasis, eg, platelet function
defects, von Willebrand disease) typically bleed from surface sites
(gingiva, skin, heavy menses) with injury. In contrast, patients
with defects in the clotting mechanism (secondary hemostasis,
eg, hemophilia A) tend to bleed into deep tissues (joints, muscle,
retroperitoneum), often with no apparent inciting event, and
bleeding may recur unpredictably.
The platelet is central to normal hemostasis and thromboem-
bolic disease, and is the target of many therapies discussed in this
chapter. Platelet-rich thrombi (white thrombi) form in the high
flow rate and high shear force environment of arteries. Occlusive
arterial thrombi cause serious disease by producing downstream
ischemia of extremities or vital organs, and they can result in limb
amputation or organ failure. Venous clots tend to be more fibrin-
rich, contain large numbers of trapped red blood cells, and are
recognized pathologically as red thrombi. Deep venous thrombi
(DVT) can cause severe swelling and pain of the affected extremity,
but the most feared consequence is pulmonary embolism (PE).
This occurs when part or all of the clot breaks off from its location
in the deep venous system and travels as an embolus through the
right side of the heart and into the pulmonary arterial circulation.
Occlusion of a large pulmonary artery by an embolic clot can pre-
cipitate acute right heart failure and sudden death. In addition lung
ischemia or infarction will occur distal to the occluded pulmonary
arterial segment. Such emboli usually arise from the deep venous
system of the proximal lower extremities or pelvis. Although all
thrombi are mixed, the platelet nidus dominates the arterial throm-
bus and the fibrin tail dominates the venous thrombus.
BLOOD COAGULATION CASCADE
Blood coagulates due to the transformation of soluble fibrinogen
into insoluble fibrin by the enzyme thrombin. Several circulat-
ing proteins interact in a cascading series of limited proteolytic
reactions (Figure 34–2). At each step, a clotting factor zymogen
undergoes limited proteolysis and becomes an active protease
(eg, factor VII is converted to factor VIIa). Each protease factor
activates the next clotting factor in the sequence, culminating in
the formation of thrombin (factor IIa). Several of these factors are
targets for drug therapy (Table 34–1).
Thrombin has a central role in hemostasis and has many func-
tions. In clotting, thrombin proteolytically cleaves small peptides
610    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

Clotting in the Lab TABLE 34–1  Blood clotting factors and drugs that
1
affect them.
Contact
factors Component Target for the
or Factor Common Synonym Action of:

XIa I Fibrinogen
Tissue
II Prothrombin Heparin, dabigatran (IIa);
factor,
warfarin (synthesis)
IXa VIIa
Intrinsic VIIIa Extrinsic III Tissue thromboplastin
pathway pathway
(PT) IV Calcium
(PTT) Xa
V Proaccelerin
Va
VII Proconvertin Warfarin (synthesis)
II IIa
VIII Antihemophilic factor
(AHF)
fibrinogen fibrin IX Christmas factor, Warfarin (synthesis)
clot plasma thromboplas-
tin component (PTC)
X Stuart-Prower factor Heparin, rivaroxiban,
Clotting in Vivo apixaban, edoxaban (Xa);
warfarin (synthesis)
Wound
XI Plasma thromboplas-
Natural Anticoagulant Systems tin antecedent (PTA)
Antithrombin III/heparin XII Hageman factor
TF/VIIa
IXa Protein C/Protein S XIII Fibrin-stabilizing factor

Tissue factor pathway Proteins C Warfarin (synthesis)

inhibitor and S
XIa VIIIa Xa
Plasminogen Thrombolytic enzymes,
Va aminocaproic acid
1
Thrombin See Figure 34–2 and text for additional details.

ensures that under normal circumstances, repair of vascular injury

Fibrin
FIGURE 34–2  A model of blood coagulation. With tissue factor
(TF), factor VII forms an activated complex (VIIa-TF) that catalyzes the
activation of factor IX to factor IXa. Activated factor XIa also catalyzes
this reaction. Tissue factor pathway inhibitor inhibits the catalytic
action of the VIIa-TF complex. The cascade proceeds as shown, result-
ing ultimately in the conversion of fibrinogen to fibrin, an essential
component of a functional clot. The two major anticoagulant drugs,
heparin and warfarin, have very different actions. Heparin, acting
in the blood, directly activates anticlotting factors, specifically anti-
thrombin, which inactivates the factors enclosed in rectangles. War-
farin, acting in the liver, inhibits the synthesis of the factors enclosed
in circles. Proteins C and S exert anticlotting effects by inactivating
activated factors Va and VIIIa.
from fibrinogen, allowing fibrinogen to polymerize and form
a fibrin clot. Thrombin also activates many upstream clotting
factors, leading to more thrombin generation, and activates fac-
tor XIII, a transaminase that cross-links the fibrin polymer and
stabilizes the clot. Thrombin is a potent platelet activator and
mitogen. Thrombin also exerts anticoagulant effects by activating
the protein C pathway, which attenuates the clotting response
(Figure 34–2). It should therefore be apparent that the response to
vascular injury is a complex and precisely modulated process that
occurs without thrombosis and downstream ischemia—that is,
the response is proportionate and reversible. Eventually vascular
remodeling and repair occur with reversion to the quiescent rest-
ing anticoagulant endothelial cell phenotype.
Initiation of Clotting: The Tissue
Factor-VIIa Complex
The main initiator of blood coagulation in vivo is the tissue factor
(TF)–factor VIIa pathway (Figure 34–2). Tissue factor is a trans-
membrane protein ubiquitously expressed outside the vasculature
but not normally expressed in an active form within vessels. The
exposure of TF on damaged endothelium or to blood that has
extravasated into tissue binds TF to factor VIIa. This complex,
in turn, activates factors X and IX. Factor Xa along with factor
Va forms the prothrombinase complex on activated cell surfaces,
which catalyzes the conversion of prothrombin (factor II) to
thrombin (factor IIa). Thrombin, in turn, activates upstream clot-
ting factors, primarily factors V, VIII, and XI, resulting in ampli-
fication of thrombin generation. The TF-factor VIIa-catalyzed
activation of factor Xa is regulated by tissue factor pathway
inhibitor (TFPI). Thus after initial activation of factor X to Xa
by TF-VIIa, further propagation of the clot occurs by feedback
amplification of thrombin through the intrinsic pathway factors
 CHAPTER 34  Drugs Used in Disorders of Coagulation     611

VIII and IX. (This provides an explanation for why patients with
deficiency of factor VIII or IX—hemophilia A and hemophilia B, Plasminogen
respectively—have a severe bleeding disorder.) Activation Inhibition
It is also important to note that the coagulation mechanism Various stimuli
in vivo does not occur in solution, but is localized to activated
+
cell surfaces expressing anionic phospholipids such as phosphati-
dylserine, and is mediated by Ca2+ bridging between the anionic Blood Blood + − Antiactivators
phospholipids and γ-carboxyglutamic acid residues of the clotting proactivator activator

factors. This is the basis for using calcium chelators such as eth- t-PA, urokinase + − Aminocaproic
ylenediamine tetraacetic acid (EDTA) or citrate to prevent blood acid
Streptokinase
from clotting in a test tube.
Antithrombin (AT) is an endogenous anticoagulant and a Activator +
member of the serine protease inhibitor (serpin) family; it inacti-
Proactivator
vates the serine proteases IIa, IXa, Xa, XIa, and XIIa. The endog- Plasmin
enous anticoagulants protein C and protein S attenuate the blood Anistreplase
clotting cascade by proteolysis of the two cofactors Va and VIIIa. + +
From an evolutionary perspective, it is of interest that factors V
Thrombin Fibrin
and VIII have an identical overall domain structure and consider- Fibrinogen
Fibrinogen Fibrin clot degradation
degradation
able homology, consistent with a common ancestor gene; likewise products
products,
Factor XIII D-dimer
the serine proteases are descendants of a trypsin-like common
ancestor. Thus, the TF-VIIa initiating complex, serine proteases,
and cofactors each have their own lineage-specific attenuation FIGURE 34–3  Schematic representation of the fibrinolytic
mechanism (Figure 34–2). Defects in natural anticoagulants system. Plasmin is the active fibrinolytic enzyme. Several clinically
result in an increased risk of venous thrombosis. The most com- useful activators are shown on the left in bold. Anistreplase is a
mon defect in the natural anticoagulant system is a mutation in combination of streptokinase and the proactivator plasminogen.
factor V (factor V Leiden), which results in resistance to inactiva- Aminocaproic acid (right) inhibits the activation of plasminogen to
plasmin and is useful in some bleeding disorders. t-PA, tissue plas-
tion by the protein C/protein S mechanism.
minogen activator.

Fibrinolysis follow massive tissue injury, advanced cancers, obstetric emergen-

Fibrinolysis refers to the process of fibrin digestion by the fibrin-
specific protease, plasmin. The fibrinolytic system is similar to
the coagulation system in that the precursor form of the serine
protease plasmin circulates in an inactive form as plasminogen.
In response to injury, endothelial cells synthesize and release tis-
sue plasminogen activator (t-PA), which converts plasminogen
to plasmin (Figure 34–3). Plasmin remodels the thrombus and
limits its extension by proteolytic digestion of fibrin.
Both plasminogen and plasmin have specialized protein
domains (kringles) that bind to exposed lysines on the fibrin clot
and impart clot specificity to the fibrinolytic process. It should be
noted that this clot specificity is only observed at physiologic levels
of t-PA. At the pharmacologic levels of t-PA used in thrombolytic
therapy, clot specificity is lost and a systemic lytic state is created,
with attendant increase in bleeding risk. As in the coagulation
cascade, there are negative regulators of fibrinolysis: endothelial
cells synthesize and release plasminogen activator inhibitor (PAI),
which inhibits t-PA; in addition α2 antiplasmin circulates in the
blood at high concentrations and under physiologic conditions
will rapidly inactivate any plasmin that is not clot-bound. How-
ever, this regulatory system is overwhelmed by therapeutic doses
of plasminogen activators.
If the coagulation and fibrinolytic systems are pathologically
activated, the hemostatic system may careen out of control, lead-
ing to generalized intravascular clotting and bleeding. This process
is called disseminated intravascular coagulation (DIC) and may
cies such as abruptio placentae or retained products of conception,
or bacterial sepsis. The treatment of DIC is to control the underly-
ing disease process; if this is not possible, DIC is often fatal.
Regulation of the fibrinolytic system is useful in therapeutics.
Increased fibrinolysis is effective therapy for thrombotic disease.
Tissue plasminogen activator, urokinase, and streptokinase
all activate the fibrinolytic system (Figure 34–3). Conversely,
decreased fibrinolysis protects clots from lysis and reduces the
bleeding of hemostatic failure. Aminocaproic acid is a clinically
useful inhibitor of fibrinolysis. Heparin and the oral anticoagulant
drugs do not affect the fibrinolytic mechanism.
■■ BASIC PHARMACOLOGY OF
THE ANTICOAGULANT DRUGS
The ideal anticoagulant drug would prevent pathologic throm-
bosis and limit reperfusion injury yet allow a normal response
to vascular injury and limit bleeding. Theoretically this could
be accomplished by preservation of the TF-VIIa initiation phase
of the clotting mechanism with attenuation of the secondary
intrinsic pathway propagation phase of clot development. At
this time such a drug does not exist; all anticoagulants and fibri-
nolytic drugs have an increased bleeding risk as their principle
toxicity.
612    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

INDIRECT THROMBIN INHIBITORS composed of d-glucosamine-l-iduronic acid and d-glucosamine-

The indirect thrombin inhibitors are so-named because their
antithrombotic effect is exerted by their interaction with a
separate protein, antithrombin. Unfractionated heparin (UFH),
also known as high-molecular-weight (HMW) heparin, low-
molecular-weight (LMW) heparin, and the synthetic pentasac-
charide fondaparinux bind to antithrombin and enhance its
inactivation of factor Xa (Figure 34–4). Unfractionated heparin
and to a lesser extent LMW heparin also enhance antithrombin’s
inactivation of thrombin.
HEPARIN
Chemistry & Mechanism of Action
Heparin is a heterogeneous mixture of sulfated mucopolysaccha-
rides. It binds to endothelial cell surfaces and a variety of plasma
proteins. Its biologic activity is dependent upon the endogenous
anticoagulant antithrombin. Antithrombin inhibits clotting
factor proteases, especially thrombin (IIa), IXa, and Xa, by form-
ing equimolar stable complexes with them. In the absence of
heparin, these reactions are slow; in the presence of heparin, they
are accelerated 1000-fold. Only about a third of the molecules
in commercial heparin preparations have an accelerating effect
because the remainder lack the unique pentasaccharide sequence
needed for high-affinity binding to antithrombin. The active
heparin molecules bind tightly to antithrombin and cause a con-
formational change in this inhibitor. The conformational change
of antithrombin exposes its active site for more rapid interaction
with the proteases (the activated clotting factors). Heparin func-
tions as a cofactor for the antithrombin-protease reaction without
being consumed. Once the antithrombin-protease complex is
formed, heparin is released intact for renewed binding to more
antithrombin.
The antithrombin binding region of commercial unfraction-
ated heparin consists of repeating sulfated disaccharide units
d-glucuronic acid. High-molecular-weight fractions of heparin
with high affinity for antithrombin markedly inhibit blood
coagulation by inhibiting all three factors, especially thrombin and
factor Xa. Unfractionated heparin has a molecular weight range of
5000–30,000 Da. In contrast, the shorter-chain, low-molecular-
weight fractions of heparin inhibit activated factor X but have
less effect on thrombin than the HMW species. Nevertheless,
numerous studies have demonstrated that LMW heparins such
as enoxaparin, dalteparin, and tinzaparin are effective in several
thromboembolic conditions. In fact, these LMW heparins—in
comparison with UFH—have equal efficacy, increased bioavail-
ability from the subcutaneous site of injection, and less frequent
dosing requirements (once or twice daily is sufficient).
USP heparin is harmonized to the World Health Organization
International Standard (IS) unit dose. Enoxaparin is obtained
from the same sources as regular UFH, but doses are specified in
milligrams. Fondaparinux also is specified in milligrams. Daltepa-
rin, tinzaparin, and danaparoid (an LMW heparinoid containing
heparan sulfate, dermatan sulfate, and chondroitin sulfate), on the
other hand, are specified in anti-factor Xa units.
Monitoring of Heparin Effect
Close monitoring of the activated partial thromboplastin time
(aPTT or PTT) is necessary in patients receiving UFH. Levels of
UFH may also be determined by protamine titration (therapeu-
tic levels 0.2–0.4 unit/mL) or anti-Xa units (therapeutic levels
0.3–0.7 unit/mL). Weight-based dosing of the LMW heparins
results in predictable pharmacokinetics and plasma levels in
patients with normal renal function. Therefore, LMW heparin
levels are not generally measured except in the setting of renal
insufficiency, obesity, and pregnancy. LMW heparin levels can be
determined by anti-Xa units. For enoxaparin, peak therapeutic
levels should be 0.5–1 unit/mL for twice-daily dosing, determined
4 hours after administration, and approximately 1.5 units/mL for
once-daily dosing.

Antithrombin III
(inactive)

Thrombin
Antithrombin III Antithrombin III Factor
Thrombin
(active) (active) Xa
Factor
Factor IXa
Unfractionated Heparin XIa
LMW Heparin

FIGURE 34–4  Differences between low-molecular-weight (LMW) heparins and high-molecular-weight heparin (unfractionated heparin).
Fondaparinux is a small pentasaccharide fragment of heparin. Activated antithrombin III (AT III) degrades thrombin, factor X, and several other
factors. Binding of these drugs to AT III can increase the catalytic action of AT III 1000-fold. The combination of AT III with unfractionated heparin
increases degradation of both factor Xa and thrombin. Combination with fondaparinux or LMW heparin more selectively increases degradation
of Xa.
 CHAPTER 34  Drugs Used in Disorders of Coagulation     613

Toxicity Administration & Dosage

A. Bleeding and Miscellaneous Effects The indications for the use of heparin are described in the section
The major adverse effect of heparin is bleeding. This risk can on clinical pharmacology. A plasma concentration of heparin of
be decreased by scrupulous patient selection, careful control of 0.2–0.4 unit/mL (by protamine titration) or 0.3–0.7 unit/mL
dosage, and close monitoring. Elderly women and patients with (anti-Xa units) is considered to be the therapeutic range for
renal failure are more prone to hemorrhage. Heparin is of animal treatment of venous thromboembolic disease. This concentra-
origin and should be used cautiously in patients with allergy. tion generally corresponds to a PTT of 1.5–2.5 times baseline.
Increased loss of hair and reversible alopecia have been reported. However, the use of the PTT for heparin monitoring is problem-
Long-term heparin therapy is associated with osteoporosis and atic. There is no standardization scheme for the PTT as there is
spontaneous fractures. Heparin accelerates the clearing of post- for the prothrombin time (PT) and its international normalized
prandial lipemia by causing the release of lipoprotein lipase from ratio (INR) in warfarin monitoring. The PTT in seconds for a
tissues, and long-term use is associated with mineralocorticoid given heparin concentration varies between different reagent/
deficiency. instrument systems. Thus, if the PTT is used for monitoring, the
laboratory should determine the clotting time that corresponds to
B. Heparin-Induced Thrombocytopenia the therapeutic range by protamine titration or anti-Xa activity,
as listed above.
Heparin-induced thrombocytopenia (HIT) is a systemic hyper-
In addition, some patients have a prolonged baseline PTT due
coagulable state that occurs in 1–4% of individuals treated with
to factor deficiency or inhibitors (which could increase bleeding
UFH. Surgical patients are at greatest risk. The reported incidence
risk) or lupus anticoagulant (which is not associated with bleeding
of HIT is lower in pediatric populations outside the critical care
risk but may be associated with thrombosis risk). Using the PTT
setting; it is relatively rare in pregnant women. The risk of HIT
to assess heparin effect in such patients is problematic. An alter-
may be higher in individuals treated with UFH of bovine origin
native is to use anti-Xa activity to assess heparin concentration, a
compared with porcine heparin and is lower in those treated
test now widely available on automated coagulation instruments.
exclusively with LMW heparin.
This approach measures heparin concentration; however, it does
Morbidity and mortality in HIT are related to thrombotic
not provide the global assessment of intrinsic pathway integrity
events. Venous thrombosis occurs most commonly, but occlusion
of the PTT.
of peripheral or central arteries is not infrequent. If an indwell-
The following strategy is recommended: prior to initiating
ing catheter is present, the risk of thrombosis is increased in that
anticoagulant therapy of any type, the integrity of the patient’s
extremity. Skin necrosis has been described, particularly in indi-
hemostatic system should be assessed by a careful history of
viduals treated with warfarin in the absence of a direct thrombin
prior bleeding events, as well as baseline PT and PTT. If there
inhibitor, presumably due to acute depletion of the vitamin K–
is a prolonged clotting time, the cause of this (deficiency or
dependent anticoagulant protein C occurring in the presence of
inhibitor) should be determined prior to initiating therapy, and
high levels of procoagulant proteins and an active hypercoagulable
treatment goals stratified to a risk-benefit assessment. In high-
state.
risk patients measuring both the PTT and anti-Xa activity may
The following points should be considered in all patients
be useful. When intermittent heparin administration is used,
receiving heparin: Platelet counts should be performed frequently;
the aPTT or anti-Xa activity should be measured 6 hours after
thrombocytopenia appearing in a time frame consistent with an
the administered dose to maintain prolongation of the aPTT to
immune response to heparin should be considered suspicious for
2–2.5 times that of the control value. However, LMW heparin
HIT; and any new thrombus occurring in a patient receiving hep-
therapy is the preferred option in this case, as no monitoring is
arin therapy should raise suspicion of HIT. Patients who develop
required in most patients.
HIT are treated by discontinuance of heparin and administration
Continuous intravenous administration of heparin is accom-
of the direct thrombin inhibitor argatroban.
plished via an infusion pump. After an initial bolus injection of
80–100 units/kg, a continuous infusion of about 15–22 units/kg
Contraindications per hour is required to maintain the anti-Xa activity in the
range of 0.3–0.7 units/mL. Low-dose prophylaxis is achieved
Heparin is contraindicated in patients with HIT, hypersensitivity
with subcutaneous administration of heparin, 5000 units
to the drug, active bleeding, hemophilia, significant thrombocy-
every 8–12 hours. Because of the danger of hematoma forma-
topenia, purpura, severe hypertension, intracranial hemorrhage,
tion at the injection site, heparin must never be administered
infective endocarditis, active tuberculosis, ulcerative lesions of the
intramuscularly.
gastrointestinal tract, threatened abortion, visceral carcinoma, or
Prophylactic enoxaparin is given subcutaneously in a dosage
advanced hepatic or renal disease. Heparin should be avoided in
of 30 mg twice daily or 40 mg once daily. Full-dose enoxaparin
patients who have recently had surgery of the brain, spinal cord,
therapy is 1 mg/kg subcutaneously every 12 hours. This cor-
or eye; and in patients who are undergoing lumbar puncture or
responds to a therapeutic anti-factor Xa level of 0.5–1 unit/mL.
regional anesthetic block. Despite the apparent lack of placental
Selected patients may be treated with enoxaparin 1.5 mg/kg
transfer, heparin should be used in pregnant women only when
once a day, with a target anti-Xa level of 1.5 units/mL.
clearly indicated.
614    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
The prophylactic dosage of dalteparin is 5000 units subcuta-
neously once a day; therapeutic dosing is 200 units/kg once a
day for venous disease or 120 units/kg every 12 hours for acute
coronary syndrome. LMW heparin should be used with caution
in patients with renal insufficiency or body weight greater than
150 kg. Measurement of the anti-Xa level is useful to guide dos-
ing in these individuals.
The synthetic pentasaccharide molecule fondaparinux
avidly binds antithrombin with high specific activity, result-
ing in efficient inactivation of factor Xa. Fondaparinux has a
long half-life of 15 hours, allowing for once-daily dosing by
subcutaneous administration. Fondaparinux is effective in the
prevention and treatment of venous thromboembolism and
does not appear to cross-react with pathologic HIT antibodies
in most individuals.
Reversal of Heparin Action
Excessive anticoagulant action of heparin is treated by discon-
tinuance of the drug. If bleeding occurs, administration of a
specific antagonist such as protamine sulfate is indicated. Prot-
amine is a highly basic, positively charged peptide that combines
with negatively charged heparin as an ion pair to form a stable
complex devoid of anticoagulant activity. For every 100 units
of heparin remaining in the patient, 1 mg of protamine sulfate
is given intravenously; the rate of infusion should not exceed
50 mg in any 10-minute period. Excess protamine must be
avoided; it also has an anticoagulant effect. Neutralization of
LMW heparin by protamine is incomplete. Limited experience
suggests that 1 mg of protamine sulfate may be used to partially
neutralize 1 mg of enoxaparin. Protamine will not reverse the
activity of fondaparinux. Excess danaparoid can be removed by
plasmapheresis.
OH OH
CH2
O O O O O
Dicumarol
O
O
Phenindione
FIGURE 34–5  Structural formulas of several oral anticoagulant drugs and of vitamin K. The carbon atom of warfarin shown at the asterisk
is an asymmetric center.
WARFARIN & OTHER COUMARIN
ANTICOAGULANTS
Chemistry & Pharmacokinetics
The clinical use of the coumarin anticoagulants began with the
discovery of an anticoagulant substance formed in spoiled sweet
clover silage, which caused hemorrhagic disease in cattle. At the
behest of local farmers, a chemist at the University of Wisconsin
identified the toxic agent as bishydroxycoumarin. Dicumarol, a
synthesized derivative, and its congeners, most notably warfarin
(Wisconsin Alumni Research Foundation, with “-arin” from cou-
marin added; Figure 34–5), were initially used as rodenticides.
In the 1950s, warfarin (under the brand name Coumadin) was
introduced as an antithrombotic agent in humans. Warfarin is one
of the most commonly prescribed drugs.
Warfarin is generally administered as the sodium salt and has
100% oral bioavailability. Over 99% of racemic warfarin is bound
to plasma albumin, which may contribute to its small volume
of distribution (the albumin space), its long half-life in plasma
(36 hours), and the lack of urinary excretion of unchanged drug.
Warfarin used clinically is a racemic mixture composed of equal
amounts of two enantiomorphs. The levorotatory S-warfarin is
four times more potent than the dextrorotatory R-warfarin. This
observation is useful in understanding the stereoselective nature of
several drug interactions involving warfarin.
Mechanism of Action
Coumarin anticoagulants block the γ-carboxylation of several glu-
tamate residues in prothrombin and factors VII, IX, and X as well
as the endogenous anticoagulant proteins C and S (Figure 34–2,
Table 34–1). The blockade results in incomplete coagulation
CH2 CO CH3
ONa
CH
*
O
Warfarin sodium
O
CH3
CH3
CH2 CH C C16H33
O
Phytonadione (vitamin K1)

factor molecules that are biologically inactive. The protein car-
boxylation reaction is coupled to the oxidation of vitamin K. The
vitamin must then be reduced to reactivate it. Warfarin prevents
reductive metabolism of the inactive vitamin K epoxide back to
its active hydroquinone form (Figure 34–6). Mutational change
of the gene for the responsible enzyme, vitamin K epoxide reduc-
tase (VKORC1), can give rise to genetic resistance to warfarin in
humans and rodents.
There is an 8- to 12-hour delay in the action of warfarin.
Its anticoagulant effect results from a balance between partially
inhibited synthesis and unaltered degradation of the four vita-
min K–dependent clotting factors. The resulting inhibition
of coagulation is dependent on their degradation half-lives in
the circulation. These half-lives are 6, 24, 40, and 60 hours for
factors VII, IX, X, and II, respectively. Importantly, protein C
has a short half-life similar to factor VIIa. Thus the immediate
effect of warfarin is to deplete the procoagulant factor VII and
anticoagulant protein C, which can paradoxically create a tran-
sient hypercoagulable state due to residual activity of the longer
half-life procoagulants in the face of protein C depletion (see
below). For this reason in patients with active hypercoagulable
states, such as acute DVT or PE, UFH or LMW heparin is
always used to achieve immediate anticoagulation until adequate
warfarin-induced depletion of the procoagulant clotting factors
is achieved. The duration of this overlapping therapy is generally
5–7 days.
COO– –
OOC COO–
CH2 CH
CH2 CH2
Descarboxy- Prothrombin
prothrombin
CO2
Carboxylase
OH O2 O
CH3 CH3
O give the same INR results for a given sample. For most reagent
R R
OH O
KH2 KO
Warfarin
FIGURE 34–6  Vitamin K cycle–metabolic interconversions of
vitamin K associated with the synthesis of vitamin K–dependent clot-
ting factors. Vitamin K1 or K2 is activated by reduction to the hydro-
quinone form (KH2). Stepwise oxidation to vitamin K epoxide (KO) is
coupled to prothrombin carboxylation by the enzyme carboxylase.
The reactivation of vitamin K epoxide is the warfarin-sensitive step
(warfarin). The R on the vitamin K molecule represents a 20-carbon
phytyl side chain in vitamin K1 and a 30- to 65-carbon polyprenyl side
chain in vitamin K2.
CHAPTER 34  Drugs Used in Disorders of Coagulation     615
Toxicity
Warfarin crosses the placenta readily and can cause a hemor-
rhagic disorder in the fetus. Furthermore, fetal proteins with
γ-carboxyglutamate residues found in bone and blood may be
affected by warfarin; the drug can cause a serious birth defect
characterized by abnormal bone formation. Thus, warfarin should
never be administered during pregnancy. Cutaneous necrosis
with reduced activity of protein C sometimes occurs during the
first weeks of therapy in patients who have inherited deficiency
of protein C. Rarely, the same process causes frank infarction of
the breast, fatty tissues, intestine, and extremities. The pathologic
lesion associated with the hemorrhagic infarction is venous throm-
bosis, consistent with a hypercoagulable state due to warfarin-
induced depletion of protein C.
Administration & Dosage
Treatment with warfarin should be initiated with standard doses
of 5–10 mg. The initial adjustment of the prothrombin time takes
about 1 week, which usually results in a maintenance dosage of
5–7 mg/d. The prothrombin time (PT) should be increased to
a level representing a reduction of prothrombin activity to 25%
of normal and maintained there for long-term therapy. When the
activity is less than 20%, the warfarin dosage should be reduced
or omitted until the activity rises above 20%. Inherited poly-
morphisms in 2CYP2C9 and VKORC1 have significant effects
on warfarin dosing; however, algorithms incorporating genomic
information to predict initial warfarin dosing were no better than
standard clinical algorithms in two of three large randomized trials
examining this issue (see Chapter 5).
The therapeutic range for oral anticoagulant therapy is defined
in terms of an international normalized ratio (INR). The INR
is the prothrombin time ratio (patient prothrombin time/mean
of normal prothrombin time for lab)ISI, where the ISI exponent
refers to the International Sensitivity Index and is dependent on
the specific reagents and instruments used for the determination.
The ISI serves to relate measured prothrombin times to a World
Health Organization reference standard thromboplastin; thus the
prothrombin times performed on different properly calibrated
instruments with a variety of thromboplastin reagents should
and instrument combinations in current use, the ISI is close to
1, making the INR roughly the ratio of the patient prothrombin
time to the mean normal prothrombin time. The recommended
INR for prophylaxis and treatment of thrombotic disease is 2–3.
Patients with some types of artificial heart valves (eg, tilting disk)
or other medical conditions increasing thrombotic risk have a
recommended range of 2.5–3.5. While a prolonged INR is widely
used as an indication of integrity of the coagulation system in liver
disease and other disorders, it has been validated only in patients
in steady state on chronic warfarin therapy.
Occasionally patients exhibit warfarin resistance, defined as
progression or recurrence of a thrombotic event while in the
therapeutic range. These individuals may have their INR target
raised (which is accompanied by an increase in bleeding risk) or
616    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

be changed to an alternative form of anticoagulation (eg, daily for their hypoprothrombinemic interaction are a stereoselective
injections of LMW heparin or one of the newer oral anticoagu- inhibition of oxidative metabolic transformation of S-warfarin
lants). Warfarin resistance is most commonly seen in patients with (the more potent isomer) and displacement of albumin-bound
advanced cancers, typically of gastrointestinal origin (Trousseau’s warfarin, increasing the free fraction. For this and other reasons,
syndrome). LMW heparin is superior to warfarin in preventing neither phenylbutazone nor sulfinpyrazone is in common use in
recurrent venous thromboembolism in patients with cancer. the United States. Metronidazole, fluconazole, and trimethoprim-
sulfamethoxazole also stereoselectively inhibit the metabolic
Drug Interactions transformation of S-warfarin, whereas amiodarone, disulfiram,
and cimetidine inhibit metabolism of both enantiomorphs of
The coumarin anticoagulants often interact with other drugs and warfarin (see Chapter 4). Aspirin, hepatic disease, and hyper-
with disease states. These interactions can be broadly divided into thyroidism augment warfarin’s effects—aspirin by its effect on
pharmacokinetic and pharmacodynamic effects (Table 34–2). platelet function and the latter two by increasing the turnover rate
Pharmacokinetic mechanisms for drug interaction with warfarin of clotting factors. The third-generation cephalosporins eliminate
mainly involve cytochrome P450 CYP2C9 enzyme induction, the bacteria in the intestinal tract that produce vitamin K and, like
enzyme inhibition, and reduced plasma protein binding. Phar- warfarin, also directly inhibit vitamin K epoxide reductase.
macodynamic mechanisms for interactions with warfarin are Barbiturates and rifampin cause a marked decrease of the
synergism (impaired hemostasis, reduced clotting factor synthesis, anticoagulant effect by induction of the hepatic enzymes that
as in hepatic disease), competitive antagonism (vitamin K), and transform racemic warfarin. Cholestyramine binds warfarin in the
an altered physiologic control loop for vitamin K (hereditary intestine and reduces its absorption and bioavailability.
resistance to oral anticoagulants). Pharmacodynamic reductions of anticoagulant effect occur
The most serious interactions with warfarin are those that with increased vitamin K intake (increased synthesis of clotting
increase the anticoagulant effect and the risk of bleeding. The factors), the diuretics chlorthalidone and spironolactone (clotting
most dangerous of these interactions are the pharmacokinetic factor concentration), hereditary resistance (mutation of vitamin
interactions with the mostly obsolete pyrazolones phenylbu- K reactivation cycle molecules), and hypothyroidism (decreased
tazone and sulfinpyrazone. These drugs not only augment the turnover rate of clotting factors).
hypoprothrombinemia but also inhibit platelet function and may Drugs with no significant effect on anticoagulant therapy
induce peptic ulcer disease (see Chapter 36). The mechanisms include ethanol, phenothiazines, benzodiazepines, acetamino-
phen, opioids, indomethacin, and most antibiotics.
TABLE 34–2  Pharmacokinetic and
pharmacodynamic drug and body Reversal of Warfarin Action
interactions with oral anticoagulants.
Excessive anticoagulant effect and bleeding from warfarin can be
Increased Prothrombin Time Decreased Prothrombin Time reversed by stopping the drug and administering oral or parenteral
vitamin K1 (phytonadione), fresh-frozen plasma, prothrombin
Pharmacokinetic Pharmacokinetic
complex concentrates, and recombinant factor VIIa (rFVIIa). A
Amiodarone Barbiturates four-factor concentrate containing factors II, VII, IX, and X (Pro-
Cimetidine Cholestyramine thrombin Complex Concentrate, [Human]; Kcentra) (4F PCC)
Disulfiram Rifampin is available. The disappearance of excessive effect is not correlated
Fluconazole 1 with plasma warfarin concentrations but rather with reestablish-
ment of normal activity of the clotting factors. A modest excess of
Metronidazole1
anticoagulant effect without bleeding may require no more than
Phenylbutazone1 cessation of the drug. The warfarin effect can be rapidly reversed
Sulfinpyrazone1 in the setting of severe bleeding with the administration of pro-
Trimethoprim-sulfamethoxazole thrombin complex or rFVIIa coupled with intravenous vitamin K.
Pharmacodynamic Pharmacodynamic
It is important to note that due to the long half-life of warfarin, a
single dose of vitamin K or rFVIIa may not be sufficient.
Drugs Drugs
Aspirin (high doses) Diuretics
Cephalosporins, third-generation Vitamin K
ORAL DIRECT FACTOR Xa
Heparin, argatroban, dabigatran, INHIBITORS
rivaroxaban, apixaban
Oral Xa inhibitors, including rivaroxaban, apixaban, and edoxa-
Body factors Body factors ban represent a new class of oral anticoagulant drugs that require
Hepatic disease Hereditary resistance no monitoring. Along with oral direct thrombin inhibitors
Hyperthyroidism Hypothyroidism (discussed below) this new class of direct oral anticoagulant
1
Stereoselectively inhibits the oxidative metabolism of the S-warfarin enantiomorph
(DOAC) drugs is having a major impact on antithrombotic
of racemic warfarin. pharmacotherapy.

Pharmacology
Rivaroxaban, apixaban, and edoxaban inhibit factor Xa, in the
final common pathway of clotting (see Figure 34–2). These drugs
are given as fixed doses and do not require monitoring. They have
a rapid onset of action and shorter half-lives than warfarin.
Rivaroxaban has high oral bioavailability when taken with
food. Following an oral dose, the peak plasma level is achieved
within 2–4 hours; the drug is extensively protein-bound. It is a
substrate for the cytochrome P450 system and the P-glycoprotein
transporter. Drugs inhibiting both CYP3A4 and P-glycoprotein
(eg, ketoconazole) result in increased rivaroxaban effect. One third
of the drug is excreted unchanged in the urine and the remainder
is metabolized and excreted in the urine and feces. The drug half-
life is 5–9 hours in patients age 20–45 years and is increased in
the elderly and in those with impaired renal or hepatic function.
Apixaban has an oral bioavailability of 50% and prolonged
absorption, resulting in a half-life of 12 hours with repeat dos-
ing. The drug is a substrate of the cytochrome P450 system and
P-glycoprotein and is excreted in the urine and feces. As with riva-
roxaban, drugs inhibiting both CYP3A4 and P-glycoprotein, as
well as impairment of renal or hepatic function, result in increased
drug effect.
Edoxaban is a once-daily Xa inhibitor with a 62% oral bio-
availability. Peak drug concentrations occur 1–2 hours after dosage
and are not affected by food. The drug half-life is 10–14 hours.
Edoxaban does not induce CYP450 enzymes. No dose reduc-
tion is required with concurrent use of P-glycoprotein inhibitors.
Edoxaban is primarily excreted unchanged in the urine.
Administration & Dosage
Rivaroxaban is approved for prevention of embolic stroke in
patients with atrial fibrillation without valvular heart disease,
prevention of venous thromboembolism following hip or knee
surgery, and treatment of venous thromboembolic disease (VTE).
The prophylactic dosage is 10 mg orally per day for 35 days for
hip replacement or 12 days for knee replacement. For treatment
of DVT/PE the dosage is 15 mg twice daily for 3 weeks followed
by 20 mg/d. Depending on clinical presentation and risk factors,
patients with VTE are treated for 3–6 months; rivaroxaban is also
approved for prolonged therapy in selected patients to reduce
recurrence risk at the treatment dose. Apixaban is approved for
prevention of stroke in nonvalvular atrial fibrillation, for preven-
tion of VTE following hip or knee surgery, and for treatment and
long-term prevention of VTE. The dosage for atrial fibrillation is
5 mg twice daily; the dose for VTE is 10 mg twice a day for the
first week, followed by 5 mg twice a day. The prophylactic dose
for prevention of VTE following hip or knee surgery or long-term
prevention of VTE following initial therapy is 2.5 mg twice a day.
The recommended duration of therapy in hip and knee replace-
ment is the same as for rivaroxaban. Edoxaban is approved for
prevention of stroke in nonvalvular atrial fibrillation, and to treat
VTE following treatment with heparin or LMWH for 5–10 days.
The dose for atrial fibrillation and VTE treatment is 60 mg once
daily. For patients with creatinine clearance of 15–50 mL/min or
those taking concomitant P-glycoprotein inhibitors, the dose is
CHAPTER 34  Drugs Used in Disorders of Coagulation     617
30 mg once daily. Edoxaban is contraindicated in patients with
atrial fibrillation and creatinine clearance >95 mL/min, due to
the increased rate of ischemic stroke in this group compared with
patients taking warfarin.
Assessment of and Reversal of Anti-Xa
Drug Effect
Measurement of anti-Xa drug effect is not needed in most situa-
tions but can be accomplished by anti-Xa assays calibrated for the
drug in question. Andexanet alfa is a factor Xa “decoy” molecule
without procoagulant activity that competes for binding to anti-
Xa drugs. In clinical trials involving apixaban and rivaroxaban,
andexanet given by IV infusion resulted in rapid decrease in anti-
Xa effect. Non-neutralizing antibodies occurred in 17% of those
treated; the effect of these antibodies with drug re-exposure is
not known. Based on the available data, andexanet is likely to be
the first antidote approved for use in patients treated with anti-
Xa agents who require rapid reversal for surgery or uncontrolled
bleeding.
DIRECT THROMBIN INHIBITORS
The direct thrombin inhibitors (DTIs) exert their anticoagulant
effect by directly binding to the active site of thrombin, thereby
inhibiting thrombin’s downstream effects. This is in contrast to
indirect thrombin inhibitors such as heparin and LMW hepa-
rin (see above), which act through antithrombin. Hirudin and
bivalirudin are large, bivalent DTIs that bind at the catalytic or
active site of thrombin as well as at a substrate recognition site.
Argatroban and melagatran are small molecules that bind only
at the thrombin active site.
PARENTERAL DIRECT THROMBIN
INHIBITORS
Leeches have been used for bloodletting since the age of Hip-
pocrates. More recently, surgeons have used medicinal leeches
(Hirudo medicinalis) to prevent thrombosis in the fine vessels
of reattached digits. Hirudin is a specific, irreversible throm-
bin inhibitor from leech saliva that for a time was available in
recombinant form as lepirudin. Its action is independent of anti-
thrombin, which means it can reach and inactivate fibrin-bound
thrombin in thrombi. Lepirudin has little effect on platelets or the
bleeding time. Like heparin, it must be administered parenterally
and is monitored by aPTT. Lepirudin was approved by the U.S.
Food and Drug Administration (FDA) for use in patients with
thrombosis related to heparin-induced thrombocytopenia (HIT).
Lepirudin is excreted by the kidney and should be used with great
caution in patients with renal insufficiency as no antidote exists.
Up to 40% of patients who receive long-term infusions develop
an antibody directed against the thrombin-lepirudin complex.
These antigen-antibody complexes are not cleared by the kidney
and may result in an enhanced anticoagulant effect. Some patients
re-exposed to the drug developed life-threatening anaphylactic
618    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
reactions. Lepirudin production was discontinued by the manu-
facturer in 2012.
Bivalirudin, another bivalent inhibitor of thrombin, is admin-
istered intravenously, with a rapid onset and offset of action. The
drug has a short half-life with clearance that is 20% renal and the
remainder metabolic. Bivalirudin also inhibits platelet activation
and has been FDA-approved for use in percutaneous coronary
angioplasty.
Argatroban is a small molecule thrombin inhibitor that is
FDA-approved for use in patients with HIT with or without
thrombosis and coronary angioplasty in patients with HIT. It,
too, has a short half-life, is given by continuous intravenous infu-
sion, and is monitored by aPTT. Its clearance is not affected by
renal disease but is dependent on liver function; dose reduction is
required in patients with liver disease. Patients on argatroban will
demonstrate elevated INRs, rendering the transition to warfarin
difficult (ie, the INR will reflect contributions from both warfarin
and argatroban). (INR is discussed in detail in the section on
warfarin administration.) A nomogram is supplied by the manu-
facturer to assist in this transition.
ORAL DIRECT THROMBIN INHIBITOR
Advantages of oral direct thrombin inhibition include predictable
pharmacokinetics and bioavailability, which allow for fixed dosing
and predictable anticoagulant response and make routine coagu-
lation monitoring unnecessary. Similar to the direct oral anti-Xa
drugs described above, the rapid onset and offset of action of these
agents allow for immediate anticoagulation.
Dabigatran etexilate mesylate is the only oral direct thrombin
inhibitor approved by the FDA. Dabigatran is approved for reduc-
tion in risk of stroke and systemic embolism with nonvalvular
atrial fibrillation, treatment of VTE following 5–7 days of initial
heparin or LMWH therapy, reduction of the risk of recurrent
VTE, and VTE prophylaxis following hip or knee replacement
surgery.
Pharmacology
Dabigatran and its metabolites are direct thrombin inhibitors.
Following oral administration, dabigatran etexilate mesylate is
converted to dabigatran. The oral bioavailability is 3–7% in
normal volunteers. The drug is a substrate for the P-glycoprotein
efflux pump; P-glycoprotein inhibitors such as ketoconazole
should be avoided in patients with impaired renal function. The
half-life of the drug in normal volunteers is 12–17 hours. Renal
impairment results in prolonged drug clearance.
Administration & Dosage
For prevention of stroke and systemic embolism in nonvalvular
atrial fibrillation, the dosage is 150 mg twice daily for patients
with creatinine clearance greater than 30 mL/min. For decreased
creatinine clearance of 15–30 mL/min, the dosage is 75 mg twice
daily. No monitoring is required.
Assessment of and Reversal of
Antithrombin Drug Effect
As with any anticoagulant drug, the primary toxicity of dabigatran
is bleeding. Dabigatran will prolong the PTT, thrombin time, and
ecarin clotting time, which can be used to estimate drug effect
if necessary. The ecarin clotting time [ECT] is another clotting
test based on the use of a protein isolated from viper venom.
Idarucizumab is a humanized monoclonal antibody Fab fragment
that binds to dabigatran and reverses the anticoagulant effect. The
drug is approved for use in situations requiring emergent surgery
or for life-threatening bleeding. The recommended dose is 5 g
given intravenously. If bleeding re-occurs a second dose may be
given. The drug is primarily excreted by the kidneys. The half-life
in patients with normal renal function is approximately 1 hour.
Summary of the Direct Oral Anticoagulant
Drugs
The direct oral anticoagulant drugs have consistently shown
equivalent antithrombotic efficacy and lower bleeding rates when
compared with traditional warfarin therapy. In addition, these
drugs offer the advantages of rapid therapeutic effect, no monitor-
ing requirement, and fewer drug interactions in comparison with
warfarin, which has a narrow therapeutic window, is affected by
diet and many drugs, and requires monitoring for dosage optimi-
zation. However, the short half-life of the newer anticoagulants
has the important consequence that patient noncompliance will
quickly lead to loss of anticoagulant effect and risk of thromboem-
bolism. Given the convenience of once- or twice-daily oral dosing,
lack of a monitoring requirement, and fewer drug and dietary
interactions documented thus far, the new direct oral anticoagu-
lants represent a significant advance in the prevention and therapy
of thrombotic disease.
■■ BASIC PHARMACOLOGY OF
THE FIBRINOLYTIC DRUGS
Fibrinolytic drugs rapidly lyse thrombi by catalyzing the forma-
tion of the serine protease plasmin from its precursor zymogen,
plasminogen (Figure 34–3). These drugs create a generalized lytic
state when administered intravenously. Thus, both protective
hemostatic thrombi and target thromboemboli are broken down.
The Box: Thrombolytic Drugs for Acute Myocardial Infarction
describes the use of these drugs in one major application.
Pharmacology
Streptokinase is a protein (but not an enzyme in itself ) syn-
thesized by streptococci that combines with the proactivator
plasminogen. This enzymatic complex catalyzes the conversion
of inactive plasminogen to active plasmin. Urokinase is a human
enzyme synthesized by the kidney that directly converts plas-
minogen to active plasmin. Plasmin itself cannot be used because
naturally occurring inhibitors (antiplasmins) in plasma prevent its

Thrombolytic Drugs For Acute Myocardial Infarction
The paradigm shift in 1980 on the causation of acute myo-
cardial infarction to acute coronary occlusion by a thrombus
created the rationale for thrombolytic therapy of this com-
mon lethal disease. At that time—and for the first time—
intravenous thrombolytic therapy for acute myocardial
infarction in the European Cooperative Study Group trial
was found to reduce mortality. Later studies, with thousands
of patients in each trial, provided enough statistical power
for the 20% reduction in mortality to be considered statisti-
cally significant. Although the standard of care in areas with
adequate facilities and experience in percutaneous coronary
intervention (PCI) now favors catheterization and placement
effects. However, the absence of inhibitors for urokinase and the
streptokinase-proactivator complex permits their use clinically.
Plasmin formed inside a thrombus by these activators is protected
from plasma antiplasmins; this allows it to lyse the thrombus from
within.
Plasminogen can also be activated endogenously by tissue
plasminogen activators (t-PAs). These activators preferentially
activate plasminogen that is bound to fibrin, which (in theory)
confines fibrinolysis to the formed thrombus and avoids sys-
temic activation. Recombinant human t-PA is manufactured
as alteplase. Reteplase is another recombinant human t-PA
from which several amino acid sequences have been deleted.
Tenecteplase is a mutant form of t-PA that has a longer half-
life, and it can be given as an intravenous bolus. Reteplase and
tenecteplase are as effective as alteplase and have simpler dosing
schemes because of their longer half-lives.
Indications & Dosage
Administration of fibrinolytic drugs by the intravenous route is
indicated in cases of pulmonary embolism with hemodynamic
instability, severe deep venous thrombosis such as the superior
vena caval syndrome, and ascending thrombophlebitis of the
iliofemoral vein with severe lower extremity edema. These drugs are
also given intra-arterially, especially for peripheral vascular disease.
Thrombolytic therapy in the management of acute myocardial
infarction requires careful patient selection, the use of a specific
thrombolytic agent, and the benefit of adjuvant therapy. Strepto-
kinase is administered by intravenous infusion of a loading dose
of 250,000 units, followed by 100,000 units/h for 24–72 hours.
Patients with antistreptococcal antibodies can develop fever,
allergic reactions, and therapeutic resistance. Urokinase requires
a loading dose of 300,000 units given over 10 minutes and a
maintenance dose of 300,000 units/h for 12 hours. Alteplase
(t-PA) is given as a 15-mg bolus followed by 0.75 mg/kg (up to
50 mg) over 30 minutes and then 0.5 mg/kg (up to 35 mg) over
60 minutes. Reteplase is given as two 10-unit bolus injections,
the second administered 30 minutes after the first injection.
CHAPTER 34  Drugs Used in Disorders of Coagulation     619
of a stent, thrombolytic therapy is still very important where
PCI is not readily available.
The proper selection of patients for thrombolytic therapy
is critical. The diagnosis of acute myocardial infarction is made
clinically and is confirmed by electrocardiography. Patients with
ST-segment elevation and bundle branch block on electrocardi-
ography have the best outcomes. All trials to date show the great-
est benefit for thrombolytic therapy when it is given early, within
6 hours after symptomatic onset of acute myocardial infarction.
Thrombolytic drugs reduce the mortality of acute myocardial
infarction. The early and appropriate use of any thrombolytic drug
probably transcends possible advantages of a particular drug.
Tenecteplase is given as a single intravenous bolus ranging from
30 to 50 mg depending on body weight. Recombinant t-PA has
also been approved for use in acute ischemic stroke within 3 hours
of symptom onset. In patients without hemorrhagic infarct or
other contraindications, this therapy has been demonstrated to
provide better outcomes in several randomized clinical trials. The
recommended dose is 0.9 mg/kg, not to exceed 90 mg, with 10%
given as a bolus and the remainder during a 1-hour infusion.
Streptokinase has been associated with increased bleeding risk in
acute ischemic stroke when given at a dose of 1.5 million units,
and its use is not recommended in this setting.
■■ BASIC PHARMACOLOGY OF
ANTIPLATELET AGENTS
Platelet function is regulated by three categories of substances. The
first group consists of agents generated outside the platelet that
interact with platelet membrane receptors, eg, catecholamines,
collagen, thrombin, and prostacyclin. The second category con-
tains agents generated within the platelet that interact with mem-
brane receptors, eg, ADP, prostaglandin D2, prostaglandin E2,
and serotonin. A third group comprises agents generated within
the platelet that act within the platelet, eg, prostaglandin endo-
peroxides and thromboxane A2, the cyclic nucleotides cAMP and
cGMP, and calcium ion. From this list of agents, several targets
for platelet inhibitory drugs have been identified (Figure 34–1):
inhibition of prostaglandin synthesis (aspirin), inhibition of ADP-
induced platelet aggregation (clopidogrel, prasugrel, ticlopidine),
and blockade of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on
platelets (abciximab, tirofiban, and eptifibatide). Dipyridamole
and cilostazol are additional antiplatelet drugs.
ASPIRIN
The prostaglandin thromboxane A2 is an arachidonate product
that causes platelets to change shape, release their granules, and
620    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
aggregate (see Chapter 18). Drugs that antagonize this pathway
interfere with platelet aggregation in vitro and prolong the bleed-
ing time in vivo. Aspirin is the prototype of this class of drugs.
As described in Chapter 18, aspirin inhibits the synthesis of
thromboxane A2 by irreversible acetylation of the enzyme cyclo-
oxygenase. Other salicylates and nonsteroidal anti-inflammatory
drugs also inhibit cyclooxygenase but have a shorter duration of
inhibitory action because they cannot acetylate cyclooxygenase;
that is, their action is reversible.
In 2014, following a review of the available data, the FDA
reversed course and concluded that aspirin for primary prophylaxis
(patients without a history of myocardial infarction or stroke)
was not supported by the available data but did carry significant
bleeding risk. In contrast, meta-analysis of many published trials
of aspirin and other antiplatelet agents have demonstrated the util-
ity of aspirin in the secondary prevention of vascular events among
patients with a history of vascular events.
THIENOPYRIDINES: TICLOPIDINE,
CLOPIDOGREL, & PRASUGREL
Ticlopidine, clopidogrel, and prasugrel reduce platelet aggregation
by inhibiting the ADP pathway of platelets. These drugs irrevers-
ibly block the ADP P2Y12 receptor on platelets. Unlike aspirin,
these drugs have no effect on prostaglandin metabolism. Use of
ticlopidine, clopidogrel, or prasugrel to prevent thrombosis is now
considered standard practice in patients undergoing placement of
a coronary stent. As the indications and adverse effects of these
drugs are different, they will be considered individually.
Ticlopidine is approved for prevention of stroke in patients with
a history of a transient ischemic attack (TIA) or thrombotic stroke,
and in combination with aspirin for prevention of coronary stent
thrombosis. Adverse effects of ticlopidine include nausea, dyspepsia,
and diarrhea in up to 20% of patients, hemorrhage in 5%, and,
most seriously, leukopenia in 1%. The leukopenia is detected by
regular monitoring of the white blood cell count during the first
3 months of treatment. Development of thrombotic thrombo-
cytopenic purpura has also been associated with the ingestion of
ticlopidine. The dosage of ticlopidine is 250 mg twice daily orally.
Because of the significant side effect profile, the use of ticlopidine
for stroke prevention should be restricted to those who are intoler-
ant of or have failed aspirin therapy. Dosages of ticlopidine less than
500 mg/d may be efficacious with fewer adverse effects.
Clopidogrel is approved for patients with unstable angina or
non-ST-elevation acute myocardial infarction (NSTEMI) in com-
bination with aspirin; for patients with ST-elevation myocardial
infarction (STEMI); or recent myocardial infarction, stroke, or
established peripheral arterial disease. For NSTEMI, the dosage
is a 300-mg loading dose orally followed by 75 mg daily of clopi-
dogrel, with a daily aspirin dosage of 75–325 mg. For patients
with STEMI, the dosage is 75 mg daily of clopidogrel orally, in
association with aspirin as above; and for recent myocardial infarc-
tion, stroke, or peripheral vascular disease, the dosage is 75 mg/d.
Clopidogrel has fewer adverse effects than ticlopidine and is
rarely associated with neutropenia. Thrombotic thrombocytopenic
purpura has been reported. Because of its superior adverse effect
profile and dosing requirements, clopidogrel is frequently preferred
over ticlopidine. The antithrombotic effects of clopidogrel are dose-
dependent; within 5 hours after an oral loading dose of 300 mg,
80% of platelet activity will be inhibited. The maintenance dosage
of clopidogrel is 75 mg/d, which achieves maximum platelet inhibi-
tion. The duration of the antiplatelet effect is 7–10 days. Clopido-
grel is a prodrug that requires activation via the cytochrome P450
enzyme isoform CYP2C19. Depending on the single nucleotide
polymorphism (SNP) inheritance pattern in CYP2C19, individuals
may be poor metabolizers of clopidogrel, and these patients may
be at increased risk of cardiovascular events due to inadequate
drug effect. The FDA has recommended CYP2C19 genotyping to
identify such patients and advises prescribers to consider alterna-
tive therapies in poor metabolizers (see Chapter 5). However, more
recent studies have questioned the impact of CYP2C19 metabolizer
status on outcomes. Drugs that impair CYP2C19 function, such as
omeprazole, should be used with caution.
Prasugrel, similar to clopidogrel, is approved for patients with
acute coronary syndromes. The drug is given orally as a 60-mg
loading dose and then 10 mg/d in combination with aspirin
as outlined for clopidogrel. The Trial to assess Improvement in
Therapeutic Outcomes by Optimizing Platelet Inhibition with
Prasugrel (TRITON-TIMI38) compared prasugrel with clopi-
dogrel in a randomized, double-blind trial with aspirin and other
standard therapies managed with percutaneous coronary inter-
ventions. This trial showed a reduction in the primary composite
cardiovascular endpoint (cardiovascular death, nonfatal stroke, or
nonfatal myocardial infarction) for prasugrel in comparison with
clopidogrel. However, the major and minor bleeding risk was
increased with prasugrel. Prasugrel is contraindicated in patients
with history of TIA or stroke because of increased bleeding risk.
In contrast to clopidogrel, cytochrome P450 genotype status is not
an important factor in prasugrel pharmacology.
Ticagrelor is a newer type of ADP inhibitor (cyclopentyl triazo-
lopyrimidine) and is also approved for oral use in combination with
aspirin in patients with acute coronary syndromes. Cangrelor is a
parenteral P2Y12 inhibitor approved for IV use in coronary interven-
tions in patients without previous ADP P2Y12 inhibitor therapy.
Aspirin & Clopidogrel Resistance
The reported incidence of resistance to these drugs varies greatly,
from less than 5% to 75%. In part this variation reflects the
definition of resistance (recurrent thrombosis while on antiplatelet
therapy versus in vitro testing), methods by which drug response
is measured, and patient compliance. Several methods for testing
aspirin and clopidogrel resistance in vitro are now FDA-approved.
However, the measures of drug resistance vary considerably by
testing method. These tests may be useful in selected patients to
assess compliance or identify patients at increased risk of recur-
rent thrombotic events. However, their utility in routine clinical
decision-making outside of clinical trials remains controversial.
A recent randomized prospective trial found no benefit over
standard therapy when information obtained from monitoring
antiplatelet drug effect was used to alter therapy.

BLOCKADE OF PLATELET
GLYCOPROTEIN IIb/IIIa RECEPTORS
The platelet GP IIb/IIIa (integrin αIIbβ3) receptor functions
as a receptor mainly for fibrinogen and vitronectin but also for
fibronectin and von Willebrand factor. Activation of this receptor
complex is the final common pathway for platelet aggregation.
Ligands for GP IIb/IIIa contain an Arg-Gly-Asp (RGD) sequence
motif important for ligand binding, and thus RGD constitutes a
therapeutic target. There are approximately 50,000 copies of this
complex on the surface of each platelet. Persons lacking this recep-
tor have a bleeding disorder, Glanzmann’s thrombasthenia.
The GP IIb/IIIa antagonists are used in patients with acute
coronary syndromes. These drugs target the platelet GP IIb/IIIa
receptor complex shown in Figure 34–1. Abciximab, a chime-
ric monoclonal antibody directed against the IIb/IIIa complex
including the vitronectin receptor, was the first agent approved
in this class of drugs. It has been approved for use in percutane-
ous coronary intervention and in acute coronary syndromes.
Eptifibatide is a cyclic peptide derived from rattlesnake venom
that contains a variation of the RGD motif (KGD). Tirofiban
is a peptidomimetic inhibitor with the RGD sequence motif.
Eptifibatide and tirofiban inhibit ligand binding to the IIb/IIIa
receptor by their occupancy of the receptor but do not block the
vitronectin receptor. Because of their short half-lives, they must be
given by continuous infusion. Oral formulations of GP IIb/IIIa
antagonists are in various stages of development.
ADDITIONAL ANTIPLATELET-DIRECTED
DRUGS
Dipyridamole is a vasodilator that also inhibits platelet function
by inhibiting adenosine uptake and cGMP phosphodiesterase
activity. Dipyridamole by itself has little or no beneficial effect.
Therefore, therapeutic use of this agent is primarily in combina-
tion with aspirin to prevent cerebrovascular ischemia. It may also
be used in combination with warfarin for primary prophylaxis of
thromboemboli in patients with prosthetic heart valves. A combi-
nation of dipyridamole complexed with 25 mg of aspirin is now
available for secondary prophylaxis of cerebrovascular disease.
Cilostazol is a phosphodiesterase inhibitor that promotes vaso-
dilation and inhibition of platelet aggregation. Cilostazol is used
primarily to treat intermittent claudication.
■■ DRUGS USED IN BLEEDING
DISORDERS
VITAMIN K
Vitamin K confers biologic activity upon prothrombin and factors
VII, IX, and X by participating in their postribosomal modifica-
tion. Vitamin K is a fat-soluble substance found primarily in
leafy green vegetables. The dietary requirement is low because
CHAPTER 34  Drugs Used in Disorders of Coagulation     621
the vitamin is additionally synthesized by bacteria that colonize
the human intestine. Two natural forms exist: vitamins K1 and
K2. Vitamin K1 (phytonadione; Figure 34–5) is found in food.
Vitamin K2 (menaquinone) is found in human tissues and is syn-
thesized by intestinal bacteria.
Vitamins K1 and K2 require bile salts for absorption from the
intestinal tract. Vitamin K1 is available clinically in oral and par-
enteral forms. Onset of effect is delayed for 6 hours but the effect
is complete by 24 hours when treating depression of prothrombin
activity caused by excess warfarin or vitamin K deficiency. Intra-
venous administration of vitamin K1 should be slow, as rapid
infusion can produce dyspnea, chest and back pain, and even
death. Vitamin K repletion is best achieved with intravenous or
oral administration because its bioavailability after subcutaneous
administration is erratic. Vitamin K1 is currently administered
to all newborns to prevent the hemorrhagic disease of vitamin K
deficiency, which is especially common in premature infants.
The water-soluble salt of vitamin K3 (menadione) should never be
used in therapeutics. It is particularly ineffective in the treatment
of warfarin overdosage. Vitamin K deficiency frequently occurs in
hospitalized patients in intensive care units because of poor diet,
parenteral nutrition, recent surgery, multiple antibiotic therapy, and
uremia. Severe hepatic failure results in diminished protein synthesis
and a hemorrhagic diathesis that is unresponsive to vitamin K.
PLASMA FRACTIONS
Sources & Preparations
Deficiencies in plasma coagulation factors can cause bleeding
(Table 34–3). Spontaneous bleeding occurs when factor activ-
ity is less than 5–10% of normal. Factor VIII deficiency (clas-
sic hemophilia, or hemophilia A) and factor IX deficiency
(Christmas disease, or hemophilia B) account for most of the
heritable coagulation defects. Concentrated plasma fractions and
recombinant protein preparations are available for the treatment
of these deficiencies. Administration of plasma-derived, heat- or
detergent-treated factor concentrates and recombinant factor con-
centrates are the standard treatments for prevention and treatment
of bleeding associated with hemophilia. Lyophilized factor VIII
concentrates are prepared from large pools of plasma. Transmis-
sion of viral diseases such as hepatitis B and C and HIV is reduced
or eliminated by pasteurization and by extraction of plasma with
solvents and detergents. However, this treatment does not remove
other potential causes of transmissible diseases such as prions. For
this reason, recombinant clotting factor preparations are recom-
mended whenever possible for factor replacement. The best use
of these therapeutic materials requires diagnostic specificity of the
deficient factor and quantitation of its activity in plasma. Recently,
several longer-acting factor VIII and IX preparations have been
developed. Eloctate is a factor VIII-Fc domain conjugate that
prolongs the factor VIII half-life and allows twice-weekly dosing
in many cases. Idelvion is a factor IX-albumin conjugate with a
half-life of 100 hours (native factor IX has a half-life of 16 hours)
and is FDA-approved for prophylaxis or treatment of bleeding
in hemophilia B patients, offering the possibility of once-weekly
622    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

TABLE 34–3  Therapeutic products for the treatment of coagulation disorders.1

Half-Life of
Factor Deficiency State Hemostatic Levels Infused Factor Replacement Source

I Hypofibrinogenemia 1 g/dL 4 days Cryoprecipitate, FFP

II Prothrombin deficiency 30–40% 3 days Prothrombin complex concentrates (intermediate purity factor
IX concentrates)
V Factor V deficiency 20% 1 day FFP
VII Factor VII deficiency 30% 4–6 hours FFP
Prothrombin complex concentrates (intermediate purity factor
IX concentrates) Recombinant factor VIIa
VIII Hemophilia A 30–50% 12 hours Recombinant factor VIII products
100% for major Plasma-derived high purity concentrates
bleeding or trauma
Cryoprecipitate2
Some patients with mild deficiency will respond to DDAVP
IX Hemophilia B 30–50% 24 hours Recombinant factor IX products
Christmas disease 100% for major Plasma-derived high purity concentrates
bleeding or trauma
X Stuart-Prower defect 25% 36 hours FFP
Prothrombin complex concentrates
XI Hemophilia C 30–50% 3 days FFP
XII Hageman defect Not required Treatment not necessary
von von Willebrand disease 30% Approximately Intermediate purity factor VIII concentrates that contain
Willebrand 10 hours von Willebrand factor
Type I patients respond to DDAVP
Cryoprecipitate2
XIII Factor XIII deficiency 5% 6 days FFP
Cryoprecipitate
FFP, fresh frozen plasma; DDAVP, 1-deamino-8-d-arginine vasopressin.
1
For warfarin overdose or coumarin rodenticide poisoning, a four-factor concentrate (II, VII, IX, X) is available. Antithrombin concentrates are available for patients with thrombosis
in the setting of antithrombin deficiency. Activated protein C concentrates were approved for treatment of sepsis but withdrawn from the market in 2011 following publication
of a study demonstrating no benefit in sepsis and increased bleeding risk.
2
Cryoprecipitate should be used to treat bleeding in the setting of factor VIII deficiency and von Willebrand disease only in an emergency in which pathogen-inactivated products
are not available.

dosing in the case of Idelvion. Intermediate purity factor VIII con-
centrates (as opposed to recombinant or high purity concentrates)
contain significant amounts of von Willebrand factor. Humate-P
is a factor VIII concentrate that is approved by the FDA for the
treatment of bleeding associated with von Willebrand disease.
Vonicog alfa is a recombinant von Willebrand factor product
approved for treatment and control of bleeding in adults with von
Willebrand disease. Fresh frozen plasma is used for factor deficien-
cies for which no recombinant form of the protein is available. A
four-factor plasma replacement preparation containing vitamin
K–dependent factors II VII, IX, and X (4F PCC, Kcentra) is avail-
able for rapid reversal of warfarin in bleeding patients.
Clinical Uses
Hemophilia A and B patients are given factor VIII and IX replace-
ment, respectively, as prophylaxis to prevent bleeding, and in
higher doses to treat bleeding events or to prepare for surgery.
Desmopressin acetate increases the factor VIII activity of
patients with mild hemophilia A or von Willebrand disease. It can
be used in preparation for minor surgery such as tooth extraction
without any requirement for infusion of clotting factors if the
patient has a documented adequate response. High-dose intrana-
sal desmopressin (see Chapter 17) is available and has been shown
to be efficacious and well tolerated by patients.
Freeze-dried concentrates of plasma containing prothrombin,
factors IX and X, and varied amounts of factor VII (Proplex,
etc) are commercially available for treating deficiencies of these
factors (Table 34–3). Each unit of factor IX per kilogram of
body weight raises its activity in plasma 1.5%. Heparin is often
added to inhibit coagulation factors activated by the manufactur-
ing process. However, addition of heparin does not eliminate all
thromboembolic risk.
Some preparations of factor IX concentrate contain activated
clotting factors, which has led to their use in treating patients
with inhibitors or antibodies to factor VIII or factor IX.

Two products are available expressly for this purpose: Autoplex
(with factor VIII correctional activity) and FEIBA (Factor
Eight Inhibitor Bypass Activity). These products are not uni-
formly successful in arresting hemorrhage, and the factor IX
inhibitor titers often rise after treatment with them. Acquired
inhibitors of coagulation factors may also be treated with
porcine factor VIII (for factor VIII inhibitors) and recombi-
nant activated factor VII. Recombinant activated factor VII
(NovoSeven) increasingly is being used to treat coagulopathy
associated with liver disease and major blood loss in trauma
and surgery. These recombinant and plasma-derived factor
concentrates are very expensive, and the indications for them
are very precise. Therefore, close consultation with a hematolo-
gist knowledgeable in this area is essential.
Cryoprecipitate is a plasma protein fraction obtainable from
whole blood. It is used to treat deficiencies or qualitative abnor-
malities of fibrinogen, such as that which occurs with dissemi-
nated intravascular coagulation and liver disease. A single unit of
cryoprecipitate contains 300 mg of fibrinogen.
Cryoprecipitate may also be used for patients with factor VIII
deficiency and von Willebrand disease if desmopressin is not
indicated and a pathogen-inactivated, recombinant, or plasma-
derived product is not available. The concentration of factor VIII
and von Willebrand factor in cryoprecipitate is not as great as that
found in the concentrated plasma fractions. Moreover, cryopre-
cipitate is not treated in any manner to decrease the risk of viral
exposure. For infusion, the frozen cryoprecipitate unit is thawed
and dissolved in a small volume of sterile citrate-saline solution
and pooled with other units. Rh-negative women with potential
for childbearing should receive only Rh-negative cryoprecipitate
because of possible contamination of the product with Rh-positive
blood cells.
RECOMBINANT FACTOR VIIa
Recombinant factor VIIa is approved for treatment of inherited
or acquired hemophilia A or B with inhibitors, treatment of
bleeding associated with invasive procedures in congenital or
acquired hemophilia, or factor VII deficiency. In the European
Union, the drug is also approved for treatment of Glanzmann’s
thrombasthenia.
Factor VIIa initiates activation of the clotting pathway by
activating factor IX and factor X in association with tissue factor
(see Figure 34–2). The drug is given by bolus injection. For
hemophilia A or B with inhibitors and bleeding, the dosage is
90 mg/kg every 2 hours until hemostasis is achieved, and then
continued at 3- to 6-hour intervals until stable. For congenital
factor VII deficiency, the recommended dosage is 15–30 mg/kg
every 4–6 hours until hemostasis is achieved.
Factor VIIa has been widely used for off-label indications,
including bleeding with trauma, surgery, intracerebral hemor-
rhage, and warfarin toxicity. A major concern of off-label use has
been the possibility that thrombotic events may be increased.
A recent study examined rates of thromboembolic events in
35 placebo-controlled trials where factor VIIa was administered
CHAPTER 34  Drugs Used in Disorders of Coagulation     623
for nonapproved indications. This study found an increase in
arterial, but not venous, thrombotic events, particularly among
elderly individuals.
ORPHAN DRUGS FOR TREATMENT OF
RARE HEREDITARY COAGULATION
DISORDERS
Orphan drug status is a designation given by the FDA to promote
development of therapies for rare disorders (see Chapter 1).
Factor XIII is a transaminase that crosslinks fibrin within a
clot, thereby stabilizing it. Congenital factor XIII deficiency is a
rare bleeding disorder. Recombinant factor XIII A-subunit is
FDA-approved for prevention of bleeding in patients with factor
XIII deficiency.
Factor X concentrate is a plasma-derived factor X preparation
that is FDA-approved for control of bleeding in patients with
factor X deficiency and for perioperative management of patients
with mild factor X deficiency.
Protein C concentrate is a plasma-derived protein C prepara-
tion approved for treatment of life-threatening thrombosis or pur-
pura fulminans, a life-threatening disorder involving thrombosis
in skin and systemic circulation.
Recombinant antithrombin is FDA-approved for preven-
tion of perioperative and peripartum thromboembolic events in
patients with hereditary antithrombin deficiency.
FIBRINOLYTIC INHIBITORS:
AMINOCAPROIC ACID
Aminocaproic acid (EACA), which is chemically similar to the
amino acid lysine, is a synthetic inhibitor of fibrinolysis. It com-
petitively inhibits plasminogen activation (Figure 34–3). It is
rapidly absorbed orally and is cleared from the body by the kidney.
The usual oral dosage of EACA is 6 g four times a day. When the
drug is administered intravenously, a 5-g loading dose should be
infused over 30 minutes to avoid hypotension. Tranexamic acid
is an analog of aminocaproic acid and has the same properties. It
is administered orally with a 15-mg/kg loading dose followed by
30 mg/kg every 6 hours.
Clinical uses of EACA are as adjunctive therapy in hemo-
philia, as therapy for bleeding from fibrinolytic therapy, and as
prophylaxis for rebleeding from intracranial aneurysms. Treat-
ment success has also been reported in patients with postsurgical
gastrointestinal bleeding and postprostatectomy bleeding and
bladder hemorrhage secondary to radiation- and drug-induced
cystitis. Adverse effects of the drug include intravascular throm-
bosis from inhibition of plasminogen activator, hypotension,
myopathy, abdominal discomfort, diarrhea, and nasal stuffiness.
The drug should not be used in patients with disseminated
intravascular coagulation or genitourinary bleeding of the upper
tract, eg, kidney and ureters, because of the potential for exces-
sive clotting.
624    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

DRUGS REMOVED FROM MARKET
FOR LACK OF EFFICACY OR SAFETY:
APROTININ AND ACTIVATED PROTEIN C
Aprotinin is a serine protease inhibitor (serpin) that inhibits
fibrinolysis by free plasmin and may have other antihemor-
rhagic effects as well. It also inhibits the plasmin-streptokinase
complex in patients who have received that thrombolytic
agent. Aprotinin was shown to reduce bleeding—by as much
as 50%—from many types of surgery, especially that involving
extracorporeal circulation for open-heart procedures and liver
transplantation. However, clinical trials and internal data from
the manufacturer suggested that use of the drug was associated
with an increased risk of renal failure, heart attack, and stroke.
A prospective trial was initiated in Canada but halted early
because of concerns that use of the drug was associated with
increased mortality. The drug was removed from the market
in 2007.
Drotrecogin alfa is a recombinant form of activated protein
C that was initially approved by the FDA in 2001 for reduction
of mortality in adults with sepsis associated with acute organ dys-
function and high mortality. The drug was voluntarily withdrawn
from the market in 2011 after a follow-up study showed no sur-
vival benefit in sepsis.

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

Abciximab ReoPro Eptifibatide Integrilin
Alteplase recombinant [t-PA] Activase Factor VIIa: see Coagulation  
Aminocaproic acid Generic, Amicar factor VIIa recombinant
Anisindione Miradon (outside the USA) Factor VIII: see  
Antihemophilic factor
Antihemophilic factor Alphanate, Bioclate, Helixate, Hemofil
[factor VIII, AHF] M, Koate-HP, Kogenate, Monoclate, Factor IX complex, human AlphaNine SD, Bebulin VH, BeneFix,
Recombinate, others Konyne 80, Mononine, Profilnine SD,
Proplex T, Proplex SX-T
Anti-inhibitor coagulant Autoplex T, Feiba VH Immuno
complex 4F PCC Kcentra
Antithrombin III Thrombate III, ATryn Fondaparinux Generic, Arixtra
Apixaban Eliquis Heparin sodium Generic, Liquaemin
Argatroban Generic Prasugrel Effient
Bivalirudin Generic, Angiomax Protamine Generic
Cilostazol Generic, Pletal Reteplase Retavase
Clopidogrel Generic, Plavix Rivaroxaban Xarelto
Coagulation factor VIIa NovoSeven Streptokinase Streptase
recombinant Tenecteplase TNKase
Dabigatran Pradaxa Ticlopidine Generic, Ticlid
Dalteparin Fragmin Tinzaparin Innohep
Danaparoid Orgaran Tirofiban Aggrastat
Desirudin Iprivask Tranexamic acid Generic, Cyklokapron, Lysteda
Dipyridamole Generic, Persantine Urokinase Abbokinase, Kinlytic
Enoxaparin (low-molecular- Generic, Lovenox Vitamin K Generic, various
weight heparin) Warfarin Generic, Coumadin

REFERENCES Mannucci PM, Levi M: Prevention and treatment of major blood loss. N Engl J
Med 2007;356:2301.
Direct Oral Anticoagulants
January C et al: 2014 AHA/ACC/HRS Guideline for the Management of Patients Drugs Used in Thrombotic Disorders
With Atrial Fibrillation: A Report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines and the Furie B: Do pharmacogenetics have a role in the dosing of vitamin K antagonists?
Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1. N Engl J Med 2013;369:2345.
Li A, Lopes RD, Garcia DA: Use of direct oral anticoagulants in special popula- Kearon C et al: Antithrombotic therapy for VTE disease: Chest guideline and
tions. Hematol Oncol Clin North Am 2016;30:1053. expert panel report. Chest 2016;149:315.
Samuelson BT, Cuker A: Measurement and reversal of the direct oral anticoagu-
lants. Blood Rev 2016;31:77.

Blood Coagulation & Bleeding Disorders

Dahlback B: Advances in understanding pathogenic mechanisms of thrombophilic
disorders. Blood 2008;112:19.

C ASE STUDY ANSWER
This patient has pulmonary embolism secondary to a
deep venous thrombosis (DVT). Options for treating this
patient include unfractionated heparin or low-molecular-
weight heparin followed by warfarin, with INR goal of
2–3; parenteral anticoagulation for 5–7 days followed by
edoxaban; or rivaroxaban, apixaban, or dabigatran alone
CHAPTER 34  Drugs Used in Disorders of Coagulation     625
without monitoring. As this situation can be considered a
provoked event given the history of oral contraceptive use,
the recommended duration of therapy would be 3–6 months
depending on individual risk factors and preferences. The
patient should be counseled to use an alternative form of
contraception.
 35
C H A P T E R
Agents Used in
Dyslipidemia
Mary J. Malloy, MD, & John P. Kane, MD, PhD
C ASE STUDY
A 42-year-old woman has heterozygous familial hyper-
cholesterolemia (HeFH) but is otherwise well and has no
symptoms of coronary or peripheral vascular disease. A
carotid ultrasound was normal. Her mother had a myo-
cardial infarction at age 51 and had no known risk factors
other than her presumed HeFH. The patient also has ele-
vated lipoprotein (a) at 2.5 times normal and low HDL-C
(43 mg/dL). She developed muscle symptoms with each
of 3 statins (atorvastatin, rosuvastatin, and simvastatin)
Plasma lipids are transported in complexes called lipoproteins.
Metabolic disorders that involve elevations in any lipoprotein
species are termed hyperlipoproteinemias or hyperlipidemias.
Hyperlipemia denotes increased levels of triglycerides.
The major clinical sequelae of hyperlipidemias are acute
pancreatitis and atherosclerosis. The former occurs in patients
with marked hyperlipemia. Control of triglycerides can prevent
recurrent attacks of this life-threatening disease.
Atherosclerosis is the leading cause of death for both genders in
the USA and other Western countries. Lipoproteins that contain
apolipoprotein (apo) B-100 convey lipids into the artery wall.
These are low-density (LDL), intermediate-density (IDL),
very-low-density (VLDL), and lipoprotein(a) (Lp[a]). Remnant
lipoproteins formed during the catabolism of chylomicrons that
contain the B-48 protein (apo B-48) can also enter the artery wall,
contributing to atherosclerosis.
Cellular components in atherosclerotic plaques (atheromas)
include foam cells, which are transformed macrophages, and
smooth muscle cells filled with cholesteryl esters. These cellular
alterations result from endocytosis of modified lipoproteins via at
least four species of scavenger receptors. Chemical modification
626
so they were discontinued although she did not develop
elevated levels of creatine kinase. Her untreated LDL-C is
235 mg/dL and triglycerides 125 mg/dL. Her LDL-C goal
for primary prevention of arteriosclerotic vascular disease
is in the 70-mg/dL range because of her multiple lipopro-
tein risk factors and her mother’s history of premature
coronary artery disease. She has no other risk factors and
her diet and exercise habits are excellent. How would you
manage this patient?
of lipoproteins by free radicals creates ligands for these receptors.
The atheroma grows with the accumulation of foam cells,
collagen, fibrin, and frequently calcium. Whereas such lesions
can slowly occlude coronary vessels, clinical symptoms are more
frequently precipitated by rupture of unstable atheromatous
plaques, leading to activation of platelets and formation of occlu-
sive thrombi.
Although treatment of hyperlipidemia can cause slow physical
regression of plaques, the well-documented reduction in acute
coronary events that follows vigorous lipid-lowering treatment
is attributable chiefly to mitigation of the inflammatory activity
of macrophages and is evident within 2–3 months after starting
therapy.
High-density lipoproteins (HDL) exert several antiathero-
genic effects. They participate in retrieval of cholesterol from the
artery wall and inhibit the oxidation of atherogenic lipoproteins.
Low levels of HDL (hypoalphalipoproteinemia) are an indepen-
dent risk factor for atherosclerotic disease and thus are a potential
target for intervention.
Cigarette smoking is a major risk factor for coronary disease. It
is associated with reduced levels of HDL, impairment of cholesterol
 CHAPTER 35  Agents Used in Dyslipidemia    627

retrieval, cytotoxic effects on the endothelium, increased oxidation
of lipoproteins, and stimulation of thrombogenesis. Diabetes, also
a major risk factor, is another source of oxidative stress.
Normal coronary arteries can dilate in response to ischemia,
increasing delivery of oxygen to the myocardium. This process
is mediated by nitric oxide, acting on smooth muscle cells of
the arterial media. The release of nitric oxide from the vascular
endothelium is impaired by atherogenic lipoproteins, thus aggra-
vating ischemia. Reducing levels of atherogenic lipoproteins and
inhibiting their oxidation restores endothelial function.
Because atherogenesis is multifactorial, therapy should be
directed toward all modifiable risk factors. Atherogenesis is a
dynamic process. Quantitative angiographic trials have demon-
strated net regression of plaques during aggressive lipid-lowering
therapy. Primary and secondary prevention trials have shown
significant reduction in mortality from new coronary events and
in all-cause mortality.
■■ PATHOPHYSIOLOGY OF
HYPERLIPOPROTEINEMIA
NORMAL LIPOPROTEIN
METABOLISM
Structure
Lipoproteins have hydrophobic core regions containing cholesteryl
esters and triglycerides surrounded by unesterified cholesterol,
phospholipids, and apoproteins. Certain lipoproteins contain
very high-molecular-weight B proteins that exist in two forms:
B-48, formed in the intestine and found in chylomicrons and
their remnants; and B-100, synthesized in liver and found in
VLDL, VLDL remnants (IDL), LDL (formed from VLDL), and
Lp(a) lipoproteins. HDL consist of at least 20 discrete molecular
species containing apolipoprotein A-I (apo A-I). About 100 other
proteins are known to be distributed variously among the HDL
species.
Synthesis & Catabolism
A. Chylomicrons
Chylomicrons are formed in the intestine and carry triglycerides
of dietary origin, unesterified cholesterol, and cholesteryl esters.
They transit the thoracic duct to the bloodstream.
Triglycerides are removed from the chylomicrons in extrahe-
patic tissues through a pathway shared with VLDL that involves
hydrolysis by the lipoprotein lipase (LPL) system. Decrease
in particle diameter occurs as triglycerides are depleted. Surface
lipids and small apoproteins are transferred to HDL. The resultant
chylomicron remnants are taken up by receptor-mediated endocy-
tosis into hepatocytes.
B. Very-Low-Density Lipoproteins
VLDL are secreted by liver and export triglycerides to peripheral
tissues (Figure 35–1). VLDL triglycerides are hydrolyzed by
LPL, yielding free fatty acids for storage in adipose tissue and for
oxidation in tissues such as cardiac and skeletal muscle. Deple-
tion of triglycerides produces remnants (IDL), some of which
undergo endocytosis directly into hepatocytes. The remainder are
converted to LDL by further removal of triglycerides mediated by
hepatic lipase. This process explains the “beta shift” phenomenon,
the increase of LDL (beta-lipoprotein) in serum as hypertriglyc-
eridemia subsides. Increased levels of LDL can also result from
increased secretion of VLDL and from decreased LDL catabolism.
C. Low-Density Lipoproteins
LDL are catabolized chiefly in hepatocytes and other cells after
receptor-mediated endocytosis. Cholesteryl esters from LDL
are hydrolyzed, yielding free cholesterol for the synthesis of cell
membranes. Cells also obtain cholesterol by synthesis via a path-
way involving the formation of mevalonic acid by HMG-CoA
reductase. Production of this enzyme and of LDL receptors is
transcriptionally regulated by the content of cholesterol in the
cell. Normally, about 70% of LDL is removed from plasma by
hepatocytes. Even more cholesterol is delivered to the liver via IDL
and chylomicrons. Unlike other cells, hepatocytes can eliminate
cholesterol by secretion in bile and by conversion to bile acids.

ACRONYMS D. Lp(a) Lipoprotein

Apo Apolipoprotein Lp(a) lipoprotein is formed from LDL and the (a) protein, linked
CETP Cholesteryl ester transfer protein
by a disulfide bridge. The (a) protein is highly homologous with
plasminogen but is not activated by tissue plasminogen activator.
CK Creatine kinase
It occurs in a number of isoforms of different molecular weights.
HDL High-density lipoproteins Levels of Lp(a) vary from nil to over 2000 nM/L and are deter-
HMG-CoA 3-Hydroxy-3-methylglutaryl-coenzyme A mined chiefly by genetic factors. Lp(a) is found in atherosclerotic
IDL Intermediate-density lipoproteins plaques and contributes to coronary disease by inhibiting throm-
LCAT Lecithin:cholesterol acyltransferase bolysis. It is also associated with aortic stenosis. Levels are elevated
LDL Low-density lipoproteins
in certain inflammatory states. The risk of coronary disease is
strongly related to the level of Lp(a). A common variant (I4399M)
Lp(a) Lipoprotein(a)
in the coding region is associated with elevated levels.
LPL Lipoprotein lipase
PCSK9 Proprotein convertase subtilisin/kexin type 9 E. High-Density Lipoproteins
PPAR Peroxisome proliferator-activated receptor The apoproteins of HDL are secreted largely by the liver and
VLDL Very-low-density lipoproteins intestine. Much of the lipid comes from the surface monolayers of
628    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

Hepatocyte Blood Capillary

ApoE endothelium
Golgi
vesicle B-100

RER ApoC
HDL
Lipoprotein
lipase
ApoB, VLDL
ApoE,
ApoC

VLDL
Cholesterol LDL receptor remnant
Lysosome

FFA
*
*

Mevalonic HDL
acid HMG-CoA LDL
reductase

Peripheral cell
Acetyl-
CoA

Cholesterol biosynthetic Cholesterol

pathway Lysosome Cholesteryl
esters

FIGURE 35–1  Metabolism of lipoproteins of hepatic origin. The heavy arrows show the primary pathways. Nascent VLDL are secreted via
the Golgi apparatus. They acquire additional apo C lipoproteins and apo E from HDL. Very-low-density lipoproteins (VLDL) are converted to
VLDL remnants (IDL) by lipolysis via lipoprotein lipase in the vessels of peripheral tissues. In the process, C apolipoproteins and a portion of the
apo E are given back to high-density lipoproteins (HDL). Some of the VLDL remnants are converted to LDL by further loss of triglycerides and
loss of apo E. A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver and the peripheral tissues,
for which apo B-100 is the ligand. Dark color denotes cholesteryl esters; light color denotes triglycerides; the asterisk denotes a functional
ligand for LDL receptors; triangles indicate apo E; circles and squares represent C apolipoproteins. FFA, free fatty acid; RER, rough endoplasmic
reticulum. (Adapted, with permission, from Kane J, Malloy M: Disorders of lipoproteins. In: Rosenberg RN et al [editors]: The Molecular and Genetic Basis of Neurological
Disease. 2nd ed. Butterworth-Heinemann, 1997.)

chylomicrons and VLDL during lipolysis. HDL also acquires cho-
lesterol from peripheral tissues, protecting the cholesterol homeo-
stasis of cells. Free cholesterol is chiefly exported from the cell
membrane by a transporter, ABCA1, acquired by a small particle
termed prebeta-1 HDL, and then esterified by lecithin:cholesterol
acyltransferase (LCAT), leading to the formation of larger HDL
species. Cholesterol is also exported by the ABCG1 transporter
and the scavenger receptor, SR-BI, to large HDL particles. The
cholesteryl esters are transferred to VLDL, IDL, LDL, and
chylomicron remnants with the aid of cholesteryl ester transfer
protein (CETP). Much of the cholesteryl ester thus transferred
is ultimately delivered to the liver by endocytosis of the acceptor
lipoproteins. HDL can also deliver cholesteryl esters directly to the
liver via SR-BI that does not cause endocytosis of the lipoproteins.
At the population level, HDL cholesterol (HDL-C) levels relate
inversely to atherosclerosis risk. Among individuals, the capacity
to accept exported cholesterol can vary widely at identical levels
of HDL-C. The ability of peripheral tissues to export cholesterol
via the transporter mechanism and the acceptor capacity of HDL
are emerging as major determinants of coronary atherosclerosis.
LIPOPROTEIN DISORDERS
Lipoprotein disorders are detected by measuring lipids in serum
after a 10-hour fast. Risk of heart disease increases with concentra-
tions of the atherogenic lipoproteins, is inversely related to levels
of HDL-C, and is modified by other risk factors. Evidence from
clinical trials suggests that an LDL cholesterol (LDL-C) level of
50-60 mg/dL is optimal for patients with coronary disease. Ideally,
triglycerides should be below 120 mg/dL. Although LDL-C is
still the primary target of treatment, reducing the levels of VLDL
and IDL also is important. Calculation of non-HDL cholesterol
provides a means of assessing levels of all the lipoproteins in the
VLDL to LDL cascade. Differentiation of the disorders requires
identification of the lipoproteins involved (Table 35–1). Diag-
nosis of a primary disorder usually requires further clinical and
 CHAPTER 35  Agents Used in Dyslipidemia    629

TABLE 35–1  The primary hyperlipoproteinemias and their treatment.

Disorder Manifestations Diet + Single Drug1 Drug Combination

Primary chylomicronemia
(familial lipoprotein lipase,
cofactor deficiency; others)
Familial hypertriglyceridemia
Familial combined
hyperlipoproteinemia
 
 
Familial dysbetalipoproteinemia
Familial hypercholesterolemia
 Heterozygous
 Homozygous
Familial ligand-defective
apo B-100
Lp(a) hyperlipoproteinemia
1
Single-drug therapy with marine omega-3 dietary supplement should be evaluated before drug combinations are used.
2
Select pharmacologically compatible reductase inhibitor (see text).
Chylomicrons, VLDL increased
VLDL increased; chylomicrons
may be increased
VLDL predominantly increased
LDL predominantly increased
VLDL, LDL increased
VLDL remnants, chylomicron
remnants increased
LDL increased
LDL increased
LDL increased
Lp(a) increased
Dietary management; Omega-3 fatty Fibrate plus niacin
acids, fibrate, or niacin
(Apo C-III antisense)
Dietary management; Omega-3 fatty Fibrate plus niacin
acids, fibrate, or niacin
Reductase inhibitor, Omega-3 fatty acids, Two or three of the single
fibrate, niacin agents2
Reductase inhibitor, ezetimibe, or niacin Two or three of the single
agents
Reductase inhibitor, Omega-3 fatty acids, Niacin or fibrate plus reductase
or niacin inhibitor2
Fibrate, reductase inhibitor, niacin, Omega Reductase inhibitor plus fibrate
3 fatty acids or niacin
Reductase inhibitor, resin, niacin, or Two or three of the individual
ezetimibe drugs
Atorvastatin, rosuvastatin, ezetimibe, Combinations of some of the
mipomersen, lomitapide or PCSK9 MAB single agents
Reductase inhibitor, niacin, or ezetimibe Two or three of the single
agents
Niacin  

genetic data as well as ruling out secondary hyperlipidemias

(Table 35–2).
THE PRIMARY
Phenotypes of abnormal lipoprotein distribution are described HYPERTRIGLYCERIDEMIAS
in this section. Drugs mentioned for use in these conditions Hypertriglyceridemia is associated with increased risk of coronary
are described in the following section on basic and clinical disease. Chylomicrons, VLDL, and IDL are found in atheroscle-
pharmacology. rotic plaques. These patients tend to have cholesterol-rich VLDL
of small particle diameter and small, dense LDL. Hypertriglyceri-
TABLE 35–2  Secondary causes of hyperlipoproteinemia. demic patients with coronary disease or risk equivalents should be
treated aggressively. Patients with triglycerides above 700 mg/dL
Hypertriglyceridemia Hypercholesterolemia
should be treated to prevent acute pancreatitis because the LPL
Diabetes mellitus Hypothyroidism clearance mechanism is saturated at about this level.
Alcohol ingestion Early nephrosis Hypertriglyceridemia is an important component of the
Severe nephrosis Resolving lipemia metabolic syndrome, which also includes insulin resistance,
Estrogens Immunoglobulin-lipoprotein
hypertension, and abdominal obesity. Reduced levels of HDL-C
complex disorders are usually observed due to transfer of cholesteryl esters to the
Uremia Anorexia nervosa
triglyceride-rich lipoprotein particles. Hyperuricemia is frequently
present. Insulin resistance appears to be central to this disorder.
HIV infection Cholestasis
Management of these patients frequently requires, in addition
Myxedema Hypopituitarism to a fibrate, the use of metformin, another antidiabetic agent, or
Glycogen storage disease Corticosteroid excess both (see Chapter 41). The severity of hypertriglyceridemia of any
Hypopituitarism Androgen overdose cause is increased in the presence of the metabolic syndrome or
Acromegaly   type 2 diabetes.
Immunoglobulin-lipoprotein  
complex disorders Primary Chylomicronemia
Lipodystrophy   Chylomicrons are not present in the serum of normal individu-
Protease inhibitors, tacrolimus,   als who have fasted 10 hours. The recessive traits of deficiency
sirolimus, other drugs of LPL, its cofactor apo C-II, the LMF1 or GPIHBP1 proteins,
630    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
or ANGPTL4 and Apo A-V, are usually associated with severe
lipemia (2000 mg/dL of triglycerides or higher when the patient
is consuming a typical American diet). These disorders might not
be diagnosed until an attack of acute pancreatitis occurs. Patients
may have eruptive xanthomas, hepatosplenomegaly, hypersplen-
ism, and lipid-laden foam cells in bone marrow, liver, and spleen.
The lipemia is aggravated by estrogens because they stimulate
VLDL production, and pregnancy may cause marked increases
in triglycerides despite strict dietary control. Although these
patients have a predominant chylomicronemia, they may also
have moderately elevated VLDL, presenting with a pattern called
mixed lipemia (fasting chylomicronemia and elevated VLDL).
Deficiency of lipolytic activity can be diagnosed after intravenous
injection of heparin. A presumptive diagnosis is made by dem-
onstrating a pronounced decrease in triglycerides 72 hours after
elimination of daily dietary fat. Marked restriction of total dietary
fat and abstention from alcohol are the basis of effective long-term
treatment. Niacin, a fibrate, or marine omega-3 fatty acids may be
of some benefit if VLDL levels are increased. Apo C-III antisense
is a potential adjunct to therapy.
Familial Hypertriglyceridemia
The primary hypertriglyceridemias probably reflect a variety of
genetic determinants. Many patients have centripetal obesity with
insulin resistance. Other factors, including alcohol and estrogens, that
increase secretion of VLDL aggravate the lipemia. Impaired removal
of triglyceride-rich lipoproteins with overproduction of VLDL
can result in mixed lipemia. Eruptive xanthomas, lipemia retinalis,
epigastric pain, and pancreatitis are variably present depending on the
severity of the lipemia. Treatment is primarily dietary, with restriction
of total fat, avoidance of alcohol and exogenous estrogens, weight
reduction, exercise, and supplementation with marine omega-3 fatty
acids. Most patients also require treatment with a fibrate. If insulin
resistance is not present, niacin may be useful.
Familial Combined Hyperlipoproteinemia
(FCH)
In this common disorder, which is associated with an increased
incidence of coronary disease, individuals may have elevated levels
of VLDL, LDL, or both, and the pattern may change with time.
Familial combined hyperlipoproteinemia involves an approximate
doubling in VLDL secretion and appears to be transmitted as a
dominant trait. Triglycerides can be increased by the factors noted
above. Elevations of cholesterol and triglycerides are generally mod-
erate, and xanthomas are absent. Diet alone does not normalize
lipid levels. A reductase inhibitor alone, or in combination with nia-
cin or fenofibrate, is usually required to treat these patients. When
fenofibrate is combined with a reductase inhibitor, either pravas-
tatin or rosuvastatin is recommended because neither is metabolized
via CYP3A4. Marine omega-3 fatty acids may be useful.
Familial Dysbetalipoproteinemia
In this disorder, remnants of chylomicrons and VLDL accumu-
late and levels of LDL are decreased. Because remnants are rich in
cholesteryl esters, the level of total cholesterol may be as high as that of
triglycerides. Diagnosis is confirmed by the absence of the ε3 and ε4
alleles of apo E, the ε2/ε2 genotype. Other apo E isoforms that lack
receptor ligand properties can also be associated with this disorder.
Patients often develop tuberous or tuberoeruptive xanthomas, or
characteristic planar xanthomas of the palmar creases. They tend to
be obese, and some have impaired glucose tolerance. These factors,
as well as hypothyroidism, can aggravate the lipemia. Coronary and
peripheral atherosclerosis occurs with increased frequency. Weight
loss, together with decreased fat, cholesterol, and alcohol consump-
tion, may be sufficient, but a fibrate or niacin is usually needed to
control the condition. These agents can be given together in more
resistant cases. Reductase inhibitors are also effective because they
increase hepatic LDL receptors that participate in remnant removal.
THE PRIMARY
HYPERCHOLESTEROLEMIAS
LDL Receptor Deficient Familial
Hypercholesterolemia (FH)
This is an autosomal dominant trait. Although levels of LDL tend
to increase throughout childhood, the diagnosis can often be made
on the basis of elevated umbilical cord blood cholesterol. In most
heterozygotes, cholesterol levels range from 260 to 500 mg/dL.
Triglycerides are usually normal. Tendon xanthomas are often
present. Arcus corneae and xanthelasma may appear in the
third decade. Coronary disease tends to occur prematurely. In
homozygous familial hypercholesterolemia, which can lead to
coronary disease in childhood, levels of cholesterol often exceed
1000 mg/dL and early tuberous and tendinous xanthomas occur.
These patients may also develop elevated plaque-like xanthomas
of the aortic valve, digital webs, buttocks, and extremities.
Some individuals have combined heterozygosity for alleles
producing nonfunctional and kinetically impaired receptors. In
heterozygous patients, LDL can be normalized with reductase
inhibitors or combined drug regimens (Figure 35–2). Homozy-
gotes and those with combined heterozygosity whose receptors
retain even minimal function may partially respond to niacin,
ezetimibe, and reductase inhibitors. Emerging therapies for these
patients include mipomersen, employing an antisense strategy
targeted at apo B-100, and lomitapide, a small molecule inhibitor
of microsomal triglyceride transfer protein (MTP), and monoclo-
nal antibodies directed at PCSK9. LDL apheresis is effective in
medication-refractory patients.
Familial Ligand-Defective Apolipoprotein
B-100
Defects in the domain of apo B-100 that binds to the LDL
receptor impair the endocytosis of LDL, leading to hypercho-
lesterolemia of moderate severity. Tendon xanthomas may occur.
Response to reductase inhibitors is variable. Upregulation of LDL
receptors in liver increases endocytosis of LDL precursors but does
not increase uptake of ligand-defective LDL particles. Fibrates or
niacin may have beneficial effects by reducing VLDL production.
 CHAPTER 35  Agents Used in Dyslipidemia    631

LDL-C, low levels of HDL-C, and often modest hypertriglyceri-

demia. Rarely, a totally ablative form, Wolman disease, occurs in
infancy. A recombinant replacement enzyme therapy, sebelipase
Blood Hepatocyte Gut alfa, effectively restores the hydrolysis of cholesteryl esters in liver,
normalizing plasma lipoprotein levels.
Acetyl-CoA

Other Disorders
HMG-CoA
Deficiency of cholesterol 7α-hydroxylase can increase LDL in
B-100

LDL R HMG-CoA
reductase
inhibitors
Ezetimibe
Cholesterol
VLDL
B-100 Niacin
Bile acids
Resins
FIGURE 35–2  Sites of action of HMG-CoA reductase inhibitors,
niacin, ezetimibe, and resins used in treating hyperlipidemias. Low-
density lipoprotein (LDL) receptors are increased by treatment with
resins and HMG-CoA reductase inhibitors. VLDL, very-low-density
lipoproteins; R, LDL receptor.
Familial Combined Hyperlipoproteinemia
(FCH)
Some persons with familial combined hyperlipoproteinemia have
only an elevation in LDL. Serum cholesterol is often less than
350 mg/dL. Dietary and drug treatment, usually with a reduc-
tase inhibitor, is indicated. It may be necessary to add niacin or
ezetimibe to normalize LDL.
Lp(a) Hyperlipoproteinemia
This familial disorder, which is associated with increased athero-
genesis and arterial thrombus formation, is determined chiefly by
alleles that dictate increased production of the (a) protein moiety.
Lp(a) can be secondarily elevated in patients with severe nephro-
sis and certain other inflammatory states. Niacin reduces levels
of Lp(a) in many patients. Reduction of levels of LDL-C below
100 mg/dL decreases the risk attributable to Lp(a), as does the
administration of low-dose aspirin. PCSK9 monoclonal antibod-
ies also reduce levels of Lp(a) by about 25%.
Cholesteryl Ester Storage Disease
Individuals lacking activity of lysosomal acid lipase (LAL) accu-
mulate cholesteryl esters in liver and certain other cell types lead-
ing to hepatomegaly with subsequent fibrosis, elevated levels of
the heterozygous state. Homozygotes also can have elevated
triglycerides, resistance to reductase inhibitors as a single agent,
and increased risk of gallstones and coronary disease. A combi-
nation of niacin with a reductase inhibitor appears to be effec-
tive. Autosomal recessive hypercholesterolemia (ARH) is due to
mutations in a protein that normally assists in endocytosis of
LDL. High-dose reductase inhibitor plus ezetimibe is effective.
The receptor chaperone PCSK9 normally conducts the receptor
to the lysosome for degradation. Gain-of-function mutations
in PCSK9 are associated with elevated levels of LDL-C and
could be managed with a PCSK9 antibody. The ABCG5 and
ABCG8 half-transporters act together in enterocytes and hepa-
tocytes to export phytosterols into the intestinal lumen and bile,
respectively. Homozygous or combined heterozygous ablative
mutations in either transporter result in elevated levels of LDL
enriched in phytosterols, tendon and tuberous xanthomas, and
accelerated atherosclerosis. Ezetimibe is a specific therapeutic for
this disorder.
HDL Deficiency
Rare genetic disorders, including Tangier disease and LCAT
(lecithin:cholesterol acyltransferase) deficiency, are associated
with extremely low levels of HDL. Familial hypoalphalipo-
proteinemia is a more common disorder with levels of HDL
cholesterol usually below 35 mg/dL in men and 45 mg/dL in
women. These patients tend to have premature atherosclerosis,
and the low HDL may be the only identified risk factor. Man-
agement should include special attention to avoidance or treat-
ment of other risk factors. Niacin increases HDL in many of
these patients but the effect on outcome is unknown. Reductase
inhibitors and fibric acid derivatives exert lesser effects. Aggres-
sive LDL reduction is indicated.
In the presence of hypertriglyceridemia, HDL cholesterol is
low because of exchange of cholesteryl esters from HDL into
triglyceride-rich lipoproteins. Treatment of the hypertriglyceride-
mia increases the HDL-C level.
SECONDARY
HYPERLIPOPROTEINEMIA
Before primary disorders can be diagnosed, secondary causes of
the phenotype must be considered. The more common conditions
are summarized in Table 35–2. The lipoprotein abnormality usu-
ally resolves if the underlying disorder can be treated successfully.
These secondary disorders can also aggravate a primary genetic
disorder.
632    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
■■ DIETARY MANAGEMENT OF
HYPERLIPOPROTEINEMIA
Dietary measures are initiated first—unless the patient has
evident coronary or peripheral vascular disease—and may
obviate the need for drugs. Patients with the familial hypercho-
lesterolemias always require drug therapy in addition to diet.
Cholesterol and saturated and trans-fats are the principal factors
that increase LDL.
Total fat, sucrose, and especially fructose increase VLDL.
Alcohol can cause significant hypertriglyceridemia by increasing
hepatic secretion of VLDL. Synthesis and secretion of VLDL
are increased by excess calories. During weight loss, LDL and
VLDL levels may be much lower than can be maintained dur-
ing neutral caloric balance. The conclusion that diet suffices for
management can be made only after weight has stabilized for at
least 1 month.
General recommendations include limiting total calories from
fat to 20–25% of daily intake, saturated fats to less than 7%, and
cholesterol to less than 200 mg/d. Reductions in serum cholesterol
range from 10% to 20% on this regimen. Use of complex carbo-
hydrates and fiber is recommended, and cis-monounsaturated fats
should predominate. Weight reduction, caloric restriction, and
avoidance of alcohol are especially important for patients with
elevated triglycerides.
The effect of dietary fats on hypertriglyceridemia is depen-
dent on the disposition of double bonds in the fatty acids.
Omega-3 fatty acids found in fish oils, but not those from plant
sources, activate peroxisome proliferator-activated receptor-alpha
(PPAR-α) and can induce profound reduction of triglycerides
in some patients. They also have anti-inflammatory and antiar-
rhythmic activities. Omega-3 fatty acids are available over the
counter as triglycerides from marine sources or as a prescription
medication containing ethyl esters of omega-3 fatty acids. It is
necessary to determine the content of docosahexaenoic acid and
eicosapentaenoic acid in over-the-counter preparations. Appro-
priate amounts should be taken to provide up to 3–4 g of these
fatty acids (combined) daily. It is important to select preparations
free of mercury and other contaminants. The omega-6 fatty acids
present in vegetable oils may cause triglycerides to increase.
Patients with primary chylomicronemia and some with mixed
lipemia must consume a diet severely restricted in total fat
(10–20 g/d, of which 5 g should be vegetable oils rich in essential
fatty acids), and fat-soluble vitamins should be given.
Homocysteine, which initiates proatherogenic changes in
endothelium, can be reduced in many patients by restriction of
total protein intake to the amount required for amino acid replace-
ment. Supplementation with folic acid plus other B vitamins, and
administration of betaine, a methyl donor, is indicated in severe
homocysteinemia. Reduction of high levels of homocysteine is
especially important in individuals with elevated levels of Lp(a).
Consumption of red meat should be minimized to reduce the
production by the intestinal biome of tetramethyl amine oxide, a
compound injurious to arteries.
■■ BASIC & CLINICAL
PHARMACOLOGY OF DRUGS
USED IN HYPERLIPIDEMIA
The decision to use drug therapy for hyperlipidemia is based
on the specific metabolic defect and its potential for causing
atherosclerosis or pancreatitis. Suggested regimens for the princi-
pal lipoprotein disorders are presented in Table 35–1. Diet should
be continued to achieve the full potential of the drug regimen.
These drugs should be avoided in pregnant and lactating women
and those likely to become pregnant. All drugs that alter plasma
lipoprotein concentrations potentially require adjustment of doses
of anticoagulants. Children with heterozygous familial hypercho-
lesterolemia may be treated with a resin or reductase inhibitor,
usually after 7 or 8 years of age, when myelination of the central
nervous system is essentially complete. The decision to treat a
child should be based on the level of LDL, other risk factors, the
family history, and the child’s age. Drugs are usually not indicated
before age 16 in the absence of multiple risk factors or compound
genetic dyslipidemias.
COMPETITIVE INHIBITORS OF
HMG-COA REDUCTASE (REDUCTASE
INHIBITORS: “STATINS”)
These compounds are structural analogs of HMG-CoA (3-hydroxy-
3-methylglutaryl-coenzyme A, Figure 35–3). Lovastatin,
atorvastatin, fluvastatin, pravastatin, simvastatin, rosuvastatin,
and pitavastatin belong to this class. They are most effective in
reducing LDL. Other effects include decreased oxidative stress and
vascular inflammation with increased stability of atherosclerotic
lesions. It has become standard practice to initiate reductase inhibi-
tor therapy immediately after acute coronary syndromes, regardless
of lipid levels.
Chemistry & Pharmacokinetics
Lovastatin and simvastatin are inactive lactone prodrugs that are
hydrolyzed in the gastrointestinal tract to the active β-hydroxyl
derivatives, whereas pravastatin has an open, active lactone ring.
Atorvastatin, fluvastatin, and rosuvastatin are fluorine-containing
congeners that are active as given. Absorption of the ingested doses
of the reductase inhibitors varies from 40% to 75% with the excep-
tion of fluvastatin, which is almost completely absorbed. All have
high first-pass extraction by the liver. Most of the absorbed dose is
excreted in the bile; 5–20% is excreted in the urine. Plasma half-
lives of these drugs range from 1 to 3 hours except for atorvastatin
(14 hours), pitavastatin (12 hours), and rosuvastatin (19 hours).
Mechanism of Action
HMG-CoA reductase mediates the first committed step in sterol
biosynthesis. The active forms of the reductase inhibitors are
structural analogs of the HMG-CoA intermediate (Figure 35–3)
 CHAPTER 35  Agents Used in Dyslipidemia    633

CH3 CH3
HO HO
–
COO COO–
OH OH

CoA

HMG-CoA reduced Mevalonate

intermediate

HO O HO
–
COO
O OH

O O

H3C O O
H3C
CH3 CH3
CH3 CH3

H3C H3C
Lovastatin Lovastatin (active form)

FIGURE 35–3  Inhibition of HMG-CoA reductase. Top: The HMG-CoA intermediate that is the immediate precursor of mevalonate, a
critical compound in the synthesis of cholesterol. Bottom: The structure of lovastatin and its active form, showing the similarity to the normal
HMG-CoA intermediate (shaded areas).

that is formed by HMG-CoA reductase in the synthesis of meva-
lonate. These analogs cause partial inhibition of the enzyme and
thus may impair the synthesis of isoprenoids such as ubiquinone
and dolichol and the prenylation of proteins. It is not known
whether this has biologic significance. However, the reductase
inhibitors clearly induce an increase in high-affinity LDL recep-
tors. This effect increases both the fractional catabolic rate
of LDL and the liver’s extraction of LDL precursors (VLDL
remnants) from the blood, thus reducing LDL (Figure 35–2).
Because of marked first-pass hepatic extraction, the major effect
is on the liver. Preferential activity in liver of some congeners
appears to be attributable to tissue-specific differences in uptake.
Modest decreases in plasma triglycerides and small increases in
HDL also occur.
Clinical trials involving many of the statins have dem-
onstrated significant reduction of new coronary events and
atherothrombotic stroke. Mechanisms other than reduction of
lipoprotein levels appear to be involved. The availability of iso-
prenyl groups from the HMG-CoA pathway for prenylation of
proteins is reduced by statins, resulting in reduced prenylation
of Rho and Rab proteins. Prenylated Rho activates Rho kinase,
which mediates a number of mechanisms in vascular biology.
The observation that reduction in new coronary events occurs
more rapidly than changes in morphology of arterial plaques
suggests that these pleiotropic effects may be important. Like-
wise, decreased prenylation of Rab reduces the accumulation of
Aβ protein in neurons, possibly mitigating the manifestations of
Alzheimer’s disease.
Therapeutic Uses & Dosage
Reductase inhibitors are useful alone or with resins, niacin, or
ezetimibe in reducing levels of LDL. Women with hyperlipidemia
who are pregnant, lactating, or likely to become pregnant should
not be given these agents. Use in children is restricted to selected
patients with familial hypercholesterolemias.
Because cholesterol synthesis occurs predominantly at night,
reductase inhibitors—except atorvastatin, rosuvastatin, and
pitavastatin—should be given in the evening. Absorption
generally (with the exception of pravastatin and pitavastatin)
is enhanced by food. Daily doses of lovastatin vary from
10 to 80 mg. Pravastatin is nearly as potent on a mass basis
as lovastatin with a maximum recommended daily dose of
80 mg. Simvastatin is twice as potent and is given in doses of
5–80 mg daily. Because of increased risk of myopathy with the
80-mg/d dose, the U.S. Food and Drug Administration (FDA)
issued labeling for scaled dosing of simvastatin and combined
ezetimibe/simvastatin in 2011. Pitavastatin is given in doses of
1–4 mg daily. Fluvastatin appears to be about half as potent as
lovastatin on a mass basis and is given in doses of 10–80 mg
daily. Atorvastatin is given in doses of 10–80 mg/d, and rosuvas-
tatin at 5–40 mg/d. The dose-response curves of pravastatin and
634    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
especially of fluvastatin tend to level off in the upper part of the
dosage range in patients with moderate to severe hypercholester-
olemia. Those of other statins are somewhat more linear.
Toxicity
Elevations of serum aminotransferase activity (up to three times
normal) occur in some patients. This is often intermittent and
usually not associated with other evidence of hepatic toxicity.
Therapy may be continued in such patients in the absence of
symptoms if aminotransferase levels are monitored and stable. In
some patients, who may have underlying liver disease or a his-
tory of alcohol abuse, levels may exceed three times normal. This
finding portends more severe hepatic toxicity. These patients may
present with malaise, anorexia, and precipitous decreases in LDL.
Medication should be discontinued immediately in these patients
and in asymptomatic patients whose aminotransferase activity is
persistently elevated to more than three times the upper limit of
normal. These agents should be used with caution and in reduced
dosage in patients with hepatic parenchymal disease, north
Asians, and the elderly. Severe hepatic disease may preclude their
use. In general, aminotransferase activity should be measured at
baseline, at 1–2 months, and then every 6–12 months (if stable).
Monitoring of liver enzymes should be more frequent if the
patient is taking other drugs that have potential interactions with
the statin. Excess intake of alcohol tends to aggravate hepatotoxic
effects of statins. Fasting plasma glucose levels tend to increase
5–7 mg/dL with statin treatment. Long-term studies have shown a
small but significant increase in the incidence of type 2 diabetes in
statin-treated patients, most of whom had findings of prediabetes
before treatment.
Minor increases in creatine kinase (CK) activity in plasma
are observed in some patients receiving reductase inhibitors, fre-
quently associated with heavy physical activity. Rarely, patients
may have marked elevations in CK activity, often accompanied
by generalized discomfort or weakness in skeletal muscles. If the
drug is not discontinued, myoglobinuria can occur, leading to
renal injury. Myopathy may occur with monotherapy, but there
is an increased incidence in patients also receiving certain other
drugs. Genetic variation in an anion transporter (OATP1B1) is
associated with severe myopathy and rhabdomyolysis induced by
statins. Variants in the gene (SLCO1B1) coding for this protein
can now be assessed (see Chapter 5).
The catabolism of lovastatin, simvastatin, and atorvastatin
proceeds chiefly through CYP3A4, whereas that of fluvastatin
and rosuvastatin, and to a lesser extent pitavastatin, is medi-
ated by CYP2C9. Pravastatin is catabolized through other
pathways, including sulfation. The 3A4-dependent reductase
inhibitors tend to accumulate in plasma in the presence of
drugs that inhibit or compete for the 3A4 cytochrome. These
include the macrolide antibiotics, cyclosporine, ketoconazole
and its congeners, some HIV protease inhibitors, tacrolimus,
nefazodone, fibrates, paroxetine, venlafaxine, and others (see
Chapters 4 and 66). Concomitant use of reductase inhibitors
with amiodarone or verapamil also causes an increased risk of
myopathy.
Conversely, drugs such as phenytoin, griseofulvin, barbiturates,
rifampin, and thiazolidinediones increase expression of CYP3A4
and can reduce the plasma concentrations of the 3A4-dependent
reductase inhibitors. Inhibitors of CYP2C9 such as ketoconazole
and its congeners, metronidazole, sulfinpyrazone, amiodarone,
and cimetidine may increase plasma levels of fluvastatin and
rosuvastatin. Pravastatin and rosuvastatin appear to be the statins
of choice for use with verapamil, the ketoconazole group of
antifungal agents, macrolides, and cyclosporine. Doses should
be kept low and the patient monitored frequently. Plasma levels
of lovastatin, simvastatin, and atorvastatin may be elevated in
patients ingesting more than 1 liter of grapefruit juice daily. All
statins undergo glycosylation, thus creating an interaction with
gemfibrozil.
Creatine kinase activity should be measured in patients
receiving potentially interacting drug combinations. In all
patients, CK should be measured at baseline. If muscle pain,
tenderness, or weakness appears, CK should be measured
immediately and the drug discontinued if activity is elevated sig-
nificantly over baseline. The myopathy usually reverses promptly
upon cessation of therapy. If the association is unclear, the
patient can be rechallenged under close surveillance. Myopathy
in the absence of elevated CK can occur. Rarely, hypersensitivity
syndromes have been reported that include a lupus-like disor-
der, dermatomyositis, peripheral neuropathy, and autoimmune
myopathy. The latter presents as severe pain and weakness in
proximal muscles that does not remit when the statin is discon-
tinued. It is HMG-CoA reductase antibody positive and requires
immunosuppressive treatment.
Reductase inhibitors may be temporarily discontinued in the
event of serious illness, trauma, or major surgery to minimize the
potential for liver and muscle toxicity.
Use of red yeast rice, a fermentation product that contains
statin activity, is not recommended because the statin content
is highly variable and some preparations contain a nephrotoxin,
citrinin. The long-term safety of these preparations, which often
contain a large number of poorly studied organic compounds, has
not been established.
FIBRIC ACID DERIVATIVES
(FIBRATES)
Gemfibrozil and fenofibrate decrease levels of VLDL and, in
some patients, LDL as well. Another fibrate, bezafibrate, is not
yet available in the USA.
Chemistry & Pharmacokinetics
Gemfibrozil is absorbed quantitatively from the intestine and
is tightly bound to plasma proteins. It undergoes enterohepatic
circulation and readily passes the placenta. The plasma half-life
is 1.5 hours. Seventy percent is eliminated through the kidneys,
mostly unmodified. The liver modifies some of the drug to
hydroxymethyl, carboxyl, or quinol derivatives. Fenofibrate is
an isopropyl ester that is hydrolyzed completely in the intestine.
 CHAPTER 35  Agents Used in Dyslipidemia    635

Its plasma half-life is 20 hours. Sixty percent is excreted in the in reduction in the exchange of triglycerides into HDL in place
urine as the glucuronide, and about 25% in feces. of cholesteryl esters.
CH3
CH3 Therapeutic Uses & Dosage
O CH2 CH2 CH2 C COOH Fibrates are useful drugs in hypertriglyceridemias in which
CH3
VLDL predominate and in dysbetalipoproteinemia. They also
CH3 may be of benefit in treating the hypertriglyceridemia that
Gemfibrozil results from treatment with antiviral protease inhibitors. The
usual dose of gemfibrozil is 600 mg orally once or twice daily.
The dosage of fenofibrate as Tricor is one to three 48-mg tablets
CH3 (or a single 145-mg tablet) daily. Dosages of other preparations
Cl C O C C O CH(CH3)2 vary. Absorption of gemfibrozil is improved when the drug is
O CH3 O
taken with food.
Fenofibrate
Toxicity
Rare adverse effects of fibrates include rashes, gastrointestinal
Mechanism of Action symptoms, myopathy, arrhythmias, hypokalemia, and high blood
Fibrates function primarily as ligands for the nuclear transcription levels of aminotransferases or alkaline phosphatase. A few patients
receptor PPAR-α. They transcriptionally upregulate LPL, apo A-I, show decreases in white blood count or hematocrit. Both agents
and apo A-II, and they downregulate apo C-III, an inhibitor of may potentiate the action of anticoagulants, and doses of these
lipolysis. A major effect is an increase in oxidation of fatty acids in agents should be adjusted. Rhabdomyolysis has occurred rarely.
liver and striated muscle (Figure 35–4). They increase lipolysis of Risk of myopathy increases when fibrates are given with reductase
lipoprotein triglyceride via LPL. Intracellular lipolysis in adipose inhibitors. Fenofibrate is the fibrate of choice for use in combi-
tissue is decreased. Levels of VLDL decrease, in part as a result of nation with a statin. Fibrates should be avoided in patients with
decreased secretion by the liver. Only modest reductions of LDL hepatic or renal dysfunction. There appears to be a modest increase
occur in most patients. In others, especially those with combined in the risk of cholesterol gallstones, reflecting an increase in the
hyperlipidemia, LDL often increases as triglycerides are reduced. cholesterol content of bile. Therefore, fibrates should be used with
HDL cholesterol increases moderately. Part of this apparent caution in patients with biliary tract disease or in those at higher
increase is a consequence of lower triglyceride in plasma, resulting risk such as women, obese patients, and Native Americans.

Skeletal muscle Fatty acid oxidation

Endothelium Fatty acids

Blood Lipoprotein lipase Transcription of LPL

vessels
Hydrolysis of VLDL
and chylomicron
VLDL, triglycerides
Chylomicron

Liver Triglycerides
Secretion
Apo Clll synthesis
Synthesis
Apo Al and Apo AII synthesis Fatty acids
Oxidation

Oxidation products

FIGURE 35–4  Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-α,
which decreases the secretion of VLDL and increases its peripheral metabolism. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins.
636    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
NIACIN (NICOTINIC ACID)
Niacin (but not niacinamide) decreases triglycerides and LDL
levels, and Lp(a) in most patients. It often increases HDL levels
significantly. Historically, combination therapy including niacin
has been associated with regression of atherosclerotic coronary
lesions in three angiographic trials and with extension of lifespan
in one large trial in which patients received niacin alone.
Chemistry & Pharmacokinetics
In its role as a vitamin, niacin (vitamin B3) is converted in the
body to the amide, which is incorporated into niacinamide
adenine dinucleotide (NAD), which in turn has a critical role
in energy metabolism. In pharmacologic doses, it has impor-
tant effects on lipid metabolism that are poorly understood. It
is excreted in the urine unmodified and as several metabolites.
One, N-methyl nicotinamide, creates a draft on methyl groups
that can occasionally result in erythrocyte macrocytosis, similar to
deficiency of folate or vitamin B12.
Mechanism of Action
Niacin inhibits VLDL secretion, in turn decreasing production
of LDL (Figure 35–2). Increased clearance of VLDL via the LPL
pathway contributes to reduction of triglycerides. Excretion of
neutral sterols in the stool is increased acutely as cholesterol is
mobilized from tissue pools and a new steady state is reached.
The catabolic rate for HDL is decreased. Fibrinogen levels are
reduced, and levels of tissue plasminogen activator appear to
increase. Niacin inhibits the intracellular lipase of adipose tissue
via receptor-mediated signaling, possibly reducing VLDL produc-
tion by decreasing the flux of free fatty acids to the liver. Sustained
inhibition of lipolysis has not been established, however.
Therapeutic Uses & Dosage
In combination with a resin or reductase inhibitor, niacin nor-
malizes LDL in most patients with heterozygous familial hyper-
cholesterolemia and other forms of hypercholesterolemia. These
combinations are also indicated in some cases of nephrosis. In
severe mixed lipemia that is incompletely responsive to diet,
niacin often produces marked reduction of triglycerides, an effect
enhanced by marine omega-3 fatty acids. It is useful in patients
with combined hyperlipidemia and in those with dysbetalipopro-
teinemia. Niacin is clearly the most effective agent for increasing
HDL and reduces Lp(a) in most patients.
For treatment of heterozygous familial hypercholesterolemia,
2–6 g of niacin daily is usually required; more than this should not
be given. For other types of hypercholesterolemia and for hypertri-
glyceridemia, 1.5–3.5 g daily is often sufficient. Crystalline niacin
should be given in divided doses with meals, starting with 100 mg
two or three times daily and increasing gradually.
Toxicity
Most persons experience a harmless cutaneous vasodilation and
sensation of warmth after each dose when niacin is started or
the dose increased. Taking 81–325 mg of aspirin 30 minutes
beforehand blunts this prostaglandin-mediated effect. Naproxen,
220 mg once daily, also mitigates the flush. Tachyphylaxis to
flushing usually occurs within a few days at doses above 1.5–3 g
daily. Patients should be warned to expect the flush and under-
stand that it is a harmless side effect. Pruritus, rashes, dry skin or
mucous membranes, and acanthosis nigricans have been reported.
The latter requires the discontinuance of niacin because of its
association with insulin resistance. Some patients experience nau-
sea and abdominal discomfort. Many can continue the drug at
reduced dosage, with inhibitors of gastric acid secretion or with
antacids not containing aluminum. Niacin should be avoided in
patients with significant peptic disease.
Reversible elevations in aminotransferases up to twice normal
may occur, usually not associated with liver toxicity. However,
liver function should be monitored at baseline and at appropri-
ate intervals. Rarely, true hepatotoxicity may occur, and the
drug should be discontinued. The association of severe hepatic
dysfunction, including acute necrosis, with the use of over-the-
counter sustained-release preparations of niacin has been reported.
This effect has not been noted to date with an extended-release
preparation, Niaspan, given at bedtime in doses of 2 g or less.
Carbohydrate tolerance may be moderately impaired, especially in
obese patients. Niacin may be given to diabetics who are receiv-
ing insulin and to some receiving oral agents but it may increase
insulin resistance. This can be addressed by increasing the dose of
insulin or the oral agents. Hyperuricemia occurs in some patients
and occasionally precipitates gout. Allopurinol can be given with
niacin if needed. Red cell macrocytosis can occur and is not
an indication for discontinuing treatment. Significant platelet
deficiency can occur rarely and is reversible on cessation of treat-
ment. Rarely, niacin is associated with arrhythmias, mostly atrial,
and with macular edema, both requiring cessation of treatment.
Patients should be instructed to report blurring of distance vision.
Niacin may potentiate the action of antihypertensive agents,
requiring adjustment of their dosages. Birth defects have been
reported in offspring of animals given very high doses.
BILE ACID–BINDING RESINS
Colestipol, cholestyramine, and colesevelam are useful only for
isolated increases in LDL. In patients who also have hypertriglyc-
eridemia, VLDL levels may be further increased during treatment
with resins.
Chemistry & Pharmacokinetics
The bile acid-binding agents are large polymeric cationic exchange
resins that are insoluble in water. They bind bile acids in the
intestinal lumen and prevent their reabsorption. The resin itself
is not absorbed.
Mechanism of Action
Bile acids, metabolites of cholesterol, are normally efficiently
reabsorbed in the jejunum and ileum (Figure 35–2). Excretion
is increased up to tenfold when resins are given, resulting in

enhanced conversion of cholesterol to bile acids in liver via
7α-hydroxylation, which is normally controlled by negative
feedback by bile acids. Decreased activation of the FXR receptor
by bile acids may result in a modest increase in plasma triglycer-
ides but can also improve glucose metabolism in patients with
diabetes. The latter effect is due to increased secretion of the
incretin glucagon-like peptide-1 from the intestine, thus increas-
ing insulin secretion. Increased uptake of LDL and IDL from
plasma results from upregulation of LDL receptors, particularly
in liver. Therefore, the resins are without effect in patients with
homozygous familial hypercholesterolemia who have no function-
ing receptors but may be useful in those with some residual recep-
tor function and in patients with receptor-defective combined
heterozygous states.
Therapeutic Uses & Dosage
The resins are used in treatment of patients with primary hyper-
cholesterolemia, producing approximately 20% reduction in LDL
cholesterol in maximal dosage. If resins are used to treat LDL ele-
vations in persons with combined hyperlipidemia, they may cause
an increase in VLDL, requiring the addition of a second agent
such as a fibrate or niacin. Resins are also used in combination
with other drugs to achieve further hypocholesterolemic effect
(see below). They may be helpful in relieving pruritus in patients
who have cholestasis and bile salt accumulation. Because the resins
bind digitalis glycosides, they may be useful in digitalis toxicity.
Colestipol and cholestyramine are available as granular prepa-
rations. A gradual increase of dosage of granules from 4 or 5 g/d
to 20 g/d is recommended. Total dosages of 30–32 g/d may
be needed for maximum effect. The usual dosage for a child is
10–20 g/d. Granular resins are mixed with juice or water and
allowed to hydrate for 1 minute. Colestipol is also available in
1-g tablets that must be swallowed whole, with a maximum dose
of 16 g daily. Colesevelam is available in 625-mg tablets and as a
suspension (1875-mg or 3750-mg packets). The maximum dose is
six tablets or 3750 mg as suspension, daily. Resins should be taken
in two or three doses with meals.
Toxicity
Common complaints are constipation and bloating, usually
relieved by increasing dietary fiber. Resins should be avoided in
patients with diverticulitis. Heartburn and diarrhea are occasion-
ally reported. In patients who have preexisting bowel disease or
cholestasis, steatorrhea may occur. Malabsorption of vitamin K
occurs rarely, leading to hypoprothrombinemia. Prothrombin
time should be measured frequently in patients who are taking
resins and anticoagulants. Malabsorption of folic acid has been
reported rarely. Increased formation of gallstones, particularly
in obese persons, was an anticipated adverse effect but has rarely
occurred in practice.
Absorption of certain drugs, including those with neutral or
cationic charge as well as anions, may be impaired by the resins.
These include digitalis glycosides, thiazides, warfarin, tetracycline,
thyroxine, iron salts, pravastatin, fluvastatin, ezetimibe, folic
acid, phenylbutazone, aspirin, and ascorbic acid, among others.
CHAPTER 35  Agents Used in Dyslipidemia    637
In general, additional medication (except niacin) should be given
1 hour before or at least 2 hours after the resin to ensure adequate
absorption. Colesevelam does not bind digoxin, warfarin, or
reductase inhibitors.
INHIBITORS OF INTESTINAL STEROL
ABSORPTION
Ezetimibe inhibits intestinal absorption of phytosterols and cho-
lesterol. Added to statin therapy, it provides an additional effect,
decreasing LDL levels and further reducing the dimensions of
atherosclerotic plaques.
Chemistry & Pharmacokinetics
Ezetimibe is readily absorbed and conjugated in the intestine to an
active glucuronide, reaching peak blood levels in 12–14 hours. It
undergoes enterohepatic circulation, and its half-life is 22 hours.
Approximately 80% of the drug is excreted in feces. Plasma con-
centrations are substantially increased when it is administered
with fibrates and reduced when it is given with cholestyramine.
Other resins may also decrease its absorption. There are no signifi-
cant interactions with warfarin or digoxin.
OH
OH
N F
O
F
Ezetimibe
Mechanism of Action
Ezetimibe selectively inhibits intestinal absorption of cholesterol
and phytosterols. A transport protein, NPC1L1, is the target of the
drug. It is effective in the absence of dietary cholesterol because it
also inhibits reabsorption of cholesterol excreted in the bile.
Therapeutic Uses & Dosage
The effect of ezetimibe on cholesterol absorption is constant over
the dosage range of 5–20 mg/d. Therefore, a daily dose of 10 mg
is used. Average reduction in LDL cholesterol with ezetimibe alone
in patients with primary hypercholesterolemia is about 18%, with
minimal increases in HDL cholesterol. It is also effective in patients
with phytosterolemia. Ezetimibe is synergistic with reductase inhib-
itors, producing decrements as great as 25% in LDL cholesterol
beyond that achieved with the reductase inhibitor alone.
Toxicity
Ezetimibe does not appear to be a substrate for cytochrome P450
enzymes. Experience to date reveals a low incidence of reversible
impaired hepatic function with a small increase in incidence when
given with a reductase inhibitor. Myositis has been reported rarely.
638    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
INHIBITION OF MICROSOMAL
TRIGLYCERIDE TRANSFER PROTEIN
Microsomal triglyceride transfer protein (MTP) plays an
essential role in the addition of triglycerides to nascent VLDL
in liver, and to chylomicrons in the intestine. Its inhibition
decreases VLDL secretion and consequently the accumulation
of LDL in plasma. An MTP inhibitor, lomitapide, is available
but is currently restricted to patients with homozygous familial
hypercholesterolemia. It causes accumulation of triglycerides in
the liver in some individuals. Elevations in transaminases can
occur. Patients must maintain a low fat diet to avoid steator-
rhea and should take steps to minimize deficiency of essential
fat-soluble nutrients. Lomitapide is given orally in gradually
increasing doses of 5- to 60-mg capsules once daily 2 hours
after the evening meal. It is available only through a restricted
(REMS) program for patients with homozygous familial
hypercholesterolemia.
ANTISENSE INHIBITION OF APO
B-100 SYNTHESIS
Mipomersen is an antisense oligonucleotide that targets apo
B-100, mainly in the liver. It is important to note that the apo
B-100 gene is also transcribed in the retina and in cardiomyo-
cytes. Subcutaneous injections of mipomersen reduce levels of
LDL and Lp(a). Mild to moderate injection site reactions and
flu-like symptoms can occur. The drug is available only for use
in homozygous familial hypercholesterolemia through a restricted
(REMS) program.
PCSK9 INHIBITION
Development of inhibitors of proprotein convertase subtilisin/
kexin type 9 (PCSK9) followed on the observation that loss
of function mutations result in very low levels of LDL and no
apparent morbidity. Therapeutic agents currently available in
this class are humanized antibodies to PCSK9 (evolocumab,
alirocumab). LDL reductions of up to 70% at the highest
doses have been achieved with these agents when administered
subcutaneously every two weeks. (Evolocumab can also be
given monthly at a higher dose). Triglycerides and apo B-100
are reduced, and Lp(a) levels decrease by about 25%. Rarely,
hypersensitivity reactions have occurred. Local reactions at the
injection site, upper respiratory and flu-like symptoms have
been observed more frequently. Use of these agents is restricted
to patients who have familial hypercholesterolemia or clinical
atherosclerotic cardiovascular disease who require additional
reduction of LDL. They are given with diet and maximal toler-
ated statin and/or ezetimibe. Development of small molecules
and antisense oligonucleotides to inhibit PCSK9 is underway.
Studies of PCSK9 inhibition should be approached with cau-
tion because of its established role in normal cell biology. These
agents are very expensive.
AGENTS UNDER DEVELOPMENT
CETP INHIBITION
Cholesteryl ester transfer protein (CETP) transfers cholesteryl
esters from mature, large diameter HDL particles to triglyceride-
rich lipoproteins that ultimately deliver the esters to liver whence
both cholesterol and bile acids can be eliminated into the intes-
tine. Inhibition of CETP leads to accumulation of mature HDL
particles and diminution of the transport of cholesteryl esters to
liver. The accumulation of large HDL particles does not have the
cardioprotective effect anticipated on the basis of epidemiologic
studies. Some reduction of LDL-C can be achieved and choles-
terol efflux capacity enhanced. Thus far no drug (eg, torcetrapib,
anacetrapib) in this class has been approved.
AMP KINASE ACTIVATION
AMP-activated protein kinase acts as a sensor of energy status in
cells. When increased ATP availability is required, AMP kinase
increases fatty acid oxidation and insulin sensitivity, and inhibits
cholesterol and triglyceride biosynthesis. Although the trials to
date have been directed at decreasing LDL-C levels, AMP kinase
activation may have merit for management of the metabolic syn-
drome and diabetes. An agent combining AMP kinase activation
and ATP citrate lyase inhibition is in clinical trials.
CYCLODEXTRINS
These are circular sugar polymers that can solubilize hydrophobic
drugs for delivery and are approved for this purpose. They can
also solubilize cholesterol from tissue sites such as arteriosclerotic
plaque. Early stage animal studies on this potential therapeutic
activity are in progress.
TREATMENT WITH DRUG
COMBINATIONS
Combined drug therapy is useful (1) when VLDL levels are signif-
icantly increased during treatment of hypercholesterolemia with a
resin; (2) when LDL and VLDL levels are both elevated initially;
(3) when LDL or VLDL levels are not normalized with a single
agent, or (4) when an elevated level of Lp(a) or an HDL deficiency
coexists with other hyperlipidemias. The lowest effective doses
should be used in combination therapy and the patient should be
monitored more closely for evidence of toxicity. In combinations
that include resins, the other agent (with the exception of niacin)
should be separated temporally to ensure absorption.
FIBRIC ACID DERIVATIVES & BILE
ACID-BINDING RESINS
This combination is sometimes useful in treating patients with
familial combined hyperlipidemia who are intolerant of niacin or
statins. However, it may increase the risk of cholelithiasis.
 CHAPTER 35  Agents Used in Dyslipidemia    639

HMG-CoA REDUCTASE INHIBITORS & REDUCTASE INHIBITORS &

BILE ACID-BINDING RESINS
This synergistic combination is useful in the treatment of familial
hypercholesterolemia but may not control levels of VLDL in some
patients with familial combined hyperlipoproteinemia.
NIACIN & BILE ACID-BINDING RESINS
This combination effectively controls VLDL levels during resin
therapy of familial combined hyperlipoproteinemia or other
disorders involving both increased VLDL and LDL levels. When
VLDL and LDL levels are both initially increased, doses of niacin
as low as 1–3 g/d may be sufficient in combination with a resin.
The niacin-resin combination is effective for treating heterozygous
familial hypercholesterolemia.
NIACIN & REDUCTASE INHIBITORS
If the maximum tolerated statin dose fails to achieve the LDL
cholesterol goal in a patient with hypercholesterolemia, niacin
may be helpful. This combination may be useful in the treatment
of familial combined hyperlipoproteinemia.
REDUCTASE INHIBITORS & EZETIMIBE
This combination is synergistic in treating primary hypercho-
lesterolemia and may be of use in the treatment of patients
with homozygous familial hypercholesterolemia who have some
receptor function.
FENOFIBRATE
Fenofibrate appears to be complementary with most statins in
the treatment of familial combined hyperlipoproteinemia and
other conditions involving elevations of both LDL and VLDL.
The combination of fenofibrate with rosuvastatin appears to
be especially well tolerated. Some other statins may interact
unfavorably owing to effects on cytochrome P450 metabolism.
In any case, particular vigilance for liver and muscle toxicity is
indicated.
COMBINATIONS OF RESINS, EZETIMIBE,
NIACIN, & REDUCTASE INHIBITORS
These agents act in a complementary fashion to normalize cho-
lesterol in patients with severe disorders involving elevated LDL.
The effects are sustained, and little compound toxicity has been
observed. Effective doses of the individual drugs may be lower
than when each is used alone; for example, as little as 1–2 g of
niacin may substantially increase the effects of the other agents.
COMBINATIONS OF PCSK9 ANTIBODY
WITH STATIN AND EZETIMIBE
These agents can be used together to achieve maximal reduction of
LDL. Because of the need for parenteral administration of PCSK9
antibody and its expense, this therapy is reserved for patients with
familial hypercholesterolemia or atherosclerotic vascular disease
who do not respond adequately to other regimens.

SUMMARY Drugs Used in Dyslipidemia

Subclass, Pharmacokinetics, Toxicities,
Drug Mechanism of Action Effects Clinical Applications Interactions

STATINS        
•  Atorvastatin, Inhibit HMG-CoA reductase Reduce cholesterol synthesis and Atherosclerotic vascular Oral • duration 12–24 h • Toxicity: Myopathy,
simvastatin, upregulate low-density disease (primary and hepatic dysfunction • Interactions:
rosuvastatin, lipoprotein (LDL) receptors on secondary prevention) CYP-dependent metabolism (3A4, 2C9)
pitavastatin hepatocytes • modest reduction • acute coronary interacts with CYP inhibitors/competitors
in triglycerides syndromes

•  Fluvastatin, pravastatin, lovastatin: Similar but somewhat less efficacious

FIBRATES        
•  Fenofibrate, Peroxisome proliferator- Decrease secretion of Hypertriglyceridemia, Oral • duration 3–24 h • Toxicity: Myopathy,
gemfibrozil activated receptor-alpha very-low-density lipoproteins low HDL hepatic dysfunction
(PPAR-α) agonists (VLDL) • increase lipoprotein
lipase activity • increase
high-density lipoproteins (HDL)

(continued)
640    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

Subclass, Pharmacokinetics, Toxicities,

Drug Mechanism of Action Effects Clinical Applications Interactions

BILE ACID SEQUESTRANTS

•  Colestipol Binds bile acids in gut
• prevents reabsorption
• increases cholesterol
catabolism • upregulates LDL
receptors
Decreases LDL Elevated LDL, digitalis Oral • taken with meals • not absorbed
toxicity, pruritus • Toxicity: Constipation, bloating • interferes
with absorption of some drugs and vitamins

•  Cholestyramine, colesevelam: Similar to colestipol

STEROL ABSORPTION INHIBITOR

•  Ezetimibe Blocks sterol transporter Inhibits reabsorption of Elevated LDL, Oral • duration 24 h • Toxicity: Low incidence
NPC1L1 in intestine brush cholesterol excreted in bile phytosterolemia of hepatic dysfunction, myositis
border • decreases LDL and phytosterols

NIACIN
  Decreases catabolism of
apo AI • reduces VLDL
secretion from liver
Increases HDL • decreases Low HDL • elevated VLDL, Oral • large doses • Toxicity: Gastric irritation,
lipoprotein(a) [Lp(a)], LDL Lp(a); elevated LDL in flushing, low incidence of hepatic toxicity
statin-unresponsive or • may reduce glucose tolerance
intolerant patients

•  Extended-release niacin: Similar to regular niacin

•  Sustained-release niacin (not the same as extended-release product): Should be avoided

PCSK9 HUMANIZED MONOCLONAL ANTIBODIES

Evolocumab Complexes PCSK9 Inhibits catabolism of LDL Familial Parenteral • Cost ~ $14,000/year • Toxicity:
receptor hypercholesterolemia not injection site reactions, nasopharyngitis,
responsive to oral therapy flu-like symptoms, rarely myalgia,
neurocognitive and ophthalmologic events

•  Alirocumab Similar to evolucumab

P R E P A R A T I O N S REFERENCES
A V A I L A B L E Afshar M, Thanassoulis G: Lipoprotein(a): new insights from modern genomics.
Curr Opin Lipidol 2017;28:170.
Ballantyne CM et al: Efficacy and safety of a novel dual modulator of adenosine
GENERIC NAME TRADE NAMES triphosphate-citrate lyase and adenosine monophosphate-activated protein
Alirocumab Praluent kinase in patients with hypercholesterolemia: Results of a multicenter, ran-
domized, double-blind, placebo-controlled, parallel-group trial. J Am Coll
Atorvastatin Generic, Lipitor
Cardiol 2013;62:1154.
Cholestyramine Generic, Questran, Prevalite Boekholdt SM et al: Levels and changes of HDL cholesterol and apolipoprotein
Colesevelam Welchol A-I in relation to risk of cardiovascular events among statin-treated patients:
Colestipol Generic, Colestid A meta-analysis. Circulation 2013;128:1504.
Evolocumab Repatha Bonow RO, Yancy CW: High-intensity statins for secondary prevention. JAMA
Cardiol 2017;2:55.
Ezetimibe Generic, Zetia
Cannon CP et al: Ezetimibe added to statin therapy after acute coronary
Fenofibrate Generic, Tricor, Antara, Lofibra syndrome. N Engl J Med 2015;372:2387.
Fluvastatin Generic, Lescol, Lescol XL Chou R et al: Statins for prevention of cardiovascular disease in adults: Evidence
Gemfibrozil Generic, Lopid report and systematic review for the US Preventive Services Task Force.
JAMA 2016;316:2008.
Lomitapide Juxtapid
Dron JS, Hegele RA: Complexity of mechanisms among human proprotein
Mipomersen Kynamro convertase subtilisin-kexin type 9 variants. Curr Opin Lipidol 2017;28:161.
Lovastatin Generic, Mevacor, Altoprev Elam M, Lovato E, Ginsberg H: The role of fibrates in cardiovascular disease
Niacin, nicotinic acid, vitamin B3 Generic only prevention, The ACCORD–lipid perspective. Curr Opin Lipidol 2011;22:55.
Omega-3 fatty acids–marine Lovaza Gaudet D et al: Antisense inhibition of apolipoprotein C-III in patients with
hypertriglyceridemia. N Engl J Med 2015;373:438.
Pitavastatin Livalo
Gouni-Berthold I et al: Systematic review of published phase 3 data on anti-
Pravastatin Generic, Pravachol PCSK9 monoclonal antibodies in patients with hypercholesterolaemia. Br J
Rosuvastatin Generic, Crestor Clin Pharmacol 2016;82:1412.
Simvastatin Generic, Zocor International Atherosclerosis Society: IAS Position Paper: Global Recommenda-
tions for the Management of Dyslipidemia. Available at: www.athero.org/
COMBINATION TABLETS
IASPositionPaper.asp.
Ezetimibe/simvastatin Vytorin Jacobson TA et al: On behalf of the NLA Expert Panel. National Lipid Association
Niacin/lovastatin extended-release Advicor recommendations for patient-centered management of dyslipidemia: Part 2.
Niacin/simvastatin extended-release Simcor J Clin Lipidol 2015;9:S1.

LaRosa JC et al: Safety and effect of very low levels of low density lipoprotein
cholesterol on cardiovascular events. Am J Cardiol 2013;111:1221.
Mampuya WM et al: Treatment strategies in patients with statin intolerance: The
Cleveland Clinic experience. Am Heart J 2013;166:597.
Nduka C et al: Impact of antiretroviral therapy on serum lipoprotein levels
and dyslipidemias: a systematic review and meta-analysis. Int J Cardiol
2015;199:307.
Perry CM: Lomitapide: A review of its use in adults with homozygous familial
hypercholesterolemia. Am J Cardiovasc Drugs 2013;13:265.
Raal FJ, Stein EA: The effects of mipomersen on inhibiting hepatic VLDL
apolipoprotein B 100 and propensity for hepatic steatosis. Clin Chem
2016;62:1052.
Reith C, Armitage J: Management of residual risk after statin therapy. Atheroscle-
rosis 2016;245;161.
Rodriguez F: Association between intensity of statin therapy and mortality
in patients with atherosclerotic cardiovascular disease. JAMA Cardiol
2016;2:47.
C ASE STUDY ANSWER
The patient’s history of muscle symptoms should be care-
fully evaluated. The genotype at the SLCO1B1 locus might be
obtained to determine whether myositis is due to impaired
metabolism of statins. If you agree that her muscle symptoms
were clearly associated with statin use but were not particu-
larly severe and not associated with creatine kinase elevations
significantly greater than normal, you could prescribe any
one the agents she tried in the past or select a different statin.
The starting dose should be low and the drug given on alter-
nate days, increasing the dose and frequency to achieve the
CHAPTER 35  Agents Used in Dyslipidemia    641
Silverman MG et al: Association between lowering LDL-C and cardiovascular risk
reduction among different therapeutic interventions: A systematic review
and meta-analysis. JAMA Cardiol 2016;316:1289.
Stone NJ et al: 2013 ACC/AHA guidelines on the treatment of blood choles-
terol to reduce atherosclerotic cardiovascular risk in adults. A report of the
American College of Cardiology/American Heart Association task force on
practice guidelines. Circulation 2014; 129 (25 Suppl 2):S1. Erratum: Cir-
culation 2015;132:e396.
Swiger JK et al: Statins and cognition: A systematic review and meta-analysis of
short and long term cognitive effects. Mayo Clin Proceed 2013;88:1213.
Tsujita K et al: Impact of dual-lipid lowering with ezetimibe and atorvastatin on
coronary plaque regression in patients with percutaneous coronary interven-
tion. The randomized controlled PRECISE-IVUS trial. J Am Coll Cardiol
2015;66:495.
Yahya R et al: Lomitapide effects HDL composition and function. Atherosclerosis
2016;251:15.
Zimmer S et al: Cyclodextrin promotes atherosclerosis regression via macrophage
reprogramming. Sci Transl Med 2016;8:333ra50.
LDL-C goal. If this is not tolerated or the goal is not reached,
alternate drugs can be used, including a bile acid binding resin,
intestinal sterol absorption inhibitor, or niacin (monitoring
uric acid, glucose, and liver enzymes). These can be used in
combinations with each other or with a low dose statin. If all
else fails, use of a PCSK9 monoclonal antibody should be con-
sidered. Her homocysteine level should be measured because
of the synergy between that amino acid and Lp(a) with respect
to thrombotic risk. Also, because of her elevated Lp(a), she
should be evaluated for aortic stenosis.
656    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
infections) is increased, although it remains very low. Activation
of latent tuberculosis is lower with etanercept than with other
TNF-α–blocking agents. Nevertheless, all patients should be
screened for latent or active tuberculosis before starting TNF-α–
blocking agents. The use of TNF-α–blocking agents is also associ-
ated with increased risk of HBV reactivation; screening for HBV
is important before starting the treatment.
TNF-α–blocking agents increase the risk of skin cancers—
including melanoma—which necessitates periodic skin examina-
tion, especially in high-risk patients. On the other hand, there is no
clear evidence of increased risk of solid malignancies or lymphomas
with TNF-α–blocking agents, and their incidence may not be
different compared with other bDMARDs or active RA itself.
A low incidence of newly formed dsDNA antibodies and
antinuclear antibodies (ANAs) has been documented when using
TNF-α–blocking agents, but clinical lupus is extremely rare and
the presence of ANA and dsDNA antibodies per se does not
contraindicate the use of TNF-α–blocking agents. In patients
with borderline or overt heart failure (HF), TNF-α–blocking
agents can exacerbate HF. TNF-α–blocking agents can induce the
immune system to develop antidrug antibodies in about 17% of
cases. These antibodies may interfere with drug efficacy and cor-
relate with infusion site reactions. Injection site reactions occur in
20–40% of patients, although they rarely result in discontinuation
of therapy. Cases of alopecia areata, hypertrichosis, and erosive
lichen planus have been reported. Cutaneous pseudo-lymphomas
are reported rarely with TNF-α–blocking agents, especially inflix-
imab. TNF-α–blocking agents may increase the risk of gastroin-
testinal ulcers and large bowel perforation including diverticular
and appendiceal perforation.
Nonspecific interstitial pneumonia, psoriasis, and sarcoidosis-
like syndrome are among the rare reported toxicities associated
with TNF-α blockers. Rare cases of leukopenia, neutropenia,
thrombocytopenia, and pancytopenia have also been reported.
The precipitating drug should be discontinued in such cases.
USTEKINUMAB
1. Mechanism of Action: Ustekinumab is an IL-12 and IL-23
antagonist. It is a fully human IgG monoclonal antibody to the
p40 protein subunit, which is part of both IL-12 and IL-23.
These two cytokines are important contributors to the chronic
inflammation in psoriasis plaques, PsA, and Crohn’s disease.
Ustekinumab prevents the binding of the p40 subunit of both
IL-12 and IL-23 to the IL-12 receptor b1 found on the surface
of CD4 T cells and NK cells. This interruption interferes with
IL-12 and IL-23 signal transduction and suppresses the forma-
tion of proinflammatory TH1 and TH17 cells.
2. Pharmacokinetics: Ustekinumab is available as a 45- and
90-mg SC injection for PsA and plaque psoriasis. Its bioavail-
ability is 57% following SC injection; time to peak plasma
concentration is 7–13.5 days and elimination half-life is
10–126 days. For adults with PsA, a loading dose at 0 and
4 weeks is followed by maintenance doses once every 12 weeks.
IV infusion as a 130 mg dose is available for Crohn’s disease.
3. Indications: Ustekinumab is indicated for treatment of adult
patients with PsA. It can be used as monotherapy or in combi-
nation with methotrexate. Other indications include plaque
psoriasis and Crohn’s disease.
4. Adverse Effects: Upper respiratory tract infection is the most
common side effect, but rare severe infection, malignancy,
and reversible posterior leukoencephalopathy syndrome have
been reported. Ustekinumab should be discontinued at least
15 weeks before live vaccines are administered and can be
resumed at least 2 weeks after.
SECUKINUMAB
1. Mechanism of Action: Secukinumab is a human IgG1 mono-
clonal antibody that selectively binds to the IL-17A cytokine,
inhibiting its interaction with the IL-17A receptor. IL-17A is
involved in normal inflammatory and immune responses.
Elevated concentrations of IL-17A are found in psoriatic
plaques and PsA.
2. Pharmakokinetics: Secukinumab is available as a SC injection
or lyophilized powder for injection. Its peak plasma concentra-
tion is 13.7 mcg/mL (150 mg dose) and 27.3 mcg/mL (300 mg
dose); elimination half-life is 22–31 days.
3. Indications and Dosage: Secukinumab is indicated for moder-
ate to severe plaque psoriasis in patients who are candidates for
systemic therapy or phototherapy. Initial loading dose is 300
mg SC at weeks 0, 1, 2, 3, and 4, followed by monthly main-
tenance (300 mg SC or 150 mg SC monthly). For adults with
active PsA and moderate to severe plaque psoriasis, the same
recommendations are followed. For patients with psoriatic
arthritis as well as AS, administer with or without a loading
dosage by SC injection; 150 mg SC every 4 weeks with or
without MTX is recommended.
4. Adverse Effects: As for any of these biologics, infection is
a common side effect (28.7%). Nasopharyngitis occurs in
about 12%. TB status should be evaluated prior to therapy.
Secukinumab may exacerbate Crohn’s disease.
TOFACITINIB
1. Mechanism of Action: Tofacitinib is a targeted synthetic small
molecule (tsDMARD) that selectively inhibits all members of
the Janus kinase (JAK; see Chapter 2) family to varying
degrees. At therapeutic doses, tofacitinib exerts its effect mainly
by inhibiting JAK3, and to a lesser extent JAK1, hence inter-
rupting the JAK-STAT signaling pathway. This pathway plays
a major role in the pathogenesis of autoimmune diseases
including RA. The JAK3/JAK1 complex is responsible for
signal transduction from the common γ-chain receptor (IL-
2RG) for IL-2, -4, -7, -9, -15, and -21, which subsequently
influences transcription of several genes that are crucial for the
differentiation, proliferation, and function of NK cells and T
and B lymphocytes. In addition, JAK1 (in combination with
 SECTION VII  ENDOCRINE DRUGS
Hypothalamic & Pituitary
Hormones
Roger K. Long, MD, & Hakan Cakmak, MD
C ASE STUDY
A 4-year-old boy (height 90 cm, –3 standard deviations
[SD]; weight 14.5 kg, approximately 15th percentile)
presents with short stature. Review of the past history
and growth chart demonstrates normal birth weight and
birth length, but a progressive decrease in height per-
centiles relative to age-matched normal ranges starting
at 6 months of age, and orthostasis with febrile illnesses.
Physical examination demonstrates short stature and
mild generalized obesity. Genital examination reveals
descended but small testes and a phallic length of –2 SD.
The control of metabolism, growth, and reproduction is medi-
ated by a combination of neural and endocrine systems located
in the hypothalamus and pituitary gland. The pituitary weighs
about 0.6 g and rests at the base of the brain in the bony sella
turcica near the optic chiasm and the cavernous sinuses. The
pituitary consists of an anterior lobe (adenohypophysis) and a
posterior lobe (neurohypophysis) (Figure 37–1). It is connected
to the overlying hypothalamus by a stalk of neurosecretory fibers
37
C H A P T E R
Laboratory evaluations demonstrate growth hormone
(GH) deficiency and a delayed bone age of 18 months.
The patient is started on replacement with recombinant
human GH at a dose of 40 mcg/kg per day subcutaneously.
After 1 year of treatment, his height velocity has increased
from 5 cm/y to 11 cm/y. How does GH stimulate growth
in children? What other hormone deficiencies are sug-
gested by the patient’s history and physical examination?
What other hormone replacements is this patient likely
to require?
and blood vessels, including a portal venous system that drains
the hypothalamus and perfuses the anterior pituitary. The portal
venous system carries small regulatory hormones (Figure 37–1,
Table 37–1) from the hypothalamus to the anterior pituitary.
The posterior lobe hormones are synthesized in the hypothala-
mus and transported via the neurosecretory fibers in the stalk of
the pituitary to the posterior lobe; from there they are released
into the circulation.
667
668    SECTION VII  Endocrine Drugs

GHRH
Hypothalamus
■■ ANTERIOR PITUITARY
TRH
CRH
DA
SST HORMONES & THEIR
GnRH HYPOTHALAMIC REGULATORS
–
All the hormones produced by the anterior pituitary except
+ prolactin are key participants in hormonal systems in which they
regulate the production of hormones and autocrine-paracrine
factors by endocrine glands and other peripheral tissues. In these
Portal venous systems, the secretion of the pituitary hormone is under the
system control of one or more hypothalamic hormones. Each hypotha-
Anterior
Posterior lamic-pituitary-endocrine gland system or axis provides multiple
pituitary opportunities for complex neuroendocrine regulation of growth
pituitary
and development, metabolism, and reproductive function.

ANTERIOR PITUITARY &

HYPOTHALAMIC HORMONE
GH
TSH
RECEPTORS
ACTH The anterior pituitary hormones can be classified according to
PRL Oxytocin
LH
hormone structure and the types of receptors that they activate.
FSH
Growth hormone (GH) and prolactin (PRL), single-chain pro-
ADH
tein hormones with significant homology, form one group. Both
hormones activate receptors of the JAK/STAT superfamily (see
Chapter 2). Three pituitary hormones—thyroid-stimulating
Endocrine hormone (TSH, thyrotropin), follicle-stimulating hormone
glands, liver, bone, (FSH), and luteinizing hormone (LH)— are dimeric pro-
& other tissues teins that activate G protein-coupled receptors (see Chapter 2).
TSH, FSH, and LH share a common α subunit. Their β sub-
units, though somewhat similar to each other, differ enough to
confer receptor specificity. Finally, adrenocorticotropic hor-
mone (ACTH), a peptide cleaved from a larger precursor, pro-
Target tissues
opiomelanocortin (POMC) represents a third category. POMC
can be cleaved into various other biologically active peptides like
FIGURE 37–1  The hypothalamic-pituitary endocrine α-melanocyte-stimulating hormone (MSH) and β-endorphin
system. Hormones released from the anterior pituitary stimulate
the production of hormones by a peripheral endocrine gland,
the liver, or other tissues, or act directly on target tissues. ACRONYMS
Prolactin and the hormones released from the posterior pituitary
ACTH Adrenocorticotropic hormone (corticotropin)
(vasopressin and oxytocin) act directly on target tissues. Hypotha-
lamic factors regulate the release of anterior pituitary hormones. CRH Corticotropin-releasing hormone
ACTH, adrenocorticotropin; ADH, antidiuretic hormone [vasopres- FSH Follicle-stimulating hormone
sin]; CRH, corticotropin-releasing hormone; DA, dopamine; FSH, GH Growth hormone
follicle-stimulating hormone; GH, growth hormone; GHRH, growth
GHRH Growth hormone–releasing hormone
hormone-releasing hormone; GnRH, gonadotropin-releasing hor-
mone; LH, luteinizing hormone; PRL, prolactin; SST, somatostatin; GnRH Gonadotropin-releasing hormone
TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hCG Human chorionic gonadotropin
hormone. hMG Human menopausal gonadotropin
IGF Insulin-like growth factor
LH Luteinizing hormone
Drugs that mimic or block the effects of hypothalamic and PRL Prolactin
pituitary hormones have pharmacologic applications in three
rhGH Recombinant human growth hormone
primary areas: (1) as replacement therapy for hormone deficiency
states; (2) as antagonists for diseases caused by excess production SST Somatostatin
of pituitary hormones; and (3) as diagnostic tools for identifying TRH Thyrotropin-releasing hormone
several endocrine abnormalities. TSH Thyroid-stimulating hormone (thyrotropin)
 CHAPTER 37  Hypothalamic & Pituitary Hormones    669

TABLE 37–1  Links between hypothalamic, anterior pituitary, and target organ hormone or mediator.1
Primary Target Organ Hormone
Anterior Pituitary Hormone Hypothalamic Hormone Target Organ or Mediator

Growth hormone (GH, Growth hormone-releasing hormone Liver, bone, muscle, Insulin-like growth factor-I (IGF-I)
somatotropin) (GHRH) (+), Somatostatin (−) kidney, and others
Thyroid-stimulating hormone (TSH) Thyrotropin-releasing hormone (TRH) (+) Thyroid Thyroxine, triiodothyronine
Adrenocorticotropin (ACTH) Corticotropin-releasing hormone (CRH) (+) Adrenal cortex Cortisol
Follicle-stimulating hormone (FSH) Gonadotropin-releasing hormone Gonads Estrogen, progesterone,
Luteinizing hormone (LH) (GnRH) (+)2 testosterone
Prolactin (PRL) Dopamine (−) Breast —
1
All of these hormones act through G protein-coupled receptors except GH and PRL, which act through JAK/STAT receptors.
2
Endogenous GnRH, which is released in pulses, stimulates LH and FSH release. When administered continuously as a drug, GnRH and its analogs inhibit LH and FSH release
through down-regulation of GnRH receptors.
(+), stimulant; (−), inhibitor.

(see Chapter 31). Like TSH, LH, and FSH, ACTH acts through Whereas all the pituitary and hypothalamic hormones described
a G protein–coupled receptor. A unique feature of the ACTH previously are available for use in humans, only a few are of major
receptor (also known as the melanocortin 2 receptor) is that a clinical importance. Because of the greater ease of administration
transmembrane protein, melanocortin 2 receptor accessory protein, of target endocrine gland hormones or their synthetic analogs,
is essential for normal ACTH receptor trafficking and signaling. the related hypothalamic and pituitary hormones are used infre-
TSH, FSH, LH, and ACTH share similarities in the regulation quently as treatments. However, many of them (TRH, TSH,
of their release from the pituitary. Each is under the control of CRH, ACTH, GnRH, GHRH) are used for specialized diagnostic
a distinctive hypothalamic peptide that stimulates their produc- testing. These agents are described in Tables 37–2 and 37–3 and
tion by acting on G protein-coupled receptors (Table 37–1). are not discussed further in this chapter. In contrast, GH, SST,
TSH release is regulated by thyrotropin-releasing hormone
(TRH), whereas the release of LH and FSH (known collectively
as gonadotropins) is stimulated by pulses of gonadotropin-
releasing hormone (GnRH). ACTH release is stimulated by
TABLE 37–2  Clinical uses of hypothalamic hormones
and their analogs.
corticotropin-releasing hormone (CRH). An important regula-
tory feature shared by these four structurally related hormones is Hypothalamic
that they and their hypothalamic releasing factors are subject to Hormone Clinical Uses
feedback inhibitory regulation by the hormones whose produc- Growth hormone- Used rarely as a diagnostic test for GH and
tion they control. TSH and TRH production are inhibited by the releasing hormone GHRH sufficiency
two key thyroid hormones, thyroxine and triiodothyronine (see (GHRH)
Chapter 38). Gonadotropin and GnRH production is inhibited in Thyrotropin- May be used to diagnose TRH or TSH
women by estrogen and progesterone, and in men by testosterone releasing- hormone deficiencies; not currently available for
(TRH, protirelin) clinical use in United States
and other androgens. ACTH and CRH production are inhibited
by cortisol. Feedback regulation is critical to the physiologic con- Corticotropin-releasing Used rarely to distinguish Cushing’s disease
hormone (CRH) from ectopic ACTH secretion
trol of thyroid, adrenal cortical, and gonadal function and is also
important in pharmacologic treatments that affect these systems. Gonadotropin- May be used in a single dose to assess
releasing hormone initiation of puberty (pubertal gonadotropin
The hypothalamic hormonal control of GH and prolac- (GnRH) response)
tin differs from the regulatory systems for TSH, FSH, LH,
May be used in pulses to treat infertility
and ACTH. The hypothalamus secretes two hormones that
caused by GnRH deficiency
regulate GH; growth hormone-releasing hormone (GHRH)
  Analogs used in long-acting formulations
stimulates GH production, whereas the peptide somatostatin to inhibit gonadal function in children with
(SST) inhibits GH production. GH and its primary peripheral precocious puberty, in some transgender/
mediator, insulin-like growth factor-I (IGF-I), also pro- gender variant early pubertal adolescents
vide feedback to inhibit GH release. Prolactin production is (to block endogenous puberty), in men
with prostate cancer and women under-
inhibited by the catecholamine dopamine acting through the going assisted reproductive technology
D2 subtype of dopamine receptors. The hypothalamus does (ART) or women who require ovarian
not produce a hormone that specifically stimulates prolactin suppression for a gynecologic disorder
secretion, although TRH can stimulate prolactin release, par- Dopamine Dopamine agonists (eg, bromocriptine,
ticularly when TRH concentrations are high in the setting of cabergoline) used for treatment of
primary hypothyroidism. hyperprolactinemia
670    SECTION VII  Endocrine Drugs
LH, FSH, GnRH, and dopamine or analogs of these hormones
are commonly used and are described in the following text.
GROWTH HORMONE (SOMATOTROPIN)
Growth hormone, an anterior pituitary hormone, is required dur-
ing childhood and adolescence for attainment of normal adult size
and has important effects throughout postnatal life on lipid and
carbohydrate metabolism, and on lean body mass and bone den-
sity. Its growth-promoting effects are primarily mediated via IGF-I
(also known as somatomedin C). Individuals with congenital or
acquired deficiency of GH during childhood or adolescence fail to
reach their midparental target adult height and have disproportion-
ately increased body fat and decreased muscle mass. Adults with
GH deficiency also have disproportionately low lean body mass.
Chemistry & Pharmacokinetics
A. Structure
Growth hormone is a 191-amino-acid peptide with two sulfhydryl
bridges. Its structure closely resembles that of prolactin. In the
past, medicinal GH was isolated from the pituitaries of human
cadavers. However, this form of GH was found to be contami-
nated with prions that could cause Creutzfeldt-Jakob disease. For
this reason, it is no longer used. Somatropin, the recombinant
form of GH, has a 191-amino-acid sequence that is identical with
the predominant native form of human GH.
B. Absorption, Metabolism, and Excretion
Circulating endogenous GH has a half-life of approximately
20 minutes and is predominantly cleared by the liver. Recom-
binant human GH (rhGH) is administered subcutaneously
6–7 times per week. Peak levels occur in 2–4 hours, and active
blood levels persist for approximately 36 hours.
Pharmacodynamics
Growth hormone mediates its effects via cell surface receptors of
the JAK/STAT cytokine receptor superfamily. The hormone has
two distinct GH receptor binding sites. Dimerization of two GH
receptors is stimulated by a single GH molecule and activates
TABLE 37–3  Diagnostic uses of thyroid-stimulating
hormone and adrenocorticotropin.
Hormone Diagnostic Use
Thyroid-stimulating- In patients who have been treated surgically
hormone (TSH; for thyroid carcinoma, to test for cancer recur-
thyrotropin) rence by assessing TSH-stimulated radioac-
tive iodine uptake and serum thyroglobulin
level (see Chapter 38)
Adrenocorticotropin In patients suspected of adrenal insufficiency,
(ACTH) either central (CRH/ACTH deficiency)
or peripheral (cortisol deficiency), in
particular in suspected cases of congenital
adrenal hyperplasia. (See Figure 39–1 and
Chapter 39.)
signaling cascades mediated by receptor-associated JAK tyrosine
kinases and STATs (see Chapter 2). The hormone has complex
effects on growth, body composition, and carbohydrate, protein,
and lipid metabolism. The growth-promoting effects are mediated
principally, but not solely, through an increase in the production
of IGF-I. Much of the circulating IGF-I is produced by the liver.
Growth hormone also stimulates production of IGF-I in bone,
cartilage, muscle, kidney, and other tissues, where it has autocrine
or paracrine roles. It stimulates longitudinal bone growth until the
epiphyseal plates fuse—near the end of puberty. In both children
and adults, GH has anabolic effects in muscle and catabolic effects
in adipose cells that shift the balance of body mass to an increase
in muscle mass and a reduction in adiposity. The direct and indi-
rect effects of GH on carbohydrate metabolism are mixed, in part
because GH and IGF-I have opposite effects on insulin sensitiv-
ity. Growth hormone reduces insulin sensitivity, which results in
mild hyperinsulinemia and increased blood glucose levels, whereas
IGF-I has insulin-like effects on glucose transport. In patients who
are unable to respond to growth hormone because of severe resistance
(caused by GH receptor mutations, post-receptor signaling muta-
tions, or GH antibodies), the administration of recombinant human
IGF-I may cause hypoglycemia because of its insulin-like effects.
Clinical Pharmacology
A. Growth Hormone Deficiency
Growth hormone deficiency can have a genetic basis, be associated
with midline developmental defect syndromes (eg, septo-optic
dysplasia), or be acquired as a result of damage to the pituitary
or hypothalamus by a traumatic event (including breech or
traumatic delivery), intracranial tumors, infection, infiltrative
or hemorrhagic processes, or irradiation. Neonates with isolated
GH deficiency are typically of normal size at birth because pre-
natal growth is not GH-dependent. In contrast, IGF-I is essen-
tial for normal prenatal and postnatal growth. Through poorly
understood mechanisms, IGF-I expression and postnatal growth
become GH-dependent during the first year of life. In childhood,
GH deficiency typically presents as short stature, often with mild
adiposity. Another early sign of GH deficiency is hypoglycemia
due to the loss of a counter-regulatory hormonal response of GH
to hypoglycemia; young children are at risk for this condition due
to high sensitivity to insulin. Criteria for diagnosis of GH defi-
ciency usually include (1) a subnormal height velocity for age and
(2) a subnormal serum GH response following provocative testing
with at least two GH secretagogues. Clonidine (α2-adrenergic
agonist), levodopa (dopaminergic agonist), and exercise are factors
that increase GHRH levels. Arginine and insulin-induced hypo-
glycemia cause diminished SST, which increases GH release. The
prevalence of GH deficiency is approximately 1:5000. If therapy
with rhGH is initiated at an early age, many children with short
stature due to GH deficiency will achieve an adult height within
their midparental target height range.
In the past, it was believed that adults with GH deficiency do
not exhibit a significant syndrome. However, more detailed stud-
ies suggest that adults with GH deficiency often have generalized
obesity, reduced muscle mass, asthenia, diminished bone mineral

density, dyslipidemia, and reduced cardiac output. Growth hor-
mone-deficient adults who have been treated with GH experience
reversal of many of these manifestations.
B. Growth Hormone Treatment of Pediatric Patients
with Short Stature
Although the greatest improvement in growth occurs in
patients with GH deficiency, exogenous GH has some effect
on height in children with short stature caused by condi-
tions other than GH deficiency. Growth hormone has been
approved for several conditions (Table 37–4) and has been
used experimentally or off-label in many others. Prader-Willi
syndrome is an autosomal dominant genetic disease associated
with growth failure, obesity, and carbohydrate intolerance. In
children with Prader-Willi syndrome and growth failure, GH
treatment decreases body fat and increases lean body mass,
linear growth, and energy expenditure.
Growth hormone treatment has also been shown to have
a strong beneficial effect on final height of girls with Turner
syndrome (45 X karyotype and variants). In clinical trials, GH
treatment has been shown to increase final height in girls with
Turner syndrome by 10–15 cm (4–6 inches). Because girls with
Turner syndrome also have either absent or rudimentary ovaries,
GH must be judiciously combined with gonadal steroids to
achieve maximal height. Other conditions of pediatric growth
failure for which GH treatment is approved include chronic renal
insufficiency pre-transplant and small-for-gestational-age at birth
TABLE 37–4  Clinical uses of recombinant human
growth hormone.
Primary Therapeutic
Objective Clinical Condition
Growth Growth failure in pediatric patients
associated with:
    Growth hormone deficiency
    Chronic renal insufficiency pre-transplant
    Noonan syndrome
    Prader-Willi syndrome
   Short stature homeobox-containing gene
(SHOX) deficiency
    Turner syndrome
   Small-for-gestational-age with failure to
catch up by age 2 years
    Idiopathic short stature
Improved metabolic Growth hormone deficiency in adults
state, increased lean
body mass, sense of
well-being
Increased lean body Wasting in patients with HIV infection
mass, weight, and
physical endurance
Improved gastrointes- Short bowel syndrome in patients who
tinal function are also receiving specialized nutritional
support
CHAPTER 37  Hypothalamic & Pituitary Hormones    671
in which the child’s height remains more than 2 standard devia-
tions below normal at 2 years of age.
A controversial but approved use of GH is for children with
idiopathic short stature (ISS). This is a heterogeneous popula-
tion that has in common no identifiable cause of the short stature.
Some have arbitrarily defined ISS clinically as having a height at
least 2.25 standard deviations below normal for children of the
same age and a predicted adult height that is less than 2.25 stan-
dard deviations below normal. In this group of children, many
years of GH therapy result in an average increase in adult height of
4–7 cm (1.57–2.76 inches) at a cost of $5000–$40,000 per year.
The complex issues involved in the cost-risk-benefit relationship
of this use of GH are important because an estimated 400,000
children in the United States fit the diagnostic criteria for ISS.
Treatment of children with short stature should be carried out
by specialists experienced in GH administration. Dose requirements
vary with the condition being treated, with GH-deficient children
typically being most responsive. Children must be observed closely
for slowing of growth velocity, which could indicate a need to
increase the dosage or the possibility of epiphyseal plate fusion or
intercurrent problems such as hypothyroidism or malnutrition.
Other Uses of Growth Hormone
Growth hormone affects many organ systems and also has a net
anabolic effect. It has been tested in a number of conditions that
are associated with a severe catabolic state and is approved for the
treatment of wasting in patients with AIDS. In 2004, GH was
approved for treatment of patients with short bowel syndrome who
are dependent on total parenteral nutrition (TPN). After intestinal
resection or bypass, the remaining functional intestine in many
patients undergoes extensive adaptation that allows it to adequately
absorb nutrients. However, other patients fail to adequately adapt
and develop a malabsorption syndrome. Growth hormone has been
shown to increase intestinal growth and improve its function in
experimental animals. Benefits of GH treatment for patients with
short bowel syndrome and dependence on TPN have mostly been
short-lived in the clinical studies that have been published to date.
Growth hormone is administered with glutamine, which also has
trophic effects on the intestinal mucosa.
Growth hormone is a popular component of “anti-aging”
programs. Serum levels of GH normally decline with aging; anti-
aging programs claim that injection of GH or administration of
drugs purported to increase GH release are effective anti-aging
remedies. These claims are largely unsubstantiated. In contrast,
studies in mice and the nematode Caenorhabditis elegans have
clearly demonstrated that analogs of human GH and IGF-I con-
sistently shorten life span and that loss-of-function mutations in
the signaling pathways for the GH and IGF-I analogs lengthen life
span. Another use of GH is by athletes for a purported increase
in muscle mass and athletic performance. Growth hormone is one
of the drugs banned by the International Olympic Committee.
In 1993, the FDA approved the use of recombinant bovine
growth hormone (rbGH) in dairy cattle to increase milk produc-
tion. Although milk and meat from rbGH-treated cows appear
to be safe, these cows have a higher incidence of mastitis, which
672    SECTION VII  Endocrine Drugs
could increase antibiotic use and result in greater antibiotic
residues in milk and meat.
Toxicity & Contraindications
Children generally tolerate growth hormone treatment well.
Adverse events are relatively rare and include pseudotumor cere-
bri, slipped capital femoral epiphysis, progression of scoliosis,
edema, hyperglycemia, and increased risk of asphyxiation in
severely obese patients with Prader-Willi syndrome and upper
airway obstruction or sleep apnea. Patients with Turner syndrome
have an increased risk of otitis media while taking GH. In chil-
dren with GH deficiency, periodic evaluation of the other anterior
pituitary hormones may reveal concurrent deficiencies, which
also require treatment (ie, with hydrocortisone, levothyroxine, or
gonadal hormones). Pancreatitis, gynecomastia, and nevus growth
have occurred in patients receiving GH. Adults tend to have more
adverse effects from GH therapy. Peripheral edema, myalgias,
and arthralgias (especially in the hands and wrists) occur com-
monly but remit with dosage reduction. Carpal tunnel syndrome
can occur. Growth hormone treatment increases the activity of
cytochrome P450 isoforms, which may reduce the serum levels of
drugs metabolized by that enzyme system (see Chapter 4). There
has been no increased incidence of malignancy among patients
receiving GH therapy, but such treatment is contraindicated in
a patient with a known active malignancy. Proliferative retinopa-
thy may rarely occur. Growth hormone treatment of critically ill
patients appears to increase mortality. The long-term health effects
of GH treatment in childhood are unknown. The results from the
Safety and Appropriateness of GH in Europe (SAGHE) study are
variable. A higher all-cause mortality (mostly due to cardiovascu-
lar disease) was found in the GH treatment group in the French
arm of the study, but no long-term risks of GH treatment were
observed in the study arm from another region of Europe.
MECASERMIN
A small number of children with growth failure have severe
IGF-I deficiency that is not responsive to exogenous GH.
Causes include mutations in the GH receptor and in the GH
receptor signaling pathway, neutralizing antibodies to GH, and
IGF-I gene defects. In 2005, the FDA approved two forms of
recombinant human IGF-I (rhIGF-I) for treatment of severe
IGF-I deficiency that is not responsive to GH: mecasermin
and mecasermin rinfabate. Mecasermin is rhIGF-I alone, while
mecasermin rinfabate is a complex of rhIGF-I and recom-
binant human insulin-like growth factor–binding protein-3
(rhIGFBP-3). This binding protein significantly increases the
circulating half-life of rhIGF-I. Normally, the great majority
of the circulating IGF-I is bound to IGFBP-3, which is pro-
duced principally by the liver under the control of GH. Due to
a patent settlement, mecasermin rinfabate is not available for
short stature-related indications. Mecasermin is administered
subcutaneously twice daily at a recommended starting dosage
of 0.04–0.08 mg/kg per dose and increased weekly up to a
maximum twice-daily dosage of 0.12 mg/kg per dose.
The most important adverse effect observed with mecaser-
min is hypoglycemia. To avoid hypoglycemia, the prescribing
instructions require consumption of a carbohydrate-containing
meal or snack 20 minutes before or after mecasermin administra-
tion. Several patients have experienced intracranial hypertension,
adenotonsillar hypertrophy, and asymptomatic elevation of liver
enzymes.
GROWTH HORMONE ANTAGONISTS
Antagonists of GH are used to reverse the effects of GH-
producing cells (somatotrophs) in the anterior pituitary that tend
to form GH-secreting tumors. Hormone-secreting pituitary ade-
nomas occur most commonly in adults. In adults, GH-secreting
adenomas cause acromegaly, which is characterized by abnormal
growth of cartilage and bone tissue, and many organs including
skin, muscle, heart, liver, and the gastrointestinal tract. When a
GH-secreting adenoma occurs before the long bone epiphyses
close, it leads to a rare condition, gigantism. Larger pituitary ade-
nomas produce greater amounts of GH and also can impair visual
and central nervous system function by encroaching on nearby
brain structures. The initial therapy of choice for GH-secreting
adenomas is endoscopic transsphenoidal surgery. Medical therapy
with GH antagonists is introduced if GH hypersecretion persists
after surgery. These agents include somatostatin analogs and dopa-
mine receptor agonists, which reduce the production of GH, and
the novel GH receptor antagonist pegvisomant, which prevents
GH from activating GH signaling pathways. Radiation therapy
is reserved for patients with inadequate response to surgical and
medical therapies.
Somatostatin Analogs
Somatostatin, a 14-amino-acid peptide (Figure 37–2), is found in
the hypothalamus, other parts of the central nervous system, the
pancreas, and other sites in the gastrointestinal tract. It functions
primarily as an inhibitory paracrine factor and inhibits the release
of GH, TSH, glucagon, insulin, and gastrin. Somatostatin is rap-
idly cleared from the circulation, with a half-life of 1–3 minutes.
S S
Somatostatin
Ala Cys
Gly Ser
1
Cys Lys
Asn Phe Phe Trp Lys Thr
Phe Thr 14
13
2
3 11 12
4 5 6 7 8 9 10
S S
Octreotide
D-Phe Cys Thr-ol Acetate
Cys Phe D-Trp Lys Thr
FIGURE 37–2  Above: Amino acid sequence of somatostatin.
Below: Sequence of the synthetic analog, octreotide.

The kidney appears to play an important role in its metabolism
and excretion.
Somatostatin has limited therapeutic usefulness because of
its short duration of action and multiple effects in many secre-
tory systems. A series of longer-acting somatostatin analogs that
retain biologic activity have been developed. Octreotide, the most
widely used somatostatin analog (Figure 37–2), is 45 times more
potent than somatostatin in inhibiting GH release but only twice
as potent in reducing insulin secretion. Because of this relatively
reduced effect on pancreatic beta cells, hyperglycemia rarely occurs
during treatment. The plasma elimination half-life of octreotide is
about 80 minutes, 30 times longer than that of somatostatin.
Octreotide, 50–200 mcg given subcutaneously every 8 hours,
reduces symptoms caused by a variety of hormone-secreting
tumors: acromegaly, carcinoid syndrome, gastrinoma, gluca-
gonoma, insulinoma, VIPoma, and ACTH-secreting tumor. Other
therapeutic use indications include diarrhea—secretory, HIV asso-
ciated, diabetic, chemotherapy, or radiation induced—and portal
hypertension. Somatostatin receptor scintigraphy, using radiola-
beled octreotide, is useful in localizing neuroendocrine tumors
having somatostatin receptors and helps predict the response to
octreotide therapy. Octreotide is also useful for the acute control
of bleeding from esophageal varices.
Octreotide acetate injectable long-acting suspension is a slow-
release microsphere formulation. It may be instituted after a brief
course of shorter-acting octreotide has been demonstrated to be
effective and tolerated. Injections into alternate gluteal muscles are
repeated at 4-week intervals in doses of 10–40 mg.
Adverse effects of octreotide therapy include nausea, vomit-
ing, abdominal cramps, flatulence, and steatorrhea with bulky
bowel movements. Biliary sludge and gallstones may occur after
6 months of use in 20–30% of patients. However, the yearly
incidence of symptomatic gallstones is about 1%. Cardiac effects
include sinus bradycardia (25%) and conduction disturbances
(10%). Pain at the site of injection is common, especially with the
long-acting octreotide suspension. Vitamin B12 deficiency may
occur with long-term use of octreotide.
A long-acting formulation of lanreotide, another octapeptide
somatostatin analog, is approved for treatment of acromegaly.
Lanreotide appears to have effects comparable to those of octreo-
tide in reducing GH levels and normalizing IGF-I concentrations.
Pegvisomant
Pegvisomant is a GH receptor antagonist used to treat acromegaly.
It is the polyethylene glycol (PEG) derivative of a mutant GH,
B2036. Pegylation reduces its clearance and improves its overall
clinical effectiveness. Like native GH, pegvisomant has two GH
receptor binding sites. However, one of its GH receptor binding
sites has increased affinity for the GH receptor, whereas its second
GH receptor binding site has reduced affinity. This differential
receptor affinity allows the initial step (GH receptor dimeriza-
tion) but blocks the conformational changes required for signal
transduction. In clinical trials, pegvisomant was administered
subcutaneously to patients with acromegaly; daily treatment for
12 months or more reduced serum levels of IGF-I into the normal
CHAPTER 37  Hypothalamic & Pituitary Hormones    673
range in 97%. Pegvisomant does not inhibit GH secretion and
may lead to increased GH levels and possible adenoma growth.
No serious problems have been observed; however, increases in
liver enzymes without liver failure have been reported.
THE GONADOTROPINS
(FOLLICLE-STIMULATING HORMONE
& LUTEINIZING HORMONE) & HUMAN
CHORIONIC GONADOTROPIN
The gonadotropins are produced by gonadotroph cells, which
comprise 7–15% of the cells in the pituitary. These hormones
serve complementary functions in the reproductive process.
In women, the principal function of FSH is to stimulate ovar-
ian follicle development. Both FSH and LH are needed for
ovarian steroidogenesis. In the ovary, LH stimulates androgen
production by theca cells in the follicular stage of the menstrual
cycle, whereas FSH stimulates the conversion of androgens to
estrogens by granulosa cells. In the luteal phase of the menstrual
cycle, estrogen and progesterone production is primarily under the
control first of LH and then, if pregnancy occurs, under the con-
trol of human chorionic gonadotropin (hCG). Human chorionic
gonadotropin is a placental glycoprotein nearly identical with LH;
its actions are mediated through LH receptors.
In men, FSH is the primary regulator of spermatogenesis,
whereas LH is the main stimulus for testosterone synthesis in
Leydig cells. FSH helps maintain high local androgen concen-
trations in the vicinity of developing sperm by stimulating the
production of androgen-binding protein in Sertoli cells. FSH
also stimulates the conversion by Sertoli cells of testosterone to
estrogen that is also required for spermatogenesis.
FSH, LH, and hCG are available in several pharmaceutical
forms. They are used in states of infertility to stimulate spermato-
genesis in men and to induce follicle development and ovulation
in women. Their most common clinical use is for the controlled
ovarian stimulation that is the cornerstone of assisted reproductive
technologies such as in vitro fertilization (IVF, see below).
Chemistry & Pharmacokinetics
All three hormones—FSH, LH, and hCG—are heterodimers that
share an identical α subunit in addition to a distinct β subunit
that confers receptor specificity. The β subunits of hCG and
LH are nearly identical, and these two hormones are used inter-
changeably. All the gonadotropin preparations are administered
by subcutaneous or intramuscular injection, usually on a daily
basis. Half-lives vary by preparation and route of injection from
10 to 40 hours.
A. Menotropins
The first commercial gonadotropin product containing both FSH
and LH was extracted from the urine of postmenopausal women.
This purified extract of FSH and LH is known as menotropins,
or human menopausal gonadotropins (hMG). From the early
1960s, these preparations were used for the stimulation of follicle
674    SECTION VII  Endocrine Drugs
development in women. The early extraction techniques were very
crude, requiring around 30 L of urine to manufacture enough
hMG needed for a single treatment cycle. These initial prepara-
tions were also contaminated with other proteins; less than 5% of
the proteins present were bioactive. The FSH-to-LH bioactivity
ratio of these early preparations was 1:1. As purity improved,
it was necessary to add hCG in order to maintain this ratio of
bioactivity.
B. Follicle-Stimulating Hormone
Three forms of purified FSH are available. Urofollitropin, also
known as uFSH, is a purified preparation of human FSH extracted
from the urine of postmenopausal women. Virtually all the LH
activity has been removed through a form of immuno-affinity
chromatography that uses anti-hCG antibodies. Urofollitropin
was withdrawn from the US market in 2015. Two recombinant
forms of FSH (rFSH) are also available: follitropin alfa and
follitropin beta. The amino acid sequences of these two products
are identical to that of human FSH. They differ from each other
and urofollitropin in the composition of carbohydrate side chains.
The rFSH preparations have a shorter half-life than preparations
derived from human urine but stimulate estrogen secretion at least
as efficiently and, in some studies, more efficiently. Compared
with urine derived gonadotropins, rFSH preparations have little
protein contamination, much less batch-to-batch variability, and
may cause less local tissue reaction. The rFSH preparations are
considerably more expensive.
C. Luteinizing Hormone
Lutropin alfa, the first and only recombinant form of human
LH, was introduced in the United States in 2004 but withdrawn
in 2012. When given by subcutaneous injection, it has a half-life
of about 10 hours. Lutropin has only been approved for use in
combination with follitropin alfa for stimulation of follicular
development in infertile hypogonadotropic hypogonadal women
with profound LH deficiency (<1.2 IU/L). Lutropin alfa with
follitropin alfa may also be of benefit in certain subgroups of nor-
mogonadotropic women (eg, those with an inadequate response
to prior follitropin alfa monotherapy). It has not been approved
for use with the other preparations of FSH or for induction of
ovulation.
D. Human Chorionic Gonadotropin
Human chorionic gonadotropin is produced by the human
placenta and excreted into the urine, whence it can be extracted
and purified. It is a glycoprotein consisting of a 92-amino-acid
α subunit virtually identical to that of FSH, LH, and TSH, and
a β subunit of 145 amino acids that resembles that of LH except
for the presence of a carboxyl terminal sequence of 30 amino acids
not present in LH. Choriogonadotropin alfa (rhCG) is a recom-
binant form of hCG. Because of its greater consistency in biologic
activity, rhCG is packaged and dosed on the basis of weight rather
than units of activity. All of the other gonadotropins, including
rFSH, are packaged and dosed on the basis of units of activity.
Both the hCG preparation that is purified from human urine
and rhCG can be administered by subcutaneous or intramuscular
injection.
Pharmacodynamics
The gonadotropins and hCG exert their effects through
G protein-coupled receptors. LH and FSH have complex effects
on reproductive tissues in both sexes. In women, these effects
change over the time course of a menstrual cycle as a result of
a complex interplay among concentration-dependent effects of
the gonadotropins, cross-talk of LH, FSH, and gonadal steroids,
and the influence of other ovarian hormones. A coordinated
pattern of FSH and LH secretion during the menstrual cycle
(see Figure 40–1) is required for normal follicle development,
ovulation, and pregnancy.
During the first 8 weeks of pregnancy, the progesterone and
estrogen required to maintain pregnancy are produced by the
ovarian corpus luteum. For the first few days after ovulation, the
corpus luteum is maintained by maternal LH. However, as mater-
nal LH concentration falls owing to increasing concentrations of
progesterone and estrogen, the corpus luteum will continue to
function only if the role of maternal LH is taken over by hCG
produced by syncytiotrophoblast cells in the placenta.
Clinical Pharmacology
A. Ovulation Induction
The gonadotropins are used to induce follicle development and
ovulation in women with anovulation that is secondary to hypo-
gonadotropic hypogonadism, polycystic ovary syndrome, and
other causes. Because of the high cost of gonadotropins and the
need for close monitoring during their administration, they are
generally reserved for anovulatory women who fail to respond
to other less complicated forms of treatment (eg, clomiphene;
see Chapter 40). Gonadotropins are also used for controlled ovar-
ian stimulation in assisted reproductive technology procedures.
Currently, a number of different protocols use gonadotropins in
ovulation induction and controlled ovulation stimulation, and
new protocols are continually being developed to improve the
rates of success and to decrease the two primary risks of ovulation
induction: multiple pregnancies and the ovarian hyperstimula-
tion syndrome (OHSS; see below).
Although the details differ, all of these protocols are based
on the complex physiology that underlies a normal menstrual
cycle. Like a menstrual cycle, controlled ovulation stimulation
is discussed in relation to a cycle that begins on the first day of
a menstrual bleed (Figure 37–3). Shortly after the first day (usu-
ally on day 2), daily injections with one of the FSH preparations
(hMG, urofollitropin, or rFSH) are begun and continued for
approximately 8–12 days. In women with hypogonadotropic
hypogonadism, follicle development requires treatment with
a combination of FSH and LH because these women do not
produce the basal level of LH that is required for normal follicle
development. The dose and duration of gonadotropin treatment
are based on the response as measured by the serum estradiol
concentration and by ultrasound evaluation of ovarian follicle
 CHAPTER 37  Hypothalamic & Pituitary Hormones    675

Oocyte
retrieval & Embryo
fertilization transfer

hCG

Gonadotropin
Progesterone
Time (days) Menses

GnRH agonist
or
GnRH
antagonist

Luteal phase Follicular phase Luteal phase

FIGURE 37–3  Controlled ovarian stimulation in preparation for an assisted reproductive technology such as in vitro fertilization. Follicular
phase: Follicle development is stimulated with gonadotropin injections that begin about 2 days after menses begin. When the follicles are
ready, as assessed by ultrasound measurement of follicle size, final oocyte maturation is induced by an injection of hCG. Luteal phase: Shortly
thereafter oocytes are retrieved and fertilized in vitro. The recipient’s luteal phase is supported with injections of progesterone. To prevent
a premature luteinizing-hormone surge, endogenous LH secretion is inhibited with either a GnRH agonist or a GnRH antagonist. In most
protocols, the GnRH agonist is started midway through the preceding luteal cycle.

development. When exogenous gonadotropins are used to stimu-
late follicle development, there is risk of a premature endogenous
surge in LH owing to the rapidly increasing serum estradiol levels.
To prevent this, gonadotropins are almost always administered
in conjunction with a drug that blocks the effects of endogenous
GnRH—either continuous administration of a GnRH agonist,
which downregulates GnRH receptors, or a GnRH receptor
antagonist (see below and Figure 37–3).
When appropriate follicular maturation has occurred, the
gonadotropin and the GnRH agonist or GnRH antagonist injec-
tions are discontinued and hCG (3300–10,000 IU) is adminis-
tered subcutaneously to induce final follicular maturation and, in
ovulation induction protocols, ovulation. The hCG administra-
tion is followed by timed intercourse or intrauterine insemination
in ovulation induction and by oocyte retrieval in assisted repro-
ductive technology procedures. Because use of GnRH agonists
or antagonists during the follicular phase of ovulation induction
suppresses endogenous LH production, it is important to provide
exogenous hormonal support of the luteal phase. In clinical trials,
exogenous progesterone, hCG, or a combination of the two have
been effective at providing adequate luteal support. However,
progesterone is preferred for luteal support because hCG carries a
higher risk of OHSS in patients with high follicular response to
gonadotropins.
B. Male Infertility
Most of the signs and symptoms of hypogonadism in males
(eg, delayed puberty, retention of prepubertal secondary sex
characteristics after puberty) can be adequately treated with
exogenous androgen; however, treatment of infertility in hypogo-
nadal men requires the activity of both LH and FSH. For many
years, conventional therapy has consisted of initial treatment
for 8–12 weeks with injections of 1000–2500 IU hCG several
times per week. After the initial phase, hMG is injected at a dose
of 75–150 units three times per week. In men with hypogo-
nadal hypogonadism, it takes an average of 4–6 months of such
treatment for sperm to appear in the ejaculate in up to 90% of
patients, but often not at normal levels. Even if pregnancy does
not occur spontaneously, the number of sperm is often sufficient
that pregnancy can be achieved by insemination with the patient’s
semen (intrauterine insemination) or with the help of an assisted
reproductive technique such as in vitro fertilization with or with-
out intracytoplasmic sperm injection (ICSI), in which a single
sperm is injected directly into a mature oocyte that has been
retrieved after controlled ovarian stimulation of a female partner.
With the advent of ICSI, the minimum threshold of spermato-
genesis required for pregnancy is greatly lowered.
C. Outdated Uses
Chorionic gonadotropin is approved for the treatment of prepu-
bertal cryptorchidism. Prepubertal boys were treated with intra-
muscular injections of hCG for 2–6 weeks. However, this clinical
use is no longer supported because the long-term efficacy of hor-
monal treatment of cryptorchidism (~20%) is much lower than
the long-term efficacy of surgical treatment (>95%), and because
of concerns that early childhood treatment with hCG treatment
has a negative impact on germ cells in addition to increasing the
risk of precocious puberty.
In the United States, chorionic gonadotropin has a black-
box warning against its use for weight loss. The use of hCG
plus severe calorie restriction for weight loss was popularized
by a publication in the 1950s claiming that the hCG selectively
676    SECTION VII  Endocrine Drugs
mobilizes body fat stores. This practice continues today, despite
a preponderance of subsequent scientific evidence from placebo-
controlled trials that hCG does not provide any weight loss
benefit beyond the weight loss associated with severe calorie
restriction alone.
Toxicity & Contraindications
In women treated with gonadotropins and hCG, the two most
serious complications are OHSS and multiple pregnancies.
Stimulation of the ovary during ovulation induction often leads
to uncomplicated ovarian enlargement that usually resolves
spontaneously. However, OHSS may occur and can be associ-
ated with ovarian enlargement, intravascular depletion, ascites,
liver dysfunction, pulmonary edema, electrolyte imbalance, and
thromboembolic events. Although OHSS is often self-limited,
with spontaneous resolution within a few days, severe disease
may require hospitalization and intensive care. Triggering the
final oocyte maturation with hCG carries the risk of inducing
OHSS. GnRH agonists also induce this final oocyte maturation
by promoting the release of endogenous gonadotropin stores from
the hypophysis and can be used as an alternative to hCG. Use of
the GnRH agonist trigger dramatically reduces the risk of OHSS,
owing to the short half-life of the GnRH agonist–induced endog-
enous LH surge.
The probability of multiple pregnancies is greatly increased
when ovulation induction and assisted reproductive technologies
are used. In ovulation induction, the risk of a multiple pregnancy
is estimated to be 5–10%, whereas the percentage of multiple
pregnancies in the general population is closer to 1%. Multiple
pregnancies carry an increased risk of complications, such as
gestational diabetes, preeclampsia, and preterm labor. For in
vitro fertilization procedures, the risk of a multiple pregnancy is
determined primarily by the number of embryos transferred to
the recipient. A strong trend in recent years has been to transfer
single embryos.
Other reported adverse effects of gonadotropin treatment are
headache, depression, edema, precocious puberty, and (rarely)
production of antibodies to hCG. In men treated with gonadotro-
pins, the risk of gynecomastia is directly correlated with the level
of testosterone produced in response to treatment.
GONADOTROPIN-RELEASING
HORMONE & ITS ANALOGS
Gonadotropin-releasing hormone is secreted by neurons in the
hypothalamus. It travels through the hypothalamic-pituitary
venous portal plexus to the anterior pituitary, where it binds to G
protein-coupled receptors on the plasma membranes of gonado-
trophs. Pulsatile GnRH secretion is required to stimulate the
gonadotrophs to produce and release LH and FSH.
Sustained nonpulsatile administration of GnRH or GnRH
analogs inhibits the release of FSH and LH by the pituitary in
both women and men, resulting in hypogonadotropic hypogo-
nadism. GnRH agonists are used to induce gonadal suppression
in men with prostate cancer or children with central precocious
puberty. They are also used in women who are undergoing assisted
reproductive technology procedures or who have a gynecologic
problem that is benefited by ovarian suppression.
Chemistry & Pharmacokinetics
A. Structure
GnRH is a decapeptide found in all mammals. Gonadorelin is
an acetate salt of synthetic human GnRH. Substitution of amino
acids at the 6 position or replacement of the C-terminal glycine-
amide produces synthetic agonists. Both modifications make
them more potent and longer-lasting than native GnRH and
gonadorelin. Such analogs of GnRH include goserelin, buserelin,
histrelin, leuprolide, nafarelin, and triptorelin.
B. Pharmacokinetics
Gonadorelin can be administered intravenously or subcutane-
ously. Other GnRH agonists can be administered subcutaneously,
intramuscularly, via nasal spray (nafarelin), or as a subcutaneous
implant. The half-life of intravenous gonadorelin is 4 minutes,
and the half-lives of subcutaneous and intranasal GnRH analogs
are approximately 3 hours. The duration of clinical uses of GnRH
agonists varies from a few days for controlled ovarian stimulation
to a number of years for treatment of metastatic prostate cancer.
Therefore, preparations have been developed with a range of dura-
tions of action from several hours (for daily administration) to 1,
4, 6, or 12 months (depot forms).
Pharmacodynamics
The physiologic actions of GnRH exhibit complex dose-response
relationships that change dramatically from the fetal period
through the end of puberty. This is not surprising in view of the
complex role that GnRH plays in normal reproduction, particu-
larly in female reproduction. Pulsatile GnRH release occurs and
is responsible for stimulating LH and FSH production during the
fetal and neonatal period. Subsequently, from the age of 2 years
until the onset of puberty, GnRH secretion falls off and the
pituitary simultaneously exhibits very low sensitivity to GnRH.
Just before puberty, an increase in the frequency and amplitude
of GnRH release occurs and then, in early puberty, pituitary sen-
sitivity to GnRH increases, which is due in part to the effect of
increasing concentrations of gonadal steroids. In females, it usu-
ally takes several months to a year after the onset of puberty for
the hypothalamic-pituitary system to produce an LH surge and
ovulation. By the end of puberty, the system is well established
so that menstrual cycles proceed at relatively constant intervals.
The amplitude and frequency of GnRH pulses vary in a regular
pattern through the menstrual cycle with the highest amplitudes
occurring during the luteal phase and the highest frequency occur-
ring late in the follicular phase. Lower pulse frequencies favor FSH
secretion, whereas higher pulse frequencies favor LH secretion.
Gonadal steroids as well as the peptide hormones activin, inhibin,
and follistatin have complex modulatory effects on the gonadotro-
pin response to GnRH.

In the pharmacologic use of GnRH and its analogs, pulsa-
tile intravenous administration of gonadorelin every 1–4 hours
stimulates FSH and LH secretion. Continuous administration
of gonadorelin or its longer-acting analogs produces a biphasic
response. During the first 7–10 days, an agonist effect results
in increased concentrations of gonadal hormones in males and
females; this initial phase is referred to as a flare. After this period,
the continued presence of GnRH results in an inhibitory action
that manifests as a drop in the concentration of gonadotropins and
gonadal steroids (ie, hypogonadotropic hypogonadal state). The
inhibitory action is due to a combination of receptor downregula-
tion and changes in the signaling pathways activated by GnRH.
Clinical Pharmacology
The GnRH agonists are occasionally used for stimulation of
gonadotropin production. They are used far more commonly for
suppression of gonadotropin release.
A. Stimulation
1. Female infertility—In the current era of widespread avail-
ability of gonadotropins and assisted reproductive technology, the
use of pulsatile GnRH administration to treat infertility is uncom-
mon. Although pulsatile GnRH is less likely than gonadotropins
to cause multiple pregnancies and OHSS, the inconvenience and
cost associated with continuous use of an intravenous pump and
difficulties obtaining native GnRH (gonadorelin) are barriers to
pulsatile GnRH. When this approach is used, a portable battery-
powered programmable pump and intravenous tubing deliver
pulses of gonadorelin every 90 minutes.
Gonadorelin or a GnRH agonist analog can be used to initi-
ate an LH surge and ovulation in women with infertility who are
undergoing ovulation induction with gonadotropins. Tradition-
ally, hCG has been used to initiate ovulation in this situation.
However, there is some evidence that gonadorelin or a GnRH
agonist is less likely than hCG to cause OHSS.
2. Male infertility—It is possible to use pulsatile gonadorelin for
infertility in men with hypothalamic hypogonadotropic hypogo-
nadism. A portable pump infuses gonadorelin intravenously every
90 minutes. Serum testosterone levels and semen analyses must
be done regularly. At least 3–6 months of pulsatile infusions are
required before significant numbers of sperm are seen. As described
above, treatment of hypogonadotropic hypogonadism is more com-
monly done with hCG and hMG or their recombinant equivalents.
3. Diagnosis of LH responsiveness—GnRH may be useful
in determining whether delayed puberty in a hypogonadotropic
adolescent is due to constitutional delay or to hypogonadotropic
hypogonadism. The LH response (but not the FSH response)
to a single dose of GnRH may distinguish between these two
conditions; however, there can be significant individual overlap
in the LH response between the two groups. Serum LH levels are
measured before and at several times after an intravenous or sub-
cutaneous bolus of GnRH. An increase in serum LH with a peak
that is greater than 5–8 mIU/mL suggests early pubertal status.
CHAPTER 37  Hypothalamic & Pituitary Hormones    677
An impaired LH response suggests hypogonadotropic hypogonad-
ism due to either pituitary or hypothalamic disease, but does not
rule out constitutional delay of puberty.
B. Suppression of Gonadotropin Production
1. Controlled ovarian stimulation—In the controlled ovar-
ian stimulation that provides multiple mature oocytes for assisted
reproductive technologies such as in vitro fertilization, it is criti-
cal to suppress an endogenous LH surge that could prematurely
trigger ovulation. This suppression is most commonly achieved by
daily subcutaneous injections of leuprolide or daily nasal applica-
tions of nafarelin. For leuprolide, treatment is commonly initiated
with 1 mg daily for about 10 days until menstrual bleeding occurs.
At that point, the dose is reduced to 0.5 mg daily until hCG is
administered (Figure 37–3). For nafarelin, the beginning dosage
is generally 400 mcg twice a day, which is decreased to 200 mcg
when menstrual bleeding occurs.
2. Endometriosis—Endometriosis is defined as the presence of
estrogen-sensitive endometrium outside the uterus that results in
cyclical abdominal pain in premenopausal women. The pain of
endometriosis is often reduced by abolishing exposure to the cycli-
cal changes in the concentrations of estrogen and progesterone that
are a normal part of the menstrual cycle. The ovarian suppression
induced by continuous treatment with a GnRH agonist greatly
reduces estrogen and progesterone concentrations and prevents
cyclical changes. The preferred duration of treatment with a GnRH
agonist is limited to 6 months because ovarian suppression beyond
this period can result in decreased bone mineral density. When relief
of pain from treatment with a GnRH agonist supports continued
therapy for more than 6 months, the addition of add-back therapy
(estrogen or progestins) reduces or eliminates GnRH agonist-
induced bone mineral loss and provides symptomatic relief without
reducing the efficacy of pain relief. Leuprolide and goserelin are
administered as depot preparations that provide 1 or 3 months of
continuous GnRH agonist activity. Nafarelin is administered twice
daily as a nasal spray at a dose of 0.2 mg per spray.
3. Uterine leiomyomata (uterine fibroids)—Uterine leio-
myomata are benign, estrogen-sensitive, smooth muscle tumors
in the uterus that can cause menorrhagia, with associated anemia
and pelvic pain. Treatment for 3–6 months with a GnRH agonist
reduces fibroid size and, when combined with supplemental iron,
improves anemia. The effects of GnRH agonists are temporary,
with gradual recurrent growth of leiomyomas to previous size
within several months after cessation of treatment. GnRH ago-
nists have been used widely for preoperative treatment of uterine
leiomyomas, both for myomectomy and hysterectomy. GnRH
agonists have been shown to improve hematologic parameters,
shorten hospital stay, and decrease blood loss, operating time, and
postoperative pain when given for 3 months preoperatively.
4. Prostate cancer—Androgen deprivation therapy is the
primary medical therapy for prostate cancer. Combined antian-
drogen therapy with continuous GnRH agonist and an andro-
gen receptor antagonist is as effective as surgical castration in
678    SECTION VII  Endocrine Drugs
reducing serum testosterone concentrations and effects. Leupro-
lide, goserelin, histrelin, buserelin, and triptorelin are approved
for this indication. The preferred formulation is one of the
long-acting depot forms that provide 1, 3, 4, 6, or 12 months of
active drug therapy. During the first 7–10 days of GnRH analog
therapy, serum testosterone levels increase because of the agonist
action of the drug; this can precipitate pain in patients with
bone metastases, and tumor growth and neurologic symptoms in
patients with vertebral metastases. It can also temporarily worsen
symptoms of urinary obstruction. Such tumor flares can usually
be avoided with the concomitant administration of an androgen
receptor antagonist (flutamide, bicalutamide, or nilutamide) (see
Chapter 40). Within about 2 weeks, serum testosterone levels fall
to the hypogonadal range.
5. Central precocious puberty—Continuous administration
of a GnRH agonist is indicated for treatment of central precocious
puberty (onset of secondary sex characteristics before 7–8 years
in girls or 9 years in boys). Before embarking on treatment with
a GnRH agonist, one must confirm central precocious puberty
by demonstrating a pubertal gonadotropin response to GnRH or
a “test dose” of a GnRH analog. Treatment is typically indicated
in a child whose final height would be otherwise significantly
compromised (as evidenced by a significantly advanced bone age)
or in whom the early development of pubertal secondary sexual
characteristics or menses causes significant emotional distress.
While central precocious puberty is most often idiopathic, it is
important to rule out central nervous system pathology with MRI
imaging of the hypothalamic-pituitary area.
Treatment is most commonly carried out with either every
month or every three months intramuscular depot injection of
leuprolide acetate or with a once-yearly implant of histrelin acetate.
Daily subcutaneous regimens and multiple daily nasal spray regi-
mens of GnRH agonists also are available but are not recommended
due to poor adherence. Treatment with a GnRH agonist is generally
continued long enough to optimize adult height and allow pubertal
development that is concurrent with peers. Typically treatment is
continued until age 11 in females and age 12 in males.
6. Other—The gonadal suppression provided by continuous
GnRH agonist treatment is used in the management of advanced
breast and ovarian cancer. In addition, recently published clini-
cal practice guidelines recommend the use of continuous GnRH
agonist administration in early pubertal transgender adolescents
to block endogenous puberty prior to subsequent treatment with
cross-gender gonadal hormones.
Toxicity
Gonadorelin can cause headache, light-headedness, nausea, and
flushing. Local swelling often occurs at subcutaneous injection
sites. Generalized hypersensitivity dermatitis has occurred after
long-term subcutaneous administration. Rare acute hypersensi-
tivity reactions include bronchospasm and anaphylaxis. Sudden
pituitary apoplexy and blindness have been reported following
administration of GnRH to a patient with a gonadotropin-
secreting pituitary tumor.
Continuous treatment of women with a GnRH analog
(leuprolide, nafarelin, goserelin) causes the typical symptoms of
menopause, which include hot flushes, sweats, and headaches.
Depression, diminished libido, generalized pain, vaginal dryness,
and breast atrophy may also occur. Ovarian cysts may develop
within the first month of therapy due to its flare effect on gonado-
tropin secretion and generally resolve after an additional 6 weeks.
Reduced bone mineral density and osteoporosis may occur with
prolonged use, so patients should be monitored with bone den-
sitometry before repeated treatment courses. Depending on the
condition being treated with the GnRH agonist, it may be pos-
sible to ameliorate the signs and symptoms of the hypoestrogenic
state without losing clinical efficacy by adding back a small dose
of a progestin alone or in combination with a low dose of an estro-
gen. Contraindications to the use of GnRH agonists in women
include pregnancy and breast-feeding.
In men treated with continuous GnRH agonist administration,
adverse effects include hot flushes and sweats, edema, gynecomas-
tia, decreased libido, decreased hematocrit, reduced bone density,
asthenia, and injection site reactions. GnRH analog treatment of
children is generally well tolerated. However, temporary exacerba-
tion of precocious puberty may occur during the first few weeks
of therapy. Nafarelin nasal spray may cause or aggravate sinusitis.
GnRH RECEPTOR ANTAGONISTS
Four synthetic decapeptides that function as competitive antago-
nists of GnRH receptors are available for clinical use. Ganirelix,
cetrorelix, abarelix, and degarelix inhibit the secretion of FSH
and LH in a dose-dependent manner. Ganirelix and cetrorelix
are approved for use in controlled ovarian stimulation proce-
dures, whereas degarelix and abarelix are approved for men with
advanced prostate cancer.
Pharmacokinetics
Ganirelix and cetrorelix are absorbed rapidly after subcutaneous
injection. Administration of 0.25 mg daily maintains GnRH antag-
onism. Alternatively, a single 3.0-mg dose of cetrorelix suppresses
LH secretion for 96 hours. Degarelix therapy is initiated with 240
mg administered as two subcutaneous injections. Maintenance dos-
ing is with an 80-mg subcutaneous injection every 28 days.
Clinical Pharmacology
A. Suppression of Gonadotropin Production
GnRH antagonists are approved for preventing the LH surge
during controlled ovarian stimulation. They offer several advan-
tages over continuous treatment with a GnRH agonist. Because
GnRH antagonists produce an immediate antagonist effect, their
use can be delayed until day 6–8 of the in vitro fertilization cycle
(Figure 37–3), and thus the duration of administration is shorter.
They also appear to have a less suppressive effect on the ovarian
response to gonadotropin stimulation, which permits a decrease in
the total duration and dose of gonadotropin. On the other hand,
because their antagonist effects reverse more quickly after their

discontinuation, adherence to the treatment regimen is critical.
The antagonists produce a more complete suppression of LH
secretion than agonists. The suppression of LH may impair fol-
licular development when recombinant or the purified form of
FSH is used during an in vitro fertilization cycle. Clinical trials
have shown a slightly lower rate of pregnancy in in vitro fertiliza-
tion cycles that used GnRH antagonist treatment compared with
cycles that used GnRH agonist treatment.
B. Advanced Prostate Cancer
Degarelix and abarelix are approved for the treatment of symp-
tomatic advanced prostate cancer. These GnRH antagonists
reduce concentrations of gonadotropins and androgens more
rapidly than GnRH agonists and avoid the testosterone surge seen
with GnRH agonist therapy.
Toxicity
When used for controlled ovarian stimulation, ganirelix and
cetrorelix are well tolerated. The most common adverse effects are
nausea and headache. During the treatment of men with prostate
cancer, degarelix caused injection-site reactions and increases in
liver enzymes. Like continuous treatment with a GnRH agonist,
degarelix and abarelix lead to signs and symptoms of androgen
deprivation, including hot flushes and weight gain.
PROLACTIN
Prolactin is a 198-amino-acid peptide hormone produced in the
anterior pituitary. Its structure resembles that of GH. Prolactin is
the principal hormone responsible for lactation. Milk production
is stimulated by prolactin when appropriate circulating levels of
estrogens, progestins, corticosteroids, and insulin are present. A
deficiency of prolactin—which can occur in rare states of pituitary
deficiency—is manifested by failure to lactate. No preparation of
prolactin is available for use in prolactin-deficient patients.
In pituitary stalk section from surgery or head trauma, stalk
compression due to a sellar mass, or rare cases of hypothalamic
destruction, prolactin levels may be elevated as a result of
impaired transport of dopamine (prolactin-inhibiting hormone)
to the pituitary. Much more commonly, prolactin is elevated as
a result of prolactin-secreting adenomas. In addition, a number
of drugs elevate prolactin levels. These include antipsychotic and
gastrointestinal motility drugs that are known dopamine receptor
antagonists, estrogens, and opiates. Hyperprolactinemia causes
hypogonadism, which manifests with infertility, oligomenorrhea
or amenorrhea, and galactorrhea in premenopausal women, and
with loss of libido, erectile dysfunction, and infertility in men.
In the case of large tumors (macroadenomas), it can be associ-
ated with symptoms of a pituitary mass, including visual changes
due to compression of the optic nerves. The hypogonadism and
infertility associated with hyperprolactinemia result from inhibi-
tion of GnRH release. For patients with symptomatic hyperpro-
lactinemia, inhibition of prolactin secretion can be achieved with
dopamine agonists, which act in the pituitary to inhibit prolactin
release.
CHAPTER 37  Hypothalamic & Pituitary Hormones    679
DOPAMINE AGONISTS
Adenomas that secrete excess prolactin usually retain the sensitiv-
ity to inhibition by dopamine exhibited by normal pituitary lacto-
trophs, prolactin secreting cells. Bromocriptine and cabergoline
are ergot derivatives (see Chapters 16 and 28) with a high affinity
for dopamine D2 receptors. Quinagolide, a drug approved in
Europe, is a nonergot agent with similarly high D2 receptor affin-
ity. The chemical structure and pharmacokinetic features of ergot
alkaloids are presented in Chapter 16.
Dopamine agonists suppress prolactin release very effectively
in patients with hyperprolactinemia and GH release is reduced in
patients with acromegaly, although not as effectively. Bromocriptine
has also been used in Parkinson’s disease to improve motor func-
tion and reduce levodopa requirements (see Chapter 28). Newer,
nonergot D2 agonists used in Parkinson’s disease (pramipexole and
ropinirole; see Chapter 28) have been reported to interfere with
lactation, but they are not approved for use in hyperprolactinemia.
Pharmacokinetics
All available dopamine agonists are active as oral preparations, and
all are eliminated by metabolism. They can also be absorbed sys-
temically after vaginal insertion of tablets to avoid nausea due to
oral administration. Cabergoline, with a half-life of approximately
65 hours, has the longest duration of action. Quinagolide has a
half-life of about 20 hours, whereas the half-life of bromocriptine
is about 7 hours. After vaginal administration, serum levels peak
more slowly.
Clinical Pharmacology
A. Hyperprolactinemia
A dopamine agonist is the standard first-line treatment for hyper-
prolactinemia. These drugs shrink pituitary prolactin-secreting
tumors, lower circulating prolactin levels, and restore ovulation
in approximately 70% of women with microadenomas and 30%
of women with macroadenomas (Figure 37–4). Cabergoline is
initiated at 0.25 mg twice weekly orally or vaginally. It can be
increased gradually, according to serum prolactin determina-
tions, up to a maximum of 1 mg twice weekly. Bromocriptine is
generally taken daily after the evening meal at the initial dose of
1.25 mg; the dose is then increased as tolerated. Most patients
require 2.5–7.5 mg daily. Long-acting oral bromocriptine formu-
lations (Parlodel SRO) and intramuscular formulations (Parlodel
LAR) are available outside the United States.
B. Physiologic Lactation
Dopamine agonists were used in the past to prevent breast
engorgement when breast-feeding was not desired. Their use for
this purpose has been discouraged because of toxicity (see Toxicity
& Contraindications).
C. Acromegaly
A dopamine agonist alone or in combination with pituitary sur-
gery, radiation therapy, or octreotide administration can be used
680    SECTION VII  Endocrine Drugs

A Dopamine agonist therapy during the early weeks of pregnancy

120 has not been associated with an increased risk of spontaneous
Serum prolactin (mcg/liter)

100 abortion or congenital malformations. Although there has been

a longer experience with the safety of bromocriptine during early
80
pregnancy, there is growing evidence that cabergoline is also safe
60 in women with macroadenomas who must continue a dopamine
40 agonist during pregnancy. In patients with small pituitary adeno-
mas, dopamine agonist therapy is discontinued upon conception
20
because growth of microadenomas during pregnancy is rare.
0 Patients with very large adenomas require vigilance for tumor
0 2 4 6 8 10 12 14 16 18 20 22 24
progression and often require a dopamine agonist throughout
Weeks of cabergoline therapy
pregnancy. There have been rare reports of stroke or coronary
B
thrombosis in postpartum women taking bromocriptine to
100
suppress postpartum lactation.
80
% of patients

60
40
20
0 are synthesized in neuronal cell bodies in the hypothalamus and
Complete Partial
success success
FIGURE 37–4  Results from a clinical trial of cabergoline in
women with hyperprolactinemia and anovulation. A: The dashed line
indicates the upper limit of normal serum prolactin concentrations.
B: Complete success was defined as pregnancy or at least two
consecutive menses with evidence of ovulation at least once. Partial
success was two menstrual cycles without evidence of ovulation or
just one ovulatory cycle. The most common reasons for withdrawal
from the trial were nausea, headache, dizziness, abdominal pain,
and fatigue. (Adapted from Webster J et al: A comparison of cabergoline and
bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med
1994;331:904.)
to treat acromegaly. The doses required are higher than those
used to treat hyperprolactinemia. For example, patients with
acromegaly require 20–30 mg/d of bromocriptine and seldom
respond adequately to bromocriptine alone unless the pituitary
tumor secretes prolactin as well as GH.
Toxicity & Contraindications
Dopamine agonists can cause nausea, headache, light-headedness,
orthostatic hypotension, and fatigue. Psychiatric manifestations
occasionally occur, even at lower doses, and may take months
to resolve. Erythromelalgia occurs rarely. High dosages of ergot-
derived preparations can cause cold-induced peripheral digital
vasospasm. Pulmonary infiltrates have occurred with chronic
high-dosage therapy. Cabergoline treatment at high doses for
Parkinson’s disease is associated with higher risk of valvular heart
disease, but probably not at the lower dose used for hyperpro-
lactinemia. Cabergoline appears to cause nausea less often than
bromocriptine. Vaginal administration can reduce nausea, but
may cause local irritation.
■■ POSTERIOR PITUITARY
HORMONES
The two posterior pituitary hormones—vasopressin and oxytocin—
Failure
transported via their axons to the posterior pituitary, where they are
stored and then released into the circulation. Each has limited but
important clinical uses.
OXYTOCIN
Oxytocin is a peptide hormone secreted by the posterior pituitary.
Oxytocin stimulates muscular contractions in the uterus and
myoepithelial contractions in the breast. Thus, it is involved in
parturition and the letdown of milk. During the second half of
pregnancy, uterine smooth muscle shows an increase in the expres-
sion of oxytocin receptors and becomes increasingly sensitive to
the stimulant action of endogenous oxytocin.
Chemistry & Pharmacokinetics
A. Structure
Oxytocin is a 9-amino-acid peptide with an intrapeptide disulfide
cross-link (Figure 37–5). Its amino acid sequence differs from that
of vasopressin at positions 3 and 8.
B. Absorption, Metabolism, and Excretion
Oxytocin is administered intravenously for initiation and aug-
mentation of labor. It also can be administered intramuscularly for
control of postpartum bleeding. Oxytocin is not bound to plasma
proteins and is rapidly eliminated by the kidneys and liver, with a
circulating half-life of 5 minutes.
Pharmacodynamics
Oxytocin acts through G protein–coupled receptors and the
phosphoinositide-calcium second-messenger system to contract
uterine smooth muscle. Oxytocin also stimulates the release of

S S
Cys - Tyr - IIe - Gln - Asn - Cys - Pro - Leu - Gly - NH2
1 2 3 4 5 6 7 8 9
Oxytocin
S S
Cys - Tyr - Phe - Gln - Asn - Cys - Pro - Arg - Gly - NH2
1 2 3 4 5 6 7 8 9 of standard fetal monitoring. High concentrations of oxytocin
Arginine vasopressin
S S
O
CH2CH2C - Tyr - Phe - Gln - Asn - Cys - Pro - D-Arg - Gly - NH2
1 2 3 4 5 6 7 8 9
Desmopressin
FIGURE 37–5  Posterior pituitary hormones and desmopressin.
(Adapted, with permission, from Ganong WF: Review of Medical Physiology, 21st ed.
McGraw-Hill, 2003. Copyright © The McGraw-Hill Companies, Inc.)
prostaglandins and leukotrienes that augment uterine contraction.
In small doses oxytocin increases both the frequency and the force
of uterine contractions. At higher doses, it produces sustained
contraction.
Oxytocin also causes contraction of myoepithelial cells sur-
rounding mammary alveoli, which leads to milk letdown. Without
oxytocin-induced contraction, normal lactation cannot occur. At
high concentrations, oxytocin has weak antidiuretic and pressor
activity due to activation of vasopressin receptors.
Clinical Pharmacology
Oxytocin is used to induce labor for conditions requiring
expedited vaginal delivery such as uncontrolled maternal diabe-
tes, worsening preeclampsia, intrauterine infection, or ruptured
membranes after 34 gestational weeks. It is also used to augment
protracted labor. Oxytocin can also be used in the immediate
postpartum period to stop vaginal bleeding due to uterine atony.
Before delivery, oxytocin is usually administered intrave-
nously via an infusion pump with appropriate fetal and maternal
monitoring. For induction of labor, an initial infusion rate of
0.5–2 mU/min is increased every 30–60 minutes until a physi-
ologic contraction pattern is established. The maximum infusion
rate is 20 mU/min. For postpartum uterine bleeding, 10–40 units
are added to 1 L of 5% dextrose, and the infusion rate is titrated
to control uterine atony. Alternatively, 10 units of oxytocin can be
administered by intramuscular injection.
During the antepartum period, oxytocin induces uterine con-
tractions that transiently reduce placental blood flow to the fetus.
The oxytocin challenge test measures the fetal heart rate response
to a standardized oxytocin infusion and provides information
about placental circulatory reserve. An abnormal response, seen as
late decelerations in the fetal heart rate, indicates fetal hypoxia and
may warrant immediate cesarean delivery.
CHAPTER 37  Hypothalamic & Pituitary Hormones    681
Toxicity & Contraindications
When oxytocin is used judiciously, serious toxicity is rare. The
toxicity that does occur is due either to excessive stimulation of
uterine contractions or to inadvertent activation of vasopressin
receptors. Excessive stimulation of uterine contractions before
delivery can cause fetal distress, placental abruption, or uterine
rupture. These complications can be detected early by means
with activation of vasopressin receptors can cause excessive fluid
retention, or water intoxication, leading to hyponatremia, heart
failure, seizures, and death. Bolus injections of oxytocin can cause
hypotension. To avoid hypotension, oxytocin is administered
intravenously as dilute solutions at a controlled rate.
Contraindications to oxytocin include fetal distress, fetal mal-
presentation, placental abruption, and other predispositions for
uterine rupture, including previous extensive uterine surgery.
OXYTOCIN ANTAGONIST
Atosiban is an antagonist of the oxytocin receptor that has been
approved outside the United States as a treatment (tocolysis) for
preterm labor. Atosiban is a modified form of oxytocin that is
administered by intravenous infusion for 2–48 hours. In a small
number of published clinical trials, atosiban appears to be as effec-
tive as β-adrenoceptor-agonist tocolytics and to produce fewer
adverse effects. In 1998, however, the FDA decided not to approve
atosiban based on concerns about efficacy and safety.
VASOPRESSIN (ANTIDIURETIC
HORMONE, ADH)
Vasopressin is a peptide hormone released by the posterior pituitary
in response to rising plasma tonicity or falling blood pressure. It pos-
sesses antidiuretic and vasopressor properties. A deficiency of this
hormone results in diabetes insipidus (see also Chapters 15 and 17).
Chemistry & Pharmacokinetics
A. Structure
Vasopressin is a nonapeptide with a 6-amino-acid ring and a
3-amino-acid side chain. The residue at position 8 is arginine in
humans and in most other mammals except pigs and related spe-
cies, whose vasopressin contains lysine at position 8 (Figure 37–5).
Desmopressin acetate (DDAVP, 1-desamino-8-d-arginine vaso-
pressin) is a long-acting synthetic analog of vasopressin with mini-
mal pressor activity and an antidiuretic-to-pressor ratio 4000 times
that of vasopressin. Desmopressin is modified at position 1 and
contains a d-amino acid at position 8. Like vasopressin and oxytocin,
desmopressin has a disulfide linkage between positions 1 and 6.
B. Absorption, Metabolism, and Excretion
Vasopressin is administered by intravenous or intramuscular
injection. The half-life of circulating vasopressin is approximately
682    SECTION VII  Endocrine Drugs

15 minutes, with renal and hepatic metabolism via reduction of
the disulfide bond and peptide cleavage.
Desmopressin can be administered intravenously, subcutane-
ously, intranasally, or orally. The half-life of circulating desmo-
pressin is 1.5–2.5 hours. Nasal desmopressin is available as a unit
dose spray that delivers 10 mcg per spray; it is also available with
a calibrated nasal tube that can be used to deliver a more precise
dose. Nasal bioavailability of desmopressin is 3–4%, whereas oral
bioavailability is less than 1%.
Pharmacodynamics
Vasopressin activates two subtypes of G protein–coupled recep-
tors (see Chapter 17). V1 receptors are found on vascular smooth
muscle cells and mediate vasoconstriction via the coupling protein
Gq and phospholipase C. V2 receptors are found on renal tubule
cells and reduce diuresis through increased water permeability
and water resorption in the collecting tubules via Gs and adenylyl
cyclase. Extrarenal V2-like receptors regulate the release of coagu-
lation factor VIII and von Willebrand factor, which increases
platelet aggregation.
Clinical Pharmacology
Vasopressin and desmopressin are treatments of choice for
pituitary diabetes insipidus. The dosage of desmopressin is
10–40 mcg (0.1–0.4 mL) in two to three divided doses as a
nasal spray or, as an oral tablet, 0.1–0.2 mg two to three times
daily. The dosage by injection is 1–4 mcg (0.25–1 mL) every
12–24 hours as needed for polyuria, polydipsia, or hypernatre-
mia. Bedtime desmopressin therapy, by intranasal or oral admin-
istration, ameliorates nocturnal enuresis by decreasing nocturnal
urine production. Vasopressin infusion is effective in some
cases of esophageal variceal bleeding and colonic diverticular
bleeding. High-dose vasopressin as a 40-unit intravenous bolus
injection may be given to replace epinephrine in the Advanced
Cardiovascular Life Support (ACLS) resuscitation protocol for
pulseless arrest.
Desmopressin is also used for the treatment of coagulopathy in
hemophilia A and von Willebrand disease (see Chapter 34).
Toxicity & Contraindications
Headache, nausea, abdominal cramps, agitation, and allergic reac-
tions occur rarely. Overdosage can result in hyponatremia and
seizures.
Vasopressin (but not desmopressin) can cause vasoconstriction
and should be used cautiously in patients with coronary artery
disease. Nasal insufflation of desmopressin may be less effective
when nasal congestion is present.
VASOPRESSIN ANTAGONISTS
A group of nonpeptide antagonists of vasopressin receptors has
been investigated for use in patients with hyponatremia or acute
heart failure, which is often associated with elevated concentrations
of vasopressin. Conivaptan has high affinity for both V1a and V2
receptors. Tolvaptan has a 30-fold higher affinity for V2 than for
V1 receptors. In several clinical trials, both agents promoted the
excretion of free water, relieved symptoms, and reduced objective
signs of hyponatremia and heart failure. Conivaptan, administered
intravenously, and tolvaptan, given orally, are approved by the
FDA for treatment of hyponatremia. Tolvaptan treatment dura-
tion is limited to 30 days due to risk of hepatotoxicity, including
life-threatening liver failure. Several other nonselective nonpeptide
vasopressin receptor antagonists are being investigated for these
conditions (see Chapter 15).

SUMMARY Hypothalamic & Pituitary Hormones1

Mechanism of Pharmacokinetics,
Subclass, Drug Action Effects Clinical Applications Toxicities, Interactions

GROWTH HORMONE (GH)

  •  Somatropin Recombinant form of Restores normal growth and
human GH • acts metabolic GH effects in
through GH receptors GH-deficient individuals
to increase production • increases final adult height
of IGF-I in some children with short
stature not due to GH
deficiency
Replacement in GH deficiency
• increased final adult height in
children with certain conditions
associated with short stature (see
Table 37–4) • wasting in HIV
infection • short bowel syndrome
SC injection • Toxicity: Pseudotumor
cerebri, slipped capital femoral
epiphysis, edema, hyperglycemia,
progression of scoliosis, risk of
asphyxia in severely obese patients
with Prader-Willi syndrome and upper
airway obstruction or sleep apnea

IGF-I AGONIST
  •  Mecasermin Recombinant form of Improves growth and Replacement in IGF-I deficiency that SC injection • Toxicity: Hypoglycemia,
IGF-I that stimulates metabolic IGF-I effects in is not responsive to exogenous GH intracranial hypertension, increased
IGF-I receptors individuals with IGF-I liver enzymes
deficiency due to severe GH
resistance

(continued)
 CHAPTER 37  Hypothalamic & Pituitary Hormones    683

Mechanism of Pharmacokinetics,
Subclass, Drug Action Effects Clinical Applications Toxicities, Interactions

SOMATOSTATIN ANALOGS
  •  Octreotide Agonist at somatostatin Inhibits production of GH Acromegaly and several other SC or IV injection • long-acting
receptors and, to a lesser extent, of TSH, hormone-secreting tumors • acute formulation injected IM monthly
glucagon, insulin, and gastrin control of bleeding from esophageal • Toxicity: Gastrointestinal
varices disturbances, gallstones, bradycardia,
cardiac conduction problems

  •  Lanreotide: Similar to octreotide; available as a long-acting formulation for acromegaly

GH RECEPTOR ANTAGONIST
  •  Pegvisomant Blocks GH receptors Ameliorates effects of excess Acromegaly SC injection • Toxicity: Increased liver
GH production enzymes

GONADOTROPINS: FOLLICLE-STIMULATING HORMONE (FSH) ANALOGS

  •  Follitropin alfa Activates FSH receptors Mimics effects of Controlled ovarian stimulation
endogenous FSH • infertility due to hypogonadotropic
hypogonadism in men
SC injection • Toxicity: Ovarian
hyperstimulation syndrome and
multiple pregnancies in women
• gynecomastia in men • headache,
depression, edema in both sexes

  •  Follitropin beta: A recombinant product with the same peptide sequence as follitropin alfa but differs in its carbohydrate side chains
  •  Urofollitropin: Human FSH purified from the urine of postmenopausal women
  •  Menotropins (hMG): Extract of the urine of postmenopausal women; contains both FSH and LH activity

GONADOTROPINS: LUTEINIZING HORMONE (LH) ANALOGS

  • Human chorionic Agonist at LH Mimics effects of Initiation of final oocyte maturation IM or SC injection • Toxicity: Ovarian
gonadotropin receptors endogenous LH and ovulation during controlled hyperstimulation syndrome
(hCG) ovarian stimulation • male • headache, depression, edema in
hypogonadotropic hypogonadism both sexes

  •  Choriogonadotropin alfa: Recombinant form of hCG

  •  Lutropin: Recombinant form of human LH
  •  Menotropins (hMG): Extract of the urine of postmenopausal women that contains both FSH and LH activity

GONADOTROPIN-RELEASING HORMONE (GnRH) ANALOGS

  •  Leuprolide Agonist at GnRH
receptors
Increased LH and FSH Ovarian suppression • controlled
secretion with intermittent ovarian stimulation • central
administration • reduced LH precocious puberty • block of
and FSH secretion with endogenous puberty in some
prolonged continuous transgender/gender variant early
administration pubertal adolescents • advanced
prostate cancer
Administered IV, SC, IM, or intranasally
• depot formulations are available
• Toxicity: Headache, light-headedness,
nausea, injection site reactions
• symptoms of hypogonadism with
continuous treatment

  •  Gonadorelin: Synthetic human GnRH

  •  Other GnRH analogs: Goserelin, buserelin, histrelin, nafarelin, and triptorelin

GONADOTROPIN-RELEASING HORMONE (GnRH) RECEPTOR ANTAGONISTS

  •  Ganirelix Blocks GnRH receptors Reduces endogenous Prevention of premature LH surge SC injection • Toxicity: Nausea,
production of LH and FSH during controlled ovarian headache
stimulation

  •  Cetrorelix: Similar to ganirelix, approved for controlled ovarian stimulation

  •  Degarelix and abarelix: Approved for advanced prostate cancer

(continued)
684    SECTION VII  Endocrine Drugs

Mechanism of Pharmacokinetics,
Subclass, Drug Action Effects Clinical Applications Toxicities, Interactions

DOPAMINE AGONISTS
  •  Bromocriptine Activates dopamine Suppresses pituitary
D2 receptors secretion of prolactin and,
less effectively, GH
• dopaminergic effects on
CNS motor control and
behavior
Treatment of hyperprolactinemia
• acromegaly • Parkinson’s disease
(see Chapter 28)
Administered orally or, for
hyperprolactinemia, vaginally
• Toxicity: Gastrointestinal
disturbances, orthostatic hypotension,
headache, psychiatric disturbances,
vasospasm and pulmonary infiltrates
in high doses

  •  Cabergoline: Another ergot derivative with similar effects

OXYTOCIN Activates oxytocin Increased uterine Induction and augmentation of IV infusion or IM injection • Toxicity:
receptors contractions labor • control of uterine Fetal distress, placental abruption,
hemorrhage after delivery uterine rupture, fluid retention,
hypotension

OXYTOCIN RECEPTOR ANTAGONIST

  •  Atosiban Blocks oxytocin Decreased uterine Tocolysis for preterm labor IV infusion • Toxicity: Concern about
receptors contractions (not available in the USA) increased rates of infant death; not
FDA approved

VASOPRESSIN RECEPTOR AGONISTS

  •  Desmopressin Relatively selective Acts in the kidney collecting
vasopressin V2 receptor duct cells to decrease the
agonist excretion of water • acts on
extrarenal V2 receptors to
increase factor VIII and von
Willebrand factor
Pituitary diabetes insipidus Oral, IV, SC, or intranasal • Toxicity:
• pediatric primary nocturnal Gastrointestinal disturbances,
enuresis • hemophilia A and von headache, hyponatremia, allergic
Willebrand disease reactions

  •  Vasopressin: Available for treatment of diabetes insipidus and sometimes used to control bleeding from esophageal varices

VASOPRESSIN RECEPTOR ANTAGONIST

  •  Conivaptan Antagonist of Reduced renal excretion of Hyponatremia in hospitalized IV infusion • Toxicity: Infusion site
vasopressin V1a and water in conditions patients reactions
V2 receptors associated with increased
vasopressin

  •  Tolvaptan: Similar but more selective for vasopressin V2 receptors; oral administration; treatment course limited to 30 days due to risk of hepatotoxicity
1
See Tables 37–2 and 37–3 for summaries of the clinical uses of the rarely used hypothalamic and pituitary hormones not described in this table.
 CHAPTER 37  Hypothalamic & Pituitary Hormones    685

P R E P A R A T I O N S A V A I L A B L E
GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS
GROWTH FACTOR AGONISTS & ANTAGONISTS Leuprolide acetate Generic, Eligard, Lupron
Lanreotide acetate Somatuline Depot Lutropin alfa (rLH) Luveris*
Mecasermin Increlex Menotropins (hMG) Menopur, Repronex
Octreotide acetate Generic, Sandostatin, Sandostatin LAR Nafarelin acetate Synarel
Depot Triptorelin pamoate Trelstar, Trelstar LA, Trelstar Depot
Pegvisomant Somavert Urofollitropin Bravelle*, Fertinex*
Somatropin Genotropin, Humatrope, Norditropin, PROLACTIN ANTAGONISTS (DOPAMINE AGONISTS)
Nutropin, Omnitrope, Saizen,
Bromocriptine mesylate Generic, Parlodel, Cycloset
Serostim, Tev-tropin, Zorbtive
Cabergoline Generic, Dostinex
GONADOTROPIN AGONISTS & ANTAGONISTS
OXYTOCIN
Abarelix Plenaxis*
Oxytocin Generic, Pitocin
Cetrorelix acetate Cetrotide
Choriogonadotropin alfa Ovidrel VASOPRESSIN AGONISTS AND ANTAGONISTS
(rhCG) Conivaptan HCl Vaprisol
Chorionic gonadotropin (hCG) Generic, Profasi, Pregnyl Desmopressin acetate Generic, Minirin, Stimate
Degarelix Firmagon (DDAVP)
Follitropin alfa (rFSH) Gonal-f Tolvaptan Samsca
Follitropin beta (rFSH) Follistim Vasopressin Generic, Pitressin
Ganirelix acetate Antagon OTHER
Gonadorelin hydrochloride Factrel Corticorelin ovine triflutate Acthrel
(GnRH) Corticotropin H.P. Acthar Gel
Goserelin acetate Zoladex Cosyntropin Generic, Cortrosyn, Cosyntropin
Histrelin acetate Supprelin LA, Vantas Thyrotropin alfa Thyrogen
*
Withdrawn from the USA.

REFERENCES Katznelson L et al: American Association of Clinical Endocrinologists medical guide-

Abramovici A, Cantu J, Jenkins SM: Tocolytic therapy for acute preterm labor.
Obstet Gynecol Clin North Am 2012;39:77.
Al-Inany HG et al: Gonadotrophin-releasing hormone antagonists for assisted
reproductive technology. Cochrane Database Syst Rev 2011;(5):CD001750.
Beall SA, DeCherney A: History and challenges surrounding ovarian stimulation
in the treatment of infertility. Fertil Steril 2012;97:795.
Caldwell PH, Deshpande AV, Von Gontard A: Management of nocturnal enuresis.
BMJ 2013;347:f6259.
Carel JC et al: Consensus statement on the use of gonadotropin-releasing hormone
analogs in children. Pediatrics 2009;123:752.
Carel JC et al: Long-term mortality after recombinant growth hormone treat-
ment for isolated growth hormone deficiency or childhood short stature:
Preliminary report of the French SAGhE study. J Clin Endocrinol Metab
2012;97:416.
Collett-Solberg PF et al: The role of recombinant human insulin-like growth
factor-I in treating children with short stature. J Clin Endocrinol Metab
2008;93:10.
Dong Q, Rosenthal SM: Endocrine disorders of the hypothalamus and pituitary.
In: Swaiman KF, Ashwal S, Ferriero DM (editors): Pediatric Neurology,
5th ed. Mosby, Inc. (Elsevier, Inc.), 2011.
Dreicer R et al: New data, new paradigms for treating prostate cancer patients—
VI: Novel hormonal therapy approaches. Urology 2011;78(5 Suppl):S494.
Gabe SG et al: Obstetrics: Normal and Problem Pregnancies, 6th ed. Churchill
Livingstone, 2012.
Han TS, Bouloux PM: What is the optimal therapy for young males with hypogo-
nadotropic hypogonadism? Clin Endocrinol 2010;72:731.
Hodson EM, Willis NS, Craig JC: Growth hormone for children with chronic
kidney disease. Cochrane Database Syst Rev 2012;(2):CD003264.
lines for clinical practice for the diagnosis and treatment of acromegaly—2011
update. Endo Pract 2011;s4:1.
Lanning NJ, Carter-Su C: Recent advances in growth hormone signaling. Rev
Endocr Metab Disord 2006;7:225.
Melmed S et al (editors): Williams Textbook of Endocrinology, 13th ed. Elsevier,
2016.
Papatsonis DN et al: Maintenance therapy with oxytocin antagonists for inhibiting
preterm birth after threatened preterm labour. Cochrane Database Syst Rev
2013;(10):CD005938.
Penson D et al: Effectiveness of hormonal and surgical therapies for cryptorchi-
dism: A systematic review. Pediatrics 2013;131:e1897.
Richmond E, Rogol AD: Current indications for growth hormone therapy for
children and adolescents. Endocr Dev 2010;18:92.
Rosenfeld RG, Hwa V: The growth hormone cascade and its role in mammalian
growth. Horm Res 2009;71(Suppl 2):36.
Sävendahl L et al: Long-term mortality and causes of death in isolated GHD,
ISS, and SGA patients treated with recombinant growth hormone during
childhood in Belgium, The Netherlands, and Sweden: Preliminary report of
3 countries participating in the EU SAGhE study. J Clin Endocrinol Metab
2012;97:E213.
Snyder PJ: Treatment of hyperprolactinemia due to lactotroph adenoma and other
causes. Available online at: www.uptodate.com.
Speroff L, Fritz MA: Clinical Gynecologic Endocrinology and Infertility, 8th ed.
Lippincott Williams & Wilkins, 2010.
Strauss JF, Barbieri RL: Yen & Jaffe’s Reproductive Endocrinology, 6th ed. Elsevier,
2009.
Surrey ES: Gonadotropin-releasing hormone agonist and add-back therapy: What
do the data show? Curr Opin Obstet Gynecol 2010;22:283.
686    SECTION VII  Endocrine Drugs
Taylor BE, Buchman TG: Is there a role for growth hormone therapy in refractory
critical illness? Curr Opin Crit Care Med 2008;14:438.
Tena-Sempere M: Deciphering puberty: Novel partners, novel mechanisms. Eur J
Endocrinol 2012;167:733.
Wales PW et al: Human growth hormone and glutamine for patients with short
bowel syndrome. Cochrane Database Syst Rev 2010;(16):CD006321.
Webster J et al: A comparison of cabergoline and bromocriptine in the treatment of
hyperprolactinemic amenorrhea. N Engl J Med 1994;331:904.
C ASE STUDY ANSWER
While growth hormone (GH) may have some direct
growth-promoting effects, it is thought to mediate skeletal
growth principally through production of insulin-like
growth factor-I (IGF-I) at the epiphyseal plate, which acts
mainly in an autocrine/paracrine manner. IGF-I may also
promote statural growth through endocrine mechanisms.
The findings of small testes and a microphallus in this
patient suggest a diagnosis of hypogonadism, likely as a
consequence of gonadotropin deficiency. This patient is
Westhoff G, Cotter AM, Tolosa JE: Prophylactic oxytocin for the third stage of
labour to prevent postpartum haemorrhage. Cochrane Database Syst Rev
2013;(10):CD001808.
Wit JM et al: Idiopathic short stature: Definition, epidemiology, and diagnostic
evaluation. Growth Horm IGF Res 2008;18:89.
Youssef MA et al: Gonadotropin-releasing hormone agonist versus HCG for
oocyte triggering in antagonist assisted reproductive technology cycles.
Cochrane Database Syst Rev 2011;(1):CD008046.
at risk for multiple hypothalamic/pituitary deficiencies.
He may already have or may subsequently develop ACTH/
cortisol and TSH/thyroid hormone deficiencies and thus
may require supplementation with hydrocortisone and
levothyroxine, in addition to supplementation with GH
and testosterone. He should also be evaluated for the pres-
ence of central diabetes insipidus and, if present, treated
with desmopressin, a V2 vasopressin receptor–selective
analog.

Thyroid & Antithyroid
*
Drugs
Betty J. Dong, PharmD, FASHP, FCCP, FAPHA
C ASE STUDY
JP is a 33-year-old woman who presents with complaints of
fatigue requiring daytime naps, weight gain, cold intoler-
ance, and muscle weakness for the last few months. These
complaints are new since she used to always feel “hot,” noted
difficulty sleeping, and could eat anything that she wanted
without gaining weight. She also would like to become preg-
nant in the near future. Because of poor medication adherence
to methimazole and propranolol, she received radioactive
iodine (RAI) therapy, developed hypothyroidism, and was
started on levothyroxine 100 mcg daily. Other medications
include calcium carbonate three times daily to “protect her
THYROID PHYSIOLOGY
The normal thyroid gland secretes sufficient amounts of the thyroid
hormones—triiodothyronine (T3) and tetraiodothyronine (T4,
thyroxine)—to normalize growth and development, body tem-
perature, and energy levels. These hormones contain 59% and
65% (respectively) of iodine as an essential part of the molecule.
Calcitonin, the second type of thyroid hormone, is important in the
regulation of calcium metabolism and is discussed in Chapter 42.
Iodide Metabolism
The recommended daily adult iodide (I−)† intake is 150 mcg (200 mcg
during pregnancy and lactation and up to 250 mcg for children).
*
This chapter is dedicated to Dr. Francis S. Greenspan, co-author,
mentor, colleague, and friend who will be sorely missed by his many
colleagues and by his patients for his kindness, generosity, and
expert care as chief of the Thyroid Clinic at UCSF.
†
In this chapter, the term “iodine” denotes all forms of the element; the
term “iodide” denotes only the ionic form, I−
38
C H A P T E R
bones” and omeprazole for “heartburn.” On physical exami-
nation, her blood pressure is 130/89 mm Hg with a pulse of
50 bpm. Her weight is 136 lb (61.8 kg), an increase of 10 lb
(4.5 kg) in the last year. Her thyroid gland is not palpable
and her reflexes are delayed. Laboratory findings include a
thyroid-stimulating hormone (TSH) level of 24.9 μIU/mL
(normal 0.45–4.12 μIU/mL) and a free thyroxine level of
8 pmol/L (normal 10–18 pmol/L). Evaluate the management
of her past history of hyperthyroidism and assess her current
thyroid status. Identify your treatment recommendations to
maximize control of her current thyroid status.
Iodide, ingested from food, water, or medication, is rapidly
absorbed and enters an extracellular fluid pool. The thyroid gland
removes about 75 mcg a day from this pool for hormone synthesis,
and the balance is excreted in the urine. If iodide intake is increased,
the fractional iodine uptake by the thyroid is diminished.
Biosynthesis of Thyroid Hormones
Once taken up by the thyroid gland, iodide undergoes a series
of enzymatic reactions that incorporate it into active thyroid
hormone (Figure 38–1). The first step is the transport of iodide
into the thyroid gland by an intrinsic follicle cell basement mem-
brane protein called the sodium/iodide symporter (NIS). This can
be inhibited by large doses of iodides as well as anions (eg, thiocya-
nate (SCN−), pertechnetate (TcO4 ), and perchlorate (CIO4 ). At
− −
−
the apical cell membrane a second I transport enzyme called pen-
drin controls the flow of iodide across the membrane. Pendrin is
also found in the cochlea of the inner ear. If pendrin is deficient or
absent (SLC26A4 mutation), a hereditary syndrome of goiter and
deafness, called Pendred syndrome (PDS), ensues. At the apical
687
688    SECTION VII  Endocrine Drugs

Thyroid gland

Transport Thyroglobulin
Peroxidase Organification
− −
I I I° MIT-DIT- T3-T4
Iodides
–
–
– Proteolysis
Iodides,
thioamides
SCN–, ClO4 –

T4, T3
Peripheral Blood
tissues
T4, T3
Radiocontrast
media,
–
β-blockers,
corticosteroids,
amiodarone
T3

FIGURE 38–1  Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown.

cell membrane, iodide is oxidized by thyroidal peroxidase (TPO)
to iodine, in which form it rapidly iodinates tyrosine residues
within the thyroglobulin molecule to form monoiodotyrosine
(MIT) and diiodotyrosine (DIT). This process is called iodide
organification. Thyroidal peroxidase is transiently blocked by
high levels of intrathyroidal iodide and blocked more persistently
by thioamide drugs. Gene expression of TPO is stimulated by
thyroid-stimulating hormone (TSH).
Two molecules of DIT combine within the thyroglobulin
molecule to form l-thyroxine (T4). One molecule of MIT and
one molecule of DIT combine to form T3. In addition to thyro-
globulin, other proteins within the gland may be iodinated, but
these iodoproteins do not have hormonal activity. Thyroxine, T3,
MIT, and DIT are released from thyroglobulin by exocytosis and
proteolysis of thyroglobulin at the apical colloid border. The MIT
and DIT are then deiodinated within the gland, and the iodine is
reutilized. This process of proteolysis is also blocked by high levels
of intrathyroidal iodide. The ratio of T4 to T3 within thyroglobu-
lin is approximately 5:1, so that most of the hormone released is
thyroxine. Eighty percent of T3 circulating in the blood is derived
from peripheral metabolism of thyroxine and the rest from direct
thyroid secretion (see below, Figure 38–2).
Transport of Thyroid Hormones
Thyroxine and T3 in plasma are reversibly bound to protein, pri-
marily thyroxine-binding globulin (TBG). Only about 0.04% of
total T4 and 0.4% of T3 exist in the free form (as FT4 and FT3).
Many physiologic and pathologic states and drugs affect T4, T3,
and thyroid transport. However, the actual levels of free hormone
generally remain normal, reflecting feedback control.
Peripheral Metabolism of Thyroid Hormones
The primary pathway for the peripheral metabolism of thyroxine
is deiodination by three 5′deiodinase enzymes (D1, D2, D3).
Deiodination of T4 may occur by monodeiodination of the outer
ring, producing 3,5,3′-triiodothyronine (T3), which is three to
four times more potent than T4. The D1 enzyme is responsible
for about 24% of the circulating T3 while 64% of peripheral T3
is generated by D2, which also regulates T3 levels in the brain
and pituitary. D3 deiodination produces metabolically inactive
3,3′,5′-triiodothyronine (reverse T3 [rT3]), (Figure 38–2). The
low serum levels of T3 and rT3 in normal individuals are due to
the high metabolic clearances of these two compounds.
Drugs such as amiodarone, iodinated contrast media, β block-
ers, and corticosteroids, as well as severe illness or starvation,
inhibit the 5′-deiodinase necessary for the conversion of T4 to T3,
resulting in low T3 and high rT3 levels in the serum. A polymor-
phism in the D2 gene can reduce T3 activation and impair thyroid
hormone response. The pharmacokinetics of thyroid hormones
are listed in Table 38–1.
Evaluation of Thyroid Function
The tests used to evaluate thyroid function are listed in Table 38–2.
 CHAPTER 38  Thyroid & Antithyroid Drugs    689

I I INACTIVATION
NH2
Deamination
HO O CH2 CH Decarboxylation
Conjugation
COOH (glucuronide or
I I sulfate)
Thyroxine

Deiodination
Activation Inactivation

I I
NH2 NH2

HO O CH2 CH HO O CH2 CH

COOH COOH
I I I I
3,5,3′-Triiodothyronine 3,3′,5′-Triiodothyronine
(T3) (reverse T3)

FIGURE 38–2  Peripheral metabolism of thyroxine. (Adapted, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology,
8th ed. McGraw-Hill, 2007. Copyright © The McGraw-Hill Companies, Inc.)

A. Thyroid-Pituitary Relationships inhibit the synthesis and secretion of TRH. Other hormones or
Control of thyroid function via thyroid-pituitary feedback is also drugs may also affect the release of TRH or TSH.
discussed in Chapter 37. Hypothalamic cells secrete thyrotropin-
releasing hormone (TRH) (Figure 38–3). TRH is secreted into B. Autoregulation of the Thyroid Gland
capillaries of the pituitary portal venous system, and in the pitu- The thyroid gland also regulates its uptake of iodide and thyroid
itary gland, TRH stimulates the synthesis and release of thyrotro- hormone synthesis by intrathyroidal mechanisms that are inde-
pin (thyroid-stimulating hormone, TSH). TSH in turn stimulates pendent of TSH. These mechanisms are primarily related to the
an adenylyl cyclase–mediated mechanism in the thyroid cell to level of iodine in the blood. Large doses of iodine inhibit iodide
increase the synthesis and release of T4 and T3. T3, the more active organification (Wolff-Chaikoff block; see Figure 38–1). In certain
of the two hormones, acts in a negative feedback fashion in the disease states (eg, Hashimoto’s thyroiditis), this can inhibit thyroid
pituitary to block the action of TSH and in the hypothalamus to hormone synthesis and result in hypothyroidism. Hyperthyroid-
ism can result from the loss of the Wolff-Chaikoff block in suscep-
tible individuals (eg, multinodular goiter).
TABLE 38–1  Summary of thyroid hormone kinetics. C. Abnormal Thyroid Stimulators
Variable T4 T3 In Graves’ disease (see below), lymphocytes secrete a TSH
receptor–stimulating antibody (TSH-R Ab [stim]), also known as
Volume of distribution 10 L 40 L
thyroid-stimulating immunoglobulin (TSI). This immunoglobu-
Extrathyroidal pool 800 mcg 54 mcg lin binds to the TSH receptor and stimulates the gland in the same
Daily production 75 mcg 25 mcg fashion as TSH itself. The duration of its effect, however, is much
Fractional turnover 10% 60% longer than that of TSH. TSH receptors are also found in orbital
per day fibrocytes, which may be stimulated by high levels of TSH-R
Metabolic clearance 1.1 L 24 L Ab [stim] and can cause ophthalmopathy.
per day
Half-life (biologic) 7 days 1 day
Serum levels
■■ BASIC PHARMACOLOGY OF
 Total 4.8–10.4 mcg/dL 60–181 ng/dL THYROID & ANTITHYROID DRUGS
(62–134 nmol/L) (0.92–2.79 nmol/L)
 Free 0.8–2.7 ng/dL 230–420 pg/dL
THYROID HORMONES
(10.3–34.7 pmol/L) (3.5–6.47 pmol/L)
Chemistry
Amount bound 99.96% 99.6%
The structural formulas of thyroxine and triiodothyronine as
Biologic potency 1 4
well as reverse triiodothyronine (rT3) are shown in Figure 38–2.
Oral absorption 70% 95%
All of these naturally occurring molecules are levo (l) isomers.
690    SECTION VII  Endocrine Drugs

TABLE 38–2  Typical adult values for thyroid function tests.

Name of Test Normal Value1 Results in Hypothyroidism Results in Hyperthyroidism

Total thyroxine (T4) 4.8–10.4 mcg/dL (62–134 nmol/L) Low High

Total triiodothyronine (T3) 59–156 ng/dL Normal or low High
  (0.9–2.4 nmol/L)    
Free T4 (FT4) 0.8–1.4 ng/dL (10–18 pmol/L) Low High
Free T3 (FT3) 169–371 ng/dL (2.6–5.7 pmol/L) Low High
Thyrotropic hormone (TSH) 0.45–4.12 μIU/mL High2 Low
  (0.45–4.12 mIU/L)    
123
I uptake at 24 hours 5–35% Low High
Antithyroglobulin antibodies (Tg-Ab) <200 IU/mL Often present Usually present
Thyroperoxidase antibodies (ATPO) ≤100 WHO units Often present Usually present
123 99m
Isotope scan with I or TcO4 Normal pattern Test not indicated Diffusely enlarged gland
Fine-needle aspiration (FNA) biopsy Normal pattern Test not indicated Test not indicated
Serum thyroglobulin Women: 1.5–38.5 mcg/L Test not indicated Test not indicated
Men: 1.4–29.2 mcg/L
TSH receptor-stimulating antibody or Negative <140% of baseline Test not indicated Elevated in Graves’ disease
thyroid-stimulating immunoglobulin (TSI)
1
Results may vary with different laboratories.
2
Exception is central hypothyroidism.

The synthetic dextro (d) isomer of thyroxine, dextrothyroxine, is restored. Thus, the concentration of total and bound hormone
has approximately 4% of the biologic activity of the l-isomer as will increase, but the concentration of free hormone and the
evidenced by its lesser ability to suppress TSH secretion and cor- steady-state elimination will remain normal. The reverse occurs
rect hypothyroidism. when thyroid binding sites are decreased.

Pharmacokinetics Mechanism of Action

Thyroxine is absorbed best in the duodenum and ileum; absorp-
tion is modified by intraluminal factors such as food, drugs,
gastric acidity, and intestinal flora. Oral bioavailability of current
preparations of l-thyroxine averages 70 to 80% (Table 38–1).
In contrast, T3 is almost completely absorbed (95%). T4 and T3
absorption appears not to be affected by mild hypothyroidism but
may be impaired in severe myxedema with ileus. These factors are
important in switching from oral to parenteral therapy. For par-
enteral use, the intravenous route is preferred for both hormones.
In patients with hyperthyroidism, the metabolic clearances of
T4 and T3 are increased and the half-lives decreased; the opposite
is true in patients with hypothyroidism. Drugs that induce hepatic
microsomal enzymes (eg, rifampin, phenobarbital, carbamaze-
pine, phenytoin, tyrosine kinase inhibitors, HIV protease inhibi-
tors) increase the metabolism of both T4 and T3 (Table 38–3).
Despite this change in clearance, the normal hormone concentra-
tion is maintained in the majority of euthyroid patients as a result
of compensatory hyperfunction of the thyroid. However, patients
dependent on T4 replacement medication may require increased
dosages to maintain clinical effectiveness. A similar compensation
occurs if binding sites are altered. If TBG sites are increased by
pregnancy, estrogens, or oral contraceptives, there is an initial shift
of hormone from the free to the bound state and a decrease in its
rate of elimination until the normal free hormone concentration
A model of thyroid hormone action is depicted in Figure 38–4,
which shows the free forms of thyroid hormones, T4 and T3,
dissociated from thyroid-binding proteins, entering the cell
by the active transporters (eg, monocarboxylate transporter
8 [MCT8], MCT10, and organic anion transporting polypep-
tide [OATP1C1]). Transporter mutations can result in a clinical
syndrome of mental retardation, myopathy, and low serum T4
levels (Allan-Herndon-Dudley syndrome). Within the cell, T4 is
converted to T3 by 5′-deiodinase, and the T3 enters the nucleus,
where T3 binds to a specific T3 thyroid receptor protein, a member
of the c-erb oncogene family. (This family also includes the steroid
hormone receptors and receptors for vitamins A and D.) The T3
receptor exists in two forms, α and β. Mutations in both α and
β genes have been associated with generalized thyroid hormone
resistance. Cigarette smoking and environmental agents (eg, poly-
chlorinated biphenyls) also may interfere with receptor action.
Differing concentrations of receptor forms in different tissues may
account for variations in T3 effect on these tissues.
Most of the effects of thyroid on metabolic processes appear
to be mediated by activation of nuclear receptors that lead to
increased formation of RNA and subsequent protein synthesis, eg,
increased formation of Na+/K+-ATPase. This is consistent with
the observation that the action of thyroid is manifested in vivo
with a time lag of hours or days after its administration.

Acute Circadian and
psychosis pulsatile rhythms
+ + Severe
Cold stress
+ –
H
Hypothalamus
Somato-
+ – statin Corticoids
– or
TRH
dopamine
– Many of the manifestations of thyroid hyperactivity resemble
AP
T4,T3
–
TSH +
+ retraction, tremor, excessive sweating, anxiety, and nervousness.
Thyroid
– I–
FIGURE 38–3  The hypothalamic-pituitary-thyroid axis. Acute
psychosis or prolonged exposure to cold may activate the axis.
Hypothalamic thyroid-releasing hormone (TRH) stimulates pituitary
thyroid-stimulating hormone (TSH) release, while somatostatin and
dopamine inhibit it. TSH stimulates T4 and T3 synthesis and release
from the thyroid, and they in turn inhibit both TRH and TSH synthesis
and release. Small amounts of iodide are necessary for hormone
production, but large amounts inhibit T3 and T4 production and
release. Solid arrows, stimulatory influence; dashed arrows,
inhibitory influence. H, hypothalamus; AP, anterior pituitary.
Large numbers of thyroid hormone receptors are found in the
most hormone-responsive tissues (pituitary, liver, kidney, heart,
skeletal muscle, lung, and intestine), while few receptor sites occur
in hormone-unresponsive tissues (spleen, testes). The brain, which
lacks an anabolic response to T3, contains an intermediate number
of receptors. In congruence with their biologic potencies, the affin-
ity of the receptor site for T4 is about ten times lower than that for
T3. Under some conditions, the number of nuclear receptors may
be altered to preserve body homeostasis. For example, starvation
lowers both circulating T3 hormone and cellular T3 receptors.
Effects of Thyroid Hormones
The thyroid hormones are responsible for optimal growth, devel-
opment, function, and maintenance of all body tissues. Excess or
inadequate amounts result in the signs and symptoms of hyper-
thyroidism or hypothyroidism, respectively (Table 38–4). Since
T3 and T4 are qualitatively similar, they may be considered as one
hormone in the discussion that follows.
CHAPTER 38  Thyroid & Antithyroid Drugs    691
Thyroid hormone is critical for the development and func-
tioning of nervous, skeletal, and reproductive tissues. Its effects
depend on protein synthesis as well as potentiation of the secretion
and action of growth hormone. Thyroid deprivation in early life
results in irreversible mental retardation and dwarfism—typical of
congenital cretinism.
Effects on growth and calorigenesis are accompanied by a per-
vasive influence on metabolism of drugs as well as carbohydrates,
fats, proteins, and vitamins. Many of these changes are dependent
upon or modified by activity of other hormones. Conversely, the
secretion and degradation rates of virtually all other hormones,
including catecholamines, cortisol, estrogens, testosterone, and
insulin, are affected by thyroid status.
sympathetic nervous system overactivity (especially in the cardio-
vascular system), although catecholamine levels are not increased.
Changes in catecholamine-stimulated adenylyl cyclase activity
as measured by cAMP are found with changes in thyroid activ-
ity. Thyroid hormone increases the numbers of β receptors and
enhances amplification of the β-receptor signal. Other clinical
symptoms reminiscent of excessive epinephrine activity (and par-
tially alleviated by adrenoceptor antagonists) include lid lag and
The opposite constellation of effects is seen in hypothyroidism
(Table 38–4).
Thyroid Preparations
See the Preparations Available section at the end of this chapter
for a list of available preparations. These preparations may be
synthetic (levothyroxine, liothyronine, liotrix) or of animal origin
(desiccated thyroid).
Thyroid hormones are not effective and can be detrimental in
the management of obesity, abnormal vaginal bleeding, or depres-
sion if thyroid hormone levels are normal. Recent meta-analysis of
T3 co-administered with antidepressants showed some depression
benefits, but the results were inconclusive and further confirma-
tion for its optimal use is required.
Synthetic levothyroxine is the preparation of choice for thyroid
replacement and suppression therapy because of its stability,
content uniformity, low cost, lack of allergenic foreign protein,
easy laboratory measurement of serum levels, and long half-life
(7 days), which permits once-daily to weekly administration.
In addition, T4 is converted to T3 intracellularly; thus, admin-
istration of T4 produces both hormones and T3 administra-
tion is unnecessary. Generic levothyroxine preparations provide
comparable efficacy and are more cost-effective than branded
preparations, It is preferable that patients remain on a consistent
levothyroxine preparation between refills to avoid changes in bio-
availability. A branded soft gel capsule (Tirosint) had faster, more
complete dissolution and was less affected by gastric pH or coffee
than a tablet formulation.
Although liothyronine (T3) is three to four times more potent
than levothyroxine, it is not recommended for routine replace-
ment therapy because of its shorter half-life (24 hours), requiring
multiple daily doses, and difficulty in monitoring its adequacy of
692    SECTION VII  Endocrine Drugs

TABLE 38–3  Drug effects and thyroid function.

Drug Effect Drugs

Change in thyroid hormone synthesis

 Inhibition of TRH or TSH secretion without induction of Bexarotene, dopamine, bromocriptine, cabergoline, levodopa, corticosteroids,
hypothyroidism or hyperthyroidism somatostatin, octreotide, metformin, interleukin-6, heroin
 Inhibition of thyroid hormone synthesis or release Iodides (including amiodarone), lithium, aminoglutethimide, thioamides, ethionamide,
with the induction of hypothyroidism (or occasionally tyrosine kinase inhibitors (eg, sunitinib, sorafenib, imatinib), HIV protease inhibitors
hyperthyroidism)
Alteration of thyroid hormone transport and serum total T3 and T4 levels, but usually no modification of FT4 or TSH
  Increased TBG Estrogens, tamoxifen, raloxifene, heroin, methadone, mitotane, 5-fluorouracil,
perphenazine
  Decreased TBG Androgens, anabolic steroids, glucocorticoids, danazol, l-asparaginase, nicotinic acid
 Displacement of T3 and T4 from TBG with transient Salicylates, fenclofenac, mefenamic acid, intravenous furosemide, heparin
hyperthyroxinemia
Alteration of T4 and T3 metabolism with modified serum T3 and T4 levels but not TSH levels (unless receiving thyroxine replacement therapy)
 Increased hepatic metabolism, enhanced degradation Nicardipine, phenytoin, carbamazepine, primidone, phenobarbital, rifampin, rifabutin,
of thyroid hormone tyrosine kinase inhibitors (eg, sunitinib, sorafenib, imatinib), sertraline, quetiapine
 Inhibition of 5′-deiodinase with decreased T3, Iopanoic acid, ipodate, amiodarone, β blockers, corticosteroids, propylthiouracil,
increased rT3 flavonoids, interleukin-6
Other interactions
  Interference with T4 absorption from the gut Oral bisphosphonates, cholestyramine, colesevelam, colestipol, chromium picolinate,
charcoal, ciprofloxacin, proton pump inhibitors, sucralfate, Kayexalate, raloxifene,
sevelamer hydrochloride, aluminum hydroxide, ferrous sulfate, calcium carbonate,
bran/fiber, soy, coffee, orlistat
 Induction of autoimmune thyroid disease with Interferon-α, interleukin-2, interferon-β, lithium, amiodarone, tyrosine kinase inhibitors
hypothyroidism or hyperthyroidism (eg, sunitinib, sorafenib, imatinib)
Effect of thyroid function on drug effects
 Anticoagulation Lower doses of warfarin required in hyperthyroidism, higher doses in hypothyroidism
  Glucose control Increased hepatic glucose production and glucose intolerance in hyperthyroidism;
impaired insulin action and glucose disposal in hypothyroidism
  Cardiac drugs Higher doses of digoxin required in hyperthyroidism; lower doses in hypothyroidism
  Sedatives; analgesics Increased sedative and respiratory depressant effects from sedatives and opioids in
hypothyroidism; converse in hyperthyroidism

replacement by conventional laboratory tests. T3 should also be
avoided in patients with cardiac disease due to significant eleva-
tions in peak levels and a greater risk of cardiotoxicity. Using the
more expensive thyroxine and liothyronine fixed-dose combina-
tion (liotrix) and desiccated thyroid has not been shown to be
more effective than T4 administration alone. T3 is best reserved
for short-term TSH suppression. Research is ongoing to clarify
whether T3 might be more appropriate in patients with a poly-
morphism in the D2 gene or in those who continue to report
fatigue, weight gain, and mental impairment while on T4 alone.
The use of desiccated thyroid rather than synthetic prepara-
tions is never justified, since the disadvantages of protein antige-
nicity, product instability, variable hormone concentrations, and
difficulty in laboratory monitoring far outweigh the advantage
of lower cost. Significant amounts of T3 found in some thyroid
extracts may produce significant elevations in T3 levels and
toxicity. Exact equi-effective doses have not been determined.
Approximate equivalence of desiccated thyroid 60 mg (1 gr) to
80 to 100 mcg of levothyroxine, and approximately 37.5 mcg of
liothyronine has been reported. Any dosage conversions should be
re-titrated based on laboratory and clinical response.
The shelf life of synthetic hormone preparations is about
2 years, particularly if they are stored in dark bottles to minimize
spontaneous deiodination. The shelf life of desiccated thyroid is
not known with certainty, but its potency is better preserved if it
is kept dry.
ANTITHYROID AGENTS
Reduction of thyroid activity and hormone effects can be
accomplished by agents that interfere with the production of
thyroid hormones, by agents that modify the tissue response to
thyroid hormones, or by glandular destruction with radiation
or surgery. Goitrogens are agents that suppress secretion of T3
and T4 to subnormal levels and thereby increase TSH, which in
turn produces glandular enlargement (goiter). The antithyroid
compounds used clinically include the thioamides, iodides, and
radioactive iodine.
 CHAPTER 38  Thyroid & Antithyroid Drugs    693

Nucleus

Coactivator
Corepressor

TR-LBD TR-LBD

TR-DBD TR-DBD

TRE

Cytoplasm
TBPs

T4 T3

B
Corepressor T4 T3

Coactivator T4

TR-LBD 5'Dl
RXR-LBD
TR-LBD T3

TR-DBD RXR-DBD TR-DBD

Transcription T3

TRE

FIGURE 38–4  Model of the interaction of T3 with the T3 receptor. A: Inactive phase—the unliganded T3 receptor dimer bound to the
thyroid hormone response element (TRE) along with corepressors acts as a suppressor of gene transcription. B: Active phase—T3 and T4
circulate bound to thyroid-binding proteins (TBPs). The free hormones are transported into the cell by a specific transport system. Within
the cytoplasm, T4 is converted to T3 by 5′-deiodinase (5′DI); T3 then moves into the nucleus. There it binds to the ligand-binding domain of
the thyroid receptor (TR) monomer. This promotes disruption of the TR homodimer and heterodimerization with retinoid X receptor (RXR)
on the TRE, displacement of corepressors, and binding of coactivators. The TR-coactivator complex activates gene transcription, which leads
to alteration in protein synthesis and cellular phenotype. TR-LBD, T3 receptor ligand-binding domain; TR-DBD, T3 receptor DNA-binding
domain; RXR-LBD, retinoid X receptor ligand-binding domain; RXR-DBD, retinoid X receptor DNA-binding domain; T3, triiodothyronine; T4,
tetraiodothyronine, l-thyroxine. (Adapted, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology, 8th ed. McGraw-Hill,
2007. Copyright © The McGraw-Hill Companies, Inc.)

THIOAMIDES methimazole (other than agranulocytosis or hepatitis). The chemical

The thioamides methimazole and propylthiouracil are major
drugs for treatment of thyrotoxicosis. In the United Kingdom,
carbimazole, which is converted to methimazole in vivo, is widely
used. Methimazole is about ten times more potent than propyl-
thiouracil and is the drug of choice in adults and children. Due
to a black box warning about severe hepatitis, propylthiouracil
should be reserved for use during the first trimester of pregnancy,
in thyroid storm, and in those experiencing adverse reactions to
structures of these compounds are shown in Figure 38–5. The
thiocarbamide group is essential for antithyroid activity.
Pharmacokinetics
Methimazole is completely absorbed but at variable rates. It is readily
accumulated by the thyroid gland and has a volume of distribution
similar to that of propylthiouracil. Excretion is slower than with pro-
pylthiouracil; 65–70% of a dose is recovered in the urine in 48 hours.
694    SECTION VII  Endocrine Drugs

TABLE 38–4  Manifestations of thyrotoxicosis and hypothyroidism.

System Thyrotoxicosis Hypothyroidism

Skin and appendages
Eyes, face
Cardiovascular system
Respiratory system
Gastrointestinal system
Central nervous system
Musculoskeletal system
Renal system
Hematopoietic system
Reproductive system
Metabolic system
1
The anemia of hyperthyroidism is usually normochromic and caused by increased red blood cell turnover. The anemia of hypothyroidism may be normochromic, hyperchromic,
or hypochromic and may be due to decreased production rate, decreased iron absorption, decreased folic acid absorption, or to autoimmune pernicious anemia. LDH, lactic
dehydrogenase; AST, aspartate aminotransferase.
Warm, moist skin; sweating; heat intolerance; fine,
thin hair; Plummer’s nails; pretibial dermopathy
(Graves’ disease)
Retraction of upper lid with wide stare; periorbital
edema; exophthalmos; diplopia (Graves’ disease)
Decreased peripheral vascular resistance; increased
heart rate, stroke volume, cardiac output, pulse pres-
sure; high-output heart failure; increased inotropic
and chronotropic effects; arrhythmias; angina
Dyspnea; hypoventilation; decreased vital capacity
Increased appetite; increased frequency of bowel
movements; hypoproteinemia
Nervousness; hyperkinesia; emotional lability,
agitation
Weakness and muscle fatigue; increased deep tendon
reflexes; tremors; hypercalcemia; osteoporosis
Mild polyuria; increased renal blood flow; increased
glomerular filtration rate
Increased erythropoiesis; anemia1
Menstrual irregularities; amenorrhea; infertility;
increased gonadal steroid metabolism
Increased basal metabolic rate; negative nitrogen
balance; hyperglycemia; increased free fatty acids;
decreased total cholesterol and triglycerides;
increased hormone degradation; increased require-
ments for fat- and water-soluble vitamins; increased
drug metabolism; decreased warfarin requirement
Pale, cool, puffy, yellowish skin, face, and hands; dry and
brittle hair; brittle nails
Drooping of eyelids; periorbital edema; loss of temporal
aspects of eyebrows; puffy, nonpitting facies; large tongue,
hoarseness
Increased peripheral vascular resistance; decreased heart
rate, stroke volume, cardiac output, pulse pressure; low-
output heart failure; ECG: bradycardia, prolonged PR interval,
flat T wave, low voltage; pericardial effusion
Pleural effusions; hypoventilation and CO2 retention; sleep
apnea
Decreased appetite; decreased frequency of bowel
movements, constipation; ascites
Lethargy/fatigue; general slowing of mental processes;
neuropathies; weakness and muscle cramps
Stiffness and muscle fatigue; carpal tunnel syndrome;
decreased deep tendon reflexes; increased alkaline
phosphatase, LDH, AST
Impaired water excretion; decreased renal blood flow;
decreased glomerular filtration rate
Decreased erythropoiesis; anemia1
Menorrhagia; infertility; decreased libido; impotence;
oligospermia; decreased gonadal steroid metabolism
Decreased basal metabolic rate; slight positive nitrogen
balance; delayed degradation of insulin with increased
sensitivity; increased total cholesterol and triglycerides;
hyponatremia; decreased hormone degradation; decreased
requirements for fat- and water-soluble vitamins; decreased
drug metabolism; increased warfarin requirement

In contrast, propylthiouracil is rapidly absorbed, reaching peak

serum levels after 1 hour. The bioavailability of 50–80% may be
H O H
N N due to incomplete absorption or a large first-pass effect in the liver.
The volume of distribution approximates total body water with
S S accumulation in the thyroid gland. Most of an ingested dose of
N N propylthiouracil is excreted by the kidney as the inactive glucuro-
H C3H7 nide within 24 hours.
CH3 The short plasma half-life of these agents (1.5 hours for pro-
Propylthiouracil Methimazole pylthiouracil and 6 hours for methimazole) has little influence
O on the duration of the antithyroid action or the dosing interval
C O C2H5 because both agents are accumulated by the thyroid gland. For
propylthiouracil, giving the drug every 6–8 hours is reasonable
N
since a single 100 mg dose can inhibit iodine organification by
S 60% for 7 hours. Since a single 30 mg dose of methimazole exerts
an antithyroid effect for longer than 24 hours, a single daily dose
N
is effective in the management of mild to severe hyperthyroidism.
CH3 Both thioamides cross the placental barrier and are concen-
Carbimazole trated by the fetal thyroid, so that caution must be employed
when using these drugs in pregnancy. Because of the risk of fetal
FIGURE 38–5  Structure of thioamides. The thiocarbamide hypothyroidism, both thioamides are classified as FDA pregnancy
moiety is shaded in color. category D (evidence of human fetal risk based on adverse reaction

data from investigational or marketing experience, see Chapter 59).
Of the two, propylthiouracil is preferable during the first trimester
of pregnancy because it is more strongly protein-bound and, there-
fore, crosses the placenta less readily. In addition, methimazole has
been, albeit rarely, associated with congenital malformations. Both
thioamides are secreted in low concentrations in breast milk but
are considered safe for the nursing infant.
Pharmacodynamics
The thioamides act by multiple mechanisms. The major action
is to prevent hormone synthesis by inhibiting the thyroid
peroxidase-catalyzed reactions and blocking iodine organifica-
tion. In addition, they block coupling of the iodotyrosines. They
do not block uptake of iodide by the gland. Propylthiouracil but
not methimazole also inhibits the peripheral deiodination of T4
and T3 (Figure 38–1). Since the synthesis rather than the release
of hormones is affected, the onset of these agents is slow, often
requiring 3–4 weeks before stores of T4 are depleted.
Toxicity
Adverse reactions to the thioamides occur in 3–12% of treated
patients. Most reactions occur early, especially nausea and gas-
trointestinal distress. An altered sense of taste or smell may
occur with methimazole. The most common adverse effect is
a maculopapular pruritic rash (4–6%), at times accompanied
by systemic signs such as fever. Rare adverse effects include an
urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy,
hypoprothrombinemia, exfoliative dermatitis, polyserositis, and
acute arthralgia. An increased risk of severe hepatitis, sometimes
resulting in death, has been reported with propylthiouracil (black
box warning), so it should be avoided in children and adults
unless no other options are available. Cholestatic jaundice is more
common with methimazole than propylthiouracil. Asymptomatic
elevations in transaminase levels can also occur.
The most dangerous complication is agranulocytosis (granulo-
cyte count < 500 cells/mm3), an infrequent but potentially fatal
adverse reaction. It occurs in 0.1–0.5% of patients taking thio-
amides, but the risk may be increased in older patients and usually
within the first 90 days in those receiving more than 40 mg/d
of methimazole. The reaction is usually rapidly reversible when
the drug is discontinued, but broad-spectrum antibiotic therapy
may be necessary for complicating infections. Colony-stimulating
factors (eg, G-CSF; see Chapter 33) may hasten recovery of the
granulocytes. The cross-sensitivity between propylthiouracil and
methimazole is about 50%; therefore, switching drugs in patients
with severe reactions is not recommended.
ANION INHIBITORS
−
Monovalent anions such as perchlorate (ClO4 ), pertechnetate
(TcO4 ), and thiocyanate (SCN−) can block uptake of iodide by
−
the gland through competitive inhibition of the iodide transport
mechanism. Since these effects can be overcome by large doses of
iodides, their effectiveness is somewhat unpredictable.
CHAPTER 38  Thyroid & Antithyroid Drugs    695
The major clinical use for potassium perchlorate is to block
thyroidal reuptake of I− in patients with iodide-induced hyper-
thyroidism (eg, amiodarone-induced hyperthyroidism). How-
ever, potassium perchlorate is rarely used clinically because it is
associated with aplastic anemia.
IODIDES
Prior to the introduction of the thioamides in the 1940s, iodides
were the major antithyroid agents; today they are rarely used as
sole therapy.
Pharmacodynamics
Iodides have several actions on the thyroid. They inhibit organifi-
cation and hormone release and decrease the size and vascularity
of the hyperplastic gland. In susceptible individuals, iodides can
induce hyperthyroidism (Jod-Basedow phenomenon) or precipi-
tate hypothyroidism.
In pharmacologic doses (>6 mg/d), the major action of iodides
is to inhibit hormone release, possibly through inhibition of
thyroglobulin proteolysis. Improvement in thyrotoxic symptoms
occurs rapidly—within 2–7 days—hence the value of iodide
therapy in thyroid storm. In addition, iodides decrease the vascu-
larity, size, and fragility of a hyperplastic gland, making the drugs
valuable as preoperative preparation for surgery.
Clinical Use of Iodide
Disadvantages of iodide therapy include an increase in intraglandu-
lar stores of iodine, which may delay onset of thioamide therapy or
prevent use of radioactive iodine therapy for several weeks. Thus,
iodides should be initiated after onset of thioamide therapy and
avoided if treatment with radioactive iodine seems likely. Iodide
should not be used alone, because the gland will escape from the
iodide block in 2–8 weeks, and its withdrawal may produce severe
exacerbation of thyrotoxicosis in an iodine-enriched gland. Chronic
use of iodides in pregnancy should be avoided, since they cross
the placenta and can cause fetal goiter. In radiation emergencies
involving release of radioactive iodine isotopes, the thyroid-blocking
effects of potassium iodide can protect the gland from subsequent
damage if administered before radiation exposure.
Toxicity
Adverse reactions to iodine (iodism) are uncommon and in most
cases reversible upon discontinuance. They include acneiform rash
(similar to that of bromism), swollen salivary glands, mucous mem-
brane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic
taste, bleeding disorders, and rarely, anaphylactoid reactions.
RADIOACTIVE IODINE
131
I is the only isotope used for treatment of thyrotoxicosis.
(Others are used in diagnosis.) Administered orally in solution as
sodium 131I, it is rapidly absorbed, concentrated by the thyroid,
696    SECTION VII  Endocrine Drugs
and incorporated into storage follicles. Its therapeutic effect
depends on emission of β rays with an effective half-life of 5 days
and a penetration range of 400–2000 μm. Within a few weeks
after administration, destruction of the thyroid parenchyma is
evidenced by epithelial swelling and necrosis, follicular disrup-
tion, edema, and leukocyte infiltration. Advantages of radioio-
dine include easy administration, effectiveness, low expense, and
absence of pain. Fears of radiation-induced genetic damage, leuke-
mia, and neoplasia have not been realized after more than 50 years
of clinical experience with radioiodine therapy for hyperthyroid-
ism. Radioactive iodine should not be administered to pregnant
women or nursing mothers, since it crosses the placenta to destroy
the fetal thyroid gland and it is excreted in breast milk.
ADRENOCEPTOR-BLOCKING AGENTS
Beta blockers without intrinsic sympathomimetic activity (eg,
metoprolol, propranolol, atenolol) are effective therapeutic
adjuncts in the management of thyrotoxicosis since many of these
symptoms mimic those associated with sympathetic stimulation.
Propranolol has been the β blocker most widely studied and
used in the therapy of thyrotoxicosis. Beta blockers cause clinical
improvement of hyperthyroid symptoms but do not typically
alter thyroid hormone levels. Propranolol at doses greater than
160 mg/d may also reduce T3 levels approximately 20% by
inhibiting the peripheral conversion of T4 to T3.
■■ CLINICAL PHARMACOLOGY OF
THYROID & ANTITHYROID DRUGS
HYPOTHYROIDISM
Hypothyroidism is a syndrome resulting from deficiency of thy-
roid hormones and is manifested largely by a reversible slowing
down of all body functions (Table 38–4). In infants and children,
there is striking retardation of growth and development that
results in dwarfism and irreversible mental retardation.
TABLE 38–5  Etiology and pathogenesis of hypothyroidism.
Cause Pathogenesis
Hashimoto’s thyroiditis Autoimmune destruction of thyroid
1 2
Drug-induced Blocked hormone formation
Dyshormonogenesis Impaired synthesis of T4 due to enzyme
deficiency
131
Radiation, I, X-ray, Destruction or removal of gland
thyroidectomy
Congenital (cretinism) Athyreosis or ectopic thyroid, iodine defi-
ciency; TSH receptor-blocking antibodies
Secondary (TSH deficit) Pituitary or hypothalamic disease
1
Iodides, lithium, fluoride, thioamides, aminosalicylic acid, phenylbutazone, amiodarone, perchlorate, ethionamide, thiocyanate, cytokines (interferons, interleukins), bexarotene,
tyrosine kinase inhibitors, etc. See Table 38–3.
2
See Table 38–3 for specific pathogenesis.
The etiology and pathogenesis of hypothyroidism are outlined
in Table 38–5. Hypothyroidism can occur with or without thy-
roid enlargement (goiter). The laboratory diagnosis of hypothy-
roidism in the adult is easily made by the combination of low free
thyroxine and elevated serum TSH levels (Table 38–2).
The most common cause of hypothyroidism in the United
States at this time is probably Hashimoto’s thyroiditis, an immu-
nologic disorder in genetically predisposed individuals. In this
condition, there is evidence of humoral immunity in the presence
of antithyroid antibodies and lymphocyte sensitization to thyroid
antigens. Genetic mutations as discussed previously and certain
medications also can cause hypothyroidism (Table 38–5).
MANAGEMENT OF HYPOTHYROIDISM
Except for hypothyroidism caused by drugs, which can be
treated in some cases by simply removing the depressant agent,
the general strategy of replacement therapy is appropriate. The
most satisfactory preparation is levothyroxine, administered as
either a branded or generic preparation. Multiple trials have
documented that combination levothyroxine plus liothyronine
is not superior to levothyroxine alone although some patients
remain unwell on thyroxine alone. Genetic variations in deio-
dinases or hormone transporters may account for some of this
lack of efficacy.
There is some variability in the absorption of thyroxine;
dosage will also vary depending on age and weight. Infants and
children require more T4 per kilogram of body weight than
adults. The average dosage for an infant 1–6 months of age is
10–15 mcg/kg per day, whereas the average dosage for an adult
is about 1.7 mcg/kg per day (0.8 mcg/lb per day ) or 125 mcg/d.
Older adults (>65 years of age) may require less thyroxine
(1.6 mcg/kg per day or 0.7 mcg/lb per day ) for replacement as
body mass declines. In patients requiring suppression therapy
post-thyroidectomy for thyroid cancer, the average daily dosage of
T4 is 2.2 mcg/kg or 1 mcg/lb. Higher thyroxine requirements have
also been reported in patients with celiac disease and Helicobacter
pylori gastritis; thyroxine doses may be lower following treatment.
Goiter Degree of Hypothyroidism
Present early, absent later Mild to severe
Present Mild to moderate
Present Mild to severe
Absent Severe
Absent or present Severe
Absent Mild

Since interactions with certain foods (eg, bran, soy, coffee) and
drugs (Table 38–3) can impair its absorption, thyroxine should be
administered on an empty stomach (eg, 60 minutes before meals,
4 hours after meals, or at bedtime) to maintain TSH within an
optimal range of 0.5–2.5 mIU/L. Its long half-life of 7 days per-
mits once-daily dosing. Children should be monitored for normal
growth and development. Serum TSH and free thyroxine should
always be measured before a change in dosage to avoid transient
serum alterations. It takes 6–8 weeks after starting a given dose of
thyroxine to reach steady-state levels in the bloodstream. Thus,
dosage changes should be made slowly.
In younger patients or those with very mild disease, full
replacement therapy may be started immediately. In older patients
(>50 years) without cardiac disease, levothyroxine can be started
at a dosage of 50 mcg/d. In long-standing hypothyroidism and in
older patients with underlying cardiac disease, it is imperative to
start with reduced dosages of levothyroxine, 12.5–25 mcg/d for
2 weeks, before increasing by 12.5–25 mcg/d every 2 weeks until
euthyroidism or drug toxicity is observed. In cardiac patients, the
heart is very sensitive to the level of circulating thyroxine, and if
angina pectoris or cardiac arrhythmia develops, it is essential to
stop or reduce the thyroxine dosage immediately.
Thyroxine toxicity is directly related to the hormone level. In
children, restlessness, insomnia, and accelerated bone maturation
and growth may be signs of thyroxine toxicity. In adults, increased
nervousness, heat intolerance, episodes of palpitation and tachycar-
dia, or unexplained weight loss may be the presenting symptoms.
If these symptoms are present, it is important to monitor serum
TSH and FT4 levels (Table 38–2), which will determine whether
the symptoms are due to excess thyroxine blood levels. Chronic
overtreatment with T4, particularly in elderly patients, can increase
the risk of atrial fibrillation and accelerated osteoporosis.
Special Problems in Management of
Hypothyroidism
A. Myxedema and Coronary Artery Disease
Since myxedema frequently occurs in older persons, it is often
associated with underlying coronary artery disease. In this situa-
tion, the low levels of circulating thyroid hormone actually protect
the heart against increasing demands that could result in angina
pectoris, atrial fibrillation, or myocardial infarction. Correction
of myxedema must be done cautiously to avoid provoking these
cardiac events. If coronary artery surgery is indicated, it should
be done first, prior to correction of the myxedema by thyroxine
administration.
B. Myxedema Coma
Myxedema coma is an end state of untreated hypothyroidism.
It is associated with progressive weakness, stupor, hypothermia,
hypoventilation, hypoglycemia, hyponatremia, water intoxication,
shock, and death.
Myxedema coma is a medical emergency. The patient should
be treated in the intensive care unit, since tracheal intubation and
mechanical ventilation may be required. Associated illnesses such
as infection or heart failure must be treated by appropriate therapy.
CHAPTER 38  Thyroid & Antithyroid Drugs    697
It is important to give all preparations intravenously, because
patients with myxedema coma absorb drugs poorly from other
routes. Intravenous fluids should be administered with caution
to avoid excessive water intake. These patients have large pools of
empty T3 and T4 binding sites that must be filled before there is
adequate free thyroxine to affect tissue metabolism. Accordingly,
the treatment of choice in myxedema coma is to give a loading
dose of levothyroxine intravenously—usually 300–400 mcg ini-
tially, followed by 50–100 mcg daily. Intravenous T3 5–20 mcg
initially, followed by 2.5–10 mcg every 8 hours also can be added
but may be more cardiotoxic and more difficult to monitor. Lower
T4 and T3 doses should be considered for smaller or older patients,
or those with concomitant cardiac disease or arrhythmias. Intra-
venous hydrocortisone is indicated if the patient has associated
adrenal or pituitary insufficiency but is probably not necessary
in most patients with primary myxedema. Opioids and sedatives
must be used with extreme caution.
C. Hypothyroidism and Pregnancy
Hypothyroid women frequently have anovulatory cycles and are
therefore relatively infertile until restoration of the euthyroid state.
This has led to the widespread use of thyroid hormone for infer-
tility, although there is no evidence for its usefulness in infertile
euthyroid patients. In a pregnant hypothyroid patient receiving
thyroxine, it is extremely important that the daily dose of thy-
roxine be adequate because early development of the fetal brain
depends on maternal thyroxine. In many hypothyroid patients,
an increase in the thyroxine dose (about 25–30%) is required to
normalize the serum TSH level during pregnancy. It is reason-
able to counsel women to take one extra dose of their current
thyroxine tablet twice a week separated by several days as soon as
they are pregnant. Thyroxine should also be administered apart
from prenatal vitamins and calcium by at least 4 hours. Because
of the elevated maternal TBG levels and, therefore, elevated total
T4 levels, adequate maternal thyroxine dosages warrant mainte-
nance of TSH between 0.1 and 3.0 mIU/L (eg, first trimester,
0.1–2.5 mIU/L; second trimester, 0.2–3.0 mIU/L; third trimester,
0.3–3.0 mIU/L) and the total T4 at or above the upper range of
normal.
D. Subclinical Hypothyroidism
Subclinical hypothyroidism, defined as an elevated TSH level and
normal thyroid hormone levels, occurs in 4–10% of the general
population and increases to 20% in women older than age 50.
Levothyroxine should be individualized based on the risks and
benefits of treatment. The consensus of expert thyroid organiza-
tions concluded that thyroid hormone therapy should be consid-
ered for patients with TSH levels greater than 10 mIU/L while
close TSH monitoring is appropriate for those with lower TSH
elevations.
E. Drug-Induced Hypothyroidism
Drug-induced hypothyroidism (Table 38–3) can be satisfactorily
managed with levothyroxine therapy if the offending agent cannot
be stopped. In the case of amiodarone-induced hypothyroidism,
698    SECTION VII  Endocrine Drugs
levothyroxine therapy may be necessary even after discontinuance
because of amiodarone’s very long half-life.
HYPERTHYROIDISM
Hyperthyroidism (thyrotoxicosis) is the clinical syndrome that
results when tissues are exposed to high levels of thyroid hormone
(Table 38–4).
GRAVES’ DISEASE
The most common form of hyperthyroidism is Graves’ disease, or
diffuse toxic goiter. The presenting signs and symptoms of Graves’
disease are set forth in Table 38–4.
Pathophysiology
Graves’ disease is considered to be an autoimmune disorder in
which a defect in suppressor T lymphocytes stimulates B lym-
phocytes to synthesize antibodies (TSH-R Ab [stim]) to thyroidal
antigens. The TSH-R Ab [stim] is directed against the TSH
receptor in the thyroid cell membrane and stimulates growth and
biosynthetic activity of the thyroid cell. Genetics, the postpartum
state, cigarette smoking, and physical and emotional stress increase
TSH-R Ab [stim] development. A genetic predisposition is shown
by a high frequency of HLA-B8 and HLA-DR3 in Caucasians,
HLA-Bw46 and HLA-B5 in Chinese, and HLA-B17 in African
Americans. Spontaneous remission occurs but some patients
require years of antithyroid therapy.
Laboratory Diagnosis
In most patients with hyperthyroidism, T3, T4, FT4, and FT3 are
elevated and TSH is suppressed (Table 38–2). Radioiodine uptake
is usually markedly elevated as well. Antithyroglobulin, thyroid
peroxidase, and TSH-R Ab [stim] antibodies are usually present.
Management of Graves’ Disease
The three primary methods for controlling hyperthyroidism are
antithyroid drug therapy, destruction of the gland with radioactive
iodine, and surgical thyroidectomy. None of these methods alters
the underlying pathogenesis of the disease.
A. Antithyroid Drug Therapy
Drug therapy is most useful in young patients with small glands
and mild disease. Methimazole (preferred) or propylthiouracil
is administered until the disease undergoes spontaneous remis-
sion. This is the only therapy that leaves an intact thyroid gland,
but it does require a long period of treatment and observation
(12–18 months), and there is a 50–60% incidence of relapse.
Methimazole is preferable to propylthiouracil (except in preg-
nancy and thyroid storm) because it has a lower risk of serious liver
injury and can be administered once daily, which may improve
adherence. Antithyroid drug therapy is usually begun with divided
doses, shifting to maintenance therapy with single daily doses
when the patient becomes clinically euthyroid. However, mild
to moderately severe thyrotoxicosis can often be controlled with
methimazole given in a single morning dose of 20–40 mg initially
for 4–8 weeks to normalize hormone levels. Maintenance therapy
requires 5–15 mg once daily. Alternatively, therapy is started
with propylthiouracil, 100–150 mg every 6 or 8 hours until the
patient is euthyroid, followed by gradual reduction of the dose to
the maintenance level of 50–150 mg once daily. In addition to
inhibiting iodine organification, propylthiouracil also inhibits the
conversion of T4 to T3, so it brings the level of activated thyroid
hormone down more quickly than does methimazole. The best
clinical guide to remission is reduction in the size of the goiter.
Laboratory tests most useful in monitoring the course of therapy
are serum FT3, FT4, and TSH levels.
Reactions to antithyroid drugs have been described above.
A minor rash can often be controlled by antihistamine therapy.
Because the more severe reaction of agranulocytosis is often her-
alded by sore throat or high fever, patients receiving antithyroid
drugs must be instructed to discontinue the drug and seek imme-
diate medical attention if these symptoms develop. White cell and
differential counts and a throat culture are indicated in such cases,
followed by appropriate antibiotic therapy. Treatment should also
be stopped if significant elevations in transaminases (two to three
times the upper limit of normal) occur.
B. Thyroidectomy
A near-total thyroidectomy is the treatment of choice for patients
with very large glands or multinodular goiters. Patients are treated
with antithyroid drugs until euthyroid (about 6 weeks). In addi-
tion, for 10–14 days prior to surgery, they receive saturated
solution of potassium iodide, 5 drops twice daily, to diminish
vascularity of the gland and simplify surgery. About 80–90% of
patients will require thyroid supplementation following near-total
thyroidectomy.
C. Radioactive Iodine
Radioiodine therapy (RAI) utilizing 131I is the preferred treat-
ment for most patients over 21 years of age. In patients without
heart disease, the therapeutic dose may be given immediately in
a range of 80–120 μCi/g of estimated thyroid weight corrected
for uptake. In patients with underlying heart disease or severe
thyrotoxicosis and in elderly patients, it is desirable to treat with
antithyroid drugs (preferably methimazole) until the patient is
euthyroid. The medication is stopped for 2 to 3 days before RAI
is administered so as not to interfere with RAI retention but
can be restarted 3–5 days later, and then gradually tapered over
4–6 weeks as thyroid function normalizes. Iodides should be
avoided to ensure maximal 131I uptake. Six to 12 weeks following
the administration of RAI, the gland will shrink in size and the
patient will usually become euthyroid or hypothyroid. A second
dose may be required if there is minimal response 3 months post-
RAI. Hypothyroidism occurs in about 80% of patients following
RAI. Serum FT4 and TSH levels should be monitored regularly.
When hypothyroidism develops, prompt replacement with oral
levothyroxine, 50–150 mcg daily, should be instituted.

D. Adjuncts to Antithyroid Therapy
During the acute phase of thyrotoxicosis, β-adrenoceptor–blocking
agents without intrinsic sympathomimetic activity are appropriate
in symptomatic patients aged 60 years or more, in those with heart
rates greater than 90 beats/min, and in those with cardiovascular
disease. Propranolol, 20–40 mg orally every 6 hours, or metopro-
lol, 25–50 mg orally every 6–8 hours, will control tachycardia,
hypertension, and atrial fibrillation. Beta-adrenoceptor–blocking
agents are gradually withdrawn as serum thyroxine levels return
to normal. Diltiazem, 90–120 mg three or four times daily, can
be used to control tachycardia in patients in whom β blockers are
contraindicated, eg, those with asthma. Dihydropyridine calcium
channel blockers may not be as effective as diltiazem or vera-
pamil. Adequate nutrition and vitamin supplements are essential.
Barbiturates accelerate T4 breakdown (by hepatic enzyme induc-
tion) and may be helpful both as sedatives and to lower T4 levels.
Bile acid sequestrants (eg, cholestyramine) can also rapidly lower
T4 levels by increasing the fecal excretion of T4.
TOXIC UNINODULAR GOITER & TOXIC
MULTINODULAR GOITER
These forms of hyperthyroidism occur often in older women
with nodular goiters. Free thyroxine is moderately elevated or
occasionally normal, but FT3 or T3 is strikingly elevated. Single
toxic adenomas can be managed with either surgical excision of
the adenoma or with radioiodine therapy. Toxic multinodular
goiter is usually associated with a large goiter and is best treated
by preparation with methimazole (preferable) or propylthiouracil
followed by subtotal thyroidectomy.
SUBACUTE THYROIDITIS
During the acute phase of a viral infection of the thyroid
gland, there is destruction of thyroid parenchyma with transient
release of stored thyroid hormones. A similar state may occur in
patients with Hashimoto’s thyroiditis. These episodes of transient
thyrotoxicosis have been termed spontaneously resolving hyperthy-
roidism. Supportive therapy is usually all that is necessary, such
as β-adrenoceptor–blocking agents without intrinsic sympatho-
mimetic activity (eg, propranolol) for tachycardia and aspirin or
nonsteroidal anti-inflammatory drugs to control local pain and
fever. Corticosteroids may be necessary in severe cases to control
the inflammation.
SPECIAL PROBLEMS
Thyroid Storm
Thyroid storm, or thyrotoxic crisis, is sudden acute exacerba-
tion of all of the symptoms of thyrotoxicosis, presenting as a
life-threatening syndrome. Vigorous management is mandatory.
Propranolol, 60–80 mg orally every 4 hours, or intravenous pro-
pranolol, 1–2 mg slowly every 5–10 minutes to a total of 10 mg,
CHAPTER 38  Thyroid & Antithyroid Drugs    699
or esmolol, 50–100 mg/kg per min, is helpful to control the severe
cardiovascular manifestations. If β blockers are contraindicated by
the presence of severe heart failure or asthma, hypertension and
tachycardia may be controlled with diltiazem, 90–120 mg orally
three or four times daily or 5–10 mg/h by intravenous infusion
(asthmatic patients only). Release of thyroid hormones from the
gland is retarded by the administration of saturated solution of
potassium iodide, 5 drops orally every 6 hours starting 1 hour
after giving thioamides. Hormone synthesis is blocked by the
administration of propylthiouracil, 500–1000 mg as a loading
dose, followed by 250 mg orally every 4 hours. If the patient is
*
unable to take propylthiouracil by mouth, a rectal formulation
can be prepared and administered in a dosage of 400 mg every
6 hours as a retention enema. Methimazole may also be pre-
pared for rectal administration in a dose of 60–80 mg daily.
Hydrocortisone, 50 mg intravenously every 6 hours, will pro-
tect the patient against shock and will block the conversion of
T4 to T3, rapidly reducing the level of thyroactive material in
the blood.
Supportive therapy is essential to control fever, heart failure,
and any underlying disease process that may have precipitated the
acute storm. In rare situations, where the above methods are not
adequate to control the problem, oral bile acid sequestrants (eg,
cholestyramine), plasmapheresis, or peritoneal dialysis has been
used to lower the levels of circulating thyroxine.
Ophthalmopathy
Although severe ophthalmopathy is rare, it is difficult to treat. A
15–20% risk of aggravating severe eye disease may occur follow-
ing RAI, especially in those who smoke. Management requires
effective treatment of the thyroid disease, usually by total surgical
excision or 131I ablation of the gland plus oral prednisone therapy
(see below). In addition, local therapy may be necessary, eg,
elevation of the head to diminish periorbital edema and artificial
tears to relieve corneal drying due to exophthalmos. Smoking
cessation should be advised to prevent progression of the ophthal-
mopathy. For the severe, acute inflammatory reaction, prednisone,
60–100 mg orally daily for about a week and then 60–100 mg
every other day, tapering the dose over 6–12 weeks, may be effec-
tive. If steroid therapy fails or is contraindicated, irradiation
of the posterior orbit, using well-collimated high-energy X-ray
therapy, will frequently result in marked improvement of the
acute process. Threatened loss of vision is an indication for sur-
gical decompression of the orbit. Eyelid or eye muscle surgery
may be necessary to correct residual problems after the acute
process has subsided.
Dermopathy
Dermopathy or pretibial myxedema will often respond to topical
corticosteroids applied to the involved area and covered with an
occlusive dressing.
*
To prepare a water suspension propylthiouracil enema, grind eight
50-mg tablets and suspend the powder in 90 mL of sterile water.
700    SECTION VII  Endocrine Drugs
Thyrotoxicosis During Pregnancy
Ideally, women in the childbearing period with severe dis-
ease should have definitive therapy with 131I or subtotal thyroid-
ectomy prior to pregnancy in order to avoid an acute exacerbation
of the disease during pregnancy or following delivery. If thyro-
toxicosis does develop during pregnancy, RAI is contraindicated
because it crosses the placenta and may injure the fetal thyroid.
Propylthiouracil (fewer teratogenic risks than methimazole) can
be given in the first trimester, and then methimazole can be given
for the remainder of the pregnancy in order to avoid potential liver
damage. The dosage of propylthiouracil must be kept to the mini-
mum necessary for control of the disease (ie, <300 mg/d), because
it may affect the function of the fetal thyroid gland. Alternatively,
a subtotal thyroidectomy can be safely performed during the mid
trimester. It is essential to give the patient a thyroid supplement
during the balance of the pregnancy.
Neonatal Graves’ Disease
Graves’ disease may occur in the newborn infant, due either to pas-
sage of maternal TSH-R Ab [stim] through the placenta, stimulat-
ing the thyroid gland of the neonate, or to genetic transmission of
the trait to the fetus. Laboratory studies reveal an elevated free T4,
a markedly elevated T3, and a low TSH—in contrast to the normal
infant, in whom TSH is elevated at birth. TSH-R Ab [stim] is
usually found in the serum of both the child and the mother.
If caused by maternal TSH-R Ab [stim], the disease is usually
self-limited and subsides over a period of 4–12 weeks, coincid-
ing with the fall in the infant’s TSH-R Ab [stim] level. However,
treatment is necessary because of the severe metabolic stress the
infant experiences. Therapy includes propylthiouracil at a dosage
of 5–10 mg/kg daily in divided doses at 8-hour intervals; Lugol’s
solution (8 mg of iodide per drop), 1 drop every 8 hours; and
propranolol, 2 mg/kg daily in divided doses. Careful supportive
therapy is essential. If the infant is very ill, oral prednisone, 2 mg/
kg daily in divided doses, will help block conversion of T4 to T3.
These medications are gradually reduced as the clinical picture
improves and can be discontinued by 6–12 weeks.
SUBCLINICAL HYPERTHYROIDISM
Subclinical hyperthyroidism is defined as a suppressed TSH level
(below the normal range) in conjunction with normal thyroid
hormone levels. Cardiac toxicity (eg, atrial fibrillation), especially
in older persons and those with underlying cardiac disease, is of
greatest concern. The consensus of thyroid experts concluded
that hyperthyroidism treatment is appropriate in those with TSH
less than 0.1 mIU/L, while close monitoring of the TSH level is
appropriate for those with less TSH suppression.
Amiodarone-Induced Thyrotoxicosis
In addition to those patients who develop hypothyroidism caused
by amiodarone, approximately 3% of patients receiving this drug
will develop hyperthyroidism instead. Two types of amiodarone-
induced thyrotoxicosis have been reported: iodine-induced (type I),
which often occurs in persons with underlying thyroid disease (eg,
multinodular goiter, Graves’ disease); and an inflammatory thyroid-
itis (type II) that occurs in patients without thyroid disease due to
leakage of thyroid hormone into the circulation. Treatment of type I
requires therapy with thioamides, while type II responds best to glu-
cocorticoids. Since it is not always possible to differentiate between
the two types, thioamides and glucocorticoids are often admin-
istered together. If possible, amiodarone should be discontinued;
however, rapid improvement does not occur due to its long half-life.
NONTOXIC GOITER
Nontoxic goiter is a syndrome of thyroid enlargement without
excessive thyroid hormone production. Enlargement of the
thyroid gland is often due to TSH stimulation from inadequate
thyroid hormone synthesis. The most common cause of nontoxic
goiter worldwide is iodide deficiency, but in the United States,
it is Hashimoto’s thyroiditis. Other causes include germ-line
or acquired mutations in genes involved in hormone synthesis,
dietary goitrogens, and neoplasms (see below).
Goiter due to iodide deficiency is best managed by prophy-
lactic administration of iodide. The optimal daily iodide intake
is 150–200 mcg. Iodized salt and iodate used as preservatives in
flour and bread are excellent sources of iodine in the diet. In areas
where it is difficult to introduce iodized salt or iodate preserva-
tives, a solution of iodized poppy-seed oil has been administered
intramuscularly to provide a long-term source of inorganic iodine.
Goiter due to ingestion of goitrogens in the diet is managed by
elimination of the goitrogen or by adding sufficient thyroxine to
shut off TSH stimulation. Similarly, in Hashimoto’s thyroiditis and
dyshormonogenesis, adequate thyroxine therapy—150–200 mcg/d
orally—will suppress pituitary TSH and result in slow regression of
the goiter as well as correction of hypothyroidism.
THYROID NEOPLASMS
Neoplasms of the thyroid gland may be benign (adenomas) or
malignant. The primary diagnostic test is a fine needle aspira-
tion biopsy and cytologic examination. Benign lesions may be
monitored for growth or symptoms of local obstruction, which
would mandate surgical excision. Levothyroxine therapy is not
recommended for the suppression of benign nodules, especially
in iodine sufficient areas. Management of thyroid carcinoma
requires a total thyroidectomy, postoperative radioiodine therapy
in selected instances, and lifetime replacement with levothyroxine.
The evaluation for recurrence of some thyroid malignancies often
involves withdrawal of thyroxine replacement for 4–6 weeks—
accompanied by the development of hypothyroidism. Tumor
recurrence is likely if there is a rise in serum thyroglobulin (ie, a
tumor marker) or a positive 131I scan when TSH is elevated. Alter-
natively, administration of recombinant human TSH (Thyrogen)
can produce comparable TSH elevations without discontinuing
thyroxine and avoiding hypothyroidism. Recombinant human
TSH is administered intramuscularly once daily for 2 days. A
rise in serum thyroglobulin or a positive 131I scan will indicate a
recurrence of the thyroid cancer.
 CHAPTER 38  Thyroid & Antithyroid Drugs    701

SUMMARY Drugs Used in the Management of Thyroid Disease

Mechanism of Action Pharmacokinetics, Toxicities,
Subclass, Drug and Effects Indications Interactions

THYROID PREPARATIONS      
•  Levothyroxine (T4) Activation of nuclear receptors Hypothyroidism See Table 38–1 • maximum effect seen
•  Liothyronine (T3) results in gene expression with RNA after 6–8 weeks of therapy • Toxicity: See
formation and protein synthesis Table 38–4 for symptoms of thyroid excess

ANTITHYROID AGENTS      
THIOAMIDES      
•  Methimazole Inhibit thyroid peroxidase reactions Hyperthyroidism Oral • duration of action: 24 h
•  Propylthiouracil (PTU) • block iodine organification • inhibit (methimazole), 6–8 h (PTU) • delayed onset
peripheral deiodination of T4 and T3 of action • Toxicity: Nausea, gastrointestinal
(primarily PTU) distress, rash, agranulocytosis, hepatitis
(PTU black box), hypothyroidism

IODIDES
•  Lugol’s solution Inhibit organification and hormone Preparation for surgical thyroidectomy Oral • acute onset within 2–7 days • Toxicity:
•  Potassium iodide release • reduce the size and Rare (see text)
vascularity of the gland

BETA BLOCKERS
•  Propranolol, other β blockers Inhibition of β adrenoreceptors Hyperthyroidism, especially thyroid Onset within hours • duration of 4–6 h (oral
lacking partial agonist activity • inhibit T4 to T3 conversion (only storm • adjunct to control tachycardia, propranolol) • Toxicity: Asthma, AV
propranolol) hypertension, and atrial fibrillation blockade, hypotension, bradycardia

RADIOACTIVE IODINE 131I (RAI)      

  Radiation destruction of thyroid Hyperthyroidism • patients should be Oral • half-life 5 days • onset in 6–12 weeks
parenchyma euthyroid or on β blockers before • maximum effect in 3–6 months • Toxicity:
RAI • avoid in pregnancy and in Sore throat, sialitis, hypothyroidism
nursing mothers

P R E P A R A T I O N S REFERENCES
A V A I L A B L E General
American Thyroid Association: Professional Guidelines. Available at: www.thyroid.
GENERIC NAME AVAILABLE AS org/professionals/ata-professional-guidelines/.
THYROID AGENTS American Thyroid Association Task Force on Radiation Safety et al: Radiation
safety in the treatment of patients with thyroid diseases by radioiodine 131I:
Levothyroxine (T4) Generic, Levoxyl, Levo-T, Practice recommendations of the American Thyroid Association. Thyroid
Levothroid, Levolet*, 2011;21:335.
Novothyrox, Synthroid,
Chen AY et al: American Thyroid Association Statement on Optimal Surgical
Tirosint (capsule), Unithroid Management of Goiter. Thyroid 2014;24:181.
Liothyronine (T3) Generic, Cytomel, Triostat (IV) Cooper DS, Ladenson PW: The thyroid gland. In: Gardner DG, Shoback D (editors):
Liotrix (a 4:1 ratio of T4: T3) Thyrolar Greenspan’s Basic & Clinical Endocrinology, 9th ed. McGraw-Hill, 2011.
Thyroid desiccated (USP) Generic, Armour, Nature- Haugen BR et al: 2015 American Thyroid Association Management Guidelines
Throid, Westhroid for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer:
The American Thyroid Association Guidelines Task Force on Thyroid
ANTITHYROID AGENTS Nodules and Differentiated Thyroid Cancer. Thyroid 2016;26:1.
Radioactive iodine (131I) sodium Iodotope, Sodium Iodide Rugge JB, Bougatsos C, Chou R: Screening and treatment of thyroid dysfunction:
I 131 Therapeutic An evidence review for the U.S. Preventive Services Task Force. Ann Intern
Methimazole Generic, Tapazole Med. 2015;162:35.
Potassium iodide   U.S. Department of Health and Human Services: Potassium iodide as a
thyroid blocking agent in radiation emergencies. Available at: www.fda.
  Oral solution (SSKI) ThyroShield
gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
  Oral solution (Lugol’s solution) Lugol’s solution UCM080542.pdf.
  Oral potassium iodide tablets IOSAT, Thyro-Block, Thyro-Safe
Propylthiouracil [PTU] Generic Thyroid Hormone Action
DIAGNOSTIC AGENT
Chatterjee VK et al: Thyroid in 2012: Advances in thyroid development, hormone
Thyrotropin; recombinant human TSH Thyrogen action and neoplasia. Nat Rev Endocrinol 2013;9:74.
* Galli E, Pingitore A, Iervasi G: The role of thyroid hormone in the pathophysiology
Not available in United States.
of heart failure: Clinical evidence. Heart Fail Rev 2010;15:155.
702    SECTION VII  Endocrine Drugs
Lin JZ et al: Gene specific actions of thyroid hormone receptor subtypes. PLoS
One 2013;8:e52407.
Porcu E et al: A meta-analysis of thyroid-related traits reveals novel loci and
gender-specific differences in the regulation of thyroid function. PLoS Genet
2013;9:e1003266.
Taylor PN, Peeters R, Dayan CM. Genetic abnormalities in thyroid hormone
deiodinases. Curr Opin Endocrinol Diabetes Obes 2015;22:402.
Warner A, Mittag J. Thyroid hormone and the central control of homeostasis.
J Mol Endocrinol 2012;49:R29.
Management of Hypothyroidism
Cappola AR: Levothyroxine prescription not as simple as it seems. JAMA Intern
Med. 2014;174:32.
Escobar-Morreale HF et al: Treatment of hypothyroidism with levothyroxine or a
combination of levothyroxine plus L-triiodothyronine. Best Pract Res Clin
Endocrinol Metab. 2015;29:57.
Gereben B et al: Scope and limitations of iodothyronine deiodinases in hypothy-
roidism. Nat. Rev Endocrinol 2015;11:642.
Jonklaas B et al: American Thyroid Association Task Force on Thyroid Hormone
Replacement: Guidelines for the Treatment of Hypothyroidism. Thyroid
2014;24:1670.
Visser WE et al: Different causes of reduced sensitivity to thyroid hormone:
Diagnosis and clinical management. Clin Endocrinol (Oxf ) 2013;79:595.
Wiersinga WM: Paradigm shifts in thyroid hormone replacement therapies for
hypothyroidism. Nat Rev Endocrinol 2014;10:164.
Subclinical Hypothyroidism and Hyperthyroidism
Blum MR et al: Subclinical thyroid dysfunction and fracture risk: A meta-analysis.
JAMA 2015;313:2055.
Burns RB et al: Should we treat for subclinical hypothyroidism? Grand rounds
discussion from Beth Israel Deaconess Medical Center. Ann Intern Med
2016;164:764.
Hennessey JV, Espaillat R: Diagnosis and management of subclinical hypo-
thyroidism in elderly adults: A review of the literature. J Am Geriatr Soc
2015;63:1663.
Javed Z, Sathyapalan T: Levothyroxine treatment of mild subclinical hypothyroid-
ism: A review of potential risks and benefits. Ther Adv Endocrinol Metab
2016;7:12.
Pasqualetti G et al: Subclinical hypothyroidism and cognitive impair-
ment: Systematic review and meta-analysis. J Clin Endocrinol Metab
2015;100:4240.
C ASE STUDY ANSWER
The initial methimazole treatment was appropriate and
preferable to propylthiouracil because of its longer duration
of action allowing once daily dosing and its improved safety
profile. JP presents with the typical signs and symptoms
of hypothyroidism following RAI despite levothyroxine
replacement. Either radioactive iodine or thyroidectomy
are reasonable and effective strategies for definitive treat-
ment of her hyperthyroidism, especially before becoming
pregnant to avoid an acute hyperthyroid exacerbation
during pregnancy or following delivery. Her hypothy-
roid symptoms should have been easily corrected by the
addition of levothyroxine dosed correctly at 1.7 mcg/kg/
day or 100 mcg daily. Because she is young and has no
cardiac disease, full replacement doses were appropriate
Antithyroid Agents and Management of Hyperthyroidism
Akmal A, Kung J: Propylthiouracil, and methimazole, and carbimazole-related
hepatotoxicity. Expert Opin Drug Saf 2014;13:1397.
Bartalena L et al: Management of hyperthyroidism due to Graves’ disease: frequently
asked questions and answers (if any). J Endocrinol Invest 2016;39:1105.
Burch HB, Cooper DS. Management of Graves disease: A review. JAMA
2015;314:2544.
Chiha M, Samarasinghe S, Kabaker AS: Thyroid storm: An updated review.
J Intensive Care Med 2015;30:131
Ma C et al: Radioiodine therapy versus antithyroid medications for Graves’ disease.
Cochrane Database Syst Rev 2016;2:CD010094.
Ross DS et al: 2016 American Thyroid Association Guidelines for Diagnosis and
Management of Hyperthyroidism and Other Causes of Thyrotoxicosis.
Thyroid 2016;26:1343.
Sundaraesh V et al: Comparative effectiveness of therapies for Graves’ hyperthy-
roidism: A systematic review and network meta-analysis. J Clin Endocrinol
Metab 2013;98:367.
Pregnancy
Pearce EN: Thyroid disorders during pregnancy and postpartum. Best Pract Res
Clin Obstet Gynaecol 2015;29:700.
Stagnaro-Green A et al: Guidelines of the American Thyroid Association for the
Diagnosis and Management of Thyroid Disease During Pregnancy and
Postpartum. Thyroid 2011;21:1081.
The Effects of Drugs on Thyroid Function
Danzi S, Klein I: Amiodarone induced thyroid dysfunction. J Intensive Care Med
2015;30:179.
Fallahi P et al: Thyroid dysfunctions induced by tyrosine kinase inhibitors. Expert
Opin Drug Saf 2014;13:723.
Hamed SA: The effect of antiepileptic drugs on thyroid hormonal function:
Causes and implications, Expert Rev Clin Pharmacol 2015:8:741.
Haugen BR: Drugs that suppress TSH or cause central hypothyroidism. Best Pract
Res Clin Endocrinol Metab 2009;23:793.
Kibirige D et al: Spectrum of lithium induced thyroid abnormalities: A current
perspective. Thyroid Res 2013;6:3.
Kundra P, Burman KD: The effect of medications on thyroid function tests. Med
Clin North Am 2012;96:283.
Zimmermann MB, Boelaert K: Iodine deficiency and thyroid disorders. Lancet
Diabetes Endocrinol 2015;3:286.
to start. However, her elevated TSH level indicates inad-
equate levothyroxine replacement which may be related
to nonadherence, or concomitant calcium and omeprazole
co-administration. For optimal absorption, levothyroxine
should be taken orally 60 minutes before meals on an
empty stomach or at bedtime, and separated by 4 hours
from her calcium administration. Lower thyroxine doses
may also be sufficient if her omeprazole is stopped. Once
weekly thyroxine injections may be effective in those with
ongoing nonadherence. Thyroid function tests should be
monitored after 6–8 weeks of therapy, obtained before
thyroxine administration to avoid transient hormone alter-
ations, and the dosage adjusted to achieve a normal TSH
level and resolution of hypothyroid symptoms.

Adrenocorticosteroids
& Adrenocortical
Antagonists
George P. Chrousos, MD
C ASE STUDY
A 19-year-old man complains of anorexia, fatigue, dizziness,
and weight loss of 8 months’ duration. The examining
physician discovers postural hypotension and moderate
vitiligo (depigmented areas of skin) and obtains routine blood
tests. She finds hyponatremia, hyperkalemia, and acidosis and
suspects Addison’s disease. She performs a standard ACTH
The natural adrenocortical hormones are steroid molecules
produced and released by the adrenal cortex. Deficiency of
the adrenocortical hormones results in the signs and symp-
toms of Addison’s disease. Excess production causes Cushing’s
syndrome. Both natural and synthetic corticosteroids are used for
the diagnosis and treatment of disorders of adrenal function. They
are also used—more often and in much larger doses—for treat-
ment of a variety of inflammatory and immunologic disorders.
Secretion of adrenocortical steroids, especially the glucocor-
ticoids, is controlled by the pituitary release of corticotropin
(ACTH) (see Chapter 37). Corticotropin is derived from a larger
protein synthesized in the pituitary, pro-opiomelanocortin
(POMC). Secretion of the salt-retaining hormone aldosterone
is primarily under the influence of circulating angiotensin and
potassium. Corticotropin has some actions that do not depend on
its effect on adrenocortical secretion. However, its pharmacologic
value as an anti-inflammatory agent and its use in testing adre-
nal function depend on its secretory action. Its pharmacology is
reviewed only briefly here.
Inhibitors of the synthesis or antagonists of the action of the
adrenocortical steroids are important in the treatment of several
conditions. These agents are described at the end of this chapter.
39
C H A P T E R
1–24 stimulation test, which reveals an insufficient plasma
cortisol response compatible with primary adrenal insuf-
ficiency. The diagnosis of autoimmune Addison’s disease is
made, and the patient must start replacement of the hormones
he cannot produce himself. How should this patient be
treated? What precautions should he take?
■■ ADRENOCORTICOSTEROIDS
The adrenal cortex releases a large number of steroids into the
circulation. Some have minimal biologic activity and func-
tion primarily as precursors, and there are some for which no
function has been established. The hormonal steroids may be
classified as those having important effects on intermediary
metabolism and immune function (glucocorticoids), those
having principally salt-retaining activity (mineralocorticoids),
and those having androgenic or estrogenic activity (see
Chapter 40). In humans, the major glucocorticoid is cortisol
and the most important mineralocorticoid is aldosterone.
Quantitatively, dehydroepiandrosterone (DHEA) in its sulfated
form (DHEAS) is the major adrenal androgen. However,
DHEA and two other adrenal androgens, androstenedione
and androstenediol, are weak androgens and androstenediol is
a potent estrogen. Androstenedione can be converted to tes-
tosterone and estradiol in extra-adrenal tissues (Figure 39–1).
Adrenal androgens constitute the major endogenous precursors
of estrogen in women after menopause and in younger patients
in whom ovarian function is deficient or absent.
703
704    SECTION VII  Endocrine Drugs

17α-Hydroxylase 17, 20-Lyase

CH3 (P450c17) CH3
Acetate
C O C O O
Cholesterol OH
(ACTH?)
NADPH
O2

Pregnenolone 17-Hydroxy- Dehydroepi-

pregnenolone androsterone
HO HO HO
CH3 CH3
3β-Dehydrogenase
∆5,∆4-Isomerase C O C O O
NAD+ OH

Progesterone 17-Hydroxy- ∆4-Androstene-

progesterone 3,17-dione
O O O
CH2OH CH2OH
21α-Hydroxylase
C O C O
(P450c21)
OH

Testosterone

11-Deoxy-
11β-Deoxycortisol
corticosterone
O O
CH2OH CH2OH

11β-Hydroxylase C O C O Estradiol
(P450c11)
HO HO OH

CH2OH

C O Corticosterone Cortisol
CHO O O
HO

Aldosterone
O

Mineralocorticoid Glucocorticoid Androgen and

pathway pathway estrogen pathway

FIGURE 39–1  Outline of major pathways in adrenocortical hormone biosynthesis. The major secretory products are underlined. Pregneno-
lone is the major precursor of corticosterone and aldosterone, and 17-hydroxypregnenolone is the major precursor of cortisol. The enzymes and
cofactors for the reactions progressing down each column are shown on the left and across columns at the top of the figure. When a particular
enzyme is deficient, hormone production is blocked at the points indicated by the shaded bars. (Reproduced, with permission, from Ganong WF: Review
of Medical Physiology, 22nd ed. McGraw-Hill, 2005. Copyright © The McGraw-Hill Companies, Inc.)

THE NATURALLY OCCURRING system, which is very sensitive to negative feedback by the circu-
lating cortisol and exogenous (synthetic) glucocorticoids. Cortisol
GLUCOCORTICOIDS; CORTISOL is synthesized from cholesterol (as shown in Figure 39–1). The
(HYDROCORTISONE) mechanisms controlling its secretion are discussed in Chapter 37.
The rate of secretion follows a circadian rhythm (Figure 39–2)
Pharmacokinetics governed by pulses of ACTH that peak in the early morning hours
Cortisol (also called hydrocortisone, compound F) exerts a wide and after meals. In plasma, cortisol is bound to circulating pro-
range of physiologic effects, including regulation of intermediary teins. Corticosteroid-binding globulin (CBG), an α2 globulin
metabolism, cardiovascular function, growth, and immunity. Its synthesized by the liver, binds about 90% of the circulating hor-
synthesis and secretion are tightly regulated by the central nervous mone under normal circumstances. The remainder is free (about

24 Hour Sampling
Normal
Serum Cortisol
8 am 8 pm Dark
Circadian Tissue Glucocorticoid Sensitivity/Gr Acetylation
Glucocorticoid Sensitivity
GR Acetylation
Target Tissue
Target Tissue
Glucocorticoid Sensitivity
8 am 8 pm Dark
FIGURE 39–2  Circadian variation in plasma cortisol throughout
the 24-hour day (upper panel). The sensitivity of tissues to gluco-
corticoids is also circadian but inverse to that of cortisol, with low
sensitivity in the late morning and high sensitivity in the evening and
early night (lower panel). The sensitivity of tissues to glucocorticoids
is inversely related to that of glucocorticoid receptor (GR) acetylation
by the transcription factor CLOCK; the acetylated receptor has
decreased transcriptional activity. (Adapted, with permission, from Nader N,
Chrousos GP, Kino T: Interactions of the circadian CLOCK system and the HPA axis.
Trends Endocrinol Metab 2010;21:277. Copyright Elsevier.)
5–10%) or loosely bound to albumin (about 5%) and is available
to exert its effect on target cells. When plasma cortisol levels
exceed 20–30 mcg/dL, CBG is saturated, and the concentration
of free cortisol rises rapidly. CBG is increased in pregnancy, with
estrogen administration, and in hyperthyroidism. It is decreased
by hypothyroidism, genetic defects in synthesis, and protein
deficiency states. Albumin has a large capacity but low affinity for
cortisol, and for practical purposes albumin-bound cortisol should
be considered free. Synthetic corticosteroids such as dexametha-
sone are largely bound to albumin rather than CBG.
The half-life of cortisol in the circulation is normally about
60–90 minutes; it may be increased when hydrocortisone (the phar-
maceutical preparation of cortisol) is administered in large amounts
or when stress, hypothyroidism, or liver disease is present. Only 1%
of cortisol is excreted unchanged in the urine as free cortisol; about
20% of cortisol is converted to cortisone by 11-hydroxysteroid
dehydrogenase in the kidney and other tissues with mineralocorti-
coid receptors (see below) before reaching the liver. Most cortisol is
metabolized in the liver. About one-third of the cortisol produced
daily is excreted in the urine as dihydroxy ketone metabolites and is
measured as 17-hydroxysteroids (see Figure 39–3 for carbon num-
bering). Many cortisol metabolites are conjugated with glucuronic
acid or sulfate at the C3 and C21 hydroxyls, respectively, in the liver;
they are then excreted in the urine.
CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    705
In some species (eg, the rat), corticosterone is the major gluco-
corticoid. It is less firmly bound to protein and therefore metabo-
lized more rapidly. The pathways of its degradation are similar to
those of cortisol.
Pharmacodynamics
A. Mechanism of Action
Most of the known effects of the glucocorticoids are mediated by
8 am
widely distributed intracellular glucocorticoid receptors. These
proteins are members of the superfamily of nuclear receptors,
which includes steroid, sterol (vitamin D), thyroid, retinoic
acid, and many other receptors with unknown or nonexistent
GR Acetylation at
ligands (orphan receptors). All these receptors interact with the
Target Tissues
promoters of—and regulate the transcription of—target genes
(Figure 39–4). In the absence of the hormonal ligand, glucocorti-
coid receptors are primarily cytoplasmic, in oligomeric complexes
with chaperone heat-shock proteins (hsp). The most important
of these are two molecules of hsp90, although other proteins (eg,
8 am hsp40, hsp70, FKBP5) are also involved. Free hormone from
the plasma and interstitial fluid enters the cell and binds to the
receptor, inducing conformational changes that allow it to dis-
sociate from the heat shock proteins and dimerize. The dimeric
ligand-bound receptor complex then is actively transported into
the nucleus, where it interacts with DNA and nuclear proteins.
As a homodimer, it binds to glucocorticoid receptor elements
(GREs) in the promoters of responsive genes. The GRE is com-
posed of two palindromic sequences that bind to the hormone
receptor dimer.
In addition to binding to GREs, the ligand-bound receptor
also forms complexes with and influences the function of other
transcription factors, such as AP1 and nuclear factor kappa-B
(NF-κB), which act on non-GRE-containing promoters, to con-
tribute to the regulation of transcription of their responsive genes.
These transcription factors have broad actions on the regulation
of growth factors, proinflammatory cytokines, etc, and to a great
extent mediate the anti-growth, anti-inflammatory, and immuno-
suppressive effects of glucocorticoids.
Two genes for the corticoid receptor have been identified: one
encoding the classic glucocorticoid receptor (GR) and the other
encoding the mineralocorticoid receptor (MR). Alternative splic-
ing of human glucocorticoid receptor pre-mRNA generates two
highly homologous isoforms, termed hGRα and hGRβ. Human
GRα is the classic ligand-activated glucocorticoid receptor,
which, in the hormone-bound state, modulates the expression
of glucocorticoid-responsive genes. In contrast, hGRβ does not
bind glucocorticoids and is transcriptionally inactive. However,
hGRβ is able to inhibit the effects of hormone-activated hGRα
on glucocorticoid-responsive genes, playing the role of a physi-
ologically relevant endogenous inhibitor of glucocorticoid action.
It was recently shown that the two hGR alternative transcripts
have eight distinct translation initiation sites—ie, in a human cell
there may be up to 16 GRα and GRβ isoforms, which may form
up to 256 homodimers and heterodimers with different transcrip-
tional and possibly nontranscriptional activities. This variability
suggests that this important class of steroid receptors has complex
706    SECTION VII  Endocrine Drugs

21 21
CH2OH CH2OH
20 20
C O C O
18 18
H3C OH H3C OH
HO 12 17 HO 12 17
11 13 11 13 16
19 16 19
H3C 14 H3C H 14 15
1 9 8 15 1 8
9
2 10 10
2
H H
3 5 7 3 5 7
4
O 6 O 4 6

Cortisol (hydrocortisone) Prednisolone

21 21
CH2OH CH2OH
20 20
C O O CH3
C O
18 18
H3C OH H3C
HO HO 12
C
12 17 17
11 13 11 13
19 16 CH3 19 16 O CH3
H3C 14 H3C 14
1 9 8 15 1 9 8 15
2 10 2 10
F F
3 5 7 3 5 7
O 4 6 O 4 6

Betamethasone Triamcinolone (acetonide moiety shaded)

FIGURE 39–3  Chemical structures of several glucocorticoids. The acetonide-substituted derivatives (eg, triamcinolone acetonide) have
increased surface activity and are useful in dermatology. Dexamethasone is identical to betamethasone except for the configuration of the
methyl group at C16: in betamethasone it is beta (projecting up from the plane of the rings); in dexamethasone it is alpha.

stochastic activities. In addition, rare mutations in hGR may
result in partial glucocorticoid resistance. Affected individuals
have increased ACTH secretion because of reduced pituitary feed-
back and additional endocrine abnormalities (see below).
The prototype GR isoform is composed of about 800 amino acids
and can be divided into three functional domains (see Figure 2–6).
The glucocorticoid-binding domain is located at the carboxyl
terminal of the molecule. The DNA-binding domain is located in the
middle of the protein and contains nine cysteine residues. This region
folds into a “two-finger” structure stabilized by zinc ions connected to
cysteines to form two tetrahedrons. This part of the molecule binds
to the GREs that regulate glucocorticoid action on glucocorticoid-
regulated genes. The zinc fingers represent the basic structure by
which the DNA-binding domain recognizes specific nucleic acid
sequences. The amino-terminal domain is involved in the transactiva-
tion activity of the receptor and increases its specificity.
The interaction of glucocorticoid receptors with GREs or
other transcription factors is facilitated or inhibited by several
families of proteins called steroid receptor coregulators, divided
into coactivators and corepressors. The coregulators do this by serv-
ing as bridges between the receptors and other nuclear proteins
and by expressing enzymatic activities such as histone acetylase or
deacetylase, which alter the conformation of nucleosomes and the
transcribability of genes.
Between 10% and 20% of expressed genes in a cell are regu-
lated by glucocorticoids. The number and affinity of receptors
for the hormone, the complement of transcription factors and
coregulators, and post-transcription events determine the relative
specificity of these hormones’ actions in various cells. The effects
of glucocorticoids are mainly due to proteins synthesized from
mRNA transcribed from their target genes.
Some of the effects of glucocorticoids can be attributed to
their binding to mineralocorticoid receptors. Indeed, MRs bind
aldosterone and cortisol with similar affinity. A mineralocor-
ticoid effect of the higher levels of cortisol is avoided in some
tissues (eg, kidney, colon, salivary glands) by expression of
11β-hydroxysteroid dehydrogenase type 2, the enzyme responsible
for biotransformation to its 11-keto derivative (cortisone), which
has minimal action on aldosterone receptors.
The GR also interacts with other regulators of cell function.
One such molecule is CLOCK/BMAL-1, a transcription factor
dimer expressed in all tissues and generating the circadian rhythm
of cortisol secretion (Figure 39–2) at the suprachiasmatic nucleus
of the hypothalamus. CLOCK is an acetyltransferase that acety-
lates the hinge region of the GR, neutralizing its transcriptional
activity and thus rendering target tissues resistant to glucocorti-
coids. As shown in Figure 39–2, lower panel, the glucocorticoid
target tissue sensitivity rhythm generated is in reverse phase to that
of circulating cortisol concentrations, explaining the increased
sensitivity of the organism to evening administration of glucocor-
ticoids. The GR also interacts with NF-κB, a regulator of produc-
tion of cytokines and other molecules involved in inflammation.
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    707

R hsp90
hsp90 x
(Unstable)
S
R

S S
S S Steroid-receptor
R* R* dimer (activated)

DNA
S
Response
CBG S R*
GRE
S R*

Protein

Transcription
mRNA pre- machinery
(Editing) mRNA (RNA poly-
merase, etc)

Cytoplasm Nucleus

FIGURE 39–4  A model of the interaction of a steroid, S (eg, cortisol), and its receptor, R, and the subsequent events in a target cell. The
steroid is present in the blood in bound form on the corticosteroid-binding globulin (CBG) but enters the cell as the free molecule. The intracel-
lular receptor is bound to stabilizing proteins, including two molecules of heat-shock protein 90 (hsp90) and several others including FKBP5,
denoted as “X” in the figure. This receptor complex is incapable of activating transcription. When the complex binds a molecule of cortisol,
an unstable complex is created and the hsp90 and associated molecules are released. The steroid-receptor complex is now able to dimerize,
enter the nucleus, bind to a glucocorticoid response element (GRE) on the regulatory region of the gene, and regulate transcription by RNA
polymerase II and associated transcription factors. A variety of regulatory factors (not shown) may participate in facilitating (coactivators) or
inhibiting (corepressors) the steroid response. The resulting mRNA is edited and exported to the cytoplasm for the production of protein that
brings about the final hormone response. An alternative to the steroid-receptor complex interaction with a GRE is an interaction with and
altering the function of other transcription factors, such as NF-κB in the nucleus of cells.

Prompt effects such as initial feedback suppression of pituitary
ACTH occur in minutes and are too rapid to be explained on the
basis of gene transcription and protein synthesis. It is not known
how these effects are mediated. Among the proposed mechanisms are
direct effects on cell membrane receptors for the hormone or nonge-
nomic effects of the classic hormone-bound glucocorticoid receptor.
The putative membrane receptors might be entirely different from
the known intracellular receptors. For example, recent studies impli-
cate G protein–coupled membrane receptors in the response of glu-
tamatergic neurons to glucocorticoids in rats. Furthermore, all steroid
receptors (except the MRs) have been shown to have palmitoylation
motifs that allow enzymatic addition of palmitate and increased local-
ization of the receptors in the vicinity of plasma membranes. Such
receptors are available for direct interactions with and effects on vari-
ous membrane-associated or cytoplasmic proteins without the need
for entry into the nucleus and induction of transcriptional actions.
B. Physiologic Effects
The glucocorticoids have widespread effects because they influ-
ence the function of most cells in the body. The major metabolic
consequences of glucocorticoid secretion or administration are due to
direct actions of these hormones in the cell. However, some impor-
tant effects are the result of homeostatic responses by insulin and
glucagon. Although many of the effects of glucocorticoids are dose-
related and become magnified when large amounts are administered
for therapeutic purposes, there are also other effects—called permissive
effects—without which many normal functions become deficient.
For example, the response of vascular and bronchial smooth muscle to
catecholamines is diminished in the absence of cortisol and restored
by physiologic amounts of this glucocorticoid. Similarly, the lipolytic
responses of fat cells to catecholamines, ACTH, and growth hormone
are attenuated in the absence of glucocorticoids.
C. Metabolic Effects
The glucocorticoids have important dose-related effects on car-
bohydrate, protein, and fat metabolism. The same effects are
responsible for some of the serious adverse effects associated with
their use in therapeutic doses. Glucocorticoids stimulate and are
required for gluconeogenesis and glycogen synthesis in the fast-
ing state. They stimulate phosphoenolpyruvate carboxykinase,
708    SECTION VII  Endocrine Drugs
glucose-6-phosphatase, and glycogen synthase and the release of
amino acids in the course of muscle catabolism.
Glucocorticoids increase serum glucose levels and thus stimu-
late insulin release but inhibit the uptake of glucose by muscle
cells, while they stimulate hormone-sensitive lipase and thus
lipolysis. The increased insulin secretion stimulates lipogenesis
and to a lesser degree inhibits lipolysis, leading to a net increase in
fat deposition combined with increased release of fatty acids and
glycerol into the circulation.
The net results of these actions are most apparent in the fasting
state, when the supply of glucose from gluconeogenesis, the release
of amino acids from muscle catabolism, the inhibition of periph-
eral glucose uptake, and the stimulation of lipolysis all contribute
to maintenance of an adequate glucose supply to the brain.
D. Catabolic and Antianabolic Effects
Although glucocorticoids stimulate RNA and protein synthesis in the
liver, they have catabolic and antianabolic effects in lymphoid and
connective tissue, muscle, peripheral fat, and skin. Supraphysiologic
amounts of glucocorticoids lead to decreased muscle mass and weak-
ness and thinning of the skin. Catabolic and antianabolic effects on
bone are the cause of osteoporosis in Cushing’s syndrome and impose
a major limitation in the long-term therapeutic use of glucocorticoids.
In children, glucocorticoids reduce growth. This effect may be par-
tially prevented by administration of growth hormone in high doses,
but this use of growth hormone is not recommended.
E. Anti-Inflammatory and Immunosuppressive Effects
Glucocorticoids dramatically reduce the manifestations of inflam-
mation. This is due to their profound effects on the concentration,
distribution, and function of peripheral leukocytes and to their
suppressive effects on inflammatory cytokines and chemokines and
on other mediators of inflammation. Inflammation, regardless of
its cause, is characterized by the extravasation and infiltration of
leukocytes into the affected tissue. These events are mediated by a
complex series of interactions of white cell adhesion molecules with
those on endothelial cells and are inhibited by glucocorticoids. After
a single dose of a short-acting glucocorticoid, the concentration
of neutrophils in the circulation increases while the lymphocytes
(T and B cells), monocytes, eosinophils, and basophils decrease.
The changes are maximal at 6 hours and are dissipated in 24 hours.
The increase in neutrophils is due both to increased influx into
the blood from the bone marrow and to decreased migration
from the blood vessels, leading to a reduction in the number
of cells at the site of inflammation. The reduction in circulating
lymphocytes, monocytes, eosinophils, and basophils is primarily the
result of their movement from the vascular bed to lymphoid tissue.
Glucocorticoids also inhibit the functions of tissue macro-
phages and other antigen-presenting cells. The ability of these
cells to respond to antigens and mitogens is reduced. The effect
on macrophages is particularly marked and limits their ability
to phagocytose and kill microorganisms and to produce tumor
necrosis factor α, interleukin 1, metalloproteinases, and plasmino-
gen activator. Both macrophages and lymphocytes produce less
interleukin 12 and interferon-γ, important inducers of Th1 cell
activity, and cellular immunity.
In addition to their effects on leukocyte function, gluco-
corticoids influence the inflammatory response by inhibiting
phospholipase A2 and thus reduce the synthesis of arachidonic
acid, the precursor of prostaglandins and leukotrienes, and of
platelet-activating factor. Finally, glucocorticoids reduce expres-
sion of cyclooxygenase 2, the inducible form of this enzyme, in
inflammatory cells, thus reducing the amount of enzyme available
to produce prostaglandins (see Chapters 18 and 36).
Glucocorticoids cause vasoconstriction when applied directly
to the skin, possibly by suppressing mast cell degranulation. They
also decrease capillary permeability by reducing the amount of
histamine released by basophils and mast cells.
The anti-inflammatory and immunosuppressive effects of
glucocorticoids are largely due to the actions described above. In
humans, complement activation is unaltered, but its effects are
inhibited. Antibody production can be reduced by large doses of
steroids, although it is unaffected by moderate doses (eg, 20 mg/d
of prednisone).
The anti-inflammatory and immunosuppressive effects of these
agents are widely useful therapeutically but are also responsible for
some of their most serious adverse effects (see text that follows).
F. Other Effects
Glucocorticoids have important effects on the nervous system.
Adrenal insufficiency causes marked slowing of the alpha rhythm
of the electroencephalogram and is associated with depression.
Increased amounts of glucocorticoids often produce behavioral
disturbances in humans: initially insomnia and euphoria and sub-
sequently depression. Large doses of glucocorticoids may increase
intracranial pressure (pseudotumor cerebri).
Glucocorticoids given chronically suppress the pituitary release
of ACTH, growth hormone, thyroid-stimulating hormone, and
luteinizing hormone.
Large doses of glucocorticoids have been associated with the devel-
opment of peptic ulcer, possibly by suppressing the local immune
response against Helicobacter pylori. They also promote fat redistribu-
tion in the body, with increase of visceral, facial, nuchal, and supracla-
vicular fat, and they appear to antagonize the effect of vitamin D on
calcium absorption. The glucocorticoids also have important effects on
the hematopoietic system. In addition to their effects on leukocytes,
they increase the number of platelets and red blood cells.
Cortisol deficiency results in impaired renal function (particu-
larly glomerular filtration), augmented vasopressin secretion, and
diminished ability to excrete a water load.
Glucocorticoids have important effects on the development
of the fetal lungs. Indeed, the structural and functional changes
in the lungs near term, including the production of pulmonary
surface-active material required for air breathing (surfactant), are
stimulated by glucocorticoids.
Recently, glucocorticoids were found to have direct effects
on the epigenetic regulation of specific target genes by altering
the activities of DNA methyltransferases and other enzymes par-
ticipating in epigenesis. This is of particular importance in the
prenatal treatment of pregnant mothers or treatment of young
infants and children, when the effects of glucocorticoids may be
long-term or even permanent. These effects may predispose these
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    709

patients to behavioral or somatic disorders, such as depression or
obesity and metabolic syndrome.
SYNTHETIC CORTICOSTEROIDS
Glucocorticoids have become important agents for use in the treat-
ment of many inflammatory, immunologic, hematologic, and other
disorders. This has stimulated the development of many synthetic
steroids with anti-inflammatory and immunosuppressive activity.
Pharmacokinetics
Pharmaceutical steroids are usually synthesized from cholic acid
obtained from cattle or steroid sapogenins found in plants. Fur-
ther modifications of these steroids have led to the marketing of
a large group of synthetic steroids with special characteristics that
are pharmacologically and therapeutically important (Table 39–1;
Figure 39–3).
The metabolism of the naturally occurring adrenal steroids has
been discussed above. The synthetic corticosteroids (Table 39–1) are
in most cases rapidly and completely absorbed when given by mouth.
Although they are transported and metabolized in a fashion similar to
that of the endogenous steroids, important differences exist.
Alterations in the glucocorticoid molecule influence its affinity
for glucocorticoid and mineralocorticoid receptors as well as its
protein-binding affinity, side chain stability, rate of elimination,
and metabolic products. Halogenation at the 9 position, unsatu-
ration of the Δ1–2 bond of the A ring, and methylation at the
2 or 16 position prolong the half-life by more than 50%. The Δ1
compounds are excreted in the free form. In some cases, the agent
given is a prodrug; for example, prednisone is rapidly converted to
the active product prednisolone in the body.
Pharmacodynamics
The actions of the synthetic steroids are similar to those of cor-
tisol (see above). They bind to the specific intracellular receptor
proteins and produce the same effects but have different ratios of
glucocorticoid to mineralocorticoid potency (Table 39–1).
CLINICAL PHARMACOLOGY
A. Diagnosis and Treatment of Disturbed Adrenal
Function
1. Adrenocortical insufficiency
a. Chronic (Addison’s disease)—Chronic adrenocortical insuf-
ficiency is characterized by weakness, fatigue, weight loss, hypo-
tension, hyperpigmentation, and inability to maintain the blood
glucose level during fasting. In such individuals, minor noxious,

TABLE 39–1  Some commonly used natural and synthetic corticosteroids for general use. See Table 61–2 for
dermatologic corticosteroids.

Activity1
Equivalent Oral
Agent  Anti-Inflammatory Topical Salt-Retaining Dose (mg)  Forms Available 

Short- to medium-acting glucocorticoids

  Hydrocortisone (cortisol) 1 1 1 20 Oral, injectable, topical
 Cortisone 0.8 0 0.8 25 Oral
 Prednisone 4 0 0.3 5 Oral
 Prednisolone 5 4 0.3 5 Oral, injectable
 Methylprednisolone 5 5 0.25 4 Oral, injectable
2
 Meprednisone 5   0 4 Oral, injectable
Intermediate-acting glucocorticoids
 Triamcinolone 5 53 0 4 Oral, injectable, topical
2
 Paramethasone 10   0 2 Oral, injectable
2
 Fluprednisolone 15 7 0 1.5 Oral
Long-acting glucocorticoids
 Betamethasone 25–40 10 0 0.6 Oral, injectable, topical
 Dexamethasone 30 10 0 0.75 Oral, injectable, topical
Mineralocorticoids
 Fludrocortisone 10 0 250 2 Oral
 Desoxycorticosterone 0 0 20   Injectable, pellets
acetate2
1
Potency relative to hydrocortisone.
2
Outside United States.
3
Triamcinolone acetonide: Up to 100.
710    SECTION VII  Endocrine Drugs
traumatic, or infectious stimuli may produce acute adrenal insuf-
ficiency with circulatory shock and even death.
In primary adrenal insufficiency, about 20–30 mg of hydrocor-
tisone must be given daily, with increased amounts during periods
of stress. Although hydrocortisone has some mineralocorticoid
activity, this must be supplemented by an appropriate amount of
a salt-retaining hormone such as fludrocortisone. Synthetic gluco-
corticoids that are long-acting and devoid of salt-retaining activity
should not be administered to these patients.
b. Acute—When acute adrenocortical insufficiency is suspected,
treatment must be instituted immediately. Therapy consists of
large amounts of parenteral hydrocortisone in addition to cor-
rection of fluid and electrolyte abnormalities and treatment of
precipitating factors.
Hydrocortisone sodium succinate or phosphate in doses of
100 mg intravenously is given every 8 hours until the patient is
stable. The dose is then gradually reduced, achieving maintenance
dosage within 5 days.
The administration of salt-retaining hormone is resumed when
the total hydrocortisone dosage has been reduced to 50 mg/d.
2. Adrenocortical hypo- and hyperfunction
a. Congenital adrenal hyperplasia—This group of disorders
is characterized by specific defects in the synthesis of cortisol. In
pregnancies at high risk for congenital adrenal hyperplasia, fetuses
can be protected from genital abnormalities by administration of
dexamethasone to the mother.
The most common defect is a decrease in or lack of P450c21
(21α-hydroxylase) activity.* As can be seen in Figure 39–1, this
would lead to a reduction in cortisol synthesis and thus produce a
compensatory increase in ACTH release. The adrenal becomes hyper-
plastic and produces abnormally large amounts of precursors such as
17-hydroxyprogesterone that can be diverted to the androgen path-
way, which leads to virilization and can result in ambiguous genitalia
in the female fetus. Metabolism of this compound in the liver leads to
pregnanetriol, which is characteristically excreted into the urine in
large amounts in this disorder and can be used to make the diagnosis
and to monitor efficacy of glucocorticoid substitution. However, the
most reliable method of detecting this disorder is the increased
response of plasma 17-hydroxyprogesterone to ACTH stimulation.
If the defect is in 11-hydroxylation, large amounts of deoxy-
corticosterone are produced, and because this steroid has miner-
alocorticoid activity, hypertension with or without hypokalemic
alkalosis ensues. When 17-hydroxylation is defective in the adre-
nals and gonads, hypogonadism is also present. However, increased
amounts of 11-deoxycorticosterone are formed, and the signs and
symptoms associated with mineralocorticoid excess—such as
hypertension and hypokalemia— also are observed.
When first seen, the infant with congenital adrenal hyperplasia
may be in acute adrenal crisis and should be treated as described
above, using appropriate electrolyte solutions and an intravenous
preparation of hydrocortisone in stress doses. Once the patient
* However, it may also result from abnormal secretion by hyper-
Names for the adrenal steroid synthetic enzymes include the follow-
ing: P450c11 (11β-hydroxylase), P450c17 (17α-hydroxylase), P450c21
(21α-hydroxylase).
is stabilized, oral hydrocortisone, 12–18 mg/m2 per day in two
unequally divided doses (two thirds in the morning, one third in
late afternoon) is begun. The dosage is adjusted to allow normal
growth and bone maturation and to prevent androgen excess.
Alternate-day therapy with prednisone has also been used to
achieve greater ACTH suppression without increasing growth
inhibition. Fludrocortisone, 0.05–0.2 mg/d, should also be
administered by mouth, with added salt to maintain normal blood
pressure, plasma renin activity, and electrolytes.
b. Cushing’s syndrome—Cushing’s syndrome is usually the
result of bilateral adrenal hyperplasia secondary to an ACTH-
secreting pituitary adenoma (Cushing’s disease) but occasionally
is due to tumors or nodular hyperplasia of the adrenal gland or
ectopic production of ACTH by other tumors. The manifesta-
tions are those associated with the chronic presence of excessive
glucocorticoids. When glucocorticoid hypersecretion is marked and
prolonged, a rounded, plethoric face and trunk obesity are striking
in appearance. Protein loss may be significant and includes muscle
wasting; thinning, purple striae, and easy bruising of the skin;
poor wound healing; and osteoporosis. Other serious disturbances
include mental disorders, hypertension, and diabetes. This disorder
is treated by surgical removal of the tumor producing ACTH or
cortisol, irradiation of the pituitary tumor, or resection of one or
both adrenals. These patients must receive large doses of cortisol
during and after the surgical procedure. Doses of up to 300 mg of
soluble hydrocortisone may be given as a continuous intravenous
infusion on the day of surgery. The dose must be reduced slowly
to normal replacement levels, since rapid reduction in dose may
produce withdrawal symptoms, including fever and joint pain. If
adrenalectomy has been performed, long-term maintenance is simi-
lar to that outlined above for adrenal insufficiency.
c. Primary generalized glucocorticoid resistance
(Chrousos syndrome)—This rare sporadic or familial genetic
condition is usually due to inactivating mutations of the glucocor-
ticoid receptor gene. The hypothalamic-pituitary-adrenal (HPA)
axis hyperfunctions in an attempt to compensate for the defect,
and the increased production of ACTH leads to high circulating
levels of cortisol and cortisol precursors such as corticosterone
and 11-deoxycorticosterone with mineralocorticoid activity, as
well as of adrenal androgens. These increased levels may result in
hypertension with or without hypokalemic alkalosis and hyper-
androgenism expressed as virilization and precocious puberty in
children and acne, hirsutism, male pattern baldness, and men-
strual irregularities (mostly oligo-amenorrhea and hypofertility) in
women. The therapy of this syndrome is high doses of synthetic
glucocorticoids such as dexamethasone with no inherent min-
eralocorticoid activity. These doses are titrated to normalize the
production of cortisol, cortisol precursors, and adrenal androgens.
d. Aldosteronism—Primary aldosteronism usually results from
the excessive production of aldosterone by an adrenal adenoma.
plastic glands or from a malignant tumor. The clinical findings of
hypertension, weakness, and tetany are related to the continued
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    711
renal loss of potassium, which leads to hypokalemia, alkalosis,
and elevation of serum sodium concentrations. This syndrome
can also be produced in disorders of adrenal steroid biosynthesis
by excessive secretion of deoxycorticosterone, corticosterone, or
18-hydroxycorticosterone—all compounds with inherent miner-
alocorticoid activity.
In contrast to patients with secondary aldosteronism (see text that
follows), these patients have low (suppressed) levels of plasma renin
activity and angiotensin II. When treated with fludrocortisone (0.2
mg twice daily orally for 3 days) or deoxycorticosterone acetate (20
mg/d intramuscularly for 3 days—but not available in the United
States), patients fail to retain sodium and the secretion of aldosterone
is not significantly reduced. When the disorder is mild, it may escape
detection if serum potassium levels are used for screening. However,
it may be detected by an increased ratio of plasma aldosterone to
renin. Patients generally improve when treated with spironolactone,
an aldosterone receptor-blocking agent, and the response to this agent
is of diagnostic and therapeutic value.
3. Use of glucocorticoids for diagnostic purposes—It is
sometimes necessary to suppress the production of ACTH to
identify the source of a particular hormone or to establish whether
its production is influenced by the secretion of ACTH. In these
circumstances, it is advantageous to use a very potent substance
such as dexamethasone because the use of small quantities reduces
the possibility of confusion in the interpretation of hormone
assays in blood or urine. For example, if complete suppression is
achieved by the use of 50 mg of cortisol, the urinary 17-hydroxy-
corticosteroids will be 15–18 mg/24 h, since one-third of the dose
given will be recovered in urine as 17-hydroxycorticosteroid. If an
equivalent dose of 1.5 mg of dexamethasone is used, the urinary
excretion will be only 0.5 mg/24 h and blood levels will be low.
The dexamethasone suppression test is used for the diagnosis of
Cushing’s syndrome and has also been used in the differential diag-
nosis of depressive psychiatric states. As a screening test, 1 mg dexa-
methasone is given orally at 11 pm, and a plasma sample is obtained
the following morning. In normal individuals, the morning cortisol
concentration is usually <3 mcg/dL, whereas in Cushing’s syndrome
the level is usually >5 mcg/dL. The results are not reliable in the
patient with depression, anxiety, concurrent illness, and other stress-
ful conditions or in the patient who is receiving a medication that
enhances the catabolism of dexamethasone in the liver. To distinguish
between hypercortisolism due to anxiety, depression, and alcoholism
(pseudo-Cushing syndrome) and bona fide Cushing’s syndrome, a
combined test is carried out, consisting of dexamethasone (0.5 mg
orally every 6 hours for 2 days) followed by a standard corticotropin-
releasing hormone (CRH) test (1 mg/kg given as a bolus intravenous
infusion 2 hours after the last dose of dexamethasone).
In patients in whom the diagnosis of Cushing’s syndrome has
been established clinically and confirmed by a finding of elevated
free cortisol in the urine, suppression with large doses of dexa-
methasone will help to distinguish patients with Cushing’s disease
from those with steroid-producing tumors of the adrenal cortex
or with the ectopic ACTH syndrome. Dexamethasone is given in
a dosage of 0.5 mg orally every 6 hours for 2 days, followed by
2 mg orally every 6 hours for 2 days, and the urine is then assayed
for cortisol or its metabolites (Liddle’s test); or dexamethasone is
given as a single dose of 8 mg at 11 pm, and the plasma cortisol
is measured at 8 am the following day. In patients with Cushing’s
disease, the suppressant effect of dexamethasone usually produces
a 50% reduction in hormone levels. In patients in whom suppres-
sion does not occur, the ACTH level will be low in the presence of
a cortisol-producing adrenal tumor and elevated in patients with
an ectopic ACTH-producing tumor.
B. Corticosteroids and Stimulation of Lung Maturation
in the Fetus
Lung maturation in the fetus is regulated by the fetal secretion of
cortisol. Treatment of the mother with large doses of glucocorticoid
reduces the incidence of respiratory distress syndrome in infants
delivered prematurely. When delivery is anticipated before 34 weeks
of gestation, intramuscular betamethasone, 12 mg, followed by an
additional dose of 12 mg 18–24 hours later, is commonly used. Beta-
methasone is chosen because maternal protein binding and placental
metabolism of this corticosteroid is less than that of cortisol, allowing
increased transfer across the placenta to the fetus. A study of more
than 10,000 infants born at 23–25 weeks of gestation indicated that
exposure to exogenous corticosteroids before birth reduced the death
rate and evidence of neurodevelopmental impairment.
C. Corticosteroids and Nonadrenal Disorders
The synthetic analogs of cortisol are useful in the treatment of
a diverse group of diseases unrelated to any known disturbance
of adrenal function (Table 39–2). The usefulness of corticoste-
roids in these disorders is a function of their ability to suppress
inflammatory and immune responses and to alter leukocyte
function, as previously described (see also Chapter 55). These
agents are useful in disorders in which host response is the cause
of the major manifestations of the disease. In instances in which
the inflammatory or immune response is important in control-
ling the pathologic process, therapy with corticosteroids may be
dangerous but justified to prevent irreparable damage from an
inflammatory response—if used in conjunction with specific
therapy for the disease process.
Since corticosteroids are not usually curative, the pathologic
process may progress while clinical manifestations are suppressed.
Therefore, chronic therapy with these drugs should be undertaken
with great care and only when the seriousness of the disorder
warrants their use and when less hazardous measures have been
exhausted.
In general, attempts should be made to bring the disease pro-
cess under control using medium- to intermediate-acting gluco-
corticoids such as prednisone and prednisolone (Table 39–1), as
well as all ancillary measures possible to keep the dose low. Where
possible, alternate-day therapy should be used (see the following
text). Therapy should not be decreased or stopped abruptly. When
prolonged therapy is anticipated, it is helpful to obtain chest
x-rays and a tuberculin test, since glucocorticoid therapy can reac-
tivate dormant tuberculosis. The presence of diabetes, peptic ulcer,
osteoporosis, and psychological disturbances should be taken into
consideration, and cardiovascular function should be assessed.
712    SECTION VII  Endocrine Drugs

TABLE 39–2  Some therapeutic indications for the use of glucocorticoids in nonadrenal disorders.
Disorder Examples

Allergic reactions Angioneurotic edema, asthma, bee stings, contact dermatitis, drug reactions, allergic rhinitis, serum sickness, urticaria
Collagen-vascular Giant cell arteritis, lupus erythematosus, mixed connective tissue syndromes, polymyositis, polymyalgia rheumatica,
disorders rheumatoid arthritis, temporal arteritis
Eye diseases Acute uveitis, allergic conjunctivitis, choroiditis, optic neuritis
Gastrointestinal diseases Inflammatory bowel disease, nontropical sprue, subacute hepatic necrosis
Hematologic disorders Acquired hemolytic anemia, acute allergic purpura, leukemia, lymphoma, autoimmune hemolytic anemia, idiopathic
thrombocytopenic purpura, multiple myeloma
Systemic inflammation Acute respiratory distress syndrome (sustained therapy with moderate dosage accelerates recovery and decreases
mortality)
Infections Acute respiratory distress syndrome, sepsis
Inflammatory conditions Arthritis, bursitis, tenosynovitis
of bones and joints
Nausea and vomiting A large dose of dexamethasone reduces emetic effects of chemotherapy and general anesthesia
Neurologic disorders Cerebral edema (large doses of dexamethasone are given to patients following brain surgery to minimize cerebral
edema in the postoperative period), multiple sclerosis
Organ transplants Prevention and treatment of rejection (immunosuppression)
Pulmonary diseases Aspiration pneumonia, bronchial asthma, prenatal prevention of infant respiratory distress syndrome, sarcoidosis
Renal disorders Nephrotic syndrome
Skin diseases Atopic dermatitis, dermatoses, lichen simplex chronicus (localized neurodermatitis), mycosis fungoides, pemphigus,
psoriasis, seborrheic dermatitis, xerosis
Thyroid diseases Malignant exophthalmos, subacute thyroiditis
Miscellaneous Hypercalcemia, mountain sickness

Treatment for transplant rejection is a very important applica-
tion of glucocorticoids. The efficacy of these agents is based on
their ability to reduce antigen expression from the grafted tissue,
delay revascularization, and interfere with the sensitization of
cytotoxic T lymphocytes and the generation of primary antibody-
forming cells.
Toxicity
The benefits obtained from glucocorticoids vary considerably.
Use of these drugs must be carefully weighed in each patient
against their widespread effects. The major undesirable effects of
glucocorticoids are the result of their hormonal actions, which
lead to the clinical picture of iatrogenic Cushing’s syndrome (see
later in text).
When glucocorticoids are used for short periods (<2 weeks), it
is unusual to see serious adverse effects even with moderately large
doses. However, insomnia, behavioral changes (primarily hypo-
mania), and acute peptic ulcers are occasionally observed even
after only a few days of treatment. Acute pancreatitis is a rare but
serious acute adverse effect of high-dose glucocorticoids.
is a function of the dosage and the genetic background of the
patient. In the face, rounding, puffiness, fat deposition, and
plethora usually appear (moon facies). Similarly, fat tends to be
redistributed from the extremities to the trunk, the back of the
neck, and the supraclavicular fossae. There is an increased growth
of fine hair over the face, thighs and trunk. Steroid-induced punc-
tate acne may appear, and insomnia and increased appetite are
noted. In the treatment of dangerous or disabling disorders, these
changes may not require cessation of therapy. However, the under-
lying metabolic changes accompanying them can be very serious
by the time they become obvious. The continuing breakdown
of protein and diversion of amino acids to glucose production
increase the need for insulin and over time result in weight gain;
visceral fat deposition; myopathy and muscle wasting; thinning of
the skin, with striae and bruising; hyperglycemia; and eventually
osteoporosis, diabetes, and aseptic necrosis of the hip. Wound
healing is also impaired under these circumstances. When diabetes
occurs, it is treated with diet and insulin. These patients are often
resistant to insulin but rarely develop ketoacidosis. In general,
patients treated with corticosteroids should be on high-protein
and potassium-enriched diets.

A. Metabolic Effects B. Other Complications

Most patients who are given daily doses of 100 mg of hydrocorti- Other serious adverse effects of glucocorticoids include peptic
sone or more (or the equivalent amount of synthetic steroid) for ulcers and their consequences. The clinical findings associated
longer than 2 weeks undergo a series of changes that have been with certain disorders, particularly bacterial and mycotic infec-
termed iatrogenic Cushing’s syndrome. The rate of development tions, may be masked by the corticosteroids, and patients must
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    713
be carefully monitored to avoid serious mishap when large doses
are used. Severe myopathy is more frequent in patients treated
with long-acting glucocorticoids. The administration of such
compounds has been associated with nausea, dizziness, and weight
loss in some patients. These effects are treated by changing drugs,
reducing dosage, and increasing potassium and protein intake.
Hypomania or acute psychosis may occur, particularly in patients
receiving very large doses of corticosteroids. Long-term therapy with
intermediate- and long-acting steroids is associated with depression
and the development of posterior subcapsular cataracts. Psychiatric
follow-up and periodic slit-lamp examination are indicated in such
patients. Increased intraocular pressure is common, and glaucoma
may be induced. Benign intracranial hypertension also occurs. In dos-
ages of 45 mg/m2 per day or more of hydrocortisone or its equivalent,
growth retardation occurs in children. Medium-, intermediate-, and
long-acting glucocorticoids have greater growth-suppressing potency
than the natural steroid at equivalent doses.
When given in larger than physiologic amounts, steroids such
as cortisone and hydrocortisone, which have mineralocorticoid
effects in addition to glucocorticoid effects, cause some sodium
and fluid retention and loss of potassium. In patients with normal
cardiovascular and renal function, this leads to a hypokalemic,
hypochloremic alkalosis and eventually to a rise in blood pressure.
In patients with hypoproteinemia, renal disease, or liver disease,
edema may also occur. In patients with heart disease, even small
degrees of sodium retention may lead to heart failure. These
effects can be minimized by using synthetic non-salt-retaining
steroids, sodium restriction, and judicious amounts of potassium
supplements.
C. Adrenal Suppression
When corticosteroids are administered for more than 2 weeks,
adrenal suppression may occur. If treatment extends over weeks
to months, the patient should be given appropriate supplemen-
tary therapy at times of minor stress (twofold dosage increases
for 24–48 hours) or severe stress (up to tenfold dosage increases
for 48–72 hours) such as accidental trauma or major surgery.
If corticosteroid dosage is to be reduced, it should be tapered
slowly. If therapy is to be stopped, the reduction process should
be quite slow when the dose reaches replacement levels. It may
take 2–12 months for the hypothalamic-pituitary-adrenal axis to
function acceptably, and cortisol levels may not return to normal
for another 6–9 months. The glucocorticoid-induced suppression
is not a pituitary problem, and treatment with ACTH does not
reduce the time required for the return of normal function.
If the dosage is reduced too rapidly in patients receiving glu-
cocorticoids for a certain disorder, the symptoms of the disorder
may reappear or increase in intensity. However, patients without
an underlying disorder (eg, patients cured surgically of Cushing’s
disease) also develop symptoms with rapid reductions in cortico-
steroid levels. These symptoms include anorexia, nausea or vomit-
ing, weight loss, lethargy, headache, fever, joint or muscle pain,
and postural hypotension. Although many of these symptoms
may reflect true glucocorticoid deficiency, they may also occur
in the presence of normal or even elevated plasma cortisol levels,
suggesting glucocorticoid dependence.
Contraindications & Cautions
A. Special Precautions
Patients receiving glucocorticoids must be monitored carefully for
the development of hyperglycemia, glycosuria, sodium retention
with edema or hypertension, hypokalemia, peptic ulcer, osteopo-
rosis, and hidden infections.
The dosage should be kept as low as possible, and intermittent
administration (eg, alternate-day) should be used when satisfactory
therapeutic results can be obtained on this schedule. Even patients
maintained on relatively low doses of corticosteroids may require
supplementary therapy at times of stress, such as when surgical
procedures are performed or intercurrent illness or accidents occur.
B. Contraindications
Glucocorticoids must be used with great caution in patients with
peptic ulcer, heart disease or hypertension with heart failure,
certain infectious illnesses such as varicella and tuberculosis,
psychoses, diabetes, osteoporosis, or glaucoma.
Selection of Drug & Dosage Schedule
Glucocorticoid preparations differ with respect to relative anti-
inflammatory and mineralocorticoid effect, duration of action,
cost, and dosage forms available (Table 39–1), and these factors
should be taken into account in selecting the drug to be used.
A. ACTH versus Adrenocortical Steroids
In patients with normal adrenals, ACTH was used in the past to
induce the endogenous production of cortisol to obtain similar
effects. However, except when an increase in androgens is desir-
able, the use of ACTH as a therapeutic agent has been abandoned.
Instances in which ACTH was claimed to be more effective than
glucocorticoids were probably due to the administration of smaller
amounts of corticosteroids than were produced by the dosage of
ACTH.
B. Dosage
In determining the dosage regimen to be used, the physician must
consider the seriousness of the disease, the amount of drug likely
to be required to obtain the desired effect, and the duration of
therapy. In some diseases, the amount required for maintenance of
the desired therapeutic effect is less than the dose needed to obtain
the initial effect, and the lowest possible dosage for the needed
effect should be determined by gradually lowering the dose until
a small increase in signs or symptoms is noted.
When it is necessary to maintain continuously elevated plasma
corticosteroid levels to suppress ACTH, a slowly absorbed par-
enteral preparation or small oral doses at frequent intervals are
required. The opposite situation exists with respect to the use
of corticosteroids in the treatment of inflammatory and allergic
disorders. The same total quantity given in a few doses may be
more effective than that given in many smaller doses or in a slowly
absorbed parenteral form.
Severe autoimmune conditions involving vital organs must
be treated aggressively, and undertreatment is as dangerous
714    SECTION VII  Endocrine Drugs
as overtreatment. To minimize the deposition of immune com-
plexes and the influx of leukocytes and macrophages, 1 mg/kg
per day of prednisone in divided doses is required initially. This
dosage is maintained until the serious manifestations respond. The
dosage can then be gradually reduced.
When large doses are required for prolonged periods of time,
alternate-day administration of the compound may be tried.
When used in this manner, very large amounts (eg, 100 mg of
prednisone) can sometimes be administered with less marked
adverse effects because there is a recovery period between each
dose. The transition to an alternate-day schedule can be made
after the disease process is under control. It should be done
gradually and with additional supportive measures between doses.
When selecting a drug for use in large doses, a medium- or
intermediate-acting synthetic steroid with little mineralocorti-
coid effect is advisable. If possible, it should be given as a single
morning dose.
C. Special Dosage Forms
Local therapy, such as topical preparations for skin disease, oph-
thalmic forms for eye disease, intra-articular injections for joint
disease, inhaled steroids for asthma, and hydrocortisone enemas
for ulcerative colitis, provides a means of delivering large amounts
of steroid to the diseased tissue with reduced systemic effects.
Beclomethasone dipropionate, and several other
glucocorticoids—primarily budesonide, flunisolide, and mometa-
sone furoate, administered as aerosols—have been found to be
extremely useful in the treatment of asthma (see Chapter 20).
Beclomethasone dipropionate, triamcinolone acetonide,
budesonide, flunisolide, fluticasone, and others are available as
nasal sprays for the topical treatment of allergic rhinitis. They
are effective at doses (one or two sprays one, two, or three times
daily) that in most patients result in plasma levels that are too low
to influence adrenal function or have any other systemic effects.
Corticosteroids incorporated in ointments, creams, lotions,
and sprays are used extensively in dermatology. These preparations
are discussed in more detail in Chapter 61.
Recently, new timed-release hydrocortisone tablets were devel-
oped for the replacement treatment of Addisonian and congenital
adrenal hyperplasia patients. These tablets produce plasma cortisol
levels that are similar to those secreted normally in a circadian
fashion.
MINERALOCORTICOIDS (ALDOSTERONE,
DEOXYCORTICOSTERONE,
FLUDROCORTISONE)
The most important mineralocorticoid in humans is aldosterone.
However, small amounts of deoxycorticosterone (DOC) are also
formed and released. Although the amount is normally insignifi-
cant, DOC was of some importance therapeutically in the past. Its
actions, effects, and metabolism are qualitatively similar to those
described below for aldosterone. Fludrocortisone, a synthetic
corticosteroid, is the most commonly prescribed salt-retaining
hormone.
Aldosterone
Aldosterone is synthesized mainly in the zona glomerulosa of
the adrenal cortex. Its structure and synthesis are illustrated in
Figure 39–1. The rate of aldosterone secretion is subject to several
influences. ACTH produces a moderate stimulation of its release,
but this effect is not sustained for more than a few days in the
normal individual. Although aldosterone is no less than one third
as effective as cortisol in suppressing ACTH, the quantities of
aldosterone produced by the adrenal cortex and its plasma concen-
trations are insufficient to participate in any significant feedback
control of ACTH secretion.
Without ACTH, aldosterone secretion falls to about half
the normal rate, indicating that other factors, eg, angiotensin,
are able to maintain and perhaps regulate its secretion (see
Chapter 17). Independent variations between cortisol and
aldosterone secretion can also be demonstrated by means of
lesions in the nervous system such as decerebration, which
decreases the secretion of cortisol while increasing the secretion
of aldosterone.
A. Physiologic and Pharmacologic Effects
Aldosterone and other steroids with mineralocorticoid proper-
ties promote the reabsorption of sodium from the distal part of
the distal convoluted renal tubule and from the cortical collect-
ing tubules, loosely coupled to the excretion of potassium and
hydrogen ion. Sodium reabsorption in the sweat and salivary
glands, gastrointestinal mucosa, and across cell membranes in
general is also increased. Excessive levels of aldosterone produced
by tumors or overdosage with synthetic mineralocorticoids lead to
hypokalemia, metabolic alkalosis, increased plasma volume, and
hypertension.
Mineralocorticoids act by binding to the mineralocorticoid
receptor in the cytoplasm of target cells, especially principal cells
of the distal convoluted and collecting tubules of the kidney.
The drug-receptor complex activates a series of events similar to
those described above for the glucocorticoids and illustrated in
Figure 39–4. It is of interest that this receptor has the same affin-
ity for cortisol, which is present in much higher concentrations in
the extracellular fluid. The specificity for mineralocorticoids in the
kidney appears to be conferred, at least in part, by the presence—
in the kidney—of the enzyme 11β-hydroxysteroid dehydrogenase
type 2, which converts cortisol to cortisone. The latter has low
affinity for the receptor and is inactive as a mineralocorticoid or
glucocorticoid in the kidney. The major effect of activation of the
aldosterone receptor is increased expression of Na+/K+-ATPase and
the epithelial sodium channel (ENaC).
B. Metabolism
Aldosterone is secreted at the rate of 100–200 mcg/d in normal
individuals with a moderate dietary salt intake. The plasma level
in men (resting supine) is about 0.007 mcg/dL. The half-life of
aldosterone injected in tracer quantities is 15–20 minutes, and it
does not appear to be firmly bound to serum proteins.
The metabolism of aldosterone is similar to that of cortisol,
about 50 mcg/24 h appearing in the urine as conjugated
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    715
tetrahydroaldosterone. Approximately 5–15 mcg/24 h is excreted
free or as the 3-oxo glucuronide.
Deoxycorticosterone (DOC)
DOC, which also serves as a precursor of aldosterone (Figure 39–1),
is normally secreted in amounts of about 200 mcg/d. Its half-life
when injected into the human circulation is about 70 minutes.
Preliminary estimates of its concentration in plasma are approxi-
mately 0.03 mcg/dL. The control of its secretion differs from that
of aldosterone in that the secretion of DOC is primarily under the
control of ACTH. Although the response to ACTH is enhanced
by dietary sodium restriction, due to adaptations, a low-salt diet
does not increase DOC secretion. The secretion of DOC may be
markedly increased in abnormal conditions such as adrenocorti-
cal carcinoma and congenital adrenal hyperplasia with reduced
P450c11 or P450c17 activity.
Fludrocortisone
This compound, a potent steroid with both glucocorticoid and
mineralocorticoid activity, is the most widely used mineralocorti-
coid. Oral doses of 0.1 mg two to seven times weekly have potent
salt-retaining activity and are used in the treatment of adrenocor-
tical insufficiency associated with mineralocorticoid deficiency.
These dosages are too small to have important anti-inflammatory
or antigrowth effects.
ADRENAL ANDROGENS
The adrenal cortex secretes large amounts of DHEA and smaller
amounts of androstenedione and testosterone. Although these
androgens are thought to contribute to the normal maturation
process, they do not stimulate or support major androgen-
dependent pubertal changes in humans. Studies suggest that
DHEA and its sulfate may have other important physiologic
actions. If that is correct, these results are probably due to the
peripheral conversion of DHEA to more potent androgens or to
estrogens and interaction with androgen and estrogen receptors,
respectively. Additional effects may be exerted through an inter-
action with the GABAA and glutamate receptors in the brain or
with a nuclear receptor in several central and peripheral sites. The
therapeutic use of DHEA in humans has been explored, but the
substance has already been adopted with uncritical enthusiasm
by members of the sports drug culture and the vitamin and food
supplement culture.
The results of a placebo-controlled trial of DHEA in patients
with systemic lupus erythematosus have been reported as well as
those of a study of DHEA replacement in women with adrenal
insufficiency. In both studies a small beneficial effect was seen,
with significant improvement of the disease in the former and
a clearly added sense of well-being in the latter. The androgenic
or estrogenic actions of DHEA could explain the effects of the
compound in both situations. In contrast, there is no evidence
to support DHEA use to increase muscle strength or improve
memory.
■■ ANTAGONISTS OF
ADRENOCORTICAL AGENTS
SYNTHESIS INHIBITORS &
GLUCOCORTICOID ANTAGONISTS
Inhibitors of steroid synthesis act at several different steps and one
glucocorticoid antagonist acts at the receptor level.
Aminoglutethimide
Aminoglutethimide (Figure 39–5) blocks the conversion of
cholesterol to pregnenolone (see Figure 39–1) and causes a
reduction in the synthesis of all hormonally active steroids. It has
been used in conjunction with dexamethasone or hydrocortisone
to reduce or eliminate estrogen production in patients with
carcinoma of the breast. In a dosage of 1 g/d it was well toler-
ated; however, with higher dosages, lethargy and skin rash were
common effects. The use of aminoglutethimide in breast cancer
patients has now been supplanted by tamoxifen or by another
class of drugs, the aromatase inhibitors (see Chapters 40 and 54).
Aminoglutethimide can be used in conjunction with metyra-
pone or ketoconazole to reduce steroid secretion in patients with
Cushing’s syndrome due to adrenocortical cancer who do not
respond to mitotane.
Aminoglutethimide also apparently increases the clearance of
some steroids. It has been shown to enhance the metabolism of
dexamethasone, reducing its half-life from 4–5 hours to 2 hours.
Ketoconazole
Ketoconazole, an antifungal imidazole derivative (see Chapter 48),
is a potent and rather nonselective inhibitor of adrenal and
gonadal steroid synthesis. This compound inhibits the cholesterol
side-chain cleavage, P450c17, C17,20-lyase, 3β-hydroxysteroid
dehydrogenase, and P450c11 enzymes required for steroid hor-
mone synthesis. The sensitivity of the P450 enzymes to this
compound in mammalian tissues is much lower than that needed
to treat fungal infections, so that its inhibitory effects on steroid
biosynthesis are seen only at high doses.
Ketoconazole has been used in the treatment of patients
with Cushing’s syndrome due to several causes. Dosages of
200–1200 mg/d have caused a reduction in hormone levels
and clinical improvement in some patients. This drug has some
hepatotoxicity and should be started at 200 mg/d and slowly
increased by 200 mg/d every 2–3 days up to a total daily dose
of 1000 mg.
Etomidate
Etomidate [R-1-(1-ethylphenyl)imidazole-5-ethyl ester] is used
for induction of general anesthesia and sedation. At subhypnotic
doses of 0.1 mg/kg per hour this drug inhibits adrenal steroido-
genesis at the level of 11β-hydroxylase and has been used as the
only parenteral medication available in the treatment of severe
Cushing’s syndrome.
716    SECTION VII  Endocrine Drugs

CI CI CI N O CH3 N
CH C C
CI C CH3
H
Mitotane Metyrapone

C2H5

NH2

O O
N

H N
Aminoglutethimide
N CI

O CH2
O CI

CH3C N N OCH2 O
H

Ketoconazole

FIGURE 39–5  Some adrenocortical blockers. Because of their toxicity, some of these compounds are no longer available in the United States.

Metyrapone In patients with Cushing’s syndrome, a normal response to

Metyrapone (Figure 39–5) is a relatively selective inhibitor of
steroid 11-hydroxylation, interfering with cortisol and corticoste-
rone synthesis. In the presence of a normal pituitary gland, there
is a compensatory increase in pituitary ACTH release and adrenal
11-deoxycortisol secretion. This response is a measure of the
capacity of the anterior pituitary to produce ACTH and has been
adapted for clinical use as a diagnostic test. Although the toxicity
of metyrapone is much lower than that of mitotane (see text that
follows), the drug may produce transient dizziness and gastroin-
testinal disturbances. This agent has not been widely used in the
treatment of Cushing’s syndrome. However, in doses of 0.25 g
twice daily to 1 g four times daily, metyrapone can reduce cortisol
production to normal levels in some patients with endogenous
Cushing’s syndrome. Thus, it may be useful in the management
of severe manifestations of cortisol excess while the cause of this
condition is being determined or in conjunction with radiation
or surgical treatment. Metyrapone is the only adrenal-inhibiting
medication that can be administered to pregnant women with
Cushing’s syndrome. The major adverse effects observed are salt
and water retention and hirsutism resulting from diversion of the
11-deoxycortisol precursor to DOC and androgen synthesis.
Metyrapone is commonly used in tests of adrenal function.
The blood levels of 11-deoxycortisol and the urinary excretion of
17-hydroxycorticoids are measured before and after administra-
tion of the compound. Normally, there is a twofold or greater
increase in the urinary 17-hydroxycorticoid excretion. A dosage of
300–500 mg every 4 hours for six doses is often used, and urine
collections are made on the day before and the day after treatment.
metyrapone indicates that the cortisol excess is not the result of a
cortisol-secreting adrenal carcinoma or adenoma, since secretion
by such tumors produces suppression of ACTH and atrophy of
normal adrenal cortex.
Pituitary function may also be tested by administering metyra-
pone, 2–3 g orally at midnight and by measuring the level of ACTH
or 11-deoxycortisol in blood drawn at 8 am or by comparing
the excretion of 17-hydroxycorticosteroids in the urine during the
24-hour periods preceding and following administration of the
drug. In patients with suspected or known lesions of the pituitary,
this procedure is a means of estimating the ability of the gland to
produce ACTH. Metyrapone has been withdrawn from the market
in the United States but is available on a compassionate basis.
Trilostane
Trilostane is a 3β-17 hydroxysteroid dehydrogenase inhibitor that
interferes with the synthesis of adrenal and gonadal hormones and
is comparable to aminoglutethimide. Trilostane’s adverse effects
are predominantly gastrointestinal; adverse effects occur in about
50% of patients with both trilostane and aminoglutethimide.
There is no cross-resistance or crossover of side effects between
these compounds. Trilostane is not available in the United States.
Abiraterone
Abiraterone is the newest of the steroid synthesis inhibitors to be
approved. It blocks 17α-hydroxylase (P450c17) and 17,20-lyase
(Figure 39–1), and predictably reduces synthesis of cortisol in
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    717
the adrenal and gonadal steroids in the gonads. A compensatory
increase occurs in ACTH and aldosterone synthesis, but this can
be prevented by concomitant administration of dexamethasone.
Abiraterone is an orally active steroid prodrug and is approved for
the treatment of refractory prostate cancer.
Mifepristone (RU-486)
The search for a glucocorticoid receptor antagonist finally
succeeded in the early 1980s with the development of the
11β-aminophenyl-substituted 19-norsteroid called RU-486, later
named mifepristone. Unlike the enzyme inhibitors previously
discussed, mifepristone is a pharmacologic antagonist at the
steroid receptor. This compound has strong antiprogestin activity
and initially was proposed as a contraceptive-contragestive agent.
High doses of mifepristone exert antiglucocorticoid activity by
blocking the glucocorticoid receptor, since mifepristone binds
to it with high affinity, causing (1) some stabilization of the hsp-
glucocorticoid receptor complex and inhibition of the dissocia-
tion of the RU-486–bound glucocorticoid receptor from the hsp
chaperone proteins; and (2) alteration of the interaction of the
glucocorticoid receptor with coregulators, favoring the formation
of a transcriptionally inactive complex in the cell nucleus. The
result is inhibition of glucocorticoid receptor activation.
The mean half-life of mifepristone is 20 hours. This is longer
than that of many natural and synthetic glucocorticoid agonists
(dexamethasone has a half-life of 4–5 hours). Less than 1% of
the daily dose is excreted in the urine, suggesting a minor role of
kidneys in the clearance of the compound. The long plasma half-
life of mifepristone results from extensive and strong binding to
plasma proteins. Less than 5% of the compound is found in the
free form when plasma is analyzed by equilibrium dialysis. Mife-
pristone can bind to albumin and α1-acid glycoprotein, but it has
no affinity for corticosteroid-binding globulin.
In humans, mifepristone causes generalized glucocorticoid
resistance. Given orally to several patients with Cushing’s syn-
drome due to ectopic ACTH production or adrenal carcinoma,
it was able to reverse the cushingoid phenotype, eliminate car-
bohydrate intolerance, normalize blood pressure, correct thyroid
and gonadal hormone suppression, and to ameliorate the psycho-
logical sequelae of hypercortisolism in these patients. At present,
this use of mifepristone can only be recommended for inoperable
patients with ectopic ACTH secretion or adrenal carcinoma who
have failed to respond to other therapeutic manipulations. Its
pharmacology and use in women as a progesterone antagonist are
discussed in Chapter 40.
Mitotane
Mitotane (Figure 39–5), a drug related to the DDT class of insec-
ticides, has a nonselective cytotoxic action on the adrenal cortex
in dogs and to a lesser extent in humans. This drug is adminis-
tered orally in divided doses up to 12 g daily. About one-third
of patients with adrenal carcinoma show a reduction in tumor
mass. In 80% of patients, the toxic effects are sufficiently severe
to require dose reduction. These include diarrhea, nausea, vomit-
ing, depression, somnolence, and skin rashes. The drug has been
withdrawn from the market in the United States but is available
on a compassionate basis.
MINERALOCORTICOID ANTAGONISTS
In addition to agents that interfere with aldosterone synthesis (see
above), there are steroids that compete with aldosterone for its
receptor and decrease its effect peripherally. Progesterone is mildly
active in this respect.
Spironolactone is a 7α-acetylthiospirolactone. Its onset of action
is slow, and the effects last for 2–3 days after the drug is discontin-
ued. It is used in the treatment of primary aldosteronism in dosages
of 50–100 mg/d. This agent reverses many of the manifestations
of aldosteronism. It has been useful in establishing the diagnosis in
some patients and in ameliorating the signs and symptoms when
surgical removal of an adenoma is delayed. When used diagnosti-
cally for the detection of aldosteronism in hypokalemic patients
with hypertension, dosages of 400–500 mg/d for 4–8 days—with an
adequate intake of sodium and potassium—restore potassium levels
to or toward normal. Spironolactone is also useful in preparing these
patients for surgery. Dosages of 300–400 mg/d for 2 weeks are used
for this purpose and may reduce the incidence of cardiac arrhythmias.
O
O
H3C
H3C
O
O
S C CH3
Spironolactone
Spironolactone is also an androgen antagonist and as such is
sometimes used in the treatment of hirsutism and acne in women.
Dosages of 50–200 mg/d cause a reduction in the density, diameter,
and rate of growth of facial hair in patients with idiopathic hirsut-
ism or hirsutism secondary to androgen excess. The effect can usu-
ally be seen in 2 months and becomes maximal in about 6 months.
Spironolactone as a diuretic is discussed in Chapter 15. The
drug has benefits in heart failure greater than those predicted from
its diuretic effects alone (see Chapter 13). Adverse effects reported
for spironolactone include hyperkalemia, cardiac arrhythmia,
menstrual abnormalities, gynecomastia, sedation, headache,
gastrointestinal disturbances, and skin rashes.
Eplerenone, another aldosterone antagonist, is approved for
the treatment of hypertension and heart failure (see Chapters 11,
13, and 15). Like spironolactone, eplerenone has also been found
to reduce mortality in heart failure. This aldosterone receptor
antagonist is somewhat more selective than spironolactone and
has no reported effects on androgen receptors. The standard dos-
age in hypertension is 50–100 mg/d. The most common toxicity
is hyperkalemia, but this is usually mild.
Drospirenone, a progestin, is an oral contraceptive (see
Chapter 40), and also antagonizes the effects of aldosterone.
718    SECTION VII  Endocrine Drugs

P R E P A R A T I O N S Chrousos GP: Stress and disorders of the stress system. Nat Rev Endocrinol
2009;5:374.
A V A I L A B L E Chrousos GP, Kino T: Glucocorticoid signaling in the cell: Expanding clinical
implications to complex human behavioral and somatic disorders. In:
Glucocorticoids and mood: Clinical manifestations, risk factors, and molec-
GENERIC NAME AVAILABLE AS ular mechanisms. Proc NY Acad Sci 2009;1179:153.
*
GLUCOCORTICOIDS FOR ORAL & PARENTERAL USE Cutolo M, Chrousos GP, Pincus T: Special issue on glucocorticoid therapy in
Betamethasone Celestone rheumatic diseases. Neuroimmunomodulation. 2015;22:3.
Betamethasone sodium phosphate Generic, Celestone Phosphate Elenkov IJ, Chrousos GP: Stress hormones, TH1/TH2 patterns, pro/anti-inflammatory
cytokines and susceptibility to disease. Trends Endocrinol Metab 1999;10:359.
Budesonide Generic, Entocort EC
Elenkov IJ et al: Cytokine dysregulation, inflammation, and wellbeing. Neuroim-
Cortisone Generic munomodulation 2005;12:255.
Dexamethasone Generic, Decadron Franchimont D et al: Glucocorticoids and inflammation revisited: The state of the
Dexamethasone sodium phosphate Generic art. Neuroimmunomodulation 2002–2003;10:247.
Hydrocortisone (cortisol) Generic, Cortef Graber AL et al: Natural history of pituitary-adrenal recovery following long-term
suppression with corticosteroids. J Clin Endocrinol Metab 1965;25:11.
Hydrocortisone acetate Generic
Hochberg Z, Pacak K, Chrousos GP: Endocrine withdrawal syndromes. Endocr
Hydrocortisone sodium phosphate Hydrocortone Rev 2003;24:523.
Hydrocortisone sodium succinate Generic, Solu-Cortef, others Kalantaridou S, Chrousos GP: Clinical review 148: Monogenic disorders of
Methylprednisolone Generic, Medrol puberty. J Clin Endocrinol Metab 2002;87:2481.
Methylprednisolone acetate Generic, Depo-Medrol Kino T, Charmandari E, Chrousos G (editors): Glucocorticoid action: Basic and
clinical implications. Ann NY Acad Sci 2004;1024.
Methylprednisolone sodium Generic, Solu-Medrol, others
Kino T et al: The GTP-binding (G) protein β interacts with the activated gluco-
succinate
corticoid receptor and suppresses its transcriptional activity in the nucleus.
Prednisolone Generic, Prelone, others J Cell Biol 2005;20:885.
Prednisolone acetate Generic, Flo-Pred Koch CA, Chrousos GP (editors): Endocrine hypertension: Underlying mecha-
Prednisolone sodium phosphate Generic, Hydeltrasol nisms and therapy. In: Contemporary Endocrinology, vol XIII. Springer, 2013.
Prednisone Generic, Deltasone, Prednicot Koch CA, Pacak K, Chrousos GP: The molecular pathogenesis of hereditary and
sporadic adrenocortical and adrenomedullary tumors. J Clin Endocrinol
Triamcinolone acetonide Generic, Kenalog, Azmacort Metab 2002;87:5367.
Triamcinolone hexacetonide Aristospan Mao J, Regelson W, Kalimi M: Molecular mechanism of RU 486 action: A review.
MINERALOCORTICOIDS Mol Cellular Biochem 1992;109:1.
Fludrocortisone acetate Generic, Florinef Acetate, Marik PE et al: Clinical practice guidelines for the diagnosis and management of
Cortineff Acetate corticosteroid insufficiency in critical illness: Recommendations of an inter-
national task force. Crit Care Med 2008;36:1937.
ADRENAL STEROID INHIBITORS
Markou A et al: Stress-induced aldosterone hyper-secretion in a substantial
Abiraterone Zytiga subset of patients with essential hypertension. J Clin Endocrinol Metab.
Ketoconazole Generic, Nizoral 2015;100:2857.
Etomidate Amidate Meduri GU et al: Activation and regulation of systemic inflammation in ARDS:
Rationale for prolonged glucocorticoid therapy. Chest 2009;136:1631.
Mifepristone Mifeprex, Korlym
Meduri GU et al: Steroid treatment in ARDS: A critical appraisal of the ARDS
Mitotane Lysodren network trial and the recent literature. Intens Care Med 2008;34:61.
Glucocorticoids for respiratory use: See Chapter 20. Glucocorticoids for dermatologic Merke DP et al: Future directions in the study and management of congenital
use: See Chapter 61. Glucocorticoids for gastrointestinal use: See Chapter 62. adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Intern Med
2002;136:320.
Nader N, Chrousos GP, Kino T: Interactions of the circadian CLOCK system and
the HPA axis. Trends Endocrinol Metab 2010;21:277.
REFERENCES Papanastasiou L et al: Primary aldosteronism in hypertensive patients: Clinical
Alesci S et al: Glucocorticoid-induced osteoporosis: From basic mechanisms to implications and target therapy. Eur J Clin Invest. 2014;44:697.
clinical aspects. Neuroimmunomodulation 2005;12:1. Pervanidou P, Kanaka-Gantenbein C, Chrousos GP: Assessment of metabolic
Bamberger CM, Schulte HM, Chrousos GP: Molecular determinants of gluco- profile in a clinical setting. Curr Opin Clin Nutr Metab Care 2006;9:589.
corticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Preda VA et al: Etomidate in the management of hypercortisolaemia in Cushing’s
Rev 1996;17:245. syndrome: A review. Eur J Endocrinol 2012;167:137.
Charmandari E et al: Peripheral CLOCK regulates target-tissue glucocorticoid Tsigos C, Chrousos GP: Differential diagnosis and management of Cushing’s
receptor transcriptional activity in a circadian fashion in man. PLoS One syndrome. Annu Rev Med 1996;47:443.
2011;6:e25612.
Whitaker MJ et al: An oral multiparticulate, modified-release, hydrocortisone
Charmandari E, Kino T: Chrousos syndrome: A seminal report, a phylogenetic replacement therapy that provides physiological cortisol exposure. Clin
enigma and the clinical implications of glucocorticoid signaling changes. Eur Endocrinol (Oxf ) 2014;80:554.
J Clin Invest 2010;40:932.
Zannas AS, Chrousos GP. Glucocorticoid signaling drives epigenetic and tran-
Charmandari E, Nicolaides NC, Chrousos GP: Adrenal insufficiency. Lancet. scription factors to induce key regulators of human parturition. Sci Signal
2014;383:2152. 2015;8:fs19.
Charmandari E, Tsigos C, Chrousos GP: Neuroendocrinology of stress. Ann Rev
Physiol 2005;67:259.
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    719

C ASE STUDY ANSWER

The patient should be placed on replacement oral hydrocor- for increased treatment at 2 times standard glucocorticoid
tisone at 10 mg/m2 per day and fludrocortisone at 75 mcg/d. dosage for 24 hours for minor stress and 10 times replace-
He should be given a MedicAlert bracelet and instructions ment of hydrocortisone for major stress over 48 hours.
 40
C H A P T E R
The Gonadal Hormones
& Inhibitors
George P. Chrousos, MD
C ASE STUDY
A 25-year-old woman with menarche at 13 years and
menstrual periods until about 1 year ago complains of hot
flushes, skin and vaginal dryness, weakness, poor sleep, and
scanty and infrequent menstrual periods of a year’s dura-
tion. She visits her gynecologist, who obtains plasma levels
of follicle-stimulating hormone and luteinizing hormone,
both of which are moderately elevated. She is diagnosed
■■ THE OVARY (ESTROGENS,
PROGESTINS, OTHER
OVARIAN HORMONES, ORAL
CONTRACEPTIVES, INHIBITORS
& ANTAGONISTS, & OVULATION-
INDUCING AGENTS)
The ovary has important gametogenic functions that are inte-
grated with its hormonal activity. In the human female, the
gonad is relatively quiescent during childhood, the period of
rapid growth and maturation. At puberty, the ovary begins a
30- to 40-year period of cyclic function called the menstrual
cycle because of the regular episodes of bleeding that are its most
obvious manifestation. It then fails to respond to gonadotropins
secreted by the anterior pituitary gland, and the cessation of cyclic
bleeding that occurs is called menopause.
The mechanism responsible for the onset of ovarian func-
tion at the time of puberty is thought to be neural in origin,
because the immature gonad can be stimulated by gonadotro-
pins already present in the pituitary and because the pituitary is
responsive to exogenous hypothalamic gonadotropin-releasing
720
with premature ovarian failure, and estrogen and pro-
gesterone replacement therapy is recommended. A dual-
energy absorptiometry scan (DEXA) reveals a bone density
t-score of <2.5 SD, ie, frank osteoporosis. How should the
ovarian hormones she lacks be replaced? What extra mea-
sures should she take for her osteoporosis while receiving
treatment?
hormone (GnRH). Despite extensive research in the field, the
mechanism of puberty initiation still remains an enigma. Pulsatile
pituitary gonadotropin secretion under the guidance of GnRH
definitely constitutes a sine qua non for pubertal onset. However,
the secretion of GnRH in the human hypothalamus is regulated
by kisspeptin and its receptor, as well as by permissive or opposing
signals mediated by neurokinin B and dynorphin acting on their
respective receptors. These three supra-GnRH regulators com-
pose the Kisspeptin, Neurokinin B, and Dynorphin neuron
(KNDy) system, a key player in pubertal onset and progression.
Recently, makorin ring finger protein 3 (MKRN3) was also
implicated in pubertal onset by contributing to the regulation
of the KNDy system. However, the inhibitory (gamma-amino
butyric acid, neuropeptide Y, and RFamide-related peptide-3)
and stimulatory (glutamate) signals acting upstream of KNDy call
into question the primary role of MKRN3 as the gatekeeper of
puberty. Recently, epigenetic mechanisms involving derepression
of genes, such as that of kisspeptin, have been implicated in puber-
tal onset. Ultimately, withdrawal of a childhood-related inhibitory
effect upon hypothalamic arcuate nucleus neurons allows these
neurons to produce GnRH in pulses with the appropriate ampli-
tude, which stimulate the release of follicle-stimulating hormone
(FSH) and luteinizing hormone (LH) (see Chapter 37). At first,
 CHAPTER 40  The Gonadal Hormones & Inhibitors     721

ACRONYMS a corpus albicans. The endometrium, which proliferated during

the follicular phase and developed its glandular function during
CBG Corticosteroid-binding globulin (transcortin)
the luteal phase, is shed in the process of menstruation. These
DHEA Dehydroepiandrosterone events are summarized in Figure 40–1.
DHEAS Dehydroepiandrosterone sulfate The ovary normally ceases its gametogenic and endocrine
ERE Estrogen response element function with time. This change is accompanied by a cessation
FSH Follicle-stimulating hormone in uterine bleeding (menopause) and occurs at a mean age of
52 years in the United States. Although the ovary ceases to secrete
GnRH Gonadotropin-releasing hormone
estrogen, significant levels of estrogen persist in many women as a
HDL High-density lipoprotein
result of conversion of adrenal and ovarian steroids such as andro-
HRT Hormone replacement therapy (also called HT) stenedione to estrone and estradiol in adipose and possibly other
LDL Low-density lipoprotein nonendocrine tissues.
LH Luteinizing hormone
PRE Progesterone response element A. Disturbances in Ovarian Function
SERM Selective estrogen receptor modulator Disturbances of cyclic function are common even during the peak
years of reproduction. A minority of these result from inflam-
SHBG Sex hormone-binding globulin
matory or neoplastic processes that influence the functions of
TBG Thyroxine-binding globulin
the uterus, ovaries, or pituitary. Many of the minor disturbances
leading to periods of amenorrhea or anovulatory cycles are

small amounts of the latter two hormones are released during the
night, and the limited quantities of ovarian estrogen secreted in Follicular development
response start to cause breast development. Subsequently, FSH
and LH are secreted throughout the day and night, causing secre-
tion of higher amounts of estrogen and leading to further breast
enlargement, alterations in fat distribution, and a growth spurt
that culminates in epiphyseal closure in the long bones. The
change of ovarian function at puberty is called gonadarche. Endometrium
A year or so after gonadarche, sufficient estrogen is produced
to induce endometrial changes and periodic bleeding (menarche).
After the first few irregular cycles, which may be anovulatory,
normal cyclic function is established. 0 7 14 21 28
At the beginning of each cycle, a variable number of follicles Days
(vesicular follicles), each containing an ovum, begin to enlarge 80
in response to FSH. After 5 or 6 days, one follicle, called the Gonadotropins
dominant follicle, begins to develop more rapidly. The outer 60
theca and inner granulosa cells of this follicle multiply and,
mIU/mL

under the influence of LH, synthesize and release estrogens at 40

an increasing rate. The estrogens appear to inhibit FSH release
LH FSH
and may lead to regression of the smaller, less mature follicles.
20
The mature dominant ovarian follicle consists of an ovum sur-
rounded by a fluid-filled antrum lined by granulosa and theca
0
cells. The estrogen secretion reaches a peak just before midcycle,
400
and the granulosa cells begin to secrete progesterone. These
Estradiol
changes stimulate the brief surge in LH and FSH release that
pg/mL

precedes and causes ovulation. When the follicle ruptures, the 200
ovum is released into the abdominal cavity near the opening of
0
the uterine tube.
Following the above events, the cavity of the ruptured fol- 20
licle fills with blood (corpus hemorrhagicum), and the lutein- Progesterone
ng/mL

ized theca and granulosa cells proliferate and replace the blood
to form the corpus luteum. The cells of this structure produce
estrogens and progesterone for the remainder of the cycle, or 0
1 7 14 21 28
longer if pregnancy occurs.
If pregnancy does not occur, the corpus luteum begins to FIGURE 40–1  The menstrual cycle, showing plasma levels of
degenerate and ceases hormone production, eventually becoming pituitary and ovarian hormones and histologic changes.
722    SECTION VII  Endocrine Drugs

self-limited. They are often associated with emotional or physical
stress and reflect temporary alterations in the stress centers in the
brain that control the secretion of GnRH. Anovulatory cycles are
also associated with eating disorders (bulimia, anorexia nervosa)
and with severe exercise such as distance running and swimming.
Among the more common organic causes of persistent ovulatory
disturbances are pituitary prolactinomas and syndromes and
tumors characterized by excessive ovarian or adrenal androgen
production. Normal ovarian function can be modified by andro-
gens produced by the adrenal cortex or tumors arising from it.
The ovary also gives rise to androgen-producing neoplasms such
as arrhenoblastomas, as well as to estrogen-producing granulosa
cell tumors.
THE ESTROGENS
Estrogenic activity is shared by a large number of chemical sub-
stances. In addition to the variety of steroidal estrogens derived
from animal sources, numerous nonsteroidal estrogens have
been synthesized. Many phenols are estrogenic, and estrogenic
activity has been identified in diverse forms of life including
those found in ocean sediments. Estrogen-mimetic compounds
(flavonoids) are found in many plants, including saw palmetto,
and soybeans and other foods. A diet rich in these plant prod-
ucts may cause slight estrogenic effects. Additionally, some
compounds used in the manufacture of plastics (bisphenols,
alkylphenols, phthalate phenols) have been found to be estro-
genic. It has been proposed that these agents are associated
with an increased breast cancer incidence in both women and
men in the industrialized world.
Natural Estrogens
The major estrogens produced by women are estradiol (estradiol-
17β, E2), estrone (E1), and estriol (E3) (Figure 40–2). Estradiol
is the major secretory product of the ovary. Although some
estrone is produced in the ovary, most estrone and estriol are
formed in the liver from estradiol or in peripheral tissues from
androstenedione and other androgens (see Figure 39–1). As
noted above, during the first part of the menstrual cycle estro-
gens are produced in the ovarian follicle by the theca and granu-
losa cells. After ovulation, the estrogens as well as progesterone

Follicular phase Luteal phase

Pregnenolone Pregnenolone

17α-Hydroxypregnenolone Progesterone

Dehydroepiandrosterone 17α-Hydroxyprogesterone

18 O OH
H3C H3C
12 17
19 11 13 16
H3C 14 15 H3C
1 9
2 10 8
3 5 7
4 6
O O
Androstenedione Testosterone

Aromatase

OH O O OH
H3C H3C H3C H3C
OH OH
C D

A B
HO HO HO HO
Estriol 16α-Hydroxyestrone Estrone 17β-Estradiol

2-Hydroxyestrone 2-Hydroxyestradiol
and other metabolites and other metabolites

FIGURE 40–2  Biosynthesis and metabolism of estrogens and testosterone.

 CHAPTER 40  The Gonadal Hormones & Inhibitors     723

are synthesized by the luteinized granulosa and theca cells of
the corpus luteum, and the pathways of biosynthesis are slightly
different.
During pregnancy, a large amount of estrogen is synthesized
by the fetoplacental unit—consisting of the fetal adrenal zone,
secreting androgen precursor, and the placenta, which aromatizes
it into estrogen. The estriol synthesized by the fetoplacental unit is
released into the maternal circulation and excreted into the urine.
Repeated assay of maternal urinary estriol excretion has been used
in the assessment of fetal well-being.
One of the most prolific natural sources of estrogenic sub-
stances is the stallion, which liberates more of these hormones than
the pregnant mare or pregnant woman. The equine estrogens—
equilenin and equilin—and their congeners are unsaturated in
the B as well as the A ring and are excreted in large quantities in
urine, from which they can be recovered and used for medicinal
purposes.
In normal women, estradiol is produced at a rate that varies
during the menstrual cycle, resulting in plasma levels as low as
50 pg/mL in the early follicular phase to as high as 350–850 pg/mL
at the time of the preovulatory peak (Figure 40–1).
Synthetic Estrogens
A variety of chemical alterations have been applied to the natural
estrogens. The most important effect of these alterations has been
to increase their oral effectiveness. Some structures are shown in
Figure 40–3. Those with therapeutic use are listed in Table 40–1.
In addition to the steroidal estrogens, a variety of nonsteroidal
compounds with estrogenic activity have been synthesized and
used clinically. These include dienestrol, diethylstilbestrol, benzes-
trol, hexestrol, methestrol, methallenestril, and chlorotrianisene.
Pharmacokinetics
When released into the circulation, estradiol binds strongly to an
α2 globulin (sex hormone–binding globulin [SHBG]) and with
lower affinity to albumin. Bound estrogen is relatively unavailable
for diffusion into cells, and it is the free fraction that is physiologi-
cally active. Estradiol is converted by the liver and other tissues
to estrone and estriol (Figure 40–2) and their 2-hydroxylated
derivatives and conjugated metabolites (which are too insoluble
in lipid to cross the cell membrane readily) and excreted in the
bile. Estrone and estriol have low affinity for the estrogen receptor.

Steroidal,
natural
OH O OH
H3C H3C H3C
OH

HO HO HO
Estradiol Estrone Estriol

Steroidal,
synthetic
OH OH OH
H3C 20 21 H3C H3C
C CH C CH C CH

HO H3C O O

Ethinyl estradiol Mestranol Quinestrol

Nonsteroidal,
synthetic

CH3 Cl

CH2 H3C O C C O CH3 C2H5 CH3

HO C C OH CH C COOH

CH2 H3C O CH3

CH3 O CH3

Diethylstilbestrol Chlorotrianisene Methallenestril

FIGURE 40–3  Compounds with estrogenic activity.

724    SECTION VII  Endocrine Drugs
TABLE 40–1  Commonly used estrogens.
Preparation Average Replacement Dosage
Ethinyl estradiol 0.005–0.02 mg/d
Micronized estradiol 1–2 mg/d
Estradiol cypionate 2–5 mg every 3–4 weeks
Estradiol valerate 2–20 mg every other week
Estropipate 1.25–2.5 mg/d
Conjugated, esterified, or mixed estrogenic substances:
 Oral 0.3–1.25 mg/d
 Injectable 0.2–2 mg/d
 Transdermal Patch
Quinestrol 0.1–0.2 mg/week
Chlorotrianisene 12–25 mg/d
Methallenestril 3–9 mg/d
However, the conjugates may be hydrolyzed in the intestine to
active, reabsorbable compounds. Estrogens are also excreted in
small amounts in the breast milk of nursing mothers.
Because significant amounts of estrogens and their active
metabolites are excreted in the bile and reabsorbed from the
intestine, the resulting enterohepatic circulation ensures that
orally administered estrogens will have a high ratio of hepatic to
peripheral effects. As noted below, the hepatic effects are thought
to be responsible for some undesirable actions such as synthesis of
increased clotting factors and plasma renin substrate. The hepatic
effects of estrogen can be minimized by routes that avoid first-pass
liver exposure, ie, vaginal, transdermal, or by injection.
Physiologic Effects
A. Mechanism
Estrogens in the blood and interstitial fluid are bound to SHBG,
from which they dissociate to cross the cell membrane, enter
the nucleus, and bind to their receptor. Two genes code for two
estrogen receptor isoforms, α and β, which are members of the
superfamily of steroid, sterol, retinoic acid, and thyroid receptors.
Unlike glucocorticoid receptors, estrogen receptors are found pre-
dominantly in the nucleus, where they are bound to heat shock
proteins that stabilize them (see Figure 39–4).
Binding of the hormone to its receptor alters the recep-
tor’s conformation and releases it from the stabilizing proteins
(predominantly Hsp90). The receptor-hormone complex forms
dimers (usually ERα-ERα, ERβ-ERβ, or ERα-ERβ) that bind
to a specific sequence of nucleotides, called estrogen response
elements (EREs), in the regulatory regions of various genes
and regulate their transcription. The ERE is composed of two
half-sites arranged as a palindrome separated by a small group of
nucleotides called the spacer. The interaction of a receptor dimer
with the ERE also involves a number of nuclear proteins, the
coregulators, as well as components of the transcription machin-
ery. Complex interactions with various coregulators appear to be
responsible for some of the tissue-specific effects that govern the
actions of selective estrogen receptor modulators (SERMs, see
below). The receptor may also bind to other transcription factors
to influence the effects of these factors on their responsive genes.
Interestingly, although ERβ has its own separate actions from
ERα, it also acts as a dominant negative inhibitor of ERα. Thus,
while ERα has many growth-promoting properties, ERβ has anti-
growth effects. Many phytoestrogens act via the ERβ protecting
cells from the pro-growth effects of ERα.
The relative concentrations and types of receptors, receptor
coregulators, and transcription factors confer the cell specificity
of the hormone’s actions. The genomic effects of estrogens are
mainly due to proteins synthesized by translation of RNA tran-
scribed from a responsive gene. Some of the effects of estrogens
are indirect, mediated by the autocrine and paracrine actions of
autacoids such as growth factors, lipids, glycolipids, and cytokines
produced by the target cells in response to estrogen.
2+
Rapid estrogen-induced effects such as granulosa cell Ca
uptake and increased uterine blood flow do not require gene
activation. These appear to be mediated by nongenomic effects of
the classic estrogen receptor-estrogen complex, influencing several
intracellular signaling pathways.
Recently, all steroid receptors except the mineralocorticoid
receptors were shown to have palmitoylation motifs that allow
enzymatic addition of palmitate and increased localization of the
receptors in the vicinity of plasma membranes. Such receptors
are available for direct interactions with, and effects on, various
membrane-associated or cytoplasmic proteins without the need
for entry into the nucleus and induction of transcriptional actions.
B. Female Maturation
Estrogens are required for the normal sexual maturation and
growth of the female. They stimulate the development of the
vagina, uterus, and uterine tubes as well as the secondary sex
characteristics. They stimulate stromal development and ductal
growth in the breast and are responsible for the accelerated growth
phase and the closing of the epiphyses of the long bones that
occur at puberty. They contribute to the growth of axillary and
pubic hair and alter the distribution of body fat to produce typical
female body contours. Larger quantities also stimulate develop-
ment of pigmentation in the skin, most prominent in the region
of the nipples and areolae and in the genital region.
C. Endometrial Effects
In addition to its growth effects on uterine muscle, estrogen plays
an important role in the development of the endometrial lin-
ing. When estrogen production is properly coordinated with the
production of progesterone during the normal human menstrual
cycle, regular periodic bleeding and shedding of the endometrial
lining occur. Continuous exposure to estrogens for prolonged
periods leads to hyperplasia of the endometrium that is usually
associated with abnormal bleeding patterns.
D. Metabolic and Cardiovascular Effects
Estrogens have a number of important metabolic and cardiovascu-
lar effects. They seem to be partially responsible for maintenance

of the normal structure and function of the skin and blood vessels
in women. Estrogens also decrease the rate of resorption of bone
by promoting the apoptosis of osteoclasts and by antagonizing
the osteoclastogenic and pro-osteoclastic effects of parathyroid
hormone and interleukin 6. Estrogens also stimulate adipose tis-
sue production of leptin and are in part responsible for the higher
levels of this hormone in women than in men.
In addition to stimulating the synthesis of enzymes and growth
factors leading to uterine and breast growth and differentiation,
estrogens alter the production and activity of many other proteins
in the body. Metabolic alterations in the liver are especially impor-
tant, so that there is a higher circulating level of proteins such as
transcortin (corticosteroid-binding globulin [CBG]), thyroxine-
binding globulin (TBG), SHBG, transferrin, renin substrate, and
fibrinogen. This leads to increased circulating levels of thyroxine,
estrogen, testosterone, iron, copper, and other substances.
Alterations in the composition of the plasma lipids caused by
estrogens are characterized by an increase in the high-density lipo-
proteins (HDL), a slight reduction in the low-density lipoproteins
(LDL), and a reduction in total plasma cholesterol levels. Plasma
triglyceride levels are increased. Estrogens decrease hepatic oxida-
tion of adipose tissue lipid to ketones and increase synthesis of
triglycerides.
E. Effects on Blood Coagulation
Estrogens enhance the coagulability of blood. Many changes
in factors influencing coagulation have been reported, includ-
ing increased circulating levels of factors II, VII, IX, and X
and decreased antithrombin III, partially as a result of the
hepatic effects mentioned above. Increased plasminogen levels
and decreased platelet adhesiveness have also been found (see
Hormonal Contraception, below).
F. Other Effects
Estrogens induce the synthesis of progesterone receptors. They
are responsible for estrous behavior in animals and may influ-
ence behavior and libido in humans. Administration of estrogens
stimulates central components of the stress system, including the
production of corticotropin-releasing hormone and the activity
of the sympathetic system, and promotes a sense of well-being
when given to women who are estrogen-deficient. They also
facilitate the loss of intravascular fluid into the extracellular space,
producing edema. The resulting decrease in plasma volume causes
a compensatory retention of sodium and water by the kidney.
Estrogens also modulate sympathetic nervous system control of
smooth muscle function.
Clinical Uses*
A. Primary Hypogonadism
Estrogens have been used extensively for replacement therapy
in estrogen-deficient patients. The estrogen deficiency may be
due to primary failure of development of the ovaries, premature
menopause, castration, or menopause.
*
The use of estrogens in contraception is discussed later in this chapter.
CHAPTER 40  The Gonadal Hormones & Inhibitors     725
Treatment of primary hypogonadism is usually begun at
11–13 years of age in order to stimulate the development of
secondary sex characteristics and menses, to stimulate optimal
growth, to prevent osteoporosis, and to avoid the psychologi-
cal consequences of delayed puberty and estrogen deficiency.
Treatment attempts to mimic the physiology of puberty. It is ini-
tiated with small doses of estrogen (0.3 mg conjugated estrogens
or 5–10 mcg ethinyl estradiol) on days 1–21 each month and
is slowly increased to adult doses and then maintained until the
age of menopause (approximately 51 years of age). A progestin is
added after the first uterine bleeding. When growth is completed,
chronic therapy consists mainly of the administration of adult
doses of both estrogens and progestins, as described below.
B. Postmenopausal Hormonal Therapy
In addition to the signs and symptoms that follow closely
upon the cessation of normal ovarian function—such as loss of
menstrual periods, vasomotor symptoms, sleep disturbances, and
genital atrophy—there are longer-lasting changes that influence
the health and well-being of postmenopausal women. These
include an acceleration of bone loss, which in susceptible women
may lead to vertebral, hip, and wrist fractures; and lipid changes,
which may contribute to the acceleration of atherosclerotic cardio-
vascular disease noted in postmenopausal women. The effects of
estrogens on bone have been extensively studied, and the effects
of hormone withdrawal have been well-characterized. However,
the role of estrogens and progestins in the cause and prevention
of cardiovascular disease, which is responsible for 350,000 deaths
per year, and breast cancer, which causes 35,000 deaths per year,
is less well understood.
When normal ovulatory function ceases and the estrogen
levels fall after menopause, oophorectomy, or premature ovarian
failure, there is an accelerated rise in plasma cholesterol and LDL
concentrations, while LDL receptors decline. HDL is not much
affected, and levels remain higher than in men. Very-low-density
lipoprotein and triglyceride levels are also relatively unaffected.
Since cardiovascular disorders account for most deaths in this age
group, the risk for these disorders constitutes a major consider-
ation in deciding whether hormonal “replacement” therapy (HRT,
also correctly called HT) is indicated and influences the selection
of hormones to be administered. Estrogen replacement therapy
has a beneficial effect on circulating lipids and lipoproteins, and
this was earlier thought to be accompanied by a reduction in myo-
cardial infarction by about 50% and of fatal strokes by as much as
40%. These findings, however, have been disputed by the results
of a large study from the Women’s Health Initiative (WHI) project
showing no cardiovascular benefit from estrogen plus progestin
replacement therapy in perimenopausal or older postmenopausal
patients. In fact, there may be a small increase in cardiovascular
problems as well as breast cancer in women who received the
replacement therapy. Interestingly, a small protective effect against
colon cancer was observed. Although current clinical guidelines
do not recommend routine hormone therapy in postmenopausal
women, the validity of the WHI report has been questioned. In
any case, there is no increased risk for breast cancer if therapy is
given immediately after menopause and for the first 7 years, while
726    SECTION VII  Endocrine Drugs
the cardiovascular risk depends on the degree of atherosclerosis
at the onset of therapy. Transdermal or vaginal administration
of estrogen may be associated with decreased cardiovascular risk
because it bypasses the liver circulation. Women with premature
menopause should definitely receive hormone therapy.
In some studies, a protective effect of estrogen replacement
therapy against Alzheimer’s disease was observed. However, several
other studies have not supported these results.
Progestins antagonize estrogen’s effects on LDL and HDL to
a variable extent. However, one large study has shown that the
addition of a progestin to estrogen replacement therapy does not
influence the cardiovascular risk.
Optimal management of the postmenopausal patient requires
careful assessment of her symptoms as well as consideration of her
age and the presence of (or risks for) cardiovascular disease, osteo-
porosis, breast cancer, and endometrial cancer. Bearing in mind
the effects of the gonadal hormones on each of these disorders,
the goals of therapy can then be defined and the risks of therapy
assessed and discussed with the patient.
If the main indication for therapy is hot flushes and sleep distur-
bances, therapy with the lowest dose of estrogen required for symp-
tomatic relief is recommended. Treatment may be required for only
a limited period of time and the possible increased risk for breast
cancer avoided. In women who have undergone hysterectomy,
estrogens alone can be given 5 days per week or continuously, since
progestins are not required to reduce the risk for endometrial hyper-
plasia and cancer. Hot flushes, sweating, insomnia, and atrophic
vaginitis are generally relieved by estrogens; many patients experi-
ence some increased sense of well-being; and climacteric depression
and other psychopathologic states are improved.
The role of estrogens in the prevention and treatment of osteo-
porosis has been carefully studied (see Chapter 42). The amount
of bone present in the body is maximal in the young active adult
in the third decade of life and begins to decline more rapidly in
middle age in both men and women. The development of osteo-
porosis also depends on the amount of bone present at the start of
this process, on vitamin D and calcium intake, and on the degree
of physical activity. The risk of osteoporosis is highest in smokers
who are thin, Caucasian, and inactive and have a low calcium
intake and a strong family history of osteoporosis. Depression also
is a major risk factor for development of osteoporosis in women.
Estrogens should be used in the smallest dosage consistent
with relief of symptoms. In women who have not undergone hys-
terectomy, it is most convenient to prescribe estrogen on the first
21–25 days of each month. The recommended dosages of estro-
gen are 0.3–1.25 mg/d of conjugated estrogen or 0.01–0.02 mg/d
of ethinyl estradiol. Dosages in the middle of these ranges have
been shown to be maximally effective in preventing the decrease
in bone density occurring at menopause. From this point of view,
it is important to begin therapy as soon as possible after the meno-
pause for maximum effect. In these patients and others not taking
estrogen, calcium supplements that bring the total daily calcium
intake up to 1500 mg are useful.
Patients at low risk of developing osteoporosis who mani-
fest only mild atrophic vaginitis can be treated with topical
preparations. The vaginal route of application is also useful in the
treatment of urinary tract symptoms in these patients. It is impor-
tant to realize, however, that although locally administered estro-
gens escape the first-pass effect (so that some undesirable hepatic
effects are reduced), they are almost completely absorbed into the
circulation, and these preparations should be given cyclically.
As noted below, the administration of estrogen is associated
with an increased risk of endometrial carcinoma. The administra-
tion of a progestational agent with the estrogen prevents endo-
metrial hyperplasia and markedly reduces the risk of this cancer.
When estrogen is given for the first 25 days of the month and the
progestin medroxyprogesterone (10 mg/d) is added during the last
10–14 days, the risk is only half of that in women not receiving
hormone replacement therapy. On this regimen, some women will
experience a return of symptoms during the period off estrogen
administration. In these patients, the estrogen can be given con-
tinuously. If the progestin produces sedation or other undesirable
effects, its dose can be reduced to 2.5–5 mg for the last 10 days of
the cycle with a slight increase in the risk for endometrial hyper-
plasia. These regimens are usually accompanied by bleeding at the
end of each cycle. Some women experience migraine headaches
during the last few days of the cycle. The use of a continuous
estrogen regimen will often prevent their occurrence. Women who
object to the cyclic bleeding associated with sequential therapy can
also consider continuous therapy. Daily therapy with 0.625 mg of
conjugated equine estrogens and 2.5–5 mg of medroxyprogester-
one will eliminate cyclic bleeding, control vasomotor symptoms,
prevent genital atrophy, maintain bone density, and show a favor-
able lipid profile with a small decrease in LDL and an increase in
HDL concentrations. These women have endometrial atrophy
on biopsy. About half of these patients experience breakthrough
bleeding during the first few months of therapy. About 70–80%
become amenorrheic after the first 4 months, and most remain
so. The main disadvantage of continuous therapy is the need for
uterine biopsy if bleeding occurs after the first few months.
As noted above, estrogens may also be administered vaginally
or transdermally. When estrogens are given by these routes, the
liver is bypassed on the first circulation, and the ratio of the liver
effects to peripheral effects is reduced.
In patients in whom estrogen replacement therapy is contra-
indicated, such as those with estrogen-sensitive tumors, relief of
vasomotor symptoms may be obtained by the use of clonidine.
C. Other Uses
Estrogens combined with progestins can be used to suppress
ovulation in patients with intractable dysmenorrhea or when sup-
pression of ovarian function is used in the treatment of hirsutism
and amenorrhea due to excessive secretion of androgens by the
ovary. Under these circumstances, greater suppression may be
needed, and oral contraceptives containing 50 mcg of estrogen
or a combination of a low-estrogen pill with GnRH suppression
may be required.
Adverse Effects
Adverse effects of variable severity have been reported with the
therapeutic use of estrogens. Many other effects reported in

conjunction with hormonal contraceptives may be related to their
estrogen content. These are discussed below.
A. Uterine Bleeding
Estrogen therapy is a major cause of postmenopausal uterine
bleeding. Unfortunately, vaginal bleeding at this time of life may
also be due to carcinoma of the endometrium. To avoid confusion,
patients should be treated with the smallest amount of estrogen
possible. It should be given cyclically so that bleeding, if it occurs,
will be more likely to occur during the withdrawal period. As
noted above, endometrial hyperplasia can be prevented by admin-
istration of a progestational agent with estrogen in each cycle.
B. Cancer
The relation of estrogen therapy to cancer continues to be the
subject of active investigation. Although no adverse effect of short-
term estrogen therapy on the incidence of breast cancer has been
demonstrated, a small increase in the incidence of this tumor may
occur with prolonged therapy. Although the risk factor is small
(1.25), the impact may be great since this tumor occurs in 10% of
women, and addition of progesterone does not confer a protective
effect. Studies indicate that following unilateral excision of breast
cancer, women receiving tamoxifen (an estrogen partial agonist,
see below) show a 35% decrease in contralateral breast cancer
compared with controls. These studies also demonstrate that
tamoxifen is well tolerated by most patients, produces estrogen-
like alterations in plasma lipid levels, and stabilizes bone mineral
loss. Studies bearing on the possible efficacy of tamoxifen and
raloxifene in postmenopausal women at high risk for breast cancer
show decreases of risk for at least 5 years, but of unknown further
duration. Another study showed that postmenopausal hormone
replacement therapy with estrogens plus progestins was associated
with greater breast epithelial cell proliferation and breast epithe-
lial cell density than estrogens alone or no replacement therapy.
Furthermore, with estrogens plus progestins, breast proliferation
was localized to the terminal duct-lobular unit of the breast, which
is the main site of development of breast cancer. Thus, further
studies are needed to conclusively assess the possible association
between progestins and breast cancer risk.
Many studies show an increased risk of endometrial carcinoma
in patients taking estrogens alone. The risk seems to vary with the
dose and duration of treatment: 15 times greater in patients taking
large doses of estrogen for 5 or more years, in contrast with two to
four times greater in patients receiving lower doses for short peri-
ods. However, as noted above, the concomitant use of a progestin
prevents this increased risk and may in fact reduce the incidence
of endometrial cancer to less than that in the general population.
There have been a number of reports of adenocarcinoma of the
vagina in young women whose mothers were treated with large
doses of diethylstilbestrol early in pregnancy. These cancers are most
common in young women (ages 14–44). The incidence is less than
1 per 1000 women exposed—too low to establish a cause-and-
effect relationship with certainty. However, the risks for infertility,
ectopic pregnancy, and premature delivery also are increased. It is
now recognized that there is no indication for the use of dieth-
ylstilbestrol during pregnancy, and it should be avoided. It is not
CHAPTER 40  The Gonadal Hormones & Inhibitors     727
known whether other estrogens have a similar effect or whether the
observed phenomena are peculiar to diethylstilbestrol. This agent
should be used only in the treatment of cancer (eg, of the prostate)
or as a “morning after” contraceptive (see page 736).
C. Other Effects
Nausea and breast tenderness are common and can be minimized
by using the smallest effective dose of estrogen. Hyperpigmenta-
tion also occurs. Estrogen therapy is associated with an increase in
frequency of migraine headaches as well as cholestasis, gallbladder
disease, and hypertension.
Contraindications
Estrogens should not be used in patients with estrogen-dependent
neoplasms such as carcinoma of the endometrium or in those
with—or at high risk for—carcinoma of the breast. They
should be avoided in patients with undiagnosed genital bleeding,
liver disease, or a history of thromboembolic disorder. In addition,
the use of estrogens should be avoided by heavy smokers.
Preparations & Dosages
The dosages of commonly used natural and synthetic preparations
are listed in Table 40–1. Although all of the estrogens produce
almost the same hormonal effects, their potencies vary both
between agents and depending on the route of administration. As
noted above, estradiol is the most active endogenous estrogen, and
it has the highest affinity for the estrogen receptor. However, its
metabolites estrone and estriol have weak uterine effects.
For a given level of gonadotropin suppression, oral estrogen prepa-
rations have more effect on the circulating levels of CBG, SHBG,
and a host of other liver proteins, including angiotensinogen, than
do transdermal preparations. The oral route of administration allows
greater concentrations of hormone to reach the liver, thus increas-
ing the synthesis of these proteins. Transdermal preparations were
developed to avoid this effect. When administered transdermally,
50–100 mcg of estradiol has effects similar to those of 0.625–1.25 mg
of conjugated oral estrogens on gonadotropin concentrations, endo-
metrium, and vaginal epithelium. Furthermore, the transdermal
estrogen preparations do not significantly increase the concentrations
of renin substrate, CBG, and TBG and do not produce the character-
istic changes in serum lipids. Combined oral preparations containing
0.625 mg of conjugated estrogens and 2.5 mg of medroxyprogester-
one acetate are available for menopausal replacement therapy. Tablets
containing 0.625 mg of conjugated estrogens and 5 mg of medroxy-
progesterone acetate are available to be used in conjunction with con-
jugated estrogens in a sequential fashion. Estrogens alone are taken on
days 1–14 and the combination on days 15–28.
THE PROGESTINS
Natural Progestins: Progesterone
Progesterone is the most important progestin in humans. In addi-
tion to having important hormonal effects, it serves as a precur-
sor to the estrogens, androgens, and adrenocortical steroids. It is
728    SECTION VII  Endocrine Drugs

TABLE 40–2  Properties of some progestational agents.

Activities1

   Route  Duration of Action  Estrogenic Androgenic Antiestrogenic Antiandrogenic Anabolic

Progesterone and derivatives

 Progesterone IM 1 day − − + − −
 Hydroxyprogesterone IM 8–14 days sl sl − − −
caproate
 Medroxyprogesterone IM, PO Tabs: 1–3 days; − + + − −
acetate injection: 4–12 weeks
  Megestrol acetate PO 1–3 days − + − + −
17-Ethinyl testosterone derivatives
 Dimethisterone PO 1–3 days − − sl − −
19-Nortestosterone derivatives
 Desogestrel PO 1–3 days − − − − −
 Norethynodrel PO 1–3 days + − − − −
 Lynestrenol2 PO 1–3 days + + − − +
 Norethindrone PO 1–3 days sl + + − +
  Norethindrone acetate PO 1–3 days sl + + − +
  Ethynodiol diacetate PO 1–3 days sl + + − −
2
  l-Norgestrel PO 1–3 days − + + − +
1
Interpretation: + = active; – = inactive; sl = slightly active. Activities have been reported in various species using various end points and may not apply to humans.
2
Not available in USA.

synthesized in the ovary, testis, and adrenal cortex from circulating
cholesterol. Large amounts are also synthesized and released by the
placenta during pregnancy.
In the ovary, progesterone is produced primarily by the corpus
luteum. Normal males appear to secrete 1–5 mg of progesterone
daily, resulting in plasma levels of about 0.03 mcg/dL. The level
is only slightly higher in the female during the follicular phase
of the cycle, when only a few milligrams per day of progesterone
are secreted. During the luteal phase, plasma levels range from
0.5 mcg/dL to more than 2 mcg/dL (Figure 40–1). Plasma levels
of progesterone are further elevated and reach their peak levels in
the third trimester of pregnancy.
Synthetic Progestins
A variety of progestational compounds have been synthesized.
Some are active when given by mouth. They are not a uniform
group of compounds, and all of them differ from progesterone in
one or more respects. Table 40–2 lists some of these compounds
and their effects. In general, the 21-carbon compounds (hydroxy-
progesterone, medroxyprogesterone, megestrol, and dimethis-
terone) are the most closely related, pharmacologically as well
as chemically, to progesterone. A new group of third-generation
synthetic progestins has been introduced, principally as compo-
nents of oral contraceptives. These “19-nor, 13-ethyl” steroid
compounds include desogestrel (Figure 40–4), gestodene, and
norgestimate. They are claimed to have lower androgenic activity
than older synthetic progestins.
Pharmacokinetics
Progesterone is rapidly absorbed following administration by any
route. Its half-life in the plasma is approximately 5 minutes, and
small amounts are stored temporarily in body fat. It is almost
completely metabolized in one passage through the liver, and for
that reason it is quite ineffective when the usual formulation is
administered orally. However, high-dose oral micronized proges-
terone preparations have been developed that provide adequate
progestational effect.
In the liver, progesterone is metabolized to pregnanediol and
conjugated with glucuronic acid. It is excreted into the urine
as pregnanediol glucuronide. The amount of pregnanediol in
the urine has been used as an index of progesterone secretion.
This measure has been very useful despite the fact that the pro-
portion of secreted progesterone converted to this compound
varies from day to day and from individual to individual. In
addition to progesterone, 20α- and 20β-hydroxyprogesterone
(20α- and 20β-hydroxy-4-pregnene-3-one) also are found.
These compounds have about one-fifth the progestational
activity of progesterone in humans and other species. Little is
known of their physiologic role, but 20α-hydroxyprogesterone
is produced in large amounts in some species and may be of
some importance biologically.
The usual routes of administration and durations of action of
the synthetic progestins are listed in Table 40–2. Most of these
agents are extensively metabolized to inactive products that are
excreted mainly in the urine.

21
CH3
20
C O
18
17
11 13
19
O O
Progesterone Hydroxyprogesterone
C C CH3
OH
O
CH3 O
Dimethisterone Norethindrone
FIGURE 40–4  Progesterone and some progestational agents in clinical use.
Physiologic Effects
A. Mechanism
The mechanism of action of progesterone—described in more
detail above—is similar to that of other steroid hormones.
Progestins enter the cell and bind to progesterone receptors that
are distributed in the nucleus and the cytoplasm. The ligand-
receptor complex binds to a progesterone response element
(PRE) to activate gene transcription. The response element for
progesterone appears to be similar to the corticosteroid response
element, and the specificity of the response depends upon which
receptor is present in the cell as well as upon other cell-specific
receptor coregulators and interacting transcription factors. The
progesterone-receptor complex forms a dimer before binding to
DNA. Like the estrogen receptor, it can form heterodimers as well
as homodimers between two isoforms, A and B. These isoforms
are produced by alternative splicing of the same gene.
B. Effects of Progesterone
Progesterone has little effect on protein metabolism. It stimulates
lipoprotein lipase activity and seems to favor fat deposition. The
effects on carbohydrate metabolism are more marked. Proges-
terone increases basal insulin levels and the insulin response to
glucose. There is usually no manifest change in carbohydrate
tolerance. In the liver, progesterone promotes glycogen storage,
possibly by facilitating the effect of insulin. Progesterone also
promotes ketogenesis.
Progesterone can compete with aldosterone for the mineralo-
corticoid receptor of the renal tubule, causing a decrease in Na+
reabsorption. This leads to an increased secretion of aldosterone
by the adrenal cortex (eg, in pregnancy). Progesterone increases
body temperature in humans. The mechanism of this effect is not
CHAPTER 40  The Gonadal Hormones & Inhibitors     729
CH3
CH3 C O
C O OH
OH
CH3
Medroxyprogesterone
C CH CH3 C CH
CH2
OH CH2 OH
Desogestrel
known, but an alteration of the temperature-regulating centers in
the hypothalamus has been suggested. Progesterone also alters the
function of the respiratory centers. The ventilatory response to CO2
is increased by progesterone but synthetic progestins with an ethinyl
group do not have respiratory effects. This leads to a measurable
reduction in arterial and alveolar Pco2 during pregnancy and in the
luteal phase of the menstrual cycle. Progesterone and related steroids
also have depressant and hypnotic effects on the brain.
Progesterone is responsible for the alveolobular development
of the secretory apparatus in the breast. It also participates in the
preovulatory LH surge and causes the maturation and secretory
changes in the endometrium that are seen following ovulation
(Figure 40–1).
Progesterone decreases the plasma levels of many amino acids
and leads to increased urinary nitrogen excretion. It induces
changes in the structure and function of smooth endoplasmic
reticulum in experimental animals.
Other effects of progesterone and its analogs are noted below
in the section, Hormonal Contraception.
C. Synthetic Progestins
The 21-carbon progesterone analogs antagonize aldosterone-
induced sodium retention (see above). The remaining compounds
(“19-nortestosterone” third-generation agents) produce a decidual
change in the endometrial stroma, do not support pregnancy
in test animals, are more effective gonadotropin inhibitors, and
may have minimal estrogenic and androgenic or anabolic activ-
ity (Table 40–2; Figure 40–4). They are sometimes referred to
as “impeded androgens.” Progestins without androgenic activity
include desogestrel, norgestimate, and gestodene. The first two
of these compounds are dispensed in combination with ethinyl
estradiol for oral contraception (Table 40–3) in the United States.
730    SECTION VII  Endocrine Drugs

TABLE 40–3  Some oral and implantable contraceptive agents in use.1

  Estrogen (mg) Progestin (mg)

Monophasic Combination Tablets

  Aviane, Falmina, Lessina, Lutera, Orsythia, Sronyx Ethinyl estradiol 0.02 l-Norgestrel 0.1
  Beyaz, Gianvi, Loryna, Yaz, Vestura Ethinyl estradiol 0.02 Drospirone 3
  Gildess 1/20, Junel, Loestrin, Microgestin, Minastrin Ethinyl estradiol 0.02 Norethindrone 1
  Apri, Desogen, Ortho-Cept, Reclipsen, Solia Ethinyl estradiol 0.03 Desonorgestrel 0.15
  Altavera, Chateal, Introvate, Jolessa, Kurvelo, Levora, Marlissa, Portia Ethinyl estradiol 0.03 l-Norgestrel 0.15
  Cryselle, Elinest, Low-Ogestrel Ethinyl estradiol 0.03 Norgestrel 0.30
  Ocella, Safyral, Syeda, Yasmin, Zarah Ethinyl estradiol 0.03 Drospirenone 3
  Gildess, Junel, Loestrin, Microgestin Ethinyl estradiol 0.03 Norethindrone 1.5
  Cyclafem 1/35, Necon 1/35, Norinyl 1/35 Ethinyl estradiol 0.035 Norethindrone 1
  Estarylla, MonoNessa, Ortho-Cyclen, Previfem, Sprintec Ethinyl estradiol 0.035 Norgestimate 0.25
 Alyacen 1/35; Cyclafem 1/35, Dasetta 1/35, Necon 1/35, Norinyl 1+35, Ethinyl estradiol 0.035 Norethindrone 1
Nortrel 1/35, Ortho-Novum 1/35, Pirmella 1/35
  Brevicon, Modicon, Necon 0.5/35, Nortrel 0.5/35, Wera Ethinyl estradiol 0.035 Norethindrone 0.5
  Ovcon-35, Femcon Fe, Balziva, Briellyn, Gildagia, others Ethinyl estradiol 0.035 Norethindrone 0.4
  Ogestrel 0.5/50 Ethinyl estradiol 0.05 d,l-Norgestrel 0.5
  Norinyl 1+50, Necon 1/50 Mestranol 0.05 Norethindrone 1
Biphasic Combination Tablets
  Azurette, Kariva, Mircette, Viorele
  Days 1–21 Ethinyl estradiol 0.02 Desogestrel 0.15
  Days 22–27 Ethinyl estradiol 0.01 None  
  Necon 10/11
  Days 1–10 Ethinyl estradiol 0.035 Norethindrone 0.5
  Days 11–21 Ethinyl estradiol 0.035 Norethindrone 1.0
Triphasic Combination Tablets
  Enpresse, Levonest, Myzilra, Triphasil, Tri-Levlen, Trivora
  Days 1–6 Ethinyl estradiol 0.03 l-Norgestrel 0.05
  Days 7–11 Ethinyl estradiol 0.04 l-Norgestrel 0.075
  Days 12–21 Ethinyl estradiol 0.03 l-Norgestrel 0.125
  Casiant, Cyclessa, Cesia, Velivet
  Days 1–6 Ethinyl estradiol 0.025 Desogestrel 0.1
  Days 7–14 Ethinyl estradiol 0.025 Desogestrel 0.125
  Days 15–21 Ethinyl estradiol 0.025 Desogestrel 0.15
  Alyacen 7/7/7, Cyclafem 7/7/7, Dasetta 7/7/7, Ortho-Novum 7/7/7, Necon 7/7/7, Nortrel 7/7/7, Pirmella 7/7/7
  Days 1–7 Ethinyl estradiol 0.035 Norethindrone 0.5
  Days 8–14 Ethinyl estradiol 0.035 Norethindrone 0.75
  Days 15–21 Ethinyl estradiol 0.035 Norethindrone 1.0
 Ortho-Tri-Cyclen
  Days 1–7 Ethinyl estradiol 0.035 Norgestimate 0.18
  Days 8–14 Ethinyl estradiol 0.035 Norgestimate 0.215
  Days 15–21 Ethinyl estradiol 0.035 Norgestimate 0.25
(continued)
 CHAPTER 40  The Gonadal Hormones & Inhibitors     731

TABLE 40–3  Some oral and implantable contraceptive agents in use.1  (Continued)
  Estrogen (mg) Progestin (mg)

4-Phasic Combination Tablet

 Natazia
  Days 1–2 Estradiol valerate 3 None —
  Days 3–8 Estradiol valerate 2 Dienogest 2
  Days 9–25 Estradiol valerate 2 Dienogest 3
  Day 26–27 Estradiol valerate 1 None —
Daily Progestin Tablets
 Camila, Errin, Heather, Jencycla, Jolivette, Lyza, Nora-BE, Nor-QD, Ortho None — Norethindrone 0.35
Micronor
Contraceptive Transdermal Patch (Apply 1 Patch per Week)
  Ortho Evra Ethinyl estradiol 0.02/24 h Norgestromin 0.150/24 h
Implantable Progestin Preparation
  Implanon, Nexplanon None Etonogestrel (one tube of 68 mg)
1
The estrogen-containing compounds are arranged in order of increasing content of estrogen. Other preparations are available. (Ethinyl estradiol and mestranol have similar
potencies.)

Oral contraceptives containing the progestin cyproterone acetate
(also an antiandrogen) in combination with ethinyl estradiol are
investigational in the United States.
Clinical Uses
A. Therapeutic Applications
The major uses of progestational hormones are for hormone
replacement therapy (see above) and hormonal contraception
(see below). In addition, they are useful in producing long-term
ovarian suppression for other purposes. When used alone in large
doses parenterally (eg, medroxyprogesterone acetate, 150 mg
intramuscularly every 90 days), prolonged anovulation and amen-
orrhea result. This therapy has been employed in the treatment
of dysmenorrhea, endometriosis, and bleeding disorders when
estrogens are contraindicated, and for contraception. The major
problem with this regimen is the prolonged time required in
some patients for ovulatory function to return after cessation of
therapy. It should not be used for patients planning a pregnancy
in the near future. Similar regimens will relieve hot flushes in
some menopausal women and can be used if estrogen therapy is
contraindicated.
Medroxyprogesterone acetate, 10–20 mg orally twice weekly—
or intramuscularly in doses of 100 mg/m2 every 1–2 weeks—will
prevent menstruation, but it will not arrest accelerated bone
maturation in children with precocious puberty.
Progestins do not appear to have any place in the therapy of
threatened or habitual abortion. Early reports of the usefulness of
these agents resulted from the unwarranted assumption that after
several abortions the likelihood of repeated abortions was over
90%. When progestational agents were administered to patients
with previous abortions, a salvage rate of 80% was achieved. It is
now recognized that similar patients abort only 20% of the time
even when untreated. On the other hand, progesterone was given
experimentally to delay premature labor with encouraging results.
Progesterone and medroxyprogesterone have been used in the
treatment of women who have difficulty in conceiving and who
demonstrate a slow rise in basal body temperature. There is no
convincing evidence that this treatment is effective.
Preparations of progesterone and medroxyprogesterone have
been used to treat premenstrual syndrome. Controlled studies
have not confirmed the effectiveness of such therapy except when
doses sufficient to suppress ovulation have been used.
B. Diagnostic Uses
Progesterone can be used as a test of estrogen secretion. The
administration of progesterone, 150 mg/d, or medroxyprogester-
one, 10 mg/d, for 5–7 days, is followed by withdrawal bleeding
in amenorrheic patients only when the endometrium has been
stimulated by estrogens. A combination of estrogen and progestin
can be given to test the responsiveness of the endometrium in
patients with amenorrhea.
Contraindications, Cautions, & Adverse
Effects
Studies of progestational compounds alone and with combination
oral contraceptives indicate that the progestin in these agents may
increase blood pressure in some patients. The more androgenic pro-
gestins also reduce plasma HDL levels in women. (See Hormonal
Contraception, below.) Two recent studies suggest that combined
progestin plus estrogen replacement therapy in postmenopausal
women may increase breast cancer risk significantly compared with
the risk in women taking estrogen alone. These findings require
careful examination and if confirmed will lead to important changes
in postmenopausal hormone replacement practice.
732    SECTION VII  Endocrine Drugs
OTHER OVARIAN HORMONES
The normal ovary produces small amounts of androgens,
including testosterone, androstenedione, and dehydroepian-
drosterone. Of these, only testosterone has a significant amount
of biologic activity, although androstenedione can be converted
to testosterone or estrone in peripheral tissues. The normal
woman produces less than 200 mcg of testosterone in 24 hours,
and about one-third of this is probably formed in the ovary
directly. The physiologic significance of these small amounts of
androgens is not established, but they may be partly responsible
for normal hair growth at puberty, for stimulation of female
libido, and, possibly, for metabolic effects. Androgen produc-
tion by the ovary may be markedly increased in some abnormal
states, usually in association with hirsutism and amenorrhea as
noted above.
The ovary also produces inhibin and activin. These pep-
tides consist of several combinations of α and β subunits and
are described in greater detail later. The αβ dimer (inhibin)
inhibits FSH secretion while the ββ dimer (activin) increases
FSH secretion. Studies in primates indicate that inhibin has
no direct effect on ovarian steroidogenesis but that activin
modulates the response to LH and FSH. For example, simul-
taneous treatment with activin and human FSH enhances
FSH stimulation of progesterone synthesis and aromatase
activity in granulosa cells. When combined with LH, activin
suppressed the LH-induced progesterone response by 50%
but markedly enhanced basal and LH-stimulated aromatase
activity. Activin may also act as a growth factor in other tis-
sues. The physiologic roles of these modulators are not fully
understood.
Relaxin is another peptide that can be extracted from the
ovary. The three-dimensional structure of relaxin is related to that
of growth-promoting peptides and is similar to that of insulin.
Although the amino acid sequence differs from that of insulin, this
hormone, like insulin, consists of two chains linked by disulfide
bonds, cleaved from a prohormone. It is found in the ovary, pla-
centa, uterus, and blood. Relaxin synthesis has been demonstrated
in luteinized granulosa cells of the corpus luteum. It has been
shown to increase glycogen synthesis and water uptake by the
myometrium and to decrease uterine contractility. In some spe-
cies, it changes the mechanical properties of the cervix and pubic
ligaments, facilitating delivery.
In women, relaxin has been measured by immunoassay.
Levels were highest immediately after the LH surge and during
menstruation. A physiologic role for this peptide has not been
established.
Clinical trials with relaxin have been conducted in patients
with dysmenorrhea. Relaxin has also been administered to patients
in premature labor and during prolonged labor. When applied to
the cervix of a woman at term, it facilitates dilation and shortens
labor.
Several other nonsteroidal substances such as corticotropin-
releasing hormone, follistatin, and prostaglandins are produced
by the ovary. These probably have paracrine effects within the
ovary.
■■ HORMONAL CONTRACEPTION
(ORAL, PARENTERAL, &
IMPLANTED CONTRACEPTIVES)
A large number of oral contraceptives containing estrogens or pro-
gestins (or both) are now available for clinical use (Table 40–3).
These preparations vary chemically and pharmacologically and
have many properties in common as well as definite differences
important for the correct selection of the optimum agent.
Two types of preparations are used for oral contraception:
(1) combinations of estrogens and progestins and (2) continuous
progestin therapy without concomitant administration of estrogens.
The combination agents are further divided into monophasic
forms (constant dosage of both components during the cycle) and
biphasic or triphasic forms (dosage of one or both components
is changed once or twice during the cycle). The preparations for
oral use are all adequately absorbed, and in combination prepara-
tions the pharmacokinetics of neither drug is significantly altered
by the other.
Only one implantable contraceptive preparation is available
at present in the USA. Etonogestrel, also used in some oral con-
traceptives, is available in the subcutaneous implant form listed
in Table 40–3. Several hormonal contraceptives are available as
vaginal rings or intrauterine devices. Intramuscular injection of
large doses of medroxyprogesterone also provides contraception
of long duration.
Pharmacologic Effects
A. Mechanism of Action
The combinations of estrogens and progestins exert their con-
traceptive effect largely through selective inhibition of pituitary
function that results in inhibition of ovulation. The combination
agents also produce a change in the cervical mucus, in the uterine
endometrium, and in motility and secretion in the uterine tubes,
all of which decrease the likelihood of conception and implanta-
tion. The continuous use of progestins alone does not always
inhibit ovulation. The other factors mentioned, therefore, play a
major role in the prevention of pregnancy when these agents are
used.
B. Effects on the Ovary
Chronic use of combination agents depresses ovarian function.
Follicular development is minimal, and corpora lutea, larger fol-
licles, stromal edema, and other morphologic features normally
seen in ovulating women are absent. The ovaries usually become
smaller even if enlarged before therapy.
The great majority of patients return to normal menstrual
patterns when these drugs are discontinued. About 75% will
ovulate in the first posttreatment cycle and 97% by the third
posttreatment cycle. About 2% of patients remain amenor-
rheic for periods of up to several years after administration is
stopped.
The cytologic findings on vaginal smears vary depending on
the preparation used. However, with almost all of the combined

drugs, a low maturation index is found because of the presence of
progestational agents.
C. Effects on the Uterus
After prolonged use, the cervix may show some hypertrophy and
polyp formation. There are also important effects on the cervical
mucus, making it more like postovulation mucus, ie, thicker and
less copious.
Agents containing both estrogens and progestins produce
further morphologic and biochemical changes of the endometrial
stroma under the influence of the progestin, which also stimulates
glandular secretion throughout the luteal phase. The agents con-
taining “19-nor” progestins—particularly those with the smaller
amounts of estrogen—tend to produce more glandular atrophy
and usually less bleeding.
D. Effects on the Breast
Stimulation of the breasts occurs in most patients receiving
estrogen-containing agents. Some enlargement is generally noted.
The administration of estrogens and combinations of estrogens
and progestins tends to suppress lactation, but when the doses are
small, the effects on breast-feeding are not appreciable. Studies of
the transport of the oral contraceptives into breast milk suggest
that only small amounts of these compounds cross into the milk,
and they have not been considered to be of importance.
E. Other Effects of Oral Contraceptives
1. Effects on the central nervous system—The central
nervous system effects of the oral contraceptives have not been
well studied in humans. A variety of effects of estrogen and pro-
gesterone have been noted in animals. Estrogens tend to increase
excitability in the brain, whereas progesterone tends to decrease it.
The thermogenic action of progesterone and some of the synthetic
progestins is also thought to occur in the central nervous system.
It is very difficult to evaluate any behavioral or emotional effects
of these compounds in humans. Although the incidence of pro-
nounced changes in mood, affect, and behavior appears to be low,
milder changes are commonly reported, and estrogens are being
successfully employed in the therapy of premenstrual tension syn-
drome, postpartum depression, and climacteric depression.
2. Effects on endocrine function—The inhibition of pituitary
gonadotropin secretion has been mentioned. Estrogens also alter
adrenal structure and function. Estrogens given orally or at high
doses increase the plasma concentration of the α2 globulin that
binds cortisol (corticosteroid-binding globulin). Plasma concen-
trations may be more than double the levels found in untreated
individuals, and urinary excretion of free cortisol is elevated.
These preparations cause alterations in the renin-angiotensin-
aldosterone system. Plasma renin activity has been found to
increase, and there is an increase in aldosterone secretion.
Thyroxine-binding globulin is increased. As a result, total
plasma thyroxine (T4) levels are increased to those commonly seen
during pregnancy. Since more of the thyroxine is bound, the free
thyroxine level in these patients is normal. Estrogens also increase
the plasma level of SHBG and decrease plasma levels of free
CHAPTER 40  The Gonadal Hormones & Inhibitors     733
androgens by increasing their binding; large amounts of estrogen
may decrease androgens by gonadotropin suppression.
3. Effects on blood—Serious thromboembolic phenomena
occurring in women taking oral contraceptives gave rise to a great
many studies of the effects of these compounds on blood coagula-
tion. A clear picture of such effects has not yet emerged. The oral
contraceptives do not consistently alter bleeding or clotting times.
The changes that have been observed are similar to those reported
in pregnancy. There is an increase in factors VII, VIII, IX, and X
and a decrease in antithrombin III. Increased amounts of couma-
rin anticoagulants may be required to prolong prothrombin time
in patients taking oral contraceptives.
There is an increase in serum iron and total iron-binding
capacity similar to that reported in patients with hepatitis.
Significant alterations in the cellular components of blood have
not been reported with any consistency. A number of patients
have been reported to develop folic acid deficiency anemias.
4. Effects on the liver—These hormones also have profound
effects on the function of the liver. Some of these effects are del-
eterious and will be considered below in the section on adverse
effects. The effects on serum proteins result from the effects of the
estrogens on the synthesis of the various α2 globulins and fibrino-
gen. Serum haptoglobins produced in the liver are depressed
rather than increased by estrogen. Some of the effects on carbohy-
drate and lipid metabolism are probably influenced by changes in
liver metabolism (see below).
Important alterations in hepatic drug excretion and metab-
olism also occur. Estrogens in the amounts seen during
pregnancy or used in oral contraceptive agents delay the clear-
ance of sulfobromophthalein and reduce the flow of bile. The
proportion of cholic acid in bile acids is increased while the pro-
portion of chenodeoxycholic acid is decreased. These changes may
be responsible for the observed increase in cholelithiasis associated
with the use of these agents.
5. Effects on lipid metabolism—As noted above, estrogens
increase serum triglycerides and free and esterified cholesterol.
Phospholipids are also increased, as are HDL; levels of LDL usu-
ally decrease. Although the effects are marked with doses of 100
mcg of mestranol or ethinyl estradiol, doses of 50 mcg or less have
minimal effects. The progestins (particularly the “19-nortestos-
terone” derivatives) tend to antagonize these effects of estrogen.
Preparations containing small amounts of estrogen and a proges-
tin may slightly decrease triglycerides and HDL.
6. Effects on carbohydrate metabolism—The administra-
tion of oral contraceptives produces alterations in carbohydrate
metabolism similar to those observed in pregnancy. There is a
reduction in the rate of absorption of carbohydrates from the
gastrointestinal tract. Progesterone increases the basal insulin
level and the rise in insulin induced by carbohydrate ingestion.
Preparations with more potent progestins such as norgestrel may
cause progressive decreases in carbohydrate tolerance over several
years. However, the changes in glucose tolerance are reversible on
discontinuing medication.
734    SECTION VII  Endocrine Drugs
7. Effects on the cardiovascular system—These agents cause
small increases in cardiac output associated with higher systolic
and diastolic blood pressure and heart rate. The pressure returns
to pretreatment levels when treatment is terminated. Although the
magnitude of the pressure change is small in most patients, it is
marked in a few. It is important that blood pressure be followed
in each patient. An increase in blood pressure has been reported to
occur in a few postmenopausal women treated with estrogens alone.
8. Effects on the skin—The oral contraceptives have been noted
to increase pigmentation of the skin (chloasma). This effect seems
to be enhanced in women with dark complexions and by exposure
to ultraviolet light. Some of the androgen-like progestins might
increase the production of sebum, causing acne in some patients.
However, since ovarian androgen is suppressed, many patients
note decreased sebum production, acne, and terminal hair growth.
The sequential oral contraceptive preparations as well as estrogens
alone often decrease sebum production.
Clinical Uses
The most important use of combined estrogens and progestins is
for oral contraception. A large number of preparations are available
for this specific purpose, some of which are listed in Table 40–3.
They are specially packaged for ease of administration. In general,
they are very effective; when these agents are taken according to
directions, the risk of conception is extremely small. The pregnancy
rate with combination agents is estimated to be about 5–12 per
100 woman-years at risk. (Under conditions of perfect adherence,
the pregnancy rate would be 0.5–1 per 100 woman-years.) Con-
traceptive failure has been observed in some patients when one or
more doses are missed, if phenytoin is also being used (which may
increase catabolism of the compounds), or if antibiotics are taken
that alter enterohepatic cycling of metabolites.
Progestins and estrogens are also useful in the treatment of
endometriosis. When severe dysmenorrhea is the major symptom,
the suppression of ovulation with estrogen alone may be followed
by painless periods. However, in most patients this approach is
inadequate. The long-term administration of large doses of pro-
gestins or combinations of progestins and estrogens prevents the
periodic breakdown of the endometrial tissue and in some cases
will lead to endometrial fibrosis and prevent the reactivation of
implants for prolonged periods.
As is true with most hormonal preparations, many of the
undesired effects are physiologic or pharmacologic actions that
are objectionable only because they are not pertinent to the
situation for which they are being used. Therefore, the product
containing the smallest effective amounts of hormones should
be selected for use.
Adverse Effects
The incidence of serious known toxicities associated with the use
of these drugs is low—far lower than the risks associated with
pregnancy. There are a number of reversible changes in intermedi-
ary metabolism. Minor adverse effects are frequent, but most are
mild and many are transient. Continuing problems may respond
to simple changes in pill formulation. Although it is not often
necessary to discontinue medication for these reasons, as many as
one third of all patients started on oral contraception discontinue
use for reasons other than a desire to become pregnant.
A. Mild Adverse Effects
1. Nausea, mastalgia, breakthrough bleeding, and edema are
related to the amount of estrogen in the preparation. These
effects can often be alleviated by a shift to a preparation con-
taining smaller amounts of estrogen or to agents containing
progestins with more androgenic effects.
2. Changes in serum proteins and other effects on endocrine
function (see above) must be taken into account when thyroid,
adrenal, or pituitary function is being evaluated. Increases in
sedimentation rate are thought to be due to increased levels of
fibrinogen.
3. Headache is mild and often transient. However, migraine is
often made worse and has been reported to be associated with
an increased frequency of cerebrovascular accidents. When this
occurs or when migraine has its onset during therapy with these
agents, treatment should be discontinued.
4. Withdrawal bleeding sometimes fails to occur—most often
with combination preparations—and may cause confusion
with regard to pregnancy. If this is disturbing to the patient, a
different preparation may be tried or other methods of contra-
ception used.
B. Moderate Adverse Effects
Any of the following may require discontinuance of oral
contraceptives:
1. Breakthrough bleeding is the most common problem in using
progestational agents alone for contraception. It occurs in as
many as 25% of patients. It is more frequently encountered in
patients taking low-dose preparations than in those taking
combination pills with higher levels of progestin and estrogen.
The biphasic and triphasic oral contraceptives (Table 40–3)
decrease breakthrough bleeding without increasing the total
hormone content.
2. Weight gain is more common with the combination agents
containing androgen-like progestins. It can usually be con-
trolled by shifting to preparations with less progestin effect or
by dieting.
3. Increased skin pigmentation may occur, especially in dark-
skinned women. It tends to increase with time, the incidence
being about 5% at the end of the first year and about 40% after
8 years. It is thought to be exacerbated by vitamin B deficiency.
It is often reversible upon discontinuance of medication but
may disappear very slowly.
4. Acne may be exacerbated by agents containing androgen-like
progestins (Table 40–2), whereas agents containing large
amounts of estrogen usually cause marked improvement in acne.
5. Hirsutism may also be aggravated by the “19-nortestosterone”
derivatives, and combinations containing nonandrogenic
progestins are preferred in these patients.

6. Ureteral dilation similar to that observed in pregnancy has been
reported, and bacteriuria is more frequent.
7. Vaginal infections are more common and more difficult to treat
in patients who are using oral contraceptives.
8. Amenorrhea occurs in some patients. Following cessation of
administration of oral contraceptives, 95% of patients with
normal menstrual histories resume normal periods and all but
a few resume normal cycles during the next few months. How-
ever, some patients remain amenorrheic for several years. Many
of these patients also have galactorrhea. Patients who have had
menstrual irregularities before taking oral contraceptives are
particularly susceptible to prolonged amenorrhea when the
agents are discontinued. Prolactin levels should be measured in
these patients, since many have prolactinomas.
C. Severe Adverse Effects
1. Vascular disorders—Thromboembolism was one of the
earliest of the serious unanticipated effects to be reported and has
been the most thoroughly studied.
a. Venous thromboembolic disease—Superficial or deep
thromboembolic disease in women not taking oral contraceptives
occurs in about 1 patient per 1000 woman years. The overall inci-
dence of these disorders in patients taking low-dose oral contracep-
tives is about threefold higher. The risk for this disorder is increased
during the first month of contraceptive use and remains constant
for several years or more. The risk returns to normal within a
month when use is discontinued. The risk of venous thrombosis or
pulmonary embolism is increased among women with predisposing
conditions such as stasis, altered clotting factors such as antithrom-
bin III, increased levels of homocysteine, or injury. Genetic disor-
ders, including mutations in the genes governing the production
of protein C (factor V Leiden), protein S, hepatic cofactor II, and
others, markedly increase the risk of venous thromboembolism. The
incidence of these disorders is too low for cost-effective screening
by current methods, but prior episodes or a family history may be
helpful in identifying patients with increased risk.
The incidence of venous thromboembolism appears to be
related to the estrogen but not the progestin content of oral
contraceptives and is not related to age, parity, mild obesity, or
cigarette smoking. Decreased venous blood flow, endothelial
proliferation in veins and arteries, and increased coagulability of
blood resulting from changes in platelet functions and fibrinolytic
systems contribute to the increased incidence of thrombosis. The
major plasma inhibitor of thrombin, antithrombin III, is substan-
tially decreased during oral contraceptive use. This change occurs
in the first month of treatment and lasts as long as treatment
persists, reversing within a month thereafter.
b. Myocardial infarction—The use of oral contraceptives is asso-
ciated with a slightly higher risk of myocardial infarction in women
who are obese, have a history of preeclampsia or hypertension, or
have hyperlipoproteinemia or diabetes. There is a much higher risk
in women who smoke. The risk attributable to oral contraceptives
in women 30–40 years of age who do not smoke is about 4 cases
per 100,000 users per year, as compared with 185 cases per 100,000
CHAPTER 40  The Gonadal Hormones & Inhibitors     735
among women 40–44 who smoke heavily. The association with
myocardial infarction is thought to involve acceleration of athero-
genesis because of decreased glucose tolerance, decreased levels of
HDL, increased levels of LDL, and increased platelet aggregation.
In addition, facilitation of coronary arterial spasm may play a role
in some of these patients. The progestational component of oral
contraceptives decreases HDL cholesterol levels, in proportion to
the androgenic activity of the progestin. The net effect, therefore,
will depend on the specific composition of the pill used and the
patient’s susceptibility to the particular effects. Recent studies sug-
gest that risk of infarction is not increased in past users who have
discontinued oral contraceptives.
c. Cerebrovascular disease—The risk of stroke is concen-
trated in women over age 35. It is increased in current users of
oral contraceptives but not in past users. However, subarachnoid
hemorrhages have been found to be increased among both current
and past users and may increase with time. The risk of thrombotic
or hemorrhagic stroke attributable to oral contraceptives (based
on older, higher-dose preparations) has been estimated at about
37 cases per 100,000 users per year.
In summary, available data indicate that oral contraceptives
increase the risk of various cardiovascular disorders at all ages and
among both smokers and nonsmokers. However, this risk appears
to be concentrated in women 35 years of age or older who are
heavy smokers. It is clear that these risk factors must be considered
in each individual patient for whom oral contraceptives are being
considered. Some experts have suggested that screening for coagu-
lopathy should be performed before starting oral contraception.
2. Gastrointestinal disorders—Many cases of cholestatic jaun-
dice have been reported in patients taking progestin-containing
drugs. The differences in incidence of these disorders from one
population to another suggest that genetic factors may be involved.
The jaundice caused by these agents is similar to that produced by
other 17-alkyl-substituted steroids. It is most often observed in the
first three cycles and is particularly common in women with a his-
tory of cholestatic jaundice during pregnancy. Jaundice and pruritus
disappear 1–8 weeks after the drug is discontinued.
These agents have also been found to increase the incidence of
symptomatic gallbladder disease, including cholecystitis and chol-
angitis. This is probably the result of the alterations responsible for
jaundice and bile acid changes described above.
It also appears that the incidence of hepatic adenomas is
increased in women taking oral contraceptives. Ischemic bowel
disease secondary to thrombosis of the celiac and superior and
inferior mesenteric arteries and veins has also been reported in
women using these drugs.
3. Depression—Depression of sufficient degree to require cessa-
tion of therapy occurs in about 6% of patients treated with some
preparations.
4. Cancer—The occurrence of malignant tumors in patients tak-
ing oral contraceptives has been studied extensively. It is now clear
that these compounds reduce the risk of endometrial and ovarian
cancer. The lifetime risk of breast cancer in the population as
736    SECTION VII  Endocrine Drugs
a whole does not seem to be affected by oral contraceptive use.
Some studies have shown an increased risk in younger women,
and it is possible that tumors that develop in younger women
become clinically apparent sooner. The relation of risk of cervical
cancer to oral contraceptive use is still controversial. It should be
noted that a number of recent studies associate the use of oral
contraceptives by women who are infected with human papillo-
mavirus with an increased risk of cervical cancer.
5. Other—In addition to the above effects, a number of other
adverse reactions have been reported for which a causal relation
has not been established. These include alopecia, erythema multi-
forme, erythema nodosum, and other skin disorders.
Contraindications & Cautions
These drugs are contraindicated in patients with thrombophlebitis,
thromboembolic phenomena, and cardiovascular and cerebrovas-
cular disorders or a past history of these conditions. They should
not be used to treat vaginal bleeding when the cause is unknown.
They should be avoided in patients with known or suspected
tumors of the breast or other estrogen-dependent neoplasms. Since
these preparations have caused aggravation of preexisting disorders,
they should be avoided or used with caution in patients with liver
disease, asthma, eczema, migraine, diabetes, hypertension, optic
neuritis, retrobulbar neuritis, or convulsive disorders.
The oral contraceptives may produce edema, and for that
reason they should be used with great caution in patients in heart
failure or in whom edema is otherwise undesirable or dangerous.
Estrogens may increase the rate of growth of fibroids. There-
fore, for women with these tumors, agents with the smallest
amounts of estrogen and the most androgenic progestins should
be selected. The use of progestational agents alone for contracep-
tion might be especially useful in such patients (see below).
These agents are contraindicated in adolescents in whom
epiphyseal closure has not yet been completed.
Women using oral contraceptives must be made aware of
an important interaction that occurs with antimicrobial drugs.
Because the normal gastrointestinal flora increase the entero-
hepatic cycling (and bioavailability) of estrogens, antimicrobial
drugs that interfere with these organisms may reduce the efficacy
of oral contraceptives. Additionally, coadministration with potent
inducers of the hepatic microsomal metabolizing enzymes, such as
rifampin, may increase liver catabolism of estrogens or progestins
and diminish the efficacy of oral contraceptives.
Contraception with Progestins Alone
Small doses of progestins administered orally or by implantation
under the skin can be used for contraception. They are particu-
larly suited for use in patients for whom estrogen administration
is undesirable. They are about as effective as intrauterine devices
or combination pills containing 20–30 mcg of ethinyl estradiol.
There is a high incidence of abnormal bleeding.
Effective contraception can also be achieved by injecting
150 mg of depot medroxyprogesterone acetate (DMPA) every
3 months. After a 150-mg dose, ovulation is inhibited for at least
14 weeks. Almost all users experience episodes of unpredictable
spotting and bleeding, particularly during the first year of use.
Spotting and bleeding decrease with time, and amenorrhea is
common. This preparation is not desirable for women planning
a pregnancy soon after cessation of therapy because ovulation
suppression can sometimes persist for as long as 18 months after
the last injection. Long-term DMPA use reduces menstrual blood
loss and is associated with a decreased risk of endometrial cancer.
Suppression of endogenous estrogen secretion may be associated
with a reversible reduction in bone density, and changes in plasma
lipids are associated with an increased risk of atherosclerosis.
The progestin implant method utilizes the subcutaneous implan-
tation of capsules containing etonogestrel. These capsules release
one-fifth to one-third as much steroid as oral agents, are extremely
effective, and last for 2–4 years. The low levels of hormone have
little effect on lipoprotein and carbohydrate metabolism or blood
pressure. The disadvantages include the need for surgical insertion
and removal of capsules and some irregular bleeding rather than
predictable menses. An association of intracranial hypertension
with an earlier type of implant utilizing norgestrel was observed in
a small number of women. Patients experiencing headache or visual
disturbances should be checked for papilledema.
Contraception with progestins is useful in patients with
hepatic disease, hypertension, psychosis or mental retardation,
or prior thromboembolism. The side effects include headache,
dizziness, bloating and weight gain of 1–2 kg, and a reversible
reduction of glucose tolerance.
A. Postcoital Contraceptives
Pregnancy can be prevented following coitus by the adminis-
tration of estrogens alone, progestin alone, or in combination
(“morning after” contraception). When treatment is begun
within 72 hours, it is effective 99% of the time. Some effective
schedules are shown in Table 40–4. The hormones are often
administered with antiemetics, since 40% of patients have nausea
or vomiting. Other adverse effects include headache, dizziness,
breast tenderness, and abdominal and leg cramps. Considerable
controversy has accompanied the proposal to make these agents
available without a prescription in the United States.
Mifepristone, an antagonist at progesterone and glucocorticoid
receptors, has a luteolytic effect and is effective as a postcoital
TABLE 40–4  Schedules for use of postcoital
contraceptives.
Conjugated estrogens: 10 mg three times daily for 5 days
Ethinyl estradiol: 2.5 mg twice daily for 5 days
Diethylstilbestrol: 50 mg daily for 5 days
Mifepristone: 600 mg once with misoprostol, 400 mcg once1
l-Norgestrel: 1.5 mg once (Plan B One-Step2)
l-Norgestrel: 0.75 mg twice daily for 1 day (eg, Plan B2)
Norgestrel, 0.5 mg, with ethinyl estradiol, 0.05 mg (eg, Ovral, Preven2):
Two tablets and then two in 12 hours
1
Mifepristone given on day 1, misoprostol on day 3.
2
Sold as emergency contraceptive kits.
 CHAPTER 40  The Gonadal Hormones & Inhibitors     737

contraceptive. When combined with a prostaglandin it is also an of patients, and many other minor adverse effects are observed.
effective abortifacient. Studies of patients treated with tamoxifen as adjuvant therapy for
early breast cancer have shown a 35% decrease in contralateral
Beneficial Effects of Oral Contraceptives breast cancer. However, adjuvant therapy extended beyond 5 years
in patients with breast cancer has shown no further improvement
It has become apparent that reduction in the dose of the constitu-
in outcome. In fact, resistant lines of tumor cells may recognize
ents of oral contraceptives has markedly reduced mild and severe
tamoxifen as an agonist rather than an antagonist, perhaps due to
adverse effects, providing a relatively safe and convenient method
changes in the coregulators that interact with the estrogen recep-
of contraception for many young women. Treatment with oral
tor. Toremifene is a structurally similar compound with very
contraceptives has also been shown to be associated with many
similar properties, indications, and toxicities.
benefits unrelated to contraception. These include a reduced
risk of ovarian cysts, ovarian and endometrial cancer, and benign
breast disease. There is a lower incidence of ectopic pregnancy.
Iron deficiency and rheumatoid arthritis are less common, and Hypothalamus
premenstrual symptoms, dysmenorrhea, endometriosis, acne, and
hirsutism may be ameliorated with their use.

■■ ESTROGEN & PROGESTERONE

INHIBITORS & ANTAGONISTS – GnRH antagonists
GnRH
+/– GnRH agonists
TAMOXIFEN & RELATED PARTIAL
AGONIST ESTROGENS
+ Clomiphene
Anterior –
Tamoxifen, a competitive partial agonist inhibitor of estradiol pituitary
Oral
contraceptives,
at the estrogen receptor (Figure 40–5), was the first selective danazol
estrogen receptor modulator (SERM) to be introduced. The
mechanism of its mixed agonist/antagonist relations to the
FSH, LH
estrogen receptor has been intensively studied but is still not
completely understood. Proposals include recruitment of differ-
ent coregulators to the estrogen receptor when it binds tamoxi-
fen rather than estrogen, differential activation of heterodimers Ovary
(ERα-ERβ) versus homodimers, competition of ERα by ERβ Progesterone
and others. Tamoxifen is extensively used in the palliative treat- (Luteal phase)
ment of breast cancer in postmenopausal women and is approved – Ketoconazole,
for chemoprevention of breast cancer in high-risk women (see danazol
Chapter 54). It is a nonsteroidal agent (see structure below) that
is given orally. Peak plasma levels are reached in a few hours. Testosterone
Tamoxifen has an initial half-life of 7–14 hours in the circulation
Androstenedione
and is predominantly excreted by the liver. One of its metabolites
via CYP2D6 is 4-hydroxytamoxifen (endoxifen), a more potent – Anastrozole,
SERM. Therefore, strong inhibitors of 2D6 should be avoided others
in patients receiving tamoxifen. It is used in doses of 10–20 mg
twice daily. Hot flushes and nausea and vomiting occur in 25% Estradiol Estrone Estriol
– Fulvestrant
CH3 +/– SERMs
OCH2CH2N
CH3
Estrogen
response
element

C C
Expression in estrogen-responsive cells
CH2CH3
FIGURE 40–5  Control of ovarian secretion and the actions of its
hormones. In the follicular phase the ovary produces mainly estro-
gens; in the luteal phase it produces estrogens and progesterone.
Tamoxifen SERMs, selective estrogen receptor modulators. See text.
738    SECTION VII  Endocrine Drugs
Prevention of the expected loss of lumbar spine bone density
and plasma lipid changes consistent with a reduction in the risk
for atherosclerosis have also been reported in tamoxifen-treated
patients following spontaneous or surgical menopause. However,
this agonist activity also affects the uterus and may increase the
risk of endometrial cancer.
Raloxifene is another partial estrogen agonist-antagonist at
some but not all target tissues. It has estrogenic effects on lipids
and bone but appears not to stimulate the endometrium or breast.
Although subject to a high first-pass effect, raloxifene has a very
large volume of distribution and a long half-life (>24 hours), so
it can be taken once a day. Raloxifene has been approved in the
United States for the prevention of postmenopausal osteoporosis
and prophylaxis of breast cancer in women with risk factors.
Newer SERMs have been developed and one, bazedoxifene, in
combination with conjugated estrogens, is approved for treatment
of menopausal symptoms and prophylaxis of postmenopausal
osteoporosis.
Clomiphene is an older partial agonist, a weak estrogen that
also acts as a competitive inhibitor of endogenous estrogens
(Figure 40–5). It has found use as an ovulation-inducing agent
(see below).
MIFEPRISTONE (RU-486)
Mifepristone is a “19-norsteroid” that binds strongly to the pro-
gesterone and glucocorticoid receptors and inhibits the activity of
progesterone and that of glucocorticoids (see Chapter 39). The
drug has luteolytic properties in 80% of women when given in the
midluteal period. The mechanism of this effect is unknown, but
it may provide the basis for using mifepristone as a contraceptive
(as opposed to an abortifacient). However, because the compound
has a long half-life of 20–40 hours, large doses may prolong the
follicular phase of the subsequent cycle and so make it difficult
to use continuously for this purpose. A single dose of 600 mg is
an effective emergency postcoital contraceptive, though it may
result in delayed ovulation in the following cycle. As noted in
Chapter 39, the drug also binds to and acts as an antagonist at
the glucocorticoid receptor. Limited clinical studies suggest that
mifepristone or other analogs with similar properties may be use-
ful in the treatment of endometriosis, Cushing’s syndrome, breast
cancer, and possibly other neoplasms such as meningiomas that
contain glucocorticoid or progesterone receptors.
H3C CH3
N of danazol, has both progestational and mild androgenic effects.
OH
H3C C CCH3
O in 2 months. About 85% of patients show marked improvement
Mifepristone
Mifepristone’s major use thus far has been to terminate early
pregnancies. Doses of 400–600 mg/d for 4 days or 800 mg/d for
2 days successfully terminated pregnancy in >85% of the women
studied. The major adverse effect was prolonged bleeding that
on most occasions did not require treatment. The combination
of a single oral dose of 600 mg of mifepristone and a vaginal
pessary containing 1 mg of prostaglandin E1 or oral misoprostol
has been found to effectively terminate pregnancy in over 95%
of patients treated during the first 7 weeks after conception. The
adverse effects of the medications included vomiting, diarrhea,
and abdominal or pelvic pain. As many as 5% of patients have
vaginal bleeding requiring intervention. Because of these adverse
effects, mifepristone is administered only by physicians at family
planning centers. Note: In a very small number of cases, use of a
vaginal tablet for the prostaglandin dose has been associated with
sepsis, so it is recommended that both drugs be given by mouth
in all patients.
ZK 98734 (lilopristone) is a potent experimental progester-
one inhibitor and abortifacient in doses of 25 mg twice daily.
Like mifepristone, it also appears to have antiglucocorticoid
activity.
DANAZOL
Danazol, an isoxazole derivative of ethisterone (17α-ethinyl-
testosterone) with weak progestational, androgenic, and gluco-
corticoid activities, is used to suppress ovarian function. Danazol
inhibits the midcycle surge of LH and FSH and can prevent
the compensatory increase in LH and FSH following castration
in animals, but it does not significantly lower or suppress basal
LH or FSH levels in normal women (Figure 40–5). Danazol
binds to androgen, progesterone, and glucocorticoid receptors
and can translocate the androgen receptor into the nucleus to
initiate androgen-specific RNA synthesis. It does not bind to
intracellular estrogen receptors, but it does bind to sex hormone–
binding and corticosteroid-binding globulins. It inhibits P450scc
(the cholesterol side chain–cleaving enzyme), 3β-hydroxysteroid
dehydrogenase, 17α-hydroxysteroid dehydrogenase, P450c17
(17α-hydroxylase), P450c11 (11β-hydroxylase), and P450c21
(21β-hydroxylase). However, it does not inhibit aromatase, the
enzyme required for estrogen synthesis. It increases the mean
clearance of progesterone, probably by competing with the
hormone for binding proteins, and may have similar effects on
other active steroid hormones. Ethisterone, a major metabolite
Danazol is slowly metabolized in humans, having a half-life of
>15 hours. This results in stable circulating levels when the drug
is administered twice daily. It is highly concentrated in the liver,
adrenals, and kidneys and is excreted in both feces and urine.
Danazol has been employed as an inhibitor of gonadal function
and has found its major use in the treatment of endometriosis.
For this purpose, it can be given in a dosage of 600 mg/d. The
dosage is reduced to 400 mg/d after 1 month and to 200 mg/d
in 3–12 months.

Danazol has also been used in the treatment of fibrocystic
disease of the breast and hematologic or allergic disorders, includ-
ing hemophilia, Christmas disease, idiopathic thrombocytopenic
purpura, and angioneurotic edema.
The major adverse effects are weight gain, edema, decreased
breast size, acne and oily skin, increased hair growth, deepening
of the voice, headache, hot flushes, changes in libido, and muscle
cramps. Although mild adverse effects are very common, it is
seldom necessary to discontinue the drug because of them. Occa-
sionally, because of its inherent glucocorticoid activity, danazol
may cause adrenal suppression.
Danazol should be used with great caution in patients with
hepatic dysfunction, since it has been reported to produce mild
to moderate hepatocellular damage in some patients, as evidenced
by enzyme changes. It is also contraindicated during pregnancy
and breast-feeding, as it may produce urogenital abnormalities in
the offspring.
OTHER INHIBITORS
Anastrozole, a selective nonsteroidal inhibitor of aromatase (the
enzyme required for estrogen synthesis, Figures 40–2 and 40–5),
is effective in some women whose breast tumors have become
resistant to tamoxifen (see Chapter 54). Letrozole is similar.
Exemestane, a steroid molecule, is an irreversible inhibitor of
aromatase. Like anastrozole and letrozole, it is approved for use in
women with advanced breast cancer (see Chapter 54).
Several other aromatase inhibitors are undergoing clinical trials
in patients with breast cancer. Fadrozole is an oral nonsteroidal
(triazole) inhibitor of aromatase activity. These compounds appear to
be as effective as tamoxifen. In addition to their use in breast cancer,
aromatase inhibitors have been successfully employed as adjuncts to
androgen antagonists in the treatment of precocious puberty and as
primary treatment in the excessive aromatase syndrome.
Fulvestrant is a pure estrogen receptor antagonist that has
been somewhat more effective than those with partial agonist
effects in some patients who have become resistant to tamoxifen.
Fulvestrant is approved for use in breast cancer patients who have
become resistant to tamoxifen. ICI 164,384 is a newer antagonist;
it inhibits dimerization of the occupied estrogen receptor and
interferes with its binding to DNA.
GnRH and its analogs (nafarelin, buserelin, etc) have become
important in both stimulating and inhibiting ovarian function.
They are discussed in Chapter 37.
OVULATION-INDUCING AGENTS
CLOMIPHENE
Clomiphene citrate, a partial estrogen agonist, is closely related
to the estrogen chlorotrianisene (Figure 40–3). This compound
is well absorbed when taken orally. It has a half-life of 5–7 days
and is excreted primarily in the urine. It exhibits significant pro-
tein binding and enterohepatic circulation and is distributed to
adipose tissues.
CHAPTER 40  The Gonadal Hormones & Inhibitors     739
Pharmacologic Effects
A. Mechanisms of Action
Clomiphene is a partial agonist at estrogen receptors. The
estrogenic agonist effects are best demonstrated in animals with
marked gonadal deficiency. Clomiphene has also been shown to
effectively inhibit the action of stronger estrogens. In humans
it leads to an increase in the secretion of gonadotropins and
estrogens by inhibiting estradiol’s negative feedback effect on the
release of gonadotropins (Figure 40–5).
B. Effects
The pharmacologic importance of clomiphene rests on its ability
to stimulate ovulation in women with oligomenorrhea or amen-
orrhea and ovulatory dysfunction. The majority of patients suffer
from polycystic ovary syndrome, a common disorder affecting
about 7% of women of reproductive age. The syndrome is char-
acterized by gonadotropin-dependent ovarian hyperandrogenism
associated with anovulation and infertility. The disorder is fre-
quently accompanied by adrenal hyperandrogenism. Clomiphene
probably blocks the feedback inhibitory influence of estrogens on
the hypothalamus, causing a surge of gonadotropins, which leads
to ovulation.
Clinical Use
Clomiphene is used in the treatment of disorders of ovulation in
patients who wish to become pregnant. Usually, a single ovulation
is induced by a single course of therapy, and the patient must be
treated repeatedly until pregnancy is achieved, since normal cyclic
ovulatory function does not usually resume. The compound is of
no value in patients with ovarian or pituitary failure.
When clomiphene is administered in a dosage of 100 mg/d for
5 days, a rise in plasma LH and FSH is observed after several days.
In patients who ovulate, the initial rise is followed by a second rise
of gonadotropin levels just prior to ovulation.
Adverse Effects
The most common adverse effects in patients treated with this
drug are hot flushes, which resemble those experienced by meno-
pausal patients. They tend to be mild, and disappear when the
drug is discontinued. There have been occasional reports of eye
symptoms due to intensification and prolongation of afterimages.
These are generally of short duration. Headache, constipation,
allergic skin reactions, and reversible hair loss have been reported
occasionally.
The effective use of clomiphene is associated with some stimu-
lation of the ovaries and usually with ovarian enlargement. The
degree of enlargement tends to be greater and its incidence higher
in patients who have enlarged ovaries at the beginning of therapy.
A variety of other symptoms such as nausea and vomiting,
increased nervous tension, depression, fatigue, breast soreness,
weight gain, urinary frequency, and heavy menses have also been
reported. However, these appear to result from the hormonal
changes associated with an ovulatory menstrual cycle rather than
from the medication. The incidence of multiple pregnancy is
740    SECTION VII  Endocrine Drugs
approximately 10%. Clomiphene has not been shown to have an
adverse effect when inadvertently given to women who are already
pregnant.
Contraindications & Cautions
Special precautions should be observed in patients with enlarged
ovaries. These women are thought to be more sensitive to this
drug and should receive small doses. Any patient who complains
of abdominal symptoms should be examined carefully. Maxi-
mum ovarian enlargement occurs after the 5-day course has been
completed, and many patients can be shown to have a palpable
increase in ovarian size by the seventh to tenth days. Treatment
with clomiphene for more than a year may be associated with an
increased risk of low-grade ovarian cancer; however, the evidence
for this effect is not conclusive.
Special precautions must also be taken in patients who have
visual symptoms associated with clomiphene therapy, since these
symptoms may make activities such as driving more hazardous.
OTHER DRUGS USED IN
OVULATORY DISORDERS
In addition to clomiphene, a variety of other hormonal and non-
hormonal agents are used in treating anovulatory disorders. They
are discussed in Chapter 37.
■■ THE TESTIS (ANDROGENS
& ANABOLIC STEROIDS,
ANTIANDROGENS, & MALE
CONTRACEPTION)
The testis, like the ovary, has both gametogenic and endocrine
functions. The onset of gametogenic function of the testes is
controlled largely by the secretion of FSH by the pituitary. High
concentrations of testosterone locally are also required for con-
tinuing sperm production in the seminiferous tubules. The Sertoli
cells in the seminiferous tubules may be the source of the estra-
diol produced in the testes via aromatization of locally produced
testosterone. With LH stimulation, testosterone is produced by
the interstitial or Leydig cells found in the spaces between the
seminiferous tubules.
The Sertoli cells in the testis synthesize and secrete a variety
of active proteins, including müllerian duct inhibitory factor,
inhibin, and activin. As in the ovary, inhibin and activin appear to
be the product of three genes that produce a common α subunit
and two β subunits, A and B. Activin is composed of the two β
subunits (βAβB). There are two inhibins (A and B), which con-
tain the α subunit and one of the β subunits. Activin stimulates
pituitary FSH release and is structurally similar to transforming
growth factor-β, which also increases FSH. The inhibins in con-
junction with testosterone and dihydrotestosterone are responsible
for the feedback inhibition of pituitary FSH secretion.
ANDROGENS & ANABOLIC
STEROIDS
In humans, the most important androgen secreted by the testis is
testosterone. The pathways of synthesis of testosterone in the tes-
tes are similar to those previously described for the adrenal gland
and ovary (Figures 39–1 and 40–2).
In men, approximately 8 mg of testosterone is produced daily.
About 95% is produced by the Leydig cells and only 5% by the
adrenals. The testis also secretes small amounts of another potent
androgen, dihydrotestosterone, as well as androstenedione and
dehydroepiandrosterone, which are weak androgens. Pregneno-
lone and progesterone and their 17-hydroxylated derivatives are
also released in small amounts. Plasma levels of testosterone in
males are about 0.6 mcg/dL after puberty and appear to decline
after age 50. Testosterone is also present in the plasma of women
in concentrations of approximately 0.03 mcg/dL and is derived in
approximately equal parts from the ovaries and adrenals and by
the peripheral conversion of other hormones.
About 65% of circulating testosterone is bound to sex hor-
mone-binding globulin. SHBG is increased in plasma by estrogen,
by thyroid hormone, and in patients with cirrhosis of the liver. It
is decreased by androgen and growth hormone and is lower in
obese individuals. Most of the remaining testosterone is bound to
albumin. Approximately 2% remains free and available to enter
cells and bind to intracellular receptors.
Metabolism
In many target tissues, testosterone is converted to dihydrotestos-
terone by 5α-reductase. In these tissues, dihydrotestosterone is the
major active androgen. The conversion of testosterone to estradiol
by P450 aromatase also occurs in some tissues, including adipose
tissue, liver, and the hypothalamus, where it may be of importance
in regulating gonadal function.
The major pathway for the degradation of testosterone in
humans occurs in the liver, with the reduction of the double bond
and ketone in the A ring, as is seen in other steroids with a Δ4-
ketone configuration in the A ring. This leads to the production of
inactive substances such as androsterone and etiocholanolone that
are then conjugated and excreted in the urine.
Androstenedione, dehydroepiandrosterone (DHEA), and
dehydroepiandrosterone sulfate (DHEAS) are also produced in
significant amounts in humans, although largely in the adrenal
gland rather than in the testes. They contribute slightly to the
normal maturation process supporting other androgen-dependent
pubertal changes in the human, primarily development of pubic
and axillary hair and bone maturation. As noted in Chapter 39,
some studies suggest that DHEA and DHEAS may have other
central nervous system and metabolic effects and may prolong
life in rabbits. In men they may improve the sense of well-
being and inhibit atherosclerosis. In a placebo-controlled clini-
cal trial in patients with systemic lupus erythematosus, DHEA
demonstrated some beneficial effects (see Adrenal Androgens,
Chapter 39). Adrenal androgens are to a large extent metabo-
lized in the same fashion as testosterone. Both steroids—but

particularly androstenedione—can be converted by peripheral
tissues to estrone in very small amounts (1–5%). The P450 aro-
matase enzyme responsible for this conversion is also found in the
brain and is thought to play an important role in development.
Physiologic Effects
In the normal male, testosterone or its active metabolite
5α-dihydrotestosterone is responsible for the many changes that
occur in puberty. In addition to the general growth-promoting
properties of androgens on body tissues, these hormones are
responsible for penile and scrotal growth. Changes in the skin
include the appearance of pubic, axillary, and beard hair. The
sebaceous glands become more active, and the skin tends to
become thicker and oilier. The larynx grows and the vocal cords
become thicker, leading to a lower-pitched voice. Skeletal growth
is stimulated and epiphyseal closure accelerated. Other effects
include growth of the prostate and seminal vesicles, darkening
of the skin, and increased skin circulation. Androgens play an
important role in stimulating and maintaining sexual function
in men. Androgens increase lean body mass and stimulate body
hair growth and sebum secretion. Metabolic effects include the
reduction of hormone binding and other carrier proteins and
increased liver synthesis of clotting factors, triglyceride lipase, α1-
antitrypsin, haptoglobin, and sialic acid. They also stimulate renal
erythropoietin secretion and decrease HDL levels.
Synthetic Steroids with Androgenic &
Anabolic Action
Testosterone, when administered by mouth, is rapidly absorbed.
However, it is largely converted to inactive metabolites, and only
about one sixth of the dose administered is available in active form.
Testosterone can be administered parenterally, but it has a more
prolonged absorption time and greater activity in the propionate,
enanthate, undecanoate, or cypionate ester forms. These derivatives
are hydrolyzed to release free testosterone at the site of injection.
Testosterone derivatives alkylated at the 17 position, eg, methyltes-
tosterone and fluoxymesterone, are active when given by mouth.
Testosterone and its derivatives have been used for their ana-
bolic effects as well as in the treatment of testosterone deficiency.
Although testosterone and other known active steroids can be iso-
lated in pure form and measured by weight, biologic assays are still
used in the investigation of new compounds. In some of these stud-
ies in animals, the anabolic effects of the compound as measured
by trophic effects on muscles or the reduction of nitrogen excretion
may be dissociated from the other androgenic effects. This has led
to the marketing of compounds claimed to have anabolic activity
associated with only weak androgenic effects. Unfortunately, this
dissociation is less marked in humans than in the animals used for
testing (Table 40–5), and all are potent androgens.
Pharmacologic Effects
A. Mechanism of Action
Like other steroids, testosterone acts intracellularly in target cells.
In skin, prostate, seminal vesicles, and epididymis, it is converted
CHAPTER 40  The Gonadal Hormones & Inhibitors     741
TABLE 40–5  Androgens: Preparations available and
relative androgenic:anabolic activity in
animals.
Drug Androgenic:Anabolic Activity
Testosterone 1:1
Testosterone cypionate 1:1
Testosterone enanthate 1:1
Methyltestosterone 1:1
Fluoxymesterone 1:2
Oxymetholone 1:3
Oxandrolone 1:3–1:13
Nandrolone decanoate 1:2.5–1:4
to 5α-dihydrotestosterone by 5α-reductase. In these tissues, dihy-
drotestosterone is the dominant androgen. The distribution of this
enzyme in the fetus is different and has important developmental
implications.
Testosterone and dihydrotestosterone bind to the intracellular
androgen receptor, initiating a series of events similar to those
described above for estradiol and progesterone, leading to growth,
differentiation, and synthesis of a variety of enzymes and other
functional proteins.
B. Effects
In the male at puberty, androgens cause development of the
secondary sex characteristics (see above). In the adult male, large
doses of testosterone—when given alone—or its derivatives sup-
press the secretion of gonadotropins and result in some atrophy
of the interstitial tissue and the tubules of the testes. Since fairly
large doses of androgens are required to suppress gonadotropin
secretion, it has been postulated that inhibin, in combination with
androgens, is responsible for the feedback control of secretion. In
women, androgens are capable of producing changes similar to
those observed in the prepubertal male. These include growth of
facial and body hair, deepening of the voice, enlargement of the
clitoris, frontal baldness, and prominent musculature. The natural
androgens stimulate erythrocyte production.
The administration of androgens reduces the excretion of nitro-
gen into the urine, indicating an increase in protein synthesis or a
decrease in protein breakdown within the body. This effect is much
more pronounced in women and children than in normal men.
Clinical Uses
A. Androgen Replacement Therapy in Men
Androgens are used to replace or augment endogenous androgen
secretion in hypogonadal men (Table 40–6). Even in the presence
of pituitary deficiency, androgens are used rather than gonadotropin
except when normal spermatogenesis is to be achieved. In patients
with hypopituitarism, androgens are not added to the treatment
regimen until puberty, at which time they are instituted in gradually
increasing doses to achieve the growth spurt and the development
of secondary sex characteristics. In these patients, therapy should
742    SECTION VII  Endocrine Drugs
TABLE 40–6  Androgen preparations for replacement
therapy.
Route of
Drug Administration Dosage
Methyltestosterone Oral 25–50 mg/d
  Sublingual (buccal) 5–10 mg/d
Fluoxymesterone Oral 2–10 mg/d
Testosterone enanthate Intramuscular See text
Testosterone cypionate Intramuscular See text
Testosterone Transdermal 2.5–10 mg/d
  Topical gel (1%) 5–10 g/d
be started with long-acting agents such as testosterone enanthate or
cypionate in doses of 50 mg intramuscularly, initially every 4, then
every 3, and finally every 2 weeks, with each change taking place
at 3-month intervals. The dose is then doubled to 100 mg every
2 weeks until maturation is complete. Finally, it is changed to the
adult replacement dose of 200 mg at 2-week intervals.
Testosterone propionate, though potent, has a short duration
of action and is not practical for long-term use. Testosterone
undecanoate can be given orally, administering large amounts
of the steroid twice daily (eg, 40 mg/d); however, this is not
recommended because oral testosterone administration has been
associated with liver tumors. Testosterone can also be administered
transdermally; skin patches or gels are available for scrotal or other
skin area application. Two applications daily are usually required
for replacement therapy. Implanted pellets and other longer-acting
preparations are under study. The development of polycythemia
or hypertension may require some reduction in dose.
B. Gynecologic Disorders
Androgens are used occasionally in the treatment of certain
gynecologic disorders, but the undesirable effects in women are
such that they must be used with great caution. Androgens have
been used to reduce breast engorgement during the postpartum
period, usually in conjunction with estrogens. The weak androgen
danazol is used in the treatment of endometriosis (see above).
Androgens are sometimes given in combination with estro-
gens for replacement therapy in the postmenopausal period in an
attempt to eliminate the endometrial bleeding that may occur when
only estrogens are used and to enhance libido. They have been used
for chemotherapy of breast tumors in premenopausal women.
C. Use as Protein Anabolic Agents
Androgens and anabolic steroids have been used in conjunction
with dietary measures and exercises in an attempt to reverse pro-
tein loss after trauma, surgery, or prolonged immobilization and
in patients with debilitating diseases. Evidence to support this use
of androgens is poor except when hypogonadism is also present.
D. Anemia
In the past, large doses of androgens were employed in the treatment
of refractory anemias such as aplastic anemia, Fanconi’s anemia, sickle
cell anemia, myelofibrosis, and hemolytic anemias. Recombinant
erythropoietin has largely replaced androgens for this purpose.
E. Osteoporosis
Androgens and anabolic agents have been used in the treatment of
osteoporosis, either alone or in conjunction with estrogens. With
the exception of substitution therapy in hypogonadism, bisphos-
phonates have largely replaced androgen use for this purpose.
F. Use as Growth Stimulators
These agents have been used to stimulate growth in boys with
delayed puberty. If the drugs are used carefully, these children will
probably achieve their expected adult height. If treatment is too
vigorous, the patient may grow rapidly at first but will not achieve
full predicted final stature because epiphyseal closure is acceler-
ated. It is difficult to control this type of therapy adequately even
with frequent x-ray examination of the epiphyses, since the action
of the hormones on epiphyseal centers may continue for many
months after therapy is discontinued.
G. Anabolic Steroid and Androgen Abuse in Sports
The use of anabolic steroids by athletes has received worldwide
attention. Many athletes and their coaches believe that anabolic
steroids—in doses 10–200 times larger than the daily normal
physiologic production—increase strength and aggressiveness,
thereby improving competitive performance. Such effects have
been unequivocally demonstrated only in women. Furthermore,
the adverse effects of these drugs clearly make their use inad-
visable. As a result, most sports organizations have developed
extremely sensitive assays, conduct random testing, and apply
strong penalties if drugs are detected.
H. Aging
Androgen production falls with age in men and may contribute to
the decline in muscle mass, strength, and libido. Preliminary studies
of androgen replacement in aging males with low androgen levels
show an increase in lean body mass and hematocrit and a decrease
in bone turnover. However, many factors other than deficient
androgen production contribute to these effects of aging. Longer
studies will be required to assess the usefulness of this therapy.
Adverse Effects
The adverse effects of these compounds are due largely to their
masculinizing actions and are most noticeable in women and
prepubertal children. In women, the administration of more than
200–300 mg of testosterone per month is usually associated with
hirsutism, acne, amenorrhea, clitoral enlargement, and deepening
of the voice. These effects may occur with even smaller doses in
some women. Some of the androgenic steroids exert progestational
activity, leading to endometrial bleeding upon discontinuation.
These hormones also alter serum lipids and could conceivably
increase susceptibility to atherosclerotic disease in women.
Except under the most unusual circumstances, androgens
should not be used in infants. Recent studies in animals suggest
that administration of androgens in early life may have profound

effects on maturation of central nervous system centers governing
sexual development, particularly in the female. Administration of
these drugs to pregnant women may lead to masculinization or
undermasculinization of the external genitalia in the female and
male fetus, respectively. Although the above-mentioned effects
may be less marked with the anabolic agents, they do occur.
Sodium retention and edema are not common but must be
carefully watched for in patients with heart and kidney disease.
Most of the synthetic androgens and anabolic agents are
17-alkyl-substituted steroids. Administration of drugs with this
structure is often associated with evidence of hepatic dysfunction.
Hepatic dysfunction usually occurs early in the course of treat-
ment, and the degree is proportionate to the dose. Bilirubin levels
may increase until clinical jaundice is apparent. The cholestatic
jaundice is reversible upon cessation of therapy, and permanent
changes do not occur. In older males, prostatic hyperplasia may
develop, causing urinary retention.
Replacement therapy in men may cause acne, sleep apnea,
erythrocytosis, gynecomastia, and azoospermia. Supraphysiologic
doses of androgens produce azoospermia and decrease in testicular
size, both of which may take months to recover after cessation of
therapy. The alkylated androgens in high doses can produce pelio-
sis hepatica, cholestasis, and hepatic failure. They lower plasma
HDL and may increase LDL. Hepatic adenomas and carcinomas
have also been reported. Behavioral effects include psychological
dependence, increased aggressiveness, and psychotic symptoms.
Contraindications & Cautions
The use of androgenic steroids is contraindicated in pregnant women
or women who may become pregnant during the course of therapy.
Androgens should not be administered to male patients with
carcinoma of the prostate or breast. Until more is known about the
effects of these hormones on the central nervous system in develop-
ing children, they should be avoided in infants and young children.
Special caution is required in giving these drugs to children to
produce a growth spurt. In most patients, the use of somatotropin
is more appropriate (see Chapter 37).
Care should be exercised in the administration of these drugs to
patients with renal or cardiac disease predisposed to edema. If sodium
and water retention occurs, it will respond to diuretic therapy.
Methyltestosterone therapy is associated with creatinuria, but
the significance of this finding is not known.
Caution: Several cases of hepatocellular carcinoma have been
reported in patients with aplastic anemia treated with androgen
anabolic therapy. Erythropoietin and colony-stimulating factors
(see Chapter 33) should be used instead.
ANDROGEN SUPPRESSION &
ANTIANDROGENS
ANDROGEN SUPPRESSION
In contrast to the lack of strong indications for the use of androgen
supplementation (except in the case of hypogonadism), the use of
inhibitors of androgen synthesis and of androgen antagonists has
CHAPTER 40  The Gonadal Hormones & Inhibitors     743
several well-documented applications. The treatment of advanced
prostatic carcinoma often requires orchiectomy or large doses of estro-
gens to reduce available endogenous androgen. The psychological
effects of the former and gynecomastia produced by the latter make
these approaches undesirable. As noted in Chapter 37, the GnRH
analogs, such as goserelin, nafarelin, buserelin, and leuprolide acetate,
produce effective gonadal suppression when blood levels are continu-
ous rather than pulsatile (see Chapter 37 and Figure 40–6).
ANTIANDROGENS
The potential usefulness of antiandrogens in the treatment of
patients producing excessive amounts of testosterone has led to the
search for effective drugs that can be used for this purpose. Several
approaches to the problem, especially inhibition of synthesis and
receptor antagonism, have met with some success.
Steroid Synthesis Inhibitors
Ketoconazole, used primarily in the treatment of fungal dis-
ease, is an inhibitor of adrenal and gonadal steroid synthesis, as
described in Chapter 39. It does not affect ovarian aromatase, but
it reduces human placental aromatase activity. It displaces estra-
diol and dihydrotestosterone from sex hormone-binding protein
in vitro and increases the estradiol:testosterone ratio in plasma in
vivo by a different mechanism. However, it does not appear to be
clinically useful in women with increased androgen levels because
of the toxicity associated with prolonged use of the 400–800 mg/d
required. The drug has also been used experimentally to treat pros-
tatic carcinoma, but the results have not been encouraging. Men
treated with ketoconazole often develop reversible gynecomastia
during therapy; this may be due to the demonstrated increase in
the estradiol:testosterone ratio.
Inhibition of Conversion of Steroid
Precursors to Androgens
Several compounds have been developed that inhibit the
17-hydroxylation of progesterone or pregnenolone, thereby
preventing the action of the side chain-splitting enzyme and
the further transformation of these steroid precursors to active
androgens. A few of these compounds have been tested clini-
cally but have been too toxic for prolonged use. As noted in
Chapter 39, abiraterone, a newer 17α-hydroxylase inhibitor,
has been approved for use in metastatic prostate cancer.
Since dihydrotestosterone—not testosterone—appears to be
the essential androgen in the prostate, androgen effects in this
and similar dihydrotestosterone-dependent tissues can be reduced
by an inhibitor of 5α-reductase (Figure 40–6). Finasteride, a
steroid-like inhibitor of this enzyme, is orally active and causes a
reduction in dihydrotestosterone levels that begins within 8 hours
after administration and lasts for about 24 hours. The half-life is
about 8 hours (longer in elderly individuals). About 40–50% of
the dose is metabolized; more than half is excreted in the feces.
Finasteride has been reported to be moderately effective in reduc-
ing prostate size in men with benign prostatic hyperplasia and is
744    SECTION VII  Endocrine Drugs

Hypothalamus O

C NHC(CH3)3
CH3

CH3

GnRH
O
N H
– GnRH antagonists (1) H
Finasteride
+/– GnRH agonists (2)

Receptor Inhibitors
Pituitary Flutamide, a substituted anilide, is a potent antiandrogen that has
gonadotrophs
been used in the treatment of prostatic carcinoma. Although not
a steroid, it behaves like a competitive antagonist at the androgen
receptor. It is rapidly metabolized in humans. It frequently causes
LH
mild gynecomastia (probably by increasing testicular estrogen
production) and occasionally causes mild reversible hepatic toxic-
ity. Administration of this compound causes some improvement
Testis
in most patients with prostatic carcinoma who have not had prior
endocrine therapy. Preliminary studies indicate that flutamide
– Ketoconazole, (3)
spironolactone is also useful in the management of excess androgen effect in
women.
Testosterone
F3C
5α- – Finasteride O
Reductase (4)
O2N NH C CH CH3
Dihydrotestosterone
CH3
Flutamide,
cyproterone, (5) Flutamide
– –
spironolactone

Androgen-receptor complex Bicalutamide, nilutamide, and enzalutamide are potent

Androgen
response
element
Expression of appropriate
genes in androgen-responsive cells
FIGURE 40–6  Control of androgen secretion and activity and
some sites of action of antiandrogens: (1) competitive inhibition of
GnRH receptors; (2) stimulation (+, pulsatile administration) or inhibi-
tion via desensitization of GnRH receptors (–, continuous administra-
tion); (3) decreased synthesis of testosterone in the testis; (4) decreased
synthesis of dihydrotestosterone by inhibition of 5α-reductase;
(5) competition for binding to cytosol androgen receptors.
approved for this use in the United States. The dosage is 5 mg/d.
Dutasteride is a similar orally active steroid derivative with a slow
onset of action and a much longer half-life than finasteride. It is
approved for treatment of benign prostatic hyperplasia at a dosage
of 0.5 mg daily. These drugs are not approved for use in women
or children, although finasteride has been used successfully in the
treatment of hirsutism in women and is approved for treatment of
early male pattern baldness in men (1 mg/d).
orally active antiandrogens that can be administered as a single
daily dose and are used in patients with metastatic carcinoma of
the prostate. Studies in patients with carcinoma of the prostate
indicate that these agents are well tolerated. Bicalutamide is rec-
ommended (to reduce tumor flare) for use in combination with
a GnRH analog and may have fewer gastrointestinal side effects
than flutamide. A dosage of 150–200 mg/d (when used alone)
is required to reduce prostate-specific antigen levels to those
achieved by castration, but, in combination with a GnRH analog,
50 mg/d may be adequate. Nilutamide is administered in a dosage
of 300 mg/d for 30 days followed by 150 mg/d. The dosage of
enzalutamide is 160 mg/d orally.
Cyproterone and cyproterone acetate are effective anti-
androgens that inhibit the action of androgens at the target
organ. The acetate form has a marked progestational effect that
suppresses the feedback enhancement of LH and FSH, leading
to a more effective antiandrogen effect. These compounds have
been used in women to treat hirsutism and in men to decrease
excessive sexual drive and are being studied in other conditions
in which the reduction of androgenic effects would be useful.
Cyproterone acetate in a dosage of 2 mg/d administered con-
currently with an estrogen is used in the treatment of hirsutism
in women, doubling as a contraceptive pill; it has orphan drug
status in the United States.
 CHAPTER 40  The Gonadal Hormones & Inhibitors     745

Spironolactone, a competitive inhibitor of aldosterone (see P R E P A R A T I *O N S

Chapter 15), also competes with dihydrotestosterone for the andro- A V A I L A B L E
gen receptors in target tissues. It also reduces 17α-hydroxylase
activity, lowering plasma levels of testosterone and androstene-
GENERIC NAME AVAILABLE AS
dione. It is used in dosages of 50–200 mg/d in the treatment of
ESTROGENS
hirsutism in women and appears to be as effective as finasteride,
Conjugated estrogens (equine) Premarin
flutamide, or cyproterone in this condition.
Diethylstilbestrol† Generic, DES, Stilphostrol
Esterified estrogens Cenestin, Enjuvia, Menest

CHEMICAL CONTRACEPTION Estradiol

Estradiol cypionate in oil
Generic, Estrace, others
Depo-Estradiol, others
IN MEN Estradiol transdermal Generic, Estraderm, Estrasorb,
Estrogel, others
Although many studies have been conducted, an effective and Estradiol valerate in oil Generic, Delestrogen
nontoxic oral contraceptive for men has not yet been found. For Estropipate Generic, Ogen
example, various androgens, including testosterone and testos- PROGESTINS
terone enanthate, in a dosage of 400 mg per month, produced Levonorgestrel Generic, Plan B, others
azoospermia in less than half the men treated. Minor adverse Medroxyprogesterone acetate Generic, Provera
reactions, including gynecomastia and acne, were encountered. Megestrol acetate Generic, Megace
Testosterone in combination with danazol was well tolerated but Norethindrone acetate Generic, Aygestin
no more effective than testosterone alone. Androgens in combina- Progesterone Generic, Prometrium, others
tion with a progestin such as medroxyprogesterone acetate were ANDROGENS & ANABOLIC STEROIDS
no more effective. However, preliminary studies indicate that the Fluoxymesterone Androxy
intramuscular administration of 100 mg of testosterone enanthate Methyltestosterone Android, others
weekly together with 500 mg of levonorgestrel daily orally can Nandrolone decanoate Generic, Deca Durabolin, others
produce azoospermia in 94% of men. Retinoic acid is important Oxandrolone Generic, Oxandrin
in the maturation of sperm and the testis contains a unique iso- Oxymetholone Androl-50
form of the alcohol dehydrogenase enzyme that converts retinol Testosterone Generic
to retinoic acid but no nontoxic inhibitor of this enzyme has been Testosterone cypionate in oil Generic, Depo-testosterone
found to date. Testosterone enanthate in oil Generic, Delatestryl
Cyproterone acetate, a very potent progestin and antian- Testosterone transdermal system Androderm, AndroGel
drogen, also produces oligospermia; however, it does not cause Testosterone pellets Testopel
reliable contraception. ANTAGONISTS & INHIBITORS
At present, pituitary hormones—and potent antagonist analogs (See also Chapter 37)  
of GnRH—are receiving increased attention. A GnRH antagonist Abiraterone Zytiga
in combination with testosterone has been shown to produce Anastrozole Generic, Arimidex
reversible azoospermia in nonhuman primates. Bazedoxifene (in combination with Duavee
conjugated equine estrogens)
Bicalutamide Generic, Casodex
GOSSYPOL Clomiphene Generic, Clomid, Serophene,
Milophene
Extensive trials of this cottonseed derivative have been conducted Danazol Generic, Danocrine
in China. This compound destroys elements of the seminiferous Dutasteride Avodart
epithelium but does not significantly alter the endocrine function Enzalutamide Xtandi
of the testis. Exemestane Generic, Aromasin
In Chinese studies, large numbers of men were treated with Finasteride Generic, Propecia, Proscar
20 mg/d of gossypol or gossypol acetic acid for 2 months, Flutamide Generic, Eulexin
followed by a maintenance dosage of 60 mg/week. On Fulvestrant Faslodex
this regimen, 99% of men developed sperm counts below Letrozole Generic, Femara
4 million/mL. Preliminary data indicate that recovery (return Mifepristone Mifeprex, Korlym
of normal sperm count) following discontinuance of gossypol Nilutamide Nilandron
administration is more apt to occur in men whose counts do not Raloxifene Evista
fall to extremely low levels and when administration is not con- Tamoxifen Generic, Nolvadex
tinued for more than 2 years. Hypokalemia is the major adverse Toremifene Fareston
effect and may lead to transient paralysis. Because of low effi- *
Oral contraceptives are listed in Table 40–3.
cacy and significant toxicity, gossypol has been abandoned as a †
Withdrawn in the United States.
candidate male contraceptive.
746    SECTION VII  Endocrine Drugs

REFERENCES Imai Y et al: Nuclear receptors in bone physiology and diseases. Physiol Rev
2013;93:481.
Acconcia F et al: Palmitoylation-dependent estrogen receptor alpha membrane
Kalantaridou S, Chrousos GP: Monogenic disorders of puberty. J Clin Endocrinol
localization: Regulation by 17beta-estradiol. Mol Biol Cell 2005;16:231.
Metab 2002;87:2481.
Anderson GL et al for the Women’s Health Initiative Steering Committee: Effects
Kalantaridou S et al: Premature ovarian failure, endothelial dysfunction, and
of conjugated equine estrogen in postmenopausal women with hysterectomy.
estrogen-progesterone replacement. Trends Endocrinol Metab 2006;17:101.
JAMA 2004;291:1701.
Kalantaridou SN et al: Impaired endothelial function in young women with
Bacopoulou F, Greydanus DE, Chrousos GP: Reproductive and contraceptive
premature ovarian failure: Normalization with hormone therapy. J Clin
issues in chronically ill adolescents. Eur J Contracept Reprod Health Carez
Endocrinol Metab 2004;89:3907.
2010;15:389.
Kanaka-Gantenbein C et al: Assisted reproduction and its neuroendocrine impact
Basaria S et al: Adverse events associated with testosterone administration. N Engl
on the offspring. Prog Brain Res 2010;182C:161.
J Med 2010;363:109.
Lidegaard Ø et al: Thrombotic stroke and myocardial infarction with hormonal
Baulieu E-E: Contragestion and other clinical applications of RU 486, an antipro-
contraception. N Engl J Med 2012;366:2257.
gesterone at the receptor. Science 1989;245:1351.
Livadas S, Chrousos GP: Control of the onset of puberty. Curr Opin Pediatr
Bechlioulis A et al: Endothelial function, but not carotid intima-media thickness,
2016;28:551.
is affected early in menopause and is associated with severity of hot flushes.
J Clin Endocrinol Metab 2010;95:1199. Manson JE et al: Estrogen plus progestin and the risk of coronary heart disease.
N Engl J Med 2003;349:523.
Bhupathiraju SN et al: Exogenous hormone use: oral contraceptives, postmeno-
pausal hormone therapy, and health outcomes in the Nurses’ Health Study. Martin KA, Barbieri RL: Menopausal hormone therapy: Benefits and risks.
Am J Pub Health 2016;106:1631. UpToDate 2016.
Binkhorst L, et al: Augmentation of endoxifen exposure in tamoxifen-treated McDonnell DP, Wardell SE: The molecular mechanisms underlying the pharma-
women following SSRI switch. Clin Pharmacokin 2016;55:259. cological actions of ER modulators: Implications for new drug discovery in
breast cancer. Curr Opin Pharmacol 2010;10:620.
Böttner M, Thelen P, Jarry H: Estrogen receptor beta: Tissue distribution and the
still largely enigmatic physiological function. J Steroid Biochem Mol Biol Merke DP et al: Future directions in the study and management of congenital
2014;139:245. adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Intern Med
2002;136:320.
Burkman R, Schlesselman JJ, Zieman M: Safety concerns and health benefits asso-
ciated with oral contraception. Am J Obstet Gynecol 2004;190(Suppl 4):S5. Naka KK et al: Effect of the insulin sensitizers metformin and pioglitazone on
endothelial function in young women with polycystic ovary syndrome: A
Chlebowski RT et al: Estrogen plus progestin and breast cancer incidence and
prospective randomized study. Fertil Steril 2011;95:203.
mortality in postmenopausal women. JAMA 2010;304:1684.
Nelson HD et al: Use of medication to reduce risk for primary breast cancer: A
Chrousos GP: Perspective: Stress and sex versus immunity and inflammation.
systematic review for the U.S. Preventive Services Task Force. Ann Intern
Sci Signal 2010;3:pe36.
Med 2013;158:604.
Chrousos GP, Torpy DJ, Gold PW: Interactions between the hypothalamic-
Paulmurugan R et al: In vitro and in vivo molecular imaging of estrogen receptor
pituitary-adrenal axis and the female reproductive system: Clinical implica-
α and β homo- and heterodimerization: exploration of new modes of recep-
tions. Ann Intern Med 1998;129:229.
tor regulation. Mol Endocrinol 2011;25:2029.
Coomarasamy A et al: A randomized trial of progesterone in women with recurrent
Price VH: Treatment of hair loss. N Engl J Med 1999;341:964.
miscarriages. N Engl J Med 2015;373:2141.
Rossouw JE et al: Risks and benefits of estrogen plus progestin in healthy post-
Cui J, Shen Y, Li R: Estrogen synthesis and signaling pathways during aging: From
menopausal women: Principal results from the Women’s Health Initiative
periphery to brain. Trends Mol Med 2013;19:197.
randomized controlled trial. JAMA 2002;288:321.
Cuzick J et al: SERM Chemoprevention of Breast Cancer Overview Group:
Scher HI et al: Increased survival with enzalutamide in prostate cancer after
Selective oestrogen receptor modulators in prevention of breast cancer: An
chemotherapy. N Engl J Med 2012;367:1187.
updated meta-analysis of individual participant data. Lancet 2013;381:1827.
Smith RE: A review of selective estrogen receptor modulators in national
Diamanti-Kandarakis E et al: Pathophysiology and types of dyslipidemia in PCOS.
surgical adjuvant breast and bowel project clinical trials. Semin Oncol
Trends Endocrinol Metab 2007;18:280.
2003;30(Suppl 16):4.
Finkelstein JS et al: Gonadal steroids and body composition, strength, and sexual
Snyder PJ et al: Effect of testosterone replacement in hypogonadal men. J Clin
function in men. N Engl J Med 2013;369:1011.
Endocrinol Metab 2000;85:2670.
Fuqua SAW, Schiff R: Mechanisms of action of selective estrogen receptor modula-
Stegeman BH et al: Different combined oral contraceptives and the risk of venous
tors and down regulators. UpToDate 2016; topic 762.
thrombosis: Systematic review and network meta-analysis. Brit Med J
Gomes MPV, Deitcher SR: Risk of venous thromboembolic disease associated 2013;347:f5298.
with hormonal contraceptives and hormone replacement therapy: A clinical
U.S. Preventive Services Task Force: Hormone therapy for the prevention of chronic
review. Arch Intern Med 2004;164:1965.
conditions in postmenopausal women. Ann Intern Med 2005;142:855.
Hall JM, McDonnell DP, Korach KS: Allosteric regulation of estrogen recep-
Wehrmacher WH, Messmore H: Women’s Health Initiative is fundamentally
tor structure, function, and co-activator recruitment by different estrogen
flawed. Gend Med 2005;2:4.
response elements. Mol Endocrinol 2002;16:469.
Zandi PP et al: Hormone replacement therapy and incidence of Alzheimer’s disease
Harman SM et al: Longitudinal effects of aging on serum total and free testoster-
in older women. JAMA 2002;288:2123.
one levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin
Endocrinol Metab 2001;86:724.

C ASE STUDY ANSWER

The patient should be advised to start daily transdermal and normal monthly uterine bleeding resume. She should
estradiol therapy (100 mcg/d) along with oral natural pro- also be advised to get adequate exercise and increase
gesterone (200 mg/d) for the last 12 days of each 28-day her calcium and vitamin D intake as treatment for her
cycle. On this regimen, her symptoms should disappear osteoporosis.

Pancreatic Hormones &
Antidiabetic Drugs
Martha S. Nolte Kennedy, MD, &
Umesh Masharani, MBBS, MRCP (UK)
C ASE STUDY
A 66-year-old obese Caucasian man presented to an
academic Diabetes Center for advice regarding his diabetes
treatment. His diabetes was diagnosed 10 years previously
on routine testing. He was initially given metformin but
when his control deteriorated, the metformin was stopped
and insulin treatment initiated. The patient was taking
50 units of insulin glargine and an average of 25 units of
insulin aspartate pre-meals. He had never seen a diabetes
educator or a dietitian. He was checking his glucose levels
■■ THE ENDOCRINE PANCREAS
The endocrine pancreas in the adult human consists of approxi-
mately 1 million islets of Langerhans interspersed throughout
the pancreatic gland. Within the islets, at least five hormone-
producing cells are present (Table 41–1). Their hormone products
include insulin, the storage and anabolic hormone of the body;
islet amyloid polypeptide (IAPP, or amylin), which modulates
appetite, gastric emptying, and glucagon and insulin secretion;
glucagon, the hyperglycemic factor that mobilizes glycogen
stores; somatostatin, a universal inhibitor of secretory cells; pan-
creatic peptide, a small protein that facilitates digestive processes
by a mechanism not yet clarified; and ghrelin, a peptide known
to increase pituitary growth hormone release.
41
C H A P T E R
4 times a day. He was smoking half a pack of cigarettes a day.
On examination, his weight was 132 kg (BMI 39.5); blood
pressure 145/71; and signs of mild peripheral neuropathy
were present. Laboratory tests noted an HbA1c value of
8.1%, urine albumin 3007 mg/g creatinine (normal <30),
serum creatinine 0.86 mg/dL (0.61–1.24), total choles-
terol 128 mg/dL, triglycerides 86 mg/dL, HDL cholesterol
38 mg/dL, and LDL cholesterol 73 mg/dL (on atorvastatin
40 mg daily). How would you treat this patient?
■■ INSULIN
Chemistry
Insulin is a small protein with a molecular weight in humans of
5808. It contains 51 amino acids arranged in two chains (A and
B) linked by disulfide bridges; there are species differences in the
amino acids of both chains. Proinsulin, a long single-chain protein
molecule, is processed within the Golgi apparatus of beta cells and
packaged into granules, where it is hydrolyzed into insulin and a
residual connecting segment called C-peptide by removal of four
amino acids (Figure 41–1).
Insulin and C-peptide are secreted in equimolar amounts
in response to all insulin secretagogues; a small quantity of
747
748    SECTION VII  Endocrine Drugs

TABLE 41–1  Pancreatic islet cells and their secretory somatostatin, and leptin; α-adrenergic sympathetic activity;
products. chronically elevated glucose; and low concentrations of fatty
acids. Inhibitory drugs include diazoxide, phenytoin, vinblas-
Approximate tine, and colchicine.
Cell Types1 Percent of Islet Mass Secretory Products
One mechanism of stimulated insulin release is diagrammed
Alpha (A) cell 20 Glucagon, proglucagon in Figure 41–2. As shown in the figure, hyperglycemia results in
Beta (B) cell 75 Insulin, C-peptide, increased intracellular ATP levels, which close ATP-dependent
proinsulin, amylin potassium channels. Decreased outward potassium efflux results
Delta (D) cell 3–5 Somatostatin in depolarization of the beta cell and opening of voltage-gated
Epsilon cell <1 Ghrelin calcium channels. The resulting increased intracellular calcium
1 triggers secretion of the hormone. The insulin secretagogue drug
Within pancreatic polypeptide-rich lobules of adult islets, located only in the poste-
rior portion of the head of the human pancreas, glucagon cells are scarce (<0.5%) and group (sulfonylureas, meglitinides, and d-phenylalanine) exploits
F cells make up as much as 80% of the cells. parts of this mechanism.

unprocessed or partially hydrolyzed proinsulin is released as well. Insulin Degradation

Although proinsulin may have some mild hypoglycemic action,
C-peptide has no known physiologic function. Granules within
the beta cells store the insulin in the form of crystals consisting of
two atoms of zinc and six molecules of insulin. The entire human
pancreas contains up to 8 mg of insulin, representing approxi-
mately 200 biologic units. Originally, the unit was defined on
the basis of the hypoglycemic activity of insulin in rabbits. With
improved purification techniques, the unit is presently defined on
the basis of weight, and present insulin standards used for assay
purposes contain 28 units per milligram.
The liver and kidney are the two main organs that remove insu-
lin from the circulation. The liver normally clears the blood of
approximately 60% of the insulin released from the pancreas by
virtue of its location as the terminal site of portal vein blood flow,
with the kidney removing 35–40% of the endogenous hormone.
However, in insulin-treated diabetics receiving subcutaneous
insulin injections, this ratio is reversed, with as much as 60%
of exogenous insulin being cleared by the kidney and the liver
removing no more than 30–40%. The half-life of circulating
insulin is 3–5 minutes.

Insulin Secretion Circulating Insulin

Insulin is released from pancreatic beta cells at a low basal rate
and at a much higher stimulated rate in response to a variety of
stimuli, especially glucose. Other stimulants such as other sugars
(eg, mannose), amino acids (especially gluconeogenic amino
acids, eg, leucine, arginine), hormones such as glucagon-like
polypeptide 1 (GLP-1), glucose-dependent insulinotropic poly-
peptide (GIP), glucagon, cholecystokinin, high concentrations
of fatty acids, and β-adrenergic sympathetic activity are recog-
nized. Stimulatory drugs include sulfonylureas, meglitinide and
nateglinide, isoproterenol, and acetylcholine. Inhibitory signals
are hormones including insulin itself, islet amyloid polypeptide,
Basal serum insulin values of 5–15 μU/mL (30–90 pmol/L) are
found in normal humans, with a peak rise to 60–90 μU/mL
(360–540 pmol/L) during meals.
The Insulin Receptor
After insulin has entered the circulation, it diffuses into tissues,
where it is bound by specialized receptors that are found on the
membranes of most tissues. The biologic responses promoted by
these insulin-receptor complexes have been identified in the pri-
mary target tissues regulating energy metabolism, ie, liver, muscle,

C-peptide

A chain S S

1 10 21
S S

S S 32
B chain
31

1 3 10 20 28 29 30

FIGURE 41–1  Structure of human proinsulin (C-peptide plus A and B chains) and insulin. Insulin is shown as the shaded (orange color)
peptide chains, A and B. Differences in the A and B chains and amino acid modifications for the rapid-acting insulin analogs (aspart, lispro,
and glulisine) and long-acting insulin analogs (glargine and detemir) are discussed in the text. (Adapted, with permission, from Gardner DG, Shoback D
[editors]: Greenspan’s Basic & Clinical Endocrinology, 9th ed. McGraw-Hill, 2011. Copyright © The McGraw-Hill Companies, Inc.)
 CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     749

K+ channel
Sulfonylurea drugs
–
(block, depolarize)

(Closes channel, K+
depolarizes cell)

Glucose
transporter ATP
Ca2+ channel
GLUT2
(depolarization
Glucose Metabolism – + opens channel)

Ca2+ Ca2+
Insulin

Exocytosis

Insulin

FIGURE 41–2  One model of control of insulin release from the pancreatic beta cell by glucose and by sulfonylurea drugs. In the resting
cell with normal (low) ATP levels, potassium diffuses down its concentration gradient through ATP-gated potassium channels, maintaining the
intracellular potential at a fully polarized, negative level. Insulin release is minimal. If glucose concentration rises, ATP production increases,
potassium channels close, and depolarization of the cell results. As in muscle and nerve, voltage-gated calcium channels open in response to
depolarization, allowing more calcium to enter the cell. Increased intracellular calcium results in increased insulin secretion. Insulin secreta-
gogues close the ATP-dependent potassium channel, thereby depolarizing the membrane and causing increased insulin release by the same
mechanism.

and adipose tissue. The receptors bind insulin with high specificity
and affinity in the picomolar range. The full insulin receptor con-
sists of two covalently linked heterodimers, each containing an α
subunit, which is entirely extracellular and constitutes the recogni-
tion site, and a β subunit that spans the membrane (Figure 41–3).
The β subunit contains a tyrosine kinase. The binding of an
insulin molecule to the α subunits at the outside surface of the
cell activates the receptor and through a conformational change
brings the catalytic loops of the opposing cytoplasmic β subunits
into closer proximity. This facilitates mutual phosphorylation of
tyrosine residues on the β subunits and tyrosine kinase activity
directed at cytoplasmic proteins.
The first proteins to be phosphorylated by the activated recep-
tor tyrosine kinases are the docking proteins: insulin receptor
substrates (IRS). After tyrosine phosphorylation at several critical
sites, the IRS molecules bind to and activate other kinases subserv-
ing energy metabolism—most significantly phosphatidylinositol-
3-kinase—which produce further phosphorylations. Alternatively,
they may stimulate a mitogenic pathway and bind to an adaptor
protein such as growth factor receptor–binding protein 2, which
translates the insulin signal to a guanine nucleotide-releasing
factor that ultimately activates the GTP binding protein, Ras,
and the mitogen-activated protein kinase (MAPK) system. The
particular IRS-phosphorylated tyrosine kinases have binding
specificity with downstream molecules based on their surround-
ing 4–5 amino acid sequences or motifs that recognize specific Src
homology 2 (SH2) domains on the other protein. This network
of phosphorylations within the cell represents insulin’s second
message and results in multiple effects, including translocation of
glucose transporters (especially GLUT 4, Table 41–2) to the cell
membrane with a resultant increase in glucose uptake; increased
glycogen synthase activity and increased glycogen formation; mul-
tiple effects on protein synthesis, lipolysis, and lipogenesis; and
activation of transcription factors that enhance DNA synthesis
and cell growth and division.
Various hormonal agents (eg, glucocorticoids) lower the affin-
ity of insulin receptors for insulin; growth hormone in excess
increases this affinity slightly. Aberrant serine and threonine
phosphorylation of the insulin receptor β subunits or IRS mol-
ecules may result in insulin resistance and functional receptor
down-regulation.
Effects of Insulin on Its Targets
Insulin promotes the storage of fat as well as glucose (both sources
of energy) within specialized target cells (Figure 41–4) and influ-
ences cell growth and the metabolic functions of a wide variety of
tissues (Table 41–3).
■■ GLUCAGON
Chemistry & Metabolism
Glucagon is synthesized in the alpha cells of the pancreatic
islets of Langerhans (Table 41–1). Glucagon is a peptide—
identical in all mammals—consisting of a single chain of
750    SECTION VII  Endocrine Drugs

Vagus

α Insulin
Insulin molecule Liver
subunits
+
Receptor
Pancreas
β +
subunits
Substrate
Extracellular
Betacytotropic
hormones Fat

Cytoplasm
Tyrosine
kinase Muscle
domains
P
Intestine

P
FIGURE 41–4  Insulin promotes synthesis (from circulating nutrients)
and storage of glycogen, triglycerides, and protein in its major target tissues: liver,
ATP fat, and muscle. The release of insulin from the pancreas is stimulated by increased
Tyr
blood glucose, incretins, vagal nerve stimulation, and other factors (see text).

IRS

Tyr – P
Glucagon is extensively degraded in the liver and kidney as
ADP well as in plasma and at its tissue receptor sites. Its half-life in
IRS plasma is between 3 and 6 minutes, which is similar to that of
insulin.
+ +
Phosphatidylinositol-3
kinase pathway
MAP kinase
pathway
Pharmacologic Effects of Glucagon
A. Metabolic Effects
The first six amino acids at the amino terminal of the gluca-
FIGURE 41–3  Schematic diagram of the insulin receptor het- gon molecule bind to specific Gs protein–coupled receptors on
erodimer in the activated state. IRS, insulin receptor substrate; MAP,
liver cells. This leads to an increase in cAMP, which facilitates
mitogen-activated protein; P, phosphate; Tyr, tyrosine.
catabolism of stored glycogen and increases gluconeogenesis and
ketogenesis. The immediate pharmacological result of glucagon
29 amino acids, with a molecular weight of 3485. Selective infusion is to raise blood glucose at the expense of stored hepatic
proteolytic cleavage converts a large precursor molecule of glycogen. There is no effect on skeletal muscle glycogen, presum-
approximately 18,000 MW to glucagon. One of the precur- ably because of the lack of glucagon receptors on skeletal muscle.
sor intermediates consists of a 69-amino-acid peptide called Pharmacological amounts of glucagon cause release of insulin
glicentin, which contains the glucagon sequence interposed from normal pancreatic beta cells, catecholamines from pheochro-
between peptide extensions. mocytoma, and calcitonin from medullary carcinoma cells.

TABLE 41–2  Glucose transporters.

Glucose Km
Transporter Tissues (mmol/L) Function

GLUT 1 All tissues, especially red cells, brain 1–2 Basal uptake of glucose; transport across the blood-brain barrier
GLUT 2 Beta cells of pancreas; liver, kidney; gut 15–20 Regulation of insulin release, other aspects of glucose homeostasis
GLUT 3 Brain, placenta <1 Uptake into neurons, other tissues
GLUT 4 Muscle, adipose ~5 Insulin-mediated uptake of glucose
GLUT 5 Gut, kidney 1–2 Absorption of fructose

TABLE 41–3  Endocrine effects of insulin.
Effect on liver:
  Reversal of catabolic features of insulin deficiency
  Inhibits glycogenolysis
   Inhibits conversion of fatty acids and amino acids to keto acids
   Inhibits conversion of amino acids to glucose
  Anabolic action
  Promotes glucose storage as glycogen (induces glucokinase and
glycogen synthase, inhibits phosphorylase)
  Increases triglyceride synthesis and very-low-density lipoprotein
formation
Effect on muscle:
  Increased protein synthesis
   Increases amino acid transport
   Increases ribosomal protein synthesis
  Increased glycogen synthesis
   Increases glucose transport
   Induces glycogen synthase and inhibits phosphorylase
Effect on adipose tissue:
  Increased triglyceride storage
  Lipoprotein lipase is induced and activated by insulin to hydro-
lyze triglycerides from lipoproteins
  Glucose transport into cell provides glycerol phosphate to permit
esterification of fatty acids supplied by lipoprotein transport
   Intracellular lipase is inhibited by insulin
B. Cardiac Effects
Glucagon has a potent inotropic and chronotropic effect on the
heart, mediated by the cAMP mechanism described above. Thus,
it produces an effect very similar to that of β-adrenoceptor ago-
nists without requiring functioning β receptors.
C. Effects on Smooth Muscle
Large doses of glucagon produce profound relaxation of the intes-
tine. In contrast to the above effects of the peptide, this action
on the intestine may be due to mechanisms other than adenylyl
cyclase activation.
Clinical Uses
A. Severe Hypoglycemia
The major clinical use of glucagon is for emergency treatment
of severe hypoglycemic reactions in patients with type 1 diabetes
when unconsciousness precludes oral feedings and intravenous
glucose treatment is not possible. Recombinant glucagon is cur-
rently available in 1-mg vials for parenteral (IV, IM, or SC) use
(Glucagon Emergency Kit).
B. Endocrine Diagnosis
Several tests use glucagon to diagnose endocrine disorders. In
patients with type 1 diabetes mellitus, a classic research test
of pancreatic beta-cell secretory reserve uses 1 mg of glucagon
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     751
administered as an intravenous bolus. Because insulin-treated
patients develop circulating anti-insulin antibodies that interfere
with radioimmunoassays of insulin, measurements of C-peptide
are used to indicate beta-cell secretion.
C. Beta-Adrenoceptor Blocker Overdose
Glucagon is sometimes useful for reversing the cardiac effects of
an overdose of β-blocking agents because of its ability to increase
cAMP production in the heart independent of β-receptor func-
tion. However, it is not clinically useful in the treatment of heart
failure.
D. Radiology of the Bowel
Glucagon has been used extensively in radiology as an aid to
x-ray visualization of the bowel because of its ability to relax the
intestine.
Adverse Reactions
Transient nausea and occasional vomiting can result from glu-
cagon administration. These are generally mild, and glucagon is
relatively free of severe adverse reactions. It should not be used in
a patient with pheochromocytoma.
■■ DIABETES MELLITUS
Diabetes mellitus is defined as an elevated blood glucose associ-
ated with absent or inadequate pancreatic insulin secretion, with or
without concurrent impairment of insulin action. The disease states
underlying the diagnosis of diabetes mellitus are now classified into
four categories: type 1, type 2, other, and gestational diabetes
mellitus.
Type 1 Diabetes Mellitus
The hallmark of type 1 diabetes is selective beta cell (B cell)
destruction and severe or absolute insulin deficiency. Type 1 dia-
betes is further subdivided into immune-mediated (type 1a) and
idiopathic causes (type 1b). The immune form is the most com-
mon form of type 1 diabetes. Although most patients are younger
than 30 years of age at the time of diagnosis, the onset can occur
at any age. Type 1 diabetes is found in all ethnic groups, but the
highest incidence is in people from northern Europe and from
Sardinia. Susceptibility appears to involve a multifactorial genetic
linkage, but only 10–15% of patients have a positive family his-
tory. Most patients with type 1 diabetes have one or more circu-
lating antibodies to glutamic acid decarboxylase 65 (GAD 65),
insulin autoantibody, tyrosine phosphatase IA2 (ICA 512), and
zinc transporter 8 (ZnT8) at the time of diagnosis. These anti-
bodies facilitate the diagnosis of type 1a diabetes and can also be
used to screen family members at risk for developing the disease.
Most type 1 patients with acute symptomatic presentation have
significant beta cell loss and insulin therapy is essential to control
glucose levels and to prevent ketosis.
Some patients have a more indolent autoimmune process
and initially retain enough beta cell function to avoid ketosis.
752    SECTION VII  Endocrine Drugs
They can be treated at first with oral hypoglycemic agents
but then need insulin as their beta cell function declines.
Antibody studies in northern Europeans indicate that up to
10–15% of “type 2” patients may actually have this milder
form of type 1 diabetes (latent autoimmune diabetes of adult-
hood; LADA).
Type 2 Diabetes Mellitus
Type 2 diabetes is a heterogenous group of conditions charac-
terized by tissue resistance to the action of insulin combined
with a relative deficiency in insulin secretion. A given indi-
vidual may have more resistance or more beta-cell deficiency,
and the abnormalities may be mild or severe. Although the
circulating endogenous insulin is sufficient to prevent ketoaci-
dosis, it is inadequate to prevent hyperglycemia. Patients with
type 2 diabetes can initially be controlled with diet, exercise
and oral glucose lowering agents or non-insulin injectables.
Some patients have progressive beta cell failure and eventually
may also need insulin therapy.
Other Specific Types of Diabetes Mellitus
The “other” designation refers to multiple other specific causes
of an elevated blood glucose: pancreatectomy, pancreatitis, non-
pancreatic diseases, drug therapy, etc. For a detailed list the reader
is referred to the reference Expert Committee, 2003.
Gestational Diabetes Mellitus
Gestational diabetes (GDM) is defined as any abnormality in glu-
cose levels noted for the first time during pregnancy. Gestational
diabetes is diagnosed in approximately 7% of all pregnancies in
the United States. During pregnancy, the placenta and placental
hormones create an insulin resistance that is most pronounced in
the last trimester. Risk assessment for diabetes is suggested start-
ing at the first prenatal visit. High-risk women should be screened
immediately. Screening may be deferred in lower-risk women
until the 24th to 28th week of gestation.
TABLE 41–4  Diagnostic criteria for diabetes.
Normal Glucose
Tolerance, mg/dL
  (mMol/L)
Fasting plasma glucose mg/dL (mmol/L) <100 (5.6)
1
Two hours after glucose load mg/dL <140 (7.8)
(mmol/L)
HbA1c (%) (ADA criteria) <5.7
1
Give 75 g of glucose dissolved in 300 mL of water after an overnight fast in persons who have been receiving at least 150–200 g of carbohydrate daily for 3 days
before the test.
2
A fasting plasma glucose ≥126 mg/dL (7.0 mmol) or HbA1c ≥ 6.5% is diagnostic of diabetes if confirmed by repeat testing.
Symptoms and random glucose level >200 mg/dL (11.1 mmol/L) are diagnostic, and there is no need to do additional testing.
Laboratory Findings
A. Plasma or Serum Glucose
A plasma glucose level of 126 mg/dL (7 mmol/L) or higher
on more than one occasion after at least 8 hours of fasting is
diagnostic of diabetes mellitus (Table 41–4). Fasting plasma
glucose levels of 100–125 mg/dL (5.6–6.9 mmol/L) are associ-
ated with increased risk of diabetes (impaired fasting glucose
tolerance).
If the fasting plasma glucose level is less than 126 mg/dL
(7 mMol/L) but diabetes is nonetheless suspected, then a stan-
dardized oral glucose tolerance test may be done (Table 41–4).
The patient should eat nothing after midnight prior to the test
day. On the morning of the test, adults are then given 75 g of
glucose in 300 mL of water; children are given 1.75 g of glucose
per kilogram of ideal body weight. The glucose load is consumed
within 5 minutes. Blood samples for plasma glucose are obtained
at 0 and 120 minutes after ingestion of glucose. An oral glucose
tolerance test is normal if the fasting venous plasma glucose value
is less than 100 mg/dL (5.6 mmol/L) and the 2-hour value falls
below 140 mg/dL (7.8 mmol/L). A fasting value of 126 mg/dL
(7 mmol/L) or higher or a 2-hour value of greater than 200 mg/dL
(11.1 mmol/L) is diagnostic of diabetes mellitus. Patients with
2-hour value of 140–199 mg/dL (7.8–11.1 mmol/L) have
impaired glucose tolerance.
B. Hemoglobin A1c Measurements
When plasma glucose levels are in the normal range, about 4–6%
of hemoglobin A has one or both of the N terminal valines of their
beta chains irreversibly glycated by glucose—referred to as hemo-
globin A1c (HbA1c). The HbA1c fraction is abnormally elevated
in people with diabetes with chronic hyperglycemia. Since red
cells have a lifespan of up to 120 days, the HbA1c value reflects
plasma glucose levels over the preceding 8–12 weeks. In patients
who monitor their glucose levels, the HbA1c value provides a
valuable check on the accuracy of their monitoring. In patients
who do not monitor their glucose levels, HbA1c measurements
are essential for adjusting treatment. HbA1c can be used to
Prediabetes Diabetes Mellitus2
100–125 (5.6–6.9) ≥126
(impaired fasting glucose) (7.0)
≥140–199 ≥200
(7.8–11.0) (11.1)
(impaired glucose tolerance)
5.7–6.4 ≥6.5

diagnose diabetes. An HbA1c of 6.5% or greater if confirmed by
repeat testing is diagnostic of diabetes. Less than 5.7% is normal,
and patients with levels of 5.7–6.4% are considered at high risk
for developing diabetes (Table 41–4).
C. Urine or Blood Ketones
Qualitative detection of ketone bodies can be accomplished by
nitroprusside tests (Acetest or Ketostix). Although these tests do
not detect beta-hydroxybutyric acid, which lacks a ketone group,
the semiquantitative estimation of ketonuria thus obtained is
nonetheless usually adequate for clinical purposes. Many laborato-
ries now measure beta-hydroxybutyric acid, and meters are avail-
able (Precision Xtra; Nova Max Plus) for patient use that measure
beta-hydroxybutyric acid levels in capillary glucose samples. Beta-
hydroxybutyrate levels >0.6 mmol/L require evaluation. A level
>3.0 mmol/L, which is equivalent to very large urinary ketones,
will require hospitalization.
D. Self-Monitoring of Blood Glucose
Capillary blood glucose measurements performed by patients
themselves, as outpatients, are extremely useful. In type 1
patients in whom “tight” metabolic control is attempted, they
are indispensable. Several paper strip methods and a large
number of blood glucose meters are now available for measur-
ing glucose on capillary blood samples. All are accurate, but
they vary with regard to speed, convenience, size of blood
samples required, reporting capability, and cost. Some meters
are designed to communicate with an insulin pump. A number
of continuous glucose monitoring (CGM) systems are also avail-
able for clinical use. The systems utilize a subcutaneous sensor
that measures glucose concentrations in the interstitial fluid
for 3–7 days. Studies show that adult type 1 patients who use
continuous systems have improved glucose control without an
increased incidence of hypoglycemia. There is great interest in
using continuous glucose monitoring systems to automatically
deliver insulin by continuous subcutaneous insulin infusion
pump. The first artificial pancreas system has been approved by
the U.S. Food and Drug Administration (FDA) and will become
available in 2017. With this system, the continuous glucose
monitor readings are used to automatically adjust the basal insu-
lin dosing by the insulin pump.
TABLE 41–5  Summary of bioavailability characteristics of the insulins.
Insulin Preparations Onset of Action
Insulins lispro, aspart, glulisine 5–15 min
Human regular 30–60 min
Technosphere inhaled insulin 5–15 min
Human NPH 2–4 h
Insulin glargine 0.5–1 h
Insulin detemir 0.5–1 h
Insulin degludec 0.5–1.5 h
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     753
■■ MEDICATIONS FOR
HYPERGLYCEMIA
Insulin Preparations
Human insulin is dispensed as regular (R) and neutral protamine
hagedorn (NPH) formulations. There are also six analogs of human
insulin. Three of the analogs are rapidly acting: insulin lispro, insu-
lin aspart, and insulin glulisine; and three are long acting: insulin
glargine, insulin detemir, and insulin degludec. Animal insulins
are not available in the United States. Pork and beef preparations
(isophane, neutral, 30/70, and lente) are still available in other parts
of the world. All the insulins in the United States are available in
a concentration of 100 units/ML (U100) and dispensed as 10-mL
vials or 0.3-mL cartridges or prefilled disposable pens. Several
insulins are also available at higher concentrations in the prefilled
disposable pen form: insulin glargine 300 units/mL (U300); insulin
degludec (U200); insulin lispro 200 units/mL (U200); and regular
insulin 500 units/mL (U500) (Tables 41–5, 41–6).
A. Short-Acting Insulin Preparations (Tables 41–5, 41–6)
The short-acting preparations include regular human insulin
and the three rapidly acting insulin analogs. All are clear solu-
tions at neutral pH. The insulin molecules exist as dimers that
assemble into hexamers in the presence of two zinc ions. The
hexamers are further stabilized by phenolic compounds such as
phenol and meta-Cresol. The mutations engineered into the rap-
idly acting insulin analogs are designed to disrupt the stabilizing
intermolecular interactions of the dimers and hexamers, leading
to more rapid absorption into the circulation after subcutaneous
injection.
1. Regular insulin—Regular insulin is a short-acting, soluble
crystalline zinc insulin whose hypoglycemic effect appears within
30 minutes after subcutaneous injection, peaks at about 2 hours,
and lasts for 5–7 hours when usual quantities (ie, 5–15 U) are
administered. For very insulin-resistant subjects who would oth-
erwise require large volumes of insulin solution, a U500 prepara-
tion of human regular insulin is available both in a vial form and
a disposable pen. If the vial form is used, it is necessary to use
a U100-insulin syringe or tuberculin syringe to measure doses.
Peak Action Effective Duration
1–1.5 h 3–4 h
2h 6–8 h
1h 3h
6–7 h 10–20 h
Flat ~24 h
Flat 17 h
Flat >42 h
754    SECTION VII  Endocrine Drugs

TABLE 41–6  Some insulin preparations available in the United States.1

Preparation Species Source Concentration

Short-acting insulins    
  Insulin lispro (Humalog, Lilly) Human analog U100, U200
  Insulin aspart (Novolog, Novo Nordisk) Human analog U100
  Insulin glulisine (Apidra, Sanofi Aventis) Human analog U100
  Regular insulin (Humulin R, Lilly; Novolin R, Novo Nordisk) Human U100, U500
  Regular insulin inhaled (MannKind) Human —
Long-acting insulins    
  NPH insulin (Humulin N, Lilly, Novolin N, Novo Nordisk) Human U100
  Insulin glargine (Lantus, Toujeo, Sanofi Aventis, Basaglar, Lilly) Human analog U100, U300
  Insulin detemir (Levemir, Novo Nordisk) Human analog U100
  Insulin degludec (Tresiba, Novo Nordisk) Human analog U100, U200
Premixed insulins    
 70 NPH/30 regular (Novolin, Novo Nordisk; Humulin, Lilly) Human U100
  75/25 NPL, Lispro (Humalog mix 75/25, Lilly) Human analog U100
  50/50 NPL, Lispro (Humalog mix 50/50, Lilly) Human analog U100
  70/30 NPA, Aspart (Novolog mix 70/30, Novo Nordisk) Human analog U100
  70/30 Degludec/Aspart (Ryzodeg, Novo Nordisk) Human analog U100
All insulins are now made by recombinant technology; they should be refrigerated and brought to room temperature just before injection.
NPA, neutral protamine aspart; NPL, neutral protamine lispro.

The physician should then carefully note dosages in both units
and volume to avoid overdosage. The disposable pen avoids this
conversion issue and dispenses the regular U500 insulin in 5-unit
increments.
Intravenous infusions of regular insulin are particularly useful
in the treatment of diabetic ketoacidosis and during the periopera-
tive management of insulin-requiring diabetics.
2. Rapidly acting insulin analogs—Insulin lispro (Huma-
log) is an insulin analog in which the proline at position B28 is
reversed with the lysine at B29. Insulin aspart (Novolog) is a single
substitution of proline by aspartic acid at position B28. Insulin
glulisine (Apidra) differs from human insulin in that the amino
acid asparagine at position B3 is replaced by lysine and the lysine
in position B29 by glutamic acid. When injected subcutaneously,
these three analogs quickly dissociate into monomers and are
absorbed very rapidly, reaching peak serum values in as little as
1 hour. The amino acid changes in these analogs do not interfere
with their binding to the insulin receptor, with the circulating
half-life, or with their immunogenicity, which are all identical to
those of human regular insulin.
Clinical trials have demonstrated that the optimal times
of preprandial subcutaneous injection of comparable doses of
the rapid-acting insulin analogs and of regular human insulin
are 15 minutes and 45 minutes before the meal, respectively.
Although the more rapid onset of action has been welcomed as a
great convenience by patients with diabetes who object to wait-
ing as long as 45 minutes after injecting regular human insulin
before they can begin their meal, patients must be taught to ingest
adequate absorbable carbohydrate early in the meal to avoid hypo-
glycemia during the meal. The analogs also have lowest variability
of absorption: approximately 5%. This compares with 25% for
regular insulin. Another desirable feature of rapidly acting insulin
analogs is that their duration of action remains at about 4 hours
for most commonly used dosages. This contrasts with regular
insulin, whose duration of action is significantly prolonged when
larger doses are used.
The rapidly acting analogs are commonly used in insulin
pumps. In a double-blind crossover study comparing insulin lis-
pro with regular insulin in insulin pumps, persons using insulin
lispro had lower HbA1c values and improved postprandial glucose
control with the same frequency of hypoglycemia. However, the
concern remains that in the event of pump failure, users of the
rapidly acting insulin analogs will have more rapid onset of hyper-
glycemia and ketosis.
While insulin aspart has been approved for intravenous
use (eg, in hyperglycemic emergencies), there is no advantage
in using insulin aspart over regular insulin by this route. A
U200 concentration of insulin lispro is available in a disposable
prefilled pen. The only advantage of the U200 over the U100
insulin lispro preparation is that it delivers the same dose in half
the volume.

B. Long-Acting Insulin Preparations (Tables 41–5, 41–6)
1. NPH (neutral protamine Hagedorn, or isophane)
insulin—NPH insulin is an intermediate-acting insulin whose
absorption and onset of action are delayed by combining appropri-
ate amounts of insulin and protamine so that neither is present
in an uncomplexed form (“isophane”). After subcutaneous injec-
tion, proteolytic tissue enzymes degrade the protamine to permit
absorption of insulin. NPH insulin has an onset of approximately
2–5 hours and duration of 4–12 hours (Figure 41–5); it is usually
mixed with regular, lispro, aspart, or glulisine insulin and given two
to four times daily for insulin replacement. The dose regulates the
action profile; specifically, small doses have lower, earlier peaks and
a short duration of action with the converse true for large doses.
2. Insulin glargine—Insulin glargine is a soluble, “peakless”
(ie, having a broad plasma concentration plateau), long-acting
insulin analog. The attachment of two arginine molecules to
the B-chain carboxyl terminal and substitution of a glycine for
asparagine at the A21 position created an analog that is soluble
in an acidic solution but precipitates in the more neutral body
pH after subcutaneous injection. Individual insulin molecules
slowly dissolve away from the crystalline depot and provide a low,
continuous level of circulating insulin. Insulin glargine has a slow
onset of action (1–1.5 hours) and achieves a maximum effect after
4–6 hours. This maximum activity is maintained for 11–24 hours
or longer. Glargine is usually given once daily, although some
very insulin-sensitive or insulin-resistant individuals benefit from
split (twice a day) dosing. To maintain solubility, the formulation
is unusually acidic (pH 4.0), and insulin glargine should not be
mixed with other insulins. Separate syringes must be used to mini-
mize the risk of contamination and subsequent loss of efficacy.
The absorption pattern of insulin glargine appears to be indepen-
dent of the anatomic site of injection, and this drug is associated
8
Insulin lispro, aspart, glulisine
7
Glucose infusion rate (mg/kg/min)
6
5
4
3
2 Insulin glargine
1
1 2 3 4
FIGURE 41–5  Extent and duration of action of various types of insulin as indicated by the glucose infusion rates (mg/kg/min) required to
maintain a constant glucose concentration. The durations of action shown are typical of an average dose of 0.2–0.3 U/kg. The durations of regu-
lar and NPH insulin increase considerably when dosage is increased.
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     755
with less immunogenicity than human insulin in animal studies.
Glargine’s interaction with the insulin receptor is similar to that of
native insulin and shows no increase in mitogenic activity in vitro.
It has sixfold to sevenfold greater binding than native insulin to
the insulin-like growth factor 1 (IGF-1) receptor, but the clinical
significance of this is unclear.
3. Insulin detemir—In this insulin the terminal threonine is
dropped from the B30 position and myristic acid (a C-14 fatty
acid chain) is attached to the B29 lysine. These modifications
prolong the availability of the injected analog by increasing both
self-aggregation in subcutaneous tissue and reversible albumin
binding. The affinity of insulin detemir is four- to fivefold lower
than that of human soluble insulin and, therefore, the U100 for-
mulation of insulin detemir has a concentration of 2400 nmol/mL
compared with 600 nmol/mL for NPH. The duration of action
for insulin detemir is about 17 hours at therapeutically relevant
doses. It is recommended that the insulin be injected once or
twice a day to achieve a stable basal coverage. This insulin has been
reported to have lower within-subject pharmacodynamic variabil-
ity compared with NPH insulin and insulin glargine.
4. Insulin Degludec—In this insulin analog, the threonine at
position B30 has been removed and the lysine at position B29 is
conjugated to hexadecanoic acid via a gamma-l-glutamyl spacer.
In the vial, in the presence of phenol and zinc, the insulin is
in the form of dihexamers but, when injected subcutaneously,
it self-associates into large multihexameric chains consisting of
thousands of dihexamers. The chains slowly dissolve in the sub-
cutaneous tissue, and insulin monomers are steadily released into
the systemic circulation. The half-life of the insulin is 25 hours.
Its onset of action is in 30–90 minutes, and its duration of action
is more than 42 hours. It is recommended that the insulin be
Regular
NPH
Insulin degludec
Insulin detemir
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Time (h)
756    SECTION VII  Endocrine Drugs
injected once or twice a day to achieve a stable basal coverage.
Insulin degludec is available in two concentrations, U100 and
U200, and dispensed in pre-filled disposable pens.
5. Mixtures of insulins—Because intermediate-acting NPH
insulins require several hours to reach adequate therapeutic levels,
their use in patients with diabetes usually requires supplements of
rapid- or short-acting insulin before meals. For convenience, these
are often mixed together in the same syringe before injection. The
regular insulin or rapidly acting insulin analog is withdrawn first,
then the NPH insulin and then injected immediately.
Stable premixed insulins (70% NPH and 30% regular) are
available as a convenience to patients who have difficulty mix-
ing insulin because of visual problems or insufficient manual
dexterity. Premixed preparations of rapidly acting insulin analogs
(lispro, aspart) and NPH are not stable because of exchange of
the rapidly acting insulin analog for the human regular insulin
in the protamine complex. Consequently, over time, the soluble
component becomes a mixture of regular and rapidly acting
insulin analog at varying ratios. To remedy this problem, inter-
mediate insulins composed of isophane complexes of protamine
with the rapidly acting insulin analogs were developed (neutral
protamine lispro [NPL]; aspart protamine). Premixed combina-
tions of NPL and insulin lispro are now available for clinical use
(Humalog Mix 75/25 and Humalog Mix 50/50). These mixtures
have a more rapid onset of glucose-lowering activity compared
with 70% NPH/30% regular human insulin mixture and can be
given within 15 minutes before or after starting a meal. A similar
70% insulin aspart protamine/30% insulin aspart (NovoLog Mix
70/30) is now available. The main advantages of these new mix-
tures are that (1) they can be given within 15 minutes of starting
a meal and (2) they are superior in controlling the postprandial
glucose rise after a carbohydrate-rich meal.
Insulin glargine or insulin detemir cannot be acutely mixed with
either regular insulin or the rapid-acting insulin analogs. Insulin
degludec, however, can be mixed and is available as 70% insulin
degludec/30% insulin aspart and is injected once or twice a day.
Insulin Delivery Systems
A. Insulin Syringes and Needles
Disposable plastic syringes with needles attached are available
in 1-mL (100 units), 0.5-mL (50 units), and 0.3-mL (30 units)
sizes. The “low-dose” 0.3-mL syringes are popular because many
patients with diabetes do not take more than 30 units of insulin
in a single injection except in rare instances of extreme insulin
resistance. They are also available in half-unit marking. Three
lengths of needles are available; longer needles are preferable in
obese patients to reduce variability of insulin absorption. If the
skin is clean it is not necessary to use alcohol. Rotation of sites is
recommended to avoid problems with absorption due to lipohy-
pertrophy from overuse of injection sites.
B. Insulin Pens
The pens eliminate the need for carrying insulin vials and syringes.
Cartridges of insulin lispro, insulin aspart, and insulin glargine
are available for reusable pens (Lilly, Novo Nordisk, and Owen
Mumford). Disposable prefilled pens are also available for regular
insulin (U100, U500), insulin lispro, insulin aspart, insulin gluli-
sine, insulin detemir, insulin glargine, insulin degludec, NPH, 70%
NPH/30% regular, 75% NPL/25% insulin lispro, 50% NPL/50%
insulin lispro, 70% insulin aspart protamine/30% insulin aspart,
and 70% insulin degludec/30% insulin aspart (Table 41–6).
C. Continuous Subcutaneous Insulin Infusion Devices
(CSII, Insulin Pumps)
Continuous subcutaneous insulin infusion devices are external
open-loop pumps for insulin delivery. The devices have a user-
programmable pump that delivers individualized basal and bolus
insulin replacement doses based on blood glucose self-monitoring
results.
Normally, the 24-hour background basal rates are prepro-
grammed and relatively constant from day to day, although
temporarily altered rates can be superimposed to adjust for a
short-term change in requirement. For example, the basal delivery
rate might need to be decreased for several hours because of the
increased insulin sensitivity associated with strenuous activity.
Boluses are used to correct high blood glucose levels and to
cover mealtime insulin requirements based on the carbohydrate
content of the food and concurrent activity. Bolus amounts are
either dynamically programmed or use pre-programmed algo-
rithms. When the boluses are dynamically programmed, the
user calculates the dose based on the amount of carbohydrate
consumed and the current blood glucose level. Alternatively, the
meal or snack dose algorithm (grams of carbohydrate covered by
a unit of insulin) and insulin sensitivity or blood glucose correc-
tion factor (fall in blood glucose level in response to a unit of
insulin) can be preprogrammed into the pump. If the user enters
the carbohydrate content of the food and current blood glucose
value, the insulin pump will calculate the most appropriate dose of
insulin. Advanced insulin pumps also have an “insulin on board”
feature that adjusts a high blood glucose correction dose to correct
for residual activity of previous bolus doses.
The traditional pump (by MiniMed, Animas, Roche, Sooil)—
which contains an insulin reservoir, the program chip, the keypad,
and the display screen—is about the size of a pager. It is usually
placed on a belt or in a pocket, and the insulin is infused through
thin plastic tubing that is connected to the subcutaneously
inserted infusion set. The abdomen is the favored site for the
infusion set, although flanks and thighs are also used. The insulin
reservoir, tubing, and infusion set need to be changed using sterile
techniques every 2 or 3 days. Currently, only one pump does not
require tubing (OmniPod, Insulet). In this model, the pump is
attached directly to the infusion set (electronic patch pump). Pro-
gramming is done through a hand-held unit that communicates
wirelessly with the pump.
Optimal use of these devices requires responsible involve-
ment and commitment by the patient. Insulin aspart, lispro,
and glulisine all are specifically approved for pump use and are
preferred pump insulins because their favorable pharmacokinetic
attributes allow glycemic control without increasing the risk of
hypoglycemia.

A mechanical patch pump (V-Go, Valeritas) designed spe-
cifically for patients with type 2 diabetes is available on a basal-
plus-bolus insulin regimen. The device is preset to deliver one of
three fixed and flat basal rates (20, 30, or 40 units) for 24 hours
(at which point it must be replaced), and there is a button that
delivers two units per press to help cover meals.
D. Inhaled Insulin
A dry powder formulation of recombinant regular insulin (techno-
sphere insulin, Afrezza) is now approved for use in adults with dia-
betes. It consists of 2- to 2.5-μm crystals of the excipient, fumaryl
diketopiperazine, that provide a large surface area for adsorption
of proteins like insulin. After inhalation from the small, single-use
device, pharmacokinetic studies show that peak levels are reached
in 12–15 minutes and decline to baseline in 3 hours, significantly
faster in onset and shorter in duration than subcutaneous insulin.
Pharmacodynamic studies show that median time to maximum
effect with inhaled insulin is approximately 1 hour and declines to
baseline by about 3 hours. In contrast, the median time to maxi-
mum effect with subcutaneous insulin lispro is about 2 hours and
declines to baseline by 4 hours. In trials, inhaled insulin combined
with injected basal insulin was as effective in lowering glucose
as injected rapid-acting insulin combined with basal insulin. It
is formulated as a single-use color coded cartridge delivering 4,
8 or 12 units immediately before the meal. The manufacturer
provides a dose conversion table; patients injecting up to 4 units
of rapid-acting insulin analog should use the 4-unit cartridge.
Those injecting 5–8 units should use the 8-unit cartridge. If the
dose is 9–12 units of rapid-acting insulin pre-meal then one 4-unit
cartridge and one 8-unit cartridge or one 12-unit cartridge should
be used. The inhaler is about the size of a referee’s whistle. The
most common adverse effect of inhaled insulin was cough, affect-
ing 27% of trial patients. A small decrease in pulmonary function
(forced expiratory volume in 1 second [FEV1]) was seen in the first
3 months of use, which persisted over 2 years of follow-up. Inhaled
insulin is contraindicated in smokers and patients with chronic
lung disease, such as asthma and chronic obstructive pulmonary
disease. Spirometry should be performed to identify potential lung
disease prior to initiating therapy. During the clinical trials, there
were two cases of lung cancer in patients who were taking inhaled
insulin and none in the comparator-treated patients.
Immunopathology of Insulin Therapy
At least five molecular classes of insulin antibodies may be pro-
duced in diabetics during the course of insulin therapy: IgA, IgD,
IgE, IgG, and IgM. There are two major types of immune disor-
ders in these patients:
1. Insulin allergy—Insulin allergy, an immediate type hyper-
sensitivity, is a rare condition in which local or systemic urticaria
results from histamine release from tissue mast cells sensitized by
anti-insulin IgE antibodies. In severe cases, anaphylaxis results.
Because sensitivity is often to non-insulin protein contaminants,
the human and analog insulins have markedly reduced the inci-
dence of insulin allergy, especially local reactions.
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     757
2. Immune insulin resistance—A low titer of circulating IgG
anti-insulin antibodies that neutralize the action of insulin to a
negligible extent develops in most insulin-treated patients. Rarely,
the titer of insulin antibodies leads to insulin resistance and may
be associated with other systemic autoimmune processes such as
lupus erythematosus.
Lipodystrophy at Injection Sites
Injection of animal insulin preparations sometimes led to atrophy
of subcutaneous fatty tissue at the site of injection. Since the
development of human and analog insulin preparations of neutral
pH, this type of immune complication is almost never seen. Injec-
tion of these newer preparations directly into the atrophic area
often results in restoration of normal contours.
Hypertrophy of subcutaneous fatty tissue remains a problem
if injected repeatedly at the same site. However, this may be cor-
rected by avoiding the specific injection site.
■■ MEDICATIONS FOR
TREATMENT OF TYPE 2 DIABETES
Several categories of glucose-lowering agents are available for
patients with type 2 diabetes: (1) agents that bind to the sulfo-
nylurea receptor and stimulate insulin secretion (sulfonylureas,
meglitinides, d-phenylalanine derivatives); (2) agents that lower
glucose levels by their actions on liver, muscle, and adipose tissue
(biguanides, thiazolidinediones); (3) agents that principally slow
the intestinal absorption of glucose (α-glucosidase inhibitors);
(4) agents that mimic incretin effect or prolong incretin action
(GLP-1 receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibi-
tors), (5) agents that inhibit the reabsorption of glucose in the
kidney (sodium-glucose co-transporter inhibitors [SGLTs]), and
(6) agents that act by other or ill-defined mechanisms (pramlint-
ide, bromocriptine, colesevelam).
DRUGS THAT PRIMARILY
STIMULATE INSULIN RELEASE BY
BINDING TO THE SULFONYLUREA
RECEPTOR
SULFONYLUREAS
Mechanism of Action
The major action of sulfonylureas is to increase insulin release
from the pancreas (Table 41–7). They bind to a 140-kDa high-
affinity sulfonylurea receptor that is associated with a beta-cell
inward rectifier ATP-sensitive potassium channel (Figure 41–2).
Binding of a sulfonylurea inhibits the efflux of potassium ions
through the channel and results in depolarization. Depolariza-
tion opens a voltage-gated calcium channel and results in calcium
influx and the release of preformed insulin.
758    SECTION VII  Endocrine Drugs
TABLE 41–7  Regulation of insulin release in humans.
Stimulants of insulin release
 Humoral: Glucose, mannose, leucine, arginine, other amino acids,
fatty acids (high concentrations)
 Hormonal: Glucagon, glucagon-like peptide 1 (7–37), glucose-
dependent insulinotropic polypeptide, cholecystokinin, gastrin
 Neural: β-Adrenergic stimulation, vagal stimulation
 Drugs: Sulfonylureas, meglitinide, nateglinide, isoproterenol,
acetylcholine
Inhibitors of insulin release
  Hormonal: Somatostatin, insulin, leptin
 Neural: α-Sympathomimetic effect of catecholamines
  Drugs: Diazoxide, phenytoin, vinblastine, colchicine
Adapted, with permission, from Greenspan FS, Gardner DG [editors]: Basic & Clinical
Endocrinology, 6th ed. McGraw-Hill, 2001. Copyright © The McGraw-Hill Companies, Inc.
Efficacy & Safety of the Sulfonylureas
Sulfonylureas are metabolized by the liver and, with the exception
of acetohexamide, the metabolites are either weakly active or inac-
tive. The metabolites are excreted by the kidney and, in the case
of the second-generation sulfonylureas, partly excreted in the bile.
Idiosyncratic reactions are rare, with skin rashes or hematologic
toxicity (leukopenia, thrombocytopenia) occurring in less than
0.1% of cases. The second-generation sulfonylureas have greater
affinity for their receptor compared with the first-generation
agents. The correspondingly lower effective doses and plasma
levels of the second-generation drugs therefore lower the risk of
drug-drug interactions based on competition for plasma binding
sites or hepatic enzyme action.
In 1970, the University Group Diabetes Program (UGDP) in
the United States reported that the number of deaths due to car-
diovascular disease in diabetic patients treated with tolbutamide
was excessive compared with either insulin-treated patients or
those receiving placebos. Owing to design flaws, this study and its
conclusions were not generally accepted. In the United Kingdom,
the UKPDS did not find an untoward cardiovascular effect of
sulfonylurea usage in their large, long-term study. The sulfonyl-
ureas continue to be widely prescribed, and six are available in the
United States.
FIRST-GENERATION SULFONYLUREAS
Tolbutamide is well absorbed but rapidly metabolized in the
liver. Its duration of effect is relatively short (6–10 hours), with
an elimination half-life of 4–5 hours, and it is best administered
in divided doses (eg, 500 mg before each meal). Some patients
only need one or two tablets daily. The maximum dosage is
3000 mg daily. Because of its short half-life and inactivation by
the liver, it is relatively safe in the elderly and in patients with
renal impairment. Prolonged hypoglycemia has been reported
rarely, mostly in patients receiving certain antibacterial sulfon-
amides (sulfisoxazole), phenylbutazone for arthralgias, or the oral
azole antifungal medications to treat candidiasis. These drugs
inhibit the metabolism of tolbutamide in the liver and increase
its circulating levels.
Chlorpropamide has a half-life of 32 hours and is slowly
metabolized in the liver to products that retain some biologic
activity; approximately 20–30% is excreted unchanged in the
urine. The average maintenance dosage is 250 mg daily, given as a
single dose in the morning. Prolonged hypoglycemic reactions are
more common in elderly patients, and the drug is contraindicated
in this group. Other adverse effects include a hyperemic flush after
alcohol ingestion in genetically predisposed patients and hypona-
tremia due to its effect on vasopressin secretion and action.
Tolazamide is comparable to chlorpropamide in potency
but has a shorter duration of action. Tolazamide is more slowly
absorbed than the other sulfonylureas, and its effect on blood
glucose does not appear for several hours. Its half-life is about
7 hours. Tolazamide is metabolized to several compounds that
retain hypoglycemic effects. If more than 500 mg/d are required,
the dosage should be divided and given twice daily.
Acetohexamide is no longer available in the United States.
Its half-life is only about 1 hour but its more active metabolite,
hydroxyhexamide, has a half-life of 4–6 hours; thus the drug
duration of action is 8–24 hours. Where available, its dosage is
0.25–1.5 g/d as single dose or in two divided doses.
Chlorpropamide, tolazamide, and acetohexamide are now
rarely used in clinical practice.
SECOND-GENERATION
SULFONYLUREAS
Glyburide, glipizide, gliclazide, and glimepiride are 100–200 times
more potent than tolbutamide. They should be used with caution in
patients with cardiovascular disease or in elderly patients, in whom
hypoglycemia would be especially dangerous.
Glyburide is metabolized in the liver into products with very
low hypoglycemic activity. The usual starting dosage is 2.5 mg/d
or less, and the average maintenance dosage is 5–10 mg/d given as
a single morning dose; maintenance dosages higher than 20 mg/d
are not recommended. A formulation of “micronized” glyburide
(Glynase PresTab) is available in a variety of tablet sizes. However,
there is some question as to its bioequivalence with non-micron-
ized formulations, and the FDA recommends careful monitoring
to re-titrate dosage when switching from standard glyburide doses
or from other sulfonylurea drugs.
Glyburide has few adverse effects other than its potential for
causing hypoglycemia. Flushing has rarely been reported after
ethanol ingestion, and the compound slightly enhances free water
clearance. Glyburide is contraindicated in the presence of hepatic
impairment and in patients with renal insufficiency.
Glipizide has the shortest half-life (2–4 hours) of the more
potent agents. For maximum effect in reducing postprandial
hyperglycemia, this agent should be ingested 30 minutes before
breakfast because absorption is delayed when the drug is taken
with food. The recommended starting dosage is 5 mg/d, with
up to 15 mg/d given as a single dose. When higher daily dos-
ages are required, they should be divided and given before meals.

The maximum total daily dosage recommended by the manufac-
turer is 40 mg/d, although some studies indicate that the maxi-
mum therapeutic effect is achieved by 15–20 mg of the drug. An
extended-release preparation (Glucotrol XL) provides 24-hour
action after a once-daily morning dose (maximum of 20 mg/d).
However, this formulation appears to have sacrificed its lower pro-
pensity for severe hypoglycemia compared with longer-acting gly-
buride without showing any demonstrable therapeutic advantages
over the latter (which can be obtained as a generic drug). At least
90% of glipizide is metabolized in the liver to inactive products,
and the remainder is excreted unchanged in the urine. Glipizide
therapy is therefore contraindicated in patients with significant
hepatic impairment. Because of its lower potency and shorter
duration for action, it is preferable to glyburide in the elderly and
for those patients with renal impairment.
Glimepiride is approved for once-daily use as monotherapy
or in combination with insulin. Glimepiride achieves blood
glucose lowering with the lowest dosage of any sulfonylurea
compound. A single daily dose of 1 mg has been shown to be
effective, and the recommended maximal daily dosage is 8 mg.
Glimepiride’s half-life under multidose conditions is 5–9 hours.
It is completely metabolized by the liver to metabolites with
weak or no activity.
Gliclazide (not available in the United States) has a half-life of
10 hours. The recommended starting dosage is 40–80 mg daily
with a maximum dosage of 320 mg daily. Higher dosages are usu-
ally divided and given twice a day. It is completely metabolized by
the liver to inactive metabolites.
MEGLITINIDE ANALOGS
Repaglinide is the first member of the meglitinide group of insu-
lin secretagogues. These drugs modulate beta-cell insulin release
by regulating potassium efflux through the potassium channels
previously discussed. There is overlap with the sulfonylureas in
their molecular sites of action because the meglitinides have two
binding sites in common with the sulfonylureas and one unique
binding site.
Repaglinide has a fast onset of action, with a peak concentra-
tion and peak effect within approximately 1 hour after ingestion,
but the duration of action is 4–7 hours. It is cleared by hepatic
CYP3A4 with a plasma half-life of 1 hour. Because of its rapid
onset, repaglinide is indicated for use in controlling postprandial
glucose excursions. The drug should be taken just before each
meal in doses of 0.25–4 mg (maximum 16 mg/d); hypoglycemia
is a risk if the meal is delayed or skipped or contains inadequate
carbohydrate. It can be used in patients with renal impairment
and in the elderly. Repaglinide is approved as monotherapy or in
combination with biguanides. There is no sulfur in its structure,
so repaglinide may be used in type 2 diabetics with sulfur or sul-
fonylurea allergy.
Mitiglinide (not available in the United States) is a benzylsuc-
cinic acid derivative that binds to the sulfonylurea receptor and is
similar to repaglinide in its clinical effects. It has been approved
for use in Japan.
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     759
d-PHENYLALANINE DERIVATIVE
Nateglinide, a d-phenylalanine derivative, stimulates rapid and
transient release of insulin from beta cells through closure of the
ATP-sensitive K+ channel. It is absorbed within 20 minutes after
oral administration with a time to peak concentration of less than
1 hour and is metabolized in the liver by CYP2C9 and CYP3A4
with a half-life of about 1 hour. The overall duration of action
is about 4 hours. It is taken before the meal and reduces the
postprandial rise in blood glucose levels. It is available as 60- and
120-mg tablets. The lower dose is used in patients with mild eleva-
tions in HbA1c. Nateglinide is efficacious when given alone or in
combination with non-secretagogue oral agents (such as metfor-
min). Hypoglycemia is the main adverse effect. It can be used in
patients with renal impairment and in the elderly.
DRUGS THAT PRIMARILY LOWER
GLUCOSE LEVELS BY THEIR
ACTIONS ON THE LIVER, MUSCLE, &
ADIPOSE TISSUE
BIGUANIDES
The structure of metformin is shown below. Phenformin (an
older biguanide) was discontinued in the United States because
of its association with lactic acidosis. Metformin is the only bigu-
anide currently available in the United States.
NH
H2N CH3
C N C N
H 2N CH3
Metformin
Mechanisms of Action
A full explanation of the mechanism of action of the biguanides
remains elusive, but their primary effect is to activate the enzyme
AMP-activated protein kinase (AMPK) and reduce hepatic glu-
cose production. Patients with type 2 diabetes have considerably
less fasting hyperglycemia as well as lower postprandial hypergly-
cemia after administration of biguanides; however, hypoglycemia
during biguanide therapy is rare. These agents are therefore more
appropriately termed “euglycemic” agents.
Metabolism & Excretion
Metformin has a half-life of 1.5–3 hours, is not bound to plasma
proteins, is not metabolized, and is excreted by the kidneys as the
active compound. As a consequence of metformin’s blockade of
gluconeogenesis, the drug may impair the hepatic metabolism
of lactic acid. In patients with renal insufficiency, the biguanide
accumulates and thereby increases the risk of lactic acidosis, which
appears to be a dose-related complication. Metformin can be
safely used in patients with estimated glomerular filtration rates
(eGFR) between 60 and 45 mL/min per 1.73 m2. It can be used
cautiously in patients with eGFR between 45 and 30 mL/min per
760    SECTION VII  Endocrine Drugs
1.73 m2. It is contraindicated if the eGFR is less than 30 mL/min
per 1.73 m2.
Clinical Use
Biguanides are recommended as first-line therapy for type
2 diabetes. Because metformin is an insulin-sparing agent and
does not increase body weight or provoke hypoglycemia, it
offers obvious advantages over insulin or sulfonylureas in treat-
ing hyperglycemia in such persons. The UKPDS reported that
metformin therapy decreases the risk of macrovascular as well as
microvascular disease; this is in contrast to the other therapies,
which only modified microvascular morbidity. Biguanides are also
indicated for use in combination with insulin secretagogues or
thiazolidinediones in type 2 diabetics in whom oral monotherapy
is inadequate. Metformin is useful in the prevention of type
2 diabetes; the landmark Diabetes Prevention Program concluded
that metformin is efficacious in preventing the new onset of type
2 diabetes in middle-aged, obese persons with impaired glucose
tolerance and fasting hyperglycemia. It is interesting that metfor-
min did not prevent diabetes in older, leaner prediabetics.
Although the recommended maximal dosage is 2.55 g daily,
little benefit is seen above a total dosage of 2000 mg daily. Treat-
ment is initiated at 500 mg with a meal and increased gradually
in divided doses. Common schedules would be 500 mg once or
twice daily increased to 1000 mg twice daily. The maximal dosage
is 850 mg three times a day. Epidemiologic studies suggest that
metformin use may reduce the risk of some cancers. These data
are still preliminary, and the speculative mechanism of action is a
decrease in insulin (which also functions as a growth factor) levels
as well as direct cellular effects mediated by AMPK. Other studies
suggest a reduction in cardiovascular deaths in humans and an
increase in longevity in mice (see Chapter 60).
Toxicities
The most common toxic effects of metformin are gastrointestinal
(anorexia, nausea, vomiting, abdominal discomfort, and diarrhea),
occurring in up to 20% of patients. They are dose related, tend
to occur at the onset of therapy, and are often transient. However,
metformin may have to be discontinued in 3–5% of patients
because of persistent diarrhea.
Metformin interferes with the calcium-dependent absorption
of vitamin B12–intrinsic factor complex in the terminal ileum,
and vitamin B12 deficiency can occur after many years of metfor-
min use. Periodic screening for vitamin B12 deficiency should be
considered, especially in patients with peripheral neuropathy or
macrocytic anemia. Increased intake of calcium may prevent the
metformin-induced B12 malabsorption.
Lactic acidosis can sometimes occur with metformin therapy.
It is more likely to occur in conditions of tissue hypoxia when
there is increased production of lactic acid and in renal failure
when there is decreased clearance of metformin. Almost all
reported cases have involved patients with associated risk factors
that should have contraindicated its use (kidney, liver, or cardio-
respiratory insufficiency; alcoholism). Acute kidney failure can
occur rarely in certain patients receiving radiocontrast agents.
Metformin therapy should therefore be temporarily halted on the
day of radiocontrast administration and restarted a day or two
later after confirmation that renal function has not deteriorated.
Renal function should be checked at least annually in patients on
metformin therapy, and lower doses should be used in the elderly
who may have limited renal reserve and in those with eGFR
between 30 and 45 mL/min per 1.73 m2.
THIAZOLIDINEDIONES
Thiazolidinediones act to decrease insulin resistance. They are
ligands of peroxisome proliferator-activated receptor gamma
(PPAR-f), part of the steroid and thyroid superfamily of nuclear
receptors. These PPAR receptors are found in muscle, fat, and liver.
PPAR-γ receptors modulate the expression of the genes involved
in lipid and glucose metabolism, insulin signal transduction, and
adipocyte and other tissue differentiation. Observed effects of the
thiazolidinediones include increased glucose transporter expression
(GLUT 1 and GLUT 4), decreased free fatty acid levels, decreased
hepatic glucose output, increased adiponectin and decreased release
of resistin from adipocytes, and increased differentiation of preadi-
pocytes to adipocytes. Thiazolidinediones have also been shown to
decrease levels of plasminogen activator inhibitor type 1, matrix
metalloproteinase 9, C-reactive protein, and interleukin 6. Two
thiazolidinediones are currently available: pioglitazone and rosigli-
tazone. Their distinct side chains create differences in therapeutic
action, metabolism, metabolite profile, and adverse effects. An
earlier compound, troglitazone, was withdrawn from the market
because of hepatic toxicity thought to be related to its side chain.
Pioglitazone has some PPAR-α as well as PPAR-γ activity. It
is absorbed within 2 hours of ingestion; although food may delay
uptake, total bioavailability is not affected. Absorption is decreased
with concomitant use of bile acid sequestrants. Pioglitazone is metab-
olized by CYP2C8 and CYP3A4 to active metabolites. The bioavail-
ability of numerous other drugs also degraded by these enzymes may
be affected by pioglitazone therapy, including estrogen-containing
oral contraceptives; additional methods of contraception are advised.
Pioglitazone may be taken once daily; the usual starting dosage is
15–30 mg/d, and the maximum is 45 mg/d. Pioglitazone is approved
as a monotherapy and in combination with metformin, sulfonylureas,
and insulin for the treatment of type 2 diabetes.
Rosiglitazone is rapidly absorbed and highly protein bound.
It is metabolized in the liver to minimally active metabolites,
predominantly by CYP2C8 and to a lesser extent by CYP2C9.
It is administered once or twice daily; 2–8 mg is the usual total
dosage. Rosiglitazone is approved for use in type 2 diabetes as
monotherapy, in double combination therapy with a biguanide
or sulfonylurea, or in quadruple combination with a biguanide,
sulfonylurea, and insulin.
The combination of a thiazolidinedione and metformin has
the advantage of not causing hypoglycemia.
These drugs also have some additional effects apart from
glucose lowering. Pioglitazone lowers triglycerides and increases
high-density lipoprotein (HDL) cholesterol without affecting
total cholesterol and low-density lipoprotein (LDL) cholesterol.

Rosiglitazone increases total cholesterol, HDL cholesterol, and
LDL cholesterol but does not have significant effect on triglyc-
erides. These drugs have been shown to improve the biochemical
and histologic features of nonalcoholic fatty liver disease. They
seem to have a positive effect on endothelial function: pioglitazone
reduces neointimal proliferation after coronary stent placement,
and rosiglitazone has been shown to reduce microalbuminuria.
Safety concerns and troublesome side effects have significantly
reduced the use of this class of drugs. A meta-analysis of 42 ran-
domized clinical trials with rosiglitazone suggested that this drug
increased the risk of angina pectoris or myocardial infarction. As
a result, its use was suspended in Europe and severely restricted
in the United States. A subsequent large prospective clinical trial
(the RECORD study) failed to confirm the meta-analysis finding
and so the United States restrictions have been lifted. The drug
remains unavailable in Europe.
Fluid retention occurs in about 3–4 % patients on thiazoli-
dinedione monotherapy and occurs more frequently (10–15%) in
patients on concomitant insulin therapy. Heart failure can occur,
and the drugs are contraindicated in patients with New York
Heart Association class III and IV cardiac status (see Chapter 13).
Macular edema is a rare adverse effect that improves when the
drug is discontinued. Loss of bone mineral density and increased
atypical extremity bone fractures in women are described for both
compounds; this is postulated to be due to decreased osteoblast
formation. Other adverse effects include anemia, which might be
due to a dilutional effect of increased plasma volume rather than
a reduction in red cell mass. Weight gain occurs, especially when
used in combination with a sulfonylurea or insulin. Some of the
weight gain is fluid retention but there is also an increase in total
fat mass. In preclinical trials, bladder tumors were observed in
male rats on pioglitazone. Initial clinical reports indicated that
this might also be true in humans. A 10-year observational cohort
study of patients taking pioglitazone, however, failed to find an
association with bladder cancer. A large multi-population pooled
analysis (1.01 million persons over 5.9 million person-years)
also failed to find an association between cumulative exposure
of pioglitazone or rosiglitazone and incidence of bladder cancer.
Another population based study generating 689,616 person-years
of follow-up did find that pioglitazone but not rosiglitazone was
associated with an increased risk of bladder cancer.
Troglitazone, the first medication in this class, was withdrawn
because of cases of fatal liver failure. Although rosiglitazone and
pioglitazone have not been reported to cause liver injury, the drugs
are not recommended for use in patients with active liver disease
or pretreatment elevation of alanine aminotransferase (ALT) 2.5
times greater than normal. Liver function tests should be per-
formed prior to initiation of treatment and periodically thereafter.
DRUGS THAT AFFECT ABSORPTION
OF GLUCOSE
The `-glucosidase inhibitors competitively inhibit the intestinal
α-glucosidase enzymes and reduce post-meal glucose excursions by
delaying the digestion and absorption of starch and disaccharides.
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     761
Acarbose and miglitol are available in the United States. Voglibose
is available in Japan, Korea, and India. Acarbose and miglitol are
potent inhibitors of glucoamylase, α-amylase, and sucrase but have
less effect on isomaltase and hardly any on trehalase and lactase.
Acarbose has the molecular mass and structural features of a tet-
rasaccharide and very little is absorbed. In contrast, miglitol has
structural similarity to glucose and is absorbed.
Acarbose treatment is initiated at a dosage of 50 mg twice daily
with gradual increase to 100 mg three times a day. It lowers post-
prandial glucose levels by 30–50%. Miglitol therapy is initiated
at a dosage of 25 mg three times a day. The usual maintenance
dosage is 50 mg three times a day, but some patients may need
100 mg three times a day. The drug is not metabolized and is
cleared by the kidney. It should not be used in renal failure.
Prominent adverse effects of α-glucosidase inhibitors include
flatulence, diarrhea, and abdominal pain and result from the
appearance of undigested carbohydrate in the colon that is then
fermented into short-chain fatty acids, releasing gas. These adverse
effects tend to diminish with ongoing use because chronic expo-
sure to carbohydrate induces the expression of α-glucosidase in
the jejunum and ileum, increasing distal small intestine glucose
absorption and minimizing the passage of carbohydrate into the
colon. Although not a problem with monotherapy or combina-
tion therapy with a biguanide, hypoglycemia may occur with con-
current sulfonylurea treatment. Hypoglycemia should be treated
with glucose (dextrose) and not sucrose, whose breakdown may be
blocked. An increase in hepatic aminotransferases has been noted
in clinical trials with acarbose, especially with dosages greater than
300 mg/d. The abnormalities resolve on stopping the drug.
These drugs are infrequently prescribed in the United States
because of their prominent gastrointestinal adverse effects and
relatively modest glucose-lowering benefit.
DRUGS THAT MIMIC INCRETIN
EFFECT OR PROLONG INCRETIN
ACTION
An oral glucose load provokes a higher insulin response com-
pared with an equivalent dose of glucose given intravenously.
This is because the oral glucose causes a release of gut hormones
(“incretins”), principally GLP-1 and glucose-dependent insuli-
notropic peptide (GIP), that amplify the glucose-induced insulin
secretion. When GLP-1 is infused in patients with type 2 diabetes,
it stimulates insulin release and lowers glucose levels. The GLP-1
effect is glucose dependent in that the insulin release is more
pronounced when glucose levels are elevated but less so when
glucose levels are normal. For this reason, GLP-1 has a lower risk
for hypoglycemia than the sulfonylureas. In addition to its insulin
stimulatory effect, GLP-1 has a number of other biologic effects.
It suppresses glucagon secretion, delays gastric emptying, and
reduces apoptosis of human islets in culture. In animals, GLP-1
inhibits feeding by a central nervous system mechanism. Type 2
diabetes patients on GLP-1 therapy are less hungry. It is unclear
whether this is mainly related to the deceleration of gastric emp-
tying or whether there is a central nervous system effect as well.
762    SECTION VII  Endocrine Drugs
GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4)
and by other enzymes such as endopeptidase 24.11 and is also
cleared by the kidney. The native peptide therefore cannot be used
therapeutically. One approach to this problem has been to develop
metabolically stable analogs or derivatives of GLP-1 that are not
subject to the same enzymatic degradation or renal clearance. Four
such GLP-1 receptor agonists, exenatide, liraglutide, albiglutide,
and dulaglutide are available for clinical use. The other approach
has been to develop inhibitors of DPP-4 and prolong the action of
endogenously released GLP-1 and GIP. Four oral DPP-4 inhibi-
tors, sitagliptin, saxagliptin, linagliptin, and alogliptin, are avail-
able in the United States. An additional inhibitor, vildagliptin, is
available in Europe.
GLUCAGON-LIKE PEPTIDE-1 (GLP-1)
RECEPTOR AGONISTS
Exenatide, a derivative of the exendin-4 peptide in Gila monster
venom, has a 53% homology with native GLP-1 and a glycine
substitution to reduce degradation by DPP-4. Exenatide is
approved as an injectable, adjunctive therapy in persons with type
2 diabetes treated with metformin or metformin plus sulfonyl-
ureas who still have suboptimal glycemic control.
Exenatide is dispensed as fixed-dose pens (5 mcg and 10 mcg).
It is injected subcutaneously within 60 minutes before breakfast
and dinner. It reaches a peak concentration in approximately
2 hours with a duration of action of up to 10 hours. Therapy
is initiated at 5 mcg twice daily for the first month and if toler-
ated can be increased to 10 mcg twice daily. Exenatide LAR is a
once-weekly preparation that is dispensed as a powder (2 mg). It
is suspended in the provided diluent just prior to injection. When
exenatide is added to preexisting sulfonylurea therapy, the oral
hypoglycemic dosage may need to be decreased to prevent hypo-
glycemia. The major adverse effect is nausea (about 44% of users),
which is dose dependent and declines with time. Exenatide mono-
therapy and combination therapy results in HbA1c reductions of
0.2–1.2%. Weight loss in the range of 2–3 kg occurs and contrib-
utes to the improvement of glucose control. In comparative trials
the long-acting (LAR) preparation lowers the HbA1c level a little
more than the twice-daily preparation. Exenatide undergoes glo-
merular filtration, and the drug is not approved for use in patients
with estimated GFR of less than 30 mL/min.
High-titer antibodies against exenatide develop in about 6% of
patients, and in half of these patients an attenuation of glycemic
response has been seen.
Liraglutide is a soluble fatty acid-acylated GLP-1 analog. The
half-life is approximately 12 hours, permitting once-daily dosing.
It is approved in patients with type 2 diabetes who achieve inad-
equate control with diet and exercise and are receiving concurrent
treatment with metformin, sulfonylureas, or thiazolidinediones.
Treatment is initiated at 0.6 mg and increased after 1 week to
1.2 mg daily. If needed the dosage can be increased to 1.8 mg
daily. In clinical trials liraglutide results in a reduction of HbA1c
of 0.8–1.5%; weight loss ranges from none to 3.2 kg. The most
frequent adverse effects are nausea (28%) and vomiting (10%).
Liraglutide at a dose of 3 mg daily has been approved for weight
loss.
Albiglutide is a human GLP-1 dimer fused to human albu-
min. The half-life of albiglutide is about 5 days and a steady state
is reached after 4–5 weeks of once weekly administration. The
usual dose is 30 mg weekly by subcutaneous injection. The drug
is supplied in a self-injection pen containing a powder that is
reconstituted just prior to administration. Weight loss is much less
common than with exenatide and liraglutide. The most frequent
adverse effects were nausea and injection-site erythema.
Dulaglutide consists of two GLP-1 analog molecules cova-
lently linked to an Fc fragment of human IgG4. The GLP-1 mol-
ecule has amino acid substitutions that resist DPP-4 action. The
half-life of dulaglutide is about 5 days. The usual dose is 0.75 mg
weekly by subcutaneous injection. The maximum recommended
dose is 1.5 mg weekly. The most frequent adverse reactions were
nausea, diarrhea, and vomiting.
All of the GLP-1 receptor agonists may increase the risk of
pancreatitis. Patients on these drugs should be counseled to seek
immediate medical care if they experience unexplained persistent
severe abdominal pain. Cases of renal impairment and acute renal
injury have been reported in patients taking exenatide. Some of
these patients had preexisting kidney disease or other risk factors
for renal injury. A number of them reported having nausea, vom-
iting, and diarrhea and it is possible that volume depletion con-
tributed to the development of renal injury. Both exenatide and
liraglutide stimulate thyroidal C-cell (parafollicular) tumors in
rodents. Human thyroidal C cells express very few GLP-1 recep-
tors, and the relevance to human therapy is unclear. The drugs,
however, should not be used in persons with a past medical or
family history of medullary thyroid cancer or multiple endocrine
neoplasia (MEN) syndrome type 2.
DIPEPTIDYL PEPTIDASE 4 (DPP-4)
INHIBITORS
Sitagliptin is given orally as 100 mg once daily, has an oral
bioavailability of over 85%, achieves peak concentrations within
1–4 hours, and has a half-life of approximately 12 hours. It is
primarily excreted in the urine, in part by active tubular secretion
of the drug. Hepatic metabolism is limited and mediated largely
by the cytochrome CYP3A4 isoform and, to a lesser degree, by
CYP2C8. The metabolites have insignificant activity. Dosage
should be reduced in patients with impaired renal function (50 mg
if estimated GFR is 30–50 mL/min and 25 mg if <30 mL/min.
Sitagliptin has been studied as monotherapy and in combination
with metformin, sulfonylureas, and thiazolidinediones. Therapy
with sitagliptin has resulted in HbA1c reductions of 0.5–1.0%.
Common adverse effects include nasopharyngitis, upper respi-
ratory infections, and headaches. Hypoglycemia can occur when
the drug is combined with insulin secretagogues or insulin. There
have been postmarketing reports of acute pancreatitis (fatal
and nonfatal) and severe allergic and hypersensitivity reactions.
Sitagliptin should be immediately discontinued if pancreatitis or
allergic and hypersensitivity reactions occur.

Saxagliptin is given orally as 2.5–5 mg daily. The drug reaches
maximal concentrations within 2 hours (4 hours for its active
metabolite). It is minimally protein bound and undergoes hepatic
metabolism by CYP3A4/5. The major metabolite is active, and
excretion is by both renal and hepatic pathways. The terminal
plasma half-life is 2.5 hours for saxagliptin and 3.1 hours for
its active metabolite. Dosage adjustment is recommended for
individuals with renal impairment and concurrent use of strong
CYP3A4/5 inhibitors such as antiviral, antifungal, and certain
antibacterial agents. It is approved as monotherapy and in com-
bination with biguanides, sulfonylureas, and thiazolidinediones.
During clinical trials, mono- and combination therapy with saxa-
gliptin resulted in an HbA1c reduction of 0.4–0.9%.
Adverse effects include an increased rate of infections (upper
respiratory tract and urinary tract), headaches, and hypersensitiv-
ity reactions (urticaria, facial edema). The dosage of a concurrently
administered insulin secretagogue or insulin may need to be low-
ered to prevent hypoglycemia. Saxagliptin may increase the risk of
heart failure. In a postmarketing study of 16,492 type 2 diabetes
patients, there were 289 cases of heart failure in the saxagliptin
group (3.5%) and 228 cases in the placebo group (2.8%)—a
hazard ratio of 1.27. Patients at the highest risk for failure were
those who had a history of heart failure or had elevated levels of
N-terminal of the prohormone brain natriuretic peptide (NT-
pBNP) or had renal impairment.
Linagliptin lowers HbA1c by 0.4–0.6% when added to met-
formin, sulfonylurea, or pioglitazone. The dosage is 5 mg daily
orally and, since it is primarily excreted via the bile, no dosage
adjustment is needed in renal failure.
Adverse reactions include nasopharyngitis and hypersensitivity
reactions (urticaria, angioedema, localized skin exfoliation, bron-
chial hyperreactivity). The risk of pancreatitis may be increased.
Alogliptin lowers HbA1c by about 0.5–0.6% when added to
metformin, sulfonylurea, or pioglitazone. The usual dose is 25 mg
orally daily. The 12.5-mg dose is used in patients with calculated
creatinine clearance of 30 to 60 mL/min; the dose is 6.25 mg for
clearance <30 mL/min. In clinical trials, pancreatitis occurred in
11 of 5902 patients on alogliptin (0.2%) and in 5 of 5183 patients
receiving all comparators (<0.1%). There have been reports of
hypersensitivity reactions (anaphylaxis, angioedema, Stevens-
Johnson syndrome). Cases of hepatic failure have been reported,
but it is unclear if alogliptin was the cause. The medication, how-
ever, should be discontinued in the event of liver failure.
Vildagliptin (not available in the United States) lowers HbA1c
levels by 0.5–1% when added to the therapeutic regimen of
patients with type 2 diabetes. The dosage is 50 mg orally once or
twice daily. Adverse reactions include upper respiratory infections,
nasopharyngitis, dizziness, and headache. Rarely, it can cause
hepatitis, and liver function tests should be performed quarterly
in the first year of use and periodically thereafter.
In animal studies, high doses of DPP-4 inhibitors and GLP-1
agonists cause expansion of pancreatic ductal glands and gen-
eration of premalignant pancreatic intraepithelial (PanIN) lesions
that have the potential to progress to pancreatic adenocarcinoma.
The relevance to human therapy is unclear and currently there is
no evidence that these drugs cause pancreatic cancer in humans.
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     763
SODIUM-GLUCOSE
CO-TRANSPORTER 2 (SGLT2)
INHIBITORS
Glucose is freely filtered by the renal glomeruli and is reabsorbed in
the proximal tubules by the action of sodium-glucose transporters
(SGLTs). Sodium-glucose transporter 2 (SGLT2) accounts for 90%
of glucose reabsorption, and its inhibition causes glycosuria and
lowers glucose levels in patients with type 2 diabetes. SGLT2 inhibi-
tors lower glucose levels by changing the renal threshold and not by
insulin action. The SGLT2 inhibitors canagliflozin, dapagliflozin,
and empagliflozin, all oral medications, are approved for clinical use.
Canagliflozin reduces the threshold for glycosuria from
a plasma glucose threshold of approximately 180 mg/dL to
70–90 mg/dL. It has been shown to reduce HbA1c by 0.6–1%
when used alone or in combination with other oral agents or
insulin. It also results in modest weight loss of 2–5 kg. The usual
dosage is 100 mg daily. Increasing the dosage to 300 mg daily in
patients with normal renal function can lower the HbA1c by an
additional 0.5%.
Dapagliflozin reduces HbA1c by 0.5–0.8% when used alone
or in combination with other oral agents or insulin. It also results
in modest weight loss of about 2–4 kg. The usual dosage is 10 mg
daily, but 5 mg daily is recommended initially in patients with
hepatic failure.
Empagliflozin reduces HbA1c by 0.5–0.7% when used alone
or in combination with other oral agents or insulin. It also results
in modest weight loss of 2–3 kg. The usual dosage is 10 mg daily,
but 25 mg/d may be used. In a postmarketing multinational study
of 7020 type 2 patients with known cardiovascular disease, the
addition of empagliflozin was associated with a lower primary
composite outcome of death from cardiovascular causes, nonfa-
tal myocardial infarction, or nonfatal stroke (hazard ratio, 0.86;
p = 0.04). The mechanisms regarding this benefit remain unclear.
Weight loss, lower blood pressure, and diuresis may have played a
role since there were fewer deaths from heart failure in the treated
group whereas the rates of myocardial infarction were unaltered.
As might be expected, the efficacy of the SGLT2 inhibitors
is reduced in chronic kidney disease. Canagliflozin and empa-
gliflozin are contraindicated in patients with estimated GFR less
than 45 mL/min per 1.73 m2. Dapagliflozin is not recommended
for use in patients with estimated GFR less than 60 mL/min per
1.73 m2. The main adverse effects are increased incidence of geni-
tal infections and urinary tract infections affecting about 8–9% of
patients. The osmotic diuresis can also cause intravascular volume
contraction and hypotension. Canagliflozin and empagliflozin
caused a modest increase in LDL cholesterol levels (4–8%). In
clinical trials patients taking dapagliflozin had higher rates of
breast cancer (nine cases versus none in comparator arms) and
bladder cancer (nine cases versus one in placebo arm). These can-
cer rates exceeded the expected rates in an age-matched reference
diabetes population. Canagliflozin has been reported to cause a
decrease in bone mineral density at the lumbar spine and the hip.
In a pooled analysis of 8 clinical trial (mean duration 68 weeks),
an increase in fractures by about 30% was observed in patients
764    SECTION VII  Endocrine Drugs
on canagliflozin. It is likely that the effect on the bones is a class
effect and not restricted to canagliflozin. A modest increase in
upper limb fractures was observed with canagliflozin therapy. It is
not known if this is due to an effect on bone strength or related
to falls due to hypotension. Interim analysis of the Canagliflozin
Cardiovascular Assessment Study clinical trial reported an approx-
imately doubled risk of leg and foot amputations in the trial group
assigned to Canagliflozin; in 2017 the FDA issued a drug safety
communication regarding the association. Cases of diabetic keto-
acidosis have been reported with off-label use of SGLT2 inhibitors
in patients with type 1 diabetes. Type 1 patients are taught to give
less insulin if their glucose levels are not elevated. Because type 1
patients on an SGLT2 inhibitor may have normal glucose levels,
they may either withhold or reduce their insulin doses to such
a degree as to induce ketoacidosis. Therefore, SGLT2 inhibitors
should not be used in patients with type 1 diabetes and in those
patients labelled as having type 2 diabetes but who are very insulin
deficient and prone to ketosis.
OTHER HYPOGLYCEMIC DRUGS
Pramlintide is an islet amyloid polypeptide (IAPP, amylin) ana-
log. IAPP is a 37-amino-acid peptide present in insulin secretory
granules and secreted with insulin. It has approximately 46%
homology with the calcitonin gene-related peptide (CGRP; see
Chapter 17) and physiologically acts as a negative feedback on
insulin secretion. At pharmacologic doses, IAPP reduces glu-
cagon secretion, slows gastric emptying by a vagally mediated
mechanism, and centrally decreases appetite. Pramlintide is an
IAPP analog with substitutions of proline at positions 25, 28,
and 29. These modifications make pramlintide soluble, non-self-
aggregating, and suitable for pharmacologic use. Pramlintide is
approved for use in insulin-treated type 1 and type 2 patients who
are unable to achieve their target postprandial blood glucose levels.
It is rapidly absorbed after subcutaneous administration; levels
peak within 20 minutes, and the duration of action is not more
than 150 minutes. It is metabolized and excreted by the kidney,
but even at low creatinine clearance there is no significant change
in bioavailability. It has not been evaluated in dialysis patients.
Pramlintide is injected immediately before eating; dosages
range from 15 to 60 mcg subcutaneously for type 1 patients and
from 60 to 120 mcg for type 2 patients. Therapy with this agent
should be initiated at the lowest dosage and titrated upward.
Because of the risk of hypoglycemia, concurrent rapid- or short-
acting mealtime insulin dosages should be decreased by 50%
or more. Pramlintide should always be injected by itself using
a separate syringe; it cannot be mixed with insulin. The major
adverse effects of pramlintide are hypoglycemia and gastrointes-
tinal symptoms, including nausea, vomiting, and anorexia. Since
the drug slows gastric emptying, recovery from hypoglycemia can
be problematic because of the delay in absorption of fast-acting
carbohydrates.
Selected patients with type 1 diabetes who have problems with
postprandial hyperglycemia can use pramlintide effectively to con-
trol the glucose rise especially in the setting of a high-carbohydrate
meal. The drug is not very useful in type 2 patients who can
instead use the GLP-1 receptor agonists.
Colesevelam hydrochloride, the bile acid sequestrant and
cholesterol-lowering drug, is approved as an antihyperglycemic
therapy for persons with type 2 diabetes who are taking other
medications or have not achieved adequate control with diet and
exercise. The exact mechanism of action is unknown but pre-
sumed to involve an interruption of the enterohepatic circulation
and a decrease in farnesoid X receptor (FXR) activation. FXR is a
nuclear receptor with multiple effects on cholesterol, glucose, and
bile acid metabolism. Bile acids are natural ligands of the FXR.
Additionally, the drug may impair glucose absorption. In clini-
cal trials, it lowered the HbA1c concentration 0.3–0.5%. Adverse
effects include gastrointestinal complaints (constipation, indiges-
tion, flatulence). It can also exacerbate the hypertriglyceridemia
that commonly occurs in people with type 2 diabetes.
Bromocriptine, the dopamine agonist, in randomized placebo-
controlled studies lowered HbA1c by 0–0.2% compared with base-
line and by 0.4–0.5% compared with placebo. The mechanism by
which it lowers glucose levels is not known. The main adverse events
are nausea, fatigue, dizziness, vomiting, and headache.
Colesevelam and bromocriptine have very modest efficacy
in lowering glucose levels, and their use for this purpose is
questionable.
■■ MANAGEMENT OF THE
PATIENT WITH DIABETES
Diet
A well-balanced, nutritious diet remains a fundamental element
of therapy for diabetes. It is recommended that the macronutri-
ent proportions (carbohydrate, protein, and fat) be individualized
based on the patient’s eating patterns, preferences, and goals.
Generally most patients with diabetes consume about 45% of
their calories as carbohydrates; 25–35% fats; and 10–35% pro-
teins. Limiting the carbohydrate intake and substituting some of
the calories with monounsaturated fats, such as olive oil, rapeseed
(canola) oil, or the oils in nuts and avocados, can lower triglycer-
ides and increase HDL cholesterol. A Mediterranean-style eating
pattern (a diet supplemented with walnuts, almonds, hazelnuts,
and olive oil) has been shown to improve glycemic control and
lower combined endpoints for cardiovascular events and stroke.
Caloric restriction and weight loss is an important goal for the
obese patient with type 2 diabetes.
Education
Education of the patient and family is a critical component of
care. The patient should be informed about the kind of diabetes
he or she has and the rationale for controlling the glucose levels
(see Box: Benefits of Tight Glycemic Control in Diabetes). Self-
monitoring of glucose levels should be emphasized, especially
if the patient is on insulin or oral secretagogues that can cause
hypoglycemia. The patient on insulin therapy should understand

the action profile of the insulins. He or she should know how to
determine if the basal insulin dose is correct and how to adjust
the rapidly acting insulin dose for carbohydrate content of meals.
Insulin adjustments for exercise and infections should be dis-
cussed. The patient and family members also should be informed
about the signs and symptoms of hypoglycemia.
Glycemic Targets
The American Diabetes Association criteria for acceptable control
include an HbA1c of less than 7% (53 mmol/mol) and pre-meal
glucose levels of 90–130 mg/dL (5–7.2 mmol/L) and less than
180 mg/dL (10 mmol/L) one hour and 150 mg/dL (8.3 mmol/L)
two hours after meals. While the HbA1c target is appropriate for
individuals treated with lifestyle interventions and euglycemic
therapy, it may need to be modified for individuals treated with
insulin or insulin secretagogues due to their increased risk of
hypoglycemia. Less stringent blood glucose control also is appro-
priate for children as well as patients with a history of severe hypo-
glycemia, limited life expectancy, and significant microvascular
Benefits of Tight Glycemic Control in Diabetes
A long-term randomized prospective study involving 1441 type
1 patients in 29 medical centers reported in 1993 that “near
normalization” of blood glucose resulted in a delay in onset
and a major slowing of progression of microvascular and neu-
ropathic complications of diabetes during follow-up periods of
up to 10 years (Diabetes Control and Complications Trial [DCCT]
Research Group, 1993). In the intensively treated group, mean
glycated hemoglobin (HbA1c) of 7.2% (normal <6%) and mean
blood glucose of 155 mg/dL were achieved, whereas in the
conventionally treated group, HbA1c averaged 8.9% with mean
blood glucose of 225 mg/dL. Over the study period, which aver-
aged 7 years, a reduction of approximately 60% in risk of diabetic
retinopathy, nephropathy, and neuropathy was noted in the
tight control group compared with the standard control group.
The DCCT study, in addition, introduced the concept of
glycemic memory, which comprises the long-term benefits of any
significant period of glycemic control. During a 6-year follow-up
period, both the intensively and conventionally treated groups
had similar levels of glycemic control, and both had progression of
carotid intimal-medial thickness. However, the intensively treated
cohort had significantly less progression of intimal thickness.
The United Kingdom Prospective Diabetes Study (UKPDS)
was a very large randomized prospective study carried out
to study the effects of intensive glycemic control with several
types of therapies and the effects of blood pressure control in
type 2 diabetic patients. A total of 3867 newly diagnosed type 2
diabetic patients were studied over 10 years. A significant frac-
tion of these were overweight and hypertensive. Patients were
given dietary treatment alone or intensive therapy with insulin,
chlorpropamide, glyburide, or glipizide. Metformin was an option
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     765
and macrovascular disease. For the elderly frail patient an HbA1c
greater than 8% may be appropriate.
Treatment
Treatment must be individualized on the basis of the type of dia-
betes and specific needs of each patient.
A. Type 1 Diabetes
For most type 1 patients, at least 3 or 4 insulin injections a day are
necessary for safe and effective control of glucose levels. A com-
bination of rapidly acting insulin analogs and long-acting insulin
analogs allow for more physiologic insulin replacement. Generally,
for an adult with type 1 diabetes, the total daily insulin require-
ment in units is equal to the weight in pounds divided by four, or
0.55 times the person’s weight in kilograms. Approximately 40%
of the total daily insulin dosage covers the background or basal
insulin requirements, and the remainder covers meal and snack
requirement and high blood sugar corrections. This is an approxi-
mate calculation and should be individualized. Examples of
for patients with inadequate response to other therapies. Tight
control of blood pressure was added as a variable, with an angio-
tensin-converting enzyme inhibitor, a β blocker, or in some cases,
a calcium channel blocker available for this purpose.
Tight control of diabetes, with reduction of HbA1c from 9.1%
to 7%, was shown to reduce the risk of microvascular complica-
tions overall compared with that achieved with conventional
therapy (mostly diet alone, which decreased HbA1c to 7.9%).
Cardiovascular complications were not noted for any particular
therapy; metformin treatment alone reduced the risk of macro-
vascular disease (myocardial infarction, stroke). Epidemiologic
analysis of the study suggested that every 1% decrease in the
HbA1c achieved an estimated risk reduction of 37% for micro-
vascular complications, 21% for any diabetes-related end point
and death related to diabetes, and 14% for myocardial infarction.
Tight control of hypertension also had a surprisingly sig-
nificant effect on microvascular disease (as well as more conven-
tional hypertension-related sequelae) in these diabetic patients.
Epidemiologic analysis of the results suggested that every
10-mmHg decrease in the systolic pressure achieved an esti-
mated risk reduction of 13% for diabetic microvascular complica-
tions, 12% for any diabetes-related complication, 15% for death
related to diabetes, and 11% for myocardial infarction.
Post-study monitoring showed that 5 years after the closure
of the UKPDS, the benefits of intensive management on diabetic
end points were maintained and the risk reduction for a myo-
cardial infarction became significant. The benefits of metformin
therapy were maintained.
These studies show that tight glycemic control benefits both
type 1 and type 2 patients.
766    SECTION VII  Endocrine Drugs

TABLE 41–8  Examples of intensive insulin regimens using rapid-acting insulin analogs
(insulin lispro, aspart, or glulisine) and NPH, or insulin detemir, glargine,
or degludec in a 70-kg man with type 1 diabetes.1–3

  Prebreakfast Prelunch Predinner Bedtime

Rapid-acting insulin 5U 4U 6U —
analog
NPH insulin 3U 3U 2U 8–9 U
or
Rapid-acting insulin 5U 4U 6U —
analog
Insulin glargine or — — — 15–16 U
degludec
Insulin detemir 6–7 U — — 8–9 U
1
Assumes that patient is consuming approximately 75 g carbohydrate at breakfast, 60 g at lunch, and 90 g at dinner.
2
The dose of rapid-acting insulin analogs can be raised by 1 or 2 U if extra carbohydrate (15–30 g) is ingested or if premeal blood glucose
is >170 mg/dL. The rapid-acting insulin analogs can be mixed in the same syringe with NPH insulin.
3
Insulin glargine or insulin detemir must be given as a separate injection.

reduced insulin requirement include newly diagnosed persons and
those with ongoing endogenous insulin production, long-standing
diabetes with insulin sensitivity, significant renal insufficiency, or
other endocrine deficiencies. Increased insulin requirements typi-
cally occur with obesity, during adolescence, and during the latter
trimesters of pregnancy. Table 41–8 illustrates regimens of rapidly
acting insulin analogs and basal analogs that might be appropriate
for a 70-kg person with type 1 diabetes. If the patient is on an
insulin pump, he or she may require about a basal infusion rate of
0.6 units per hour throughout the 24 hours with the exception of
4:00 am to 8:00 am, when 0.7 units per hour might be appropriate
(dawn phenomenon). The ratios might be one unit for 12 grams
carbohydrate plus one unit for 50 mg/dL (2.8 mmol/L) of blood
glucose above a target value of 120 mg/dL (6.7 mmol/L).
intensive lifestyle interventions (diet and exercise), diabetes self-
management education, and metformin. If clinical failure occurs
with metformin monotherapy, a second agent is added. Options
include sulfonylureas, repaglinide or nateglinide, pioglitazone,
GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors,
and insulin. In the choice of the second agent, consideration
should be given to efficacy of the agent, hypoglycemic risk, effect
on weight, adverse effects, and cost. In patients who experience
Weight loss + exercise + metformin
*

B. Type 2 Diabetes Metformin + another agent

Normalization of glucose levels can occur with weight loss and
improved insulin sensitivity in the obese patient with type 2 diabetes.
A combination of caloric restriction and increased exercise is neces-
sary if a weight reduction program is to be successful. Understand-
ing the long-term consequences of poorly controlled diabetes may
motivate some patients to lose weight. For selected patients, medical
or surgical options should be considered. Orlistat, phentermine/
topiramate, lorcaserin, naltrexone plus extended release bupropion,
and high-dose liraglutide are approved weight loss medications
for use in combination with diet and exercise. Bariatric surgery
(Roux-en-Y, gastric banding, gastric sleeve, biliopancreatic diver-
sion/duodenal switch) typically result in significant weight loss and
can result in remission of the diabetes.
Nonobese patients with type 2 diabetes frequently have
increased visceral adiposity—the so-called metabolically obese
normal weight patient. There is less emphasis on weight loss in
such patients, but exercise is important.
Multiple medications may be required to achieve glycemic con-
trol (Figure 41–6) in patients with type 2 diabetes. Unless there
is a contraindication, medical therapy should be initiated with
*
Metformin + two other agents
*
Metformin + more complex insulin
regimen ± other non-insulin agent
* Step taken if needed to reach individualized HbA1c
target after ~ 3 months.
FIGURE 41–6  Suggested algorithm for the treatment of type
2 diabetes. The seven main classes of agents are metformin, sul-
fonylureas (includes nateglinide, repaglinide), pioglitazone, GLP-1
receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors, insulins.
(α-Glucosidase inhibitors, colesevelam, pramlintide, and bromocrip-
tine not included because of limited efficacy and significant adverse
reactions). (Data from the consensus panel of the American Diabetes Association/
European Association for the Study of Diabetes, as described in Inzucchi SE et al:
Diabetes Care 2012;35:1364.)

hyperglycemia after a carbohydrate-rich meal (such as dinner), a
short-acting secretagogue before that meal may suffice to control
the glucose levels. Patients with severe insulin resistance may
be candidates for pioglitazone. Patients who are very concerned
about weight gain may benefit from a trial of a GLP-1 receptor
agonist, a DPP-4 inhibitor, or an SGLT2 inhibitor, although the
average weight loss with these medication is not great. If two
agents are inadequate a third agent is added, although data regard-
ing efficacy of such combined therapy are limited.
When the combination of oral agents and injectable GLP-1
receptor agonists fails to adequately control glucose levels, insulin
therapy should be instituted. Various insulin regimens may be
effective. Simply adding nighttime intermediate- or long-acting
insulin to the oral regimen may lead to improved fasting glucose
levels and adequate control during the day. If daytime glucose
levels are problematic, premixed insulins before breakfast and
dinner may help. If such a regimen does not achieve adequate
control or leads to unacceptable rates of hypoglycemia, a more
intensive basal bolus insulin regimen (long-acting basal insulin)
combined with rapid-acting analog before meals can be instituted.
Metformin has been shown to be effective when combined with
insulin therapy and should be continued. Pioglitazone can be used
with insulin, but this combination is associated with more weight
gain and peripheral and macular edema. Continuing with sulfo-
nylureas, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2
inhibitors can be of benefit in selected patients. Cost, complexity,
and risk for adverse events should be considered when deciding
which drugs to continue once the patient starts on insulin therapy.
Acute Complications of Diabetes
A. Hypoglycemia
Hypoglycemic reactions are the most common complication of insulin
therapy. It can also occur in any patient taking oral agents that stimu-
late insulin secretion (eg, sulfonylureas, meglitinide, d-phenylalanine
analogs), particularly if the patient is elderly, has renal or liver disease,
or is taking certain other medications that alter metabolism of the
sulfonylureas (eg, phenylbutazone, sulfonamides, warfarin). It occurs
more frequently with the use of long-acting sulfonylureas.
Rapid development of hypoglycemia in persons with intact
hypoglycemic awareness causes signs of autonomic hyperactivity—
both sympathetic (tachycardia, palpitations, sweating, tremulous-
ness) and parasympathetic (nausea, hunger)—and may progress to
convulsions and coma if untreated.
In persons exposed to frequent hypoglycemic episodes during
tight glycemic control, autonomic warning signals of hypogly-
cemia are less common or even absent. This dangerous acquired
condition is termed hypoglycemic unawareness. When patients lack
the early warning signs of low blood glucose, they may not take
corrective measures in time. In patients with persistent, untreated
hypoglycemia, the manifestations of insulin excess may develop—
confusion, weakness, bizarre behavior, coma, seizures—at which
point they may not be able to procure or safely swallow glucose-
containing foods. Hypoglycemic awareness may be restored by
preventing frequent hypoglycemic episodes. An identification
bracelet, necklace, or card in the wallet or purse, as well as some
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     767
form of rapidly absorbed glucose, should be carried by every dia-
betic person who is receiving hypoglycemic drug therapy.
All the manifestations of hypoglycemia are relieved by glu-
cose administration. To expedite absorption, simple sugar or
glucose should be given, preferably in liquid form. To treat mild
hypoglycemia in a patient who is conscious and able to swallow,
dextrose tablets, glucose gel, or any sugar-containing beverage or
food may be given. If more severe hypoglycemia has produced
unconsciousness or stupor, the treatment of choice is 1 mg of
glucagon injected either subcutaneously or intramuscularly. This
may restore consciousness within 15 minutes to permit ingestion
of sugar. Emergency medical services should be called in the event
of loss of consciousness. The emergency personnel can restore
consciousness by giving 20–50 mL of 50% glucose solution by
intravenous bolus over a period of 2–3 minutes.
B. Diabetic Coma
1. Diabetic ketoacidosis—Diabetic ketoacidosis (DKA) is
a life-threatening medical emergency caused by inadequate or
absent insulin replacement, which occurs in people with type 1
diabetes and infrequently in those with type 2 diabetes. It typi-
cally occurs in newly diagnosed type 1 patients or in those who
have experienced interrupted insulin replacement, and rarely
in people with type 2 diabetes who have concurrent unusually
stressful conditions such as sepsis or pancreatitis or are on high-
dose steroid therapy. DKA occurs more frequently in patients on
insulin pumps. Poor compliance—either for psychological reasons
or because of inadequate education—is one of the most common
causes of DKA, particularly when episodes are recurrent.
Signs and symptoms include nausea, vomiting, abdominal pain,
deep slow (Kussmaul) breathing, change in mental status (including
coma), elevated blood and urinary ketones and glucose, an arterial
blood pH lower than 7.3, and low bicarbonate (15 mmol/L).
The fundamental treatment for DKA includes aggressive intrave-
nous hydration and insulin therapy and maintenance of potassium
and other electrolyte levels. Fluid and insulin therapy is based on
the patient’s individual needs and requires frequent reevaluation and
modification. Close attention must be given to hydration and renal
status, sodium and potassium levels, and the rate of correction of
plasma glucose and plasma osmolality. Fluid therapy generally begins
with normal saline. Regular human insulin should be used for intra-
venous therapy with a usual starting dosage of about 0.1 U/kg/h.
2. Hyperosmolar hyperglycemic syndrome—Hyperosmolar
hyperglycemic syndrome (HHS) is diagnosed in persons with
type 2 diabetes and is characterized by profound hyperglycemia
and dehydration. It is associated with inadequate oral hydration,
especially in elderly patients; with other illnesses; with the use of
medication that elevates the blood sugar or causes dehydration, such
as phenytoin, steroids, diuretics, and calcium channel blockers; and
with peritoneal dialysis and hemodialysis. The diagnostic hallmarks
are declining mental status and even seizures, a plasma glucose
>600 mg/dL, and a calculated serum osmolality >320 mmol/L.
Persons with HHS are not acidotic unless DKA is also present.
The treatment of HHS centers around aggressive rehydration
and restoration of glucose and electrolyte homeostasis; the rate of
768    SECTION VII  Endocrine Drugs

correction of these variables must be monitored closely. Low-dose
insulin therapy may be required.
Chronic Complications of Diabetes
Late clinical manifestations of diabetes mellitus include a number of
pathologic changes that involve small and large blood vessels, cranial
and peripheral nerves, the skin, and the lens of the eye. These lesions
lead to hypertension, end-stage chronic kidney disease, blindness,
autonomic and peripheral neuropathy, amputations of the lower
extremities, myocardial infarction, and cerebrovascular accidents.
These late manifestations correlate with the duration of the diabetic
state subsequent to the onset of puberty and glycemic control. In
type 1 diabetes, end-stage chronic kidney disease develops in up
to 40% of patients, compared with less than 20% of patients with
type 2 diabetes. Proliferative retinopathy ultimately develops in
both types of diabetes but has a slightly higher prevalence in type
1 patients (25% after 15 years’ duration). In patients with type 1
diabetes, complications from end-stage chronic kidney disease are
a major cause of death, whereas patients with type 2 diabetes are
more likely to have macrovascular diseases leading to myocardial
infarction and stroke as the main causes of death. Cigarette use adds
significantly to the risk of both microvascular and macrovascular
complications in diabetic patients.

SUMMARY Drugs Used for Diabetes

Mechanism of Clinical Pharmacokinetics,
Subclass, Drug Action Effects Applications Toxicities, Interactions

INSULINS
  • Rapid-acting: Lispro, aspart, Activate insulin receptor Reduce circulating glucose Type 1 and type 2 Parenteral (SC or IV) • duration
glulisine, inhaled regular diabetes varies (see text) • Toxicity:
  •  Short-acting: Regular Hypoglycemia, weight gain,
  •  Intermediate-acting: NPH lipodystrophy (rare)
  • Long-acting: Detemir, glargine,
degludec

SULFONYLUREAS
  •  Glipizide Insulin secretagogues: Reduce circulating glucose in Type 2 diabetes Orally active • duration 10–24 h
  •  Glyburide Close K+ channels in patients with functioning • Toxicity: Hypoglycemia, weight
  •  Glimepiride beta cells • increase beta cells gain
  • Gliclazide1 insulin release

  • Tolazamide, tolbutamide, chlorpropamide, acetohexamide: Older sulfonylureas, lower potency, greater toxicity; rarely used

MEGLITINIDE ANALOGS; d-PHENYLANALINE DERIVATIVE

  •  Repaglinide, nateglinide Insulin secretagogue: In patients with functioning Type 2 diabetes Oral • very fast onset of action
  •  Mitiglinide1 Similar to sulfonylureas beta cells, reduce circulating • duration 5–8 h, nateglinide • 4 h
with some overlap in glucose • Toxicity: Hypoglycemia
binding sites

BIGUANIDES
  •  Metformin Activates AMP kinase
• reduces hepatic and
renal gluconeogenesis
Decreases circulating Type 2 diabetes Oral • maximal plasma
glucose concentration in 2–3 h • Toxicity:
Gastrointestinal symptoms, lactic
acidosis (rare) • cannot use if
impaired renal/hepatic function
• congestive heart failure (CHF),
hypoxic/acidotic states, alcoholism

ALPHA-GLUCOSIDASE INHIBITORS
  •  Acarbose, miglitol Inhibit intestinal Reduce conversion of starch Type 2 diabetes Oral • rapid onset • Toxicity:
  •  Voglibose1 α-glucosidases and disaccharides to Gastrointestinal symptoms • cannot
monosaccharides • reduce use if impaired renal/hepatic
postprandial hyperglycemia function, intestinal disorders

THIAZOLIDINEDIONES
  •  Pioglitazone, rosiglitazone
Regulate gene
expression by binding
to PPAR-γ and PPAR-α
Reduce insulin resistance
Type 2 diabetes Oral • long-acting (>24 h) • Toxicity:
Fluid retention, edema, anemia,
weight gain, macular edema, bone
fractures in women • cannot use if
CHF, hepatic disease

(continued)
 CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     769

Mechanism of Clinical Pharmacokinetics,

Subclass, Drug Action Effects Applications Toxicities, Interactions

GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS

  • Exenatide, liraglutide, Analogs of GLP-1: Bind Reduce post-meal glucose Type 2 diabetes, Parenteral (SC) • Toxicity: Nausea,
albiglutide, dulaglutide to GLP-1 receptors excursions: Increase glucose- liraglutide only: headache, vomiting, anorexia, mild
mediated insulin release, obesity weight loss, pancreatitis, C-cell
lower glucagon levels, slow tumors in rodents
gastric emptying, decrease
appetite

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

  • Sitagliptin, saxagliptin,
linagliptin, alogliptin,
vildagliptin1
Block degradation of Reduces post-meal glucose Type 2 diabetes Oral • half-life ~12 h • 24-h duration
GLP-1, raise circulating excursions: Increases of action • Toxicity: Rhinitis, upper
GLP-1 levels glucose-mediated insulin respiratory infections, headaches,
release, lowers glucagon pancreatitis, rare allergic reactions
levels, slows gastric
emptying, decreases
appetite

SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

  • Canagliflozin, dapagliflozin, Block renal glucose Increase glucosuria, lower Type 2 diabetes Oral • half-life ~10–14 h • Toxicity:
empagliflozin resorption plasma glucose levels Genital and urinary tract infections,
polyuria, pruritus, thirst, osmotic
diuresis, constipation

ISLET AMYLOID POLYPEPETIDE ANALOG

  •  Pramlintide Analog of amylin: Binds Reduces post-meal glucose
to amylin receptors excursions: Lowers glucagon
levels, slows gastric
emptying, decreases
appetite
Type 1 and type 2 Parenteral (SC) • rapid onset
diabetes • half-life ~48 min • Toxicity: Nausea,
anorexia, hypoglycemia, headache

BILE ACID SEQUESTRANT

  •  Colesevelam hydrochloride Bile acid binder: Lowers Reduces glucose levels Type 2 diabetes Oral • 24-h duration of action
glucose through • Toxicity: Constipation, indigestion,
unknown mechanisms flatulence

DOPAMINE AGONIST
  •  Bromocriptine D2 receptor agonist: Reduces glucose levels Type 2 diabetes Oral • 24-h action • Toxicity: Nausea,
Lowers glucose through vomiting, dizziness, headache
unknown mechanism
1
Not available in United States.
770    SECTION VII  Endocrine Drugs

P R E P A R A T I O N S A V A I L A B L E*
GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS
SULFONYLUREAS THIAZOLIDINEDIONE COMBINATION
Acetohexamide‡ Generic, Dymelor Pioglitazone plus glimepiride Duetact
Chlorpropamide Generic, Diabinese Alogliptin plus pioglitazone Oseni
Gliclazide‡ Generic, Diamicron Rosiglitazone plus glimepiride Avandaryl
Glimepiride Generic, Amaryl ALPHA-GLUCOSIDASE INHIBITORS
Glipizide Generic, Glucotrol, Glucotrol XL Acarbose Generic, Precose
Glyburide Generic, Diaβeta, Micronase, Miglitol Glyset
Glynase PresTab Voglibose‡
Tolazamide Generic, Tolinase GLUCAGON-LIKE POLYPEPTIDE-1 RECEPTOR AGONISTS
Tolbutamide Generic, Orinase Exenatide Byetta
MEGLITINIDES Liraglutide Victoza
Repaglinide Generic, Prandin Albiglutide Tanzeum, Eperzan
Mitiglinide‡   Dulaglutide Trulicity
d - PHENYLALANINE
DERIVATIVE DIPEPTIDYL PEPTIDASE-4 INHIBITORS
Nateglinide Generic, Starlix Linagliptin Tradjenta
BIGUANIDE Saxagliptin Onglyza
Metformin Generic, Glucophage, Sitagliptin Januvia
Glucophage XR
Alogliptin Nesina
METFORMIN COMBINATIONS †
Vildagliptin‡  
Glipizide plus metformin Generic, Metaglip
SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITORS
Glyburide plus metformin Generic, Glucovance
Canagliflozin Invokana
Pioglitazone plus metformin ACTOplus Met
Dapagliflozin Farxiga
Repaglinide plus metformin Prandi-Met
Empagliflozin Jardiance
Rosiglitazone plus metformin Avandamet
SODIUM GLUCOSE CO-TRANSPORTER
Saxagliptin plus metformin Kombiglyze INHIBITORS COMBINATION
Sitagliptin plus metformin Janumet Empagliflozin plus linagliptin Glyxambi
Linagliptin plus metformin Jentadueto ISMISCELLANEOUS DRUGSLET AMYLOID POLYPEPTIDE ANALOG
Alogliptin plus metformin Kazano Pramlintide Symlin
Dapagliflozin plus metformin Xigduo BILE ACID SEQUESTRANT
Canagliflozin plus metformin Invokamet Colesevelam hydrochloride Welchol
Empagliflozin plus metformin Synjardy DOPAMINE RECEPTOR AGONIST
THIAZOLIDINEDIONE DERIVATIVES Bromocriptine Generic, Parlodel, Cycloset
Pioglitazone Generic, Actos GLUCAGON
Rosiglitazone Avandia Glucagon Generic
*
See Table 41–5 for insulin preparations.
†
Other combinations are available.
‡
Not available in the United States.

REFERENCES Andrianesis V, Doupis J: The role of kidney in glucose homeostasis—SGLT2

Action to Control Cardiovascular Risks in Diabetes Study Group: Effects of
intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545.
Adler AI et al: Association of systolic blood pressure with macrovascular and
microvascular complications of type 2 diabetes (UKPDS 36): Prospective
observational study. Br Med J 2000;321:412.
ADVANCE Collaborative Group: Intensive blood glucose control and vascular
outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560.
Ahmadian M et al: PPARγ signaling and metabolism: The good, the bad and the
future. Nat Med 2013;19:557.
American Diabetes Association: Diagnosis and classification of diabetes mellitus.
Diabetes Care 2013;36(Suppl 1):S67.
inhibitors, a new approach in diabetes treatment. Expert Rev Clin Pharma-
col 2013;6:519.
Bennett WL et al: Comparative effectiveness and safety of medications for type
2 diabetes: An update including new drugs and 2-drug combinations. Ann
Intern Med 2011;154:602. Erratum in: Ann Intern Med 2011;155:67.
Butler PC et al: A critical analysis of the clinical use of incretin-based therapies: Are
the GLP-1 therapies safe? Diabetes Care 2013;36:2118.
Diabetes Prevention Program Research Group: Reduction in the incidence of
type 2 diabetes with lifestyle intervention or metformin. N Engl J Med
2002;346:393.
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus:
Report of the Expert Committee on the Diagnosis and Classification of
Diabetes Mellitus. Diabetes Care 2003;26(Suppl 1):S5.

Gaede P et al: Effect of a multifactorial intervention on mortality in type 2
diabetes. N Engl J Med 2008;358:580.
Guo S: Insulin signaling, resistance, and the metabolic syndrome: Insights from
mouse models to disease mechanisms. J Endocrinol 2014;220:T1.
Inzucchi SE et al: Management of hyperglycaemia in type 2 diabetes, 2015: a
patient-centred approach. Update to a position statement of the American
Diabetes Association and the European Association for the Study of
Diabetes. Diabetologia 2015;58:429.
Karagiannis T et al: Dipeptidyl peptidase-4 inhibitors for treatment of type 2
diabetes mellitus in the clinical setting: Systematic review and meta-analysis.
BMJ 2012;344:e1369.
Kitabchi A et al: Thirty years of personal experience in hyperglycemic crises: Dia-
betic ketoacidosis and hyperglycemic hyperosmolar state. J Clin Endocrinol
Metab 2008;93:1541.
Lefebvre P et al: Role of bile acids and bile acid receptors in metabolic regulation.
Physiol Rev 2009;89:147.
Levin D et al: Pioglitazone and bladder cancer risk: A multipopulation pooled,
cumulative exposure analysis. Diabetologia 2015;58:493.
Miyazaki Y, DeFronzo RA: Rosiglitazone and pioglitazone similarly improve insu-
lin sensitivity and secretion, glucose tolerance and adipocytokines in type 2
diabetic patients. Diabetes Obes Metab 2008;10:1204.
Nauck M: Incretin therapies: Highlighting common features and differences in the
modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl
peptidase-4 inhibitors. Diabetes Obes Metab 2016;18:203.
Nwose OM, Jones MR: Atypical mechanism of glucose modulation by colesevelam
in patients with type 2 diabetes. Clin Med Insights Endocrinol Diabetes
2013;6:75.
C ASE STUDY ANSWER
This patient had significant insulin resistance, taking about
125 units of insulin daily (approximately 1 unit per kilogram).
He had had limited instruction on how to manage his dia-
betes. He had peripheral neuropathy, proteinuria, low HDL
cholesterol levels, and hypertension. The patient underwent
multifactorial intervention targeting his weight, glucose
levels, and blood pressure. He was advised to stop smoking.
He attended structured diabetes classes and received indi-
vidualized instruction from a diabetes educator and a dieti-
tian. Metformin therapy was reinitiated and his insulin doses
were reduced. The patient was then given the GLP1 receptor
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     771
Ratner RE et al: Amylin replacement with pramlintide as an adjunct to insulin
therapy improves long term glycemic and weight control in type 1 dia-
betes mellitus: A 1-year randomized controlled trial. Diabetic Med 2004;
21:1204.
Reitman ML et al: Pharmacogenetics of metformin response: A step in the path
toward personalized medicine. J Clin Invest 2007;117:1226.
Rizzo M et al: Non-glycemic effects of pioglitazone and incretin-based therapies.
Expert Opin Ther Targets 2013;17:739.
Rosenstock J, Ferrannini E: Euglycemic diabetic ketoacidosis: A predictable,
detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes
Care 2015;38:1638.
Standl E, Schnell O: Alpha-glucosidase inhibitors 2012—cardiovascular consider-
ations and trial evaluation. Diab Vasc Dis Res 2012;9:163.
Switzer SM et al: Intensive insulin therapy in patients with type 1 diabetes mellitus.
Endocrinol Metab Clin North Am 2012;41:89.
Tuccori M et al: Pioglitazone use and risk of bladder cancer: population based
cohort study. BMJ 2016;352:i1541.
United Kingdom Prospective Diabetes Study (UKPDS) Group: Glycemic control
with diet, sulfonylurea, metformin, or insulin in patients with type 2 dia-
betes mellitus: Progressive requirement for multiple therapies: UKPDS 49.
JAMA 1999;281:2005.
United Kingdom Prospective Diabetes Study (UKPDS) Group: Tight blood pres-
sure control and risk of macrovascular and microvascular complications in
type 2 diabetes: UKPDS 38. BMJ 1998;317:703.
agonist, exenatide. The patient lost about 8 kg in weight over
the next 3 years and was able to stop his insulin. He had
excellent control with an HbA1c of 6.5 % on a combination
of metformin, exenatide, and glimepiride. His antihyperten-
sive therapy was optimized and his urine albumin excretion
declined to 1569 mg/g creatinine. This case illustrates the
importance of weight loss in controlling glucose levels in the
obese patient with type 2 diabetes. It also shows that simply
increasing the insulin dose is not always effective. Combin-
ing metformin with other oral agents and non-insulin inject-
ables may be a better option.
 42
C H A P T E R
Agents That Affect Bone
Mineral Homeostasis
Daniel D. Bikle, MD, PhD
C ASE STUDY
A 65-year-old man is referred to you from his primary care
physician (PCP) for evaluation and management of pos-
sible osteoporosis. He saw his PCP for evaluation of low
back pain. X-rays of the spine showed some degenerative
changes in the lumbar spine plus several wedge deformities
in the thoracic spine. The patient is a long-time smoker
(up to two packs per day) and has two to four glasses of
wine with dinner, more on the weekends. He has chronic
bronchitis, presumably from smoking, and has been treated
on numerous occasions with oral prednisone for exacerba-
tions of bronchitis. He is currently on 10 mg/d prednisone.
■■ BASIC PHARMACOLOGY
Calcium and phosphate, the major mineral constituents of bone,
are also two of the most important minerals for general cellular
function. Accordingly, the body has evolved complex mecha-
nisms to carefully maintain calcium and phosphate homeostasis
(Figure 42–1). Approximately 98% of the 1–2 kg of calcium and
85% of the 1 kg of phosphorus in the human adult are found in
bone, the principal reservoir for these minerals. This reservoir is
dynamic, with constant remodeling of bone and ready exchange
of bone mineral with that in the extracellular fluid. Bone also
serves as the principal structural support for the body and pro-
vides the space for hematopoiesis. This relationship is more
than fortuitous, as elements of the bone marrow affect skeletal
processes just as skeletal elements affect hematopoietic processes.
During aging and in nutritional diseases such as anorexia nervosa
and obesity, fat accumulates in the marrow, suggesting a dynamic
interaction between marrow fat and bone. Furthermore, bone has
772
Examination shows kyphosis of the thoracic spine, with
some tenderness to fist percussion over the thoracic spine.
The dual-energy x-ray absorptiometry (DEXA) measure-
ment of the lumbar spine is “within the normal limits,” but
the radiologist noted that the reading may be misleading
because of degenerative changes. The hip measurement
shows a T score (number of standard deviations by which
the patient’s measured bone density differs from that of
a normal young adult) in the femoral neck of –2.2. What
further workup should be considered, and what therapy
should be initiated?
been implicated as an endocrine tissue with release of osteocalcin,
which in its uncarboxylated form stimulates insulin secretion and
testicular function. Abnormalities in bone mineral homeostasis
can lead to a wide variety of cellular dysfunctions (eg, tetany,
coma, muscle weakness), disturbances in structural support of the
body (eg, osteoporosis with fractures), and loss of hematopoietic
capacity (eg, infantile osteopetrosis).
Calcium and phosphate enter the body from the intestine. The
average American diet provides 600–1000 mg of calcium per day,
of which approximately 100–250 mg is absorbed. This amount
represents net absorption, because both absorption (principally
in the duodenum and upper jejunum) and secretion (principally
in the ileum) occur. The quantity of phosphorus in the American
diet is about the same as that of calcium. However, the efficiency
of absorption (principally in the jejunum) is greater, ranging from
70% to 90%, depending on intake. In the steady state, renal
excretion of calcium and phosphate balances intestinal absorp-
tion. In general, more than 98% of filtered calcium and 85% of
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     773
Ca, P
D(+) Serum D(+), PTH (+)
Gut Ca, P Bone
D(+), PTH (+)
CT(–)
Ca, P
Kidney
D(–)
D(–)
PTH(+)
PTH(–)
CT(+)
CT(+)
FGF23(+)
Ca P (1,25[OH]2D) in the kidney and elsewhere. PTH stimulates the
FIGURE 42–1  Mechanisms contributing to bone mineral
homeostasis. Serum calcium (Ca) and phosphorus (P) concentrations
are controlled principally by three hormones, 1,25-dihydroxyvitamin
D (D), fibroblast growth factor 23 (FGF23), and parathyroid hormone
(PTH), through their action on absorption from the gut and from
bone and on renal excretion. PTH and 1,25(OH)2D increase the input
of calcium and phosphorus from bone into the serum and stimulate
bone formation. 1,25(OH)2D also increases calcium and phosphate
absorption from the gut. In the kidney, 1,25(OH)2D decreases excre-
tion of both calcium and phosphorus, whereas PTH reduces calcium
but increases phosphorus excretion. FGF23 stimulates renal excretion
of phosphate. Calcitonin (CT) is a less critical regulator of calcium
homeostasis, but in pharmacologic concentrations can reduce serum
calcium and phosphorus by inhibiting bone resorption and stimulat-
ing their renal excretion. Feedback may alter the effects shown; for
example, 1,25(OH)2D increases urinary calcium excretion indirectly
through increased calcium absorption from the gut and inhibition
of PTH secretion and may increase urinary phosphate excretion
because of increased phosphate absorption from the gut and stimu-
lation of FGF23 production.
filtered phosphate are reabsorbed by the kidney. The movement
of calcium and phosphate across the intestinal and renal epithelia
is closely regulated. Dysfunction of the intestine (eg, nontropi-
cal sprue) or kidney (eg, chronic renal failure) can disrupt bone
mineral homeostasis.
Three hormones serve as the principal regulators of calcium
and phosphate homeostasis: parathyroid hormone (PTH),
fibroblast growth factor 23 (FGF23), and vitamin D via its
active metabolite 1,25-dihydroxyvitamin D (1,25[OH]2D)
(Figure 42–2). The role of calcitonin (CT) is less critical dur-
ing adult life but may play a greater role during pregnancy and
lactation. The term vitamin D, when used without a subscript,
refers to both vitamin D2 (ergocalciferol) and vitamin D3 (cho-
lecalciferol). This applies also to the metabolites of vitamin D2
and D3. Vitamin D2 and its metabolites differ from vitamin D3
and its metabolites only in the side chain where they con-
tain a double bond between C-22–23 and a methyl group at
C-24 (Figure 42–3). Vitamin D is considered a prohormone
because it must be further metabolized to gain biologic activity
(Figure 42–3). Vitamin D3 is produced in the skin under ultra-
violet B (UVB) radiation (eg, in sunlight) from its precursor,
7-dehydrocholesterol. The initial product, pre-vitamin D3, under-
goes a temperature-sensitive isomerization to vitamin D3. The
precursor of vitamin D2 is ergosterol, found in plants and fungi
(mushrooms). It undergoes a similar transformation to vitamin D2
with UVB radiation. Vitamin D2 thus comes only from the diet,
whereas vitamin D3 comes from the skin or the diet, or both.
The subsequent metabolism of these two forms of vitamin D is
essentially the same and follows the illustration for vitamin D3
metabolism in Figure 42–3. The first step is the 25-hydroxylation
of vitamin D to 25-hydroxyvitamin D (25[OH]D). A number of
enzymes in the liver and other tissues perform this function,
of which CYP2R1 is the most important. 25(OH)D is then
metabolized to the active hormone 1,25-dihydroxyvitamin D
production of 1,25(OH)2D in the kidney, whereas FGF23 is
inhibitory. Elevated levels of blood phosphate and calcium also
inhibit 1,25(OH)2D production in part by their effects on FGF23
(high phosphate stimulates FGF23 production) and PTH (high
calcium inhibits PTH production). 1,25(OH)2D regulates its
own levels by stimulating the enzyme 24-hydroxyase (CYP24A1),
which begins the catabolism of 1,25(OH)2D, suppressing PTH
production, and stimulating FGF23 production, all of which
combine to reduce 1,25(OH)2D levels. Other tissues also produce
1,25(OH)2D; the control of this production differs from that
in the kidney, as will be discussed subsequently. The complex
interplay among PTH, FGF23, and 1,25(OH)2D is discussed in
detail later.
To summarize: 1,25(OH)2D suppresses the production of PTH,
as does calcium, but stimulates the production of FGF23. Phos-
phate stimulates both PTH and FGF23 secretion. In turn PTH
stimulates 1,25(OH)2D production, whereas FGF23 is inhibitory.
1,25(OH)2D stimulates the intestinal absorption of calcium and
phosphate. 1,25(OH)2D and PTH promote both bone formation
and resorption in part by stimulating the proliferation and differen-
tiation of osteoblasts and osteoclasts. Both PTH and 1,25(OH)2D
enhance renal retention of calcium, but PTH promotes renal phos-
phate excretion, as does FGF23, whereas 1,25(OH)2D promotes
renal reabsorption of phosphate.
Other hormones—calcitonin, prolactin, growth hormone,
insulin, insulin-like growth factors, thyroid hormone, glucocorti-
coids, and sex steroids—influence calcium and phosphate homeo-
stasis under certain physiologic circumstances and can be considered
secondary regulators. Deficiency or excess of these secondary regula-
tors within a physiologic range does not produce the disturbance of
calcium and phosphate homeostasis that is observed in situations
of deficiency or excess of PTH, FGF23, and vitamin D. However,
certain of these secondary regulators—especially calcitonin, gluco-
corticoids, and estrogens—are useful therapeutically and discussed
in subsequent sections.
In addition to these hormonal regulators, calcium and phos-
phate themselves, other ions such as sodium and fluoride, and a
variety of drugs (bisphosphonates, anticonvulsants, and diuretics)
also alter calcium and phosphate homeostasis.
774    SECTION VII  Endocrine Drugs

A 1,25(OH)2D Bone
Gut
+ +

Ca2+
in blood

+ 1,25(OH)2D
–

Thyroid PTH + – FGF23

1,25(OH)2D

–
Kidney
PTH

Calcitonin 25(OH)D
Parathyroids

B Monocyte
Stem cells

+ +
Preosteoclast PTH
1,25(OH)2D Preosteoblasts
+ +

Osteoclast Osteoblasts

RANKL +
MCSF + Osteoid
OPG –
–
Calcified
Bisphosphonates bone
Calcitonin
Estrogen

FIGURE 42–2  The hormonal interactions controlling bone mineral homeostasis. In the body (A), 1,25-dihydroxyvitamin D (1,25[OH]2D)
is produced by the kidney under the control of parathyroid hormone (PTH), which stimulates its production, and fibroblast growth factor 23
(FGF23), which inhibits its production. 1,25(OH)2D in turn inhibits the production of PTH by the parathyroid glands and stimulates FGF23 release
from bone. 1,25(OH)2D is the principal regulator of intestinal calcium and phosphate absorption. At the level of the bone (B), both PTH and
1,25(OH)2D regulate bone formation and resorption, with each capable of stimulating both processes. This is accomplished by their stimulation
of preosteoblast proliferation and differentiation into osteoblasts, the bone-forming cell. PTH also stimulates osteoblast formation indirectly
by inhibiting the osteocyte’s production of sclerostin, a protein that blocks osteoblast proliferation by inhibiting the wnt pathway (not shown).
PTH and 1,25(OH)2D stimulate the expression of RANKL by the osteoblast, which, with MCSF, stimulates the differentiation and subsequent
activation of osteoclasts, the bone-resorbing cell. OPG blocks RANKL action, and may be inhibited by PTH and 1,25(OH)2D. FGF23 in excess leads
to osteomalacia indirectly by inhibiting 1,25(OH)2D production and lowering phosphate levels. MCSF, macrophage colony-stimulating factor;
OPG, osteoprotegerin; RANKL, ligand for receptor for activation of nuclear factor-κB.

PRINCIPAL HORMONAL Within the gland is a calcium-sensitive protease capable of cleav-

REGULATORS OF BONE MINERAL
HOMEOSTASIS
PARATHYROID HORMONE
Parathyroid hormone (PTH) is a single-chain peptide hormone
composed of 84 amino acids. It is produced in the parathyroid
gland in a precursor form of 115 amino acids, the excess 31
amino terminal amino acids being cleaved off before secretion.
ing the intact hormone into fragments, thereby providing one
mechanism by which calcium limits the production of PTH. A
second mechanism involves the calcium-sensing receptor (CaSR)
which, when stimulated by calcium, reduces PTH production
and secretion. The parathyroid gland also contains the vitamin
D receptor (VDR) and the enzyme, CYP27B1, that produces
1,25(OH)2D, thus enabling circulating or endogenously pro-
duced 1,25(OH)2D to suppress PTH production. 1,25(OH)2D
also induces the CaSR, making the parathyroid gland more sensi-
tive to suppression by calcium. Biologic activity resides in the
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     775
amino terminal region of PTH such that synthetic PTH 1-34
(available as teriparatide) is fully active. However, a full length
form of PTH (rhPTH 1-84, Natpara) has recently been approved
for treatment of hypoparathyroidism, as has an analog of PTHrP
(abaloparatide). Loss of the first two amino terminal amino acids
eliminates most biologic activity.
The metabolic clearance of intact PTH is rapid, with a
half-time of disappearance measured in minutes. Most of the
clearance occurs in the liver and kidney. The inactive carboxyl
terminal fragments produced by metabolism of the intact hor-
mone have a much lower clearance, especially in renal failure. In
the past, this accounted for the very high PTH values observed
in patients with renal failure when the hormone was measured
by radioimmunoassays directed against the carboxyl terminal
region. Currently, most PTH assays differentiate between intact
PTH 1-34 and large inactive fragments, so that it is possible
to more accurately evaluate biologically active PTH status in
patients with renal failure.
PTH regulates calcium and phosphate flux across cellular
membranes in bone and kidney, resulting in increased serum
calcium and decreased serum phosphate (Figure 42–1). In bone,
PTH increases the activity and number of osteoclasts, the cells
responsible for bone resorption (Figure 42–2). However, this
stimulation of osteoclasts is not a direct effect. Rather, PTH acts
on the osteoblast (the bone-forming cell) to induce membrane-
bound and secreted soluble forms of a protein called RANK
ligand (RANKL). RANKL acts on osteoclasts and osteoclast pre-
cursors to increase both the numbers and activity of osteoclasts.
This action increases bone remodeling, a specific sequence of
cellular events initiated by osteoclastic bone resorption and fol-
lowed by osteoblastic bone formation. Denosumab, an antibody
that inhibits the action of RANKL, has been developed for the
treatment of excess bone resorption in patients with osteoporosis
and certain cancers. PTH also inhibits the production and secre-
tion of sclerostin from osteocytes. Sclerostin is one of several
proteins that blocks osteoblast proliferation by inhibiting the
wnt pathway. Antibodies against sclerostin (eg, romosozumab)
are in clinical trials for the treatment of osteoporosis. Thus, PTH
directly and indirectly increases proliferation of osteoblasts, the
cells responsible for bone formation. Although both bone resorp-
tion and bone formation are enhanced by PTH, the net effect of
excess endogenous PTH is to increase bone resorption. However,
administration of exogenous PTH in low and intermittent doses
increases bone formation without first stimulating bone resorp-
tion. This net anabolic action may be indirect, involving other
growth factors such as insulin-like growth factor 1 (IGF1) as well
as inhibition of sclerostin as noted above. These anabolic actions
have led to the approval of recombinant PTH 1-34 (teriparatide
and abaloparatide) for the treatment of osteoporosis. In the
kidney, PTH stimulates 1,25(OH)2D production, and increases
tubular reabsorption of calcium and magnesium, but reduces
reabsorption of phosphate, amino acids, bicarbonate, sodium,
chloride, and sulfate. As mentioned earlier, full-length PTH
(rhPTH 1-84) has been approved in part for these renal effects,
which otherwise limit standard calcium and calcitriol treatment
of hypoparathyroidism.
VITAMIN D
Vitamin D is a secosteroid produced in the skin from 7-dehydro-
cholesterol under the influence of ultraviolet radiation. Vitamin
D is also found in certain foods and is used to supplement dairy
products and other foods. Both the natural form (vitamin D3,
cholecalciferol) and the plant-derived form (vitamin D2, ergocal-
ciferol) are present in the diet. As discussed earlier these forms dif-
fer in that ergocalciferol contains a double bond and an additional
methyl group in the side chain (Figure 42–3). Ergocalciferol and
its metabolites bind less well than cholecalciferol and its metabo-
lites to vitamin D–binding protein (DBP), the major transport
protein of these compounds in blood, and have a somewhat dif-
ferent path of catabolism. As a result their half-lives are shorter
than those of the cholecalciferol metabolites. This influences
treatment strategies, as will be discussed. However, the key steps
in metabolism and biologic activities of the active metabolites are
comparable, so with this exception the following comments apply
equally well to both forms of vitamin D.
Vitamin D is a precursor to a number of biologically active
metabolites (Figure 42–3). Vitamin D is first hydroxylated in the
liver and other tissues to form 25(OH)D, (calcifediol). As noted
earlier there are a number of enzymes with 25-hydroxylase activity.
This metabolite is further converted in the kidney to a number of
other forms, the best studied of which are 1,25(OH)2D (calcitriol)
and 24,25-dihydroxyvitamin D (secalciferol, 24,25[OH]2D), by
the enzymes CYP27B1 and CYP24A1, respectively. The regula-
tion of vitamin D metabolism is complex, involving calcium,
phosphate, and a variety of hormones, the most important of
which are PTH, which stimulates, and FGF23, which inhibits
the production of 1,25(OH)2D by the kidney while recipro-
cally inhibiting or promoting the production of 24,25(OH)2D.
The importance of CYP24A1, the enzyme that 24-hydroxylates
25(OH)D and 1,25(OH)2D, is well demonstrated in chil-
dren lacking this enzyme who have high levels of calcium and
1,25(OH)2D resulting in kidney damage from nephrocalcinosis
and stones. Of the natural metabolites, vitamin D, 25(OH)D
(calcifediol) and 1,25(OH)2D (as calcitriol) are available for
clinical use (Table 42–1). A number of analogs of 1,25(OH)2D
have been synthesized to extend the usefulness of this metabolite
to a variety of nonclassic conditions. Calcipotriene (calcipotriol),
for example, is being used to treat psoriasis, a hyperproliferative
skin disorder (see Chapter 61). Doxercalciferol and paricalcitol
are approved for the treatment of secondary hyperparathyroidism
in patients with chronic kidney disease. Eldecalcitol is approved
in Japan for the treatment of osteoporosis. Other analogs are being
investigated for the treatment of various malignancies.
Vitamin D and its metabolites circulate in plasma tightly bound
to the DBP. This α-globulin binds 25(OH)D and 24,25(OH)2D
with comparable high affinity and vitamin D and 1,25(OH)2D
with lower affinity. There is increasing evidence that it is the free
or unbound forms of these metabolites that have biologic activity.
This is of clinical importance because patients with liver disease
or nephrotic syndrome have lower levels of DBP, whereas DBP
levels are increased with estrogen therapy and during the later
stages of pregnancy. Furthermore, there are several different forms
776    SECTION VII  Endocrine Drugs

21 22 26
24
20 23 25
18 27
19 12 17
11 13 16
CH3 14 15 CH3
1 9 1
2 10 8
Ultraviolet 2 10 Heat
3 5 67 3 5
4
HO HO 4

CH2

7-Dehydrocholesterol Pre D3 D3 (cholecalciferol)

HO

O
H O
H

+ P + Ca
+ 1,25(OH)2D
− PTH CH2
O + FGF23
H
HO
Liver Kidney
CH2 24,25 (OH)2D3 (secalciferol)

− P − Ca
HO CH2 + PTH
− FGF23
D3
HO O
H
25 (OH)D3
28
CH3

22 26 CH2
21
24
20 23 25 HO OH
27
1,25 (OH)2D3 (calcitriol)

FIGURE 42–3  Conversion of 7-dehydrocholesterol to vitamin D3 in the skin and its subsequent metabolism to 25-hydroxyvitamin D3
(25[OH]D3) in the liver and to 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) and 24,25-dihydroxyvitamin D3 (24,25[OH]2D3) in the kidney. Control of
vitamin D metabolism is exerted primarily at the level of the kidney, where high concentrations of serum phosphorus (P) and calcium (Ca) as
well as fibroblast growth factor 23 (FGF23) inhibit production of 1,25(OH)2D3 (indicated by a minus [−] sign), but promote that of 24,25(OH)2D3
(indicated by a plus [+] sign). Parathyroid hormone (PTH), on the other hand, stimulates 1,25(OH)2D3 production but inhibits 24,25(OH)2D3
production. The insert (shaded) shows the side chain for ergosterol, vitamin D2, and the active vitamin D2 metabolites. Ergosterol is converted to
vitamin D2 (ergocalciferol) by UV radiation similar to the conversion of 7-dehydrocholesterol to vitamin D3. Vitamin D2, in turn, is metabolized to
25-hydroxyvitamin D2, 1,25-dihydroxyvitamin D2, and 24,25-dihydroxyvitamin D2 via the same enzymes that metabolize vitamin D3. In humans,
corresponding D2 and D3 metabolites have equivalent biologic effects, although they differ in pharmacokinetics. +, facilitation; –, inhibition; P,
phosphorus; Ca, calcium; PTH, parathyroid hormone; FGF23, fibroblast growth factor 23.

of DBP in the population with different affinities for the vitamin
D metabolites, and, as noted earlier, the affinity of DBP for the
D2 metabolites is less than that for the D3 metabolites. Thus
individuals can vary with respect to the fraction of free metabolite
available, so that measuring only the total metabolite concentra-
tion may be misleading with respect to assessing vitamin D status.
In normal subjects, the terminal half-life of injected calcifediol
(25[OH]D) is around 23 days, whereas in anephric subjects it is
around 42 days. The half-life of 24,25(OH)2D is probably similar.
Tracer studies with vitamin D have shown a rapid clearance from
the blood. The liver appears to be the principal organ for clear-
ance. Excess vitamin D is stored in adipose tissue. The metabolic
clearance of calcitriol (1,25[OH]2D) in humans likewise indicates
a rapid turnover, with a terminal half-life measured in hours.
Several of the 1,25(OH)2D analogs are bound poorly by DBP.
As a result, their clearance is very rapid, with a terminal half-life
of minutes. Such analogs have less hypercalcemic, hypercalciuric
effects than calcitriol, an important aspect of their use in the man-
agement of conditions such as psoriasis and hyperparathyroidism.
The mechanism of action of the vitamin D metabolites
remains under active investigation. However, 1,25(OH)2D is well
established as the most potent stimulant of intestinal calcium
and phosphate transport and bone resorption. 1,25(OH)2D
appears to act on the intestine both by induction of new protein
synthesis (eg, calcium-binding protein and TRPV6, an intestinal
calcium channel) and by modulation of calcium flux across the
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     777
TABLE 42–1  Vitamin D and its major metabolites
and analogs.
Chemical and Generic Names Abbreviation
Vitamin D3; cholecalciferol D3
Vitamin D2; ergocalciferol D2
25-Hydroxyvitamin D3; calcifediol 25(OH)D3
1,25-Dihydroxyvitamin D3; calcitriol 1,25(OH)2D3
24,25-Dihydroxyvitamin D3; secalciferol 24,25(OH)2D3
Dihydrotachysterol DHT
Calcipotriene (calcipotriol) None
1α-Hydroxyvitamin D2; doxercalciferol 1α(OH)D2
19-nor-1,25-Dihydroxyvitamin D2; paricalcitol 19-nor-1,25(OH)D2
brush border and basolateral membranes by processes that do
not all require new protein synthesis. The molecular action of
1,25(OH)2D on bone is more complex and controversial as it is
both direct and indirect. Much of the skeletal effect is attributed
to the provision of adequate calcium and phosphate from the
diet by stimulation of their intestinal absorption. However,
like PTH, 1,25(OH)2D can induce RANKL in osteoblasts to
regulate osteoclast activity and proteins such as osteocalcin and
alkaline phosphatase, which may regulate the mineralization pro-
cess by osteoblasts. The metabolites 25(OH)D and 24,25(OH)2D
are far less potent stimulators of intestinal calcium and phosphate
transport or bone resorption.
Specific receptors for 1,25(OH)2D (VDR) exist in nearly all
tissues, not just intestine, bone, and kidney. As a result much
effort has been made to develop analogs of 1,25(OH)2D that will
target these non-classic target tissues without increasing serum
calcium. These non-classic actions include regulation of the secre-
tion of PTH, insulin, and renin; regulation of innate and adaptive
immune function through actions on dendritic cell and T-cell
differentiation; enhanced muscle function; and proliferation and
differentiation of a number of cancer cells. Thus, the potential
clinical utility of 1,25(OH)2D and its analogs is expanding.
FIBROBLAST GROWTH FACTOR 23
Fibroblast growth factor 23 (FGF23) is a single-chain protein with
251 amino acids, including a 24-amino-acid leader sequence. It
inhibits 1,25(OH)2D production and phosphate reabsorption
(via the sodium phosphate co-transporters NaPi 2a and 2c) in the
kidney and can lead to both hypophosphatemia and inappropri-
ately low levels of circulating 1,25(OH)2D. Whereas FGF23 was
originally identified in certain mesenchymal tumors, osteoblasts
and osteocytes in bone appear to be its primary site of production.
Other tissues can also produce FGF23, though at lower levels.
FGF23 requires O-glycosylation for its secretion, a glycosylation
mediated by the glycosyl transferase GALNT3. Mutations in
GALNT3 result in abnormal deposition of calcium phosphate in
periarticular tissues (tumoral calcinosis) with elevated phosphate
and 1,25(OH)2D. FGF23 is normally inactivated by cleavage at
an RXXR site (amino acids 176–179). Mutations in this site lead
to excess FGF23, the underlying problem in autosomal dominant
hypophosphatemic rickets. A similar disease, X-linked hypophos-
phatemic rickets, is due to mutations in PHEX, an endopeptidase,
which initially was thought to cleave FGF23. However, this concept
has been shown to be invalid, and the mechanism by which PHEX
mutations lead to increased FGF23 levels remains obscure. FGF23
binds to FGF receptors (FGFR) 1 and 3c in the presence of the
accessory receptor Klotho-α. Both Klotho and the FGFR must
be present for signaling in most tissues, although high levels of
FGF23 appear to affect cardiomyocytes lacking Klotho. Mutations
in Klotho disrupt FGF23 signaling, resulting in elevated phosphate
and 1,25(OH)2D levels, a phenotype quite similar to inactivating
mutations in FGF23 or GALNT3. FGF23 production is stimulated
by 1,25(OH)2D and phosphate and directly or indirectly inhibited
by the dentin matrix protein DMP1 found in osteocytes. Mutations
in DMP1 lead to increased FGF23 levels and osteomalacia.
INTERACTION OF PTH, FGF23, &
VITAMIN D
A summary of the principal actions of PTH, FGF23, and vitamin
D on the three main target tissues—intestine, kidney, and bone—
is presented in Table 42–2. The net effect of PTH is to raise
serum calcium and reduce serum phosphate; the net effect of
FGF23 is to decrease serum phosphate; the net effect of vitamin D
is to raise both. Regulation of calcium and phosphate homeostasis
is achieved through important feedback loops. Calcium is one
of two principal regulators of PTH secretion. It binds to a novel
ion recognition site that is part of a Gq protein–coupled recep-
tor called the calcium-sensing receptor (CaSR) that employs the
phosphoinositide second messenger system to link changes in the
extracellular calcium concentration to changes in the intracellular
free calcium. As serum calcium levels rise and activate this recep-
tor, intracellular calcium levels increase and inhibit PTH secretion.
This inhibition by calcium of PTH secretion, along with inhibi-
tion of renin and atrial natriuretic peptide secretion, is the opposite
of the effect in other tissues such as the beta cell of the pancreas,
in which calcium stimulates secretion. Phosphate regulates PTH
secretion directly and indirectly. Its indirect actions are the result
of forming complexes with calcium in the serum. Because it is the
ionized free concentration of extracellular calcium that is detected
by the parathyroid gland, increases in serum phosphate levels
reduce the ionized calcium levels, leading to enhanced PTH secre-
tion. Whether the parathyroid gland expresses phosphate receptors
that mediate the direct action of phosphate on PTH secretion
remains unclear. Such feedback regulation is appropriate to the net
effect of PTH to raise serum calcium and reduce serum phosphate
levels. Likewise, both calcium and phosphate at high levels reduce
the amount of 1,25(OH)2D produced by the kidney and increase
the amount of 24,25(OH)2D produced.
High serum calcium works directly and indirectly by reducing
PTH secretion. High serum phosphate works directly and indirectly
by increasing FGF23 levels. Since 1,25(OH)2D raises serum calcium
and phosphate, whereas 24,25(OH)2D has less effect, such feedback
778    SECTION VII  Endocrine Drugs
TABLE 42–2  Actions of parathyroid hormone (PTH), vitamin D, and FGF23 on gut, bone, and kidney.
PTH
Intestine Increased calcium and phosphate
absorption (by increased 1,25[OH]2D
production)
Kidney Decreased calcium excretion,
increased phosphate excretion,
stimulation of 1,25(OH)2D production
Bone Calcium and phosphate resorption
increased by high doses. Low doses
increase bone formation.
Net effect on Serum calcium increased, serum
serum levels phosphate decreased
1
Direct effect. Vitamin D also indirectly increases urine calcium owing to increased calcium absorption from the intestine and decreased PTH.
regulation is again appropriate. 1,25(OH)2D directly inhibits PTH
secretion (independent of its effect on serum calcium) by a direct
inhibitory effect on PTH gene transcription. The parathyroid gland
expresses both the VDR and CYP27B1, so that endogenous pro-
duction of 1,25(OH)2D within the parathyroid gland may be more
important for the regulation of PTH secretion than serum levels of
1,25(OH)2D. This provides yet another negative feedback loop. In
patients with chronic renal failure who frequently are deficient in
producing 1,25(OH)2D due in part to elevated FGF23 levels, loss
of this 1,25(OH)2D-mediated feedback loop coupled with impaired
phosphate excretion and intestinal calcium absorption leads to sec-
ondary hyperparathyroidism. The ability of 1,25(OH)2D to inhibit
PTH secretion directly is being exploited with calcitriol analogs
that have less effect on serum calcium because of their lesser effect
on intestinal calcium absorption. Such drugs are proving useful in
the management of secondary hyperparathyroidism accompany-
ing chronic kidney disease and may be useful in selected cases of
primary hyperparathyroidism. 1,25(OH)2D also stimulates the
production of FGF23. This completes the negative feedback loop
in that FGF23 inhibits 1,25(OH)2D production while promoting
hypophosphatemia, which in turn inhibits FGF23 production and
stimulates 1,25(OH)2D production. However, the rise in FGF23 in
the early stages of renal failure remains unexplained and is not due
to increases in either 1,25OH)2D or phosphate, and appears not
to be under the same feedback control as operates under normal
physiologic conditions.
SECONDARY HORMONAL
REGULATORS OF BONE MINERAL
HOMEOSTASIS
A number of hormones modulate the actions of PTH, FGF23,
and vitamin D in regulating bone mineral homeostasis. Com-
pared with that of PTH, FGF23, and vitamin D, the physiologic
impact of such secondary regulation on bone mineral homeostasis
is minor. However, in pharmacologic amounts, several of these
hormones, including calcitonin, glucocorticoids, and estrogens,
have actions on bone mineral homeostatic mechanisms that can
be exploited therapeutically.
Vitamin D FGF23
Increased calcium and phosphate Decreased calcium and phosphate
absorption by 1,25(OH)2D absorption by decreased 1,25(OH)2
production
Calcium and phosphate excretion may be Increased phosphate excretion, decreased
decreased by 25(OH)D and 1,25(OH)2D1 1,25(OH)2D production
Increased calcium and phosphate Decreased mineralization due to
resorption by 1,25(OH)2D; bone formation hypophosphatemia and low 1,25(OH)2D
may be increased by 1,25(OH)2D levels.
Serum calcium and phosphate both Decreased serum phosphate
increased
CALCITONIN
The calcitonin secreted by the parafollicular cells of the mam-
malian thyroid is a single-chain peptide hormone with 32
amino acids and a molecular weight of 3600. A disulfide bond
between positions 1 and 7 is essential for biologic activity. Cal-
citonin is produced from a precursor with a molecular weight
of 15,000. The circulating forms of calcitonin are multiple,
ranging in size from the monomer (molecular weight 3600) to
forms with an apparent molecular weight of 60,000. Whether
such heterogeneity includes precursor forms or covalently
linked oligomers is not known. Because of its chemical hetero-
geneity, calcitonin preparations are standardized by bioassay
in rats. Activity is compared to a standard maintained by the
British Medical Research Council (MRC) and expressed as
MRC units.
Human calcitonin monomer has a half-life of about 10 min-
utes. Salmon calcitonin has a longer half-life of 40–50 minutes,
making it more attractive as a therapeutic agent. Much of the
clearance occurs in the kidney by metabolism; little intact calcito-
nin appears in the urine.
The principal effects of calcitonin are to lower serum calcium and
phosphate by actions on bone and kidney. Calcitonin inhibits osteo-
clastic bone resorption. Although bone formation is not impaired at
first after calcitonin administration, with time both formation and
resorption of bone are reduced. In the kidney, calcitonin reduces
both calcium and phosphate reabsorption as well as reabsorption of
other ions, including sodium, potassium, and magnesium. Tissues
other than bone and kidney are also affected by calcitonin. Calcitonin
in pharmacologic amounts decreases gastrin secretion and reduces
gastric acid output while increasing secretion of sodium, potassium,
chloride, and water in the gut. Pentagastrin is a potent stimulator
of calcitonin secretion (as is hypercalcemia), suggesting a possible
physiologic relationship between gastrin and calcitonin. In the adult
human, no readily demonstrable problem develops in cases of calcito-
nin deficiency (thyroidectomy) or excess (medullary carcinoma of the
thyroid). However, the ability of calcitonin to block bone resorption
and lower serum calcium makes it a useful drug for the treatment of
Paget’s disease, hypercalcemia, and osteoporosis, albeit a less effica-
cious drug than other available agents.
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     779
GLUCOCORTICOIDS
Glucocorticoid hormones alter bone mineral homeostasis by
antagonizing vitamin D–stimulated intestinal calcium transport,
stimulating renal calcium excretion, blocking bone formation,
and at least initially stimulating bone resorption. Although these
observations underscore the negative impact of glucocorticoids
on bone mineral homeostasis, these hormones have proved useful
in reversing the hypercalcemia associated with lymphomas and
granulomatous diseases such as sarcoidosis (in which unregulated
ectopic production of 1,25[OH]2D occurs) or in cases of vitamin
D intoxication. Prolonged administration of glucocorticoids is a
common cause of osteoporosis in adults and can cause stunted
skeletal development in children (see Chapter 39).
ESTROGENS
Estrogens can prevent accelerated bone loss during the immediate
postmenopausal period and at least transiently increase bone in
postmenopausal women.
The prevailing hypothesis advanced to explain these observa-
tions is that estrogens reduce the bone-resorbing action of PTH.
Estrogen administration leads to an increased 1,25(OH)2D level in
blood, but estrogens have no direct effect on 1,25(OH)2D produc-
tion in vitro. The increased 1,25(OH)2D levels in vivo following
estrogen treatment may result from decreased serum calcium and
phosphate and increased PTH. However, estrogens also increase
DBP production by the liver, which increases the total concentra-
tions of the vitamin D metabolites in circulation without necessar-
ily increasing the free levels. Estrogen receptors have been found
in bone, and estrogen has direct effects on bone remodeling. Case
reports of men who lack the estrogen receptor or who are unable
to produce estrogen because of aromatase deficiency noted marked
osteopenia and failure to close epiphyses. This further substantiates
the role of estrogen in bone development, even in men. The princi-
pal therapeutic application for estrogen administration in disorders
of bone mineral homeostasis is the treatment or prevention of
postmenopausal osteoporosis. However, long-term use of estrogen
has fallen out of favor due to concern about adverse effects. Selec-
tive estrogen receptor modulators (SERMs) have been developed to
retain the beneficial effects on bone while minimizing deleterious
effects on breast, uterus, and the cardiovascular system (see Box:
Newer Therapies for Osteoporosis and Chapter 40).
NONHORMONAL AGENTS
AFFECTING BONE MINERAL
HOMEOSTASIS
BISPHOSPHONATES
The bisphosphonates are analogs of pyrophosphate in which the
P-O-P bond has been replaced with a nonhydrolyzable P-C-P
bond (Figure 42–4). Currently available bisphosphonates include
etidronate, pamidronate, alendronate, risedronate, tiludronate,
OH OH
O P O P O Inorganic pyrophosphoric acid
OH OH
OH OH OH
O P C P O
Etidronate: ethane-1-hydroxy-1,
1-bisphosphonate
OH CH3 OH
OH OH OH
Pamidronate: 3-Amino-1-hydroxy-
O P C P O
propylidene bisphosphonate
OH CH2 OH
CH2 NH2
OH OH OH
Alendronate: 4-Amino-1-hydroxy-butylidene
O P C P O
bisphosphonate
OH CH2 OH
CH2 CH2 NH2
FIGURE 42–4  The structure of pyrophosphate and of the
first three bisphosphonates—etidronate, pamidronate, and
alendronate—that were approved for use in the United States.
ibandronate, and zoledronate. With the development of the more
potent bisphosphonates, etidronate is seldom used.
Results from animal and clinical studies indicate that less than
10% of an oral dose of these drugs is absorbed. Food reduces
absorption even further, necessitating their administration on
an empty stomach. A major adverse effect of oral forms of the
bisphosphonates (risedronate, alendronate, ibandronate) is esoph-
ageal and gastric irritation, which limits the use of this route by
patients with upper gastrointestinal disorders. This complication
can be circumvented with infusions of pamidronate, zoledronate,
and ibandronate. Intravenous dosing also allows a larger amount
of drug to enter the body and markedly reduces the frequency of
administration (eg, zoledronate is infused once per year). Nearly
half of the absorbed drug accumulates in bone; the remainder
is excreted unchanged in the urine. Decreased renal function
dictates a reduction in dosage. The portion of drug retained in
bone depends on the rate of bone turnover; drug in bone often is
retained for months to years.
The bisphosphonates exert multiple effects on bone mineral
homeostasis, which make them useful for the treatment of hyper-
calcemia associated with malignancy, for Paget’s disease, and for
osteoporosis (see Box: Newer Therapies for Osteoporosis). They
owe at least part of their clinical usefulness and toxicity to their
ability to retard formation and dissolution of hydroxyapatite
crystals within and outside the skeletal system. Some of the newer
bisphosphonates appear to increase bone mineral density well
beyond the 2-year period predicted for a drug whose effects are
limited to slowing bone resorption. This may be due to their
other cellular effects, which include inhibition of 1,25(OH)2D
production, inhibition of intestinal calcium transport, metabolic
780    SECTION VII  Endocrine Drugs
Newer Therapies for Osteoporosis
Bone undergoes a continuous remodeling process involving
resorption and formation. Any process that disrupts this bal-
ance by increasing bone resorption relative to formation results
in osteoporosis. Inadequate gonadal hormone production is
a major cause of osteoporosis in men and women. Estrogen
replacement therapy at menopause is a well-established means
of preventing osteoporosis in the female, but many women
fear its adverse effects, particularly the increased risk of breast
cancer from continued estrogen use (the well-demonstrated
increased risk of endometrial cancer is prevented by combining
the estrogen with a progestin) and do not like the persistence
of menstrual bleeding that often accompanies this form of
therapy. Medical enthusiasm for this treatment has waned with
the demonstration that it does not protect against and may
increase the risk of heart disease. Raloxifene was the first of the
selective estrogen receptor modulators (SERMs; see Chapter 40)
to be approved for the prevention of osteoporosis. Raloxifene
shares some of the beneficial effects of estrogen on bone with-
out increasing the risk of breast or endometrial cancer (it may
actually reduce the risk of breast cancer). Although not as effec-
tive as estrogen in increasing bone density, raloxifene has been
shown to reduce vertebral fractures.
Nonhormonal forms of therapy for osteoporosis have
been developed with proven efficacy in reducing fracture risk.
Bisphosphonates such as alendronate, risedronate, ibandronate,
and zoledronate have been conclusively shown to increase
bone density and reduce fractures over at least 5 years when
used continuously at a dosage of 10 mg/d or 70 mg/week for
alendronate; 5 mg/d or 35 mg/week for risedronate; 2.5 mg/d or
150 mg/month for ibandronate; and 5 mg annually for intrave-
nous zoledronate. Side-by-side trials between alendronate and
calcitonin (another approved nonestrogen drug for osteoporo-
sis) indicated a greater efficacy of alendronate. Bisphosphonates
are poorly absorbed and must be given on an empty stomach
changes in bone cells such as inhibition of glycolysis, inhibition of
cell growth, and changes in acid and alkaline phosphatase activity.
Amino bisphosphonates such as alendronate and risedronate
inhibit farnesyl pyrophosphate synthase, an enzyme in the mevalon-
ate pathway that appears to be critical for osteoclast survival. The cho-
lesterol-lowering statin drugs (eg, lovastatin), which block mevalonate
synthesis (see Chapter 35), stimulate bone formation, at least in ani-
mal studies. Thus, the mevalonate pathway appears to be important
in bone cell function and provides new targets for drug development.
The mevalonate pathway effects vary depending on the bisphospho-
nate used (only amino bisphosphonates have this property) and may
account for some of the clinical differences observed in the effects of
the various bisphosphonates on bone mineral homeostasis.
With the exception of the induction of a mineralization defect
by higher than approved doses of etidronate and gastric and
esophageal irritation by the oral bisphosphonates, these drugs
or infused intravenously. At the higher oral doses used in the
treatment of Paget’s disease, alendronate causes gastric irrita-
tion, but this is not a significant problem at the doses recom-
mended for osteoporosis when patients are instructed to take
the drug with a glass of water and remain upright. Denosumab
is a human monoclonal antibody directed against RANKL, and
it is very effective in inhibiting osteoclastogenesis and activity.
Denosumab is given in 60-mg doses subcutaneously every 6
months. All of these drugs inhibit bone resorption with second-
ary effects to inhibit bone formation. On the other hand, teripa-
ratide, the recombinant form of PTH 1-34 and abaloparatide, an
analog of PTHrP, directly stimulate bone formation as well as
bone resorption. However, teriparatide and abaloparatide are
given daily by subcutaneous injection. Their efficacy in prevent-
ing fractures is at least as great as that of the bisphosphonates.
In all cases, adequate intake of calcium and vitamin D needs to
be maintained.
Furthermore, there are several other forms of therapy in devel-
opment. In Europe, strontium ranelate, a drug that appears to
stimulate bone formation and inhibit bone resorption, has been
used for several years with favorable results in large clinical tri-
als; approval for use in the United States is expected. Additional
promising new treatments undergoing clinical trials include
antibodies against sclerostin. Romosozumab, for example,
is showing promising results in phase 3 trials by stimulating
bone formation and at least initially inhibiting bone resorption.
Phase 3 trials with odanacatib, an inhibitor of cathepsin K, an
enzyme in osteoclasts that facilitates bone resorption, showed
efficacy with respect to fracture reduction. However, this drug
also showed an unexpected increase in strokes, and it will
not be further developed. In Japan, eldecalcitol, an analog of
1,25(OH)2D, has been approved for the treatment of osteoporo-
sis with minimal effects on serum calcium. It is not yet available
in the United States.
have proved to be remarkably free of adverse effects when used
at the doses recommended for the treatment of osteoporosis.
Esophageal irritation can be minimized by taking the drug with
a full glass of water and remaining upright for 30 minutes or by
using the intravenous forms of these compounds. The initial infu-
sion of zoledronate is commonly associated with several days of a
flu-like syndrome that generally does not recur with subsequent
infusions. Of other complications, osteonecrosis of the jaw has
received considerable attention but is rare in patients receiving
usual doses of bisphosphonates (perhaps 1/100,000 patient-years).
This complication is more frequent when high intravenous doses
of zoledronate are used to control bone metastases and cancer-
induced hypercalcemia. More recently, concern has been raised
about over-suppressing bone turnover. This may underlie the
occurrence of subtrochanteric femur fractures in patients on long-
term bisphosphonate treatment. This complication appears to be
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     781
rare, comparable to that of osteonecrosis of the jaw, but has led
some authorities to recommend a “drug holiday” after 5 years of
treatment if the clinical condition warrants it (ie, if the fracture
risk of discontinuing the bisphosphonate is not deemed high).
DENOSUMAB
Denosumab is a fully humanized monoclonal antibody that
binds to and prevents the action of RANKL. As described earlier,
RANKL is produced by osteoblasts and other cells, including
T lymphocytes. It stimulates osteoclastogenesis via RANK, the
receptor for RANKL that is present on osteoclasts and osteoclast
precursors. By interfering with RANKL function, denosumab
inhibits osteoclast formation and activity. It is at least as effective
as the potent bisphosphonates in inhibiting bone resorption and
has been approved for treatment of postmenopausal osteoporosis
and some cancers (prostate and breast). The latter application is
to limit the development of bone metastases or bone loss resulting
from the use of drugs that suppress gonadal function. Denosumab
is administered subcutaneously every 6 months. The drug appears
to be well tolerated, but three concerns remain. First, a number of
cells in the immune system also express RANKL, suggesting that
there could be an increased risk of infection associated with the use
of denosumab. Second, because the suppression of bone turnover
with denosumab is similar to that of the potent bisphosphonates,
the potential risk of osteonecrosis of the jaw and subtrochanteric
fractures is comparable. Third, denosumab can lead to transient
hypocalcemia, especially in patients with marked bone loss (and
bone hunger) or compromised calcium regulatory mechanisms,
including chronic kidney disease and vitamin D deficiency. That
said, denosumab can be used in patients with advanced renal dis-
ease, unlike the bisphosphonates, as it is not cleared by the kidney,
and it has the advantage over bisphosphonates in that it is readily
reversible because it does not deposit in bone.
CALCIMIMETICS
Cinacalcet is the first representative of a new class of drugs that
activates the calcium-sensing receptor (CaSR) described above.
CaSR is widely distributed but has its greatest concentration in
the parathyroid gland. By activating the parathyroid gland CaSR,
cinacalcet inhibits PTH secretion. Cinacalcet is approved for the
treatment of secondary hyperparathyroidism in chronic kidney
disease and for the treatment of parathyroid carcinoma. CaSR
antagonists are also being developed, and may be useful in condi-
tions of hypoparathyroidism or as a means to stimulate intermit-
tent PTH secretion in the treatment of osteoporosis.
THIAZIDE DIURETICS
The chemistry and pharmacology of the thiazide family of
drugs are discussed in Chapter 15. The principal application
of thiazides in the treatment of bone mineral disorders is in
reducing renal calcium excretion. Thiazides may increase the
effectiveness of PTH in stimulating reabsorption of calcium by
the renal tubules or may act on calcium reabsorption secondarily
by increasing sodium reabsorption in the proximal tubule. In
the distal tubule, thiazides block sodium reabsorption at the
luminal surface, increasing the calcium-sodium exchange at the
basolateral membrane and thus enhancing calcium reabsorption
into the blood at this site (see Figure 15–4). Thiazides have
proved to be useful in reducing the hypercalciuria and incidence
of urinary stone formation in subjects with idiopathic hypercal-
ciuria. Part of their efficacy in reducing stone formation may lie
in their ability to decrease urine oxalate excretion and increase
urine magnesium and zinc levels, both of which inhibit calcium
oxalate stone formation.
FLUORIDE
Fluoride is well established as effective for the prophylaxis of den-
tal caries and has previously been investigated for the treatment of
osteoporosis. Both therapeutic applications originated from epide-
miologic observations that subjects living in areas with naturally
fluoridated water (1–2 ppm) had fewer dental caries and fewer
vertebral compression fractures than subjects living in nonfluori-
dated water areas. Fluoride accumulates in bones and teeth, where
it may stabilize the hydroxyapatite crystal. Such a mechanism may
explain the effectiveness of fluoride in increasing the resistance of
teeth to dental caries, but it does not explain its ability to promote
new bone growth.
Fluoride in drinking water appears to be most effective in
preventing dental caries if consumed before the eruption of the
permanent teeth. The optimum concentration in drinking water
supplies is 0.5–1 ppm. Topical application is most effective if done
just as the teeth erupt. There is little further benefit to giving fluo-
ride after the permanent teeth are fully formed. Excess fluoride in
drinking water leads to mottling of the enamel proportionate to
the concentration above 1 ppm.
Fluoride has also been evaluated for the treatment of osteo-
porosis. Results of earlier studies indicated that fluoride alone,
without adequate calcium supplementation, produced osteoma-
lacia. Subsequent studies in which calcium supplementation has
been adequate demonstrated an improvement in calcium balance,
an increase in bone mineral, and an increase in trabecular bone
volume. Despite these promising effects of fluoride on bone mass,
clinical studies have failed to demonstrate a reliable reduction in
fractures, and some studies showed an increase in fracture rate.
At present, fluoride is not approved by the U.S. Food and Drug
Administration (FDA) for treatment or prevention of osteoporo-
sis, and it is unlikely to be.
Adverse effects observed—at the higher doses used for test-
ing fluoride’s effect on bone—include nausea and vomiting,
gastrointestinal blood loss, arthralgias, and arthritis in a
substantial proportion of patients. Such effects are usually
responsive to reduction of the dose or giving fluoride with
meals (or both).
782    SECTION VII  Endocrine Drugs
STRONTIUM RANELATE
Strontium ranelate is composed of two atoms of strontium bound
to an organic ion, ranelic acid. Although not yet approved for use
in the United States, this drug is used in Europe for the treatment
of osteoporosis. Strontium ranelate appears to block differentia-
tion of osteoclasts while promoting their apoptosis, thus inhibit-
ing bone resorption. At the same time, strontium ranelate appears
to promote bone formation. Unlike bisphosphonates, denosumab,
or teriparatide, this drug increases bone formation markers while
inhibiting bone resorption markers. Large clinical trials have
demonstrated its efficacy in increasing bone mineral density and
decreasing fractures in the spine and hip. Toxicities reported thus
far are similar to placebo.
■■ CLINICAL PHARMACOLOGY
Individuals with disorders of bone mineral homeostasis usually
present with abnormalities in serum or urine calcium levels (or
both), often accompanied by abnormal serum phosphate levels.
These abnormal mineral concentrations may themselves cause
symptoms requiring immediate treatment (eg, coma in malignant
hypercalcemia, tetany in hypocalcemia). More commonly, they
serve as clues to an underlying disorder in hormonal regula-
tors (eg, primary hyperparathyroidism), target tissue response
(eg, chronic kidney disease), or drug misuse (eg, vitamin D
intoxication). In such cases, treatment of the underlying disorder
is of prime importance.
Since bone and kidney play central roles in bone mineral
homeostasis, conditions that alter bone mineral homeostasis
usually affect one or both of these tissues secondarily. Effects
on bone can result in osteoporosis (abnormal loss of bone;
remaining bone histologically normal), osteomalacia (abnor-
mal bone formation due to inadequate mineralization), or
osteitis fibrosa (excessive bone resorption with fibrotic replace-
ment of resorption cavities and marrow). Biochemical markers
of skeletal involvement include changes in serum levels of the
skeletal isoenzyme of alkaline phosphatase, osteocalcin, and
N- and C-terminal propeptides of type I collagen (reflecting
osteoblastic activity), and serum and urine levels of tartrate-
resistant acid phosphatase and collagen breakdown products
(reflecting osteoclastic activity). The kidney becomes involved
when the calcium × phosphate product in serum rises above
the point at which ectopic calcification occurs (nephrocalci-
nosis) or when the calcium × oxalate (or phosphate) product
in urine exceeds saturation, leading to nephrolithiasis. Subtle
early indicators of such renal involvement include polyuria,
nocturia, and hyposthenuria. Radiologic evidence of neph-
rocalcinosis and stones is not generally observed until later.
The degree of the ensuing renal failure is best followed by
monitoring the decline in creatinine clearance. On the other
hand, chronic kidney disease can be a primary cause of bone
disease because of altered handling of calcium and phosphate,
decreased 1,25(OH)2D production, increased FGF23 levels,
and secondary hyperparathyroidism.
ABNORMAL SERUM CALCIUM &
PHOSPHATE LEVELS
HYPERCALCEMIA
Hypercalcemia causes central nervous system depression, including
coma, and is potentially lethal. Its major causes (other than thia-
zide therapy) are hyperparathyroidism and cancer, with or without
bone metastases. Less common causes are hypervitaminosis D,
sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insuf-
ficiency, and immobilization. With the possible exception of
hypervitaminosis D, the latter disorders seldom require emergency
lowering of serum calcium. A number of approaches are used to
manage the hypercalcemic crisis.
Saline Diuresis
In hypercalcemia of sufficient severity to produce symptoms, rapid
reduction of serum calcium is required. The first steps include
rehydration with saline and diuresis with furosemide, although the
efficacy of furosemide in this setting has not been proved. Most
patients presenting with severe hypercalcemia have a substantial
component of prerenal azotemia owing to dehydration, which pre-
vents the kidney from compensating for the rise in serum calcium
by excreting more calcium in the urine. Therefore, the initial infu-
sion of 500–1000 mL/h of saline to reverse the dehydration and
restore urine flow can by itself substantially lower serum calcium.
The addition of a loop diuretic such as furosemide following rehy-
dration enhances urine flow and also inhibits calcium reabsorp-
tion in the ascending limb of the loop of Henle (see Chapter 15).
Monitoring of central venous pressure is important to forestall the
development of heart failure and pulmonary edema in predisposed
subjects. In many subjects, saline diuresis suffices to reduce serum
calcium to a point at which more definitive diagnosis and treatment
of the underlying condition can be achieved. If this is not the case or
if more prolonged medical treatment of hypercalcemia is required,
the following agents are available (discussed in order of preference).
Bisphosphonates
Pamidronate, 60–90 mg, infused over 2–4 hours, and zoledro-
nate, 4 mg, infused over at least 15 minutes, have been approved
for the treatment of hypercalcemia of malignancy and have largely
replaced the less effective etidronate for this indication. The
bisphosphonate effects generally persist for weeks, but treatment
can be repeated after a 7-day interval if necessary and if renal
function is not impaired. Some patients experience a self-limited
flu-like syndrome after the initial infusion, but subsequent infu-
sions generally do not have this side effect. Repeated doses of these
drugs have been linked to renal deterioration and osteonecrosis of
the jaw, but this adverse effect is rare.
Calcitonin
Calcitonin has proved useful as ancillary treatment in some
patients. Calcitonin by itself seldom restores serum calcium to
normal, and refractoriness frequently develops. However, its lack
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     783
of toxicity permits frequent administration at high doses (200
MRC units or more). An effect on serum calcium is observed
within 4–6 hours and lasts for 6–10 hours. Calcimar (salmon
calcitonin) is available for parenteral and nasal administration.
Gallium Nitrate
Gallium nitrate is approved by the FDA for the management of
hypercalcemia of malignancy. This drug inhibits bone resorp-
tion. At a dosage of 200 mg/m2 body surface area per day given
as a continuous intravenous infusion in 5% dextrose for 5 days,
gallium nitrate proved superior to calcitonin in reducing serum
calcium in cancer patients. Because of potential nephrotoxicity,
patients should be well hydrated and have good renal output
before starting the infusion.
Phosphate
Intravenous phosphate administration is probably the fastest
and surest way to reduce serum calcium, but it is a hazardous
procedure if not done properly. Intravenous phosphate should
be used only after other methods of treatment (bisphosphonates,
calcitonin, and saline diuresis) have failed to control symptomatic
hypercalcemia. Phosphate must be given slowly (50 mmol or 1.5 g
elemental phosphorus over 6–8 hours) and the patient switched
to oral phosphate (1–2 g/d elemental phosphorus, as one of the
salts indicated below) as soon as symptoms of hypercalcemia have
cleared. The risks of intravenous phosphate therapy include sud-
den hypocalcemia, ectopic calcification, acute renal failure, and
hypotension. Oral phosphate can also lead to ectopic calcifica-
tion and renal failure if serum calcium and phosphate levels are
not carefully monitored, but the risk is less and the time of onset
much longer. Phosphate is available in oral and intravenous forms
as sodium or potassium salts. Amounts required to provide 1 g of
elemental phosphorus are as follows:
Intravenous:
In-Phos, 40 mL; or Hyper-Phos-K, 15 mL
Oral:
Fleet Phospho-Soda, 6.2 mL; or Neutra-Phos, 300 mL; or
K-Phos-Neutral, 4 tablets
Glucocorticoids
Glucocorticoids have no clear role in the immediate treatment of
hypercalcemia. However, the chronic hypercalcemia of sarcoid-
osis, vitamin D intoxication, and certain cancers may respond
within several days to glucocorticoid therapy. Prednisone in oral
doses of 30–60 mg daily is generally used, although equivalent
doses of other glucocorticoids are effective. The rationale for
the use of glucocorticoids in these diseases differs, however. The
hypercalcemia of sarcoidosis is secondary to increased production
of 1,25(OH)2D by the sarcoid tissue itself. Glucocorticoid therapy
directed at the reduction of sarcoid tissue results in restoration of
normal serum calcium and 1,25(OH)2D levels. The treatment
of hypervitaminosis D with glucocorticoids probably does not
alter vitamin D metabolism significantly but is thought to reduce
vitamin D–mediated intestinal calcium transport and increase
renal excretion of calcium. An action of glucocorticoids to reduce
vitamin D–mediated bone resorption has not been excluded,
however. The effect of glucocorticoids on the hypercalcemia of
cancer is probably twofold. The malignancies responding best to
glucocorticoids (ie, multiple myeloma and related lymphoprolif-
erative diseases) are sensitive to the lytic action of glucocorticoids.
Therefore part of the effect may be related to decreased tumor
mass and activity. Glucocorticoids have also been shown to inhibit
the secretion or effectiveness of cytokines elaborated by multiple
myeloma and related cancers that stimulate osteoclastic bone
resorption. Other causes of hypercalcemia—particularly primary
hyperparathyroidism—do not respond to glucocorticoid therapy.
HYPOCALCEMIA
The main features of hypocalcemia are neuromuscular: tetany, par-
esthesias, laryngospasm, muscle cramps, and seizures. The major
causes of hypocalcemia in the adult are hypoparathyroidism,
vitamin D deficiency, chronic kidney disease, and malabsorption.
Hypocalcemia can also accompany the infusion of potent bisphos-
phonates and denosumab for the treatment of osteoporosis, but
this is seldom of clinical significance unless the patient is already
hypocalcemic at the onset of the infusion. Neonatal hypocalcemia
is a common disorder that usually resolves without therapy. The
roles of PTH, vitamin D, and calcitonin in the neonatal syndrome
are under investigation. Large infusions of citrated blood can pro-
duce hypocalcemia secondary to the formation of citrate-calcium
complexes. Calcium and vitamin D (or its metabolites) form the
mainstay of treatment of hypocalcemia. However, in patients with
hypoparathyroidism, teriparatide or rhPTH 1-84 may prove use-
ful (only rhPTH 1-84 has been FDA approved for this condition).
Calcium
A number of calcium preparations are available for intravenous,
intramuscular, and oral use. Calcium gluceptate (0.9 mEq
calcium/mL), calcium gluconate (0.45 mEq calcium/mL), and
calcium chloride (0.68–1.36 mEq calcium/mL) are available for
intravenous therapy. Calcium gluconate is preferred because it
is less irritating to veins. Oral preparations include calcium car-
bonate (40% calcium), calcium lactate (13% calcium), calcium
phosphate (25% calcium), and calcium citrate (21% calcium).
Calcium carbonate is often the preparation of choice because of
its high percentage of calcium, ready availability (eg, Tums), low
cost, and antacid properties. In achlorhydric patients, calcium
carbonate should be given with meals to increase absorption, or
the patient should be switched to calcium citrate, which is some-
what better absorbed. Combinations of vitamin D and calcium
are available, but treatment must be tailored to the individual
patient and the individual disease, a flexibility lost by fixed-dosage
combinations.
Treatment of severe symptomatic hypocalcemia can be accom-
plished with slow infusion of 5–20 mL of 10% calcium gluco-
nate. Rapid infusion can lead to cardiac arrhythmias. Less severe
hypocalcemia is best treated with oral forms sufficient to provide
784    SECTION VII  Endocrine Drugs
approximately 1000–1500 mg of elemental calcium per day. Dos-
age must be adjusted to avoid hypercalcemia and hypercalciuria.
Vitamin D
When rapidity of action is required, 1,25(OH)2D3 (calcitriol),
0.25–1 mcg daily, is the vitamin D metabolite of choice because it
is capable of raising serum calcium within 24–48 hours. Calcitriol
also raises serum phosphate, although this action is usually not
observed early in treatment. The combined effects of calcitriol
and all other vitamin D metabolites and analogs on both calcium
and phosphate make careful monitoring of these mineral levels
especially important to prevent ectopic calcification secondary to
an abnormally high serum calcium × phosphate product. Since
the choice of the appropriate vitamin D metabolite or analog for
long-term treatment of hypocalcemia depends on the nature of
the underlying disease, further discussion of vitamin D treatment
is found under the headings of the specific diseases.
HYPERPHOSPHATEMIA
Hyperphosphatemia is a common complication of renal failure and
is also found in all types of hypoparathyroidism (idiopathic, surgi-
cal, and pseudohypoparathyroidism), vitamin D intoxication, and
the rare syndrome of tumoral calcinosis (usually due to insufficient
bioactive FGF23). Emergency treatment of hyperphosphatemia is
seldom necessary but can be achieved by dialysis or glucose and
insulin infusions. In general, control of hyperphosphatemia involves
restriction of dietary phosphate plus phosphate-binding gels such
as sevelamer, or lanthanum carbonate and calcium supplements.
Because of their potential to induce aluminum-associated bone dis-
ease, aluminum-containing antacids should be used sparingly and
only when other measures fail to control the hyperphosphatemia. In
patients with chronic kidney disease, enthusiasm for the use of large
doses of calcium to control hyperphosphatemia has waned because
of the risk of ectopic calcification.
HYPOPHOSPHATEMIA
Hypophosphatemia is associated with a variety of conditions,
including primary hyperparathyroidism, vitamin D deficiency,
idiopathic hypercalciuria, conditions associated with increased
bioactive FGF23 (eg, X-linked and autosomal dominant hypophos-
phatemic rickets and tumor-induced osteomalacia), other forms of
renal phosphate wasting (eg, Fanconi’s syndrome), overzealous use
of phosphate binders, and parenteral nutrition with inadequate
phosphate content. Acute hypophosphatemia may cause a reduc-
tion in the intracellular levels of high-energy organic phosphates
(eg, ATP), interfere with normal hemoglobin-to-tissue oxygen
transfer by decreasing red cell 2,3-diphosphoglycerate levels, and
lead to rhabdomyolysis. However, clinically significant acute effects
of hypophosphatemia are seldom seen, and emergency treatment
is generally not indicated. The long-term effects include proximal
muscle weakness and abnormal bone mineralization (osteomalacia).
Therefore, hypophosphatemia should be avoided when using forms
of therapy that can lead to it (eg, phosphate binders, certain types
of parenteral nutrition) and treated in conditions that cause it, such
as the various forms of hypophosphatemic rickets. Oral forms of
phosphate are listed above.
SPECIFIC DISORDERS INVOLVING
BONE MINERAL-REGULATING
HORMONES
PRIMARY HYPERPARATHYROIDISM
This rather common disease, if associated with symptoms, signifi-
cant hypercalcemia, and hypercalciuria, osteoporosis, and kidney
disease is best treated surgically. Oral phosphate and bisphospho-
nates have been tried but cannot be recommended. A substantial
proportion of asymptomatic patients with mild disease do not get
worse and may be followed without treatment, although a number
of such patients do end up requiring surgery. The calcimimetic agent
cinacalcet, discussed previously, has been approved for secondary
hyperparathyroidism and is in clinical trials for the treatment of
primary hyperparathyroidism. If such drugs prove efficacious and
cost effective, medical management of this disease will need to be
reconsidered. Primary hyperparathyroidism is often associated with
low levels of 25(OH)D, suggesting that mild vitamin D deficiency
may be contributing to the elevated PTH levels, although this could
also be due to the stimulation by PTH of 1,25(OH)2D produc-
tion that in turn induces CYP24A1, which will increase 25(OH)
D (and 1,25(OH)2D) catabolism. Vitamin D supplementation in
such situations has proved safe with respect to further elevations of
serum and urine calcium levels, but calcium should be monitored
nevertheless when vitamin D supplementation is provided.
HYPOPARATHYROIDISM
In PTH deficiency (idiopathic or surgical hypoparathyroidism) or
an abnormal target tissue response to PTH (pseudohypoparathy-
roidism), serum calcium falls and serum phosphate rises. In such
patients, 1,25(OH)2D levels are usually low, presumably reflecting
the lack of stimulation by PTH of 1,25(OH)2D production. The
skeletons of patients with idiopathic or surgical hypoparathyroidism
are normal except for a slow turnover rate. A number of patients
with pseudohypoparathyroidism appear to have osteitis fibrosa, sug-
gesting that the normal or high PTH levels found in such patients
are capable of acting on bone but not on the kidney. The distinction
between pseudohypoparathyroidism and idiopathic hypoparathy-
roidism is made on the basis of normal or high PTH levels but
deficient renal response (ie, diminished excretion of cAMP or phos-
phate) in patients with pseudohypoparathyroidism.
The principal therapeutic goal is to restore normocalcemia
and normophosphatemia. Standard therapy involves the use
of calcitriol and dietary calcium supplements. However, many
patients develop hypercalciuria with this regimen, which limits
the ability to correct the hypocalcemia. Full-length PTH (rhPTH
1-84, Natpara) has recently been approved for the treatment
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     785
of hypoparathyroidism and reduces the need for large doses of
calcium and calcitriol with less risk of hypercalciuria.
NUTRITIONAL VITAMIN D DEFICIENCY
OR INSUFFICIENCY
The level of vitamin D thought to be necessary for good health
is being reexamined with the appreciation that vitamin D acts on
a large number of cell types beyond those responsible for bone
and mineral metabolism. A level of 25(OH)D above 10 ng/mL
is necessary for preventing rickets or osteomalacia. However,
substantial epidemiologic and some prospective trial data indicate
that a higher level, such as 20–30 ng/mL, is required to optimize
intestinal calcium absorption, optimize the accrual and mainte-
nance of bone mass, reduce falls and fractures, and prevent a wide
variety of diseases including diabetes mellitus, hyperparathyroid-
ism, autoimmune diseases, and cancer. An expert panel for the
Institute of Medicine (IOM) has recommended that a level of
20 ng/mL (50 nM) was sufficient, although up to 50 ng/mL
(125 nM) was considered safe. For individuals between the ages
of 1 and 70 years, 600 IU/d vitamin D was thought to be suffi-
cient to meet these goals, although up to 4000 IU was considered
safe. These recommendations are based primarily on data from
randomized placebo-controlled clinical trials (RCTs) that evalu-
ated falls and fractures; data supporting the nonskeletal effects of
vitamin D were considered too preliminary to be used in their
recommendations because of lack of RCTs for these other actions.
The lower end of these recommendations has been considered too
low and the upper end too restrictive by a number of vitamin D
experts, and the Endocrine Society has published a different set of
recommendations suggesting that 30 ng/mL was a more appropri-
ate lower limit. Nevertheless, the call for better clinical data from
RCTs, especially for the nonskeletal actions, is appropriate. The
IOM guidelines—at least with respect to the lower recommended
levels of vitamin D supplementation—are unlikely to correct
vitamin D deficiency in individuals with obesity, dark complex-
ions, limited capacity for sunlight exposure, or malabsorption.
Vitamin D deficiency or insufficiency can be treated by higher
dosages (either D2 or D3, 1000–4000 IU/d or 50,000 IU/week
for several weeks). No other vitamin D metabolite is indicated.
Because the half-life of vitamin D3 metabolites in blood is greater
than that of vitamin D2, there are advantages to using vitamin D3
rather than vitamin D2 supplements, although when administered
on a daily or weekly schedule these differences may be moot. The
diet should also contain adequate amounts of calcium as several
studies indicate a synergism between calcium and vitamin D with
respect to a number of their actions.
CHRONIC KIDNEY DISEASE
The major sequelae of chronic kidney disease (CKD) that impact
bone mineral homeostasis are deficient 1,25(OH)2D production,
retention of phosphate with an associated reduction in ionized
calcium levels, and the secondary hyperparathyroidism that results
from the parathyroid gland response to lowered serum ionized
calcium and low 1,25(OH)2D. FGF23 levels rise early in this dis-
order for unclear reasons and this can further reduce 1,25(OH)2D
production by the kidney. Moreover, the increase in FGF23 is
associated with increased morbidity and mortality in CKD in
part due to its impact on the heart. Although still investigational,
antibodies to FGF23 in the early stages of renal failure result in
normalization of 1,25(OH)2D levels, and may prove useful in
CKD treatment. However, inhibition of FGF23 may further the
rise in serum phosphate with the potential for increased vascular
calcification, a major issue in CKD. With impaired 1,25(OH)2D
production, less calcium is absorbed from the intestine, and less
bone is resorbed under the influence of PTH. As a result hypocal-
cemia usually develops, furthering the development of secondary
hyperparathyroidism. The bones show a mixture of osteomalacia
and osteitis fibrosa.
In contrast to the hypocalcemia that is more often associated
with chronic kidney disease, some patients may become hyper-
calcemic from overzealous treatment with calcium. However,
the most common cause of hypercalcemia is the development of
severe secondary (sometimes referred to as tertiary) hyperpara-
thyroidism. In such cases, the PTH level in blood is very high.
Serum alkaline phosphatase levels also tend to be high. Treatment
often requires parathyroidectomy. A less common circumstance
leading to hypercalcemia is development of a form of bone disease
characterized by a profound decrease in bone cell activity and loss
of the calcium buffering action of bone (adynamic bone disease).
In the absence of kidney function, any calcium absorbed from the
intestine accumulates in the blood. Such patients are very sensitive
to the hypercalcemic action of 1,25(OH)2D. These individuals
generally have a high serum calcium but nearly normal alkaline
phosphatase and PTH levels. The bone in such patients may have
a high aluminum content, especially in the mineralization front,
which blocks normal bone mineralization. These patients do not
respond favorably to parathyroidectomy. Deferoxamine, an agent
used to chelate iron (see Chapter 57), also binds aluminum and
is being used to treat this disorder. However, with the reduction
in use of aluminum-containing phosphate binders, most cases of
adynamic bone disease are not associated with aluminum deposi-
tion but are attributed in some cases to overzealous suppression of
PTH secretion.
Vitamin D Preparations
The choice of vitamin D preparation to be used in the setting of
chronic kidney disease depends on the type and extent of bone
disease and hyperparathyroidism. Individuals with vitamin D
deficiency or insufficiency should first have their 25(OH)D levels
restored to normal (20–30 ng/mL) with vitamin D. Calcifediol
or 1,25(OH)2D3 (calcitriol) rapidly corrects hypocalcemia and at
least partially reverses secondary hyperparathyroidism and osteitis
fibrosa. Many patients with muscle weakness and bone pain gain
an improved sense of well-being.
Two analogs of calcitriol—doxercalciferol and paricalcitol—
are approved in the United States for the treatment of second-
ary hyperparathyroidism of chronic kidney disease. (In Japan,
786    SECTION VII  Endocrine Drugs
maxacalcitol [22-oxa-calcitriol] and falecalcitriol [26,27 F6-
1,25(OH)2D3] are approved for this purpose.) Their principal
advantage is that they are less likely than calcitriol to induce
hypercalcemia for any given reduction in PTH (less true for fale-
calcitriol). Their greatest impact is in patients in whom the use
of calcitriol may lead to unacceptably high serum calcium levels.
Regardless of the drug used, careful attention to serum calcium
and phosphate levels is required. A calcium × phosphate product
(in mg/dL units) less than 55 is desired with both calcium and
phosphate in the normal range. Calcium adjustments in the diet
and dialysis bath and phosphate restriction (dietary and with oral
ingestion of phosphate binders) should be used along with vitamin
D metabolites. Monitoring of serum PTH and alkaline phospha-
tase levels is useful in determining whether therapy is correcting
or preventing secondary hyperparathyroidism. In patients on
dialysis, a PTH value of approximately twice the upper limits of
normal is considered desirable to prevent adynamic bone disease.
Although not generally available, percutaneous bone biopsies for
quantitative histomorphometry may help in choosing appropriate
therapy and following the effectiveness of such therapy, especially
in cases suspected of adynamic bone disease. Unlike the rapid
changes in serum values, changes in bone morphology require
months to years. Monitoring of serum vitamin D metabolite levels
is useful for determining adherence, absorption, and metabolism.
INTESTINAL OSTEODYSTROPHY
A number of gastrointestinal and hepatic diseases cause disordered
calcium and phosphate homeostasis, which ultimately leads to
bone disease. As bariatric surgery becomes more common, this
problem is likely to increase. The bones in such patients show a
combination of osteoporosis and osteomalacia. Osteitis fibrosa
does not occur, in contrast to renal osteodystrophy. The important
common feature in this group of diseases appears to be malabsorp-
tion of calcium and vitamin D. Liver disease may, in addition,
reduce the production of 25(OH)D from vitamin D, although its
importance in patients other than those with terminal liver failure
remains in dispute. The major explanation for the low 25(OH)D
levels in patients with liver disease is the reduction in D-binding
protein production, the major carrier of vitamin D metabolites
in the blood. Free 25(OH)D is generally normal in patients with
liver disease. The malabsorption of vitamin D is probably not
limited to exogenous vitamin D as the liver secretes into bile a
substantial number of vitamin D metabolites and conjugates that
are normally reabsorbed in (presumably) the distal jejunum and
ileum. Interference with this process could deplete the body of
endogenous vitamin D metabolites in addition to limiting absorp-
tion of dietary vitamin D.
In mild forms of malabsorption, high doses of vitamin D
(25,000–50,000 IU one to three times per week) should suffice
to raise serum levels of 25(OH)D into the normal range. Many
patients with severe disease do not respond to vitamin D. Clinical
experience with the other metabolites is limited, but both calcitriol
and calcifediol have been used successfully in doses similar to those
recommended for treatment of renal osteodystrophy. Theoretically,
calcifediol should be the drug of choice under these conditions,
because no impairment of the renal metabolism of 25(OH)D to
1,25(OH)2D and 24,25(OH)2D exists in these patients. However,
calcifediol is only approved in the United States for use in chronic
kidney disease and secondary hyperparathyroidism. Both calcitriol
and 24,25(OH)2D may be of importance in reversing the bone
disease. Intramuscular injections of vitamin D would be an alter-
native form of therapy, but there are currently no FDA-approved
intramuscular preparations available in the United States. The skin
remains a good source of vitamin D production, although care is
needed to prevent UVB overexposure (ie, by avoiding sunburn) to
reduce the risk of photoaging and skin cancer.
As in the other diseases discussed, treatment of intestinal
osteodystrophy with vitamin D and its metabolites should be
accompanied by appropriate dietary calcium supplementation and
monitoring of serum calcium and phosphate levels.
OSTEOPOROSIS
Osteoporosis is defined as abnormal loss of bone predisposing
to fractures. It is most common in postmenopausal women but
also occurs in men. The annual direct medical cost of fractures in
older women and men in the United States is estimated to be at
least $20 billion per year and is increasing as the population ages.
Osteoporosis is most commonly associated with loss of gonadal
function as in menopause but may also occur as an adverse effect
of long-term administration of glucocorticoids or other drugs,
including those that inhibit sex steroid production; as a manifesta-
tion of endocrine disease such as thyrotoxicosis or hyperparathy-
roidism; as a feature of malabsorption syndrome; as a consequence
of alcohol abuse and cigarette smoking; or without obvious cause
(idiopathic). The ability of some agents to reverse the bone loss of
osteoporosis is shown in Figure 42–5. The postmenopausal form
of osteoporosis may be accompanied by lower 1,25(OH)2D levels
and reduced intestinal calcium transport. This form of osteoporo-
sis is due to reduced estrogen production and can be treated with
estrogen (combined with a progestin in women with a uterus to
prevent endometrial carcinoma). However, concern that estrogen
increases the risk of breast cancer and fails to reduce or may actu-
ally increase the development of heart disease has reduced enthu-
siasm for this form of therapy, at least in older individuals.
Bisphosphonates are potent inhibitors of bone resorption.
They increase bone density and reduce the risk of fractures in
the hip, spine, and other locations. Alendronate, risedronate,
ibandronate, and zoledronate are approved for the treatment of
osteoporosis, using daily dosing schedules of alendronate, 10 mg/d,
risedronate, 5 mg/d, or ibandronate, 2.5 mg/d; or weekly sched-
ules of alendronate, 70 mg/week, or risedronate, 35 mg/week; or
monthly schedules of ibandronate, 150 mg/month; or quarterly
(every 3 months) injections of ibandronate, 3 mg; or annual infu-
sions of zoledronate, 5 mg. These drugs are effective in men as well
as women and for various causes of osteoporosis.
As previously noted, estrogen-like SERMs (selective estrogen
receptor modulators, Chapter 40) have been developed that prevent
the increased risk of breast and uterine cancer associated with estrogen
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     787

Vitamin D, PTH,
40 Sr2+, anti-sclerostin

bone mineral density

Estrogen,

Percent change in
denosumab,
20 calcitonin, or
bisphosphonate

−10 No treatment

0 1 2 3 4 5
Time (y)

FIGURE 42–5  Typical changes in bone mineral density with time after the onset of menopause, with and without treatment. In the
untreated condition, bone is lost during aging in both men and women. Strontium (Sr2+), parathyroid hormone (PTH), and vitamin D promote
bone formation and can increase bone mineral density in subjects who respond to them throughout the period of treatment, although PTH
and vitamin D in high doses also activate bone resorption. Sclerostin antibodies, currently in clinical trials, provide a pure anabolic action in
the treatment of osteoporosis by promoting bone formation and inhibiting bone resorption. In contrast, estrogen, calcitonin, denosumab,
and bisphosphonates block bone resorption. This leads to a transient increase in bone mineral density because bone formation is not initially
decreased. However, with time, both bone formation and bone resorption decrease with these pure antiresorptive agents, and bone mineral
density reaches a new plateau.

while maintaining the benefit to bone. The SERM raloxifene is
approved for treatment of osteoporosis. Like tamoxifen, raloxifene
reduces the risk of breast cancer. It protects against spine fractures but
not hip fractures—unlike bisphosphonates, denosumab, and teripa-
ratide, which protect against both. Raloxifene does not prevent hot
flushes and imposes the same increased risk of venous thromboembo-
lism as estrogen. To counter the reduced intestinal calcium transport
associated with osteoporosis, vitamin D therapy is often used in com-
bination with dietary calcium supplementation. In several large stud-
ies, vitamin D supplementation (800 IU/d) with calcium has been
shown to improve bone density, reduce falls, and prevent fractures,
although calcium and vitamin D are generally used as supplements
with other drugs in the treatment of osteoporosis. Calcitriol and its
analog, 1α(OH)D3, have also been shown to increase bone mass and
reduce fractures. Use of these agents for osteoporosis is not FDA-
approved, although they are used for this purpose in other countries.
The 1,25(OH)2D analog eldecalcitol is approved for use in Japan,
largely replacing the use of 1α( OH)D3.
Teriparatide, the recombinant form of PTH 1-34, is approved
for treatment of osteoporosis. It is given in a dosage of 20 mcg
subcutaneously daily. Teriparatide stimulates new bone formation,
but unlike fluoride, this new bone appears structurally normal
and is associated with a substantial reduction in the incidence
of fractures. The drug is approved for only 2 years of use. Trials
examining the sequential use of teriparatide followed by a bisphos-
phonate after 1 or 2 years are in progress and look promising. Use
of the drug with a bisphosphonate has not shown greater efficacy
than the bisphosphonate alone, although recent trials with the
concomitant use of teriparatide and denosumab show promise.
Calcitonin is approved for use in the treatment of postmeno-
pausal osteoporosis. It has been shown to increase bone mass and
reduce fractures, but only in the spine. It does not appear to be as
effective as bisphosphonates or teriparatide.
Denosumab, the RANKL inhibitor, is of comparable efficacy
to bisphosphonates in the treatment of postmenopausal osteopo-
rosis. It is given subcutaneously every 6 months in 60-mg doses.
Like the bisphosphonates it suppresses bone resorption and sec-
ondarily bone formation. Denosumab reduces the risk of both
vertebral and nonvertebral fractures with comparable effectiveness
to the potent bisphosphonates.
Strontium ranelate has not been approved in the United States
for the treatment of osteoporosis but is being used in Europe,
generally at a dose of 2 g/d.
X-LINKED & AUTOSOMAL DOMINANT
HYPOPHOSPHATEMIA & RELATED
DISEASES
These disorders usually manifest in childhood as rickets and hypo-
phosphatemia, although they may first present in adults. In both
X-linked and autosomal dominant hypophosphatemia, biologi-
cally active FGF23 accumulates, leading to phosphate wasting in
the urine and hypophosphatemia. In autosomal dominant hypo-
phosphatemia, mutations in the FGF23 gene replace an arginine
required for proteolysis and result in increased FGF23 stability.
X-linked hypophosphatemia is caused by mutations in the gene
encoding the PHEX protein, an endopeptidase. Initially, it was
thought that FGF23 was a direct substrate for PHEX, but this no
longer appears to be the case. Tumor-induced osteomalacia is a
phenotypically similar but acquired syndrome in adults that results
from overexpression of FGF23 in tumor cells. The current concept
for all of these diseases is that FGF23 blocks the renal uptake of
phosphate and blocks 1,25(OH)2D production leading to rickets in
children and osteomalacia in adults. Phosphate is critical to normal
bone mineralization; when phosphate stores are deficient, a clinical
788    SECTION VII  Endocrine Drugs
and pathologic picture resembling vitamin D–dependent rickets
develops. However, affected children fail to respond to the standard
doses of vitamin D used in the treatment of nutritional rickets. A
defect in 1,25(OH)2D production by the kidney contributes to
the phenotype as 1,25(OH)2D levels are low relative to the degree
of hypophosphatemia observed. This combination of low serum
phosphate and low or low-normal serum 1,25(OH)2D provides
the rationale for treating these patients with oral phosphate (1–3 g
daily) and calcitriol (0.25–2 mcg daily). Reports of such combina-
tion therapy are encouraging in this otherwise debilitating disease,
although prolonged treatment often leads to secondary hyperpara-
thyroidism. More recently the use of FGF23 antibodies for children
with X-linked hypophosphatemic (XLH) rickets has shown promise
and may become the treatment of choice for these conditions.
PSEUDOVITAMIN D DEFICIENCY
RICKETS & HEREDITARY VITAMIN D–
RESISTANT RICKETS
These distinctly different autosomal recessive diseases present as child-
hood rickets that do not respond to conventional doses of vitamin D.
Pseudovitamin D–deficiency rickets is due to an isolated deficiency
of 1,25(OH)2D production caused by mutations in 25(OH)-D-
1α-hydroxylase (CYP27B1). This condition is treated with cal-
citriol (0.25–0.5 mcg daily). Hereditary vitamin D–resistant rickets
(HVDRR) is caused by mutations in the gene for the vitamin D
receptor. The serum levels of 1,25(OH)2D are very high in HVDRR
but inappropriately low for the level of calcium in pseudovitamin
D–deficient rickets. Treatment with large doses of calcitriol has been
claimed to be effective in restoring normocalcemia in some HVDRR
patients, presumably those with a partially functional vitamin D
receptor, although many patients are completely resistant to all forms
of vitamin D. Calcium and phosphate infusions have been shown
to correct the rickets in some children, similar to studies in mice in
which the VDR gene has been deleted. These diseases are rare.
IDIOPATHIC INFANTILE
HYPERCALCEMIA
Mutations in CYP24A1, the enzyme catabolizing 25(OH)D and
1,25(OH)2D, have recently been found to account for a number of
cases of idiopathic infantile hypercalcemia. However, these muta-
tions have also been described in adults with previously unexplained
hypercalcemia and elevated 1,25(OH)2D levels. At this point no
definitive therapy has been established, but vitamin D supplemen-
tation needs to be avoided. The diagnosis can be made by finding a
reduced ratio of 24,25(OH)2D to 25(OH)D in the blood.
NEPHROTIC SYNDROME
Patients with nephrotic syndrome can lose vitamin D metabolites in
the urine, presumably by loss of the vitamin D–binding protein.
Such patients may have very low 25(OH)D levels. Some of them
develop bone disease. It is not yet clear what value vitamin D ther-
apy has in such patients, because therapeutic trials with vitamin D
(or any vitamin D metabolite) have not yet been carried out.
Because the problem is not related to vitamin D metabolism, one
would not anticipate any advantage in using the more expensive
vitamin D metabolites in place of vitamin D.
IDIOPATHIC HYPERCALCIURIA
Individuals with idiopathic hypercalciuria, characterized by hyper-
calciuria and nephrolithiasis with normal serum calcium and PTH
levels, have been divided into three groups: (1) hyperabsorbers,
patients with increased intestinal absorption of calcium, resulting
in high-normal serum calcium, low-normal PTH, and a second-
ary increase in urine calcium; (2) renal calcium leakers, patients
with a primary decrease in renal reabsorption of filtered calcium,
leading to low-normal serum calcium and high-normal serum
PTH; and (3) renal phosphate leakers, patients with a primary
decrease in renal reabsorption of phosphate, leading to increased
1,25(OH)2D production, increased intestinal calcium absorption,
increased ionized serum calcium, low-normal PTH levels, and a
secondary increase in urine calcium. There is some disagreement
about this classification, and many patients are not readily catego-
rized. Many such patients present with mild hypophosphatemia,
and oral phosphate has been used with some success in reduc-
ing stone formation. However, a clear role for phosphate in the
treatment of this disorder has not been established and is not
recommended.
Therapy with hydrochlorothiazide, up to 50 mg twice daily, or
chlorthalidone, 50–100 mg daily, is recommended. Loop diuret-
ics such as furosemide and ethacrynic acid should not be used
because they increase urinary calcium excretion. The major toxic-
ity of thiazide diuretics, besides hypokalemia, hypomagnesemia,
and hyperglycemia, is hypercalcemia. This is seldom more than
a biochemical observation unless the patient has a disease such
as hyperparathyroidism in which bone turnover is accelerated.
Accordingly, one should screen patients for such disorders before
starting thiazide therapy and monitor serum and urine calcium
when therapy has begun.
An alternative to thiazides is allopurinol. Some studies indicate
that hyperuricosuria is associated with idiopathic hypercalcemia
and that a small nidus of urate crystals could lead to the calcium
oxalate stone formation characteristic of idiopathic hypercalcemia.
Allopurinol, 100–300 mg daily, may reduce stone formation by
reducing uric acid excretion.
OTHER DISORDERS OF BONE
MINERAL HOMEOSTASIS
PAGET’S DISEASE OF BONE
Paget’s disease is a localized bone disorder characterized by uncon-
trolled osteoclastic bone resorption with secondary increases in
poorly organized bone formation. The cause of Paget’s disease is
obscure, although some studies suggest that a measles-related virus
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     789

may be involved. The disease is fairly common, although symp-
tomatic bone disease is less common. Recent studies indicate that
this infection may produce a factor that increases the stimulation
of bone resorption by 1,25(OH)2D. The biochemical parameters
of elevated serum alkaline phosphatase and urinary hydroxypro-
line are useful for diagnosis. Along with the characteristic radio-
logic and bone scan findings, these biochemical determinations
provide good markers by which to follow therapy.
The goal of treatment is to reduce bone pain and stabilize or
prevent other problems such as progressive deformity, fractures,
hearing loss, high-output cardiac failure, and immobilization
hypercalcemia. Calcitonin and bisphosphonates are the first-line
agents for this disease. Calcitonin is administered subcutaneously
or intramuscularly in doses of 50–100 MRC (Medical Research
Council) units every day or every other day. Nasal inhalation at
200–400 units/d is also effective. Higher or more frequent doses
have been advocated when this initial regimen is ineffective.
Improvement in bone pain and reduction in serum alkaline phos-
phatase and urine hydroxyproline levels require weeks to months.
Often a patient who responds well initially loses the response to
calcitonin. This refractoriness is not correlated with the develop-
ment of antibodies.
Sodium etidronate, alendronate, risedronate, and tiludronate
are the bisphosphonates currently approved for clinical use in Pag-
et’s disease of bone in the United States. Other bisphosphonates,
including pamidronate, are being used in other countries. The
recommended doses of bisphosphonates are etidronate, 5 mg/kg
per day; alendronate, 40 mg/d; risedronate, 30 mg/d; and tiludro-
nate, 400 mg/d. Long-term remission (months to years) may be
expected in patients who respond to a bisphosphonate. Treatment
should not exceed 6 months per course but can be repeated after
6 months if necessary. The principal toxicity of etidronate is the
development of osteomalacia and an increased incidence of frac-
tures when the dosage is raised substantially above 5 mg/kg per
day. The newer bisphosphonates such as risedronate and alendro-
nate do not share this adverse effect. Some patients treated with
etidronate develop bone pain similar in nature to the bone pain of
osteomalacia. This subsides after stopping the drug. The principal
adverse effect of alendronate and the newer bisphosphonates is
gastric irritation when used at these high doses. This is reversible
on cessation of the drug.
ENTERIC OXALURIA
Patients with short bowel syndromes and associated fat malab-
sorption can present with renal stones composed of calcium and
oxalate. Such patients characteristically have normal or low urine
calcium levels but elevated urine oxalate levels. The reasons for
the development of oxaluria in such patients are thought to be
twofold: first, in the intestinal lumen, calcium (which is now
bound to fat) fails to bind oxalate and no longer prevents its
absorption; second, enteric flora, acting on the increased sup-
ply of nutrients reaching the colon, produce larger amounts of
oxalate. Although one would ordinarily avoid treating a patient
with calcium oxalate stones with calcium supplementation, this
is precisely what is done in patients with enteric oxaluria. The
increased intestinal calcium binds the excess oxalate and prevents
its absorption. Calcium carbonate (1–2 g) can be given daily in
divided doses, with careful monitoring of urinary calcium and
oxalate to be certain that urinary oxalate falls without a danger-
ous increase in urinary calcium.

SUMMARY Major Drugs Used in Diseases of Bone Mineral Homeostasis

Mechanism of Clinical
Subclass, Drug Action Effects Applications Toxicities

VITAMIN D, METABOLITES, ANALOGS

  •  Cholecalciferol (D3) Regulate gene transcription Stimulate intestinal calcium Osteoporosis, Hypercalcemia, hypercalciuria
  •  Ergocalciferol (D2) via the vitamin D receptor absorption, bone resorption, renal osteomalacia, renal • the vitamin D preparations
  •  Calcitriol calcium and phosphate reabsorption failure, malabsorption, have much longer half-lives
  •  Calcifediol • decrease parathyroid hormone psoriasis than the metabolites and
  •  Doxercalciferol (PTH) • promote innate immunity analogs
  •  Paricalcitol • inhibit adaptive immunity
  •  Calcipotriene

BISPHOSPHONATES
  •  Alendronate Suppress the activity of Inhibit bone resorption and Osteoporosis, bone Adynamic bone, possible renal
  •  Risedronate osteoclasts in part via secondarily bone formation metastases, failure, rare osteonecrosis of the
  •  Ibandronate inhibition of farnesyl hypercalcemia jaw, rare subtrochanteric (femur)
  •  Pamidronate pyrophosphate synthesis fractures
  •  Zoledronate

(continued)
790    SECTION VII  Endocrine Drugs

Mechanism of Clinical
Subclass, Drug Action Effects Applications Toxicities
HORMONES
  •  Teriparatide These hormones act via their Teriparatide stimulates bone turnover Both are used in Teriparatide may cause
  •  Abaloparatide cognate G protein–coupled • calcitonin suppresses bone osteoporosis • calcitonin hypercalcemia and
  •  Calcitonin receptors resorption is used for hypercalcemia hypercalciuria
  •  rhPTH1-84 Recombinant full-length rhPTH1-84 increases RANKL, Hypoparathyroidism Hypercalcemia, hypercalciuria
PTH; acts on the same decreases sclerostin, enhances
receptors as teriparatide calcium reabsorption from the kidney

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

  •  Raloxifene Interacts selectively with Inhibits bone resorption without Osteoporosis Does not prevent hot flashes
estrogen receptors stimulating breast or endometrial • increased risk of venous
hyperplasia thromboembolism

RANK LIGAND (RANKL) INHIBITOR

  •  Denosumab Monoclonal antibody • binds Blocks bone resorption Osteoporosis May increase risk of infections
to RANKL and prevents it
from stimulating osteoclast
differentiation and function

CALCIUM RECEPTOR AGONIST

  •  Cinacalcet Activates the calcium- Inhibits PTH secretion Hyperparathyroidism Nausea
sensing receptor

MINERALS
  • Calcium, Multiple physiologic actions Strontium suppresses bone Osteoporosis Ectopic calcification
phosphate through regulation of resorption and increases bone • osteomalacia
  •  Strontium multiple enzymatic formation • calcium and phosphate • deficiencies in calcium
pathways required for bone mineralization or phosphate

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

VITAMIN D, METABOLITES, AND ANALOGS PHOSPHATE AND PHOSPHATE BINDER
Calcifediol (25(OH)D3) Rayaldee Phosphate  
Calcitriol     Oral: solution Fleet Phospho-soda, K-Phos-
 Oral Generic, Rocaltrol Neutral, Neutra-Phos, Neutra-
Phos-K
 Parenteral Calcijex
Sevelamer carbonate or HCl Renagel, Renvela
Cholecalciferol (D3) Generic, Delta-D
(vitamin D3) Lanthanum carbonate Fosrenol
Doxercalciferol Generic, Hectorol BISPHOSPHONATES
Ergocalciferol (D2) (vitamin Generic, Drisdol, others Alendronate sodium Generic, Fosamax
D2, calciferol) Etidronate disodium Generic, Didronel
Paricalcitol Generic, Zemplar Ibandronate sodium Generic, Boniva
CALCIUM Pamidronate disodium Generic, Aredia
Calcium acetate (25% calcium) Generic, PhosLo Risedronate sodium Actonel, Atelvia
Calcium carbonate (40% calcium) Generic, Tums, Cal-Sup, Os-Cal 500 Tiludronate disodium Skelid
Calcium chloride (27% calcium) Generic Zoledronic acid Zometa
Calcium citrate (21% calcium) Generic, Cal-C-Caps, Cal-Cee OTHER DRUGS
Calcium glubionate Neo-Calglucon, Calcionate, Calcitonin-salmon Miacalcin, Calcimar, Salmonine
(6.5% calcium) Calciquid Cinacalcet Sensipar
Calcium gluceptate Generic Denosumab Prolia, Xgeva
(8% calcium)
Gallium nitrate Ganite
Calcium gluconate Generic
(9% calcium) Sodium fluoride Generic
Calcium lactate (13% calcium) Generic Teriparatide (1-34 active segment Forteo
of PTH)
Tricalcium phosphate Posture
(39% calcium) Recombinant human PTH 1-84 Natpara
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     791
REFERENCES
Becker DJ, Kilgore ML, Morrisey MA: The societal burden of osteoporosis. Curr
Rheumatol Rep 2010;12:186.
Bhattacharyya N et al: Fibroblast growth factor 23: State of the field and future
directions. Trends Endocrinol Metab 2012;23:610.
Bikle DD: Extraskeletal actions of vitamin D. Ann NY Acad Sci 2016;1376:29.
Cosman F et al: Clinician’s guide to prevention and treatment of osteoporosis.
Osteoporos Int 2014;25:2359.
Hagino H: Eldecalcitol: Newly developed active vitamin D3 analog for the treat-
ment of osteoporosis. Expert Opin Pharmacother 2013;14:817.
Holick MF et al: Evaluation, treatment, and prevention of vitamin D deficiency:
An Endocrine Sociey Clinical Practice Guideline. J Clin Endocrinol Metab
2011;96:1911.
Martin A, David V, Quarles LD: Regulation and function of the FGF23/Klotho
endocrine pathways. Physiol Rev 2012;92:131.
Mirrakhimov AE: Hypercalcemia of malignancy: An update on pathogenesis and
management. N Am J Med Sci 2015;7:483.
C ASE STUDY ANSWER
There are multiple reasons for this patient’s osteoporo-
sis, including a heavy smoking history, possible alco-
holism, and chronic inflammatory disease treated with
glucocorticoids. High levels of cytokines from the chronic
inflammation activate osteoclasts. Glucocorticoids increase
urinary losses of calcium, suppress bone formation, and
inhibit intestinal calcium absorption as well as decreasing
Mosekilde L et al: The pathogenesis, treatment, and prevention of osteoporosis in
men. Drugs 2013;73:15.
Nemeth EF, Shoback D: Calcimimetic and calcilytic drugs for treating bone
and mineral-related disorders. Best Pract Res Clin Endocrinol Metab
2013;27:373.
Nigwekar SU, Tamez H, Thadhani RI: Vitamin D and chronic kidney disease–
mineral bone disease (CKD–MBD). Bonekey Rep 2014;3:498.
Pettifor JM: Rickets and vitamin D deficiency in children and adolescents. Endo-
crinol Metab Clin North Am 2005;34:537.
Ross AC et al: The 2011 report on dietary reference intakes for calcium and vita-
min D from the Institute of Medicine: What clinicians need to know. J Clin
Endocrinol Metab 2011;96:53.
White KE, Hum JM, Michael J: Econs MJ. Hypophosphatemic rickets: Reveal-
ing novel control points for phosphate homeostasis. Curr Osteoporos Rep
2014;12:252.
Zwolak P, Dudek AZ: Antineoplastic activity of zoledronic acid and denosumab.
Anticancer Res 2013;33:2981.
gonadotropin production, leading to hypogonadism. Man-
agement should include measurement of serum testoster-
one, calcium, 25(OH)D, and the 24-hour urine calcium
and creatinine levels (to verify completeness of collection),
with treatment as appropriate for these secondary causes,
plus initiation of bisphosphonate or denosumab therapy as
primary treatment.
 SECTION VIII  CHEMOTHERAPEUTIC DRUGS
INTRODUCTION TO ANTIMICROBIAL
AGENTS
Antimicrobial agents provide some of the most dramatic exam-
ples of the advances of modern medicine. Many infectious dis-
eases once considered incurable and potentially lethal can now
be treated effectively with antibiotics. The remarkably powerful
and specific activity of antimicrobial drugs is due to their selec-
tivity for targets that are either unique to prokaryote and fungal
microorganisms or much more important in these organisms
than in humans. Among these targets are bacterial and fungal
cell wall-synthesizing enzymes (Chapters 43 and 48), the bacte-
rial ribosome (Chapters 44 and 45), the enzymes required for
nucleotide synthesis and DNA replication (Chapter 46), and
the machinery of viral replication (Chapter 49). The special
group of drugs used in mycobacterial infections is discussed in
Chapter 47. Cytotoxic antiseptics and disinfectants are discussed
in Chapter 50. The clinical uses of many antimicrobial agents
are summarized in Chapter 51.
The major problem threatening the continued success of anti-
microbial drugs is the development of resistant organisms. Anti-
biotic resistance mechanisms existed long before the clinical use
of antibiotics, even resistance to synthetic drugs that were created
in the 20th century. Because resistance mechanisms are already
present in nature, an inevitable consequence of antimicrobial use
is the selection of resistant microorganisms. Since the start of the
antibiotic era, antibiotic use in patients and animals has fueled a
major increase in the prevalence of drug-resistant pathogens. In
recent years, highly resistant Gram-negative organisms with novel
mechanisms of resistance have been increasingly reported. Some
of these strains have spread over vast geographic areas as a result of
patients seeking medical care in different countries.
Much attention has been focused on eliminating the misuse of
antibiotics to slow the tide of resistance. Antibiotics are misused
in a variety of ways, including use in patients who are unlikely
to have bacterial infections, use over unnecessarily prolonged
periods, and use of multiple agents or broad-spectrum agents
when not needed. Large quantities of antibiotics have been used
in agriculture to stimulate growth and prevent infection in live-
stock, and this has added to the selection pressure that results in
resistant organisms. In December 2013, the U.S. Food and Drug
Administration (FDA) announced a program to phase out the
nontherapeutic use of antibiotics in livestock. In 2015, President
Obama announced a 5-year National Action Plan with the goals
of improving antimicrobial stewardship efforts, tools for diagnos-
ing infectious diseases, and surveillance for resistant organisms.
However, even if these programs are successful, it will take years
before the benefits are apparent.
Antibiotic resistance has many negative consequences. The prev-
alence of resistant organisms drives the use of broader-spectrum,
less efficacious, or more toxic antibiotics. Not surprisingly, infec-
tions caused by antibiotic-resistant pathogens are associated with
increased costs, morbidity, and mortality. The Centers for Disease
Control and Prevention estimates that every year in the United
States at least 2 million people acquire infections due to and 23,000
people die from infections caused by resistant bacteria.
Unfortunately, as the need has grown in recent years, develop-
ment of novel antibiotics has slowed. Several of the largest phar-
maceutical companies have abandoned research and development
in this area because of diminished success and profits; the resulting
reduction in new drug introductions is shown in the figure below,
which shows new systemic antibacterial agents approved by the
FDA per 5-year period through 2012. Several new antimicrobial
agents have been approved between 2013 and 2015; however,
most are slight modifications of existing drugs. Some novel tar-
gets are under investigation. For example, tarocin was found to
successfully inhibit teichoic acid, a structure essential for bacterial
cell wall synthesis. When combined with a β-lactam antibiotic in a
mouse model, tarocin effectively killed methicillin-resistant strains
of Staphylococcus aureus that were resistant to either agent alone.
793
794    SECTION VIII  Chemotherapeutic Drugs

These compounds have not yet been studied in humans. Pend- of drugs. In the face of continuing development of resistance,
ing the identification and development of new targets and considerable effort will be required to maintain the effectiveness
compounds, we will have to rely on currently available families of these drug groups.

18

16

14

12
Approvals

10

0
1983–1987 1988–1992 1993–1997 1998–2002 2003–2007 2008–2012

Decline in the number of new systemic antibacterial drugs approved by the FDA over a 30-year period. (Reproduced, with permission, from Boucher
HW et al: 10 × '20 progress-development of new drugs active against Gram-negative bacilli: An update from the Infectious Diseases Society of America. Clin Infect Dis
2013;56:1685. By permission of Oxford University Press on behalf of the Infectious Diseases Society of America. Modified, with permission, from Spellberg B et al: Trends in
antimicrobial drug development: Implications for the future. Clin Infect Dis 2004;38:1279. By permission of Oxford University Press.)

Beta-Lactam & Other Cell
Wall- & Membrane-Active
Antibiotics
Camille E. Beauduy, PharmD, & Lisa G. Winston, MD*
C ASE STUDY
A 45-year-old man is brought to the local hospital emer-
gency department by ambulance. His wife reports that
he had been in his normal state of health until 3 days ago
when he developed a fever and a productive cough. Dur-
ing the last 24 hours he has complained of a headache and
is increasingly confused. His wife reports that his medical
history is significant only for hypertension, for which he
takes hydrochlorothiazide and lisinopril, and that he is
allergic to amoxicillin. She says that he developed a rash
many years ago when prescribed amoxicillin for bron-
chitis. In the emergency department, the man is febrile
■■ BETA-LACTAM COMPOUNDS
PENICILLINS
The penicillins share features of chemistry, mechanism of action,
pharmacology, and immunologic characteristics with cephalospo-
rins, monobactams, carbapenems, and β-lactamase inhibitors.
All are β-lactam compounds, so named because of their four-
membered lactam ring.
Chemistry
All penicillins have the basic structure shown in Figure 43–1. A
thiazolidine ring (A) is attached to a β-lactam ring (B) that car-
ries a secondary amino group (RNH–). Substituents (R; examples
shown in Figure 43–2) can be attached to the amino group.
*
The authors thank Dr. Henry F. Chambers and Dr. Daniel Deck for
their contributions to this chapter in previous editions.
43
C H A P T E R
(38.7°C [101.7°F]), hypotensive (90/54 mmHg), tachypneic
(36/min), and tachycardic (110/min). He has no signs of
meningismus but is oriented only to person. A stat chest
x-ray shows a left lower lung consolidation consistent with
pneumonia. A CT scan is not concerning for lesions or
elevated intracranial pressure. The plan is to start empiric
antibiotics and perform a lumbar puncture to rule out
bacterial meningitis. What antibiotic regimen should be
prescribed to treat both pneumonia and meningitis? Does
the history of amoxicillin rash affect the antibiotic choice?
Why or why not?
Structural integrity of the 6-aminopenicillanic acid nucleus (rings
A plus B) is essential for the biologic activity of these compounds.
Hydrolysis of the β-lactam ring by bacterial β-lactamases yields
penicilloic acid, which lacks antibacterial activity.
A. Classification
Substituents of the 6-aminopenicillanic acid moiety determine the
essential pharmacologic and antibacterial properties of the result-
ing molecules. Penicillins can be assigned to one of three groups
(below). Within each of these groups are compounds that are
relatively stable to gastric acid and suitable for oral administration,
eg, penicillin V, dicloxacillin, and amoxicillin. The side chains of
some representatives of each group are shown in Figure 43–2.
1. Penicillins (eg, penicillin G)—These have greatest activ-
ity against Gram-positive organisms, Gram-negative cocci, and
non-β-lactamase-producing anaerobes. However, they have little
activity against Gram-negative rods, and they are susceptible to
hydrolysis by β-lactamases.
795
796    SECTION VIII  Chemotherapeutic Drugs

H H H H
Amidase S
S CH3
CH3
R N C C C R N CH CH C
CH3 Penicillin CH3
B A H
C N C C N CH COOH
O COOH
Lactamase O
Substituted 6-aminopenicillanic acid
6-Aminopenicillanic acid
The following structures can each be substituted
O H H H
at the R to produce a new penicillin.
S H
R1 C N C C C R
B A H
Cephalosporin
C N C
O C CH2 R2 CH2 Penicillin G
COOH
Substituted 7-aminocephalosporanic acid

OCH2 Penicillin V
O H H H

R C N C C CH3
B Monobactam
C N
C C Oxacillin
O SO3H
N C
Substituted 3-amino-4-methylmonobactamic acid O CH3
(aztreonam)
Cl

HO H H C C Dicloxacillin
HC C C N C
B S R Cl O CH3
H3C
C N
Carbapenem
O COOH
OC2H5
NH
Nafcillin
R: CH2 CH2 NH CH

Substituted 3-hydroxyethylcarbapenemic acid

(imipenem)

CH Ampicillin
FIGURE 43–1  Core structures of four β-lactam antibiotic
NH2
families. The ring marked B in each structure is the β-lactam ring.
The penicillins are susceptible to inactivation by amidases and
lactamases at the points shown. Note that the carbapenems have HO CH Amoxicillin
a different stereochemical configuration in the lactam ring that
imparts resistance to most common β-lactamases. Substituents for NH2
the penicillin and cephalosporin families are shown in Figures 43–2
and 43–6, respectively.
CH

NHCO
2. Antistaphylococcal penicillins (eg, nafcillin)—These Piperacillin
penicillins are resistant to staphylococcal β-lactamases. They N O
are active against staphylococci and streptococci but not against
enterococci, anaerobic bacteria, and Gram-negative cocci and
rods. O
N
3. Extended-spectrum penicillins (aminopenicillins and C2H5
antipseudomonal penicillins)—These drugs retain the anti-
bacterial spectrum of penicillin and have improved activity against
FIGURE 43–2  Side chains of some penicillins (R groups).
Gram-negative rods. Like penicillin, however, they are relatively
susceptible to hydrolysis by β-lactamases.
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     797

B. Penicillin Units and Formulations
The activity of penicillin G was originally defined in units. Crys-
talline sodium penicillin G contains approximately 1600 units
per mg (1 unit = 0.6 mcg; 1 million units of penicillin = 0.6 g).
Semisynthetic penicillins are prescribed by weight rather than
units. The minimum inhibitory concentration (MIC) of any
penicillin (or other antimicrobial) is usually given in mcg/mL.
Most penicillins are formulated as the sodium or potassium salt of
the free acid. Potassium penicillin G contains about 1.7 mEq of
K+ per million units of penicillin (2.8 mEq/g). Nafcillin contains
Na+, 2.8 mEq/g. Procaine salts and benzathine salts of penicillin G
provide repository forms for intramuscular injection. In dry crys-
talline form, penicillin salts are stable for years at 4°C. Solutions
lose their activity rapidly (eg, within 24 hours at 20°C) and must
be prepared fresh for administration.
polysaccharides and peptides known as peptidoglycan. The poly-
saccharide contains alternating amino sugars, N-acetylglucosamine
and N-acetylmuramic acid (Figure 43–4). A five-amino-acid
peptide is linked to the N-acetylmuramic acid sugar. This peptide
terminates in d-alanyl-d-alanine. Penicillin-binding protein (PBP,
an enzyme) removes the terminal alanine in the process of forming
a cross-link with a nearby peptide. Cross-links give the cell wall its
rigidity. Beta-lactam antibiotics, structural analogs of the natural
d-Ala-d-Ala substrate, covalently bind to the active site of PBPs.
This binding inhibits the transpeptidation reaction (Figure 43–5)
and halts peptidoglycan synthesis, and the cell dies. The exact
mechanism of cell death is not completely understood, but auto-
lysins are involved in addition to the disruption of cross linking of
the cell wall. Beta-lactam antibiotics kill bacterial cells only when
they are actively growing and synthesizing cell wall.

Mechanism of Action Resistance

Penicillins, like all β-lactam antibiotics, inhibit bacterial growth
by interfering with the transpeptidation reaction of bacterial cell
wall synthesis. The cell wall is a rigid outer layer that completely
surrounds the cytoplasmic membrane (Figure 43–3), maintains
cell integrity, and prevents cell lysis from high osmotic pressure.
The cell wall is composed of a complex, cross-linked polymer of
Resistance to penicillins and other β-lactams is due to one of four
general mechanisms: (1) inactivation of antibiotic by β-lactamase,
(2) modification of target PBPs, (3) impaired penetration of drug
to target PBPs, and (4) antibiotic efflux. Beta-lactamase produc-
tion is the most common mechanism of resistance. Hundreds
of different β-lactamases have been identified. Some, such as

Porin

Outer
membrane

Cell
wall

Peptidoglycan

β Lactamase
Periplasmic
space

PBP PBP

Cytoplasmic
membrane

FIGURE 43–3  A highly simplified diagram of the cell envelope of a Gram-negative bacterium. The outer membrane, a lipid bilayer, is
present in Gram-negative but not Gram-positive organisms. It is penetrated by porins, proteins that form channels providing hydrophilic
access to the cytoplasmic membrane. The peptidoglycan layer is unique to bacteria and is much thicker in Gram-positive organisms than in
Gram-negative ones. Together, the outer membrane and the peptidoglycan layer constitute the cell wall. Penicillin-binding proteins (PBPs) are
membrane proteins that cross-link peptidoglycan. Beta-lactamases, if present, reside in the periplasmic space or on the outer surface of the
cytoplasmic membrane, where they may destroy β-lactam antibiotics that penetrate the outer membrane.
798    SECTION VIII  Chemotherapeutic Drugs

those produced by Staphylococcus aureus, Haemophilus influenzae,

and Escherichia coli, are relatively narrow in substrate specificity,
preferring penicillins to cephalosporins. Other β-lactamases, eg,
M AmpC β-lactamase produced by Pseudomonas aeruginosa and
M
L-Ala Enterobacter sp and extended-spectrum β-lactamases (ESBLs) in
Enterobacteriaceae, hydrolyze both cephalosporins and penicil-
L-Ala
R
G
lins. Carbapenems are highly resistant to hydrolysis by peni-
R cillinases and cephalosporinases, but they are hydrolyzed by
G metallo-β-lactamases and carbapenemases.
Altered target PBPs are the basis of methicillin resistance in
M staphylococci and of penicillin resistance in pneumococci and
L-Ala
most resistant enterococci. These resistant organisms produce
M
PBPs that have low affinity for binding β-lactam antibiotics, and
L-Ala +
D-Glu
they are not inhibited except at relatively high, often clinically
G
unachievable, drug concentrations.
G D-Glu L-Lys [Gly]5 Resistance due to impaired penetration of antibiotic occurs
only in Gram-negative species because of the impermeable outer
L-Lys [Gly]5* D-Ala * membrane of their cell wall, which is absent in Gram-positive bac-
R teria. Beta-lactam antibiotics cross the outer membrane and enter
D-Ala D-Ala Gram-negative organisms via outer membrane protein channels
called porins. Absence of the proper channel or down-regulation
D-Ala of its production can greatly impair drug entry into the cell. Poor
Transpeptidase penetration alone is usually not sufficient to confer resistance
because enough antibiotic eventually enters the cell to inhibit
growth. However, this barrier can become important in the pres-
ence of a β-lactamase, even a relatively inefficient one, as long as
M
it can hydrolyze drug faster than it enters the cell. Gram-negative
M L-Ala organisms also may produce an efflux pump, which consists of
R
cytoplasmic and periplasmic protein components that efficiently
L-Ala
G transport some β-lactam antibiotics from the periplasm back
R across the cell wall outer membrane.
G

M Pharmacokinetics
M L-Ala Absorption of orally administered drug differs greatly for indi-
vidual penicillins, depending in part on their acid stability and
L-Ala
G protein binding. Gastrointestinal absorption of nafcillin is erratic,
D-Glu
D-Glu
so it is not suitable for oral administration. Dicloxacillin, ampicil-
G lin, and amoxicillin are acid-stable and relatively well absorbed,
producing serum concentrations in the range of 4–8 mcg/mL after
L-Lys [Gly]5 D-Ala L-Lys [Gly]5
a 500-mg oral dose. Absorption of most oral penicillins (amoxicil-
lin being an exception) is impaired by food, and the drugs should
D-Ala
be administered at least 1–2 hours before or after a meal.
Intravenous administration of penicillin G is preferred to
D-Ala + D-Ala
the intramuscular route because of irritation and local pain
from intramuscular injection of large doses. Serum concen-
FIGURE 43–4  The transpeptidation reaction in Staphylococcus trations 30 minutes after an intravenous injection of 1 g of
aureus that is inhibited by β-lactam antibiotics. The cell wall of Gram- penicillin G (equivalent to approximately 1.6 million units) are
positive bacteria is made up of long peptidoglycan polymer chains 20–50 mcg/mL. Only a fraction of the total drug in serum is
consisting of the alternating aminohexoses N-acetylglucosamine (G) present as free drug, the concentration of which is determined by
and N-acetylmuramic acid (M) with pentapeptide side chains linked (in protein binding. Highly protein-bound penicillins (eg, nafcillin)
S aureus) by pentaglycine bridges. The exact composition of the side
generally achieve lower free-drug concentrations in serum than
chains varies among species. The diagram illustrates small segments of
less protein-bound penicillins (eg, penicillin G or ampicillin).
two such polymer chains and their amino acid side chains. These linear
polymers must be cross-linked by transpeptidation of the side chains at
Penicillins are widely distributed in body fluids and tissues with a
the points indicated by the asterisk to achieve the strength necessary for few exceptions. They are polar molecules, so intracellular concen-
cell viability. trations are well below those found in extracellular fluids.
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     799

Peptidoglycan Amino acid peptide

G = N-acetylglucos-amine
(N-Ag)
G M G M G M G M
Bacterial cell wall M = N-acetylmuramic acid
(N-Am)

Periplasmic space M G M G M G M G

Cytoplasmic membrane
G M G M G M G M
Cytoplasm

Schematic of normal bacterial cell wall peptidoglycan

synthesis transpeptidation reaction.

G M + M G G M G M
Transpeptidase

M G M G

Beta-lactams bind the transpeptidase

at the Penicillin Binding Protein site,
resulting in inhibition of transpeptidation,
thus halting peptidoglycan synthesis. No transpeptidation reaction

Transpeptidase β-lactam
G M + M G G M + M G

FIGURE 43–5  Schematic of a bacterial cell wall and normal synthesis of cell wall peptidoglycan via transpeptidation; M, N-acetylmuramic
acid; Glc, glucose; NAcGlc or G, N-acetylglucosamine. Beta-lactams work by binding the transpeptidase at the penicillin-binding protein site,
resulting in inhibition of transpeptidation, thus halting peptidoglycan synthesis.

Benzathine and procaine penicillins are formulated to delay
absorption, resulting in prolonged blood and tissue concentra-
tions. A single intramuscular injection of 1.2 million units of
benzathine penicillin maintains serum levels above 0.02 mcg/mL
for 10 days, sufficient to treat β-hemolytic streptococcal infec-
tions. After 3 weeks, levels still exceed 0.003 mcg/mL, which is
enough to prevent most β-hemolytic streptococcal infections. A
600,000-unit dose of procaine penicillin yields peak concentra-
tions of 1–2 mcg/mL and clinically useful concentrations for
12–24 hours after a single intramuscular injection.
Penicillin concentrations in most tissues are equal to those in
serum. Penicillin is also excreted into sputum and breast milk to
levels 3–15% of those in the serum. Penetration into the eye, the
prostate, and the central nervous system is poor. However, with
active inflammation of the meninges, as in bacterial meningitis,
penicillin concentrations of 1–5 mcg/mL can be achieved with
a daily parenteral dose of 18–24 million units. These concentra-
tions are sufficient to kill susceptible strains of pneumococci and
meningococci.
Penicillin is rapidly excreted by the kidneys; small amounts
are excreted by other routes. Tubular secretion accounts
for about 90% of renal excretion, and glomerular filtration
accounts for the remainder. The normal half-life of penicillin
G is approximately 30 minutes but, in renal failure, may be
as long as 10 hours. Ampicillin and the extended-spectrum
penicillins are secreted more slowly than penicillin G and
have half-lives of 1 hour. For penicillins that are cleared by the
kidney, the dose must be adjusted according to renal function,
with approximately one-fourth to one-third the normal dose
being administered if creatinine clearance is 10 mL/min or less
(Table 43–1).
Nafcillin is primarily cleared by biliary excretion. Oxacillin,
dicloxacillin, and cloxacillin are eliminated by both the kidney
and biliary excretion, and no dosage adjustment is required for
these drugs in patients in renal failure. Because clearance of peni-
cillins is less efficient in the newborn, doses adjusted for weight
alone result in higher systemic concentrations for longer periods
than in the adult.
800    SECTION VIII  Chemotherapeutic Drugs

TABLE 43–1  Guidelines for dosing of some commonly used penicillins.

Adjusted Dose as a Percentage of
Normal Dose for Renal Failure Based
on Creatinine Clearance (Clcr)

Antibiotic (Route of Clcr Approx Clcr Approx

Administration) Adult Dose Pediatric Dose1 Neonatal Dose2 50 mL/min 10 mL/min

Penicillins
  Penicillin G (IV) 1–4 × 106 units 25,000–400,000 units/kg/d 75,000–150,000 units/ 50–75% 25%
q4–6h in 4–6 doses kg/d in 2 or 3 doses
  Penicillin V (PO) 0.25–0.5 g qid 25–75 mg/kg/d in 4 doses   None None
Antistaphylococcal penicillins
 Cloxacillin, 0.25–0.5 g qid 15–25 mg/kg/d in 4 doses   100% 100%
dicloxacillin (PO)
  Nafcillin (IV) 1–2 g q4–6h 100–200 mg/kg/d in 50–75 mg/kg/d in 100% 100%
4–6 doses 2 or 3 doses
  Oxacillin (IV) 1–2 g q4–6h 50–100 mg/kg/d in 50–75 mg/kg/d in 100% 100%
4–6 doses 2 or 3 doses
Extended-spectrum penicillins
  Amoxicillin (PO) 0.25–0.5 g tid 20–40 mg/kg/d in 3 doses   66% 33%
 Amoxicillin/potassium 500/125 mg tid– 20–40 mg/kg/d in 3 doses   66% 33%
clavulanate (PO) 875/125 mg bid
3
 Piperacillin/ 3.375–4.5 g q4–6h 300 mg/kg/d in 4–6 doses 150 mg/kg/d in 50–75% 25–33%
tazobactam (IV) 2 doses3
1
The total dose should not exceed the adult dose.
2
The dose shown is during the first week of life. The daily dose should be increased by approximately 33–50% after the first week of life. The lower dosage range should be used
for neonates weighing less than 2 kg. After the first month of life, pediatric doses may be used.
3
Dose is based on piperacillin component.

Clinical Uses Penicillin V, the oral form of penicillin, is indicated only in

Except for amoxicillin, oral penicillins should be given 1–2 hours
before or after a meal; they should not be given with food to mini-
mize binding to food proteins and acid inactivation. Amoxicillin
may be given without regard to meals. Blood levels of all penicil-
lins can be raised by simultaneous administration of probenecid,
0.5 g (10 mg/kg in children) every 6 hours orally, which impairs
renal tubular secretion of weak acids such as β-lactam compounds.
Penicillins, like all antibacterial antibiotics, should never be used
for viral infections and should be prescribed only when there is
reasonable suspicion of, or documented infection with, susceptible
organisms.
A. Penicillin
Penicillin G is a drug of choice for infections caused by strep-
tococci, meningococci, some enterococci, penicillin-susceptible
pneumococci, staphylococci confirmed to be non-β-lactamase-
producing, Treponema pallidum and certain other spirochetes,
some Clostridium species, Actinomyces and certain other Gram-
positive rods, and non-β-lactamase-producing Gram-negative
anaerobic organisms. Depending on the organism, the site, and
the severity of infection, effective doses range between 4 and
24 million units per day administered intravenously in four to
six divided doses. High-dose penicillin G can also be given as a
continuous intravenous infusion.
minor infections because of its relatively poor bioavailability, the
need for dosing four times a day, and its narrow antibacterial spec-
trum. Amoxicillin (see below) is often used instead.
Benzathine penicillin and procaine penicillin G for intra-
muscular injection yield low but prolonged drug levels. A single
intramuscular injection of benzathine penicillin, 1.2 million units,
is effective treatment for β-hemolytic streptococcal pharyngitis.
Given intramuscularly once every 3–4 weeks, it prevents reinfec-
tion. Benzathine penicillin G, 2.4 million units intramuscularly
once a week for 1–3 weeks, is effective in the treatment of syphilis.
Procaine penicillin G was once a commonly used treatment for
pneumococcal pneumonia and gonorrhea; however, it is rarely
used now because many gonococcal strains are penicillin-resistant,
and many pneumococci require higher doses of penicillin G or the
use of more potent β-lactams.
B. Penicillins Resistant to Staphylococcal Beta-
Lactamase (Methicillin, Nafcillin, and Isoxazolyl Penicillins)
These semisynthetic penicillins are indicated for infections caused
by β-lactamase-producing staphylococci, although penicillin-
susceptible strains of streptococci and pneumococci are also sus-
ceptible to these agents. Listeria monocytogenes, enterococci, and
methicillin-resistant strains of staphylococci are resistant. In recent
years the empirical use of these drugs has decreased substantially
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     801
because of increasing rates of methicillin resistance in staphylo-
cocci. However, for infections caused by methicillin-susceptible
and penicillin-resistant strains of staphylococci, these are consid-
ered drugs of choice.
An isoxazolyl penicillin such as dicloxacillin, 0.25–0.5 g orally
every 4–6 hours (15–25 mg/kg/d for children), is suitable for
treatment of mild to moderate localized staphylococcal infections.
These drugs are relatively acid-stable and have reasonable bioavail-
ability. However, food interferes with absorption, and the drugs
should be administered 1 hour before or after meals.
Methicillin, the first antistaphylococcal penicillin to be devel-
oped, is no longer used clinically due to high rates of adverse
effects. Oxacillin and nafcillin, 8–12 g/d, given by intermittent
intravenous infusion of 1–2 g every 4–6 hours (50–200 mg/kg/d
for children), are considered drugs of choice for serious staphylo-
coccal infections such as endocarditis.
C. Extended-Spectrum Penicillins (Aminopenicillins,
Carboxypenicillins, and Ureidopenicillins)
These drugs have greater activity than penicillin against Gram-
negative bacteria because of their enhanced ability to penetrate
the Gram-negative outer membrane. Like penicillin G, they are
inactivated by many β-lactamases.
The aminopenicillins, ampicillin and amoxicillin, have very
similar spectrums of activity, but amoxicillin is better absorbed
orally. Amoxicillin, 250–500 mg three times daily, is equivalent to
the same amount of ampicillin given four times daily. Amoxicillin
is given orally to treat bacterial sinusitis, otitis, and lower respira-
tory tract infections. Ampicillin and amoxicillin are the most active
of the oral β-lactam antibiotics against pneumococci with elevated
MICs to penicillin and are the preferred β-lactam antibiotics for
treating infections suspected to be caused by these strains. Ampi-
cillin (but not amoxicillin) is effective for shigellosis. Ampicillin,
at dosages of 4–12 g/d intravenously, is useful for treating serious
infections caused by susceptible organisms, including anaerobes,
enterococci, L monocytogenes, and β-lactamase-negative strains of
Gram-negative cocci and bacilli such as E coli, and Salmonella sp.
Non-β-lactamase-producing strains of H influenzae are generally
susceptible, but strains that are resistant because of altered PBPs
are emerging. Due to production of β-lactamases by Gram-
negative bacilli, ampicillin can no longer be used for empirical
therapy of urinary tract infections and typhoid fever. Ampicillin
is not active against Klebsiella sp, Enterobacter sp, P aeruginosa,
Citrobacter sp, Serratia marcescens, indole-positive Proteus species,
and other Gram-negative aerobes that are commonly encountered
in hospital-acquired infections. These organisms intrinsically pro-
duce β-lactamases that inactivate ampicillin.
The carboxypenicillins, carbenicillin and ticarcillin, were
developed to broaden the spectrum of penicillins against Gram-
negative pathogens, including P aeruginosa; however, neither
agent is available in the USA. The ureidopenicillin piperacillin is
also active against many Gram-negative bacilli, such as Klebsiella
pneumoniae and P aeruginosa. Piperacillin is available only as a
co-formulation with the β-lactamase inhibitor tazobactam. Due
to the propensity of P aeruginosa to develop resistance during
therapy, an antipseudomonal β-lactam is sometimes used in com-
bination with an aminoglycoside or fluoroquinolone, particularly
in infections outside the urinary tract, despite a lack of data sup-
porting combination therapy over single-drug therapy.
Ampicillin, amoxicillin, piperacillin, and, historically, ticarcil-
lin, are available in combination with one of several β-lactamase
inhibitors: clavulanic acid, sulbactam, or tazobactam. The
addition of a β-lactamase inhibitor extends the activity of these
penicillins to include β-lactamase-producing strains of S aureus as
well as some β-lactamase-producing Gram-negative bacteria (see
Beta-Lactamase Inhibitors).
Adverse Reactions
The penicillins are generally well tolerated, and, unfortunately,
this may encourage inappropriate use. Most of the serious adverse
effects are due to hypersensitivity. The antigenic determinants are
degradation products of penicillins, particularly penicilloic acid
and products of alkaline hydrolysis bound to host protein. A his-
tory of a penicillin reaction is not reliable. About 5–8% of people
claim such a history, but only a small number of these will have
a serious reaction when given penicillin. Less than 1% of persons
who previously received penicillin without incident will have an
allergic reaction when given penicillin. Because of the potential
for anaphylaxis, however, penicillin should be administered with
caution or a substitute drug given if the person has a history of
serious penicillin allergy. Penicillin skin testing may also be used
to evaluate Type I hypersensitivity. If skin testing is negative, most
patients can safely receive penicillin.
Allergic reactions include anaphylactic shock (very rare—0.05%
of recipients); serum sickness–type reactions (now rare—urticaria,
fever, joint swelling, angioedema, pruritus, and respiratory com-
promise occurring 7–12 days after exposure); and a variety of skin
rashes. Oral lesions, fever, interstitial nephritis (an autoimmune
reaction to a penicillin-protein complex), eosinophilia, hemolytic
anemia and other hematologic disturbances, and vasculitis may
also occur. Most patients allergic to penicillins can be treated
with alternative drugs. However, if necessary (eg, treatment of
enterococcal endocarditis or neurosyphilis in a patient with seri-
ous penicillin allergy), desensitization can be accomplished with
gradually increasing doses of penicillin.
In patients with renal failure, penicillin in high doses can
cause seizures. Nafcillin is associated with neutropenia and
interstitial nephritis; oxacillin can cause hepatitis; and methi-
cillin commonly caused interstitial nephritis (and is no longer
used for this reason). Large doses of penicillins given orally may
lead to gastrointestinal upset, particularly nausea, vomiting, and
diarrhea. Ampicillin has been associated with pseudomembra-
nous colitis. Secondary infections such as vaginal candidiasis
may occur. Ampicillin and amoxicillin can be associated with
skin rashes when prescribed in the setting of viral illnesses,
particularly noted during acute Epstein-Barr virus infection,
but the incidence of rash may be lower than originally reported.
Piperacillin-tazobactam, when combined with vancomycin, has
been associated with greater incidence of acute kidney injury
compared to alternate β-lactam agents.
802    SECTION VIII  Chemotherapeutic Drugs

■■ CEPHALOSPORINS & O

CEPHAMYCINS R1 C NH
B
S
A
N R2
O
Cephalosporins are similar to penicillins but are more stable COO
–

to many bacterial β-lactamases and, therefore, have a broader N N

R1 R2
N N
spectrum of activity. However, strains of E coli and Klebsiella sp Cefazolin N CH2
CH2 S CH3
expressing extended-spectrum β-lactamases that can hydrolyze N S

most cephalosporins are a growing clinical concern. Cephalo- Cephalexin CH CH3

sporins are not active against L monocytogenes, and of the avail- NH2

able cephalosporins, only ceftaroline has some activity against Cefadroxil HO CH CH3
enterococci. NH2

O
Cefoxitin
Chemistry S
CH2 CH2 O C NH2

The nucleus of the cephalosporins, 7-aminocephalosporanic acid Cefaclor CH Cl

(Figure 43–6), bears a close resemblance to 6-aminopenicillanic NH2
acid (Figure 43–1). The intrinsic antimicrobial activity of HO

natural cephalosporins is low, but the attachment of various R1 Cefprozil CH CH CH3

and R2 groups has yielded hundreds of potent compounds, many O

NH
C 2
O
with low toxicity. Cephalosporins have traditionally been classi- Cefuroxime O
N CH2 C NH2
fied into four major groups or generations, depending mainly O
OCH3
N N
on the spectrum of antimicrobial activity. Several cephalosporins 1 H2NC C C S C
CH2 S N
Cefotetan N
developed more recently do not fit the traditional classification HOOC S
CH3
groups. Their unique characteristics and spectra of activity are N C
O
Cefotaxime
outlined below. H 2N S
N
OCH3
CH2 O C CH3

N C
1
Cefpodoxime N
CH2 O CH3

FIRST-GENERATION CEPHALOSPORINS H 2N
O
S
OH
OCH3

C
First-generation cephalosporins include cefazolin, cefadroxil, Ceftibuten
C H
N
cephalexin, cephalothin, cephapirin, and cephradine; cefazolin H2N
S
and cephalexin are the only two available in the USA. These drugs H2N
OH
S
are very active against Gram-positive cocci, such as streptococci Cefdinir
N CH CH2
N
and staphylococci. Traditional cephalosporins are not active C
H
N C H3C
against methicillin-resistant strains of staphylococci; however, Ceftriaxone N
N N O

new compounds have been developed that have activity against H2N S OCH3
N O
CH2 S
methicillin-resistant strains (see below). E coli, K pneumoniae, and N C
CH3
N
Proteus mirabilis are often sensitive to first-generation cephalo- Ceftazidime
H2N S O C COOH
CH2 N
sporins, but activity against P aeruginosa, indole-positive Proteus CH3

species, Enterobacter sp, S marcescens, Citrobacter sp, and Acineto- N C

CH2 N+
bacter sp is poor. Anaerobic cocci (eg, peptococci, peptostrepto- Cefepime
H2N S
N
OCH3 CH3
cocci) are usually sensitive, but Bacteroides fragilis is not.
O
N N+ CH3
N N
Pharmacokinetics & Dosage Ceftaroline S
N
S
S
H2N
A. Oral S
H2N N
Cephalexin is the oral first generation agent widely used in N
the USA. After oral doses of 500 mg, peak serum levels are N O
Ceftolozane R1 NH
15–20 mcg/mL. Urine concentration is usually very high, but in O N
NH
most tissues levels are variable and generally lower than in serum. H3C OH
H3C
N
N
H 3C
Cephalexin is typically given in oral dosages of 0.25–0.5 g four O

times daily (15–30 mg/kg/d). Excretion is mainly by glomerular

filtration and tubular secretion into the urine. Drugs that block FIGURE 43–6  Structures of some cephalosporins. R1 and R2
tubular secretion, eg, probenecid, may increase serum levels sub- structures are substituents on the 7-aminocephalosporanic acid
stantially. In patients with impaired renal function, dosage must nucleus pictured at the top. Other structures (cefoxitin and below)
be reduced (Table 43–2). are complete in themselves. 1Additional substituents not shown.
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     803

TABLE 43–2  Guidelines for dosing of some commonly used cephalosporins and other cell-wall inhibitor antibiotics.
Adjusted Dose as a Percentage
of Normal Dose for Renal Failure
Based on Creatinine Clearance (Clcr)

Antibiotic (Route of Clcr Approx Clcr Approx

Administration) Adult Dose Pediatric Dose1 Neonatal Dose2 50 mL/min 10 mL/min

First-generation cephalosporins
  Cephalexin (PO) 0.25–0.5 g qid 25–50 mg/kg/d in 4 doses   50% 25%
  Cefazolin (IV) 0.5–2 g q8h 25–100 mg/kg/d in 3 or 4   50% 25%
doses
Second-generation cephalosporins
  Cefoxitin (IV) 1–2 g q6–8h 75–150 mg/kg/d in 3 or 4   50–75% 25%
doses
  Cefotetan (IV) 1–2 g q12h     50% 25%
  Cefuroxime (IV) 0.75–1.5 g q8h 50–100 mg/kg/d in 3 or   66% 25–33%
4 doses
Third- and fourth-generation cephalosporins including ceftaroline fosamil
  Cefotaxime (IV) 1–2 g q6–12h 50–200 mg/kg/d in 4–6 doses 100 mg/kg/d in 2 doses 50% 25%
  Ceftazidime (IV) 1–2 g q8–12h 75–150 mg/kg/d in 3 doses 100–150 mg/kg/d in 50% 25%
2 or 3 doses
  Ceftriaxone (IV) 1–4 g q24h 50–100 mg/kg/d in 1 or 50 mg/kg/d qd None None
2 doses
  Cefepime (IV) 0.5–2 g q12h 75–120 mg/kg/d in 2 or   50% 25%
3 divided doses
  Ceftaroline fosamil (IV) 600 mg q12h     50–66% 33%
Cephalosporin–β-lactamase inhibitor combinations
 Ceftazidime- 2.5 g q8h     25–50% 6.25–12.5%
avibactam (IV)
 Ceftolozane- 1.5 g q8h     25–50% Not studied
tazobactam (IV)
Carbapenems
  Ertapenem (IM or IV) 1 g q24h     100%3 50%
 Doripenem 500 mg q8h     50% 33%
  Imipenem (IV) 0.25–0.5 g q6–8h     75% 50%
  Meropenem (IV) 1 g q8h (2 g q8h 60–120 mg/kg/d in 3 doses   66% 50%
for meningitis) (maximum of 2 g q8h)
Glycopeptides
  Vancomycin (IV) 30–60 mg/kg/d in 40 mg/kg/d in 3 or 4 doses 15 mg/kg load, then 40% 10%
2–3 doses 20 mg/kg/d in 2 doses
  Telavancin (IV) 10 mg/kg daily     75% 50%
  Dalbavancin (IV) 1000 mg on day 1,     None 75%
500 mg day 8 >30 mL/min
Alternative:
1500 mg × 1
  Oritavancin (IV) 1200 mg × 1     None Not studied
>30 mL/min
Lipopeptides (IV)
 Daptomycin 4–6 mg/kg IV daily     None 50%
>30 mL/min
1
The total dose should not exceed the adult dose.
2
The dose shown is during the first week of life. The daily dose should be increased by approximately 33–50% after the first week of life. The lower dosage range should be used
for neonates weighing less than 2 kg. After the first month of life, pediatric doses may be used.
3
50% of dose for Clcr <30 mL/min.
804    SECTION VIII  Chemotherapeutic Drugs
B. Parenteral
Cefazolin is the only first-generation parenteral cephalosporin
still in general use. After an intravenous infusion of 1 g, the
peak level of cefazolin is approximately 185 mcg/mL. The usual
intravenous dosage of cefazolin for adults is 0.5–2 g intravenously
every 8 hours. Cefazolin can also be administered intramuscularly.
Excretion is via the kidney, and dose adjustments must be made
for impaired renal function.
Clinical Uses
Oral drugs may be used for the treatment of urinary tract infec-
tions and staphylococcal or streptococcal infections, including cel-
lulitis or soft tissue abscess. However, oral cephalosporins should
not be relied on in serious systemic infections.
Cefazolin penetrates well into most tissues. It is a drug of choice
for surgical prophylaxis and for many streptococcal and staphylo-
coccal infections requiring intravenous therapy. Cefazolin may be
used for infections due to E coli or K pneumoniae when the organ-
ism has been documented to be susceptible. Cefazolin does not
penetrate the central nervous system and cannot be used to treat
meningitis. Cefazolin is better tolerated than antistaphylococcal
penicillins, and it has been shown to be effective for serious staphy-
lococcal infections, eg, bacteremia. It can also be used in patients
with mild penicillin allergy other than immediate hypersensitivity.
SECOND-GENERATION
CEPHALOSPORINS
Members of the second-generation cephalosporins include
cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil,
loracarbef, and ceforanide—of which cefaclor, cefuroxime,
and cefprozil are available in the USA—and the structurally
related cephamycins cefoxitin and cefotetan, which have activity
against anaerobes. This is a heterogeneous group with individual
differences in activity, pharmacokinetics, and toxicity. In general,
second-generation cephalosporins are relatively active against
organisms inhibited by first-generation drugs, but, in addition,
they have extended Gram-negative coverage. Klebsiella sp (includ-
ing those resistant to first-generation cephalosporins) are usually
sensitive. Cefuroxime and cefaclor are active against H influenzae
but not against Serratia or B fragilis. In contrast, cefoxitin and
cefotetan are active against B fragilis and some Serratia strains
but are less active against H influenzae. As with first-generation
agents, no member of this group is active against enterococci or
P aeruginosa. Compared with other cephalosporins, cefoxitin
shows improved stability in the presence of extended-spectrum
β-lactamases produced by E coli and Klebsiella sp. Clinical data
are limited, but it may offer an alternative to carbapenems in
treating certain infections due to these organisms. Second-
generation cephalosporins may exhibit in vitro activity against
Enterobacter sp, but resistant mutants that constitutively express a
chromosomal β-lactamase that hydrolyzes these compounds (and
third-generation cephalosporins) are readily selected, and they
should not be used to treat Enterobacter infections.
Pharmacokinetics & Dosage
A. Oral
Cefuroxime axetil is the most commonly used oral cephalosporin
in the USA. The usual dosage for adults is 250–500 mg orally
twice daily; children should be given 20–40 mg/kg/d up to a
maximum of 1 g/d. These drugs are not predictably active against
penicillin-non-susceptible pneumococci.
B. Parenteral
After a 1-g intravenous infusion, serum levels are 75–125 mcg/mL
for most second-generation cephalosporins. Intramuscular admin-
istration is painful and should be avoided. Doses and dosing
intervals vary depending on the specific agent (Table 43–2). There
are differences in half-life, protein binding, and interval between
doses. All are renally cleared and require dosage adjustment in
renal failure.
Clinical Uses
The oral second-generation cephalosporins are active against
β-lactamase-producing H influenzae or Moraxella catarrhalis and
have been used primarily to treat sinusitis, otitis, and lower respi-
ratory tract infections. Because of their activity against anaerobes
(including many B fragilis strains), cefoxitin and cefotetan can be
used to treat mixed anaerobic infections such as peritonitis, diver-
ticulitis, and pelvic inflammatory disease. Cefuroxime is some-
times used to treat community-acquired pneumonia because it is
active against β-lactamase-producing H influenzae and also many
pneumococci. Although cefuroxime crosses the blood-brain bar-
rier, it is less effective in treatment of meningitis than ceftriaxone
or cefotaxime and should not be used.
THIRD-GENERATION CEPHALOSPORINS
Third-generation agents include cefoperazone, cefotaxime, ceftazi-
dime, ceftizoxime, ceftriaxone, cefixime, cefpodoxime proxetil,
cefdinir, cefditoren pivoxil, ceftibuten, and moxalactam. Cefo-
perazone, ceftizoxime, and moxalactam are no longer commer-
cially available in the USA.
Antimicrobial Activity
Compared with second-generation agents, these drugs have
expanded Gram-negative coverage, and some are able to cross the
blood-brain barrier. Third-generation drugs may be active against
Citrobacter, S marcescens, and Providencia. They are also effective
against β-lactamase-producing strains of Haemophilus and Neis-
seria. Ceftazidime is the only agent with useful activity against
P aeruginosa. Like the second-generation drugs, third-generation
cephalosporins are hydrolyzed by constitutively produced AmpC
β-lactamase, and they are not reliably active against Enterobacter
species. Serratia, Providencia, Acinetobacter, and Citrobacter also
produce a chromosomally encoded cephalosporinase that, when
constitutively expressed, can confer resistance to third-generation
cephalosporins. Cefixime, cefdinir, ceftibuten, and cefpodoxime
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     805
proxetil are oral agents possessing similar activity except that cefix-
ime and ceftibuten are much less active against pneumococci and
have poor activity against S aureus.
Pharmacokinetics & Dosage
Intravenous infusion of 1 g of a parenteral cephalosporin produces
serum levels of 60–140 mcg/mL. Third-generation cephalosporins
penetrate body fluids and tissues well and intravenous cephalospo-
rins achieve levels in the cerebrospinal fluid sufficient to inhibit
most susceptible pathogens.
The half-lives of these drugs and the necessary dosing
intervals vary greatly: ceftriaxone (half-life 7–8 hours) can be
injected once every 24 hours at a dosage of 15–50 mg/kg/d. A
single daily 1-g dose is sufficient for most serious infections,
with 2 g every 12 hours recommended for treatment of men-
ingitis and 2 g every 24 hours recommended for endocarditis.
The remaining drugs in the group (half-life 1–1.7 hours) can
be infused every 6–8 hours in dosages between 2 and 12 g/d,
depending on the severity of infection. Cefixime can be given
orally (200 mg twice daily or 400 mg once daily) for urinary
tract infections. Due to increasing resistance, cefixime is no
longer recommended for the treatment of uncomplicated
gonococcal urethritis and cervicitis. Intramuscular ceftriaxone
in combination with azithromycin is the regimen of choice
for treating most gonococcal infections. The adult dose for
cefpodoxime proxetil or cefditoren pivoxil is 200–400 mg
twice daily; for ceftibuten, 400 mg once daily; and for cefdinir,
300 mg/12 h. Ceftriaxone excretion is mainly through the
biliary tract, and no dosage adjustment is required in renal
insufficiency. The other third-generation cephalosporins are
excreted by the kidney and therefore require dosage adjustment
in renal insufficiency.
Clinical Uses
Third-generation cephalosporins are used to treat a wide variety of
serious infections caused by organisms that are resistant to most
other drugs. Strains expressing extended-spectrum β-lactamases,
however, are not susceptible. Third-generation cephalosporins
should be avoided in treatment of Enterobacter infections—even
if the clinical isolate appears susceptible in vitro—because of
emergence of resistance. Ceftriaxone and cefotaxime are approved
for treatment of meningitis, including meningitis caused by pneu-
mococci, meningococci, H influenzae, and susceptible enteric
Gram-negative rods, but not by L monocytogenes. Ceftriaxone and
cefotaxime are the most active cephalosporins against penicillin-
non-susceptible strains of pneumococci and are recommended
for empirical therapy of serious infections that may be caused
by these strains. Meningitis caused by strains of pneumococci
with penicillin MICs >1 mcg/mL may not respond even to these
agents, and addition of vancomycin is recommended. Other
potential indications include empirical therapy of sepsis in both
the immunocompetent and the immunocompromised patient
and treatment of infections for which a cephalosporin is the least
toxic drug available.
FOURTH-GENERATION
CEPHALOSPORINS
Cefepime is the only available fourth-generation cephalosporin.
It is more resistant to hydrolysis by chromosomal β-lactamases
(eg, those produced by Enterobacter). However, like the third-
generation compounds, it is hydrolyzed by extended-spectrum
β-lactamases. Cefepime has good activity against P aeruginosa,
Enterobacteriaceae, methicillin-susceptible S aureus, and S pneu-
moniae. It is highly active against Haemophilus and Neisseria sp. It
penetrates well into cerebrospinal fluid. It is cleared by the kidneys
and has a half-life of 2 hours, and its pharmacokinetic proper-
ties are very similar to those of ceftazidime. Unlike ceftazidime,
however, cefepime has good activity against most penicillin-non-
susceptible strains of streptococci, and it is useful in treatment of
Enterobacter infections. The standard dose for cefepime is 1–2 g
infused every 12 hours; however, when treating more complicated
infections due to P aeruginosa or in the setting of immunocom-
promise, doses are typically increased to 2 g every 8 hours. Because
of its broad-spectrum activity, cefepime is commonly used empiri-
cally in patients presenting with febrile neutropenia, in combina-
tion with other agents.
Cephalosporins Active against Methicillin-
Resistant Staphylococci
Beta-lactam antibiotics with activity against methicillin-resistant
staphylococci are currently under development. Ceftaroline
fosamil, the prodrug of the active metabolite ceftaroline, is the
first such drug to be approved for clinical use in the USA. Cef-
taroline has increased binding to penicillin-binding protein 2a,
which mediates methicillin resistance in staphylococci, resulting
in bactericidal activity against these strains. It has some in vitro
activity against enterococci and a broad Gram-negative spectrum
similar to ceftriaxone. It is not active against AmpC or extended-
spectrum β-lactamase-producing organisms. Ceftaroline is cur-
rently approved for the treatment of skin and soft tissue infections
and community-acquired pneumonia at a dose of 600 mg infused
every 12 hours. It has been used off-label to treat complicated
infections such as bacteremia, endocarditis, and osteomyelitis,
sometimes in combination with other agents and often at an
increased dose of 600 mg every 8 hours. The normal half-life
is about 2.7 hours; ceftaroline is primarily excreted renally and
requires dose adjustment in renal impairment.
Cephalosporins Combined with
a-lactamase Inhibitors
Novel cephalosporin-β-lactamase inhibitor combinations have
been developed to combat resistant Gram-negative infections;
see the subsequent section for more information on β-lactamase
inhibitors. Ceftolozane-tazobactam and ceftazidime-avibactam
were both FDA-approved for the treatment of complicated
intra-abdominal infections and urinary tract infections. Both
agents have potent in vitro activity against Gram-negative organ-
isms, including P aeruginosa and AmpC and extended-spectrum
806    SECTION VIII  Chemotherapeutic Drugs

β-lactamase producing Enterobacteriaceae. While neither agent is
active against organisms producing metallo-β-lactamases, ceftazi-
dime-avibactam may be an option for carbapenemase-producing
organisms. Due to limited activity against anaerobic pathogens,
both should be combined with metronidazole when treating
complicated intra-abdominal infections. Both agents have short
half-lives of 2–3 hours and are dosed every 8 hours. Both are
primarily renally excreted and require dose adjustment in patients
with impaired renal clearance.
ADVERSE EFFECTS OF
CEPHALOSPORINS
A. Allergy
Like penicillins, cephalosporins may elicit a variety of hyper-
sensitivity reactions, including anaphylaxis, fever, skin rashes,
nephritis, granulocytopenia, and hemolytic anemia. Patients
with documented penicillin anaphylaxis have an increased risk
of reacting to cephalosporins compared with patients without a
history of penicillin allergy. However, the chemical nucleus of
cephalosporins is sufficiently different from that of penicillins
such that many individuals with a history of penicillin allergy tol-
erate cephalosporins. Overall, the frequency of cross-allergenicity
between the two groups of drugs is low (~1%). Cross-allergenicity
appears to be most common among penicillin, aminopenicillins,
and early-generation cephalosporins, which share similar R-1 side
chains. Patients with a history of anaphylaxis to penicillins should
not receive first- or second-generation cephalosporins, while third-
and fourth-generation cephalosporins should be administered
with caution, preferably in a monitored setting.
reactions; consequently, alcohol and alcohol-containing medica-
tions must be avoided.
■■ OTHER BETA-LACTAM DRUGS
MONOBACTAMS
Monobactams are drugs with a monocyclic β-lactam ring
(Figure 43–1). Their spectrum of activity is limited to aerobic
Gram-negative organisms (including P aeruginosa). Unlike other
β-lactam antibiotics, they have no activity against Gram-positive
bacteria or anaerobes. Aztreonam is the only monobactam avail-
able in the USA. It has structural similarities to ceftazidime,
and its Gram-negative spectrum is similar to that of the third-
generation cephalosporins. It is stable to many β-lactamases with
notable exceptions being AmpC β-lactamases and extended-
spectrum β-lactamases. It penetrates well into the cerebrospinal
fluid. Aztreonam is given intravenously every 8 hours in a dose of
1–2 g, providing peak serum levels of 100 mcg/mL. The half-life
is 1–2 hours and is greatly prolonged in renal failure.
Penicillin-allergic patients tolerate aztreonam without reaction.
Notably, because of its structural similarity to ceftazidime, there is
potential for cross-reactivity; aztreonam should be used with caution
in the case of documented severe allergies to ceftazidime. Occasional
skin rashes and elevations of serum aminotransferases occur during
administration of aztreonam, but major toxicity is uncommon. In
patients with a history of penicillin anaphylaxis, aztreonam may be
used to treat serious infections such as pneumonia, meningitis, and
sepsis caused by susceptible Gram-negative pathogens.

B. Toxicity BETA-LACTAMASE INHIBITORS

Local irritation can produce pain after intramuscular injection
and thrombophlebitis after intravenous injection. Renal toxicity,
including interstitial nephritis and tubular necrosis, may occur
uncommonly.
Cephalosporins that contain a methylthiotetrazole group may
cause hypoprothrombinemia and bleeding disorders. Historically,
this group included cefamandole, cefmetazole, and cefoperazone;
however, cefotetan is the only methylthiotetrazole-containing
agent used in the USA. Oral administration of vitamin K, 10 mg
twice weekly, can prevent this uncommon problem. Drugs with
the methylthiotetrazole ring can also cause severe disulfiram-like
(CLAVULANIC ACID, SULBACTAM,
TAZOBACTAM, & AVIBACTAM)
Traditional β-lactamase inhibitors (clavulanic acid, sulbactam,
and tazobactam) resemble β-lactam molecules (Figure 43–7), but
they have very weak antibacterial action. They are potent inhibi-
tors of many but not all bacterial β-lactamases and can protect
hydrolyzable penicillins from inactivation by these enzymes. The
traditional β-lactamase inhibitors are most active against Ambler
class A β-lactamases (plasmid-encoded transposable element
[TEM] β-lactamases in particular), such as those produced by

– O
O O
S C
CH3
H2C CH O H2C CH H 2N
CH2 R
C N C N
C N
O CH CH2OH O COOH R= N N C N
COOH R=H N O OSO3–
Clavulanic acid Sulbactam Tazobactam Avibactam

FIGURE 43–7  Beta-lactamase inhibitors.

 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     807
staphylococci, H influenzae, N gonorrhoeae, Salmonella, Shigella,
E coli, and K pneumoniae. They are not good inhibitors of class
C β-lactamases, which typically are chromosomally encoded
and inducible, produced by Enterobacter sp, Citrobacter sp,
S marcescens, and P aeruginosa, but they do inhibit chromosomal
β-lactamases of B fragilis and M catarrhalis. The novel non-β-
lactam β-lactamase inhibitor avibactam is active against Ambler
class A β-lactamases but also active against Ambler class C and
some Ambler class D β-lactamases.
Beta-lactamase inhibitors are available only in fixed combi-
nations with specific penicillins and cephalosporins. (The fixed
combinations available in the USA are listed in Preparations
Available.) An inhibitor extends the spectrum of its compan-
ion β-lactam provided that the inactivity against a particular
organism is due to destruction by a β-lactamase and that the
inhibitor is active against the β-lactamase that is produced. Thus,
ampicillin-sulbactam is active against β-lactamase-producing
S aureus and H influenzae but not against Serratia, which produces
a β-lactamase that is not inhibited by sulbactam. Similarly, if a
strain of P aeruginosa is resistant to piperacillin, it is also resistant
to piperacillin-tazobactam because tazobactam does not inhibit
the chromosomal β-lactamase produced by P aeruginosa.
Beta-lactam–β-lactamase inhibitor combinations are fre-
quently used as empirical therapy for infections caused by a wide
range of potential pathogens in both immunocompromised and
immunocompetent patients. Adjustments for renal insufficiency
are made based on the β-lactam component.
CARBAPENEMS
The carbapenems are structurally related to other β-lactam anti-
biotics (Figure 43–1). Doripenem, ertapenem, imipenem, and
meropenem are licensed for use in the USA. Imipenem, the first
drug of this class, has a wide spectrum with good activity against
most Gram-negative rods, including P aeruginosa, Gram-positive
organisms, and anaerobes. It is resistant to most β-lactamases but
not carbapenemases or metallo-β-lactamases. Enterococcus faecium,
methicillin-resistant strains of staphylococci, Clostridium difficile,
Burkholderia cepacia, and Stenotrophomonas maltophilia are resistant.
Imipenem is inactivated by dehydropeptidases in renal tubules,
resulting in low urinary concentrations. Consequently, it is admin-
istered together with an inhibitor of renal dehydropeptidase, cilas-
tatin, for clinical use. Doripenem and meropenem are similar to
imipenem but have slightly greater activity against Gram-negative
aerobes and slightly less activity against Gram-positives. They are
not significantly degraded by renal dehydropeptidase and do not
require an inhibitor. Unlike the other carbapenems, ertapenem does
not have appreciable activity against P aeruginosa and Acinetobacter
species. It is not degraded by renal dehydropeptidase.
Carbapenems penetrate body tissues and fluids well, including
the cerebrospinal fluid for all but ertapenem. All are cleared renally,
and the dose must be reduced in patients with renal insufficiency.
The usual dosage of imipenem is 0.25–0.5 g given intravenously
every 6–8 hours (half-life 1 hour). The usual adult dosage of
meropenem is 0.5–1 g intravenously every 8 hours. The usual adult
dosage of doripenem is 0.5 g administered as a 1- or 4-hour infu-
sion every 8 hours. Ertapenem has the longest half-life (4 hours)
and is administered as a once-daily dose of 1 g intravenously or
intramuscularly. Intramuscular ertapenem is irritating, and the drug
is formulated with 1% lidocaine for administration by this route.
A carbapenem is indicated for infections caused by suscep-
tible organisms that are resistant to other available drugs, eg,
P aeruginosa, and for treatment of mixed aerobic and anaerobic
infections. Carbapenems are active against many penicillin-non-
susceptible strains of pneumococci. Carbapenems are highly
active in the treatment of Enterobacter infections because they
are resistant to destruction by the β-lactamase produced by these
organisms. Clinical experience suggests that carbapenems are also
the treatment of choice for serious infections caused by extended-
spectrum β-lactamase-producing Gram-negative bacteria. Ertape-
nem is insufficiently active against P aeruginosa and should not
be used to treat infections caused by this organism. Imipenem,
meropenem, or doripenem, with or without an aminoglycoside,
may be effective treatment for febrile neutropenic patients.
The most common adverse effects of carbapenems—which
tend to be more common with imipenem—are nausea, vomiting,
diarrhea, skin rashes, and reactions at the infusion sites. Exces-
sive levels of imipenem in patients with renal failure may lead
to seizures. Meropenem, doripenem, and ertapenem are much
less likely to cause seizures than imipenem. Patients allergic to
penicillins may be allergic to carbapenems, but the incidence of
cross-reactivity is thought to be less than 1%.
■■ GLYCOPEPTIDE ANTIBIOTICS
VANCOMYCIN
Vancomycin is an antibiotic isolated from the bacterium now
known as Amycolatopsis orientalis. It is active primarily against
Gram-positive bacteria due to its large molecular weight and
lack of penetration through Gram-negative cell membranes. The
intravenous product is water soluble and stable for 14 days in the
refrigerator following reconstitution.
Mechanisms of Action & Basis of
Resistance
Vancomycin inhibits cell wall synthesis by binding firmly to the
d-Ala-d-Ala terminus of nascent peptidoglycan pentapeptide
(Figure 43–8). This inhibits the transglycosylase, preventing
further elongation of peptidoglycan and cross-linking. The pep-
tidoglycan is thus weakened, and the cell becomes susceptible to
lysis. The cell membrane is also damaged, which contributes to
the antibacterial effect.
Resistance to vancomycin in enterococci is due to modifica-
tion of the d-Ala-d-Ala binding site of the peptidoglycan building
block in which the terminal d-Ala is replaced by d-lactate. This
results in the loss of a critical hydrogen bond that facilitates high-
affinity binding of vancomycin to its target and loss of activity.
This mechanism is also present in vancomycin-resistant S aureus
808    SECTION VIII  Chemotherapeutic Drugs

Peptidoglycan Amino acid peptide

G = N-acetylglucos-amine
(N-Ag)
G M G M G M G M
Bacterial cell wall M = N-acetylmuramic acid
(N-Am)

Periplasmic space M G M G M G M G

Cytoplasmic membrane
G M G M G M G M
Cytoplasm

Schematic of normal bacterial cell wall peptidoglycan

synthesis transpeptidation reaction.

G M + M G G M G M
Transpeptidase
Crosslinking

M G M G

Vancomycin binds the D-Alanine D-Alanine

terminus of the amino acid peptide, inhibiting V
crosslinkage. V A
A N
N

Vancomycin
G M + M G G M M G

V No crosslinking
A
N

FIGURE 43–8  Schematic of a bacterial cell wall and normal synthesis of cell wall peptidoglycan via transpeptidation; M, N-acetylmuramic
acid; Glc, glucose; NAcGlc or G, N-acetylglucosamine. Vancomycin binds the d-Alanine d-Alanine (d-Ala d-Ala) terminus of the amino acid
peptide, inhibiting cross-linkage of the cell wall.

strains (MIC ≥ 16 mcg/mL), which have acquired the enterococcal
resistance determinants. The underlying mechanism for reduced
vancomycin susceptibility in vancomycin-intermediate strains
(MIC = 4–8 mcg/mL) of S aureus is not fully known. However,
these strains have altered cell wall metabolism that results in a
thickened cell wall with increased numbers of d-Ala-d-Ala resi-
dues, which serve as dead-end binding sites for vancomycin. Van-
comycin is sequestered within the cell wall by these false targets
and may be unable to reach its site of action.
Antibacterial Activity
Vancomycin is bactericidal for Gram-positive bacteria in con-
centrations of 0.5–10 mcg/mL. Most pathogenic staphylococci,
including those producing β-lactamase and those resistant to naf-
cillin and methicillin, are killed by 2 mcg/mL or less. Vancomycin
kills staphylococci relatively slowly and only if cells are actively
dividing; the rate is less than that of the penicillins both in vitro
and in vivo. Vancomycin is synergistic in vitro with gentamicin
and streptomycin against Enterococcus faecium and Enterococcus
faecalis strains that do not exhibit high levels of aminoglycoside
resistance. Vancomycin is active against many Gram-positive
anaerobes including C difficile.
Pharmacokinetics
Vancomycin is poorly absorbed from the intestinal tract and is
administered orally only for the treatment of colitis caused by
C difficile. Parenteral doses must be administered intravenously.
A 1-hour intravenous infusion of 1 g produces blood levels of
15–30 mcg/mL for 1–2 hours. The drug is widely distributed
in the body including adipose tissue. Cerebrospinal fluid levels
7–30% of simultaneous serum concentrations are achieved if there
is meningeal inflammation. Ninety percent of the drug is excreted
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     809
by glomerular filtration. In the presence of renal insufficiency,
striking accumulation may occur (Table 43–2). In functionally
anephric patients, the half-life of vancomycin is 6–10 days. A
significant amount of vancomycin is removed during a standard
hemodialysis run using a high-flux membrane.
Clinical Uses
Important indications for parenteral vancomycin are bloodstream
infections and endocarditis caused by methicillin-resistant staphy-
lococci. However, vancomycin is not as effective as an antistaphy-
lococcal penicillin for treatment of serious infections such as
endocarditis caused by methicillin-susceptible strains. Vancomy-
cin in combination with gentamicin is an alternative regimen for
treatment of enterococcal endocarditis in a patient with serious
penicillin allergy. Vancomycin (in combination with cefotaxime,
ceftriaxone, or rifampin) is also recommended for treatment
of meningitis suspected or known to be caused by a penicillin-
resistant strain of pneumococcus. The recommended dosage in
a patient with normal renal function is 30–60 mg/kg/d in two
or three divided doses. The traditional dosing regimen in adults
with normal renal function is 1 g every 12 hours (~30 mg/kg/d);
however, this dose will not typically achieve the trough concentra-
tions (15–20 mcg/mL) recommended for serious infections. For
serious infections (see below), a starting dose of 45–60 mg/kg/d
should be given with titration of the dose to achieve trough levels
of 15–20 mcg/mL. The dosage in children is 40 mg/kg/d in
three or four divided doses. Clearance of vancomycin is directly
proportional to creatinine clearance, and the dosage is reduced
accordingly in patients with renal insufficiency. For patients
receiving hemodialysis, a common dosing regimen is a 1-g load-
ing dose followed by 500 mg after each dialysis session. Patients
receiving a prolonged course of therapy should have serum trough
concentrations checked. For S aureus infections, recommended
trough concentrations are 10–15 mcg/mL for mild to moderate
infections and 15–20 mcg/mL for more serious infections such as
endocarditis, meningitis, and necrotizing pneumonia.
Oral vancomycin, 0.125–0.5 g every 6 hours, is used to treat
colitis caused by C difficile. Because of the emergence of vancomy-
cin-resistant enterococci and the potential selective pressure of oral
vancomycin for these resistant organisms, metronidazole had been
preferred as initial therapy. However, use of oral vancomycin does
not appear to be a significant risk factor for acquisition of van-
comycin-resistant enterococci. Additionally, recent clinical data
suggest that vancomycin is associated with higher initial response
rates than metronidazole, particularly for moderate to severe cases
of C difficile colitis. Therefore, oral vancomycin may be used as a
first-line treatment, especially for severe cases.
Adverse Reactions
Adverse reactions with parenteral administration of vancomycin
are encountered fairly frequently. Most reactions are relatively
minor and reversible. Vancomycin is irritating to tissue, resulting
in phlebitis at the site of injection. Chills and fever may occur.
Ototoxicity is rare but nephrotoxicity is still encountered regu-
larly with current preparations, especially with high trough levels.
Administration with another ototoxic or nephrotoxic drug, such
as an aminoglycoside, increases the risk of these toxicities. Ototox-
icity can be minimized by maintaining peak serum concentrations
below 60 mcg/mL. Among the more common reactions is the
so-called “red man” syndrome. This infusion-related flushing is
caused by release of histamine. It can be largely prevented by pro-
longing the infusion period to 1–2 hours (preferred) or pretreat-
ment with an antihistamine such as diphenhydramine.
TEICOPLANIN
Teicoplanin is a glycopeptide antibiotic that is very similar to
vancomycin in mechanism of action and antibacterial spectrum.
Unlike vancomycin, it can be given intramuscularly as well as
intravenously. Teicoplanin has a long half-life (45–70 hours),
permitting once-daily dosing. This drug is available in Europe but
has not been approved for use in the USA.
TELAVANCIN
Telavancin is a semisynthetic lipoglycopeptide derived from van-
comycin. Telavancin is active versus Gram-positive bacteria and
has in vitro activity against many strains with reduced susceptibil-
ity to vancomycin. Telavancin has two mechanisms of action. Like
vancomycin, telavancin inhibits cell wall synthesis by binding to
the d-Ala-d-Ala terminus of peptidoglycan in the growing cell
wall. In addition, it disrupts the bacterial cell membrane potential
and increases membrane permeability. The half-life of telavancin
is approximately 8 hours, which supports once-daily intravenous
dosing. The drug is approved for treatment of complicated skin
and soft tissue infections and hospital-acquired pneumonia at a
dose of 10 mg/kg IV daily. Unlike vancomycin therapy, monitor-
ing of serum telavancin levels is not required. Telavancin was asso-
ciated with substantial nephrotoxicity and concern for increased
mortality associated with renal impairment in clinical trials, lead-
ing to boxed warnings. It is potentially teratogenic, so administra-
tion to pregnant women must be avoided.
DALBAVANCIN AND ORITAVANCIN
Dalbavancin and oritavancin are semisynthetic lipoglycopeptides
derived from teicoplanin. Dalbavancin and oritavancin inhibit cell
wall synthesis via the same mechanism of action as vancomycin
and teicoplanin; oritavancin works by additional mechanisms,
including disruption of cell membrane permeability and inhibi-
tion of RNA synthesis. Compared with vancomycin, both agents
have lower MICs against many Gram-positive bacteria including
methicillin-resistant and vancomycin-intermediate S aureus. Dal-
bavancin is not active against most strains of vancomycin-resistant
enterococci (VRE). Oritavancin has in vitro activity against VRE,
but its clinical utility in treating VRE infections remains unclear.
Both agents have extremely long half-lives of greater than 10 days,
which allows for once-weekly intravenous administration. Dal-
bavancin and oritavancin have been approved for the treatment
810    SECTION VIII  Chemotherapeutic Drugs
of skin and soft tissue infections. There are limited clinical data
supporting the use of dalbavancin for uncomplicated catheter-
associated bloodstream infections, though it is not approved for
use in this setting. Dalbavancin was originally approved as a two-
dose, once-weekly intravenous regimen (1000 mg infused on day
1 and 500 mg infused on day 8), but a subsequent phase 3 study
comparing the two-dose regimen with a single, 1500-mg intra-
venous dose showed that the single-dose regimen is noninferior.
The results of this study allowed for updated labelling, making
both dalbavancin and oritavancin appropriate for single-dose
treatments for complicated skin and soft tissue infections. A prac-
tical difference between the two is the infusion time: dalbavancin
can be administered over 30 minutes, while oritavancin must be
infused over 3 hours. Neither requires dose adjustment in mild
to moderate renal or hepatic impairment, and neither is removed
by dialysis.
■■ OTHER CELL WALL- OR
MEMBRANE-ACTIVE AGENTS
DAPTOMYCIN
Daptomycin is a novel cyclic lipopeptide fermentation product of
Streptomyces roseosporus (Figure 43–9). Its spectrum of activity is
similar to that of vancomycin except that it may be active against
vancomycin-resistant strains of enterococci and S aureus. In vitro,
it has more rapid bactericidal activity than vancomycin. The pre-
cise mechanism of action is not fully understood, but it is known
to bind to the cell membrane via calcium-dependent insertion of
its lipid tail. This results in depolarization of the cell membrane
with potassium efflux and rapid cell death (Figure 43–10). Dap-
tomycin is cleared renally. The approved doses are 4 mg/kg/dose
for treatment of skin and soft tissue infections and 6 mg/kg/dose
for treatment of bacteremia and endocarditis once daily in patients
with normal renal function and every other day in patients with
creatinine clearance of less than 30 mL/min. For serious infec-
tions, many experts recommend using 8–10 mg/kg/dose. These
higher doses appear to be safe and well tolerated, although
L-Asp D-Ala L-Asp
L-Orn Gly L-Thr
L-Asp
FIGURE 43–9  Structure of daptomycin. (Kyn, deaminated tryptophan.)
evidence supporting increased efficacy is lacking. In clinical tri-
als, daptomycin was noninferior in efficacy to vancomycin. It
can cause myopathy, and creatine phosphokinase levels should be
monitored weekly. Pulmonary surfactant antagonizes daptomycin,
and it should not be used to treat pneumonia. Daptomycin can
also cause an allergic pneumonitis in patients receiving prolonged
therapy (>2 weeks). Treatment failures have been reported in
association with an increase in daptomycin MIC during therapy.
Daptomycin is an effective alternative to vancomycin, and its role
continues to unfold.
FOSFOMYCIN
Fosfomycin trometamol, a stable salt of fosfomycin (phosphono-
mycin), inhibits a very early stage of bacterial cell wall synthesis.
An analog of phosphoenolpyruvate, it is structurally unrelated to
any other antimicrobial agent. It inhibits the cytoplasmic enzyme
enolpyruvate transferase by covalently binding to the cysteine resi-
due of the active site and blocking the addition of phosphoenol-
pyruvate to UDP-N-acetylglucosamine. This reaction is the first
step in the formation of UDP-N-acetylmuramic acid, the precur-
sor of N-acetylmuramic acid, which is found only in bacterial cell
walls. The drug is transported into the bacterial cell by glycero-
phosphate or glucose 6-phosphate transport systems. Resistance is
due to inadequate transport of drug into the cell.
Fosfomycin is active against both Gram-positive and Gram-
negative organisms at concentrations ≥ 125 mcg/mL. Susceptibil-
ity tests should be performed in growth medium supplemented
with glucose 6-phosphate to minimize false-positive indications of
resistance. In vitro synergism occurs when fosfomycin is combined
with β-lactam antibiotics, aminoglycosides, or fluoroquinolones.
Fosfomycin trometamol is available in both oral and par-
enteral formulations, although only the oral preparation is
approved for use in the USA. Oral bioavailability is approxi-
mately 40%. Peak serum concentrations are 10 mcg/mL and
30 mcg/mL following a 2-g or 4-g oral dose, respectively. The
half-life is approximately 4 hours. The active drug is excreted
by the kidney, with urinary concentrations exceeding MICs for
most urinary tract pathogens.
Gly D-Ser 3-MeGlu (L-theo)
O
=
O C L-Kyn
L-Asn L-Trp NH
O
=
Decanoic acid
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     811

Daptomycin

Ca2+
Step 1

Ca2+ Step 2 Step 3

Ca2+

K+

FIGURE 43–10  Proposed mechanism of action of daptomycin. Daptomycin first binds to the cytoplasmic membrane (step 1) and then
forms complexes in a calcium-dependent manner (steps 2 and 3). Complex formation causes a rapid loss of cellular potassium, possibly by pore
formation, and membrane depolarization. This is followed by arrest of DNA, RNA, and protein synthesis resulting in cell death. Cell lysis does not
occur.

Fosfomycin is approved for use as a single 3-g dose for treat-
ment of uncomplicated lower urinary tract infections (UTI) in
women. Limited data in case reports have suggested efficacy in
males with UTI and prostatitis; in these cases, a 3-g dose has
been given every 3 days for 9 days when treating UTI or 21 days
for prostatitis. There are no supportive data for using fosfomycin
to treat pyelonephritis. The drug appears to be safe for use in
pregnancy.
BACITRACIN
Bacitracin is a cyclic peptide mixture first obtained from the Tracy
strain of Bacillus subtilis in 1943. It is active against Gram-positive
microorganisms. Bacitracin inhibits cell wall formation by inter-
fering with dephosphorylation in cycling of the lipid carrier that
transfers peptidoglycan subunits to the growing cell wall. There
is no cross-resistance between bacitracin and other antimicrobial
drugs.
Bacitracin is highly nephrotoxic when administered systemi-
cally and is only used topically (Chapter 61). Bacitracin is poorly
absorbed, and topical application results in local antibacterial
activity. Bacitracin, 500 units/g in an ointment base (often com-
bined with polymyxin or neomycin), is used for the treatment of
infections due to mixed bacterial flora in surface lesions of the
skin or on mucous membranes. Bacitracin is commonly associated
with hypersensitivity and should not be applied to wounds for the
purpose of preventing infection.
CYCLOSERINE
Cycloserine is an antibiotic produced by Streptomyces orchidaceous.
It is water soluble and very unstable at acid pH. Cycloserine
inhibits many Gram-positive and Gram-negative organisms, but it
is used almost exclusively to treat tuberculosis caused by strains of
Mycobacterium tuberculosis resistant to first-line agents. Cycloser-
ine is a structural analog of d-alanine and inhibits the incorpora-
tion of d-alanine into peptidoglycan pentapeptide by inhibiting
alanine racemase, which converts l-alanine to d-alanine, and
d-alanyl-d-alanine ligase. After ingestion of 0.25 g of cycloserine
blood levels reach 20–30 mcg/mL—sufficient to inhibit many
strains of mycobacteria and Gram-negative bacteria. The drug is
widely distributed in tissues. Most of the drug is excreted in active
form into the urine. The dosage for treating tuberculosis is 0.5 to
1 g/d in two or three divided doses.
Cycloserine causes serious, dose-related central nervous system
toxicity with headaches, tremors, acute psychosis, and convul-
sions. If oral dosages are maintained below 0.75 g/d, such effects
can usually be avoided.
812    SECTION VIII  Chemotherapeutic Drugs

SUMMARY  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics

Subclass, Mechanism of Pharmacokinetics,
Drug Action Effects Clinical Applications Toxicities, Interactions

PENICILLINS
  •  Penicillin G Prevents bacterial cell
wall synthesis by binding
to and inhibiting cell wall
transpeptidases
Rapid bactericidal activity Streptococcal infections, IV administration • rapid renal clearance (half-life
against susceptible bacteria meningococcal infections, 30 min, so requires dosing every 4 h) • Toxicity:
neurosyphilis Immediate hypersensitivity, rash, seizures

  •  Penicillin V: Oral, low systemic levels limit widespread use

  •  Benzathine penicillin, procaine penicillin: Intramuscular, long-acting formulations
  •  Nafcillin, oxacillin: Intravenous, added stability to staphylococcal β-lactamase, biliary clearance
  • Ampicillin, amoxicillin, piperacillin: Greater activity versus Gram-negative bacteria; addition of β-lactamase inhibitor restores activity against many β-lactamase-producing bacteria

CEPHALOSPORINS
  •  Cefazolin Prevents bacterial cell
wall synthesis by binding
to and inhibiting cell wall
transpeptidases
Rapid bactericidal activity Skin and soft tissue IV administration • renal clearance (half-life 1.5 h)
against susceptible bacteria infections, urinary tract • given every 8 h • poor penetration into the
infections, surgical central nervous system (CNS) • Toxicity: Rash,
prophylaxis drug fever

  •  Cephalexin: Oral, first-generation drug used for treating skin and soft tissue infections and urinary tract infections
  •  Cefuroxime: Oral and intravenous, second-generation drug, improved activity versus pneumococcus and Haemophilus influenzae
  •  Cefotetan, cefoxitin: Intravenous, second-generation drugs, activity versus Bacteroides fragilis allows for use in abdominal/pelvic infections
  • Ceftriaxone: Intravenous, third-generation drug, mixed clearance with long half-life (6 hours), good CNS penetration, many uses including pneumonia, meningitis,
pyelonephritis, and gonorrhea
  •  Cefotaxime: Intravenous, third-generation, similar to ceftriaxone; however, clearance is renal and half-life is 1 hour
  •  Ceftazidime: Intravenous, third-generation drug, poor Gram-positive activity, good activity versus Pseudomonas aeruginosa
  •  Cefepime: Intravenous, fourth-generation drug, broad activity with improved stability to chromosomal β-lactamases
  •  Ceftaroline: Intravenous, active against methicillin-resistant staphylococci, broad Gram-negative activity not including Pseudomonas aeruginosa
  • Ceftazidime-avibactam, ceftolozane-tazobactam: Intravenous, cephalosporin-β-lactamase inhibitor combination drugs, broad activity with improved stability to
chromosomal β-lactamase and some extended-spectrum β-lactamases

CARBAPENEMS
  • Imipenem- Prevents bacterial cell Rapid bactericidal activity Serious infections such as IV administration • renal clearance (half-life 1 h),
cilastatin wall synthesis by binding against susceptible bacteria pneumonia and sepsis dosed every 6–8 h, cilastatin added to prevent
to and inhibiting cell wall hydrolysis by renal dehydropeptidase • Toxicity:
transpeptidases Seizures especially in renal failure or with high
doses (>2 g/d)

  •  Meropenem, doripenem: Intravenous, similar activity to imipenem; stable to renal dehydropeptidase, lower incidence of seizures
  •  Ertapenem: Intravenous, longer half-life allows for once-daily dosing, lacks activity versus Pseudomonas aeruginosa and Acinetobacter

MONOBACTAMS
  •  Aztreonam Prevents bacterial cell
wall synthesis by binding
to and inhibiting cell wall
transpeptidases
Rapid bactericidal activity Infections caused by aerobic, IV administration • renal clearance half-life 1.5 h
against susceptible bacteria Gram-negative bacteria in • dosed every 8 h • Toxicity: No cross-allergenicity
patients with immediate with penicillins
hypersensitivity to penicillins

GLYCOPEPTIDE
  •  Vancomycin Inhibits cell wall synthesis
by binding to the d-Ala-d-
Ala terminus of nascent
peptidoglycan
Bactericidal activity against
susceptible bacteria, slower
kill than β-lactam
antibiotics
Infections caused by
Gram-positive bacteria
including sepsis, endocarditis,
and meningitis • C difficile
colitis (oral formulation)
Oral, IV administration • renal clearance (half-life
6 h) • starting dose of 30 mg/kg/d in two or three
divided doses in patients with normal renal
function • trough concentrations of
10–15 mcg/mL sufficient for most infections
• Toxicity: “Red man” syndrome • nephrotoxicity

  •  Teicoplanin: Intravenous, similar to vancomycin except that long half-life (45–70 h) permits once-daily dosing
  •  Dalbavancin: Intravenous, very long half-life (>10 days) permits once-weekly dosing
  •  Oritavancin: Intravenous, very long half-life (>10 days) permits once-weekly dosing
  •  Telavancin: Intravenous, once-daily dosing

LIPOPEPTIDE
  •  Daptomycin Binds to cell membrane,
causing depolarization
and rapid cell death
Bactericidal activity against
susceptible bacteria • more
rapidly bactericidal than
vancomycin
Infections caused by Gram-
positive bacteria including
sepsis and endocarditis
IV administration • renal clearance (half-life 8 h)
• dosed once daily • inactivated by pulmonary
surfactant so cannot be used to treat pneumonia
• Toxicity: Myopathy • monitoring of weekly
creatine phosphokinase levels recommended
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     813

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

PENICILLINS Broad-spectrum (third- & fourth-generation) cephalosporins
Amoxicillin Generic, Amoxil, others  Cefdinir Generic
Amoxicillin/potassium Generic, Augmentin   Cefditoren pivoxil Spectracef
clavulanate*  Cefepime Generic, Maxipime
Ampicillin Generic  Cefixime Suprax
Ampicillin/sulbactam sodium† Generic, Unasyn  Cefotaxime Generic, Claforan
Dicloxacillin Generic, Dynapen   Cefpodoxime proxetil Generic
Nafcillin Generic, Nallpen   Ceftaroline fosamil Teflaro
Oxacillin Generic, Bactocill  Ceftazidime Generic, Fortaz, Tazicef
Penicillin G Generic, Pfizerpen Ceftazidime/avibactam§ Avycaz
Penicillin G benzathine Permapen, Bicillin L-A  Ceftibuten Generic, Cedax
Penicillin G procaine Generic Ceftolozane/tazobactam|| Zerbaxa
Penicillin V Generic, V-Cillin, Pen-Vee K,  Ceftriaxone Generic, Rocephin
others Monobactam & Carbapenems
Piperacillin and tazobactam Zosyn  Aztreonam Generic, Azactam, Cayston
‡
sodium
 Doripenem Doribax
CEPHALOSPORINS & OTHER BETA-LACTAM DRUGS
 Ertapenem Invanz
Narrow-spectrum (first-generation) cephalosporins
 Imipenem/cilastatin Generic, Primaxin IM, Primaxin IV
 Cefadroxil Generic
 Meropenem Generic, Merrem IV
 Cefazolin Generic, Ancef, Kefzol
OTHER DRUGS DISCUSSED IN THIS CHAPTER
 Cephalexin Generic, Keflex, others
Cycloserine Generic
Intermediate-spectrum (second-generation) cephalosporins
Dalbavancin Dalvance
 Cefaclor Generic Daptomycin Cubicin
 Cefotetan Generic, Cefotan Fosfomycin Monurol
 Cefoxitin Generic Oritavancin Orbactiv
 Cefprozil Generic Telavancin Vibativ
 Cefuroxime Generic, Ceftin, Zinacef Vancomycin Generic, Vancocin
*
Clavulanate content varies with the formulation; see package insert.
†
Sulbactam content is half the ampicillin content.
‡
Tazobactam content is 12.5% of the piperacillin content.
§
Avibactam content is 25% of the ceftazidime content.
||
Tazobactam content is half the ceftolozane content.

REFERENCES Corey GR et al: Single-dose oritavancin versus 7-10 days of vancomycin in the
treatment of gram-positive acute bacterial skin and skin structure infections:
Biek D et al: Ceftaroline fosamil: A novel broad-spectrum cephalosporin with The SOLO II noninferiority study. Clin Infect Dis 2015;60:254.
expanded Gram-positive activity. J Antimicrob Chemother 2010;65(Suppl
DePestel DD et al: Cephalosporin use in treatment of patients with penicillin aller-
4):iv9.
gies. J Am Pharm Assoc 2008;48:530.
Billeter M et al: Dalbavancin: A novel once-weekly lipoglycopeptide antibiotic.
Fowler VG et al: Daptomycin versus standard therapy for bacteremia and endocar-
Clin Infect Dis 2008;46:577.
ditis caused by Staphylococcus aureus. N Engl J Med 2006;355:653.
Boucher HW et al: Once-weekly dalbavancin versus daily conventional therapy for
Jacoby GA, Munoz-Price LS: The new beta-lactamases. N Engl J Med
skin infection. N Engl J Med 2014;370:2169.
2005;352:380.
Carpenter CF, Chambers HF: Daptomycin: Another novel agent for treating
Keating GM, Perry CM: Ertapenem: A review of its use in the treatment of bacte-
infections due to drug-resistant gram-positive pathogens. Clin Infect Dis
rial infections. Drugs 2005;65:2151.
2004;38:994.
Kerneis S et al: Cefoxitin as a carbapenem-sparing antibiotic for infections caused
Centers for Disease Control and Prevention (CDC): Antibiotic resistance threats
by extended-spectrum beta-lactamase producing Escherichia coli and Klebsi-
in the United States, 2013. Available at: www.cdc.gov/drugresistance/
ella pneumoniae. Infect Dis 2015;47:789.
threat-report-2013/.
Lee SH et al: TarO-specific inhibitors of wall teichoic acid biosynthesis restore
Chang C et al: Overview of penicillin allergy. Clinic Rev Allerg Immunol
β-lactam efficacy against methicillin-resistant staphylococci. Sci Transl Med
2012;43:84.
2016;8:329.
Chovel-Sella A et al: The incidence of rash after amoxicillin treatment in children
with infectious mononucleosis. Pediatrics 2013;131:1424.
814    SECTION VIII  Chemotherapeutic Drugs
Leonard SN, Rybak MJ: Telavancin: An antimicrobial with a multifunctional
mechanism of action for the treatment of serious gram-positive infections.
Pharmacotherapy 2008;28:458.
Mandell L: Doripenem: A new carbapenem in the treatment of nosocomial infec-
tions. Clin Infect Dis 2009;49(Suppl 1):S1.
Marston HD et al: Antimicrobial resistance. JAMA 2016;316:1193.
Noskin GA et al: National trends in Staphylococcus aureus infection rates: Impact
on economic burden and mortality over a 6-year period. Clin Infect Dis
2007;45:1132.
Rybak M et al: Therapeutic monitoring of vancomycin in adult patients: A con-
sensus review of the American Society of Health-System Pharmacists, the
C ASE STUDY ANSWER
An intravenous third-generation cephalosporin (ceftriaxone
or cefotaxime) with adequate penetration into inflamed
meninges that is active against the common bacteria that
cause community-acquired pneumonia and meningitis
(pneumococcus, meningococcus, Haemophilus) should be
ordered. Vancomycin also should be administered until
culture and sensitivity results are available in case the patient
is infected with a resistant pneumococcus. Although the
Infectious Diseases Society of America, and the Society of Infectious Diseases
Pharmacists. Am J Health Syst Pharm 2009;66:82.
Sievart DM et al: Vancomycin-resistant Staphylococcus aureus in the United
States, 2002-2006. Clin Infect Dis 2008;46:668.
Tamma PD et al: The use of cefepime for treating AmpC β-lactamase-producing
enterobacteriaceae. Clin Infect Dis 2013;57:781.
Van Duin D and Bonomo RA: Ceftazidime/avibactam and ceftolozane/tazobac-
tam: Second-generation β-lactam/β-lactamase combinations. Clin Infect
Dis 2016;63;234.
Zar FA et al: A comparison of vancomycin and metronidazole for the treatment of
Clostridium difficile-associated diarrhea. Clin Infect Dis 2007;45:302.
patient has a history of rash to amoxicillin, the presentation
was not consistent with an anaphylactic reaction. The ami-
nopenicillins are frequently associated with rashes that are
not caused by Type I hypersensitivity. In this instance, cross-
reactivity with a cephalosporin is unlikely—particularly
with a third-generation drug—and the patient presents with
life-threatening illness necessitating appropriate and proven
antibiotic coverage.
 44
C H A P T E R

Tetracyclines,
Macrolides, Clindamycin,
Chloramphenicol,
Streptogramins, &
Oxazolidinones
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD

C ASE STUDY

A 22-year-old woman presents to her college medical clinic
complaining of a 2-week history of vaginal discharge. She
denies any fever or abdominal pain but does report vaginal
bleeding after sexual intercourse. When questioned about
her sexual activity, she reports having vaginal intercourse,
at times unprotected, with two men in the last 6 months. A
pelvic examination is performed and is positive for muco-
purulent discharge from the endocervical canal. No cervical
motion tenderness is present. A first-catch urine specimen is
obtained for chlamydia and gonorrhea nucleic acid amplifi-
cation testing. A urine pregnancy test is also ordered as the
patient reports she “missed her last period.” Pending these
results, the decision is made to treat her presumptively for
chlamydial cervicitis. What are two potential treatment
options for her possible chlamydial infection? How does her
potential pregnancy affect the treatment decision?

The drugs described in this chapter inhibit bacterial protein OH O OH O

OH
synthesis by binding to and interfering with ribosomes. Most are 11 1 O
10 12 C
bacteriostatic, but a few are bactericidal against certain organ- 9 2
NH2
isms. Tetracycline and macrolide resistance is common. Except 8
7
3
OH
6 5 4
for tigecycline and the streptogramins, these antibiotics may be R6 OH H R5 H N(CH3)2
R7
administered orally. Renal
Clearance
R7 R6 R5 (mL/min)

■■ TETRACYCLINES
Chlortetracycline CI CH3 H 35
Oxytetracycline H CH3 OH 90
Tetracycline H CH3 H 65
Demeclocycline CI H H 35
All of the tetracyclines have the basic structure shown at right: Methacycline H CH2* OH 31
Doxycycline H CH3* OH 16
Minocycline N(CH3)2 H H 10
*There is no OH at position 6 on methacycline and doxycycline.

815
816    SECTION VIII  Chemotherapeutic Drugs

Free tetracyclines are crystalline amphoteric substances of low
solubility. They are available as hydrochlorides, which are more
soluble. Such solutions are acidic and fairly stable. Tetracyclines
chelate divalent metal ions, which can interfere with their absorp-
tion and activity. Tigecycline is a glycylcycline and a semisynthetic
derivative of minocycline.
Mechanism of Action & Antimicrobial
Activity
Tetracyclines are broad-spectrum bacteriostatic antibiotics that
inhibit protein synthesis. Tetracyclines enter microorganisms in
part by passive diffusion and in part by an energy-dependent
process of active transport. Susceptible organisms concentrate
the drug intracellularly. Once inside the cell, tetracyclines bind
reversibly to the 30S subunit of the bacterial ribosome, block-
ing the binding of aminoacyl-tRNA to the acceptor site on the
mRNA-ribosome complex (Figure 44–1). This prevents addition
of amino acids to the growing peptide.
Tetracyclines are active against many Gram-positive and Gram-
negative bacteria, including certain anaerobes, rickettsiae, chla-
mydiae, and mycoplasmas. For susceptible organisms, differences
in clinical efficacy may be attributable to features of absorption,
distribution, and excretion of individual drugs. Tetracycline-
resistant strains may be susceptible to doxycycline, minocycline,
and tigecycline, all of which are poor substrates for the efflux
pump, if that is the mechanism of resistance.
Resistance
Three mechanisms of resistance to tetracycline analogs have
been described: (1) impaired influx or increased efflux by
an active transport protein pump; (2) ribosome protection
due to production of proteins that interfere with tetracycline
binding to the ribosome; and (3) enzymatic inactivation. The
most important of these are production of an efflux pump
and ribosomal protection. Tet(AE) efflux pump-expressing
Gram-negative species are resistant to the older tetracyclines,

50S
ribosome

Amino acid
1 C
6
2
M
3

4
2 t6
5 6 1

Charged
tRNA
t5 4
t6
3

mRNA
30S
T

t5 Uncharged tRNA

FIGURE 44–1  Steps in bacterial protein synthesis and targets of several antibiotics. Amino acids are shown as numbered circles. The 70S
ribosomal mRNA complex is shown with its 50S and 30S subunits. In step 1, the charged tRNA unit carrying amino acid 6 binds to the acceptor
site on the 70S ribosome. The peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid chain to amino
acid 6 (peptide bond formation, step 2). The uncharged tRNA left at the donor site is released (step 3), and the new 6-amino acid chain with its
tRNA shifts to the peptidyl site (translocation, step 4). The antibiotic binding sites are shown schematically as triangles. Chloramphenicol (C) and
macrolides (M) bind to the 50S subunit and block peptide bond formation (step 2). The tetracyclines (T) bind to the 30S subunit and prevent
binding of the incoming charged tRNA unit (step 1).
 CHAPTER 44  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones     817
doxycycline, and minocycline. They are susceptible, how-
ever, to tigecycline, which is not a substrate of these pumps.
Similarly, a different pump [Tet(K)] of staphylococci confers
resistance to tetracycline, but not to doxycycline, minocycline,
or tigecycline, none of which are pump substrates. The Tet(M)
ribosomal protection protein expressed by Gram-positives
produces resistance to tetracycline, doxycycline, and mino-
cycline, but not to tigecycline, which, because of its bulky
t-butylglycylamido substituent, has a steric hindrance effect on
Tet(M) binding to the ribosome. Tigecycline is a substrate of
the chromosomally encoded multidrug efflux pumps of Proteus
sp and Pseudomonas aeruginosa, accounting for their intrinsic
resistance to all tetracyclines including tigecycline.
Pharmacokinetics
Tetracyclines differ in their absorption after oral administration
and in their elimination. Absorption after oral administration is
approximately 60–70% for tetracycline and demeclocycline (not
typically used as an antibiotic; see below); and 95–100% for doxy-
cycline and minocycline. Tigecycline is poorly absorbed orally and
must be administered intravenously. A portion of an orally admin-
istered dose of tetracycline remains in the gut lumen, alters intes-
tinal flora, and is excreted in the feces. Absorption occurs mainly
in the upper small intestine and is impaired by multivalent cations
(Ca2+, Mg2+, Fe2+, Al3+); by dairy products and antacids, which
contain multivalent cations; and by alkaline pH. Tetracycline and
demeclocycline should be administered on an empty stomach,
while doxycycline and minocycline absorption is not impaired by
food. Specially buffered doxycycline and minocycline solutions are
formulated for intravenous administration.
Tetracyclines are 40–80% bound by serum proteins. Oral
dosages of 500 mg every 6 hours of tetracycline hydrochlo-
ride produce peak blood levels of 4–6 mcg/mL. Peak levels of
2–4 mcg/mL are achieved with a 200-mg dose of doxycycline or
minocycline. Steady-state peak serum concentrations of tigecy-
cline are 0.6 mcg/mL at the standard dosage. Tetracyclines are dis-
tributed widely to tissues and body fluids except for cerebrospinal
fluid, where concentrations are 10–25% of those in serum. Tet-
racyclines cross the placenta and are also excreted in breast milk.
As a result of chelation with calcium, tetracyclines bind to—and
damage—growing bones and teeth. Carbamazepine, phenytoin,
barbiturates, and chronic alcohol ingestion may shorten the half-
life of tetracycline and doxycycline by 50% due to induction of
hepatic enzymes that metabolize the drugs.
Tetracyclines are excreted mainly in bile and urine. Concen-
trations in bile exceed those in serum tenfold. Some of the drug
excreted in bile is reabsorbed from the intestine (enterohepatic
circulation) and may contribute to maintenance of serum levels.
Ten to fifty percent of various tetracyclines is excreted into the
urine, mainly by glomerular filtration. Ten to forty percent of the
drug is excreted in feces. Doxycycline and tigecycline, in contrast
to other tetracyclines, are eliminated by nonrenal mechanisms
and do not accumulate significantly in renal failure, requiring no
dosage adjustment.
Tetracyclines are classified as short-acting (tetracycline, as well
as the agricultural agents chlortetracycline and oxytetracycline),
intermediate-acting (demeclocycline), or long-acting (doxycy-
cline and minocycline) based on serum half-lives of 6–8 hours,
12 hours, and 16–18 hours, respectively. Tigecycline has a half-life
of 36 hours. The almost complete absorption and slow excretion
of doxycycline and minocycline allow for once-daily dosing for
certain indications, but, by convention, these two drugs are usu-
ally dosed twice daily.
Clinical Uses
A tetracycline is the drug of choice in the treatment of most
infections caused by rickettsiae and Borrelia sp, including Rocky
Mountain spotted fever and Lyme disease. Tetracyclines are used
preferentially to treat Anaplasma phagocytophilum and Ehrlichia
sp. Tetracyclines are also excellent drugs for the treatment of
Mycoplasma pneumoniae, chlamydiae, and some spirochetes. They
are used in combination regimens to treat gastric and duodenal
ulcer disease caused by Helicobacter pylori. They may be used in
various Gram-positive and Gram-negative bacterial infections,
including vibrio infections, provided the organism is not resistant.
In cholera, tetracyclines rapidly stop the shedding of vibrios, but
tetracycline resistance is an increasing problem. Tetracyclines
remain effective in most chlamydial infections, including sexually
transmitted infections. Doxycycline is also an alternative agent
recommended by the Centers for Disease Control and Preven-
tion for primary and secondary syphilis in patients with penicillin
allergy. A tetracycline—in combination with other antibiotics—is
indicated for plague, tularemia, and brucellosis. Tetracyclines are
sometimes used in the treatment or prophylaxis of protozoal infec-
tions, eg, those due to Plasmodium falciparum (see Chapter 52).
Other uses include treatment of acne, exacerbations of bronchitis,
community-acquired pneumonia, leptospirosis, and some nontu-
berculous mycobacterial infections (eg, Mycobacterium marinum).
Tetracyclines formerly were used for a variety of common
infections, including bacterial gastroenteritis and urinary tract
infections. However, many strains of bacteria causing these infec-
tions are now resistant, and other agents have largely supplanted
tetracyclines.
Minocycline, 100 mg orally twice daily for 5 days, can eradi-
cate the meningococcal carrier state, but because of side effects
and resistance of many meningococcal strains, ciprofloxacin or
rifampin is preferred. Demeclocycline is rarely used as an antibac-
terial, but it has been used off-label in the treatment of inappropri-
ate secretion of antidiuretic hormone because of its inhibition of
antidiuretic hormone in the renal tubule (see Chapter 15).
Tigecycline, the first glycylcycline to reach clinical practice, has
several unique features that warrant its consideration apart from the
older tetracyclines. Its spectrum is very broad, and many tetracy-
cline-resistant strains are susceptible to tigecycline because it is not
affected by the common resistance determinants. Susceptible organ-
isms include coagulase-negative staphylococci and Staphylococcus
aureus, including methicillin-resistant, vancomycin-intermediate,
and vancomycin-resistant strains; streptococci, penicillin-susceptible
818    SECTION VIII  Chemotherapeutic Drugs
and resistant; enterococci, including vancomycin-resistant strains;
Gram-positive rods; Enterobacteriaceae; multidrug-resistant strains
of Acinetobacter sp; anaerobes, both Gram-positive and Gram-
negative; rickettsiae, Chlamydia sp, and Legionella pneumophila;
and rapidly growing mycobacteria. Proteus and Providencia sp and
P aeruginosa, however, are intrinsically resistant.
Tigecycline, formulated for intravenous administration only,
is given as a 100-mg loading dose, then 50 mg every 12 hours.
As with all tetracyclines, tissue and intracellular penetration is
excellent; consequently, the volume of distribution is quite large
and peak serum concentrations are low. Elimination is primarily
biliary, and no dosage adjustment is needed for patients with renal
insufficiency. In addition to the tetracycline class effects, the chief
adverse effect of tigecycline is nausea, which occurs in up to one
third of patients, and occasionally vomiting. Neither nausea nor
vomiting usually requires discontinuation of the drug.
Tigecycline is approved for treatment of skin and skin-
structure infection, intra-abdominal infections, and community-
acquired pneumonia. However, in a meta-analysis of clinical trials,
tigecycline was associated with a small but significant increase in
the risk of death compared with other antibiotics used to treat
these infections. The increased risk was most apparent in hospital-
acquired and ventilator-associated pneumonia but was also seen in
other infections. This has led the U.S. Food and Drug Adminis-
tration (FDA) to issue a black box warning that tigecycline should
be reserved for situations where alternative treatments are not suit-
able. Because active drug concentrations in the urine and serum
are relatively low, tigecycline may not be effective for urinary tract
infections or primary bacteremia. Tigecycline has in vitro activ-
ity against a wide variety of multidrug-resistant pathogens (eg,
methicillin-resistant S aureus, extended-spectrum β-lactamase-
producing Gram-negatives, and Acinetobacter sp); however, its
clinical efficacy in infections with multidrug-resistant organisms,
compared with other agents, is unproven.
A. Oral Dosage
The oral dosage for rapidly excreted tetracyclines, equivalent to
tetracycline hydrochloride, is 0.25–0.5 g four times daily for
adults and 25–50 mg/kg/d for children (8 years of age and older).
For severe systemic infections, the higher dosage is indicated, at
least for the first few days. The dosage for doxycycline is 100 mg
once or twice daily; the minocycline dose is 100 mg twice daily.
Doxycycline is the oral tetracycline of choice for most indications
because it is generally well tolerated, it can be given twice daily,
and its absorption is not significantly affected by food. All tetracy-
clines chelate with metals, and none should be orally administered
with milk, antacids, or ferrous sulfate. To avoid deposition in
growing bones or teeth, tetracyclines should be avoided in preg-
nant women and children younger than 8 years.
B. Parenteral Dosage
Doxycycline and minocycline are available for intravenous injec-
tion at the same doses as the oral formulations. Intramuscular
injection is not recommended because of pain and inflammation
at the injection site.
Adverse Reactions
Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines
are uncommon. Most adverse effects are due to direct toxicity of
the drug or to alteration of microbial flora.
A. Gastrointestinal Adverse Effects
Nausea, vomiting, and diarrhea are the most common reasons for
discontinuing tetracyclines. These effects are attributable to direct
local irritation of the intestinal tract. Oral tetracyclines can rarely
cause esophageal ulceration, so patients should be instructed to
take them with 8 ounces of water and remain upright for at least
30 minutes after each dose.
Tetracyclines alter the normal gastrointestinal flora, with sup-
pression of susceptible coliform organisms and overgrowth of
Pseudomonas, Proteus, staphylococci, resistant coliforms, clostridia,
and Candida. This can result in intestinal functional disturbances,
anal pruritus, vaginal or oral candidiasis, or Clostridium difficile–
associated colitis. However, the risk of C difficile colitis may be
lower with tetracyclines than with other antibiotics.
B. Bony Structures and Teeth
Tetracyclines are readily bound to calcium deposited in newly
formed bone or teeth in young children. When a tetracycline
is given during pregnancy, it can be deposited in the fetal teeth,
leading to fluorescence, discoloration, and enamel dysplasia. It
can also be deposited in bone, where it may cause deformity or
growth inhibition. Because of these effects, tetracyclines are gener-
ally avoided in pregnancy. If the drug is given for long periods to
children younger than 8 years, similar changes can result.
C. Other Toxicities
Tetracyclines can impair hepatic function, especially during
pregnancy, in patients with preexisting liver disease, and when
high doses are given intravenously. Hepatic necrosis has been
reported with daily doses of 4 g or more intravenously. Renal
tubular acidosis and Fanconi syndrome have been attributed to
the administration of outdated tetracycline preparations. Tetracy-
clines given along with diuretics may cause nephrotoxicity. Tetra-
cycline and minocycline may accumulate to toxic levels in patients
with impaired kidney function. Intravenous injection can lead
to venous thrombosis. Intramuscular injection produces painful
local irritation and should be avoided. Systemically administered
tetracyclines commonly induce sensitivity to sunlight or ultravio-
let light, particularly in fair-skinned persons. Dizziness, vertigo,
and tinnitus have been noted, particularly with high doses or
prolonged administration of minocycline. These symptoms may
also occur with higher doses of doxycycline.
■■ MACROLIDES
The macrolides are a group of closely related compounds charac-
terized by a macrocyclic lactone ring (usually containing 14 or 16
atoms) to which deoxy sugars are attached. The prototype drug,
erythromycin, which consists of two sugar moieties attached to
 CHAPTER 44  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones     819

a 14-atom lactone ring, was obtained in 1952 from Streptomyces Resistance to erythromycin is usually plasmid-encoded. Three
erythreus, now called Saccharopolyspora erythraea. Clarithromycin general mechanisms have been identified: (1) reduced perme-
and azithromycin are semisynthetic derivatives of erythromycin. ability of the cell membrane or active efflux; (2) production
(by Enterobacteriaceae) of esterases that hydrolyze macrolides;
Macrolide O and (3) modification of the ribosomal binding site (so-called
ring
R1 R1 ribosomal protection) by chromosomal mutation or by a mac-
rolide-inducible or constitutive methylase. Efflux and methylase
OH
production are the most important resistance mechanisms in
R2 O R1
R1 6 OH
Gram-positive organisms. Cross-resistance is complete between
R1 R1 erythromycin and the other macrolides. Constitutive methylase
O
O O C2H5 production also confers resistance to structurally unrelated but
N(R1)2 mechanistically similar compounds such as clindamycin and strep-
Desosamine
O O togramin B (so-called macrolide-lincosamide-streptogramin, or
OH MLS-type B, resistance), which share the same ribosomal binding
R1
O site. Because nonmacrolides are poor inducers of the methylase,
HO R1 strains expressing an inducible methylase will appear susceptible
OR1
Cladinose in vitro. However, constitutive mutants that are resistant can be
R1 selected out and emerge during therapy with clindamycin.
Erythromycin (R1 = CH3, R2 = H)
Clarithromycin (R1, R2 = CH3) Pharmacokinetics
Erythromycin base is destroyed by stomach acid and must be
administered with enteric coating. Food interferes with absorp-
ERYTHROMYCIN
tion. The stearate and ethylsuccinate formulations are fairly acid-
resistant and somewhat better absorbed. A 500-mg intravenous
Chemistry dose of erythromycin lactobionate produces serum concentrations
The general structure of erythromycin is shown with the mac- of 10 mcg/mL 1 hour after dosing. The serum half-life is approxi-
rolide ring and the sugars desosamine and cladinose. It is poorly mately 1.5 hours normally and 5 hours in patients with anuria.
soluble in water (0.1%) but dissolves readily in organic solvents. Adjustment for renal failure is not necessary. Erythromycin is
Solutions are fairly stable at 4°C but lose activity rapidly at 20°C not removed by dialysis. Large amounts of an administered dose
and at acid pH. Erythromycins are usually dispensed as various are excreted in the bile, and only 5% is excreted in the urine.
esters and salts. Absorbed drug is distributed widely except to the brain and cere-
brospinal fluid. Erythromycin is taken up by polymorphonuclear
Mechanism of Action & Antimicrobial leukocytes and macrophages. It traverses the placenta and reaches
Activity the fetus.
The antibacterial action of erythromycin and other macrolides
may be inhibitory or bactericidal, particularly at higher concentra- Clinical Uses
tions, for susceptible organisms. Activity is enhanced at alkaline Erythromycin is a traditional drug of choice in corynebacterial
pH. Inhibition of protein synthesis occurs via binding to the 50S infections (diphtheria, corynebacterial sepsis, erythrasma) and
ribosomal RNA. The binding site is near the peptidyltransferase in respiratory, neonatal, ocular, or genital chlamydial infections.
center, and peptide chain elongation (ie, transpeptidation) is While it was used in treatment of community-acquired pneu-
prevented by blocking of the polypeptide exit tunnel. As a result, monia because its spectrum of activity includes pneumococcus,
peptidyl-tRNA is dissociated from the ribosome. Erythromy- M pneumoniae, and L pneumophila, newer macrolides are better
cin also inhibits the formation of the 50S ribosomal subunit tolerated and more commonly selected. Macrolide resistance is
(Figure 44–1). increasing in pneumococci and M pneumoniae. Erythromycin had
Erythromycin is active against susceptible strains of Gram-pos- also been useful as a penicillin substitute in penicillin-allergic indi-
itive organisms, especially pneumococci, streptococci, staphylo- viduals with infections caused by staphylococci and streptococci.
cocci, and corynebacteria. Mycoplasma pneumoniae, L pneumophila, Emergence of erythromycin resistance in staphylococci and in
Chlamydia trachomatis, Chlamydophila psittaci, Chlamydophila strains of group A streptococci has made macrolides less attractive
pneumoniae, H pylori, Listeria monocytogenes, and certain myco- as first-line agents for treatment of pharyngitis and skin and soft
bacteria (Mycobacterium kansasii, Mycobacterium scrofulaceum) tissue infections. Erythromycin has been studied as prophylaxis
also are susceptible. Gram-negative organisms such as Neisseria sp, against endocarditis during dental procedures in individuals with
Bordetella pertussis, Bartonella henselae, and Bartonella quintana as valvular heart disease, but clindamycin, which is better tolerated,
well as some Rickettsia species, Treponema pallidum, and Campylo- has largely replaced it.
bacter species are susceptible. Haemophilus influenzae is somewhat The oral dosage of erythromycin base or stearate is
less susceptible. 0.25–0.5 g every 6 hours (for children, 40 mg/kg/d). The dosage
820    SECTION VIII  Chemotherapeutic Drugs
of erythromycin ethylsuccinate is 0.4–0.8 g every 6 hours. Oral
erythromycin base (1 g) is sometimes combined with oral neo-
mycin or kanamycin for preoperative preparation of the colon.
The intravenous dosage of erythromycin lactobionate is 0.5–1.0 g
every 6 hours for adults and 15–20 mg/kg/d divided every 6 hours
for children. The higher dosage is recommended when treating
pneumonia caused by L pneumophila.
Adverse Reactions
Anorexia, nausea, vomiting, and diarrhea are common. Gastro-
intestinal intolerance, which is due to a direct stimulation of gut
motility, is the most common reason for selecting an alternative to
erythromycin. This side effect may actually be desirable in some
circumstances, leading to the off-label use of erythromycin to treat
patients with gastroparesis.
Erythromycins, particularly the older estolate formulation, can
produce acute cholestatic hepatitis (fever, jaundice, impaired liver
function), probably as a hypersensitivity reaction. Most patients
recover from this, but hepatitis recurs if the drug is readministered.
Other allergic reactions include fever, eosinophilia, and rashes.
Erythromycin metabolites inhibit cytochrome P450 enzymes
and, thus increase the serum concentrations of numerous drugs,
including theophylline, warfarin, cyclosporine, and methylpred-
nisolone. Erythromycin increases serum concentrations of oral
digoxin by increasing its bioavailability.
CLARITHROMYCIN
Clarithromycin is derived from erythromycin by addition of a
methyl group and has improved acid stability and oral absorption
compared with erythromycin. Its mechanism of action is the same
as that of erythromycin. Clarithromycin and erythromycin are
similar with respect to antibacterial activity except that clarithro-
mycin is more active against Mycobacterium avium complex (see
Chapter 47). Clarithromycin also has activity against Mycobacte-
rium leprae, Toxoplasma gondii, and H influenzae. Erythromycin-
resistant streptococci and staphylococci are also resistant to
clarithromycin.
A 500-mg dose of clarithromycin produces serum concen-
trations of 2–3 mcg/mL. The longer half-life of clarithromycin
(6 hours) compared with erythromycin permits twice-daily
dosing. The recommended dosage is 250–500 mg twice daily or
1000 mg of the extended-release formulation once daily. Clar-
ithromycin penetrates most tissues well, with concentrations equal
to or exceeding serum concentrations.
Clarithromycin is metabolized in the liver and is partially
eliminated in the urine. The major metabolite, 14-hydroxyclar-
ithromycin, also has antibacterial activity and is eliminated in the
urine. Dosage reduction (eg, a 500-mg loading dose, then 250 mg
once or twice daily) is recommended for patients with creatinine
clearances less than 30 mL/min. Clarithromycin has drug interac-
tions similar to those described for erythromycin.
The advantages of clarithromycin compared with erythromy-
cin are lower incidence of gastrointestinal intolerance and less
frequent dosing.
AZITHROMYCIN
Azithromycin, a 15-atom lactone macrolide ring compound, is
derived from erythromycin by addition of a methylated nitrogen
into the lactone ring. Its spectrum of activity, mechanism of action,
and clinical uses are similar to those of clarithromycin. Azithromy-
cin is active against M avium complex and T gondii. Azithromycin
is slightly less active than erythromycin and clarithromycin against
staphylococci and streptococci and slightly more active against
H influenzae. Azithromycin is highly active against Chlamydia sp.
Azithromycin differs from erythromycin and clarithromy-
cin mainly in pharmacokinetic properties. A 500-mg dose of
azithromycin produces relatively low serum concentrations of
approximately 0.4 mcg/mL. However, azithromycin penetrates
into most tissues (except cerebrospinal fluid) and phagocytic
cells extremely well, with tissue concentrations exceeding serum
concentrations by 10- to 100-fold. The drug is slowly released
from tissues (tissue half-life of 2–4 days) to produce an elimina-
tion half-life approaching 3 days. These unique properties permit
once-daily dosing and shortening of the duration of treatment in
many cases. For example, a single 1-g dose of azithromycin is as
effective as a 7-day course of doxycycline for chlamydial cervicitis
and urethritis. Azithromycin, as a 500-mg loading dose, followed
by a 250-mg single daily dose for the next 4 days, is commonly
used alone or in combination with a beta-lactam antibiotic to treat
community-acquired pneumonia.
Azithromycin is rapidly absorbed and well tolerated orally. Alumi-
num and magnesium antacids do not alter bioavailability but delay
absorption and reduce peak serum concentrations. Because it has a
15-member (not 14-member) lactone ring, azithromycin does not
inactivate cytochrome P450 enzymes and, therefore, is free of the
drug interactions that occur with erythromycin and clarithromycin.
Macrolide antibiotics prolong the electrocardiographic QT
interval due to an effect on potassium ion channels. Prolongation
of the QT interval can lead to the torsades de pointes arrhythmia.
Recent studies have suggested that azithromycin may be associated
with a small increased risk of cardiac death.
FIDAXOMICIN
Fidaxomicin, a minimally absorbed macrolide used to treat
Clostridium difficile infections, is discussed in Chapter 50.
KETOLIDES
Ketolides are semisynthetic, 14-membered-ring macrolides, dif-
fering from erythromycin by substitution of a 3-keto group for
the neutral sugar l-cladinose. Telithromycin is approved for
limited clinical use. It is active in vitro against Streptococcus pyo-
genes, S pneumoniae, S aureus, H influenzae, Moraxella catarrhalis,
Mycoplasma sp, L pneumophila, Chlamydia sp, H pylori, Neisseria
gonorrhoeae, B fragilis, T gondii, and certain nontuberculous
mycobacteria. Many macrolide-resistant strains are susceptible to
ketolides because the structural modification of these compounds
 CHAPTER 44  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones     821
renders them poor substrates for efflux pump–mediated resis-
tance, and they bind to ribosomes of some bacterial species with
higher affinity than macrolides.
Oral bioavailability of telithromycin is 57%, and tissue and
intracellular penetration is generally good. Telithromycin is
metabolized in the liver and eliminated by a combination of
biliary and urinary routes of excretion. It is administered as a
once-daily dose of 800 mg, which results in peak serum concen-
trations of approximately 2 mcg/mL. It is a reversible inhibitor of
the CYP3A4 enzyme system and may slightly prolong the QTc
interval. In the USA, telithromycin is now indicated only for
treatment of community-acquired bacterial pneumonia. Other
respiratory tract infections were removed as indications when it
was recognized that use of telithromycin can result in hepatitis
and liver failure. Telithromycin is also contraindicated in patients
with myasthenia gravis because it may exacerbate this condition.
Due to its potential for serious toxicity, an FDA-approved patient
medication guide detailing these risks must be dispensed to any
patient receiving the medication.
Solithromycin is a novel fluoroketolide that is pending FDA
approval after two phase 3 clinical trials showed noninferior-
ity when compared with moxifloxacin in the treatment of
community-acquired pneumonia. Although not yet marketed,
the dose used in clinical trials was a loading dose of 800 mg
orally or intravenously, followed by 400 mg daily for a total of
5 days. The intravenous formulation was associated with higher
rates of infusion-related reactions compared with moxifloxacin.
Similar to telithromycin, solithromycin maintains in vitro activ-
ity against macrolide-resistant bacteria, including S pneumoniae,
staphylococci, enterococci, Chlamydia trachomatis, and Neisseria
gonorrhoeae. Its chemical structure lacks the pyridine-imidazole
side chain group, which is thought to contribute to telithromy-
cin’s hepatotoxicity; severe toxicity has not been demonstrated in
Phase II or III clinical trials.
■■ CLINDAMYCIN
Clindamycin is a chlorine-substituted derivative of lincomycin,
an antibiotic that is elaborated by Streptomyces lincolnensis.
CH3
CH3
N
CI CH
C3H7
C NH CH
O
O HO
OH
S CH3
OH
Clindamycin
Mechanism of Action & Antibacterial
Activity
Clindamycin, like erythromycin, inhibits protein synthesis
by interfering with the formation of initiation complexes and
with aminoacyl translocation reactions. The binding site for
clindamycin on the 50S subunit of the bacterial ribosome is
identical with that for erythromycin. Streptococci, staphy-
lococci, and pneumococci are inhibited by clindamycin at
a concentration of 0.5–5 mcg/mL. Enterococci and Gram-
negative aerobic organisms are resistant. Bacteroides sp and
other anaerobes are often susceptible, though resistance may
be increasing, particularly in Gram-negative anaerobes. Resis-
tance to clindamycin, which generally confers cross-resistance
to macrolides, is due to (1) mutation of the ribosomal recep-
tor site; (2) modification of the receptor by a constitutively
expressed methylase (see section on erythromycin resistance,
above); and (3) enzymatic inactivation of clindamycin. Gram-
negative aerobic species are intrinsically resistant because of
poor permeability of the outer membrane.
Pharmacokinetics
Oral dosages of clindamycin, 0.15–0.3 g every 8 hours
(10–20 mg/kg/d for children), yield serum levels of 2–3 mcg/mL.
When administered intravenously, 600 mg of clindamycin every
8 hours gives levels of 5–15 mcg/mL. The drug is about 90%
protein-bound. Clindamycin penetrates well into most tissues,
with brain and cerebrospinal fluid being important exceptions.
It penetrates well into abscesses and is actively taken up and con-
centrated by phagocytic cells. Clindamycin is metabolized by the
liver, and both active drug and active metabolites are excreted in
bile and urine. The half-life is about 2.5 hours in normal indi-
viduals, increasing to 6 hours in patients with anuria. No dosage
adjustment is required for renal failure.
Clinical Use
Clindamycin is indicated for the treatment of skin and soft-
tissue infections caused by streptococci and staphylococci. It
may be active against community-acquired strains of methi-
cillin-resistant S aureus, though resistance has been increasing.
It is commonly used in conjunction with penicillin G to treat
toxic shock syndrome or necrotizing fasciitis caused by Group
A Streptococcus. In this setting, its use is typically limited to the
initial 48 to 72 hours of treatment with the goal of inhibiting
toxin production. Clindamycin is also indicated for treatment
of infections caused by susceptible Bacteroides sp and other
anaerobes. Clindamycin, sometimes in combination with an
aminoglycoside or cephalosporin, is used to treat penetrating
wounds of the abdomen and the gut; infections originating in
the female genital tract, eg, septic abortion, pelvic abscesses, or
pelvic inflammatory disease; and lung and periodontal abscesses.
Clindamycin is recommended for prophylaxis of endocarditis in
patients with specific valvular heart disease who are undergoing
certain dental procedures and have significant penicillin aller-
gies. Clindamycin plus primaquine is an effective alternative
to trimethoprim-sulfamethoxazole for moderate to moderately
severe Pneumocystis jiroveci pneumonia in AIDS patients. It is
also used in combination with pyrimethamine for AIDS-related
toxoplasmosis of the brain.
822    SECTION VIII  Chemotherapeutic Drugs
Adverse Effects
Common adverse effects are diarrhea, nausea, and skin rashes.
Impaired liver function (with or without jaundice) and neutro-
penia sometimes occur. Administration of clindamycin is a risk
factor for diarrhea and colitis due to C difficile.
■■ STREPTOGRAMINS
MECHANISM OF ACTION &
ANTIBACTERIAL ACTIVITY
Quinupristin-dalfopristin is a combination of two
streptogramins—quinupristin, a streptogramin B, and dalfopris-
tin, a streptogramin A—in a 30:70 ratio. The streptogramins share
the same ribosomal binding site as the macrolides and clindamy-
cin and thus inhibit protein synthesis in an identical manner.
Quinupristin-dalfopristin is rapidly bactericidal for most suscep-
tible organisms except Enterococcus faecium, which is killed slowly.
Quinupristin-dalfopristin is active against Gram-positive cocci,
including multidrug-resistant strains of streptococci, penicillin-
resistant strains of S pneumoniae, methicillin-susceptible and resis-
tant strains of staphylococci, and E faecium (but not Enterococcus
faecalis). Resistance is due to modification of the quinupristin
binding site (MLS-B type resistance), enzymatic inactivation of
dalfopristin, or efflux.
Pharmacokinetics
Quinupristin-dalfopristin is administered intravenously at a
dosage of 7.5 mg/kg every 8–12 hours. Peak serum concentra-
tions following an infusion of 7.5 mg/kg over 60 minutes are
3 mcg/mL for quinupristin and 7 mcg/mL for dalfopristin.
Quinupristin and dalfopristin are rapidly metabolized, with
half-lives of 0.85 and 0.7 hours, respectively. Elimination is prin-
cipally by the fecal route. Dose adjustment is not necessary for
renal failure, peritoneal dialysis, or hemodialysis. Patients with
hepatic insufficiency may not tolerate the drug at usual doses,
however, because of increased area under the concentration
curve of both parent drugs and metabolites. This may neces-
sitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg
every 8 hours. Quinupristin and dalfopristin significantly inhibit
CYP3A4, which metabolizes warfarin, diazepam, quetiapine,
simvastatin, and cyclosporine, among many others. Dosage
reduction of cyclosporine may be necessary.
Clinical Uses & Adverse Effects
Quinupristin-dalfopristin is approved for treatment of infec-
tions caused by staphylococci or by vancomycin-resistant strains
of E faecium, but not E faecalis, which is intrinsically resistant,
probably because of an efflux-type resistance mechanism. The
principal toxicities are infusion-related events, such as pain at the
infusion site, and an arthralgia-myalgia syndrome. Quinupristin-
dalfopristin is used to a limited extent in the USA due to the
availability of better-tolerated alternatives.
■■ CHLORAMPHENICOL
Crystalline chloramphenicol is a neutral, stable compound with
the following structure:
OH CH2OH O
NO2 C C N C CHCI2
H H H
Chloramphenicol
It is soluble in alcohol but poorly soluble in water. Chloram-
phenicol succinate, which is used for parenteral administration,
is highly water-soluble. It is hydrolyzed in vivo with liberation of
free chloramphenicol.
Mechanism of Action & Antimicrobial
Activity
Chloramphenicol is an inhibitor of microbial protein synthesis and
is bacteriostatic against most susceptible organisms. It binds revers-
ibly to the 50S subunit of the bacterial ribosome (Figure 44–1)
and inhibits peptide bond formation (step 2). Chloramphenicol
is a broad-spectrum antibiotic that is active against both aerobic
and anaerobic Gram-positive and Gram-negative organisms. It is
active also against rickettsiae but not chlamydiae. Most Gram-
positive bacteria are inhibited at concentrations of 1–10 mcg/mL,
and many Gram-negative bacteria are inhibited by concentrations
of 0.2–5 mcg/mL. H influenzae, Neisseria meningitidis, and some
strains of Bacteroides are highly susceptible; for these organisms,
chloramphenicol may be bactericidal.
Low-level resistance to chloramphenicol may emerge from
large populations of chloramphenicol-susceptible cells by selection
of mutants that are less permeable to the drug. Clinically signifi-
cant resistance is due to production of chloramphenicol acetyl-
transferase, a plasmid-encoded enzyme that inactivates the drug.
Pharmacokinetics
The usual dosage of chloramphenicol is 50–100 mg/kg/d divided
every 6 hours. It is no longer available in the USA as an oral for-
mulation. The parenteral formulation is a prodrug, chlorampheni-
col succinate, which is hydrolyzed to yield free chloramphenicol,
giving blood levels somewhat lower than those achieved with
orally administered drug. Chloramphenicol is widely distributed
to virtually all tissues and body fluids, including the central ner-
vous system and cerebrospinal fluid, such that the concentration
of chloramphenicol in brain tissue may be equal to that in serum.
The drug penetrates cell membranes readily.
Most of the drug is inactivated either by conjugation with gluc-
uronic acid (principally in the liver) or by reduction to inactive
aryl amines. Active chloramphenicol, about 10% of the total dose
administered, and its inactive degradation products are eliminated
in the urine. A small amount of active drug is excreted into bile
and feces. There are no specific dosage adjustments recommended
in renal or hepatic insufficiency; however, the drug will accumu-
late and should be used with extra caution in these situations.
 CHAPTER 44  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones     823
Newborns less than a week old and premature infants also clear
chloramphenicol less well, and the dosage should be reduced to
25 mg/kg/d.
Clinical Uses
Because of potential toxicity, bacterial resistance, and the availabil-
ity of many other effective alternatives, chloramphenicol is rarely
used in the United States. It may be considered for treatment of
serious rickettsial infections such as typhus and Rocky Mountain
spotted fever. It is an alternative to a β-lactam antibiotic for treat-
ment of bacterial meningitis occurring in patients who have major
hypersensitivity reactions to penicillin.
Adverse Reactions
Adults occasionally develop gastrointestinal disturbances, includ-
ing nausea, vomiting, and diarrhea. These symptoms are rare
in children. Oral or vaginal candidiasis may occur as a result of
alteration of normal microbial flora.
Chloramphenicol commonly causes a dose-related revers-
ible suppression of red cell production at dosages exceeding
50 mg/kg/d after 1–2 weeks. Aplastic anemia, a rare consequence
(1 in 24,000 to 40,000 courses of therapy) of chloramphenicol
administration by any route, is an idiosyncratic reaction unrelated
to dose, although it occurs more frequently with prolonged use.
Aplastic anemia tends to be irreversible and can be fatal, although
it may respond to bone marrow transplantation or immunosup-
pressive therapy. Due to the severity of this reaction, a boxed
warning has been added to its U.S. labeling.
Newborn infants lack an effective glucuronic acid conjugation
mechanism for the degradation and detoxification of chloram-
phenicol. Consequently, when infants are given dosages above
50 mg/kg/d, the drug may accumulate, resulting in the gray baby
syndrome, with vomiting, flaccidity, hypothermia, gray color,
shock, and vascular collapse. To avoid this toxic effect, chloram-
phenicol should be used with caution in infants and the dosage
limited to 50 mg/kg/d (or less during the first week of life) in full-
term infants and 25 mg/kg/d in premature infants.
Chloramphenicol inhibits hepatic microsomal enzymes that
metabolize several drugs. Half-lives of these drugs are prolonged,
and the serum concentrations of phenytoin, tolbutamide, chlor-
propamide, and warfarin are increased.
■■ OXAZOLIDINONES
MECHANISM OF ACTION &
ANTIMICROBIAL ACTIVITY
Linezolid is a member of the oxazolidinone class of synthetic
antimicrobials. It is active against Gram-positive organisms
including staphylococci, streptococci, enterococci, Gram-positive
anaerobic cocci, and Gram-positive rods such as corynebacteria,
Nocardia sp, and L monocytogenes. It is primarily a bacteriostatic
agent but is bactericidal against streptococci. It is also active
against Mycobacterium tuberculosis.
Linezolid inhibits protein synthesis by preventing formation of the
ribosome complex that initiates protein synthesis. Its unique binding
site, located on 23S ribosomal RNA of the 50S subunit, results in no
cross-resistance with other drug classes. Resistance is caused by muta-
tion of the linezolid binding site on 23S ribosomal RNA.
Pharmacokinetics
Linezolid is 100% bioavailable after oral administration and has a
half-life of 4–6 hours. It is metabolized by oxidative metabolism,
yielding two inactive metabolites. It is neither an inducer nor an
inhibitor of cytochrome P450 enzymes. Peak serum concentra-
tions average 18 mcg/mL following a 600-mg oral dose; cerebro-
spinal fluid (CSF) concentrations reach approximately 60–70% of
the serum level. The recommended dosage for most indications is
600 mg twice daily, either orally or intravenously.
Clinical Uses
Linezolid is approved for vancomycin-resistant E faecium infec-
tions, health care–associated pneumonia, community-acquired
pneumonia, and both complicated and uncomplicated skin and
soft tissue infections caused by susceptible Gram-positive bacte-
ria. Off-label uses of linezolid include treatment of multidrug-
resistant tuberculosis and Nocardia infections.
Adverse Effects
The principal toxicity of linezolid is hematologic; the effects are
reversible and generally mild. Thrombocytopenia is the most
common manifestation (seen in approximately 3% of treatment
courses), particularly when the drug is administered for longer
than 2 weeks. Anemia and neutropenia may also occur, most
commonly in patients with a predisposition to or underlying bone
marrow suppression. Cases of optic and peripheral neuropathy
and lactic acidosis have been reported with prolonged courses of
linezolid. These side effects are thought to be related to linezolid-
induced inhibition of mitochondrial protein synthesis. There are
case reports of serotonin syndrome (see Chapter 16) occurring
when linezolid is co-administered with serotonergic drugs, most
frequently selective serotonin reuptake inhibitor antidepressants.
The FDA has issued a warning regarding the use of the drug with
serotonergic agents.
Tedizolid is the active moiety of the prodrug tedizolid phos-
phate, a next-generation oxazolidinone, with high potency against
Gram-positive bacteria, including methicillin-resistant S aureus.
It is FDA-approved at a dose of 200 mg orally or intravenously
once daily for 6 days for the treatment of skin and soft tissue
infection. Potential advantages over linezolid include increased
potency against staphylococci and a longer half-life of 12 hours,
allowing once-daily dosing. It may be associated with a decreased
risk of marrow suppression; however, it has not been studied over
a prolonged duration of therapy. It is thought to have a lower risk
of serotonergic toxicity, but concomitant use with serotonin reup-
take inhibitors has not been formally evaluated. Tedizolid is more
highly protein-bound (70–90%) than linezolid (31%); there are
no data on CSF penetration of tedizolid.
824    SECTION VIII  Chemotherapeutic Drugs

SUMMARY  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol,

Streptogramins, & Oxazolidinones
Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions

TETRACYCLINES
  •  Tetracycline Prevents bacterial protein
synthesis by binding to the
30S ribosomal subunit
Bacteriostatic activity
against susceptible
bacteria
Infections caused by
mycoplasma, chlamydiae,
rickettsiae, some spirochetes
• malaria • H pylori • acne
Oral • mixed clearance (half-life 8 h) • dosed
every 6 h • divalent cations impair oral
absorption • Toxicity: Gastrointestinal upset,
hepatotoxicity, photosensitivity, deposition in
bone and teeth

  • Doxycycline: Oral and IV; longer half-life (18 h) so dosed twice daily; nonrenal elimination; absorption is minimally affected by divalent cations; used to treat community-
acquired pneumonia and exacerbations of bronchitis
  •  Minocycline: Oral and IV; longer half-life (16 h) so dosed twice daily; frequently causes reversible vestibular toxicity
  •  Tigecycline: IV; unaffected by common tetracycline resistance mechanisms; very broad spectrum of activity against Gram-positive, Gram-negative, and anaerobic
bacteria; nausea and vomiting are the primary toxicities

MACROLIDES
  •  Erythromycin Prevents bacterial protein
synthesis by binding to the
50S ribosomal subunit
Bacteriostatic activity Community-acquired Oral, IV • hepatic clearance (half-life 1.5 h)
against susceptible pneumonia • pertussis • dosed every 6 h • cytochrome P450 inhibitor
bacteria • corynebacterial and • Toxicity: Gastrointestinal upset, hepatotoxicity,
chlamydial infections QTc prolongation

  •  Clarithromycin: Oral; longer half-life (6 h) so dosed twice daily; added activity versus M avium complex, toxoplasma, and M leprae
  • Azithromycin: Oral, IV; very long half-life (68 h) allows for once-daily dosing and 5-day course of therapy of community-acquired pneumonia; does not inhibit cytochrome
P450 enzymes
  • Telithromycin: Oral; unaffected by efflux-mediated resistance so is active versus many erythromycin-resistant strains of pneumococci; rare cases of fulminant hepatic
failure

LINCOSAMIDE
  •  Clindamycin Prevents bacterial protein Bacteriostatic activity Skin and soft tissue infections Oral, IV • hepatic clearance (half-life 2.5 h)
synthesis by binding to the against susceptible • anaerobic infections • dosed every 6–8 hours • Toxicity:
50S ribosomal subunit bacteria Gastrointestinal upset, C difficile colitis

STREPTOGRAMINS
  • Quinupristin- Prevents bacterial protein Rapid bactericidal Infections caused by IV • hepatic clearance • dosed every 8–12 h
dalfopristin synthesis by binding to the activity against most staphylococci or vancomycin- • cytochrome P450 inhibitor • Toxicity: Severe
50S ribosomal subunit susceptible bacteria resistant strains of E faecium infusion-related myalgias and arthralgias

CHLORAMPHENICOL
  Prevents bacterial protein
synthesis by binding to the
50S ribosomal subunit
Bacteriostatic activity Use is rare in the developed IV • hepatic clearance (half-life 2.5 h) • dosage is
against susceptible world because of serious 50–100 mg/kg/d in four divided doses
bacteria toxicities • Toxicity: Dose-related anemia, idiosyncratic
aplastic anemia, gray baby syndrome

OXAZOLIDINONES
  •  Linezolid Prevents bacterial protein
synthesis by binding to the
23S ribosomal RNA of 50S
subunit
Bacteriostatic activity
against susceptible
bacteria
Infections caused by
methicillin-resistant
staphylococci and vancomycin-
resistant enterococci
Oral, IV • hepatic clearance (half-life 6 h) • dosed
twice-daily • Toxicity: Duration-dependent bone
marrow suppression, neuropathy, and optic
neuritis • serotonin syndrome may occur when
co-administered with other serotonergic drugs
(eg, selective serotonin reuptake inhibitors)

Tedizolid: Oral and IV; longer half-life (12 h) so dosed once daily; increased potency versus staphylococci; approved for use in skin and soft tissue infections.
 CHAPTER 44  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones     825

P R E P A R A T I O N S Chopra I, Roberts M: Tetracycline antibiotics: Mode of action, applications,

molecular biology, and epidemiology of bacterial resistance. Microbiol Mol
A V A I L A B L E Biol Rev 2001;65:232.
De Vriese AS et al: Linezolid-induced inhibition of mitochondrial protein synthe-
sis. Clin Infect Dis 2006;42:1111.
GENERIC NAME AVAILABLE AS
Dryden MS: Linezolid pharmacokinetics and pharmacodynamics in clinical treat-
Chloramphenicol Generic, Chloromycetin ment. 2011;66(Suppl 4):S7.
TETRACYCLINES File Jr. TM et al: SOLITAIRE-IV: A randomized, double-blind, multicenter study
Demeclocycline Generic, Declomycin comparing the efficacy and safety of intravenous-to-oral solithromycin to
intravenous-to-oral moxifloxacin for treatment of community-acquired
Doxycycline Generic, Vibramycin, others bacterial pneumonia. Clin Infect Dis 2016;63:1007.
Minocycline Generic, Minocin, others Hancock RE: Mechanisms of action of newer antibiotics for gram-positive
Tetracycline Generic, others pathogens. Lancet Infect Dis 2005;5:209.
Tigecycline Tygacil Leclerq R: Mechanisms of resistance to macrolides and lincosamides: Nature
of the resistance elements and their clinical implications. Clin Infect Dis
MACROLIDES
2002;34:482.
Azithromycin Generic, Zithromax Lee M et al: Linezolid for treatment of chronic extensively drug-resistant tubercu-
Clarithromycin Generic, Biaxin losis. N Engl J Med 2012;367:1508.
Erythromycin Generic, others Livermore DM: Tigecycline: What is it, and where should it be used? J Antimicrob
KETOLIDES Chemother 2005;56:611.
Moran GJ et al: Methicillin-resistant S aureus infections among patients in the
Telithromycin Ketek
emergency department. N Engl J Med 2006;355:666.
LINCOMYCIN Moran GJ et al: Tedizolid for 6 days versus linezolid for 10 days for acute bacterial
Clindamycin Generic, Cleocin skin and skin-structure infections (ESTABLISH-2): A randomized, double-
STREPTOGRAMINS blind, phase 3, non-inferiority trial. Lancet 2014;14:696.
Quinupristin and dalfopristin Synercid Prokocimer P et al: Tedizolid phosphate vs linezolid for treatment of acute bacterial
skin and skin structure infections. JAMA 2013;309:559.
OXAZOLIDINONE
Tasina E et al: Efficacy and safety of tigecycline for the treatment of infectious
Linezolid Generic, Zyvox diseases: A meta-analysis. Lancet Infect Dis 2011;11:834.
Tedizolid Sivextro Van Bambeke F: Renaissance of antibiotics against difficult infections: Focus on
oritavancin and new ketolides and quinolones. Ann Med 2014;46:512.
Wayne RA et al: Azithromycin and risk of cardiovascular death. N Engl J Med
2012;366:1881.
Woytowish MR, Rowe AS: Clinical relevance of linezolid-associated serotonin
toxicity. Ann Pharmacother 2013;47:388.
REFERENCES Zuckerman JM: Macrolides and ketolides: Azithromycin, clarithromycin, telithro-
Barrera CM et al: Efficacy and safety of oral solithromycin versus oral moxifloxa- mycin. Infect Dis Clin North Am 2004;18:621.
cin for treatment of community-acquired bacterial pneumonia: A global,
double-blind, multicenter, randomized, active-controlled, non-inferiority
trial (SOLITAIRE-ORAL). Lancet 2016;16:421.

C ASE STUDY ANSWER

A tetracycline or a macrolide is effective in the treatment of patient is pregnant, then tetracyclines would be contraindi-
chlamydial cervicitis. Doxycycline at a dose of 100 mg PO cated and she should receive azithromycin, which is safe in
bid for 7 days is the preferred tetracycline, while azithro- pregnancy.
mycin as a single 1 g dose is the preferred macrolide. If the
 45
C H A P T E R
Aminoglycosides &
Spectinomycin
Camille E. Beauduy, PharmD, & Lisa G. Winston, MD*
C ASE STUDY
A 45-year-old man with no significant medical history was
admitted to the intensive care unit (ICU) 10 days ago after
suffering third-degree burns over 40% of his body. He had
been relatively stable until the last 24 hours. Now, he is febrile
(39.5°C [103.1°F]), and his white blood cell count has risen
from 8500 to 20,000/mm3. He has also had an episode of hypo-
tension (86/50 mmHg) that responded to a fluid bolus. Blood
cultures were obtained at the time of his fever and results are
The drugs described in this chapter are bactericidal inhibitors of pro-
tein synthesis that interfere with ribosomal function. These agents
are useful mainly against aerobic Gram-negative microorganisms.
■■ AMINOGLYCOSIDES
The aminoglycosides include streptomycin, neomycin, kanamy-
cin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin,
and others. They are used most widely in combination with other
agents to treat drug-resistant organisms; for example, they are
used with a β-lactam antibiotic in serious infections with Gram-
negative bacteria, with a β-lactam antibiotic or vancomycin for
Gram-positive endocarditis, and with one or more agents for treat-
ment of mycobacterial infections, such as tuberculosis.
General Properties of Aminoglycosides
A. Physical and Chemical Properties
Aminoglycosides have a hexose ring, either streptidine (in strep-
tomycin) or 2-deoxystreptamine (in other aminoglycosides), to
*
The authors thank Drs. Henry F. Chambers and Daniel H. Deck for
their contributions to previous editions.
826
pending. The ICU attending physician is concerned about a
bloodstream infection and decides to treat with empiric com-
bination therapy directed against Pseudomonas aeruginosa.
The combination therapy includes tobramycin. The patient
weighs 70 kg (154 lb) and has an estimated creatinine clear-
ance of 90 mL/min. How should tobramycin be dosed using
once-daily and conventional dosing strategies? How should
each regimen be monitored for efficacy and toxicity?
which various amino sugars are attached by glycosidic linkages
(Figures 45–1 and 45–2). They are water-soluble, stable in solu-
tion, and more active at alkaline than at acid pH.
B. Mechanism of Action
The mode of action of streptomycin has been studied more
closely than that of other aminoglycosides, but all aminoglyco-
sides are thought to act similarly. Aminoglycosides are irrevers-
ible inhibitors of protein synthesis, but the precise mechanism
for bactericidal activity is unclear. The initial event is passive dif-
fusion via porin channels across the outer membrane (see Figure
43–3). Drug is then actively transported across the cell mem-
brane into the cytoplasm by an oxygen-dependent process. The
transmembrane electrochemical gradient supplies the energy for
this process, and transport is coupled to a proton pump. Low
extracellular pH and anaerobic conditions inhibit transport by
reducing the gradient. Transport may be enhanced by cell wall-
active drugs such as penicillin or vancomycin; this enhancement
may be the basis of the synergism of those antibiotics with
aminoglycosides.
Inside the cell, aminoglycosides bind to 30S-subunit ribosomal
proteins. Protein synthesis is inhibited by aminoglycosides in at
least three ways (Figure 45–3): (1) interference with the initiation
 CHAPTER 45  Aminoglycosides & Spectinomycin    827

complex of peptide formation; (2) misreading of mRNA, which

NH2 causes incorporation of incorrect amino acids into the peptide and
C NH results in a nonfunctional protein; and (3) breakup of polysomes
CH3
into nonfunctional monosomes. These activities occur more or
HO NH CH2OH
NH O
CHO
O
less simultaneously, and the overall effect is irreversible and leads
OH
H2N C NH O O OH
to cell death.

HO OH NH OH C. Mechanisms of Resistance
Three principal mechanisms of resistance have been established:
CH3
(1) production of a transferase enzyme that inactivates the amino-
Streptidine Streptose N-methyl-L- glycoside by adenylylation, acetylation, or phosphorylation. This
glucosamine
is the principal type of resistance encountered clinically. (2) There
Streptobiosamine is impaired entry of aminoglycoside into the cell. This may result
from mutation or deletion of a porin protein involved in transport
FIGURE 45–1  Structure of streptomycin. and maintenance of the electrochemical gradient or from growth

1 2
H2C NH2 NH2 H2C NH2 NH2
O O
5 3 2 NH R NH2
HO 4 I 1 O 4 II 1 HO I O II
3 2 5 6 CH2 OH CH2 OH
O O
HO OH HO O 5 NH2 HO O
4 3 1 III 4 OH III OH
2 3

HO NH2 HO NH2
5 Tobramycin

Kanamycin R =H
O OH NH2
HO
Amikacin R = C CH CH2 CH2 NH2 NH O

I O II NH R
R1

HC NH R2 NH2
NH2 HO O O
O OH
5 3 2 NH R3 Plazomicin
I II III
4 O 1
O OH
CH3
O R C CH CH2 CH2 NH2
NH2 HO O OH HO NH–CH3
III
2 CH3

HO NH CH3
Gentamicin, netilmicin

Ring I Ring II

C4–C5
R1 R2 bond R3
Gentamicin C1 CH3 CH3 Single H
Gentamicin C2 CH3 H Single H
Gentamicin C1a H H Single H
Netilmicin H H Double C 2H 5

FIGURE 45–2  Structures of several important aminoglycoside antibiotics. Ring II is 2-deoxystreptamine. The resemblance between kana-
mycin and amikacin and between gentamicin, netilmicin, and tobramycin can be seen. Plazomicin’s ring II and III are similar to the other struc-
tures; it shares the same hydroxyl-aminobutyric acid R group as amikacin. Its ring I differs from amikacin in that it is unsaturated. The circled
numerals on the kanamycin molecule indicate points of attack of plasmid-mediated bacterial transferase enzymes that can inactivate this drug.
➀, ➁, and ➂, acetyltransferase; ➃, phosphotransferase; ➄, adenylyltransferase. Amikacin is resistant to modification at ➁,➂,➃, and ➄; whereas
plazomicin is resistant to modification at ➀, ➁, ➃, and ➄.
828    SECTION VIII  Chemotherapeutic Drugs

Normal bacterial cell

Initiation 50S subunit Nascent peptide chain

codon

5´

30S subunit
mRNA 3´

Aminoglycoside-treated bacterial cell

Drug (block of Drug (miscoded peptide chain)

initiation complex)
Drug (block of
–
translocation)

5´

30S subunit
mRNA 3´

FIGURE 45–3  Putative mechanisms of action of the aminoglycosides in bacteria. Normal protein synthesis is shown in the top panel. At
least three aminoglycoside effects have been described, as shown in the bottom panel: block of formation of the initiation complex; miscoding
of amino acids in the emerging peptide chain due to misreading of the mRNA; and block of translocation on mRNA. Block of movement of the
ribosome may occur after the formation of a single initiation complex, resulting in an mRNA chain with only a single ribosome on it, a so-called
monosome. (Reproduced, with permission, from Trevor AT, Katzung BG, Masters SB: Pharmacology: Examination & Board Review, 6th ed. McGraw-Hill, 2002. Copyright © The
McGraw-Hill Companies, Inc.)

conditions under which the oxygen-dependent transport process
is not functional. (3) The receptor protein on the 30S ribosomal
subunit may be deleted or altered as a result of a mutation.
D. Pharmacokinetics and Once-Daily Dosing
Aminoglycosides are absorbed very poorly from the intact gastro-
intestinal tract, and almost the entire oral dose is excreted in feces
after oral administration. However, the drugs may be absorbed if
ulcerations are present. Aminoglycosides are usually administered
intravenously as a 30–60 minute infusion. After intramuscular
injection, aminoglycosides are well absorbed, giving peak concen-
trations in blood within 30–90 minutes. After a brief distribution
phase, peak serum concentrations are identical to those following
intravenous injection. The normal half-life of aminoglycosides
in serum is 2–3 hours, increasing to 24–48 hours in patients
with significant impairment of renal function. Aminoglycosides
are only partially and irregularly removed by hemodialysis—eg,
40–60% for gentamicin—and even less effectively by peritoneal
dialysis. Aminoglycosides are highly polar compounds that do not
enter cells readily. They are largely excluded from the central ner-
vous system and the eye. In the presence of active inflammation,
however, cerebrospinal fluid levels reach 20% of plasma levels,
and, in neonatal meningitis, the levels may be higher. Intrathecal
or intraventricular injection is required for high levels in cerebro-
spinal fluid. Even after parenteral administration, concentrations
of aminoglycosides are not high in most tissues except the renal
cortex. Concentration in most secretions is also modest; in the
bile, the level may reach 30% of that in blood. With prolonged
therapy, diffusion into pleural or synovial fluid may result in con-
centrations 50–90% of that of plasma.
Traditionally, aminoglycosides have been administered in two
or three equally divided doses per day in patients with normal
renal function. However, administration of the entire daily dose
in a single injection may be preferred in many clinical situations
for at least two reasons. Aminoglycosides exhibit concentration-
dependent killing; that is, higher concentrations kill a larger pro-
portion of bacteria and kill at a more rapid rate. They also have a
significant postantibiotic effect, such that the antibacterial activity
persists beyond the time during which measurable drug is present.
The postantibiotic effect of aminoglycosides can last several hours.
Because of these properties, a given total amount of aminoglycoside
may have better efficacy when administered as a single large dose
than when administered as multiple smaller doses.
When administered with a cell wall-active antibiotic (a β-lactam
or vancomycin), aminoglycosides may exhibit synergistic killing
against certain bacteria. The effect of the drugs in combination
is greater than the anticipated effect of each individual drug; ie,
the killing effect of the combination is more than additive. This
synergy may be important in certain clinical situations, such as
endocarditis.
Adverse effects from aminoglycosides are both time- and
concentration-dependent. Toxicity is unlikely to occur until a
certain threshold concentration is reached, but, once that concentra-
tion is achieved, the time beyond this threshold becomes critical.

This threshold is not precisely defined, but a trough concentration
above 2 mcg/mL is predictive of toxicity. At clinically relevant
doses, the total time above this threshold is greater with multiple
smaller doses of drug than with a single large dose.
Numerous clinical studies demonstrate that a single daily dose
of aminoglycoside is just as effective—and probably less toxic—
than multiple smaller doses. Therefore, many authorities recom-
mend that aminoglycosides be administered as a single daily dose
in most clinical situations. However, the efficacy of once-daily
aminoglycoside dosing in combination therapy of enterococcal
and staphylococcal endocarditis in patients with a prosthetic valve
remains to be defined, and administration of lower doses two or
three times daily is still recommended. In contrast, limited data do
support once-daily dosing in streptococcal endocarditis. The role
of once-daily dosing in pregnancy, obesity, and in neonates also is
not well defined.
Once-daily dosing has potential practical advantages. For
example, repeated determinations of serum concentrations are
unnecessary unless an aminoglycoside is given for more than 3
days. A drug administered once a day rather than three times a
day is less labor intensive. And once-a-day dosing is more feasible
for outpatient therapy.
Aminoglycosides are cleared by the kidney, and excretion is
directly proportional to creatinine clearance. To avoid accumu-
lation and toxic levels, once-daily dosing of aminoglycosides is
generally avoided if renal function is impaired. Rapidly changing
renal function, which may occur with acute kidney injury, must
also be monitored to avoid overdosing or underdosing. Provided
these pitfalls are avoided, once-daily aminoglycoside dosing is safe
and effective. If the creatinine clearance is >60 mL/min, then a
single daily dose of 5–7 mg/kg of gentamicin or tobramycin is
recommended (15 mg/kg for amikacin). For patients with cre-
atinine clearance <60 mL/min, traditional dosing as described
below is recommended. With once-daily dosing, serum concen-
trations need not be routinely checked until the second or third
day of therapy, depending on the stability of renal function and
the anticipated duration of therapy. In most circumstances, it is
unnecessary to check peak concentrations; an exception may be
when ensuring adequately high peak concentrations for treat-
ing infections caused by drug-resistant pathogens. The goal is to
administer drug so that concentrations of <1 mcg/mL are present
between 18 and 24 hours after dosing. This provides sufficient
time for washout of drug to occur before the next dose is given.
Several nomograms have been developed and validated to assist
clinicians with once-daily dosing (eg, Freeman reference).
With traditional dosing, adjustments must be made to pre-
vent accumulation of drug and toxicity in patients with renal
insufficiency. Either the dose of drug is kept constant and the
interval between doses is increased, or the interval is kept con-
stant and the dose is reduced. Nomograms and formulas have
been constructed relating serum creatinine levels to adjust-
ments in traditional treatment regimens. Because aminoglycoside
clearance is directly proportional to the creatinine clearance, a
method for determining the aminoglycoside dose is to estimate
creatinine clearance using the Cockcroft-Gault formula described
in Chapter 60. For a traditional twice- or thrice-daily dosing
CHAPTER 45  Aminoglycosides & Spectinomycin    829
regimen, peak serum concentrations should be determined from
a blood sample obtained 30–60 minutes after a dose, and trough
concentrations from a sample obtained just before the next dose.
Doses of gentamicin and tobramycin should be adjusted to main-
tain peak levels between 5 and 10 mcg/mL (typically between
8 and 10 mcg/mL in more serious infections) and trough levels
<2 mcg/mL (<1 mcg/mL is optimal).
E. Adverse Effects
All aminoglycosides are ototoxic and nephrotoxic. Ototoxicity and
nephrotoxicity are more likely to be encountered when therapy is
continued for more than 5 days, at higher doses, in the elderly,
and in the setting of renal insufficiency. Concurrent use with loop
diuretics (eg, furosemide, ethacrynic acid) or other nephrotoxic
antimicrobial agents (eg, vancomycin or amphotericin) can poten-
tiate nephrotoxicity and should be avoided if possible. Ototoxicity
can manifest either as auditory damage, resulting in tinnitus and
high-frequency hearing loss initially, or as vestibular damage with
vertigo, ataxia, and loss of balance. Nephrotoxicity results in rising
serum creatinine levels or reduced creatinine clearance, although
the earliest indication often is an increase in trough serum ami-
noglycoside concentrations. Neomycin, kanamycin, and amikacin
are the agents most likely to cause auditory damage. Streptomycin
and gentamicin are the most vestibulotoxic. Neomycin, tobramy-
cin, and gentamicin are the most nephrotoxic.
In very high doses, aminoglycosides can produce a curare-like
effect with neuromuscular blockade that results in respiratory
paralysis. This paralysis is usually reversible by calcium gluconate,
when given promptly, or neostigmine. Hypersensitivity occurs
infrequently.
F. Clinical Uses
Aminoglycosides are mostly used against aerobic Gram-negative
bacteria, especially when there is concern for drug-resistant patho-
gens or in critically ill patients. They are almost always used in
combination with a β-lactam antibiotic to extend empiric cover-
age and to take advantage of the potential synergism between these
two classes of drugs. Penicillin-aminoglycoside combinations have
also been used to achieve bactericidal activity in treatment of
enterococcal endocarditis and to shorten duration of therapy for
viridans streptococcal endocarditis. Due to toxicity, these com-
binations are used less frequently when alternate regimens are
available. For example, in the case of enterococcal endocarditis,
studies suggest that the combination of ampicillin and ceftriaxone
is an effective regimen with less risk for nephrotoxicity. When
aminoglycosides are used, the selection of agent and dose depends
on the infection being treated and the susceptibility of the isolate.
STREPTOMYCIN
Streptomycin (Figure 45–1) was isolated from a strain of Strepto-
myces griseus. The antimicrobial activity of streptomycin is typical
of that of other aminoglycosides, as are the mechanisms of resis-
tance. Resistance has emerged in most species, restricting the cur-
rent usefulness of streptomycin, with the exceptions listed below.
830    SECTION VIII  Chemotherapeutic Drugs
Ribosomal resistance to streptomycin develops readily, limiting its
role as a single agent.
Clinical Uses
A. Mycobacterial Infections
Streptomycin is mainly used as a second-line agent for treatment
of tuberculosis. The dosage is 15 mg/kg/d with a maximum
of 1 g/d (20–40 mg/kg/d for children), and it may be given
intramuscularly or intravenously. It should be used only in com-
bination with other agents to prevent emergence of resistance.
See Chapter 47 for additional information regarding the use of
streptomycin in mycobacterial infections.
B. Nontuberculous Infections
In plague, tularemia, and sometimes, brucellosis, streptomycin,
1 g twice daily (15 mg/kg twice daily for children), is given intra-
muscularly in combination with an oral tetracycline.
Penicillin plus streptomycin is effective for enterococcal endo-
carditis and 2-week therapy of viridans streptococcal endocarditis;
however, for susceptible strains, gentamicin is used more commonly
when an aminoglycoside is selected as adjunct therapy. Streptomy-
cin remains a useful agent for treating gentamicin non-susceptible
enterococcal infections, as some isolates that are resistant to gen-
tamicin (and therefore resistant to netilmicin, tobramycin, and
amikacin) will remain susceptible to streptomycin.
Adverse Reactions
Fever, skin rashes, and other allergic manifestations may result
from hypersensitivity to streptomycin. This occurs most frequently
with a prolonged course of treatment (eg, for tuberculosis).
Pain at the injection site is common but usually not severe.
The most serious toxic effect with streptomycin is disturbance of
vestibular function—vertigo and loss of balance. The frequency
and severity of this disturbance are in proportion to the age of
the patient, the blood levels of the drug, and the duration of
administration. Vestibular dysfunction may follow a few weeks of
unusually high blood levels (eg, in individuals with impaired renal
function) or months of relatively low blood levels. Vestibular tox-
icity tends to be irreversible. Streptomycin given during pregnancy
can cause deafness in the newborn.
GENTAMICIN
Gentamicin is a mixture of three closely related constituents,
C1, C1A, and C2 (Figure 45–2) isolated from Micromonospora
purpurea. It is effective against both Gram-positive and Gram-
negative organisms, and many of its properties resemble those of
other aminoglycosides.
Antimicrobial Activity
Gentamicin sulfate, 2–10 mcg/mL, inhibits in vitro many
strains of staphylococci and Gram-negative bacteria, including
P. aeruginosa and Enterobacteriaceae. Like all aminoglycosides, it
has no activity against anaerobes.
Resistance
Streptococci and enterococci are relatively resistant to gentamicin
owing to failure of the drug to penetrate into the cell. However,
gentamicin in combination with some penicillins or vancomycin
produces a potent bactericidal effect, which in part is due to
enhanced uptake of drug that occurs with inhibition of cell wall
synthesis. Resistance to gentamicin rapidly emerges in staphy-
lococci during monotherapy owing to selection of permeability
mutants. Ribosomal resistance is rare. Among Gram-negative
bacteria, resistance is most commonly due to plasmid-encoded
aminoglycoside-modifying enzymes. Gram-negative bacteria that
are gentamicin-resistant usually are susceptible to amikacin, which
is much more resistant to modifying enzyme activity. The entero-
coccal enzyme that modifies gentamicin is a bifunctional enzyme
that also inactivates amikacin, netilmicin, and tobramycin but not
streptomycin; the latter is modified by a different enzyme. This
is why some gentamicin-resistant enterococci are susceptible to
streptomycin.
Clinical Uses
A. Intramuscular or Intravenous Administration
Gentamicin is used mainly in severe infections caused by Gram-
negative bacteria that are likely to be resistant to other drugs,
especially P aeruginosa, Enterobacter sp, Serratia marcescens,
Proteus sp, Acinetobacter sp, and Klebsiella sp. It usually is used
in combination with a second agent because an aminoglycoside
alone may not be effective for infections outside the urinary tract.
Aminoglycosides should not be used as single agents for therapy
of pneumonia because penetration of infected lung tissue is poor
and local conditions of low pH and low oxygen tension contribute
to limited activity. Gentamicin 5–7 mg/kg/d traditionally is given
intravenously in three equal doses, but once-daily administration
is just as effective for some organisms and less toxic (see above).
Gentamicin, in combination with a cell wall-active antibiotic,
may also be indicated in the treatment of endocarditis caused by
Gram-positive bacteria (streptococci, staphylococci, and entero-
cocci) as discussed earlier.
B. Topical and Ocular Administration
Creams, ointments, and solutions containing 0.1–0.3% genta-
micin sulfate have been used for the treatment of infected burns,
wounds, or skin lesions and in attempts to prevent intravenous
catheter infections. The effectiveness of topical preparations for
these indications is unclear. Topical gentamicin is partly inacti-
vated by purulent exudates. Gentamicin can be injected intraocu-
larly for treatment of certain eye infections.
C. Intrathecal Administration
Meningitis caused by Gram-negative bacteria has been treated
by the intrathecal injection of gentamicin sulfate, 1–10 mg/d.
However, neither intrathecal nor intraventricular gentamicin was
beneficial in neonates with meningitis, and intraventricular gen-
tamicin was toxic, raising questions about the usefulness of this
form of therapy. Moreover, the availability of third-generation
cephalosporins for Gram-negative meningitis has rendered this

therapy obsolete in most cases. It may be used in cases of drug-
resistant meningitis or severe β-lactam allergy.
Adverse Reactions
Nephrotoxicity is usually reversible upon drug discontinuation. It
occurs in 5–25% of patients receiving gentamicin for longer than
3–5 days. Such toxicity requires, at the very least, adjustment of the
dosing regimen and should prompt reconsideration of the need for the
drug, particularly if there is a less toxic alternative agent. Measurement
of gentamicin serum levels is essential. Ototoxicity, which tends to be
irreversible, manifests itself mainly as vestibular dysfunction. Loss of
hearing can also occur. Ototoxicity is in part genetically determined,
having been linked to point mutations in mitochondrial DNA, and
occurs in 1–5% for patients receiving gentamicin for more than
5 days. Hypersensitivity reactions to gentamicin are uncommon.
TOBRAMYCIN
This aminoglycoside (Figure 45–2) has an antibacterial spectrum
similar to that of gentamicin. Although there is some cross-
resistance between gentamicin and tobramycin, it is unpredictable
in individual strains. Separate laboratory susceptibility tests are
therefore necessary.
A. Intramuscular or Intravenous Administration
The pharmacokinetic properties of tobramycin are virtually iden-
tical with those of gentamicin. The daily dose of tobramycin is
5–7 mg/kg intramuscularly or intravenously, traditionally divided
into three equal amounts and given every 8 hours but now often
given as a single daily dose. Monitoring blood levels in renal insuf-
ficiency is an essential guide to proper dosing.
Tobramycin has almost the same antibacterial spectrum as gen-
tamicin with a few exceptions. Gentamicin is slightly more active
against S marcescens, whereas tobramycin is slightly more active against
P aeruginosa; Enterococcus faecalis is susceptible to both gentamicin and
tobramycin, but E faecium is resistant to tobramycin. Gentamicin and
tobramycin are otherwise interchangeable clinically.
Like other aminoglycosides, tobramycin is ototoxic and neph-
rotoxic. Nephrotoxicity of tobramycin may be slightly less than
that of gentamicin.
B. Inhaled and Ophthalmic Administration
Tobramycin is formulated in solution (300 mg in 5 mL) for inha-
lation for treatment of P aeruginosa lower respiratory tract infec-
tions complicating cystic fibrosis. The drug is recommended as a
300-mg dose regardless of the patient’s age or weight for admin-
istration twice daily in repeated cycles of 28 days on therapy, fol-
lowed by 28 days off therapy. Serum concentrations 1 hour after
inhalation average 1 mcg/mL; consequently, nephrotoxicity and
ototoxicity rarely occur. Caution should be used when adminis-
tering tobramycin to patients with preexisting renal, vestibular, or
hearing disorders. Tobramycin is also available as 0.3% ophthal-
mic ointment and drops for the treatment of superficial eye infec-
tions. These formulations result in minimal systemic absorption
and are unlikely to cause systemic adverse effects.
CHAPTER 45  Aminoglycosides & Spectinomycin    831
AMIKACIN
Amikacin is a semisynthetic derivative of kanamycin; it is less
toxic than the parent molecule (Figure 45–2). It is resistant to
many enzymes that inactivate gentamicin and tobramycin, and,
therefore, can be used against some microorganisms resistant to
the latter drugs. Many Gram-negative bacteria, including many
strains of Proteus, Pseudomonas, Enterobacter, and Serratia, are
inhibited by 1–20 mcg/mL amikacin in vitro. After injection of
500 mg of amikacin every 12 hours (15 mg/kg/d) intramuscularly,
peak levels in serum are 10–30 mcg/mL.
Strains of multidrug-resistant Mycobacterium tuberculosis,
including streptomycin-resistant strains, are usually susceptible
to amikacin. Kanamycin-resistant strains may be cross-resis-
tant to amikacin. The dosage of amikacin for tuberculosis is
10–15 mg/kg/d as a once-daily or two to three times weekly
injection and always in combination with other drugs to which
the isolate is susceptible.
Like all aminoglycosides, amikacin is nephrotoxic and ototoxic
(particularly for the auditory portion of the eighth nerve). Serum
concentrations should be monitored. Target peak serum concen-
trations for an every-12-hours dosing regimen are 20–40 mcg/mL,
and trough levels should be maintained between 4 and 8 mcg/mL.
NETILMICIN
Netilmicin shares many characteristics with gentamicin and tobra-
mycin. However, the addition of an ethyl group to the 1-amino
position of the 2-deoxystreptamine ring (ring II, Figure 45–2)
sterically protects the netilmicin molecule from enzymatic degra-
dation at the 3-amino (ring II) and 2-hydroxyl (ring III) positions.
Consequently, netilmicin may be active against some gentamicin-
resistant and tobramycin-resistant bacteria.
The dosage (5–7 mg/kg/d) and the routes of administration are
the same as for gentamicin. Netilmicin is largely interchangeable
with gentamicin or tobramycin but is no longer available in the
United States.
NEOMYCIN, KANAMYCIN, &
PAROMOMYCIN
Neomycin, kanamycin, and paromomycin have similar pharma-
cologic properties.
Antimicrobial Activity & Resistance
Drugs of the neomycin group are active against Gram-positive and
Gram-negative bacteria and some mycobacteria. P aeruginosa and
streptococci are generally resistant. Mechanisms of antibacterial
action and resistance are the same as with other aminoglycosides.
The former widespread use of these drugs in bowel preparation for
elective surgery contributed to the selection of resistant organisms
and some outbreaks of enterocolitis in hospitals. Cross-resistance
between kanamycin and neomycin is complete and may result in
amikacin cross-resistance.
832    SECTION VIII  Chemotherapeutic Drugs
Pharmacokinetics
Like all aminoglycosides, drugs of the neomycin group are poorly
absorbed from the gastrointestinal tract. After oral administra-
tion, the intestinal flora is suppressed or modified, and the drug
is excreted in the feces. Excretion of any absorbed drug is mainly
through glomerular filtration into the urine.
Clinical Uses
Neomycin is generally limited to topical and oral use due to toxicity
associated with parenteral use and higher resistance rates compared
to other aminoglycosides. Kanamycin use is limited to treatment of
multi-drug-resistant tuberculosis, although alternate agents, such as
amikacin, may be preferred. It is no longer available in the USA.
Paromomycin has been shown to be effective against visceral leish-
maniasis when given parenterally (see Chapter 52), and this serious
infection may represent an important use for this drug. Paromomy-
cin can be used for intestinal Entamoeba histolytica infection and is
sometimes used for intestinal infections with other parasites.
A. Topical Administration
Solutions containing 1–5 mg/mL neomycin have been used on
infected surfaces or injected into joints, the pleural cavity, tissue
spaces, or abscess cavities where infection is present. The total
amount of drug given in this fashion must be limited to 15 mg/kg/d
because at higher doses enough drug may be absorbed to produce
systemic toxicity. Whether topical application for active infection
adds anything to appropriate systemic therapy is questionable.
Ointments, often formulated as a neomycin-polymyxin-bacitracin
combination, can be applied to infected skin lesions or in the nares
for suppression of staphylococci but they are largely ineffective.
B. Oral Administration
In preparation for elective bowel surgery, 1 g of neomycin may
be given orally every 6–8 hours for 1–2 days, often combined
with 1 g of erythromycin base. This reduces the aerobic bowel
flora with little effect on anaerobes. In hepatic encephalopathy,
coliform flora can be suppressed by giving 1 g every 6–8 hours
together with reduced protein intake, thus reducing ammonia
production. Use of neomycin for hepatic encephalopathy has been
largely supplanted by lactulose and other medications that are less
toxic. Use of paromomycin in the treatment of protozoal infec-
tions is discussed in Chapter 52.
C. Intravenous and Intramuscular Administration
When used intravenously, the standard dose for kanamycin is
15 mg/kg/day in two to three divided doses, whereas for treatment
of tuberculosis, 15 mg/kg is usually given intramuscularly as a sin-
gle daily dose. In the case of once daily administration, kanamycin
peak concentrations are typically between 35 and 45 mcg/mL,
while trough concentrations should be undetectable.
Adverse Reactions
All members of the neomycin group have significant nephro-
toxicity and ototoxicity. Auditory function is affected more than
vestibular function. Deafness may occur, especially in adults with
impaired renal function and prolonged elevation of drug levels.
The sudden absorption of postoperatively instilled kanamycin
from the peritoneal cavity (3–5 g) has resulted in curare-like neu-
romuscular blockade and respiratory arrest. Calcium gluconate
and neostigmine can act as antidotes.
Although hypersensitivity is not common, prolonged appli-
cation of neomycin-containing ointments to skin and eyes has
resulted in severe allergic reactions.
PLAZOMICIN
Plazomicin is a new aminoglycoside under development and is
expected to undergo review by the U.S. Food and Drug Admin-
istration in 2017. It has been studied in phase II clinical trials for
treatment of urinary tract infections; phase III clinical trials are
underway for treatment of carbapenem-resistant Enterobacteria-
ceae. It is a synthetic molecule derived from sisomicin, an ami-
noglycoside no longer available,. Various structural modifications
have yielded a compound less susceptible to most aminoglycoside
modifying enzymes, thus retaining activity against aminogly-
coside-resistant pathogens. It appears to have similarly potent
in vitro activity against Enterobacteriaceae and displays two- to
four-fold lower MICs against nonfermenting Gram-negative
bacilli (eg, P aeruginosa) when compared with gentamicin, tobra-
mycin, and amikacin. It has activity similar to gentamicin against
staphylococci. A 15-mg/kg dose yields mean peak and trough con-
centrations of 113 mcg/mL and 0.43 mcg/mL, respectively. The
half-life is about 4 hours, and it is being studied as a single daily
dose. Due to limited clinical experience, it is unclear whether the
toxicity profile will be similar to other aminoglycosides; however,
no ototoxicity or nephrotoxicity has been observed in early trials.
■■ SPECTINOMYCIN
Spectinomycin is an aminocyclitol antibiotic that is structurally
related to aminoglycosides. It lacks amino sugars and glycosidic
bonds.
CH3 OH
O O
HN CH3
HO
O OH
NH O
CH3
Spectinomycin
Spectinomycin is active in vitro against many Gram-positive
and Gram-negative organisms, but it is used almost solely as
an alternative treatment for drug-resistant gonorrhea or gonor-
rhea in penicillin-allergic patients. The majority of gonococcal
isolates are inhibited by 6 mcg/mL of spectinomycin. Strains of
gonococci may be resistant to spectinomycin, but there is no
cross-resistance with other drugs used in gonorrhea. Notably, it is
 CHAPTER 45  Aminoglycosides & Spectinomycin    833

not recommended for treatment of pharyngeal gonococcal infec- children).There is pain at the injection site and, occasionally, fever
tions due to high failure rates regardless of in vitro susceptibility. and nausea. Nephrotoxicity and anemia have been observed rarely.
Spectinomycin is rapidly absorbed after intramuscular injection. Spectinomycin is no longer available for use in the USA but is still
The standard regimen is a single dose of 2–4 g/d (40 mg/kg in recommended elsewhere.

SUMMARY Aminoglycosides
Subclass, Mechanism of Pharmacokinetics, Toxicities,
Drug Action Effects Clinical Applications Interactions

AMINOGLYCOSIDES & SPECTINOMYCIN

  •  Gentamicin Prevents bacterial Bactericidal activity against Sepsis caused by aerobic IV • renal clearance (half-life 2.5 h) • conventional
protein synthesis susceptible bacteria • synergistic Gram-negative bacteria dosing 1.3–1.7 mg/kg q8h with goal peak levels
by binding to the effects against Gram-positive bacteria • synergistic activity in 5–8 mcg/mL • trough levels <2 mcg/mL
30S ribosomal when combined with β-lactams or endocarditis caused by • once-daily dosing at 5–7 mg/kg as effective and
subunit vancomycin • concentration- streptococci, staphylococci, may have less toxicity than conventional dosing
dependent killing and a significant and enterococci • Toxicity: Nephrotoxicity (reversible), ototoxicity
post-antibiotic effect (irreversible), neuromuscular blockade

  •  Tobramycin: Intravenous; more active than gentamicin versus Pseudomonas; may also have less nephrotoxicity
  • Amikacin: Intravenous; resistant to many enzymes that inactivate gentamicin and tobramycin; higher doses and target peaks and troughs than gentamicin and
tobramycin
  •  Streptomycin: Intramuscular, widespread resistance limits use to specific indications such as tuberculosis and enterococcal endocarditis
  •  Neomycin: Oral or topical, poor bioavailability; used before bowel surgery to decrease aerobic flora
  • Spectinomycin: Intramuscular; sole use is for treatment of antibiotic-resistant gonococcal infections or gonococcal infections in penicillin-allergic patients; not available
in the USA

P R E P A R A T I O N S Cheer SM, Waugh J, Noble S: Inhaled tobramycin (TOBI): A review of its use in
the management of Pseudomonas aeruginosa infections in patients with cystic
A V A I L A B L E fibrosis. Drugs 2003;63:2501.
Freeman CD et al: Once-daily dosing of aminoglycosides: Review and recommen-
dations for clinical practice. J Antimicrob Chemother 1997;39:677.
GENERIC NAME AVAILABLE AS
Jackson J et al: Aminoglycosides: How should we use them in the 21st century?
Amikacin Generic, Amikin Curr Opin Infect Dis 2013;26:516.
Gentamicin Generic Le T, Bayer AS: Combination antibiotic therapy for infective endocarditis. Clin
Kanamycin Generic, Kantrex Infect Dis 2003;36:615.
Neomycin Generic, Mycifradin Olsen KM et al: Effect of once-daily dosing vs. multiple daily dosing of tobramycin
on enzyme markers of nephrotoxicity. Crit Care Med 2004;32:1678.
Paromomycin Generic, Humatin
Paul M et al: Beta-lactam monotherapy versus beta-lactam-aminoglycoside combi-
Streptomycin Generic nation therapy in cancer patients with neutropenia. Cochrane Database Syst
Tobramycin Generic, Nebcin Rev 2013 Jun 29;6:CD003038.
Peña C et al: Effect of adequate single-drug versus combination antimicrobial
therapy on mortality in Pseudomonas aeruginosa bloodstream infections. Clin
REFERENCES Infect Dis 2013;57:208.
Baddour L et al: Infective Endocarditis in Adults: Diagnosis, Antimicrobial Poole K: Aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob Agents
Therapy, and Management of Complications. Circulation 2015;132:1435. Chemother 2005;49:479.
Busse H-J, Wöstmann C, Bakker EP: The bactericidal action of streptomycin: Zhanel G et al: Comparison of the next generation aminoglycoside plazomicin
Membrane permeabilization caused by the insertion of mistranslated pro- to gentamicin, tobramycin, and amikacin. Expert Rev Anti Infect Ther
teins into the cytoplasmic membrane of Escherichia coli and subsequent 2012;10:459.
caging of the antibiotic inside the cells due to degradation of these proteins.
J Gen Microbiol 1992;138:551.

C ASE STUDY ANSWER

The patient has normal renal function and thus qualifies
for once-daily dosing. Tobramycin could be administered
as a single once-daily injection at a dose of 350–490 mg
(5–7 mg/kg). A serum level between 1.5 and 6 mcg/mL mea-
sured 8 hours after infusion correlates with an appropriate
trough level. Alternatively, the same total daily dose could be
divided and administered every 8 hours, as a conventional
dosing strategy. With conventional dosing, peak and trough
concentrations should be monitored with the target peak
concentration of 5–10 mcg/mL and the target trough con-
centration of <2 mcg/mL.
 46
C H A P T E R
Sulfonamides,
Trimethoprim, &
Quinolones
Camille E. Beauduy, PharmD, & Lisa G. Winston, MD*
C ASE STUDY
A 59-year-old woman presents to an urgent care clinic with
a 4-day history of frequent and painful urination. She has
had fevers, chills, and flank pain for the past 2 days. Her
physician advised her to come immediately to the clinic for
evaluation. In the clinic she is febrile (38.5°C [101.3°F])
but otherwise stable and states she is not experiencing any
nausea or vomiting. Her urine dipstick test is positive for
leukocyte esterase. Urinalysis and urine culture are ordered.
Her past medical history is significant for three urinary
■■ ANTIFOLATE DRUGS
SULFONAMIDES
Chemistry
The basic formulas of the sulfonamides and their structural simi-
larity to p-aminobenzoic acid (PABA) are shown in Figure 46–1.
Sulfonamides with varying physical, chemical, pharmacologic,
and antibacterial properties are produced by attaching sub-
stituents to the amido group ( ⎯  SO2   ⎯  NH   ⎯   R) or the amino
group ( ⎯  NH2) of the sulfanilamide nucleus. Sulfonamides tend
to be much more soluble at alkaline than at acid pH. Most can
be prepared as sodium salts, which are used for intravenous
administration.
*
The authors thank Henry F. Chambers, MD and Daniel H. Deck, for
their contributions to previous editions.
834
tract infections in the past year. Each episode was uncom-
plicated, treated with trimethoprim-sulfamethoxazole, and
promptly resolved. She also has osteoporosis for which she
takes a daily calcium supplement. The decision is made to
treat her with oral antibiotics for a complicated urinary
tract infection with close follow-up. Given her history,
what would be a reasonable empiric antibiotic choice?
Depending on the antibiotic choice are there potential drug
interactions?
Mechanism of Action & Antimicrobial
Activity
Sulfonamide-susceptible organisms, unlike mammals, cannot
use exogenous folate but must synthesize it from PABA. This
pathway (Figure 46–2) is thus essential for production of
purines and nucleic acid synthesis. As structural analogs of
PABA, sulfonamides inhibit dihydropteroate synthase and folate
production. Sulfonamides inhibit both Gram-positive bacteria,
such as Staphylococcus sp and Gram-negative enteric bacteria such
as Escherichia coli, Klebsiella pneumoniae, Salmonella, Shigella, and
Enterobacter sp, as well as Nocardia sp, Chlamydia trachomatis, and
some protozoa. Rickettsiae are not inhibited by sulfonamides but
are instead stimulated in their growth. Activity is poor against
anaerobes. Pseudomonas aeruginosa is intrinsically resistant to
sulfonamide antibiotics.
Combination of a sulfonamide with an inhibitor of dihy-
drofolate reductase (trimethoprim or pyrimethamine) provides
 CHAPTER 46  Sulfonamides, Trimethoprim, & Quinolones    835

synthase with low sulfonamide affinity is often encoded on a plas-

SO2NH2 COOH mid that is transmissible and can disseminate rapidly and widely.
Sulfonamide-resistant dihydropteroate synthase mutants also can
emerge under selective pressure.

NH2 NH2
Pharmacokinetics
Sulfanilamide p-Aminobenzoic acid (PABA) Sulfonamides can be divided into three major groups: (1)
oral, absorbable; (2) oral, nonabsorbable; and (3) topical.
SO2NH Oral absorbable sulfonamides are absorbed from the stomach
SO2NH and small intestine and distributed widely to tissues and body
N N
N fluids (including the central nervous system and cerebrospinal
O CH3 fluid), placenta, and fetus. Protein binding varies from 20%
to over 90%. Therapeutic concentrations are in the range of
NH2 40–100 mcg/mL of blood. Blood levels generally peak 2–6 hours
NH2 after oral administration.
Sulfadiazine Sulfamethoxazole A portion of absorbed drug is acetylated or glucuronidated in
the liver. Sulfonamides and inactive metabolites are then excreted
FIGURE 46–1  Structures of some sulfonamides and in the urine, mainly by glomerular filtration. The dosage of
p-aminobenzoic acid. sulfonamides must be reduced in patients with significant renal
failure.

synergistic activity because of sequential inhibition of folate

synthesis (Figure 46–2). Clinical Uses
Sulfonamides are infrequently used as single agents. Many
Resistance strains of formerly susceptible species, including meningococci,
pneumococci, streptococci, staphylococci, and gonococci, are
Some bacteria lack the enzymes required for folate synthesis from now resistant. The fixed-drug combination of trimethoprim-
PABA and, like mammals, depend on exogenous sources of folate; sulfamethoxazole is the drug of choice for infections such
therefore, they are not susceptible to sulfonamides. Sulfonamide as Pneumocystis jiroveci (formerly P carinii) pneumonia,
resistance may also occur as a result of mutations that (1) cause toxoplasmosis, and nocardiosis.
overproduction of PABA, (2) cause production of a folic acid-
synthesizing enzyme that has low affinity for sulfonamides, or
A. Oral Absorbable Agents
(3) impair permeability to the sulfonamide. Dihydropteroate
Sulfamethoxazole is a commonly used absorbable agent; however,
in the USA, it is available only as the fixed-dosed combination
trimethoprim-sulfamethoxazole. Typical dosing and indications
are discussed below.
p-Aminobenzoic acid
Administration of sulfadiazine with pyrimethamine is first-
line therapy for treatment of acute toxoplasmosis. Using sulfa-
Sulfonamides
Dihydropteroate − (compete diazine plus pyrimethamine, a potent inhibitor of dihydrofolate
synthase
with PABA) reductase, is synergistic because these drugs block sequential steps
in the folate synthesis pathway (Figure 46–2). However, since
Dihydrofolic acid 2015, there have been challenges with manufacturing, supply,
and pricing of pyrimethamine in the USA. In some cases, clini-
cians have obtained a compounded product through specialty
Dihydrofolate − Trimethoprim pharmacies or prescribed alternate agents, such as trimethoprim-
reductase
sulfamethoxazole. Sulfadoxine is a long-acting sulfonamide that is
coformulated with pyrimethamine (Fansidar). This combination
Tetrahydrofolic acid
is no longer commercially available in the USA but may be found
in other parts of the world where it is used as a second-line treat-
ment for malaria (see Chapter 52).
Purines

B. Oral Nonabsorbable Agents

DNA Sulfasalazine (salicylazosulfapyridine) is widely used in ulcer-
ative colitis, enteritis, and other inflammatory bowel disease (see
FIGURE 46–2  Actions of sulfonamides and trimethoprim. Chapter 62).
836    SECTION VIII  Chemotherapeutic Drugs
C. Topical Agents
Sodium sulfacetamide ophthalmic solution or ointment is effec-
tive in the treatment of bacterial conjunctivitis and as adjunctive
therapy for trachoma. Another sulfonamide, mafenide acetate, is
used topically but can be absorbed from burn sites. The drug and
its primary metabolite inhibit carbonic anhydrase and can cause
metabolic acidosis, a side effect that limits its usefulness. Silver
sulfadiazine is a less toxic topical sulfonamide and is preferred to
mafenide for prevention of infection of burn wounds.
Adverse Reactions
Historically, drugs containing a sulfonamide moiety, including
antimicrobial sulfas, diuretics, diazoxide, and the sulfonylurea hypo-
glycemic agents, were considered to be cross-allergenic. However,
more recent evidence suggests cross-reactivity is uncommon and
many patients who are allergic to nonantibiotic sulfonamides toler-
ate sulfonamide antibiotics. The most common adverse effects are
fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria,
nausea, vomiting, diarrhea, and difficulties referable to the urinary
tract (see below). Stevens-Johnson syndrome, although relatively
uncommon (<1% of treatment courses), is a particularly serious
and potentially fatal type of skin and mucous membrane eruption
associated with sulfonamide use. Other unwanted effects include
stomatitis, conjunctivitis, arthritis, hematopoietic disturbances (see
below), hepatitis, and, rarely, polyarteritis nodosa and psychosis.
A. Urinary Tract Disturbances
Sulfonamides may precipitate in urine, especially at neutral or acid
pH, producing crystalluria, hematuria, or even obstruction. This is
rarely a problem with the more soluble sulfonamides (eg, sulfisoxa-
zole). Sulfadiazine and sulfamethoxazole are relatively insoluble in
acidic urine and can cause crystalluria, particularly when given in
large doses or if fluid intake is poor. Crystalluria is treated by admin-
istration of sodium bicarbonate to alkalinize the urine and fluids
to increase urine flow. Sulfonamides have also been implicated in
various types of nephrosis and in allergic nephritis.
B. Hematopoietic Disturbances
Sulfonamides can cause hemolytic or aplastic anemia, granulocy-
topenia, thrombocytopenia, or leukemoid reactions. Sulfonamides
may provoke hemolytic reactions in patients with glucose-
6-phosphate dehydrogenase deficiency. Sulfonamides taken near
the end of pregnancy increase the risk of kernicterus in newborns.
TRIMETHOPRIM & TRIMETHOPRIM-
SULFAMETHOXAZOLE MIXTURES
Mechanism of Action
Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhib-
its bacterial dihydrofolic acid reductase, which converts dihy-
drofolic acid to tetrahydrofolic acid, a step leading to the
synthesis of purines and ultimately to DNA (Figure 46–2).
Trimethoprim is a much less efficient inhibitor of mammalian
dihydrofolic acid reductase. The combination of trimethoprim
and sulfamethoxazole is often bactericidal, compared with the
bacteriostatic activity of a sulfonamide alone.
NH2 OCH3
N
H2N CH2 OCH3
N
OCH3
Trimethoprim
NH2
N
H2N CI
N
C2H5
Pyrimethamine
Resistance
Resistance to trimethoprim can result from reduced cell perme-
ability, overproduction of dihydrofolate reductase, or production
of an altered reductase with reduced drug binding. Resistance
can emerge by mutation, although more commonly it is due to
plasmid-encoded trimethoprim-resistant dihydrofolate reductases.
These resistant enzymes may be coded within transposons on con-
jugative plasmids that exhibit a broad host range, accounting for
rapid and widespread dissemination of trimethoprim resistance
among numerous bacterial species.
Pharmacokinetics
Trimethoprim is usually given orally, alone or in combination with
sulfamethoxazole, which has a similar half-life. Trimethoprim-
sulfamethoxazole can also be given intravenously. Trimethoprim is
well absorbed from the gut and distributed widely in body fluids
and tissues, including cerebrospinal fluid.
Because trimethoprim is more lipid-soluble than sulfamethoxa-
zole, it has a larger volume of distribution than the latter drug.
Therefore, when 1 part of trimethoprim is given with 5 parts of
sulfamethoxazole (the ratio in the formulation), the peak plasma con-
centrations are in the ratio of 1:20, which is optimal for the combined
effects of these drugs in vitro. About 30–50% of the sulfonamide and
50–60% of the trimethoprim (or their respective metabolites) are
excreted in the urine within 24 hours. The dose should be reduced by
half for patients with creatinine clearances of 15–30 mL/min.
Trimethoprim (a weak base) concentrates in prostatic fluid and
in vaginal fluid, which are more acidic than plasma. Therefore, it
has more antibacterial activity in prostatic and vaginal fluids than
many other antimicrobial drugs.
Clinical Uses
A. Oral Trimethoprim
Trimethoprim can be given alone (100 mg twice daily) in acute
urinary tract infections. Many community-acquired organisms are
susceptible to the high concentrations that are found in the urine
(200–600 mcg/mL).

B. Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ)
A combination of trimethoprim-sulfamethoxazole is effective
treatment for a wide variety of infections including P jiroveci
pneumonia, urinary tract infections, prostatitis, and some
infections caused by susceptible strains of Shigella, Salmonella,
and nontuberculous mycobacteria. It is active against most
Staphylococcus aureus strains, both methicillin-susceptible and
methicillin-resistant, and against respiratory tract pathogens such
as Haemophilus sp, Moraxella catarrhalis, and K pneumoniae (but
not Mycoplasma pneumoniae). However, the increasing prevalence
of strains of E coli (up to 30% or more) and pneumococci that are
resistant to trimethoprim-sulfamethoxazole must be considered
before using this combination for empiric therapy of upper uri-
nary tract infections or pneumonia. Trimethoprim-sulfamethoxa-
zole is commonly used for the treatment of uncomplicated skin
and soft tissue infections.
One double-strength tablet (each tablet contains trimethoprim
160 mg plus sulfamethoxazole 800 mg) given every 12 hours is
effective treatment for urinary tract infections, prostatitis, uncom-
plicated skin and soft tissue infections, and infections caused by
susceptible strains of Shigella and Salmonella. Bone and joint
infections caused by S. aureus can be effectively treated, typically
at doses of 8–10 mg/kg per day of the trimethoprim component.
One single-strength tablet (containing trimethoprim 80 mg plus
sulfamethoxazole 400 mg) given three times weekly may serve as
prophylaxis in recurrent urinary tract infections of some women.
The dosage for children treated for shigellosis, urinary tract infec-
tion, or otitis media is trimethoprim 8 mg/kg per day and sulfa-
methoxazole 40 mg/kg per day divided every 12 hours.
Infections with P jiroveci and some other pathogens, such as
Nocardia or Stenotrophomonas maltophilia, can be treated with high
doses of the either the oral or intravenous combination (dosed on
the basis of the trimethoprim component at 15–20 mg/kg/d).
P jiroveci can be prevented in immunosuppressed patients by a
number of low dose regimens such as one double-strength tablet
daily or three times weekly.
C. Intravenous Trimethoprim-Sulfamethoxazole
A solution of the mixture containing 80 mg trimethoprim plus
400 mg sulfamethoxazole per 5 mL diluted in 125 mL of 5%
dextrose in water can be administered by intravenous infusion
over 60–90 minutes. It is the agent of choice for moderately
severe to severe pneumocystis pneumonia. It has been used for
Gram-negative bacterial sepsis, but has largely been replaced by
extended spectrum β-lactams and fluoroquinolones. It may be
an effective alternative for infections caused by some multidrug-
resistant species such as Enterobacter and Serratia; shigellosis; or
typhoid. It is the preferred alternate therapy for serious Listeria
infections in patients unable to tolerate ampicillin. The dosage is
10–20 mg/kg/d of the trimethoprim component.
D. Oral Pyrimethamine with Sulfonamide
Pyrimethamine and sulfadiazine are used in the treatment of toxo-
plasmosis. The dosage of sulfadiazine is 1–1.5 g four times daily,
with pyrimethamine given as a 200-mg loading dose followed by
a once-daily dose of 50–75 mg. Leucovorin, also known as folinic
CHAPTER 46  Sulfonamides, Trimethoprim, & Quinolones    837
acid, 10 mg orally each day, should be administered to minimize
bone marrow suppression seen with pyrimethamine. Some clini-
cians recommend using trimethoprim-sulfamethoxazole as an
alternate option if pyrimethamine is not available.
In falciparum malaria, the combination of pyrimethamine
with sulfadoxine (Fansidar) has been used (see Chapter 52); how-
ever, it is no longer commercially available in the USA.
Adverse Effects
Trimethoprim produces the predictable adverse effects of an
antifolate drug, especially megaloblastic anemia, leukopenia, and
granulocytopenia. The combination trimethoprim-sulfamethox-
azole may cause all of the untoward reactions associated with
sulfonamides. Nausea and vomiting, drug fever, vasculitis, renal
damage, and central nervous system disturbances occasionally
occur. Patients with AIDS and pneumocystis pneumonia have
a particularly high frequency of untoward reactions to trime-
thoprim-sulfamethoxazole, especially fever, rashes, leukopenia,
diarrhea, elevations of hepatic aminotransferases, hyperkalemia,
and hyponatremia. Trimethoprim inhibits secretion of creatinine
at the distal renal tubule, resulting in mild elevation of serum
creatinine without impairment of glomerular filtration rate. This
nontoxic effect is important to distinguish from true nephrotoxic-
ity that may be caused by sulfonamides.
■■ DNA GYRASE INHIBITORS
FLUOROQUINOLONES
The clinically relevant quinolones are synthetic fluorinated ana-
logs of nalidixic acid (Figure 46–3). They are active against a
variety of Gram-positive and Gram-negative bacteria.
Mechanism of Action
Quinolones block bacterial DNA synthesis by inhibiting bacterial
topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition
of DNA gyrase prevents the relaxation of positively supercoiled
DNA that is required for normal transcription and replication.
Inhibition of topoisomerase IV interferes with separation of repli-
cated chromosomal DNA into the respective daughter cells during
cell division.
Antibacterial Activity
Earlier quinolones such as nalidixic acid did not achieve systemic
antibacterial levels and were useful only in the treatment of lower
urinary tract infections. Fluorinated derivatives (ciprofloxacin,
levofloxacin, and others; Figure 46–3 and Table 46–1) have
greatly improved antibacterial activity compared with nalidixic
acid and achieve bactericidal levels in blood and tissues.
Fluoroquinolones were originally developed because of their
excellent activity against Gram-negative aerobic bacteria; the ear-
liest agents had limited activity against Gram-positive organisms.
Subsequent members of the group have improved activity against
Gram-positive cocci. The relative activity against Gram-negative
838    SECTION VIII  Chemotherapeutic Drugs

O
O
COOH F COOH

CH3 N N HN N N
C2H5
C2H5
Nalidixic acid Norfloxacin

O O
F COOH F COOH

HN N N CH3 N N N
O
CH3
Ciprofloxacin Levofloxacin

O
O
F COOH
CH2O F CO2H
H N N
N N
N N N
O
H3C H2N

Moxifloxacin Gemifloxacin

FIGURE 46–3  Structures of nalidixic acid and some fluoroquinolones.

versus Gram-positive species is useful for differentiating these
agents. Norfloxacin, which is no longer available in the USA,
is the least active of the fluoroquinolones against both Gram-
negative and Gram-positive organisms, with minimum inhibitory
concentrations (MICs) fourfold to eightfold higher than those
of ciprofloxacin. Ciprofloxacin, enoxacin, lomefloxacin, levo-
floxacin, ofloxacin, and pefloxacin comprise a second group
of similar agents possessing excellent Gram-negative activity and
moderate to good activity against Gram-positive bacteria. Cip-
rofloxacin and levofloxacin are the two agents from this group
that are used systemically in the USA. MICs for Gram-negative
cocci and bacilli, including Enterobacter sp, P aeruginosa, Neis-
seria meningitidis, Haemophilus sp, and Campylobacter jejuni, are
1–2 mcg/mL and often less. Methicillin-susceptible strains of S
aureus are generally susceptible to these fluoroquinolones, but
methicillin-resistant strains of staphylococci are often resistant.
When treating staphylococcal infections, fluoroquinolones are
typically used in combination with a second active agent, such
as rifampin, to prevent emergence of resistance while on therapy.
Enterococci tend to be less susceptible than staphylococci, limit-
ing the efficacy of fluoroquinolones in infections caused by these
organisms. Ciprofloxacin is the most active agent of this group
against Gram-negative organisms, particularly P aeruginosa. Levo-
floxacin, the l-isomer of ofloxacin, has superior activity against
Gram-positive organisms, especially Streptococcus pneumoniae.
Gatifloxacin, gemifloxacin, and moxifloxacin make up a third
group of fluoroquinolones with improved activity against Gram-
positive organisms, particularly S pneumoniae and some staphylo-
cocci. Gemifloxacin is active in vitro against ciprofloxacin-resistant
strains of S pneumoniae, but in vivo efficacy is unproven. Although
MICs of these agents for staphylococci are lower than those of cip-
rofloxacin (and the other compounds mentioned in the paragraph
above), it is not known whether the enhanced activity is sufficient
to permit use of these agents for treatment of infections caused by

TABLE 46–1  Pharmacokinetic properties of some fluoroquinolones.

Oral Peak Serum Primary Route of
Drug Half-Life (h) Bioavailability (%) Concentration (mcg/mL) Oral Dose (mg) Excretion

Ciprofloxacin 3–5 70 2.4 500 twice daily Renal

Gemifloxacin 8 70 1.6 320 once daily Renal and nonrenal
Levofloxacin 5–7 95 5.7 500 once daily Renal
Moxifloxacin 9–10 >85 3.1 400 once daily Nonrenal
Norfloxacin 3.5–5 80 1.5 400 twice daily Renal
Ofloxacin 5–7 95 2.9 400 twice daily Renal

ciprofloxacin-resistant strains. In general, none of these agents is as
active as ciprofloxacin against Gram-negative organisms. Fluoro-
quinolones also are active against agents of atypical pneumonia (eg,
mycoplasmas and chlamydiae) and against intracellular pathogens
such as Legionella and some mycobacteria, including Mycobacterium
tuberculosis and Mycobacterium avium complex. Moxifloxacin has
modest activity against anaerobic bacteria but lacks appreciable
activity against P aeruginosa. Because of toxicity when systemically
administered, gatifloxacin is available only as an ophthalmic solu-
tion in the USA.
Resistance
During fluoroquinolone therapy, resistant organisms emerge in
about 1 of every 107–109 organisms, especially among staphylo-
cocci, P aeruginosa, and Serratia marcescens. Emerging resistance
is due to one or more point mutations in the quinolone binding
region of the target enzyme or to a change in the permeability of
the organism. However, additional mechanisms seem to account
for the relative ease with which resistance develops in highly sus-
ceptible bacteria. Two types of plasmid-mediated resistance have
been described. The first type utilizes Qnr proteins, which protect
DNA gyrase from the fluoroquinolones. The second is a variant
of an aminoglycoside acetyltransferase capable of modifying cip-
rofloxacin. Both mechanisms confer low-level resistance that may
facilitate the point mutations that confer high-level resistance and
also may be associated with resistance to other antibacterial drug
classes. Resistance to one fluoroquinolone, particularly if it is of
high level, generally confers cross-resistance to all other members
of this class.
Pharmacokinetics
After oral administration, the fluoroquinolones are well absorbed
(bioavailability of 80–95%) and distributed widely in body fluids
and tissues (Table 46–1). Serum half-lives range from 3 to 10
hours. The relatively long half-lives of levofloxacin, gemifloxacin,
and moxifloxacin permit once-daily dosing. Oral absorption is
impaired by divalent and trivalent cations, including those in ant-
acids. Therefore, oral fluoroquinolones should be taken 2 hours
before or 4 hours after any products containing these cations.
Serum concentrations of intravenously administered drug are sim-
ilar to those of orally administered drug. Most fluoroquinolones,
moxifloxacin being an important exception, are eliminated by
renal mechanisms, either tubular secretion or glomerular filtration
(Table 46–1). Dosage adjustment is required for patients with
creatinine clearances less than 50 mL/min, the exact adjustment
depending on the degree of renal impairment and the specific
fluoroquinolone being used. Dosage adjustment for renal failure is
not necessary for moxifloxacin since it is metabolized in the liver;
it should be used with caution in patients with hepatic failure.
Clinical Uses
Fluoroquinolones (other than moxifloxacin, which achieves rela-
tively low urinary levels) are effective in urinary tract infec-
tions caused by many organisms, including P aeruginosa. These
CHAPTER 46  Sulfonamides, Trimethoprim, & Quinolones    839
agents are also effective for bacterial diarrhea caused by Shigella,
Salmonella, toxigenic E coli, and Campylobacter. Fluoroquinolones
(except norfloxacin, which does not achieve adequate systemic
concentrations) are used in infections of soft tissues, bones, and
joints and in intra-abdominal and respiratory tract infections,
including those caused by multidrug-resistant organisms such as
Pseudomonas and Enterobacter. Ciprofloxacin is a drug of choice
for prophylaxis and treatment of anthrax; the newer fluoroquino-
lones are active in vitro, and levofloxacin is also approved by the
U.S. Food and Drug Administration (FDA) for prophylaxis.
Ciprofloxacin and levofloxacin are no longer recommended
for the treatment of gonococcal infection in the USA, as resis-
tance is now common; however, gemifloxacin may be used in
combination with azithromycin as an alternate to ceftriaxone.
Levofloxacin and ofloxacin are recommended by the Centers for
Disease Control and Prevention as alternative treatment options
for chlamydial urethritis or cervicitis. Ciprofloxacin, levofloxacin,
or moxifloxacin is occasionally used as part of a treatment regimen
for tuberculosis and non-tuberculous mycobacterial infections.
These agents are suitable for eradication of meningococci from
carriers and for prophylaxis of bacterial infection in neutropenic
cancer patients.
With their enhanced Gram-positive activity and activity
against atypical pneumonia agents (chlamydiae, Mycoplasma,
and Legionella), levofloxacin, gemifloxacin, and moxifloxacin—
so-called respiratory fluoroquinolones—are effective for treatment
of lower respiratory tract infections.
Adverse Effects
Fluoroquinolones are generally well tolerated. The most common
effects are nausea, vomiting, and diarrhea. Occasionally, headache,
dizziness, insomnia, skin rash, or abnormal liver function tests
develop. Photosensitivity has been reported with lomefloxacin
and pefloxacin. Prolongation of the QTc interval may occur with
gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin; these
drugs should be avoided or used with caution in patients with
known QTc interval prolongation or uncorrected hypokalemia;
in those receiving class 1A (eg, quinidine or procainamide) or
class 3 antiarrhythmic agents (sotalol, ibutilide, amiodarone);
and in patients receiving other agents known to increase the QTc
interval (eg, erythromycin, tricyclic antidepressants). Gatifloxacin
has been associated with hyperglycemia in diabetic patients and
with hypoglycemia in patients also receiving oral hypoglycemic
agents. Because of these serious effects (including some fatalities),
gatifloxacin was withdrawn from sale in the United States in 2006.
In animal models, fluoroquinolones may damage growing car-
tilage and cause an arthropathy. Thus, these drugs have not been
recommended as first-line agents for patients under 18 years of
age. However, there is a growing consensus that fluoroquinolones
may be used in children if needed (eg, for treatment of pseu-
domonal infections in patients with cystic fibrosis). Tendinitis,
a complication in adults, can be serious because of the risk of
tendon rupture. Risk factors for tendinitis include advanced age,
renal insufficiency, and concurrent steroid use. Fluoroquinolones
should be avoided during pregnancy in the absence of specific
840    SECTION VIII  Chemotherapeutic Drugs

data documenting their safety. Oral or intravenously adminis-
tered fluoroquinolones have also been associated with peripheral
neuropathy. Neuropathy can occur at any time during treatment
with fluoroquinolones and may persist for months to years after
the drug is stopped. In some cases it may be permanent. Although
many potential adverse effects are uncommon, the FDA called for
updated warnings for all fluoroquinolones in 2016, stating that
these agents should be reserved for patients who do not have alter-
native options, particularly in less severe infections such as upper
respiratory infections or uncomplicated cystitis.

SUMMARY Sulfonamides, Trimethoprim, and Fluoroquinolones

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions

FOLATE ANTAGONISTS
  • Trimethoprim- Synergistic combination of
sulfamethoxazole folate antagonists blocks
purine production and
nucleic acid synthesis
Bactericidal activity Urinary tract infections • soft
against susceptible tissue infections • bone and
bacteria joint infections • P jiroveci
pneumonia • toxoplasmosis
• nocardiosis
Oral, IV • renal clearance (half-life 8 h)
• dosed every 8–12 h • formulated in a
5:1 ratio of sulfamethoxazole to
trimethoprim • Toxicity: Rash, fever, bone
marrow suppression, hyperkalemia,
nephrotoxicity

  •  Sulfadiazine: Oral; first-line therapy for toxoplasmosis when combined with pyrimethamine
  •  Trimethoprim: Oral; used alone only for lower urinary tract infections; may be safely prescribed to patients with sulfonamide allergy
  •  Pyrimethamine: Oral; first-line therapy for toxoplasmosis when combined with sulfadiazine; coadminister with leucovorin to limit bone marrow toxicity
  •  Pyrimethamine-sulfadoxine: Oral; second-line malaria treatment

FLUOROQUINOLONES
  •  Ciprofloxacin
Inhibits DNA replication by
binding to DNA gyrase and
topoisomerase IV
Bactericidal activity Urinary tract infections Oral, IV • mixed clearance (half-life 4 h)
against susceptible • gastroenteritis • dosed every 12 h • divalent and trivalent
bacteria • osteomyelitis • anthrax cations impair oral absorption • Toxicity:
Gastrointestinal upset, neurotoxicity,
tendonitis

  • Levofloxacin: Oral, IV; l-isomer of ofloxacin; once-daily dosing; renal clearance; “respiratory” fluoroquinolone with improved activity versus pneumococcus
  • Moxifloxacin: Oral, IV; “respiratory” fluoroquinolone; once-daily dosing; improved activity versus anaerobes and M tuberculosis; hepatic clearance results in lower urinary
levels so use in urinary tract infections is not recommended
  •  Gemifloxacin: Oral; “respiratory” fluoroquinolone

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

GENERAL-PURPOSE SULFONAMIDES PYRIMETHAMINE
Sulfadiazine Generic Pyrimethamine Daraprim
SULFONAMIDES FOR SPECIAL APPLICATIONS Pyrimethamine-sulfadoxine Generic, Fansidar
Mafenide Generic, Sulfamylon QUINOLONES & FLUOROQUINOLONES
Silver sulfadiazine Generic, Silvadene Ciprofloxacin Generic, Cipro, Cipro I.V., Ciloxan
Sulfacetamide sodium Generic (ophthalmic)
(ophthalmic) Gemifloxacin Factive
TRIMETHOPRIM Levofloxacin Levaquin, Quixin (ophthalmic)
Trimethoprim Generic, Proloprim, Moxifloxacin Generic, Avelox, others
Trimpex Norfloxacin Noroxin
Trimethoprim-sulfamethoxazole Generic, Bactrim, Septra, others Ofloxacin Generic, Floxin, Ocuflox
(co-trimoxazole, TMP-SMZ) (ophthalmic), Floxin Otic (otic)
 CHAPTER 46  Sulfonamides, Trimethoprim, & Quinolones    841

REFERENCES trial of trimethoprim-sulfamethoxazole versus ciprofloxacin. Clin Infect Dis

2010;51:143.
Briasoulis A et al: QT prolongation and torsade de pointes induced by fluoroquino-
Rodriguez-Martinez JM et al: Plasmid-mediated quinolone resistance: An update.
lones: Infrequent side effects from commonly used medications. Cardiology
J Infect Chemother 2011;17:149.
2011;120:103.
Scheld WM: Maintaining fluoroquinolone class efficacy: Review of influencing
Cohen JS: Peripheral neuropathy associated with fluoroquinolones. Ann Pharma-
factors. Emerg Infect Dis 2003;9:1.
cother 2001;35:1540.
Schmitz GR et al: Randomized controlled trial of trimethoprim-sulfamethoxazole
Davidson R et al: Resistance to levofloxacin and failure of treatment of pneumo-
for uncomplicated skin abscesses in patients at risk for community-associated
coccal pneumonia. N Engl J Med 2002;346:747.
methicillin-resistant Staphylococcus aureus infection. Ann Emerg Med
Gupta K et al: International clinical practice guidelines for the treatment of 2010;56:283.
acute uncomplicated cystitis and pyelonephritis in women. Clin Infect Dis
Strom BL et al: Absence of cross-reactivity between sulfonamide antibiotics and
2011;52:103.
sulfonamide nonantibiotics. N Engl J Med 2003;349:1628.
Keating GM, Scott LJ: Moxifloxacin: A review of its use in the management of
Talan DA et al: Prevalence of and risk factor analysis of trimethoprim-sulfamethox-
bacterial infections. Drugs 2004;64:2347.
azole- and fluoroquinolone-resistant E. coli infection among emergency
Mandell LA et al: Infectious Disease Society of America/American Thoracic department patients with pyelonephritis. Clin Infect Dis 2008;47:1150.
Society consensus guidelines on the management of community-acquired
Workowski KA et al: Sexually Transmitted Diseases Treatment Guidelines, 2015.
pneumonia. Clin Infect Dis 2007;44:S27.
MMWR Recomm Rep 2015;64(RR-03):1.
Mwenya DM et al: Impact of cotrimoxazole on carriage and antibiotic resistance
Ziganshina LE et al: Fluoroquinolones for treating tuberculosis (presumed drug
of Streptococcus pneumoniae and Haemophilus influenzae in HIV-infected
sensitive). Cochrane Database Syst Rev 2013;(6):CD004795.
children in Zambia. Antimicrob Agents Chemother 2010;54:3756.
Nouira S et al: Standard versus newer antibacterial agents in the treatment of severe
acute exacerbation of chronic obstructive pulmonary disease: A randomized

C ASE STUDY ANSWER

A fluoroquinolone that achieves good urinary and systemic
levels (ciprofloxacin or levofloxacin) would be a reasonable
choice for empiric treatment of this patient’s complicated
urinary tract infection. Given the possibility of a fluoroqui-
nolone-resistant organism, one dose of a parenteral agent
such as ceftriaxone (given IV or IM) would be reason-
able pending culture results confirming fluoroquinolone
susceptibility. Her recent exposure to multiple courses of
trimethoprim-sulfamethoxazole increases her chances of
having a urinary tract infection with an isolate that is resis-
tant to this antibiotic. The patient should be told to take the
oral fluoroquinolone 2 hours before or 4 hours after her
calcium supplement, as divalent and trivalent cations can
significantly impair the absorption of oral fluoroquinolones.
 47
C H A P T E R
Antimycobacterial Drugs
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD*
C ASE STUDY
A 60-year-old man presents to the emergency department
with a 2-month history of fatigue, weight loss (10 kg), fevers,
night sweats, and a productive cough. He is currently living
with friends and has been intermittently homeless, spending
time in shelters. He reports drinking about 6 beers per day.
In the emergency department, a chest x-ray shows a right
apical infiltrate. Given the high suspicion for pulmonary
Mycobacteria are intrinsically resistant to most antibiotics.
Because they grow more slowly than other bacteria, antibiotics
that are most active against rapidly growing cells are relatively
ineffective. Mycobacterial cells can also be dormant and, thus,
resistant to many drugs or killed only very slowly. The lipid-rich
mycobacterial cell wall is impermeable to many agents. Mycobac-
terial species are intracellular pathogens, and organisms residing
within macrophages are inaccessible to drugs that penetrate these
cells poorly. Finally, mycobacteria are notorious for their ability
to develop resistance. Combinations of two or more drugs are
required to overcome these obstacles and to prevent emergence of
resistance during the course of therapy. The response of mycobac-
terial infections to chemotherapy is slow, and treatment must be
administered for months to years, depending on which drugs are
used. The drugs used to treat tuberculosis, atypical mycobacterial
infections, and leprosy are described in this chapter.
■■ DRUGS USED IN TUBERCULOSIS
Isoniazid (INH), rifampin (or other rifamycin), pyrazinamide,
and ethambutol are the traditional first-line agents for treatment
of tuberculosis (Table 47–1). Isoniazid and rifampin are the most
*
The authors thank Henry F. Chambers, MD and Daniel H. Deck,
PharmD for their contributions to previous editions.
842
tuberculosis, the patient is placed in respiratory isolation.
His first sputum smear shows many acid-fast bacilli, and an
HIV test returns with a positive result. What drugs should
be started for treatment of presumptive pulmonary tubercu-
losis? Does the patient have a heightened risk of developing
medication toxicity? If so, which medication(s) would be
likely to cause toxicity?
active drugs. An isoniazid-rifampin combination administered for
9 months will cure 95–98% of cases of tuberculosis caused by sus-
ceptible strains. An initial intensive phase of treatment is recom-
mended for the first 2 months due to the prevalence of resistant
strains. The addition of pyrazinamide during this intensive phase
allows the total duration of therapy to be reduced to 6 months
without loss of efficacy. In practice, therapy is usually initiated
with a four-drug regimen of isoniazid, rifampin, pyrazinamide,
and ethambutol until susceptibility of the clinical isolate has
been determined. In susceptible isolates, the continuation phase
consists of an additional 4 months with isoniazid and rifampin
(Table 47–2). Neither ethambutol nor other drugs such as strep-
tomycin adds substantially to the overall activity of the regimen
(ie, the duration of treatment cannot be further reduced if another
drug is used), but the fourth drug provides additional cover-
age if the isolate proves to be resistant to isoniazid, rifampin,
or both. If therapy is initiated after the isolate is known to be
susceptible to isoniazid and rifampin, ethambutol does not
need to be added. The prevalence of isoniazid resistance among
clinical isolates in the USA is approximately 10%. Prevalence
of resistance to both isoniazid and rifampin (which is termed
multidrug resistance) ranged from 1 to 1.6% from the years
2000 to 2013 in the USA. Multidrug resistance is much more
prevalent in many other parts of the world. Resistance to
rifampin alone is rare.
 CHAPTER 47  Antimycobacterial Drugs    843

TABLE 47–1  Antimicrobials used in the treatment of growing tubercle bacilli. It is less effective against nontuberculous
tuberculosis. mycobacteria. Isoniazid penetrates into macrophages and is active
against both extracellular and intracellular organisms.
Drug Typical Adult Dosage1

First-line agents Mechanism of Action & Basis of Resistance

 Isoniazid 300 mg/d Isoniazid inhibits synthesis of mycolic acids, which are essential
 Rifampin 600 mg/d components of mycobacterial cell walls. Isoniazid is a prodrug that
 Pyrazinamide 25 mg/kg/d is activated by KatG, the mycobacterial catalase-peroxidase. The
 Ethambutol 15–25 mg/kg/d activated form of isoniazid forms a covalent complex with an acyl
carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein
Second-line agents
synthetase, which blocks mycolic acid synthesis. Resistance to
 Amikacin 15 mg/kg/d
isoniazid is associated with mutations resulting in overexpression
  Aminosalicylic acid 8–12 g/d of inhA, which encodes an NADH-dependent acyl carrier pro-
 Bedaquiline 400 mg/d tein reductase; mutation or deletion of the katG gene; promoter
 Capreomycin 15 mg/kg/d mutations resulting in overexpression of ahpC, a gene involved
 Clofazimine 200 mg/d in protection of the cell from oxidative stress; and mutations in
kasA. Overproducers of inhA express low-level isoniazid resis-
 Cycloserine 500–1000 mg/d, divided
tance and cross-resistance to ethionamide. KatG mutants express
 Ethionamide 500–750 mg/d
high-level isoniazid resistance and often are not cross-resistant to
 Levofloxacin 500–750 mg/d ethionamide.
 Linezolid 600 mg/d Drug-resistant mutants are normally present in susceptible
 Moxifloxacin 400 mg/d mycobacterial populations at about 1 bacillus in 106. Since
 Rifabutin2 300 mg/d tuberculous lesions often contain more than 108 tubercle bacilli,
3 resistant mutants are readily selected if isoniazid or any other
 Rifapentine 600 mg once weekly
drug is given as a single agent. The use of two independently
 Streptomycin 15 mg/kg/d
acting drugs in combination is much more effective. The
1
Assuming normal renal function. probability that a bacillus is initially resistant to both drugs is
2
150 mg/d if used concurrently with a protease inhibitor or cobicistat; 600 mg/d with approximately 1 in 106 × 106, or 1 in 1012, several orders of
efavirenz.
3
magnitude greater than the number of infecting organisms.
No longer recommended, but may be considered in selected cases if HIV-uninfected
without cavitation on chest radiograph. Thus, at least two (or more in certain cases) active agents should
always be used to treat active tuberculosis to prevent emergence
of resistance during therapy.
ISONIAZID
Pharmacokinetics
Isoniazid is the most active drug for the treatment of tuberculosis
Isoniazid is readily absorbed from the gastrointestinal tract,
caused by susceptible strains. It is a small molecule (molecular
optimally on an empty stomach; peak concentrations may be
weight 137) that is freely soluble in water. The structural similarity
decreased by up to 50% when taken with a fatty meal. A 300 mg
to pyridoxine is shown below.
oral dose (5 mg/kg in children) achieves peak plasma concentra-
N tions of 3–5 mcg/mL within 1–2 hours. Isoniazid diffuses readily
into all body fluids and tissues. The concentration in the central
nervous system and cerebrospinal fluid ranges between 20% and
100% of simultaneous serum concentrations.
CONHNH2 Metabolism of isoniazid, especially acetylation by liver
Isoniazid
N-acetyltransferase, is genetically determined (see Chapter 4).
The average plasma concentration of isoniazid in rapid acetyl-
ators is about one third to one half of that in slow acetylators,
N and average half-lives are less than 1 hour and 3 hours, respec-
CH3
tively. More rapid clearance of isoniazid by rapid acetylators is
OH usually of no therapeutic consequence when appropriate doses
HOH2C
are administered daily, but subtherapeutic concentrations may
CH2OH occur if drug is administered as a once-weekly dose or if there is
Pyridoxine malabsorption.
Isoniazid metabolites and a small amount of unchanged drug
In vitro, isoniazid inhibits most tubercle bacilli at a concen- are excreted in the urine. The dosage need not be adjusted in renal
tration of 0.2 mcg/mL or less and is bactericidal for actively failure. Dose adjustment is not well defined in patients with severe
844    SECTION VIII  Chemotherapeutic Drugs

TABLE 47–2  Recommended treatment for drug-susceptible tuberculosis.

Intensive Phase Continuation Phase
Regimen (min duration = 8 weeks) (min duration = 18 weeks)1  
(in order of
preference) Drugs Dosing Interval Drugs Dosing Interval Comments
2 2
1 INH 7 days per week INH 7 days per week Preferred regimen.
RIF RIF
PZA
EMB
2 INH 7 days per week2 INH 3 days per week Preferred alternative if less frequent DOT is
RIF RIF needed.
PZA
EMB
3 INH 3 days per week INH 3 days per week Caution in patients with HIV and/or cavitary
RIF RIF disease due to concerns for treatment
failure, relapse, drug resistance.
PZA
EMB
4 INH 7 days per week × INH 2 days per week Avoid in patients with HIV or those with
RIF 2 weeks, then RIF smear-positive and/ or cavitary disease.
PZA 2 days per week ×
EMB 6 weeks
1
Experts recommend prolonged continuation phase (31 weeks) for patients with cavitation on initial chest radiograph and positive cultures at the end of the intensive
treatment phase.
2
May consider 5 days per week if needed for DOT. No studies compare 5 versus 7 doses per week, but extensive experience suggests efficacy of this regimen.
DOT, directly observed therapy; EMB, ethambutol; HIV, human immunodeficiency virus; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin.

preexisting hepatic insufficiency and should be guided by serum A. Immunologic Reactions

concentrations if a reduction in dose is contemplated. Isoniazid
inhibits several cytochrome P450 enzymes, leading to increased
concentrations of such medications as phenytoin, carbamazepine,
and benzodiazepines. However, when used in combination with
rifampin, a potent CYP enzyme inducer, the concentrations of
these medications are usually decreased.
Clinical Uses
The typical dosage of isoniazid is 5 mg/kg/d; a typical adult dose is
300 mg given once daily. Up to 10 mg/kg/d may be used for seri-
ous infections or if malabsorption is a problem. A 15-mg/kg dose,
or 900 mg, may be used in a twice to three times-weekly dosing
regimen in combination with a second antituberculous agent (eg,
rifampin, 600 mg). Pyridoxine, 25–50 mg/d, is recommended
for those with conditions predisposing to neuropathy, an adverse
effect of isoniazid. Isoniazid is usually given by mouth but can be
given parenterally in the same dosage.
Isoniazid as a single agent is also indicated for treatment
of latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or
900 mg twice weekly, and the duration is usually 9 months.
Adverse Reactions
The incidence and severity of untoward reactions to isoniazid are
related to dosage and duration of administration.
Fever and skin rashes are occasionally seen. Drug-induced sys-
temic lupus erythematosus has been reported.
B. Direct Toxicity
Isoniazid-induced hepatitis is the most common major toxic effect.
This is distinct from the minor increases in liver aminotransferases
(up to three or four times normal), which do not require cessa-
tion of the drug and which are seen in 10–20% of patients, who
usually are asymptomatic. Clinical hepatitis with loss of appetite,
nausea, vomiting, jaundice, and right upper quadrant pain occurs
in 1% of isoniazid recipients and can be fatal, particularly if the
drug is not discontinued promptly. There is histologic evidence of
hepatocellular damage and necrosis. The risk of hepatitis depends
on age. It occurs rarely under age 20, in 0.3% of those age 21–35,
1.2% of those age 36–50, and 2.3% for those age 50 and above.
The risk of hepatitis is greater in individuals with alcohol depen-
dence and possibly during pregnancy and the postpartum period.
Development of isoniazid hepatitis contraindicates further use of
the drug.
Peripheral neuropathy is observed in 10–20% of patients given
dosages greater than 5 mg/kg/d, but it is infrequently seen with
the standard 300-mg adult dose. Peripheral neuropathy is more
likely to occur in slow acetylators and patients with predisposing
conditions such as malnutrition, alcoholism, diabetes, AIDS, and
uremia. Neuropathy is due to a relative pyridoxine deficiency.

Isoniazid promotes excretion of pyridoxine, and this toxicity is
readily reversed by administration of pyridoxine in a dosage as low
as 10 mg/d. Central nervous system toxicity, which is less com-
mon, includes memory loss, psychosis, ataxia, and seizures. These
effects may also respond to pyridoxine.
Miscellaneous other reactions include hematologic abnormali-
ties, provocation of pyridoxine deficiency anemia, tinnitus, and
gastrointestinal discomfort.
RIFAMPIN
Rifampin is a semisynthetic derivative of rifamycin, an antibi-
otic produced by Amycolatopsis rifamycinica, formerly named
Streptomyces mediterranei. It is active in vitro against Gram-positive
organisms, some Gram-negative organisms, such as Neisseria and
Haemophilus species, mycobacteria, and chlamydiae. Susceptible
organisms are inhibited by less than 1 mcg/mL. Resistant mutants
are present in all microbial populations at approximately 1 in
106 organisms and are rapidly selected out if rifampin is used as
a single drug, especially in a patient with active infection. There
is no cross-resistance to other classes of antimicrobial drugs, but
there is cross-resistance to other rifamycin derivatives, eg, rifabutin
and rifapentine.
Mechanism of Action, Resistance, &
Pharmacokinetics
Rifampin binds to the β subunit of bacterial DNA-dependent
RNA polymerase and thereby inhibits RNA synthesis. Resistance
results from any one of several possible point mutations in rpoB,
the gene for the β subunit of RNA polymerase. These muta-
tions result in reduced binding of rifampin to RNA polymerase.
Human RNA polymerase does not bind rifampin and is not
inhibited by it. Rifampin is bactericidal for mycobacteria. It read-
ily penetrates most tissues and penetrates into phagocytic cells. It
can kill organisms that are poorly accessible to many other drugs,
such as intracellular organisms and those sequestered in abscesses
and lung cavities.
Rifampin is well absorbed after oral administration and
excreted mainly through the liver into bile. It then undergoes
enterohepatic recirculation, with the bulk excreted as a deacylated
metabolite in feces and a small amount excreted in the urine.
Dosage adjustment for renal or hepatic insufficiency is not neces-
sary. Usual doses result in serum levels of 5–7 mcg/mL. Rifampin
is distributed widely in body fluids and tissues. The drug is
relatively highly protein-bound, and adequate cerebrospinal fluid
concentrations are achieved only in the presence of meningeal
inflammation.
Rifampin strongly induces most cytochrome P450 isoforms
(CYP1A2, 2C9, 2C19, 2D6, and 3A4), which increases the elimi-
nation of numerous other drugs including methadone, antico-
agulants, cyclosporine, some anticonvulsants, protease inhibitors,
some nonnucleoside reverse transcriptase inhibitors or integrase
strand transfer inhibitors, contraceptives, and a host of others
CHAPTER 47  Antimycobacterial Drugs    845
(see Chapters 4 and 66). Co-administration of rifampin results in
significantly lower serum levels of these drugs.
Clinical Uses
A. Mycobacterial Infections
Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be
administered with isoniazid or other antituberculous drugs to
patients with active tuberculosis to prevent emergence of drug-
resistant mycobacteria. In some short-course therapies, 600 mg
of rifampin is given twice weekly. Rifampin, 600 mg daily or
twice weekly for 6 months, also is effective in combination with
other agents in some atypical mycobacterial infections and in
leprosy. Rifampin, 600 mg daily for 4 months as a single drug,
is an alternative to isoniazid for patients with latent tuberculosis
who are unable to take isoniazid or who have had exposure to
a case of active tuberculosis caused by an isoniazid-resistant,
rifampin-susceptible strain.
B. Other Indications
Rifampin has other uses in bacterial infections. An oral dosage
of 600 mg twice daily for 2 days can eliminate meningococcal
carriage. Rifampin, 20 mg/kg (maximum 600 mg) once daily
for 4 days, is used as prophylaxis in contacts of children with
Haemophilus influenzae type b disease. Rifampin combined
with a second agent is sometimes used to eradicate staphy-
lococcal carriage. Rifampin combination therapy is also used
for treatment of serious staphylococcal infections such as
osteomyelitis, prosthetic joint infections, and prosthetic valve
endocarditis.
Adverse Reactions
Rifampin imparts a harmless orange color to urine, sweat, and
tears (soft contact lenses may be permanently stained). Occasional
adverse effects include rashes, thrombocytopenia, and nephritis.
Rifampin may cause cholestatic jaundice and occasionally hepa-
titis, and it commonly causes light-chain proteinuria. If adminis-
tered less often than twice weekly, rifampin may cause a flu-like
syndrome characterized by fever, chills, myalgias, anemia, and
thrombocytopenia. Its use has been associated with acute tubular
necrosis.
ETHAMBUTOL
Ethambutol is a synthetic, water-soluble, heat-stable compound,
the dextro-isomer of the structure shown below, dispensed as the
dihydrochloride salt.
CH2OH C2H5
H C NH (CH2)2 NH C H
C2H5 CH2OH
Ethambutol
846    SECTION VIII  Chemotherapeutic Drugs
Mechanism of Action & Clinical Uses
Ethambutol inhibits mycobacterial arabinosyl transferases, which
are encoded by the embCAB operon. Arabinosyl transferases are
involved in the polymerization reaction of arabinoglycan, an
essential component of the mycobacterial cell wall. Resistance to
ethambutol is due to mutations resulting in overexpression of emb
gene products or within the embB structural gene. Susceptible
strains of Mycobacterium tuberculosis and other mycobacteria are
inhibited in vitro by ethambutol, 1–5 mcg/mL.
Ethambutol is well absorbed from the gut. After ingestion
of 25 mg/kg, a blood level peak of 2–5 mcg/mL is reached in
2–4 hours. About 20% of the drug is excreted in feces and 50% in
urine in unchanged form. Ethambutol accumulates in renal failure,
and the dose should be reduced to three times weekly if creatinine
clearance is less than 30 mL/min. Ethambutol crosses the blood-
brain barrier only when the meninges are inflamed. Concentrations
in cerebrospinal fluid are highly variable, ranging from 4% to 64%
of serum levels in the setting of meningeal inflammation.
As with all antituberculous drugs, resistance to ethambutol
emerges rapidly when the drug is used alone. Therefore, etham-
butol is always given in combination with other antituberculous
drugs. Ethambutol hydrochloride, 15–25 mg/kg, is usually given
as a single daily dose in combination with isoniazid, rifampin, and
pyrazinamide during the initial intensive phase of active tuber-
culosis treatment. The higher dose may be used for treatment of
tuberculous meningitis. Higher doses have been used with inter-
mittent dosing regimens for directly observed therapy; for example,
25–30 mg/kg three times weekly or 50 mg/kg administered twice
weekly. Ethambutol is also used in combination with other agents
for the treatment of nontuberculous mycobacterial infections, such
as Mycobacterium avium complex (MAC) or M. kansasii; the typical
dose for these infections is 15 mg/kg once daily.
Adverse Reactions
Hypersensitivity to ethambutol is rare. The most common serious
adverse event is retrobulbar neuritis, resulting in loss of visual acu-
ity and red-green color blindness. This dose-related adverse effect
is more likely to occur at dosages of 25 mg/kg/d continued for
several months. At 15 mg/kg/d or less, visual disturbances occur in
approximately 2% of patients, typically after at least one month of
treatment. Experts recommend baseline and monthly visual acu-
ity and color discrimination testing, with particular attention to
patients on higher doses or with impaired renal function. Etham-
butol is relatively contraindicated in children too young to permit
assessment of visual acuity and red-green color discrimination.
PYRAZINAMIDE
Pyrazinamide (PZA) is a relative of nicotinamide, and it is used
only for treatment of tuberculosis. It is stable and slightly soluble in
water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle
bacilli at concentrations of approximately 20 mcg/mL. The drug is
taken up by macrophages and exerts its activity against mycobacte-
ria residing within the acidic environment of lysosomes.
O
N
C NH2
N
Pyrazinamide (PZA)
Mechanism of Action & Clinical Uses
Pyrazinamide is converted to pyrazinoic acid—the active form of
the drug—by mycobacterial pyrazinamidase, which is encoded
by pncA. Pyrazinoic acid disrupts mycobacterial cell membrane
metabolism and transport functions. Resistance may be due
to impaired uptake of pyrazinamide or mutations in pncA that
impair conversion of PZA to its active form.
Serum concentrations of 30–50 mcg/mL at 1–2 hours after
oral administration are achieved with dosages of 25 mg/kg/d.
Pyrazinamide is well absorbed from the gastrointestinal tract and
widely distributed in body tissues, including inflamed meninges.
The half-life is 8–11 hours. The parent compound is metabolized
by the liver, but metabolites are renally cleared; therefore, PZA
should be administered at 25–35 mg/kg three times weekly (not
daily) in hemodialysis patients and those in whom the creatinine
clearance is less than 30 mL/min. In patients with normal renal
function, a dose of 30–50 mg/kg is used for thrice-weekly or
twice-weekly treatment regimens.
Pyrazinamide is an important front-line drug used in conjunc-
tion with isoniazid and rifampin in short-course (ie, 6-month)
regimens as a “sterilizing” agent active against residual intracellular
organisms that may cause relapse. Tubercle bacilli develop resis-
tance to pyrazinamide fairly readily, but there is no cross-resistance
with isoniazid or other antimycobacterial drugs.
Adverse Reactions
Major adverse effects of PZA include hepatotoxicity (in 1–5%
of patients), nausea, vomiting, drug fever, photosensitivity, and
hyperuricemia. The latter occurs uniformly and is not a reason to
halt therapy if patients are asymptomatic.
SECOND-LINE DRUGS FOR
TUBERCULOSIS
The alternative drugs listed below are usually considered only (1)
in case of resistance to first-line agents; (2) in case of failure of
clinical response to conventional therapy; and (3) in case of serious
treatment-limiting adverse drug reactions. Expert guidance is desir-
able in dealing with the toxic effects of these second-line drugs. For
many drugs listed in the following text, the dosage, emergence of
resistance, and long-term toxicity have not been fully established.
Streptomycin
The mechanism of action and other pharmacologic features of
streptomycin, an aminoglycoside, are discussed in Chapter 45.
The typical adult dosage is 1 g/d (15 mg/kg/d). If the creatinine

clearance is less than 30 mL/min or the patient is on hemodialy-
sis, the dosage is 15 mg/kg two or three times per week. Most
tubercle bacilli are inhibited by streptomycin, 1–10 mcg/mL,
in vitro. Nontuberculous species of mycobacteria other than
Mycobacterium avium complex (MAC) and Mycobacterium
kansasii are resistant. All large populations of tubercle bacilli
contain some streptomycin-resistant mutants. On average, 1
in 108 tubercle bacilli can be expected to be resistant to strep-
tomycin at levels of 10–100 mcg/mL. Resistance may be due
to a point mutation in either the rpsL gene encoding the S12
ribosomal protein or the rrs gene encoding 16S ribosomal RNA,
which alters the ribosomal binding site.
Streptomycin penetrates into cells poorly and is active mainly
against extracellular tubercle bacilli. The drug crosses the blood-
brain barrier and achieves therapeutic concentrations with
inflamed meninges.
Clinical Use in Tuberculosis
Streptomycin sulfate is used when an injectable drug is needed
or desirable and in the treatment of infections resistant to other
drugs. The usual dosage is 15 mg/kg/d intramuscularly or intrave-
nously daily for adults (20–40 mg/kg/d for children, not to exceed
1 g) for several weeks, followed by 15 mg/kg two or three times
weekly for several months. Serum concentrations of approxi-
mately 40 mcg/mL are achieved 30–60 minutes after intramuscu-
lar injection of a 15 mg/kg dose. Other drugs are always given in
combination to prevent emergence of resistance.
Adverse Reactions
Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing
loss are the most common adverse effects and may be permanent.
Toxicity is dose-related, and the risk is increased in the elderly. As
with all aminoglycosides, the dose must be adjusted according to
renal function (see Chapter 45). Toxicity can be reduced by limit-
ing therapy to no more than 6 months whenever possible.
Ethionamide
Ethionamide is chemically related to isoniazid and similarly blocks
the synthesis of mycolic acids. It is poorly water soluble and avail-
able only for oral use. It is metabolized by the liver.
N dose should be reduced by half if creatinine clearance is less than
H5C2
C central nervous system dysfunction, including depression and
S NH2
Ethionamide
Most tubercle bacilli are inhibited in vitro by ethionamide,
2.5 mcg/mL or less. Some other species of mycobacteria also are
inhibited by ethionamide, 10 mcg/mL. Serum concentrations in
plasma and tissues of approximately 1-5 mcg/mL are achieved by
a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to
those in serum.
CHAPTER 47  Antimycobacterial Drugs    847
Ethionamide is administered at an initial dose of 250 mg
once daily, which is increased in 250 mg increments to the
recommended dosage of 1 g/d (or 15 mg/kg/d), if possible. The
1-g/d dosage, though theoretically desirable, is poorly tolerated
because of gastric irritation and neurologic symptoms, often
limiting the tolerable daily dose to 500–750 mg. Ethionamide
is also hepatotoxic. Neurologic symptoms may be alleviated by
pyridoxine.
Resistance to ethionamide as a single agent develops rapidly in
vitro and in vivo. There can be low-level cross-resistance between
isoniazid and ethionamide.
Capreomycin
Capreomycin is a peptide protein synthesis inhibitor antibiotic
obtained from Streptomyces capreolus. Daily injection of 15 mg/kg
intramuscularly results in peak serum levels of 35–45 mcg/mL
2 hours after a dose. Such concentrations in vitro are inhibitory
for many mycobacteria, including multidrug-resistant strains of
M tuberculosis.
Capreomycin (15 mg/kg/d) is an important injectable agent
for treatment of drug-resistant tuberculosis. Strains of M tuber-
culosis that are resistant to streptomycin usually are susceptible
to capreomycin, though some data suggest cross-resistance with
strains resistant to amikacin and kanamycin. Resistance to cap-
reomycin, when it occurs, has been associated with rrs, eis, or tlyA
gene mutations.
Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness,
and vestibular disturbances occur. The injection causes significant
local pain, and sterile abscesses may develop.
Typical dosing of capreomycin is 15 mg/kg/day initially,
which is then reduced to two or three times weekly after an initial
response has been achieved with a daily dosing schedule. The
intermittent dosing regimen may minimize risk of toxicity.
Cycloserine
Cycloserine—a structural analog of d-alanine—inhibits cell
wall synthesis, as discussed in Chapter 43. Concentrations of
15–20 mcg/mL inhibit many strains of M tuberculosis. The usual
dosage of cycloserine in tuberculosis is 0.5–1 g/d in two divided
oral doses. The drug is widely distributed to tissues, including
the central nervous system. This drug is cleared renally, and the
50 mL/min. Alternatively, it may be reduced to 500 mg three
times weekly.
The most serious toxic effects are peripheral neuropathy and
psychoses. Pyridoxine, 100 mg or more per day, should be given
with cycloserine because this ameliorates neurologic toxicity.
Adverse effects, which are most common during the first 2 weeks
of therapy, occur in 25% or more of patients, especially at higher
doses leading to peak concentrations greater than 35 mcg/mL.
Adverse effects can be minimized by monitoring peak serum
concentrations. The peak concentration is reached 2–4 hours
after dosing. The recommended range of peak concentrations is
20–35 mcg/mL.
848    SECTION VIII  Chemotherapeutic Drugs
Aminosalicylic Acid (PAS)
Aminosalicylic acid is a folate synthesis antagonist that is active
almost exclusively against M tuberculosis. It is structurally similar
to p-amino-benzoic acid (PABA) and is thought to have a similar
mechanism of action to the sulfonamides (see Chapter 46). In the
USA, PAS is commercially available as a 4-g packet of delayed-
release granules. In order to protect the integrity of the delayed-
release coating, the granules must be administered sprinkled over
applesauce or yogurt, or swirled in fruit juice and swallowed
whole.
COOH
OH
NH2
Aminosalicylic acid (PAS)
Tubercle bacilli are usually inhibited in vitro by aminosalicylic
acid, 1–5 mcg/mL. The granule formulation of aminosalicylic
acid results in improved absorption from the gastrointestinal
tract. Peak serum levels are expected to be 20–60 mcg/mL 6 hours
after a 4 g oral dose. The dosage is 8–12 g/d orally for adults and
300 mg/kg/d for children, administered in two or three divided
doses. The drug is widely distributed in tissues and body fluids
except the cerebrospinal fluid. Aminosalicylic acid is rapidly
excreted in the urine, in part as active PAS and in part as the
acetylated compound and other metabolic products. To avoid
accumulation in renal impairment, the maximum dose is 4 g twice
daily when creatinine clearance is less than 30 mL/min. Very high
concentrations of aminosalicylic acid are reached in the urine,
which can result in crystalluria.
Aminosalicylic acid is used infrequently in the USA because
other oral drugs are better tolerated. Gastrointestinal symptoms
are common but occur less frequently with the delayed-release
granules; they may be diminished by giving the drug with meals
and with antacids. Peptic ulceration and hemorrhage may occur.
Hypersensitivity reactions manifested by fever, joint pains, skin
rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulo-
cytopenia often occur after 3–8 weeks of PAS therapy, making it
necessary to stop administration temporarily or permanently.
Kanamycin & Amikacin
The aminoglycoside antibiotics are discussed in Chapter 45.
Kanamycin had been used for treatment of tuberculosis caused by
streptomycin-resistant strains, but it is no longer available in the
USA, and less toxic alternatives (eg, capreomycin and amikacin)
have taken its place.
Amikacin is playing a greater role in the treatment of tuberculo-
sis due to the prevalence of multidrug-resistant strains. Prevalence
of amikacin-resistant strains is low (<5%), and most multidrug-
resistant strains remain amikacin-susceptible. M tuberculosis is
inhibited at concentrations of 1 mcg/mL or less. Amikacin is also
active against atypical mycobacteria. There is no cross-resistance
between streptomycin and amikacin, but kanamycin resistance
often indicates resistance to amikacin as well. Peak serum con-
centrations of 30–45 mcg/mL are achieved 30–60 minutes after
a 15-mg/kg intravenous infusion or intramuscular injection.
Amikacin is indicated for treatment of tuberculosis suspected
or known to be caused by streptomycin-resistant or multidrug-
resistant strains. This drug must be used in combination with at
least one and preferably two or three other drugs to which the
isolate is susceptible for treatment of drug-resistant cases. The
recommended dosage is 15 mg/kg once daily initially, followed by
intermittent dosing two or three times per week.
Fluoroquinolones
In addition to their activity against many Gram-positive and
Gram-negative bacteria (discussed in Chapter 46), ciprofloxacin,
levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of
M tuberculosis at concentrations less than 2 mcg/mL. They are
also active against atypical mycobacteria. Moxifloxacin is the
most active against M tuberculosis in vitro. Levofloxacin tends to
be slightly more active than ciprofloxacin against M tuberculo-
sis, whereas ciprofloxacin is slightly more active against atypical
mycobacteria.
Fluoroquinolones are an important addition to the drugs avail-
able for tuberculosis, especially for strains that are resistant to first-
line agents. The World Health Organization recommends using a
later generation fluoroquinolone such as moxifloxacin or levoflox-
acin. Resistance, which may result from one of several single point
mutations in the gyrase A subunit, develops rapidly if a fluoroqui-
nolone is used as a single agent; thus, the drug must be used in
combination with two or more additional active agents. Typically,
resistance to one fluoroquinolone indicates class resistance. How-
ever, moxifloxacin may retain some activity in strains resistant to
ofloxacin. The dosage of levofloxacin is 500–750 mg once a day,
and some clinicians increase to 1000 mg daily if tolerated. The
dosage of moxifloxacin is 400 mg once a day. Some experts rec-
ommend checking peak serum concentrations. Expected levels at
about two hours post-dose are 8–12 mcg/mL for levofloxacin and
3–5 mcg/mL for moxifloxacin.
Linezolid
Linezolid (discussed in Chapter 44) inhibits strains of M tuberculosis
in vitro at concentrations of 4–8 mcg/mL. It achieves good intra-
cellular concentrations, and it is active in murine models of
tuberculosis. Linezolid has been used in combination with other
second- and third-line drugs to treat patients with tuberculosis
caused by multidrug-resistant strains. Conversion of sputum
cultures to negative was associated with linezolid use in these
cases. Significant adverse effects, including bone marrow suppres-
sion and irreversible peripheral and optic neuropathy, have been
reported with the prolonged courses of therapy that are necessary
for treatment of tuberculosis. A 600-mg (adult) dose administered
once a day (half of that used for treatment of other bacterial infec-
tions) seems to be sufficient and may limit the occurrence of these
adverse effects. Experts recommend supplemental pyridoxine for
patients treated with linezolid. Although linezolid may prove to

be an important new agent for treatment of tuberculosis, at this
point it should be used only for multidrug-resistant strains that
also are resistant to several other first- and second-line agents. It is
generally avoided in patients on concomitant serotonergic agents
due to concern for serotonin syndrome.
Rifabutin
Rifabutin is derived from rifamycin and is related to rifampin.
It has significant activity against M tuberculosis, MAC, and
Mycobacterium fortuitum (see below). Its activity is similar to
that of rifampin, and cross-resistance with rifampin is virtually
complete. Some rifampin-resistant strains may appear susceptible
to rifabutin in vitro, but a clinical response is unlikely because
the molecular basis of resistance, rpoB mutation, is the same.
Rifabutin is both substrate and inducer of cytochrome P450
enzymes. Because it is a less potent inducer, rifabutin is often
used in place of rifampin for treatment of tuberculosis in patients
with HIV infection who are receiving antiretroviral therapy with
a protease inhibitor, a nonnucleoside reverse transcriptase inhibi-
tor (eg, efavirenz), or an integrase strand transfer inhibitor (eg
dolutegravir), drugs that also are cytochrome P450 or UDP gluc-
uronosyltransferase (UGT) substrates.
The typical dosage of rifabutin is 300 mg/d unless the patient
is receiving a protease inhibitor, in which case the dosage should
be reduced, typically by half. If efavirenz (also a cytochrome
P450 inducer) is used, the recommended dosage of rifabutin is
600 mg/d. Rifabutin may accumulate in severe renal impairment,
and the dose should be reduced by half if creatinine clearance is
less than 30 mL/min. Rifabutin is associated with similar rates
of hepatotoxicity or rash compared to rifampin; it can also cause
leukopenia, thrombocytopenia, and optic neuritis.
Rifapentine
Rifapentine is another analog of rifampin. It is active against both
M tuberculosis and MAC. As with all rifamycins, it is a bacterial
RNA polymerase inhibitor, and cross-resistance between rifampin
and rifapentine is complete. Like rifampin, rifapentine is a potent
inducer of cytochrome P450 enzymes, and it has the same drug
interaction profile; however, when rifapentine is administered
intermittently, induction of metabolism of other medications is
less pronounced compared to rifampin. Toxicity is similar to that
of rifampin. Rifapentine and its microbiologically active metabo-
lite, 25-desacetylrifapentine, have an elimination half-life of
13 hours. Rifapentine, 600 mg (10 mg/kg) once or twice weekly,
has been used for treatment of tuberculosis caused by rifampin-
susceptible strains during the continuation phase (ie, after the
first 2 months of therapy and ideally after conversion of sputum
cultures to negative); however, this regimen has decreased efficacy
compared with the standard rifampin-based regimen. Revised
guidelines for treatment of drug-susceptible tuberculosis pub-
lished in 2016 recommend against it. In particular, its use should
be avoided in patients at higher risk of failure, including those
with positive cultures at the end of the intensive treatment phase
and those with evidence of cavitation on chest radiographs. Rifa-
pentine should not be used to treat active tuberculosis in patients
CHAPTER 47  Antimycobacterial Drugs    849
with HIV infection because of an unacceptably high relapse rate
with rifampin-resistant organisms. Rifapentine in combination
with isoniazid, typically both dosed at 900 mg once weekly for
3 months (12 doses each in total), is an effective short course treat-
ment for latent tuberculosis infection.
Bedaquiline
Bedaquiline, a diarylquinoline, is the first drug with a novel mech-
anism of action against M tuberculosis to be approved since 1971.
Bedaquiline inhibits adenosine 5′-triphosphate (ATP) synthase
in mycobacteria, has in vitro activity against both replicating and
nonreplicating bacilli, and has bactericidal and sterilizing activity
in the murine model of tuberculosis. Cross-resistance has been
reported between bedaquiline and clofazimine, likely via upregu-
lation of the multisubstrate efflux pump, MmpL5.
Peak plasma concentration and plasma exposure to bedaquiline
increase approximately twofold when administered with high-fat
food. Bedaquiline is highly protein-bound (>99%), is metabolized
chiefly through the cytochrome P450 system, and is excreted
primarily via the feces. The mean terminal half-life of bedaquiline
and its major metabolite (M2), which is four to six times less
active in terms of antimycobacterial potency, is approximately
5.5 months. This long elimination phase probably reflects slow
release of bedaquiline and M2 from peripheral tissues. CYP3A4 is
the major isoenzyme involved in the metabolism of bedaquiline,
and potent inhibitors or inducers of this enzyme cause clinically
significant drug interactions.
Current recommendations state that bedaquiline, in combina-
tion with at least three other active medications, may be used for
24 weeks of treatment in adults with laboratory-confirmed pul-
monary tuberculosis if the isolate is resistant to both isoniazid and
rifampin. The recommended dosage for bedaquiline is 400 mg
once daily orally for 2 weeks, followed by 200 mg three times a
week for 22 weeks taken orally with food in order to maximize
absorption. The most common adverse effects, occurring at rates
of 25% or more, are nausea, arthralgia, and headache. Bedaquiline
has been associated with both hepatotoxicity and cardiac toxicity.
The FDA has issued a black-box warning related to the risk of
QTc prolongation and associated mortality. It should be reserved
for patients who do not have other treatment options and used
with caution in patients with other risk factors for cardiac conduc-
tion abnormalities.
■■ DRUGS ACTIVE AGAINST
NONTUBERCULOUS
MYCOBACTERIA
Many mycobacterial infections seen in clinical practice in the
United States are caused by nontuberculous mycobacteria (NTM),
formerly known as “atypical mycobacteria.” These organisms have
distinctive laboratory characteristics, are present in the environ-
ment, and are generally not communicable from person to person.
As a rule, these mycobacterial species are less susceptible than
M tuberculosis to antituberculous drugs. On the other hand, agents
850    SECTION VIII  Chemotherapeutic Drugs
TABLE 47–3  Clinical features and treatment options for infections with atypical mycobacteria.
Species Clinical Features
M kansasii Resembles tuberculosis
M marinum Granulomatous cutaneous disease
M scrofulaceum Cervical adenitis in children
M avium complex Pulmonary disease in patients with chronic
(MAC) lung disease; disseminated infection in AIDS
M chelonae Abscess, sinus tract, ulcer; bone, joint, tendon
infection
M fortuitum Abscess, sinus tract, ulcer; bone, joint, tendon
infection
M ulcerans Skin ulcers
such as macrolides, sulfonamides, and tetracyclines, which are not
active against M tuberculosis, may be effective for infections caused
by NTM. Emergence of resistance during therapy is also a prob-
lem with these mycobacterial species, and active infection should
be treated with combinations of drugs. M kansasii is susceptible
to rifampin and ethambutol, partially susceptible to isoniazid, and
completely resistant to pyrazinamide. A three-drug combination
of isoniazid, rifampin, and ethambutol is the conventional treat-
ment for M kansasii infection. A few representative pathogens,
with the clinical presentation and the drugs to which they are
often susceptible, are given in Table 47–3.
M avium complex (MAC), which includes both M avium
and M intracellulare, is an important and common cause of dis-
seminated disease in late stages of AIDS (CD4 counts < 50/μL).
MAC is much less susceptible than M tuberculosis to most anti-
tuberculous drugs. Combinations of agents are required to sup-
press the infection. Azithromycin, 500–600 mg once daily, or
clarithromycin, 500 mg twice daily, plus ethambutol, 15 mg/kg/d,
is an effective and well-tolerated regimen for treatment of dissemi-
nated disease. Some authorities recommend use of a third agent,
especially rifabutin, 300 mg once daily. Other agents that may be
useful are listed in Table 47–3. Azithromycin and clarithromycin
are the prophylactic drugs of choice for preventing disseminated
MAC in AIDS patients with CD4 cell counts less than 50/μL.
Rifabutin in a single daily dose of 300 mg has been shown to
reduce the incidence of MAC bacteremia but is less effective than
macrolides.
■■ DRUGS USED IN LEPROSY
Mycobacterium leprae has never been grown in vitro, but animal
models, such as growth in injected mouse footpads, have permit-
ted laboratory evaluation of drugs. Only those drugs with the wid-
est clinical use are presented here. Because of increasing reports of
dapsone resistance, treatment of leprosy with combinations of the
drugs listed below is recommended.
Treatment Options
Amikacin, clarithromycin, ethambutol, isoniazid, moxifloxacin, rifampin,
streptomycin, trimethoprim-sulfamethoxazole
Amikacin, clarithromycin, ethambutol, doxycycline, levofloxacin, minocycline,
rifampin, trimethoprim-sulfamethoxazole
Amikacin, erythromycin (or other macrolide), rifampin, streptomycin
(Surgical excision is often curative and the treatment of choice.)
Amikacin, azithromycin, clarithromycin, ethambutol, moxifloxacin, rifabutin
Amikacin, doxycycline, imipenem, linezolid, macrolides, tobramycin
Amikacin, cefoxitin, ciprofloxacin, doxycycline, imipenem, minocycline,
moxifloxacin, ofloxacin, trimethoprim-sulfamethoxazole
Clarithromycin, isoniazid, streptomycin, rifampin, minocycline, moxifloxacin
(Surgical excision may be effective.)
DAPSONE & OTHER SULFONES
Several drugs closely related to the sulfonamides have been used
effectively in the long-term treatment of leprosy. The most widely
used is dapsone (diaminodiphenylsulfone). Like the sulfon-
amides, it inhibits folate synthesis. Resistance can emerge in large
populations of M leprae, eg, in lepromatous leprosy, particularly
if low doses are given. Therefore, the combination of dapsone,
rifampin, and clofazimine is recommended for initial therapy of
lepromatous leprosy. A combination of dapsone plus rifampin is
commonly used for leprosy with a lower organism burden. Dap-
sone may also be used to prevent and treat Pneumocystis jiroveci
pneumonia in AIDS patients.
O
NH2 S NH2
O
Dapsone
Sulfones are well absorbed from the gut and widely distributed
throughout body fluids and tissues. Dapsone’s half-life is 1–2 days,
and drug tends to be retained in skin, muscle, liver, and kidney. Skin
heavily infected with M leprae may contain several times more drug
than normal skin. Sulfones are excreted into bile and reabsorbed
in the intestine. Excretion into urine is variable, and most excreted
drug is acetylated. In renal failure, the dose may have to be adjusted.
The usual adult dosage in leprosy is 100 mg daily. For children, the
dose is proportionately less, depending on weight.
Dapsone is usually well tolerated. Many patients develop some
hemolysis, particularly if they have glucose-6-phosphate dehydro-
genase deficiency. Methemoglobinemia is common but usually
is not clinically significant. Gastrointestinal intolerance, fever,
pruritus, and rash occur. During dapsone therapy of lepromatous
leprosy, erythema nodosum leprosum often develops. It is some-
times difficult to distinguish reactions to dapsone from manifesta-
tions of the underlying illness. Erythema nodosum leprosum may
be suppressed by thalidomide (see Chapter 55).
 CHAPTER 47  Antimycobacterial Drugs    851

RIFAMPIN and a major portion of the drug is excreted in feces. Clofazimine

Rifampin (see earlier discussion) in a dosage of 600 mg daily is
highly effective in leprosy and is given with at least one other drug
to prevent emergence of resistance. Even a dose of 600 mg per
month may be beneficial in combination therapy.
CLOFAZIMINE
Clofazimine is a phenazine dye used in the treatment of multi-
bacillary leprosy, which is defined as having a positive smear from
any site of infection. Its mechanism of action has not been clearly
established. Absorption of clofazimine from the gut is variable,
is stored widely in reticuloendothelial tissues and skin, and its
crystals can be seen inside phagocytic reticuloendothelial cells. It
is slowly released from these deposits, so the serum half-life may
be 2 months. A common dosage of clofazimine is 100–200 mg/d
orally. The most prominent adverse effect is discoloration of the
skin and conjunctivae. Gastrointestinal side effects are common.
This medication is no longer commercially available, but it can
be obtained through established programs. For example, an inves-
tigational new drug (IND) program is established in the USA
through the National Hansen’s Disease Program. Internation-
ally, ministries of health can make requests directly to the World
Health Organization.

SUMMARY  First-Line Antimycobacterial Drugs

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions

ISONIAZID Inhibits synthesis of mycolic
acids, an essential
component of mycobacterial
cell walls
Bactericidal activity against
susceptible strains of
M tuberculosis
First-line agent for
tuberculosis • treatment of
latent infection • less active
against nontuberculous
mycobacteria
Oral, IV • hepatic clearance (half-life 1 h)
• reduces levels of phenytoin • Toxicity:
Hepatotoxic, peripheral neuropathy (give
pyridoxine to prevent)

RIFAMYCINS

  •  Rifampin Inhibits DNA-dependent RNA
polymerase, thereby blocking
production of RNA
Bactericidal activity against
susceptible bacteria and
mycobacteria • resistance
rapidly emerges when used
as a single drug in the
treatment of active infection
First-line agent for
tuberculosis • nontuberculous
mycobacterial infections
• eradication of
meningococcal colonization,
staphylococcal infections
Oral, IV • hepatic clearance (half-life 3.5 h)
• potent cytochrome P450 inducer • turns
body fluids orange color • Toxicity: Rash,
nephritis, thrombocytopenia, cholestasis,
flu-like syndrome with intermittent
dosing

  •  Rifabutin: Oral; similar to rifampin but less cytochrome P450 induction and fewer drug interactions
  • Rifapentine: Oral; long-acting analog of rifampin that may be given once weekly in select cases during the continuation phase of tuberculosis treatment or for treatment
of latent tuberculosis

PYRAZINAMIDE Not fully understood •
pyrazinamide is converted to
the active pyrazinoic acid
under acidic conditions in
macrophage lysosomes
Bacteriostatic activity against
susceptible strains of
M tuberculosis • may be
bactericidal against actively
dividing organisms
“Sterilizing” agent used
during first 2 months of
therapy • allows total
duration of therapy to be
shortened to 6 months
Oral • hepatic clearance (half-life 9 h), but
metabolites are renally cleared so use
3 doses weekly if creatinine clearance
<30 mL/min • Toxicity: Hepatotoxic,
hyperuricemia

ETHAMBUTOL Inhibits mycobacterial
arabinosyl transferases, which
are involved in the
polymerization reaction of
arabinoglycan, an essential
component of the
mycobacterial cell wall
Bacteriostatic activity against
susceptible mycobacteria
Given in four-drug initial Oral • mixed clearance (half-life 4 h)
combination therapy for • dose must be reduced in renal failure
tuberculosis until drug • Toxicity: Retrobulbar neuritis
sensitivities are known • also
used for nontuberculous
mycobacterial infections
852    SECTION VIII  Chemotherapeutic Drugs

P R E P A R A T I *O N S Centers for Disease Control and Prevention (CDC): Update: Adverse event data
and revised American Thoracic Society/CDC recommendations against
A V A I L A B L E the use of rifampin and pyrazinamide for treatment of latent tubercu-
losis infection—United States, 2003. MMWR Morb Mortal Wkly Rep
2003;52:735.
GENERIC NAME AVAILABLE AS
Curry International Tuberculosis Center and California Department of Public
DRUGS USED IN TUBERCULOSIS Health, 2016: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians,
Aminosalicylic acid Paser Third Edition [1-305].
Bedaquiline fumarate Sirturo Gillespie SH et al: Early bactericidal activity of a moxifloxacin and isoniazid
combination in smear-positive pulmonary tuberculosis. J Antimicrob
Capreomycin Capastat Chemother 2005;56:1169.
Ethambutol Generic, Myambutol Griffith DE et al: An official ATS/IDSA statement: Diagnosis, treatment, and
Ethionamide Trecator, Trecator-SC prevention of nontuberculous mycobacterial disease. Am J Respir Crit Care
Isoniazid Generic Med 2007;175:367.
Hugonnet J-E et al: Meropenem-clavulanate is effective against extensively drug-
Pyrazinamide Generic
resistant Mycobacterium tuberculosis. Science 2009;323:1215.
Rifabutin Generic, Mycobutin Jasmer RM, Nahid P, Hopewell PC: Latent tuberculosis infection. N Engl J Med
Rifampin Generic, Rifadin, Rimactane 2002;347:1860.
Rifapentine Priftin Kinzig-Schippers M et al: Should we use N-acetyltransferase type 2 genotyping to
Streptomycin Generic personalize isoniazid doses? Antimicrob Agents Chemother 2005;49:1733.
Lee M et al: Linezolid for treatment of chronic extensively drug-resistant tubercu-
DRUGS USED IN LEPROSY
losis. N Engl J Med 2012;367:1508.
Clofazimine Lamprene Mitnick CD et al: Comprehensive treatment of extensively drug-resistant tubercu-
Dapsone Generic losis. N Engl J Med 2008;359:563.
*
Nahid P et al: Official American Thoracic Society/Centers for Disease Control
Drugs used against nontuberculous mycobacteria are listed in Chapters 43–46. and Prevention/Infectious Diseases Society of America Clinical Practice
Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis
REFERENCES 2016;63:e147.
Sulochana S, Rahman F, Paramasivan CN: In vitro activity of fluoroquinolones
Centers for Disease Control and Prevention (CDC): Provisional CDC Guidelines against Mycobacterium tuberculosis. J Chemother 2005;17:169.
for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the
treatment of multidrug-resistant tuberculosis. MMWR Morb Mortal Wkly Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J
Rep 2013;62:1. Respir Crit Care Med 2000;161(4 Part 2):S221.
Centers for Disease Control and Prevention (CDC): Recommendations for use Zhang Y, Yew WW: Mechanisms of drug resistance in Mycobacterium tuberculosis.
of an isoniazid-rifapentine regimen with direct observation to treat latent Int J Tuberc Lung Dis 2009;13:1320.
Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep Zumla A et al: Current concepts—Tuberculosis. N Engl J Med 2013;368:745.
2011;60:1650.

C ASE STUDY ANSWER

The patient should be started on four-drug therapy with
rifampin, isoniazid, pyrazinamide, and ethambutol. He should
also be started on antiretroviral therapy for HIV. If a protease-
inhibitor-based antiretroviral regimen is used to treat his HIV,
rifabutin should replace rifampin because of the serious drug-
drug interactions between rifampin and protease inhibitors.
If dolutegravir is chosen, it must be administered twice daily
due to the interaction with rifampin; alternatively, rifabutin
can be used in place of rifampin, and dolutegravir can be
dosed once daily. The patient is at increased risk of developing
hepatotoxicity from both isoniazid and pyrazinamide given
his history of alcohol use.

Antifungal Agents
Harry W. Lampiris, MD, &
Daniel S. Maddix, Pharm D
C ASE STUDY
The patient is a 37-year-old African-American man who
lives in San Jose, California. He was recently incarcerated
near Bakersfield, California and returned to Oakland about
3 months ago. He is currently experiencing one month of
severe headache and double vision. He has a temperature
of 38.6°C (101.5°F) and the physical exam reveals nuchal
rigidity and right-sided sixth cranial nerve palsy. MRI of
his brain is normal, and lumbar puncture reveals 330 WBC
Human fungal infections have increased dramatically in incidence
and severity in recent years, owing mainly to advances in surgery,
cancer treatment, treatment of patients with solid organ and bone
marrow transplantation, the HIV epidemic, and increasing use
of broad-spectrum antimicrobial therapy in critically ill patients.
These changes have resulted in increased numbers of patients at
risk for fungal infections.
For many years, amphotericin B was the only efficacious
antifungal drug available for systemic use. While highly effec-
tive in many serious infections, it is also quite toxic. In the last
several decades, pharmacotherapy of fungal disease has been
revolutionized by the introduction of the relatively nontoxic
azole drugs (both oral and parenteral formulations) and the
echinocandins (only available for parenteral administration).
The new agents in these classes offer more targeted, less toxic
therapy than older agents such as amphotericin B for patients
with serious systemic fungal infections. Combination therapy
is being reconsidered, and new formulations of old agents are
becoming available. Unfortunately, the appearance of azole-
resistant and echinocandin-resistant organisms, as well as the
rise in the number of patients at risk for mycotic infections, has
created new challenges.
48
C H A P T E R
with 20% eosinophils, protein 75, and glucose 20. HIV
test is negative, TB skin test is negative, CSF cryptococcal
antigen is negative, and CSF gram stain is negative. Patient
receives empiric therapy for bacterial meningitis with van-
comycin and ceftriaxone, and is unimproved after 72 hours
of treatment. After 3 days a white mold is identified growing
from his CSF culture. What medical therapy would be most
appropriate now?
The antifungal drugs presently available fall into the follow-
ing categories: systemic drugs (oral or parenteral) for systemic
infections, oral systemic drugs for mucocutaneous infections, and
topical drugs for mucocutaneous infections.
■■ SYSTEMIC ANTIFUNGAL DRUGS
FOR SYSTEMIC INFECTIONS
AMPHOTERICIN B
Amphotericin A and B are antifungal antibiotics produced by
Streptomyces nodosus. Amphotericin A is not in clinical use.
Chemistry & Pharmacokinetics
Amphotericin B is an amphoteric polyene macrolide (polyene =
containing many double bonds; macrolide = containing a large
lactone ring of 12 or more atoms). It is nearly insoluble in water
and is therefore prepared as a colloidal suspension of amphoteri-
cin B and sodium deoxycholate for intravenous injection. Several
formulations have been developed in which amphotericin B is
853
854    SECTION VIII  Chemotherapeutic Drugs

TABLE 48–1  Properties of conventional amphotericin B and some lipid formulations.1

Drug Physical Form Dosing (mg/kg/d) Cmax Clearance Nephrotoxicity Infusional Toxicity Daily Cost ($)

Conventional formulation       
Fungizone Micelles 1 — — — — 24
Lipid formulations       
AmBisome Spheres 3–5 ↑ ↓ ↓ ↓ 1300
Amphotec Disks 5 ↓ ↑ ↓ ↑(?) 660
Abelcet Ribbons 5 ↓ ↑ ↓ ↓(?) 570
1
Changes in Cmax (peak plasma concentration), clearance, nephrotoxicity, and infusional toxicity are relative to conventional amphotericin B.

packaged in a lipid-associated delivery system (Table 48–1 and in the urine over a period of several days. The serum half-life is
Box: Lipid Formulation of Amphotericin B). approximately 15 days. Hepatic impairment, renal impairment,
and dialysis have little impact on drug concentrations, and there-
OH
fore no dose adjustment is required. The drug is widely distributed
CH3 O OH
37
1
OH
in most tissues, but only 2–3% of the blood level is reached in
HO
CH3
O OH OH OH OH O
COOH
cerebrospinal fluid, thus occasionally necessitating intrathecal
OH therapy for certain types of fungal meningitis.
CH3 NH2
O

Mechanisms of Action & Resistance

O OH

CH3
Amphotericin B
Amphotericin B is poorly absorbed from the gastrointesti-
nal tract. Oral amphotericin B is thus effective only on fungi
within the lumen of the tract and cannot be used for treatment
of systemic disease. The intravenous injection of 0.6 mg/kg/d of
amphotericin B results in average blood levels of 0.3–1 mcg/mL;
the drug is more than 90% bound by serum proteins. Although
it is mostly metabolized, some amphotericin B is excreted slowly
Amphotericin B is selective in its fungicidal effect because it
exploits the difference in lipid composition of fungal and mam-
malian cell membranes. Ergosterol, a cell membrane sterol, is
found in the cell membrane of fungi, whereas the predominant
sterol of bacteria and human cells is cholesterol. Amphotericin
B binds to ergosterol and alters the permeability of the cell by
forming amphotericin B–associated pores in the cell membrane
(Figure 48–1). As suggested by its chemistry, amphotericin B
combines avidly with lipids (ergosterol) along the double bond–
rich side of its structure and associates with water molecules

Lipid Formulation of Amphotericin B

Therapy with amphotericin B is often limited by toxicity, espe-
cially drug-induced renal impairment. This has led to the devel-
opment of lipid drug formulations on the assumption that
lipid-packaged drug binds to the mammalian membrane less
readily, permitting the use of effective doses of the drug with
lower toxicity. Liposomal amphotericin preparations package the
active drug in lipid delivery vehicles, in contrast to the colloidal
suspensions, which were previously the only available forms.
Amphotericin binds to the lipids in these vehicles with an affinity
between that for fungal ergosterol and that for human choles-
terol. The lipid vehicle then serves as an amphotericin reservoir,
reducing nonspecific binding to human cell membranes. This
preferential binding allows for a reduction of toxicity without
sacrificing efficacy and permits use of larger doses. Furthermore,
some fungi contain lipases that may liberate free amphotericin B
directly at the site of infection.
Three such formulations are now available and have
differing pharmacologic properties as summarized in
Table 48–1. Although clinical trials have demonstrated
different renal and infusion-related toxicities for these
preparations compared with regular amphotericin B,
there are no trials comparing the different formula-
tions with each other. Limited studies have suggested
at best a moderate improvement in the clinical efficacy
of the lipid formulations compared with conventional
amphotericin B. Because the lipid preparations are much
more expensive, their use is usually restricted to patients
intolerant to, or not responding to, conventional ampho-
tericin treatment.

Fungal cell
DNA, RNA
synthesis
–
Flucytosine
Squalene Ergosterol
– Terbinafine
Squalene epoxide Lanosterol
FIGURE 48–1  Targets of antifungal drugs. Except for flucytosine (and possibly griseofulvin, not shown), all currently available antifungals
target the fungal cell membrane or cell wall.
along the hydroxyl-rich side. This amphipathic characteristic
facilitates pore formation by multiple amphotericin molecules,
with the lipophilic portions around the outside of the pore and
the hydrophilic regions lining the inside. The pore allows the
leakage of intracellular ions and macromolecules, eventually
leading to cell death. Some binding to human membrane ste-
rols does occur, probably accounting for the drug’s prominent
toxicity.
Resistance to amphotericin B occurs if ergosterol binding is
impaired, either by decreasing the membrane concentration of
ergosterol or by modifying the sterol target molecule to reduce its
affinity for the drug.
Antifungal Activity & Clinical Uses
Amphotericin B remains the antifungal agent with the broadest
spectrum of action. It has activity against the clinically significant
yeasts, including Candida albicans and Cryptococcus neoformans;
the organisms causing endemic mycoses, including Histoplasma
capsulatum, Blastomyces dermatitidis, and Coccidioides immitis; and
the pathogenic molds, such as Aspergillus fumigatus and the agents
of mucormycosis. Some fungal organisms such as Candida lusita-
niae and Pseudallescheria boydii display intrinsic amphotericin B
resistance.
Owing to its broad spectrum of activity and fungicidal action,
amphotericin B remains a useful agent for nearly all life-threatening
mycotic infections, although newer, less toxic agents have largely
replaced it for most conditions. Amphotericin B is often used as
the initial induction regimen to rapidly reduce fungal burden and
CHAPTER 48  Antifungal Agents    855
Fungal cell membrane and cell wall
Proteins
β-glucans
Chitin
Cell membrane
bilayer
β-glucan
Amphotericin B, synthase
nystatin
–
– Azoles Echinocandins
then replaced by one of the newer azole drugs (described below) for
chronic therapy or prevention of relapse. Such induction therapy
is especially important for immunosuppressed patients and those
with severe fungal pneumonia, severe cryptococcal meningitis, or
disseminated infections with one of the endemic mycoses such
as histoplasmosis or coccidioidomycosis. Once a clinical response
has been elicited, these patients then often continue maintenance
therapy with an azole; therapy may be lifelong in patients at high
risk for disease relapse. For treatment of systemic fungal disease,
amphotericin B is given by slow intravenous infusion at a dosage of
0.5–1 mg/kg/d. Intrathecal therapy for fungal meningitis is poorly
tolerated and fraught with difficulties related to maintaining cere-
brospinal fluid access. Thus, intrathecal therapy with amphotericin
B is being increasingly supplanted by other therapies but remains an
option in cases of fungal central nervous system infections that have
not responded to other agents.
Local or topical administration of amphotericin B has been
used with success. Mycotic corneal ulcers and keratitis can be
cured with topical drops as well as by direct subconjunctival
injection. Fungal arthritis has been treated with adjunctive local
injection directly into the joint. Candiduria responds to bladder
irrigation with amphotericin B, and this route has been shown to
produce no significant systemic toxicity.
Adverse Effects
The toxicity of amphotericin B can be divided into two broad cat-
egories: immediate reactions, related to the infusion of the drug,
and those occurring more slowly.
856    SECTION VIII  Chemotherapeutic Drugs
A. Infusion-Related Toxicity
Infusion-related reactions are nearly universal and consist of fever,
chills, muscle spasms, vomiting, headache, and hypotension. They
can be ameliorated by slowing the infusion rate or decreasing
the daily dose. Premedication with antipyretics, antihistamines,
meperidine, or corticosteroids can be helpful. When starting ther-
apy, many clinicians administer a test dose of 1 mg intravenously
to gauge the severity of the reaction. This can serve as a guide to
an initial dosing regimen and premedication strategy.
B. Cumulative Toxicity
Renal damage is the most significant toxic reaction. Renal impair-
ment occurs in nearly all patients treated with clinically significant
doses of amphotericin. The degree of azotemia is variable and
often stabilizes during therapy, but it can be serious enough to
necessitate dialysis. A reversible component is associated with
decreased renal perfusion and represents a form of prerenal renal
failure. An irreversible component results from renal tubular
injury and subsequent dysfunction. The irreversible form of
amphotericin nephrotoxicity usually occurs in the setting of
prolonged administration (>4 g cumulative dose). Renal toxicity
commonly manifests as renal tubular acidosis and severe potas-
sium and magnesium wasting. There is some evidence that the
prerenal component can be attenuated with sodium loading, and
it is common practice to administer normal saline infusions with
the daily doses of amphotericin B.
Abnormalities of liver function tests are occasionally seen, as is
a varying degree of anemia due to reduced erythropoietin produc-
tion by damaged renal tubular cells. After intrathecal therapy with
amphotericin, seizures and a chemical arachnoiditis may develop,
often with serious neurologic sequelae.
FLUCYTOSINE
Chemistry & Pharmacokinetics
Flucytosine (5-FC) was discovered in 1957 during a search for
novel antineoplastic agents. Though devoid of anti-cancer prop-
erties, it became apparent that it is a potent antifungal agent.
Flucytosine is a water-soluble pyrimidine analog related to the
chemotherapeutic agent 5-fluorouracil (5-FU). Its spectrum of
action is much narrower than that of amphotericin B.
H drug levels and resistance developing rapidly at subtherapeutic
N
O be helpful in reducing the incidence of toxic reactions, especially
N amphotericin B.
F
NH2
Flucytosine
Flucytosine is currently available in North America only in an
oral formulation. The dosage is 100 mg/kg/d in divided doses in
patients with normal renal function. It is well absorbed (>90%),
with serum concentrations peaking 1–2 hours after an oral dose.
It is poorly protein-bound and penetrates well into all body fluid
compartments, including the cerebrospinal fluid. It is eliminated
by glomerular filtration with a half-life of 3–4 hours and is
removed by hemodialysis. Levels rise rapidly with renal impair-
ment and can lead to toxicity. Toxicity is more likely to occur
in AIDS patients and those with renal insufficiency. Peak serum
concentrations should be measured periodically in patients with
renal insufficiency and maintained between 50 and 100 mcg/mL.
Mechanisms of Action & Resistance
Flucytosine is taken up by fungal cells via the enzyme cytosine
permease. It is converted intracellularly first to 5-FU and then to
5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine
triphosphate (FUTP), which inhibit DNA and RNA synthesis,
respectively (Figure 48–1). Human cells are unable to convert the
parent drug to its active metabolites, resulting in selective toxicity.
Synergy with amphotericin B has been demonstrated in vitro
and in vivo. It may be related to enhanced penetration of the flu-
cytosine through amphotericin-damaged fungal cell membranes.
In vitro synergy with azole drugs also has been seen, although the
mechanism is unclear.
Resistance is thought to be mediated through altered metabo-
lism of flucytosine, and, although uncommon in primary isolates,
it develops rapidly in the course of flucytosine monotherapy.
Clinical Uses & Adverse Effects
The spectrum of activity of flucytosine is restricted to C neofor-
mans, some Candida sp, and the dematiaceous molds that cause
chromoblastomycosis. Flucytosine is rarely used as a single agent
because of its demonstrated synergy with other agents and to
avoid the development of secondary resistance. At present clinical
use is confined to combination therapy with amphotericin B for
cryptococcal meningitis, or with itraconazole for chromoblasto-
mycosis. Flucytosine also has limited utility as monotherapy for
fluconazole-resistant candidal urinary tract infections.
The adverse effects of flucytosine result from metabolism (pos-
sibly by intestinal flora) to the toxic antineoplastic compound
fluorouracil. Bone marrow toxicity with anemia, leukopenia,
and thrombocytopenia are the most common adverse effects,
with derangement of liver enzymes occurring less frequently. A
form of toxic enterocolitis can occur. There seems to be a narrow
therapeutic window, with an increased risk of toxicity at higher
concentrations. The use of drug concentration measurements may
when flucytosine is combined with nephrotoxic agents such as
AZOLES
Chemistry & Pharmacokinetics
Azoles are synthetic compounds that can be classified as either
imidazoles or triazoles according to the number of nitrogen
atoms in the five-membered azole ring, as indicated below. The
imidazoles consist of ketoconazole, miconazole, and clotrimazole
 CHAPTER 48  Antifungal Agents    857

N
N CH3 F
Cl N HO
N N
N H
H2C C O CH2 Cl N N N
C F
Cl
Cl

F
Cl
Clotrimazole Miconazole Voriconazole

N
N

CH2 CH3
O
Cl C O N CH CH2 CH3

O CH2 O N N N
Cl
N
Itraconazole

N
OH N
N
Cl
N N CH2 C CH2 N
N
H2C N F
Cl

O O O

CH2 O N N C CH3
F

Ketoconazole Fluconazole

FIGURE 48–2  Structural formulas of some antifungal azoles.

(Figure 48–2). The latter two drugs are now used only in topical enzymes (Figure 48–1). The selective toxicity of azole drugs results
therapy. The triazoles include itraconazole, fluconazole, voricon- from their greater affinity for fungal than for human cytochrome
azole, isavuconazole, and posaconazole. Other triazoles are cur- P450 enzymes. Imidazoles exhibit a lesser degree of selectivity
rently under investigation. than the triazoles, accounting for their higher incidence of drug
interactions and adverse effects.
R
Resistance to azoles occurs via multiple mechanisms. Once
N rare, increasing numbers of resistant strains are being reported,
X X = C, imidazole
X = N, triazole suggesting that increasing use of these agents for prophylaxis and
N therapy may be selecting for clinical drug resistance in certain
Azole nucleus settings.

The pharmacology of each of the azoles is unique and accounts
for some of the variations in clinical use. Table 48–2 summarizes
the differences among six of the azoles.
Mechanisms of Action & Resistance
The antifungal activity of azole drugs results from the reduction
of ergosterol synthesis by inhibition of fungal cytochrome P450
Clinical Uses, Adverse Effects, & Drug
Interactions
The spectrum of action of azole medications is broad, including
many species of Candida, C neoformans, the endemic mycoses
(blastomycosis, coccidioidomycosis, histoplasmosis), the derma-
tophytes, and, in the case of itraconazole, posaconazole, isavu-
conazole, and voriconazole, even Aspergillus infections. They are
858    SECTION VIII  Chemotherapeutic Drugs
TABLE 48–2  Pharmacologic properties of six systemic azole drugs.
CSF: Serum
  Water Solubility Absorption Concentration Ratio
Ketoconazole Low Variable
Itraconazole Low Variable
Fluconazole High High
Voriconazole High High
Posaconazole Low High
Isavuconazole High High
also useful in the treatment of intrinsically amphotericin-resistant
organisms such as P boydii.
As a group, the azoles are relatively nontoxic. The most com-
mon adverse reaction is relatively minor gastrointestinal upset. All
azoles have been reported to cause abnormalities in liver enzymes
and, very rarely, clinical hepatitis. Adverse effects specific to indi-
vidual agents are discussed below.
All azole drugs are prone to drug interactions because
they affect the mammalian cytochrome P450 enzyme system
to some extent. The most significant reactions are indicated
below.
KETOCONAZOLE
Ketoconazole was the first oral azole introduced into clinical
use. It is distinguished from triazoles by its greater propensity to
inhibit mammalian cytochrome P450 enzymes; that is, it is less
selective for fungal P450 than are the newer azoles. As a result,
systemic ketoconazole has fallen out of clinical use in the USA and
is not discussed in any detail here. It is no longer recommended
for the treatment of fungal nail or skin infections.
ITRACONAZOLE
Itraconazole is available in oral and intravenous formulations
and is used at a dosage of 100–400 mg/d. Drug absorption from
capsules is increased by food and by low gastric pH. Like other
lipid-soluble azoles, it interacts with hepatic microsomal enzymes,
though to a lesser degree than ketoconazole. An important drug
interaction is reduced bioavailability of itraconazole when taken
with rifamycins (rifampin, rifabutin, rifapentine). It does not affect
mammalian steroid synthesis, and its effects on the metabolism of
other hepatically cleared medications are much less than those of
ketoconazole. While itraconazole displays potent antifungal activ-
ity, effectiveness can be limited by reduced bioavailability. Newer
formulations, including an oral liquid and an intravenous prepara-
tion, have utilized cyclodextrin as a carrier molecule to enhance
solubility and bioavailability. Like ketoconazole, itraconazole
penetrates poorly into the cerebrospinal fluid. Itraconazole is the
azole of choice for treatment of disease due to the dimorphic fungi
Histoplasma, Blastomyces, and Sporothrix. Itraconazole has activity
against Aspergillus sp, but it has been replaced by voriconazole as
t½ (hours) Elimination Formulations
<0.1 7–10 Hepatic Oral
<0.01 24–42 Hepatic Oral, IV
>0.7 22–31 Renal Oral, IV
>0.21 6 Hepatic Oral, IV
— 25 Hepatic Oral, IV
— 130 Hepatic Oral, IV
the azole of choice for aspergillosis. Itraconazole is used extensively
in the treatment of dermatophytoses and onychomycosis.
FLUCONAZOLE
Fluconazole displays a high degree of water solubility and good
cerebrospinal fluid penetration. Unlike ketoconazole and itracon-
azole, its oral bioavailability is high. Drug interactions are also less
common because fluconazole has the least effect of all the azoles
on hepatic microsomal enzymes. Because of fewer hepatic enzyme
interactions and better gastrointestinal tolerance, fluconazole has
the widest therapeutic index of the azoles, permitting more aggres-
sive dosing in a variety of fungal infections. The drug is available
in oral and intravenous formulations and is used at a dosage of
100–800 mg/d.
Fluconazole is the azole of choice in the treatment and
secondary prophylaxis of cryptococcal meningitis. Intravenous
fluconazole has been shown to be equivalent to amphotericin B
in treatment of candidemia in ICU patients with normal white
blood cell counts, although echinocandins may have superior
activity for this indication. Fluconazole is the agent most com-
monly used for the treatment of mucocutaneous candidiasis.
Activity against the dimorphic fungi is mainly limited to coccidi-
oidal disease, and in particular for meningitis, where high doses
of fluconazole often obviate the need for intrathecal ampho-
tericin B. Fluconazole displays no activity against Aspergillus or
other filamentous fungi.
Prophylactic use of fluconazole has been demonstrated to
reduce fungal disease in bone marrow transplant recipients and
AIDS patients, but the emergence of fluconazole-resistant fungi
has raised concerns about this indication.
VORICONAZOLE
Voriconazole is available in intravenous and oral formulations.
The recommended dosage is 400 mg/d. The drug is well absorbed
orally, with a bioavailability exceeding 90%, and it exhibits less
protein binding than itraconazole. Metabolism is predominantly
hepatic. Voriconazole is a clinically relevant inhibitor of mam-
malian CYP3A4, and dose reduction of a number of medica-
tions is required when voriconazole is started. These include
cyclosporine, tacrolimus, and HMG-CoA reductase inhibitors.

Iatrogenic Fungal Meningitis
In September 2012, the U.S. Centers for Disease Control and
Prevention (CDC) in Atlanta received reports of a number
of cases of fungal meningitis in patients who had received
injections with the corticosteroid methylprednisolone. An
investigation revealed a multistate outbreak of septic arthritis,
paraspinal infections, and meningitis due to environmental
molds, with the black mold Exserohilum rostratum being the
most commonly isolated species. The outbreak was traced to
the injection of methylprednisolone that was contaminated
during its preparation by a compounding pharmacy facility
in New England. Methylprednisolone injections are com-
monly given to patients with joint or back arthritis, and in
the affected cases the patients were not only inadvertently
injected with spores of environmental molds, but the nor-
mal immune response to this infection was inhibited by the
potent immunosuppressive effect of the corticosteroid. As of
November 2013 more than 750 cases of fungal infection had
been identified in 20 states, with over 60 deaths. Treatment of
these infections was challenging, and the CDC recommended
the use of intravenous voriconazole as first-line therapy, with
the addition of liposomal amphotericin B in cases of severe
infection.
Observed toxicities include rash and elevated hepatic enzymes.
Visual disturbances are common, occurring in up to 30% of
patients receiving intravenous voriconazole, and include blurring
and changes in color vision or brightness. These visual changes
usually occur immediately after a dose of voriconazole and resolve
within 30 minutes. Photosensitivity dermatitis is commonly
observed in patients receiving chronic oral therapy.
Voriconazole is similar to itraconazole in its spectrum of
action, having excellent activity against Candida sp (including
some fluconazole-resistant species such as Candida krusei) and
the dimorphic fungi. Voriconazole is less toxic than amphoteri-
cin B and is the treatment of choice for invasive aspergillosis
and some environmental molds (see Box: Iatrogenic Fungal
Meningitis). Measurement of voriconazole levels may predict
toxicity and clinical efficacy, especially in immunocompro-
mised patients. Therapeutic trough levels should be between
1 and 5 mcg/mL.
POSACONAZOLE
Posaconazole was originally available only in a liquid oral formula-
tion and is used at a dosage of 800 mg/d, divided into two or four
doses. Absorption is improved when taken with meals high in fat.
An intravenous form of posaconazole and a sustained acting tablet
form with higher bioavailability are now available. Posaconazole
is rapidly distributed to the tissues, resulting in high tissue levels
but relatively low blood levels. Measurement of posaconazole
CHAPTER 48  Antifungal Agents    859
levels is recommended in patients with serious invasive fungal
infections (especially mold infections); steady-state posaconazole
levels should be between 0.5 and 1.5 mcg/mL. Drug interactions
with increased levels of CYP3A4 substrates such as tacrolimus and
cyclosporine have been documented.
Posaconazole is the broadest-spectrum member of the azole
family, with activity against most species of Candida and
Aspergillus. It is the first azole with significant activity against
the agents of mucormycosis. It is currently licensed for salvage
therapy in invasive aspergillosis, as well as prophylaxis of fungal
infections during induction chemotherapy for leukemia, and
for allogeneic bone marrow transplant patients with graft-versus-
host disease.
ISAVUCONAZOLE (ISAVUCONAZONIUM
SULFATE)
Isavuconazonium sulfate is a prodrug of the newest triazole, isa-
vuconazole; 186 mg of the water-soluble prodrug is equivalent
to 100 mg of isavuconazole. It is available as highly bioavail-
able oral capsules and an intravenous formulation. Following
a 2-day loading dose of 372 mg administered every 8 hours,
isavuconazonium sulfate is given as a single 372-mg daily dose.
Food does not significantly impact the oral absorption of isavu-
conazonium sulfate. Measurement of isavuconazole levels has
not been demonstrated to be of benefit. Coadministration with
strong 3A4 inhibitors (eg, ritonavir) or inducers (eg, rifampin)
is not recommended.
Isavuconazole has an antifungal spectrum similar to that of
posaconazole. It is currently licensed for the treatment of invasive
aspergillosis and invasive mucormycosis. Data from published
clinical trials are limited. Preliminary evidence indicates that it is
better tolerated than voriconazole.
ECHINOCANDINS
Chemistry & Pharmacokinetics
Echinocandins are the newest class of antifungal agents to be
developed. They are large cyclic peptides linked to a long-chain
fatty acid. Caspofungin, micafungin, and anidulafungin are
the only licensed agents in this category of antifungals, although
other drugs are under active investigation. These agents are active
against Candida and Aspergillus, but not C neoformans or the
agents of zygomycosis and mucormycosis.
Echinocandins are available only in intravenous formulations.
Caspofungin is administered as a single loading dose of 70 mg,
followed by a daily dose of 50 mg. Caspofungin is water soluble
and highly protein-bound. The half-life is 9–11 hours, and the
metabolites are excreted by the kidneys and gastrointestinal tract.
Dosage adjustments are required only in the presence of severe
hepatic insufficiency. Micafungin displays similar properties with
a half-life of 11–15 hours and is used at a dose of 150 mg/d for
treatment of esophageal candidiasis, 100 mg/d for treatment of
candidemia, and 50 mg/d for prophylaxis of fungal infections.
860    SECTION VIII  Chemotherapeutic Drugs
Anidulafungin has a half-life of 24–48 hours. For esophageal
candidiasis, it is administered intravenously at 100 mg on the first
day and 50 mg/d thereafter for 14 days. For candidemia, a loading
dose of 200 mg is recommended with 100 mg/d thereafter for at
least 14 days after the last positive blood culture.
Mechanism of Action
Echinocandins act at the level of the fungal cell wall by inhibit-
ing the synthesis of β(1–3)-glucan (Figure 48–1). This results in
disruption of the fungal cell wall and cell death.
Clinical Uses & Adverse Effects
Caspofungin is currently licensed for disseminated and muco-
cutaneous candidal infections, as well as for empiric antifungal
therapy during febrile neutropenia, and has largely replaced
amphotericin B for the latter indication. Of note, caspofungin is
licensed for use in invasive aspergillosis only as salvage therapy in
patients who have failed to respond to amphotericin B, and not
as primary therapy. Micafungin is licensed for mucocutaneous
candidiasis, candidemia, and prophylaxis of candidal infections in
bone marrow transplant patients. Anidulafungin is approved for
use in esophageal candidiasis and invasive candidiasis, including
candidemia.
Echinocandin agents are extremely well tolerated, with minor
gastrointestinal side effects and flushing reported infrequently.
Elevated liver enzymes have been noted in several patients receiv-
ing caspofungin in combination with cyclosporine, and this
combination should be avoided. Micafungin has been shown to
increase levels of nifedipine, cyclosporine, and sirolimus. Anidu-
lafungin does not seem to have significant drug interactions, but
histamine release may occur during intravenous infusion. Clini-
cally significant echinocandin resistance is an emerging concern
especially with invasive Candida glabrata infections in immuno-
compromised patients.
■■ ORAL SYSTEMIC ANTIFUNGAL
DRUGS FOR MUCOCUTANEOUS
INFECTIONS
GRISEOFULVIN
Griseofulvin is a very insoluble fungistatic drug derived from a
species of penicillium. Its only use is in the systemic treatment of
dermatophytosis (see Chapter 61). It is administered in a micro-
crystalline oral form at a dosage of up to 1 g/d. Absorption is
improved when it is given with fatty foods. Griseofulvin’s mecha-
nism of action at the cellular level is unclear, but it is deposited in
newly forming skin where it binds to keratin, protecting the skin
from new infection. Because its action is to prevent infection of
these new skin structures, griseofulvin must be administered for
2–6 weeks for skin and hair infections to allow the replacement
of infected keratin by the resistant structures. Nail infections may
require therapy for months to allow regrowth of the new protected
nail and is often followed by relapse. Adverse effects include an
allergic syndrome much like serum sickness, serious skin reac-
tions, a lupus-like syndrome, hepatotoxicity, and drug interactions
with warfarin and phenobarbital. Griseofulvin has been largely
replaced by newer antifungal medications such as itraconazole
and terbinafine.
TERBINAFINE
Terbinafine is a synthetic allylamine that is available in an oral
formulation and is used at a dosage of 250 mg/d. It is used in
the treatment of dermatophytoses, especially onychomycosis
(see Chapter 61). Like griseofulvin, terbinafine is a keratophilic
medication, but unlike griseofulvin, it is fungicidal. Like the
azole drugs, it interferes with ergosterol biosynthesis, but rather
than interacting with the P450 system, terbinafine inhibits the
fungal enzyme squalene epoxidase (Figure 48–1). This leads to
the accumulation of the sterol squalene, which is toxic to the
organism. One 250-mg tablet given daily for 12 weeks achieves
a cure rate of up to 90% for onychomycosis and is more effec-
tive than griseofulvin or itraconazole. Adverse effects are rare,
consisting primarily of gastrointestinal upset and headache, but
serious hepatotoxicity has been reported. Terbinafine does not
seem to affect the P450 system and has demonstrated no signifi-
cant drug interactions to date.
■■ TOPICAL ANTIFUNGAL
THERAPY
NYSTATIN
Nystatin is a polyene macrolide much like amphotericin B. It
is too toxic for parenteral administration and is only used topi-
cally. Nystatin is currently available in creams, ointments, sup-
positories, and other forms for application to skin and mucous
membranes. It is not absorbed to a significant degree from skin,
mucous membranes, or the gastrointestinal tract. As a result,
nystatin has little toxicity, although oral use is often limited by
the unpleasant taste.
Nystatin is active against most Candida sp and is most com-
monly used for suppression of local candidal infections. Some
common indications include oropharyngeal thrush, vaginal can-
didiasis, and intertriginous candidal infections.
TOPICAL AZOLES
The two azoles most commonly used topically are clotrimazole
and miconazole; several others are available (see Preparations
Available). Both are available over the counter and are often
used for vulvovaginal candidiasis. Oral clotrimazole troches are
available for treatment of oral thrush and are a pleasant-tasting
alternative to nystatin. In cream form, both agents are useful for
dermatophytic infections, including tinea corporis, tinea pedis,
and tinea cruris. Absorption is negligible, and adverse effects are
rare.
 CHAPTER 48  Antifungal Agents    861

Topical and shampoo forms of ketoconazole are also available

and useful in the treatment of seborrheic dermatitis and pityriasis
versicolor. Several other azoles are available for topical use (see
Preparations Available).
TOPICAL ALLYLAMINES
Terbinafine and naftifine are allylamines available as topical
creams (see Chapter 61). Both are effective for treatment of tinea
cruris and tinea corporis. These are prescription drugs in the USA.

SUMMARY  Antifungal Drugs

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions

POLYENE MACROLIDE
  •  Amphotericin B Forms pores in fungal
membranes (which contain
ergosterol) but not in
mammalian (cholesterol-
containing) membranes
Loss of intracellular contents
through pores is fungicidal
• broad spectrum of action
Localized and systemic
candidemia • Cryptococcus
• Histoplasma • Blastomyces
• Coccidioides • Aspergillus
Oral form is not absorbed • IV for
systemic use • intrathecal for fungal
meningitis • topical for ocular and
bladder infections • duration, days •
Toxicity: Infusion reactions • renal
impairment • Interactions: Additive with
other renal toxic drugs

  •  Lipid formulations: Lower toxicity, higher doses can be used

PYRIMIDINE ANALOG
  •  Flucytosine Interferes with DNA and RNA Synergistic with
synthesis selectively in fungi amphotericin • systemic
toxicity in host due to DNA
and RNA effects
Cryptococcus and Oral • duration, hours • renal excretion
chromoblastomycosis • Toxicity: Myelosuppression
infections

AZOLES
  •  Ketoconazole Blocks fungal P450 enzymes Poorly selective • also Broad spectrum but toxicity Oral, topical • Toxicity and interactions:
and interferes with interferes with mammalian restricts use to topical Interferes with steroid hormone
ergosterol synthesis P450 function therapy synthesis and phase I drug metabolism

  •  Itraconazole Same as for ketoconazole Much more selective than Broad spectrum: Candida, Oral and IV • duration, 1–2 d • poor entry
ketoconazole Cryptococcus, blastomycosis, into central nervous system (CNS)
coccidioidomycosis, • Toxicity and interactions: Low toxicity
histoplasmosis

  •  Fluconazole, voriconazole, posaconazole, isavuconazole: Fluconazole has excellent CNS penetration, used in fungal meningitis

ECHINOCANDINS
  •  Caspofungin Blocks β-glucan synthase Prevents synthesis of fungal Fungicidal Candida sp • also IV only • duration, 11–15 h • Toxicity:
cell wall used in aspergillosis Minor gastrointestinal effects, flushing
• Interactions: Increases cyclosporine
levels (avoid combination)

  •  Micafungin, anidulafungin: Micafungin increases levels of nifedipine, cyclosporine, sirolimus; anidulafungin is relatively free of this interaction

ALLYLAMINE
  •  Terbinafine Inhibits epoxidation of
squalene in fungi • increased
levels are toxic to fungi
Reduces ergosterol Mucocutaneous fungal Oral • duration, days • Toxicity:
• prevents synthesis of infections Gastrointestinal upset, headache,
fungal cell membrane hepatotoxicity • Interactions: None
reported
862    SECTION VIII  Chemotherapeutic Drugs

P R E P A R A T I O N S REFERENCES
A V A I L A B L E Ashbee HR et al: Therapeutic drug monitoring (TDM) of antifungal agents:
Guidelines from the British Society for Medical Mycology. J Antimicrob
Chemother 2014;69:1162.
GENERIC NAME AVAILABLE AS Cornely OA et al: Posazonacole vs. fluconazole or itraconazole prophylaxis in
Amphotericin B   patients with neutropenia. N Engl J Med 2007;356:348.
 Parenteral:   Diekema DJ et al: Activities of caspofungin, itraconazole, posaconazole, ravucon-
azole, voriconazole, and amphotericin B against 448 recent clinical isolates
  Conventional formulation Generic of filamentous fungi. J Clin Microbiol 2003;41:3623.
  Lipid formulations Abelcet, AmBisome Felton T, Troke PF, Hope WW: Tissue penetration of antifungal agents. Clin
Anidulafungin Eraxis Microbiol Rev 2014:27:68.
Butenafine Mentax Herbrecht R et al: Voriconazole versus amphotericin B for primary therapy of
invasive aspergillosis. N Engl J Med 2002;347:408.
Butoconazole Gynazole-1
Lewis RE: Current concepts in antifungal pharmacology. Mayo Clin Proc
Caspofungin Cancidas 2011;86:805.
Clotrimazole Generic, Lotrimin, Mycelex, others Nett JE, Andes DR: Antifungal agents: Spectrum of activity, pharmacology, and
Econazole Generic, Ecoza clinical indications. Infect Dis Clin North Am 2016;30:51.
Fluconazole Generic, Diflucan Pasqualotto AC, Denning DW: New and emerging treatments for fungal infection.
J Antimicrob Chemother 2008;61(Suppl 1):i19.
Flucytosine Generic, Ancobon
Perlin DS: Echinocandin resistance, susceptibility testing and prophylaxis: Impli-
Griseofulvin Grifulvin, Gris-Peg cations for patient management. Drugs 2014;74:1573.
Itraconazole Generic, Sporanox, Onmel Rogers TR: Treatment of zygomycosis: Current and new options. J Antimicrob
Ketoconazole Generic, Nizoral, others Chemother 2008;61(Suppl 1):i35.
Micafungin Mycamine Wong-Beringer A, Jacobs RA, Guglielmo BJ: Lipid formulations of amphotericin
B: Clinical efficacy and toxicities. Clin Infect Dis 1998;27:603.
Miconazole Generic, Oravig, Micatin
Naftifine Naftin
Natamycin Natacyn
Nystatin Generic
Oxiconazole Generic, Oxistat, others
Posaconazole Noxafil
Sulconazole Exelderm
Terbinafine Generic, Lamisil
Terconazole Generic, Terazol 3, Terazol 7
Tioconazole Vagistat-1, Monistat 1
Tolnaftate Generic, Aftate, Tinactin, others
Voriconazole Generic, Vfend

C ASE STUDY ANSWER

The mold subsequently isolated from the patient’s CSF
was identified as Coccidioides immitis. Patients of African-
American and Southeast Asian descent as well as immuno-
compromised patients are at an increased risk for developing
chronic forms of coccidioidomycosis such as meningitis. C.
immitis is a dimorphic fungus that grows in the soil of the San
Joaquin Valley in California, while closely related C posadasii is
found elsewhere in desert regions of the southwest USA, parts
of Mexico, and Central and South America. Oral therapy with
fluconazole was initiated at a dose of 800 mg/day and patient’s
headache, fever, and double vision resolved within 7 days.
Patients experiencing treatment failure with fluconazole may
require treatment with intrathecal amphotericin B. Generally,
coccidioidal meningitis requires lifelong therapy because of a
high incidence of disease relapse with treatment discontinua-
tion and is 100% fatal without antifungal treatment.

Antiviral Agents
Sharon Safrin, MD
C ASE STUDY
A 35-year-old white woman who recently tested
seropositive for both HIV and hepatitis B virus surface
antigen is referred for evaluation. She is feeling well
overall but reports a 25-pack-year smoking history. She
drinks 3–4 beers per week and has no known medication
allergies. She has a history of heroin use and is currently
receiving methadone. Physical examination reveals
Viruses are obligate intracellular parasites; their replication
depends primarily on synthetic processes of the host cell. There-
fore, to be effective, antiviral agents must either block viral entry
into or exit from the cell or be active inside the host cell. As a
corollary, nonselective inhibitors of virus replication may interfere
with host cell function and result in toxicity.
Progress in antiviral chemotherapy began in the early 1950s,
when the search for anti-cancer drugs generated several new
compounds capable of inhibiting viral DNA synthesis. The
two first-generation antiviral agents, 5-iododeoxyuridine and
trifluorothymidine, had poor specificity (ie, they inhibited host
cell DNA as well as viral DNA) that rendered them too toxic
for systemic use. However, both agents are effective when used
topically for the treatment of herpes keratitis.
Knowledge of the mechanisms of viral replication has provided
insights into critical steps in the viral life cycle that can serve as
49
C H A P T E R
normal vital signs and no abnormalities. White blood
cell count is 5800 cells/mm3 with a normal differential,
hemoglobin is 11.8 g/dL, all liver tests are within normal
limits, CD4 cell count is 278 cells/mm3, and viral load
(HIV RNA) is 110,000 copies/mL. What other laboratory
tests should be ordered? Which antiretroviral medica-
tions would you begin?
potential targets for antiviral therapy. Recent research has focused
on identifying agents with greater selectivity, higher potency, in
vivo stability, and reduced toxicity. Antiviral therapy is now avail-
able for herpes simplex virus (HSV), cytomegalovirus (CMV),
varicella zoster virus (VZV), hepatitis C virus (HCV), hepatitis B
virus (HBV), influenza, human immunodeficiency virus (HIV),
and respiratory syncytial virus (RSV). Antiviral drugs share the
common property of being virustatic; they are active only against
replicating viruses and do not affect latent virus. Whereas some
infections require monotherapy for brief periods of time (eg, HSV,
influenza), others require multiple drug therapy for indefinite
periods (HIV). In chronic illnesses such as viral hepatitis and HIV
infection, potent inhibition of viral replication is crucial in limit-
ing the extent of systemic damage.
Viral replication requires several steps (see Figure 49–1). Anti-
viral agents can potentially target any of these steps.
863
864    SECTION VIII  Chemotherapeutic Drugs

ACRONYMS & OTHER NAMES ■■ AGENTS TO TREAT HERPES

3TC Lamivudine
SIMPLEX VIRUS (HSV) &
AZT Zidovudine (previously azidothymidine)
CMV Cytomegalovirus
VARICELLA-ZOSTER VIRUS (VZV)
CYP Cytochrome P450 INFECTIONS
d4T Stavudine
Three oral nucleoside analogs are licensed for the treatment
ddC Zalcitabine of HSV and VZV infections: acyclovir, valacyclovir, and fam-
ddI Didanosine ciclovir. They have similar mechanisms of action and compa-
EBV Epstein-Barr virus rable indications for clinical use (see Table 49–1); all are well
FTC Emtricitabine tolerated.
HBeAg Hepatitis e antigen
Comparative trials have demonstrated similar efficacies of
these three agents for the treatment of HSV, with shortening
HBV, HCV Hepatitis B virus, C virus
of the duration of symptoms by approximately 2 days, the time
HHV-6, -8 Human herpesvirus-6, human herpesvirus-8 to lesion healing by 4 days, and the duration of viral shedding
HIV Human immunodeficiency virus by 7 days in first episodes of genital herpes and shortening of
HSV Herpes simplex virus the overall time course by 1–2 days in recurrent genital herpes.
INSTI Integrase strand transfer inhibitor Treatment of first-episode genital herpes does not alter the
NNRTI Nonnucleoside reverse transcriptase inhibitor
frequency or severity of recurrent outbreaks. Long-term sup-
pression with antiherpes agents in patients with frequent recur-
NRTI Nucleoside/nucleotide reverse transcriptase inhibitor
rences of genital herpes decreases the frequency of symptomatic
PI Protease inhibitor recurrences and of asymptomatic viral shedding, thus decreasing
RSV Respiratory syncytial virus the rate of sexual transmission. However, outbreaks may resume
SVR Sustained viral response upon discontinuation of suppression. The efficacy of the anti-
UGT1A1 UDP-glucuronosyltransferase 1A1 herpes agents in orolabial herpes is generally less than that in
VZV Varicella-zoster virus
anogenital herpes.

Blocked by
enfuvirtide (HIV); Blocked by
docosanol (HSV), amantadine,
maraviroc (HIV), rimantadine
palivizumab (RSV) (influenza)

Viral Penetration
attachment
and entry Uncoating
Blocked by
interferon-alfa
(HBV, HCV)

Blocked by NRTIs,
Mammalian Nucleic acid NNRTIs (HIV),
cell synthesis Nucleoside/nucleotide
Blocked by analogs (HSV, HBV)
neuraminidase
inhibitors Packaging
(influenza) and Integration
assembly (retroviruses)
Viral Transcription
release
Viral protein
synthesis Blocked by INSTIs (HIV)

Blocked by PIs
(HIV, HCV)

FIGURE 49–1  The major sites of antiviral drug action. Note: Interferon alfas are speculated to have multiple sites of action. (Modified and
reproduced, with permission, from Trevor AJ, Katzung BG, Masters SB: Pharmacology: Examination & Board Review, 9th ed. McGraw-Hill, 2010. Copyright © The McGraw-Hill
Companies, Inc.)
 CHAPTER 49  Antiviral Agents    865

TABLE 49–1  Agents to treat or prevent herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections.
Agent Treatment of First Episode Treatment of Recurrent Episodes Suppression

Genital Herpes
Acyclovir, oral1 400 mg tid × 7–10 days 800 mg tid × 2 days or 800 mg bid × 5 days 400–800 mg bid-tid2
or 200 mg 5 times daily or 400 mg tid × 5 days
Famciclovir, oral1 250 mg tid × 7–10 days 1000 mg bid × 1 day or 125 mg bid × 5 days 250–500 mg bid2
or 500 mg once then 250 mg bid × 2 days2
Valacyclovir, oral1 1000 mg bid × 10 days 500 mg bid × 3 days or 1 g qd × 5 days 500–1000 mg qd–bid2
Orolabial herpes
Acyclovir, oral1 400 mg tid × 7–10 days 200–400 mg 5 times daily × 5 days 400–800 mg bid–tid2
or 200 mg 5 times daily
Famciclovir, oral1 500 mg tid × 7–10 days 1500 mg once or 750 mg bid 500 mg bid
Valacyclovir, oral1 1 g bid × 7–10 days 2 g bid × 1 day 500–1000 mg qd
Acyclovir, topical (5% cream)   5 times daily × 4 days  
Docosanol, topical (10% cream)   5 times daily  
Penciclovir, topical (1% cream)   Every 2 h while awake  
Herpes proctitis, treatment
Acyclovir, oral1 400 mg 5 times daily until healed
Severe HSV infection or HSV infection in the immunocompromised host, treatment
Acyclovir, IV1 5–10 mg/kg q8h × 7–14 days
Herpes encephalitis, treatment
Acyclovir, IV1 10–15 mg/kg q8h × 21 days
Neonatal HSV infection, treatment
Acyclovir, IV1 10–20 mg/kg q8h × 14–21 days
Herpetic keratoconjunctivitis, treatment
Ganciclovir, topical (0.15% gel) 5 times daily
Trifluridine, topical (1% solution) Every 2 h while awake
Varicella infection, treatment
Acyclovir, oral1 20 mg/kg (maximum 800 mg) qid × 5 days
1
Valacyclovir, oral 20 mg/kg (maximum, 1 g) tid × 5 days
Zoster infection, treatment
Acyclovir, oral1 800 mg 5 times daily × 7–10 days
Famciclovir, oral1 500 mg tid × 7 days
1
Valacyclovir, oral 1 g tid × 7 days
Severe VZV infection or VZV infection in the immunocompromised host, treatment
Acyclovir, IV1 10–15 mg/kg q8h × ≥7 days
Acyclovir-resistant HSV or VZV infection, treatment
Foscarnet, IV1 40–60 mg/kg q8h until healed2
1
Dose adjustment is necessary for renal insufficiency.
2
Higher doses may be necessary in HIV-infected patients.
HIV, human immunodeficiency virus; HSV, herpes simplex virus; IV, intravenous; VZV, varicella-zoster virus.

The antiherpes agents significantly decrease the total number of
lesions, duration of symptoms, and viral shedding in patients with
varicella (if begun within 24 hours after the onset of rash) or cutane-
ous zoster (if begun within 72 hours); the risk of post-herpetic neu-
ralgia is also reduced if treatment is initiated early. In comparative
trials with acyclovir for the treatment of patients with zoster, rates of
cutaneous healing with valacyclovir or famciclovir were similar, but
the latter agents were associated with a shorter duration of zoster-
associated pain. Since VZV is less susceptible to the antiherpes
agents than HSV, higher doses are required (Table 49–1).
The antiherpes agents may also be administered prophylacti-
cally for the prevention of HSV or VZV infection in patients
undergoing organ transplantation, as well as for the treatment of
these infections should they occur.
866    SECTION VIII  Chemotherapeutic Drugs

ACYCLOVIR diffuses readily into most tissues and body fluids. Cerebrospinal
fluid concentrations are 20–50% of serum values.
Acyclovir is an acyclic guanosine derivative with clinical activ- Acyclovir is the only one of the three antiherpes agents that
ity against HSV-1, HSV-2, and VZV, but it is approximately is available for intravenous use in the United States. Intrave-
10 times more potent against HSV-1 and HSV-2 than against nous acyclovir is the treatment of choice for herpes simplex
VZV. In vitro activity against Epstein-Barr virus (EBV), cyto- encephalitis, neonatal HSV infection, and serious HSV or
megalovirus (CMV), and human herpesvirus-6 (HHV-6) is VZV infections (Table 49–1). In neonates with central nervous
present but weaker. system HSV, oral acyclovir suppression for 6 months follow-
Acyclovir requires three phosphorylation steps for activation. ing acute treatment improves neurodevelopmental outcomes.
It is converted first to the monophosphate derivative by the virus- In immunocompromised patients with VZV infection, intrave-
specified thymidine kinase and then to the di- and triphosphate nous acyclovir reduces the incidence of cutaneous and visceral
compounds by host cell enzymes (Figure 49–2). Because it dissemination.
requires the viral kinase for initial phosphorylation, acyclovir is Topical acyclovir cream is substantially less effective than oral
selectively activated—and the active metabolite accumulates— therapy for primary HSV infection. It is of no benefit in treating
only in infected cells. Acyclovir triphosphate inhibits viral DNA recurrent genital herpes.
synthesis by two mechanisms: competition with deoxyGTP for Resistance to acyclovir can develop in HSV or VZV through
the viral DNA polymerase, resulting in binding to the DNA tem- alteration in either the viral thymidine kinase or the DNA poly-
plate as an irreversible complex; and chain termination following merase, and clinically resistant infections have been reported in
incorporation into the viral DNA. immunocompromised hosts. Most clinical isolates are resistant
The bioavailability of oral acyclovir is low (15–20%) and is on the basis of deficient thymidine kinase activity and thus
unaffected by food. Topical formulations produce high concentra- are cross-resistant to valacyclovir, famciclovir, and ganciclovir.
tions in herpetic lesions, but systemic concentrations are undetect- Agents such as foscarnet, cidofovir, and trifluridine do not
able by this route. require activation by viral thymidine kinase and therefore have
Acyclovir is cleared primarily by glomerular filtration and preserved activity against the most prevalent acyclovir-resistant
tubular secretion. The half-life is 2.5–3 hours in patients with nor- strains (Figure 49–2).
mal renal function and 20 hours in patients with anuria. Acyclovir Acyclovir is generally well tolerated, although nausea, diarrhea,
and headache may occur. Intravenous infusion may be associ-
ated with reversible renal toxicity (ie, crystalline nephropathy or
interstitial nephritis) or neurologic effects (eg, tremors, delirium,
Nucleoside seizures). However, these are uncommon with adequate hydration
Blocked by Virus-specified
acyclovir and avoidance of rapid infusion rates. High doses of acyclovir
penciclovir enzymes
ganciclovir
cause chromosomal damage and testicular atrophy in rats, but
(eg, thymidine
kinase, UL97) there has been no evidence of teratogenicity, reduction in sperm
Monophosphate production, or cytogenetic alterations in peripheral blood lym-
phocytes in patients receiving daily suppression of genital herpes
for more than 10 years. A recent study found no evidence of
Blocked by increased birth defects in infants exposed to acyclovir during the
trifluridine first trimester. In fact, the American College of Obstetricians and
cidofovir Host
kinases Gynecologists recommends suppressive acyclovir therapy begin-
ning at week 36 in pregnant women with active recurrent genital
herpes to reduce the risk of recurrence at delivery and possibly the
Diphosphate
need for cesarean section.
Blocked by Concurrent use of nephrotoxic agents may enhance the
foscarnet potential for nephrotoxicity. Probenecid and cimetidine decrease
acyclovir clearance and increase exposure. Somnolence and leth-
Triphosphate argy may occur in patients receiving concomitant zidovudine
and acyclovir.

Incorporation into Inhibits viral DNA

viral DNA polymerase
VALACYCLOVIR
Chain
Valacyclovir is the l-valyl ester of acyclovir. It is rapidly converted
termination to acyclovir after oral administration via first-pass enzymatic
hydrolysis in the liver and intestine, resulting in serum levels
FIGURE 49–2  Mechanism of action of antiherpes agents. that are three to five times greater than those achieved with oral

acyclovir and approximate those achieved with intravenous acy-
clovir. Oral bioavailability is 54–70%, and cerebrospinal fluid
levels are about 50% of those in serum. Elimination half-life is
2.5–3.3 hours.
Valacyclovir is generally well tolerated, although nausea,
headache, vomiting, or rash may occur. At high doses, confu-
sion, hallucinations, and seizures have been reported. AIDS
patients who received high-dosage valacyclovir chronically
(ie, 8 g/d) had increased gastrointestinal intolerance as well as
thrombotic thrombocytopenic purpura/hemolytic-uremic syn-
drome; this dose has also been associated with confusion and
hallucinations in transplant patients. There is no evidence of an
increased risk of birth defects in infants exposed to valacyclovir
during pregnancy.
FAMCICLOVIR
Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, an
acyclic guanosine analog. After oral administration, famciclovir
is rapidly deacetylated and oxidized by first-pass metabolism to
penciclovir. It is active in vitro against HSV-1, HSV-2, VZV, EBV,
and HBV. As with acyclovir, activation by phosphorylation is
catalyzed by the virus-specified thymidine kinase in infected cells,
followed by competitive inhibition of the viral DNA polymerase
to block DNA synthesis. Unlike acyclovir, however, penciclovir
does not cause chain termination. Penciclovir triphosphate has
lower affinity for the viral DNA polymerase than acyclovir tri-
phosphate, but it achieves higher intracellular concentrations.
The most commonly encountered clinical mutants of HSV are
thymidine kinase-deficient; these are cross-resistant to acyclovir
and famciclovir.
The bioavailability of penciclovir from orally administered
famciclovir is 70%. The intracellular half-life of penciclovir tri-
phosphate is prolonged, at 7–20 hours. Penciclovir is excreted
primarily in the urine.
Oral famciclovir is generally well tolerated, although headache,
nausea, or diarrhea may occur. As with acyclovir, testicular toxicity
has been demonstrated in animals receiving repeated doses. How-
ever, men receiving daily famciclovir (250 mg every 12 hours) for
18 weeks had no changes in sperm morphology or motility. In one
study, there was no evidence of increased birth defects in infants
exposed to famciclovir during the first trimester. The incidence of
mammary adenocarcinoma was increased in female rats receiving
famciclovir for 2 years.
PENCICLOVIR
The guanosine analog penciclovir, the active metabolite of
famciclovir, is available for topical use. Penciclovir cream (1%)
shortened the median duration of recurrent herpes labialis by
~17 hours compared to placebo when applied within 1 hour of
the onset of prodromal symptoms and continued every 2 hours
during waking hours for 4 days. Adverse effects are uncommon,
other than application site reactions in ~1%.
CHAPTER 49  Antiviral Agents    867
DOCOSANOL
Docosanol is a saturated 22-carbon aliphatic alcohol that inhibits
fusion between the host cell plasma membrane and the HSV
envelope, thereby preventing viral entry into cells and subsequent
viral replication. Topical docosanol 10% cream is available with-
out a prescription. When applied within 12 hours of the onset of
prodromal symptoms, five times daily, median healing time was
shortened by 18 hours compared with placebo in recurrent orola-
bial herpes. Application site reactions occur in ~2%.
TRIFLURIDINE
Trifluridine (trifluorothymidine) is a fluorinated pyrimidine
nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2,
CMV, vaccinia, and some adenoviruses. It is phosphorylated intra-
cellularly by host cell enzymes, and then competes with thymidine
triphosphate for incorporation by the viral DNA polymerase
(Figure 49–2). Incorporation of trifluridine triphosphate into
both viral and host DNA prevents its systemic use. Application
of a 1% solution is effective in treating keratoconjunctivitis and
recurrent epithelial keratitis due to HSV-1 or HSV-2. Cutaneous
application of trifluridine solution, alone or in combination with
interferon-alfa, has been used successfully in the treatment of
acyclovir-resistant HSV infections.
INVESTIGATIONAL AGENTS
Two compounds (pritelivir and amenamevir) belong to the new
class of helicase-primase inhibitors and are under development
for HSV infection. Valomaciclovir, an inhibitor of the viral
DNA polymerase, is currently under clinical evaluation for the
treatment of patients with acute zoster and acute EBV infection
(infectious mononucleosis).
■■ AGENTS TO TREAT
CYTOMEGALOVIRUS (CMV)
INFECTIONS
CMV infections occur primarily in the setting of advanced
immunosuppression and are typically due to reactivation of latent
infection. Dissemination of infection results in end-organ disease,
including retinitis, colitis, esophagitis, central nervous system dis-
ease, and pneumonitis. Although the incidence in HIV-infected
patients has markedly decreased with the advent of potent antiret-
roviral therapy, clinical reactivation of CMV infection after organ
transplantation is still prevalent.
The availability of oral valganciclovir has decreased the use of
intravenous ganciclovir, intravenous foscarnet, and intravenous
cidofovir for the prophylaxis and treatment of end-organ CMV
disease (Table 49–2). Oral valganciclovir has replaced oral ganci-
clovir because of its lower pill burden.
868    SECTION VIII  Chemotherapeutic Drugs
TABLE 49–2  Agents to treat cytomegalovirus (CMV) infection.
Route of
Agent Administration Use
1
Valganciclovir Oral CMV retinitis treatment
     
  Oral CMV prophylaxis (transplant patients)
Ganciclovir1 Intravenous CMV retinitis treatment
     
Foscarnet1 Intravenous CMV retinitis treatment
     
Cidofovir1 Intravenous CMV retinitis treatment
1
Dosage must be reduced in patients with renal insufficiency.
GANCICLOVIR
Ganciclovir is an acyclic guanosine analog that requires activation
by triphosphorylation before inhibiting the viral DNA poly-
merase. Initial phosphorylation is catalyzed by the virus-specified
protein kinase phosphotransferase UL97 in CMV-infected cells.
The activated compound competitively inhibits viral DNA
polymerase and causes termination of viral DNA elongation
(Figure 49–2). Ganciclovir has in vitro activity against CMV,
HSV, VZV, EBV, HHV-6, and HHV-8. Its activity against CMV
is up to 100 times greater than that of acyclovir.
Ganciclovir is administered intravenously; the bioavailability
of oral ganciclovir is poor, and it is no longer available in the USA.
Ganciclovir gel is available for the treatment of acute herpetic ker-
atitis. Cerebrospinal fluid concentrations are approximately 50%
of serum concentrations. The elimination half-life is 4 hours, and
the intracellular half-life is prolonged at 16–24 hours. Clearance
of the drug is linearly related to creatinine clearance. Ganciclovir
is readily cleared by hemodialysis.
Intravenous ganciclovir has been shown to delay progression
of CMV retinitis in immunocompromised patients. Dual therapy
with foscarnet and ganciclovir is more effective in delaying pro-
gression of retinitis than either drug alone in patients with AIDS
(see Foscarnet), although adverse effects are compounded. Intra-
venous ganciclovir is also used to treat CMV colitis, esophagitis,
and pneumonitis (the latter often in combination with intrave-
nous cytomegalovirus immunoglobulin) in immunocompromised
patients. Intravenous ganciclovir, followed by either oral ganciclo-
vir or high-dose oral acyclovir, reduces the risk of CMV infection
in transplant recipients. Limited data in infants with symptomatic
congenital neurologic CMV disease suggest that treatment with
IV ganciclovir may reduce hearing loss. The risk of Kaposi’s sar-
coma is reduced in AIDS patients receiving long-term ganciclovir,
presumably because of activity against HHV-8.
Intravitreal injections of ganciclovir or the intraocular ganci-
clovir implant may be used to treat CMV retinitis. Concurrent
therapy with a systemic anti-CMV agent is necessary to prevent
other sites of end-organ CMV disease.
Recommended Adult Dosage
Induction: 900 mg bid × 21 days
Maintenance: 900 mg daily
900 mg daily
Induction: 5 mg/kg q12h × 14–21 days
Maintenance: 5 mg/kg/d or 6 mg/kg five times per week
Induction: 60 mg/kg q8h or 90 mg/kg q12h × 14–21 days
Maintenance: 90–120 mg/kg/d
Induction: 5 mg/kg/wk × 2 weeks
Maintenance: 5 mg/kg every week
Resistance to ganciclovir increases with duration of use. The
more common mutation, in UL97, results in decreased levels of
the triphosphorylated (ie, active) form of ganciclovir. The less
common UL54 mutation in DNA polymerase results in higher
levels of resistance and potential cross-resistance with cidofovir
and foscarnet. Antiviral susceptibility testing is recommended in
patients in whom resistance is suspected clinically.
The most common adverse effect of intravenous ganciclovir
treatment is myelosuppression, which although reversible may
be dose-limiting. Other potential adverse effects are nausea, diar-
rhea, fever, rash, headache, insomnia, and peripheral neuropathy.
Central nervous system toxicity (confusion, seizures, psychiatric
disturbance) and hepatotoxicity have been rarely reported. Intra-
vitreal ganciclovir has been associated with vitreous hemorrhage
and retinal detachment. Ganciclovir is mutagenic in mammalian
cells and carcinogenic and embryotoxic at high doses in animals
and causes aspermatogenesis; the clinical significance of these
preclinical data is unclear.
Levels of ganciclovir may rise in patients concurrently taking
probenecid or trimethoprim. Concurrent use of ganciclovir with
didanosine may result in increased levels of didanosine.
VALGANCICLOVIR
Valganciclovir is an l-valyl ester prodrug of ganciclovir that exists
as a mixture of two diastereomers. After oral administration, both
diastereomers are rapidly hydrolyzed to ganciclovir by esterases in
the intestinal wall and liver.
Valganciclovir has a bioavailability of 60% and should be
taken with food. The AUC0–24h resulting from oral valganciclovir
(900 mg once daily) is similar to that after 5 mg/kg once daily
of intravenous ganciclovir and approximately 1.65 times that of
oral ganciclovir. The major route of elimination is renal, through
glomerular filtration and active tubular secretion. Plasma concen-
trations of valganciclovir are reduced ~50% by hemodialysis.
Valganciclovir is as effective as intravenous ganciclovir for the
treatment of CMV retinitis and is also indicated for the prevention

of CMV disease in high-risk solid organ and bone marrow trans-
plant recipients. Adverse effects, drug interactions, and resistance
patterns are the same as those associated with ganciclovir.
FOSCARNET
Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate
analog that inhibits herpesvirus DNA polymerase, RNA poly-
merase, and HIV reverse transcriptase directly without requiring
activation by phosphorylation. Foscarnet blocks the pyrophos-
phate binding site of these enzymes and inhibits cleavage of
pyrophosphate from deoxynucleotide triphosphates. It has in vitro
activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV-1,
and HIV-2.
Foscarnet is available in an intravenous formulation only; poor
oral bioavailability and gastrointestinal intolerance preclude oral
use. Cerebrospinal fluid concentrations are 43–67% of steady-
state serum concentrations. Although the mean plasma half-life is
3–7 hours, up to 30% of foscarnet may be deposited in bone, with
a half-life of several months. The clinical repercussions of this are
unknown. Clearance of foscarnet is primarily renal and is directly
proportional to creatinine clearance. Serum drug concentrations
are reduced ~50% by hemodialysis.
Foscarnet is effective in the treatment of end-organ CMV dis-
ease (ie, retinitis, colitis, and esophagitis), including ganciclovir-
resistant disease; it is also effective against acyclovir-resistant HSV
and VZV infections. The dosage of foscarnet must be titrated
according to the patient’s calculated creatinine clearance before
each infusion. Use of an infusion pump to control the rate of infu-
sion is important to prevent toxicity, and large volumes of fluid are
required because of the drug’s poor solubility. The combination of
ganciclovir and foscarnet is synergistic in vitro against CMV and
has been shown to be superior to either agent alone in delaying
progression of retinitis; however, toxicity is also increased when
these agents are administered concurrently. As with ganciclovir, a
decrease in the incidence of Kaposi’s sarcoma has been observed in
patients who have received long-term foscarnet.
Foscarnet has been administered intravitreally for the treat-
ment of CMV retinitis in patients with AIDS, but data regarding
efficacy and safety are incomplete.
Resistance to foscarnet in HSV and CMV isolates is due to
point mutations in the DNA polymerase gene and is typically
associated with prolonged or repeated exposure to the drug.
Mutations in the HIV-1 reverse transcriptase gene have also been
described. Although foscarnet-resistant CMV isolates are typically
cross-resistant to ganciclovir, foscarnet activity is usually main-
tained against ganciclovir- and cidofovir-resistant isolates of CMV.
Potential adverse effects of foscarnet include renal impairment,
hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypo-
kalemia, and hypomagnesemia. Saline preloading helps prevent
nephrotoxicity, as does avoidance of concomitant administration
of drugs with nephrotoxic potential (eg, amphotericin B, pentami-
dine, aminoglycosides). The risk of severe hypocalcemia, caused
by chelation of divalent cations, is increased with concomitant
use of pentamidine. Genital ulcerations associated with foscarnet
CHAPTER 49  Antiviral Agents    869
therapy may be due to high levels of ionized drug in the urine.
Nausea, vomiting, anemia, elevation of liver enzymes, and fatigue
have been reported; the risk of anemia may be additive in patients
receiving concurrent zidovudine. Central nervous system toxicity
includes headache, hallucinations, and seizures; the risk of seizures
may be increased with concurrent use of imipenem. Foscarnet
caused chromosomal damage in preclinical studies.
CIDOFOVIR
Cidofovir is a cytosine nucleotide analog with in vitro activity
against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8,
adenovirus, poxviruses, polyomaviruses, and human papillomavi-
rus. In contrast to ganciclovir, phosphorylation of cidofovir to the
active diphosphate is independent of viral enzymes (Figure 49–2);
thus activity is maintained against thymidine kinase-deficient or
altered strains of CMV or HSV. Cidofovir diphosphate acts both
as a potent inhibitor of and as an alternative substrate for viral
DNA polymerase, competitively inhibiting DNA synthesis and
becoming incorporated into the viral DNA chain. Cidofovir-
resistant isolates tend to be cross-resistant with ganciclovir but
retain susceptibility to foscarnet.
Although the terminal half-life of cidofovir is approximately
2.6 hours, the active metabolite cidofovir diphosphate has a pro-
longed intracellular half-life of 17–65 hours, thus allowing infre-
quent dosing. A separate metabolite, cidofovir phosphocholine,
has a half-life of at least 87 hours and may serve as an intracellular
reservoir of active drug. Cerebrospinal fluid penetration is poor.
Elimination is by active renal tubular secretion. High-flux hemo-
dialysis reduces serum levels of cidofovir by approximately 75%.
Intravenous cidofovir is effective for the treatment of CMV
retinitis and is used experimentally to treat adenovirus, human pap-
illomavirus, BK polyomavirus, vaccinia, and poxvirus infections.
Intravenous cidofovir must be administered with high-dose pro-
benecid (2 g at 3 hours before the infusion and 1 g at 2 and 8 hours
after), which blocks active tubular secretion and decreases nephro-
toxicity. Before each infusion, cidofovir dosage must be adjusted for
alterations in the calculated creatinine clearance or for the presence
of urine protein, and aggressive adjunctive hydration is required.
Initiation of cidofovir therapy is contraindicated in patients with
existing renal insufficiency. Direct intravitreal administration of
cidofovir is not recommended because of ocular toxicity.
The primary adverse effect of intravenous cidofovir is a dose-
dependent proximal tubular nephrotoxicity, which may be reduced
with prehydration using normal saline. Proteinuria, azotemia,
metabolic acidosis, and Fanconi’s syndrome may occur. Concurrent
administration of other potentially nephrotoxic agents (eg, ampho-
tericin B, aminoglycosides, nonsteroidal anti-inflammatory drugs,
pentamidine, foscarnet) should be avoided. Prior administration of
foscarnet may increase the risk of nephrotoxicity. Other potential
adverse effects include uveitis, ocular hypotony, and neutropenia
(15–24%). Concurrent probenecid use may result in other toxicities
or drug-drug interactions (see Chapter 36). Cidofovir is mutagenic,
gonadotoxic, and embryotoxic, and causes hypospermia and mam-
mary adenocarcinomas in animals.
870    SECTION VIII  Chemotherapeutic Drugs
EXPERIMENTAL AGENTS
Brincidofovir is a nucleoside agent with activity against HSV,
CMV, adenovirus, BK virus, and poxvirus. It is currently under
clinical investigation for CMV and adenovirus infections.
■■ ANTIRETROVIRAL AGENTS
Substantial advances have been made in antiretroviral therapy
since the introduction of the first agent, zidovudine, in 1987. Six
classes of antiretroviral agents are currently available for use: nucle-
oside/nucleotide reverse transcriptase inhibitors (NRTIs), non-
nucleoside reverse transcriptase inhibitors (NNRTIs), protease
inhibitors (PIs), fusion inhibitors, CCR5 co-receptor antagonists,
and integrase strand transfer inhibitors (INSTIs) (Table 49–3).
These agents inhibit HIV replication at different parts of the cycle
(Figure 49–3).
Knowledge of viral dynamics through the use of viral load and
resistance testing has made it clear that combination therapy with
maximally potent agents will reduce viral replication to the lowest
possible level, thereby reducing the number of cumulative muta-
tions and decreasing the likelihood of emergence of resistance.
Thus, administration of combination antiretroviral therapy, typi-
cally including at least three antiretroviral agents with differing
susceptibility patterns, has become the standard of care. Viral
susceptibility to specific agents varies among patients and may
change with time. Therefore, such combinations must be chosen
with care and tailored to the individual, as must changes to a given
regimen. In addition to potency and susceptibility, important
factors in the selection of agents for any given patient are toler-
ability, convenience, and optimization of adherence. New drugs
with high potency, low toxicity, and good tolerability increase the
feasibility of early, lifelong treatment. As new agents have become
available, several older ones have had diminished usage, because
of either suboptimal safety or inferior efficacy. Zalcitabine (ddC;
dideoxycytidine) is no longer marketed, and regimens containing
zidovudine (AZT; azidothymidine), ddI (didanosine), or stavu-
dine (d4T) are infrequently recommended as first-line regimens.
Decrease of the circulating viral load by antiretroviral therapy
is correlated with enhanced survival as well as decreased morbidity.
Also, the use of antiretroviral therapy strongly reduces the risk for
heterosexual and same-sex HIV transmission.
Discussion of antiretroviral agents in this chapter is specific to
HIV-1. Patterns of susceptibility of HIV-2 to these agents may
vary; however, there is innate resistance to the NNRTIs and enfu-
virtide as well as a lower barrier of resistance to NRTIs and PIs.
NUCLEOSIDE & NUCLEOTIDE
REVERSE TRANSCRIPTASE
INHIBITORS (NRTIs)
The NRTIs act by competitive inhibition of HIV-1 reverse tran-
scriptase; incorporation into the growing viral DNA chain causes
premature chain termination due to inhibition of binding with
the incoming nucleotide (Figure 49–3). Each agent requires intra-
cytoplasmic activation via phosphorylation by cellular enzymes to
the triphosphate form.
Typical resistance mutations include M184V, L74V, D67N,
and M41L. Lamivudine or emtricitabine therapy tends to select
rapidly for the M184V mutation in regimens that are not fully
suppressive. While the M184V mutation confers reduced suscep-
tibility to abacavir, didanosine, and zalcitabine, its presence may
restore phenotypic susceptibility to zidovudine. The K65R/N
mutation is associated with reduced susceptibility to tenofovir,
abacavir, lamivudine, and emtricitabine.
All NRTIs may be associated with mitochondrial toxicity,
which may manifest as peripheral neuropathy, pancreatitis, lipoat-
rophy, and hepatic steatosis. Less commonly, lactic acidosis may
occur, which can be fatal. NRTI treatment should be suspended
in the setting of rapidly rising aminotransferase levels, progressive
hepatomegaly, or metabolic acidosis of unknown cause. Lipoat-
rophy and insulin resistance may occur most frequently with use
of the thymidine analogs stavudine and zidovudine, and least
frequently with use of tenofovir, lamivudine, emtricitabine, and
abacavir.
ABACAVIR
Abacavir is a guanosine analog that is well absorbed following oral
administration (83%) and is unaffected by food. The serum half-
life is 1.5 hours. The drug undergoes hepatic glucuronidation and
carboxylation. Dosage reduction is recommended in mild hepatic
impairment; no data are available for patients with moderate or
severe liver disease. Since the drug is metabolized by alcohol dehy-
drogenase, serum levels of abacavir may be increased with concur-
rent alcohol (ie, ethanol) ingestion. Cerebrospinal fluid levels are
approximately one-third those of plasma. Abacavir is one of the
NRTI agents recommended for use in pregnancy (Table 49–5).
Hypersensitivity reactions, occasionally fatal, have been
reported in up to 8% of patients receiving abacavir and may be
more severe in association with once-daily dosing. Symptoms,
which generally occur within the first 6 weeks of therapy, include
fever, fatigue, nausea, vomiting, diarrhea, and abdominal pain.
Dyspnea, pharyngitis, and cough, and elevations in serum ami-
notransferase or creatine kinase levels may also be present, with
skin rash in ~50% of patients. Rechallenge is contraindicated.
Screening for HLA-B*5701 before initiation of abacavir therapy is
important to identify patients with an increased risk for abacavir-
associated hypersensitivity reaction (see Table 5–4). Although the
positive predictive value of this test is only about 50%, it has a
negative predictive value approaching 100%.
Rash occurs in approximately 5% of patients, typically in
the first 6 weeks of treatment. Less frequent adverse events are
fever, nausea, vomiting, diarrhea, headache, dyspnea, fatigue,
and pancreatitis. In some studies but not in others, abacavir has
been associated with an increased risk of myocardial infarction.
The class effects of mitochondrial toxicity and disorders of lipid
metabolism seem to be less common with abacavir than with
other nucleoside analogs.
 TABLE 49–3  Currently available antiretroviral agents.
Administration Characteristic Adverse
Agent Class of Agent Recommended Adult Dosage Recommendation Effects Comments
1
Abacavir NRTI 300 mg bid or 600 mg qd Test to rule out the presence Rash, hypersensitivity Avoid alcohol.
of the HLA-B5701 allele prior reaction, nausea;
to initiation of therapy. possible increase in
myocardial infarction
Atazanavir PI2 400 mg qd or 300 mg qd with ritonavir Take with food. Avoid Nausea, rash, myalgia, See footnote 4. Avoid elvitegravir/
100 mg qd or cobicistat 150 mg qd; adjust concomitant antacids. indirect hyperbilirubinemia, cobicistat, etravirine, fosamprenavir,
dose in hepatic insufficiency Separate dosing acid- diarrhea, ↑ liver enzymes, nevirapine, tipranavir. Avoid in severe
reducing agents by ≥10 h. prolonged PR interval hepatic insufficiency. The oral powder
contains phenylalanine.
Darunavir PI2 Treatment-naïve: 800 mg qd with ritonavir Take with food. Diarrhea, headache, nausea, See footnote 4. Avoid elvitegravir/
100 mg qd or cobicistat 150 mg qd rash, hyperlipidemia, ↑ liver cobicistat and simeprevir. Avoid in
enzymes, ↑ serum amylase patients with sulfa allergy.
Treatment-experienced: 600 mg bid with
ritonavir 100 mg bid
Delavirdine NNRTI 400 mg tid Separate dosing from ddI or Rash, ↑ liver enzymes, head- See footnote 4. Avoid concurrent
antacids by ≥1 h. ache, nausea, diarrhea fosamprenavir. Teratogenic in rats.
Didanosine NRTI1 Tablets, 400 mg qd or 200 mg bid3 Take on an empty stomach. Peripheral neuropathy, pan- Avoid concurrent neuropathic drugs (eg,
(ddI) adjusted for weight creatitis, diarrhea. stavudine, zalcitabine, isoniazid), ribavirin,
or allopurinol. Chewable tablets contain
Buffered powder, 250 mg bid3 phenylalanine.
Dolutegravir INSTI INSTI-naïve: 50 mg qd Separate dosing from antac- Insomnia, headache, Avoid carbamazepine, dofetilide, nevirapine,
ids and polyvalent cations hypersensitivity reaction, phenobarbital, phenytoin.
If co-administered with efavirenz, fosam- by ≥2 h. ↑ liver enzymes
prenavir/ritonavir, tipranavir/ritonavir, or
rifampin or if certain INSTI mutations: 50
mg bid
Efavirenz NNRTI 600 mg qd Take on an empty stomach, Neuropsychiatric symptoms, See footnote 4. Avoid elvitegravir/
at bedtime. rash, ↑ liver enzymes, head- cobicistat, etravirine, indinavir, simeprevir.
ache, nausea Teratogenic in primates.
Elvitegravir INSTI Treatment-naïve: 150 mg qd with cobici- Take with food. Separate dos- Diarrhea, rash, ↑ liver See footnote 4. Avoid efavirenz and
stat 150, emtricitabine 200, and tenofovir ing from antacids by ≥2 h. enzymes nevirapine.
Treatment-experienced: 85 mg–150 mg qd
with a protease inhibitor
Emtricitabine NRTI1 200 mg qd3   Headache, diarrhea, nausea, Avoid concurrent lamivudine.
rash, hyperpigmentation

(continued)

871
 TABLE 49–3  Currently available antiretroviral agents. (Continued)

872 
Administration Characteristic Adverse
Agent Class of Agent Recommended Adult Dosage Recommendation Effects Comments

Enfuvirtide Fusion inhibitor 90 mg subcutaneously bid   Injection site reactions,  

hypersensitivity reaction,
insomnia, headache,
dizziness, nausea, eosinophilia;
possible increased bacterial
pneumonia
Etravirine NNRTI 200 mg bid Take with food. Rash, nausea, diarrhea See footnote 4. Avoid atazanavir, efavirenz,
elvitegravir/cobicistat, fosamprenavir,
indinavir, tipranavir.
Fosamprenavir PI2 1400 mg bid or 700 mg bid with ritonavir   Rash, diarrhea, nausea, head- See footnote 4. Avoid elvitegravir/
100 mg bid or 1400 mg daily with ritonavir ache, ↑ liver enzymes cobicistat, etravirine, lopinavir/ritonavir,
100–200 mg qd; adjust dose in hepatic nevirapine. Avoid in patients with sulfa
insufficiency allergy or severe hepatic insufficiency.
Avoid cimetidine, disulfiram, metronidazole,
vitamin E, ritonavir oral solution, and
alcohol with the oral solution.
Indinavir PI2 800 mg tid or 800 mg bid with ritonavir Best on an empty stomach. Nephrolithiasis, nausea, See footnote 4. Avoid efavirenz and
100–200 mg bid; adjust dose in cirrhosis Drink at least 48 oz liquid indirect hyperbilirubinemia, etravirine.
daily. Separate dosing from headache, diarrhea; pos-
ddI by ≥1 h. sible increase in myocardial
infarction
Lamivudine NRTI1 150 mg bid or 300 mg qd3   Nausea, headache, dizziness, Do not administer with emtricitabine or
fatigue zalcitabine.
Lopinavir/ PI/PI2 400/100 mg bid or 800/200 mg qd Separate dosing from ddI Diarrhea, nausea, hyper- See footnote 4. Avoid darunavir, elvitegravir/
ritonavir by 1 h. triglyceridemia, ↑ liver cobicistat, fosamprenavir, tipranavir. Avoid
enzymes; possible increase in disulfiram and metronidazole with oral
myocardial infarction solution.
Maraviroc CCR5 inhibitor 300 mg bid; 150 bid with CYP3A inhibitors;   Cough, muscle pain, diarrhea, See footnote 4. Do not administer in
600 mg bid with CYP3A inducers sleep disturbance, ↑ liver patients with severe renal dysfunction.
enzymes; possible increase in
myocardial infarction
Nelfinavir PI2 750 mg tid or 1250 mg bid Take with food. Diarrhea, nausea, flatulence See footnote 4. The oral powder contains
phenylalanine.
Nevirapine NNRTI 200 mg bid Dose-escalate from 200 mg Rash, hepatitis (occasionally See footnote 4. Avoid atazanavir, dolute-
daily over 14 days. fulminant), nausea, headache gravir, elvitegravir/cobicistat, fosampre-
navir. Contraindicated with moderate or
severe hepatic impairment.
Raltegravir INSTI 400 mg bid   Nausea, headache, fatigue, The chewable tablets contain
muscle aches, ↑ amylase phenylalanine.
levels, ↑ liver enzymes
Rilpivirine NNRTI 25 mg qd Take with food. Separate Headache, insomnia, depres- See footnote 4.
dosing from antacids or H2 sion, rash, ↑ liver enzymes
blockers by ≥4 h.
 Rilpivirine PI2 1000 mg bid with ritonavir 100 mg bid Take within 2 h of a full meal. Nausea, diarrhea, abdominal See footnote 4. Avoid darunavir, garlic
pain, dyspepsia, rash capsules, tipranavir and drugs that
increase the QT interval. Avoid in severe
hepatic insufficiency.
Stavudine NRTI1 30–40 mg bid, depending on weight3   Peripheral neuropathy, pan- Avoid zidovudine and neuropathic drugs
creatitis, rapidly progressive (eg, ddI, zalcitabine, isoniazid).
ascending neuromuscular
weakness (rare)
Tenofovir NRTI1 10 mg qd with emtricitabine plus   Gastrointestinal symptoms, Avoid inducers of p-glycoprotein
alafenamide elvitegravir/cobicistat; 25 mg qd with headache, ↑ creatinine, (rifampin, rifabutin, phenytoin,
emtricitabine ± rilpivirine proteinuria phenobarbital, St John’s Wort, tipranavir/
ritonavir). Also avoid in severe renal
insufficiency.
Tenofovir diso- NRTI1 300 mg qd3   Nausea, diarrhea, vomiting, Avoid atazanavir, didanosine, probenecid.
proxil fumarate flatulence, headache, renal
insufficiency
Tipranavir PI2 500 mg bid with ritonavir 200 mg bid Take with food. Separate Diarrhea, nausea, vomiting, See footnote 4. Avoid concurrent ata-
from ddI by ≥2 h. Avoid abdominal pain, rash, ↑ liver zanavir, elvitegravir/cobicistat, etravirine,
antacids. enzymes, hyperlipidemia fosamprenavir, lopinavir/ritonavir,
saquinavir. Avoid in patients with severe
hepatic insufficiency, who are at risk for
bleeding, or with sulfa allergy. Avoid vita-
min E with the oral solution.
Zidovudine NRTI1 200 mg tid or 300 mg bid3   Macrocytic anemia, neutro- Avoid concurrent stavudine and
penia, nausea, headache, myelosuppressive drugs (eg, ganciclovir,
insomnia, myopathy ribavirin).
1
All NRTI agents carry the risk of lactic acidosis with hepatic steatosis as a potential adverse event.
2
All PI agents carry the risk of hyperlipidemia, fat maldistribution, hyperglycemia, and insulin resistance as potential adverse events.
3
Adjust dose in renal insufficiency.
4
Because of altered systemic exposures, concurrent drugs that interact with the CYP3A4 system should be used with caution, including alfuzosin, amiodarone, aprepitant, artemether/lumefantrine, astemizole, atovaquone, benzodi-
azepines (diazepam, midazolam, triazolam), bexarotene, bepridil, bosentan, bupropion, calcium channel blockers (diltiazem, felodipine, nifedipine, nimodipine, verapamil), carbamazepine, ceritinib , cimetidine, cisapride, clopidogrel,
colchicine, conivaptan, corticosteroids, cyclosporine, dabrafenib, dapsone, desipramine, direct Factor Xa inhibitors (apixaban, rivaroxaban), disopyramide, dofetilide, dronedarone, enzalutamide, ergot alkaloid derivatives, ethinyl
estradiol/norethindrone acetate, flecainide, fluticasone, gestodene, idelalisib, irinotecan, ivacaftor, levodopa, lidocaine, lumacaftor, lurasidone, macrolide agents (clarithromycin, telithromycin), methadone, mitotane, nafcillin, PDE5
inhibitors, phenobarbital, phenytoin, pimozide, primidone, propafenone, protein pump inhibitors, quinidine, ranolazine, rifabutin, salmeterol, spironolactone, statin agents, St. John’s wort, tacrolimus, triazole antifungal agents (itra-
conazole ketoconazole, posaconazole, voriconazole), terfenadine, and warfarin.
INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; PI, protease inhibitor.

873
874    SECTION VIII  Chemotherapeutic Drugs

gp41
gp120

Blocked by CCR5
receptor antagonists

Host cell membrane

Binding

Chemokine receptors

CD4 Fusion and

Blocked by uncoating
fusion inhibitors

RNA

Blocked by Reverse
NRTIs, NNRTIs transcription

DNA
Integration
Blocked by integrase inhibitors

Transcription Translation

RNA Virion
assembly
Nucleus
Budding and
maturation
Blocked by protease
inhibitors

FIGURE 49–3  Life cycle of HIV. Binding of viral glycoproteins to host cell CD4 and chemokine receptors leads to fusion of the viral and host
cell membranes via gp41 and entry of the virion into the cell. After uncoating, reverse transcription copies the single-stranded HIV RNA genome
into double-stranded DNA, which is integrated into the host cell genome. Gene transcription by host cell enzymes produces messenger RNA,
which is translated into proteins that assemble into immature noninfectious virions that bud from the host cell membrane. Maturation into fully
infectious virions is through proteolytic cleavage. NNRTIs, nonnucleoside reverse transcriptase inhibitors; NRTIs, nucleoside/nucleotide reverse
transcriptase inhibitors.

DIDANOSINE The drug is eliminated by both cellular metabolism and renal

Didanosine (ddI) is a synthetic analog of deoxyadenosine. Oral
bioavailability is approximately 40%. Buffered or enteric-coated
formulations are necessary to prevent inactivation by gastric acid.
Cerebrospinal fluid concentrations of the drug are approximately
20% of serum concentrations. Serum half-life is 1.5 hours, but the
intracellular half-life of the activated compound is 20–24 hours.
excretion.
The major clinical toxicities associated with didanosine therapy
are peripheral distal sensory neuropathy and dose-dependent pan-
creatitis. Therefore, co-administration with drugs or conditions that
increase the risk of either (eg, alcohol abuse, hypertriglyceridemia,
pregnancy, zalcitabine, stavudine, isoniazid, vincristine, ribavirin,
and hydroxyurea), should be avoided. Other reported adverse effects

include diarrhea (particularly with the buffered formulation), hepa-
titis, esophageal ulceration, cardiomyopathy, central nervous system
toxicity (headache, irritability, insomnia), and hypertriglyceridemia.
Concurrent stavudine increases the risk of lactic acidosis. Reports of
retinal changes and optic neuritis in patients receiving didanosine,
particularly in adults receiving high doses and in children, mandate
periodic retinal examinations.
Increased levels of didanosine when administered with tenofo-
vir necessitate dose reduction. Concurrent allopurinol or ribavirin
is contraindicated. The buffer in didanosine tablets interferes with
the absorption of delavirdine and nelfinavir, necessitating separa-
tion in time. The chewable tablets contain phenylalanine, which
can be harmful to patients with phenylketonuria.
EMTRICITABINE
Emtricitabine (FTC) is a fluorinated analog of lamivudine with
a long intracellular half-life (>24 hours), allowing for once-daily
dosing. Oral bioavailability of the capsules is 93% and is unaf-
fected by food, but penetration into the cerebrospinal fluid is low.
Elimination is by both glomerular filtration and active tubular
secretion. The serum half-life is about 10 hours.
Emtricitabine is one of the NRTI agents recommended for
use in pregnancy (Table 49–5). The combination of tenofovir
and emtricitabine is recommended as pre-exposure prophylaxis to
reduce HIV acquisition in high-risk persons.
Both emtricitabine and lamivudine may select for the M184V/I
mutation and therefore should not be used together.
The most common adverse effects observed in patients
receiving emtricitabine are headache, diarrhea, nausea, and rash.
Hyperpigmentation of the palms or soles may be observed (~ 3%),
particularly in African Americans (up to 13%). Clinically signifi-
cant drug-drug interactions involving emtricitabine have not been
identified. Due to its activity against HBV, exacerbation of HBV
may occur if therapy is interrupted or discontinued in patients
co-infected with HIV.
LAMIVUDINE
Lamivudine (3TC) is a cytosine analog with in vitro activity
against both HIV-1 and HBV.
Oral bioavailability exceeds 80% and is not food-dependent.
The mean cerebrospinal fluid:plasma ratio of lamivudine is
0.1–0.2. Serum half-life is 2.5 hours, whereas the intracellular
half-life of the triphosphorylated compound is 11–14 hours.
Lamivudine is predominantly eliminated in the urine by active
organic cation secretion.
Lamivudine is one of the recommended NRTI agents for use
in pregnant women (Table 49–5).
Adverse effects are uncommon but include headache, dizziness,
insomnia, fatigue, dry mouth, and gastrointestinal discomfort.
Due to its activity against HBV, exacerbation of HBV may occur if
therapy is interrupted or discontinued in patients co-infected with
HIV and HBV. Since both emtricitabine and lamivudine may
select for the M184V/I mutation, these agents should not be used
CHAPTER 49  Antiviral Agents    875
together. Levels of lamivudine may increase when administered
with trimethoprim-sulfamethoxazole. Lamivudine and zalcitabine
may inhibit the intracellular phosphorylation of one another;
therefore, their concurrent use should be avoided if possible.
STAVUDINE
The thymidine analog stavudine (d4T) has high oral bioavail-
ability (86%) that is not food-dependent. The serum half-life is
1.1 hours, the intracellular half-life is 3.0–3.5 hours, and mean
cerebrospinal fluid concentrations are 55% of those of plasma.
Excretion is by active tubular secretion and glomerular filtration.
The major toxicity is a dose-related peripheral sensory neu-
ropathy; incidence may be increased with concomitant neurotoxic
drugs such as didanosine, vincristine, isoniazid, or ribavirin, or
in patients with advanced immunosuppression. Other potential
adverse effects are pancreatitis, arthralgias, and elevation in serum
aminotransferases. Caution is advised in patients with liver dys-
function. A rare adverse effect is a rapidly progressive ascending
neuromuscular weakness. Lactic acidosis with hepatic steatosis, as
well as lipodystrophy, appear to occur more frequently in patients
receiving stavudine than in those receiving other NRTI agents.
Stavudine should not be administered with didanosine due to
increased risk of both lactic acidosis and pancreatitis. This com-
bination has been implicated in several deaths in HIV-infected
pregnant women. Since zidovudine may reduce the intracellular
phosphorylation of stavudine, these two drugs should not be used
together.
TENOFOVIR DISOPROXIL FUMARATE
Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide)
analog of adenosine with activity against HIV and HBV. Like
the nucleoside analogs, tenofovir competitively inhibits HIV
reverse transcriptase and causes chain termination after incorpo-
ration into DNA. However, only two rather than three intracel-
lular phosphorylations are required for active inhibition of DNA
synthesis.
Tenofovir disoproxil fumarate is a water-soluble prodrug of
active tenofovir. The oral bioavailability increases from 25% in
the fasted state to 39% after a high-fat meal. The prolonged serum
(12–17 hours) and intracellular half-lives allow once-daily dos-
ing. Elimination occurs by both glomerular filtration and active
tubular secretion, and dosage adjustment in patients with renal
insufficiency is recommended.
Tenofovir disoproxil fumarate is one of the NRTI agents rec-
ommended for use in pregnancy (Table 49–5). The combination
of tenofovir and emtricitabine is recommended as pre-exposure
prophylaxis to reduce HIV acquisition in high-risk persons.
Gastrointestinal complaints (eg, nausea, diarrhea, vomiting,
flatulence) are the most common adverse effects but rarely require
discontinuation. Since tenofovir is formulated with lactose, these
may occur more frequently in patients with lactose intolerance.
Cumulative loss of renal function has been observed, possibly
increased with concurrent use of boosted PI regimens. Acute renal
876    SECTION VIII  Chemotherapeutic Drugs
failure and Fanconi’s syndrome have also been reported. For this
reason, tenofovir should be used with caution in patients at risk
for renal dysfunction. Serum creatinine levels should be monitored
during therapy and tenofovir discontinued for new proteinuria,
glycosuria, or calculated glomerular filtration rate <30 mL/min.
Tenofovir-associated proximal renal tubulopathy causes excessive
renal phosphate and calcium losses and 1-hydroxylation defects
of vitamin D; loss of bone mineral density and osteomalacia have
been reported. Tenofovir may compete with other drugs that are
actively secreted by the kidneys, such as cidofovir, acyclovir, and
ganciclovir. Concurrent use of probenecid is contraindicated.
Tenofovir levels may increase, and levels of telaprevir decrease,
when these agents are co-administered. Due to its activity against
HBV, exacerbation of HBV may occur if therapy is interrupted or
discontinued in patients co-infected with HIV and HBV.
TENOFOVIR ALAFENAMIDE
Tenofovir alafenamide is a phosphonoamidate prodrug of
tenofovir that is currently available in co-formulation with
other antiretroviral agents (with emtricitabine, with elvitegra-
vir plus cobicistat plus emtricitabine, and with rilpivirine plus
emtricitabine). Plasma levels of active tenofovir in plasma are
approximately 90% lower with tenofovir alafenamide than with
tenofovir disoproxil, since metabolism occurs in lymphocytes
and macrophages (as well as hepatocytes and some other cells)
rather than blood.
Tenofovir alafenamide is a substrate of P-glycoprotein, and
levels of tenofovir can be affected by inhibitors or inducers of
P-glycoprotein. Ritonavir and cobicistat can increase plasma con-
centrations of tenofovir, while darunavir can decrease tenofovir
concentrations.
Tenofovir alafenamide appears to have less renal and bone tox-
icity than tenofovir disoproxil fumarate; however this is still under
investigation. It does not require dose adjustment in patients with
creatinine clearance >30 mL/min.
Tenofovir alafenamide is a substrate of P-glycoprotein, and
levels of tenofovir can be affected by inhibitors or inducers of
P-glycoprotein. Ritonavir and cobicistat can increase plasma con-
centrations of tenofovir, while darunavir can decrease tenofovir
concentrations.
Adverse effects appear to be uncommon but may include
gastrointestinal symptoms or headache. Tenofovir alafenamide is
active against hepatitis B and has been approved for treatment of
HBV infection.
ZIDOVUDINE
Zidovudine (azidothymidine; AZT) is a deoxythymidine analog
that is well absorbed (63%) and distributed to most body tissues
and fluids, including the cerebrospinal fluid, where drug levels
are 60–65% of those in serum. Although the serum half-life
averages 1 hour, the intracellular half-life of the phosphorylated
compound is 3–4 hours, allowing twice-daily dosing. Zidovudine
is eliminated primarily by renal excretion following glucuronida-
tion in the liver.
Zidovudine was the first antiretroviral agent to be approved
and has been well studied. Studies evaluating the use of zidovu-
dine during pregnancy, labor, and postpartum showed significant
reductions in the rate of vertical transmission, and zidovudine
remains one of the NRTI agents recommended for use in preg-
nant women (Table 49–5). Zidovudine is also recommended as
an option for postexposure prophylaxis in individuals exposed to
HIV.
The most common adverse effects of zidovudine are macro-
cytic anemia (1–4%) and neutropenia (2–8%). Gastrointestinal
intolerance, headaches, and insomnia may occur but tend to
resolve during therapy. A symptomatic myopathy may occur
with prolonged use. Lipoatrophy appears to be more common in
patients receiving zidovudine or other thymidine analogs. High
doses can cause anxiety, confusion, and tremulousness.
Induction or inhibition of glucuronidation may alter serum
levels of zidovudine when co-administered with atovaquone,
lopinavir/ritonavir, probenecid, or valproic acid. Concurrent
stavudine is contraindicated due to competitive inhibition of
intracellular phosphorylation.
NONNUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS
(NNRTIs)
The NNRTIs bind directly to HIV-1 reverse transcriptase
(Figure 49–3), resulting in allosteric inhibition of RNA- and
DNA-dependent DNA polymerase activity. The binding site of
NNRTIs is near to but distinct from that of NRTIs. Unlike the
NRTI agents, NNRTIs neither compete with nucleoside triphos-
phates nor require phosphorylation to be active.
The second-generation NNRTIs (etravirine, rilpivirine) have
higher potency, longer half-lives and reduced side-effect profiles
compared with older NNRTIs (delavirdine, efavirenz, nevirapine).
Baseline genotypic testing is recommended prior to initiating
NNRTI treatment because primary resistance rates range from
approximately 2% to 8%. NNRTI resistance occurs rapidly with
monotherapy and can result from a single mutation. The K103N
and Y181C mutations confer resistance to the first-generation
NNRTIs, but not to etravirine or rilpivirine. Other mutations (eg,
L100I, Y188C, G190A) may also confer cross-resistance among
the NNRTI class. However, there is no cross-resistance between
the NNRTIs and the NRTIs; in fact, some nucleoside-resistant
viruses display hypersusceptibility to NNRTIs.
As a class, NNRTI agents tend to be associated with varying
levels of gastrointestinal intolerance and skin rash, the latter of
which may infrequently be serious (eg, Stevens-Johnson syn-
drome). A further limitation to use of NNRTI agents as a compo-
nent of antiretroviral therapy is their metabolism by the CYP450
system, leading to innumerable potential drug-drug interactions
(Tables 49–3 and 49–4). All NNRTI agents are substrates for
CYP3A4 and can act as inducers (nevirapine), inhibitors (dela-
virdine), or mixed inducers and inhibitors (efavirenz, etravirine).
 CHAPTER 49  Antiviral Agents    877

TABLE 49–4  Clinically significant drug-drug interactions pertaining to two-drug antiretroviral combinations.1
Agent Drugs That Increase Its Serum Levels Drugs That Decrease Its Serum Levels

Atazanavir Ritonavir Didanosine, efavirenz, elvitegravir/cobicistat, etravirine,

fosamprenavir, nevirapine, stavudine, tenofovir, tipranavir
Darunavir Indinavir Efavirenz, lopinavir/ritonavir, saquinavir
2
Delavirdine   Didanosine, fosamprenavir
Didanosine Tenofovir Atazanavir, ritonavir
Dolutegravir   Efavirenz, etravirine, nevirapine
Efavirenz2 Darunavir  
3
Elvitegravir Ritonavir Efavirenz, nevirapine
Etravirine Atazanavir, delavirdine, indinavir, lopinavir/ritonavir Efavirenz, nevirapine, ritonavir, saquinavir, tipranavir
Fosamprenavir Atazanavir, delavirdine, etravirine, ritonavir Didanosine, efavirenz, lopinavir/ritonavir, maraviroc, nevirapine,
tipranavir
Indinavir Darunavir, delavirdine, nelfinavir, ritonavir Didanosine, efavirenz, etravirine, nevirapine
Lopinavir/ritonavir Darunavir Didanosine, efavirenz, fosamprenavir, nelfinavir, nevirapine,
tipranavir
Maraviroc Atazanavir, darunavir, lopinavir/ritonavir, nevirapine, Efavirenz, etravirine, tipranavir
saquinavir, ritonavir
Nelfinavir Delavirdine, indinavir, ritonavir, saquinavir  
Nevirapine2 Fosamprenavir  
Raltegravir Atazanavir Etravirine, tipranavir
Rilpivirine2 Darunavir, lopinavir/ritonavir  
Saquinavir Atazanavir, delavirdine, indinavir, lopinavir/ritonavir, Efavirenz, etravirine, nevirapine, tipranavir
nelfinavir, ritonavir
Tenofovir alafenamide Ritonavir Darunavir
Tenofovir disoproxil Atazanavir  
fumarate
Tipranavir   Efavirenz
1
Dose adjustment may be necessary if co-administered.
2
NNRTI-NNRTI drug-drug interactions are not listed.
3
Drug-drug interactions are rare with elvitegravir as a single agent but multiple if co-administered with either cobicistat or ritonavir.

Given the large number of non-HIV medications that are also
metabolized by this pathway (see Chapter 4), drug-drug interac-
tions must be expected and looked for; dosage adjustments are
frequently required and some combinations are contraindicated.
DELAVIRDINE
Delavirdine has an oral bioavailability of about 85%, but this
is reduced by antacids or H2-blockers. It is extensively bound
(~98%) to plasma proteins and has correspondingly low cerebro-
spinal fluid levels. Serum half-life is approximately 6 hours.
Skin rash occurs in up to 38% of patients receiving delavir-
dine; it typically occurs during the first 1–3 weeks of therapy
and does not preclude rechallenge. However, severe rash such
as erythema multiforme and Stevens-Johnson syndrome have
rarely been reported. Other possible adverse effects are headache,
fatigue, nausea, diarrhea, and increased serum aminotransferase
levels. Delavirdine has been shown to be teratogenic in rats, caus-
ing ventricular septal defects and other malformations at dosages
not unlike those achieved in humans. Thus, pregnancy should be
avoided when taking delavirdine.
Delavirdine is extensively metabolized by CYP3A and CYP2D6
enzymes. Therefore, there are numerous potential drug-drug
interactions to consider (Tables 49–3 and 49–4). The concur-
rent use of delavirdine with fosamprenavir is not recommended
because of bidirectional interactions. Co-administration of dela-
virdine with indinavir or saquinavir prolongs the elimination
half-life of the latter agents, thus allowing them to be dosed twice
rather than thrice daily.
EFAVIRENZ
Efavirenz can be given once daily because of its long half-life
(40–55 hours). It is moderately well absorbed following oral
administration (45%). Since toxicity may increase owing to
increased bioavailability after a high-fat meal, efavirenz should be
taken on an empty stomach. Efavirenz is principally metabolized
by CYP3A4 and CYP2B6 to inactive hydroxylated metabolites;
878    SECTION VIII  Chemotherapeutic Drugs

the remainder is eliminated in the feces as unchanged drug. It is cobicistat, fosamprenavir, indinavir, and tipranavir. In addition,
highly bound to albumin (~ 99%), and cerebrospinal fluid levels co-administration with clarithromycin or with the antimalarial
range from 0.3% to 1.2% of plasma levels. agent artemether/lumefantrine should be avoided if possible.
The principal adverse effects of efavirenz involve the central
nervous system. Dizziness, drowsiness, insomnia, nightmares,
and headache tend to diminish with continued therapy; dosing at NEVIRAPINE
bedtime may also be helpful. Psychiatric symptoms such as depres-
The oral bioavailability of nevirapine is excellent (>90%) and is
sion, mania, and psychosis have been observed in the weeks fol-
not food-dependent. The drug is highly lipophilic and achieves
lowing initiation and may necessitate discontinuation. Skin rash
cerebrospinal fluid levels that are 45% of those in plasma. Serum
has been reported early in therapy in up to 28% of patients; the
half-life is 25–30 hours. It is extensively metabolized by the
rash is usually mild to moderate in severity and typically resolves
CYP3A isoform to hydroxylated metabolites and then excreted,
despite continuation. Rarely, rash has been severe or life-threat-
primarily in the urine.
ening. Other potential adverse reactions are nausea, vomiting,
A single dose of nevirapine (200 mg) is effective in the pre-
diarrhea, crystalluria, elevated liver enzymes, and an increase in
vention of transmission of HIV from mother to newborn when
total serum cholesterol by 10–20%. High rates of fetal abnormali-
administered at the onset of labor and followed by a 2-mg/kg dose
ties, such as neural tube defects, occurred in pregnant monkeys
to the neonate within 3 days of delivery. However, nevirapine is no
exposed to efavirenz in doses roughly equivalent to the human
longer recommended for use in pregnancy due to the potential for
dosage; several cases of congenital anomalies have been reported
adverse events and low barrier to resistance.
in humans. Efavirenz is one of the NNRTI agents recommended
Rash, usually a maculopapular eruption that spares the palms
for use in pregnancy (Table 49–5), but should be initiated after
and soles, occurs in up to 20% of patients, usually in the first
the first 8 weeks due to birth defects observed in a primate study.
4–6 weeks of therapy. Although typically mild and self-limited,
As both an inducer and an inhibitor of CYP3A4, efavirenz
rash is dose-limiting in about 7% of patients. Women appear to
induces its own metabolism and interacts with the metabolism
have an increased incidence of rash. When initiating therapy, grad-
of many other drugs (Tables 49–3 and 49–4). Co-administration
ual dose escalation over 14 days is recommended to decrease the
with boceprevir, elvitegravir/cobicistat, etravirine, indinavir, itra-
incidence of rash. Severe and life-threatening skin rashes, includ-
conazole, ketoconazole, and simeprevir is contraindicated. Levels
ing Stevens-Johnson syndrome and toxic epidermal necrolysis, are
of efavirenz may be reduced by concomitant nevirapine. Levels of
rare but are more common than with other NNRTIs. Nevirapine
lopinavir/ritonavir, maraviroc, methadone, and telaprevir may be
therapy should be immediately discontinued in patients with
reduced when administered with efavirenz.
severe rash and in those with accompanying constitutional symp-
toms; since rash may accompany hepatotoxicity, liver tests should
be assessed. Symptomatic liver toxicity may occur in up to 4% of
ETRAVIRINE patients, may be severe, and is more frequent in those with higher
pretherapy CD4 cell counts (ie, >250 cells/mm3 in women and
Etravirine, a diarylpyrimidine, was designed to be effective against
>400 cells/mm3 in men), in women, and in those with HBV or
strains of HIV that had developed resistance to first-generation
HCV co-infection. Fulminant, life-threatening hepatitis has been
NNRTIs due to mutations such as K103N and Y181C. Although
reported, typically within the first 18 weeks of therapy. Other
etravirine has a higher genetic barrier to resistance than the other
adverse effects include fever, nausea, headache, and somnolence.
NNRTIs, mutations selected by etravirine usually are associated
Nevirapine is a moderate inducer of CYP3A metabolism,
with resistance to efavirenz, nevirapine, and delavirdine.
resulting in numerous potential drug-drug interactions (see
Etravirine should be taken with a meal to increase systemic
Tables 49–3 and 49–4). Co-administration of artemether/lume-
exposure. It is highly protein-bound and is primarily metabolized
fantrine, atazanavir, dolutegravir, elvitegravir/cobicistat, fosampre-
by the liver. Mean terminal half-life is ~41 hours.
navir, ketoconazole, and rifampin should be avoided.
The most common adverse effects of etravirine are rash, nau-
sea, and diarrhea. The rash is typically mild and usually resolves
after 1–2 weeks without discontinuation of therapy. Rarely, rash RILPIVIRINE
has been severe or life-threatening. Laboratory abnormalities
include elevations in serum cholesterol, triglyceride, glucose, and Rilpivirine, a diarylpyrimidine, must be administered with a
hepatic aminotransferase levels. Aminotransferase elevations are meal (preferably high fat or >400 kcal). Its oral bioavailability is
more common in patients with HBV or HCV co-infection. dependent on an acid gastric environment for optimal absorption;
Etravirine is a substrate as well as an inducer of CYP3A4 and thus antacids and H2-receptor antagonists should be separated in
an inhibitor of CYP2C9 and CYP2C19 and thus has potential time and proton pump inhibitors are contraindicated. The drug
for numerous drug-drug interactions (Tables 49–3 and 49–4). is highly protein bound and the terminal elimination half-life is
Some of the interactions are difficult to predict. For example, 50 hours.
etravirine may decrease itraconazole and ketoconazole concentra- Rilpivirine is one of the NNRTI agents recommended for use
tions but increase voriconazole concentrations. Etravirine should in pregnancy (Table 49–5). Rilpivirine is primarily metabolized
not be given with atazanavir, clopidogrel, efavirenz, elvitegravir/ by CYP3A4, and drugs that induce or inhibit CYP3A4 may thus

TABLE 49–5  The use of antiretroviral agents in
pregnancy.
Recommended Agents Alternate Agents
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
 Abacavir, emtricitabine, lamivudine,
tenofovir disoproxil fumarate, zidovudine
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
 Efavirenz Rilpivirine
Protease inhibitors (PIs)
  Atazanavir/ritonavir, darunavir/ritonavir Lopinavir/ritonavir
Integrase inhibitors
 Raltegravir  
affect the clearance of rilpivirine (see Table 49–3). However, clini-
cally significant drug-drug interactions with other antiretroviral
agents have not been identified to date.
The most common adverse effects associated with rilpivirine
therapy are rash, depression, headache, insomnia, and increased
serum aminotransferases. Increased serum cholesterol, and fat
redistribution syndrome have also been reported. Higher doses
have been associated with QTc prolongation. Inhibition of renal
tubular secretion of creatinine causes a reversible elevation in
serum creatinine, but glomerular filtration rate is not affected.
PROTEASE INHIBITORS (PIs)
During the later stages of the HIV growth cycle, the gag and
gag-pol gene products are translated into polyproteins, and
these become immature budding particles. The HIV protease is
responsible for cleaving these precursor molecules to produce the
final structural proteins of the mature virion core. By preventing
post-translational cleavage of the Gag-Pol polyprotein, protease
inhibitors (PIs) prevent the processing of viral proteins into func-
tional conformations, resulting in the production of immature,
noninfectious viral particles (Figure 49–3). Unlike the NRTIs, PIs
do not need intracellular activation.
Specific genotypic alterations that confer phenotypic resistance
are fairly common with these agents, thus contraindicating mono-
therapy. Some of the most common mutations conferring broad
resistance to PIs are substitutions at the 10, 46, 54, 82, 84, and 90
codons; the number of mutations may predict the level of pheno-
typic resistance. The I50L substitution emerging during atazanavir
therapy has been associated with increased susceptibility to other
PIs. Darunavir and tipranavir appear to have improved virologic
activity in patients harboring HIV-1 resistant to other PIs.
As a class, PIs are associated with gastrointestinal intolerance,
which may be dose-limiting, and lipodystrophy, which includes
both metabolic (hyperglycemia, hyperlipidemia) and morphologic
(lipoatrophy, fat deposition) derangements. A syndrome of redis-
tribution and accumulation of body fat that results in central obe-
sity, dorsocervical fat enlargement (buffalo hump), peripheral and
facial wasting, breast enlargement, and a cushingoid appearance
has been observed, least commonly with atazanavir. PIs may be
CHAPTER 49  Antiviral Agents    879
associated with cardiac conduction abnormalities, including PR
and QT interval prolongation. A baseline electrocardiogram and
avoidance of other agents causing prolonged PR or QT intervals
should be considered. Abacavir, lopinavir/ritonavir, and fosam-
prenavir/ritonavir have been associated with an increased risk of
cardiovascular disease in some, but not all, studies. Drug-induced
hepatitis and rare severe hepatotoxicity have been reported to
varying degrees with all PIs; the frequency of hepatic events is
higher with tipranavir/ritonavir than with other PIs. Unconju-
gated hyperbilirubinemia may occur with atazanavir or indinavir.
Whether PI agents are associated with bone loss and osteoporosis
after long-term use is under investigation. PIs have been associated
with increased spontaneous bleeding in patients with hemophilia
A or B; an increased risk of intracranial hemorrhage has been
reported in patients receiving tipranavir/ritonavir. Darunavir,
amprenavir, fosamprenavir, and tipranavir are sulfonamides; cau-
tion should be used in patients with a history of sulfa allergy.
All of the antiretroviral PIs are extensively metabolized by
CYP3A4, with ritonavir having the most pronounced inhibitory
effect and saquinavir the least. Some PI agents, such as amprena-
vir and ritonavir, are also inducers of specific CYP isoforms. As
a result, there is enormous potential for drug-drug interactions
with other antiretroviral agents and other commonly used medi-
cations (Tables 49–3 and 49–4). Expert resources about drug-
drug interactions should be consulted, as dosage adjustments are
frequently required and some combinations are contraindicated.
It is noteworthy that the potent CYP3A4 inhibitory properties of
ritonavir are used to clinical advantage by having it “boost” the
levels of other PI agents when given in combination, thus acting
as a pharmacokinetic enhancer rather than an antiretroviral agent.
Ritonavir boosting increases drug exposure, thereby prolonging
the drug’s half-life and allowing reduction in frequency; in addi-
tion, the genetic barrier to resistance is raised.
ATAZANAVIR
Atazanavir is an azapeptide PI with a pharmacokinetic profile that
allows once-daily dosing. Atazanavir requires an acidic medium
for absorption and exhibits pH-dependent aqueous solubility;
therefore, it should be taken with meals. Separation of ingestion
from acid-reducing agents by at least 12 hours is recommended
and concurrent proton pump inhibitors are contraindicated.
Atazanavir is able to penetrate both the cerebrospinal and semi-
nal fluids. The plasma half-life is 6–7 hours, which increases to
approximately 11 hours when co-administered with ritonavir. The
primary route of elimination is biliary; atazanavir should not be
given to patients with severe hepatic insufficiency.
Boosted atazanavir is one of the recommended PI agents for
use in pregnant women (Table 49–5).
The most common adverse effects in patients receiving
atazanavir are diarrhea and nausea; vomiting, abdominal pain,
headache, and peripheral neuropathy may also occur. Skin rash,
reported in ~20% of patients, is generally mild; however severe
rash and Stevens Johnson syndrome have been reported. As with
indinavir, indirect hyperbilirubinemia with overt jaundice may
880    SECTION VIII  Chemotherapeutic Drugs
occur in approximately 10% of patients, owing to inhibition of
the UGT1A1 glucuronidation enzyme. Elevation of serum ami-
notransferases has separately been observed, usually in patients
with underlying HBV or HCV co-infection. Kidney stones,
gallstones, PR prolongation, and decreased bone mineral density
have also been reported. In contrast to the other PIs, atazanavir
does not appear to be associated with dyslipidemia or hypergly-
cemia. The oral powder contains phenylalanine, which can be
harmful to patients with phenylketonuria.
As an inhibitor of CYP3A4, CYP2C9, and UGT1A1, the
potential for drug-drug interactions with atazanavir is great
(Tables 49–3 and 49–4). Due to decreased atazanavir levels, ata-
zanavir should not be administered with bosentan, elvitegravir/
cobicistat, etravirine, fosamprenavir, nevirapine, proton pump
inhibitors, or tipranavir. Tenofovir and efavirenz should not be
co-administered with atazanavir unless ritonavir is added to boost
levels. In addition, co-administration of atazanavir with other
drugs that inhibit UGT1A1, such as irinotecan, may increase its
levels. Atovaquone and voriconazole levels may be decreased with
coadministration, and levels of maraviroc and ranolazine may be
increased.
DARUNAVIR
Darunavir must be co-administered with ritonavir or cobicistat.
Darunavir should be taken with meals to improve bioavailability.
It is highly protein-bound and primarily metabolized by the liver.
Boosted darunavir is one of the PI agents recommended for use
in pregnancy (Table 49–5).
Adverse effects include diarrhea, nausea, headache, and
increases in amylase and hepatic aminotransferase levels. Rash
occurs in 2–7% of patients and may occasionally be severe. Liver
toxicity, including severe hepatitis, has been reported, such that
liver function tests should be monitored; the risk may be higher
for persons with HBV, HCV, or other chronic liver disease.
Darunavir contains a sulfonamide moiety and may cause a hyper-
sensitivity reaction, particularly in patients with sulfa allergy.
Darunavir both inhibits and is metabolized by the CYP3A
enzyme system, conferring many possible drug-drug interac-
tions (Tables 49–3 and 49–4). In addition, the co-administered
ritonavir is a potent inhibitor of CYP3A and CYP2D6, and an
inducer of other hepatic enzyme systems. Co-administration with
elvitegravir/cobicistat or simeprevir is contraindicated due to
bidirectional drug-drug interactions. Levels of cyclophosphamide,
digoxin, and simeprevir may be increased when administered
with darunavir, and levels of paroxetine and sertraline may be
decreased.
FOSAMPRENAVIR
Fosamprenavir is a prodrug of amprenavir that is rapidly hydro-
lyzed by enzymes in the intestinal epithelium. Because of its
significantly lower daily pill burden, fosamprenavir tablets have
replaced amprenavir capsules for adults. Fosamprenavir is most
often administered in combination with low-dose ritonavir.
After hydrolysis of fosamprenavir, amprenavir is rapidly
absorbed from the gastrointestinal tract, and its prodrug can be
taken with or without food. However, high-fat meals decrease
absorption and thus should be avoided. The plasma half-life is
relatively long (7–11 hours). Amprenavir is metabolized in the
liver and should be used with caution in the setting of hepatic
insufficiency.
The most common adverse effects of fosamprenavir are
headache, nausea, diarrhea, perioral paresthesias, depression.
Fosamprenavir contains a sulfa moiety and may cause a rash in
up to 19% of patients, sometimes severe enough to warrant drug
discontinuation.
Amprenavir is both an inducer and an inhibitor of CYP3A4
(Tables 49–3 and 49–4). Co-administration of elvitegravir/cobi-
cistat, etravirine, lopinavir/ritonavir, nevirapine, posaconazole, or
ranolazine is contraindicated. The oral suspension, which contains
propylene glycol, is contraindicated in young children, pregnant
women, patients with renal or hepatic failure, and those using
metronidazole or disulfiram. Also, the oral solutions of ampre-
navir and ritonavir should not be co-administered because the
propylene glycol in one and the ethanol in the other may compete
for the same metabolic pathway, leading to accumulation of either.
Because the oral solution contains vitamin E at several times the
recommended daily dosage, supplemental vitamin E should be
avoided.
INDINAVIR
Indinavir requires an acidic environment for optimum solubil-
ity and therefore must be consumed on an empty stomach or
with a small, low-fat, low-protein meal for maximal absorption
(60–65%). The serum half-life is 1.5–2 hours, protein binding is
~60%, and the drug has a high level of cerebrospinal fluid pen-
etration (up to 76% of serum levels). Excretion is primarily fecal.
An increase in AUC by 60% and in half-life to 2.8 hours in the
setting of hepatic insufficiency necessitates dose reduction.
The most common adverse effects of indinavir are uncon-
jugated hyperbilirubinemia and nephrolithiasis due to urinary
crystallization of the drug. Nephrolithiasis can occur within days
after initiating therapy, with an estimated incidence of approxi-
mately 10%. Acute renal failure and interstitial fibrosis have also
been reported. Consumption of at least 48 ounces of water daily is
important to maintain adequate hydration, and serum creatinine
levels should be monitored. Nausea, diarrhea, sicca syndrome,
headache, blurred vision, and elevations of serum aminotransfer-
ase levels have also been reported. Insulin resistance may be more
common with indinavir than with the other PIs, occurring in
3–5% of patients. In some studies but not in others, indinavir has
been associated with a higher risk of myocardial infarction. There
have also been rare cases of acute hemolytic anemia.
Since indinavir is an inhibitor of CYP3A4, numerous and
complex drug interactions can occur (Tables 49–3 and 49–4).
Boosting with ritonavir allows for twice-daily rather than thrice-
daily dosing and eliminates the food restriction associated with
use of indinavir. However, there is potential for an increase in

nephrolithiasis with this combination compared with indinavir
alone; thus, a high fluid intake (1.5–2 L/d) is advised. Indinavir
should not be co-administered with astemizole, cerivastatin, efavi-
renz, ergotamine, etravirine, lovastatin, pimozide, rifampin, simv-
astatin, terfenadine, or triazolam. Levels of amlodipine, levodopa,
and trazodone may be increased with concurrent administration
of indinavir.
LOPINAVIR
Lopinavir is available only in combination with low-dose rito-
navir as a pharmacologic “booster” via inhibition of its CYP3A-
mediated metabolism, resulting in increased exposure and a
reduced pill burden.
Lopinavir is highly protein bound (98–99%), and its half-life is
5–6 hours. It is extensively metabolized by CYP3A, which is inhib-
ited by ritonavir. Lopinavir/ritonavir is one of the recommended
antiretroviral agents for use in pregnant women (Table 49–5).
The most common adverse effects of lopinavir are diarrhea,
nausea, vomiting, increased serum lipids, and increased serum
aminotransferases (more common in patients with HBV or HCV
co-infection). Prolongation of the PR and/or QT interval may
occur. In some studies but not in others, lopinavir/ritonavir has
been associated with a higher risk of myocardial infarction. Pan-
creatitis has rarely been reported. Ritonavir-boosted lopinavir may
be more commonly associated with gastrointestinal adverse events
than other PIs.
Potential drug-drug interactions are extensive (Tables 49–3
and 49–4). Levels of lamotrigine and methadone may be reduced
with co-administration, and levels of bosentan may be increased.
Concurrent use of darunavir, elvitegravir/cobicistat, fosamprena-
vir, and tipranavir is contraindicated. Since the oral solution of
lopinavir/ritonavir contains alcohol, concurrent disulfiram and
metronidazole are contraindicated. The oral solution also contains
propylene glycol, contraindicating the co-administration of other
drugs containing propylene glycol.
NELFINAVIR
Nelfinavir has high absorption in the fed state (70–80%), under-
goes metabolism by CYP3A, and is excreted primarily in the feces.
The plasma half-life in humans is 3.5–5 hours, and the drug is
more than 98% protein-bound.
The most common adverse effects associated with nelfinavir
(10–30%) are diarrhea and flatulence. Diarrhea responds to
anti-diarrheal medications but may be dose-limiting. Nelfinavir
is an inhibitor of the CYP3A system, and multiple drug interac-
tions may occur (Tables 49–3 and 49–4). An increased dosage
of nelfinavir is recommended when co-administered with rifabu-
tin (with a decreased dose of rifabutin), whereas a decrease in
saquinavir dose is suggested with concurrent nelfinavir. Do not
co-administer with astemizole, cerivastatin, cisapride, ergotamine,
lovastatin, omeprazole, pimozide, quinidine, rifampin, simvas-
tatin, or terfenadine. The oral powder contains phenylalanine,
which can be harmful to patients with phenylketonuria.
CHAPTER 49  Antiviral Agents    881
RITONAVIR
Ritonavir has a high bioavailability (~75%) that increases with
food. It is 98% protein-bound and has a serum half-life of
3–5 hours. Metabolism to an active metabolite occurs via the
CYP3A and CYP2D6 isoforms; excretion is primarily in the feces.
Ritonavir as a pharmacologic “booster” is one of the recommended
antiretroviral agents for use in pregnant women (Table 49–5).
Adverse effects of full-dose ritonavir include asthenia, gastroin-
testinal disturbances, and hepatitis; these are greatly reduced with
the lower doses used for boosting. Dose escalation over 1–2 weeks
decreases these side effects. Other potential adverse effects include
altered taste, paresthesias (circumoral or peripheral), elevated
serum aminotransferase and lipid levels, headache, elevations in
serum creatine kinase, and pancreatitis. Inhibition of renal tubular
secretion of creatinine causes a reversible elevation in serum creati-
nine, but glomerular filtration rate is not affected.
Ritonavir is a potent inhibitor of CYP3A4, resulting in many
potential drug interactions (Tables 49–3 and 49–4). However,
this characteristic has been used to great advantage when ritonavir
is administered in low doses (100–200 mg twice daily) in com-
bination with any of the other PI agents, to permit lower or less
frequent dosing (or both) with greater tolerability as well as the
potential for greater efficacy against resistant virus. Therapeutic
levels of digoxin and theophylline should be monitored when
co-administered with ritonavir. The concurrent use of saquinavir
and ritonavir is contraindicated due to an increased risk of QT
prolongation (with torsades de pointes arrhythmia) and PR inter-
val prolongation. Concurrent simeprevir is also contraindicated.
SAQUINAVIR
In its original formulation as a hard gel capsule, oral saquinavir
was poorly bioavailable (~4% after food). However, reformulation
of saquinavir for once-daily dosing in combination with low-dose
ritonavir has both improved antiviral efficacy and decreased gas-
trointestinal adverse effects. A previous formulation of saquinavir
in soft gel capsules is no longer available.
Saquinavir should be taken within 2 hours after a fatty meal for
enhanced absorption. Saquinavir is 97% protein-bound, and serum
half-life is approximately 2 hours. Saquinavir has a large volume of
distribution, but penetration into the cerebrospinal fluid is negligible.
Excretion is primarily in the feces. Gastrointestinal discomfort (nau-
sea, diarrhea, abdominal discomfort, dyspepsia) may occur. When
administered in combination with low-dose ritonavir, there appears
to be less dyslipidemia or gastrointestinal toxicity than with some of
the other boosted PI regimens. Since prolongation of the QT interval
and torsades de pointes have rarely been reported, saquinavir should
not be used in patients with congenital long QT syndrome, AV block,
refractory hypokalemia or hypomagnesemia, or in combination with
drugs that both increase saquinavir plasma concentrations and pro-
long the QT interval. The concurrent use of saquinavir and ritonavir
may confer an increased risk of QT or PR prolongation.
Saquinavir is subject to extensive first-pass metabolism by
CYP3A4 and functions as a CYP3A4 inhibitor as well as a
882    SECTION VIII  Chemotherapeutic Drugs

substrate; thus, there are many potential drug-drug interactions
(Tables 49–3 and 49–4). Increased saquinavir levels when co-
administered with omeprazole necessitate close monitoring for
toxicities. Digoxin levels should be monitored. Liver tests should
be monitored if saquinavir is co-administered with delavirdine or
rifampin. Concurrent darunavir or tipranavir is contraindicated.
TIPRANAVIR
Tipranavir is a newer PI indicated for use in treatment-experienced
patients who harbor strains resistant to other PI agents. It is used
in combination with ritonavir to achieve effective serum levels.
Bioavailability is poor but is increased when taken with a high-
fat meal. The drug is metabolized by the liver microsomal system
and is contraindicated in patients with hepatic insufficiency.
Tipranavir contains a sulfonamide moiety and should not be
administered to patients with known sulfa allergy.
The most common adverse effects of tipranavir are diarrhea,
nausea, vomiting, and abdominal pain. An urticarial or maculo-
papular rash occurs in 10–14%, and may be more common with
co-administered ethinyl estradiol. Liver toxicity, including life-threat-
ening hepatic decompensation, has been observed and may be more
common than with other PIs, particularly in patients with chronic
HBV or HCV infection. Because of an increased risk for intracranial
hemorrhage in patients receiving tipranavir/ritonavir, the drug should
be avoided in patients with head trauma or bleeding diathesis. Other
potential adverse effects include depression, elevation in serum amy-
lase, increased serum lipids, and decreased white blood cell count.
Tipranavir both inhibits and induces the CYP3A4 system.
When used in combination with ritonavir, its net effect is inhibi-
tion. Tipranavir also induces the P-glycoprotein transporter and
thus may alter the disposition of many other drugs (Tables 49–3
and 49–4). Concurrent use with atazanavir, elvitegravir/cobici-
stat, etravirine, fosamprenavir, lopinavir/ritonavir and saquinavir
should be avoided. Supplemental vitamin E is contraindicated in
patients receiving the oral solution.
FUSION INHIBITORS
The process of HIV-1 entry into host cells is complex; each step
presents a potential target for inhibition. Viral attachment to the
host cell entails binding of the viral envelope glycoprotein com-
plex gp160 (consisting of gp120 and gp41) to its cellular receptor
CD4. This binding induces conformational changes in gp120 that
enable access to the chemokine receptors CCR5 or CXCR4. Che-
mokine receptor binding induces further conformational changes
in gp120, allowing exposure to gp41 and leading to fusion of the
viral envelope with the host cell membrane and subsequent entry
of the viral core into the cellular cytoplasm.
ENFUVIRTIDE
Enfuvirtide is a synthetic 36-amino-acid peptide fusion inhibitor
that blocks HIV entry into the cell (Figure 49–3). Enfuvirtide
binds to the gp41 subunit of the viral envelope glycoprotein,
preventing the conformational changes required for the fusion of
the viral and cellular membranes.
Enfuvirtide, which must be administered by subcutaneous
injection, is the only parenterally administered antiretroviral
agent. Metabolism appears to be by proteolytic hydrolysis with-
out involvement of the CYP450 system. Elimination half-life is
3.8 hours.
Resistance to enfuvirtide can result from mutations in gp41;
the frequency and significance of this phenomenon are being
investigated. However, enfuvirtide lacks cross-resistance with the
other currently approved antiretroviral drug classes.
The most common adverse effects are local injection site reac-
tions, consisting of painful erythematous nodules. Although fre-
quent, these are typically mild-to-moderate in severity and rarely
lead to discontinuation. Other potential side effects include insom-
nia, headache, dizziness, and nausea. Hypersensitivity reactions may
rarely occur, are of varying severity, and may recur on rechallenge.
Eosinophilia is the primary laboratory abnormality seen with enfu-
virtide administration. In Phase 3 studies, bacterial pneumonia was
seen at a higher rate in patients who received enfuvirtide than in
those who did not receive enfuvirtide. No drug-drug interactions
have been identified that would require the alteration of the dosage
of concomitant antiretroviral or other drugs.
ENTRY INHIBITORS
MARAVIROC
Maraviroc is approved for use in combination with other antiret-
roviral agents in adult patients infected only with CCR5-tropic
HIV-1. Maraviroc binds specifically and selectively to the host
protein CCR5, one of two chemokine receptors necessary for
entrance of HIV into CD4+ cells. Since maraviroc is active against
HIV that uses the CCR5 co-receptor exclusively, and not against
HIV strains with CXCR4, dual, or mixed tropism, co-receptor
tropism should be determined by specific testing before maraviroc
is started. Substantial proportions of patients, particularly those
with advanced HIV infection, are likely to have virus that is not
exclusively CCR5-tropic.
The absorption of maraviroc is rapid but variable, with the
time to maximum absorption generally 1–4 hours after inges-
tion of the drug. Most of the drug (≥ 75%) is excreted in the
feces, whereas approximately 20% is excreted in urine. The
recommended dose of maraviroc varies according to renal func-
tion and the concomitant use of CYP3A inducers or inhibitors
(Table 49–3). Maraviroc is contraindicated in patients with severe
or end-stage renal impairment and caution is advised when used
in patients with preexisting hepatic impairment and in those co-
infected with HBV or HCV. Maraviroc has excellent penetration
into the cervicovaginal fluid, with levels almost four times higher
than the corresponding concentrations in blood plasma.
Resistance to maraviroc is associated with one or more
mutations in the V3 loop of gp120. However, emergence of
CXCR4 virus (either previously undetected or newly developed)
appears to be a more common cause of virologic failure than the
development of resistance mutations. There appears to be no

cross-resistance with drugs from any other class, including the
fusion inhibitor enfuvirtide.
Maraviroc is a substrate for CYP3A4 and therefore requires
adjustment in the presence of drugs that interact with these enzymes
(Tables 49–3 and 49–4). It is also a substrate for P-glycoprotein,
which limits intracellular concentrations of the drug. The dosage
of maraviroc must be decreased if it is co-administered with strong
CYP3A inhibitors (eg, delavirdine, ketoconazole, itraconazole,
clarithromycin, or any protease inhibitor other than tipranavir)
and must be increased if co-administered with CYP3A inducers
(eg, efavirenz, etravirine, carbamazepine, phenytoin, or St. John’s
wort). Concurrent use of rifampin is contraindicated.
Potential adverse effects of maraviroc include upper respiratory
tract infection, cough, pyrexia, rash, dizziness, muscle and joint
pain, diarrhea, sleep disturbance, and elevations in serum ami-
notransferases. Hepatotoxicity has been reported, which may be
preceded by a systemic allergic reaction (ie, pruritic rash, eosino-
philia, or elevated IgE); discontinuation of maraviroc should be
prompt if this constellation occurs. Myocardial ischemia and
infarction have been observed in patients receiving maraviroc;
therefore caution is advised in patients at increased cardiovascular
risk. There is an increased risk of postural hypotension in patients
with severe renal impairment.
There has been concern that blockade of the chemokine CCR5
receptor—a human protein—may result in decreased immune
surveillance, with a subsequent increased risk of malignancy or
infection. To date, however, there has been no evidence of an
increased risk of either malignancy or infection in patients receiv-
ing maraviroc.
INTEGRASE STRAND TRANSFER
INHIBITORS (INSTIs)
This class of agents binds integrase, a viral enzyme essential to the
replication of both HIV-1 and HIV-2. By doing so, it inhibits
strand transfer, the third and final step of provirus integration,
thus interfering with the integration of reverse-transcribed HIV
DNA into the chromosomes of host cells (Figure 49–3). As a
class, these agents tend to be well tolerated, with headache and
gastrointestinal effects the most commonly reported adverse
events. Their use in combination antiretroviral regimens or with
cobicistat (ie, elvitegravir) means that additional adverse events
and/or drug-drug interactions need to be considered as well. The
available data suggest that effects upon lipid metabolism are favor-
able compared with efavirenz and PIs. Rare severe events include
systemic hypersensitivity reactions and rhabdomyolysis.
DOLUTEGRAVIR
The frequency of dosing of dolutegravir depends on the presence
or absence of integrase inhibitor-associated resistance mutations
and the concurrent use of efavirenz, fosamprenavir/ritonavir,
tipranavir/ritonavir, or rifampin. Dolutegravir should be taken
2 hours before or 6 hours after cation-containing antacids or laxa-
tives, sucralfate, oral iron supplements, oral calcium supplements,
CHAPTER 49  Antiviral Agents    883
or buffered medications. Peak plasma concentrations occur within
2–3 hours of ingestion. Dolutegravir is highly protein bound
(99%). The terminal half-life is ~14 hours. Serum levels may be
reduced in patients with severe renal insufficiency.
Adverse effects of dolutegravir are infrequent but may include
insomnia, headache, increased serum aminotransferase levels,
and, rarely, rash. A hypersensitivity reaction, including rash and
systemic symptoms, has been reported; the drug should be dis-
continued immediately if this occurs and not restarted. Dolute-
gravir increases serum creatinine by inhibiting tubular secretion
of creatinine but has no effect on actual glomerular filtration rate.
Dolutegravir is primarily metabolized via UGT1A1 with
some contribution from CYP3A. Therefore, multiple drug-
drug interactions may occur (Table 49–3 and 49–4). Levels of
dolutegravir may decrease when co-administered with efavirenz,
etravirine, nevirapine, rifampin, or rifapentine, in some instances
necessitating increased doses of dolutegravir or boosting or both.
Co-administration with the metabolic inducers oxcarbazepine,
phenytoin, phenobarbital, carbamazepine, and St. John’s wort
should be avoided. Dolutegravir inhibits the renal organic cation
transporter OCT2, thereby increasing plasma concentrations of
drugs eliminated via OCT2 such as dofetilide and metformin. For
this reason, co-administration with dofetilide is contraindicated
and close monitoring, with potential for dose adjustment, is rec-
ommended for co-administration with metformin.
ELVITEGRAVIR
Elvitegravir should be taken with food, and it should be taken
2 hours before or 6 hours after cation-containing antacids or laxa-
tives, sucralfate, oral iron supplements, oral calcium supplements,
or buffered medications. Peak levels occur within 4 hours of inges-
tion; elvitegravir is highly protein bound (>98%).
Elvitegravir requires boosting with an additional drug, such as
cobicistat (a pharmacokinetic enhancer that inhibits CYP3A4 as
well as certain intestinal transport proteins) or ritonavir. Cobici-
stat inhibits renal tubular secretion of creatinine; therefore, fixed-
dose combinations need to be adjusted for renal function.
There appear to be few adverse effects associated with elvitegra-
vir per se but may include diarrhea, rash, and elevation in hepatic
aminotransferases.
Elvitegravir is primarily metabolized by CYP3A enzymes, so
drugs that induce or inhibit the action of CYP3A may affect serum
levels of elvitegravir (Table 49–3 and 49–4). In addition, cobicistat
and ritonavir strongly inhibit CYP3A. Elvitegravir levels may be
lowered by concurrent efavirenz or nevirapine, rifampin, rifabutin,
carbamazepine, phenytoin, or St. John’s wort. Concurrent use of
azole antifungal drugs is contraindicated due to a potential increase
in elvitegravir levels; rifabutin levels may also be increased by con-
current elvitegravir. Elvitegravir also induces CYP2D9 and may
lower concentrations of substrates of this enzyme. With the fixed
dose combination, concurrent alfuzosin or atazanavir, cisapride,
darunavir, efavirenz, etravirine, fosamprenavir, ledipasvir, lopinavir/
ritonavir, methylprednisolone, midazolam, nevirapine, pimozide,
prednisolone, rifampin, rifabutin are contraindicated.
884    SECTION VIII  Chemotherapeutic Drugs

RALTEGRAVIR presence of decompensated cirrhosis and hypersplenism, thyroid

Absolute bioavailability of the pyrimidinone analog raltegravir has
not been established but does not appear to be food-dependent.
Terminal half-life is ~ 9 hours. The drug does not interact with
the cytochrome P450 system but is metabolized by glucuronida-
tion, particularly UGT1A1. Therefore, concurrent use of inducers
or inhibitors of UGT1A1 such as rifampin and rifapentine may
necessitate dosage adjustment of raltegravir. The chewable tablets
contain phenylalanine, which can be harmful to patients with
phenylketonuria.
Raltegravir is one of the antiretroviral agents recommended for
use in pregnancy (Table 49–5).
Adverse effects of raltegravir are uncommon but include nau-
sea, headache, fatigue, muscle aches, and increased serum amylase
and aminotransferase levels. Severe, potentially life-threatening
and fatal skin reactions have been reported, including Stevens-
Johnson syndrome, hypersensitivity reaction, and toxic epidermal
necrolysis.
■■ ANTIHEPATITIS AGENTS
The advantages of nucleoside/nucleotide analogs (NA) therapy
of hepatitis over interferons (IFN) include fewer adverse effects
and a one-pill-a-day oral administration. The main advantages
of IFN over NAs are the absence of resistance, and achieve-
ment of higher rates of viral agglutinin reduction. However, the
disadvantages of IFN are that less than 50% of persons treated
will respond, its high cost, administration by injection, and com-
mon adverse effects, which preclude its use in many persons,
particularly in resource-limited settings. A number of relative and
absolute contraindications to IFN also exist, which include the
disease, autoimmune diseases, severe coronary artery disease, renal
transplant disease, pregnancy, seizures and psychiatric illness, con-
comitant use of certain drugs, retinopathy, thrombocytopenia and
leucopenia. IFN also cannot be used in infants less than 1 year and
in pregnant women.
INTERFERON ALFA
Interferons are host cytokines that exert complex antiviral, immu-
nomodulatory, and antiproliferative actions (see Chapter 55).
Interferon alfa appears to function by induction of intracellular
signals following binding to specific cell membrane receptors,
resulting in inhibition of viral penetration, translation, tran-
scription, protein processing, maturation, and release, as well as
increased host expression of major histocompatibility complex
antigens, enhanced phagocytic activity of macrophages, and aug-
mentation of the proliferation and survival of cytotoxic T cells.
Interferon alfa-2b is licensed for the treatment for chronic
HBV infection; interferon alfa-2a, interferon alfa-2b, and
interferon alfacon-1 are licensed for treatment of chronic HCV
infection (Table 49–6). Interferon alfa-2a and interferon alfa-2b
may be administered either subcutaneously or intramuscularly;
half-life is 2–5 hours, depending on the route of administra-
tion. Alfa interferons are filtered at the glomerulus and undergo
rapid proteolytic degradation during tubular reabsorption, such
that detection in the systemic circulation is negligible. Liver
metabolism and subsequent biliary excretion are considered
minor pathways.
Pegylation (the attachment of polyethylene glycol to a pro-
tein) reduces the rate of absorption following subcutaneous
injection, reduces renal and cellular clearance, and decreases

TABLE 49–6  Drugs used to treat chronic hepatitis B virus infection.

Agent Recommended Adult Dosage Potential Adverse Effects

Nucleoside/nucleotide analogs
Entecavir1 500 or 1000 mg qd orally Headache, fatigue, upper abdominal pain; lactic acidosis
Tenofovir alafenamide 25 mg qd orally Nausea, abdominal pain, diarrhea, dizziness, fatigue, nephropathy, lactic
fumarate acidosis
Tenofovir disoproxil1 300 mg qd orally Nausea, abdominal pain, diarrhea, dizziness, fatigue, nephropathy, lactic
acidosis
Adefovir dipivoxil1 10 mg qd orally Renal dysfunction, lactic acidosis
Lamivudine1 100 mg qd orally Headache, nausea, diarrhea, dizziness, myalgia, and malaise, lactic acidosis
1
Telbivudine 600 mg qd orally Fatigue, headache, cough, nausea, diarrhea, myopathy, peripheral neuropathy,
lactic acidosis
Interferon alfa-2b 5 million IU/d or 10 million IU three Flu-like symptoms, fatigue, mood disturbances, cytopenias, autoimmune
times weekly subcutaneously or disorders
intramuscularly
Pegylated interferon 180 mcg once weekly subcutaneously Flu-like symptoms, fatigue, mood disturbances, cytopenias, autoimmune
alfa-2a1 disorders
1
Dose must be reduced in patients with renal insufficiency.
IU, international units.

TABLE 49–7  Direct-acting antiviral combination regimens for the treatment of chronic hepatitis C infection in
1
adult patients without cirrhosis.
Regimen
Velpatasvir 100 mg /sofosbuvir 400 mg once daily × 12 weeks
2
Elbasvir 50 mg/grazoprevir 100 mg once daily × 12 weeks
Ledipasvir 90 mg/sofosbuvir 400 mg once daily × 12 weeks
Paritaprevir 150/ritonavir 100/ombitasvir 25 once daily plus dasabuvir
250 mg bid plus weight-based ribavirin × 12 weeks
Paritaprevir 150/ritonavir 100/ombitasvir 25 once daily plus weight-
based ribavirin × 12 weeks
Simeprevir 150 mg plus sofosbuvir 400 mg once daily × 12 weeks
3
Daclatasvir 60 mg plus sofosbuvir 400 mg once daily × 12 weeks
Sofosbuvir 400 mg once daily plus weight-based ribavirin × 12 weeks
1
Regimens may differ in the presence of cirrhosis.
2
As an alternative regimen, elbasvir 50 mg/grazoprevir 100 mg once daily may be given in combination with weight-based ribavirin for 16 weeks.
3
Dose adjustment may be required if co-administered with a CYP 3A substrate.
the immunogenicity of the protein, resulting in a longer half-
life and steadier plasma concentrations. Renal elimination of
pegylated interferon alfa-2a and pegylated interferon alfa-2b
accounts for about 30% of clearance; dose must be adjusted in
renal insufficiency due to impaired clearance. The polyethylene
glycol moiety is a nontoxic polymer that is readily excreted in
the urine.
Pegylated interferon alfa-2a is licensed to treat chronic HBV
and HCV infection; pegylated interferon alfa-2b is licensed to
treat chronic HCV infection. However, the availability of newer
and highly effective antiviral agents for HCV infection has greatly
diminished the use of the interferons for this indication.
The adverse effects of interferon alfa include a flu-like syn-
drome (ie, headache, fevers, chills, myalgias, and malaise) that
occurs within 6 hours after dosing in more than 30% of patients;
it tends to resolve upon continued administration. Transient
hepatic enzyme elevations may occur in the first 8–12 weeks of
therapy and appear to be more common in responders. Potential
adverse effects during chronic therapy include neurotoxicities
(mood disorders, depression, somnolence, confusion, seizures),
myelosuppression, profound fatigue, weight loss, rash, cough,
myalgia, alopecia, tinnitus, reversible hearing loss, retinopathy,
pneumonitis, and possibly cardiotoxicity. Induction of autoanti-
bodies may occur, causing exacerbation or unmasking of autoim-
mune disease (particularly thyroiditis).
Contraindications to interferon alfa therapy include hepatic
decompensation, autoimmune disease, and history of cardiac
arrhythmia. Caution is advised in the setting of psychiatric dis-
ease, epilepsy, thyroid disease, ischemic cardiac disease, severe
renal insufficiency, and cytopenia. Alfa interferons are abortifa-
cient in primates and should not be administered in pregnancy.
Potential drug-drug interactions include increased theophylline and
methadone levels. Co-administration with didanosine is not recom-
mended because of a risk of hepatic failure, and co-administration
with zidovudine may exacerbate cytopenias.
CHAPTER 49  Antiviral Agents    885
Class of Agent(s) HCV Genotype(s)
NS5A inhibitor/NS5B polymerase inhibitor 1, 2, 3, 4, 5, 6
NS5A inhibitor/NS 3/4A protease inhibitor 1a, 1b, 4
NS5A inhibitor/NS5B polymerase inhibitor 1a, 1b, 4, 5, 6
NS 3/4A protease inhibitor/ NS5A inhibitor plus 1a, 1b
NS5B polymerase inhibitor plus guanosine analog
NS 3/4A protease inhibitor/ NS5A inhibitor plus 4
guanosine analog
NS3/4A protease inhibitor plus NS5B polymerase 1a, 1b
inhibitor
NS5A inhibitor plus NS5B polymerase inhibitor 1a, 1b, 2, 3
NS5B polymerase inhibitor plus guanosine analog 2, 3
TREATMENT OF HEPATITIS B
VIRUS INFECTION
No specific treatment is available for the treatment of acute hepa-
titis B infection, which most often resolves spontaneously.
The goals of chronic HBV therapy are the suppression of HBV
DNA to undetectable levels, seroconversion of HBeAg (or more
rarely, HBsAg) from positive to negative, and reduction in elevated
serum aminotransferase levels. These endpoints are correlated
with improvement in necroinflammatory disease, a decreased risk
of hepatocellular carcinoma and cirrhosis, and a decreased need
for liver transplantation. All of the currently licensed therapies
achieve these goals. In contrast to the treatment of HCV infection
(see below), cure is rare. In addition, because current therapies
suppress HBV replication without eradicating the virus, initial
responses may not be durable. The covalently closed circular (ccc)
viral DNA exists in stable form indefinitely within the cell, serving
as a reservoir for HBV throughout the life of the cell and resulting
in the capacity to reactivate. Relapse is more common in patients
co-infected with hepatitis D virus.
As of 2017 eight drugs were approved for treatment of chronic
HBV infection in the United States: five oral nucleoside/nucleo-
tide analogs (lamivudine, adefovir dipivoxil, tenofovir disoproxil,
tenofovir alafenamide, entecavir, telbivudine) and two injectable
interferon drugs (interferon alfa-2b, pegylated interferon alfa-2a)
(Table 49–6). The use of standard interferon has been supplanted
by long-acting pegylated interferon, allowing once-weekly rather
than daily or thrice-weekly dosing. The advantages of interferon
are its finite duration of treatment, the absence of selection of
resistant variants, and a more durable response. However, adverse
effects from interferon are more frequent, and may be severe. Fur-
thermore, interferon cannot be used in patients with decompen-
sated disease. In general, nucleoside/nucleotide analog therapies
have better tolerability and produce a higher response rate than
the interferons, and are now considered the first line of therapy.
886    SECTION VIII  Chemotherapeutic Drugs
Combination therapies may reduce the development of resistance.
The optimal duration of therapy remains unknown.
Several anti-HBV agents have anti-HIV activity as well, includ-
ing tenofovir disoproxil, tenofovir alafenamide, lamivudine, and
adefovir dipivoxil. Emtricitabine, an NRTI used in HIV infection,
has resulted in excellent biochemical, virologic, and histologic
improvement in patients with chronic HBV infection, although
it is not approved for this indication. Although agents with dual
HBV and HIV activity are particularly useful as part of a first-
line regimen in co-infected patients, it is important to note that
acute exacerbation of hepatitis may occur upon discontinuation
or interruption of these agents; this may be severe or even fatal.
ADEFOVIR DIPIVOXIL
Although initially and abortively developed for treatment of HIV
infection, adefovir dipivoxil gained approval, at lower and less
toxic doses, for treatment of HBV infection. Adefovir dipivoxil is
the diester prodrug of adefovir, an acyclic phosphonated adenine
nucleotide analog. It is phosphorylated by cellular kinases to the
active diphosphate metabolite and then competitively inhibits HBV
DNA polymerase and causes chain termination after incorporation
into viral DNA. Adefovir is active in vitro against a wide range of
DNA and RNA viruses, including HBV, HIV, and herpesviruses.
Oral bioavailability of adefovir dipivoxil is ~ 59% and is unaf-
fected by meals; it is rapidly and completely hydrolyzed to the
parent compound by intestinal and blood esterases. Protein bind-
ing is low (<5%). The intracellular half-life of the diphosphate is
prolonged, ranging from 5 to 18 hours in various cells; this makes
once-daily dosing feasible. Adefovir is excreted by both glomerular
filtration and active tubular secretion and requires dose adjust-
ment for renal dysfunction; however, it may be administered to
patients with decompensated liver disease.
Of the oral agents, adefovir may be slower to suppress HBV
DNA levels and the least likely to induce HBeAg seroconversion.
Emergence of resistance is up to 29% after 5 years of use. How-
ever, there is no cross-resistance between adefovir and lamivudine
or entecavir.
Adefovir is well tolerated at doses used to treat HBV infec-
tion. A reversible increase in serum creatinine has been reported
in 3–9% of patients after 4–5 years of treatment. Other potential
adverse effects are headache, diarrhea, asthenia, and abdominal
pain. As with other NRTI agents, lactic acidosis and hepatic ste-
atosis are a risk owing to mitochondrial dysfunction. Pivalic acid,
a by-product of adefovir metabolism, can esterify free carnitine
and result in decreased carnitine levels. However, it is not neces-
sary to administer carnitine supplementation with the low doses
used to treat patients with HBV (10 mg/d). Adefovir is embryo-
toxic in rats at high doses and is genotoxic in preclinical studies.
ENTECAVIR
Entecavir is an orally administered cyclopentyl guanosine nucleo-
side analog that competitively inhibits all three functions of HBV
DNA polymerase, including base priming, reverse transcription of
the negative strand, and synthesis of the positive strand of HBV
DNA. Oral bioavailability approaches 100% but is decreased by
food; therefore, entecavir should be taken on an empty stomach.
The intracellular half-life of the active phosphorylated compound
is 15 hours and plasma half-life is prolonged at 128–149 hours,
allowing once-daily dosing. It is excreted by the kidney, undergo-
ing both glomerular filtration and net tubular secretion, and dos-
age should be adjusted in the setting of renal insufficiency.
Suppression of HBV DNA levels was greater with entecavir
than with lamivudine or adefovir in comparative trials. Entecavir
appears to have a higher barrier to the emergence of resistance
than lamivudine. Although selection of resistant isolates with the
S202G mutation has been documented during therapy, clinical
resistance is rare (<1% at 5 years). However, resistance is more
frequent in lamivudine-refractory patients (~ 50% at 5 years).
Entecavir has weak anti-HIV activity and can induce development
of the M184V variant in HBV/HIV co-infected patients, resulting
in resistance to emtricitabine and lamivudine.
Entecavir is well tolerated. Potential adverse events are headache,
fatigue, dizziness, nausea, and upper abdominal pain. Co-adminis-
tration of entecavir with drugs that reduce renal function or com-
pete for active tubular secretion may increase serum concentrations
of either entecavir or the co-administered drug. Severe lactic acidosis
was reported in a case series of entecavir; thus caution is advised
for administration in the setting of severe hepatic decompensation.
Lung adenomas and carcinomas in mice, hepatic adenomas and
carcinomas in rats and mice, vascular tumors in mice, and brain
gliomas and skin fibromas in rats have been observed at varying
exposures, although clinical relevance is unknown.
LAMIVUDINE
The pharmacokinetics of lamivudine are described earlier in this
chapter (see Nucleoside and Nucleotide Reverse Transcriptase
Inhibitors). The more prolonged intracellular half-life in HBV-
infected cell lines (17–19 hours) than in HIV-infected cell lines
(10.5–15.5 hours) allows for lower doses and less frequent admin-
istration. Lamivudine can be safely administered to patients with
decompensated liver disease. Prolonged treatment has been shown
to decrease clinical progression of HBV, as well as development of
hepatocellular cancer by approximately 50%. Also, lamivudine has
been effective in preventing vertical transmission of HBV from
mother to newborn when given in the last 4 weeks of gestation.
Lamivudine inhibits HBV DNA polymerase and HIV reverse
transcriptase by competing with deoxycytidine triphosphate for
incorporation into the viral DNA, resulting in chain termination.
Although lamivudine results in rapid and potent virus suppres-
sion, chronic therapy is limited by the emergence of lamivudine-
resistant HBV isolates (eg, L180M or M204I/V), estimated to
occur in 15–30% of patients at 1 year and in up to 65% after
5 years of therapy. Resistance has been associated with flares of
hepatitis and progressive liver disease. Cross-resistance between
lamivudine and emtricitabine or entecavir may occur; however,
adefovir and tenofovir maintain activity against lamivudine-
resistant strains of HBV.

In the doses used for HBV infection, lamivudine has an excel-
lent safety profile. Headache, nausea, diarrhea, dizziness, myalgia,
and malaise are rare. Co-infection with HIV may increase the risk
of pancreatitis.
TELBIVUDINE
Telbivudine is a thymidine nucleoside analog with activity against
HBV DNA polymerase. It is phosphorylated by cellular kinases to
the active triphosphate form, which has an intracellular half-life of
14 hours. The phosphorylated compound competitively inhibits
HBV DNA polymerase, resulting in incorporation into viral DNA
and chain termination. It is not active in vitro against HIV-1.
Oral bioavailability is unaffected by food. Plasma protein
binding is low (3%) and distribution wide. The serum half-life
is approximately 15 hours and excretion is renal. There are no
known metabolites and no known interactions with the CYP450
system or other drugs.
Telbivudine induced greater rates of virologic response than
either lamivudine or adefovir in comparative trials. However,
emergence of resistance, typically due to the M204I mutation,
may occur in up to 22% of patients with durations of therapy
exceeding 1 year, and may result in virologic rebound. Telbivudine
is not effective in patients with lamivudine-resistant HBV.
Adverse effects are mild; they include fatigue, headache, cough,
nausea, and diarrhea. Both uncomplicated myalgia and myopathy
with elevated creatinine kinase levels have been reported, as has
peripheral neuropathy. As with other nucleoside analogs, lactic
acidosis and severe hepatomegaly with steatosis may occur during
therapy as well as flares of hepatitis after discontinuation.
TENOFOVIR DISOPROXIL
Tenofovir, a nucleotide analog of adenosine in use as an antiretro-
viral agent, has potent activity against HBV. The characteristics of
tenofovir disoproxil are described earlier in this chapter. Tenofovir
maintains activity against lamivudine- and entecavir-resistant hep-
atitis virus isolates. Although similar in structure to adefovir dip-
ivoxil, comparative trials show a higher rate of virologic response
and histologic improvement, and a lower rate of emergence of
resistance in patients with chronic HBV infection. Resistance to
tenofovir has not been documented in clinical trials, even among
patients who have been treated with tenofovir for up to 8 years.
However, efficacy is lower in patients who have resistance to
adefovir and double mutations (A181T/V and N236T).
The most common adverse effects of tenofovir in patients with
HBV infection are nausea, abdominal pain, diarrhea, dizziness,
and fatigue. Chronic renal insufficiency secondary to a proxi-
mal tubulopathy may occur, and may progress to renal failure.
Decreases in bone mineral density and Fanconi’s syndrome, as
observed in HIV-infected patients treated with tenofovir, have not
been described in patients with HBV infection receiving tenofovir
disoproxil. Tenofovir alafenamide fumarate (TAF) is an orally
bioavailable prodrug of tenofovir that enables enhanced delivery
CHAPTER 49  Antiviral Agents    887
of the parent nucleotide and its active diphosphate metabolite into
lymphoid cells and hepatocytes, so that the dose of tenofovir can
be reduced and toxicities minimized.
EXPERIMENTAL AGENTS
The nucleoside analog emtricitabine (see HIV) is under clinical
investigation for treatment of HBV infection. The entry inhibitors
Myrcludex B and cyclosporine, as well as cccDNA inhibitors, are
being evaluated. Research is also ongoing to develop and test new
agents that can “cure” HBV by eliminating all replicative forms,
including covalently closed circular DNA (cccDNA). Broadly
curative antiviral strategies include agents that could directly
target infected cells as well as novel immunotherapeutic strategies
that boost HBV-specific adaptive immune responses or activate
innate intrahepatic immunity. New molecules under investigation
include entry inhibitors and short-interfering RNAs (siRNAs),
and capsid inhibitors
TREATMENT OF HEPATITIS C
INFECTION
In contrast to the treatment of patients with chronic HBV infec-
tion, the primary goal of treatment in patients with HCV infection
is viral eradication. In clinical trials, the primary efficacy end point
is typically achievement of sustained viral response (SVR), defined
as the absence of detectable viremia 24 weeks after completion of
therapy. SVR is associated with improvement in liver histology,
reduction in risk of end-stage liver disease and hepatocellular car-
cinoma, and, occasionally, with regression of cirrhosis as well. Late
relapse occurs in less than 5% of patients who achieve SVR.
In acute hepatitis C, the rate of clearance of the virus without
therapy is estimated at 20–35%. Therefore, most practitioners
choose to delay therapy for a minimum of 6 months after the ini-
tial infection. If treatment is initiated thereafter due to persistent
HCV RNA viremia, the regimens are the same as those adminis-
tered or chronic HCV infection.
The advent of the first-generation direct-acting antiviral
agents (DAAs) boceprevir and telaprevir dramatically altered the
landscape for the optimal treatment of chronic HCV infection,
which was previously treated with the combination of interferon-
alfa (replaced by pegylated interferon-alfa) and ribavirin. Since
interferon-containing regimens tend to be associated with higher
rates of serious adverse events (including anemia and rash), longer
treatment durations, more frequent dosing, and clinically sig-
nificant drug-drug interactions, they are gradually being replaced
by combination regimens of DAAs (see Table 49–7). Moreover,
while the first-generation HCV protease inhibitors (ie, bocepre-
vir, telaprevir) markedly improved the effectiveness of pegylated
interferon plus ribavirin, they have been replaced by newer DAAs
over the past 2 years, which can be administered in all-oral,
interferon-free combinations—with or without ribavirin—with
improved efficacy and tolerability, improved dosing schedules,
lesser genotype specificity, and fewer potential drug-drug interac-
tions. However, the DAA regimens are expensive.
888    SECTION VIII  Chemotherapeutic Drugs
There are four current classes of DAAs, which are defined by
their mechanism of action and therapeutic target: nonstructural
protein (NS) 3/4A protease inhibitors, NS5B nucleoside poly-
merase inhibitors, NS5B non-nucleoside polymerase inhibitors,
and NS5A inhibitors. The main targets of the DAAs are the
HCV-encoded proteins that are vital to the replication of the virus
(Figure 49–1).
The safety profiles of all the combination regimens (see
Table 49–7) are generally excellent, with adverse events of mild
severity and very low rates of discontinuation due to adverse
events in clinical trials in the absence of concurrent ribavirin use.
NS5A INHIBITORS
The NS5A protein plays a role in both viral replication and the
assembly of HCV; however the exact mechanism of action of the
HCV NS5A inhibitors remains unclear.
Daclatasvir
Daclatasvir is used in combination with sofosbuvir for treatment
of HCV genotypes 1, 2, and 3. It may be taken with or without
food and does not require adjustment for renal or hepatic impair-
ment. Exposure of daclatasvir was similar between healthy and
HCV-infected subjects. Protein binding is ~99%. It is metabo-
lized via CYP3A and excreted primarily in the feces. Terminal
elimination half-life is 12–15 hours.
Daclatasvir is generally well tolerated. The most common
adverse effects in patients receiving daclatasvir/sofosbuvir were
headache and fatigue, usually mild or moderate in severity. Serious
symptomatic bradycardia has been reported in patients receiving
daclatasvir with sofosbuvir and amiodarone.
Daclatasvir is primarily metabolized through CYP3A metabo-
lism and should not be given with strong inducers of this enzyme.
In addition, dose adjustment is required when co-administered
with strong CYP3A inhibitors or moderate CYP3A inducers.
Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp),
organic anion transporting polypeptide (OATP) 1B1 and 1B3,
and breast cancer resistance protein (BCRP).
Elbasvir
Elbasvir has in vitro activity against most major HCV genotypes,
as well as some viral variants resistant to earlier NS5A inhibitors.
It is only available as a fixed-dose combination with grazoprevir,
recommended for treatment of HCV genotypes 1 and 4 (see
Table 49–7).
The presence of baseline NS5A resistance-associated variants
(RAVs) significantly reduced rates of SVR at 12 weeks using
elbasvir/grazoprevir regimen in patients with genotype 1a. Since
10–15% of patients without prior exposure will have NS5A RAVs,
baseline testing should be considered prior initiation of therapy.
Absorption is not food-dependent. Peak concentrations after
ingestion occur at a median of 3 hours. Elbasvir is extensively
bound to plasma proteins (>99.9%), partially eliminated by oxi-
dative metabolism, and primarily excreted in the feces. Elbasvir/
grazoprevir should not be administered to patients with moder-
ate or severe hepatic impairment or in conjunction with organic
anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors,
strong inducers or inhibitors of CYP3A, or efavirenz.
The most commonly reported side effects during therapy with
elbasvir/grazoprevir were fatigue, headache, and nausea. Eleva-
tions in serum aminotransferases may occur.
Ledipasvir
Ledipasvir was the first NS5A inhibitor to be available in the
United States. It is available in a fixed-dose combination with
sofosbuvir. Ledipasvir is not recommended for treatment of HCV
genotype 2 infection (since potency is lost in the presence of the
highly prevalent L31M polymorphism) or genotype 3 (due to the
availability of more efficacious therapies (see Table 49–7).
Ledipasvir is not affected by food intake. Median peak plasma
concentrations occur 4–4.5 hours after oral administration of ledi-
pasvir/sofosbuvir. It is highly bound (>99.8%) to plasma proteins;
unchanged ledipasvir is the major species present in feces. The
median terminal half-life of ledipasvir following administration of
ledipasvir/sofosbuvir is 47 hours. No dose adjustment is required
in the setting of mild or moderate renal insufficiency or mild,
moderate or severe hepatic insufficiency. The dose in patients with
severe renal insufficiency has not yet been determined.
Ledipasvir is an inhibitor of the drug transporters P-gp and
BCRP and may increase intestinal absorption of co-administered
substrates for these transporters. Additionally, co-administration
of P-gp inducers (e.g., rifampin or St. John’s wort) with ledipasvir/
sofosbuvir may decrease plasma concentrations of both of these
agents.
The most common adverse reactions in patients receiving
ledipasvir/sofosbuvir were fatigue, headache and asthenia. Serious
symptomatic bradycardia has been reported in patients receiving
ledipasvir with sofosbuvir and amiodarone.
Ombitasvir
Ombitasvir is available only as a fixed-dose combination with
paritaprevir and ritonavir for the treatment of HCV genotype 4,
and is given in combination with dasabuvir, paritaprevir, and rito-
navir to treat genotype 1 (see Table 49–7). As in HIV infection,
ritonavir is administered as a pharmacologic “booster” to increase
plasma concentrations of paritaprevir via its effect on CYP3A,
although it does not have activity against HCV.
The absolute bioavailability of ombitasvir is 48%. Peak plasma
concentrations are reached 5 hours post-ingestion of the combi-
nation. It is 99.9% protein-bound; the route of metabolism is via
biliary excretion. Ombitasvir/paritaprevir/ritonavir is contrain-
dicated in patients with moderate or severe hepatic impairment.
Ombitasvir is an inhibitor of UGT1A1. Although ombitasvir
is not metabolized by the CYP3A system, paritaprevir, ritonavir,
and dasabuvir are, with the resulting potential for multiple drug-
drug interactions. Co-administration of the combination with
drugs that highly dependent on CYP3A for clearance, moderate or
strong inducers of CYP3A, strong inducers of CYP2C8, or strong
inhibitors of CYP2C8 is contraindicated.

The most commonly reported adverse reactions in patients
receiving ombitasvir were nausea, pruritus and insomnia. Increased
serum aminotransferases have also been reported, particularly in
women using concomitant ethinyl estradiol-containing contracep-
tive medications.
Velpatasvir
Velpatasvir is available only in a fixed-dose combination with the
sofosbuvir. It is the first once-daily single-tablet regimen with
pangenotypic activity. No dose adjustment is required for patients
with mild or moderate renal insufficiency, or any degree of hepatic
impairment. Sofosbuvir exposure is increased in patients with
severe renal impairment, including those on dialysis.
Velpatasvir is administered without regard to food; peak
plasma concentrations are observed at 3 hours post-dose. It is
>99% bound to plasma proteins. Metabolism is by CYP2B6
CYP2C8, and CYP3A4. Its median terminal half-lives is 15 hours.
Velpatasvir and sofosbuvir are substrates of P-gp and BCRP;
velpatasvir is also transported by OATP1B1 and OATP1B3.
Inducers of P-gp and/or moderate or potent inducers of CYP2B6,
CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamaze-
pine) may decrease plasma concentrations of velpatasvir and/or
sofosbuvir; co-administration with drugs that inhibit P-gp and/
or BCRP may increase velpatasvir and/or sofosbuvir concentra-
tions and drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may
increase plasma concentration of velpatasvir.
The most common adverse events in patients receiving velpa-
tasvir/sofosbuvir were headache and fatigue.
NS5B RNA POLYMERASE INHIBITORS
NS5B is an RNA-dependent RNA polymerase involved in post-
translational processing that is necessary for replication of HCV.
The enzyme has a catalytic site for nucleoside binding and at least
four other sites at which a non-nucleoside compound can bind
and cause allosteric alteration. The enzyme’s structure is highly
conserved across all HCV genotypes, giving agents that inhibit
NS5B efficacy against all six genotypes.
There are two classes of polymerase inhibitors; these act at
distinct stages of RNA synthesis. Nucleoside/nucleotide analogs
(eg, sofosbuvir) target the catalytic site of NS5B, and are activated
within the hepatocyte through phosphorylation to nucleoside
triphosphate, which competes with nucleotides, resulting in chain
termination. Non-nucleoside analogues (e.g., dasabuvir) act as
allosteric inhibitors of NS5B.
Dasabuvir
Dasabuvir is a non-nucleoside NS5B polymerase inhibitor, avail-
able only as a fixed-dose combination with ombitasvir, paritapre-
vir, and ritonavir for treatment of HCV genotype 1. Ritonavir
functions as a pharmacologic booster to increase paritaprevir
plasma concentrations.
The absolute bioavailability of dasabuvir is 70%. Peak
plasma concentrations are reached 4 hours post-ingestion of the
CHAPTER 49  Antiviral Agents    889
combination. It is >99.5% protein-bound. The primary route of
metabolism is via CYP2C8, as well as CYP3A. This combination
is contraindicated in patients with moderate or severe hepatic
impairment.
The metabolism of paritaprevir, ritonavir, and dasabuvir by the
CYP3A system incurs multiple potential drug-drug interactions.
Co-administration of the combination with drugs that highly
dependent on CYP3A for clearance, moderate or strong inducers
of CYP3A, strong inducers of CYP2C8, or strong inhibitors of
CYP2C8 is contraindicated.
The most commonly reported adverse reactions in patients
receiving dasabuvir were nausea, pruritus and insomnia. Increased
serum aminotransferases have also been reported, particularly in
women using concomitant ethinyl estradiol-containing contracep-
tive medications.
Sofosbuvir
The nucleotide analog sofosbuvir is administered in combination
with several other anti-HCV medications, including daclatasvir,
simeprevir, peginterferon-alfa plus ribavirin, or ribavirin alone.
It is also available in a fixed-dose combination with ledipasvir for
treatment of HCV genotypes 1, 4, 5, and 6 (see Table 49–7).
Sofosbuvir is a prodrug that is rapidly converted after ingestion
to GS-331007, which is efficiently taken up by hepatocytes and
converted by cellular kinase to its pharmacologically active uridine
analog 5’-triphosphate form GS-461203. The triphosphate is
incorporated by the HCV RNA polymerase into the elongating
RNA primer strand, resulting in chain termination.
Sofosbuvir is administered without regard to food; peak plasma
concentrations are observed at 0.5–1 hour post-dose. It is 61–65%
bound to plasma proteins and is metabolized in the liver. Renal
clearance is the major elimination pathway for GS-331007. The
median terminal half-lives of sofosbuvir and GS-331007 are
0.4 and 27 hours, respectively. No dose adjustment is required
for patients with mild or moderate renal insufficiency, or any
degree of hepatic impairment. Sofosbuvir exposure is increased in
patients with severe renal impairment, including those on dialysis.
Sofosbuvir is a substrate of drug transporter P-gp; therefore,
potent P-gp inducers in the intestine may decrease sofosbuvir
concentrations and should not be co-administered.
Sofosbuvir is generally well tolerated. Drug-specific adverse
effects are difficult to discern since it is always administered with
other antiviral agents. In patients receiving sofosbuvir with ledi-
pasvir, the most commonly reported adverse effects were fatigue,
headache, and asthenia. Rare cases of symptomatic bradycardia
have been reported patients taking sofosbuvir and amiodarone
in combination with another DAAs, particularly in patients
also receiving beta blockers, or in those with underlying cardiac
comorbidities and/or advanced liver disease.
NS3/4A PROTEASE INHIBITORS
NS3/4A protease inhibitors are inhibitors of the NS3/4A serine
protease, an enzyme involved in post-translational processing and
replication of HCV (Figure 49–4).
890    SECTION VIII  Chemotherapeutic Drugs
5’ NTR Structural proteins
Envelope
Capsid glycoproteins
C E1 E2 NS1 NS2
NS3/4A protease NS5A inhibitors
inhibitors “ ... previr ” “ ... asvir ”
Telaprevir Daclatasvir
Boceprevir Ledipasvir
Simeprevir Velpatasvir
Paritaprevir Ombitasvir
Grazoprevir Elbasvir
FIGURE 49–4  HCV genome and potential targets of drug action. C, E1, E2, etc, protein products of specific genes; Nucs, nucleoside
inhibitors; Non-Nucs, nonnucleoside inhibitors. (Adapted, with permission, from Asselah T, Marcellin P: Direct-acting antivirals for the treatment of chronic hepatitis
C: One pill a day for tomorrow. Liver Int 2012;32 Suppl 1:88.)
Grazoprevir
Grazoprevir is a potent, pan-genotypic protease inhibitor,
reversibly binding to HCV NS3/4A protease. It is distinct from
earlier-generation protease inhibitors due to its pan-genotypic
activity, as well activity against some of the major resistance-
associated variants (R155K and D168Y) resulting in failure with
first-generation protease inhibitors. It is only available in combi-
nation with elbasvir for treatment of HCV genotypes 1 and 4.
Grazoprevir can be taken without regard to food. Oral expo-
sures are ~2-fold greater in HCV-infected subjects than in healthy
subjects. Peak plasma concentrations are reached at a median of 2
hours after ingestion. Grazoprevir is extensively bound to plasma
proteins (98.8%), and distributes predominantly to the liver,
likely facilitated by active transport through the OATP1B1/3 liver
uptake transporter. It is partially eliminated by oxidative metabo-
lism, primarily by CYP3A and is mostly eliminated in the feces.
Its geometric mean terminal half-life is 31 hours.
Elbasvir/grazoprevir should not be administered to patients with
moderate or severe hepatic impairment, or in conjunction with
organic anion transporting polypeptides 1B1/3 (OATP1B1/3)
inhibitors, strong inducers or inhibitors of CYP3A, or efavirenz.
The most commonly reported side effects during therapy with
elbasvir/grazoprevir were fatigue, headache, and nausea. Eleva-
tions in serum aminotransferases may occur.
Paritaprevir
Paritaprevir is only available as a fixed-dose combination with
ombitasvir and ritonavir for treatment of HCV genotype 4, and is
administered in combination with dasabuvir for genotype 1 infec-
tion. Ritonavir functions as a pharmacologic booster of paritapre-
vir concentrations via its effect on CYP metabolism, although it
does not have activity against HCV.
Nonstructural proteins 3’ NTR
Metalloprotease
Serine protease RNA
RNA helicase Cofactors polymerase
NS3 NS4A NS4B NS5A NS5B
NS5B polymerase
inhibitors “ ... buvir ”
Nucleosides Non-
Sofosbuvir nucleosides
Dasabuvir
The absolute bioavailability of paritaprevir is 53%. Peak
plasma concentrations are reached 4–5 hours post-ingestion of
the combination. It is ~98% protein-bound. The primary route
of metabolism is via CYP3A4, as well as CYP3A5. Ombitasvir/
paritaprevir/ritonavir is contraindicated in patients with moderate
or severe hepatic impairment.
The metabolism of paritaprevir, ritonavir, and dasabuvir by
the CYP3A system incurs multiple potential drug-drug interac-
tions. Co-administration of the combination with drugs highly
dependent on CYP3A for clearance, moderate or strong inducers
of CYP3A, strong inducers of CYP2C8, or strong inhibitors of
CYP2C8 is contraindicated.
The most commonly reported adverse reactions in patients
receiving paritaprevir were nausea, pruritus and insomnia.
Increased serum aminotransferases have also been reported, partic-
ularly in women using concomitant ethinyl estradiol–containing
contraceptive medications.
Simeprevir
Simeprevir was one of the earliest protease inhibitors available;
however, it is considered a second-generation HCV protease
inhibitor because of the enhanced binding affinity and specificity
for NS3/4A. It is used in combination with sofosbuvir, with or
without ribavirin, for treatment of HCV genotype 1, or it may be
administered in combination with peg interferon-alfa and ribavi-
rin. Simeprevir must be taken with food to maximize absorption.
Mean absolute bioavailability is 62%. Peak plasma concentrations
are reached 4–6 hours post-ingestion. It is extensively bound to
plasma proteins (>99%), metabolized in the liver by CYP3A path-
ways, and undergoes biliary excretion. Simeprevir is not recom-
mended in patients with moderate or severe hepatic impairment
because of 2- to 5-fold increases in exposure. In addition, mean

simeprevir exposures are more than threefold higher in patients of
East Asian ancestry compared with Caucasians, leading to poten-
tially higher frequencies of adverse events.
Simeprevir is a substrate and mild inhibitor of CYP3A and a
substrate and inhibitor of P-gp and OATP1B1/3. Co-adminis-
tration with moderate or strong inhibitors or inducers of CYP3A
may significantly increase or decrease the plasma concentration of
simeprevir.
In patients with genotype 1a, the presence of a baseline NS3A
polymorphism Q80K was associated with significantly reduced
SVR at 12 weeks in patients treated with simeprevir plus pegin-
terferon and ribavirin. Therefore, baseline screening for the Q80K
mutation is recommended prior to initiation of therapy.
Simeprevir is generally well tolerated. Photosensitivity and
rash have been reported, occasionally severe; pruritus or nausea
may also occur. Transient, mild elevations in bilirubin have been
observed with simeprevir due to decreased bilirubin elimination
related to inhibition of the hepatic transporters OATP1B1 and
MRP2, but no pattern to suggest liver toxicity has been observed.
Since simeprevir contains a sulfa moiety, caution should be used
in patients with a history of sulfa allergy.
RIBAVIRIN
Ribavirin is a guanosine analog that is phosphorylated intracellularly
by host cell enzymes. Although its mechanism of action has not been
fully elucidated, it appears to interfere with the synthesis of guano-
sine triphosphate, to inhibit capping of viral messenger RNA, and
to inhibit the viral RNA–dependent polymerase of certain viruses.
Ribavirin triphosphate inhibits the replication of a wide range of
DNA and RNA viruses, including influenza A and B, parainfluenza,
respiratory syncytial virus, paramyxoviruses, HCV, and HIV-1.
The absolute oral bioavailability of ribavirin is 45–64%,
increases with high-fat meals, and decreases with co-administra-
tion of antacids. Plasma protein binding is negligible, volume of
distribution is large, and cerebrospinal fluid levels are about 70%
of those in plasma. Ribavirin elimination is primarily through the
urine; therefore, clearance is decreased in patients with creatinine
clearances <30 mL/min.
Higher doses of ribavirin (ie, 1000–1200 mg/d rather than
800 mg/d) and/or a longer duration of therapy may be more
efficacious, but the risk of toxicity is also increased. A dose-dependent
hemolytic anemia occurs in 10–20% of patients, usually within
the first weeks of therapy. Other potential adverse effects are
depression, fatigue, irritability, rash, cough, insomnia, nausea,
and pruritus. Contraindications include anemia, end-stage renal
failure, ischemic vascular disease, and pregnancy. Ribavirin is
teratogenic and embryotoxic in animals as well as mutagenic in
mammalian cells. Therefore, two effective forms of contraception
should be used by both sexual partners during treatment and for
several months thereafter.
The co-administration of ribavirin with didanosine causes sig-
nificantly increased levels of didanosine; co-administration with
azathioprine may result in myelotoxicity due to accumulation of
azathioprine.
CHAPTER 49  Antiviral Agents    891
■■ ANTI-INFLUENZA AGENTS
Influenza virus strains are classified by their core proteins (ie, A,
B, or C), species of origin (eg, avian, swine), and geographic site
of isolation. Influenza A, the only strain that causes pandemics,
is classified into 16 H (hemagglutinin) and 9 N (neuraminidase)
known subtypes based on surface proteins. Although influenza B
viruses usually infect only people, influenza A viruses can infect
a variety of animal hosts, including birds, providing an extensive
reservoir. Current influenza A subtypes that are circulating among
worldwide populations include H1N1, H1N2, and H3N2.
Although avian influenza subtypes are typically highly species-
specific, they have on rare occasions crossed the species barrier
to infect humans and cats. Viruses of the H5 and H7 subtypes
(eg, H5N1, H7N9) may rapidly mutate within poultry flocks
from a low to high pathogenic form and have recently expanded
their host range to cause both avian and human disease. However,
person-to-person spread of these avian viruses to date has been
rare, limited, and unsustained.
There are 5 anti-influenza drugs approved for use: 3 are
neuraminidase inhibitors (oral oseltamivir, inhaled zanamivir, IV
peramivir) and 2 are adamantanes (amantadine, rimantadine).
Treatment is recommended for individuals with severe infection
or at high risk for complications. The neuraminidase inhibitors
have activity against both influenza A and influenza B, and there is
currently a low level of resistance. The adamantanes have activity
against influenza A viruses only, and in recent past seasons there
was a high level of resistance (>99%) among both influenza H3N2
and influenza A H1N1.
OSELTAMIVIR & ZANAMIVIR
The neuraminidase inhibitors oseltamivir and zanamivir, analogs
of sialic acid, interfere with release of progeny influenza A and
B virus from infected host cells, thus halting the spread of infec-
tion within the respiratory tract. These agents competitively and
reversibly interact with the active enzyme site to inhibit viral neur-
aminidase activity at low nanomolar concentrations, resulting in
clumping of newly released influenza virions to each other and to
the membrane of the infected cell. Early administration is crucial
because replication of influenza virus peaks at 24–72 hours after
the onset of illness. Initiation of a 5-day course of therapy within
48 hours after the onset of illness (75 mg twice daily) modestly
decreases the duration of symptoms, as well as duration of viral
shedding and viral titer; some studies have also shown a decrease
in the incidence of complications. Once-daily prophylaxis
(75 mg once daily) is 70–90% effective in preventing disease after
exposure.
Oseltamivir is an orally administered prodrug that is activated
by hepatic esterases and widely distributed throughout the body.
Oral bioavailability is ~ 80%, plasma protein binding is low, and
concentrations in the middle ear and sinus fluid are similar to
those in plasma. The half-life of oseltamivir is 6–10 hours, and
excretion is by glomerular filtration and tubular secretion. Pro-
benecid reduces renal clearance by 50%. Serum concentrations
892    SECTION VIII  Chemotherapeutic Drugs
of oseltamivir carboxylate, the active metabolite of oseltamivir,
increase with declining renal function; therefore, dosage should
be adjusted in patients with renal insufficiency. Potential adverse
effects include nausea, vomiting, and headache. Taking oseltami-
vir with food does not interfere with absorption and may decrease
nausea and vomiting. Fatigue and diarrhea have also been reported
and appear to be more common with prophylactic use. Rash is
rare. Neuropsychiatric events (self-injury or delirium) have been
reported, particularly in adolescents and adults living in Japan.
Zanamivir is administered directly to the respiratory tract via
inhalation. Of the active compound, 10–20% reaches the lungs;
the remainder is deposited in the oropharynx. The concentration
of the drug in the respiratory tract is estimated to be more than
1000 times the 50% inhibitory concentration for neuraminidase,
and the pulmonary half-life is 2.8 hours. Of the total dose (10 mg
twice daily for 5 days for treatment or 10 mg once daily for
prevention), 5–15% is absorbed and excreted in the urine with
minimal metabolism. Potential adverse effects include cough,
bronchospasm (occasionally severe), reversible decrease in pul-
monary function, and transient nasal and throat discomfort.
Zanamivir administration is not recommended for patients with
underlying airway disease.
Although resistance to oseltamivir and zanamivir may emerge
during therapy and be transmissible, >98% of H1N1 and H3N2
strains as well as 100% of influenza B virus tested by the Centers
for Disease Control in the 2014–2015 season retained susceptibil-
ity to both agents.
PERAMIVIR
The neuraminidase inhibitor peramivir, a cyclopentane analog, has
activity against both influenza A and B viruses, and is approved as
a single 600-mg IV dose for the treatment of acute uncomplicated
influenza in adults. As with the other neuraminidase inhibitors,
early treatment is optimal (ie, within 48 hours).
Less than 30% of peramivir is protein-bound. Peramivir is
not significantly metabolized in humans and the major route of
elimination is the kidney. Dose adjustment is required for renal
insufficiency. The elimination half-life following IV administra-
tion is ~20 hours.
The main potential side effect is diarrhea, although serious skin
or hypersensitivity reactions (e.g., Stevens-Johnson syndrome, ery-
thema multiforme) have been rarely reported. In addition, as with
the other neuraminidase inhibitors, an increased risk of hallucina-
tions, delirium, and abnormal behavior in patients with influenza
receiving peramivir has been reported.
AMANTADINE & RIMANTADINE
Amantadine (1-aminoadamantane hydrochloride) and its
α-methyl derivative, rimantadine, are tricyclic amines of the ada-
mantane family that block the M2 proton ion channel of the virus
particle and inhibit uncoating of the viral RNA within infected
host cells, thus preventing its replication. They are active against
influenza A only. Rimantadine is four to ten times more active
than amantadine in vitro. Amantadine is well absorbed and 67%
protein-bound, with a plasma half-life of 12–18 hours that varies
by creatinine clearance. Rimantadine is about 40% protein-bound
and has a half-life of 24–36 hours. Nasal mucus concentrations of
rimantadine average 50% higher than those in plasma, and cere-
brospinal fluid levels are 52–96% of those in the serum. Aman-
tadine is excreted unchanged in the urine, whereas rimantadine
undergoes extensive metabolism by hydroxylation, conjugation,
and glucuronidation before urinary excretion. Dose reductions are
required for both agents in the elderly and in patients with renal
insufficiency, and for rimantadine in patients with severe hepatic
insufficiency.
In the absence of resistance, both amantadine and rimantadine
are 70–90% protective in the prevention of clinical illness when
initiated before exposure and limit the duration of clinical illness
by 1–2 days when administered as treatment. However, due to
high rates of resistance in both H1N1 and H3N2 viruses, these
agents are no longer recommended for the prevention or treat-
ment of influenza.
The most common adverse effects are gastrointestinal (nausea,
anorexia) and central nervous system (nervousness, difficulty in
concentrating, insomnia, light-headedness). More serious side
effects (eg, marked behavioral changes, delirium, hallucinations,
agitation, and seizures) may be due to alteration of dopamine
neurotransmission (see Chapter 28); are less frequent with riman-
tadine than with amantadine; are associated with high plasma
concentrations; may occur more frequently in patients with
renal insufficiency, seizure disorders, or advanced age; and may
increase with concomitant antihistamines, anticholinergic drugs,
hydrochlorothiazide, and trimethoprim-sulfamethoxazole. Clini-
cal manifestations of anticholinergic activity tend to be present
in acute amantadine overdose. Both agents are teratogenic and
embryotoxic in rodents, and birth defects have been reported after
exposure during pregnancy.
INVESTIGATIONAL AGENTS
An IV formulation of zanamivir is being evaluated in clinical tri-
als and is available for compassionate use from the manufacturer.
A long-acting neuraminidase inhibitor, laninamivir octanoate,
may retain activity against oseltamivir-resistant virus. DAS181 is
a host-directed antiviral agent with activity against influenza and
parainfluenza that acts by removing the virus receptor, sialic acid,
from adjacent glycan structures.
■■ OTHER ANTIVIRAL AGENTS
INTERFERONS
Interferons have been studied for numerous clinical indications. In
addition to HBV and HCV infections (see Antihepatitis Agents),
intralesional injection of interferon alfa-2b or alfa-n3 may be used
for treatment of condylomata acuminata (see Chapter 61).
 CHAPTER 49  Antiviral Agents    893

RIBAVIRIN
In addition to oral administration for HCV infection in combi-
nation with interferon alfa (see Antihepatitis Agents), aerosolized
ribavirin is administered by nebulizer (20 mg/mL for 12–18
hours continuously per day) to children and infants with severe
respiratory syncytial virus (RSV) bronchiolitis or pneumonia to
reduce the severity and duration of illness. Systemic absorption
is low (<1%). Aerosolized ribavirin may cause conjunctival or
bronchial irritation and the aerosolized drug may precipitate on
contact lenses. Ribavirin is teratogenic and embryotoxic. Health
care workers and pregnant women should be protected against
extended inhalation exposure.
Ribavirin has in vitro activity against a number of viruses,
including Lassa, West Nile, measles, influenza, and parainfluenza.
However, clinical data regarding effectiveness are lacking.
PALIVIZUMAB
Palivizumab is a humanized monoclonal antibody directed against
an epitope in the A antigen site on the F surface protein of RSV.
It is licensed for the prevention of RSV infection in high-risk
infants and children, such as premature infants and those with
bronchopulmonary dysplasia or congenital heart disease. A pla-
cebo-controlled trial using once-monthly intramuscular injections
(15 mg/kg) for 5 months beginning at the start of the RSV sea-
son demonstrated a 55% reduction in the risk of hospitalization
for RSV in treated patients, as well as decreases in the need for
supplemental oxygen, the illness severity score, and need for
intensive care. Although resistant strains have been isolated in the
laboratory, no resistant clinical isolates have yet been identified.
Potential adverse effects include upper respiratory tract infection,
fever, rhinitis, rash, diarrhea, vomiting, cough, otitis media, and
elevation in serum aminotransferase levels.
Agents under investigation for the treatment or prophylaxis
of patients with RSV infection include small molecule inhibitors
that interfere with RSV fusion through interaction with the F
protein of RSV (e.g., GS-5806) and the oral nucleoside analog
ALS-008176.
IMIQUIMOD
Imiquimod is an immune response modifier shown to be effec-
tive in the topical treatment of external genital and perianal warts
(ie, condyloma acuminatum; see Chapter 61). The 5% cream
is applied three times weekly and washed off 6–10 hours after
each application. Recurrences appear to be less common than
after ablative therapies. Imiquimod may also be effective against
molluscum contagiosum but is not licensed in the USA for this
indication. Local skin reactions are the most common adverse
effect; these tend to resolve within weeks after therapy. However,
pigmentary skin changes may persist. Systemic adverse effects
such as fatigue and influenza-like syndrome have occasionally
been reported.

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

Abacavir Generic, Ziagen Etravirine Intelence
Abacavir/lamivudine Epzicom Famciclovir Generic, Famvir
Abacavir/lamivudine/zidovudine Trizivir Fosamprenavir Lexiva
Acyclovir Generic, Zovirax Foscarnet Generic, Foscavir
Adefovir Generic, Hepsera Ganciclovir Generic, Cytovene
Amantadine Generic, Symmetrel Imiquimod Generic, Aldara, others
Atazanavir Reyataz Indinavir Crixivan
Boceprevir Victrelis Interferon alfa-2a Roferon-A
Cidofovir Generic, Vistide Interferon alfa-2b Intron-A
Darunavir Prezista (must be taken with Interferon alfa-2b/ribavirin Rebetron
ritonavir) Interferon alfa-n3 Alferon N
Delavirdine Rescriptor Interferon alfacon-1 Infergen
Didanosine (dideoxyinosine, ddI) Generic, Videx, Videx-EC Lamivudine Generic, Epivir, Epivir-HBV
Docosanol Abreva (over-the-counter) Lamivudine/zidovudine Combivir
Efavirenz Sustiva Lamivudine/abacavir/zidovudine Trizivir
Emtricitabine Emtriva Lopinavir/ritonavir Kaletra
Emtricitabine/tenofovir Truvada Maraviroc Selzentry
Emtricitabine/tenofovir/efavirenz Atripla Nelfinavir Viracept
Enfuvirtide Fuzeon Nevirapine Generic, Viramune
Entecavir Baraclude Oseltamivir Tamiflu
(continued)
894    SECTION VIII  Chemotherapeutic Drugs

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

Palivizumab Synagis Sofosbuvir Sovaldi
Peginterferon alfa-2a Pegasys Stavudine Generic, Zerit, Zerit XR
(pegylated interferon alfa-2a) Telaprevir Incivek
Peginterferon alfa-2b PEG-Intron
Telbivudine Tyzeka
(pegylated interferon alfa-2b)
Tenofovir Viread
Penciclovir Denavir
Tipranavir Aptivus
Raltegravir Isentress
Ribavirin Generic, Rebetol Trifluridine Generic, Viroptic
Ribavirin/interferon alfa-2b Rebetron Valacyclovir Generic, Valtrex
Ribavirin Aerosol Virazole Valganciclovir Valcyte
Rilpivirine Edurant Zalcitabine (dideoxycytidine, ddC) Hivid (withdrawn)
Rilpivirine/emtricitabine/-tenofovir Complera Zanamivir Relenza
Rimantadine Generic, Flumadine Zidovudine (azidothymidine, AZT) Generic, Retrovir
Ritonavir Norvir Zidovudine/lamivudine Combivir
Saquinavir Invirase Zidovudine/lamivudine/abacavir Trizivir

REFERENCES in Pregnant HIV-1-Infected Women for Maternal Health and Interventions

to Reduce Perinatal HIV Transmission in the United States. https://www.
American Association for the Study of Liver Diseases (AASLD)-Infectious Diseases aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf.
Society of America (IDSA): Recommendations for testing, managing, and
Terrault NA et al: AASLD Guidelines for Treatment of Chronic Hepatitis B.
treating hepatitis C. www.hcvguidelines.org.
Hepatology 2016;63:261.
Günthard HF et al: Antiretroviral Treatment of Adult HIV Infection: 2014
Recommendations of the International Antiviral Society–USA Panel. JAMA
2014;312:410. RELEVANT WEBSITES
Medical Letter: Antiviral drugs. Med Lett Drugs Ther 2013;11:19. https://www.aidsinfo.nih.gov
Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use www.hiv-druginteractions.org
of antiretroviral agents in HIV-1 infected adults and adolescents. Department
of Health and Human Services. https://www.aidsinfo.nih.gov/guidelines. www.hivinsite.com
Panel on Treatment of HIV-Infected Pregnant Women and Prevention of www.iasusa.org
Perinatal Transmission: Recommendations for Use of Antiretroviral Drugs www.hepatitisc.uw.edu/page/treatment/drugs

C ASE STUDY ANSWER

Combination antiviral therapy against both HIV and hepa-
titis B virus (HBV) is indicated in this patient, given the
high viral load and low CD4 cell count. However, the use
of methadone and possibly excessive alcohol consumption
necessitate caution. Tenofovir plus emtricitabine (two nucle-
oside/nucleotide reverse transcriptase inhibitors) would be
excellent choices as the NRTI “backbone” of a fully sup-
pressive regimen, since both are active against HIV-1 and
HBV, do not interact with methadone, and are available in
a once-daily, fixed-dose combination. A strand inhibitor
such as raltegravir or dolutegravir, or the boosted combina-
tion of darunavir/ritonavir could be added. There are other
alternatives as well. Prior to initiation of this regimen, renal
and liver function should be checked, HBV DNA level
should be assessed, the patient should be screened for Hepa-
titis A and HCV infection, and a bone mineral density test
should be considered. Pregnancy should be ruled out, and
the patient should be counseled that efavirenz should not be
taken during pregnancy. Avoidance of alcohol should be rec-
ommended. The potential for lowered methadone levels with
darunavir, if used, necessitates close monitoring and possibly
an increased dose of methadone. Finally, the patient should
be made aware that abrupt cessation of these medications
may precipitate an acute flare of hepatitis.

Miscellaneous
Antimicrobial Agents;
Disinfectants, Antiseptics,
& Sterilants
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD*
C ASE STUDY
A 56-year-old man is admitted to the intensive care unit of
a hospital for treatment of community-acquired pneumonia.
He receives ceftriaxone and azithromycin upon admission,
rapidly improves, and is transferred to a semiprivate ward
room. On day 7 of his hospitalization, he develops copi-
ous diarrhea with eight bowel movements but is otherwise
■■ METRONIDAZOLE,
FIDAXOMYCIN, RIFAXIMIN,
MUPIROCIN, POLYMYXINS, &
URINARY ANTISEPTICS
METRONIDAZOLE
Metronidazole is a nitroimidazole antiprotozoal drug (see
Chapter 52) that also has potent antibacterial activity against
anaerobes, including Bacteroides and Clostridium species. Metro-
nidazole is selectively absorbed by anaerobic bacteria and sensitive
protozoa. Once taken up by anaerobes, it is nonenzymatically
reduced by reacting with reduced ferredoxin. This reduction
*
The authors thank Henry F. Chambers, MD and Daniel H. Deck,
PharmD, for their contributions to previous editions of this chapter.
50
C H A P T E R
clinically stable. Clostridium difficile infection is confirmed
by stool testing. What is an acceptable treatment for the
patient’s diarrhea? The patient is transferred to a single-bed
room. The housekeeping staff asks what product should be
used to clean the patient’s old room.
results in products that accumulate in and are toxic to anaerobic
cells. The metabolites of metronidazole are taken up into bacterial
DNA, forming unstable molecules. This action occurs only when
metronidazole is partially reduced, and, because this reduction
usually happens only in anaerobic cells, it has relatively little effect
on human cells or aerobic bacteria.
Metronidazole is well absorbed after oral administration,
is widely distributed in tissues, and reaches serum levels of
4–6 mcg/mL after a 250-mg oral dose. It can also be given
intravenously. The drug penetrates well into the cerebrospinal
fluid and brain, reaching levels similar to those in serum. Met-
ronidazole is metabolized in the liver and may accumulate in
hepatic insufficiency.
Metronidazole is indicated for treatment of anaerobic or mixed
intra-abdominal infections (in combination with other agents
with activity against aerobic organisms), vaginitis (trichomonas
infection, bacterial vaginosis), Clostridium difficile infection, and
brain abscess. The typical dosage is 500 mg three times daily orally
895
896    SECTION VIII  Chemotherapeutic Drugs
or intravenously (30 mg/kg/d). Vaginitis may respond to a single
2-g dose. A vaginal gel is available for topical use.
Adverse effects include nausea, diarrhea, stomatitis, and
peripheral neuropathy with prolonged use. Metronidazole has a
disulfiram-like effect, and patients should be instructed to avoid
alcohol. Although teratogenic in some animals, metronidazole has
not been associated with this effect in humans. Other properties
of metronidazole are discussed in Chapter 52.
A structurally similar agent, tinidazole, is a once-daily drug
approved for treatment of trichomonas infection, giardiasis,
amebiasis, and bacterial vaginosis. It also is active against anaero-
bic bacteria, but is not approved in the USA for treatment of
anaerobic infections.
FIDAXOMICIN
Fidaxomicin is a narrow-spectrum, macrocyclic antibiotic that is
active against Gram-positive aerobes and anaerobes but lacks activity
against Gram-negative bacteria. Fidaxomicin inhibits bacterial pro-
tein synthesis by binding to the sigma subunit of RNA polymerase.
When administered orally, systemic absorption is negligible but fecal
concentrations are high. Fidaxomicin has been approved by the
U.S. Food and Drug Administration (FDA) for the treatment for
C difficile infection in adults. It is as effective as oral vancomycin and
may be associated with lower rates of relapsing disease. Fidaxomicin is
administered orally as a 200 mg tablet twice daily for 10 days.
RIFAXIMIN
Rifaximin is a derivative of rifampin. It is active against Gram-
positive and Gram-negative aerobes and anaerobes. Rifaximin
inhibits bacterial protein synthesis by binding to the beta sub-
unit of DNA-dependent RNA polymerase. When administered
orally, systemic absorption is <0.5%, but fecal concentrations
are high; following a three day course for travelers’ diarrhea, the
fecal concentrations were 8000 mcg/g. Rifaximin was originally
approved by the FDA for the treatment of travelers’ diarrhea,
and it is now used in the management of hepatic encephalopathy,
irritable bowel syndrome with diarrhea, and, occasionally, as an
adjunct in cases of recurrent or refractory C difficile infection in
adults. Typical doses of rifaximin range from 200 mg to 550 mg
administered orally twice to three times daily depending on the
indication. Unlike other rifamycins, rifaximin is not thought to
be associated with cytochrome-P450-mediated drug interactions
due to its limited absorption.
MUPIROCIN
Mupirocin (pseudomonic acid) is a natural substance produced by
Pseudomonas fluorescens. It is rapidly inactivated after absorption,
and systemic levels are undetectable. It is available as an ointment
for topical application.
Mupirocin is active against Gram-positive cocci, includ-
ing methicillin-susceptible and methicillin-resistant strains of
Staphylococcus aureus. Mupirocin inhibits staphylococcal isoleucyl
tRNA synthetase. Low-level resistance, defined as a minimum
inhibitory concentration (MIC) of up to 100 mcg/mL, is due to
point mutation in the gene of the target enzyme. Low-level resis-
tance has been observed after prolonged use. However, local con-
centrations achieved with topical application are well above this
MIC, and this level of resistance does not lead to clinical failure.
High-level resistance, with MICs exceeding 1000 mcg/mL, is due
to the presence of a second isoleucyl tRNA synthetase gene, which
is plasmid-encoded. High-level resistance results in complete loss
of activity. Strains with high-level resistance have caused hospital-
associated outbreaks of staphylococcal infection and colonization.
Although higher rates of resistance are encountered with extensive
use of mupirocin, most staphylococcal isolates are still susceptible.
Mupirocin is indicated for topical treatment of minor skin
infections, such as impetigo (see Chapter 61). Topical application
over large open areas, such as pressure ulcers or surgical wounds,
is an important factor leading to emergence of mupirocin-resistant
strains and is not recommended. Mupirocin temporarily elimi-
nates S aureus nasal carriage by patients or health care workers, but
results are mixed with respect to its ability to prevent subsequent
staphylococcal infection. Patients most likely to benefit from
decolonization are those undergoing orthopedic or cardiothoracic
procedures.
POLYMYXINS
The polymyxins are a group of basic peptides active against Gram-
negative bacteria and include polymyxin B and polymyxin E
(colistin). Polymyxins act as cationic detergents. They attach to
and disrupt bacterial cell membranes. They also bind and inacti-
vate endotoxin. Gram-positive organisms, Proteus sp, and Neisseria
sp are resistant.
Owing to their significant toxicity with systemic administra-
tion (especially nephrotoxicity), polymyxins were, until recently,
largely restricted to topical use. Ointments containing polymyxin
B, 5000 units/g, in mixtures with bacitracin or neomycin (or
both) are commonly applied to infected superficial skin lesions.
Emergence of strains of Acinetobacter baumannii, Pseudomonas
aeruginosa, and Enterobacteriaceae that are resistant to all other
agents has renewed interest in polymyxins as parenteral agents for
salvage therapy of infections caused by these organisms.
URINARY ANTISEPTICS
Urinary antiseptics are oral agents that exert antibacterial activ-
ity in the urine but have little or no systemic antibacterial effect.
Their usefulness is limited to lower urinary tract infections.
Nitrofurantoin
At therapeutic doses, nitrofurantoin is bactericidal for many
Gram-positive and Gram-negative bacteria; however, P aerugi-
nosa and many strains of Proteus are inherently resistant. Nitro-
furantoin has a complex mechanism of action that is not fully
 CHAPTER 50  Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Sterilants     897
understood. Antibacterial activity appears to correlate with rapid
intracellular conversion of nitrofurantoin to highly reactive inter-
mediates by bacterial reductases. These intermediates react non-
specifically with many ribosomal proteins and disrupt metabolic
processes and the synthesis of proteins, RNA, and DNA. It is not
known which of the multiple actions of nitrofurantoin is primarily
responsible for its bactericidal activity.
There is no cross-resistance between nitrofurantoin and other
antimicrobial agents, and resistance emerges slowly. As resis-
tance to trimethoprim-sulfamethoxazole and fluoroquinolones
has become more common in Escherichia coli, nitrofurantoin
has become an important alternative oral agent for treatment of
uncomplicated urinary tract infection.
Nitrofurantoin is well absorbed after ingestion. It is metabo-
lized and excreted so rapidly that no systemic antibacterial action
is achieved. The drug is excreted into the urine by both glo-
merular filtration and tubular secretion. With average daily doses,
concentrations of 200 mcg/mL are reached in urine. In renal
failure, urine levels are insufficient for antibacterial action, but
high blood levels may cause toxicity. Nitrofurantoin is contrain-
dicated in patients with significant renal insufficiency. Traditional
recommendations are to avoid use in patients with creatinine
clearance <60 mL/min; however, some data suggest short-term
nitrofurantoin treatment is acceptable in patients with creatinine
clearance >30 mL/min.
The dosage for urinary tract infection in adults is 100 mg
orally taken four times daily. A long-acting formulation (Macro-
bid) can be taken twice daily. Each long-acting capsule contains
two forms of nitrofurantoin. Macrocrystalline nitrofurantoin,
which has slower dissolution and absorption than nitrofurantoin
monohydrate, constitutes 25%. The remaining 75% is nitrofu-
rantoin monohydrate contained in a powder blend, which, upon
exposure to gastric and intestinal fluids, forms a gel matrix that
releases nitrofurantoin over time.
The drug should not be used to treat upper urinary tract infec-
tion. It is desirable to keep urinary pH below 5.5, which greatly
enhances drug activity. A single daily dose of nitrofurantoin, 100
mg, can prevent recurrent urinary tract infections in some women.
Anorexia, nausea, and vomiting are the principal side effects
of nitrofurantoin. Neuropathies and pulmonary toxicities may
occur, particularly with prolonged use or in patients with renal
impairment. Hemolytic anemia can occur in patients with
glucose-6-phosphate dehydrogenase deficiency. Nitrofurantoin
antagonizes the action of nalidixic acid. Rashes, pulmonary infil-
tration and fibrosis, and other hypersensitivity reactions have been
reported.
Methenamine Mandelate &
Methenamine Hippurate
Methenamine mandelate is the salt of mandelic acid and methena-
mine and possesses properties of both of these urinary antiseptics.
Methenamine hippurate is the salt of hippuric acid and methena-
mine. Below pH 5.5, methenamine releases formaldehyde, which
is antibacterial (see Aldehydes, below). Oral mandelic acid or hip-
puric acid is absorbed and excreted unchanged in the urine. These
drugs are bactericidal for some Gram-negative bacteria when urine
pH is less than 5.5.
Methenamine mandelate, 1 g four times daily, or methenamine
hippurate, 1 g twice daily by mouth (in children age 6 to 12 years,
500 mg four times daily or twice daily, respectively), is used only
as a urinary antiseptic to prevent, not treat, symptomatic urinary
tract infection. Acidifying agents (eg, ascorbic acid, 4–12 g/d) may
be given to lower urinary pH below 5.5. Sulfonamides should not
be given at the same time because they may form an insoluble
compound with the formaldehyde released by methenamine. Per-
sons taking methenamine mandelate may exhibit falsely elevated
tests for catecholamine metabolites.
■■ DISINFECTANTS,
ANTISEPTICS, & STERILANTS
Disinfectants are chemical agents or physical procedures that
inhibit or kill microorganisms (Table 50–1). Antiseptics are dis-
infecting chemical agents with sufficiently low toxicity for host
cells that they can be used directly on skin, mucous membranes,
or wounds. Sterilants kill both vegetative cells and spores when
applied to materials for appropriate times and temperatures. Some
of the terms used in this context are defined in Table 50–2.
Disinfection prevents infection by reducing the number of
potentially infective organisms by killing, removing, or diluting
them. Disinfection can be accomplished by application of chemi-
cal agents or use of physical agents such as ionizing radiation, dry
or moist heat, or superheated steam (autoclave, 120°C) to kill
microorganisms. Often a combination of agents is used, eg, water
and moderate heat over time (pasteurization); ethylene oxide and
moist heat (a sterilant); or addition of disinfectant to a detergent.
Prevention of infection also can be achieved by washing, which
dilutes the potentially infectious organism.
Hand hygiene is probably the most important means of pre-
venting transmission of infectious agents from person to person
or from regions of high microbial load, eg, mouth, nose, or gut,
to potential sites of infection. Alcohol-based hand rubs and soap
and warm water are used to remove bacteria. Skin disinfectants
along with detergent and water are usually used preoperatively as
a surgical scrub for surgeons’ hands.
Evaluation of effectiveness of antiseptics, disinfectants, and
sterilants, although seemingly simple in principle, is very complex.
Factors in any evaluation include the intrinsic resistance of the
microorganism, the number of microorganisms present, mixed
populations of organisms, amount of organic material present (eg,
blood, feces, tissue), concentration and stability of disinfectant or
sterilant, time and temperature of exposure, pH, and hydration
and binding of the agent to surfaces. Specific, standardized assays
of activity are defined for each use. Toxicity for humans also must
be evaluated. In the USA, the Environmental Protection Agency
(EPA) regulates disinfectants and sterilants and the FDA regulates
antiseptics.
Users of antiseptics, disinfectants, and sterilants need to
consider their short-term and long-term toxicity because they
may have general biocidal activity and may accumulate in the
898    SECTION VIII  Chemotherapeutic Drugs

TABLE 50–1  Activities of disinfectants.

Bacteria Viruses Other
 
Gram- Gram- Amebic
  Positive Negative Acid-Fast Spores Lipophilic Hydrophilic Fungi Cysts Prions

Alcohols (isopropanol, HS HS S R S V — — R
ethanol)
Aldehydes (glutaraldehyde, HS HS MS S (slow) S MS S — R
formaldehyde)
Chlorhexidine gluconate HS MS R R V R — — R
Sodium hypochlorite, chlorine HS HS MS S (pH 7.6) S S (at high MS S MS (at high
dioxide conc) conc)
Hexachlorophene S (slow) R R R R R R R R
Povidone, iodine HS HS S S (at high S R S S R
conc)
Phenols, quaternary ammo- HS HS MS R S R S — R
nium compounds
conc, concentration; HS, highly susceptible; MS, moderately susceptible; —, no data; R, resistant; S, susceptible; V, variable.

environment or in the body. Disinfectants and antiseptics may tuberculosis, and many fungi, and inactivating lipophilic viruses.
also become contaminated by resistant microorganisms—eg, The optimum bactericidal concentration is 60–90% by volume
spores, P aeruginosa, or Serratia marcescens—and actually transmit in water. They probably act by denaturation of proteins. They
infection. Most topical antiseptics interfere with wound healing are not used as sterilants because they are not sporicidal, do not
to some degree. Cleansing of wounds with soap and water may be penetrate protein-containing organic material, and may not be
less damaging than the application of antiseptics. active against hydrophilic viruses. Their skin-drying effect can be
Some of the chemical classes of antiseptics, disinfectants, and alleviated by addition of emollients to the formulation. Use of
sterilants are described briefly in the text that follows. The reader alcohol-based hand rubs has been shown to reduce transmission
is referred to the general references for descriptions of physical of health care–associated bacterial pathogens and is recommended
disinfection and sterilization methods. by the Centers for Disease Control and Prevention (CDC) as the
preferred method of hand decontamination in health care set-
ALCOHOLS tings. Alcohol-based hand rubs are ineffective against spores of
C difficile, and handwashing with soap and water is required for
The two alcohols most frequently used for antisepsis and dis- decontamination after caring for a patient with infection from
infection are ethanol and isopropyl alcohol (isopropanol). this organism.
They are rapidly active, killing vegetative bacteria, Mycobacterium Alcohols are flammable and must be stored in cool, well-
ventilated areas. They must be allowed to evaporate before cau-
TABLE 50–2  Commonly used terms related to tery, electrosurgery, or laser surgery. Alcohols may be damaging if
chemical and physical killing of applied directly to corneal tissue. Therefore, instruments such as
microorganisms. tonometers that have been disinfected in alcohol should be rinsed
with sterile water, or the alcohol should be allowed to evaporate
Antisepsis Application of an agent to living tissue for the before they are used.
purpose of preventing infection
Decontamination Process that produces marked reduction in
number or activity of microorganisms CHLORHEXIDINE
Disinfection Chemical or physical treatment that destroys
most vegetative microbes and viruses, but not Chlorhexidine is a cationic biguanide with very low water solu-
spores, in or on inanimate surfaces
bility. Water-soluble chlorhexidine digluconate is used in water-
Sanitization Reduction of microbial load on an inanimate based formulations as an antiseptic. It is active against vegetative
surface to a level considered acceptable for
public health purposes
bacteria and mycobacteria and has variable activity against fungi
and viruses. It strongly adsorbs to bacterial membranes, causing
Sterilization A process intended to kill or remove all types
of microorganisms, including spores, and usu- leakage of small molecules and precipitation of cytoplasmic pro-
ally including viruses, with an acceptably low teins. It is active at pH 5.5–7.0. Chlorhexidine gluconate is slower
probability of their survival in its action than alcohols, but, because of its persistence, it has
Pasteurization A process that kills nonsporulating microor- residual activity, producing bactericidal action equivalent to alco-
ganisms by hot water or steam at 65–100°C hols. It is most effective against Gram-positive cocci and less active
 CHAPTER 50  Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Sterilants     899
against Gram-positive and Gram-negative rods. Spore germina-
tion is inhibited by chlorhexidine. Chlorhexidine digluconate is
resistant to inhibition by blood and organic materials. However,
anionic and nonionic agents in moisturizers, neutral soaps, and
surfactants may neutralize its action. Chlorhexidine digluconate
formulations of 4% concentration have slightly greater antibacte-
rial activity than newer 2% formulations. The combination of
chlorhexidine gluconate in 70% alcohol, available in some coun-
tries including the USA, is the preferred agent for skin antisepsis
in many surgical and percutaneous procedures. The advantage of
this combination over povidone-iodine may derive from its more
rapid action after application, its retained activity after exposure to
body fluids, and its persistent activity on the skin. Chlorhexidine
has a very low skin-sensitizing or irritating capacity. Oral toxicity
is low because it is poorly absorbed from the alimentary tract.
Chlorhexidine must not be used during surgery on the middle ear
because it causes sensorineural deafness. Similar neural toxicity
may be encountered during neurosurgery.
HALOGENS
Iodine
Iodine in a 1:20,000 solution is bactericidal in 1 minute and kills
spores in 15 minutes. Tincture of iodine USP contains 2% iodine
and 2.4% sodium iodide in alcohol. It is the most active antiseptic
for intact skin. It is not commonly used due to serious hypersensi-
tivity reactions and staining of clothing and dressings.
Iodophors
Iodophors are complexes of iodine with a surface-active agent
such as polyvinyl pyrrolidone (PVP; povidone-iodine). Iodo-
phors retain the activity of iodine. They kill vegetative bacteria,
mycobacteria, fungi, and lipid-containing viruses. They may be
sporicidal with prolonged exposure. Iodophors can be used as
antiseptics or disinfectants, the latter containing more iodine. The
amount of free iodine is low, but it is released as the solution is
diluted. An iodophor solution must be diluted according to the
manufacturer’s directions to obtain full activity.
Iodophors are less irritating and less likely to produce skin
hypersensitivity than tincture of iodine. They require drying time
on skin before becoming active, which can be a disadvantage.
Although iodophors have a somewhat broader spectrum of activ-
ity than chlorhexidine, including sporicidal action, they lack its
persistent activity on skin.
Chlorine
Chlorine is a strong oxidizing agent and universal disinfectant that
is commonly provided as a 5.25% sodium hypochlorite solution,
a typical formulation for household bleach. Because formulations
may vary, the exact concentration should be verified on the label. A
1:10 dilution of household bleach (producing a 0.525% concentra-
tion) provides 5000 ppm of available chlorine. The CDC recom-
mends this concentration for disinfection of blood spills. Less than
5 ppm kills vegetative bacteria, whereas up to 5000 ppm is necessary
to kill bacterial spores. A concentration of 1000–10,000 ppm is
tuberculocidal. One hundred ppm kills vegetative fungal cells in
1 hour, but fungal spores require 500 ppm. Viruses are inactivated
by 200–500 ppm. Dilutions of sodium hypochlorite made up in
pH 7.5–8.0 tap water retain their activity for months when kept in
tightly closed, opaque containers. Frequent opening and closing of
the container reduces the activity markedly.
Because chlorine is inactivated by blood, serum, feces, and
protein-containing materials, surfaces should be cleaned before
chlorine disinfectant is applied. Undissociated hypochlorous acid
(HOCl) is the active biocidal agent. When pH is increased, the
less active hypochlorite ion, OCl–, is formed. When hypochlorite
solutions contact formaldehyde, the carcinogen bischloromethyl
is formed. Rapid evolution of irritating chlorine gas occurs when
hypochlorite solutions are mixed with acid and urine. Solutions
are corrosive to aluminum, silver, and stainless steel.
Alternative chlorine-releasing compounds include chlorine
dioxide and chloramine-T. These agents have a prolonged bac-
tericidal action.
PHENOLICS
Phenol itself (perhaps the oldest of the surgical antiseptics) is
no longer used even as a disinfectant because of its corrosive
effect on tissues, its toxicity when absorbed, and its carcinogenic
effect. These adverse actions are diminished by forming deriva-
tives in which a functional group replaces a hydrogen atom in
the aromatic ring. The phenolic agents most commonly used
are o-phenylphenol, o-benzyl-p-chlorophenol, and p-tertiary
amylphenol. Mixtures of phenolic derivatives are often used.
Some of these are derived from coal tar distillates, eg, cresols and
xylenols. Skin absorption and skin irritation still occur with these
derivatives, and appropriate care is necessary in their use. Deter-
gents are often added to formulations to clean and remove organic
material that may decrease the activity of a phenolic compound.
Phenolic compounds disrupt cell walls and membranes, precipi-
tate proteins, and inactivate enzymes. They are bactericidal (includ-
ing mycobacteria) and fungicidal and are capable of inactivating
lipophilic viruses. They are not sporicidal. Dilution and time of
exposure recommendations of the manufacturer must be followed.
Phenolic disinfectants are used for hard surface decontamination
in hospitals and laboratories, eg, floors, beds, and counter or bench
tops. They are not recommended for use in nurseries and especially
near infants, where their use has been associated with hyperbiliru-
binemia. Use of hexachlorophene as a skin disinfectant has caused
cerebral edema and seizures in premature infants and, occasionally,
in adults. It is no longer available in the United States.
QUATERNARY AMMONIUM
COMPOUNDS
The quaternary ammonium compounds (“quats”) are cationic
surface-active detergents. The active cation has at least one long
water-repellent hydrocarbon chain, which causes the molecules to
concentrate as an oriented layer on the surface of solutions and
900    SECTION VIII  Chemotherapeutic Drugs
colloidal or suspended particles. The charged nitrogen portion
of the cation has high affinity for water and prevents separation
out of solution. The bactericidal action of quaternary compounds
has been attributed to inactivation of energy-producing enzymes,
denaturation of proteins, and disruption of the cell membrane.
These agents are fungistatic and sporistatic and also inhibit algae.
They are bactericidal for Gram-positive bacteria and moderately
active against Gram-negative bacteria. Lipophilic viruses are
inactivated. They are not tuberculocidal or sporicidal, and they
do not inactivate hydrophilic viruses. Quaternary ammonium
compounds bind to the surface of colloidal protein in blood,
serum, and milk and to the fibers in cotton, mops, cloths, and
paper towels used to apply them, which can cause inactivation of
the agent by removing it from solution. They are inactivated by
anionic detergents (soaps), by many nonionic detergents, and by
calcium, magnesium, ferric, and aluminum ions.
Quaternary compounds are used for sanitation of noncriti-
cal surfaces (floors, bench tops, etc). Their low toxicity has led
to their use as sanitizers in food production facilities. The CDC
recommends that quaternary ammonium compounds such as
benzalkonium chloride not be used as antiseptics because several
outbreaks of infections have occurred that were due to growth
of Pseudomonas and other Gram-negative bacteria in quaternary
ammonium antiseptic solutions.
ALDEHYDES
Formaldehyde and glutaraldehyde are used for disinfection or
sterilization of instruments such as fiberoptic endoscopes, respira-
tory therapy equipment, hemodialyzers, and dental instruments
that cannot withstand exposure to the high temperatures of steam
sterilization. They are not corrosive for metal, plastic, or rubber.
These agents have a broad spectrum of activity against microor-
ganisms. They act by alkylation of chemical groups in proteins
and nucleic acids. Failures of disinfection or sterilization can
occur as a result of dilution below the known effective concentra-
tion, the presence of organic material, and the failure of liquid to
penetrate into small channels in the instruments. Automatic cir-
culating baths are available that increase penetration of aldehyde
solution into the instrument while decreasing exposure of the
operator to irritating fumes.
Formaldehyde is available as a 40% weight per volume solu-
tion in water (100% formalin). An 8% formaldehyde solution
in water has a broad spectrum of activity against bacteria, fungi,
and viruses. Sporicidal activity may take as long as 18 hours. Its
rapidity of action is increased by solution in 70% isopropanol.
Formaldehyde solutions are used for high-level disinfection of
hemodialyzers, preparation of vaccines, and preservation and
embalming of tissues. The 4% formaldehyde (10% formalin)
solutions used for fixation of tissues and embalming may not be
mycobactericidal.
Glutaraldehyde is a dialdehyde (1,5-pentanedial). Solutions of
2% weight per volume glutaraldehyde are most commonly used.
The solution must be alkalinized to pH 7.4–8.5 for activation.
Activated solutions are bactericidal, sporicidal, fungicidal, and
viricidal for both lipophilic and hydrophilic viruses. Glutaralde-
hyde has greater sporicidal activity than formaldehyde, but it may
have less tuberculocidal activity. Lethal action against mycobacte-
ria and spores may require prolonged exposure. Once activated,
solutions have a shelf life of 14 days, after which polymerization
reduces activity. Other means of activation and stabilization can
increase the shelf life. Because glutaraldehyde solutions are fre-
quently reused, the most common reason for loss of activity is
dilution and exposure to organic material. Test strips to measure
residual activity are recommended.
Formaldehyde has a characteristic pungent odor and is highly
irritating to respiratory mucous membranes and eyes at concen-
trations of 2–5 ppm. The U.S. Occupational Safety and Health
Administration (OSHA) has declared that formaldehyde is a
potential carcinogen and has established an employee exposure
standard that limits the 8-hour time-weighted average (TWA)
exposure to 0.75 ppm. Protection of health care workers from
exposure to glutaraldehyde concentrations greater than 0.2 ppm
is advisable. Increased air exchange, enclosure in hoods with
exhausts, tight-fitting lids on exposure devices, and use of protec-
tive personal equipment such as goggles, respirators, and gloves
may be necessary to achieve these exposure limits.
Ortho-phthalaldehyde (OPA) is a phenolic dialdehyde chemi-
cal sterilant with a spectrum of activity comparable to glutaralde-
hyde, although it is several times more rapidly bactericidal. OPA
solution typically contains 0.55% OPA. Its label claim is that
high-level disinfection can be achieved in 12 minutes at room
temperature compared with 45 minutes for 2.4% glutaraldehyde.
Unlike glutaraldehyde, OPA requires no activation, is less irritating
to mucous membranes, and does not require exposure monitoring.
It has good materials compatibility and an acceptable environmen-
tal safety profile. OPA is useful for disinfection or sterilization of
endoscopes, surgical instruments, and other medical devices.
SUPEROXIDIZED WATER
Electrolysis of saline yields a mixture of oxidants, primarily hypo-
chlorous acid and chlorine, with potent disinfectant and sterilant
properties. The solution generated by the process, which has been
commercialized and marketed as Sterilox for disinfection of endo-
scopes and dental materials, is rapidly bactericidal, fungicidal,
tuberculocidal, and sporicidal. High-level disinfection is achieved
with a contact time of 10 minutes. The solution is nontoxic and
nonirritating and requires no special disposal precautions.
PEROXYGEN COMPOUNDS
The peroxygen compounds, hydrogen peroxide and peracetic
acid, have high killing activity and a broad spectrum against bacte-
ria, spores, viruses, and fungi when used in appropriate concentra-
tion. They have the advantage that their decomposition products
are not toxic and do not injure the environment. They are powerful
oxidizers that are used primarily as disinfectants and sterilants.
Hydrogen peroxide is a very effective disinfectant when used
for inanimate objects or materials with low organic content such
 CHAPTER 50  Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Sterilants     901
as water. Systems that produce hydrogen peroxide vapor or dry
mist are now available for room decontamination in healthcare
facilities. Organisms that produce the enzymes catalase and
peroxidase rapidly degrade hydrogen peroxide. The innocuous
degradation products are oxygen and water. Concentrated solu-
tions containing 90% weight per volume H2O2 are prepared
electrochemically. When diluted in high-quality deionized water
to 6% and 3% and put into clean containers, the products
remain stable. Concentrations of 10–25% hydrogen peroxide
are sporicidal. Vapor phase hydrogen peroxide (VPHP) is a cold
gaseous sterilant that has the potential to replace the toxic or
carcinogenic gases ethylene oxide and formaldehyde. VPHP does
not require a pressurized chamber and is active at temperatures
as low as 4°C and concentrations as low as 4 mg/L. It is incom-
patible with liquids and cellulose products. It penetrates the
surface of some plastics. Automated equipment using vaporized
hydrogen peroxide or hydrogen peroxide mixed with formic acid
is available for sterilizing endoscopes.
Peracetic acid (CH3COOOH) is prepared commercially from
hydrogen peroxide, acetic acid, and a catalyst such as sulfuric acid.
It is explosive in the pure form. It is usually used in dilute solu-
tion and transported in containers with vented caps to prevent
increased pressure as oxygen is released. Peracetic acid is more
active than hydrogen peroxide as a bactericidal and sporicidal
agent. Concentrations of 250–500 ppm are effective against a
broad range of bacteria in 5 minutes at pH 7.0 at 20°C. Bacterial
spores are inactivated by 500–30,000 ppm peracetic acid. Only
slightly increased concentrations are necessary in the presence of
organic matter. Viruses require variable exposures. Enteroviruses
require 2000 ppm for 15–30 minutes for inactivation.
An automated machine that uses buffered peracetic acid liquid
of 0.1–0.5% concentration has been developed for sterilization of
medical, surgical, and dental instruments. Peracetic acid steriliza-
tion systems have also been adopted for hemodialyzers. The food
processing and beverage industries use peracetic acid extensively
because the breakdown products in high dilution do not produce
objectionable odor, taste, or toxicity, and rinsing is not necessary.
Peracetic acid is a potent tumor promoter but a weak carcino-
gen. It is not mutagenic in the Ames test.
ULTRAVIOLET IRRADIATION
Ultraviolet irradiation is used in some health care facilities as an
alternate mode of disinfection for patient care areas. It is typically
employed via an automated system, allowing for less staff exposure
to decontamination products. It has rapid cidal activity against
numerous pathogens, providing effective decontamination for
most vegetative bacteria in less than 25 minutes and against C.
difficile in less than one hour.
HEAVY METALS
Heavy metals, principally mercury and silver, are now rarely used
as disinfectants. Mercury is an environmental hazard, and some
pathogenic bacteria have developed plasmid-mediated resistance
to mercurials. Hypersensitivity to thimerosal is common, possibly
in up to 40% of the population. These compounds are absorbed
from solution by rubber and plastic closures. Thimerosal 0.001–
0.004% is still used safely as a preservative of vaccines, antitoxins,
and immune sera. Although a causative link to autism has never
been established and the original claim was found to be fraudu-
lent, thimerosal-free vaccines are available for use in children and
pregnant women.
Inorganic silver salts are strongly bactericidal. Silver nitrate,
1:1000, had been most commonly used, particularly as a pre-
ventive for gonococcal ophthalmitis in newborns. Antibiotic
ointments have replaced silver nitrate for this indication. Silver
sulfadiazine slowly releases silver and is used to suppress bacterial
growth in burn wounds (see Chapter 46).
STERILANTS
For many years, pressurized steam (autoclaving) at 120°C for
30 minutes has been the basic method for sterilizing instruments
and other heat-resistant materials. When autoclaving is not
possible, as with lensed instruments and materials containing
plastic and rubber, ethylene oxide—diluted with either fluo-
rocarbon or carbon dioxide to diminish explosive hazard—has
been used at 440–1200 mg/L at 45–60°C with 30–60% relative
humidity. The higher concentrations have been used to increase
penetration.
Ethylene oxide is classified as a mutagen and carcinogen. The
OSHA permissible exposure limit (PEL) for ethylene oxide is
1 ppm calculated as a time-weighted average. Alternative steril-
ants now being used increasingly include vapor-phase hydrogen
peroxide, peracetic acid, ozone, gas plasma, chlorine dioxide,
formaldehyde, and propylene oxide. Each of these sterilants has
potential advantages and problems. Automated peracetic acid
systems are being used increasingly for high-level decontamina-
tion and sterilization of endoscopes and hemodialyzers because of
their effectiveness, automated features, and the low toxicity of the
residual products of sterilization.
PRESERVATIVES
Disinfectants are used as preservatives to prevent the over-
growth of bacteria and fungi in pharmaceutical products,
laboratory sera and reagents, cosmetic products, and contact
lenses. Multi-use vials of medication that may be reentered
through a rubber diaphragm, eye drops, and nose drops require
preservatives. Preservatives should not be irritating or toxic to
tissues to which they will be applied, they must be effective in
preventing growth of microorganisms likely to contaminate
solutions, and they must have sufficient solubility and stability
to remain active.
Commonly used preservative agents include organic acids such
as benzoic acid and salts, the parabens, (alkyl esters of p-hydroxy-
benzoic acid), sorbic acid and salts, phenolic compounds, quater-
nary ammonium compounds, alcohols, and mercurials such as
thimerosal in 0.001–0.004% concentration.
902    SECTION VIII  Chemotherapeutic Drugs

SUMMARY Miscellaneous Antimicrobials

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions

NITROIMIDAZOLE
  •  Metronidazole Disruption of electron Bactericidal activity Anaerobic infections • vaginitis Oral or IV • hepatic clearance (t½ 8 h)
transport chain against susceptible • C difficile colitis • disulfiram-like reaction when given with
anaerobic bacteria and alcohol • Toxicity: Gastrointestinal upset
protozoa • metallic taste • neuropathy • seizures

  •  Tinidazole: Oral; similar to metronidazole but dosed once daily; approved for trichomonas, giardiasis, and amebiasis

MACROLIDE
  •  Fidaxomicin Inhibits bacterial RNA Bactericidal in C difficile colitis Oral • blood levels negligible • Toxicity:
polymerase Gram-positive bacteria Nonspecific gastrointestinal upset

RIFAMYCIN
  •  Rifaximin Inhibits bacterial RNA Bactericidal activity in Travelers’ diarrhea, hepatic Oral • blood levels negligible • Toxicity:
polymerase Gram-positive and encephalopathy, C difficile Nausea
Gram-negative bacteria colitis, irritable bowel syndrome

URINARY ANTISEPTICS
  •  Nitrofurantoin Not fully understood
• disrupts protein synthesis
and inhibits multiple
bacterial enzyme systems
Bacteriostatic or Uncomplicated urinary tract Oral • rapid renal clearance (t½ 0.5 h) • blood
bactericidal activity infections • long-term levels are negligible • contraindicated in renal
against susceptible prophylaxis failure • Toxicity: Gastrointestinal upset
bacteria • neuropathies • hypersensitivity pneumonitis

  • Methenamine hippurate and methenamine mandelate: Oral; release formaldehyde at acidic pH in the urine; used only for prophylaxis, not treatment, of urinary tract infections

P R E P A R A T I O N S
A V A I L A B L E REFERENCES
Bischoff WE et al: Handwashing compliance by health care workers: The impact
of introducing an accessible, alcohol-based hand antiseptic. Arch Intern Med
GENERIC NAME AVAILABLE AS 2000;160:1017.
MISCELLANEOUS ANTIMICROBIAL DRUGS Chambers HF, Winston LG: Mupirocin prophylaxis misses by a nose. Ann Intern
Colistimethate sodium Generic, Coly-Mycin M Med 2004;140:484.
Fidaxomicin Dificid Gordin FM et al: Reduction in nosocomial transmission of drug-resistant bacte-
ria after introduction of an alcohol-based hand-rub. Infect Control Hosp
Methenamine hippurate Generic, Hiprex Epidemiol 2005;26:650.
Methenamine mandelate Generic, Mandelamine Hoonmo LK, DuPont HL: Rifaximin: A unique gastrointestinal-selective antibi-
Metronidazole Generic, Flagyl, Metro otic for enteric diseases. Curr Opin Gastroenterol 2010;26:17.
Mupirocin Generic, Bactroban, Centany Humphreys PN: Testing standards for sporicides. J Hosp Infect 2011;77:193.
Nitrofurantoin Generic, Macrodantin, Macrobid Louie TJ et al: Fidaxomicin versus vancomycin for Clostridium difficile infection.
N Engl J Med 2011;364:422.
Polymyxin B (Polymyxin B sulfate) Generic
Medical Letter: Tinidazole (Tindamax)—a new anti-protozoal drug. Med Lett
DISINFECTANTS, ANTISEPTICS, & STERILANTS Drugs Ther 2004;46:70.
Benzalkonium Generic, Zephiran Meyer GW: Endoscope disinfection. www.uptodate.com/contents/endoscope-
Benzoyl peroxide Generic disinfection. UpToDate 2017.
Chlorhexidine gluconate topical Generic, Hibiclens, Betasept, Noorani A et al: Systematic review and meta-analysis of preoperative antisepsis
with chlorhexidine versus povidone-iodine in clean-contaminated surgery.
others
Br J Surg 2010;97:1614.
Chlorhexidine gluconate, Peridex, Periogard Rutala WA, Weber DJ: Disinfection and sterilization in health care facilities: an
oral rinse: 0.12% overview and current issues. Infect Dis Clin N Am 2016;30:609.
Glutaraldehyde Cidex Rutala WA, Weber DJ: New disinfection and sterilization methods. Emerg Infect
Iodine aqueous Generic, Lugol’s Solution Dis 2001;7:348.
Iodine tincture Generic Widmer AF, Frei R: Decontamination, disinfection, and sterilization. In: Murray
PR et al (editors): Manual of Clinical Microbiology, 7th ed. American Society
Nitrofurazone Generic, Furacin
for Microbiology, 1999.
Ortho-phthalaldehyde Cidex OPA
Povidone-iodine Generic, Betadine
Silver nitrate Generic
Thimerosal Generic, Mersol
 CHAPTER 50  Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Sterilants     903

C ASE STUDY ANSWER

The patient may be treated with oral metronidazole,
which is an appropriate drug for mild to moderate cases
of C difficile infection. Oral vancomycin is also a reason-
able alternative and is the preferred treatment for severe
cases and for older patients. Fidaxomicin is an effective
treatment for C. difficile infection, but it is more expen-
sive than other first-line medications. The room should
be cleaned with a bleach solution (5000 ppm) because it
is sporicidal. Other sporicidal disinfectants also may be
effective.
 51
C H A P T E R
Clinical Use of
Antimicrobial Agents
Harry W. Lampiris, MD, &
Daniel S. Maddix, PharmD
C ASE STUDY
A 65-year-old man undergoes cystoscopy because of the
presence of microscopic hematuria in order to rule out
urologic malignancy. The patient has mild dysuria and
pyuria and empirically receives oral therapy with cip-
rofloxacin for presumed urinary tract infection prior to
the procedure and tolerates the procedure well. Approxi-
mately 48 hours after the procedure, the patient presents
to the emergency department with confusion, dysuria
and chills. Physical exam reveals a blood pressure of
The development of antimicrobial drugs represents one of the
most important advances in therapeutics, both in the control
or cure of serious infections and in the prevention and treat-
ment of infectious complications of other therapeutic modalities
such as cancer chemotherapy, immunosuppression, and surgery.
However, evidence is overwhelming that antimicrobial agents
are vastly overprescribed in outpatient settings in the USA, and
the availability of antimicrobial agents without prescription in
many developing countries has—by facilitating the development
of resistance—already severely limited therapeutic options in the
treatment of life-threatening infections. Therefore, the clinician
should first determine whether antimicrobial therapy is warranted
for a given patient. The specific questions one should ask include
the following:
1. Is an antimicrobial agent indicated on the basis of clinical find-
ings? Or is it prudent to wait until such clinical findings
become apparent?
2. Have appropriate clinical specimens been obtained to establish
a microbiologic diagnosis?
904
90/50, pulse of 120, temperature of 38.5° C and respira-
tory rate of 24. The patient is disoriented but the physical
exam is otherwise unremarkable. Laboratory test shows
WBC 24,000/mm3 and elevated serum lactate; urinalysis
shows 300 WBC per high power field and 4+ bacteria.
What possible organisms are likely to be responsible for
the patient’s symptoms? At this point, what antibiotic(s)
would you choose for initial therapy of this potentially
life-threatening infection?
3. What are the likely etiologic agents for the patient’s illness?
4. What measures should be taken to protect individuals exposed
to the index case to prevent secondary cases, and what measures
should be implemented to prevent further exposure?
5. Is there clinical evidence (eg, from well-executed clinical trials) that
antimicrobial therapy will confer clinical benefit for the patient?
Once a specific cause is identified based on specific microbio-
logic tests, the following further questions should be considered:
1. If a specific microbial pathogen is identified, can a narrower-
spectrum agent be substituted for the initial empiric drug?
2. Is one agent or a combination of agents necessary?
3. What are the optimal dose, route of administration, and dura-
tion of therapy?
4. What specific tests (eg, susceptibility testing) should be under-
taken to identify patients who will not respond to treatment?
5. What adjunctive measures can be undertaken to eradicate
the infection? For example, is surgery feasible for removal
of devitalized tissue or foreign bodies—or drainage of an

abscess—into which antimicrobial agents may be unable to
penetrate? Is it possible to decrease the dosage of immunosup-
pressive therapy in patients who have undergone organ trans-
plantation? Is it possible to reduce morbidity or mortality due
to the infection by reducing host immunologic response to the
infection (eg, by the use of corticosteroids for the treatment
of severe Pneumocystis jiroveci pneumonia or meningitis due to
Streptococcus pneumoniae)?
■■ EMPIRIC ANTIMICROBIAL
THERAPY
Antimicrobial agents are frequently used before the pathogen
responsible for a particular illness or the susceptibility to a par-
ticular antimicrobial agent is known. This use of antimicrobial
agents is called empiric (or presumptive) therapy and is based on
experience with a particular clinical entity. The usual justifica-
tion for empiric therapy is the hope that early intervention will
improve the outcome; in the best cases, this has been established
by placebo-controlled, double-blind, prospective clinical trials.
For example, treatment of febrile episodes in neutropenic cancer
patients with empiric antimicrobial therapy has been demon-
strated to have impressive morbidity and mortality benefits even
though the specific bacterial agent responsible for fever is deter-
mined for only a minority of such episodes.
Finally, there are many clinical entities, such as certain episodes
of community-acquired pneumonia, in which it is difficult to
identify a specific pathogen. In such cases, a clinical response to
empiric therapy may be an important clue to the likely pathogen.
Frequently, the signs and symptoms of infection diminish as
a result of empiric therapy, and microbiologic test results become
available to establish a specific microbiologic diagnosis. At the
time that the pathogenic organism responsible for the illness is
identified, empiric therapy is optimally modified to definitive
therapy, which is typically narrower in coverage and is given for
an appropriate duration based on the results of clinical trials, or
experience when clinical trial data are not available.
Approach to Empiric Therapy
Initiation of empiric therapy should follow a specific and system-
atic approach.
A. Formulate a Clinical Diagnosis of Microbial Infection
Using all available data, the clinician should determine that there
is a clinical syndrome compatible with infection (eg, pneumonia,
cellulitis, sinusitis).
B. Obtain Specimens for Laboratory Examination
Examination of stained specimens by microscopy or simple
examination of an uncentrifuged sample of urine for white blood
cells and bacteria may provide important immediate etiologic
clues. Cultures of selected anatomic sites (blood, sputum, urine,
cerebrospinal fluid, and stool) and nonculture methods (antigen
CHAPTER 51  Clinical Use of Antimicrobial Agents     905
testing, polymerase chain reaction, and serology) also may confirm
specific etiologic agents.
C. Formulate a Microbiologic Diagnosis
The history, physical examination, and immediately available lab-
oratory results (eg, Gram stain of urine or sputum) may provide
highly specific information. For example, in a young man with
urethritis and a Gram-stained smear from the urethral meatus
demonstrating intracellular Gram-negative diplococci, the most
likely pathogen is Neisseria gonorrhoeae. In the latter instance,
however, the clinician should be aware that a significant number
of patients with gonococcal urethritis have negative Gram stains
for the organism and that a significant number of patients with
gonococcal urethritis harbor concurrent chlamydial infection that
is not demonstrated on the Gram-stained smear.
D. Determine the Necessity for Empiric Therapy
Whether to initiate empiric therapy is an important clinical deci-
sion based partly on experience and partly on data from clinical
trials. Empiric therapy is indicated when there is a significant risk
of serious morbidity or mortality if therapy is withheld until a
specific pathogen is detected by the clinical laboratory.
In other settings, empiric therapy may be indicated for public
health reasons rather than for demonstrated superior outcome of
therapy in a specific patient. For example, urethritis in a young
sexually active man usually requires treatment for N gonorrhoeae
and Chlamydia trachomatis despite the absence of microbiologic
confirmation at the time of diagnosis. Because the risk of noncom-
pliance with follow-up visits in this patient population may lead
to further transmission of these sexually transmitted pathogens,
empiric therapy is warranted.
E. Institute Treatment
Selection of empiric therapy may be based on the microbiologic
diagnosis or a clinical diagnosis without available microbiologic
clues. If no microbiologic information is available, the antimicro-
bial spectrum of the agent or agents chosen must necessarily be
broader, taking into account the most likely pathogens responsible
for the patient’s illness.
Choice of Antimicrobial Agent
Selection from among several drugs depends on host factors that
include the following: (1) concomitant disease states (eg, AIDS,
neutropenia due to the use of cytotoxic chemotherapy, organ
transplantation, severe chronic liver or kidney disease) or the use of
immunosuppressive medications; (2) prior adverse drug effects; (3)
impaired elimination or detoxification of the drug (may be geneti-
cally predetermined but more frequently is associated with impaired
renal or hepatic function due to underlying disease); (4) age of the
patient; (5) pregnancy status; and (6) epidemiologic exposure (eg,
exposure to a sick family member or pet, recent hospitalization,
recent travel, occupational exposure, or new sexual partner).
Pharmacologic factors include (1) the kinetics of absorption,
distribution, and elimination; (2) the ability of the drug to be
delivered to the site of infection; (3) the potential toxicity of an
906    SECTION VIII  Chemotherapeutic Drugs
agent; and (4) pharmacokinetic or pharmacodynamic interactions
with other drugs.
Knowledge of the susceptibility of an organism to a specific
agent in a hospital or community setting is important in the
selection of empiric therapy. Pharmacokinetic differences among
agents with similar antimicrobial spectrums may be exploited to
reduce the frequency of dosing (eg, ceftriaxone, ertapenem, or
daptomycin may be conveniently given once every 24 hours).
Finally, increasing consideration is being given to the cost of
antimicrobial therapy, especially when multiple agents with com-
parable efficacy and toxicity are available for a specific infection.
Changing from intravenous to oral antibiotics for prolonged
administration can be particularly cost-effective.
Brief guides to empiric therapy based on presumptive microbial
diagnosis and site of infection are given in Tables 51–1 and 51–2.
■■ ANTIMICROBIAL THERAPY
OF INFECTIONS WITH KNOWN
ETIOLOGY
INTERPRETATION OF CULTURE RESULTS
Properly obtained and processed specimens for culture frequently
yield reliable information about the cause of infection. The lack of a
confirmatory microbiologic diagnosis may be due to the following:
1. Sample error, eg, obtaining cultures after antimicrobial agents
have been administered, inadequate volume or quantity of speci-
men obtained, or contamination of specimens sent for culture
2. Noncultivable or slow-growing organisms (Histoplasma capsu-
latum, Bartonella or Brucella species), in which cultures are
often discarded before sufficient growth has occurred for
detection
3. Requesting bacterial cultures when infection is due to other
organisms
4. Not recognizing the need for special media or isolation tech-
niques (eg, charcoal yeast extract agar for isolation of Legionella
species, shell-vial tissue culture system for rapid isolation of
cytomegalovirus)
Even in the setting of a classic infectious disease for which
isolation techniques have been established for decades (eg, pneu-
mococcal pneumonia, pulmonary tuberculosis, streptococcal
pharyngitis), the sensitivity of the culture technique may be inad-
equate to identify all cases of the disease.
GUIDING ANTIMICROBIAL THERAPY OF
ESTABLISHED INFECTIONS
Susceptibility Testing
Testing bacterial pathogens in vitro for their susceptibility to
antimicrobial agents is extremely valuable in confirming suscepti-
bility, ideally to a narrow-spectrum nontoxic antimicrobial drug.
Tests measure the concentration of drug required to inhibit
growth of the organism (minimal inhibitory concentration
[MIC]) or to kill the organism (minimal bactericidal concen-
tration [MBC]). The results of these tests can then be correlated
with known drug concentrations in various body compartments.
Only MICs are routinely measured in most infections, whereas
in infections in which bactericidal therapy is required for eradi-
cation of infection (eg, meningitis, endocarditis, sepsis in the
granulocytopenic host), MBC measurements occasionally may
be useful.
Specialized Assay Methods
A. Beta-Lactamase Assay
For some bacteria (eg, Haemophilus species), the susceptibility
patterns of strains are similar except for the production of β lac-
tamase. In these cases, extensive susceptibility testing may not be
required, and a direct test for β lactamase using a chromogenic
β-lactam substrate (nitrocefin disk) may be substituted.
B. Synergy Studies
Synergy studies are in vitro tests that attempt to measure syner-
gistic, additive, indifferent, or antagonistic drug interactions. In
general, these tests have not been standardized and have not cor-
related well with clinical outcome. (See section on Antimicrobial
Drug Combinations for details.)
MONITORING THERAPEUTIC
RESPONSE: DURATION OF THERAPY
The therapeutic response may be monitored microbiologically or
clinically. Cultures of specimens taken from infected sites should
eventually become sterile or demonstrate eradication of the patho-
gen and are useful for documenting recurrence or relapse. Follow-
up cultures may also be useful for detecting superinfections or the
development of resistance. Clinically, the patient’s systemic mani-
festations of infection (malaise, fever, leukocytosis) should abate,
and the clinical findings should improve (eg, as shown by clearing
of radiographic infiltrates or lessening hypoxemia in pneumonia).
The duration of definitive therapy required for cure depends on
the pathogen, the site of infection, and host factors (immunocom-
promised patients generally require longer courses of treatment).
Precise data on duration of therapy exist for some infections (eg,
streptococcal pharyngitis, syphilis, gonorrhea, tuberculosis, and
cryptococcal meningitis). In many other situations, duration of
therapy is determined empirically. Minimizing duration of anti-
microbial therapy for specific infections is an intervention that
may help prevent the development of antimicrobial resistance.
For many infections, a combined medical-surgical approach may
be required for clinical cure.
Clinical Failure of Antimicrobial Therapy
When the patient has an inadequate clinical or microbiologic
response to antimicrobial therapy selected by in vitro suscepti-
bility testing, systematic investigation should be undertaken to

TABLE 51–1  Empiric antimicrobial therapy based on microbiologic etiology.
Suspected or Proven Disease or Pathogen
Gram-negative cocci (aerobic)
  Moraxella (Branhamella) catarrhalis
  Neisseria gonorrhoeae
  Neisseria meningitidis
Gram-negative rods (aerobic)
  E coli, Klebsiella, Proteus
  Enterobacter, Citrobacter, Serratia
  Shigella
  Salmonella
  Campylobacter jejuni
  Brucella species
  Helicobacter pylori
  Vibrio species
  Pseudomonas aeruginosa
Burkholderia cepacia (formerly
  TMP-SMZ1
Pseudomonas cepacia)
Stenotrophomonas maltophilia (formerly
  TMP-SMZ1
Xanthomonas maltophilia)
  Legionella species
Gram-positive cocci (aerobic)
  Streptococcus pneumoniae
  Streptococcus pyogenes (group A)
  Streptococcus agalactiae (group B)
  Viridans streptococci
  Staphylococcus aureus
  β-Lactamase negative
  β-Lactamase positive
  Methicillin-resistant
10
  Enterococcus species
Gram-positive rods (aerobic)
  Bacillus species (non-anthracis)
  Listeria species
  Nocardia species
Anaerobic bacteria
 Gram-positive (clostridia, Peptococcus,
Actinomyces, Peptostreptococcus)
  Clostridium difficile
  Bacteroides fragilis
Fusobacterium, Prevotella,
  Metronidazole, clindamycin,
Porphyromonas
CHAPTER 51  Clinical Use of Antimicrobial Agents     907
Drugs of First Choice Alternative Drugs
TMP-SMZ,1 cephalosporin (second- Quinolone,3 macrolide4
or third-generation)2
Ceftriaxone, cefixime Spectinomycin, azithromycin
Penicillin G Chloramphenicol, ceftriaxone, cefotaxime
Cephalosporin (first- or second- Quinolone,3 aminoglycoside5
generation),2 TMP-SMZ1
TMP-SMZ,1 quinolone,3 carbapenem6 Antipseudomonal penicillin,7 aminoglycoside,5 cefepime
Quinolone3 TMP-SMZ,1 ampicillin, azithromycin, ceftriaxone
3
Quinolone, ceftriaxone Chloramphenicol, ampicillin, TMP-SMZ1
Erythromycin or azithromycin Tetracycline, quinolone3
Doxycycline + rifampin or Chloramphenicol + aminoglycoside5 or TMP-SMZ1
5
aminoglycoside
Proton pump inhibitor + amoxicillin Bismuth + metronidazole + tetracycline + proton pump
+ clarithromycin inhibitor
Tetracycline Quinolone,3 TMP-SMZ1
Antipseudomonal penicillin + Antipseudomonal penicillin ± quinolone,3 cefepime,
aminoglycoside5 ceftazidime, antipseudomonal carbapenem,6 or aztreonam ±
aminoglycoside5
Ceftazidime, chloramphenicol
Minocycline, ticarcillin-clavulanate, tigecycline, ceftazidime,
quinolone3
Azithromycin or quinolone3 Clarithromycin, erythromycin
Penicillin8 Doxycycline, ceftriaxone, antipneumococcal quinolone,3
macrolide,4 linezolid
Penicillin, clindamycin Erythromycin, cephalosporin (first-generation)2
5
Penicillin (± aminoglycoside ) Vancomycin
Penicillin Cephalosporin (first- or third-generation),2 vancomycin
   
2
Penicillin Cephalosporin (first-generation), vancomycin
9
Penicillinase-resistant penicillin As above
Vancomycin TMP-SMZ,1 minocycline, linezolid, daptomycin, tigecycline
5
Penicillin + aminoglycoside Vancomycin + aminoglycoside5
Vancomycin Imipenem, quinolone,3 clindamycin
1
Ampicillin (± aminoglycoside5) TMP-SMZ
1
Sulfadiazine, TMP-SMZ Minocycline, imipenem, amikacin, linezolid
Penicillin, clindamycin Vancomycin, carbapenem,6 chloramphenicol
Metronidazole Vancomycin, bacitracin
Metronidazole Chloramphenicol, carbapenem,6 β-lactam—β-lactamase-
inhibitor combinations, clindamycin
As for B fragilis
penicillin
(Continued)
908    SECTION VIII  Chemotherapeutic Drugs

TABLE 51–1  Empiric antimicrobial therapy based on microbiologic etiology. (Continued)

Suspected or Proven Disease or Pathogen Drugs of First Choice Alternative Drugs

Mycobacteria
  Mycobacterium tuberculosis Isoniazid + rifampin + ethambutol + Streptomycin, moxifloxacin, amikacin, ethionamide,
pyrazinamide cycloserine, PAS, linezolid
  Mycobacterium leprae    
  Multibacillary Dapsone + rifampin + clofazimine  
  Paucibacillary Dapsone + rifampin  
Mycoplasma pneumoniae Tetracycline, erythromycin Azithromycin, clarithromycin, quinolone3
Chlamydia
  C trachomatis Tetracycline, azithromycin Clindamycin, ofloxacin
  C pneumoniae Tetracycline, erythromycin Clarithromycin, azithromycin
  C psittaci Tetracycline Chloramphenicol
Spirochetes
  Borrelia recurrentis Doxycycline Erythromycin, chloramphenicol, penicillin
  Borrelia burgdorferi    
  Early Doxycycline, amoxicillin Cefuroxime axetil, penicillin
  Late Ceftriaxone  
  Leptospira species Penicillin Tetracycline
  Treponema species Penicillin Tetracycline, azithromycin, ceftriaxone
Fungi
  Aspergillus species Voriconazole Amphotericin B, itraconazole, caspofungin, isavuconazole
  Blastomyces species Amphotericin B Itraconazole, fluconazole
  Candida species Amphotericin B, echinocandin11 Fluconazole, itraconazole, voriconazole
  Cryptococcus neoformans Amphotericin B ± flucytosine (5-FC) Fluconazole, voriconazole
  Coccidioides immitis Amphotericin B Fluconazole, itraconazole, voriconazole, posaconazole
  Histoplasma capsulatum Amphotericin B Itraconazole
  Mucoraceae (Rhizopus, Absidia) Amphotericin B Posaconazole, isavuconazole
  Sporothrix schenckii Amphotericin B Itraconazole
1
Trimethoprim-sulfamethoxazole (TMP-SMZ) is a mixture of one part trimethoprim plus five parts sulfamethoxazole.
2
First-generation cephalosporins: cefazolin for parenteral administration; cefadroxil or cephalexin for oral administration. Second-generation cephalosporins: cefuroxime for par-
enteral administration; cefaclor, cefuroxime axetil, cefprozil for oral administration. Third-generation cephalosporins: ceftazidime, cefotaxime, ceftriaxone for parenteral admin-
istration; cefixime, cefpodoxime, ceftibuten, cefdinir, cefditoren for oral administration. Fourth-generation cephalosporin: cefepime for parenteral administration. Cephamycins:
cefoxitin and cefotetan for parenteral administration.
3
Quinolones: ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin. Norfloxacin is not effective for the treatment of systemic infections. Gemifloxacin,
levofloxacin, and moxifloxacin have excellent activity against pneumococci. Ciprofloxacin and levofloxacin have good activity against Pseudomonas aeruginosa.
4
Macrolides: azithromycin, clarithromycin, dirithromycin, erythromycin.
5
Generally, streptomycin and gentamicin are used to treat infections with Gram-positive organisms, whereas gentamicin, tobramycin, and amikacin are used to treat infections
with Gram-negatives.
6
Carbapenems: doripenem, ertapenem, imipenem, meropenem. Ertapenem lacks activity against enterococci, Acinetobacter, and P aeruginosa.
7
Antipseudomonal penicillin: piperacillin, piperacillin/tazobactam, ticarcillin/clavulanic acid.
8
See footnote 3 in Table 51–2 for guidelines on the treatment of penicillin-resistant pneumococcal meningitis.
9
Parenteral nafcillin or oxacillin; oral dicloxacillin.
10
There is no regimen that is reliably bactericidal for vancomycin-resistant enterococcus for which there is extensive clinical experience; daptomycin has bactericidal activity in
vitro. Regimens that have been reported to be efficacious include nitrofurantoin (for urinary tract infection); potential regimens for bacteremia include daptomycin, linezolid, and
dalfopristin/quinupristin.
11
Echinocandins: anidulafungin, caspofungin, micafungin.
 CHAPTER 51  Clinical Use of Antimicrobial Agents     909

TABLE 51–2  Empiric antimicrobial therapy based on site of infection.

Presumed Site of Infection Common Pathogens Drugs of First Choice Alternative Drugs

Bacterial endocarditis
 Acute Staphylococcus aureus Vancomycin + ceftriaxone Penicillinase-resistant penicillin1 +
gentamicin
 Subacute Viridans streptococci, enterococci Penicillin + gentamicin Vancomycin + gentamicin
Septic arthritis
 Child Haemophilus influenzae, S aureus, Vancomycin + ceftriaxone Vancomycin + ampicillin-sulbactam or
β-hemolytic streptococci ertapenem
 Adult S aureus, Enterobacteriaceae, Vancomycin + ceftriaxone Vancomycin + ertapenem, or quinolone
Neisseria gonorrhoeae
Acute otitis media, H influenzae, Streptococcus Amoxicillin Amoxicillin-clavulanate, cefuroxime
sinusitis pneumoniae, Moraxella catarrhalis axetil, TMP-SMZ
Cellulitis S aureus, group A streptococcus Penicillinase-resistant penicillin, Vancomycin, clindamycin, linezolid,
cephalosporin (first-generation)2 daptomycin
Meningitis
 Neonate Group B streptococcus, Escherichia Ampicillin + cephalosporin Ampicillin + aminoglycoside,
coli, Listeria (third-generation) chloramphenicol, meropenem
 Child H influenzae, pneumococcus, Ceftriaxone or cefotaxime ± Chloramphenicol, meropenem
meningococcus vancomycin3
 Adult Pneumococcus, meningococcus Ceftriaxone, cefotaxime Vancomycin + ceftriaxone or cefotaxime3
Peritonitis due to Coliforms, Bacteroides fragilis Metronidazole + cephalosporin Carbapenem, tigecycline
ruptured viscus (third-generation), piperacillin/
tazobactam
Pneumonia
 Neonate As in neonatal meningitis    
 Child Pneumococcus, S aureus, Ceftriaxone, cefuroxime, Ampicillin-sulbactam
H influenzae cefotaxime
 Adult Pneumococcus, Mycoplasma, Outpatient: Macrolide,4 Outpatient: Quinolone
(community-acquired) Legionella, H influenzae, S aureus, amoxicillin, tetracycline
Chlamydophila pneumonia,
coliforms
    Inpatient: Macrolide4 + Inpatient: Doxycycline + cefotaxime,
cefotaxime, ceftriaxone, ceftriaxone, ertapenem, or ampicillin;
ertapenem, or ampicillin respiratory quinolone5
Septicemia6 Any Vancomycin + cephalosporin (third-generation) or piperacillin/tazobactam or
imipenem or meropenem
Septicemia with Any Antipseudomonal penicillin + aminoglycoside; ceftazidime; cefepime;
granulocytopenia imipenem or meropenem; consider addition of systemic antifungal therapy if
fever persists beyond 5 days of empiric therapy
1
See footnote 9, Table 51–1.
2
See footnote 2, Table 51–1.
3
When meningitis with penicillin-resistant pneumococcus is suspected, empiric therapy with this regimen is recommended.
4
Erythromycin, clarithromycin, or azithromycin (an azalide) may be used.
5
Quinolones used to treat pneumonococcal infections include levofloxacin, moxifloxacin, and gemifloxacin.
6
Adjunctive immunomodulatory drugs such as drotrecogin-alfa can also be considered for patients with severe sepsis.

determine the cause of failure. Errors in susceptibility testing are
rare, but the original results should be confirmed by repeat test-
ing. Drug dosing and absorption should be scrutinized and tested
directly using serum measurements, pill counting, or directly
observed therapy.
The clinical data should be reviewed to determine whether
the patient’s immune function is adequate and, if not, what
can be done to maximize it. For example, are adequate numbers
of granulocytes present and is undiagnosed immunodeficiency,
malignancy, or malnutrition present? The presence of abscesses
or foreign bodies should also be considered. Finally, culture and
susceptibility testing should be repeated to determine whether
superinfection has occurred with another organism or whether the
original pathogen has developed drug resistance.
910    SECTION VIII  Chemotherapeutic Drugs

ANTIMICROBIAL
PHARMACODYNAMICS
The time course of drug concentration is closely related to the
antimicrobial effect at the site of infection and to any toxic effects.
Pharmacodynamic factors include pathogen susceptibility testing,
drug bactericidal versus bacteriostatic activity, drug synergism,
antagonism, and postantibiotic effects. Together with pharmaco-
kinetics, pharmacodynamic information permits the selection of
optimal antimicrobial dosage regimens.
Bacteriostatic versus Bactericidal Activity
Antibacterial agents may be classified as bacteriostatic or bacte-
ricidal (Table 51–3). For agents that are primarily bacteriostatic,
inhibitory drug concentrations are much lower than bactericidal
drug concentrations. In general, cell wall-active agents are bacte-
ricidal, and drugs that inhibit protein synthesis are bacteriostatic.
The classification of antibacterial agents as bactericidal or bac-
teriostatic has limitations. Some agents that are considered to be
bacteriostatic may be bactericidal against selected organisms. On
the other hand, enterococci are inhibited but not killed by vanco-
mycin, penicillin, or ampicillin used as single agents.
Bacteriostatic and bactericidal agents are equivalent for the
treatment of most infectious diseases in immunocompetent
hosts. Bactericidal agents should be selected over bacteriostatic
ones in circumstances in which local or systemic host defenses
are impaired. Bactericidal agents are required for treatment of
endocarditis and other endovascular infections, meningitis, and
infections in neutropenic cancer patients.
Bactericidal agents can be divided into two groups: agents that
exhibit concentration-dependent killing (eg, aminoglycosides
and quinolones) and agents that exhibit time-dependent killing
(eg, β-lactams and vancomycin). For drugs whose killing action is
concentration-dependent, the rate and extent of killing increase
with increasing drug concentrations. Concentration-dependent
killing is one of the pharmacodynamic factors responsible for the
efficacy of once-daily dosing of aminoglycosides. For drugs whose
killing action is time-dependent, bactericidal activity continues as
long as serum concentrations are greater than the MBC.
Postantibiotic Effect
Persistent suppression of bacterial growth after limited exposure to
an antimicrobial agent is known as the postantibiotic effect (PAE).
The PAE can be expressed mathematically as follows:
PAE = T – C
where T is the time required for the viable count in the test (in
vitro) culture to increase tenfold above the count observed imme-
diately before drug removal and C is the time required for the
count in an untreated culture to increase tenfold above the count
observed immediately after completion of the same procedure
used on the test culture. The PAE reflects the time required for
bacteria to return to logarithmic growth.
Proposed mechanisms include (1) slow recovery after reversible
nonlethal damage to cell structures; (2) persistence of the drug at
a binding site or within the periplasmic space; and (3) the need
to synthesize new enzymes before growth can resume. Most anti-
microbials possess significant in vitro PAEs (≥1.5 hours) against
susceptible Gram-positive cocci (Table 51–4). Antimicrobials
TABLE 51–4  Antibacterial agents with in vitro
postantibiotic effects ≥1.5 hours.

Against Gram-Positive Cocci Against Gram-Negative Bacilli

Aminoglycosides Aminoglycosides
TABLE 51–3  Bactericidal and bacteriostatic
Carbapenems Carbapenems
antibacterial agents.
Cephalosporins Chloramphenicol
Bactericidal Agents Bacteriostatic Agents Chloramphenicol Quinolones
Aminoglycosides Chloramphenicol Clindamycin Rifampin
Bacitracin Clindamycin Daptomycin Tetracyclines
β-Lactam antibiotics Ethambutol Glycopeptide antibiotics Tigecycline
Daptomycin Macrolides Ketolides  
Fosfomycin Nitrofurantoin Macrolides  
Glycopeptide antibiotics Novobiocin Oxazolidinones  
Isoniazid Oxazolidinones Penicillins  
Ketolides Sulfonamides Quinolones  
Metronidazole Tetracyclines Rifampin  
Polymyxins Tigecycline Streptogramins  
Pyrazinamide Trimethoprim Sulfonamides  
Quinolones   Tetracyclines  
Rifampin   Tigecycline  
Streptogramins   Trimethoprim  

with significant PAEs against susceptible Gram-negative bacilli are
limited to carbapenems and agents that inhibit protein or DNA
synthesis.
In vivo PAEs are usually much longer than in vitro PAEs.
This is thought to be due to postantibiotic leukocyte enhance-
ment (PALE) and exposure of bacteria to subinhibitory antibiotic
concentrations. The efficacy of once-daily dosing regimens is in
part due to the PAE. Aminoglycosides and quinolones possess
concentration-dependent PAEs; thus, high doses of aminoglyco-
sides given once daily result in enhanced bactericidal activity and
extended PAEs. This combination of pharmacodynamic effects
allows aminoglycoside serum concentrations that are below the
MICs of target organisms to remain effective for extended periods
of time.
PHARMACOKINETIC CONSIDERATIONS
Route of Administration
Many antimicrobial agents have similar pharmacokinetic proper-
ties when given orally or parenterally (ie, tetracyclines, trime-
thoprim-sulfamethoxazole, quinolones, metronidazole, clindamycin,
rifampin, linezolid, and fluconazole). In most cases, oral therapy
with these drugs is equally effective, is less costly, and results in fewer
complications than parenteral therapy.
The intravenous route is preferred in the following situations:
(1) for critically ill patients; (2) for patients with bacterial menin-
gitis or endocarditis; (3) for patients with nausea, vomiting, gas-
trectomy, ileus, or diseases that may impair oral absorption; and
(4) when giving antimicrobials that are poorly absorbed following
oral administration.
Conditions That Alter Antimicrobial
Pharmacokinetics
Various diseases and physiologic states alter the pharmacokinetics
of antimicrobial agents. Impairment of renal or hepatic function
TABLE 51–5  Antimicrobial agents that require dosage adjustment or are contraindicated in patients with renal
or hepatic impairment.
Dosage Adjustment Needed in Renal Impairment
Acyclovir, amantadine, aminoglycosides, aztreonam,
carbapenems, cephalosporins,1 clarithromycin, colistin,
cycloserine, dalbavancin, daptomycin, didanosine, emtricitabine,
ethambutol, ethionamide, famciclovir, fluconazole,
flucytosine, foscarnet, ganciclovir, lamivudine, oseltamivir,
penicillins,2 peramivir, polymyxin B, pyrazinamide, quinolones,3
ribavirin, rifabutin, rimantadine, stavudine, telavancin,
telbivudine, telithromycin, tenofovir, terbinafine, trimethoprim-
sulfamethoxazole, valacyclovir, vancomycin, zidovudine
1
Except ceftriaxone.
2
Except antistaphylococcal penicillins (eg, nafcillin and dicloxacillin).
3
Except moxifloxacin.
4
Except doxycycline and minocycline.
CHAPTER 51  Clinical Use of Antimicrobial Agents     911
may result in decreased elimination. Table 51–5 lists drugs that
require dosage reduction in patients with renal or hepatic insuf-
ficiency. Failure to reduce antimicrobial agent dosage in such
patients may cause toxic effects. Conversely, patients with burns,
cystic fibrosis, or trauma may have increased dosage requirements
for selected agents. The pharmacokinetics of antimicrobials is
also altered in the elderly (see Chapter 60), in neonates (see
Chapter 59), and in pregnancy.
Drug Concentrations in Body Fluids
Most antimicrobial agents are well distributed to most body
tissues and fluids. Penetration into the cerebrospinal fluid is an
exception. Most do not penetrate uninflamed meninges to an
appreciable extent. In the presence of meningitis, however, the
cerebrospinal fluid concentrations of many antimicrobials increase
(Table 51–6).
Monitoring Serum Concentrations of
Antimicrobial Agents
For most antimicrobial agents, the relation between dose and
therapeutic outcome is well established, and serum concentra-
tion monitoring is unnecessary for these drugs. To justify routine
serum concentration monitoring, it should be established (1)
that a direct relationship exists between drug concentrations
and efficacy or toxicity; (2) that substantial interpatient vari-
ability exists in serum concentrations on standard doses; (3) that
a small difference exists between therapeutic and toxic serum
concentrations; (4) that the clinical efficacy or toxicity of the
drug is delayed or difficult to measure; and (5) that an accurate
assay is available.
In clinical practice, serum concentration monitoring is rou-
tinely performed on patients receiving aminoglycosides or van-
comycin. Flucytosine serum concentration monitoring has been
shown to reduce toxicity when doses are adjusted to maintain peak
concentrations below 100 mcg/mL.
Contraindicated in Dosage Adjustment Needed in
Renal Impairment Hepatic Impairment
Cidofovir, methenamine, Abacavir, atazanavir, caspofungin,
nalidixic acid, nitrofurantoin, chloramphenicol, clindamycin,
sulfonamides (long-acting), erythromycin, fosamprenavir, indinavir,
tetracyclines4 metronidazole, rimantadine, tigecycline
912    SECTION VIII  Chemotherapeutic Drugs

TABLE 51–6  Cerebrospinal fluid (CSF) penetration of ■■ ANTIMICROBIAL DRUG

selected antimicrobials.
COMBINATIONS
CSF Concentration CSF Concentration
(Uninflamed
Meninges) as
(Inflamed
Meninges) as
RATIONALE FOR COMBINATION
Antimicrobial % of Serum % of Serum ANTIMICROBIAL THERAPY
Agent Concentration Concentration

Ampicillin 2–3 2–100

Most infections should be treated with a single antimicrobial
agent. Although indications for combination therapy exist, anti-
Aztreonam 2 5
microbial combinations are often overused in clinical practice.
Cefepime 0–2 4–12 The unnecessary use of antimicrobial combinations increases tox-
Cefotaxime 22.5 27–36 icity and costs and may occasionally result in reduced efficacy due
Ceftazidime 0.7 20–40 to antagonism of one drug by another. Antimicrobial combina-
Ceftriaxone 0.8–1.6 16 tions should be selected for one or more of the following reasons:
Cefuroxime 20 17–88 1. To provide broad-spectrum empiric therapy in seriously ill
Ciprofloxacin 6–27 26–37 patients.
Imipenem 3.1 11–41 2. To treat polymicrobial infections (such as intra-abdominal
Meropenem 0–7 1–52 abscesses, which typically are due to a combination of anaero-
bic and aerobic Gram-negative organisms, and enterococci).
Nafcillin 2–15 5–27
The antimicrobial combination chosen should cover the most
Penicillin G 1–2 8–18
common known or suspected pathogens but need not cover all
Sulfamethoxazole 40 12–47 possible pathogens. The availability of antimicrobials with
Trimethoprim <41 12–69 excellent polymicrobial coverage (eg, β-lactamase inhibitor
Vancomycin 0 1–53 combinations or carbapenems) may reduce the need for com-
bination therapy in the setting of polymicrobial infections.
3. To decrease the emergence of resistant strains. The value of
■■ MANAGEMENT OF combination therapy in this setting has been clearly demon-
strated for tuberculosis.
ANTIMICROBIAL DRUG TOXICITY 4. To decrease dose-related toxicity by using reduced doses of one
Owing to the large number of antimicrobials available, it is usually or more components of the drug regimen. The use of flucyto-
possible to select an effective alternative in patients who develop sine in combination with amphotericin B for the treatment of
serious drug toxicity (Table 51–1). However, for some infections cryptococcal meningitis in non-HIV-infected patients allows
there are no effective alternatives to the drug of choice. For example, for a reduction in amphotericin B dosage with decreased
in patients with neurosyphilis who have a history of anaphylaxis to amphotericin B–induced nephrotoxicity.
penicillin, it is necessary to perform skin testing and desensitization 5. To obtain enhanced inhibition or killing. This use of antimi-
to penicillin. It is important to obtain a clear history of drug allergy crobial combinations is discussed in the paragraphs that follow.
and other adverse drug reactions. A patient with a documented
antimicrobial allergy should carry a card with the name of the drug
and a description of the reaction. Cross-reactivity between penicil- SYNERGISM & ANTAGONISM
lins and cephalosporins is less than 10%. Cephalosporins may be
When the inhibitory or killing effects of two or more antimicrobi-
administered to patients with penicillin-induced maculopapular
als used together are significantly greater than expected from their
rashes but should be avoided in patients with a history of penicillin-
effects when used individually, synergism is said to result. Syner-
induced immediate hypersensitivity reactions. On the other hand,
gism is marked by a fourfold or greater reduction in the MIC or
aztreonam does not cross-react with penicillins and can be safely
MBC of each drug when used in combination versus when used
administered to patients with a history of penicillin-induced ana-
alone. Antagonism occurs when the combined inhibitory or kill-
phylaxis. For mild reactions, it may be possible to continue therapy
ing effects of two or more antimicrobial drugs are significantly less
with use of adjunctive agents or dosage reduction.
than observed when the drugs are used individually.
Adverse reactions to antimicrobials occur with increased fre-
quency in several groups, including neonates, geriatric patients,
renal failure patients, and AIDS patients. Dosage adjustment of Mechanisms of Synergistic Action
the drugs listed in Table 51–5 is essential for the prevention of The need for synergistic combinations of antimicrobials has been
adverse effects in patients with renal failure. In addition, several clearly established for the treatment of enterococcal endocarditis.
agents are contraindicated in patients with renal impairment Bactericidal activity is essential for the optimal management of
because of increased rates of serious toxicity (Table 51–5). See the bacterial endocarditis. Penicillin or ampicillin in combination
preceding chapters for discussions of specific drugs. with gentamicin or streptomycin is superior to monotherapy with

a penicillin or vancomycin. When tested alone, penicillins and
vancomycin are only bacteriostatic against susceptible enterococ-
cal isolates. When these agents are combined with an amino-
glycoside, however, bactericidal activity results. The addition of
gentamicin or streptomycin to penicillin allows for a reduction in
the duration of therapy for selected patients with viridans strepto-
coccal endocarditis.
Other synergistic antimicrobial combinations have been shown
to be more effective than monotherapy with individual compo-
nents. Trimethoprim-sulfamethoxazole has been successfully used
in the treatment of bacterial infections and P jiroveci (carinii)
pneumonia.* β-Lactamase inhibitors restore the activity of intrin-
sically active but hydrolyzable β lactams against organisms such as
Staphylococcus aureus and Bacteroides fragilis. Three major mecha-
nisms of antimicrobial synergism have been established:
1. Blockade of sequential steps in a metabolic sequence:
Trimethoprim-sulfamethoxazole is the best-known example of
this mechanism of synergy (see Chapter 46). Blockade of the
two sequential steps in the folic acid pathway by trimethoprim-
sulfamethoxazole results in a much more complete inhibition
of growth than achieved by either component alone.
2. Inhibition of enzymatic inactivation: Enzymatic inactivation
of β-lactam antibiotics is a major mechanism of antibiotic
resistance. Inhibition of β lactamase by β-lactamase inhibitor
drugs (eg, sulbactam) results in synergism.
3. Enhancement of antimicrobial agent uptake: Penicillins and
other cell wall-active agents can increase the uptake of amino-
glycosides by a number of bacteria, including staphylococci,
enterococci, streptococci, and P aeruginosa. Enterococci are
thought to be intrinsically resistant to aminoglycosides because
of permeability barriers. Similarly, amphotericin B is thought
to enhance the uptake of flucytosine by fungi.
Mechanisms of Antagonistic Action
There are few clinically relevant examples of antimicrobial
antagonism. The most striking example was reported in a study of
patients with pneumococcal meningitis. Patients who were treated
with the combination of penicillin and chlortetracycline had a
mortality rate of 79% compared with a mortality rate of 21% in
patients who received penicillin monotherapy (illustrating the first
mechanism set forth below).
The use of an antagonistic antimicrobial combination does
not preclude other potential beneficial interactions. For example,
rifampin may antagonize the action of anti-staphylococcal penicil-
lins or vancomycin against staphylococci. However, the aforemen-
tioned antimicrobials may prevent the emergence of resistance to
rifampin.
Two major mechanisms of antimicrobial antagonism have been
established:
1. Inhibition of cidal activity by static agents: Bacteriostatic
agents such as tetracyclines and chloramphenicol can
*
Pneumocystis jiroveci is a fungal organism found in humans (P carinii
infects animals) that responds to antiprotozoal drugs. See Chapter 52.
CHAPTER 51  Clinical Use of Antimicrobial Agents     913
antagonize the action of bactericidal cell wall-active agents
because cell wall-active agents require that the bacteria be
actively growing and dividing.
2. Induction of enzymatic inactivation: Some Gram-negative bacilli,
including Enterobacter species, P aeruginosa, Serratia marcescens,
and Citrobacter freundii, possess inducible β-lactamases. β-Lactam
antibiotics such as imipenem, cefoxitin, and ampicillin are potent
inducers of β-lactamase production. If an inducing agent is com-
bined with an intrinsically active but hydrolyzable β-lactam such
as piperacillin, antagonism may result.
■■ ANTIMICROBIAL
PROPHYLAXIS
Antimicrobial agents are effective in preventing infections in
many settings. Antimicrobial prophylaxis should be used in cir-
cumstances in which efficacy has been demonstrated and benefits
outweigh the risks of prophylaxis. Antimicrobial prophylaxis may
be divided into surgical prophylaxis and nonsurgical prophylaxis.
Surgical Prophylaxis
Surgical wound infections are a major category of nosocomial
infections. The estimated annual cost of surgical wound infections
in the USA is more than $1.5 billion.
The National Research Council (NRC) Wound Classification
Criteria have served as the basis for recommending antimicrobial
prophylaxis. NRC criteria consist of four classes (see Box: National
Research Council [NRC] Wound Classification Criteria).
The Study of the Efficacy of Nosocomial Infection Control
(SENIC) identified four independent risk factors for postop-
erative wound infections: operations on the abdomen, operations
lasting more than 2 hours, contaminated or dirty wound classifi-
cation, and at least three medical diagnoses. Patients with at least
two SENIC risk factors who undergo clean surgical procedures
have an increased risk of developing surgical wound infections and
should receive antimicrobial prophylaxis.
Surgical procedures that necessitate the use of antimicrobial
prophylaxis include contaminated and clean-contaminated opera-
tions, selected operations in which postoperative infection may
be catastrophic such as open heart surgery, clean procedures that
involve placement of prosthetic materials, and any procedure
in an immunocompromised host. The operation should carry a
significant risk of postoperative site infection or cause significant
bacterial contamination.
General principles of antimicrobial surgical prophylaxis include
the following:
1. The antibiotic should be active against common surgical
wound pathogens; unnecessarily broad coverage should be
avoided.
2. The antibiotic should have proved efficacy in clinical trials.
3. The antibiotic must achieve concentrations greater than the
MIC of suspected pathogens, and these concentrations must be
present at the time of incision.
914    SECTION VIII  Chemotherapeutic Drugs

The proper selection and administration of antimicrobial

National Research Council (NRC) Wound
Classification Criteria
Clean: Elective, primarily closed procedure; respiratory, gas-
trointestinal, biliary, genitourinary, or oropharyngeal tract
not entered; no acute inflammation and no break in tech-
nique; expected infection rate ≤ 2%.
Clean contaminated: Urgent or emergency case that is
otherwise clean; elective, controlled opening of respiratory,
gastrointestinal, biliary, or oropharyngeal tract; minimal
spillage or minor break in technique; expected infection
rate ≤ 10%.
Contaminated: Acute nonpurulent inflammation; major
technique break or major spill from hollow organ; penetrat-
ing trauma less than 4 hours old; chronic open wounds to be
grafted or covered; expected infection rate about 20%.
Dirty: Purulence or abscess; preoperative perforation of
respiratory, gastrointestinal, biliary, or oropharyngeal tract;
penetrating trauma more than 4 hours old; expected infec-
tion rate about 40%.
4. The shortest possible course—ideally a single dose—of the
most effective and least toxic antibiotic should be used.
5. The newer broad-spectrum antibiotics should be reserved for
therapy of resistant infections.
6. If all other factors are equal, the least expensive agent should
be used.
prophylaxis are of utmost importance. Common indications for
surgical prophylaxis are shown in Table 51–7. Cefazolin is the
prophylactic agent of choice for head and neck, gastroduodenal,
biliary tract, gynecologic, and clean procedures. Local wound
infection patterns should be considered when selecting antimicro-
bial prophylaxis. The selection of vancomycin over cefazolin may
be necessary in hospitals with high rates of methicillin-resistant
S aureus or S epidermidis infections. The antibiotic should be pres-
ent in adequate concentrations at the operative site before incision
and throughout the procedure; initial dosing is dependent on the
volume of distribution, peak levels, clearance, protein binding,
and bioavailability. Parenteral agents should be administered dur-
ing the interval beginning 60 minutes before incision. In cesarean
section, the antibiotic is administered after umbilical cord clamp-
ing. For many antimicrobial agents, doses should be repeated if
the procedure exceeds 2–6 hours in duration. Single-dose pro-
phylaxis is effective for most procedures and results in decreased
toxicity and antimicrobial resistance.
Improper administration of antimicrobial prophylaxis leads
to excessive surgical wound infection rates. Common errors in
antibiotic prophylaxis include selection of the wrong antibiotic,
administering the first dose too early or too late, failure to repeat
doses during prolonged procedures, excessive duration of prophy-
laxis, and inappropriate use of broad-spectrum antibiotics.
Nonsurgical Prophylaxis
Nonsurgical prophylaxis includes the administration of antimi-
crobials to prevent colonization or asymptomatic infection as

TABLE 51–7  Recommendations for surgical antimicrobial prophylaxis.

Type of Operation Common Pathogens Drug of Choice

Cardiac (with median sternotomy) Staphylococci, enteric Gram-negative rods Cefazolin

Noncardiac, thoracic Staphylococci, streptococci, enteric Gram-negative rods Cefazolin
Vascular (abdominal and lower Staphylococci, enteric Gram-negative rods Cefazolin
extremity)
Neurosurgical (craniotomy) Staphylococci Cefazolin
Orthopedic (with hardware insertion) Staphylococci Cefazolin
Head and neck (with entry into the Staphylococcus aureus, oral flora Cefazolin + metronidazole
oropharynx)
Gastroduodenal S aureus, oral flora, enteric Gram-negative rods Cefazolin
Biliary tract S aureus, enterococci, enteric Gram-negative rods Cefazolin
Colorectal (elective surgery) Enteric Gram-negative rods, anaerobes Oral erythromycin + neomycin1
Colorectal (emergency surgery or Enteric Gram-negative rods, anaerobes Cefoxitin, cefotetan, ertapenem, or
obstruction) cefazolin + metronidazole
Appendectomy, nonperforated Enteric Gram-negative rods, anaerobes Cefoxitin, cefotetan, or cefazolin +
metronidazole
Hysterectomy Enteric Gram-negative rods, anaerobes, enterococci, group B Cefazolin, cefotetan, or cefoxitin
streptococci
Cesarean section Enteric Gram-negative rods, anaerobes, enterococci, group B Cefazolin
streptococci
1
In conjunction with mechanical bowel preparation.
 CHAPTER 51  Clinical Use of Antimicrobial Agents     915

TABLE 51–8  Recommendations for nonsurgical antimicrobial prophylaxis.

Infection to Be
Prevented Indication(s) Drug of Choice Efficacy

Anthrax Suspected exposure Ciprofloxacin or doxycycline Proposed effective

Cholera Close contacts of a case Tetracycline Proposed effective
Diphtheria Unimmunized contacts Penicillin or erythromycin Proposed effective
Endocarditis Dental, oral, or upper respiratory tract procedures1 in Amoxicillin or clindamycin Proposed effective
at-risk patients2
Genital herpes simplex Recurrent infection (≥4 episodes per year) Acyclovir Excellent
Perinatal herpes simplex Mothers with primary HSV or frequent recurrent Acyclovir Proposed effective
type 2 infection genital HSV
Group B streptococcal Mothers with cervical or vaginal GBS colonization and Ampicillin or penicillin Excellent
(GBS) infection their newborns with one or more of the following: (a)
onset of labor or membrane rupture before 37 weeks’ ges-
tation, (b) prolonged rupture of membranes (>12 hours),
(c) maternal intrapartum fever, (d) history of GBS bacteri-
uria during pregnancy, (e) mothers who have given birth
to infants who had early GBS disease or with a history of
streptococcal bacteriuria during pregnancy
Haemophilus influenzae Close contacts of a case in incompletely immunized Rifampin Excellent
type B infection children (>48 months old)
HIV infection Health care workers exposed to blood after needle-stick Tenofovir/emtricitabine and Good
injury raltegravir
  Pregnant HIV-infected women who are at ≥14 weeks of HAART3 Excellent
gestation; newborns of HIV-infected women for the first
6 weeks of life, beginning 8–12 hours after birth
Influenza A and B Unvaccinated geriatric patients, immunocompromised Oseltamivir Good
hosts, and health care workers during outbreaks
Malaria Travelers to areas endemic for chloroquine-susceptible Chloroquine Excellent
disease
  Travelers to areas endemic for chloroquine-resistant Mefloquine, doxycycline, or Excellent
disease atovaquone/proguanil
Meningococcal infection Close contacts of a case Rifampin, ciprofloxacin, or Excellent
ceftriaxone
Mycobacterium avium HIV-infected patients with CD4 count <75/μL Azithromycin, clarithromycin, Excellent
complex or rifabutin
Otitis media Recurrent infection Amoxicillin Good
Pertussis Close contacts of a case Azithromycin Excellent
Plague Close contacts of a case Tetracycline Proposed effective
Pneumococcemia Children with sickle cell disease or asplenia Penicillin Excellent
Pneumocystis jiroveci High-risk patients (eg, AIDS, leukemia, transplant) Trimethoprim-sulfamethoxa- Excellent
pneumonia (PCP) zole, dapsone, or atovaquone
Rheumatic fever History of rheumatic fever or known rheumatic heart Benzathine penicillin Excellent
disease
Toxoplasmosis HIV-infected patients with IgG antibody to Toxoplasma Trimethoprim- Good
and CD4 count <100/μL sulfamethoxazole
Tuberculosis Persons with positive tuberculin skin tests and one or Isoniazid or rifampin or iso- Excellent
more of the following: (a) HIV infection, (b) close contacts niazid + rifapentine
with newly diagnosed disease, (c) recent skin test conver-
sion, (d) medical conditions that increase the risk of devel-
oping tuberculosis, (e) age < 35 y
Urinary tract infections Recurrent infection Trimethoprim-sulfamethox- Excellent
(UTI) azole
1
Prophylaxis is recommended for the following: dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa,
and invasive procedure of the respiratory tract that involves incision or biopsy of the respiratory mucosa, such as tonsillectomy and adenoidectomy.
2
Prophylaxis should be targeted to those with the following risk factors: prosthetic heart valves, previous bacterial endocarditis, congenital cardiac malformations, cardiac trans-
plantation patients who develop cardiac valvulopathy.
3
Highly active antiretroviral therapy. See aidsinfo.nih.gov/ for updated guidelines.
916    SECTION VIII  Chemotherapeutic Drugs
well as the administration of drugs following colonization by or
inoculation of pathogens but before the development of disease.
Nonsurgical prophylaxis is indicated in individuals who are at
high risk for temporary exposure to selected virulent pathogens
and in patients who are at increased risk for developing infection
REFERENCES
Baddour LM et al: Infective endocarditis: Diagnosis, antimicrobial therapy, and
management of complications. Circulation 2015;132:1435.
Baron EJ et al: Guide to utilization of the microbiology laboratory for diagnosis of
infectious diseases: 2013 recommendations by the Infectious Diseases Soci-
ety of America (IDSA) and the American Society for Microbiology (ASM).
Clin Infect Dis 2013;57:e22.
Blumberg HM et al: American Thoracic Society/Centers for Disease Control and
Prevention/Infectious Diseases Society of America: Treatment of tuberculo-
sis. Am J Respir Crit Care Med 2003;167:603.
Boucher HW: 10 × ‘20 Progress—Development of new drugs active against gram-
negative bacilli: An update from the Infectious Diseases Society of America.
Clin Infect Dis 2013;56:1685.
Bratzler DW et al: Clinical practice guidelines for antimicrobial prophylaxis in
surgery. Am J Health Syst Pharm 2013;70:195.
Chow AW et al: IDSA clinical practice guideline for acute bacterial rhinosinusitis
in children and adults. Clin Infect Dis 2012;54:e72.
Holmes AH et al: Understanding the mechanisms and drivers of antimicrobial
resistance. Lancet 2016;387:176.
Kalil AC et al: Management of adults with hospital-acquired and ventilator-
associated pneumonia: 2016 Clinical practice guidelines by the Infectious
Disease Society of America and the American Thoracic Society. Clin Infect
Dis 2016;63:e61.
Kaye KS, Kaye D: Antibacterial therapy and newer agents. Infect Dis Clin North
Am 2009;23:757.
Mandell LA et al: Infectious Diseases Society of America/American Thoracic
Society Consensus guidelines on the management of community-acquired
pneumonia in adults. Clin Infect Dis 2007;44:S27.
C ASE STUDY ANSWER
This patient is experiencing a post-procedure urinary
tract infection which may have been introduced into
his bloodstream at the time of his cystoscopy. It is likely
that the patient is experiencing a sepsis-like syndrome
and has a systemic infection with a uropathogen that
is resistant to the antibiotic that he has received. Pos-
sible bacteria that may be responsible for the patient’s
symptoms are methicillin-resistant Staphylococcus aureus,
Enterococcus sp., and enteric Gram-negative rods that are
resistant to ciprofloxacin such as ESBL-positive E coli or
Klebsiella pneumoniae, or other hospital-acquired Gram
because of underlying disease (eg, immunocompromised hosts).
Prophylaxis is most effective when directed against organisms
that are predictably susceptible to antimicrobial agents. Common
indications and drugs for nonsurgical prophylaxis are listed in
Table 51–8.
Martin RF: Surgical infections. Surg Clin North Am 2014;94:1135.
Mirakian R et al: Management of allergy to penicillins and other beta-lactams.
Clin Exp Allergy 2015;45:300.
National Nosocomial Infections Surveillance System: National Nosocomial Infec-
tions Surveillance (NNIS) System Report, Data Summary from January
1992–June 2004, issued October 2004. Am J Infect Control 2004;32:470.
Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents:
Guidelines for the prevention and treatment of opportunistic infections in
HIV-infected adults and adolescents: Recommendations from the Centers
for Disease Control and Prevention, the National Institutes of Health, and
the HIV Medicine Association of the Infectious Diseases Society of America.
Available at: https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.
Peleg AY et al: Hospital-acquired infections due to gram negative bacteria. N Engl
J Med 2010;362:1804.
Simons FE: Anaphylaxis. J Allergy Clin Immunol 2010;125(Suppl 2):S161.
Spellberg B et al: The future of antibiotics and resistance. N Engl J Med
2013;368:299.
Tunkel AR et al: Practice guidelines for the management of bacterial meningitis.
Clin Infect Dis 2004;39:1267.
Wilson W et al: Prevention of infective endocarditis: Guidelines from the
American Heart Association. Circulation 2007;116:1736.
Workowski KA, Bolan GA: Sexually transmitted diseases treatment guidelines
2015. Centers for Disease Control and Prevention. MMWR Morb Mortal
Wkly Rep 2015;64(RR-3):1.
negative organisms such as Pseudomonas aeruginosa. The
patient was treated with vancomycin and meropenem,
and blood and urine cultures were both positive for
ESBL-positive E coli that was resistant to ciprofloxacin.
The patient defervesced and hemodynamically stabilized
over the subsequent 48 hours. ESBL-positive E coli is an
emerging urinary tract pathogen that may be acquired in
the outpatient setting, and oral antibiotic therapy may not
reliably be effective; empiric therapy with a carbapenem
(ertapenem, doripenem, meropenem, imipenem) is recom-
mended for serious infections due to this organism.

Antiprotozoal Drugs
Philip J. Rosenthal, MD
C ASE STUDY
A 5-year-old American girl presents with a 1-week history of
intermittent chills, fever, and sweats. She had returned home
2 weeks earlier after leaving the USA for the first time to spend
3 weeks with her grandparents in Nigeria. She received all
standard childhood immunizations, but no additional treat-
ment before travel, since her parents have returned to their
native Nigeria frequently without medical consequences.
Three days ago, the child was seen in an outpatient clinic
■■ MALARIA
Malaria is the most important parasitic disease of humans and
causes hundreds of millions of illnesses per year. Four species
of plasmodium typically cause human malaria: Plasmodium
falciparum, P vivax, P malariae, and P ovale. A fifth species,
P knowlesi, is primarily a pathogen of monkeys but has recently
been recognized to cause illness, including severe disease, in
humans in Asia. Although all of the latter species may cause
significant illness, P falciparum is responsible for the majority of
serious complications and deaths. Drug resistance is an important
therapeutic problem, most notably with P falciparum.
PARASITE LIFE CYCLE
An anopheline mosquito inoculates plasmodium sporozoites to
initiate human infection (Figure 52–1). Circulating sporozoites
rapidly invade liver cells, and exoerythrocytic stage tissue schizonts
mature in the liver. Merozoites are subsequently released from
the liver and invade erythrocytes. Only erythrocytic parasites
cause clinical illness. Repeated cycles of infection can lead to the
52
C H A P T E R
and diagnosed with a viral syndrome. Examination reveals
a lethargic child, with a temperature of 39.8°C (103.6°F) and
splenomegaly. She has no skin rash or lymphadenopathy. Ini-
tial laboratory studies are remarkable for hematocrit 29.8%,
platelets 45,000/mm3, creatinine 2.5 mg/dL (220 μmol/L), and
mildly elevated bilirubin and transaminases. A blood smear
shows ring forms of Plasmodium falciparum at 1.5% parasit-
emia. What treatment should be started?
infection of many erythrocytes and serious disease. Sexual stage
gametocytes also develop in erythrocytes before being taken up by
mosquitoes, where they develop into infective sporozoites.
In P falciparum and P malariae infection, only one cycle of liver
cell invasion and multiplication occurs, and liver infection ceases
spontaneously in less than 4 weeks. Thus, treatment that elimi-
nates erythrocytic parasites will cure these infections. In P vivax
and P ovale infections, a dormant hepatic stage, the hypnozoite, is
not eradicated by most drugs, and relapses can occur after therapy
directed against erythrocytic parasites. Eradication of both erythro-
cytic and hepatic parasites is required to cure these infections.
DRUG CLASSIFICATION
Several classes of antimalarial drugs are available (Table 52–1 and
Figure 52–2). Drugs that eliminate developing or dormant liver
forms are called tissue schizonticides; those that act on erythro-
cytic parasites are blood schizonticides; and those that kill sexual
stages and prevent transmission to mosquitoes are gametocides.
No single available agent can reliably effect a radical cure, ie,
eliminate both hepatic and erythrocytic stages. Few available
917
918    SECTION VIII  Chemotherapeutic Drugs
Blood
schizonticide Gametocide
Blood
Liver
Schizonts
Tissue
schizonticide
Hypnozoites
FIGURE 52–1  Life cycle of malaria parasites. Only the asexual
erythrocytic stage of infection causes clinical malaria. All effective
antimalarial treatments are blood schizonticides that kill this stage.
(Reproduced from Baird JK: Effectiveness of antimalarial drugs. N Engl J Med
2005;352:1565.)
agents are causal prophylactic drugs, ie, capable of preventing
erythrocytic infection. However, all effective chemoprophylactic
agents kill erythrocytic parasites before they increase sufficiently
in number to cause clinical disease.
CHEMOPROPHYLAXIS & TREATMENT
When patients are counseled on the prevention of malaria, it is
imperative to emphasize measures to prevent mosquito bites (eg,
with insect repellents, insecticides, and bed nets), because parasites
are increasingly resistant to multiple drugs and no chemoprophy-
lactic regimen is fully protective. Current recommendations from
the U.S. Centers for Disease Control and Prevention (CDC)
include the use of chloroquine for chemoprophylaxis in the few
areas infested by only chloroquine-sensitive malaria parasites
(principally Hispaniola and Central America west of the Panama
Canal), and mefloquine, Malarone,* or doxycycline for most other
malarious areas, with doxycycline preferred for areas with a high
prevalence of multidrug-resistant falciparum malaria (principally
border areas of Thailand) (Table 52–2). CDC recommenda-
tions should be checked regularly (Phone: 770-488-7788; after
hours 770-488-7100; Internet: www.cdc.gov/malaria), because
these may change in response to changing resistance patterns and
increasing experience with new drugs. In some circumstances, it
*
†
Malarone
is a proprietary formulation of atovaquone plus proguanil.
Coartem is a proprietary formulation of artemether and lumefantrine.
may be appropriate for travelers to carry supplies of drugs with
them in case they develop a febrile illness when medical atten-
tion is unavailable. Regimens for self-treatment include new
artemisinin-based combination therapies (see below), which are
widely available internationally (and, in the case of Coartem†, in
the USA); Malarone; mefloquine; and quinine. Most authorities
do not recommend routine terminal chemoprophylaxis with pri-
maquine to eradicate dormant hepatic stages of P vivax and P ovale
after travel, but this may be appropriate in some circumstances,
especially for travelers with major exposure to these parasites.
Multiple drugs are available for the treatment of malaria that
presents in the USA (Table 52–3). Most nonfalciparum infections
and falciparum malaria from areas without known resistance should
be treated with chloroquine. For vivax malaria from areas with sus-
pected chloroquine resistance, including Indonesia and Papua New
Guinea, other therapies effective against falciparum malaria may be
used. Vivax and ovale malaria should subsequently be treated with
primaquine to eradicate liver forms. Uncomplicated falciparum
malaria from most areas is most often treated with Malarone, but new
artemisinin-based combinations are increasingly the international
standard of care, and one combination, Coartem, is now available in
the USA. Other agents that are generally effective against resistant fal-
ciparum malaria include mefloquine, quinine, and halofantrine, all of
which have toxicity concerns at treatment dosages. Severe falciparum
malaria is treated with intravenous artesunate, quinidine, or quinine
(intravenous quinine is not available in the USA).
CHLOROQUINE
Chloroquine has been a drug of choice for both treatment and
chemoprophylaxis of malaria since the 1940s, but its usefulness
against P falciparum has been seriously compromised by drug
resistance. It remains the drug of choice in the treatment of sensi-
tive P falciparum and other species of human malaria parasites.
Chemistry & Pharmacokinetics
Chloroquine is a synthetic 4-aminoquinoline (Figure 52–2) for-
mulated as the phosphate salt for oral use. It is rapidly and almost
completely absorbed from the gastrointestinal tract, reaches
maximum plasma concentrations in about 3 hours, and is rapidly
distributed to the tissues. It has a very large apparent volume of
distribution of 100–1000 L/kg and is slowly released from tissues
and metabolized. Chloroquine is principally excreted in the urine
with an initial half-life of 3–5 days but a much longer terminal
elimination half-life of 1–2 months.
Antimalarial Action & Resistance
When not limited by resistance, chloroquine is a highly effective
blood schizonticide. Chloroquine is not reliably active against liver
stage parasites or gametocytes. The drug probably acts by concen-
trating in parasite food vacuoles, preventing the biocrystallization
 CHAPTER 52  Antiprotozoal Drugs    919

CH3 H2N
C2H5 N Cl
NH CH CH2 CH2 CH2 N
C2H5 Cl NH2

N
C2H5 Cl Cl
Cl
N Pyrimethamine (folate antagonist)
Chloroquine (4-aminoquinoline)
HO CH3
H3C CH3 N
CH3
HC N
NH OH
Lumefantrine (phenanthrene methanol)
Cl NH NH2
C2H5 Cl
CH2 N N
C2H5 H 2N
Cl
N Proguanil (folate antagonist)
Amodiaquine (4-aminoquinoline) O

N CH CH2
N CH2
N N CH2 OH
O
HO CH N
Atovaquone (quinone)
N CH3O
Cl
CH3
N
Cl Quinine (quinoline methanol) H3C O
N
Piperaquine (4-aminoquinoline) O
O
HO

HC O
CH3O CH3
N R2 R1
H
Artemisinins (endoperoxides)
(multiple structures)
N CF3
N
NH CH CH2 CH2 CH2 NH2
CF3
N
CH3 Mefloquine (quinoline methanol)

Primaquine (8-aminoquinoline)
CH2CH2CH2CH3 OH
HOCHCH2CH2N
CH2CH2CH2CH3
N
N N Cl
O O HN
S
OCH3 N OCH3
N
H
OCH3
H 2N F3C Cl
Cl
N
Sulfadoxine (folate antagonist) Halofantrine (phenanthrene methanol)
Pyronaridine

FIGURE 52–2  Structural formulas of some antimalarial drugs.

of the hemoglobin breakdown product, heme, into hemozoin, and
thus eliciting parasite toxicity due to the buildup of free heme.
Resistance to chloroquine is now very common among strains of
P falciparum and uncommon but increasing for P vivax. In P falciparum,
mutations in a putative transporter, PfCRT, are the primary mediators
of resistance. Chloroquine resistance can be reversed by certain agents,
including verapamil, desipramine, and chlorpheniramine, but the clini-
cal value of resistance-reversing drugs is not established.
malaria. It rapidly terminates fever (usually in 24–48 hours) and
clears parasitemia (in 48–72 hours) caused by sensitive parasites.
Chloroquine has been replaced by other drugs, principally arte-
misinin-based combination therapies, as the standard therapy to
treat falciparum malaria in most endemic countries. Chloroquine
does not eliminate dormant liver forms of P vivax and P ovale, and
for that reason primaquine must be added for the radical cure of
these species.

2. Chemoprophylaxis—Chloroquine is the preferred che-

Clinical Uses moprophylactic agent in malarious regions without resistant
1. Treatment—Chloroquine is the drug of choice in the treat- falciparum malaria. Eradication of P vivax and P ovale requires a
ment of uncomplicated nonfalciparum and sensitive falciparum course of primaquine to clear hepatic stages.
920    SECTION VIII  Chemotherapeutic Drugs

TABLE 52–1  Major antimalarial drugs.

Drug Class Use

Chloroquine 4-Aminoquinoline Treatment and chemoprophylaxis of infection with sensitive parasites

Amodiaquine1 4-Aminoquinoline Treatment of infection with some chloroquine-resistant P falciparum strains and in
fixed combination with artesunate
Piperaquine1 Bisquinoline Treatment of P falciparum infection in fixed combination with dihydroartemisinin
Quinine Quinoline methanol Oral and intravenous1 treatment of P falciparum infections
Quinidine Quinoline methanol Intravenous therapy of severe infections with P falciparum
Mefloquine Quinoline methanol Chemoprophylaxis and treatment of infections with P falciparum
Primaquine 8-Aminoquinoline Radical cure and terminal prophylaxis of infections with P vivax and P ovale;
alternative chemoprophylaxis for all species
Sulfadoxine-pyrimethamine Folate antagonist combination Treatment of infections with some chloroquine-resistant P falciparum, including
(Fansidar) combination with artesunate; intermittent preventive therapy in endemic areas
Atovaquone-proguanil Quinone-folate antagonist Treatment and chemoprophylaxis of P falciparum infection
(Malarone) combination
Doxycycline Tetracycline Treatment (with quinine) of infections with P falciparum; chemoprophylaxis
1
Halofantrine Phenanthrene methanol Treatment of P falciparum infections
2
Lumefantrine Amyl alcohol Treatment of P falciparum malaria in fixed combination with artemether (Coartem)
Pyronaridine Mannich base acridine Treatment of P falciparum malaria in fixed combination with artesunate (Pyramax)
Artemisinins Sesquiterpene lactone Treatment of P falciparum infections; oral combination therapies for uncomplicated
(artesunate, artemether,2 endoperoxides disease; intravenous artesunate for severe disease
dihydroartemisinin1)
1
Not available in the USA.
2
Available in the USA only as the fixed combination Coartem.

3. Amebic liver abscess—Chloroquine reaches high liver con-
centrations and may be used for amebic abscesses that fail initial
therapy with metronidazole (see below).
Adverse Effects
Chloroquine is usually very well tolerated, even with prolonged
use. Pruritus is common, primarily in Africans. Nausea, vomiting,
abdominal pain, headache, anorexia, malaise, blurring of vision,
and urticaria are uncommon. Dosing after meals may reduce
some adverse effects. Rare reactions include hemolysis in glucose-
6-phosphate dehydrogenase (G6PD)-deficient persons, impaired
hearing, confusion, psychosis, seizures, agranulocytosis, exfoliative
dermatitis, alopecia, bleaching of hair, hypotension, and electrocar-
diographic changes. The long-term administration of high doses of
chloroquine for rheumatologic diseases (see Chapter 36) can result
in irreversible ototoxicity, retinopathy, myopathy, and peripheral
neuropathy, but these are rarely seen with standard-dose weekly

TABLE 52–2  Drugs for the prevention of malaria in travelers.1

Drug Use2 Adult Dosage3

Chloroquine Areas without resistant P falciparum 500 mg weekly

Malarone Areas with chloroquine-resistant P falciparum 1 tablet (250 mg atovaquone/100 mg proguanil) daily
Mefloquine Areas with chloroquine-resistant P falciparum 250 mg weekly
Doxycycline Areas with multidrug-resistant P falciparum 100 mg daily
4
Primaquine Terminal prophylaxis of P vivax and P ovale infections; 52.6 mg (30 mg base) daily for 14 days after travel; for primary
alternative for primary prevention prevention 52.6 mg (30 mg base) daily
1
Recommendations may change, as resistance to all available drugs is increasing. See text for additional information on toxicities and cautions. For additional details and pediatric
dosing, see CDC guidelines (phone: 877-FYI-TRIP; www.cdc.gov). Travelers to remote areas should consider carrying effective therapy (see text) for use if they develop a febrile
illness and cannot reach medical attention quickly.
2
Areas without known chloroquine-resistant P falciparum are Central America west of the Panama Canal, Haiti, Dominican Republic, Egypt, and most malarious countries of the
Middle East. Malarone or mefloquine are currently recommended for other malarious areas except for border areas of Thailand, where doxycycline is recommended.
3
For drugs other than primaquine, begin 1–2 weeks before departure (except 2 days before for doxycycline and Malarone) and continue for 4 weeks after leaving the endemic
area (except 1 week for Malarone). All dosages refer to salts.
4
Screen for glucose-6-phosphate dehydrogenase (G6PD) deficiency before using primaquine.
 CHAPTER 52  Antiprotozoal Drugs    921

TABLE 52–3  Treatment of malaria.

Clinical Setting Drug Therapy1 Alternative Drugs

Chloroquine-sensitive Chloroquine phosphate, 1 g, followed by  

P falciparum and P malariae 500 mg at 6, 24, and 48 hours
infections   
or
   Chloroquine phosphate, 1 g at 0 and 24 hours,
then 0.5 g at 48 hours
P vivax and P ovale Chloroquine (as above), then (if G6PD normal) For infections from Indonesia, Papua New Guinea, and
infections primaquine, 52.6 mg (30 mg base) for 14 days other areas with suspected resistance: therapies listed for
uncomplicated chloroquine-resistant P falciparum plus
primaquine
Uncomplicated infections Coartem (artemether, 20 mg, plus lumefantrine, Malarone, four tablets (total of 1 g atovaquone, 400 mg
with chloroquine-resistant 120 mg), four tablets twice daily for 3 days proguanil) daily for 3 days
P falciparum or
Mefloquine, 15 mg/kg once or 750 mg, then 500 mg in
6–8 hours
or
Quinine sulfate, 650 mg 3 times daily for 3 days, plus
doxycycline, 100 mg twice daily for 7 days, or clindamycin,
600 mg twice daily for 7 days
or
Other artemisinin-based combination regimens (see
Table 52–4)
Severe or complicated Artesunate,2 2.4 mg/kg IV, every 12 hours for Artemether,3 3.2 mg/kg IM, then 1.6 mg/kg/d IM; follow with
infections with P falciparum 1 day, then daily for 2 additional days; follow with oral therapy as for artesunate
7-day oral course of doxycycline or clindamycin or
or full treatment course of Coartem, Malarone, or
mefloquine Quinine dihydrochloride,3–5 20 mg/kg IV, then 10 mg/kg every
8 hours
or
Quinidine gluconate,4,5 10 mg/kg IV over
1–2 hours, then 0.02 mg/kg IV/min
or
Quinidine gluconate4,5 15 mg/kg IV over
4 hours, then 7.5 mg/kg IV over 4 hours every
8 hours
1
All dosages are oral and refer to salts unless otherwise indicated. See text for additional information on all agents, including toxicities and cautions. See CDC guidelines
(phone: 770-488-7788; www.cdc.gov) for additional information and pediatric dosing.
2
Available in the United States only on an investigational basis through the CDC (phone: 770-488-7788).
3
Not available in the USA.
4
Cardiac monitoring should be in place during intravenous administration of quinidine or quinine. Change to an oral regimen as soon as the patient can tolerate it.
5
Avoid loading doses in persons who have received quinine, quinidine, or mefloquine in the prior 24 hours.
G6PD, glucose-6-phosphate dehydrogenase.

chemoprophylaxis. Intramuscular injections or intravenous infu- OTHER QUINOLINES

sions of chloroquine hydrochloride can result in severe hypotension
and respiratory and cardiac arrest, and should be avoided.
Contraindications & Cautions
Chloroquine is contraindicated in patients with psoriasis or
porphyria. It should generally not be used in those with retinal
or visual field abnormalities or myopathy, and should be used
with caution in patients with liver, neurologic, or hematologic
disorders. The antidiarrheal agent kaolin and calcium- and
magnesium-containing antacids interfere with the absorption of
chloroquine and should not be co-administered. Chloroquine is
considered safe in pregnancy and for young children.
Amodiaquine is closely related to chloroquine, and it probably
shares mechanisms of action and resistance. Amodiaquine was
widely used to treat malaria because of its low cost, limited toxicity,
and, in some areas, effectiveness against chloroquine-resistant strains
of P falciparum, but toxicities, including agranulocytosis, aplastic
anemia, and hepatotoxicity, have limited its use. However, recent
reevaluation has shown that serious toxicity from amodiaquine is
uncommon. The most important current use of amodiaquine is
in combination therapy. The World Health Organization (WHO)
lists artesunate plus amodiaquine as a recommended therapy for
falciparum malaria (Table 52–4). This combination is now available
as a single tablet (ASAQ, Arsucam, Coarsucam) and is the first-line
922    SECTION VIII  Chemotherapeutic Drugs
TABLE 52–4  WHO recommendations for the
treatment of falciparum malaria.
Regimen Notes
Artemether-lumefantrine Co-formulated; first-line therapy in
(Coartem, Riamet) many countries; approved in the USA
Artesunate-amodiaquine Co-formulated; first-line therapy in
(ASAQ, Arsucam, Coarsucam) many African countries
Artesunate-mefloquine Co-formulated; first-line therapy in
parts of Southeast Asia and South
America
Dihydroartemisinin-pipera- Co-formulated; first-line therapy in
quine (Artekin, Duocotecxin) some countries in Southeast Asia
Artesunate-sulfadoxine- First-line therapy in some countries,
pyrimethamine but efficacy lower than other
regimens in most areas
Data from World Health Organization: Guidelines for the Treatment of Malaria, 3rd ed.
World Health Organization. Geneva, 2015.
therapy for the treatment of uncomplicated falciparum malaria in
many countries in Africa. Long-term chemoprophylaxis with amo-
diaquine is best avoided because of its apparent increased toxicity
with long-term use, but short-term seasonal malaria chemopreven-
tion with amodiaquine plus sulfadoxine-pyrimethamine (monthly
treatment doses for 3–4 months during the transmission season) is
now recommended by the WHO for the Sahel sub-region of Africa.
Piperaquine is a bisquinoline that was used widely to
treat chloroquine-resistant falciparum malaria in China in the
1970s–1980s, but its use waned after resistance became widespread.
More recently, piperaquine combined with dihydroartemisinin
(Artekin, Duocotecxin) showed excellent efficacy and safety for the
treatment of falciparum malaria, although very recently decreased
efficacy has been seen in southeast Asia, linked to decreased activity
of both components of the combination. Piperaquine has a longer
half-life (~28 days) than amodiaquine (~14 days), mefloquine
(~14 days), or lumefantrine (~4 days), leading to a longer period
of post-treatment prophylaxis with dihydroartemisinin-piperaquine
than with the other leading artemisinin-based combinations; this
feature should be particularly advantageous in high-transmission
areas. Dihydroartemisinin-piperaquine is now the first-line ther-
apy for the treatment of uncomplicated falciparum malaria in
some countries in Asia. As dihydroartemisinin-piperaquine offers
extended protection against malaria, there is interest in chemopre-
vention with monthly dosing of the drug, which has shown excel-
lent efficacy in children and pregnant women in Africa.
ARTEMISININ & ITS DERIVATIVES
Artemisinin (qinghaosu) is a sesquiterpene lactone endoperoxide
(Figure 52–2), the active component of an herbal medicine that
has been used as an antipyretic in China for more than 2000 years.
Artemisinin is insoluble and can only be used orally. Analogs have
been synthesized to increase solubility and improve antimalarial
efficacy. The most important of these analogs are artesunate (water-
soluble; oral, intravenous, intramuscular, and rectal administration),
artemether (lipid-soluble; oral, intramuscular, and rectal administra-
tion), and dihydroartemisinin (water-soluble; oral administration).
Chemistry & Pharmacokinetics
Artemisinin and its analogs are complex 3- and 4-ring struc-
tures (Figure 52-2). They are rapidly absorbed, with peak plasma
levels occurring promptly. Half-lives after oral administration are
30–60 minutes for artesunate and dihydroartemisinin, and 2–3 hours
for artemether. Artemisinin, artesunate, and artemether are rapidly
metabolized to the active metabolite dihydroartemisinin. Drug levels
appear to decrease after a number of days of therapy.
Antimalarial Action & Resistance
The artemisinins are now widely available, but monotherapy for
the treatment of uncomplicated malaria is strongly discouraged.
Rather, co-formulated artemisinin-based combination therapies
are recommended to improve efficacy and prevent the selection
of artemisinin-resistant parasites. The oral combination regimen
Coartem (artemether-lumefantrine) was approved by the U.S.
Food and Drug Administration (FDA) in 2009, and it may be
considered the new first-line therapy in the USA for uncompli-
cated falciparum malaria, although it may not be widely available.
Intravenous artesunate is available from the CDC; use is initiated
by contacting the CDC, which will release it for appropriate indi-
cations (falciparum malaria with signs of severe disease or inability
to take oral medications) from stocks stored around the USA.
Artemisinin and its analogs are very rapidly acting blood schi-
zonticides against all human malaria parasites. Artemisinins have
no effect on hepatic stages. They are active against young, but
not mature gametocytes. The antimalarial activity of artemisinins
appears to result from the production of free radicals that follows the
iron-catalyzed cleavage of the artemisinin endoperoxide bridge. Arte-
misinin resistance is not yet a widespread problem, but delayed clear-
ance of P falciparum infections and decreased treatment efficacy in
parts of Southeast Asia demonstrate a worrisome focus of resistance.
Clinical Uses
Artemisinin-based combination therapy is now the standard of
care for treatment of uncomplicated falciparum malaria in nearly
all endemic areas. The leading regimens are highly efficacious,
safe, and well tolerated. These regimens were developed because
the short plasma half-lives of the artemisinins led to unaccept-
ably high recrudescence rates after short-course therapy, which
were reversed by inclusion of longer-acting drugs. Combination
therapy also helps to protect against the selection of artemisinin
resistance. However, with completion of dosing after 3 days, the
artemisinin components are rapidly eliminated, and so selection of
resistance to partner drugs is of concern.
The WHO recommends five artemisinin-based combina-
tions for the treatment of uncomplicated falciparum malaria
(Table 52–4). One of these, artesunate-sulfadoxine-pyrimethamine
is not recommended in many areas owing to unacceptable levels
of resistance to sulfadoxine-pyrimethamine, but it is the first-line
therapy in some countries. The other recommended regimens are

available as combination formulations, although manufacturing
standards may vary. Artesunate-mefloquine is highly effective in
Southeast Asia, where resistance to many antimalarials is com-
mon; it is the first-line therapy in some countries in Southeast
Asia and South America. This regimen is less practical for other
areas, particularly Africa, because of its relatively high cost and
poor tolerability. Either artesunate-amodiaquine or artemether-
lumefantrine is the standard treatment for uncomplicated falci-
parum malaria in most countries in Africa and some additional
endemic countries on other continents. Dihydroartemisinin-
piperaquine is a newer regimen that has shown excellent effi-
cacy; it is a first-line therapy for falciparum malaria in parts of
Southeast Asia. Artesunate-pyronaridine (Pyramax) was recently
approved, and it appears to offer efficacy similar to that of other
combinations, but data are limited, especially for young children.
Of concern, increased failure rates for artesunate-mefloquine and
dihydroartemisinin-piperaquine have been reported recently in
parts of Southeast Asia, in the setting of decreased activity of both
components of the regimens.
Artemisinins also have outstanding efficacy in the treatment
of complicated falciparum malaria. Large randomized trials and
meta-analyses have shown that intramuscular artemether has an
efficacy equivalent to that of quinine and that intravenous artesu-
nate is superior to intravenous quinine in terms of parasite clear-
ance time and—most important—patient survival. Intravenous
artesunate also has a superior side-effect profile when compared
with intravenous quinine or quinidine. Thus, intravenous arte-
sunate has replaced quinine as the standard of care for the treat-
ment of severe falciparum malaria. Artesunate and artemether
have also been effective in the treatment of severe malaria when
administered rectally, offering a valuable treatment modality when
parenteral therapy is not available.
Adverse Effects & Cautions
Artemisinins are generally very well tolerated. The most com-
monly reported adverse effects are nausea, vomiting, diarrhea, and
dizziness, and these may often be due to underlying malaria rather
than the medications. Rare serious toxicities include neutropenia,
anemia, hemolysis, elevated liver enzymes, and allergic reactions.
In addition, delayed hemolysis after artemisinins for severe malaria
appears to be quite common (estimated in 13% of cases), typically
beginning 2–3 weeks after therapy, with 73% of identified cases
requiring transfusion. Irreversible neurotoxicity has been seen in
animals, but only after doses much higher than those used to treat
malaria. Artemisinins have been embryotoxic in animal studies,
but rates of congenital abnormalities, stillbirths, and abortions
were not elevated in women who received artemisinins during
pregnancy, compared with those of controls. Based on this infor-
mation and the significant risk of malaria during pregnancy, the
WHO recommends artemisinin-based combination therapies for
the treatment of uncomplicated falciparum malaria during the
second and third trimesters of pregnancy (quinine plus clindamy-
cin is recommended during the first trimester), and intravenous
artesunate for the treatment of severe malaria during all stages of
pregnancy.
CHAPTER 52  Antiprotozoal Drugs    923
QUININE & QUINIDINE
Quinine and quinidine remain important therapies for falciparum
malaria—especially severe disease—although toxicity may compli-
cate therapy.
Chemistry & Pharmacokinetics
Quinine is derived from the bark of the cinchona tree, a tradi-
tional remedy for intermittent fevers from South America. The
alkaloid quinine was purified in 1820 and has been used in the
treatment and prevention of malaria since that time. Quinidine,
the dextrorotatory stereoisomer of quinine, is at least as effective as
parenteral quinine in the treatment of severe falciparum malaria.
After oral administration, quinine is rapidly absorbed, reaches
peak plasma levels in 1–3 hours, and is widely distributed in body
tissues. The use of a loading dose in severe malaria allows the
achievement of peak levels within a few hours. Individuals with
malaria develop higher plasma levels of quinine than healthy con-
trols, but toxicity is not increased, apparently because of increased
protein binding. The half-life of quinine also is longer in those
with severe malaria (18 hours) than in healthy controls (11 hours).
Quinidine has a shorter half-life than quinine, mostly as a result
of decreased protein binding. Quinine is primarily metabolized in
the liver and excreted in the urine.
Antimalarial Action & Resistance
Quinine is a rapid-acting, highly effective blood schizonticide against
the four species of human malaria parasites. The drug is gametocidal
against P vivax and P ovale but not P falciparum. It is not active
against liver stage parasites. The mechanism of action of quinine is
unknown. Resistance to quinine is common in some areas of South-
east Asia, especially border areas of Thailand, where the drug may
fail if used alone to treat falciparum malaria. However, quinine still
provides at least a partial therapeutic effect in most patients.
Clinical Uses
1. Parenteral treatment of severe falciparum malaria—For
many years quinine dihydrochloride or quinidine gluconate were
the treatments of choice for severe falciparum malaria, although
intravenous artesunate is now preferred. Quinine can be adminis-
tered slowly intravenously or, in a dilute solution, intramuscularly,
but parenteral preparations are not available in the USA. Quinidine
is available (although not always readily accessible) in the USA for
the parenteral treatment of severe falciparum malaria. Quinidine
can be administered in divided doses or by continuous intravenous
infusion; treatment should begin with a loading dose to achieve
effective plasma concentrations promptly. Because of its cardiac
toxicity (see Chapter 14) and the relative unpredictability of its
pharmacokinetics, intravenous quinidine should be administered
slowly with cardiac monitoring. Therapy should be changed to an
effective oral agent as soon as the patient has improved sufficiently.
2. Oral treatment of falciparum malaria—Quinine sulfate is
appropriate therapy for uncomplicated falciparum malaria except
924    SECTION VIII  Chemotherapeutic Drugs
when the infection was transmitted in an area without docu-
mented chloroquine resistance. Quinine is commonly used with a
second drug (most often doxycycline or, in children, clindamycin)
to shorten the duration of use (usually to 3 days) and limit toxic-
ity. Quinine is not generally used to treat nonfalciparum malaria.
3. Malarial chemoprophylaxis—Quinine is not generally used
in chemoprophylaxis owing to its toxicity, although a daily dose
of 325 mg is effective.
4. Babesiosis—Quinine is first-line therapy, in combination
with clindamycin, in the treatment of infection with Babesia
microti or other human babesial infections.
Adverse Effects
Therapeutic dosages of quinine and quinidine commonly cause
tinnitus, headache, nausea, dizziness, flushing, and visual distur-
bances, a constellation of symptoms termed cinchonism. Mild
symptoms of cinchonism do not warrant the discontinuation
of therapy. More severe findings, often after prolonged therapy,
include more marked visual and auditory abnormalities, vomiting,
diarrhea, and abdominal pain. Hypersensitivity reactions include
skin rashes, urticaria, angioedema, and bronchospasm. Hema-
tologic abnormalities include hemolysis (especially with G6PD
deficiency), leukopenia, agranulocytosis, and thrombocytopenia.
Therapeutic doses may cause hypoglycemia through stimulation
of insulin release; this is a particular problem in severe infections
and in pregnant patients, who may have increased sensitivity to
insulin. Quinine can stimulate uterine contractions, especially in
the third trimester. However, this effect is mild, and quinine and
quinidine remain appropriate for treatment of severe falciparum
malaria during pregnancy. Intravenous infusions of the drugs may
cause thrombophlebitis.
Severe hypotension can follow too-rapid intravenous infu-
sions of quinine or quinidine. Electrocardiographic abnor-
malities (QT interval prolongation) are fairly common with
intravenous quinidine, but dangerous arrhythmias are uncom-
mon when the drug is administered appropriately in a moni-
tored setting.
Blackwater fever is a rare severe illness that includes marked
hemolysis and hemoglobinuria in the setting of quinine therapy
for malaria. It appears to be due to a hypersensitivity reaction to
the drug, although its pathogenesis is uncertain.
Contraindications & Cautions
Quinine (or quinidine) should be discontinued if signs of severe
cinchonism, hemolysis, or hypersensitivity occur. It should be
avoided if possible in patients with underlying visual or audi-
tory problems. It must be used with great caution in those with
underlying cardiac abnormalities. Quinine should not be given
concurrently with mefloquine and should be used with caution
in a patient with malaria who has recently received mefloquine.
Absorption may be blocked by aluminum-containing antacids.
Quinine can raise plasma levels of warfarin and digoxin. Dosage
must be reduced in renal insufficiency.
MEFLOQUINE
Mefloquine is effective therapy for many chloroquine-resistant
strains of P falciparum and against other species. Although toxic-
ity is a concern, mefloquine is one of the recommended chemo-
prophylactic drugs for use in most malaria-endemic regions with
chloroquine-resistant strains.
Chemistry & Pharmacokinetics
Mefloquine hydrochloride is a synthetic 4-quinoline methanol
that is chemically related to quinine. It can only be given orally
because severe local irritation occurs with parenteral use. It is
well absorbed, and peak plasma concentrations are reached in
about 18 hours. Mefloquine is highly protein-bound, extensively
distributed in tissues, and eliminated slowly, allowing a single-dose
treatment regimen. The terminal elimination half-life is about
20 days, allowing weekly dosing for chemoprophylaxis. With
weekly dosing, steady-state drug levels are reached over a number
of weeks. Mefloquine and its metabolites are slowly excreted,
mainly in the feces.
Antimalarial Action & Resistance
Mefloquine has strong blood schizonticidal activity against
P falciparum and P vivax, but it is not active against hepatic stages
or gametocytes. The mechanism of action is unknown. Sporadic
resistance to mefloquine has been reported from many areas, but
resistance appears to be uncommon except in regions of Southeast
Asia with high rates of multidrug resistance (especially border
areas of Thailand). Mefloquine resistance does not appear to be
associated with resistance to chloroquine.
Clinical Uses
1. Chemoprophylaxis—Mefloquine is effective in prophy-
laxis against most strains of P falciparum and probably all other
human malarial species. Mefloquine is therefore among the
drugs recommended by the CDC for chemoprophylaxis in all
malarious areas except those with no chloroquine resistance
(where chloroquine is preferred) and some rural areas of South-
east Asia with a high prevalence of mefloquine resistance. As
with chloroquine, eradication of P vivax and P ovale requires a
course of primaquine.
2. Treatment—Mefloquine is effective in treating uncompli-
cated falciparum malaria. The drug is not appropriate for treating
individuals with severe or complicated malaria, since quinine,
quinidine, and artemisinins are more rapidly active, and since
drug resistance is less likely with those agents. The combination of
artesunate plus mefloquine showed excellent antimalarial efficacy
in regions of Southeast Asia with some resistance to mefloquine,
and this regimen is now one of the combination therapies rec-
ommended by the WHO for the treatment of uncomplicated
falciparum malaria (Table 52–4). Artesunate-mefloquine is the
first-line therapy for uncomplicated falciparum malaria in a num-
ber of countries in Asia and South America.

Adverse Effects
Weekly dosing with mefloquine for chemoprophylaxis may cause
nausea, vomiting, dizziness, sleep and behavioral disturbances, epi-
gastric pain, diarrhea, abdominal pain, headache, rash, and dizziness.
Neuropsychiatric toxicities have received a good deal of publicity,
but despite frequent anecdotal reports of seizures and psychosis, a
number of controlled studies have found the frequency of serious
adverse effects from mefloquine to be similar to that with other com-
mon antimalarial chemoprophylactic regimens. However, concern
about reported long-term effects of short-term use of mefloquine led
in 2013 to the FDA adding a black box warning regarding potential
neurologic and psychiatric toxicities. Leukocytosis, thrombocytope-
nia, and aminotransferase elevations have also been reported.
Adverse effects are more common with the higher dosages of
mefloquine required for treatment. These effects may be lessened
by administering the drug in two doses separated by 6–8 hours.
The incidence of neuropsychiatric symptoms appears to be about
ten times greater than with chemoprophylactic dosing, with
widely varying frequencies of up to about 50% reported. Serious
neuropsychiatric toxicities (depression, confusion, acute psychosis,
or seizures) have been reported in less than 1 in 1000 treatments,
but some authorities believe that these toxicities are actually more
common. Mefloquine can also alter cardiac conduction, and
arrhythmias and bradycardia have been reported.
Contraindications & Cautions
Mefloquine is contraindicated in a patient with a history of epi-
lepsy, psychiatric disorders, arrhythmia, cardiac conduction defects,
or sensitivity to related drugs. It should not be co-administered
with quinine, quinidine, or halofantrine, and caution is required
if quinine or quinidine is used to treat malaria after mefloquine
chemoprophylaxis. The CDC no longer advises against mefloquine
use in patients receiving β-adrenoceptor antagonists. Mefloquine
is also now considered safe in young children, and it is the only
chemoprophylactic other than chloroquine approved for children
weighing less than 5 kg and for pregnant women. Available data
suggest that mefloquine is safe throughout pregnancy, although
experience in the first trimester is limited. An older recommenda-
tion to avoid mefloquine use in those requiring fine motor skills (eg,
airline pilots) is controversial. Mefloquine chemoprophylaxis should
be discontinued if significant neuropsychiatric symptoms develop.
PRIMAQUINE
Primaquine is the drug of choice for the eradication of dormant
liver forms of P vivax and P ovale and can also be used for chemo-
prophylaxis against all malarial species.
Chemistry & Pharmacokinetics
Primaquine phosphate is a synthetic 8-aminoquinoline (Figure 52–2).
The drug is well absorbed orally, reaching peak plasma levels in
1–2 hours. The plasma half-life is 3–8 hours. Primaquine is widely
distributed to the tissues, but only a small amount is bound there. It
is rapidly metabolized and excreted in the urine.
CHAPTER 52  Antiprotozoal Drugs    925
Antimalarial Action & Resistance
Primaquine is active against hepatic stages of all human malaria
parasites. It is the only available agent active against the dormant
hypnozoite stages of P vivax and P ovale. The drug is also game-
tocidal against the four human malaria species and it has weak
activity against erythrocytic stage parasites. The mechanism of
antimalarial action is unknown.
Some strains of P vivax in New Guinea, Southeast Asia, Cen-
tral and South America, and other areas are relatively resistant to
primaquine. Liver forms of these strains may not be eradicated
by a single standard treatment and may require repeated therapy.
Clinical Uses
1. Therapy (radical cure) of acute vivax and ovale
malaria—Standard therapy for these infections includes chloro-
quine to eradicate erythrocytic forms and primaquine to eradicate
liver hypnozoites and prevent a subsequent relapse. Chloroquine is
given acutely, and therapy with primaquine is withheld until the
G6PD status of the patient is known. If the G6PD level is normal,
a 14-day course of primaquine is given. Prompt evaluation of the
G6PD level is helpful, since primaquine appears to be most effec-
tive when instituted before completion of dosing with chloroquine.
2. Terminal prophylaxis of vivax and ovale malaria—
Standard chemoprophylaxis does not prevent a relapse of vivax or
ovale malaria, because the hypnozoite forms of these parasites are
not eradicated by available blood schizonticides. To diminish the
likelihood of relapse, some authorities advocate the use of prima-
quine after the completion of travel to an endemic area.
3. Chemoprophylaxis of malaria—Daily treatment with
30 mg (0.5 mg/kg) of primaquine base provided good protection
against falciparum and vivax malaria, and the drug is now listed as
an alternative chemoprophylactic regimen by the CDC.
4. Gametocidal action—Primaquine renders P falciparum
gametocytes noninfective to mosquitoes. Including primaquine
with treatment for falciparum malaria is used in some areas to
decrease transmission, and routine inclusion of single low doses
of primaquine (which may be safe without testing for G6PD
deficiency) is under study.
5. Pneumocystis jiroveci infection—The combination of
clindamycin and primaquine is an alternative regimen in the treat-
ment of pneumocystosis, particularly mild to moderate disease.
This regimen offers improved tolerance compared with high-dose
trimethoprim-sulfamethoxazole or pentamidine, although its efficacy
against severe pneumocystis pneumonia is not well studied.
Adverse Effects
Primaquine in recommended doses is generally well tolerated. It
infrequently causes nausea, epigastric pain, abdominal cramps,
and headache, and these symptoms are more common with higher
dosages and when the drug is taken on an empty stomach. More
serious but rare adverse effects are leukopenia, agranulocytosis,
926    SECTION VIII  Chemotherapeutic Drugs
leukocytosis, and cardiac arrhythmias. Standard doses of prima-
quine may cause hemolysis or methemoglobinemia (manifested
by cyanosis), especially in persons with G6PD deficiency or other
hereditary metabolic defects.
Contraindications & Cautions
Primaquine should be avoided in patients with a history of granu-
locytopenia or methemoglobinemia, in those receiving potentially
myelosuppressive drugs (eg, quinidine), and in those with disor-
ders that commonly include myelosuppression.
Patients should be tested for G6PD deficiency before pri-
maquine is prescribed. When a patient is deficient in G6PD,
treatment strategies may include withholding therapy and treat-
ing subsequent relapses, if they occur, with chloroquine; treating
patients with standard dosing, paying close attention to their
hematologic status; or treating with weekly primaquine (45 mg
base) for 8 weeks. G6PD-deficient individuals of Mediter-
ranean and Asian ancestry are most likely to have severe
deficiency, whereas those of African ancestry usually have a
milder biochemical defect. This difference can be taken into
consideration in choosing a treatment strategy. In any event,
primaquine should be discontinued if there is evidence of
hemolysis or anemia. Primaquine should be avoided in preg-
nancy because the fetus is relatively G6PD-deficient and thus
at risk of hemolysis.
ATOVAQUONE
Atovaquone, a hydroxynaphthoquinone (Figure 52–2), is a com-
ponent of Malarone, which is recommended for the treatment and
prevention of malaria. Atovaquone has also been approved by the
FDA for the treatment of mild to moderate P jiroveci pneumonia.
The drug is only administered orally. Its bioavailability is low
and erratic, but absorption is increased by fatty food. The drug is
heavily protein-bound, has a half-life of 2–3 days, and is mostly
eliminated unchanged in the feces. Atovaquone acts against plas-
modia by disrupting mitochondrial electron transport. It is active
against tissue and erythrocytic schizonts, allowing chemoprophy-
laxis to be discontinued only 1 week after the end of exposure
(compared with 4 weeks for mefloquine or doxycycline, which
lack activity against tissue schizonts).
Initial use of atovaquone to treat malaria led to disappoint-
ing results, with frequent failures due to the selection of resistant
parasites during therapy. In contrast, Malarone, a fixed combina-
tion of atovaquone (250 mg) and proguanil (100 mg), is highly
effective for both the treatment and chemoprophylaxis of falci-
parum malaria, and it is now approved for both indications in
the USA. For chemoprophylaxis, Malarone must be taken daily
(Table 52–2). It has an advantage over mefloquine and doxycy-
cline in requiring shorter periods of treatment before and after the
period at risk for malaria transmission, but it is more expensive
than the other agents. It should be taken with food.
Atovaquone is an alternative therapy for P jir-
oveci infection, although its efficacy is lower than that of
trimethoprim-sulfamethoxazole. Standard dosing is 750 mg taken
with food twice daily for 21 days. Atovaquone has also been
effective in small numbers of immunocompromised patients with
toxoplasmosis unresponsive to other agents.
Malarone is generally well tolerated. Adverse effects include
abdominal pain, nausea, vomiting, diarrhea, headache, insomnia,
and rash, and these are more common with the higher dosage
required for treatment. Reversible elevations in liver enzymes
have been reported. The safety of atovaquone in pregnancy is
unknown, and its use is not advised in pregnant women. It is
considered safe for use in children with body weight above 5 kg.
Plasma concentrations of atovaquone are decreased about 50% by
co-administration of tetracycline or rifampin.
INHIBITORS OF FOLATE SYNTHESIS
Inhibitors of enzymes involved in folate metabolism are used,
generally in combination regimens, in the treatment and preven-
tion of malaria.
Chemistry & Pharmacokinetics
Pyrimethamine is a 2,4-diaminopyrimidine related to trime-
thoprim (see Chapter 46). Proguanil is a biguanide derivative
(Figure 52–2). Both drugs are slowly but adequately absorbed
from the gastrointestinal tract. Pyrimethamine reaches peak
plasma levels 2–6 hours after an oral dose, is bound to plasma
proteins, and has an elimination half-life of about 3.5 days.
Proguanil reaches peak plasma levels about 5 hours after an
oral dose and has an elimination half-life of about 16 hours.
Therefore, proguanil must be administered daily for che-
moprophylaxis, whereas pyrimethamine can be given once
a week. Pyrimethamine is extensively metabolized before
excretion. Proguanil is a prodrug; its triazine metabolite,
cycloguanil, is active. Fansidar, a fixed combination of the
sulfonamide sulfadoxine (500 mg per tablet) and pyrimeth-
amine (25 mg per tablet), is well absorbed. Its components
display peak plasma levels within 2–8 hours and are excreted
mainly by the kidneys. The average half-life of sulfadoxine is
about 170 hours.
Antimalarial Action & Resistance
Pyrimethamine and proguanil act slowly against erythrocytic
forms of susceptible strains of all four human malaria species.
Proguanil also has activity against hepatic forms. Neither drug
is adequately gametocidal or effective against hypnozoites of
P vivax or P ovale. Sulfonamides and sulfones are weakly active
against erythrocytic schizonts but not against liver stages or
gametocytes.
Pyrimethamine and proguanil inhibit plasmodial dihydrofolate
reductase, a key enzyme in the pathway for synthesis of folate.
Sulfonamides and sulfones inhibit another enzyme in the folate
pathway, dihydropteroate synthase. As described in Chapter 46,
inhibitors of these two enzymes provide synergistic activity when
used together (see Figure 46–2).

Resistance of P falciparum to folate antagonists and sulfon-
amides is common in many areas. Resistance is due primarily
to mutations in dihydrofolate reductase and dihydropteroate
synthase, with increasing numbers of mutations leading to increas-
ing levels of resistance. Resistance seriously limits the efficacy of
sulfadoxine-pyrimethamine for the treatment of malaria in most
areas, but in Africa most parasites exhibit an intermediate level
of resistance, such that antifolates may continue to offer some
preventive efficacy.
Clinical Uses
1. Chemoprophylaxis—Chemoprophylaxis with single folate
antagonists is no longer recommended because of frequent
resistance and toxicity. However, the antifolate combination
trimethoprim-sulfamethoxazole is commonly used as a daily pro-
phylactic therapy for HIV-infected patients in developing coun-
tries, and this regimen offers partial preventive efficacy against
malaria in Africa.
2. Intermittent preventive therapy—A new strategy for
malaria control is intermittent preventive therapy, in which
high-risk patients receive intermittent treatment for malaria,
regardless of their infection status. This practice is most accepted
in pregnancy, with the use of two or more doses of sulfadoxine-
pyrimethamine after the first trimester now standard policy in
Africa, although efficacy is limited. In children intermittent
preventive therapy has not been widely accepted, but the WHO
now recommends seasonal malaria chemoprevention with amo-
diaquine plus sulfadoxine-pyrimethamine in the Sahel sub-
region of Africa, where malaria is highly seasonal and resistance
to antifolates is relatively uncommon. In most other areas drug
resistance seriously limits the preventive efficacy of antifolates.
3. Treatment of chloroquine-resistant falciparum
malaria—Fansidar is no longer a recommended therapy for
malaria, and in particular it should not be used for severe malaria,
since it is slower-acting than other available agents. Fansidar
is also not reliably effective in vivax malaria, and its usefulness
against P ovale and P malariae has not been adequately studied.
Artesunate plus sulfadoxine-pyrimethamine is listed by the WHO
to treat falciparum malaria (Table 52–4), but other artemisinin-
based combinations are generally preferred.
4. Toxoplasmosis—Pyrimethamine, in combination with sul-
fadiazine, is first-line therapy in the treatment of toxoplasmosis,
including acute infection, congenital infection, and disease
in immunocompromised patients. For immunocompromised
patients, high-dose therapy is required followed by chronic sup-
pressive therapy. Folinic acid is included to limit myelosuppres-
sion. The replacement of sulfadiazine with clindamycin provides
an effective alternative regimen. Recent problems with pricing and
availability of pyrimethamine in the USA made the use of this
drug more difficult.
5. Pneumocystosis—P jiroveci is the cause of human pneumo-
cystosis and is now recognized to be a fungus, but this organism
CHAPTER 52  Antiprotozoal Drugs    927
is discussed in this chapter because it responds to antiprotozoal
drugs, not antifungals. First-line therapy of pneumocystosis is
trimethoprim plus sulfamethoxazole (see also Chapter 46). Stan-
dard treatment includes high-dose intravenous or oral therapy
(15 mg/kg trimethoprim and 75 mg/kg sulfamethoxazole per
day in three or four divided doses) for 21 days. High-dose
therapy entails significant toxicity, especially in patients with
AIDS. Important toxicities include nausea, vomiting, fever, rash,
leukopenia, hyponatremia, elevated hepatic enzymes, azotemia,
anemia, and thrombocytopenia. Less common effects include
severe skin reactions, mental status changes, pancreatitis, and
hypocalcemia. Trimethoprim-sulfamethoxazole is also the stan-
dard chemoprophylactic drug for the prevention of P jiroveci
infection in immunocompromised individuals. Dosing is one
double-strength tablet daily or three times per week. The che-
moprophylactic dosing schedule is much better tolerated than
high-dose therapy, but rash, fever, leukopenia, or hepatitis may
necessitate changing to another drug.
Adverse Effects & Cautions
Most patients tolerate pyrimethamine and proguanil well.
Gastrointestinal symptoms, skin rashes, and itching are rare.
Mouth ulcers and alopecia have been described with proguanil.
Fansidar uncommonly causes severe cutaneous reactions, includ-
ing erythema multiforme, Stevens-Johnson syndrome, and toxic
epidermal necrolysis. Severe reactions appear to be much less com-
mon with single-dose or intermittent therapy, compared to regular
chemoprophylaxis, and use of the drug has been justified by the
risks associated with falciparum malaria.
Rare adverse effects with Fansidar are those associated with
other sulfonamides, including hematologic, gastrointestinal, cen-
tral nervous system, dermatologic, and renal toxicity. Folate antag-
onists should be used cautiously in the presence of renal or hepatic
dysfunction. Although pyrimethamine is teratogenic in animals,
Fansidar has been safely used in pregnancy. Proguanil is consid-
ered safe in pregnancy. In pregnant women receiving Fansidar
preventive therapy, high-dose folate supplementation (eg, 5 mg
daily) should be replaced by the standard recommended dosage
(0.4–0.6 mg daily) to avoid potential loss of protective efficacy.
ANTIBIOTICS
A number of antibiotics are modestly active antimalarials. Bacterial
protein synthesis inhibitors appear to act against malaria parasites
by inhibiting protein synthesis in a plasmodial prokaryote-like
organelle, the apicoplast. None of the antibiotics should be used
as single agents in the treatment of malaria because their action is
much slower than that of standard antimalarials.
Tetracycline and doxycycline (see Chapter 44) are active
against erythrocytic schizonts of all human malaria parasites.
They are not active against liver stages. Doxycycline is used in
the treatment of falciparum malaria in conjunction with qui-
nine, allowing a shorter and better-tolerated course of that drug.
Doxycycline is also used to complete treatment courses after initial
treatment of severe malaria with intravenous quinine, quinidine,
928    SECTION VIII  Chemotherapeutic Drugs
or artesunate. In all of these cases a 1-week treatment course of
doxycycline is carried out. Doxycycline has also become a standard
chemoprophylactic drug, especially for use in areas of Southeast
Asia with high rates of resistance to other antimalarials, including
mefloquine. Doxycycline adverse effects include gastrointestinal
symptoms, esophagitis, candidal vaginitis, and photosensitivity.
Clindamycin (see Chapter 44) is slowly active against erythrocytic
schizonts and can be used after treatment courses of quinine,
quinidine, or artesunate in those for whom doxycycline is not
recommended, such as children and pregnant women. Antima-
larial activity of azithromycin and fluoroquinolones has also been
demonstrated, but efficacy for the therapy or chemoprophylaxis of
malaria has been suboptimal.
Antibiotics are also active against other protozoans. Tetracy-
cline and erythromycin are alternative therapies for the treatment
of intestinal amebiasis. Clindamycin, in combination with other
agents, is effective therapy for toxoplasmosis, pneumocystosis, and
babesiosis. Spiramycin is a macrolide antibiotic that is used to treat
primary toxoplasmosis acquired during pregnancy. Treatment low-
ers the risk of the development of congenital toxoplasmosis.
HALOFANTRINE, LUMEFANTRINE, &
PYRONARIDINE
Halofantrine hydrochloride, a phenanthrene-methanol, is effective
against erythrocytic (but not other) stages of all four human malaria
species. Oral absorption is variable and enhanced by food. Because
of toxicity concerns, it should not be taken with meals. The half-life
is about 4 days and excretion is mainly in the feces. Halofantrine
is not available in the USA (although it has been approved by the
FDA), but it is available in malaria-endemic countries.
Halofantrine (three 500 mg doses at 6-hour intervals, repeated
in 1 week for nonimmune individuals) is rapidly effective against
P falciparum, but its use is limited by cardiac toxicity. It is generally
well tolerated. The most common adverse effects are abdominal pain,
diarrhea, vomiting, cough, rash, headache, pruritus, and elevated liver
enzymes. Of greater concern, the drug alters cardiac conduction, with
dose-related prolongation of QT and PR intervals. Rare instances of
dangerous arrhythmias and deaths have been reported. The drug is
contraindicated in patients who have cardiac conduction defects or
who have recently taken mefloquine. Halofantrine is embryotoxic in
animals and therefore contraindicated in pregnancy.
Lumefantrine, an aryl alcohol, is available only as a fixed-
dose combination with artemether (Coartem, Riamet), which is
now the first-line therapy for uncomplicated falciparum malaria
in many countries. In addition, Coartem is approved in many
nonendemic countries, including the USA. The half-life of lume-
fantrine, when used in combination, is 3–4 days. Drug levels
may be altered by interactions with other drugs, including those
that affect CYP3A4 metabolism. Oral absorption is variable and
improved when the drug is taken with food. Since lumefantrine is
not associated with the toxicity concerns of halofantrine, Coartem
should be administered with fatty food to maximize antimalarial
efficacy. Coartem is highly effective in the treatment of falciparum
malaria when administered twice daily for 3 days. Coartem can
cause minor prolongation of the QT interval, but this appears
to be clinically insignificant, and the drug does not carry the risk
of dangerous arrhythmias seen with halofantrine and quinidine.
Coartem is very well tolerated. The most commonly reported
adverse events have been gastrointestinal disturbances, headache,
dizziness, rash, and pruritus, and in many cases these toxicities
may have been due to underlying malaria or concomitant medica-
tions rather than to Coartem.
Pyronaridine, a Mannich base acridine, has been studied
as an antimalarial for many years and used as monotherapy in
China. It is now available in combination with artesunate as
Pyramax. Pyronaridine is well absorbed orally without important
food effects. It has a half life of about 8 days, with primarily renal
elimination. Artesunate-pyronaridine has generally demonstrated
excellent efficacy against falciparum and vivax malaria, although a
recent report showed lower efficacy in Cambodia. It has generally
been well tolerated. Adverse events have included eosinophilia and
transaminitis. A general recommendation for use of artesunate-
pyronaridine to treat malaria awaits further evaluation of efficacy
in children and of potential hepatic toxicity.
■■ AMEBIASIS
Amebiasis is infection with Entamoeba histolytica. This organ-
ism can cause asymptomatic intestinal infection, mild to
moderate colitis, severe intestinal infection (dysentery), ame-
boma, liver abscess, and other extraintestinal infections. The
choice of drugs for amebiasis depends on the clinical presenta-
tion (Table 52–5).
Treatment of Specific Forms of Amebiasis
1. Asymptomatic intestinal infection—Asymptomatic car-
riers generally are not treated in endemic areas, but in nonen-
demic areas they are treated with a luminal amebicide. A tissue
amebicidal drug is unnecessary. Standard luminal amebicides are
diloxanide furoate, iodoquinol, and paromomycin. Each drug
eradicates carriage in about 80–90% of patients. Therapy with
a luminal amebicide is also required in the treatment of all other
forms of amebiasis.
2. Amebic Colitis—Metronidazole plus a luminal amebicide is
the treatment of choice for amebic colitis and dysentery. Tetracy-
clines and erythromycin are alternative drugs for moderate colitis
but are not effective against extraintestinal disease. Dehydroem-
etine or emetine can also be used, but are best avoided because
of toxicity.
3. Extraintestinal Infections—The treatment of choice for
extraintestinal infections is metronidazole plus a luminal ame-
bicide. A 10-day course of metronidazole cures over 95% of
uncomplicated liver abscesses. For unusual cases in which initial
therapy with metronidazole has failed, aspiration of the abscess
and the addition of chloroquine to a repeat course of metronida-
zole should be considered. Dehydroemetine and emetine are toxic
alternative drugs.
 CHAPTER 52  Antiprotozoal Drugs    929

TABLE 52–5  Treatment of amebiasis. Not all preparations are available in the USA.1
Clinical Setting
Asymptomatic intestinal
infection
Mild to moderate
intestinal infection
Drugs of Choice and Adult Dosage Alternative Drugs and Adult Dosage
2
Luminal agent: Diloxanide furoate, 500 mg 3 times daily  
for 10 days
or
Iodoquinol, 650 mg 3 times daily for 21 days
or
Paromomycin, 10 mg/kg 3 times daily for 7 days
Metronidazole, 750 mg 3 times daily (or 500 mg IV every Luminal agent (see above)
6 hours) for 10 days
or plus either

Tinidazole, 2 g daily for 3 days Tetracycline, 250 mg 3 times daily for 10 days
or
plus
Erythromycin, 500 mg 4 times daily for 10 days
Luminal agent (see above)
Severe intestinal Metronidazole, 750 mg 3 times daily (or 500 mg IV every Luminal agent (see above)
infection 6 hours) for 10 days
or plus either

Hepatic abscess,
ameboma, and other
extraintestinal disease
Tinidazole, 2 g daily for 3 days Tetracycline, 250 mg 3 times daily for 10 days
or
plus
Dehydroemetine2 or emetine,2 1 mg/kg SC or IM for
Luminal agent (see above) 3–5 days
Metronidazole, 750 mg 3 times daily (or 500 mg IV every Dehydroemetine2 or emetine,2 1 mg/kg SC or IM for
6 hours) for 10 days 8–10 days, followed by (liver abscess only) chloroquine,
or 500 mg twice daily for 2 days, then 500 mg daily for
Tinidazole, 2 g daily for 5 days 21 days

plus plus

Luminal agent (see above) Luminal agent (see above)

1
Route is oral unless otherwise indicated. See text for additional details and cautions.
2
Not available in the USA.

METRONIDAZOLE & TINIDAZOLE Clinical Uses

Metronidazole, a nitroimidazole (Figure 52–3), is the drug of
choice in the treatment of extraluminal amebiasis. It kills tro-
phozoites but not cysts of E histolytica and effectively eradicates
intestinal and extraintestinal tissue infections. Tinidazole, a related
nitroimidazole, appears to have similar activity and a better toxic-
ity profile. It offers simpler dosing regimens and can be substi-
tuted for the indications listed below.
Pharmacokinetics & Mechanism of Action
Oral metronidazole and tinidazole are readily absorbed and per-
meate all tissues by simple diffusion. Intracellular concentrations
rapidly approach extracellular levels. Peak plasma concentrations
are reached in 1–3 hours. Protein binding of both drugs is low
(10–20%); the half-life of unchanged drug is 7.5 hours for met-
ronidazole and 12–14 hours for tinidazole. Metronidazole and its
metabolites are excreted mainly in the urine. Plasma clearance of
metronidazole is decreased in patients with impaired liver function.
The nitro group of metronidazole is chemically reduced in anaero-
bic bacteria and sensitive protozoans. Reactive reduction products
appear to be responsible for antiprotozoal and antibacterial activity.
The mechanism of tinidazole is assumed to be the same.
1. Amebiasis—Metronidazole or tinidazole is the drug of choice
in the treatment of all tissue infections with E histolytica. Neither
drug is reliably effective against luminal parasites and so must be
used with a luminal amebicide to ensure eradication of the infection.
2. Giardiasis—Metronidazole is the treatment of choice for
giardiasis. The dosage for giardiasis is much lower than that for
amebiasis, and the drug is thus better tolerated. Efficacy after
a single treatment is about 90%. Tinidazole is at least equally
effective, and can be used as a single dose.
3. Trichomoniasis—Metronidazole is the treatment of choice.
A single dose of 2 g is effective. Metronidazole-resistant organisms
can lead to treatment failures. Tinidazole may be effective against
some of these resistant organisms.
Adverse Effects & Cautions
Nausea, headache, dry mouth, and a metallic taste in the mouth
occur commonly. Infrequent adverse effects include vomiting,
diarrhea, insomnia, weakness, dizziness, thrush, rash, dysuria,
dark urine, vertigo, paresthesias, encephalopathy, and neutrope-
nia. Taking the drug with meals lessens gastrointestinal irritation.
930    SECTION VIII  Chemotherapeutic Drugs

I
N
H C
C CH3
O2N C
N I N
CH2CH2OH OH

Metronidazole Iodoquinol

OH
CH2OH H2N NH2
O H2N OH

O OH COO N COCHCl2
OH
HO O
CH2NH2 O
O O O
CH3
NH2
OH
CH2OH
Diloxanide furoate

Paromomycin

CH2OH HOH2C

CHOH HOHC
HN NH
–
CHO OH O OHC
C OCH2(CH2)3CH2O C
H2N NH2 CHO Sb O Sb OHC 3Na+

Pentamidine CHO OHC

–
COO– OOC

Sodium stibogluconate

FIGURE 52–3  Structural formulas of other antiprotozoal drugs.

Pancreatitis and severe central nervous system toxicity (ataxia,
encephalopathy, seizures) are rare. Metronidazole has a disulfiram-
like effect, so that nausea and vomiting can occur if alcohol is
ingested during therapy. The drug should be used with caution
in patients with central nervous system disease. Intravenous infu-
sions have rarely caused seizures or peripheral neuropathy. The
dosage should be adjusted for patients with severe liver or renal
disease. Tinidazole has a similar adverse-effect profile, although it
appears to be somewhat better tolerated than metronidazole.
Metronidazole has been reported to potentiate the anticoagulant
effect of coumarin-type anticoagulants. Phenytoin and phenobarbi-
tal may accelerate elimination of the drug, whereas cimetidine may
decrease plasma clearance. Lithium toxicity may occur when the
drug is used with metronidazole. Metronidazole and its metabo-
lites are mutagenic in bacteria and tumorigenic in mice. Data on
teratogenicity are inconsistent. Metronidazole is thus best avoided
in pregnant or nursing women, although congenital abnormalities
have not clearly been associated with use in humans.
IODOQUINOL
Iodoquinol (diiodohydroxyquin), a halogenated hydroxyquino-
line, is an effective luminal amebicide. Pharmacokinetic data are
incomplete but 90% of the drug is retained in the intestine and
excreted in the feces. The remainder enters the circulation, has
a half-life of 11–14 hours, and is excreted in the urine as gluc-
uronides. Iodoquinol is effective against organisms in the bowel
lumen but not against trophozoites.
Infrequent adverse effects include diarrhea—which usually
stops after several days—anorexia, nausea, vomiting, abdominal
pain, headache, rash, and pruritus. Some halogenated hydroxy-
quinolines can produce severe neurotoxicity with prolonged use.
Iodoquinol is not known to produce these effects at its recom-
mended dosage, and this dosage (Table 52-5) should never be
exceeded. Iodoquinol should be taken with meals to limit gas-
trointestinal toxicity. It should be used with caution in patients
with optic neuropathy, renal or thyroid disease, or nonamebic
hepatic disease. The drug should be discontinued if it produces
persistent diarrhea or signs of iodine toxicity (dermatitis, urti-
caria, pruritus, fever). It is contraindicated in patients with
intolerance to iodine.
DILOXANIDE FUROATE
Diloxanide furoate is a dichloroacetamide derivative. It is an
effective luminal amebicide but is not active against tropho-
zoites. In the gut, diloxanide furoate is split into diloxanide
and furoic acid; about 90% of the diloxanide is rapidly

absorbed and then conjugated to form the glucuronide, which
is promptly excreted in the urine. The unabsorbed diloxanide
is the active antiamebic substance. Diloxanide furoate is not
available commercially in the USA but can be obtained from
some compounding pharmacies. It does not produce serious
adverse effects. Flatulence is common, but nausea and abdomi-
nal cramps are infrequent and rashes are rare. The drug is not
recommended in pregnancy.
PAROMOMYCIN SULFATE
Paromomycin sulfate is an aminoglycoside antibiotic (see also
Chapter 45) that is not significantly absorbed from the gas-
trointestinal tract. It is used as a luminal amebicide and has
no effect against extraintestinal organisms. The small amount
absorbed is slowly excreted unchanged, mainly by glomerular
filtration. However, the drug may accumulate with renal insuf-
ficiency and contribute to renal toxicity. Paromomycin appears
to have similar efficacy and less toxicity than other luminal
agents; in one study it was superior to diloxanide furoate in
clearing asymptomatic infections. As it is readily available, par-
omomycin can be considered the antiamebic luminal agent of
choice in the USA. Adverse effects include occasional abdomi-
nal distress and diarrhea. Parenteral paromomycin is now used
to treat visceral leishmaniasis and is discussed separately in the
text that follows.
EMETINE & DEHYDROEMETINE
Emetine, an alkaloid derived from ipecac, and dehydroemetine,
a synthetic analog, are effective against tissue trophozoites of
E histolytica, but because of major toxicity concerns their use
is limited to unusual circumstances in which severe amebiasis
requires effective therapy and metronidazole cannot be used.
Dehydroemetine is preferred because of its somewhat better
toxicity profile. The drugs should be used for the minimum
period needed to relieve severe symptoms (usually 3–5 days) and
administered subcutaneously (preferred) or intramuscularly in a
supervised setting. Adverse effects, which are generally mild with
use for 3–5 days but increase over time, include pain, tenderness,
and sterile abscesses at the injection site; diarrhea, nausea, and
vomiting; muscle weakness and discomfort; and minor electrocar-
diographic changes. Serious toxicities include cardiac arrhythmias,
heart failure, and hypotension.
TABLE 52–6  Treatment of African trypanosomiasis.
Disease Stage
West African Early
  CNS involvement
East African Early
  CNS involvement
1
Available in the USA from the Drug Service, CDC, Atlanta, Georgia (phone: 404-639-3670; www.cdc.gov/laboratory/drugservice/).
CHAPTER 52  Antiprotozoal Drugs    931
■■ OTHER ANTIPROTOZOAL
DRUGS
The primary drugs used to treat African trypanosomiasis are listed
in Table 52–6, and those for other protozoal infections are listed
in Table 52–7. Important antiprotozoal drugs that are not covered
elsewhere are discussed below.
PENTAMIDINE
Pentamidine has activity against trypanosomatid protozoans and
against P jiroveci, but toxicity is significant.
Chemistry & Pharmacokinetics
Pentamidine is an aromatic diamidine (Figure 52–3) formulated
as an isethionate salt. The drug is only administered parenter-
ally. It leaves the circulation rapidly, with an initial half-life
of about 6 hours, but is bound avidly by tissues. Pentamidine
thus accumulates and is eliminated very slowly, with a terminal
elimination half-life of about 12 days. Only trace amounts of
pentamidine appear in the central nervous system, so it is not
effective against CNS African trypanosomiasis. Pentamidine
can also be inhaled as a nebulized powder for the prevention of
pneumocystosis. Absorption into the systemic circulation after
inhalation appears to be minimal. The mechanism of action of
pentamidine is unknown.
Clinical Uses
1. Pneumocystosis—Pentamidine is a well-established alterna-
tive therapy for pulmonary and extrapulmonary disease caused by
P jiroveci. The drug has somewhat lower efficacy and greater tox-
icity than trimethoprim-sulfamethoxazole. The standard dosage is
3 mg/kg/d intravenously for 21 days. Significant adverse reactions
are common, and with multiple regimens now available to treat
P jiroveci infection, pentamidine is best reserved for patients with
severe disease who cannot tolerate or fail other drugs.
Pentamidine is also an alternative agent for primary or sec-
ondary prophylaxis against pneumocystosis in immunocom-
promised individuals, including patients with advanced AIDS.
For this indication, pentamidine is administered as an inhaled
aerosol (300 mg inhaled monthly). The drug is well tolerated
in this form. Its efficacy is good but less than that of daily
trimethoprim-sulfamethoxazole.
First-Line Drugs Alternative Drugs
Pentamidine Suramin, eflornithine
Eflornithine Melarsoprol,1 eflornithine-nifurtimox1
Suramin1 Pentamidine
Melarsoprol1  
932    SECTION VIII  Chemotherapeutic Drugs

TABLE 52–7  Treatment of other protozoal infections. Not all preparations are available in the USA.1
Organism or
Clinical Setting Drugs of Choice2 Alternative Drugs

Babesia species Clindamycin, 600 mg 3 times daily for 7 days Atovaquone or azithromycin
plus
Quinine, 650 mg for 7 days
Balantidium coli Tetracycline, 500 mg 4 times daily for 10 days Metronidazole, 750 mg 3 times daily for 5 days
Cryptosporidium species Paromomycin, 500–750 mg 3 or 4 times daily for 10 days Azithromycin, 500 mg daily for 21 days
Cyclospora cayetanensis Trimethoprim-sulfamethoxazole, one double-strength tablet 4 times  
daily for 7–14 days
Dientamoeba fragilis Iodoquinol, 650 mg 3 times daily for 20 days Tetracycline, 500 mg 4 times daily for 10 days
or
Paromomycin, 500 mg 3 times daily for 7 days
Giardia lamblia Metronidazole, 250 mg 3 times daily or 500 mg twice daily for 5 days Furazolidone, 100 mg 4 times daily for 7 days
or or
Tinidazole, 2 g once Albendazole, 400 mg daily for 5 days
Isospora belli Trimethoprim-sulfamethoxazole, one double-strength tablet 4 times Pyrimethamine, 75 mg daily for 14 days
daily for 10 days, then twice daily for 21 days
plus
Folinic acid, 10 mg daily for 14 days
Microsporidia Albendazole, 400 mg twice daily for 20–30 days  
3
Leishmaniasis    
 Visceral (L donovani, Sodium stibogluconate, 20 mg/kg/d IV or IM for 28 days Meglumine antimoniate
L chagasi, L infan-
tum) or mucosal or or
(L braziliensis) Amphotericin (liposomal preparations preferred (3 mg/kg/d IV on Pentamidine, 2–4 mg/kg IM daily or every
days 1–5, 14, and 21)); various other dosing regimens, including other day for up to 15 doses
single dose
or
or Combinations of listed drugs
Miltefosine, 2.5 mg/kg/d for 28 days
or
Paromomycin,15 mg/kg for 21 days
 Cutaneous (L major, Sodium stibogluconate, 20 mg/kg/d IV or IM for 20 days Meglumine antimoniate
L tropica, L mexicana,
L braziliensis) or
Miltefosine
or
Topical or intralesional therapies
Pneumocystis jiroveci, Trimethoprim-sulfamethoxazole, 15–20 mg trimethoprim Pentamidine
P carinii4 component/kg/d IV, or two double-strength tablets every 8 hours
for 21 days or
Trimethoprim-dapsone
or
Clindamycin plus primaquine
or
Atovaquone
Toxoplasma gondii    
 Acute, congenital, Pyrimethamine plus clindamycin plus folinic acid Pyrimethamine plus sulfadiazine plus
immunocompromised folinic acid
 Pregnancy Spiramycin, 3 g daily until delivery  
(Continued)
 CHAPTER 52  Antiprotozoal Drugs    933

TABLE 52–7  Treatment of other protozoal infections. Not all preparations are available in the USA.1 (Continued)
Organism or
Clinical Setting Drugs of Choice2 Alternative Drugs

Trichomonas vaginalis Metronidazole, 2 g once or 250 mg 3 times daily for 7 days  

  or  
  Tinidazole, 2 g once  
Trypanosoma cruzi Nifurtimox  
  or  
  Benznidazole  
1
Additional information may be obtained from the Parasitic Disease Drug Service, Parasitic Diseases Branch, CDC, Atlanta, Georgia (phone: 404-639-3670; www.cdc.gov/
laboratory/drugservice/).
2
Established, relatively simple dosing regimens are provided. Route is oral unless otherwise indicated. See text for additional information, toxicities, cautions, and discussions of
dosing for the more rarely used drugs, many of which are highly toxic.
3
Specific recommendations for leishmaniasis vary geographically. Combination regimens are increasingly used.
4
P jiroveci (carinii in animals) has traditionally been considered a protozoan because of its morphology and drug sensitivity, but molecular analyses have shown it to be most
closely related to fungi.

2. African trypanosomiasis (sleeping sickness)—Pentami- SODIUM STIBOGLUCONATE

dine has been used since 1940 and is the drug of choice to treat
the early hemolymphatic stage of disease caused by Trypanosoma
brucei gambiense (West African sleeping sickness). The drug is
inferior to suramin for the treatment of early East African sleeping
sickness. Pentamidine should not be used to treat late trypanoso-
miasis with central nervous system involvement. A number of dos-
ing regimens have been described, generally providing 2–4 mg/kg
daily or on alternate days for a total of 10–15 doses. Pentamidine
has also been used for chemoprophylaxis against African trypano-
somiasis, with dosing of 4 mg/kg every 3–6 months.
3. Leishmaniasis—Pentamidine is an alternative to sodium
stibogluconate and newer agents for the treatment of visceral leish-
maniasis. The drug has been successful in some cases that have failed
therapy with antimonials. The dosage is 2–4 mg/kg intramuscularly
daily or every other day for up to 15 doses, and a second course may
be necessary. Pentamidine has also shown success against cutaneous
leishmaniasis, but it is not routinely used for this purpose.
Adverse Effects & Cautions
Pentamidine is a highly toxic drug, with adverse effects noted in
about 50% of patients receiving 4 mg/kg/d. Rapid intravenous
administration can lead to severe hypotension, tachycardia, dizzi-
ness, and dyspnea, so the drug should be administered slowly (over
2 hours), and patients should be recumbent and monitored closely
during treatment. With intramuscular administration, pain at the
injection site is common, and sterile abscesses may develop.
Pancreatic toxicity is common. Hypoglycemia due to inappro-
priate insulin release often appears 5–7 days after onset of treat-
ment, can persist for days to several weeks, and may be followed
by hyperglycemia. Reversible renal insufficiency is also common.
Other adverse effects include rash, metallic taste, fever, gastroin-
testinal symptoms, abnormal liver function tests, acute pancreati-
tis, hypocalcemia, thrombocytopenia, hallucinations, and cardiac
arrhythmias. Inhaled pentamidine is generally well tolerated but
may cause cough, dyspnea, and bronchospasm.
Pentavalent antimonials, including sodium stibogluconate (pen-
tostam; Figure 52–3) and meglumine antimoniate, are first-line
agents for cutaneous and visceral leishmaniasis except in parts of
India, where the efficacy of these drugs has diminished greatly.
The drugs are rapidly absorbed and distributed after intravenous
(preferred) or intramuscular administration and eliminated in two
phases, with a short initial (about 2-hour) half-life and a much
longer terminal (>24-hour) half-life. Treatment is given at a dos-
age of 20 mg/kg once daily intravenously or intramuscularly for
20 days in cutaneous leishmaniasis and 28 days in visceral and
mucocutaneous disease.
The mechanism of action of the antimonials is unknown.
Their efficacy against different species may vary, possibly based on
local drug resistance patterns. Cure rates are generally quite good,
but resistance to sodium stibogluconate is increasing in some
endemic areas, notably in India where other agents (eg, ampho-
tericin or miltefosine) are generally recommended.
Few adverse effects occur initially, but the toxicity of stibo-
gluconate increases over the course of therapy. Most common are
gastrointestinal symptoms, fever, headache, myalgias, arthralgias,
and rash. Intramuscular injections can be very painful and lead
to sterile abscesses. Electrocardiographic changes may occur,
most commonly T-wave changes and QT prolongation. These
changes are generally reversible, but continued therapy may lead
to dangerous arrhythmias. Thus, the electrocardiogram should be
monitored during therapy. Hemolytic anemia and serious liver,
renal, and cardiac effects are rare.
NITAZOXANIDE
Nitazoxanide is a nitrothiazolyl-salicylamide prodrug. It is approved
in the USA for use against Giardia lamblia and Cryptosporidium
parvum. It is rapidly absorbed and converted to tizoxanide and
tizoxanide conjugates, which are subsequently excreted in both
urine and feces. The active metabolite, tizoxanide, inhibits
934    SECTION VIII  Chemotherapeutic Drugs
the pyruvate-ferredoxin oxidoreductase pathway. Nitazoxanide
appears to have activity against metronidazole-resistant protozoal
strains and is well tolerated. Unlike metronidazole, nitazoxanide
and its metabolites appear to be free of mutagenic effects. Other
organisms that may be susceptible to nitazoxanide include
E histolytica, Helicobacter pylori, Ascaris lumbricoides, several tape-
worms, and Fasciola hepatica. The recommended adult dosage is
500 mg twice daily for 3 days.
OTHER DRUGS FOR TRYPANOSOMIASIS
& LEISHMANIASIS
Current therapies for all forms of trypanosomiasis are seriously
deficient in efficacy, safety, or both. Availability of these therapies
is also a concern, since they are supplied mainly through dona-
tion or nonprofit production by pharmaceutical companies. For
visceral leishmaniasis, liposomal amphotericin, miltefosine, and
paromomycin are effective, and combinations of these agents have
shown promising results.
Suramin
Suramin is a sulfated naphthylamine that was introduced in the
1920s. It is the first-line therapy for early hemolymphatic East Afri-
can trypanosomiasis (T brucei rhodesiense infection), but because it
does not enter the central nervous system, it is not effective against
advanced disease. Suramin is less effective than pentamidine for
early West African trypanosomiasis. The drug’s mechanism of
action is unknown. It is administered intravenously and displays
complex pharmacokinetics with very tight protein binding. Sura-
min has a short initial half-life but a terminal elimination half-life of
about 50 days. The drug is slowly cleared by renal excretion.
Suramin is administered after a 200-mg intravenous test dose.
Regimens that have been used include 1 g on days 1, 3, 7, 14,
and 21 or 1 g each week for 5 weeks. Combination therapy with
pentamidine may improve efficacy. Suramin can also be used
for chemoprophylaxis against African trypanosomiasis. Adverse
effects are common. Immediate reactions can include fatigue, nau-
sea, vomiting, and, more rarely, seizures, shock, and death. Later
reactions include fever, rash, headache, paresthesias, neuropa-
thies, renal abnormalities including proteinuria, chronic diarrhea,
hemolytic anemia, and agranulocytosis.
Melarsoprol
Melarsoprol is a trivalent arsenical that has been available since
1949 and is first-line therapy for advanced central nervous system
East African trypanosomiasis, and second-line therapy (after eflo-
rnithine) for advanced West African trypanosomiasis. After intra-
venous administration it is excreted rapidly, but clinically relevant
concentrations accumulate in the central nervous system within
4 days. Melarsoprol is administered in propylene glycol by slow
intravenous infusion at a dosage of 3.6 mg/kg/d for 3–4 days, with
repeated courses at weekly intervals, if needed. A new regimen of
2.2 mg/kg daily for 10 days had efficacy and toxicity similar to
what was observed with three courses over 26 days. Melarsoprol is
extremely toxic. The use of such a toxic drug is justified only by
the severity of advanced trypanosomiasis and the lack of available
alternatives. Immediate adverse effects include fever, vomiting,
abdominal pain, and arthralgias. The most important toxicity is
a reactive encephalopathy that generally appears within the first
week of therapy (in 5–10% of patients) and is probably due to
disruption of trypanosomes in the central nervous system. Coad-
ministration of corticosteroids may decrease the likelihood of
encephalopathy. Common consequences of the encephalopathy
include cerebral edema, seizures, coma, and death. Other serious
toxicities include renal and cardiac disease and hypersensitivity
reactions. Failure rates with melarsoprol appear to have increased
recently in parts of Africa, suggesting drug resistance.
Eflornithine
Eflornithine (difluoromethylornithine), an inhibitor of ornithine
decarboxylase, is the only new drug registered to treat African
trypanosomiasis in the last half-century. It is now the first-line
drug for advanced West African trypanosomiasis, but is not effec-
tive for East African disease. Eflornithine is administered intrave-
nously, and good central nervous system drug levels are achieved.
The elimination half-life is about 3 hours. The usual regimen is
100 mg/kg intravenously every 6 hours for 7–14 days (14 days was
superior for a newly diagnosed infection). Eflornithine appears to
be as effective as melarsoprol against advanced T brucei gambiense
infection, but its efficacy against T brucei rhodesiense is limited by
drug resistance. Combining eflornithine with a 10-day course of
nifurtimox afforded efficacy against West African trypanosomiasis
similar to a 14-day regimen of eflornithine alone, with simpler
and shorter treatment (injections every 12 hours for 7 days). Tox-
icity from eflornithine is significant, but considerably less than
that from melarsoprol. Adverse effects include diarrhea, vomiting,
anemia, thrombocytopenia, leukopenia, and seizures. These effects
are generally reversible. Increased experience with eflornithine and
increased availability of the compound in endemic areas may lead
to its replacement of suramin, pentamidine, and melarsoprol in
the treatment of T brucei gambiense infection.
Benznidazole
Benznidazole is an orally administered nitroimidazole for the treat-
ment of American trypanosomiasis (Chagas disease) that probably
has improved efficacy and safety compared to nifurtimox. These
drugs can eliminate parasites and prevent progression when used
to treat acute infection, but activity against chronic Chagas disease
is suboptimal. In a recent randomized trial, treatment of Chagas
cardiomyopathy with benznidazole did not offer clinical benefit.
Standard dosage is 5 mg/kg/d in two or three divided doses for 60
days, given with meals. Important toxicities, which are generally
reversible, include rash (in 20–30% of those treated), peripheral
neuropathy, gastrointestinal symptoms, and myelosuppression.
Nifurtimox
Nifurtimox, a nitrofuran, is a standard drug for Chagas dis-
ease. Nifurtimox is also used in the treatment of African

trypanosomiasis in combination with eflornithine. Nifurtimox
is well absorbed after oral administration and eliminated with a
plasma half-life of about 3 hours. The drug is administered at a
dosage of 8–10 mg/kg/d in three divided doses with meals for
60–90 days. Toxicity related to nifurtimox is common. Adverse
effects include nausea, vomiting, abdominal pain, fever, rash,
headache, restlessness, insomnia, neuropathies, and seizures.
These effects are generally reversible but often lead to cessation of
therapy before completion of a standard course.
Amphotericin
This important antifungal drug (see Chapter 48) is an alternative
therapy for visceral leishmaniasis, especially in parts of India with
high-level resistance to sodium stibogluconate. Liposomal ampho-
tericin has shown excellent efficacy at a dosage of 3 mg/kg/d
intravenously on days 1–5, 14, and 21. Other regimens that have
shown good efficacy in India include 4 doses of 5 mg/kg over
4–10 days and a single dose of 15 mg/kg. With single-dose ther-
apy, an amphotericin lipid emulsion had similar efficacy to that
of the liposomal formulation. Efficacy of amphotericin appears to
be lower in Africa. Nonliposomal amphotericin (1 mg/kg intrave-
nously every other day for 30 days) is more toxic, less expensive,
also efficacious, and widely used in India. However, in an Indian
trial a single infusion of liposomal amphotericin showed nonin-
ferior efficacy and decreased cost compared to a standard 30-day
course of amphotericin. Amphotericin is also used for cutaneous
leishmaniasis in some areas. The use of amphotericin, and espe-
cially liposomal preparations, is limited in developing countries by
difficulty of administration, cost, and toxicity.
Miltefosine
Miltefosine is an alkylphosphocholine analog that is the first
effective oral drug for visceral leishmaniasis. It has recently shown
excellent efficacy in the treatment of visceral leishmaniasis in
India, where it is administered orally (2.5 mg/kg/d with varied
dosing schedules) for 28 days. It was also recently shown to be
effective in regimens including a single dose of liposomal ampho-
tericin followed by 7–14 days of miltefosine. A 28-day course of
miltefosine (2.5 mg/kg/d) was also effective for the treatment of
New World cutaneous leishmaniasis. Vomiting and diarrhea are
common but generally short-lived toxicities. Transient elevations
in liver enzymes and nephrotoxicity are also seen. The drug should
CHAPTER 52  Antiprotozoal Drugs    935
be avoided in pregnancy (or in women who may become pregnant
within 2 months of treatment) because of its teratogenic effects.
Miltefosine is registered for the treatment of visceral leishmaniasis
in India and some other countries, and—considering the serious
limitations of other drugs, including parenteral administration,
toxicity, and resistance—it may become the treatment of choice
for that disease. Miltefosine may also have a role in the treatment
of cutaneous leishmaniasis; the drug was noninferior to meglu-
mine antimoniate for this indication in South American children.
Resistance to miltefosine develops readily in vitro.
Paromomycin
Paromomycin sulfate is an aminoglycoside antibiotic that until
recently was used in parasitology only for oral therapy of intes-
tinal parasitic infections (see previous text). It has recently been
developed for the treatment of visceral leishmaniasis. It is much
less expensive than amphotericin or miltefosine. A trial in India
showed excellent efficacy, with a daily intramuscular dosage of 11
mg/kg for 21 days yielding a 95% cure rate, and noninferiority
compared with amphotericin. However, a recent trial showed
poorer efficacy in Africa, with the cure rate for paromomycin
significantly inferior to that with sodium stibogluconate. In initial
studies, paromomycin was well tolerated, with common mild
injection pain, uncommon ototoxicity and reversible liver enzyme
elevations, and no nephrotoxicity. Paromomycin has also shown
good efficacy when topically applied, alone or with gentamicin,
for the treatment of cutaneous leishmaniasis.
Drug Combinations Used in the
Treatment of Visceral Leishmaniasis
The use of drug combinations to improve treatment efficacy,
shorten treatment courses, and reduce the selection of resistant
parasites has been an active area of research. In a recent trial in
India, compared to a standard 30-day (treatment on alternate
days) course of amphotericin, noninferior efficacy and decreased
adverse events were seen with a single dose of liposomal amphoter-
icin plus a 7-day course of miltefosine, a single dose of liposomal
amphotericin plus a 10-day course of paromomycin, or a 10-day
course of miltefosine plus paromomycin. In a trial in East Africa,
compared to a standard 30-day course of sodium stibogluconate,
similar efficacy was seen with a 17-day course of sodium stiboglu-
conate plus paromomycin.
936    SECTION VIII  Chemotherapeutic Drugs

P R E P A R A T I O N S German PI, Aweeka FT: Clinical pharmacology of artemisinin-based combination

therapies. Clin Pharmacokinet 2008;47:91.
A V A I L A B L E Hill DR et al: Primaquine: Report from CDC expert meeting on malaria chemo-
prophylaxis I. Am J Trop Med Hyg 2006;75:402.
John GK et al: Primaquine radical cure of Plasmodium vivax: A critical review of
GENERIC NAME AVAILABLE AS
the literature. Malar J 2012;11:280.
Artemether/lumefantrine Coartem, Riamet McGready R et al: Adverse effects of falciparum and vivax malaria and the safety of
Artesunate*   antimalarial treatment in early pregnancy: A population-based study. Lancet
Artesunate-pyronaridine Pyramax Infect Dis 2012;12:388.
Atovaquone Generic, Mepron Morris CA et al: Review of the clinical pharmacokinetics of artesunate and its
active metabolite dihydroartemisinin following intravenous, intramuscular,
Atovaquone-proguanil Malarone oral or rectal administration. Malar J 2011;10:263.
Benznidazole*   Nadjm B, Behrens RH: Malaria: An update for physicians. Infect Dis Clin North
Chloroquine Generic, Aralen Am 2012;26:243.
Clindamycin Generic, Cleocin Nosten F et al: Antimalarial drugs in pregnancy: A review. Curr Drug Saf 2006;1:1.
Doxycycline Generic, Vibramycin Rehman K, et al: Haemolysis associated with the treatment of malaria with arte-
misinin derivatives: a systematic review of current evidence. Int J Infect Dis
Eflornithine Vaniqa, Ornidyl 2014;29:268.
Iodoquinol Diquinol, Yodoxin Rosenthal PJ: Artesunate for the treatment of severe falciparum malaria. N Engl J
Mefloquine Generic, Lariam Med 2008;358:1829.
Melarsoprol* Mel B Rosenthal PJ: The interplay between drug resistance and fitness in malaria para-
sites. Mol Microbiol 2013;89:1025.
Metronidazole Generic, Flagyl
Stepniewska K, White NJ: Pharmacokinetic determinants of the window of
Nifurtimox*   selection for antimalarial drug resistance. Antimicrob Agents Chemother
Nitazoxanide Alinia 2008;52:1589.
Paromomycin Generic, Humatin Taylor WR, White NJ: Antimalarial drug toxicity: A review. Drug Saf 2004;
27:25.
Pentamidine Pentam 300, Pentacarinat, pentami-
dine isethionate, Nebupent (aerosol) Tilley L et al: Artemisinin Action and Resistance in Plasmodium falciparum. Trends
Parasitol 2016 32:682.
Primaquine Generic
White NJ: Cardiotoxicity of antimalarial drugs. Lancet Infect Dis 2007;7:549.
Pyrimethamine Daraprim White NJ et al: Malaria. Lancet 2014;383:723.
Quinidine gluconate Generic Whitty CJ, Chiodini PL, Lalloo DG: Investigation and treatment of imported
Quinine Generic malaria in non-endemic countries. BMJ 2013;346:f2900.
Sodium stibogluconate*   World Health Organization: Guidelines for the treatment of malaria. Geneva.
2015. www.who.int/malaria/publications/atoz/9789241549127/en/.
Sulfadoxine-pyrimethamine Fansidar
Suramin*  
Tinidazole Generic, Tindamax Intestinal Protozoal Infections
* Fox LM, Saravolatz LD: Nitazoxanide: A new thiazolide antiparasitic agent. Clin
Available in the USA only from the Drug Service, CDC, Atlanta, Georgia (phone:
Infect Dis 2005;40:1173.
404-639-3670; www.cdc.gov/laboratory/drugservice/).
Granados CE et al: Drugs for treating giardiasis. Cochrane Database Syst Rev
2012;(12):CD007787.
Leitsch D: Drug resistance in the microaerophilic parasite Giardia lamblia. Curr
REFERENCES Trop Med Rep 2015;2:128.
General Marcos LA, Gotuzzo E: Intestinal protozoan infections in the immunocompro-
mised host. Curr Opin Infect Dis 2013;26:295.
Kappagoda S, Singh U, Blackburn BG: Antiparasitic therapy. Mayo Clin Proc
Pierce KK et al: Update on human infections caused by intestinal protozoa. Curr
2011;86:561.
Opin Gastroenterol 2009;25:12.
Medical Letter: Drugs for parasitic infections. Med Lett Drugs Ther
Pritt BS, Clark DG: Amebiasis. Mayo Clin Proc 2008;83:1154.
2013;Supplement.
Ross AG et al: Enteropathogens and chronic illness in returning travelers. N Engl
J Med 2013;368:1817.
Malaria Rossignol JF: Cryptosporidium and Giardia: Treatment options and prospects for
Ashley EA et al: Tracking Resistance to Artemisinin Collaboration (TRAC). Spread new drugs. Exp Parasitol 2010;124:45.
of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med Wright SG: Protozoan infections of the gastrointestinal tract. Infect Dis Clin
2014;371:411. North Am 2012;26:323.
Baird KJ, Maguire JD, Price RN: Diagnosis and treatment of Plasmodium vivax
malaria. Adv Parasitol 2012;80:203.
Trypanosomiasis & Leishmaniasis
Boggild AK et al: Atovaquone-proguanil: Report from the CDC expert meeting on
malaria chemoprophylaxis (II). Am J Trop Med Hyg 2007;76:208. Aronson NE et al: A randomized controlled trial of local heat therapy versus intra-
Bukirwa H et al: Artesunate plus pyronaridine for treating uncomplicated Plasmo- venous sodium stibogluconate for the treatment of cutaneous Leishmania
dium falciparum malaria. Cochrane Database Syst Rev 2014;(3):CD006404. major infection. PLoS Negl Trop Dis 2010;4:e628.
Dondorp AM et al: Artesunate versus quinine in the treatment of severe falciparum Ben Salah A et al: Topical paromomycin with or without gentamicin for cutaneous
malaria in African children (AQUAMAT): An open-label, randomised trial. leishmaniasis. N Engl J Med 2013;368:524.
Lancet 2010;376:1647. Bern C: Chagas’ disease. N Engl J Med 2015;373:456.
Efferth T, Kaina B: Toxicity of the antimalarial artemisinin and its derivatives. Crit Bhattacharya SK et al: Phase 4 trial of miltefosine for the treatment of Indian
Rev Toxicol 2010;40:405. visceral leishmaniasis. J Infect Dis 2007;196:591.

Bisser S et al: Equivalence trial of melarsoprol and nifurtimox monotherapy and
combination therapy for the treatment of second-stage Trypanosoma brucei
gambiense sleeping sickness. J Infect Dis 2007;195:322.
Brun R, Blum J: Human African trypanosomiasis. Infect Dis Clin North Am
2012;26:261.
Brun R et al: Human African trypanosomiasis. Lancet 2010;375:148.
Burza S et al: Five-year field results and long-term effectiveness of 20 mg/kg lipo-
somal amphotericin B (Ambisome) for visceral leishmaniasis in Bihar, India.
PLoS Negl Trop Dis 2014;8:e2603.
Goto H, Lauletta Lindoso JA: Cutaneous and mucocutaneous leishmaniasis. Infect
Dis Clin North Am 2012;26:293.
Hailu A et al: Geographical variation in the response of visceral leishmaniasis to
paromomycin in East Africa: A multicentre, open-label, randomized trial.
PLoS Negl Trop Dis 2010;4:e709.
Jackson Y et al: Tolerance and safety of nifurtimox in patients with chronic Chagas
disease. Clin Infect Dis 2010;51:e69.
Kennedy PG: Clinical features, diagnosis, and treatment of human African try-
panosomiasis (sleeping sickness). Lancet Neurol 2013;12:186.
Lescure FX et al: Chagas disease: Changes in knowledge and management. Lancet
Infect Dis 2010;10:556.
Lutje V, Seixas J, Kennedy A: Chemotherapy for second-stage human African try-
panosomiasis. Cochrane Database Syst Rev 2013;(6):CD006201.
Morillo CA et al: Randomized trial of benznidazole for chronic Chagas’ cardiomy-
opathy. N Engl J Med 2015;373:1295.
Murray HW: Leishmaniasis in the United States: Treatment in 2012. Am J Trop
Med Hyg 2012;86:434.
Murray HW et al: Advances in leishmaniasis. Lancet 2005;366:1561.
Musa A et al: Sodium stibogluconate (SSG) & paromomycin combination
compared to SSG for visceral leishmaniasis in East Africa: A randomised
controlled trial. PLoS Negl Trop Dis 2012;6:e1674.
C ASE STUDY ANSWER
This child has acute falciparum malaria, and her lethargy
and abnormal laboratory tests are consistent with progres-
sion to severe disease. She should be hospitalized and treated
urgently with intravenous artesunate or, if this is unavailable,
intravenous quinine or quinidine. She should be followed
CHAPTER 52  Antiprotozoal Drugs    937
Priotto G et al: Nifurtimox-eflornithine combination therapy for second-stage
African Trypanosoma brucei gambiense trypanosomiasis: A multicentre, ran-
domised, phase III, non-inferiority trial. Lancet 2009;374:56.
Rassi A Jr, Rassi A, Marcondes de Rezende J: American trypanosomiasis (Chagas
disease). Infect Dis Clin North Am 2012;26:275.
Rassi A et al: Chagas disease. Lancet 2010;375:1388.
Rubiano LC et al: Noninferiority of miltefosine versus meglumine antimoniate for
cutaneous leishmaniasis in children. J Infect Dis 2012;205:684.
Sosa N et al: Randomized, double-blinded, phase 2 trial of WR 279,396 (paromo-
mycin and gentamicin) for cutaneous leishmaniasis in Panama. Am J Trop
Med Hyg 2013;89:557.
Sundar S et al: Comparison of short-course multidrug treatment with standard
therapy for visceral leishmaniasis in India: An open-label, non-inferiority,
randomised controlled trial. Lancet 2011;377:477.
Sundar S et al: Efficacy of miltefosine in the treatment of visceral leishmaniasis in
India after a decade of use. Clin Infect Dis 2012;55:543.
Sundar S et al: Efficacy and safety of amphotericin B emulsion versus liposomal
formulation in Indian patients with visceral leishmaniasis: a randomized,
open-label study. PLoS Negl Trop Dis 2014;8:e3169.
Sundar S, Singh A: Recent developments and future prospects in the treatment of
visceral leishmaniasis. Ther Adv Infect Dis 2016;3:98.
Sundar S et al: Single-dose liposomal amphotericin B for visceral leishmaniasis in
India. N Engl J Med 2010;362:504.
van Griensven J, Diro E: Visceral leishmaniasis. Infect Dis Clin North Am
2012;26:309.
van Griensven J et al: Combination therapy for visceral leishmaniasis. Lancet Infect
Dis 2010;10:184.
Vélez I et al: Efficacy of miltefosine for the treatment of American cutaneous leish-
maniasis. Am J Trop Med Hyg 2010;83:351.
closely for progression of severe malaria, in particular neu-
rologic, renal, or pulmonary complications, and if treated
with quinine or quinidine should have cardiac monitoring
for potential toxicities.
 53
C H A P T E R
Clinical Pharmacology of
the Antihelminthic Drugs
Philip J. Rosenthal, MD
C ASE STUDY
A 29-year-old Peruvian man presents with the incidental
finding of a 10 × 8 × 8-cm liver cyst on an abdominal com-
puted tomography (CT) scan. The patient had noted 2 days
of abdominal pain and fever, and his clinical evaluation and
CT scan were consistent with appendicitis. His clinical find-
ings resolved after laparoscopic appendectomy. The patient
■■ CHEMOTHERAPY OF
HELMINTHIC INFECTIONS
Helminths (worms) are multicellular organisms that infect very
large numbers of humans and cause a broad range of diseases.
More than 1 billion people are infected with intestinal nematodes,
and many millions are infected with filarial nematodes, flukes,
and tapeworms in other organs. Many drugs, directed against
a number of different targets, are available to treat helminthic
infections. In many cases, especially in the developing world, the
goal is control of infection, with elimination of most parasites,
alleviating disease symptoms, and decreasing the transmission of
infection. In other cases, complete elimination of parasites is the
goal of therapy, although this goal can be challenging with certain
helminthic infections, because of both limited efficacy of drugs
and frequent reinfection after therapy in endemic areas.
Table 53–1 lists the major helminthic infections and provides
a guide to the drug of choice and alternative drugs for each infec-
tion. In the text that follows, these drugs are arranged alphabeti-
cally. In general, parasites should be identified before treatment
is started.
938
immigrated to the USA 10 years ago from a rural area of
Peru where his family trades in sheepskins. His father and
sister have undergone resection of abdominal masses,
but details of their diagnoses are unavailable. What is
your differential diagnosis? What are your diagnostic and
therapeutic plans?
ALBENDAZOLE
Albendazole, a broad-spectrum oral antihelminthic, is the drug of
choice and is approved in the USA for treatment of hydatid disease
and cysticercosis. It is also used in the treatment of pinworm and
hookworm infections, ascariasis, trichuriasis, and strongyloidiasis.
Basic Pharmacology
Albendazole is a benzimidazole carbamate. After oral adminis-
tration, it is erratically absorbed (increased with a fatty meal)
and then rapidly undergoes first-pass metabolism in the liver to
the active metabolite albendazole sulfoxide. It reaches variable
maximum plasma concentrations about 3 hours after a 400-mg
oral dose, and its plasma half-life is 8–12 hours. The sulfoxide is
mostly protein-bound, distributes well to tissues, and enters bile,
cerebrospinal fluid, and hydatid cysts. Albendazole metabolites are
excreted in the urine.
Benzimidazoles are thought to act against nematodes by inhibit-
ing microtubule synthesis. Albendazole also has larvicidal effects in
hydatid disease, cysticercosis, ascariasis, and hookworm infection
and ovicidal effects in ascariasis, ancylostomiasis, and trichuriasis.
 CHAPTER 53  Clinical Pharmacology of the Antihelminthic Drugs     939

TABLE 53–1  Drugs for the treatment of helminthic infections.1

Infecting Organism Drug of Choice Alternative Drugs

Roundworms (nematodes)    
  Ascaris lumbricoides (roundworm) Albendazole or pyrantel pamoate or mebendazole Ivermectin, piperazine
  Trichuris trichiura (whipworm) Mebendazole or albendazole Ivermectin, oxantel pamoate, drug
combinations
Necator americanus (hookworm); Ancylostoma
  Albendazole or mebendazole or pyrantel pamoate  
duodenale (hookworm)
  Strongyloides stercoralis (threadworm) Ivermectin Albendazole or thiabendazole
  Enterobius vermicularis (pinworm) Mebendazole or pyrantel pamoate Albendazole
  Trichinella spiralis (trichinosis) Mebendazole or albendazole; add corticosteroids  
for severe infection
  Trichostrongylus species Pyrantel pamoate or mebendazole Albendazole
  Cutaneous larva migrans (creeping eruption) Albendazole or ivermectin Thiabendazole (topical)
  Visceral larva migrans Albendazole Mebendazole
  Angiostrongylus cantonensis Albendazole or mebendazole  
Wuchereria bancrofti (filariasis); Brugia malayi
  Diethylcarbamazine Ivermectin
(filariasis); tropical eosinophilia; Loa loa (loiasis)
  Onchocerca volvulus (onchocerciasis) Ivermectin  
  Dracunculus medinensis (guinea worm) Metronidazole Thiabendazole or mebendazole
Capillaria philippinensis (intestinal capillariasis)
  Albendazole Mebendazole
Flukes (trematodes)    
  Schistosoma haematobium (bilharziasis) Praziquantel Metrifonate
  Schistosoma mansoni Praziquantel Oxamniquine
  Schistosoma japonicum Praziquantel  
Clonorchis sinensis (liver fluke); Opisthorchis
  Praziquantel Albendazole
species
  Paragonimus westermani (lung fluke) Praziquantel Bithionol
  Fasciola hepatica (sheep liver fluke) Bithionol or triclabendazole  
  Fasciolopsis buski (large intestinal fluke) Praziquantel or niclosamide  
Heterophyes heterophyes; Metagonimus yokogawai
  Praziquantel or niclosamide  
(small intestinal flukes)
Tapeworms (cestodes)    
  Taenia saginata (beef tapeworm) Praziquantel or niclosamide Mebendazole
  Diphyllobothrium latum (fish tapeworm) Praziquantel or niclosamide  
  Taenia solium (pork tapeworm) Praziquantel or niclosamide  
  Cysticercosis (pork tapeworm larval stage) Albendazole Praziquantel
  Hymenolepis nana (dwarf tapeworm) Praziquantel Niclosamide, nitazoxanide
Echinococcus granulosus (hydatid disease);
  Albendazole  
Echinococcus multilocularis
1
Additional information may be obtained from the Parasitic Disease Drug Service, Parasitic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, 30333.
Telephone: (404) 639-3670. Some of the drugs listed are not generally available in the USA.

Clinical Uses
Albendazole is administered on an empty stomach when used
against intraluminal parasites but with a fatty meal when used
against tissue parasites.
1. Ascariasis, trichuriasis, and hookworm and pinworm
infections—For adults and children older than 2 years with
ascariasis and pinworm infections, the treatment for ascariasis
is a single dose of 400 mg orally (repeated daily for 2–3 days
for heavy infections and in 2 weeks for pinworm infections).
These treatments typically achieve good cure rates and marked
reduction in egg counts in those not cured. For hookworm
infections and trichuriasis, albendazole at 400 mg orally once
daily for 3 days is now recommended, with albendazole showing
improved efficacy over mebendazole. For trichuriasis, combina-
tion of either mebendazole or albendazole with ivermectin and
940    SECTION VIII  Chemotherapeutic Drugs
combination of albendazole with oxantel pamoate markedly
improved treatment outcomes.
2. Hydatid disease—Albendazole is the treatment of choice
for medical therapy and is a useful adjunct to surgical removal or
aspiration of cysts. It is more active against Echinococcus granu-
losus than against Echinococcus multilocularis. Dosing is 400 mg
twice daily with meals for 1 month or longer. Daily therapy for
up to 6 months has been well tolerated. One reported thera-
peutic strategy is to treat with albendazole and praziquantel, to
assess response after 1 month or more, and, depending on the
response, to then manage the patient with continued chemo-
therapy or combined surgical and drug therapy.
3. Neurocysticercosis—Indications for medical therapy for neu-
rocysticercosis are controversial, since antihelminthic therapy is
not clearly superior to therapy with corticosteroids alone and may
exacerbate neurologic disease. Therapy is probably most appro-
priate for symptomatic parenchymal or intraventricular cysts.
Corticosteroids are usually given with the antihelminthic drug to
decrease inflammation caused by dying organisms. Albendazole
is now generally considered the drug of choice over praziquantel
because of its shorter course, lower cost, improved penetration
into the subarachnoid space, and increased drug levels (as opposed
to decreased levels of praziquantel) when administered with cor-
ticosteroids. Albendazole is given in a dosage of 400 mg twice
daily for up to 21 days. Albendazole combined with praziquantel
improves efficacy in patients with multiple brain cysts.
4. Other infections—Albendazole is the drug of choice in the
treatment of cutaneous larva migrans (400 mg daily for 3 days),
visceral larva migrans (400 mg twice daily for 5 days), intestinal
capillariasis (400 mg daily for 10 days), microsporidial infections
(400 mg twice daily for 2 weeks or longer), and gnathostomiasis
(400 mg twice daily for 3 weeks). It also has activity against
taeniasis (400 mg daily for 3 days), trichinosis (400 mg twice
daily for 1–2 weeks), and clonorchiasis (400 mg twice daily for
1 week). There have been reports of effectiveness in treatment of
opisthorchiasis, toxocariasis, and loiasis. Albendazole is included
in programs to control lymphatic filariasis. It appears to be less
active than diethylcarbamazine or ivermectin for this purpose,
but it is included in combination with either of those drugs in
control programs. Albendazole has been recommended as empiric
therapy to treat those who return from the tropics with persistent
unexplained eosinophilia. Albendazole has activity against giardia-
sis, but with decreased efficacy compared to tinidazole.
Adverse Reactions, Contraindications, &
Cautions
When used for 1–3 days, albendazole is nearly free of significant
adverse effects. Mild and transient epigastric distress, diarrhea,
headache, nausea, dizziness, lassitude, and insomnia can occur. In
long-term use for hydatid disease, albendazole is well tolerated,
but it can cause abdominal distress, headaches, fever, fatigue, alo-
pecia, increases in liver enzymes, and pancytopenia.
Blood counts and liver function should be monitored during
long-term therapy. The drug should not be given to patients with
known hypersensitivity to other benzimidazole drugs or to those
with cirrhosis. The safety of albendazole in pregnancy and in
children younger than 2 years has not been established. Exposure
to albendazole is increased by dexamethasone, praziquantel, and
cimetidine, and decreased by phenytoin, phenobarbital, carbam-
azepine, and ritonavir.
BITHIONOL
Bithionol is an alternative to triclabendazole for the treatment of
fascioliasis (sheep liver fluke) and an alternative to praziquantel for
the treatment of paragonimiasis.
Basic Pharmacology & Clinical Uses
After ingestion, bithionol reaches peak blood levels in 4–8 hours.
Excretion appears to be mainly via the kidney.
For treatment of paragonimiasis and fascioliasis, the dos-
age of bithionol is 30–50 mg/kg in two or three divided doses,
given orally after meals on alternate days for 10–15 doses. For
pulmonary paragonimiasis, cure rates are over 90%. For cerebral
paragonimiasis, repeat courses may be necessary.
Adverse Reactions, Contraindications, &
Cautions
Adverse effects, which occur in up to 40% of patients, are generally
mild and transient, but occasionally their severity requires inter-
ruption of therapy. These problems include diarrhea, abdominal
cramps, anorexia, nausea, vomiting, dizziness, and headache. Skin
rashes may occur after a week or more of therapy, suggesting a
reaction to antigens released from dying worms. Bithionol should
be used with caution in children younger than 8 years because
there has been limited experience in this age group.
DIETHYLCARBAMAZINE CITRATE
Diethylcarbamazine is a drug of choice in the treatment of fila-
riasis, loiasis, and tropical eosinophilia. It has been replaced by
ivermectin for the treatment of onchocerciasis.
Basic Pharmacology
Diethylcarbamazine, a synthetic piperazine derivative, is rapidly
absorbed from the gastrointestinal tract; after a dose of 0.5 mg/kg,
peak plasma levels are reached within 1–2 hours. The plasma half-
life is 2–3 hours in the presence of acidic urine but about 10 hours
if the urine is alkaline, a Henderson-Hasselbalch trapping effect
(see Chapter 1). The drug rapidly equilibrates with all tissues
except fat. It is excreted, principally in the urine, as unchanged
drug and the N-oxide metabolite. Dosage should be reduced in
patients with renal impairment.
Diethylcarbamazine immobilizes microfilariae and alters their
surface structure, displacing them from tissues and making them
 CHAPTER 53  Clinical Pharmacology of the Antihelminthic Drugs     941
more susceptible to destruction by host defense mechanisms. The
mode of action against adult worms is unknown.
Clinical Uses
The drug should be taken after meals.
1. Wuchereria bancrofti, Brugia malayi, Brugia timori, and
Loa loa—Diethylcarbamazine is the drug of choice for treatment
of infections with these parasites because of its efficacy and lack of
serious toxicity. Microfilariae of all species are rapidly killed; adult
parasites are killed more slowly, often requiring several courses of
treatment. The drug is highly effective against adult L loa. The extent
to which W bancrofti and B malayi adults are killed is not known,
but after appropriate therapy microfilariae do not reappear in the
majority of patients. Lymphatic filariasis is treated with 2 mg/kg
three times a day for 12 days, and loiasis is treated with the same
regimen for 2–3 weeks. Antihistamines may be given for the first few
days of therapy to limit allergic reactions, and corticosteroids should
be started and doses of diethylcarbamazine lowered or interrupted
if severe reactions occur. Cures may require several courses of treat-
ment. For patients with high L loa worm burdens (more than 2500
circulating parasites/mL), strategies to decrease risks of severe toxic-
ity include (a) apheresis, if available, to remove microfilariae before
treatment with diethylcarbamazine, or (b) therapy with albendazole,
which is slower acting and better tolerated, followed by therapy with
diethylcarbamazine or ivermectin. Diethylcarbamazine may also
be used for chemoprophylaxis against filarial infections (300 mg
weekly or 300 mg on 3 successive days each month for loiasis; 50 mg
monthly for bancroftian and Malayan filariasis).
2. Other uses—For tropical eosinophilia, diethylcarbamazine is
given orally at a dosage of 2 mg/kg three times daily for 2–3 weeks.
Diethylcarbamazine is effective in Mansonella streptocerca infections,
since it kills both adults and microfilariae. Limited information
suggests that the drug is not effective, however, against adult
Mansonella ozzardi or Mansonella perstans and that it has limited
activity against microfilariae of these parasites. An important appli-
cation of diethylcarbamazine has been mass treatment to reduce the
prevalence of W bancrofti infection, generally in combination with
ivermectin or albendazole. This strategy has led to excellent progress
in disease control in a number of countries.
Adverse Reactions, Contraindications,
& Cautions
Reactions to diethylcarbamazine, which are generally mild and
transient, include headache, malaise, anorexia, weakness, nausea,
vomiting, and dizziness. Adverse effects also occur as a result of
the release of proteins from dying microfilariae or adult worms.
Reactions can be particularly severe with onchocerciasis, but
diethylcarbamazine is no longer commonly used for this infection
because ivermectin is equally efficacious and less toxic. Reactions
to dying microfilariae are usually mild in W bancrofti, more
intense in B malayi, and occasionally severe in L loa infections.
Reactions include fever, malaise, papular rash, headache, gas-
trointestinal symptoms, cough, chest pain, and muscle or joint
pain. Leukocytosis is common and eosinophilia may increase with
treatment. Proteinuria also may occur. Symptoms are most likely
to occur in patients with heavy loads of microfilariae. Retinal
hemorrhages and, rarely, encephalopathy have been described.
Local reactions may occur in the vicinity of dying adult or imma-
ture worms. These include lymphangitis with localized swellings in
W bancrofti and B malayi, small wheals in the skin in L loa, and flat
papules in M streptocerca infections. Patients with attacks of lym-
phangitis due to W bancrofti or B malayi should be treated during
a quiescent period between attacks. Caution is advised when using
diethylcarbamazine in patients with hypertension or renal disease.
DOXYCYCLINE
This tetracycline antibiotic is described in more detail in
Chapter 44. Doxycycline has recently been shown to have
significant macrofilaricidal activity against W bancrofti, suggesting
better activity than any other available drug against adult worms.
Activity is also seen against onchocerciasis. Doxycycline acts indi-
rectly, by killing Wolbachia, an intracellular bacterial symbiont of
filarial parasites. It may prove to be an important drug for filariasis
and onchocerciasis, both for treatment of active disease and in
mass chemotherapy campaigns.
IVERMECTIN
Ivermectin is the drug of choice in strongyloidiasis and onchocer-
ciasis. It is also an alternative drug for a number of other helmin-
thic infections (Table 53–1).
Basic Pharmacology
Ivermectin, a semisynthetic macrocyclic lactone derived from the
soil actinomycete Streptomyces avermitilis, is a mixture of avermec-
tin B1a and B1b. Ivermectin is available only for oral administration
in humans. The drug is rapidly absorbed, reaching maximum
plasma concentrations 4 hours after a 12-mg dose. Ivermectin has
a wide tissue distribution and a volume of distribution of about
50 L. Its half-life is about 16 hours. Excretion of the drug and its
metabolites is almost exclusively in the feces.
Ivermectin appears to paralyze nematodes and arthropods by
intensifying γ-aminobutyric acid (GABA)-mediated transmission of
signals in peripheral nerves. In onchocerciasis, ivermectin is micro-
filaricidal. It does not effectively kill adult worms but blocks the
release of microfilariae for some months after therapy. After a single
standard dose, microfilariae in the skin diminish rapidly within
2–3 days, remain low for months, and then gradually increase;
microfilariae in the anterior chamber of the eye decrease slowly over
months, eventually clear, and then gradually return. With repeated
doses of ivermectin, the drug appears to have a low-level macrofilar-
icidal action and to permanently reduce microfilarial production.
Clinical Uses
1. Onchocerciasis—Treatment is with a single oral dose of
ivermectin, 150 mcg/kg, with water on an empty stomach.
942    SECTION VIII  Chemotherapeutic Drugs
Doses are repeated; regimens vary from monthly to less frequent
(every 6–12 months) dosing schedules. After acute therapy,
treatment is repeated at 12-month intervals until the adult
worms die, which may take 10 years or longer. With the first
treatment only, patients with microfilariae in the cornea or
anterior chamber may be treated with corticosteroids to avoid
inflammatory eye reactions.
Ivermectin also now plays a key role in onchocerciasis control.
Annual mass treatments have led to major reductions in disease
transmission. However, evidence of diminished responsiveness
after mass administration of ivermectin has raised concern regard-
ing selection of drug-resistant parasites.
2. Strongyloidiasis—Treatment consists of 200 mcg/kg once
daily for 2 days. In immunosuppressed patients with dissemi-
nated infection, repeated treatment is often needed, and cure
may not be possible. In this case, suppressive therapy—ie, once
monthly—may be helpful.
3. Other parasites—Ivermectin reduces microfilariae in
B malayi and M ozzardi infections but not in M perstans infec-
tions. It has been used with diethylcarbamazine and albendazole
for the control of W bancrofti, but it does not kill adult worms.
In loiasis, although the drug reduces microfilaria concentrations,
it can occasionally induce severe reactions and appears to be more
dangerous in this regard than diethylcarbamazine. Ivermectin
is also effective in controlling scabies, lice, and cutaneous larva
migrans and in eliminating a large proportion of ascarid worms.
Adverse Reactions, Contraindications, &
Cautions
In strongyloidiasis treatment, infrequent adverse effects of iver-
mectin include fatigue, dizziness, nausea, vomiting, abdominal
pain, and rashes. In onchocerciasis treatment, adverse effects
are principally from the killing of microfilariae and can
include fever, headache, dizziness, somnolence, weakness, rash,
increased pruritus, diarrhea, joint and muscle pains, hypoten-
sion, tachycardia, lymphadenitis, lymphangitis, and peripheral
edema. This reaction starts on the first day and peaks on the
second day after treatment. It occurs in 5–30% of persons and
is generally mild, but it may be more frequent and more severe
in individuals who are not long-term residents of onchocercia-
sis-endemic areas. A more intense reaction occurs in 1–3% of
persons and a severe reaction in 0.1%, including high fever,
hypotension, and bronchospasm. Corticosteroids are indicated
in these cases, at times for several days. Toxicity diminishes
with repeated dosing. Swellings and abscesses occasionally
occur at 1–3 weeks, presumably at sites of adult worms. Some
patients develop corneal opacities and other eye lesions several
days after treatment. These are rarely severe and generally
resolve without corticosteroid treatment. It is best to avoid
concomitant use of ivermectin with other drugs that enhance
GABA activity, eg, barbiturates, benzodiazepines, and valproic
acid. Ivermectin should not be used during pregnancy. Safety
in children younger than 5 years has not been established.
MEBENDAZOLE
Mebendazole is a synthetic benzimidazole that has a wide spec-
trum of antihelminthic activity and a low incidence of adverse
effects.
Basic Pharmacology
Less than 10% of orally administered mebendazole is absorbed.
The absorbed drug is protein-bound (>90%), is rapidly converted
to inactive metabolites (primarily during its first pass in the liver),
and has a half-life of 2–6 hours. It is excreted mostly in the urine,
principally as decarboxylated derivatives, as well as in the bile.
Absorption is increased if the drug is ingested with a fatty meal.
Mebendazole probably acts by inhibiting microtubule synthe-
sis; the parent drug appears to be the active form. Efficacy of the
drug varies with gastrointestinal transit time, with intensity of
infection, and perhaps with the strain of parasite. The drug kills
hookworm, Ascaris, and Trichuris eggs.
Clinical Uses
Mebendazole is indicated for use in ascariasis, trichuriasis, hook-
worm and pinworm infections, and certain other helminthic
infections. It can be taken before or after meals; the tablets should
be chewed before swallowing. For pinworm infection, the dose
is 100 mg once, repeated at 2 weeks. For ascariasis, trichuriasis,
hookworm, and Trichostrongylus infections, a dosage of 100 mg
twice daily for 3 days is used for adults and for children older than
2 years. Cure rates are good for pinworm infections and ascaria-
sis but have been disappointing in recent studies of trichuriasis,
although efficacy for trichuriasis is better than that of albendazole.
Cure rates are also low for hookworm infections, but a marked
reduction in the worm burden occurs in those not cured. For
intestinal capillariasis, mebendazole is used at a dosage of 200 mg
twice daily for 21 or more days. In trichinosis, limited reports
suggest efficacy against adult worms in the intestinal tract and
tissue larvae. Treatment is three times daily, with fatty foods, at
200–400 mg per dose for 3 days and then 400–500 mg per dose
for 10 days; corticosteroids should be co-administered for severe
infections.
Adverse Reactions, Contraindications,
& Cautions
Short-term mebendazole therapy for intestinal nematodes is nearly
free of adverse effects. Mild nausea, vomiting, diarrhea, and
abdominal pain have been reported infrequently. Rare side effects,
usually with high-dose therapy, are hypersensitivity reactions (rash,
urticaria), agranulocytosis, alopecia, and elevation of liver enzymes.
Mebendazole is teratogenic in animals and therefore contrain-
dicated in pregnancy. It should be used with caution in children
younger than 2 years because of limited experience and rare
reports of convulsions in this age group. Plasma levels may be
decreased by concomitant use of carbamazepine, phenytoin, or
ritonavir, and increased by cimetidine. Mebendazole should be
used with caution in patients with cirrhosis.
 CHAPTER 53  Clinical Pharmacology of the Antihelminthic Drugs     943
METRIFONATE (TRICHLORFON)
Metrifonate is a safe, low-cost alternative drug for the treatment
of Schistosoma haematobium infections. It is not active against
Schistosoma mansoni or Schistosoma japonicum. It is not available
in the USA.
Basic Pharmacology
Metrifonate, an organophosphate, is rapidly absorbed after oral
administration. After the standard oral dose, peak blood levels
are reached in 1–2 hours; the half-life is about 1.5 hours. Clear-
ance appears to be through nonenzymatic transformation to
dichlorvos, its active metabolite. Metrifonate and dichlorvos are
well distributed to the tissues and are completely eliminated in
24–48 hours.
The mode of action is thought to be cholinesterase inhibition,
temporarily paralyzing adult worms, resulting in their transit from
bladder vasculature to small arterioles in the lungs, where they are
killed. The drug is not effective against S haematobium eggs; live
eggs continue to pass in the urine for several months after all adult
worms have been killed.
Clinical Uses
In the treatment of S haematobium, an oral dose of 7.5–10 mg/kg
is given three times at 14-day intervals. Cure rates on this schedule
are 44–93%, with marked reductions in egg counts in those not
cured. Metrifonate was also effective as a prophylactic agent when
given monthly to children in a highly endemic area, and it has
been used in mass treatment programs. In mixed infections with
S haematobium and S mansoni, metrifonate has been successfully
combined with oxamniquine.
Adverse Reactions, Contraindications,
& Cautions
Some studies note mild and transient cholinergic symptoms,
including nausea and vomiting, diarrhea, abdominal pain, bron-
chospasm, headache, sweating, fatigue, weakness, dizziness, and
vertigo. Metrifonate should not be used after recent exposure to
insecticides or drugs that might potentiate cholinesterase inhibi-
tion. It is contraindicated in pregnancy.
NICLOSAMIDE
Niclosamide is a second-line drug for the treatment of most tape-
worm infections, but it is not available in the USA.
Basic Pharmacology
Niclosamide is a salicylamide derivative. It appears to be mini-
mally absorbed from the gastrointestinal tract—neither the drug
nor its metabolites have been recovered from the blood or urine.
Adult worms (but not ova) are rapidly killed, presumably due to
inhibition of oxidative phosphorylation or stimulation of ATPase
activity.
Clinical Uses
The adult dose of niclosamide is 2 g once, given in the morning
on an empty stomach. The tablets must be chewed thoroughly
and then swallowed with water.
1. Taenia saginata (beef tapeworm), Taenia solium
(pork tapeworm), and Diphyllobothrium latum (fish
tapeworm)—A single 2-g dose of niclosamide results in cure
rates of over 85% for D latum and about 95% for T saginata.
It is probably equally effective against T solium. Cysticercosis
can theoretically occur after treatment of T solium infections,
because viable ova are released into the gut lumen after digestion
of segments, but no such cases have been reported.
2. Other tapeworms—Most patients treated with niclosamide
for Hymenolepis diminuta and Dipylidium caninum infections
are cured with a 7-day course of treatment; a few require a
second course. Praziquantel is superior for Hymenolepis nana
(dwarf tapeworm) infection. Niclosamide is not effective against
cysticercosis or hydatid disease.
3. Intestinal fluke infections—Niclosamide can be used
as an alternative drug in the treatment of Fasciolopsis buski,
Heterophyes heterophyes, and Metagonimus yokogawai infections.
The standard dose is given every other day for three doses.
Adverse Reactions, Contraindications,
& Cautions
Infrequent, mild, and transitory adverse events include nausea,
vomiting, diarrhea, and abdominal discomfort. Alcohol should
not be consumed during or for 1 day after treatment. Safety has
not been established in pregnancy or for children younger than
2 years.
OXAMNIQUINE
Oxamniquine is an alternative to praziquantel for the treat-
ment of S mansoni infections. It has also been used extensively
for mass treatment. It is not effective against S haematobium or
S japonicum. It is not available in the USA.
Basic Pharmacology
Oxamniquine, a semisynthetic tetrahydroquinoline, is readily
absorbed orally; it should be taken with food. Its plasma half-life
is about 2.5 hours. The drug is extensively metabolized to inac-
tive metabolites and excreted in the urine—up to 75% in the first
24 hours. Intersubject variations in serum concentration have
been noted, which may explain some treatment failures.
Oxamniquine is active against both mature and immature stages
of S mansoni but does not appear to be cercaricidal. The mechanism
of action is unknown. Contraction and paralysis of the worms
results in detachment from terminal venules in the mesentery and
transit to the liver, where many die; surviving females return to
the mesenteric vessels but cease to lay eggs. Strains of S mansoni in
944    SECTION VIII  Chemotherapeutic Drugs
different parts of the world vary in susceptibility. Oxamniquine has
been effective in instances of praziquantel resistance.
Clinical Uses
Oxamniquine is safe and effective in all stages of S mansoni
disease, including advanced hepatosplenomegaly. The drug is
generally less effective in children, who require higher doses than
adults. It is better tolerated with food.
Optimal dosage schedules vary for different regions of the
world. In the western hemisphere and western Africa, the adult
oxamniquine dosage is 12–15 mg/kg given once. In northern and
southern Africa, standard schedules are 15 mg/kg twice daily for
2 days. In eastern Africa and the Arabian peninsula, standard dos-
age is 15–20 mg/kg twice in 1 day. Cure rates are 70–95%, with
marked reduction in egg excretion in those not cured. In mixed
schistosome infections, oxamniquine has been successfully used in
combination with metrifonate.
Adverse Reactions, Contraindications,
& Cautions
Mild symptoms occur in more than one-third of patients receiv-
ing oxamniquine. Central nervous system symptoms (dizziness,
headache, drowsiness) are most common; nausea and vomiting,
diarrhea, colic, pruritus, and urticaria also occur. Infrequent
adverse effects are low-grade fever, an orange to red discoloration
of the urine, proteinuria, microscopic hematuria, and transient
leukopenia. Seizures have been reported rarely.
Since the drug makes many patients dizzy or drowsy, it should
be used with caution in patients whose work or activity requires
mental alertness (eg, no driving for 24 hours). It should be used
with caution in those with a history of epilepsy. Oxamniquine is
contraindicated in pregnancy.
PIPERAZINE
Piperazine is an alternative for the treatment of ascariasis, with
cure rates over 90% when taken for 2 days, but it is not recom-
mended for other helminth infections. Piperazine is available as
the hexahydrate and as a variety of salts. It is readily absorbed,
and maximum plasma levels are reached in 2–4 hours. Most of
the drug is excreted unchanged in the urine in 2–6 hours, and
excretion is complete within 24 hours. Piperazine causes paralysis
of ascaris by blocking acetylcholine at the myoneural junction; live
worms are expelled by peristalsis.
For ascariasis, the dosage of piperazine (as the hexahydrate) is
75 mg/kg (maximum dose, 3.5 g) orally once daily for 2 days. For
heavy infections, treatment should be continued for 3–4 days or
repeated after 1 week.
Occasional mild adverse effects include nausea, vomiting,
diarrhea, abdominal pain, dizziness, and headache. Neurotoxic-
ity and allergic reactions are rare. Piperazine should not be given
to pregnant women, patients with impaired renal or hepatic
function, or those with a history of epilepsy or chronic neuro-
logic disease.
PRAZIQUANTEL
Praziquantel is effective in the treatment of schistosome infections
of all species and most other trematode and cestode infections,
including cysticercosis. The drug’s safety and effectiveness as a
single oral dose have also made it useful in mass treatment of
several infections.
Basic Pharmacology
Praziquantel is a synthetic isoquinoline-pyrazine derivative. It is rap-
idly absorbed, with a bioavailability of about 80% after oral admin-
istration. Peak serum concentrations are reached 1–3 hours after a
therapeutic dose. Cerebrospinal fluid concentrations of praziquantel
reach 14–20% of the drug’s plasma concentration. About 80% of
the drug is bound to plasma proteins. Most of the drug is rapidly
metabolized to inactive mono- and polyhydroxylated products after
a first pass in the liver. The half-life is 0.8–1.5 hours. Excretion
is mainly via the kidneys (60–80%) and bile (15–35%). Plasma
concentrations of praziquantel increase when the drug is taken
with a high-carbohydrate meal or with cimetidine; bioavailability is
markedly reduced by phenytoin, carbamazepine, or corticosteroids.
Praziquantel appears to increase the permeability of trematode
and cestode cell membranes to calcium, resulting in paralysis, dis-
lodgement, and death. In schistosome infections of experimental
animals, praziquantel is effective against adult worms and immature
stages, and it has a prophylactic effect against cercarial infection.
Clinical Uses
Praziquantel tablets are taken with liquid after a meal; they should
be swallowed without chewing because their bitter taste can
induce retching and vomiting.
1. Schistosomiasis—Praziquantel is the drug of choice for
all forms of schistosomiasis. The dosage is 20 mg/kg per dose
for two (S mansoni and S haematobium) or three (S japonicum
and S mekongi) doses at intervals of 4–6 hours. High cure
rates (75–95%) are achieved when patients are evaluated at
3–6 months; there is marked reduction in egg counts in those not
cured. The drug is effective in adults and children and is generally
well tolerated by patients in the hepatosplenic stage of advanced
disease. There is no standard regimen for acute schistosomiasis
(Katayama syndrome), but standard doses as described above,
often with corticosteroids to limit inflammation from the acute
immune response and dying worms, are recommended. Increas-
ing evidence indicates rare S mansoni drug resistance, which may
be countered with extended courses of therapy (eg, 3–6 days at
standard dosing) or treatment with oxamniquine. Effectiveness
of praziquantel for chemoprophylaxis has not been established.
2. Clonorchiasis, opisthorchiasis, and paragonimiasis—
Standard dosing is 25 mg/kg three times daily for 2 days for each
of these fluke infections.
3. Taeniasis and diphyllobothriasis—A single dose of pra-
ziquantel, 5–10 mg/kg, results in nearly 100% cure rates for
 CHAPTER 53  Clinical Pharmacology of the Antihelminthic Drugs     945
T saginata, T solium, and D latum infections. Because praziqu-
antel does not kill eggs, it is theoretically possible that larvae of
T solium released from eggs in the large bowel could penetrate
the intestinal wall and give rise to cysticercosis, but this hazard
is probably minimal.
4. Neurocysticercosis—Albendazole is now the preferred
drug, but when it is not appropriate or available, praziquantel
has similar efficacy. Indications for praziquantel are similar to
those for albendazole. The praziquantel dosage is 100 mg/kg/d
in three divided doses for 1 day, then 50 mg/kg/d to com-
plete a 2- to 4-week course. Clinical responses to therapy vary
from dramatic improvements of seizures and other neurologic
findings to no response and even progression of the disease.
Praziquantel—but not albendazole—has diminished bioavail-
ability when taken concurrently with a corticosteroid. Recom-
mendations on use of both antihelminthics and corticosteroids
in neurocysticercosis vary.
5. Hymenolepis nana—Praziquantel is the drug of choice
for H nana infections and the first drug to be highly effec-
tive. A single dose of 25 mg/kg is taken initially and repeated
in 1 week.
6. Hydatid disease—In hydatid disease, praziquantel kills
protoscoleces but does not affect the germinal membrane.
Praziquantel may be used as an adjunct with albendazole pre-
and post-surgery. In addition to its direct action, praziquantel
enhances the plasma concentration of albendazole.
7. Other parasites—Limited trials showed effectiveness of pra-
ziquantel at a dosage of 25 mg/kg three times daily for 1–2 days
against fasciolopsiasis, metagonimiasis, and other forms of
heterophyiasis. Praziquantel was not effective for fascioliasis,
however, even at dosages as high as 25 mg/kg three times daily
for 3–7 days.
Adverse Reactions, Contraindications,
& Cautions
Mild and transient adverse effects are common. They begin within
hours after ingestion of praziquantel and may persist for about 1 day.
Most common are headache, dizziness, drowsiness, and lassitude;
others include nausea, vomiting, abdominal pain, loose stools, pru-
ritus, urticaria, arthralgia, myalgia, and low-grade fever. Mild and
transient elevations of liver enzymes have been reported. Several days
after starting praziquantel, low-grade fever, pruritus, and skin rashes
(macular and urticarial), sometimes associated with worsened eosino-
philia, may occur, probably due to the release of proteins from dying
worms rather than direct drug toxicity. The intensity and frequency
of adverse effects increase with dosage such that they occur in up to
50% of patients who receive 25 mg/kg three times daily.
In neurocysticercosis, neurologic abnormalities may be exac-
erbated by inflammatory reactions around dying parasites.
Common findings in patients who do not receive corticoste-
roids, usually presenting during or shortly after therapy, are
headache, meningismus, nausea, vomiting, mental changes, and
seizures (often accompanied by increased cerebrospinal fluid
pleocytosis). More serious reactions, including arachnoiditis,
hyperthermia, and intracranial hypertension, may also occur.
Corticosteroids are commonly used with praziquantel in the
treatment of neurocysticercosis to decrease the inflammatory
response, but this is controversial and complicated by knowledge
that corticosteroids decrease the plasma level of praziquantel up
to 50%. Praziquantel is contraindicated in ocular cysticercosis,
because parasite destruction in the eye may cause irreparable
damage. Some workers also caution against use of the drug in
spinal neurocysticercosis.
Praziquantel is safe and well tolerated in children. Recent
data suggest that the drug can be given safely during preg-
nancy. Because praziquantel induces dizziness and drowsiness,
patients should not drive during therapy and should be warned
regarding activities requiring particular physical coordination
or alertness.
PYRANTEL PAMOATE
Pyrantel pamoate is a broad-spectrum antihelminthic highly effec-
tive for the treatment of pinworm, ascaris, and Trichostrongylus
orientalis infections. It is moderately effective against both species
of hookworm. It is not effective in trichuriasis or strongyloidiasis.
Oxantel pamoate, an analog of pyrantel not available in the USA,
has shown better efficacy against trichuriasis than any other single
agent and promising activity in combination with albendazole or
ivermectin for this indication. Pyrantel/oxantel pamoate combina-
tions are widely used in veterinary medicine and have been studied
for some human indications.
Basic Pharmacology
Pyrantel pamoate is a tetrahydropyrimidine derivative. It is poorly
absorbed from the gastrointestinal tract and active mainly against
luminal organisms. Peak plasma levels are reached in 1–3 hours.
Over half of the administered dose is recovered unchanged in the
feces. Pyrantel is effective against mature and immature forms of
susceptible helminths within the intestinal tract but not against
migratory stages in the tissues or against ova. The drug is a neu-
romuscular blocking agent that causes release of acetylcholine and
inhibition of cholinesterase; this results in paralysis of worms,
followed by expulsion.
Clinical Uses
The standard dose is 11 mg (base)/kg (maximum, 1 g), given
orally once with or without food. For pinworm, the dose is
repeated in 2 weeks, and cure rates are greater than 95%. The drug
is available in the USA without prescription for this indication.
For ascariasis, a single dose yields cure rates of 85–100%.
Treatment should be repeated if eggs are found 2 weeks after treat-
ment. For hookworm infections, a single dose is effective against
light infections; but for heavy infections, especially with Necator
americanus, a 3-day course is necessary to achieve 90% cure rates.
A course of treatment can be repeated in 2 weeks.
946    SECTION VIII  Chemotherapeutic Drugs

Adverse Reactions, Contraindications, P R E P A R A T I O N S

& Cautions A V A I L A B L E
Pyrantel’s adverse effects are infrequent, mild, and transient.
They may include nausea, vomiting, diarrhea, abdominal cramps, GENERIC NAME AVAILABLE AS
dizziness, drowsiness, headache, insomnia, rash, fever, and weak- Albendazole Albenza
ness. Pyrantel should be used with caution in patients with liver Bithionol Bitin
dysfunction, as transient aminotransferase elevations have been Diethylcarbamazine Hetrazan
noted. Experience with the drug in pregnant women and children Ivermectin Mectizan, Stromectol
younger than 2 years is limited. Mebendazole Generic, Vermox
Metrifonate Trichlorfon, Bilarcil
Niclosamide Niclocide
THIABENDAZOLE Oxamniquine Vansil, Mansil
Oxantel pamoate Quantrel
Thiabendazole is an alternative to ivermectin or albendazole for Oxantel/pyrantel pamoate Telopar
the treatment of strongyloidiasis and cutaneous larva migrans. Piperazine Generic, Vermizine
Praziquantel Biltricide; others outside the USA

Basic Pharmacology Pyrantel pamoate Ascarel, Pamix, Pin Rid, Pin-X

Thiabendazole is a benzimidazole compound. Although it is a
chelating agent that forms stable complexes with a number of
metals, including iron, it does not bind calcium. Thiabendazole
is rapidly absorbed after ingestion. With a standard dose, drug
concentrations in plasma peak within 1–2 hours; the half-life is
1.2 hours. The drug is almost completely metabolized in the liver
to the 5-hydroxy form; 90% is excreted in the urine in 48 hours,
largely as the glucuronide or sulfonate conjugate. Thiabendazole
can also be absorbed from the skin. The mechanism of action of
thiabendazole is probably the same as that of other benzimidazoles
(inhibition of microtubule synthesis). The drug has ovicidal effects
against some parasites.
Clinical Uses
The standard dosage, 25 mg/kg (maximum 1.5 g) twice daily,
should be given after meals. Tablets should be chewed. For
Strongyloides infection, treatment is for 2 days. Cure rates are
reportedly 93%. A course can be repeated in 1 week if indicated.
In patients with hyperinfection syndrome, the standard dose is
continued twice daily for 5–7 days. For cutaneous larva migrans,
thiabendazole cream can be applied topically, or the oral drug can
be given for 2 days (although albendazole is less toxic and there-
fore preferred).
Adverse Reactions, Contraindications,
& Cautions
Thiabendazole is much more toxic than other benzimidazoles and
more toxic than ivermectin, so other agents are now preferred
for most indications. Common adverse effects include dizziness,
anorexia, nausea, and vomiting. Less common problems are
epigastric pain, abdominal cramps, diarrhea, pruritus, headache,
drowsiness, and neuropsychiatric symptoms. Irreversible liver
failure and fatal Stevens-Johnson syndrome have been reported.
Experience with thiabendazole is limited in children weighing less
than 15 kg. The drug should not be used in pregnancy or in the
presence of hepatic or renal disease.
Thiabendazole Mintezol
REFERENCES
Ashrafi K et al: Fascioliasis: A worldwide parasitic disease of importance in travel
medicine. Travel Med Infect Dis 2014;12:636.
Bagheri H et al: Adverse drug reactions to anthelmintics. Ann Pharmacother
2004;38:383.
Brunetti E, White AC Jr: Cestode infestations: Hydatid disease and cysticercosis.
Infect Dis Clin North Am 2012;26:421.
Colley DG et al: Human schistosomiasis. Lancet 2014;383:2253.
Danso-Appiah A et al: Drugs for treating Schistosoma mansoni infection. Cochrane
Database Syst Rev 2013;2:CD000528.
Debrah AY et al: Doxycycline leads to sterility and enhanced killing of female
Onchocerca volvulus worms in an area with persistent microfilaridermia after
repeated ivermectin treatment: A randomized, placebo-controlled, double-
blind trial. Clin Infect Dis 2015;61:517.
Del Brutto OH: Clinical management of neurocysticercosis. Expert Rev Neurother
2014;14:389.
Fox LM: Ivermectin: Uses and impact 20 years on. Curr Opin Infect Dis 2006;
19:588.
Fürst T et al: Manifestation, diagnosis, and management of foodborne trematodiasis.
BMJ 2012;344:e4093.
Garcia HH et al: Efficacy of combined antiparasitic therapy with praziquantel and
albendazole for neurocysticercosis: A double-blind, randomised controlled
trial. Lancet Infect Dis 2014;14:687.
Henriquez-Camacho C et al: Ivermectin versus albendazole or thiabenda-
zole for Strongyloides stercoralis infection. Cochrane Database Syst Rev
2016:CD007745.
Kappagoda S, Singh U, Blackburn BG: Antiparasitic therapy. Mayo Clin Proc
2011;86:561.
Keiser J, Utzinger J: Efficacy of current drugs against soil-transmitted helminth
infections: Systematic review and meta-analysis. JAMA 2008;299:1937.
Kincaid L et al: Management of imported cutaneous larva migrans: A case series
and mini-review. Travel Med Infect Dis 2015;13:382.
Knopp S et al: Albendazole and mebendazole administered alone or in combina-
tion with ivermectin against Trichuris trichiura: A randomized controlled
trial. Clin Infect Dis 2010;51:1420.
Knopp S et al: Nematode infections: Filariases. Infect Dis Clin North Am
2012;26:359.
Knopp S et al: Nematode infections: Soil-transmitted helminths and trichinella.
Infect Dis Clin North Am 2012;26:341.
Levecke B et al: Assessment of anthelmintic efficacy of mebendazole in school chil-
dren in six countries where soil-transmitted helminths are endemic. PLoS
Negl Trop Dis 2014;8:e3204.
 CHAPTER 53  Clinical Pharmacology of the Antihelminthic Drugs     947
Matthaiou DK et al: Albendazole versus praziquantel in the treatment of neu-
rocysticercosis: A meta-analysis of comparative trials. PLoS Negl Trop Dis
2008;2:e194.
McManus DP et al: Diagnosis, treatment, and management of echinococcosis.
BMJ 2012;344:e3866.
Medical Letter: Drugs for parasitic infections. Med Lett Drugs Ther 2013;
Supplement.
Mejia R, Nutman TB: Screening, prevention, and treatment for hyperinfection
syndrome and disseminated infections caused by Strongyloides stercoralis.
Curr Opin Infect Dis 2012;25:458.
Metzger WG, Mordmüller B: Loa loa-does it deserve to be neglected? Lancet Infect
Dis 2014;14:353.
Moser W et al: Efficacy and safety of oxantel pamoate in school-aged children
infected with Trichuris trichiura on Pemba Island, Tanzania: A parallel,
randomised, controlled, dose-ranging study. Lancet Infect Dis 2016;16:53.
Nash TE, Garcia HH: Diagnosis and treatment of neurocysticercosis. Nat Rev
Neurol 2011;7:584.
Olveda RM et al: Efficacy and safety of praziquantel for the treatment of human
schistosomiasis during pregnancy: A phase 2, randomised, double-blind,
placebo-controlled trial. Lancet Infect Dis 2016;16:199.
Pawluk SA et al: A review of pharmacokinetic drug-drug interactions with the
anthelmintic medications albendazole and mebendazole. Clin Pharmacoki-
net 2015;54:371.
Qian MB, et al: Clonorchiasis. Lancet 2016;387:800.
C ASE STUDY ANSWER
The presentation is highly suggestive of cystic hydatid
disease (infection with Echinococcus granulosus), which is
transmitted by eggs from the feces of dogs in contact with
livestock. Other causes of liver fluid collections include ame-
bic and pyogenic abscesses, but these are usually not cystic
in appearance. For echinococcosis, a typical cystic lesion
Reddy M et al: Oral drug therapy for multiple neglected tropical diseases: A sys-
tematic review. JAMA 2007;298:1911.
Soukhathammavong PA et al: Low efficacy of single-dose albendazole and meben-
dazole against hookworm and effect on concomitant helminth infection in
Lao PDR. PLoS Negl Trop Dis 2012;6:e1417.
Speich B et al: Efficacy and safety of albendazole plus ivermectin, albendazole plus
mebendazole, albendazole plus oxantel pamoate, and mebendazole alone
against Trichuris trichiura and concomitant soil-transmitted helminth infec-
tions: A four-arm, randomised controlled trial. Lancet Infect Dis 2015;15:277.
Speich B et al: Oxantel pamoate-albendazole for Trichuris trichiura infection.
N Engl J Med 2014;370:610.
Steinmann P et al: Efficacy of single-dose and triple-dose albendazole and meben-
dazole against soil-transmitted helminths and Taenia spp.: A randomized
controlled trial. PLoS One 2011;6:e25003.
Supali T et al: Doxycycline treatment of Brugia malayi-infected persons reduces
microfilaremia and adverse reactions after diethylcarbamazine and albenda-
zole treatment. Clin Infect Dis 2008;46:1385.
Tamarozzi F et al: Acceptance of standardized ultrasound classification, use of
albendazole, and long-term follow-up in clinical management of cystic echi-
nococcosis: A systematic review. Curr Opin Infect Dis 2014;27:425.
Taylor MJ et al: Lymphatic filariasis and onchocerciasis. Lancet 2010;376:1175.
Zwang J, Olliaro PL: Clinical efficacy and tolerability of praziquantel for intestinal
and urinary schistosomiasis-a meta-analysis of comparative and non-com-
parative clinical trials. PLoS Negl Trop Dis 2014;8:e3286.
and positive serology support the diagnosis, and treatment
generally entails albendazole in conjunction with cautious
surgery or percutaneous aspiration. One approach entails
treatment with albendazole followed by aspiration to con-
firm the diagnosis and, if it is confirmed, to remove most of
the infecting worms.
 54
C H A P T E R
Cancer Chemotherapy
Edward Chu, MD
C ASE STUDY
A 55-year-old man presents with increasing fatigue,
15-pound weight loss, and a microcytic anemia.
Colonoscopy identifies a mass in the ascending colon,
and biopsy specimens reveal well-differentiated colorectal
cancer (CRC). He undergoes surgical resection and is
found to have high-risk stage III CRC with five positive
lymph nodes. After surgery, he feels entirely well with no
symptoms. Of note, he has no other illnesses. What is this
patient’s overall prognosis? Based on his prognosis, what
In 2016, approximately 1.68 million new cancer cases were diag-
nosed in the USA, and nearly 600,000 individuals are expected to
die from this disease. Cancer is the second most common cause of
death in the United States, accounting for 1 in 4 deaths. It is a dis-
ease characterized by a defect in the normal control mechanisms
that govern cell survival, proliferation, and differentiation. Cells
that have undergone neoplastic transformation usually express
cell surface antigens that may be of normal fetal type, and they
may display other signs of apparent immaturity. They may exhibit
qualitative or quantitative chromosomal abnormalities, includ-
ing various translocations and the appearance of amplified gene
sequences. It is now well established that a small subpopulation
of cells, referred to as tumor stem cells, reside within a tumor mass.
They retain the ability to undergo repeated cycles of prolifera-
tion as well as to migrate to distant sites in the body to colonize
various organs in the process called metastasis. Such tumor stem
cells thus can express clonogenic (colony-forming) capability, and
they are characterized by chromosome abnormalities reflecting
their genetic instability, which leads to progressive selection of
subclones that can survive more readily in the multicellular envi-
ronment of the host. This genetic instability also allows them to
948
are the possible benefits of adjuvant chemotherapy? The
patient receives a combination of 5-fluorouracil (5-FU),
leucovorin, and oxaliplatin (FOLFOX) as adjuvant therapy.
One week after receiving the first cycle of therapy, he
experiences significant toxicity in the form of myelosup-
pression, diarrhea, and altered mental status. What is the
most likely explanation for this increased toxicity? Is there
any role for genetic testing to determine the etiology of the
increased toxicity?
become resistant to chemotherapy and radiotherapy. The invasive
and metastatic processes as well as a series of metabolic abnormali-
ties associated with the cancer result in tumor-related symptoms
and eventual death of the patient unless the neoplasm can be
eradicated with treatment.
CAUSES OF CANCER
The incidence, geographic distribution, and behavior of specific
types of cancer are related to multiple factors, including sex, age,
race, genetic predisposition, and exposure to environmental car-
cinogens. Of these factors, environmental exposure is probably
most important. Exposure to ionizing radiation has been well
documented as a significant risk factor for a number of cancers,
including acute leukemias, thyroid cancer, breast cancer, lung
cancer, soft tissue sarcoma, and basal cell and squamous cell skin
cancers. Chemical carcinogens (particularly those in tobacco
smoke) as well as azo dyes, aflatoxins, asbestos, benzene, and
radon all have been well documented as leading to a wide range
of human cancers.
 CHAPTER 54  Cancer Chemotherapy    949

Another class of genes, known as tumor suppressor genes,

ACRONYMS
may be deleted or mutated, which gives rise to the neoplastic
ABVD Doxorubicin (Adriamycin, hydroxydaunorubicin),
phenotype. The p53 gene is the best-established tumor suppressor
bleomycin, vinblastine, dacarbazine
gene identified to date, and the normal wild-type gene appears to
BCNU Carmustine
play an important role in suppressing malignant transformation.
CCNU Lomustine Of note, p53 is mutated in up to 50% of all human solid tumors,
CHOP Cyclophosphamide, doxorubicin (Adriamycin, hydroxy- including liver, breast, colon, lung, cervix, bladder, prostate, and
daunorubicin), vincristine (Oncovin), prednisone skin.
CMF Cyclophosphamide, methotrexate, fluorouracil
COP Cyclophosphamide, vincristine (Oncovin), prednisone
CRC Colorectal cancer CANCER TREATMENT MODALITIES
FAC 5-Fluorouracil, doxorubicin (Adriamycin, hydroxydau-
norubicin), cyclophosphamide With present methods of treatment, when the tumor remains
FEC 5-Fluorouracil, epirubicin, cyclophosphamide
localized at the time of diagnosis, about one-third of patients
are cured with local treatment strategies, such as surgery or
5-FU 5-Fluorouracil
radiotherapy. Earlier diagnosis might lead to increased cure rates
FOLFIRI 5-Fluorouracil, leucovorin, irinotecan with such local treatment. In the remaining cases, however,
FOLFOX 5-Fluorouracil, leucovorin, oxaliplatin early micrometastasis is a characteristic feature, indicating that
MP Melphalan, prednisone a systemic approach with chemotherapy is required for effective
6-MP 6-Mercaptopurine cancer management. In patients with locally advanced disease,
MOPP Mechlorethamine, vincristine (Oncovin), procarbazine,
chemotherapy is often combined with radiotherapy to allow for
prednisone subsequent surgical resection to take place, and such a combined
MTX Methotrexate
modality approach has led to improved clinical outcomes. At pres-
ent, about 50% of patients who are initially diagnosed with cancer
NSCLC Non-small cell lung cancer
can be cured. In contrast, chemotherapy alone is able to cure less
PCV Procarbazine, lomustine, vincristine than 10% of all cancer patients when the tumor is diagnosed at
PEB Cisplatin (platinum), etoposide, bleomycin an advanced stage.
6-TG 6-Thioguanine Chemotherapy is presently used in three main clinical settings:
VAD Vincristine, doxorubicin (Adriamycin, hydroxydaunoru- (1) primary induction treatment for advanced disease or for cancers
bicin), dexamethasone for which there are no other effective treatment approaches, (2)
XELOX Capecitabine, oxaliplatin neoadjuvant treatment for patients who present with localized dis-
ease, for whom local forms of therapy such as surgery or radiation,
or both, are inadequate by themselves, (3) adjuvant treatment to
local methods of treatment, including surgery, radiation therapy,
Several viruses have been implicated in the etiology of various or both.
human cancers. For example, hepatitis B (HBV) and hepatitis C Primary chemotherapy refers to chemotherapy administered
(HCV) are associated with the development of hepatocellular as the primary treatment in patients who present with advanced
cancer; HIV is associated with Hodgkin’s and non-Hodgkin’s lym- cancer for which no alternative treatment exists. This has been the
phomas; human papillomavirus (HPV) is associated with cervical main approach in treating patients with advanced metastatic dis-
cancer, anal and penile cancers, and oropharyngeal head and neck ease, and in most cases, the goals of therapy are to relieve tumor-
cancer; Epstein-Barr virus (EBV), also known as human herpesvi- related symptoms, improve overall quality of life, and prolong
rus 4 (HHV-4), is associated with nasopharyngeal cancer, Burkitt’s time to tumor progression. Studies in a wide range of solid tumors
lymphoma, and Hodgkin’s lymphoma; and Merkel cell polyoma- have shown that chemotherapy in patients with advanced disease
virus (MCV) causes Merkel cell cancer, a rare but aggressive form confers survival benefit when compared with supportive care, pro-
of skin cancer. Expression of virus-induced neoplasia may also viding sound rationale for the early initiation of drug treatment.
depend on additional host and environmental factors that modu- However, cancer chemotherapy can be curative in only a small
late the transformation process. Cellular genes are known that are subset of patients who present with advanced disease. In adults,
homologous to the transforming genes of the retroviruses, a fam- these curable cancers include Hodgkin’s and non-Hodgkin’s lym-
ily of RNA viruses, and induce oncogenic transformation. These phoma, acute myelogenous leukemia, germ cell cancer, and cho-
mammalian cellular genes, known as oncogenes, have been shown riocarcinoma, while the curable childhood cancers include acute
to code for specific growth factors and their corresponding recep- lymphoblastic leukemia, Burkitt’s lymphoma, Wilms’ tumor, and
tors. These genes may be amplified (increased number of gene embryonal rhabdomyosarcoma.
copies) or mutated, both of which can lead to constitutive over- Neoadjuvant chemotherapy refers to the use of chemotherapy
expression in malignant cells. The bcl-2 family of genes represents in patients who present with localized cancer for which alternative
a series of pro-survival genes that promotes survival by directly local therapies, such as surgery, exist but which have been shown to
inhibiting apoptosis, a key pathway of programmed cell death. be less than completely effective. At present, neoadjuvant therapy
950    SECTION VIII  Chemotherapeutic Drugs
is most often administered in the treatment of anal cancer, bladder
cancer, breast cancer, gastroesophageal cancer, laryngeal cancer,
locally advanced non-small cell lung cancer (NSCLC), osteogenic
sarcoma, and locally advanced rectal cancer. For diseases such as
anal cancer, gastroesophageal cancer, laryngeal cancer, NSCLC,
and rectal cancer, optimal clinical benefit is derived when chemo-
therapy is administered with radiation therapy either concurrently
or sequentially. The goal of the neoadjuvant approach is to reduce
the size of the primary tumor so that surgical resection can be
made easier and more effective. In addition, with rectal cancer and
laryngeal cancer, the administration of combined modality ther-
apy prior to surgery can result in sparing of vital normal organs,
such as the rectum or larynx. In general, additional chemotherapy
is given for a defined period of time, usually 3–4 months, after
surgery has been performed.
One of the most important roles for cancer chemotherapy is as
an adjuvant to local treatment modalities such as surgery, and this
has been termed adjuvant chemotherapy. In this setting, chemo-
therapy is administered after surgery has been performed, and the
goal of chemotherapy is to reduce the incidence of both local and
systemic recurrence and to improve the overall survival of patients.
In general, chemotherapy regimens with clinical activity against
advanced disease may have curative potential following surgical
resection of the primary tumor, provided the appropriate dose and
schedule are administered. Adjuvant chemotherapy is effective in
prolonging both disease-free survival (DFS) and overall survival
(OS) in patients with breast cancer, colon cancer, gastric cancer,
NSCLC, Wilms’ tumor, anaplastic astrocytoma, and osteogenic
sarcoma. Patients with primary malignant melanoma at high
risk of local or systemic recurrence derive clinical benefit from
adjuvant treatment with the biologic agent interferon α (IFN-α),
although this treatment must be given for 1 year’s duration for
maximal clinical efficacy. Finally, the antihormonal agents tamoxi-
fen, anastrozole, and letrozole are effective in the adjuvant therapy
of postmenopausal women with early-stage breast cancer whose
breast tumors express the estrogen receptor (see Chapter 40 for
additional details). However, because these agents are cytostatic
rather than cytocidal, they must be administered on a long-term
basis, with the standard recommendation being 5 years’ duration.
ROLE OF CELL CYCLE KINETICS &
ANTI-CANCER EFFECT
The key principles of cell cycle kinetics were initially developed
using the murine L1210 leukemia as the experimental model
system (Figure 54–1). However, drug treatment of human
cancers requires a clear understanding of the differences between
the characteristics of this rodent leukemia and of human cancers,
as well as an understanding of the differences in growth rates of
normal target tissues between mice and humans. For example,
L1210 is a rapidly growing leukemia with a high percentage of
cells synthesizing DNA, as measured by the uptake of tritiated
thymidine (the labeling index). Because L1210 leukemia has a
growth fraction of 100% (ie, all its cells are actively progressing
through the cell cycle), its life cycle is consistent and predictable.
Death
1012
Symptoms
1010
Diagnosis
Number of cancer cells (log scale)
Subclinical
108
106
Surgery
104
102
100
Time
FIGURE 54–1  Log-kill hypothesis: relationship of tumor cell
number to time of diagnosis, symptoms, treatment, and survival.
Three alternative approaches to drug treatment are shown for
comparison with the course of tumor growth when no treatment
is given (dashed line). In the protocol diagrammed at top, treat-
ment (indicated by the arrows) is given infrequently, and the result
is manifested as prolongation of survival but with recurrence of
symptoms between courses of treatment and eventual death of the
patient. The combination chemotherapy treatment diagrammed
in the middle section is begun earlier and is more intensive. Tumor
cell kill exceeds regrowth, drug resistance does not develop, and
“cure” results. In this example, treatment has been continued long
after all clinical evidence of cancer has disappeared (1–3 years).
This approach has been established as effective in the treatment
of childhood acute leukemia, testicular cancers, and Hodgkin’s
lymphoma. In the treatment diagrammed near the bottom of the
graph, early surgery has been employed to remove the primary
tumor and intensive adjuvant chemotherapy has been administered
long enough (up to 1 year) to eradicate the remaining tumor cells
that comprise the occult micrometastases.
Based on the murine L1210 model, the cytotoxic effects of anti-
cancer drugs follow log cell-kill kinetics. As such, a given agent
would be predicted to kill a constant fraction of cells as opposed
to a constant number.
Thus, if a particular dose of an individual drug leads to a 3-log
10 7
kill of cancer cells and reduces the tumor burden from 10 to 10
5
cells, the same dose used at a tumor burden of 10 cells reduces the
tumor mass to 102 cells. Cell kill is, therefore, proportional, regard-
less of tumor burden. The cardinal rule of chemotherapy—the
invariable inverse relation between cell number and curability—
was established with the murine L1210 leukemia model, and this
relationship is clearly applicable to hematologic malignancies,
such as acute leukemias and lymphomas.
Although growth of murine leukemias simulates exponential
cell kinetics, mathematical modeling data suggest that most
 CHAPTER 54  Cancer Chemotherapy    951

human solid tumors do not grow in such an exponential manner. TABLE 54–1  Cell cycle effects of major classes of
Rather, the experimental data in human solid cancers support a anti-cancer drugs.
Gompertzian model of tumor growth and regression. The critical
distinction between Gompertzian and exponential growth is Cell Cycle-Specific Cell Cycle-Nonspecific
(CCS) Agents (CCNS) Agents
that the growth fraction of the tumor is not constant with
Gompertzian kinetics but instead decreases exponentially Antimetabolites (S phase) Alkylating agents
with time (exponential growth is matched by exponential retarda-  Capecitabine  Altretamine
tion of growth, due to blood supply limitations and other factors).  Cladribine  Bendamustine
The growth fraction peaks when the tumor is approximately one-
 Clofarabine  Busulfan
third its maximum size. According to the Gompertzian model,
  Cytarabine (ara-C)  Carmustine
when a patient with advanced cancer is treated, the tumor mass
is larger, its growth fraction is low, and the fraction of cells  Fludarabine  Chlorambucil
killed is, therefore, small. An important feature of Gompertzian   5-Fluorouracil (5-FU)  Cyclophosphamide
growth is that response to chemotherapy in drug-sensitive tumors  Gemcitabine  Dacarbazine
depends, in large measure, on where the tumor is in its particular   6-Mercaptopurine (6-MP)  Lomustine
growth curve.
  Methotrexate (MTX)  Mechlorethamine
Information on cell and population kinetics of cancer cells
 Nelarabine  Melphalan
explains, in part, the limited effectiveness of most available
anticancer drugs. A schematic summary of cell cycle kinetics  Pralatrexate  Temozolomide
is presented in Figure 54–2. This information is relevant to   6-Thioguanine (6-TG)  Thiotepa
the mode of action, indications, and scheduling of cell cycle– Topoisomerase II inhibitor Antitumor antibiotics
specific (CCS) and cell cycle–nonspecific (CCNS) drugs. (G1–S phase)  Dactinomycin
Agents falling into these two major classes are summarized
 Etoposide  Mitomycin
in Table 54–1.
Topoisomerase I inhibitors Platinum analogs
(Camptothecins, G2-M)  Carboplatin
The Role of Drug Combinations
 Irinotecan  Cisplatin
With rare exceptions (eg, choriocarcinoma and Burkitt’s lym-
 Topotecan  Oxaliplatin
phoma), single drugs are unable to cure cancers when they
are in an advanced stage. In the 1960s and early 1970s, drug Taxanes (M phase) Anthracyclines
  Albumin-bound paclitaxel  Daunorubicin
 Cabazitaxel  Doxorubicin
Mitosis
Synthesis Differentiation  Docetaxel  Epirubicin
2%
of cellular
 Paclitaxel  Idarubicin
components
M G0
for mitosis Vinca alkaloids (M phase)  Mitoxantrone
G2
 Vinblastine
19%
G1  Vincristine
Synthesis  Vinorelbine
The cell 40%
of cellular
D NA s

cycle Antimicrotubule inhibitor (M phase)

components
nt needed for  Ixabepilone
y

he DNA synthesis
sis  Eribulin
39%
S Antitumor antibiotics (G2–M phase)
Replication  Bleomycin
of DNA genome

FIGURE 54–2  Cell cycle and cancer. A conceptual depiction of

the cell cycle phases that all cells—normal and neoplastic—must
traverse before and during cell division. The percentages given
represent the approximate percentage of time spent in each phase
by a typical malignant cell; the duration of G1, however, can vary
markedly. Many of the effective anti-cancer drugs exert their action
on cells traversing the cell cycle and are called cell cycle-specific
(CCS) drugs (see Table 54–1). A second group of agents called cell
cycle-nonspecific (CCNS) drugs can sterilize tumor cells whether they
are cycling or resting in the G0 compartment. CCNS drugs can kill
both G0 and cycling cells (although cycling cells are more sensitive).
combination regimens were developed based on the known bio-
chemical actions of available anti-cancer drugs rather than on their
clinical efficacy. Such regimens were, however, largely ineffective.
The era of effective combination chemotherapy began when a
number of active drugs from different classes became available
for use in combination in the treatment of the acute leukemias
and lymphomas. Following this initial success with hematologic
malignancies, combination chemotherapy was extended to the
treatment of solid tumors.
952    SECTION VIII  Chemotherapeutic Drugs
The use of combination chemotherapy is important for several
reasons. First, it provides maximal cell kill within the range of
toxicity tolerated by the host for each drug as long as dosing is
not compromised. Second, it provides a broader range of interac-
tion between drugs and tumor cells with different genetic abnor-
malities in a heterogeneous tumor population. Finally, it may
prevent and/or slow the subsequent development of cellular drug
resistance. Of note, these same concepts apply to the therapy of
chronic infections, such as HIV and tuberculosis.
Certain principles have guided the selection of drugs in the
most effective drug combinations, and they provide a paradigm
for the development of new drug therapeutic programs.
1. Efficacy: Only drugs known to have some level of clinical effi-
cacy when used alone against a given tumor should be selected
for use in combination. If available, drugs that produce com-
plete remission in some fraction of patients are preferred to
those that produce only partial responses.
2. Toxicity: When several drugs of a given class are available and
are equally effective, a drug should be selected on the basis of
toxicity that does not overlap with the toxicity of other drugs
in the combination. Although such selection leads to a wider
range of adverse effects, it minimizes the risk of a lethal effect
caused by multiple insults to the same organ system by differ-
ent drugs and allows dose intensity to be maximized.
3. Optimum scheduling: Drugs should be used in their optimal
dose and schedule, and drug combinations should be given at
consistent intervals. Because long intervals between cycles
negatively affect dose intensity, the treatment-free interval
between cycles should be the shortest time necessary for recov-
ery of the most sensitive normal target tissue, which is usually
the bone marrow.
4. Mechanism of interaction: There should be a clear under-
standing of the biochemical, molecular, and pharmacokinetic
mechanisms of interaction between the individual drugs in a
given combination, to allow for maximal antitumor effect.
Omission of a drug from a combination may allow overgrowth
by a tumor clone sensitive to that drug alone and resistant to
other drugs in the combination.
5. Avoidance of arbitrary dose changes: An arbitrary reduc-
tion in the dose of an effective drug in order to add other less
effective drugs may reduce the dose of the most effective agent
below the threshold of effectiveness and destroy the ability of
the combination to cure disease in a given patient.
Dosage Factors
Dose intensity is one of the main factors limiting the ability of
chemotherapy or radiation therapy to achieve cure. As described
in Chapter 2, the dose-response curve in biologic systems is usu-
ally sigmoidal in shape, with a threshold, a linear phase, and a pla-
teau phase. For chemotherapy, therapeutic selectivity is dependent
on the difference between the dose-response curves of normal and
tumor tissues. In experimental animal models, the dose-response
curve is usually steep in the linear phase, and a reduction in dose
when the tumor is in the linear phase of the dose-response curve
almost always results in a loss in the capacity to cure the tumor
effectively before a reduction in the antitumor activity is observed.
Although complete remissions may continue to be observed with
dose reductions down to as low as 20% of the optimal dose, resid-
ual tumor cells may not be entirely eliminated, thereby allowing
for eventual relapse. Because toxicities are usually associated with
anticancer drugs, it is often appealing for clinicians to avoid acute
toxicity by simply reducing the dose and/or by increasing the time
interval between each cycle of treatment. However, such empiric
modifications in dose represent a major cause of treatment failure,
especially in patients with drug-sensitive tumors.
A positive relationship between dose intensity and clinical
efficacy has been documented in several solid tumors, including
advanced ovarian, breast, lung, and colon cancers, as well as in
hematologic malignancies, such as the lymphomas. At present,
there are three main approaches to dose-intense delivery of che-
motherapy. The first approach, dose escalation, involves increas-
ing the doses of the respective anti-cancer agents. The second
strategy is administration of anti-cancer agents in a dose-intense
manner by reducing the interval between treatment cycles, while
the third approach involves sequential scheduling of either
single agents or combination regimens. Each of these strategies is
presently being applied to the treatment of a wide range of solid
cancers, including breast, colorectal, and NSCLC, and in general,
such dose-intense regimens have significantly improved clinical
outcomes.
DRUG RESISTANCE
A fundamental problem in cancer chemotherapy is the develop-
ment of cellular drug resistance. Primary or inherent resistance
refers to drug resistance in the absence of prior exposure to avail-
able standard agents. The presence of inherent drug resistance was
first proposed by Goldie and Coleman in the early 1980s and was
thought to result from the genomic instability associated with the
development of most cancers. For example, mutations in the p53
tumor suppressor gene occur in up to 50% of all human tumors.
Preclinical and clinical studies have shown that loss of p53 func-
tion leads to resistance to radiation therapy as well as resistance
to a wide range of anti-cancer agents. Defects in the mismatch
repair enzyme family, which are tightly linked to the development
of familial and sporadic colorectal cancer, are associated with
resistance to several unrelated anti-cancer agents, including fluo-
ropyrimidines, thiopurines, and cisplatin/carboplatin. In contrast
to primary resistance, acquired resistance develops in response to
exposure to a given anti-cancer agent. Experimentally, drug resis-
tance can be highly specific to a single drug and is usually based
on a specific change in the genetic machinery of a given tumor
cell with amplification or increased expression of one or more
genes. In other instances, a multidrug-resistant phenotype occurs,
associated with increased expression of the MDR1 gene, which
encodes a cell surface transporter glycoprotein (P-glycoprotein,
see Chapter 5). This form of drug resistance leads to enhanced
drug efflux and reduced intracellular accumulation of a broad
range of structurally unrelated anti-cancer agents, including
 CHAPTER 54  Cancer Chemotherapy    953

the anthracyclines, vinca alkaloids, taxanes, camptothecins, Mechanism of Action

epipodophyllotoxins, and even small molecule inhibitors, such
as imatinib.
■■ BASIC PHARMACOLOGY OF
CANCER CHEMOTHERAPEUTIC
DRUGS
ALKYLATING AGENTS
The major clinically useful alkylating agents (Figure 54–3)
have a structure containing a bis(chloroethyl)amine, ethyl-
eneimine, or nitrosourea moiety, and they are classified in
several different groups. Among the bis(chloroethyl)amines,
cyclophosphamide, mechlorethamine, melphalan, and chlo-
rambucil are the most useful. Ifosfamide is closely related to
cyclophosphamide but has a somewhat different spectrum of
activity and toxicity. Thiotepa and busulfan are used to treat
breast and ovarian cancer, and chronic myeloid leukemia,
respectively. The major nitrosoureas are carmustine (BCNU)
and lomustine (CCNU).
As a class, the alkylating agents exert their cytotoxic effects via
transfer of their alkyl groups to various cellular constituents.
Alkylation of DNA within the nucleus probably represents the
major interaction leading to cell death. However, these drugs
react chemically with sulfhydryl, amino, hydroxyl, carboxyl, and
phosphate groups of other cellular nucleophiles as well. The gen-
eral mechanism of action of these drugs involves intramolecular
cyclization to form an ethyleneimonium ion that may directly
or through formation of a carbonium ion transfer an alkyl group
to a cellular constituent. In addition to alkylation, a secondary
mechanism that occurs with nitrosoureas involves carbamoylation
of lysine residues of proteins through formation of isocyanates.
The major site of alkylation within DNA is the N7 position
of guanine; however, other bases are also alkylated albeit to lesser
degrees, including N1 and N3 of adenine, N3 of cytosine, and
O6 of guanine, as well as phosphate atoms and proteins associated
with DNA. These interactions can occur on a single strand or on
both strands of DNA through cross-linking, as most major alkyl-
ating agents are bifunctional, with two reactive groups. Alkylation
of guanine can result in miscoding through abnormal base pairing
with thymine or in depurination by excision of guanine residues.

Bis(chloroethyl)amines Nitrosoureas Aziridines

CH2CH2CI R

R N NH N

CH2CH2CI O C N P N

N CH2 CH2CI S
Where R is:
O N Thiotepa
H
N O
P Where R is:
N
O CH2CH2CI
Cyclophosphamide N N
BCNU
(carmustine)

CH3 N N N

Mechlorethamine
Triethylenemelamine

O
Alkylsulfonate
HOC (CH2)3 CCNU O
(lomustine)
CH2 O S CH3
Chlorambucil
CH2 O

O NH2 CH2 O
CH3
HOC C CH2 CH2 O S CH3

H O
Methyl-CCNU
Melphalan (semustine) Busulfan

FIGURE 54–3  Structures of major classes of alkylating agents.

954    SECTION VIII  Chemotherapeutic Drugs

The latter effect leads to DNA strand breakage through scission
of the sugar-phosphate backbone of DNA. Cross-linking of DNA
appears to be of major importance to the cytotoxic action of alkyl-
ating agents, and replicating cells are most susceptible to these
drugs. Thus, although alkylating agents are not cell cycle-specific,
cancer cells are most susceptible to this class of drugs in late G1
and S phases of the cell cycle.
Resistance
The mechanism of acquired resistance to alkylating agents may
involve increased capability to repair DNA lesions through
increased expression and activity of DNA repair enzymes,
decreased cellular transport of the alkylating drug, and increased
expression or activity of glutathione and glutathione-associated
proteins, which are needed to conjugate the alkylating agent, or
increased glutathione S-transferase activity, which catalyzes the
conjugation.
Cyclophosphamide is one of the most widely used alkylating
agents. One significant advantage of this compound relates to its
high oral bioavailability. As a result, it can be administered via the
oral and intravenous routes with equal clinical efficacy. It is inac-
tive in its parent form and must be activated to cytotoxic metabo-
lites by liver microsomal enzymes (Figure 54–4). The cytochrome
P450 mixed-function oxidase system converts cyclophosphamide
to 4-hydroxycyclophosphamide, which is in equilibrium with
aldophosphamide. These active metabolites are delivered to both
tumor and normal tissue, where nonenzymatic cleavage of aldo-
phosphamide to the cytotoxic forms—phosphoramide mustard
and acrolein—occurs. The liver appears to be protected through
the enzymatic formation of the inactive metabolites 4-ketocyclo-
phosphamide and carboxyphosphamide.
The major toxicities of the individual alkylating agents are
outlined in Table 54–2 and discussed below.

Adverse Effects NITROSOUREAS

The adverse effects associated with alkylating agents are generally
dose-related and occur primarily in rapidly growing tissues such
as bone marrow (myelosuppression), gastrointestinal tract (diar-
rhea), and reproductive system. Nausea and vomiting also can be
a serious issue with a number of these agents. In addition, they
are potent vesicants and can damage tissues at the site of admin-
istration as well as produce systemic toxicity. As a class, alkylating
agents are carcinogenic in nature, and there is an increased risk of
secondary malignancies, especially acute myelogenous leukemia.
These drugs appear to be non-cross-resistant with other alkylating
agents; all require biotransformation, which occurs by nonenzy-
matic decomposition, to metabolites with both alkylating and
carbamoylating activities. The nitrosoureas are highly lipid-soluble
and are able to readily cross the blood-brain barrier, making them
effective in the treatment of brain tumors. Although the major-
ity of alkylations by the nitrosoureas are on the N7 position of
guanine in DNA, the critical alkylation responsible for cytotoxic-
ity appears to be on the O6 position of guanine, which leads to

NH O

P O
O N(CH2CH2Cl)2
CH H 2N O
Cyclophosphamide
CH2 P

CH2 O N(CH2CH2Cl)2
Liver cytochrome
P450 oxidase Aldophosphamide
(active)

OH
Aldehyde oxidase Nonenzymatic
NH O

O N(CH2CH2Cl)2 H 2N O CH2 CH CHO

4-Hydroxycyclophosphamide Acrolein
O P
(active) (cytotoxic)
HOC CH2 CH2 O N(CH2CH2Cl)2 +
O Carboxyphosphamide
H 2N O
(inactive)
NH O
P
P
HO N(CH2CH2Cl)2
O N(CH2CH2Cl)2
Phosphoramide mustard
4-Ketocyclophosphamide (cytotoxic)
(inactive)

FIGURE 54–4  Cyclophosphamide metabolism.

 CHAPTER 54  Cancer Chemotherapy    955

TABLE 54–2  Alkylating agents and platinum analogs: Clinical activity and toxicities.
Mechanism of
Alkylating Agent Action Clinical Applications Acute Toxicity Delayed Toxicity

Mechlorethamine Forms DNA cross- Hodgkin’s and non-Hodgkin’s Nausea and Moderate depression of peripheral
links, resulting in lymphoma vomiting blood count; excessive doses produce
inhibition of DNA severe bone marrow depression with
synthesis and leukopenia, thrombocytopenia, and
function bleeding; alopecia and hemorrhagic cys-
titis occasionally occur with cyclophos-
Chlorambucil Same as above CLL and non-Hodgkin’s Nausea and
phamide; cystitis can be prevented with
lymphoma vomiting
adequate hydration; busulfan is associ-
Cyclophosphamide Same as above Breast cancer, ovarian cancer, Nausea and ated with skin pigmentation, pulmonary
non-Hodgkin’s lymphoma, vomiting fibrosis, and adrenal insufficiency
CLL, soft tissue sarcoma,
neuroblastoma, Wilms’ tumor,
rhabdomyosarcoma
Bendamustine Same as above CLL and non-Hodgkin’s Nausea and
lymphoma vomiting
Melphalan Same as above Multiple myeloma, breast Nausea and
cancer, ovarian cancer vomiting
Thiotepa Same as above Breast cancer, ovarian cancer, Nausea and
superficial bladder cancer vomiting
Busulfan Same as above CML Nausea and
vomiting
Carmustine Same as above Brain cancer, Hodgkin’s and Nausea and Myelosuppression; rarely interstitial lung
non-Hodgkin’s lymphoma vomiting disease and interstitial nephritis
Lomustine Same as above Brain cancer Nausea and
vomiting
Altretamine Same as above Ovarian cancer Nausea and Myelosuppression, peripheral neuropa-
vomiting thy, flu-like syndrome
Temozolomide Methylates DNA Brain cancer, melanoma Nausea and Myelosuppression, mild elevation in liver
and inhibits DNA vomiting, head- function tests, photosensitivity
synthesis and ache and fatigue
function
Procarbazine Methylates DNA Hodgkin’s and non-Hodgkin’s Central nervous Myelosuppression, hypersensitivity
and inhibits DNA lymphoma, brain tumors system depression reactions
synthesis and
function
Dacarbazine Methylates DNA Hodgkin’s lymphoma, Nausea and Myelosuppression, central nervous
and inhibits DNA melanoma, soft tissue sarcoma vomiting system toxicity with neuropathy, ataxia,
synthesis and lethargy, and confusion
function
Cisplatin Forms intrastrand Non-small cell and small cell Nausea and Nephrotoxicity, peripheral sen-
and interstrand lung cancer, breast cancer, vomiting sory neuropathy, ototoxicity, nerve
DNA cross-links; bladder cancer, cholangio- dysfunction
binding to nuclear carcinoma, gastroesophageal
and cytoplasmic cancer, head and neck cancer,
proteins ovarian cancer, germ cell
cancer
Carboplatin Same as cisplatin Non-small cell and small cell Nausea and Myelosuppression; rarely peripheral
lung cancer, breast cancer, vomiting neuropathy, renal toxicity, hepatic
bladder cancer, head and neck dysfunction
cancer, ovarian cancer
Oxaliplatin Same as cisplatin Colorectal cancer, Nausea and Myelosuppression, peripheral sensory
gastroesophageal cancer, vomiting, laryn- neuropathy, diarrhea
pancreatic cancer gopharyngeal
dysesthesias
CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia.
956    SECTION VIII  Chemotherapeutic Drugs
G-C crosslinks in DNA. After oral administration of lomustine,
peak plasma levels of metabolites appear within 1–4 hours; cen-
tral nervous system concentrations reach 30–40% of the activity
present in the plasma. Urinary excretion appears to be the major
route of elimination from the body. One naturally occurring
sugar-containing nitrosourea, streptozocin, is interesting because
it has minimal bone marrow toxicity. This agent has activity in the
treatment of insulin-secreting islet cell carcinoma of the pancreas.
NONCLASSIC ALKYLATING AGENTS
Several other compounds have mechanisms of action that involve
DNA alkylation as their cytotoxic mechanism of action. These
agents include procarbazine, dacarbazine, and bendamustine.
Their clinical activities and toxicities are listed in Table 54–2.
Procarbazine
Procarbazine is an orally active methylhydrazine derivative, and in
the clinical setting, it is used in combination regimens for Hodg-
kin’s and non-Hodgkin’s lymphoma as well as for brain tumors.
The precise mechanism of action of procarbazine is uncer-
tain; however, it inhibits DNA, RNA, and protein biosynthesis;
prolongs interphase; and produces chromosome breaks. Oxida-
tive metabolism of this drug by microsomal enzymes generates
azoprocarbazine and H2O2, which may be responsible for DNA
strand scission. A variety of other drug metabolites are formed that
may be cytotoxic. One metabolite is a weak monoamine oxidase
(MAO) inhibitor, and adverse events can occur when procarbazine
is given with other MAO inhibitors as well as with sympatho-
mimetic agents, tricyclic antidepressants, antihistamines, central
nervous system depressants, antidiabetic agents, alcohol, and
tyramine-containing foods.
There is an increased risk of secondary cancers in the form of
acute leukemia, and its carcinogenic potential is thought to be
higher than that of other alkylating agents.
Dacarbazine
Dacarbazine is a synthetic compound that functions as an alkylat-
ing agent following metabolic activation in the liver by oxidative
N-demethylation to the monomethyl derivative. This metabolite
spontaneously decomposes to diazomethane, which generates a
methyl carbonium ion that is believed to be the key cytotoxic spe-
cies. Dacarbazine is administered parenterally and is used in the
treatment of malignant melanoma, Hodgkin’s lymphoma, soft tis-
sue sarcomas, and neuroblastoma. The main dose-limiting toxicity
is myelosuppression, but nausea and vomiting can be severe in
some cases. This agent is a potent vesicant, and care must be taken
to avoid extravasation during drug administration.
Bendamustine
Bendamustine is a bifunctional alkylating agent consisting of a
purine benzimidazole ring and a nitrogen mustard moiety. As with
other alkylating agents, it forms cross-links with DNA resulting in
single- and double-stranded breaks, leading to inhibition of DNA
synthesis and function. This molecule also inhibits mitotic check-
points and induces mitotic catastrophe, which leads to cell death.
Of note, the cross-resistance between bendamustine and other
alkylating agents is only partial, thereby providing a rationale for
its clinical activity despite the development of resistance to other
alkylating agents. This agent is approved for use in chronic lym-
phocytic leukemia, with activity also observed in Hodgkin’s and
non-Hodgkin’s lymphoma, multiple myeloma, and breast cancer.
The main dose-limiting toxicities include myelosuppression and
mild nausea and vomiting. Hypersensitivity infusion reactions,
skin rash, and other skin reactions occur rarely.
PLATINUM ANALOGS
Three platinum analogs are currently used in clinical practice:
cisplatin, carboplatin, and oxaliplatin. Cisplatin (cis-diamminedi-
chloroplatinum [II]) is an inorganic metal complex that was ini-
tially discovered through a serendipitous observation that neutral
platinum complexes inhibited division and filamentous growth
of Escherichia coli. Several platinum analogs were subsequently
synthesized. Although the precise mechanism of action of the
platinum analogs is unclear, they exert their cytotoxic effects in the
same manner as alkylating agents. As such, they kill tumor cells in
all stages of the cell cycle and bind DNA through the formation of
intrastrand and interstrand cross-links, thereby leading to inhibi-
tion of DNA synthesis and function. The primary binding site is
the N7 position of guanine, but covalent interaction with the N3
position of adenine and O6 position of cytosine also can occur.
In addition to targeting DNA, the platinum analogs have been
shown to bind to both cytoplasmic and nuclear proteins, which
may also contribute to their cytotoxic and antitumor effects. The
platinum complexes appear to synergize with certain other anti-
cancer drugs, including alkylating agents, fluoropyrimidines, and
taxanes. The major toxicities of the individual platinum analogs
are outlined in Table 54–2.
H3N Cl
Pt
H3N Cl
Cisplatin
Cisplatin has major antitumor activity in a broad range of
solid tumors, including non-small cell and small cell lung cancer,
esophageal and gastric cancer, cholangiocarcinoma, head and neck
cancer, and genitourinary cancers, particularly testicular, ovar-
ian, and bladder cancer. When used in combination regimens,
cisplatin-based therapy has led to the cure of nonseminomatous
testicular cancer. Cisplatin and the other platinum analogs are
cleared by the kidneys and excreted in the urine. As a result, dose
modification is required in patients with renal dysfunction.
Carboplatin is a second-generation platinum analog whose
mechanisms of cytotoxic action, mechanisms of resistance, and
clinical pharmacology are identical to those described for cisplatin.
As with cisplatin, carboplatin has broad-spectrum activity against
 CHAPTER 54  Cancer Chemotherapy    957

a wide range of solid tumors. However, in contrast to cisplatin, 5–7 glutamate residues, is critically important for the therapeu-
it exhibits significantly less renal and gastrointestinal toxicity. Its tic action of MTX, and this process is catalyzed by the enzyme
main dose-limiting toxicity is myelosuppression. It has, there- folylpolyglutamate synthase (FPGS). MTX polyglutamates are
fore, been widely used in transplant regimens to treat refractory selectively retained within cancer cells, and they display increased
hematologic malignancies. Moreover, since vigorous intravenous inhibitory effects on enzymes involved in de novo purine nucleo-
hydration is not required for carboplatin therapy, carboplatin is tide and thymidylate biosynthesis, making them important deter-
viewed as an easier agent to administer to patients, and as such, minants of MTX’s cytotoxic action.
it has replaced cisplatin in various combination chemotherapy
regimens. N N NH2
COOH H
Oxaliplatin is a third-generation diaminocyclohexane plati-
num analog. Its mechanism of action and clinical pharmacology CH N C N C N
H2 N
are identical to those of cisplatin and carboplatin. However, CH2 H O
tumors that are resistant to cisplatin or carboplatin on the basis of OH
CH2
mismatch repair defects are not cross-resistant to oxaliplatin, and
this finding may explain the clinical activity of this platinum com- COOH
pound in colorectal cancer. Oxaliplatin was initially approved for Folic acid
use as second-line therapy in combination with the fluoropyrimi-
dine 5-fluorouracil (5-FU) and leucovorin, termed the FOLFOX
regimen, for metastatic colorectal cancer. There are various itera- N N NH2
tions of the FOLFOX regimen, which have now become the most COOH CH3

widely used combinations in the first-line treatment of advanced CH N C N C N

colorectal cancer. This regimen also plays a major role in the
adjuvant therapy of stage III colon cancer and high-risk stage
II colon cancer. Clinical activity has also been observed in other
gastrointestinal cancers, such as pancreatic, gastroesophageal, and
hepatocellular cancer. Neurotoxicity is the main dose-limiting
toxicity, and it is manifested by a peripheral sensory neuropathy.
There are two forms of neurotoxicity, an acute form that is often
triggered and worsened by exposure to cold, and a chronic form
that is dose-dependent. Although the chronic form of oxaliplatin
toxicity is dependent on the cumulative dose of drug adminis-
tered, it tends to be more readily reversible than that observed
with cisplatin-induced neurotoxicity.
ANTIMETABOLITES
The antimetabolites represent an important class of agents that
have been rationally designed and synthesized based on knowl-
edge of critical cellular processes involved in DNA biosynthesis.
The individual antimetabolites and their respective clinical
spectrum and toxicities are presented in Table 54–3 and are
discussed below.
ANTIFOLATES
Methotrexate
Methotrexate (MTX) is a folic acid analog that binds with high
affinity to the active catalytic site of dihydrofolate reductase
(DHFR). This results in inhibition of synthesis of tetrahydrofo-
late (THF), the key one-carbon carrier for enzymatic processes
involved in de novo synthesis of thymidylate, purine nucleotides,
and the amino acids serine and methionine. Inhibition of these
metabolic processes interferes with the formation of DNA, RNA,
and key cellular proteins (see Figure 33–3). Intracellular forma-
tion of polyglutamate metabolites, with the addition of up to
H2 N
CH2 H O
NH2
CH2
COOH
Methotrexate
Several resistance mechanisms to MTX have been identified,
and they include (1) decreased drug transport via the reduced
folate carrier or folate receptor protein, (2) decreased formation of
cytotoxic MTX polyglutamates, (3) increased levels of the target
enzyme DHFR through gene amplification and other genetic
mechanisms, and (4) altered DHFR protein with reduced affinity
for MTX. Recent studies have suggested that decreased accu-
mulation of drug through activation of the multidrug resistance
transporter P170 glycoprotein also may result in drug resistance.
MTX is administered by the intravenous, intrathecal, or oral
route. However, oral bioavailability is saturable and erratic at
doses greater than 25 mg/m2. Renal excretion is the main route of
elimination and is mediated by glomerular filtration and tubular
secretion. As a result, dose modification is required in the set-
ting of renal dysfunction. Care must also be taken when MTX
is used in the presence of drugs such as aspirin, nonsteroidal
anti-inflammatory agents, penicillin, and cephalosporins, as these
agents inhibit the renal excretion of MTX. The biologic effects
of MTX can be reversed by administration of the reduced folate
leucovorin (5-formyltetrahydrofolate) or by L-leucovorin, which
is the active enantiomer. Leucovorin rescue is used in conjunction
with high-dose MTX therapy to rescue normal cells from undue
toxicity, and it has also been used in cases of accidental drug over-
dose. The main adverse effects are listed in Table 54–3.
Pemetrexed
Pemetrexed is a pyrrolopyrimidine antifolate analog with activ-
ity in the S phase of the cell cycle. As in the case of MTX, it is
958    SECTION VIII  Chemotherapeutic Drugs

TABLE 54–3  Antimetabolites: Clinical activity and toxicities.

Drug Mechanism of Action Clinical Applications Toxicity

Capecitabine Inhibits TS; incorporation of FUTP into RNA
resulting in alteration in RNA processing;
incorporation of FdUTP into DNA resulting
in inhibition of DNA synthesis and function
5-Fluorouracil Inhibits TS; incorporation of FUTP into RNA
resulting in alteration in RNA processing;
incorporation of FdUTP into DNA resulting
in inhibition of DNA synthesis and function
Methotrexate Inhibits DHFR; inhibits TS; inhibits de novo
purine nucleotide synthesis
Pemetrexed Inhibits TS, DHFR, and purine nucleotide
synthesis
Cytarabine Inhibits DNA chain elongation, DNA
synthesis and repair; inhibits ribonucleotide
reductase with reduced formation of dNTPs;
incorporation of cytarabine triphosphate
into DNA
Gemcitabine Inhibits DNA synthesis and repair; inhibits
ribonucleotide reductase with reduced
formation of dNTPs; incorporation of
gemcitabine triphosphate into DNA
resulting in inhibition of DNA synthesis
and function
Fludarabine Inhibits DNA synthesis and repair; inhibits
ribonucleotide reductase; incorporation
of fludarabine triphosphate into DNA;
induction of apoptosis
Cladribine Inhibits DNA synthesis and repair; inhibits
ribonucleotide reductase; incorporation of
cladribine triphosphate into DNA; induction
of apoptosis
6-Mercaptopurine Inhibits de novo purine nucleotide synthe-
(6-MP) sis; incorporation of triphosphate into RNA;
incorporation of triphosphate into DNA
6-Thioguanine Same as 6-MP
ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; DHFR, dihydrofolate reductase;
dNTP, deoxyribonucleotide triphosphate; FdUTP, 5-fluorodeoxyuridine-5′-triphosphate; FUTP, 5-fluorouridine-5′-triphosphate; TS, thymidylate synthase.
Breast cancer, colorectal can-
cer, gastroesophageal cancer,
hepatocellular cancer, pancreatic
cancer
Colorectal cancer, anal cancer, breast
cancer, gastroesophageal cancer,
head and neck cancer, hepatocellular
cancer
Breast cancer, head and neck cancer,
osteogenic sarcoma, primary central
nervous system lymphoma, non-
Hodgkin’s lymphoma, bladder cancer,
choriocarcinoma
Mesothelioma, non-small cell lung
cancer
AML, ALL, CML in blast crisis
Pancreatic cancer, bladder cancer,
breast cancer, non-small cell lung
cancer, ovarian cancer, non-Hodgkin’s
lymphoma, soft tissue sarcoma
Non-Hodgkin’s lymphoma, CLL
Hairy cell leukemia, CLL,
non-Hodgkin’s lymphoma
AML
ALL, AML
Diarrhea, hand-foot syndrome,
myelosuppression, nausea and
vomiting
Nausea, mucositis, diarrhea, bone
marrow depression, neurotoxicity
Mucositis, diarrhea, myelosup-
pression with neutropenia and
thrombocytopenia
Myelosuppression, skin rash,
mucositis, diarrhea, fatigue,
hand-foot syndrome
Nausea and vomiting,
myelosuppression with neutro-
penia and thrombocytopenia,
cerebellar ataxia
Nausea, vomiting, diarrhea,
myelosuppression
Myelosuppression, immunosup-
pression, nausea and vomiting,
fever, myalgias, arthralgias
Myelosuppression, nau-
sea and vomiting, and
immunosuppression
Myelosuppression, immunosup-
pression, and hepatotoxicity
Same as 6-MP

transported into the cell via the reduced folate carrier and requires
activation by FPGS to yield higher polyglutamate forms. While
this agent targets DHFR and enzymes involved in de novo
purine nucleotide biosynthesis, its main mechanism of action is
inhibition of thymidylate synthase (TS). Pemetrexed is currently
approved for use in combination with cisplatin in the treatment
of mesothelioma, as a single agent in the second-line therapy of
NSCLC, in combination with cisplatin for the first-line treatment
of NSCLC, and most recently, as maintenance therapy in patients
with NSCLC whose disease has not progressed after four cycles
of platinum-based chemotherapy. As with MTX, pemetrexed is
mainly excreted in urine, and dose modification is required in
patients with renal dysfunction. The main adverse effects include
myelosuppression, skin rash, mucositis, diarrhea, fatigue, and
hand-foot syndrome. Of note, vitamin supplementation with folic
acid and vitamin B12 has been shown to significantly reduce the
toxicities associated with pemetrexed, while not interfering with
clinical efficacy. The hand-foot syndrome is manifested by painful
erythema and swelling of the hands and feet, and treatment with
the steroid dexamethasone is effective in reducing the incidence
and severity of this skin toxicity.
Pralatrexate
Pralatrexate is a 10-deaza-aminopterin antifolate analog, and
as in the case of MTX, it is transported into the cell via the

reduced folate carrier (RFC) and requires activation by FPGS to
yield higher polyglutamate forms. This molecule was originally
designed to be a more potent substrate for the RFC-1 carrier pro-
tein and to serve as an improved substrate for FPGS. This agent
inhibits DHFR, inhibits enzymes involved in de novo purine
nucleotide biosynthesis, and also inhibits TS. Pralatrexate is pres-
ently approved for use in the treatment of relapsed or refractory
peripheral T-cell lymphoma. Consistent with other antifolate
analogs, pralatrexate is mainly excreted in the urine, and dose
modification is required in renal dysfunction. The main adverse
effects include myelosuppression, skin rash, mucositis, diarrhea,
and fatigue. As with pemetrexed, vitamin supplementation with
folic acid and vitamin B12 appears to reduce the toxicities associ-
ated with pralatrexate, without interfering with clinical efficacy.
FLUOROPYRIMIDINES
5-Fluorouracil
5-Fluorouracil (5-FU) is inactive in its parent form and requires
activation via a complex series of enzymatic reactions to ribosyl
and deoxyribosyl nucleotide metabolites. One of these metab-
olites, 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP),
forms a covalently bound ternary complex with the enzyme TS
and the reduced folate 5,10-methylenetetrahydrofolate, a reaction
critical for the de novo synthesis of thymidylate. Formation of this
ternary complex results in inhibition of DNA synthesis through
“thymineless death.” 5-FU is converted to 5-fluorouridine-5′-
triphosphate (FUTP), which is then incorporated into RNA,
where it interferes with RNA processing and mRNA translation.
5-FU is also converted to 5-fluorodeoxyuridine-5′-triphosphate
(FdUTP), which is subsequently incorporated into cellular DNA,
resulting in inhibition of DNA synthesis and function. Thus, the
cytotoxicity of 5-FU is thought to be mediated by the combined
effects of both DNA- and RNA-mediated events.
5-FU is administered intravenously, and the clinical activity of
this drug is highly schedule-dependent. Because of its extremely
short half-life, approximately 10–15 minutes, infusion adminis-
tration schedules have been generally favored over bolus schedules.
Up to 80–85% of an administered dose of 5-FU is catabolized
by the enzyme dihydropyrimidine dehydrogenase (DPD). There
is an autosomal recessive pharmacogenetic syndrome involving
partial or complete deficiency of the DPD enzyme that is seen
in up to 5% of cancer patients. In this particular setting, severe,
excessive toxicity is observed with the classic triad of myelosup-
pression, GI toxicity in the form of diarrhea and/or mucositis,
and neurotoxicity.
O O
H F
HN HN
O
N
O
N leading to inhibition of DNA synthesis and function. The role
H H
Uracil 5-FU
CHAPTER 54  Cancer Chemotherapy    959
5-FU remains the most widely used agent in the treatment
of colorectal cancer, both as adjuvant therapy and for advanced
disease. It also has activity against a wide range of solid tumors,
including cancers of the breast, stomach, pancreas, esophagus,
liver, head and neck, and anus. Major toxicities include myelo-
suppression, gastrointestinal toxicity in the form of mucositis and
diarrhea, skin toxicity manifested by the hand-foot syndrome, and
neurotoxicity.
Capecitabine
Capecitabine is a fluoropyrimidine carbamate prodrug with
70–80% oral bioavailability. As with 5-FU, capecitabine is inac-
tive in its parent form and undergoes extensive metabolism in
the liver by the enzyme carboxylesterase to an intermediate,
5′-deoxy-5-fluorocytidine. This metabolite is then converted
to 5′-deoxy-5-fluorouridine by the enzyme cytidine deaminase.
These two initial steps occur mainly in the liver. The 5′-deoxy-
5-fluorouridine metabolite is finally hydrolyzed by thymidine
phosphorylase to 5-FU directly in the tumor. The expression
of thymidine phosphorylase has been shown to be significantly
higher in a broad range of solid tumors than in corresponding
normal tissue, particularly in breast cancer and colorectal cancer
(CRC).
Capecitabine is used in the treatment of metastatic breast
cancer either as a single agent or in combination with other
anti-cancer agents, including docetaxel, paclitaxel, lapatinib,
ixabepilone, and trastuzumab. It is also approved for use in the
adjuvant therapy of stage III and high-risk stage II colon cancer,
and used in the treatment of metastatic CRC as monotherapy
or in combination with other active cytotoxic agents, includ-
ing irinotecan and oxaliplatin. The capecitabine/oxaliplatin
(XELOX) regimen is now widely used for the first-line treat-
ment of metastatic CRC as well as in the adjuvant setting for
patients with stage III and high-risk stage II colon cancer. The
main toxicities of capecitabine include diarrhea and the hand-
foot syndrome. While myelosuppression, nausea and vomiting,
mucositis, and alopecia are also observed with capecitabine,
their incidence is significantly less than that observed with
intravenous 5-FU.
TAS-102
TAS-102 is an oral fluoropyrimidine analog approved in 2015
by the U.S. Food and Drug Administration (FDA) for the treat-
ment of progressive, refractory metastatic CRC. As with 5-FU,
TAS-102 is inactive in its parent form. It is made up of trifluri-
dine, a fluorinated pyrimidine nucleoside analog, and tipiracil, a
thymidine phosphorylase (TP) inhibitor, in a 1/0.5 ratio. Triflu-
ridine is metabolized to the monophosphate form, which inhibits
TS, albeit a much weaker TS inhibitor than FdUMP, and also to
the triphosphate form, which is directly incorporated into DNA,
of tipiracil is to inhibit TP, a key enzyme that degrades trifluri-
dine to inactive forms. Thus, tipiracil allows for higher levels of
960    SECTION VIII  Chemotherapeutic Drugs
trifluridine, which can then be activated to the active metabolite
forms. The advantages of TAS-102 are that it retains clinical activ-
ity in 5-FU resistant tumors and it displays similar clinical activity
in the setting of wild-type and mutant RAS colorectal cancer. The
main dose-limiting toxicity is myelosuppression, with neutropenia
more commonly observed than anemia and thrombocytopenia.
The other adverse effects commonly observed with this oral fluo-
ropyrimidine are GI toxicity with diarrhea and nausea/vomiting,
fatigue, and anorexia.
DEOXYCYTIDINE ANALOGS
Cytarabine
Cytarabine (ara-C) is an S phase–specific antimetabolite that
is converted by deoxycytidine kinase to the 5′-mononucleotide
(ara-CMP). Ara-CMP is further metabolized to the diphosphate
and triphosphate metabolites, and the ara-CTP triphosphate is
thought to be the main cytotoxic metabolite. Ara-CTP com-
petitively inhibits DNA polymerase-α and DNA polymerase-β,
thereby resulting in blockade of DNA synthesis and DNA repair,
respectively. This metabolite is also incorporated into RNA and
DNA. Incorporation into DNA leads to interference with chain
elongation and defective ligation of fragments of newly synthe-
sized DNA. The cellular retention of ara-CTP appears to correlate
with its lethality to malignant cells.
NH2 NH2
N N
O O
N N
HOCH2 O HOCH2
O tropenia is the principal dose-limiting toxicity. Nausea and vomit-
HO
HO HO
Cytosine Cytosine
deoxyriboside arabinoside
(cytarabine)
After intravenous administration, the drug is cleared rap-
idly, with most of an administered dose being deaminated to
inactive forms. The stoichiometric balance between the level of
activation and catabolism of cytarabine is important in deter-
mining its eventual cytotoxicity. The clinical activity of cyta-
rabine is highly schedule-dependent and, because of its rapid
degradation, it is usually administered via continuous infusion
over a 5- to 7-day period. Its activity is limited exclusively to
hematologic malignancies, including acute myelogenous leuke-
mia and non-Hodgkin’s lymphoma. This agent has absolutely
no activity in solid tumors. The main adverse effects associated
with cytarabine therapy include myelosuppression, mucosi-
tis, nausea and vomiting, and neurotoxicity when high-dose
therapy is administered.
Gemcitabine
Gemcitabine is a fluorine-substituted deoxycytidine analog that is
phosphorylated initially by the enzyme deoxycytidine kinase to the
monophosphate form and then by other nucleoside kinases to the
diphosphate and triphosphate nucleotide forms. The antitumor
effect is considered to result from several mechanisms: inhibition
of ribonucleotide reductase by gemcitabine diphosphate, which
reduces the level of deoxyribonucleoside triphosphates required
for DNA synthesis; inhibition by gemcitabine triphosphate of
DNA polymerase-α and DNA polymerase-β, thereby resulting in
blockade of DNA synthesis and DNA repair; and incorporation
of gemcitabine triphosphate into DNA, leading to inhibition of
DNA synthesis and function.
NH2
N
O
N
HOCH2
O
F
OH F
Gemcitabine
In contrast to cytarabine, which has no activity in solid tumors,
gemcitabine has broad-spectrum activity against both solid tumors
and hematologic malignancies. In fact, this nucleoside analog was
initially approved for use in advanced pancreatic cancer and is
now widely used to treat a broad range of malignancies, including
NSCLC, bladder cancer, ovarian cancer, soft tissue sarcoma, and
non-Hodgkin’s lymphoma. Myelosuppression in the form of neu-
ing occur in 70% of patients, and a flu-like syndrome has also
been observed. In rare cases, renal microangiopathy syndromes,
including hemolytic-uremic syndrome (HUS) and thrombotic
thrombocytopenic purpura (TTP), have been reported.
PURINE ANTAGONISTS
6-Thiopurines
6-Mercaptopurine (6-MP) was the first of the thiopurine analogs
found to have clinical efficacy in cancer therapy. This agent is
used primarily in the treatment of childhood acute leukemia, and
a closely related analog, azathioprine, is used as an immunosup-
pressive agent (see Chapter 55). As with other thiopurines, 6-MP
is inactive in its parent form and must be metabolized by hypo-
xanthine-guanine phosphoribosyl transferase (HGPRT) to form
the monophosphate nucleotide 6-thioinosinic acid, which in turn,
inhibits several enzymes of de novo purine nucleotide synthesis
(Figure 54–6). The monophosphate form is eventually metabolized
to the triphosphate form, which can then be incorporated into
both RNA and DNA. Significant levels of thioguanylic acid and

6-methylmercaptopurine ribotide (MMPR) also are formed from
6-MP. These metabolites may contribute to its cytotoxic action.
6-Thioguanine (6-TG) also inhibits several enzymes in the de
novo purine nucleotide biosynthetic pathway. Various metabolic
lesions result, including inhibition of purine nucleotide intercon-
version; decrease in intracellular levels of guanine nucleotides,
which leads to inhibition of glycoprotein synthesis; interference
with the formation of DNA and RNA; and incorporation of
thiopurine nucleotides into both DNA and RNA. 6-TG has a
synergistic action when used together with cytarabine in the treat-
ment of adult acute leukemia.
6-MP is converted to an inactive metabolite (6-thiouric
acid) by an oxidation reaction catalyzed by xanthine oxidase,
whereas 6-TG undergoes deamination. This is an important
difference because the purine analog allopurinol, a potent xanthine
oxidase inhibitor, is frequently used as a supportive care measure
in the treatment of acute leukemias to prevent the development
of hyperuricemia that often occurs with tumor cell lysis. Because
allopurinol inhibits xanthine oxidase, simultaneous therapy with
allopurinol and 6-MP would result in increased levels of 6-MP,
thereby leading to excessive toxicity. In this setting, the dose of
mercaptopurine must be reduced by 50–75%. In contrast, such
an interaction does not occur with 6-TG, which can be used in
full doses with allopurinol.
OH SH OH
N N
N N N phosphate form, which can then be incorporated into DNA. The
N triphosphate metabolite can also interfere with DNA synthesis
N
N
N
N
N
N and DNA repair by inhibiting DNA polymerase-α and DNA
H H H
Hypoxanthine 6-Mercaptopurine Allopurinol
OH SH
N N
N N
H2N
N
N H2N
N
N has immunosuppressive effects, and a decrease in CD4 and CD8
H H
Guanine 6-Thioguanine
The thiopurines are also metabolized by the enzyme thiopurine
methyltransferase (TPMT), in which a methyl group is attached
to the thiopurine ring. Patients who have a pharmacogenetic
syndrome involving partial or complete deficiency of this enzyme
are at increased risk for developing severe toxicities in the form
of myelosuppression and gastrointestinal toxicity with mucositis
and diarrhea.
Fludarabine
Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-
arabinofuranosyladenosine and then phosphorylated intra-
cellularly by deoxycytidine kinase to the monophosphate,
which is eventually converted to the triphosphate. Fludarabine
CHAPTER 54  Cancer Chemotherapy    961
triphosphate interferes with the processes of DNA synthesis
and DNA repair through inhibition of DNA polymerase-α
and DNA polymerase-β. The triphosphate form can also be
directly incorporated into DNA, resulting in inhibition of DNA
synthesis and function. The diphosphate metabolite of fludara-
bine inhibits ribonucleotide reductase, leading to inhibition of
essential deoxyribonucleotide triphosphates. Finally, fludarabine
induces apoptosis in susceptible cells through as yet unde-
termined mechanisms. This purine nucleotide analog is used
mainly in the treatment of low-grade non-Hodgkin’s lymphoma
and chronic lymphocytic leukemia (CLL). It is given parenter-
ally, and up to 25–30% of parent drug is excreted in the urine.
The main dose-limiting toxicity is myelosuppression. This agent
is a potent immunosuppressant with inhibitory effects on CD4
and CD8 T cells. Patients are at increased risk for opportunistic
infections, including fungi, herpes, and Pneumocystis jiroveci
pneumonia (PCP). Patients should receive PCP prophylaxis with
trimethoprim-sulfamethoxazole (double strength) at least three
times a week, and this should continue for up to 1 year after
stopping fludarabine therapy.
Cladribine
Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside ana-
log with high specificity for lymphoid cells. Inactive in its parent
form, it is initially phosphorylated by deoxycytidine kinase to
the monophosphate form and eventually metabolized to the tri-
polymerase-β, respectively. Cladribine is indicated for the treat-
ment of hairy cell leukemia, with activity in other low-grade lym-
phoid malignancies such as CLL and low-grade non-Hodgkin’s
lymphoma. It is normally administered as a single continuous
7-day infusion; under these conditions, it has a very manage-
able safety profile with the main toxicity consisting of transient
myelosuppression. As with other purine nucleoside analogs, it
T cells, lasting for over 1 year, is observed in patients.
NATURAL PRODUCT CANCER
CHEMOTHERAPY DRUGS
VINCA ALKALOIDS
The vinca alkaloids inhibit the process of tubulin polymerization,
which disrupts assembly of microtubules, especially those involved
in the mitotic spindle apparatus. This inhibitory effect results in
mitotic arrest in metaphase, bringing cell division to a halt, which
then leads to cell death. Thus, the vinca alkaloids work in the M
phase of the cell cycle. Microtubules also play an important role
in maintaining cell shape and cellular motility, and they facilitate
the intracellular transport of cellular proteins. As such, inhibition
of microtubule formation has important consequences that can
lead to cell death.
962    SECTION VIII  Chemotherapeutic Drugs

Vinblastine
Vinblastine is an alkaloid derived from the periwinkle plant
Vinca rosea. Vinblastine and other vinca alkaloids are metabo-
lized by the liver P450 system, and the majority of the drug
is excreted in feces via the hepatobiliary system. As such, dose
modification is required in the setting of liver dysfunction.
The main adverse effects are outlined in Table 54–4, and they
include nausea and vomiting, bone marrow suppression, and
alopecia. This agent is also a potent vesicant, and care must
be taken in its administration. It has clinical activity in the
treatment of Hodgkin’s and non-Hodgkin’s lymphomas, breast
cancer, and germ cell cancer.

TABLE 54–4  Natural product cancer chemotherapy drugs: Clinical activity and toxicities.
Drug Mechanism of Action Clinical Applications Acute Toxicity Delayed Toxicity

Bleomycin Oxygen free radicals bind
to DNA causing single- and
double-strand DNA breaks
Daunorubicin Oxygen free radicals bind
to DNA causing single- and
double-strand DNA breaks;
inhibits topoisomerase II;
intercalates into DNA
Docetaxel Inhibits mitosis
Doxorubicin Oxygen free radicals bind to
DNA causing single- and double-
strand DNA breaks; inhibits
topoisomerase II; intercalates
into DNA
Etoposide Inhibits topoisomerase II
Idarubicin Oxygen free radicals bind to
DNA causing single- and double-
strand DNA breaks; inhibits
topoisomerase II; intercalates
into DNA
Irinotecan Inhibits topoisomerase I
Mitomycin Acts as an alkylating agent and
forms cross-links with DNA; for-
mation of oxygen free radicals,
which target DNA
Paclitaxel Inhibits mitosis
Topotecan Inhibits topoisomerase I
Vinblastine Inhibits mitosis
Vincristine Inhibits mitosis
Vinorelbine Inhibits mitosis
ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CML, chronic myelogenous leukemia.
Hodgkin’s and non-Hodgkin’s Allergic reactions, Skin toxicity, pulmo-
lymphoma, germ cell cancer, head fever, hypotension nary fibrosis, mucositis,
and neck cancer alopecia
AML, ALL Nausea and vomit- Cardiotoxicity (see
ing, fever, red urine text), alopecia,
(not hematuria) myelosuppression
Breast cancer, non-small cell lung Hypersensitivity Neurotoxicity, fluid reten-
cancer, prostate cancer, gastric cancer, tion, myelosuppression
head and neck cancer, ovarian cancer, with neutropenia
bladder cancer
Breast cancer, Hodgkin’s and non-Hodg- Nausea, red urine Cardiotoxicity (see text),
kin’s lymphoma, soft tissue sarcoma, (not hematuria) alopecia, myelosuppres-
ovarian cancer, non-small cell and small sion, stomatitis
cell lung cancer, thyroid cancer, Wilms’
tumor, neuroblastoma
Non-small cell and small cell lung can- Nausea, vomiting, Alopecia,
cer; non-Hodgkin’s lymphoma, gastric hypotension myelosuppression
cancer
AML, ALL, CML in blast crisis Nausea and Myelosuppression, muco-
vomiting sitis, cardiotoxicity
Colorectal cancer, gastroesophageal Diarrhea, nausea, Diarrhea, myelosuppres-
cancer, non-small cell and small cell vomiting sion, nausea and vomiting
lung cancer
Superficial bladder cancer, gastric can- Nausea and Myelosuppression,
cer, breast cancer, non-small cell lung vomiting mucositis, anorexia and
cancer, head and neck cancer (in combi- fatigue, hemolytic-uremic
nation with radiotherapy) syndrome
Breast cancer, non-small cell and small Nausea, vomit- Myelosuppression, periph-
cell lung cancer, ovarian cancer, gas- ing, hypotension, eral sensory neuropathy
troesophageal cancer, prostate cancer, arrhythmias,
bladder cancer, head and neck cancer hypersensitivity
Small cell lung cancer, ovarian cancer Nausea and Myelosuppression
vomiting
Hodgkin’s and non-Hodgkin’s lym- Nausea and Myelosuppression, muco-
phoma, germ cell cancer, breast cancer, vomiting sitis, alopecia, syndrome
Kaposi’s sarcoma of inappropriate secretion
of antidiuretic hormone
(SIADH), vascular events
ALL, Hodgkin’s and non-Hodgkin’s None Neurotoxicity with periph-
lymphoma, rhabdomyosarcoma, eral neuropathy, paralytic
neuroblastoma, Wilms’ tumor ileus, myelosuppression,
alopecia, SIADH
Non-small cell lung cancer, breast Nausea and Myelosuppression,
cancer, ovarian cancer vomiting constipation, SIADH
 CHAPTER 54  Cancer Chemotherapy    963

Vincristine microtubules with enhancement of tubulin polymerization. This

promotion of microtubule assembly by paclitaxel results in inhibi-
Vincristine is another alkaloid derivative of Vinca rosea and is
tion of mitosis and cell division. As such, paclitaxel and the other
closely related in structure to vinblastine. Its mechanism of action,
taxanes work in the M phase of the cell cycle.
mechanism of resistance, and clinical pharmacology are identical
Paclitaxel has significant activity in a broad range of solid
to those of vinblastine. Despite these similarities to vinblastine,
tumors, including ovarian, advanced breast, NSCLC and small
vincristine has a strikingly different spectrum of clinical activity
cell lung cancer (SCLC), head and neck, esophageal, prostate,
and safety profile, which results, in large part, from its higher
and bladder cancers, as well as AIDS-related Kaposi’s sarcoma. It
affinity for axonal microtubules.
is metabolized extensively by the liver P450 system, and nearly
80% of the drug is excreted in feces via the hepatobiliary route.
CH3O
N Dose reduction is required in patients with liver dysfunction. The
C primary dose-limiting toxicities are listed in Table 54–4. Hyper-
HO O N
H N sensitivity reactions may be observed in up to 5% of patients,
CH3 CH2
H but the incidence is significantly reduced by premedication with
H
dexamethasone, diphenhydramine, and an H2 blocker.
CH2CH3
An albumin-bound paclitaxel nanoparticle formulation
OH
CH3O
N OCOCH3 (Abraxane) is approved for several solid tumors, including breast
H H
O C O CH3
cancer, pancreatic cancer, and non-small cell lung cancer. In con-
R
trast to paclitaxel, this nanoparticle formulation is not associated
R: O C H R: CH3
with hypersensitivity reactions, and premedication to prevent such
reactions is not required. Moreover, this agent has significantly
Vincristine Vinblastine
reduced myelosuppressive effects compared with paclitaxel, and
the neurotoxicity that results appears to be more readily reversible
Vincristine has been effectively combined with prednisone for
than is typically observed with paclitaxel.
remission induction in acute lymphoblastic leukemia in children.
Docetaxel is a semisynthetic taxane derived from the European
It is also active in various hematologic malignancies such as Hodg-
yew tree. Its mechanism of action, metabolism, and elimination
kin’s and non-Hodgkin’s lymphomas, and multiple myeloma, and
are identical to those of paclitaxel. It is approved for use as second-
in several pediatric tumors including rhabdomyosarcoma, neuro-
line therapy in advanced breast cancer and NSCLC, and it also
blastoma, Ewing’s sarcoma, and Wilms’ tumor.
has major activity in head and neck cancer, small cell lung cancer,
The main dose-limiting toxicity is neurotoxicity, usually
gastric cancer, advanced platinum-refractory ovarian cancer, and
expressed as a peripheral sensory neuropathy, although autonomic
bladder cancer. Its major toxicities are listed in Table 54–4.
nervous system dysfunction with orthostatic hypotension, urinary
Cabazitaxel is a semisynthetic taxane and its mechanism of
retention, and paralytic ileus or constipation, cranial nerve palsies,
action, metabolism, and elimination are identical to those of the
ataxia, seizures, and coma have been observed. While myelosup-
other taxanes. However, unlike other taxanes, cabazitaxel is a poor
pression occurs, it is generally milder and much less significant
substrate for the multidrug resistance P-glycoprotein efflux pump
than with vinblastine. The other adverse effect that may develop is
and may, therefore, be useful for treating multidrug-resistant
the syndrome of inappropriate secretion of antidiuretic hormone
tumors. It is approved for use in combination with prednisone in
(SIADH).
the second-line therapy of hormone-refractory metastatic prostate
cancer previously treated with a docetaxel-containing regimen.
Vinorelbine Its major toxicities include myelosuppression, neurotoxicity, and
Vinorelbine is a semisynthetic derivative of vinblastine whose allergic reactions.
mechanism of action is identical to that of vinblastine and vin- Ixabepilone is a semisynthetic epothilone B analog, not
cristine, ie, inhibition of mitosis of cells in the M phase through a taxane, that functions as a microtubule inhibitor and binds
inhibition of tubulin polymerization. This agent has activity in directly to β-tubulin subunits on microtubules, leading to
NSCLC, breast cancer, and ovarian cancer. Myelosuppression inhibition of normal microtubule dynamics. As such, it is active
with neutropenia is the dose-limiting toxicity, but other adverse in the M phase of the cell cycle. This agent is presently approved
effects include nausea and vomiting, transient elevations in liver for metastatic breast cancer in combination with the oral fluoro-
function tests, neurotoxicity, and SIADH. pyrimidine capecitabine or as monotherapy. Of note, this agent
continues to have activity in drug-resistant tumors that overexpress
P-glycoprotein or tubulin mutations. The main adverse effects
TAXANES & OTHER ANTI-MICROTUBULE include myelosuppression, hypersensitivity reactions, and neuro-
DRUGS toxicity in the form of peripheral sensory neuropathy.
Eribulin is a synthetic analog of halichondrin B, and it inhibits
Paclitaxel is an alkaloid ester derived from the Pacific yew (Taxus microtubule function, leading to a block in the G2-M phase of the
brevifolia) and the European yew (Taxus baccata). The drug func- cell cycle. This agent appears to be less sensitive to the multidrug
tions as a mitotic spindle poison through high-affinity binding to resistance-mediated P-glycoprotein efflux pump, and one of the
964    SECTION VIII  Chemotherapeutic Drugs
advantages of this agent is that it has activity in drug-resistant
tumors that overexpress P-glycoprotein. It is presently approved
for the treatment of patients with metastatic breast cancer.
EPIPODOPHYLLOTOXINS
Etoposide is a semisynthetic derivative of podophyllotoxin, which
is extracted from the mayapple root (Podophyllum peltatum). Intra-
venous and oral formulations of etoposide are approved for clini-
cal use in the USA. Oral bioavailability is about 50%, requiring
oral dosage to be twice that of intravenous dosage. Up to 30–50%
of an administered dose of drug is excreted in the urine, and dose
reduction is required in patients with renal dysfunction. Etoposide
forms a complex with topoisomerase II, the enzyme responsible
for cutting and religating double stranded DNA, and DNA,
leading to inhibition of the functional activity of topoisomerase
II with inhibition of DNA synthesis and function. Etoposide has
clinical activity in germ cell cancer, small cell and NSCLC, Hodg-
kin’s and non-Hodgkin’s lymphomas, and gastric cancer. Major
toxicities are listed in Table 54–4.
CAMPTOTHECINS
The camptothecins are natural products derived from the Camp-
totheca acuminata tree originally found in China; they inhibit
the activity of topoisomerase I, the key enzyme responsible for
cutting and religating single DNA strands. Inhibition of this
enzyme results in DNA damage. Topotecan and irinotecan are
the two camptothecin analogs used in clinical practice in the
USA. Although they both inhibit the same molecular target, their
spectrum of clinical activity is quite different.
Topotecan is indicated in the treatment of advanced ovarian
cancer as second-line therapy following initial treatment with
platinum-based chemotherapy. It is also approved as second-line
therapy of small cell lung cancer. The main route of elimination is
renal excretion, and dosage must be adjusted in patients with renal
impairment. Irinotecan is a prodrug that is converted mainly in
the liver by the carboxylesterase enzyme to the SN-38 metabolite,
which is 1000-fold more potent as an inhibitor of topoisomerase
I than the parent compound. In contrast to topotecan, irinotecan
and SN-38 are mainly eliminated in bile and feces, and dose
reduction is required in the setting of liver dysfunction. Irinotecan
was originally approved as second-line monotherapy in patients
with metastatic colorectal cancer who had failed fluorouracil-
based therapy. It is now approved as first-line therapy when used
in combination with 5-FU and leucovorin, and this combination
is known as FOLFIRI. Myelosuppression and diarrhea are the two
most common adverse events (Table 54–4). There are two forms
of diarrhea: an early form that occurs within 24 hours after admin-
istration and is thought to be a cholinergic event effectively treated
with atropine, and a late form that usually occurs 2–10 days after
treatment. The late diarrhea can be severe, leading to significant
electrolyte imbalance and dehydration in some cases.
Liposomal irinotecan is approved in combination with 5-FU
and leucovorin for the treatment of metastatic adenocarcinoma of
the pancreas after disease progression following gemcitabine-based
therapy. The main adverse effects associated with the liposomal
formulation are myelosuppression and GI toxicity with diarrhea
and nausea and vomiting. Relatively little is known about the
clinical pharmacology and metabolism of this liposomal formula-
tion of irinotecan.
ANTITUMOR ANTIBIOTICS
Screening of microbial products led to the discovery of a number
of growth-inhibiting compounds that have proved to be clinically
useful in cancer chemotherapy. Many of these antibiotics bind to
DNA through intercalation between specific bases and block the
synthesis of RNA, DNA, or both; cause DNA strand scission; and
interfere with cell replication. All of the anti-cancer antibiotics
now being used in clinical practice are products of various strains
of the soil microbe Streptomyces. These include the anthracyclines,
bleomycin, and mitomycin.
ANTHRACYCLINES
The anthracycline antibiotics, isolated from Streptomyces peucetius
var caesius, are among the most widely used cytotoxic anti-cancer
drugs. The structures of the two original anthracyclines, doxoru-
bicin and daunorubicin, are shown below. Several other anthracy-
cline analogs have entered clinical practice, including idarubicin,
epirubicin, and mitoxantrone. The anthracyclines exert their
cytotoxic action through four major mechanisms: (1) inhibition of
topoisomerase II; (2) generation of semiquinone free radicals and
oxygen free radicals through an iron-dependent, enzyme-mediated
reductive process; (3) high-affinity binding to DNA through
intercalation, with consequent blockade of the synthesis of DNA
and RNA, and DNA strand scission; and (4) binding to cellular
membranes to alter fluidity and ion transport. While the precise
mechanisms by which the anthracyclines exert their cytotoxic
effects remain to be defined in particular tumors, the free radical
mechanism is well-established to be the cause of the cardiotoxicity
associated with the anthracyclines (Table 54–4).
O OH
R
OH
H
CH3 O O OH O
O
CH3
HO
NH2
O O
R: C CH3 R: C CH2OH
Daunorubicin Doxorubicin
Anthracyclines are administered via the intravenous route.
They are metabolized extensively in the liver, with reduction and
hydrolysis of the ring substituents. The hydroxylated metabolite
is an active species, whereas the aglycone is inactive. Up to 50%

of drug is eliminated in the feces via biliary excretion, and dose
reduction is required in patients with liver dysfunction. Although
anthracyclines are usually administered on an every-3-week
schedule, alternative schedules such as low-dose weekly or 72- to
96-hour continuous infusions have been shown to yield equivalent
clinical efficacy with reduced toxicity.
Doxorubicin is one of the most important anti-cancer drugs
in clinical practice, with major clinical activity in cancers of the
breast, endometrium, ovary, testicle, thyroid, stomach, bladder,
liver, and lung; in soft tissue sarcomas; and in several childhood
cancers, including neuroblastoma, Ewing’s sarcoma, osteosarcoma,
and rhabdomyosarcoma. It also has clinical activity in hematologic
malignancies, including acute lymphoblastic leukemia, multiple
myeloma, and Hodgkin’s and non-Hodgkin’s lymphomas. It is
generally used in combination with other anti-cancer agents (eg,
cyclophosphamide, cisplatin, and 5-FU), and clinical activity is
improved with combination regimens as opposed to single-agent
therapy.
Daunorubicin was the first agent in this class to be isolated,
and it is still used in the treatment of acute myeloid leukemia.
In contrast to doxorubicin, its efficacy in solid tumors is limited.
Idarubicin is a semisynthetic anthracycline glycoside analog
of daunorubicin, and it is approved for use in combination with
cytarabine for induction therapy of acute myeloid leukemia.
When combined with cytarabine, idarubicin appears to be more
active than daunorubicin in producing complete remissions and in
improving survival in patients with acute myelogenous leukemia.
Epirubicin is an anthracycline analog whose mechanism of
action and clinical pharmacology are identical to those of all other
anthracyclines. It was initially approved for use as a component
of adjuvant therapy in early-stage, node-positive breast cancer
but is also used in the treatment of metastatic breast cancer and
gastroesophageal cancer.
Mitoxantrone (dihydroxyanthracenedione) is an anthracene
compound whose structure resembles the anthracycline ring.
It binds to DNA to produce strand breakage and inhibits both
DNA and RNA synthesis. It is currently used in the treatment
of advanced, hormone-refractory prostate cancer and low-grade
non-Hodgkin’s lymphoma. It is also indicated in breast cancer and
in pediatric and adult acute myeloid leukemias. Myelosuppression
with leukopenia is the dose-limiting toxicity, and mild nausea and
vomiting, mucositis, and alopecia also occur. Although the drug
is thought to be less cardiotoxic than doxorubicin, both acute and
chronic cardiac toxicities are observed. A blue discoloration of
the fingernails, sclera, and urine is observed 1–2 days after drug
administration.
The main dose-limiting toxicity of all anthracyclines is myelo-
suppression, with neutropenia more commonly observed than
thrombocytopenia. In some cases, mucositis is dose-limiting. Two
forms of cardiotoxicity are observed. The acute form occurs within
the first 2–3 days and presents as arrhythmias and conduction
abnormalities, other electrocardiographic changes, pericarditis,
and myocarditis. This form is usually transient and in most cases
is asymptomatic. The chronic form is a dose-dependent, dilated
cardiomyopathy associated with heart failure. The chronic cardiac
toxicity appears to result from increased production of oxygen free
CHAPTER 54  Cancer Chemotherapy    965
radicals within the myocardium. This effect is rarely seen at total
doxorubicin dosages below 400–450 mg/m2. Use of lower weekly
doses or continuous infusions of doxorubicin appear to reduce the
incidence of cardiac toxicity. In addition, treatment with the iron-
chelating agent dexrazoxane (ICRF-187) is currently approved to
prevent or reduce anthracycline-induced cardiotoxicity in women
with metastatic breast cancer who have received a total cumulative
dose of doxorubicin of 300 mg/m2. The anthracyclines can also
produce a “radiation recall reaction,” with erythema and desqua-
mation of the skin observed at sites of prior radiation therapy.
MITOMYCIN
Mitomycin (mitomycin C) is an antibiotic isolated from Strep-
tomyces caespitosus. It undergoes metabolic activation through an
enzyme-mediated reduction to generate an alkylating agent that
cross-links DNA. Hypoxic tumor stem cells of solid tumors exist
in an environment conducive to reductive reactions and are more
sensitive to the cytotoxic effects of mitomycin than normal cells
and oxygenated tumor cells. This agent is active in all phases of
the cell cycle and is the best available drug for use in combination
with radiation therapy to attack hypoxic tumor cells. Its clinical
use is mainly limited to the treatment of squamous cell cancer of
the anus in combination with 5-FU and radiation therapy. One
special application of mitomycin has been in the intravesical treat-
ment of superficial bladder cancer. Because virtually none of the
agent is absorbed, there is little to no systemic toxicity when used
in this way.
The common adverse events of mitomycin are outlined in
Table 54–4. Hemolytic-uremic syndrome, manifested as microan-
giopathic hemolytic anemia, thrombocytopenia, and renal failure,
as well as occasional instances of interstitial pneumonitis have
been reported.
BLEOMYCIN
Bleomycin is a small peptide that contains a DNA-binding
region and an iron-binding domain at opposite ends of the
molecule. It acts by binding to DNA, which results in single-
and double-strand breaks following free radical formation, and
inhibition of DNA biosynthesis. The fragmentation of DNA
is due to oxidation of a DNA-bleomycin-Fe(II) complex and
leads to chromosomal aberrations. Bleomycin is a cell cycle–
specific drug that causes accumulation of cells in the G2 phase
of the cell cycle.
Bleomycin is indicated for the treatment of Hodgkin’s and
non-Hodgkin’s lymphomas, germ cell tumor, head and neck
cancer, and squamous cell cancer of the skin, cervix, and vulva.
One advantage of this agent is that it can be administered sub-
cutaneously, intramuscularly, or intravenously. Elimination of
bleomycin is mainly via renal excretion, and dose modification is
recommended in patients with renal dysfunction.
Pulmonary toxicity is dose-limiting for bleomycin and usually
presents as pneumonitis with cough, dyspnea, dry inspiratory
crackles on physical examination, and infiltrates on chest x-ray.
966    SECTION VIII  Chemotherapeutic Drugs
The incidence of pulmonary toxicity is increased in patients older
than 70 years of age, in those who receive cumulative doses greater
than 400 units, in those with underlying pulmonary disease, and
in those who have received prior mediastinal or chest irradiation.
In rare cases, pulmonary toxicity can be fatal. Other toxicities are
listed in Table 54–4.
TABLE 54–5  Miscellaneous anti-cancer drugs: Clinical activity and toxicities.
Drug Mechanism of Action1
Bortezomib Inhibitor of the 26S proteosome;
results in down-regulation of the
NF-κB signaling pathway
Carfilzomib Inhibitor of the 26S proteosome;
results in down-regulation of the
NF-κB signaling pathway; maintains
activity in bortezomib-resistant
tumors
Erlotinib Inhibits EGFR tyrosine kinase leading
to inhibition of EGFR signaling
Imatinib Inhibits Bcr-Abl tyrosine kinase and
other receptor tyrosine kinases,
including PDGFR, and c-kit
Bosutinib Inhibits Bcr-Abl tyrosine kinase and
retains activity in imatinib-resistant
Bcr-Abl mutations except for the
T315I and V299L mutations. Inhibits
Src family tyrosine kinases.
Cetuximab Binds to EGFR and inhibits down-
stream EGFR signaling; enhances
response to chemotherapy and
radiotherapy
Panitumumab Binds to EGFR and inhibits down-
stream EGFR signaling; enhances
response to chemotherapy and
radiotherapy
Bevacizumab Inhibits binding of VEGF-A to VEGFR
leading to inhibition of VEGF signal-
ing; inhibits tumor vascular perme-
ability; enhances tumor blood flow
and drug delivery
Ziv-aflibercept Inhibits binding of VEGF-A, VEGF-B,
and PlGF to VEGFR leading to inhibi-
tion of VEGF signaling; inhibits tumor
vascular permeability; enhances
tumor blood flow and drug delivery
Sorafenib Inhibits multiple RTKs, including
raf kinase, VEGF-R2, VEGF-R3, and
PDGFR-β leading to inhibition
of angiogenesis, invasion, and
metastasis
Sunitinib, Inhibits multiple RTKs, includ-
pazopanib ing VEGF-R1, VEGF-R2, VEGF-R3,
PDGFR-α and PDGFR-β leading to
inhibition of angiogenesis, invasion,
and metastasis
1
See text for acronyms.
MISCELLANEOUS ANTI-CANCER
DRUGS
A large number of anti-cancer drugs that do not fit traditional
categories have been approved for clinical use; they are listed in
Table 54–5.
Clinical Applications1 Acute Toxicity Delayed Toxicity
Multiple myeloma, Nausea and Peripheral sensory neuropathy, diarrhea,
mantle cell lymphoma vomiting, fever orthostatic hypotension, fever, pulmonary
toxicity, reversible posterior leukoenceph-
alopathy (RPLS), congestive heart failure
(CHF), rare cases of QT prolongation
Multiple myeloma Fever Fatigue, cardiac toxicity with CHF and
myocardial infarction, myelosuppression,
pulmonary toxicity, hepatotoxicity, ortho-
static hypotension
Non-small cell lung can- Diarrhea Skin rash, diarrhea, anorexia, interstitial
cer, pancreatic cancer lung disease
CML, gastrointestinal Nausea and Fluid retention with ankle and periorbital
stromal tumor (GIST), vomiting edema, diarrhea, myalgias, congestive
Philadelphia chromo- heart failure
some-positive ALL
CML Nausea and Diarrhea, fluid retention, myelosuppres-
vomiting sion, skin rash hepatotoxicity
Colorectal cancer, head Infusion Skin rash, hypomagnesemia, fatigue,
and neck cancer (used in reaction interstitial lung disease
combination with radio-
therapy), non-small cell
lung cancer
Colorectal cancer Infusion Skin rash, hypomagnesemia, fatigue,
reaction interstitial lung disease
(rarely)
Colorectal cancer, breast Hyperten- Arterial thromboembolic events, gastro-
cancer, non-small cell sion, infusion intestinal perforations, wound healing
lung cancer, renal cell reaction complications, bleeding complications,
cancer, glioblastoma proteinuria
multiformae
Colorectal cancer Hypertension Arterial thromboembolic events, gastro-
intestinal perforations, wound healing
complications, bleeding complications,
diarrhea, mucositis, proteinuria
Renal cell cancer, hepa- Nausea, Skin rash, fatigue and asthenia, bleeding
tocellular cancer hypertension complications, hypophosphatemia
Renal cell cancer, GIST Hypertension Skin rash, fatigue and asthenia, bleeding
complications, cardiac toxicity leading to
congestive heart failure in rare cases

IMATINIB & OTHER TYROSINE KINASE
INHIBITORS (TKIs)
Imatinib is an inhibitor of the tyrosine kinase domain of the
Bcr-Abl oncoprotein and prevents phosphorylation of the kinase
substrate by ATP. It is indicated for the treatment of chronic
myelogenous leukemia (CML), a pluripotent hematopoietic stem
cell disorder characterized by the t(9:22) Philadelphia chromo-
somal translocation. This translocation results in the Bcr-Abl
fusion protein, the causative agent in CML, and is present in up
to 95% of patients with this disease. This agent also inhibits other
receptor tyrosine kinases for platelet-derived growth factor recep-
tor (PDGFR), and c-kit.
Imatinib is well absorbed orally, and it is metabolized in the
liver, with elimination of metabolites occurring mainly in feces
via biliary excretion. This agent is approved for use as first-line
therapy in chronic phase CML, in blast crisis, and as second-line
therapy for chronic phase CML that has progressed on prior
IFN-α therapy. Imatinib is also effective in the treatment of gas-
trointestinal stromal tumors (GIST) expressing the c-kit tyrosine
kinase. The main adverse effects are listed in Table 54–5.
Dasatinib is an oral inhibitor of several tyrosine kinases,
including Bcr-Abl, Src, c-kit, and PDGFR-α. It differs from
imatinib in that it binds to the active and inactive conforma-
tions of the Abl kinase domain and overcomes imatinib resistance
resulting from mutations in the Bcr-Abl kinase. It is approved for
use in CML and Philadelphia chromosome-positive (Ph+) acute
lymphoblastic leukemia (ALL) with resistance or intolerance to
imatinib therapy.
Nilotinib is a second-generation phenylamino-pyrimidine mol-
ecule that inhibits Bcr-Abl, c-kit, and PDGFR-β tyrosine kinases.
It has a higher binding affinity (up to 20- to 50-fold) for the Abl
kinase when compared with imatinib, and it overcomes imatinib
resistance resulting from Bcr-Abl mutations. It was originally
approved for chronic phase and accelerated phase CML with resis-
tance or intolerance to prior therapy that included imatinib and
was recently approved as first-line therapy of chronic phase CML.
Bosutinib is a potent inhibitor of the Bcr-Abl tyrosine kinase,
and it retains activity in 16 of 18 imatinib-resistant Bcr-Abl muta-
tions. However, it is not effective against T315I and V299L muta-
tions, which reside within the ATP-binding domain of the Abl
tyrosine kinase. It is currently approved for the treatment of adult
patients with chronic, accelerated, or blast phase Ph chromosome–
positive CML with resistance or intolerance to prior therapy.
Ponatinib is a potent inhibitor of the Bcr-Abl tyrosine kinase,
and it inhibits all known mutant forms of BCR-ABL, includ-
ing the gatekeeper mutation T315I. It inhibits other kinases,
including members of VEGF-R, PDGF, FGF, Flt3, TIE-2, Src
family kinases, Kit, TET, and EPH. This agent is currently FDA-
approved for adult patients with chronic, accelerated, or blast
phase CML that is resistant or intolerant to prior TKI therapy
and also approved for Ph+ ALL that is resistant or intolerant to
prior TKI therapy.
Imatinib and the other TKIs are metabolized in the liver,
mainly by the CYP3A4 liver microsomal enzymes and then
CHAPTER 54  Cancer Chemotherapy    967
eliminated in feces via the hepatobiliary route. It is also important
to review the patient’s current list of prescription and nonpre-
scription drugs because these agents have potential drug-drug
interactions, especially with those that are also metabolized by
the CYP3A4 system. In addition, patients should avoid grapefruit
products, starfruit, and pomelos, as they may inhibit the metabo-
lism of these small molecule inhibitors, leading to increased drug
levels and toxicity (see Chapter 4).
GROWTH FACTOR RECEPTOR
INHIBITORS
Cetuximab, Panitumumab,
& Necitumumab
The epidermal growth factor receptor (EGFR) is a member of the
erb-B family of growth factor receptors, and it is overexpressed
in a number of solid tumors, including colorectal cancer, head
and neck cancer, NSCLC, and pancreatic cancer. Activation of
the EGFR signaling pathway results in downstream activation of
several key cellular events involved in cellular growth and prolif-
eration, invasion and metastasis, and angiogenesis. In addition,
this pathway inhibits the cytotoxic activity of various anti-cancer
agents and radiation therapy, presumably through suppression of
key apoptotic mechanisms, thereby leading to the development of
cellular drug resistance.
Cetuximab is a chimeric monoclonal antibody directed against
the extracellular domain of the EGFR, and it is presently approved
for use in combination with irinotecan for metastatic colon cancer
in the refractory setting or as monotherapy in patients who are
deemed to be irinotecan-refractory. Because cetuximab is of the
G1 isotype, its antitumor activity may also be mediated, in part, by
immunologic-mediated mechanisms. There is growing evidence
that cetuximab can be effectively and safely combined with irino-
tecan- and oxaliplatin-based chemotherapy in the first-line treat-
ment of metastatic colorectal cancer as well. Of note, the efficacy
of cetuximab is restricted to only those patients whose tumors
express the wild-type RAS gene, which includes both KRAS and
NRAS. Combination regimens of cetuximab with cytotoxic che-
motherapy may be of particular benefit in the neoadjuvant therapy
of patients with liver-limited disease. Although this antibody was
initially approved to be administered on a weekly schedule, phar-
macokinetic studies have shown that an every-2-week schedule
provides the same level of clinical activity as the weekly schedule.
This agent is also approved for use in combination with radiation
therapy in patients with locally advanced head and neck cancer.
Cetuximab is well tolerated, with the main adverse effects being
an acneiform skin rash, hypersensitivity infusion reaction, and
hypomagnesemia. However, when cetuximab is combined with
radiation therapy for head and neck cancer, there is a very low but
real increased risk (1%) of sudden death, which has resulted in a
black-box warning for the drug.
Panitumumab is a fully human monoclonal antibody directed
against the EGFR and works through inhibition of the EGFR
signaling pathway. In contrast to cetuximab, this antibody is
968    SECTION VIII  Chemotherapeutic Drugs
of the G2 isotype and, as such, would not be expected to exert
any immunologic-mediated effects. Panitumumab was originally
approved for patients with refractory metastatic CRC who have
been treated with all other active agents. However, it is now also
approved for use in combination with FOLFOX chemotherapy in
the front-line treatment of metastatic CRC. As with cetuximab,
this antibody is only effective in patients whose tumors express
wild-type RAS. Recent clinical studies have shown that this anti-
body can also be effectively and safely combined with irinotecan-
based chemotherapy in the second-line treatment of metastatic
CRC. Acneiform skin rash and hypomagnesemia are the two main
adverse effects associated with its use. Despite being a fully human
antibody, infusion-related reactions can still be observed, although
much less commonly than cetuximab.
Necitumumab is a fully human IgG1 monoclonal antibody
directed against EGFR. Like cetuximab and panitumumab,
it works through inhibition of the EGFR signaling pathway.
However, as with cetuximab, necitumumab is of the G1 isotype,
and as such, its antitumor activity may also be mediated, at least
in part, through immunologically mediated mechanisms. It is
approved for use in combination with gemcitabine and cisplatin
chemotherapy for the treatment of squamous NSCLC. The main
adverse effects are what have been previously described for other
anti-EGFR antibodies, and both venothrombolic and arterioem-
bolic events have also been described.
Erlotinib
Erlotinib is a small molecule inhibitor of the tyrosine kinase
domain associated with the EGFR. It is now approved as first-
line treatment of metastatic NSCLC in patients whose tumors
have EGFR exon 19 deletions or exon 21 (L858R) mutations
and are refractory to at least one prior chemotherapy regimen. It
is also approved for maintenance therapy of patients with meta-
static NSCLC whose disease has not progressed after four cycles
of platinum-based chemotherapy. Patients who are nonsmokers
and who have a bronchoalveolar histologic subtype appear to be
more responsive to these agents. In addition, erlotinib has been
approved for use in combination with gemcitabine for the treat-
ment of advanced pancreatic cancer. It is metabolized in the liver
by the CYP3A4 enzyme system, and elimination is mainly hepatic
with excretion in feces. Caution must be taken when using these
agents with drugs that also are metabolized by the liver CYP3A4
system, such as phenytoin and warfarin, and the use of grapefruit
products should be avoided. An acneiform skin rash, diarrhea,
and anorexia and fatigue are the most common adverse effects
observed with these small molecules (Table 54–5).
Afatinib is a small molecule inhibitor of the tyrosine kinase
domains associated with EGFR, HER2 and HER4, and causes
inhibition of downstream ErbB signaling. It is approved for the
first-line treatment of metastatic NSCLC with EGFR exon 19
deletions or exon 21 substitution mutations. The toxicities associ-
ated with this agent are similar to those seen with erlotinib.
Osimertinib is a small molecule inhibitor approved in 2015
for the treatment of metastatic EGFR T790M mutant NSCLC
following progression on or after EGFR tyrosine kinase inhibitor
therapy. In addition to targeting the T790M mutant, this agent
targets the L858R and exon 19 EGFR mutations. The adverse
effect profile is similar to erlotinib and afatinib, but unique cardiac
toxicities are associated with this agent, including QTc prolonga-
tion and cardiomyopathy.
Bevacizumab, Ziv-Aflibercept,
Ramucirumab, Sorafenib, Sunitinib,
& Pazopanib
Vascular endothelial growth factor (VEGF) is one of the most
important angiogenic growth factors. The growth of both primary
and metastatic solid tumors requires an intact vasculature; thus the
VEGF signaling pathway represents an attractive target for chemo-
therapy. Several approaches have been taken to inhibit VEGF signal-
ing; they include inhibition of VEGF interactions with its receptor
by targeting either the VEGF ligand with antibodies or soluble
chimeric decoy receptors, or by direct inhibition of VEGF recep-
tor–associated tyrosine kinase activity by small molecule inhibitors.
Bevacizumab is a recombinant humanized monoclonal anti-
body that targets all forms of VEGF-A. This antibody binds to
and prevents VEGF-A from interacting with the target VEGF
receptors. Bevacizumab can be safely and effectively combined
with 5-FU-, irinotecan-, and oxaliplatin-based chemotherapy
in the treatment of metastatic colorectal cancer. Bevacizumab is
FDA approved as a first-line treatment for metastatic colorectal
cancer in combination with any intravenous fluoropyrimidine-
containing regimen and is now also approved in combination
with chemotherapy for metastatic NSCLC and breast cancer. One
potential advantage of this antibody is that it does not appear to
exacerbate the toxicities typically observed with cytotoxic chemo-
therapy. The main safety concerns associated with bevacizumab
include hypertension, an increased incidence of arterial throm-
boembolic events (transient ischemic attack, stroke, angina, and
myocardial infarction), wound healing complications, gastrointes-
tinal perforations, and proteinuria.
Ziv-aflibercept is a recombinant fusion protein made up of
portions of the extracellular domains of human VEGF receptors
(VEGFR) 1 and 2 fused to the Fc portion of the human IgG1
molecule. This molecule serves as a soluble receptor to VEGF-
A, VEGF-B, and placental growth factor (PlGF), and it binds
with significantly higher affinity to VEGF-A than bevacizumab.
Presumably, binding of the VEGF ligands prevents their subse-
quent interactions with the target VEGF receptors, which then
results in inhibition of downstream VEGFR signaling. This agent
is FDA-approved in combination with the FOLFIRI regimen
for patients with metastatic colorectal cancer that has progressed
on oxaliplatin-based chemotherapy. The main adverse effects are
similar to what has been observed with bevacizumab.
Ramucirumab is an IgG1 antibody that targets the VEGF-
R2 receptor. This agent inhibits binding of the VEGF ligands,
VEGF-A, VEGF-C, and VEGF-D, to the target VEGF-R2
receptor, which then results in inhibition of downstream VEGFR
signaling. This agent is now FDA-approved for advanced gas-
tric or gastroesophageal junction adenocarcinoma, metastatic
NSCLC, and metastatic CRC. The main adverse events are similar to
those observed with bevacizumab and other anti-VEGF inhibitors.

Sorafenib is a small molecule that inhibits multiple receptor
tyrosine kinases (RTKs), especially VEGF-R2 and VEGF-R3,
platelet-derived growth factor-β (PDGFR-β), and raf kinase. It
was initially approved for advanced renal cell cancer and is also
approved for advanced hepatocellular cancer.
Sunitinib is similar to sorafenib in that it inhibits multiple
RTKs, although the specific types are somewhat different. They
include PDGFR-α and PDGFR-β, VEGF-R1, VEGF-R2, VEGF-
R3, and c-kit. It is approved for the treatment of advanced renal
cell cancer and for the treatment of gastrointestinal stromal tumors
after disease progression on or with intolerance to imatinib.
Pazopanib is a small molecule that inhibits multiple RTKs,
especially VEGF-R2 and VEGF-R3, PDGFR-β, and raf kinase. This
oral agent is approved for the treatment of advanced renal cell cancer.
Sorafenib, sunitinib, and pazopanib are metabolized in the liver
by the CYP3A4 system, and elimination is primarily hepatic with
excretion in feces. Therefore, each of these agents has potential
interactions with drugs that are also metabolized by the CYP3A4
system, especially warfarin. In addition, patients should avoid
grapefruit products, starfruit, pomelos, and St. John’s Wort, as they
may alter the metabolism of these agents. Hypertension, bleeding
complications, and fatigue are the most common adverse effects
seen with these drugs. With respect to sorafenib, skin rash and the
hand-foot syndrome are observed in up to 30–50% of patients.
For sunitinib, there is also an increased risk of cardiac dysfunction,
which in some cases can lead to congestive heart failure.
■■ CLINICAL PHARMACOLOGY OF
CANCER CHEMOTHERAPEUTIC
DRUGS
The use of specific cytotoxic and biologic agents for each of the
main cancers is discussed in the following sections.
THE LEUKEMIAS
ACUTE LEUKEMIA
Childhood Leukemia
Acute lymphoblastic leukemia (ALL) is the main form of leuke-
mia in childhood, and it is the most common form of cancer in
children. Children with this disease now have a relatively good
prognosis. A subset of patients with neoplastic lymphocytes
expressing surface antigenic features of T lymphocytes has a poor
prognosis (see Chapter 55). A cytoplasmic enzyme expressed by
normal thymocytes, terminal deoxycytidyl transferase (terminal
transferase), is also expressed in many cases of ALL. T-cell ALL
also expresses high levels of the enzyme adenosine deaminase
(ADA). This led to interest in the use of the ADA inhibitor
pentostatin (deoxycoformycin) for treatment of such T-cell cases.
Until 1948, the median length of survival in ALL was 3 months.
With the advent of methotrexate, the length of survival was greatly
increased. Subsequently, corticosteroids, 6-mercaptopurine, cyclo-
phosphamide, vincristine, daunorubicin, and asparaginase all
CHAPTER 54  Cancer Chemotherapy    969
have been found to be active against this disease. A combination
of vincristine and prednisone plus other agents is currently used
to induce remission. More than 90% of children enter complete
remission with this therapy with only minimal toxicity. However,
circulating leukemic cells often migrate to sanctuary sites located
in the brain and testes. The value of prophylactic intrathecal
methotrexate therapy for prevention of central nervous system
leukemia (a major mechanism of relapse) has been clearly demon-
strated. Intrathecal therapy with methotrexate should therefore be
considered as a standard component of the induction regimen for
children with ALL.
Adult Leukemia
Acute myelogenous leukemia (AML) is the most common leuke-
mia in adults. The single most active agent for AML is cytarabine;
however, it is best used in combination with an anthracycline,
which leads to complete remissions in about 70% of patients.
While there are several anthracyclines that can be effectively com-
bined with cytarabine, idarubicin is preferred.
Patients often require intensive supportive care during the
period of induction chemotherapy. Such care includes plate-
let transfusions to prevent bleeding, the granulocyte colony-
stimulating factor filgrastim to shorten periods of neutropenia,
and antibiotics to combat infections. Younger patients (eg, age
< 55) who are in complete remission and have an HLA-matched
donor are candidates for allogeneic bone marrow transplan-
tation. The transplant procedure is preceded by high-dose
chemotherapy and total body irradiation followed by immuno-
suppression. This approach may cure up to 35–40% of eligible
patients. Patients over age 60 respond less well to chemotherapy,
primarily because their tolerance for aggressive therapy and resis-
tance to infection are lower.
Once remission of AML is achieved, consolidation chemother-
apy is required to maintain a durable remission and to induce cure.
CHRONIC MYELOGENOUS LEUKEMIA
Chronic myelogenous leukemia (CML) arises from a chromo-
somally abnormal hematopoietic stem cell in which a balanced
translocation between the long arms of chromosomes 9 and 22,
t(9:22), is observed in 90–95% of cases. This translocation results
in constitutive expression of the Bcr-Abl fusion oncoprotein with
a molecular weight of 210 kDa. The clinical symptoms and course
are related to the white blood cell count and its rate of increase.
Most patients with white cell counts greater than 50,000/μL
should be treated. The goals of treatment are to reduce the granu-
locytes to normal levels, to raise the hemoglobin concentration
to normal, and to relieve disease-related symptoms. The tyrosine
kinase inhibitor imatinib is considered as standard first-line
therapy in previously untreated patients with chronic phase CML.
Nearly all patients treated with imatinib exhibit a complete hema-
tologic response, and up to 40–50% of patients show a complete
cytogenetic response. As described previously, this drug is gener-
ally well tolerated and is associated with relatively minor adverse
effects. Initially, dasatinib and nilotinib were approved for patients
970    SECTION VIII  Chemotherapeutic Drugs
who were intolerant or resistant to imatinib; each shows clinical
activity, and both are now also indicated as first-line treatment of
chronic phase CML. In addition to these tyrosine kinase inhibi-
tors, other treatment options include IFN-α, busulfan, other oral
alkylating agents, and hydroxyurea.
CHRONIC LYMPHOCYTIC LEUKEMIA
Patients with early-stage chronic lymphocytic leukemia (CLL)
have a relatively good prognosis, and therapy has not changed
the course of the disease. However, in the setting of high-risk
disease or in the presence of disease-related symptoms, treatment
is indicated.
Chlorambucil and cyclophosphamide are the two most widely
used alkylating agents for this disease. Chlorambucil is frequently
combined with prednisone, although there is no clear evidence
that the combination yields better response rates or survival com-
pared with chlorambucil alone. In most cases, cyclophosphamide
is combined with vincristine and prednisone (COP), or it can also
be given with these same drugs along with doxorubicin (CHOP).
Bendamustine is the newest alkylating agent to be approved for use
in this disease, either as monotherapy or in combination with pred-
nisone. The purine nucleoside analog fludarabine also is effective in
treating CLL. This agent can be given alone, in combination with
cyclophosphamide and with mitoxantrone and dexamethasone, or
combined with rituximab. Monoclonal antibody targeted therapies
are being widely used in CLL, especially in relapsed or refractory
disease. Rituximab is an anti-CD20 antibody that has documented
clinical activity in this setting. This chimeric antibody appears to
enhance the antitumor effects of cytotoxic chemotherapy and is also
effective in settings in which resistance to chemotherapy has devel-
oped. Ofatumumab is a fully human IgG1 antibody that binds
to a different CD20 epitope than rituximab. Of note, it maintains
activity in rituximab-resistant tumors, and it is presently approved
for CLL that is refractory to fludarabine and alemtuzumab therapy.
HODGKIN’S & NON-HODGKIN’S
LYMPHOMAS
HODGKIN’S LYMPHOMA
The treatment of Hodgkin’s lymphoma has undergone dra-
matic evolution over the last 40 years. This lymphoma is now
widely recognized as a B-cell neoplasm in which the malignant
Reed-Sternberg cells have rearranged VH genes. In addition, the
Epstein-Barr virus genome has been identified in up to 80% of
tumor specimens.
Complete staging evaluation is required before a definitive
treatment plan can be made. For patients with stage I and stage
IIA disease, there has been a significant change in the treatment
approach. Initially, these patients were treated with extended-
field radiation therapy. However, given the well-documented late
effects of radiation therapy, which include hypothyroidism, an
increased risk of secondary cancers, and coronary artery disease,
combined-modality therapy with a brief course of combination
chemotherapy and involved field radiation therapy is now the
recommended approach. The main advance for patients with
advanced stage III and IV Hodgkin’s lymphoma came with the
development of MOPP (mechlorethamine, vincristine, procarba-
zine, and prednisone) chemotherapy in the 1960s. This regimen
resulted initially in high complete response rates, on the order of
80–90%, with cures in up to 60% of patients. More recently, the
anthracycline-containing regimen termed ABVD (doxorubicin,
bleomycin, vinblastine, and dacarbazine) has been shown to be
more effective and less toxic than MOPP, especially with regard
to the incidence of infertility and secondary malignancies. In
general, four cycles of ABVD are given to patients. An alternative
regimen, termed Stanford V, utilizes a 12-week course of combina-
tion chemotherapy (doxorubicin, vinblastine, mechlorethamine,
vincristine, bleomycin, etoposide, and prednisone), followed by
involved radiation therapy.
With all of these regimens, over 80% of previously untreated
patients with advanced Hodgkin’s lymphoma (stages III and IV)
are expected to go into complete remission, with disappearance
of all disease-related symptoms and objective evidence of disease.
In general, approximately 50–60% of all patients with Hodgkin’s
lymphoma are cured of their disease.
NON-HODGKIN’S LYMPHOMA
Non-Hodgkin’s lymphoma is a heterogeneous disease, and the
clinical characteristics of non-Hodgkin’s lymphoma subsets are
related to the underlying histopathologic features and the extent
of disease involvement. In general, the nodular (or follicular)
lymphomas have a far better prognosis, with a median survival up
to 7 years, compared with the diffuse lymphomas, which have a
median survival of about 1–2 years.
Combination chemotherapy is the treatment standard for
patients with diffuse non-Hodgkin’s lymphoma. The anthracy-
cline-containing regimen CHOP (cyclophosphamide, doxoru-
bicin, vincristine, and prednisone) has been considered the best
treatment in terms of initial therapy. Randomized phase III clini-
cal studies now have shown that the combination of CHOP with
rituximab results in improved response rates, disease-free survival,
and overall survival compared with CHOP chemotherapy alone.
The nodular follicular lymphomas are low-grade, relatively
slow-growing tumors that tend to present in an advanced stage
and are usually confined to lymph nodes, bone marrow, and
spleen. This form of non-Hodgkin’s lymphoma, when presenting
at an advanced stage, is considered incurable, and treatment is
generally palliative. To date, there is no evidence that immediate
treatment with combination chemotherapy offers clinical benefit
over close observation and “watchful waiting” with initiation of
chemotherapy at the onset of disease symptoms.
MULTIPLE MYELOMA
This plasma cell malignancy is one of the models of neoplastic
disease in humans, as it arises from a single tumor stem cell.
Moreover, the tumor cells produce a marker protein (myeloma

immunoglobulin) that allows the total body burden of tumor cells
to be quantified. Multiple myeloma principally involves the bone
marrow and bone, causing bone pain, lytic lesions, bone fractures,
and anemia as well as an increased susceptibility to infection.
Most patients with multiple myeloma are symptomatic at the
time of initial diagnosis and require treatment with cytotoxic
chemotherapy. Treatment with the combination of the alkylating
agent melphalan and prednisone (MP protocol) has been a stan-
dard regimen for nearly 30 years. About 40% of patients respond
to the MP combination, and the median duration of remission is
2–2.5 years.
In patients who are considered candidates for high-dose ther-
apy with stem cell transplantation, melphalan and other alkylating
agents are to be avoided, as they can affect the success of stem cell
harvesting.
Thalidomide is a well-established agent for treating refractory or
relapsed disease, and about 30% of patients will achieve a response
to this therapy. More recently, thalidomide has been used in com-
bination with dexamethasone, and response rates approaching 65%
have been observed. Studies are now under way to directly compare
the combination of vincristine, doxorubicin, and dexamethasone
(VAD protocol) with the combination of thalidomide and dexa-
methasone. In some patients, especially those with poor perfor-
mance status, single-agent pulse dexamethasone administered on a
weekly basis can be effective in palliating symptoms. Lenalidomide
and pomalidomide are two immunomodulatory analogs (IMiDs)
of thalidomide. Lenalidomide is approved in combination with
dexamethasone for multiple myeloma patients who have received at
least one prior therapy, and clinical data show that this combination
is effective as first-line therapy. Pomalidomide is the most recent
IMiD to receive approval, and this drug may be able to overcome
resistance to thalidomide and lenalidomide. The side-effect profiles
of these IMiDs appear to be similar, although neurotoxicity is
observed more commonly with thalidomide, somewhat less often
with pomalidomide, and rarely with lenalidomide.
Bortezomib was first approved for use in relapsing or refractory
multiple myeloma and is now widely used as first-line therapy. This
agent is thought to exert its main cytotoxic effects through inhibition
of the 26S proteosome, resulting in downregulation of the nuclear
factor kappa B (NF-κB) signaling pathway, which is thought to be
a major signaling pathway for this disease. Of note, inhibition of
NF-κB has also been shown to restore chemosensitivity. One poten-
tial advantage of bortezomib is that it can be administered by the
intravenous or subcutaneous route. Carfilzomib is an epoxyketone
26S proteosome inhibitor that is approved for patients with multi-
ple myeloma who have received at least two prior therapies, includ-
ing bortezomib and an immunomodulatory agent. This agent is
important as it is able to overcome resistance to bortezomib, and
preclinical and clinical studies suggest that it has broad-spectrum
activity in hematologic malignancies and solid tumors. Ixazomib
is the newest proteosome inhibitor to be approved in multiple
myeloma, and in contrast to the other proteosome inhibitors, it
is orally administered with good oral bioavailability. This agent
can cause peripheral sensory neuropathy, but it is also associated
with GI toxicity in the form of diarrhea and nausea and vomiting,
thrombocytopenia, and hepatotoxicity.
CHAPTER 54  Cancer Chemotherapy    971
BREAST CANCER
STAGE I & STAGE II DISEASE
The management of primary breast cancer has undergone a
remarkable evolution as a result of major efforts at early diagnosis
(through encouragement of self-examination as well as through
the use of cancer detection centers) and the implementation of
combined modality approaches incorporating systemic chemo-
therapy as an adjuvant to surgery and radiation therapy. Women
with stage I disease (small primary tumors and negative axillary
lymph node dissections) are currently treated with surgery alone,
and they have an 80% chance of cure.
Women with node-positive disease have a high risk of both
local and systemic recurrence. Thus, lymph node status directly
indicates the risk of occult distant micrometastasis. In this situa-
tion, postoperative use of systemic adjuvant chemotherapy with
six cycles of cyclophosphamide, methotrexate, and fluorouracil
(CMF protocol) or of fluorouracil, doxorubicin, and cyclo-
phosphamide (FAC) has been shown to significantly reduce
the relapse rate and prolong survival. Alternative regimens with
equivalent clinical benefit include four cycles of doxorubicin
and cyclophosphamide and six cycles of fluorouracil, epirubicin,
and cyclophosphamide (FEC). Each of these chemotherapy
regimens has benefited women with stage II breast cancer with
one to three involved lymph nodes. Women with four or more
involved nodes have had limited benefit thus far from adjuvant
chemotherapy. Long-term analysis has clearly shown improved
survival rates in node-positive premenopausal women who have
been treated aggressively with multiagent combination chemo-
therapy. The results from three randomized clinical trials clearly
show that the addition of trastuzumab, a monoclonal antibody
directed against the HER-2/neu receptor, to anthracycline- and
taxane-containing adjuvant chemotherapy benefits women with
HER-2-overexpressing breast cancer with respect to disease-free
and overall survival.
Breast cancer was the first neoplasm shown to be responsive
to hormonal manipulation. Tamoxifen is beneficial in postmeno-
pausal women when used alone or in combination with cytotoxic
chemotherapy. The present recommendation is to administer
tamoxifen for 5 years of continuous therapy after surgical resec-
tion. Longer durations of tamoxifen therapy do not appear to offer
additional clinical benefit. Postmenopausal women who complete
5 years of tamoxifen therapy should be placed on an aromatase
inhibitor such as anastrozole for at least 2.5 years, although the
optimal duration is unknown. In women who have completed
2–3 years of tamoxifen therapy, treatment with an aromatase
inhibitor for a total of 5 years of hormonal therapy is now recom-
mended (see Chapter 40).
Results from several randomized trials for breast cancer
have established that adjuvant chemotherapy for premenopausal
women and adjuvant tamoxifen for postmenopausal women are
of benefit to women with stage I (node-negative) breast cancer.
While this group of patients has the lowest overall risk of recur-
rence after surgery alone (about 35–50% over 15 years), this risk
can be further reduced with adjuvant therapy.
972    SECTION VIII  Chemotherapeutic Drugs
STAGE III & STAGE IV DISEASE
The approach to women with advanced breast cancer remains a
major challenge, as current treatment options are only palliative.
Combination chemotherapy, endocrine therapy, or a combina-
tion of both results in overall response rates of 40–50%, but
only a 10–20% complete response rate. Breast cancers expressing
estrogen receptors (ER) or progesterone receptors (PR) retain the
intrinsic hormonal sensitivities of the normal breast—including
the growth-stimulatory response to ovarian, adrenal, and pituitary
hormones. Patients who show improvement with hormonal abla-
tive procedures also respond to the addition of tamoxifen. The
aromatase inhibitors anastrozole and letrozole are now approved
as first-line therapy in women with advanced breast cancer whose
tumors are hormone receptor–positive. In addition, these agents
and exemestane are approved as second-line therapy following
treatment with tamoxifen.
Patients with significant involvement of the lung, liver, or brain
and those with rapidly progressive disease rarely benefit from hor-
monal maneuvers, and initial systemic chemotherapy is indicated
in such cases. For the 25–30% of breast cancer patients whose
tumors express the HER-2/neu cell surface receptor, trastuzumab,
is available for therapeutic use alone or in combination with
cytotoxic chemotherapy. Other agents that target HER-2/neu
signaling include pertuzumab, ado-trastuzumab emtansine, and
the small molecule lapatinib. Pertuzumab is a humanized IgG1
antibody that targets a different epitope on the HER-2/neu recep-
tor than trastuzumab, and this antibody inhibits heterodimeriza-
tion of HER2 with other HER family members, including EGFR,
HER3, and HER4. This drug is used in combination with trastu-
zumab and docetaxel for HER2-positive metastatic breast cancer
in patients who have not previously received anti-HER chemo-
therapy for metastatic disease. Ado-trastuzumab emtansine is an
antibody-drug conjugate composed of trastuzumab and the small
molecule microtubule inhibitor DM1; it is approved for women
with HER2-positive metastatic breast cancer who have received
prior therapy with trastuzumab and taxane-based chemotherapy.
Finally, lapatinib is a small molecule inhibitor of the tyrosine
kinases associated with EGFR (ErbB1) and HER2 (ErbB2),
resulting in inhibition of downstream signaling. This agent is
used in combination with the oral fluoropyrimidine capecitabine
for metastatic breast cancer whose tumors overexpress HER2 and
who have received prior therapy with an anthracycline, a taxane,
and trastuzumab.
About 50–60% of patients with metastatic disease respond to
initial chemotherapy. A broad range of anti-cancer agents have
activity in this disease, including the anthracyclines (doxorubicin,
mitoxantrone, and epirubicin) and the taxanes (docetaxel, pacli-
taxel, and albumin-bound paclitaxel), along with the microtubule
inhibitor ixabepilone, navelbine, capecitabine, gemcitabine, cyclo-
phosphamide, methotrexate, and cisplatin. The anthracyclines
and the taxanes are two of the most active classes of cytotoxic
drugs. Combination chemotherapy has been found to induce
higher and more durable remissions in up to 50–80% of patients,
and anthracycline-containing regimens are now considered the
standard of care in first-line therapy. With most combination
regimens, partial remissions have a median duration of about
10 months and complete remissions have a duration of about
15 months. Unfortunately, only 10–20% of patients achieve
complete remissions with any of these regimens, and as noted,
complete remissions are usually not long-lasting.
PROSTATE CANCER
Prostate cancer was the second cancer shown to be responsive to
hormonal manipulation. The treatment of choice for patients with
metastatic prostate cancer is elimination of testosterone production
by the testes through either surgical or chemical castration. Bilateral
orchiectomy or estrogen therapy in the form of diethylstilbestrol
was previously used as first-line therapy. Presently, the use of lutein-
izing hormone-releasing hormone (LHRH) agonists—including
leuprolide and goserelin agonists, alone or in combination with
an antiandrogen (eg, flutamide, bicalutamide, or nilutamide)—
is the preferred approach (see Chapter 40). There appears to be
no survival advantage of total androgen blockade using a com-
bination of LHRH agonist and antiandrogen agent compared
with single-agent therapy. Abiraterone, an inhibitor of steroid
synthesis (see Chapter 39), has recently been approved. Hormonal
treatment reduces symptoms—especially bone pain—in 70–80%
of patients and may cause a significant reduction in the prostate-
specific antigen (PSA) level, which is now widely accepted as a
surrogate marker for response to treatment in prostate cancer.
Although initial hormonal manipulation is able to control symp-
toms for up to 2 years, patients usually develop progressive disease.
Second-line hormonal therapies include aminoglutethimide plus
hydrocortisone, the antifungal agent ketoconazole plus hydrocor-
tisone, or hydrocortisone alone.
Unfortunately, nearly all patients with advanced prostate
cancer eventually become refractory to hormone therapy. A regi-
men of mitoxantrone and prednisone is approved in patients with
hormone-refractory prostate cancer because it provides effective
palliation in those who experience significant bone pain. Estra-
mustine is an antimicrotubule agent that produces an almost
20% response rate as a single agent. However, when used in
combination with either etoposide or a taxane such as docetaxel or
paclitaxel, response rates are more than doubled to 40–50%. The
combination of docetaxel and prednisone was recently shown to
confer survival advantage when compared with the mitoxantrone-
prednisone regimen, and this combination has now become the
standard of care for hormone-refractory prostate cancer.
GASTROINTESTINAL CANCERS
Colorectal cancer (CRC) is the most common type of gastroin-
testinal malignancy. Nearly 150,000 new cases are diagnosed each
year in the USA; worldwide, nearly 1.2 million cases are diagnosed
annually. At the time of initial presentation, only about 40–45%
of patients are potentially curable with surgery. Patients presenting
with high-risk stage II disease and stage III disease are candidates
for adjuvant chemotherapy with an oxaliplatin-based regimen in
combination with 5-FU plus leucovorin (FOLFOX) or with oral

capecitabine (XELOX) and are generally treated for 6 months fol-
lowing surgical resection. Treatment with this combination regi-
men reduces the recurrence rate after surgery by 35% and clearly
improves overall patient survival compared with surgery alone.
Significant advances have been made over the past 10 years
with respect to treatment of metastatic CRC. Five active cytotoxic
agents have been approved during this time period—5-FU, the
oral fluoropyrimidine analogs capecitabine and TAS-102, oxali-
platin, and irinotecan. In addition, 5 novel biologic agents and
one small molecule inhibitor have been approved, including the
anti-VEGF antibody bevacizumab; the recombinant fusion pro-
tein ziv-aflibercept, which targets VEGF-A, VEGF-B, and PlGF;
the anti-VEGF-R2 antibody ramucirumab, which inhibits bind-
ing of the VEGF ligands VEGF-A, VEGF-C, and VEGF-D; the
two anti-EGFR antibodies cetuximab and panitumumab; and the
small molecule TKI inhibitor regorafenib. In general, a fluoropy-
rimidine—either intravenous 5-FU or oral capecitabine—serves
as the main foundation of cytotoxic chemotherapy regimens.
Recent clinical studies have shown that in tumors with wild-type
KRAS and NRAS, FOLFOX/FOLFIRI regimens in combination
with the anti-VEGF antibody bevacizumab or with the anti-
EGFR antibody cetuximab or panitumumab result in significantly
improved clinical efficacy with no worsening of the toxicities nor-
mally observed with chemotherapy. In order for patients to derive
maximal benefit, they should be treated with each of these active
agents in a continuum of care approach. Regorafenib and TAS-
102 are approved for the chemo-refractory disease setting, but
unfortunately, each drug is associated with significant toxicities
and only limited clinical efficacy with very low overall response
rates; median progression-free survival is about 2-months. Given
all of the available treatment regimens, median overall survival for
metastatic CRC is now in the 28- to 30-month range and, in some
cases, approaches or even exceeds 3 years.
The incidence of gastric cancer, esophageal cancer, and pancre-
atic cancer is much lower than for CRC, but these malignancies
tend to be more aggressive and result in greater tumor-related
symptoms. In most cases, they cannot be completely resected
surgically, as most patients present with either locally advanced or
metastatic disease at the time of their initial diagnosis. 5-FU-based
chemotherapy, using either intravenous 5-FU or oral capecitabine,
is generally considered the main backbone for regimens targeting
gastroesophageal cancers. In addition, cisplatin-based regimens in
combination with either irinotecan or one of the taxanes (pacli-
taxel or docetaxel) also exhibit clinical activity. Response rates in
the 40–50% range are now being reported. The addition of the
biologic agent trastuzumab to cisplatin-containing chemotherapy
regimens provides significant clinical benefit in metastatic gastric
cancer patients whose tumors overexpress the HER-2/neu recep-
tor. At present, the optimal fluoropyrimidine backbone has not
been established, and either infused 5-FU or oral capecitabine
can be combined with cisplatin plus trastuzumab. For second-
line therapy, the combination of ramucirumab plus paclitaxel is
recommended for patients with a good performance status and
favorable comorbidity profile. In patients who are unable to toler-
ate more intensive therapy, single-agent ramucirumab or paclitaxel
monotherapy are more appropriate treatment options.
CHAPTER 54  Cancer Chemotherapy    973
Although gemcitabine is approved for use as a single agent in
metastatic pancreatic cancer, the overall response rate is low at
less than 10%, with complete responses being exceedingly rare.
Intense efforts have focused on incorporating gemcitabine into
various combination regimens, and currently, the most commonly
used regimen for the first-line treatment of metastatic pancreatic
cancer is gemcitabine plus nanoparticle albumin-bound paclitaxel
(nab-paclitaxel [Abraxane]). In patients who are able to tolerate
a more aggressive approach, the FOLFIRINOX regimen, which
includes intravenous 5-FU, irinotecan, and oxaliplatin, has become
a widely used therapy. Single-agent irinotecan or liposomal iri-
notecan in combination with intravenous 5-FU are appropriate
treatment options in the second-line setting. In patients with
early-stage pancreatic cancer who have undergone successful sur-
gical resection, adjuvant chemotherapy with either single-agent
gemcitabine or 5-FU/leucovorin is recommended.
Hepatocellular cancer (HCC) has been a relatively difficult
tumor to treat as it frequently occurs in the context of chronic
liver disease and cirrhosis. It is usually diagnosed late in the course
of chronic liver disease, and a large majority of patients have
underlying poor liver function and only limited hepatic reserve.
In general, HCC is considered to be a chemotherapy-resistant dis-
ease, and palliative chemotherapy is usually not recommended as
first-line therapy in patients with unresectable or advanced HCC.
Single-agent sorafenib therapy is currently approved for advanced
or unresectable HCC, and in patients who have progressed on
front-line sorafenib therapy, the small molecule tyrosine kinase
inhibitor regorafenib is recommended.
LUNG CANCERS
Lung cancer is divided into two main histopathologic sub-
types, non-small cell and small cell. Non-small cell lung cancer
(NSCLC) makes up about 75–80% of all cases of lung cancer,
and this group includes adenocarcinoma, squamous cell cancer,
and large cell cancer, while small cell lung cancer (SCLC) makes
up the remaining 20–25%. When NSCLC is diagnosed in an
advanced stage with metastatic disease, the prognosis is extremely
poor, with a median survival of about 8 months. It is clear that
prevention (primarily through avoidance of cigarette smoking)
and early detection remain the most important means of control.
When diagnosed at an early stage, surgical resection results in
patient cure. Moreover, recent studies have shown that adjuvant
platinum-based chemotherapy provides a survival benefit in
patients with pathologic stage IB, II, and IIIA disease. However,
in most cases, distant metastases have occurred at the time of
diagnosis. In certain instances, radiation therapy can be offered
for palliation of pain, airway obstruction, or bleeding and to
treat patients whose performance status would not allow for more
aggressive treatments.
In patients with advanced disease, systemic chemotherapy
is generally recommended. Combination regimens that include
a platinum agent (“platinum doublets”) appear superior to
non-platinum doublets, and either cisplatin or carboplatin
are appropriate platinum agents for such regimens. For the
second drug, paclitaxel and vinorelbine appear to have activity
974    SECTION VIII  Chemotherapeutic Drugs
independent of histology, while the antifolate pemetrexed should
be used for non-squamous cell cancer, and gemcitabine for squa-
mous cell cancer. For patients with good performance status and
those with non-squamous histology, the combination of the anti-
VEGF antibody bevacizumab with carboplatin and paclitaxel
is a standard treatment option. In patients deemed not to be
appropriate candidates for bevacizumab therapy and those with
squamous cell histology, a platinum-based chemotherapy regi-
men in combination with the anti-EGFR antibody cetuximab
is a reasonable treatment strategy. Maintenance chemotherapy
with pemetrexed is now used in patients with non-squamous
NSCLC whose disease has remained stable after four cycles of
platinum-based first-line chemotherapy.
Patients with advanced NSCLC should have molecular test-
ing of their tumor. Patients whose tumors contain an actionable
mutation should then receive a targeted therapy. For example,
first-line therapy with erlotinib significantly improves outcomes
in advanced NSCLC patients with sensitizing EGFR mutations,
which include exon 19 deletions or exon 21 (L858R) substitu-
tion mutations. Afatinib is a small molecule inhibitor of EGFR,
HER2, and HER4, and it is approved for the first-line treatment
of metastatic NSCLC whose tumors have EGFR exon 19 dele-
tions or exon 21 mutations. Osimertinib is approved for the
treatment of metastatic EGFR T790M-mutant NSCLC following
progression on or after EGFR TKI therapy. This small molecule
is important as it is able to overcome the resistance that arises
from the emergence of the T790M gatekeeper mutation either
de novo or following previous EGFR TKI therapy. In NSCLC
that is ALK-positive, three new small molecules have been
developed: crizotinib, ceritinib, and alectinib. Crizotinib is the
first-generation ALK inhibitor, while ceritinib and alectinib have
clinical efficacy in patients whose disease has progressed on or who
have become intolerant to crizotinib.
Squamous cell NSCLC makes up approximately 30% of
NSCLC. This form of NSCLC is responsive to platinum-based
chemotherapy with either cisplatin or carboplatin in combina-
tion with gemcitabine. Recent studies have shown superior clini-
cal activity when cisplatin and gemcitabine are combined with
the anti-EGFR antibody necitumumab when compared to the
cisplatin-gemcitabine combination in the first-line treatment
of metastatic disease. In 2015, the immune checkpoint inhibi-
tor nivolumab was approved to treat metastatic squamous cell
NSCLC whose cancer has progressed during or after standard
platinum-based chemotherapy. This agent binds to the PD-1
receptor and inhibits the PD-1 immune signaling pathway, which
then leads to activation and proliferation of T cells as well as inhi-
bition of T-regulatory cells.
Small cell lung cancer is the most aggressive form of lung can-
cer. It is usually exquisitely sensitive, at least initially, to platinum-
based combination regimens, including cisplatin and etoposide or
cisplatin and irinotecan. Unfortunately, drug resistance eventually
develops in nearly all patients with extensive disease. When diag-
nosed at an early stage, this disease is potentially curable using
combined chemotherapy and radiation therapy. Topotecan is
used as second-line monotherapy in patients who have failed a
platinum-based regimen.
OVARIAN CANCER
In the majority of patients, ovarian cancer remains occult and
becomes symptomatic only after it has already metastasized to the
peritoneal cavity. At this stage, it usually presents with malignant
ascites. It is important to accurately stage this cancer with laparos-
copy, ultrasound, and CT scanning. Patients with stage I disease
appear to benefit from whole-abdomen radiotherapy and may
receive additional benefit from combination chemotherapy with
cisplatin and cyclophosphamide.
Combination chemotherapy is the standard approach to stage
III and stage IV disease. Randomized clinical studies have shown
that the combination of paclitaxel and cisplatin provides survival
benefit compared with the previous standard combination of
cisplatin plus cyclophosphamide. More recently, carboplatin plus
paclitaxel has become the treatment of choice. In patients who
present with recurrent disease, topotecan, altretamine, or liposo-
mal doxorubicin are used as single-agent monotherapy.
TESTICULAR CANCER
The introduction of platinum-based combination chemotherapy
has made an impressive change in the treatment of patients with
advanced testicular cancer. Presently, chemotherapy is recommended
for patients with stage IIC or stage III seminomas and nonsemi-
nomatous disease. Over 90% of patients respond to chemotherapy
and, depending upon the extent and severity of disease, complete
remissions are observed in 70–80% of patients. More than 50% of
patients achieving complete remission are cured with chemotherapy.
In patients with good risk features, three cycles of cisplatin, etoposide,
and bleomycin (PEB protocol) or four cycles of cisplatin and etopo-
side yield virtually identical results. In patients with high-risk disease,
the combination of cisplatin, etoposide, and ifosfamide can be used as
well as etoposide and bleomycin with high-dose cisplatin.
MALIGNANT MELANOMA
Malignant melanoma is curable with surgical resection when it
presents locally (see also Chapter 61). However, once metastasis has
occurred, it is one of the most difficult cancers to treat because of
drug resistance. While dacarbazine, temozolomide, and cisplatin are
the most active cytotoxic agents for this disease, the overall response
rates to these agents remain low. Biologic agents, including IFN-α
and interleukin 2 (IL-2), have greater activity than traditional cyto-
toxic agents, and treatment with high-dose IL-2 has led to cures,
albeit in a relatively small subset of patients. Ipilimumab binds
to cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), which
is expressed on the surface of activated CD4 and CD8 T-cells.
CTLA-4 normally acts as a brake on T-cell antitumor activity. Bind-
ing of ipilimumab results in inhibition of the interaction between
CTLA-4 and its target ligands CD80/CD86 and thus enhances
T-cell immune responses, which include T-cell activation and pro-
liferation. This agent is approved for the treatment of metastatic
melanoma. More recently, ipilimumab is recommended as adjuvant
therapy for cutaneous melanoma following complete surgical resec-
tion, with treatment for up to 3 years.

Nivolumab and pembrolizumab are IgG4 antibodies that
bind to the programmed death (PD)-1 receptor, which is
expressed on T cells, and they inhibit the interaction between
the programmed death ligand 1 (PD-L1) and ligand 2 (PD-L2)
and the PD-1 receptor. The PD-1 signaling pathway mediates
an immune escape mechanism, and inhibition of this pathway
enhances T-cell immune response, leading to T cell activation and
proliferation. Each of these agents is approved for unresectable or
metastatic melanoma as monotherapy. In addition, nivolumab is
also approved in combination with ipilimumab for BRAF V600
mutation–positive unresectable or metastatic melanoma.
The BRAF V600E mutation has been identified in the large
majority of melanomas. This mutation results in constitutive
activation of BRAF kinase, which then leads to activation of
downstream signaling pathways involved in cell growth and pro-
liferation. Two oral and highly selective small molecule inhibitors
of BRAF V600E are approved for metastatic melanoma: vemu-
rafenib and dabrafenib. Studies are ongoing to determine their
activity in combination with other cytotoxic and biologic agents
for metastatic melanoma as well as their potential role in the adju-
vant and neoadjuvant therapy of early stage melanoma.
Trametinib and cobimetinib are reversible inhibitors of
mitogen-activated extracellular signal-regulated kinase 1 (MEK1)
and kinase 2 (MEK2), and in combination with a BRAF inhibitor
molecule, they are approved for patients with metastatic mela-
noma whose tumors express the BRAF V600E or V600K muta-
tion. While these agents have clinical activity as monotherapies,
clinical studies suggest that the most promising clinical activity is
seen when they are used in combination with a BRAF inhibitor.
BRAIN CANCER
In general, chemotherapy has had only limited efficacy in the
treatment of malignant gliomas. Because of their ability to cross
the blood-brain barrier, the nitrosoureas have historically been
the most active agents in this disease. Carmustine (BCNU) has
been used as a single agent, or lomustine (CCNU) can be used in
SUMMARY  Anti-cancer Drugs
See Tables 54–2, –3, –4, and –5.
P R E P A R A T I O N S A V A I L A B L E
The reader is referred to the Internet and manufacturers’ literature for the most recent information on preparations available.
CHAPTER 54  Cancer Chemotherapy    975
combination with procarbazine and vincristine (PCV regimen).
In addition, the alkylating agent temozolomide is active when
combined with radiotherapy and is also used in patients with
newly diagnosed glioblastoma multiforme (GBM) as well as in
those with recurrent disease. The histopathologic subtype oligo-
dendroglioma has been shown to be especially chemosensitive,
and the PCV combination regimen is the treatment of choice for
this disease. It is now well-established that the anti-VEGF anti-
body bevacizumab alone or in combination with chemotherapy
has documented clinical activity in adult GBM. Bevacizumab is
presently approved as a single agent for adult GBM in the setting
of progressive disease following first-line chemotherapy.
SECONDARY MALIGNANCIES &
CANCER CHEMOTHERAPY
The development of secondary malignancies is a late complication
of the alkylating agents and the epipodophyllotoxin etoposide.
For both drug classes, the most frequent secondary malignancy
is acute myelogenous leukemia (AML). AML develops in up to
15% of patients with Hodgkin’s lymphoma who have received
radiotherapy plus MOPP chemotherapy and in patients with
multiple myeloma, ovarian carcinoma, or breast carcinoma treated
with melphalan. The increased risk of AML is observed as early
as 2–4 years after the initiation of chemotherapy and typically
peaks at 5 and 9 years. With improvements in the clinical efficacy
of various combination chemotherapy regimens resulting in pro-
longed survival and in some cases actual cure of cancer, the issue of
how second cancers may affect long-term survival assumes greater
importance. Certain alkylating agents (eg, cyclophosphamide)
may be less carcinogenic than others (eg, melphalan). In addition
to AML, other secondary malignancies have been well-described,
including non-Hodgkin’s lymphoma and bladder cancer, the
latter most typically associated with cyclophosphamide therapy.
Etoposide can give rise to an 11:23 translocation, which has been
associated with the development of the M4 and M5 AML histo-
logic subtypes.
976    SECTION VIII  Chemotherapeutic Drugs
REFERENCES
Books & Monographs
Abeloff MD et al: Clinical Oncology, 5th ed. Elsevier, 2014.
Barakat RR et al: Principles and Practice of Gynecologic Oncology, 5th ed. Lippincott
Williams & Wilkins, 2009.
Chabner BA, Longo DL: Cancer Chemotherapy and Biotherapy: Principles and
Practice, 5th ed. Lippincott Williams & Wilkins, 2011.
Chu E, DeVita VT Jr: Cancer Chemotherapy Drug Manual 2017, 17th ed. Jones
& Bartlett.
DeVita VT Jr, Hellman S, Rosenberg SA: Cancer: Principles and Practice of Oncol-
ogy, 10th ed. Lippincott Williams & Wilkins, 2015.
Harris JR et al: Diseases of the Breast, 4th ed. Lippincott Williams & Wilkins, 2009.
Hoppe R et al: Textbook of Radiation Oncology, 3rd ed. Elsevier, 2010.
Kantoff PW et al: Prostate Cancer: Principles and Practice. Lippincott Williams &
Wilkins, 2001.
C ASE STUDY ANSWER
The 5-year survival rate for patients with high-risk stage III
CRC is on the order of 25–30%. Because the patient has
no symptoms after surgery and has no comorbid illnesses,
he would be an appropriate candidate to receive aggressive
adjuvant chemotherapy. Adjuvant chemotherapy is usually
begun 4–6 weeks after surgery to allow sufficient time for the
surgical wound to heal. The usual recommendation would
be to administer 6 months of oxaliplatin-based chemo-
therapy using either intravenous 5-FU or oral capecitabine as
the fluoropyrimidine base in combination with oxaliplatin.
Patients with partial or complete deficiency in the
enzyme dihydropyrimidine dehydrogenase (DPD) experi-
ence an increased incidence of severe toxicity to fluoropy-
rimidines in the form of myelosuppression, gastrointestinal
Kelsen DP et al: Gastrointestinal Oncology: Principles and Practices, 2nd ed.
Lippincott Williams & Wilkins, 2007.
Kufe D et al: Cancer Medicine, 7th ed. BC Decker, 2006.
Mendelsohn J et al: The Molecular Basis of Cancer, 3rd ed. Saunders, 2008.
Pass HI et al: Principles and Practice of Lung Cancer: The Official Reference Text of
the International Association for the Study of Lung Cancer (IASLC), 4th ed.
Lippincott Williams & Wilkins, 2010.
Pizzo PA, Poplack AG: Principles and Practice of Pediatric Oncology, 6th ed.
Lippincott Williams & Wilkins, 2010.
Weinberg RA: Biology of Cancer, 2nd ed. Taylor & Francis, 2013.
Articles & Reviews
DeVita VT, Chu E: The history of cancer chemotherapy. Cancer Res 2008;68:8643.
Redmond KM et al: Resistance mechanisms to cancer chemotherapy. Front Biosci
2008;13:5138.
toxicity in the form of mucositis and diarrhea, and neu-
rotoxicity. This is an autosomal recessive pharmacoge-
netic syndrome that is present in up to 10% of the North
American population (see Chapter 5). Although mutations
in DPD can be identified in peripheral blood mononuclear
cells, nearly 50% of patients who exhibit severe 5-FU
toxicity do not have a defined mutation in the DPD gene. In
addition, such mutations may not result in reduced expres-
sion of the DPD protein or in altered enzymatic activity. For
this reason, genetic testing is not recommended at this time
as part of routine clinical practice. There is now an immu-
noassay that can measure 5-FU drug levels in the peripheral
blood that can help guide 5-FU dosing even in patients with
DPD deficiency.

Immunopharmacology
Douglas F. Lake, PhD & Adrienne D. Briggs, MD
C ASE STUDY
A 45-year-old man with high-risk acute myelogenous leu-
kemia undergoes high-dose chemotherapy followed by an
allogeneic stem cell transplant from an unrelated donor. He
receives tacrolimus and low-dose methotrexate as prophy-
laxis for graft-vs-host disease. One month after blood count
Agents that suppress the immune system play an important role
in preventing the rejection of organ or tissue grafts and in the
treatment of certain diseases that arise from dysregulation of the
immune response. While precise details of the mechanisms of
action of a number of these agents are still obscure, knowledge
of the elements of the immune system is useful in understand-
ing their effects. Agents that augment the immune response or
selectively alter the balance of various components of the immune
system are also becoming important in the management of certain
diseases such as cancer, AIDS, and autoimmune or inflamma-
tory diseases. A growing number of other conditions (infections,
cardiovascular diseases, organ transplantation) are also areas for
immune manipulation.
■■ ELEMENTS OF THE IMMUNE
SYSTEM
NORMAL IMMUNE RESPONSES
The immune system has evolved to protect the host from invad-
ing pathogens and to eliminate disease. When functioning at its
best, the immune system is exquisitely responsive to invading
pathogens while retaining the capacity to recognize self tissues
and antigens to which it is tolerant. Protection from infection and
disease is provided by the collaborative efforts of the innate and
adaptive immune systems.
55
C H A P T E R
recovery, he develops a skin rash despite ongoing tacrolimus
therapy. A skin biopsy confirms grade II acute graft-vs-host
disease. How should this case be pharmacologically man-
aged at this point?
The Innate Immune System
The innate immune system is the first line of defense against
invading pathogens (eg, bacteria, viruses, fungi, parasites) and
consists of mechanical, biochemical, and cellular components.
Mechanical components include skin/epidermis and mucus;
biochemical components include antimicrobial peptides and
proteins (eg, defensins), complement, enzymes (eg, lysozyme,
acid hydrolases), interferons, acidic pH, and free radicals (eg,
hydrogen peroxide, superoxide anions); cellular components
include neutrophils, monocytes, macrophages, natural killer
(NK) cells, and natural killer-T (NKT) cells. Unlike adaptive
immunity, the innate immune response exists prior to infection,
is not enhanced by repeated infection, and is generally not
antigen-specific. An intact skin or mucosa is the first barrier to
infection. When this barrier is breached, an immediate innate
immune response, referred to as “inflammation,” is provoked
and ultimately leads to destruction of the pathogen. The process
of pathogen destruction can be accomplished, for example, by
biochemical components such as lysozyme (which breaks down
bacterial peptidoglycan cell walls) and complement activation.
Complement components (Figure 55–1) enhance macrophage
and neutrophil phagocytosis by acting as opsonins (C3b) and
chemoattractants (C3a, C5a), which recruit immune cells from
the bloodstream to the site of infection. The activation of com-
plement eventually leads to pathogen lysis via the generation of
a membrane attack complex that creates holes in the pathogen
membrane, killing it. Although the complement cascade helps
977
978    SECTION VIII  Chemotherapeutic Drugs

Complement (C1–C9)
C5 → C5a, C5b B
Bacterial lysis
C5b, C6, C7, C8, C9
Chemotaxis
(MAC)
C3a, C5a Eculizumab
Release of salts,
blocks
proteins, water, etc
cleavage of
C5

A Inflammator y 3
site
C3a, Opsonization Bacterial destruction
C5a C3b
2 Bacteria

Macrophage C3b

C3a, C
1
C5a

C3b
Monocyte Bloodstream receptor Macrophage
3

Endothelial cell

FIGURE 55–1  Role of complement in innate immunity. Complement is made up of nine proteins (C1–C9), which are split into fragments
during activation. A: Complement components (C3a, C5a) attract phagocytes (1) to inflammatory sites (2), where they ingest and degrade
pathogens (3). B: Complement components C5b, C6, C7, C8, and C9 associate to form a membrane attack complex (MAC) that lyses bacteria,
causing their destruction. Eculizumab is a monoclonal antibody that blocks cleavage of C5. C: Complement component C3b is an opsonin that
coats bacteria (1) and facilitates their ingestion (2) and digestion (3) by phagocytes.

eliminate invading pathogens from the host, in some indi-
viduals with complement inhibitor deficiency, complement
may lyse host red blood cells and cause a disease called parox-
ysmal nocturnal hemoglobinuria (PNH). These patients can be
treated with a monoclonal antibody (Mab) that binds the C5
component of complement (see Mab section below), disrupting
the lytic cascade. Patients taking a C5 inhibitor are at risk of
life-threatening meningococcal infections.
During the inflammatory response triggered by infection,
neutrophils and monocytes enter the tissue sites from the
peripheral circulation. This cellular influx is mediated by the
action of chemoattractant cytokines (chemokines) (eg, inter-
leukin-8 [IL-8; CXCL8], macrophage chemotactic protein-1
[MCP-1; CCL2], and macrophage inflammatory protein-1α
[MIP-1α; CCL3]) released from activated endothelial cells
and immune cells (mostly tissue macrophages) at the inflam-
matory site. Egress of the immune cells from blood vessels
into the inflammatory site is mediated by adhesive interactions
between cell surface receptors (eg, l-selectin, integrins) on
the immune cells and ligands (eg, sialyl-Lewis x, intercellular
adhesion molecule-1 [ICAM-1]) on the activated endothelial
cell surface. The tissue macrophages as well as dendritic cells
express pattern recognition receptors (PRRs) that include
Toll-like receptors (TLRs), nucleotide-binding oligomerization
domain-like receptors (NLRs), scavenger receptors, mannose
receptors, and lipopolysaccharide (LPS)-binding protein,
which recognize key evolutionarily conserved pathogen com-
ponents referred to as pathogen-associated molecular pat-
terns (PAMPs). Examples of PAMPs include microbe-derived
unmethylated CpG DNA, flagellin, double-stranded RNA,
peptidoglycan, and LPS. The PRRs recognize PAMPs in vari-
ous components of pathogens and stimulate the release of pro-
inflammatory cytokines, chemokines, and interferons. If the
innate immune response is successfully executed, the invading
pathogen is ingested, degraded, and eliminated, and disease is
either prevented or is of short duration.
In addition to monocytes and neutrophils, natural
killer (NK), natural killer-T (NKT), and gamma-delta T
(fc T) cells recruited to the inflammatory site contribute to
the innate response by secreting interferon-gamma (IFN-γ) and
 CHAPTER 55  Immunopharmacology    979

ACRONYMS known as CD1 and have been implicated in host defense against
microbial agents, autoimmune diseases, and tumors.
ADA Adenosine deaminase
ADC Antibody-drug conjugate
ALG Antilymphocyte globulin
The Adaptive Immune System
APC Antigen-presenting cell The adaptive immune system is mobilized by cues from the innate
ATG Antithymocyte globulin
response when the innate processes are incapable of coping with
an infection. The adaptive immune system has a number of char-
CD Cluster of differentiation
acteristics that contribute to its success in eliminating pathogens.
CSF Colony-stimulating factor These include the ability to (1) respond to a variety of antigens,
CTL Cytotoxic T lymphocyte each in a specific manner; (2) discriminate between foreign (“non-
DC Dendritic cell self ”) antigens (pathogens) and self antigens of the host; and
DTH Delayed-type hypersensitivity (3) respond to a previously encountered antigen in a learned way
FKBP FK-binding protein
by initiating a vigorous memory response. This adaptive response
culminates in the production of antibodies, which are the effec-
GVHD Graft-versus-host disease
tors of humoral immunity; and the activation of T lymphocytes,
HAMA Human antimouse antibody which are the effectors of cell-mediated immunity.
HLA Human leukocyte antigen The induction of specific adaptive immunity requires the par-
IFN Interferon ticipation of professional antigen-presenting cells (APCs), which
IGIV Immune globulin intravenous include dendritic cells (DCs), macrophages, and B lymphocytes.
IL Interleukin
These cells play pivotal roles in the induction of an adaptive
immune response because of their capacity to phagocytize particu-
LFA Leukocyte function-associated antigen
late antigens (eg, pathogens) or endocytose protein antigens, and
Mab Monoclonal antibody enzymatically digest them to generate peptides, which are then
MHC Major histocompatibility complex loaded onto class I or class II MHC proteins and “presented” to
NK cell Natural killer cell the cell surface T-cell receptor (TCR) (Figure 55–2). CD8 T cells
SCID Severe combined immunodeficiency disease recognize class I–MHC peptide complexes while CD4 T cells rec-
TCR T-cell receptor
ognize class II–MHC peptide complexes. At least two signals are
necessary for the activation of T cells. The first signal is delivered
TGF-a Transforming growth factor-β
following engagement of the TCR with peptide-bound MHC
Th1, Th2 T helper cell types 1 and 2 molecules. In the absence of a second signal, the T cells become
TNF Tumor necrosis factor

LFA-3 CD2
interleukin-17 (IL-17),* which activate resident tissue macro- CD80/86
Dendritic CD28
phages and dendritic cells and recruit neutrophils, respectively, to cell 2
successfully eliminate invading pathogens. NK cells are so called CTLA-4
T cell
because they are able to recognize and destroy virus-infected
normal cells as well as tumor cells without prior stimulation. TCR
1
MHC
This activity is regulated by “killer cell immunoglobulin-like
receptors” (KIRs) on the NK cell surface that are specific for CD40 CD40L
major histocompatibility complex (MHC) class I molecules.
When NK cells bind self MHC class I proteins (expressed on ICAM-1 LFA-1
all nucleated cells), these receptors deliver inhibitory signals, T lymphocyte
Antigen- PD-L1/L2 PD-1
preventing them from killing normal host cells. Tumor cells or
presenting cell
virus-infected cells that have downregulated MHC class I expres-
sion do not engage these KIRs, resulting in activation of NK
cells and subsequent destruction of the target cell. NK cells kill FIGURE 55–2  T-cell activation by an antigen-presenting cell
requires engagement of the T-cell receptor by the MHC-peptide
target cells by releasing cytotoxic granules such as perforins and
complex (signal 1) and binding of the costimulatory molecules
granzymes that induce programmed cell death. (CD80, CD86) on the dendritic cell to CD28 on the T cell (signal 2).
NKT cells express T-cell receptors as well as receptors com- The activation signals are strengthened by CD40/CD40L and ICAM-1/
monly found on NK cells. NKT cells recognize microbial lipid LFA-1 interactions. In a normal immune response, T-cell activation is
antigens presented by a unique class of MHC-like molecules regulated by T-cell–derived CTLA-4 and PD-1. CTLA-4 binds to CD80
or CD86 with higher affinity than CD28 and sends inhibitory signals
* to the nucleus of the T cell, while ligation of PD-1 by PD-L1 or -L2
Interferons and interleukins are cytokines, which are discussed later in
this chapter. also inhibits T cell proliferation.
980    SECTION VIII  Chemotherapeutic Drugs
unresponsive (anergic) or undergo apoptosis. The second signal
involves binding of costimulatory molecules (CD40, CD80 [also
known as B7-1], and CD86 [also known as B7-2]) on the APC
to their respective ligands (CD40L for CD40, CD28 for CD80
or CD86). Activation of T cells is regulated via a negative feed-
back loop involving another molecule known as T-lymphocyte–
associated antigen 4 (CTLA-4). Following engagement of CD28
with CD80 or CD86, CTLA-4 in the cytoplasm is mobilized to
the cell surface where, because of its higher affinity of binding to
CD80 and CD86, it outcompetes or displaces CD28 resulting
in suppression of T-cell activation and proliferation. This prop-
erty of CTLA-4 has been exploited as a strategy for sustaining a
desirable immune response such as that directed against cancer.
A recombinant humanized antibody (ipilimumab) that binds
CTLA-4 prevents its association with CD80/CD86. In so doing,
the activated state of T cells is sustained. Programmed cell death
protein-1 (PD-1) is another negative regulator of T cells. Ligation
of PD-1 with its ligands (PD-L1 or PD-L2) suppresses T-cell
activity. Like CTLA-4, Mabs have been developed to block the
interaction of PD-1 with PD-L1, having the effect of sustained
T cell activation. Mabs to CTLA-4 and PD-1/PD-L1 are immune
checkpoint inhibitors. They have been associated in some patients
with the development of autoimmune toxicity that subsides upon
discontinuation of Mab therapy.
T lymphocytes develop and learn to recognize self and non-self
antigens in the thymus; those T cells that bind with high affinity
to self antigens in the thymus undergo apoptosis (negative selec-
tion), while those that are capable of recognizing foreign antigens
in the presence of self MHC molecules are retained and expanded
(positive selection) for export to the periphery (lymph nodes,
spleen, mucosa-associated lymphoid tissue, peripheral blood),
where they become activated after encountering MHC-presented
peptides (Figures 55–2 and 55–3).
Studies using murine T-cell clones have demonstrated the
presence of two subsets of T helper lymphocytes (Th1 and Th2)
based on the cytokines they secrete after activation. The Th1 sub-
set characteristically produces IFN-γ, IL-2, and IL-12 and induces
cell-mediated immunity by activation of macrophages, cytotoxic
T cells (CTLs), and NK cells. The Th2 subset produces IL-4,
IL-5, IL-6, and IL-10 (and sometimes IL-13), which induce B-cell
proliferation and differentiation into antibody-secreting plasma
cells. IL-10 produced by Th2 cells inhibits cytokine production
by Th1 cells via the downregulation of MHC expression by APCs.
Conversely, IFN-γ produced by Th1 cells inhibits the proliferation
of Th2 cells (Figure 55–3). Although these subsets have been
well described in vitro, the nature of the antigenic challenge that
elicits a Th1 or Th2 phenotype is less clear. Extracellular bacteria
typically cause the elaboration of Th2 cytokines, culminating in
the production of neutralizing or opsonic antibodies. In contrast,
intracellular organisms (eg, mycobacteria) elicit the production of
Th1 cytokines, which lead to the activation of effector cells such
as macrophages.
Another subset of CD4 T cells that secrete IL-17 (Th17)
is important in leukocyte recruitment to sites of bacterial and
fungal pathogens. Th17 cells also contribute to the pathogenesis
of autoimmune diseases such as psoriasis, inflammatory bowel
disease, rheumatoid arthritis, and multiple sclerosis. In fact, new
Mabs for some of these diseases that neutralize IL-17 by binding
to the cytokine itself or to its receptor (see Mab section below)
have recently been FDA-approved.
Regulatory T (Treg) cells constitute a population of CD4
T cells that is essential for preventing autoimmunity and allergy
as well as maintaining homeostasis and tolerance to self antigens.
This cell population exists as natural Treg (nTreg), derived directly
from the thymus, and induced (adaptive) Treg (iTreg), generated
from naïve CD4 T cells in the periphery. Both populations have
also been shown to inhibit antitumor immune responses and are
implicated in fostering tumor growth and progression. Recent
attempts to distinguish both populations have resulted in the
discovery of a transcription factor, Helios, in nTreg but not in
iTreg cells.
CD8 T lymphocytes recognize endogenously processed pep-
tides presented by virus-infected cells or tumor cells. These pep-
tides are usually nine-amino-acid fragments derived from virus
or protein tumor antigens in the cytoplasm and are loaded onto
MHC class I molecules (Figure 55–2) in the endoplasmic reticu-
lum. In contrast, class II MHC molecules present peptides (usu-
ally 11–22 amino acids) derived from extracellular (exogenous)
pathogens to CD4 T helper cells. In some instances, exogenous
antigens, upon ingestion by APCs, can be presented on class I
MHC molecules to CD8 T cells. This phenomenon, referred to as
“cross-presentation,” involves retro-translocation of antigens from
the endosome to the cytosol for peptide generation in the proteo-
some and is thought to be useful in generating effective immune
responses against infected host cells that are incapable of priming
T lymphocytes. Upon activation, CD8 T cells induce target cell
death via lytic granule enzymes (“granzymes”), perforin, and the
Fas-Fas ligand (Fas-FasL) apoptosis pathways.
B lymphocytes undergo selection in the bone marrow, during
which self-reactive B lymphocytes are clonally deleted while B-cell
clones specific for foreign antigens are retained and expanded.
The repertoire of antigen specificities by T cells is genetically
determined and arises from T-cell receptor gene rearrangement
while the specificities of B cells arise from immunoglobulin gene
rearrangement; for both types of cells, these determinations occur
prior to encounters with antigen. Upon an encounter with anti-
gen, a mature B cell binds the antigen, internalizes and processes
it, and presents its peptide—bound to class II MHC—to CD4
helper cells, which in turn secrete IL-4 and IL-5. These inter-
leukins stimulate B-cell proliferation and differentiation into
memory B cells and antibody-secreting plasma cells. The primary
antibody response consists mostly of IgM-class immunoglobulins.
Subsequent antigenic stimulation results in a vigorous “booster”
response accompanied by class (isotype) switching to produce
IgG, IgA, and IgE antibodies with diverse effector functions
(Figure 55–3). These antibodies also undergo affinity matura-
tion, which allows them to bind more efficiently to the antigen.
With the passage of time, this results in accelerated elimination
of microorganisms in subsequent infections. Antibodies mediate
their functions by acting as opsonins to enhance phagocytosis and
cellular cytotoxicity and by activating complement to elicit an
inflammatory response and induce bacterial lysis (Figure 55–4).
 CHAPTER 55  Immunopharmacology    981

Opsonized
bacteria

Lysosome

Macrophage

Antigen- B lymphocyte
presenting
cell
Class I MHC
IL-1, 6, 23 peptide
TGF-β IL-1
T lymphocyte

IL-17 TH IL-2
IL-22 Class II MHC
Th17
Peptide

IL-2 IL-2
IL-10
IL-4, IL-5
TH1

IFN-γ TH2
IFN-γ
TNF-β
IFN-γ Differentiation Immunoglobulin
Proliferation classes
IgG
IgM
IgA
IgD
Activated Activated Activated IgE
macrophage NK cell cytotoxic T cell
(kills bacteria) (kills virus- (kills tumor Memory B cells
infected cells cells and Plasma cells
and tumor virus-infected
cells) cells)

Cell-mediated immunity Humoral immunity

FIGURE 55–3  Scheme of cellular interactions during the generation of cell-mediated and humoral immune responses (see text).
The cell-mediated arm of the immune response involves the ingestion and digestion of antigen by antigen-presenting cells such as
macrophages. Activated Th cells secrete IL-2, which causes proliferation and activation of cytotoxic T lymphocytes as well as Th1 and Th2
cell subsets. Th1 cells also produce IFN-γ and TNF-β, which can directly activate macrophages and NK cells. Th17 cells may be induced by
IL-1, -6, -23 or TGF-β secretion by antigen-presenting cells; Th17 cells are inflammatory and secrete IL-17 and -22. The humoral response is
triggered when B lymphocytes bind antigen via their surface immunoglobulin. They are then induced by Th2-derived IL-4 and IL-5 to prolif-
erate and differentiate into memory cells and antibody-secreting plasma cells. Regulatory cytokines such as IFN-γ and IL-10 down-regulate
Th2 and Th1 responses, respectively (dashed arrows).

ABNORMAL IMMUNE RESPONSES Hypersensitivity

Whereas the normally functioning immune response can suc-
cessfully neutralize toxins, inactivate viruses, destroy transformed
cells, and eliminate pathogens, inappropriate responses can lead
to extensive tissue damage (hypersensitivity) or reactivity against
self antigens (autoimmunity); conversely, impaired reactivity to
appropriate targets (immunodeficiency) may occur and abrogate
essential defense mechanisms.
Hypersensitivity can be classified as antibody-mediated or cell-
mediated. Three types of hypersensitivity are antibody-mediated
(types I–III), while the fourth is cell-mediated (type IV). Hypersen-
sitivity occurs in two phases: the sensitization phase and the effector
phase. Sensitization occurs upon initial encounter with an antigen;
the effector phase involves immunologic memory and results in
tissue pathology upon a subsequent encounter with that antigen.
982    SECTION VIII  Chemotherapeutic Drugs

A
Bacteria

Epitope

Antigen-
binding Hinge
region region
CH1 VH
Complementarity-
determining
region (CDR)
–S
- S– –S-S– -S
– VL
–S –S-S– CL
CH2
Fc region
CH3
B

Fc receptor Opsonization

Complement
activation
Macrophage

Bacterial lysis

FIGURE 55–4  Antibody has multiple functions. The prototypical antibody consists of two heavy (H) and two light (L) chains, each subdivided
into constant (CL, CH) and variable (VL, VH) domains. The structure is held together by intra- and interchain disulfide bridges. A: The complementarity-
determining region (CDR) of the antigen-binding portion of the antibody engages the antigenic determinant (epitope) in a lock-and-key fashion.
B: Antigen-antibody complexes activate complement to produce split complement components that cause bacterial lysis. C: The Fc portion of anti-
bodies binds to Fc receptors on phagocytes (eg, macrophages, neutrophils) and facilitates uptake of bacteria (opsonization).

1. Type I—Immediate, or type I, hypersensitivity is IgE-mediated,
with symptoms usually occurring within minutes following the
patient’s reencounter with antigen. Type I hypersensitivity results
from cross-linking of membrane-bound IgE on blood basophils
or tissue mast cells by antigen. This cross-linking causes cells to
degranulate, releasing substances such as histamine, leukotrienes, and
eosinophil chemotactic factor, which induce anaphylaxis, asthma,
hay fever, or urticaria (hives) in affected individuals (Figure 55–5).
A severe type I hypersensitivity reaction such as systemic anaphylaxis
(eg, from insect envenomation, ingestion of certain foods, or drug
hypersensitivity) requires immediate medical intervention.
2. Type II—Type II hypersensitivity results from the formation of
antigen-antibody complexes between foreign antigen and IgM or
IgG immunoglobulins. One example of this type of hypersensitiv-
ity is a blood transfusion reaction that can occur if blood is not
cross-matched properly. Preformed antibodies bind to red blood
cell membrane antigens that activate the complement cascade,
generating a membrane attack complex that lyses the transfused
red blood cells. In hemolytic disease of the newborn, anti-Rh
IgG antibodies produced by an Rh-negative mother cross the pla-
centa, bind to red blood cells of an Rh-positive fetus, and damage
them. The disease is prevented in subsequent pregnancies by the
administration of anti-Rh antibodies to the mother 24–48 hours
after delivery (see Immunosuppressive Antibodies, below). Type II
hypersensitivity can also be drug-induced and may occur during
the administration of penicillin (for example) to allergic patients.
In these patients, penicillin binds to red blood cells or other host
 CHAPTER 55  Immunopharmacology    983

Sensitization phase

Naive B cell
Effector phase

+IL-4,-5
T helper cell
IgE binds IgE Fcε
receptors on mast
cells or basophils
Omalizumab, mepolizumab
block IgE from binding
to IgE receptor
IgE-secreting plasma cell
IgE is specific for allergen Allergen cross-links IgE on mast
cell (or basophil) and triggers
degranulation and release of
pharmacologic mediators

Mediators Effects Clinical symptoms

Histamine Smooth muscle contraction Asthma
Serotonin Vasodilation Hay fever
Leukotrienes Increased vascular Skin rashes
Prostaglandins permeability Local anaphylaxis
Bradykinins Platelet aggregation Systemic anaphylaxis
Proteases Complement activation
Eosinophil chemotactic factor Mucus secretion
Neutrophil chemotactic factor

FIGURE 55–5  Mechanism of type I hypersensitivity. Initial exposure to allergen (sensitization phase) leads to production of IgE by plasma
cells differentiated from allergen-specific B cells (not shown). The secreted IgE binds IgE-specific receptors (FcεR) on blood basophils and tissue
mast cells. Re-exposure to allergen leads to cross-linking of membrane-bound IgE (effector phase). This cross-linking causes degranulation of
cytoplasmic granules and release of mediators that induce vasodilation, smooth muscle contraction, and increased vascular permeability. These
effects lead to the clinical symptoms characteristic of type I hypersensitivity. Omalizumab prevents IgE from binding to IgE receptors on mast
cells and basophils, preventing degranulation.

tissue to form a neoantigen that evokes production of antibodies
capable of inducing complement-mediated red cell lysis. In some
circumstances, subsequent administration of the drug can lead to
systemic anaphylaxis (type I hypersensitivity).
3. Type III—Type III hypersensitivity is due to the presence of
elevated levels of antigen-antibody complexes in the circulation that
ultimately deposit on basement membranes in tissues and vessels.
Immune complex deposition activates complement to produce
components with anaphylatoxic and chemotactic activities (C5a,
C3a, C4a) that increase vascular permeability and recruit neutro-
phils to the site of complex deposition. Complex deposition and the
action of lytic enzymes released by neutrophils can cause skin rashes,
glomerulonephritis, and arthritis in these individuals. If patients
have type III hypersensitivity against a particular antigen, clinical
symptoms usually occur 3–4 days after exposure to the antigen.
4. Type IV: Delayed-type hypersensitivity—Unlike
type I, II, and III hypersensitivities, delayed-type hypersensi-
tivity (DTH) is cell-mediated, and responses occur 2–3 days
after exposure to the sensitizing antigen. DTH is caused by
antigen-specific DTH Th1 cells and induces a local inflamma-
tory response that causes tissue damage characterized by the
influx of antigen-non-specific inflammatory cells, especially
macrophages. These cells are recruited under the influence of
Th1-produced cytokines (Figure 55–6), which chemoattract
circulating monocytes and neutrophils, induce myelopoiesis,
and activate macrophages. The activated macrophages are pri-
marily responsible for the tissue damage associated with DTH.
Although widely considered to be deleterious, DTH responses
are very effective in eliminating infections caused by intracellular
pathogens such as Mycobacterium tuberculosis and Leishmania
species. Clinical manifestations of DTH include tuberculin and
contact hypersensitivities. Tuberculosis exposure is determined
using a DTH skin test. Positive responses show erythema and
induration caused by accumulation of macrophages and DTH
T (TDTH) cells at the site of the tuberculin injection. Poison ivy
is the most common cause of contact hypersensitivity, in which
pentadecacatechol, the lipophilic chemical in poison ivy, modi-
fies cellular tissue and results in a DTH T-cell response.
984    SECTION VIII  Chemotherapeutic Drugs

Sensitization phase: Effector phase: Cytokines Effects

initial contact secondary contact
with antigen with antigen

IL-8 Chemotaxis
IL-1 IL-2 receptor TDTH MIF of macrophages
MCP
Allergen
CD4 IL-2 IL-2 Activation of
macrophages
IFN-γ (increased
IL-1 TNF-β phagocytic
Proliferation and and microbicidal
TCR T helper differentiation
cell (TH1) activities)
Class II MHC IL-2
Induction of
Antigen-presenting myelopoiesis of
IL-3
cell (eg, macrophage,
GM-CSF macrophage and
Langerhans cell) neutrophil precursors

Macrophage IL-8 Chemotaxis and

Memory TDTH TNF-α extravasation of
MIP macrophages

FIGURE 55–6  Mechanism of type IV hypersensitivity (DTH). In the sensitization phase, the processed allergen (eg, from poison ivy)
is presented to CD4 Th1 cells by antigen-presenting cells in association with class II MHC. T cells are induced to express IL-2 receptors and
are stimulated to proliferate and differentiate into memory TDTH cells. Secondary contact with antigen triggers the effector phase, in which
memory TDTH cells release cytokines that attract and activate nonspecific inflammatory macrophages and neutrophils. These cells display
increased phagocytic and microbicidal activities and release large quantities of lytic enzymes that cause extensive tissue damage.

Autoimmunity Immunodeficiency Diseases

Autoimmune disease arises when the body mounts an immune
response against itself due to failure to distinguish self tissues
and cells from foreign (non-self ) antigens or loss of tolerance
to self. This phenomenon derives from the activation of self-
reactive T and B lymphocytes that generate cell-mediated or
humoral immune responses directed against self antigens. The
pathologic consequences of this reactivity constitute several
types of autoimmune diseases. Autoimmune diseases are highly
complex due to MHC genetics, environmental conditions,
infectious entities, and dysfunctional immune regulation.
Examples of such diseases include rheumatoid arthritis, pso-
riasis, systemic lupus erythematosus, multiple sclerosis, and
insulin-dependent diabetes mellitus (type 1 diabetes). In
rheumatoid arthritis, IgM antibodies (rheumatoid factors) are
produced that react with the Fc portion of IgG and may form
immune complexes that activate the complement cascade,
causing chronic inflammation of the joints and kidneys. In sys-
temic lupus erythematosus, antibodies are made against DNA,
histones, red blood cells, platelets, and other cellular compo-
nents. In multiple sclerosis and type 1 diabetes, cell-mediated
autoimmune attack destroys myelin surrounding nerve cells
and insulin-producing islet beta cells of the pancreas, respec-
tively. In type 1 diabetes, activated CD4 TDTH cells that
infiltrate the islets of Langerhans and recognize self islet beta
cell peptides are thought to produce cytokines that stimulate
macrophages to produce lytic enzymes, which destroy islet beta
cells. Autoantibodies directed against the islet beta cell antigens
are produced but do not contribute significantly to disease.
Immunodeficiency diseases result from inadequate function in the
immune system; the consequences include increased susceptibil-
ity to infections and prolonged duration and severity of disease.
Immunodeficiency diseases are either congenital or arise from
extrinsic factors such as bacterial or viral infections or drug treat-
ment. Affected individuals frequently succumb to infections caused
by opportunistic organisms of low pathogenicity for the immuno-
competent host. Examples of congenitally acquired immunodefi-
ciency diseases include X-linked agammaglobulinemia, DiGeorge’s
syndrome, and severe combined immunodeficiency disease (SCID)
due to adenosine deaminase (ADA) deficiency.
X-linked agammaglobulinemia is a disease affecting males that is
characterized by a failure of immature B lymphocytes to mature into
antibody-producing plasma cells. These individuals are susceptible to
recurrent bacterial infections, although the cell-mediated responses
directed against viruses and fungi are preserved. DiGeorge’s syndrome
is due to failure of the thymus to develop, resulting in diminished
T-cell responses (TDTH, CTL), while the humoral response remains
functional but does not benefit from T-cell help.
The ADA enzyme normally prevents the accumulation of toxic
deoxy-ATP in cells. Deoxy-ATP is particularly toxic to lymphocytes,
and it leads to death of T and B cells. Absence of the enzyme there-
fore results in SCID. Infusion of the purified enzyme (pegademase,
from bovine sources) and transfer of ADA gene-modified lympho-
cytes have both been used successfully to treat this disease.
AIDS represents the classic example of immunodeficiency dis-
ease caused by extrinsic viral infection, in this instance the human
immunodeficiency virus (HIV). This virus exhibits a strong
 CHAPTER 55  Immunopharmacology    985

tropism for CD4 T helper cells; these become depleted, giving
rise to increased frequency of opportunistic infections and
malignancies in infected individuals. AIDS is also characterized
by an imbalance in Th1 and Th2 cells, and the ratios of cells
and their functions are skewed toward Th2. This results in loss of
cytotoxic T-lymphocyte activity, loss of delayed hypersensitivity,
and hypergammaglobulinemia.
■■ IMMUNOSUPPRESSIVE
THERAPY
Immunosuppressive agents have proved very useful in minimizing
the occurrence or impact of deleterious effects of exaggerated or
inappropriate immune responses. Unfortunately, these agents also
have the potential to cause disease and to increase the risk of infec-
tion and malignancies.
GLUCOCORTICOIDS
Glucocorticoids (corticosteroids) were the first hormonal agents
recognized as having lympholytic properties. Administration of
any glucocorticoid reduces the size and lymphoid content of the
lymph nodes and spleen, although it has no toxic effect on prolif-
erating myeloid or erythroid stem cells in the bone marrow.
Glucocorticoids are thought to interfere with the cell cycle
of activated lymphoid cells. The mechanism of their action is
described in Chapter 39. Glucocorticoids are quite cytotoxic
to certain subsets of T cells, but their immunologic effects are
probably due to their ability to modify cellular functions rather
than to direct cytotoxicity. Although cellular immunity is more
affected than humoral immunity, the primary antibody response
can be diminished, and with continued use, previously established
antibody responses also are decreased. Additionally, continuous
administration of corticosteroid increases the fractional catabolic
rate of IgG, the major class of antibody immunoglobulins, thus
lowering the effective concentration of specific antibodies. Con-
tact hypersensitivity mediated by DTH T cells, for example, is
usually abrogated by glucocorticoid therapy.
Glucocorticoids are used in a wide variety of conditions
(Table 55–1). It is thought that the immunosuppressive and
anti-inflammatory properties of corticosteroids account for their
beneficial effects in diseases like idiopathic thrombocytopenic
purpura and rheumatoid arthritis. Glucocorticoids modulate
allergic reactions and are useful in the treatment of diseases like

TABLE 55–1  Clinical uses of immunosuppressive agents.

Source Immunopharmacologic Agents Used Response

Autoimmune diseases
1
 Idiopathic thrombocytopenic Prednisone, vincristine, occasionally cyclophosphamide, mercaptopurine, or azathioprine; Usually good
purpura (ITP) commonly high-dose gamma globulin, plasma immunoadsorption or plasma exchange
1
 Autoimmune hemolytic Prednisone, cyclophosphamide, chlorambucil, mercaptopurine, azathioprine, high-dose Usually good
anemia gamma globulin
 Acute glomerulonephritis Prednisone,1 mercaptopurine, cyclophosphamide Usually good
 Acquired factor XIII antibodies Cyclophosphamide plus factor XIII Usually good
 Autoreactive tissue disorders Prednisone, cyclophosphamide, methotrexate, interferon-α and -β, azathioprine, Often good,
(autoimmune diseases)2 cyclosporine, infliximab, etanercept, adalimumab variable
Isoimmune disease
 Hemolytic disease of the Rho(D) immune globulin Excellent
newborn
Organ transplantation
 Renal Cyclosporine, azathioprine, prednisone, ALG, OKT3, tacrolimus, basiliximab,3 daclizumab,3 Very good
sirolimus
 Heart Cyclosporine, azathioprine, prednisone, ALG, OKT3, tacrolimus, basiliximab,3 daclizumab,3 Good
sirolimus
 Liver Cyclosporine, prednisone, azathioprine, tacrolimus, sirolimus Fair
  Bone marrow Cyclosporine, cyclophosphamide, prednisone, methotrexate, ALG Good
Prevention of cell proliferation
  Coronary stents Sirolimus (impregnated stent) Good
 Neovascular macular Ranibizumab (labeled), bevacizumab (off-label) Fair
degeneration
1
Drug of choice.
2
Including systemic lupus erythematosus, rheumatoid arthritis, scleroderma, dermatomyositis, mixed tissue disorder, multiple sclerosis, Wegener’s granulomatosis, chronic active
hepatitis, lipoid nephrosis, and inflammatory bowel disease.
3
Basiliximab and daclizumab are approved for renal transplant only.
986    SECTION VIII  Chemotherapeutic Drugs
asthma or as premedication for other agents (eg, blood products,
chemotherapy) that might cause undesirable immune responses.
Glucocorticoids are first-line immunosuppressive therapy for both
solid organ and hematopoietic stem cell transplant recipients, with
variable results. The toxicities of long-term glucocorticoid therapy
can be severe and are discussed in Chapter 39.
CALCINEURIN INHIBITORS
Cyclosporine
Cyclosporine (cyclosporin A, CSA) is an immunosuppressive
agent with efficacy in human organ transplantation, in the
treatment of graft-versus-host (GVH) disease after hematopoi-
etic stem cell transplantation, and in the treatment of selected
autoimmune disorders. Cyclosporine is a peptide antibiotic that
appears to act at an early stage in the antigen receptor–induced
differentiation of T cells and blocks their activation. Cyclospo-
rine binds to cyclophilin, a member of a class of intracellular
proteins called immunophilins. Cyclosporine and cyclophilin
form a complex that inhibits the cytoplasmic phosphatase,
calcineurin, which is necessary for the activation of a T cell–
specific transcription factor. This transcription factor, NF-AT, is
involved in the synthesis of interleukins (eg, IL-2) by activated
T cells. In vitro studies have indicated that cyclosporine inhibits
the gene transcription of IL-2, IL-3, IFN-γ, and other factors
produced by antigen-stimulated T cells, but it does not block
the effect of such factors on primed T cells nor does it block
interaction with antigen.
Cyclosporine may be given intravenously or orally, though it is
slowly and incompletely absorbed (20–50%). The absorbed drug
is primarily metabolized by the P450 3A enzyme system in the
liver with resultant multiple drug interactions. This propensity
for drug interactions contributes to significant interpatient vari-
ability in bioavailability, such that cyclosporine requires individual
patient dosage adjustments based on steady-state blood levels and
the desired therapeutic ranges for the drug. Cyclosporine ophthal-
mic solution is now available for severe dry eye syndrome, as well
as ocular GVH disease. Inhaled cyclosporine is being investigated
for use in lung transplantation.
Toxicities are numerous and include nephrotoxicity, hyper-
tension, hyperglycemia, liver dysfunction, hyperkalemia, altered
mental status, seizures, and hirsutism. Cyclosporine causes very
little bone marrow toxicity. While an increased incidence of lym-
phoma and other cancers (Kaposi’s sarcoma, skin cancer) have
been observed in transplant recipients receiving cyclosporine,
other immunosuppressive agents may also predispose recipients
to cancer. Some evidence suggests that tumors may arise after
cyclosporine treatment because the drug induces TGF-β, which
promotes tumor invasion and metastasis.
Cyclosporine may be used alone or in combination with
other immunosuppressants, particularly glucocorticoids. It has
been used successfully as the sole immunosuppressant for cadav-
eric transplantation of the kidney, pancreas, and liver, and it
has proved extremely useful in cardiac transplantation as well.
In combination with methotrexate, cyclosporine is a standard
prophylactic regimen to prevent GVH disease after allogeneic
stem cell transplantation. Cyclosporine has also proved useful in
a variety of autoimmune disorders, including uveitis, rheumatoid
arthritis, psoriasis, and asthma. Its combination with newer agents
is showing considerable efficacy in clinical and experimental set-
tings where effective and less toxic immunosuppression is needed.
Newer formulations of cyclosporine are improving patient com-
pliance (smaller, better-tasting pills) and increasing bioavailability.
Tacrolimus
Tacrolimus (FK 506) is an immunosuppressant macrolide anti-
biotic produced by Streptomyces tsukubaensis. It is not chemically
related to cyclosporine, but their mechanisms of action are simi-
lar. Both drugs bind to cytoplasmic peptidylprolyl isomerases
that are abundant in all tissues. While cyclosporine binds to
cyclophilin, tacrolimus binds to the immunophilin FK-binding
protein (FKBP). Both complexes inhibit calcineurin, which is
necessary for the activation of the T cell–specific transcription
factor NF-AT.
On a weight basis, tacrolimus is 10–100 times more potent
than cyclosporine in inhibiting immune responses. Tacrolimus
is utilized for the same indications as cyclosporine, particularly
in organ and stem cell transplantation. Multicenter studies in
the USA and in Europe indicate that both graft and patient
survival are similar for the two drugs. Tacrolimus has proven
to be effective therapy for preventing rejection in solid organ
transplant patients even after failure of standard rejection therapy,
including anti–T-cell antibodies. It is now considered a standard
prophylactic agent (usually in combination with methotrexate or
mycophenolate mofetil) for GVH disease.
Tacrolimus can be administered orally or intravenously. The
half-life of the intravenous form is approximately 9–12 hours.
Like cyclosporine, tacrolimus is metabolized primarily by P450
enzymes in the liver, and there is potential for drug interactions.
The dosage is determined by trough blood level at steady state. Its
toxic effects are similar to those of cyclosporine and include neph-
rotoxicity, neurotoxicity, hyperglycemia, hypertension, hyperkale-
mia, and gastrointestinal complaints.
Because of the effectiveness of systemic tacrolimus in some
dermatologic diseases, a topical preparation is now available.
Tacrolimus ointment is currently used in the therapy of atopic
dermatitis and psoriasis.
PROLIFERATION SIGNAL INHIBITORS
A newer class of immunosuppressive agents called proliferation-
signal inhibitors (PSIs) includes sirolimus (rapamycin) and its
derivative everolimus. The mechanism of action of PSIs differs
from that of the calcineurin inhibitors. PSIs bind the circulating
immunophilin FK506-binding protein 12, resulting in an active
complex that blocks the molecular target of rapamycin (mTOR).
The mTOR is a key component of a complex intracellular signal-
ing pathway involved in cellular processes such as cell growth and
proliferation, angiogenesis, and metabolism. Thus, blockade of
mTOR ultimately can lead to inhibition of interleukin-driven

T-cell proliferation. Both everolimus and sirolimus also may
inhibit B-cell proliferation and immunoglobulin production.
Sirolimus is available only as an oral drug. Its half-life is about
60 hours, while that of everolimus is about 43 hours. Both drugs
are rapidly absorbed and elimination is similar to that of cyclospo-
rine and tacrolimus, being substrates for both cytochrome P450
3A and P-glycoprotein. Hence, significant drug interactions can
occur. For example, use with cyclosporine can increase the plasma
levels of both sirolimus and everolimus such that drug levels need
to be monitored. Target dose-ranges of these drugs vary depending
on clinical use.
Sirolimus has been used effectively alone and in combination
with other immunosuppressants (corticosteroids, cyclosporine,
tacrolimus, and mycophenolate mofetil) to prevent rejection of
solid organ allografts. It is used as prophylaxis and as therapy
for steroid-refractory acute and chronic GVH disease in hema-
topoietic stem cell transplant recipients. Topical sirolimus is
also used in some dermatologic disorders and, in combination
with cyclosporine, in the management of uveoretinitis. Recently,
sirolimus-eluting coronary stents have been shown to reduce
restenosis and additional adverse cardiac events in patients with
severe coronary artery disease, due to the drug’s antiproliferative
effects. Everolimus is a newer drug that has shown clinical efficacy
similar to sirolimus in solid organ transplant recipients; it is under
investigation as an additional therapeutic agent for the treatment
of chronic cardiac allograft vasculopathy.
Toxicities of the PSIs can include profound myelosuppression
(especially thrombocytopenia), hepatotoxicity, diarrhea, hypertri-
glyceridemia, pneumonitis, and headache. Because nephrotoxicity
is of major concern when administering calcineurin inhibitors,
and since renal toxicity is less common with PSIs, there is interest
in increased early use of the latter agents. However, increased use
in stem cell transplantation regimens as GVH disease prophylaxis,
particularly when combined with tacrolimus, has revealed an
increased incidence of hemolytic-uremic syndrome.
Tofacitinib (Xeljanz) inhibits JAK enzymes that stimulate
hematopoiesis and immune cell function in response to cyto-
kine or growth factor signaling. Tofacitinib reduces circulating
NK cells, serum immunoglobulins, and C-reactive protein. It is
approved for adults with moderate to severe RA. It has a black
box warning for serious infections and malignancies, similar to
anti–TNF-α Mabs (see below).
MYCOPHENOLATE MOFETIL
Mycophenolate mofetil (MMF) is a semisynthetic derivative of
mycophenolic acid, isolated from the mold Penicillium glaucus. In
vitro, it inhibits T- and B-lymphocyte responses, including mito-
gen and mixed lymphocyte responses, probably by inhibition of
de novo synthesis of purines. Mycophenolate mofetil is hydrolyzed
to mycophenolic acid, the active immunosuppressive moiety; it is
synthesized and administered as MMF to enhance bioavailability.
Mycophenolate mofetil is available in both oral and intrave-
nous forms. The oral form is rapidly metabolized to mycophenolic
acid. Although the cytochrome P450 3A system is not involved,
CHAPTER 55  Immunopharmacology    987
some drug interactions still occur. Plasma drug levels should be
monitored frequently.
Mycophenolate mofetil is used in solid organ transplant
patients for refractory rejection and, in combination with pred-
nisone, as an alternative to cyclosporine or tacrolimus in patients
who do not tolerate those drugs. Its antiproliferative properties
make it the first-line drug for preventing or reducing chronic
allograft vasculopathy in cardiac transplant recipients. Mycophe-
nolate mofetil is used as prophylaxis for and treatment of both
acute and chronic GVH disease in hematopoietic stem cell trans-
plant patients. Newer immunosuppressant applications for MMF
include lupus nephritis, rheumatoid arthritis, inflammatory bowel
disease, and some dermatologic disorders.
Toxicities include gastrointestinal disturbances (nausea and
vomiting, diarrhea, abdominal pain) headache, hypertension, and
reversible myelosuppression (primarily neutropenia).
THALIDOMIDE
Thalidomide is an oral sedative drug that was withdrawn from
the market in the 1960s because of disastrous teratogenic effects
when used during pregnancy. Nevertheless, it has significant
immunomodulatory actions and is currently in active use or
in clinical trials for more than 40 different illnesses. Tha-
lidomide inhibits angiogenesis and has anti-inflammatory and
immunomodulatory effects. It inhibits tumor necrosis factor-
alpha (TNF-α), reduces phagocytosis by neutrophils, increases
production of IL-10, alters adhesion molecule expression, and
enhances cell-mediated immunity via interactions with T cells.
The complex actions of thalidomide continue to be studied as
its clinical use evolves.
Thalidomide is currently used in the treatment of multiple
myeloma at initial diagnosis and for relapsed-refractory disease.
Patients generally show signs of response within 2–3 months
of starting the drug, with response rates of 20–70%. When
combined with dexamethasone, the response rates in myeloma
are 90% or more in some studies. Many patients have durable
responses—up to 12–18 months in refractory disease and even
longer in some patients treated at diagnosis. The success of tha-
lidomide in myeloma has led to numerous clinical trials in other
diseases such as myelodysplastic syndrome, acute myelogenous
leukemia, and GVH disease, as well as in solid tumors like colon
cancer, renal cell carcinoma, melanoma, and prostate cancer, with
variable results to date. Thalidomide has been used for many years
in the treatment of some manifestations of leprosy and has been
reintroduced in the USA for erythema nodosum leprosum; it is
also useful in management of the skin manifestations of lupus
erythematosus.
The adverse effect profile of thalidomide is extensive. The most
important toxicity is teratogenesis. Because of this effect, thalido-
mide prescription and use is closely regulated by the manufacturer.
Other adverse effects of thalidomide include peripheral neuropa-
thy, constipation, rash, fatigue, hypothyroidism, and increased
risk of deep-vein thrombosis. Thrombosis is sufficiently frequent,
particularly in the hematologic malignancy population, that most
988    SECTION VIII  Chemotherapeutic Drugs
patients are placed on some type of anticoagulant when thalido-
mide treatment is initiated.
Owing to thalidomide’s serious toxicity profile, considerable
effort has been expended in the development of analogs. Immuno-
modulatory derivatives of thalidomide are termed IMiDs. Some
IMiDs are much more potent than thalidomide in regulating
cytokines and affecting T-cell proliferation. Lenalidomide is an
oral IMiD that in animal and in vitro studies has been shown to be
similar to thalidomide in action, but with less toxicity, especially
teratogenicity. Lenalidomide was approved by the FDA when tri-
als showed its effectiveness in the treatment of the myelodysplastic
syndrome with the chromosome 5q31 deletion. Clinical trials
using lenalidomide to treat multiple myeloma showed similar effi-
cacy, leading to approval for both primary and relapsed/refractory
myeloma. Pomalidomide (originally called CC-4047) is a newer
oral IMiD that is FDA approved. Like the other IMiDs, it has
myriad mechanisms of actions including antiangiogenic activity,
inhibition of TNF-α, and stimulation of apoptosis and cytotoxic
T-cell activity. Most clinical trials of pomalidomide have targeted
patients with relapsed/refractory multiple myeloma, for which the
FDA approved the drug in 2013. Both lenalidomide and pomalid-
omide have side effect profiles similar to that of thalidomide.
CYTOTOXIC AGENTS
Azathioprine
Azathioprine is a prodrug of mercaptopurine and, like mer-
captopurine, functions as an antimetabolite (see Chapter 54).
Although its action is presumably mediated by conversion to
mercaptopurine and further metabolites, it has been more widely
used than mercaptopurine for immunosuppression in humans.
These agents represent prototypes of the antimetabolite group
of cytotoxic immunosuppressive drugs, and many other agents
that kill proliferative cells appear to work at a similar level in the
immune response.
Azathioprine is well absorbed from the gastrointestinal tract
and is metabolized primarily to mercaptopurine. Xanthine oxidase
converts much of the active material to 6-thiouric acid prior to
excretion in the urine. After administration of azathioprine, small
amounts of unchanged drug and mercaptopurine are also excreted
by the kidney, and as much as a twofold increase in toxicity may
occur in anephric or anuric patients. Since much of the drug’s
inactivation depends on xanthine oxidase, patients who are also
receiving allopurinol (see Chapters 36 and 54) for control of
hyperuricemia should have the dose of azathioprine reduced to
one-fourth to one-third the usual amount to prevent excessive
toxicity.
Azathioprine and mercaptopurine appear to produce immuno-
suppression by interfering with purine nucleic acid metabolism at
steps that are required for the wave of lymphoid cell proliferation
that follows antigenic stimulation. The purine analogs are thus
cytotoxic agents that destroy stimulated lymphoid cells. Although
continued messenger RNA synthesis is necessary for sustained
antibody synthesis by plasma cells, these analogs appear to have
less effect on this process than on nucleic acid synthesis in prolif-
erating cells. Cellular immunity as well as primary and secondary
serum antibody responses can be blocked by these agents.
Azathioprine and mercaptopurine appear to be of definite
benefit in maintaining renal allografts and may be of value in
transplantation of other tissues. These antimetabolites have
also been used with some success in the management of acute
glomerulonephritis, in the renal component of systemic lupus
erythematosus, and in some cases of rheumatoid arthritis, Crohn’s
disease, and multiple sclerosis. The drugs have been of occasional
use in prednisone-resistant antibody-mediated idiopathic throm-
bocytopenic purpura and autoimmune hemolytic anemias.
The chief toxic effect of azathioprine and mercaptopurine
is bone marrow suppression, usually manifested as leukopenia,
although anemia and thrombocytopenia may occur. Skin rashes,
fever, nausea and vomiting, and sometimes diarrhea occur, with
the gastrointestinal symptoms seen mainly at higher dosages.
Hepatic dysfunction, manifested by very high serum alkaline
phosphatase levels and mild jaundice, occurs occasionally, particu-
larly in patients with preexisting hepatic dysfunction.
Cyclophosphamide
The alkylating agent cyclophosphamide is one of the most effica-
cious immunosuppressive drugs available. Cyclophosphamide
destroys proliferating lymphoid cells (see Chapter 54) but also
appears to alkylate some resting cells. It has been observed that
very large doses (eg, >120 mg/kg intravenously over several days)
may induce an apparent specific tolerance to a new antigen if the
drug is administered simultaneously with, or shortly after, the
antigen. In smaller doses, it has been effective against autoim-
mune disorders (including systemic lupus erythematosus) and in
patients with acquired factor XIII antibodies and bleeding syn-
dromes, autoimmune hemolytic anemia, antibody-induced pure
red cell aplasia, and Wegener’s granulomatosis.
Treatment with large doses of cyclophosphamide carries con-
siderable risk of pancytopenia and therefore is generally combined
with stem cell rescue (transplant) procedures. Although cyclo-
phosphamide appears to induce tolerance for marrow or immune
cell grafting, its use does not prevent the subsequent GVH
syndrome, which may be serious or lethal if the donor is a poor
histocompatibility match (despite the severe immunosuppression
induced by high doses of cyclophosphamide). The drug may also
cause hemorrhagic cystitis, which can be prevented or treated
with mesna. Other adverse effects of cyclophosphamide include
nausea, vomiting, cardiac toxicity, and electrolyte disturbances.
Pyrimidine Synthesis Inhibitors
Leflunomide is a prodrug of an inhibitor of pyrimidine syn-
thesis. Teriflunomide is the principal active metabolite of leflu-
nomide. They both reversibly inhibit the mitochondrial enzyme
dihydroorotate dehydrogenase, which is involved in pyrimidine
synthesis and ultimately results in decreased lymphocyte activa-
tion. They have anti-inflammatory activity in addition to immu-
nomodulatory properties.

Leflunomide is orally active, and the active metabolite has a
long half-life of several weeks. Thus, the drug should be started
with a loading dose, but it can be taken once daily after reach-
ing steady state. It is approved only for rheumatoid arthritis at
present, though studies are underway combining leflunomide
with mycophenolate mofetil for a variety of autoimmune and
inflammatory skin disorders, as well as preservation of allografts
in solid organ transplantation. Leflunomide also appears (from
murine data) to have antiviral activity. Toxicities include eleva-
tion of liver enzymes with some risk of liver damage and renal
impairment. Patients with severe liver disease should not receive
leflunomide. This drug is teratogenic and contraindicated in
pregnancy. A low frequency of cardiovascular effects (angina,
tachycardia) has been reported.
Teriflunomide is FDA-approved for the treatment of relapsing-
remitting multiple sclerosis. Although immunomodulatory, its
exact mechanism of action in the treatment of multiple sclerosis
is unclear. It is hypothesized to decrease the number of activated
lymphocytes in the central nervous system. It is a once-daily oral
drug that, unlike leflunomide, does not require a loading dose.
Teriflunomide’s side effect profile is similar to that of leflunomide,
and it is contraindicated in pregnancy and severe liver disease. The
incidence of neutropenia in patients taking the drug is 15%, and
10% of patients have a decrease in platelet counts.
Hydroxychloroquine
Hydroxychloroquine is an antimalarial agent with immunosup-
pressant properties. It is thought to suppress intracellular antigen
processing and loading of peptides onto MHC class II molecules
by increasing the pH of lysosomal and endosomal compartments,
thereby decreasing T-cell activation.
Because of these immunosuppressant activities, hydroxychlo-
roquine is used to treat some autoimmune disorders (see Chapter
36), eg, rheumatoid arthritis and systemic lupus erythematosus.
It has also been used to both treat and prevent GVH disease after
allogeneic stem cell transplantation.
Other Cytotoxic Agents
Other cytotoxic agents, including methotrexate, vincristine,
and cytarabine (see Chapter 54), also have immunosuppressive
properties. Methotrexate has been used extensively in rheumatoid
arthritis (see Chapter 36) and in the treatment of GVH disease.
Although the other agents can be used for immunosuppression,
their use has not been as widespread as the purine antagonists,
and their indications for immunosuppression are less certain. The
use of methotrexate (which can be given orally) appears reason-
able in patients with idiosyncratic reactions to purine antagonists.
The antibiotic dactinomycin has also been used with some success
at the time of impending renal transplant rejection. Vincristine
appears to be quite useful in idiopathic thrombocytopenic pur-
pura refractory to prednisone. The related vinca alkaloid vinblas-
tine has been shown to prevent mast cell degranulation in vitro by
binding to microtubule units within the cell and to prevent release
of histamine and other vasoactive compounds.
CHAPTER 55  Immunopharmacology    989
Pentostatin is an adenosine deaminase inhibitor that has been
used mainly as an antineoplastic agent for lymphoid malignan-
cies; it produces a profound lymphopenia. It is now frequently
used for steroid-resistant GVH disease after allogeneic stem cell
transplantation, as well as in preparative regimens prior to those
transplants to provide severe immunosuppression to prevent
allograft rejection.
Miscellaneous Agents
Three other FDA-approved immunomodulators are used exclu-
sively in the treatment of relapsing-remitting multiple sclerosis.
Dimethyl fumarate (DMF) is the methyl ester of fumaric
acid. Its exact mechanism of action is unknown, but it appears to
activate the nuclear factor (erythroid-derived 2)-like 2 (NRF-2)
transcriptional pathway. Activation of the NRF-2 pathway results
in reduction of the oxidative stress that contributes to demyelin-
ation; it also appears to help protect the nerve cells from inflam-
mation. DMF is given orally. Lymphopenia may be significant, so
blood counts must be monitored regularly and the drug may be
withheld if active infection is present. Flushing is common with
treatment initiation and usually improves with time. Other less
common adverse effects include nausea, diarrhea, abdominal pain,
increased hepatic enzymes, and eosinophilia.
Glatiramer acetate (GA) is a mixture of synthetic polypep-
tides and four amino acids (l-glutamic acid, l-alanine, l-lysine,
and l-tyrosine) in a fixed molar ratio. Its mechanism of immu-
nomodulation in multiple sclerosis is unknown. Studies suggest
that GA downregulates the immune response to myelin antigens
by induction and activation of suppressor T cells that migrate to
the central nervous system. It is given as a subcutaneous injection
(not intravenously) in variable dosages and schedules. Toxicities
include skin hypersensitivity, and rarely lipoatrophy and skin
necrosis at the injection site. Other adverse effects include flush-
ing, chest pain, dyspnea, throat constriction, and palpitations, all
of which are usually mild and self-limited.
Fingolimod hydrochloride (FH) is an orally active sphingo-
sine 1-phosphate (S1P) receptor modulator that is derived from
the fungal metabolite myriocin. The S1P receptor (subtype 1)
controls the release of lymphocytes from lymph nodes and the
thymus. FH is metabolized to fingolimod phosphate, which
subsequently binds the S1P receptor and ultimately decreases
circulating lymphocyte numbers in the periphery and central
nervous system. S1P receptors are also expressed on neurons, such
that FH may also be affecting neurodegeneration, gliosis, and
endogenous repair mechanisms as well as resulting in lymphope-
nia to modify disease activity in multiple sclerosis. FH can cause
serious cardiac toxicity including bradycardia, prolongation of the
QT interval, and other abnormalities. Because of these potential
complications, the drug requires cardiac monitoring for 6 hours
after the first dose is given. FH is contraindicated in patients with
preexisting conditions such as type II or III heart block, prolonged
QTc, recent myocardial infarction, or heart failure. Less common
adverse effects include macular edema, elevated hepatic enzymes,
headache, diarrhea, and cough. The drug is metabolized primarily
990    SECTION VIII  Chemotherapeutic Drugs
by the cytochrome P450 system; thus caution is needed when it
is used in combination with other drugs metabolized in the same
manner.
IMMUNOSUPPRESSIVE ANTIBODIES
The development of hybridoma technology by Milstein and
Köhler in 1975 revolutionized the antibody field and radically
increased the purity and specificity of antibodies used in the clinic
and for diagnostic tests in the laboratory. Hybridomas are B cells
fused to immortal plasmacytoma cells that secrete monoclonal
antibodies specific for a target antigen. Large-scale hybridoma
culture facilities are employed by the pharmaceutical industry to
produce diagnostic and clinical-grade monoclonal antibodies.
More recently, molecular biology has been used to develop
monoclonal antibodies. Combinatorial libraries of cDNAs encod-
ing immunoglobulin heavy and light chains expressed on bac-
teriophage surfaces are screened against purified antigens. The
result is an antibody fragment with specificity and high affinity for
the antigen of interest. This technique has been used to develop
antibodies specific for viruses (eg, HIV), bacterial proteins, tumor
antigens, and even cytokines. Many antibodies developed in this
manner are FDA-approved for use in humans.
Other genetic engineering techniques involve production of
chimeric and humanized versions of murine monoclonal antibod-
ies in order to reduce their antigenicity and increase the half-life
of the antibody in the patient. Murine antibodies administered
as such to human patients elicit production of human antimouse
antibodies (HAMAs), which clear the original murine proteins
very rapidly. Humanization involves replacing most of the murine
antibody with equivalent human regions while keeping only the
variable, antigen-specific regions intact. Chimeric mouse-human
antibodies have similar properties with less complete replacement
of the murine components. The current naming convention for
these engineered substances uses the suffix “-umab” or “-zumab”
for humanized antibodies, and “-imab” or “-ximab” for chimeric
products. These molecular engineering procedures have been suc-
cessful in reducing or preventing HAMA production for many of
the antibodies discussed below.
Antilymphocyte & Antithymocyte
Antibodies, & Chimeric Molecules
Antisera directed against lymphocytes have been prepared spo-
radically for over 100 years. With the advent of human organ
transplantation as a realistic therapeutic option, heterologous
antilymphocyte globulin (ALG) took on new importance. ALG
and antithymocyte globulin (ATG) are now in clinical use in
many medical centers, especially in transplantation programs. The
antiserum is usually obtained by immunization of horses, sheep,
or rabbits with human lymphoid cells.
ALG acts primarily on the small, long-lived peripheral lympho-
cytes that circulate between the blood and lymph. With continued
administration, “thymus-dependent” (T) lymphocytes from lym-
phoid follicles also are depleted, as they normally participate in
the recirculating pool. As a result of the destruction or inactivation
of T cells, an impairment of delayed hypersensitivity and cellular
immunity occurs while humoral antibody formation remains
relatively intact. ALG and ATG are useful for suppressing certain
major compartments (ie, T cells) of the immune system and play
a definite role in the management of solid organ and bone marrow
transplantation.
Monoclonal antibodies directed against specific cell surface
proteins such as CD2, CD3, CD25, or cytokine receptors and
various integrins much more selectively influence T-cell subset
function. The high specificity of these antibodies improves selec-
tivity and reduces toxicity of the therapy, altering the disease
course in several different autoimmune disorders.
In the management of transplants, ALG and monoclonal anti-
bodies can be used in the induction of immunosuppression, in
the treatment of initial rejection, and in the treatment of steroid-
resistant rejection. There has been some success in the use of ALG
and ATG plus cyclosporine to prepare recipients for bone marrow
transplantation. In this procedure, the recipient is treated with
ALG or ATG in large doses for 7–10 days prior to transplantation
of bone marrow cells from the donor. ALG appears to destroy the
T cells in the donor marrow graft, and the probability of severe
GVH disease is reduced.
The adverse effects of ALG are mostly those associated with
injection of a foreign protein. Local pain and erythema often
occur at the injection site (type III hypersensitivity). Since the
humoral antibody response remains active in the recipient, skin-
reactive and precipitating antibodies may be formed against the
foreign ALG. Similar reactions occur with monoclonal antibodies
of murine origin caused by the release of cytokines by T cells and
monocytes.
Anaphylactic and serum sickness reactions to ALG and murine
monoclonal antibodies have been observed and usually require
cessation of therapy. Complexes of host antibodies with horse
ALG may precipitate and localize in the glomeruli of the kidneys
causing kidney damage.
Immune Globulin Intravenous (IGIV)
A different approach to immunomodulation is the intravenous
use of polyclonal human immunoglobulin. This immunoglobulin
preparation (usually IgG) is prepared from pools of thousands of
healthy donors, and no single, specific antigen is the target of the
“therapeutic antibody.” Rather, one expects that the pool of dif-
ferent antibodies will have a normalizing effect upon the patient’s
immune networks.
IGIV in high doses (2 g/kg) has proved effective in a variety
of different applications ranging from immunoglobulin deficien-
cies to autoimmune disorders to HIV disease to bone marrow
transplantation. In patients with Kawasaki’s disease, it has been
shown to be safe and effective, reducing systemic inflammation
and preventing coronary artery aneurysms. It has also brought
about good clinical responses in systemic lupus erythemato-
sus and refractory idiopathic thrombocytopenic purpura. Pos-
sible mechanisms of action of IGIV include a reduction of T
helper cells, increase of regulatory T cells, decreased spontaneous

immunoglobulin production, Fc receptor blockade, increased
antibody catabolism, and idiotypic–anti-idiotypic interactions
with “pathologic antibodies.” Although its precise mechanism of
action is still unknown, IGIV brings undeniable clinical benefit to
many patients with a variety of immune syndromes.
Rho(D) Immune Globulin
One of the earliest major advances in immunopharmacology was
the development of a technique for preventing Rh hemolytic
disease of the newborn. The technique is based on the observa-
tion that a primary antibody response to a foreign antigen can be
blocked if specific antibody to that antigen is administered pas-
sively at the time of exposure to antigen. Rho(D) immune globulin
is a concentrated (15%) solution of human IgG containing high-
titer antibodies against the Rho(D) antigen of the red cell.
Sensitization of Rh-negative mothers to the D antigen occurs
usually at the time of birth of an Rho(D)-positive or Du-positive
infant, when fetal red cells leak into the mother’s bloodstream.
Sensitization might also occur occasionally with miscarriages or
ectopic pregnancies. In subsequent pregnancies, maternal anti-
body against Rh-positive cells is transferred to the fetus during
the third trimester, leading to the development of erythroblastosis
fetalis (hemolytic disease of the newborn).
If an injection of Rho(D) antibody is administered to the
Rh-negative mother within 24–72 hours after the birth of an Rh-
positive infant, the mother’s own antibody response to the foreign
Rho(D)-positive cells is suppressed because the infant’s red cells are
cleared from circulation before the mother can generate a B-cell
response against Rho(D). Therefore she has no memory B cells
that can activate upon subsequent pregnancies with an Rho(D)-
positive fetus.
When the mother has been treated in this fashion, Rh hemo-
lytic disease of the newborn has not been observed in subsequent
pregnancies. For this prophylactic treatment to be successful, the
mother must be Rho(D)-negative and Du-negative and must not
already be immunized to the Rho(D) factor. Treatment is also
often advised for Rh-negative mothers antepartum at 26–28
weeks’ gestation who have had miscarriages, ectopic pregnancies,
or abortions, when the blood type of the fetus is unknown. Note:
Rho(D) immune globulin is administered to the mother and must not
be given to the infant.
The usual dose of Rho(D) immune globulin is 2 mL intra-
muscularly, containing approximately 300 mcg anti-Rho(D) IgG.
Adverse reactions are infrequent and consist of local discomfort at
the injection site or, rarely, a slight temperature elevation.
Hyperimmune Immunoglobulins
Hyperimmune immunoglobulins are IGIV preparations made
from pools of selected human or animal donors with high titers
of antibodies against particular agents of interest such as viruses
or toxins (see also Appendix). Various hyperimmune IGIVs are
available for treatment of respiratory syncytial virus, cyto-
megalovirus, varicella zoster, human herpesvirus 3, hepatitis
B virus, rabies, tetanus, and digoxin overdose. Intravenous
CHAPTER 55  Immunopharmacology    991
administration of the hyperimmune globulins is a passive transfer
of high-titer antibodies that either reduces risk or reduces the
severity of infection. Rabies hyperimmune globulin is injected
around the wound and given intravenously. Tetanus hyperim-
mune globulin is administered intravenously when indicated for
prophylaxis. Rattlesnake and coral snake hyperimmune globu-
lins (antivenoms) are of equine or ovine origin and are effective
for North and South American rattlesnakes and some coral snakes
(but not Arizona coral snake). Equine and ovine antivenoms are
available for rattlesnake envenomations, but only equine antive-
nom is available for coral snake bite. An Arizona bark scorpion
antivenom is also available as equine (Fab)′2. This preparation
prevents neurologic manifestations of scorpion envenomation and
is generally used in young children and infants.
MONOCLONAL ANTIBODIES (Mabs)
Advances in the ability to manipulate the genes for immunoglobu-
lins have resulted in development of a wide array of humanized
and chimeric monoclonal antibodies directed against therapeutic
targets. As described above, the only murine elements of human-
ized monoclonal antibodies are the complementarity-determining
regions in the variable domains of immunoglobulin heavy and
light chains. Complementarity-determining regions are primarily
responsible for the antigen-binding capacity of antibodies. Chi-
meric antibodies typically contain antigen-binding murine vari-
able regions and human constant regions. The following are brief
descriptions of the engineered antibodies that have been approved
for clinical use; they are presented alphabetically by indication.
Antitumor Mabs
Alemtuzumab is a humanized IgG1 with a kappa chain that binds
to CD52 found on normal and malignant B and T lymphocytes,
NK cells, monocytes, macrophages, and a small population of
granulocytes. Alemtuzumab was previously approved for the treat-
ment of B-cell chronic lymphocytic leukemia (CLL) in patients
who have been treated with alkylating agents and have failed
fludarabine therapy. Alemtuzumab appears to deplete leukemic
(and normal) cells by direct antibody-dependent lysis. More
recently, alemtuzumab was approved by the EU for the treatment
of patients diagnosed with relapsing remitting multiple sclerosis.
In the latter, alemtuzumab depletes autoimmune inflammatory
T and B cells while the drug is in the circulation. Repopulating
lymphocytes appear to temporarily rebalance the immune system.
Patients receiving this antibody become lymphopenic and may
also become neutropenic, anemic, and thrombocytopenic. As
a result, patients should be closely monitored for opportunistic
infections and hematologic toxicity.
Bevacizumab is a humanized IgG1 monoclonal antibody that
binds to vascular endothelial growth factor (VEGF) and inhibits
VEGF from binding to its receptor, especially on endothelial cells. It
is an antiangiogenic drug that has been shown to inhibit growth of
blood vessels (angiogenesis) in tumors. It is approved for first- and
second-line treatment of patients with metastatic colorectal cancer
992    SECTION VIII  Chemotherapeutic Drugs
alone or in combination with appropriate chemotherapy. It is also
approved for treatment of non-small cell lung cancer, glioblastoma
multiforme that has progressed after prior treatment, and metastatic
kidney cancer when used with IFN-α. Since bevacizumab is anti-
angiogenic, it should not be administered until patients heal from
surgery. Patients taking the drug should be watched for hemorrhage,
gastrointestinal perforations, and wound healing problems. Bevaci-
zumab has also been used off label by intravitreal injection to slow
progression of neovascular macular degeneration (see ranibizumab
under Other Mabs, below).
Catumaxomab is a recombinant bi-specific trifunctional rat-
mouse IgG hybrid monoclonal antibody that targets the epithelial
cell adhesion molecule (EpCAM) on tumor cells and the CD3 pro-
tein on T cells. This bi-specific monoclonal antibody is approved in
the USA and EU as an orphan drug for treating abdominal ascites
in ovarian and gastric cancers. The rationale behind the bi-specific
characteristics of catumaxomab is that it brings CD3-expressing
anti-tumor T cells into close proximity of tumor cells expressing
EpCAM. The Fc portion of the antibody also recruits phagocytic
cells that mediate antibody-dependent cellular cytotoxicity and
complement, resulting in complement-dependent cytotoxicity of
tumor cells.
Cetuximab is a human-mouse chimeric monoclonal antibody
that targets epidermal growth factor receptor (EGFR). Binding
of cetuximab to EGFR inhibits tumor cell growth by a variety
of mechanisms, including decreases in kinase activity, matrix
metalloproteinase activity, and growth factor production, as well
as increased apoptosis. It is approved for use in patients with
EGFR-positive head and neck squamous cell carcinoma in com-
bination with radiotherapy or appropriate chemotherapy. It is also
approved for treatment of KRAS-negative, EGFR-positive meta-
static colorectal cancer in combination with radiotherapy or appro-
priate chemotherapy, or as a single agent in patients who cannot
tolerate certain chemotherapies. Cetuximab may be administered
in combination with irinotecan or alone in patients who cannot
tolerate irinotecan. HAMAs are generated by about 4% of patients
being treated with cetuximab.
Daratumumab binds to CD38, which is over-expressed on
myeloma cells. Binding of daratumumab to CD38 on myeloma
cells likely induces cell death by apoptosis, complement-dependent
cytotoxicity, or antibody-dependent cytotoxicity. It is approved by
the FDA for use in multiple myeloma patients who are refractory to
standard treatments, although phase III trials are ongoing regard-
ing its use as a frontline therapy. Elotuzumab is FDA approved
for the treatment of relapsed multiple myeloma. This Mab binds
signaling lymphocytic activation molecule F7 (SLAMF7) on
myeloma cells. It enables killing of multiple myeloma tumor cells
by antibody-dependent cell-mediated cytotoxicity (ADCC).
Dinutuximab is a ganglioside D2 (GD2)-binding Mab
approved for pediatric patients with high-risk neuroblastoma in
combination with granulocyte-macrophage colony-stimulating fac-
tor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA)
who achieve at least a partial response to prior first-line multiagent,
multimodality therapy. It has a black box warning for serious infu-
sion reactions and neurotoxicity in the majority of patients.
Necitumumab is a Mab directed against epidermal growth fac-
tor receptor (EGFR) and approved for use in patients with squa-
mous non-small cell lung cancer in combination with gemcitabine
and cisplatin. There is a black box warning for cardiopulmonary
arrest and hypomagnesemia.
Immune Checkpoint Inhibitor Mabs
Ipilimumab (Yervoy) binds to CTLA-4 on T cells, preventing
CD80/86 from delivering a suppressive signal to T cells. This has the
effect of maintaining T-cell activation. It is approved for the treatment
of unresectable or metastatic melanoma and treatment of cutaneous
melanoma with regional nodes in the adjuvant surgical setting.
Nivolumab, Pembrolizumab, and Atezolizumab allow
potential anti-tumor T cells to remain activated. By binding to
the PD-1 marker on T cells, nivolumab and pembrolizumab block
the binding of PD ligand-1 (PD-L1) on tumor cells, which sup-
presses T cell activity. Atezolizumab and avelumab bind to PD-L1
on tumor cells, also interfering with PD-1 signaling in T cells.
Nivolumab is approved for Hodgkin’s lymphoma, renal cell
carcinoma, non-small cell lung cancer, and melanoma. Pembro-
lizumab is approved for the treatment of head and neck cancer,
melanoma (and ipilimumab-resistant melanoma), Merkel cell car-
cinoma, non-small cell lung cancer, and cancers in HIV-positive
patients. Atezolizumab is approved for bladder cancer and is in
late-stage clinical trials for several other cancer types.
Panitumumab is a fully human IgG2 kappa light chain mono-
clonal antibody. It is approved for the treatment of EGFR-express-
ing metastatic colorectal carcinoma with disease progression on or
following fluoropyrimidine-, oxaliplatin-, and irinotecan-contain-
ing chemotherapy regimens. Panitumumab binds to EGFR (similar
to cetuximab), inhibiting epidermal growth factor from binding
to its receptor, and prevents ligand-induced receptor autophos-
phorylation and activation of receptor-associated kinases. It inhibits
cell growth, induces apoptosis, decreases vascular growth factor
production, and suppresses internalization of the EGFR. Although
dermatologic and infusion-related toxicities are common following
infusion of panitumumab, the distinct advantage over cetuximab
is that it is fully human (ie, does not elicit HAMAs) and thus has
an extended half-life in circulation. This is the first FDA-approved
monoclonal antibody produced from transgenic mice expressing the
human immunoglobulin gene loci.
Pertuzumab is a recombinant humanized IgG1 monoclonal
antibody. It is approved for the treatment of metastatic or locally
advanced HER-2/neu-positive breast cancer in combination with
trastuzumab (see below) and docetaxel as neoadjuvant therapy. This
antibody suppresses tumor growth by preventing heterodimeriza-
tion of the human epidermal growth factor receptor HER-2/neu
with other HER family members, thus inhibiting ligand-mediated
intracellular signaling through MAP kinase and PI3 kinase path-
ways. Pertuzumab also mediates antibody-dependent cell-mediated
cytotoxicity on HER-2/neu-positive tumor cells.
Ofatumumab is a human IgG1 monoclonal antibody directed
against an epitope on CD20 on lymphocytes. Rituximab, the first
approved CD20 monoclonal antibody (see below), also binds

CD20, but to a different epitope. Ofatumumab is approved for
patients with CLL who are refractory to fludarabine and alem-
tuzumab. Ofatumumab binds to all B cells including B-CLL.
It is thought to lyse B-CLL cells in the presence of complement
and to mediate antibody-dependent cellular cytotoxicity. There
is a slight risk of hepatitis B virus reactivation in patients taking
ofatumumab.
Ramucirumab is a human Mab that binds to VEGF receptor
2 on tumor cells as a receptor antagonist, blocking the binding of
VEGF to VEGFR2. It is FDA approved for the following indica-
tions: metastatic colon cancer in combination with a FOLFIRI
chemotherapy regimen (folinic acid, fluorouracil, and irinotecan),
platinum-resistant metastatic small cell lung cancer in combina-
tion with docetaxel, and advanced gastric or gastroesophageal
junction adenocarcinoma with or without paclitaxel.
Rituximab is a chimeric murine-human monoclonal IgG1
(human Fc) that binds to the CD20 molecule on normal and
malignant B lymphocytes and is approved for the therapy of
patients with CD20-positive large-B-cell diffuse non-Hodgkin’s
lymphoma, and relapsed or refractory low-grade or follicular
B-cell non-Hodgkin’s lymphoma as a single agent or in combina-
tion with appropriate chemotherapy. It is approved for treatment
of CLL in combination with chemotherapy. It is also approved
for the treatment of rheumatoid arthritis in combination with
methotrexate in patients for whom anti-TNF-α therapy has
failed. The most recent indication for rituximab is for the treat-
ment of Wegener’s granulomatosis and microscopic polyangiitis.
The mechanism of action includes complement-mediated lysis,
antibody-dependent cellular cytotoxicity, and induction of apop-
tosis in malignant lymphoma cells and in B cells involved in the
pathogenesis of rheumatoid arthritis and granulomatosis and
polyangiitis. In lymphoma this drug appears to be synergistic with
chemotherapy (eg, fludarabine, CHOP; see Chapter 54). Anemia
or neutropenia is an important adverse effect, which can be
countered with granulocyte colony-stimulating factor (G-CSF).
Other adverse effects include hypotension, rash, gastrointestinal
disturbance, fever, and fatigue.
Trastuzumab is a recombinant DNA-derived, humanized
monoclonal antibody that binds to the extracellular domain of
HER-2/neu. This antibody blocks the natural ligand from binding
and downregulates the receptor. Trastuzumab is approved for the
treatment of HER-2/neu-positive tumors in patients with breast
cancer and patients with metastatic gastric or gastroesophageal
junction adenocarcinoma. As a single agent it induces remission
in 15–20% of breast cancer patients; in combination with chemo-
therapy, it increases response rates and duration as well as 1-year
survival. Trastuzumab is under investigation for other tumors that
express HER-2/neu (see Chapter 54). Patients should be monitored
for potential cardiomyopathy while taking this drug.
Mabs Used to Deliver Isotopes
& Toxins to Tumors
Ado-trastuzumab emtansine is an antibody-drug conjugate in
which the anti-HER-2/neu antibody, trastuzumab (see above),
CHAPTER 55  Immunopharmacology    993
is chemically linked to the cytotoxic agent, mertansine, a micro-
tubule disruptor. Ado-trastuzumab emtansine is approved for
patients with HER-2/neu-positive breast cancer who have previ-
ously received trastuzumab and a taxane separately or in com-
bination, and whose disease recurred or progressed during prior
treatment. Toxicities are identical to trastuzumab alone and also
include hepatotoxicity due to emtansine.
Arcitumomab is a murine Fab fragment from an anti-carci-
noembryonic antigen (CEA) antibody labeled with technetium
99m
99m ( Tc) that is used for imaging patients with metastatic
colorectal carcinoma (immunoscintigraphy) to determine extent
of disease. CEA is often upregulated in patients with gastroin-
testinal carcinomas. The use of the Fab fragment decreases the
immunogenicity of the agent so that it can be given more than
once; intact murine monoclonal antibodies would elicit stronger
HAMA.
Brentuximab vedotin is an antibody-drug conjugate that
binds CD30, a cell surface marker in the TNF receptor superfam-
ily that is expressed on anaplastic large T-cell lymphomas and
on Reed-Sternberg cells in Hodgkin’s lymphoma; it may also be
expressed on activated leukocytes. Brentuximab vedotin consists
of a chimeric (mouse-human) IgG1 linked to monomethylau-
ristatin E (MMAE), a microtubule-disrupting agent that induces
cell cycle arrest and apoptosis. When this ADC binds CD30 on
the cell surface, the complex is internalized followed by proteolytic
cleavage of MMAE from the IgG. Brentuximab is approved for
treatment of patients with Hodgkin’s lymphoma after failure of
autologous stem cell transplantation or after failure of at least two
previous chemotherapy regimens. It is also approved for patients
with systemic anaplastic large cell lymphoma after failure of at
least one previous multiagent chemotherapy regimen. Patients
taking brentuximab vedotin should be monitored primarily for
neutropenia and peripheral sensory neuropathy.
Capromab pendetide is a murine monoclonal antibody spe-
cific for prostate specific membrane antigen. It is coupled to isoto-
pic indium (111In) and is used in immunoscintigraphy for patients
with biopsy-confirmed prostate cancer and post-prostatectomy in
patients with rising prostate-specific antibody level to determine
extent of disease.
Ibritumomab tiuxetan is an anti-CD20 murine monoclonal
antibody labeled with isotopic yttrium (90Y) or 111In. The radia-
tion of the isotope coupled to the antibody provides the major
antitumor activity of this drug. Ibritumomab is approved for
use in patients with relapsed or refractory low-grade, follicular,
or B-cell non-Hodgkin’s lymphoma, including patients with
rituximab-refractory follicular disease. It is used in conjunction
with rituximab in a two-step therapeutic regimen.
Mabs and Fusion Proteins
Used as Immunomodulatory &
Anti-Inflammatory Agents
Adalimumab, certolizumab pegol, etanercept, golimumab, and
infliximab are antibodies that bind and neutralize the biological
activity of TNF-α, a proinflammatory cytokine that is important
994    SECTION VIII  Chemotherapeutic Drugs

in adult and juvenile rheumatoid arthritis and similar inflamma-
tory diseases such as psoriatic arthritis, ankylosing spondylitis,
Crohn’s disease, and ulcerative colitis.
Abatacept and belatacept are recombinant fusion proteins
composed of the extracellular domain of cytotoxic T-lymphocyte-
associated antigen 4 (CTLA-4) fused to the Fc domains of human
IgG1 (Figure 55–7). Abatacept is approved for use in rheumatoid
and other forms of arthritis and is discussed in Chapter 36. Belata-
cept is approved to help prevent rejection in kidney transplants.
Both fusion proteins block the activation of T cells by binding
CD80, blocking the CD28 activation signal in T cells.
Anakinra is a recombinant form of the naturally occurring IL-1
receptor antagonist that prevents IL-1 from binding to its receptor,
stemming the cascade of cytokines that would otherwise be released.
Anakinra is approved for use in adult rheumatoid arthritis patients
who have failed treatment with one or more disease-modifying anti-
rheumatic drugs. Rilonacept is a dimeric fusion protein consisting
of the ligand-binding domains of the extracellular portions of the
human interleukin-1 receptor component (IL-1RI) and IL-1 recep-
tor accessory protein (IL-1RAcP) fused to the Fc portion of human
IgG1. These molecules are indicated for treatment of cryopyrin-
associated periodic syndromes.
Ixekizumab, secukinumab, and brodalumab are FDA-
approved for the treatment of patients with moderate to severe
plaque psoriasis. Ixekizumab and secukinumab bind the IL-17
cytokine and block it from binding to its receptor, while broda-
lumab blocks IL-17 by binding to the IL-17 receptor itself.
Reslizumab binds and neutralizes the biological activity of
IL-5, thereby suppressing the production and survival of eosino-
phils. It is approved for adult patients with severe eosinophilic
asthma. Mepolizumab also binds to IL-5 and selectively inhibits
eosinophilic inflammation in patients with severe eosinophilic
asthma.
Siltuximab is a Mab that binds to and blocks IL-6 from
binding to its cellular receptor. It is approved for the treatment
of patients with multicentric Castleman’s disease who are HIV-
negative and HHV-8-negative.
Tocilizumab is recombinant humanized IgG1 that binds to solu-
ble and membrane-associated IL-6 receptors. It inhibits IL-6-medi-
ated signaling on lymphocytes, suppressing inflammatory processes.
Similar to anti-TNF-α Mabs, patients receiving tocilizumab should
be closely monitored for infectious diseases such as tuberculosis and
other invasive bacterial, fungal, and viral infections.
Basiliximab is a chimeric mouse-human IgG1 that binds
to CD25, the IL-2 receptor α chain on activated lymphocytes.
Daclizumab is a humanized IgG1 that also binds to the α subunit
of the IL-2 receptor. Both agents function as IL-2 antagonists,
blocking IL-2 from binding to activated lymphocytes, and are
therefore immunosuppressive. They are indicated for prophylaxis
of acute organ rejection in renal transplant patients, and either
drug may be used as part of an immunosuppressive regimen that
also includes glucocorticoids and cyclosporine.
Belimumab is a Mab that inhibits B cell activating factor, also
known as B lymphocyte stimulator, preventing B cells from being
stimulated. It is approved for treatment of adults with active,
autoantibody-positive systemic lupus erythematosus (SLE) who
are also receiving standard therapy.
Canakinumab is a human IgG kappa chain monoclonal
antibody that prevents IL-1β from binding to its receptor. It is
approved for cryopyrin-associated periodic syndromes (CAPS)
in adults and children 4 years old and older. CAPS includes
familial cold autoinflammatory syndrome, Muckle-Wells syn-
drome, and systemic juvenile idiopathic arthritis in children 2
years old or older. These diseases are caused by mutations in a
gene (NLRP-3) that encodes cryopyrin, an important compo-
nent of the inflammasome. NLRP-3 mutations cause excessive

Alefacept
Basiliximab
LFA-3 and
CD2
Daclizumab
CD80/86 Abatacept CD28
CD25
Dendritic
cell
Ipilimumab CTLA-4
T cell

TCR Pembrolizumab
MHC
PD-1
Nivolumab
CD40 CD40L PD-L1 Tumor
cell
ICAM-1 LFA-1
T lymphocyte Atezolizumab
and
Antigen-
Avelumab
presenting cell

FIGURE 55–7  Actions of some monoclonal antibodies (shown in red). CTLA-4-lgFc fusion protein (CTLA-4-lg, abatacept) binds to CD80/86
on DC and inhibits T-cell costimulation. Alefacept inhibits activation of T cells by blocking the interaction of LFA-3 and CD2. Basiliximab and
daclizumab block IL-2 from binding to the IL-2 receptor (CD25) on T cells, preventing activation; CD25 is also important for the survival of
T regulatory cells. T-cell activation can be maintained or restored if CTLA-4 interaction with CD80/86 is blocked using an anti–CTLA-4 antibody
(ipilimumab); ipilimumab inhibits CTLA-4 signaling and prolongs activation. Pembrolizumab and nivolumab bind to PD-1, while atezolizumab
binds to PD-L1. Each of these three Mabs inhibits the negative signal delivery by PD-1, also prolonging T cell activation.

release of IL-1β, causing autoimmune inflammation resulting
in fever, urticarial-like rash, arthralgia, myalgia, fatigue, and
conjunctivitis.
Natalizumab is a humanized IgG4 monoclonal antibody that
binds to the α4-subunit of α4β1 and α4β7 integrins expressed
on the surfaces of all leukocytes except neutrophils. It inhibits the
α4-mediated adhesion of leukocytes to their cognate receptor. It
is indicated for patients with multiple sclerosis and Crohn’s disease
who have not tolerated or had inadequate responses to conven-
tional treatments. Natalizumab should not be used with any of
the anti-TNF-α drugs listed above. Natalizumab increases risk of
progressive multifocal leukoencephalopathy.
Omalizumab is an anti-IgE recombinant humanized mono-
clonal antibody that is approved for the treatment of allergic
asthma in adult and adolescent patients whose symptoms are
refractory to inhaled corticosteroids (see Chapter 20). The drug
is also approved for chronic urticaria. The antibody blocks the
binding of IgE to the high-affinity Fcε receptor on basophils
and mast cells, which suppresses IgE-mediated release of type I
allergy mediators such as histamine and leukotrienes. Total serum
IgE levels may remain elevated in patients for up to 1 year after
administration of omalizumab.
Ustekinumab is a human IgG1 monoclonal antibody that binds
to the p40 subunit of IL-12 and IL-23 cytokines. It blocks IL-12 and
IL-23 from binding to their receptors, therefore inhibiting receptor-
mediated signaling in lymphocytes. Ustekinumab is indicated for
adult patients with moderate to severe plaque psoriasis either alone
or with methotrexate. The advantage of ustekinumab over anti-
TNF-α drugs for psoriasis is faster and longer-term improvement in
symptoms along with very infrequent dosing.
Vedolizumab is a humanized monoclonal antibody that tar-
gets the α4β7 integrin in the gastrointestinal tract. It does not
appear to induce systemic immunosuppression of other α4β7
integrin-binding antibodies such as natalizumab because it does
not bind to the majority of α4β7 integrin on lymphocytes. It has
been recommended for approval for the treatment of adults with
Crohn’s disease and ulcerative colitis.
Other Mabs
Abciximab is a Fab fragment of a murine-human monoclonal
antibody that binds to the integrin GPIIb/IIIa receptor on acti-
vated platelets and inhibits fibrinogen, von Willebrand factor,
and other adhesion molecules from binding to activated platelets,
thus preventing their aggregation. It is indicated as an adjunct to
percutaneous coronary intervention in combination with aspirin
and heparin for the prevention of cardiac ischemic complications.
See Chapter 34 for additional details.
Alirocumab and Evolocumab are anti-cholesterol Mabs (see
Chapter 35). They lower LDL levels by blocking proprotein
convertase subtilisin/kexin type 9 (PCSK9) from binding to LDL
receptors (LDRL) and causing LDL receptor degradation. There-
fore, these Mabs have the effect of increasing LDLR on hepato-
cytes, which lowers LDL levels in circulation. They are approved
as an adjunct to diet and maximally tolerated statin therapy in
adults with homo- or heterozygous familial hypercholesterolemia
CHAPTER 55  Immunopharmacology    995
or atherosclerotic cardiovascular disease who require additional
lowering of LDL-C.
Denosumab is a human IgG2 monoclonal antibody specific
for human RANKL (receptor activator of nuclear factor kappa-
B ligand; see Chapter 42). By binding RANKL it inhibits the
maturation of osteoclasts, the cells responsible for bone resorp-
tion. Denosumab is indicated for treatment of postmenopausal
women with osteoporosis at high risk for fracture. Before starting
denosumab, patients must be evaluated to be sure they are not
hypocalcemic. During treatment, patients should receive supple-
ments of calcium and vitamin D.
Eculizumab is a humanized IgG monoclonal antibody that
binds the C5 complement component, inhibiting its cleavage
into C5a and C5b thereby inhibiting the terminal pore-forming
lytic activity of complement. Eculizumab is approved for patients
with paroxysmal nocturnal hemoglobinuria (PNH) and atypical
hemolytic uremic syndrome (aHUS). It dramatically reduces the
need for red blood cell transfusions. It prevents PNH symptoms of
anemia, fatigue, thrombosis, and hemoglobinemia by inhibiting
intravascular hemolysis. Similarly in aHUS eculizumab prevents
complement-mediated thrombotic microangiopathy. Clinicians
must be aware of increased risk of meningococcal infection in
patients receiving this anti-C5 monoclonal antibody.
Palivizumab is a humanized IgG1 monoclonal antibody that
binds to the fusion protein of respiratory syncytial virus (RSV), pre-
venting serious lower respiratory tract disease. It is used in neonates
at risk for this viral infection and reduces the frequency of infection
and hospitalization by about 50% (see Chapter 49).
Ranibizumab is a recombinant human IgG1 Fab that binds
to VEGF-A. It prevents new blood vessel formation by blocking
VEGF from binding to its receptor. Ranibizumab is approved for
intravitreal injection in patients with neovascular age-related mac-
ular degeneration, diabetic macular edema, and sudden blurring
or vision loss secondary to macular edema following retinal vein
occlusion. Pegaptanib is a pegylated oligonucleotide that binds
extracellular VEGF and is also given by intravitreous injection to
slow macular degeneration.
Obiltoxaximab and raxibacumab are FDA-approved Mabs for
treatment of patients after inhalation exposure to Bacillus anthracis
spores. Both Mabs block the binding of B anthracis “protective
antigen” to its cellular receptor, preventing entry of anthrax lethal
and edema factors into cells. They are approved for the treatment
or prophylaxis of adults and children with inhalational anthrax in
combination with appropriate antibacterial drugs. Interestingly,
these Mabs were not tested in humans because exposing a control
cohort to inhalational anthrax is unethical and there are too few
naturally infected persons to conduct a proper clinical trial.
■■ CLINICAL USES OF
IMMUNOSUPPRESSIVE DRUGS
Immunosuppressive agents are commonly used in two clinical
circumstances: transplantation and autoimmune disorders. The
agents used differ somewhat for the specific disorders treated (see
specific agents and Table 55–1), as do administration schedules.
996    SECTION VIII  Chemotherapeutic Drugs
Because autoimmune disorders are very complex, optimal treat-
ment schedules have yet to be established in many of them.
SOLID ORGAN & BONE MARROW
TRANSPLANTATION
In organ transplantation, tissue typing—based on donor and recipi-
ent histocompatibility matching with the human leukocyte antigen
(HLA) haplotype system—is required. Close histocompatibility
matching reduces the likelihood of graft rejection and may also reduce
the requirements for intensive immunosuppressive therapy. Prior to
transplant, patients may receive an immunosuppressive regimen,
including antithymocyte globulin, daclizumab, or basiliximab. Four
types of rejection can occur in a solid organ transplant recipient:
hyperacute, accelerated, acute, and chronic. Hyperacute rejection
is due to preformed antibodies against the donor organ, such as anti–
blood group antibodies. Hyperacute rejection occurs within hours
of the transplant and cannot be stopped with immunosuppressive
drugs. It results in rapid necrosis and failure of the transplanted organ.
Accelerated rejection is mediated by both antibodies and T cells, and
it also cannot be stopped by immunosuppressive drugs. Acute rejec-
tion of an organ occurs within days to months and involves mainly
cellular immunity. Reversal of acute rejection is usually possible with
general immunosuppressive drugs such as azathioprine, mycophe-
nolate mofetil, cyclosporine, tacrolimus, glucocorticoids, cyclophos-
phamide, methotrexate, and sirolimus. Recently, biologic agents such
as anti-CD3 monoclonal antibodies have been used to stem acute
rejection. Chronic rejection usually occurs months or even years after
transplantation. It is characterized by thickening and fibrosis of the
vasculature of the transplanted organ, involving both cellular and
humoral immunity. Chronic rejection is treated with the same drugs
as those used for acute rejection.
Allogeneic hematopoietic stem cell transplantation is a well-
established treatment for many malignant and nonmalignant
diseases. An HLA-matched donor, usually a family member, is
located, patients are conditioned with high-dose chemotherapy
and/or radiation therapy, and then donor stem cells are infused. The
conditioning regimen is used not only to kill cancer cells in the case
of malignant disease, but also to totally suppress the immune system
so that the patient does not reject the donor stem cells. As patients’
blood counts recover (after reduction by the conditioning regimen)
they develop a new immune system that is created from the donor
stem cells. Rejection of donor stem cells is uncommon and can only
be treated by infusion of more stem cells from the donor.
GVH disease, however, is very common, occurring in the major-
ity of patients who receive an allogeneic transplant. GVH disease
occurs because donor T cells fail to recognize the patient’s skin, liver,
and gut (usually) as self and attack those tissues. Although patients
are given immunosuppressive therapy (cyclosporine, methotrexate,
and others) early in the transplant course to help prevent this devel-
opment, it often occurs despite these medications. Acute GVH dis-
ease occurs within the first 100 days and is usually manifested as a
skin rash, severe diarrhea, or hepatotoxicity. Additional medications
are added, invariably starting with high-dose corticosteroids and
adding drugs such as mycophenolate mofetil, sirolimus, tacrolimus,
daclizumab, and others, with variable success rates. Patients gener-
ally progress to chronic GVH disease (after 100 days) and require
therapy for variable periods thereafter. Unlike solid-organ transplant
patients, however, most stem cell transplant patients are able to
eventually discontinue immunosuppressive drugs as GVH disease
resolves (usually 1–2 years after their transplant).
AUTOIMMUNE DISORDERS
The effectiveness of immunosuppressive drugs in autoimmune
disorders varies widely. Nonetheless, with immunosuppressive
therapy, remissions can be obtained in many instances of autoim-
mune hemolytic anemia, idiopathic thrombocytopenic purpura,
type 1 diabetes, Hashimoto’s thyroiditis, and temporal arteritis.
Improvement is also often seen in patients with systemic lupus
erythematosus, acute glomerulonephritis, acquired factor VIII
inhibitors (antibodies), rheumatoid arthritis, inflammatory myop-
athy, scleroderma, and certain other autoimmune states.
Immunosuppressive therapy is utilized in chronic severe
asthma, where cyclosporine is often effective and sirolimus is
another alternative (see Chapter 20). Omalizumab (anti-IgE anti-
body) has been approved for the treatment of severe asthma (see
previous section). Tacrolimus is currently under clinical investiga-
tion for the management of autoimmune chronic active hepatitis
and of multiple sclerosis, where IFN-β has a definitive role.
■■ IMMUNOMODULATION
THERAPY
The development of agents that modulate the immune response
rather than suppress it has become an important area of pharmacol-
ogy. The rationale underlying this approach is that such drugs may
increase the immune responsiveness of patients who have either
selective or generalized immunodeficiency. The major potential uses
are in immunodeficiency disorders, chronic infectious diseases, and
cancer. The AIDS epidemic has greatly increased interest in devel-
oping more effective immunomodulating drugs.
CYTOKINES
The cytokines are a large and heterogeneous group of proteins
with diverse functions. Some are immunoregulatory proteins syn-
thesized by leukocytes and play numerous interacting roles in the
function of the immune system and in the control of hematopoie-
sis. The cytokines that have been clearly identified are summarized
in Table 55–2. In most instances, cytokines mediate their effects
through receptors on relevant target cells and appear to act in a
manner similar to the mechanism of action of hormones. In other
instances, cytokines may have antiproliferative, antimicrobial, and
antitumor effects.
The first group of cytokines discovered, the interferons (IFNs),
were followed by the colony-stimulating factors (CSFs, discussed
 CHAPTER 55  Immunopharmacology    997

TABLE 55–2  The cytokines.

Cytokine Properties

Interferon-α (IFN-α) Antiviral, oncostatic, activates NK cells

Interferon-β (IFN-β) Antiviral, oncostatic, activates NK cells
Interferon-γ (IFN-γ) Antiviral, oncostatic, secreted by and activates or up-regulates Th1 cells, NK cells, CTLs, and
macrophages
Interleukin-1 (IL-1) T-cell activation, B-cell proliferation and differentiation
Interleukin-2 (IL-2) T-cell proliferation, Th1, NK, and LAK cell activation
Interleukin-3 (IL-3) Hematopoietic precursor proliferation and differentiation
Interleukin-4 (IL-4) Th2 and CTL activation, B-cell proliferation
Interleukin-5 (IL-5) Eosinophil proliferation, B-cell proliferation and differentiation
Interleukin-6 (IL-6) HCF, Th2, CTL, and B-cell proliferation
Interleukin- 7 (IL-7) CTL, NK, LAK, and B-cell proliferation, thymic precursor stimulation
Interleukin-8 (IL-8) Neutrophil chemotaxis, proinflammatory
Interleukin-9 (IL-9) T-cell proliferation
Interleukin-10 (IL-10) Th1 suppression, CTL activation, B-cell proliferation
Interleukin-11 (IL-11) Megakaryocyte proliferation, B-cell differentiation
Interleukin-12 (IL-12) Th1 and CTL proliferation and activation
Interleukin-13 (IL-13) Macrophage function modulation, B cell proliferation
Interleukin-14 (IL-14) B-cell proliferation and differentiation
Interleukin-15 (IL-15) Th1, CTL, and NK/LAK activation, expansion of T-cell memory pools
Interleukin-16 (IL-16) T-lymphocyte chemotaxis, suppresses HIV replication
Interleukin-17 (IL-17) Stromal cell cytokine production
Interleukin-18 (IL-18) Induces Th1 responses
Interleukin-19 (IL-19) Proinflammatory
Interleukin-20 (IL-20) Promotes skin differentiation
Interleukin-21 (IL-21) Promotes proliferation of activated T cells, maturation of NK cells
Interleukin-22 (IL-22) Regulator of Th2 cells
Interleukin-23 (IL-23) Promotes proliferation of Th1 memory cells
Interleukin-24 (IL-24) Induces tumor apoptosis, induces Th1 responses
Interleukin-27 (IL-27) Stimulates naive CD4 cells to produce IFN-γ
Interleukin-28 and -29 (IL-28, IL-29) Antiviral, interferon-like properties
Interleukin-30 (IL-30) p28 subunit of IL-27
Interleukin-31 (IL-31) Contributes to type I hypersensitivities and Th2 responses
Interleukin-32 (IL-32) Involved in inflammation
Interleukin-34 (IL-34) Stimulates monocyte proliferation via the CSF-1 receptor (CSF-1R)
Interleukin-35 (IL-35) Induces regulatory T cells (iTR35)
Tumor necrosis factor-α (TNF-α) Oncostatic, macrophage activation, proinflammatory
Tumor necrosis factor-β (TNF-β) Oncostatic, proinflammatory, chemotactic
Granulocyte colony-stimulating factor Granulocyte production
Granulocyte-macrophage colony-stimulating Granulocyte, monocyte, eosinophil production
factor
Macrophage colony-stimulating factor Monocyte production, activation
Erythropoietin (epoetin, EPO) Red blood cell production
Thrombopoietin (TPO) Platelet production
Note: Many interleukin activities overlap and are influenced by each other.
HCF, hematopoietic cofactor; LAK, lymphokine-activated killer cell.
998    SECTION VIII  Chemotherapeutic Drugs
in Chapter 33). The latter regulate the proliferation and differen-
tiation of bone marrow progenitor cells. Most of the more recently
discovered cytokines have been classified as interleukins (ILs) and
numbered in the order of their discovery. Pharmaceutical cyto-
kines are produced using gene cloning techniques.
Most cytokines (including TNF-α, IFN-γ, IL-2, G-CSF, and
granulocyte-macrophage colony-stimulating factor [GM-CSF])
have very short serum half-lives (minutes). The usual subcuta-
neous route of administration provides slower release into the
circulation and a longer duration of action. Each cytokine has its
own unique toxicity, but some toxicities are shared. For example,
IFN-α, IFN-β, IFN-γ, IL-2, and TNF-α all induce fever, flu-like
symptoms, anorexia, fatigue, and malaise.
Interferons are proteins that are currently grouped into three
families: IFN-`, IFN-a, and IFN-f. The IFN-α and IFN-β fami-
lies constitute type I IFNs, ie, acid-stable proteins that bind to the
same receptor on target cells. IFN-γ, a type II IFN, is acid-labile
and binds to a separate receptor on target cells. Type I IFNs are
usually induced by virus infections, with leukocytes producing
IFN-α. Fibroblasts and epithelial cells produce IFN-β. IFN-γ is
usually the product of activated T lymphocytes.
IFNs interact with cell receptors to produce a wide variety of
effects that depend on the cell and IFN types. IFNs, particularly
IFN-γ, display immune-enhancing properties, which include
increased antigen presentation and macrophage, NK cell, and
cytotoxic T-lymphocyte activation. IFNs also inhibit cell prolif-
eration. In this respect, IFN-α and IFN-β are more potent than
IFN-γ. Another striking IFN action is increased expression of
MHC molecules on cell surfaces. While all three types of IFN
induce MHC class I molecules, only IFN-γ induces class II expres-
sion. In glial cells, IFN-β antagonizes this effect and may, in fact,
decrease antigen presentation within the nervous system.
IFN-α is approved for the treatment of several neoplasms,
including hairy cell leukemia, chronic myelogenous leukemia,
malignant melanoma, and Kaposi’s sarcoma, and for treatment
of hepatitis B and C infections. It has also shown activity as an
anti-cancer agent in renal cell carcinoma, carcinoid syndrome,
and T-cell leukemia. IFN-β is approved for use in relapsing-type
multiple sclerosis. IFN-γ is approved for the treatment of chronic
granulomatous disease and IL-2, for metastatic renal cell carci-
noma and malignant melanoma. Clinical investigations of other
cytokines, including IL-1, -3, -4, -6, -10, -11, and -12, are ongo-
ing. Toxicities of IFNs, which include fever, chills, malaise, myal-
gias, myelosuppression, headache, and depression, can severely
restrict their clinical use.
TNF-α has been extensively tested in the therapy of various
malignancies, but results have been disappointing due to dose-
limiting toxicities. One exception is the use of intra-arterial high-
dose TNF-α for malignant melanoma and soft tissue sarcoma of
the extremities. In these settings, response rates greater than 80%
were noted.
Denileukin diftitox is IL-2 fused to diphtheria toxin, used for
the treatment of patients with CD25+ cutaneous T-cell lympho-
mas. IL-12 and GM-CSF have also shown adjuvant effects with
vaccines. GM-CSF is of particular interest because it promotes
recruitment of professional antigen-presenting cells such as
the dendritic cells required for priming naive antigen-specific
T-lymphocyte responses. There are some reports that GM-CSF
can itself stimulate an antitumor immune response, resulting in
tumor regression in melanoma and prostate cancer.
It is important to emphasize that cytokine interactions with
target cells often result in the release of a cascade of different
endogenous cytokines, which exert their effects sequentially or
simultaneously. For example, IFN-γ exposure increases the num-
ber of cell-surface receptors on target cells for TNF-α. Therapy
with IL-2 induces the production of TNF-α, while experimental
therapy with IL-12 induces the production of IFN-γ.
■■ IMMUNOLOGIC REACTIONS TO
DRUGS & DRUG ALLERGY
The basic immune mechanism and the ways in which it can be
suppressed or stimulated by drugs have been discussed in previous
sections of this chapter. Drugs also activate the immune system
in undesirable ways that are manifested as adverse drug reactions.
These reactions are generally grouped in a broad classification as
“drug allergy.” Indeed, many drug reactions such as those to peni-
cillin, iodides, phenytoin, and sulfonamides are allergic in nature.
These drug reactions are manifested as skin eruptions, edema, ana-
phylactoid reactions, glomerulonephritis, fever, and eosinophilia.
Drug reactions mediated by immune responses can have sev-
eral different mechanisms. Thus, any of the four major types of
hypersensitivity discussed earlier in this chapter (pages 981–983)
can be associated with allergic drug reactions:
•  Type I: IgE-mediated acute allergic reactions to stings, pollens,
and drugs, including anaphylaxis, urticaria, and angioedema.
IgE is fixed to tissue mast cells and blood basophils, and after
interaction with antigen the cells release potent mediators.
•  Type II: Drugs often modify host proteins, thereby eliciting
antibody responses to the modified protein. These allergic
responses involve IgG or IgM in which the antibody becomes
fixed to a host cell, which is then subject to complement-
dependent lysis or to antibody-dependent cellular cytotoxicity.
•  Type III: Drugs may cause serum sickness, which involves
immune complexes containing IgG complexed with a foreign
antigen and is a multisystem complement-dependent vasculitis
that may also result in urticaria.
•  Type IV: Cell-mediated allergy is the mechanism involved in
allergic contact dermatitis from topically applied drugs or indu-
ration of the skin at the site of an antigen injected intradermally.
In some drug reactions, several of these hypersensitivity
responses may occur simultaneously. Some adverse reactions to
drugs may be mistakenly classified as allergic or immune when
they are actually genetic deficiency states or are idiosyncratic
and not mediated by immune mechanisms (eg, hemolysis due to
primaquine in glucose-6-phosphate dehydrogenase deficiency, or
aplastic anemia caused by chloramphenicol). See Figure 55–6.

IMMEDIATE (TYPE I) DRUG ALLERGY
Type I (immediate) sensitivity allergy to certain drugs occurs when
the drug, not capable of inducing an immune response by itself,
covalently links to a host carrier protein (hapten). When this hap-
pens, the immune system detects the drug-hapten conjugate as
“modified self” and responds by generating IgE antibodies specific
for the drug-hapten. It is not known why some patients mount an
IgE response to a drug while others mount IgG responses. Under the
influence of IL-4, -5, and -13 secreted by Th2 cells, B cells specific
for the drug secrete IgE antibody. The mechanism for IgE-mediated
immediate hypersensitivity is diagrammed in Figure 55–5.
Fixation of the IgE antibody to high-affinity Fc receptors
(FcεRs) on blood basophils or their tissue equivalent (mast cells)
sets the stage for an acute allergic reaction. The most important
sites for mast cell distribution are skin, nasal epithelium, lung,
and gastrointestinal tract. When the offending drug is reintro-
duced into the body, it binds and cross-links basophil and mast
cell-surface IgE to signal release of the mediators (eg, histamine,
leukotrienes; see Chapters 16 and 18) from granules. Mediator
release is associated with calcium influx and a fall in intracel-
lular cAMP within the mast cell. Many of the drugs that block
mediator release appear to act through the cAMP mechanism
(eg, catecholamines, glucocorticoids, theophylline), others block
histamine release, and still others block histamine receptors. Other
vasoactive substances such as kinins may also be generated during
histamine release. These mediators initiate immediate vascular
smooth muscle relaxation, increased vascular permeability, hypo-
tension, edema, and bronchoconstriction.
Drug Treatment of Immediate Allergy
One can test an individual for possible sensitivity to a drug by a
simple scratch test, ie, by applying an extremely dilute solution of
the drug to the skin and making a scratch with the tip of a needle.
If allergy is present, an immediate (within 10–15 minutes) wheal
(edema) and flare (increased blood flow) will occur. However, skin
tests may be negative in spite of IgE hypersensitivity to a hapten
or to a metabolic product of the drug, especially if the patient is
taking steroids or antihistamines.
Drugs that modify allergic responses act at several links in this
chain of events. Prednisone, often used in severe allergic reactions,
is immunosuppressive; it blocks proliferation of the IgE-producing
clones and inhibits IL-4 production by T helper cells in the IgE
response, since glucocorticoids are generally toxic to lympho-
cytes. In the efferent limb of the allergic response, isoproterenol,
epinephrine, and theophylline reduce the release of mediators
from mast cells and basophils and produce bronchodilation.
Epinephrine opposes histamine; it relaxes bronchiolar smooth
muscle and contracts vascular muscle, relieving both broncho-
spasm and hypotension. As noted in Chapter 8, epinephrine is
the drug of choice in anaphylactic reactions. The antihistamines
competitively inhibit histamine, which would otherwise produce
bronchoconstriction and increased capillary permeability in end
organs. Glucocorticoids may also act to reduce tissue injury and
CHAPTER 55  Immunopharmacology    999
edema in the inflamed tissue, as well as facilitating the actions
of catecholamines in cells that may have become refractory to
epinephrine or isoproterenol. Several agents directed toward the
inhibition of leukotrienes may be useful in acute allergic and
inflammatory disorders (see Chapter 20).
Desensitization to Drugs
When reasonable alternatives are not available, certain drugs (eg,
penicillin, insulin) must be used for life-threatening illnesses even in
the presence of known allergic sensitivity. In such cases, desensitiza-
tion (also called hyposensitization) can sometimes be accomplished
by starting with very small doses of the drug and gradually increas-
ing the dose over a period of hours or days to the full therapeutic
range (see Chapter 43). This practice is hazardous and must be
performed under direct medical supervision with epinephrine
available for immediate injection, as anaphylaxis may occur before
desensitization has been achieved. It is thought that slow and pro-
gressive administration of the drug gradually binds all available IgE
on mast cells, triggering a gradual release of granules. Once all of
the IgE on the mast cell surfaces has been bound and the cells have
been degranulated, therapeutic doses of the offending drug may be
given with minimal further immune reaction. Therefore, a patient
is desensitized only during administration of the drug.
AUTOIMMUNE (TYPE II) REACTIONS TO
DRUGS
Certain autoimmune syndromes can be induced by drugs. Exam-
ples include systemic lupus erythematosus following hydralazine
or procainamide therapy, “lupoid hepatitis” due to cathartic sensi-
tivity, autoimmune hemolytic anemia resulting from methyldopa
administration, thrombocytopenic purpura due to quinidine, and
agranulocytosis due to a variety of drugs. As indicated in other
chapters of this book, a number of drugs are associated with type I
and type II reactions. In these drug-induced autoimmune states,
IgG antibodies bind to drug-modified tissue and are destroyed
by the complement system or by phagocytic cells with Fc recep-
tors. Fortunately, autoimmune reactions to drugs usually subside
within several months after the offending drug is withdrawn.
Immunosuppressive therapy is warranted only when the autoim-
mune response is unusually severe.
SERUM SICKNESS & VASCULITIC
(TYPE III) REACTIONS
Immunologic reactions to drugs resulting in serum sickness
are more common than immediate anaphylactic responses,
but type II and type III hypersensitivities often overlap. The
clinical features of serum sickness include urticarial and erythema-
tous skin eruptions, arthralgia or arthritis, lymphadenopathy,
glomerulonephritis, peripheral edema, and fever. The reactions
generally last 6–12 days and usually subside once the offending
drug is eliminated. Antibodies of the IgM or IgG class are usually
1000    SECTION VIII  Chemotherapeutic Drugs

involved. The mechanism of tissue injury is immune complex
formation and deposition on basement membranes (eg, lung,
kidney), followed by complement activation and infiltration of
leukocytes, causing tissue destruction. Glucocorticoids are useful
in attenuating severe serum sickness reactions to drugs. In severe
cases plasmapheresis can be used to remove the offending drug
and immune complexes from circulation.
Immune vasculitis can also be induced by drugs. The sulfon-
amides, penicillin, thiouracil, anticonvulsants, and iodides all
have been implicated in the initiation of hypersensitivity angiitis.
Erythema multiforme is a relatively mild vasculitic skin disorder
that may be secondary to drug hypersensitivity. Stevens-Johnson
syndrome is probably a more severe form of this hypersensitivity
reaction and consists of erythema multiforme, arthritis, nephritis,
central nervous system abnormalities, and myocarditis. It fre-
quently has been associated with sulfonamide therapy. Adminis-
tration of nonhuman monoclonal or polyclonal antibodies such as
rattlesnake antivenom may cause serum sickness.
CELL-MEDIATED (TYPE IV) REACTIONS
Type IV hypersensitivity occurs 24–48 hours after exposure to
the allergen and therefore is called delayed type hypersensitivity
(DTH). Like other drug hypersensitivities, the drug may chemi-
cally react with host tissue to create a new antigen. Upon first
exposure to the allergen (drug), antigen-presenting cells stimulate
a T-cell response specific for that allergen. This takes 1–2 weeks.
Upon second and all subsequent exposures, tissue-derived anti-
gen-presenting cells that come in contact with the new antigen
(allergen-modified host protein) secrete chemokines and cytokines
that attract memory T cells to the site of allergen re-exposure. This
takes only 24–48 hours. Lymphocytes and antigen-presenting
cells such as macrophages accumulate at the site, causing indura-
tion, erythema, and swelling. Contact hypersensitivity is a form
of DTH and occurs when an allergen elicits DTH on the skin,
resulting in spongiosis such as when an ointment containing an
allergen is applied to skin.

P R E P A R A T I O N S A V A I L A B L E*

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

Abatacept Orencia Etanercept Enbrel
Abciximab ReoPro Everolimus Afinitor, Zortress
Adalimumab Humira Evolocumab Repatha
Ado-trastuzumab emtansine Kadcyla Fingolimod hydrochloride Gilenya
Alefacept Amevive Glatiramer acetate Copaxone
Alemtuzumab Campath Golimumab Simponi
Alirocumab Praluent Ibritumomab tiuxetan Zevalin
Anakinra Kineret Immune globulin Various
Antithymocyte globulin Thymoglobulin intravenous [IGIV]
Arcitumomab CEA-Scan Infliximab Remicade
Atezolizumab Tecentriq Interferon alfa-2a Roferon
Azathioprine Generic, Imuran Interferon alfa-2b Intron-A
Basiliximab Simulect Interferon beta-1a Avonex, Rebif
Belimumab Benlysta Interferon beta-1b Betaseron, Extavia
Bevacizumab Avastin Interferon gamma-1b Actimmune
Brentuximab vedotin Adcetris Interleukin-2 (IL-2, aldesleukin) Proleukin
Canakinumab Ilaris Ipilimumab Yervoy
Capromab pendetide ProstaScint Leflunomide Arava
Catumaxomab Removab Lenalidomide Revlimid
Certolizumab Cimzia Lymphocyte immune globulin Atgam
Cetuximab Erbitux Mepolizumab Nucala
Cyclophosphamide generic Mycophenolate mofetil Generic, CellCept
Cyclosporine Generic, Sandimmune, Natalizumab Tysabri
Restasis Necitumumab Portrazza
Daclizumab Zenapax Nivolumab Opdivo
Daratumumab Darzalex Obiltoxaximab Anthim
Denileukin diftitox Ontak Ofatumumab Arzerra
Denosumab Prolia Omalizumab Xolair
Dimethyl fumarate Tecfidera Palivizumab Synagis
Eculizumab Soliris Panitumumab Vectibix
 CHAPTER 55  Immunopharmacology    1001

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

Pegademase bovine Adagen Rilonacept Arcalyst
(bovine adenosine deaminase) Rituximab Rituxan
Pegaptanib Macugen Scorpion antivenom Anascorp
Peginterferon alfa-2a Pegasys (equine (Fab)¢2)
Peginterferon alfa-2b PEG-Intron Siltuximab Sylvant
Pembrolizumab Keytruda Sirolimus Generic, Rapamune
Pertuzumab Perjeta Tacrolimus (FK 506) Generic, Prograf, others
Pomalidomide Pomalyst Teriflunomide Aubagio
Ramucirumab Cyramza Thalidomide Thalomid
Ranibizumab Lucentis Tocilizumab Actemra
Raxibacumab ABthrax Trastuzumab Herceptin
Reslizumab Cinqair Ustekinumab Stelara
Rho(D) immune globulin RhoGam, others Vedolizumab Entyvio
micro-dose
*
Several drugs discussed in this chapter are available as orphan drugs but are not listed here. Other drugs not listed here will be found in other chapters (see Index).

REFERENCES Immunosuppressive Agents

General Immunology
Levinson WE: Review of Medical Microbiology and Immunology, 13th ed.
McGraw-Hill, 2014.
Lubberts E: The IL-23–IL-17 axis in inflammatory arthritis. Nat Rev Rheumatol
2015;11:415.
Murphy KM, Travers P, Walport M (editors): Janeway’s Immunobiology, 9th ed.
Garland Science, 2016.
Sharma P, Allison JP: The future of immune checkpoint therapy. Science
2015;348:56.
Hypersensitivity
Borroni RG: Role of dermatology in pharmacogenomics: Drug-induced skin
injury. Pharmacogenomics 2015;16:401.
De Groot AC: New contact allergens: 2008 to 2015. Dermatitis 2015;26:199.
Autoimmunity
Aytan J: Use of biologics in SLE: A review of the evidence from a clinical perspec-
tive. Rheumatology 2016;55:775
Cantini F et al: Tailored first-line biologic therapy in patient with rheumatoid
arthritis, spondyloarthritis, and psoriatic arthritis. Semin Arthritis Rheum
2016;45:519.
Marzano AV et al: Immune-mediated inflammatory reactions and tumors as
skin side effects of inflammatory bowel disease therapy. Autoimmunity
2014;47:146.
Tiligada E et al: The expanding role of immunopharmacology: IUPHAR review 16.
Br J Pharmacol 2015;172:4217.
Immunodeficiency Diseases
Sriaroon P, Ballow M: Immunoglobulin replacement therapy for primary immuno-
deficiency. Immunol Allergy Clin North Am 2015;35:713.
Capron A et al: Intra-cellular immunosuppressive drug monitoring: A step forward
towards better therapeutic efficacy after organ transplantation? Pharmacol
Res 2016;111:610.
Choi WE, Reddy P: Current and emerging strategies for the prevention of graft-
versus-host disease. Nat Rev Clin Oncol 2014;11:536.
Lee JH et al: A comprehensive review of the treatment of atopic eczema. Allergy
Asthma Immunol Res 2016;8:181.
Sharma P, Scott DG: Optimizing methotrexate treatment in rheumatoid arthritis:
Prior to biologics. Drugs 2015;75:1953.
Waldner M et al: New perspectives on mTOR inhibitors (rapamycin, rapalogs, and
TORKinibs) in transplantation. Br J Clin Pharmacol 2016;82:1158.
Antilymphocyte Globulin & Monoclonal Antibodies
Costa AG, Bilezikian JP: How long to treat with Denosumab. Curr Osteoporos
Rep 2015;13:415.
Cummings SR: Denosumab for prevention of fractures in postmenopausal women
with osteoporosis. N Engl J Med 2009;361:756.
Spain L et al: Management of toxicities of immune checkpoint inhibitors. Cancer
Treat Rev 2013;44:51.
Wolf M et al: Peripheral administration of antithymocyte globulins: A review of
current literature. Transplant Rev (Orlando) 2013;27:17.
Cytokines
Akdis M et al: Interleukins (from IL-1 to IL-38), interferons, transforming growth
factor β and TNF-α: Receptors, functions and roles in diseases. J Allergy
Clin Immunol 2016;138:984.
Drug Allergy
Khan DA: Hypersensitivity and immunologic reactions to biologics: Opportuni-
ties for the allergist. Ann Allergy Asthma Immunol 2016;117:115.
Macy E: Practical management of patients with a history of immediate hypersensitivity
to common non-beta-lactam drugs. Curr Allergy Asthma Rep 2016;16:4.
Wickner PG, Hong D: Immediate drug hypersensitivity Curr Allergy Asthma Rep
2016;16:49.
1002    SECTION VIII  Chemotherapeutic Drugs

C ASE STUDY ANSWER

Glucocorticoids (steroids) are first-line treatment for acute as tacrolimus. Adding a steroid (eg, prednisone) can amelio-
graft-vs-host disease. Acute graft-vs-host disease is the pro- rate the T-cell response of graft-vs-host disease in most cases
cess of donor T cells attacking host recipient tissues (includ- of grade II disease. See section in this chapter on Clinical
ing skin), despite ongoing immunosuppressive therapy such Uses of Immunosuppressive Drugs.
 SECTION IX  TOXICOLOGY
Introduction to Toxicology:
Occupational &
Environmental
Daniel T. Teitelbaum, MD*
C ASE STUDY
A 6-year-old girl is brought to the emergency department
by her parents. She is comatose, tachypneic (25 breaths per
minute), and tachycardic (150 bpm), but she appears flushed,
and fingertip pulse oximetry is normal (97%) breathing
room air. Questioning of her parents reveals that they are
homeless and have been living in their car (a small van).
Humans live in a chemical world. They inhale, ingest,
and absorb through the skin many of these chemicals. The
occupational-environmental toxicologist is primarily concerned
with adverse effects in humans resulting from exposure to
chemicals encountered at work or in the general environment.
In clinical practice, the occupational-environmental toxicolo-
gist must identify and treat the adverse health effects of these
*
The author thanks the late Gabriel L. Plaa, PhD, previous author of
this chapter, for his enduring contributions.
56
C H A P T E R
The nights have been cold, and they have used a small char-
coal burner to keep warm inside the vehicle. What is the
most likely diagnosis? What treatment should be instituted
immediately? If her mother is pregnant, what additional
measures should be taken?
exposures. In addition, the trained occupational-environmental
toxicologist will be called upon to assess and identify hazards asso-
ciated with chemicals used in the workplace or introduced into the
human environment.
Occupational and environmental toxicology cases present
unusually complex problems. Occupational and environmental
exposure is rarely limited to a single type of molecule. Most work-
place or environmental materials are compounds or mixtures,
and the ingredients are often poorly described in the documen-
tation that is available for physician review. Moreover, although
1003
1004    SECTION IX Toxicology
regulatory agencies in many countries have requirements for
disclosure of hazardous materials and their health impacts, pro-
prietary information exclusions often make it difficult for those
who treat occupationally and environmentally poisoned patients
to understand the nature and scope of the presenting illness.
Because many of these illnesses have long latency periods before
they become manifest, it is often a matter of detective work, when
patients finally present with disease, to ascertain past exposure and
relate it to present clinical effect. Monitoring of exposure concen-
trations both in the workplace and in the general environment has
become more common, but it is far from widespread, and so it is
often very difficult to establish the extent of exposure, its duration,
and its dose rate when this information is critical to the identifica-
tion of the toxic disorder and its management.
Occupational Toxicology
Occupational toxicology deals with the chemicals found in the
workplace. The major emphasis of occupational toxicology is
to identify the agents of concern, identify the acute and chronic
diseases that they cause, define the conditions under which they
may be used safely, and prevent absorption of harmful amounts of
these chemicals. The occupational toxicologist will also be called
upon to treat the diseases caused by these chemicals if he or she is
a physician. Occupational toxicologists may also define and carry
out programs for the surveillance of exposed workers and the
environment in which they work. They frequently work hand in
hand with occupational hygienists, certified safety professionals,
and occupational health nurses in their activities.
Regulatory limits and voluntary guidelines have been elabo-
rated to establish safe ambient air concentrations for many
chemicals found in the workplace. Governmental and supragov-
ernmental bodies throughout the world have generated workplace
health and safety rules, including short- and long-term exposure
limits for workers. These permissible exposure limits (PELs) have
the power of law in the United States. Copies of the US Occupa-
tional Safety and Health Administration (OSHA) standards may
be found on OSHA’s website at http://www.osha.gov. Copies of
the US Mine Safety and Health Administration (MSHA) stan-
dards may be found at http://www.msha.gov. In addition to the
PELs that appear in the OSHA publications and on the website,
OSHA promulgates standards for specific materials of particularly
serious toxicity. These standards are developed following extensive
scientific study, stakeholder input at hearings, public comment,
and other steps such as publication in the Federal Register. Such
standards have the force of law and employers who use these
materials are obligated to comply with the standards. OSHA
standards may be found in full on the OSHA website at http://
www.osha.gov.
Voluntary organizations, such as the American Conference
of Governmental Industrial Hygienists (ACGIH), periodically
prepare lists of recommended threshold limit values (TLVs)
for many chemicals. These guidelines are periodically updated.
Regulatory imperatives in the United States may also be updated
from time to time when new information about toxicity becomes
available. However, this process is slow and requires input from
many sources except under certain extraordinary circumstances.
In those cases, emergency alterations to standards may be made
and an emergency temporary standard may be promulgated after
appropriate regulatory procedures. The ACGIH TLV guidelines
are useful as reference points in the evaluation of potential work-
place exposures. Compliance with these voluntary guidelines is
not a substitute for compliance with the OSHA requirements in
the United States. TLVs do not have the force of law. Current TLV
lists may be obtained from the ACGIH at http://www.acgih.org.
Environmental Toxicology
Environmental toxicology deals with the potentially deleterious
impact of chemicals, present as pollutants of the environment,
on living organisms. The term environment includes all the
surroundings of an individual organism, but particularly the air,
soil, and water. Although humans are considered a target species of
particular interest, other species are of considerable importance as
potential biologic targets. Scientific study of signal occurrences in
animals often provides early warning of impending human events
as a result of ecotoxic impacts.
Air pollution is usually a product of industrialization, techno-
logic development, and increased urbanization. On rare occasions,
natural phenomena such as volcanic eruptions may result in air
pollution with gases, vapors, or particulates that are harmful to
humans. Humans may also be exposed to chemicals used in the
agricultural environment as pesticides or in food processing that
may persist as residues or ingredients in food products. Air con-
taminants are regulated in the United States by the Environmental
Protection Agency (EPA) based on both health and esthetic con-
siderations. Tables of primary and secondary regulated air contam-
inants and other regulatory issues that relate to air contaminants
in the United States may be found at http://www.epa.gov. Many
states within the USA also have individual air contaminant regu-
lations that may be more rigorous than those of the EPA. Many
other nations and some supragovernmental organizations regulate
air contaminants. In the case of adjoining countries, transborder
air and water pollution problems have been of concern in recent
years. Particulates, radionuclides, acid rain, and similar problems
have resulted in cross-contamination of air and water in differ-
ent countries. Maritime contamination, too, has raised concern
about oceanic pollution and has had an impact on the fisheries of
some countries. This type of pollution is now the subject of much
research and of new international treaties.
The United Nations Food and Agriculture Organization and
the World Health Organization (FAO/WHO) Joint Expert Com-
mission on Food Additives adopted the term acceptable daily
intake (ADI) to denote the daily intake of a chemical from food
that, during an entire lifetime, appears to be without appreciable
risk. These guidelines are reevaluated as new information becomes
available. In the United States, the Food and Drug Administra-
tion (FDA) and the Department of Agriculture are responsible
for the regulation of contaminants such as pesticides, drugs, and
chemicals in foods. Major international problems have occurred
because of traffic among nations in contaminated or adulterated
foods from countries whose regulations and enforcement of pure
 CHAPTER 56  Introduction to Toxicology: Occupational & Environmental     1005
food and drug laws are lax or nonexistent. Recently, for example,
both human and animal illnesses have resulted from ingestion of
products imported from China that contained melamine.
Ecotoxicology
Ecotoxicology is concerned with the toxic effects of chemical and
physical agents on populations and communities of living organ-
isms within defined ecosystems; it includes the transfer pathways
of those agents and their interactions with the environment. Tra-
ditional toxicology is concerned with toxic effects on individual
organisms; ecotoxicology is concerned with the impact on popula-
tions of living organisms or on ecosystems. Ecotoxicology research
has become one of the foremost areas of study for toxicologists.
TOXICOLOGIC TERMS & DEFINITIONS
Hazard & Risk
Hazard is the ability of a chemical agent to cause injury in a
given situation or setting; the conditions of use and exposure
are primary considerations. To assess hazard, one needs to have
knowledge about both the inherent toxicity of the substance and
the amounts to which individuals are liable to be exposed. Hazard
is often a description based on subjective estimates rather than
objective evaluation.
Risk is defined as the expected frequency of the occurrence
of an undesirable effect arising from exposure to a chemical or
physical agent. Estimation of risk makes use of dose-response data
and extrapolation from the observed relationships to the expected
responses at doses occurring in actual exposure situations. The
quality and suitability of the biologic data used in such estimates
are major limiting factors. Risk assessment has become an integral
part of the regulatory process in most countries. However, many
of the assumptions of risk assessment scientists remain unproven,
and only long-term observation of population causes and out-
comes will provide the basis for validation of newer risk assess-
ment technologies.
Routes of Exposure
The route of entry for chemicals into the body differs in differ-
ent exposure situations. In the industrial setting, inhalation is the
major route of entry. The transdermal route is also quite impor-
tant, but oral ingestion is a relatively minor route. Consequently,
primary prevention should be designed to reduce or eliminate
absorption by inhalation or by topical contact. Atmospheric pol-
lutants gain entry by inhalation and by dermal contact. Water and
soil pollutants are absorbed through inhalation, ingestion, and
dermal contact.
Quantity, Duration, & Intensity of
Exposure
Toxic reactions may differ depending on the quantity of exposure,
its duration, and the rate at which the exposure takes place. An
exposure to a toxic substance that is absorbed by the target human
or animal results in a dose. Acute exposure indicates a single
exposure or multiple exposures that occur over a brief period
from seconds to 1–2 days. Intense, rapidly absorbed acute doses of
substances that may ordinarily be detoxified by enzymatic mecha-
nisms in small doses may overwhelm the body’s ability to detoxify
the substance and may result in serious or even fatal toxicity. The
same amount of the substance, absorbed slowly, may result in little
or no toxicity. This is the case with cyanide exposure. Rhodanese,
a mitochondrial enzyme present in humans, effectively detoxifies
cyanide to relatively nontoxic thiocyanate when cyanide is pre-
sented in small amounts, but the enzyme is overwhelmed by large,
rapidly encountered cyanide doses, with lethal effect.
Single or multiple exposures over a longer period of time rep-
resent chronic exposure. In the occupational setting, both acute
(eg, accidental discharge) and chronic (eg, repetitive handling of
a chemical) exposures occur. Exposures to chemicals found in the
environment such as air and water pollutants are often chronic,
resulting in chronic disease, as in the Minamata Bay, Japan,
methyl mercury disaster. Sudden large chemical releases may
result in acute massive population exposure with serious or lethal
consequences. The tragedy in Bhopal, India, was such an event, in
which methyl isocyanate was released into a crowded population
area, resulting in almost 4000 deaths and more than half a million
injuries. The release of dioxin in Seveso, Italy, contaminated a
populated area with a persistent organic chemical having both
acute and long-term chronic effects. More recently, the massive oil
spill caused by the explosion of BP’s Deepwater Horizon drilling
rig in the Gulf of Mexico highlighted the potential for long-term
ecotoxic impacts involving widespread geographic areas.
ENVIRONMENTAL CONSIDERATIONS
Certain chemical and physical characteristics are important for
the estimation of the potential hazard of environmental toxicants.
Data on toxic effects of different organisms, along with knowledge
about degradability, bioaccumulation, and transport and biomag-
nification through food chains, help in this estimation. (See Box:
Bioaccumulation & Biomagnification for a classic example involv-
ing the Great Lakes.) Poorly degraded chemicals (by abiotic or
biotic pathways) exhibit environmental persistence and can accu-
mulate. Such chemicals include the persistent organic pollutants
(POPs), polychlorinated biphenyls, dioxins and furans, and simi-
lar substances. Lipophilic substances such as the largely banned
or abandoned organochlorine pesticides tend to bioaccumulate
in body fat. This results in tissue residues that are slowly released
over time. These residues and their metabolites may have chronic
adverse effects such as endocrine disruption. When the toxicant
is incorporated into the food chain, biomagnification occurs as
one species feeds on others. This concentrates the chemical in
organisms higher on the food chain. Humans stand at the apex of
the food chain. They may be exposed to highly concentrated pol-
lutant loads as bioaccumulation and biomagnification occur. The
pollutants that have the widest environmental impact are poorly
degradable; are relatively mobile in air, water, and soil; exhibit
bioaccumulation; and also exhibit biomagnification.
1006    SECTION IX Toxicology
Bioaccumulation & Biomagnification
If the intake of a long-lasting contaminant by an organism
exceeds the latter's ability to metabolize or excrete the sub-
stance, the chemical accumulates within the tissues of the organ-
ism. This is called bioaccumulation.
Although the concentration of a contaminant may be virtu-
ally undetectable in water, it may be magnified hundreds or
thousands of times as the contaminant passes up the food chain.
This is called biomagnification.
The biomagnification of polychlorinated biphenyls (PCBs)
in the Great Lakes of North America is illustrated by the follow-
ing residue values available from a classic Environment Canada
report published by the Canadian government, and elsewhere.
The biomagnification for this substance in the food chain, begin-
ning with phytoplankton and ending with the herring gull, is nearly
■■ SPECIFIC CHEMICALS
AIR POLLUTANTS
Air pollution may result from vapors, aerosols, smokes, particu-
lates, and individual chemicals. Five major substances have been
said to account for about 98% of air pollution: carbon monoxide
(about 52%); sulfur oxides (about 14%); hydrocarbons (about
14%); nitrogen oxides (about 14%) and ozone, their breakdown
product; and particulate matter (about 4%). Agriculture, espe-
cially industrial-scale farming, contributes a variety of air pollut-
ants: dusts as particulates, pesticidal chemicals, hydrogen sulfide,
and others. Sources of pollutants include fossil fuel burning,
transportation, manufacturing, other industrial activities, genera-
tion of electric power, space heating, refuse disposal, and others.
Studies in Helsinki and other cities have shown that uncatalyzed
automobile traffic emissions are larger contributors to ground-
level air pollution than any other source. The introduction of cata-
lytic converters on automobiles and their mandatory use in many
countries has greatly reduced automobile-released air pollution.
In addition, the ban on tetraethyl lead in gasoline has eliminated
a major source of lead contamination and childhood lead poison-
ing in urban environments. In emerging economies, the use of
transport based on two-cycle engines creates heavy ground-level
air pollution in very crowded cities. The introduction of “clean,
low-sulfur” diesel fuels is helping to reduce urban and highway
pollutants such as sulfur oxides.
Sulfur dioxide and smoke from incomplete combustion of coal
have been associated with acute adverse effects among children,
the elderly, and individuals with preexisting cardiac or respiratory
disease. Ambient air pollution has been implicated as a cause of
cardiac disease, bronchitis, obstructive ventilatory disease, pulmo-
nary emphysema, bronchial asthma, and airway or lung cancer.
Extensive basic science and clinical epidemiologic literature on air
pollutant toxicology has been published and has led to modifica-
tions of regulatory standards for air pollutants. EPA standards for
50,000-fold. Domestic animals and humans may eat fish from the
Great Lakes, resulting in PCB residues in these species as well.
PCB Concentration
Concentration Relative to
Source (ppm)1 Phytoplankton
Phytoplankton 0.0025 1
Zooplankton 0.123 49.2
Rainbow smelt 1.04 416
Lake trout 4.83 1,932
Herring gull 124 49,600
1
Sources: Environment Canada, The State of Canada's Environment, 1991,
Government of Canada, Ottawa; and other publications.
these substances apply to the general environment, and OSHA
standards apply to workplace exposure. Ambient air standards for
carbon monoxide and five other harmful pollutants—particulate
matter, nitrogen dioxide, ozone, sulfur dioxide, and lead—may be
found at https://www.epa.gov/criteria-air-pollutants.
Carbon Monoxide
Carbon monoxide (CO) is a colorless, tasteless, odorless, and
nonirritating gas, a byproduct of incomplete combustion. The
average concentration of CO in the atmosphere is about 0.1 ppm;
in heavy traffic, the concentration may exceed 100 ppm. Current
recommended permissible exposure limit (PEL) values are shown
in Table 56–1 (see also http://www.osha.gov, Standard Number
1910.1000, Table Z-1).
1. Mechanism of action—CO combines tightly but reversibly
with the oxygen-binding sites of hemoglobin and has an affin-
ity for hemoglobin that is about 220 times that of oxygen. The
product formed—carboxyhemoglobin—cannot transport oxygen.
Furthermore, the presence of carboxyhemoglobin interferes with
the dissociation of oxygen from the remaining oxyhemoglobin as
a result of the Bohr effect. This reduces the transfer of oxygen to
tissues. Organs with the highest oxygen demand (the brain, heart,
and kidneys) are most seriously affected. Normal nonsmoking
adults have carboxyhemoglobin levels of less than 1% saturation
(1% of total hemoglobin is in the form of carboxyhemoglobin);
this has been attributed to the endogenous formation of CO from
heme catabolism. Smokers may exhibit 5–10% CO saturation.
The level depends on their smoking habits. A person who breathes
air that contains 0.1% CO (1000 ppm) would have a carboxyhe-
moglobin level of about 50% in a short period of time.
2. Clinical effects—The principal signs of CO intoxication
are those of hypoxia. They progress in the following sequence:
(1) psychomotor impairment; (2) headache and tightness in
the temporal area; (3) confusion and loss of visual acuity;
 CHAPTER 56  Introduction to Toxicology: Occupational & Environmental     1007
TABLE 56–1  Examples of permissible exposure
limit values (PELs) of some common
air pollutants and solvents in parts per
million (ppm).1
Compound PEL2 (ppm)
Benzene 1.0
Carbon monoxide 50
Carbon tetrachloride 10
Chloroform 50
Nitrogen dioxide 5
Ozone 0.1
Sulfur dioxide 5
Tetrachloroethylene 100
Toluene 200
1,1,1-Trichloroethane 350
Trichloroethylene 100
1
These exposure limits can be found at http://www.osha.gov, 1910.1000, Tables Z-1
and Z-2. The OSHA standards are updated frequently and readers are referred to the
website for the most current information.
2
PELs are 8-hour TWA (time-weighted average) values for a normal 8-hour workday to
which workers may be repeatedly exposed without adverse effects.
(4) tachycardia, tachypnea, syncope, and coma; and (5) deep
coma, convulsions, shock, and respiratory failure. There is great
variability in individual responses to carboxyhemoglobin con-
centration. Carboxyhemoglobin levels below 15% may produce
headache and malaise; at 25% many workers complain of head-
ache, fatigue, decreased attention span, and loss of fine motor
coordination. Collapse and syncope may appear at around 40%;
and with levels above 60%, death may ensue as a result of irrevers-
ible damage to the brain and myocardium. The clinical effects
may be aggravated by heavy labor, high altitudes, and high ambi-
ent temperatures. CO intoxication is usually thought of as a form
of acute toxicity. There is evidence that chronic exposure to low CO
levels may lead to adverse cardiac effects, neurologic disturbance,
and emotional disorders. The developing fetus is quite susceptible
to the effects of CO exposure. Exposure of a pregnant woman to
elevated CO levels at critical periods of fetal development may cause
fetal death or serious and irreversible but survivable birth defects.
3. Treatment—Patients who have been exposed to CO must be
removed from the exposure source immediately. Respiration must
be maintained and high flow and concentration of oxygen—the
specific antagonist to CO—should be administered promptly. If
respiratory failure is present, mechanical ventilation is required,
High concentrations of oxygen may be toxic and may contribute
to the development of acute respiratory distress syndrome. There-
fore, patients should be treated with high concentrations only for
a short period. With room air at 1 atm, the elimination half-time
of CO is about 320 minutes; with 100% oxygen, the half-time is
about 80 minutes; and with hyperbaric oxygen (2–3 atm), the
half-time can be reduced to about 20 minutes. Although some
controversy exists about hyperbaric oxygen for CO poisoning,
it may be used if it is readily available. It is particularly recom-
mended for the management of pregnant women exposed to
CO. Hypothermic therapy to reduce metabolic demand of the
brain has also been useful. Cerebral edema that results from CO
poisoning does not seem to respond to either mannitol or steroid
therapy and may be persistent. Progressive recovery from treated
CO poisoning, even of a severe degree can be complete but some
patients manifest neuropsychological and motor dysfunction for a
long time after recovery from acute CO poisoning.
Sulfur Dioxide
Sulfur dioxide (SO2) is a colorless irritant gas generated primarily
by the combustion of sulfur-containing fossil fuels. The current
OSHA PEL (Table 56–1) is given on the OSHA website (see
http://www.osha.gov, Standard Number 1910.1000, Table Z-1).
1. Mechanism of action—At room temperature, the solubility
of SO2 is approximately 200 g SO2/L of water. Because of its high
solubility, when SO2 contacts moist membranes, it transiently
forms sulfurous acid. This acid has severe irritant effects on the
eyes, mucous membranes, and skin. Approximately 90% of
inhaled SO2 is absorbed in the upper respiratory tract, the site of its
principal effect. The inhalation of SO2 causes bronchial constric-
tion and produces profuse bronchorrhea; parasympathetic reflexes
and altered smooth muscle tone appear to be involved. The clinical
outcome is an acute irritant asthma. Exposure to 5 ppm SO2 for
10 minutes leads to increased resistance to airflow in most humans.
Exposures of 5–10 ppm are reported to cause severe bronchospasm;
10–20% of the healthy young adult population is estimated to be
reactive to even lower concentrations. The phenomenon of adap-
tation to irritating concentrations has been reported in workers.
However, current studies have not confirmed this phenomenon.
Asthmatic individuals are especially sensitive to SO2.
2. Clinical effects and treatment—The signs and symptoms
of intoxication include irritation of the eyes, nose, and throat,
reflex bronchoconstriction, and increased bronchial secretions.
In asthmatic subjects, exposure to SO2 may result in an acute
asthmatic episode. If severe exposure has occurred, delayed-onset
pulmonary edema may be observed. Cumulative effects from
chronic low-level exposure to SO2 are not striking, particularly in
humans, but these effects have been associated with aggravation
of chronic cardiopulmonary disease. When combined exposure to
high respirable particulate loads and SO2 occurs, the mixed irri-
tant load may increase the toxic respiratory response. Treatment is
not specific for SO2 but depends on therapeutic maneuvers used
to treat irritation of the respiratory tract and asthma. In some
severely polluted urban air basins, elevated SO2 concentrations
combined with elevated particulate loads has led to air pollution
emergencies and a marked increase in cases of acute asthmatic
bronchitis. Children and the elderly seem to be at greatest risk.
The principal source of urban SO2 is the burning of coal, both
for domestic heating and in coal-fired power plants. High-sulfur
transportation fuels also contribute. Both also contribute to the
respirable fine particulate load and to increased urban cardiorespi-
ratory morbidity and mortality.
1008    SECTION IX Toxicology
Nitrogen Oxides
Nitrogen dioxide (NO2) is a brownish irritant gas sometimes associ-
ated with fires. It is formed also from fresh silage; exposure of farm-
ers to NO2 in the confines of a silo can lead to silo-filler’s disease, a
severe and potentially lethal form of acute respiratory distress syn-
drome. The disorder is uncommon today. Miners who are regularly
exposed to diesel equipment exhaust have been particularly affected
by nitrogen oxide emissions with serious respiratory effects. Today,
the most common source of human exposure to oxides of nitrogen,
including NO2, is automobile and truck traffic emissions. Recent
air pollution inventories in cities with high traffic congestion have
demonstrated the important role that internal combustion engines
have in the increasing NO2 urban air pollution. A variety of dis-
orders of the respiratory system, cardiovascular system, and other
problems have been linked to NO2 exposure.
1. Mechanism of action—NO2 is a relatively insoluble deep lung
irritant. It is capable of producing pulmonary edema and acute
adult respiratory distress syndrome (ARDS). Inhalation damages
the lung infrastructure that produces the surfactant necessary to
allow smooth and low-effort lung alveolar expansion. The type I
cells of the alveoli appear to be the cells chiefly affected by acute
low to moderate inhalation exposure. At higher exposure, both
type I and type II alveolar cells are damaged. If only type I cells
are damaged, after an acute period of severe distress, it is likely that
treatment with modern ventilation equipment and medications
will result in recovery. Some patients develop nonallergic asthma,
or “twitchy airway” disease, after such a respiratory insult. If severe
damage to the type I and type II alveolar cells occurs, replacement of
the type I cells may be impaired; progressive fibrosis may ensue that
eventually leads to bronchial ablation and alveolar collapse. This
can result in permanent restrictive respiratory disease. In addition to
the direct deep lung effect, long-term exposure to lower concentra-
tions of nitrogen dioxide has been linked to cardiovascular disease,
increased incidence of stroke, and other chronic disease.
The current PEL for NO2 is given in Table 56–1. Exposure
to 25 ppm of NO2 is irritating to some individuals; 50 ppm is
moderately irritating to the eyes and nose. Exposure for 1 hour
to 50 ppm can cause pulmonary edema and perhaps subacute or
chronic pulmonary lesions; 100 ppm can cause pulmonary edema
and death.
2. Clinical effects—The signs and symptoms of acute exposure
to NO2 include irritation of the eyes and nose, cough, mucoid or
frothy sputum production, dyspnea, and chest pain. Pulmonary
edema may appear within 1–2 hours. In some individuals, the
clinical signs may subside in about 2 weeks; the patient may then
pass into a second stage of abruptly increasing severity, including
recurring pulmonary edema and fibrotic destruction of terminal
bronchioles (bronchiolitis obliterans). Chronic exposure of labora-
tory animals to 10–25 ppm NO2 has resulted in emphysematous
changes; thus, chronic effects in humans are of concern.
3. Treatment—There is no specific treatment for acute intoxi-
cation by NO2; therapeutic measures for the management of
deep lung irritation and noncardiogenic pulmonary edema are
used. These measures include maintenance of gas exchange with
adequate oxygenation and alveolar ventilation. Drug therapy
may include bronchodilators, sedatives, and antibiotics. New
approaches to the management of NO2-induced ARDS have been
developed and considerable controversy now exists about the pre-
cise respiratory protocol to use in any given patient.
Ozone & Other Oxides
Ozone (O3) is a bluish irritant gas found in the earth’s atmo-
sphere, where it is an important absorbent of ultraviolet light
at high altitude. At ground level, ozone is an important pollut-
ant. Atmospheric ozone pollution is derived from photolysis of
oxides of nitrogen, volatile organic compounds, and CO. These
compounds are produced primarily when fossil fuels such as
gasoline, oil, or coal are burned or when some chemicals (eg, sol-
vents) evaporate. Nitrogen oxides are emitted from power plants,
motor vehicles, and other sources of high-heat combustion.
Volatile organic compounds are emitted from motor vehicles,
chemical plants, refineries, factories, gas stations, paint, and other
sources. More information on ground-level ozone and its sources
and consequences may be found at https://www.epa.gov/arc-x/
climate-adaptation-ground-level-ozone-and-health.
Ozone can be generated in the workplace by high-voltage elec-
trical equipment, and around ozone-producing devices used for
air and water purification. Agricultural sources of ozone are also
important. There is a near-linear gradient between exposure to
ozone (1-hour level, 20–100 ppb) and bronchial smooth muscle
response. See Table 56–1 for the current PEL for ozone.
1. Mechanism of action and clinical effects—Ozone is an
irritant of mucous membranes. Mild exposure produces upper
respiratory tract irritation. Severe exposure can cause deep lung
irritation, with pulmonary edema when inhaled at sufficient
concentrations. Ozone penetration in the lung depends on tidal
volume; consequently, exercise can increase the amount of ozone
reaching the distal lung. Some of the effects of O3 resemble
those seen with radiation, suggesting that O3 toxicity may result
from the formation of reactive free radicals. The gas causes shal-
low, rapid breathing and a decrease in pulmonary compliance.
Enhanced sensitivity of the lung to bronchoconstrictors is also
observed. Exposure around 0.1 ppm O3 for 10–30 minutes causes
irritation and dryness of the throat; above 0.1 ppm, one finds
changes in visual acuity, substernal pain, and dyspnea. Pulmonary
function is impaired at concentrations exceeding 0.8 ppm.
Airway hyperresponsiveness and airway inflammation have
been observed in humans. The response of the lung to O3 is a
dynamic one. The morphologic and biochemical changes are the
result of both direct injury and secondary responses to the initial
damage. Long-term exposure in animals results in morphologic
and functional pulmonary changes. Chronic bronchitis, bronchi-
olitis, fibrosis, and emphysematous changes have been reported in
a variety of species, including humans, exposed to concentrations
above 1 ppm. Increased visits to hospital emergency depart-
ments for cardiopulmonary disease during ozone alerts have been
reported. A study of the basic physiologic responses of humans to
 CHAPTER 56  Introduction to Toxicology: Occupational & Environmental     1009
ozone exposure and the biomarkers evoked provides useful insight
into the fundamental toxicologic impacts of ozone.
2. Treatment—There is no specific treatment for acute O3
intoxication. Management depends on therapeutic measures
used for deep lung irritation and noncardiogenic pulmonary
edema that have resulted in ARDS. Current national ambient
air quality standards for ozone are listed at https://www.epa.gov/
criteria-air-pollutants.
SOLVENTS
Halogenated Aliphatic Hydrocarbons
These “halohydrocarbon” agents once found wide use as industrial
solvents, degreasing agents, and cleaning agents. The substances
include carbon tetrachloride, chloroform, trichloroethylene, tet-
rachloroethylene (perchloroethylene), and 1,1,1-trichloroethane
(methyl chloroform). Many halogenated aliphatic hydrocarbons
are classified as known or probable human carcinogens. Carbon
tetrachloride and trichloroethylene have largely been removed
from the workplace. Perchloroethylene and trichloroethane are
still in use for dry cleaning and solvent degreasing, but it is likely
that their use will be very limited in the future. In 2016, the
National Institute of Environmental Sciences (NIEHS) listed
trichloroethylene as a known carcinogen. The EPA now consid-
ers perchloroethylene a likely human carcinogen. The EPA data
sheet may be found at https://www.epa.gov/haps/health-effects-
notebook-hazardous-air-pollutants. Dry cleaning as an occupation
is listed as a class 2B carcinogenic activity by the International
Agency for Research on Cancer (IARC). The Canadian Center for
Occupational Health and Safety lists occupations and exposures
to occupational carcinogens at http://www.ccohs.ca/oshanswers/
diseases/carcinogen_occupation.html.
Fluorinated aliphatics such as the freons and closely related
compounds have also been used in the workplace, in consumer
goods, and in stationary and mobile air conditioning systems.
Because of the severe damage they cause to the ozone layer in the
troposphere, their use has been limited or eliminated by inter-
national treaty agreements. The common halogenated aliphatic
solvents also create serious problems as persistent water pollutants.
They are widely found in both groundwater and drinking water as
a result of poor disposal practices.
Table 56–1 includes recommended OSHA PELs for several of
these compounds (see also http://www.osha.gov, Table Z-1).
1. Mechanism of action and clinical effects—In laboratory
animals, the halogenated hydrocarbons cause central nervous
system (CNS) depression, liver injury, kidney injury, and some
degree of cardiotoxicity. Several are also carcinogenic in animals
and are considered probable human carcinogens. Trichloroethyl-
ene and tetrachloroethylene are listed as “reasonably anticipated to
be a human carcinogen” by the US National Toxicology Program,
and as class 2A probable human carcinogens by IARC. These
substances are depressants of the CNS in humans. Chronic work-
place exposure to halogenated hydrocarbon solvents can cause
significant neurotoxicity with impaired memory and peripheral
neuropathy. All halohydrocarbon solvents can cause cardiac
arrhythmias in humans, particularly in situations involving sym-
pathetic excitation and norepinephrine release.
Hepatotoxicity is also a common toxic effect that can occur in
humans after acute or chronic halohydrocarbon exposures. Neph-
rotoxicity can occur in humans exposed to carbon tetrachloride,
chloroform, and trichloroethylene. Chloroform, carbon tetrachlo-
ride, trichloroethylene, and tetrachloroethylene carcinogenicity
have been observed in lifetime exposure studies performed in rats
and mice and in some human epidemiologic studies. Dichloro-
methane (methylene chloride) is a potent neurotoxin, a generator
of CO in humans, and a probable human carcinogen. It has been
widely used as a paint stripper, plastic glue, and for other pur-
poses. Epidemiologic studies of workers who have been exposed
to aliphatic hydrocarbon solvents that include dichloromethane,
trichloroethylene, and tetrachloroethylene have found significant
associations between the agents and renal, prostate, and testicular
cancer. Trichloroethylene is now considered a class 1, known
human carcinogen by IARC; renal cancers and non-Hodgkin’s
lymphoma have been reported. Other cancers are increased but
their incidence has not reached statistical significance.
2. Treatment—There is no specific treatment for acute intoxica-
tion resulting from exposure to halogenated hydrocarbons. Man-
agement depends on the organ system involved.
Aromatic Hydrocarbons
Benzene is used for its solvent properties and as an intermediate
in the synthesis of other chemicals. It remains an important com-
ponent of gasoline. Benzene may be found in premium gasolines
at concentrations of about 1.5%. In cold climates such as Alaska,
benzene concentrations in gasoline may reach 5% in order to pro-
vide an octane boost. It is one of the most widely used industrial
chemicals in the world. The current PEL is 1.0 ppm in the air (see
Table 56–1 and http://www.osha.gov, Table Z-1), and a 5 ppm
limit is recommended for skin exposure. The National Institute
for Occupational Safety and Health (NIOSH) and others have
recommended that the exposure limits for benzene be further
reduced to 0.1 ppm because excess blood cancers occur at the
current PEL.
The acute toxic effect of benzene is depression of the CNS.
Exposure to 7500 ppm for 30 minutes can be fatal. Exposure to
concentrations greater than 3000 ppm may cause euphoria, nausea,
locomotor problems, and coma. Vertigo, drowsiness, headache,
and nausea may occur at concentrations ranging from 250 to
500 ppm. No specific treatment exists for the acute toxic effect
of benzene.
Chronic exposure to benzene can result in very serious toxic
effects, the most significant of which is bone marrow injury.
Aplastic anemia, leukopenia, pancytopenia, and thrombocyto-
penia occur, as does leukemia. Chronic exposure to low levels
of benzene has been associated with leukemia of several types as
well as lymphomas, myeloma, and myelodysplastic syndrome.
Recent studies have shown the occurrence of leukemia following
1010    SECTION IX Toxicology
exposures as low as 2 ppm-years. The pluripotent bone marrow
stem cells appear to be targets of benzene or its metabolites and
other stem cells may also be targets.
Benzene has long been known to be a potent clastogen, ie,
a mutagen that acts by causing chromosomal breakage. Recent
studies have suggested specific chromosome reorganization and
genomic patterns that are associated with benzene-induced leu-
kemia. Epidemiologic data confirm a causal association between
benzene exposure and leukemia and other bone marrow cancers
in workers. IARC classifies benzene as a class 1, known human
carcinogen. Most national and international organizations classify
benzene as a known human carcinogen.
Toluene (methylbenzene) does not possess the myelotoxic
properties of benzene, nor has it been associated with leukemia.
It is not carcinogenic and is listed as class 3 by IARC. It is, how-
ever, a CNS depressant and a skin and eye irritant. It is also feto-
toxic. See Table 56–1 and OSHA Tables Z-1 and Z-2 (http://
www.osha.gov) for the PELs. Exposure to 800 ppm can lead to
severe fatigue and ataxia; 10,000 ppm can produce rapid loss of
consciousness. Chronic effects of long-term toluene exposure
are unclear because human studies indicating behavioral effects
usually concern exposures to several solvents. In limited occu-
pational studies, however, metabolic interactions and modifica-
tion of toluene’s effects have not been observed in workers also
exposed to other solvents. Less refined grades of toluene contain
benzene. If technical grade toluene is to be used where there is
human contact or exposure, analysis of the material for benzene
content is advisable.
Xylene (dimethylbenzene) has been substituted for benzene
in many solvent degreasing operations. Like toluene, the three
xylenes do not possess the myelotoxic properties of benzene,
nor have they been associated with leukemia. Xylene is a CNS
depressant and a skin irritant. Less refined grades of xylene
contain benzene. Estimated TLV–time-weighted average and
TLV–short-term exposure limit are 100 and 150 ppm, respec-
tively. The current OSHA PELs may be found at http://www.
osha.gov, Table Z-1.
TABLE 56–2  Organochlorine pesticides.
Chemical Class Compounds
DDT and analogs Dichlorodiphenyltrichloroethane (DDT)
  Methoxychlor
  Tetrachlorodiphenylethane (TDE)
Benzene hexachlorides Benzene hexachloride (BHC; hexachlorocyclohexane)
  Lindane
Cyclodienes Aldrin
  Chlordane
  Dieldrin
  Heptachlor
Toxaphenes Toxaphene (camphechlor)
1
Toxicity rating: Probable human oral lethal dosage for class 3 = 500−5000 mg/kg, class 4 = 50−500 mg/kg, and class 5 = 5−50 mg/kg. (See Gosselin et al, 1984.)
2
ADI, acceptable daily intake (mg/kg/d).
PESTICIDES
Organochlorine Pesticides
These agents are usually classified into four groups: DDT (chloro-
phenothane) and its analogs, benzene hexachlorides, cyclodienes,
and toxaphenes (Table 56–2). They are aryl, carbocyclic, or het-
erocyclic compounds containing chlorine substituents. The indi-
vidual compounds differ widely in their biotransformation and
capacity for storage in tissues; toxicity and storage are not always
correlated. They can be absorbed through the skin as well as by
inhalation or oral ingestion. There are, however, important quanti-
tative differences between the various derivatives; DDT in solution
is poorly absorbed through the skin, whereas dieldrin absorption
from the skin is very efficient. Organochlorine pesticides have
largely been abandoned because they cause severe environmental
damage. They are now known to be endocrine disrupters in
animals and humans. DDT continues to have very restricted use
for domestic mosquito elimination in malaria-infested areas of
Africa. This use is controversial, but it is very effective and is likely
to remain in place for the foreseeable future. Organochlorine pes-
ticide residues in humans, animals, and the environment present
long-term problems that are not yet fully understood.
1. Human toxicology—The acute toxic properties of all the
organochlorine pesticides in humans are qualitatively similar.
These agents interfere with inactivation of the sodium channel
in excitable membranes and cause rapid repetitive firing in most
neurons. Calcium ion transport is inhibited. These events affect
repolarization and enhance the excitability of neurons. The major
effect is CNS stimulation. With DDT, tremor may be the first
manifestation, possibly continuing to convulsions, whereas with
the other compounds convulsions often appear as the first sign of
intoxication. There is no specific treatment for the acute intoxi-
cated state, and management is symptomatic.
The potential carcinogenic properties of organochlorine pes-
ticides have been extensively studied, and results indicate that
Toxicity Rating1 ADI2
4 0.005
3 0.1
3 —
4 0.008
4 0.008
5 0.0001
4 0.0005
5 0.0001
4 0.0001
4 —
 CHAPTER 56  Introduction to Toxicology: Occupational & Environmental     1011
chronic administration to laboratory animals over long periods
results in enhanced carcinogenesis. Endocrine pathway disrup-
tion is the postulated mechanism. Numerous mechanisms for
xenoestrogen (estrogen-like) carcinogenesis have been postulated.
To date, however, several large epidemiologic studies in humans
have not found a significant association between the risk of cancer
and specific compounds or serum levels of organochlorine pesti-
cide metabolites. The results of a case-control study conducted to
investigate the relation between dichlorodiphenyldichloroethylene
(DDE, the primary metabolite of DDT) and DDT breast adipose
tissue levels and breast cancer risk did not confirm a positive asso-
ciation. In contrast, recent work supports an association between
prepubertal exposure to DDT and brain cancer. Recent studies
also suggest that the risk of testicular cancer and non-Hodgkin’s
lymphoma is increased in persons with elevated organochlorine
levels. Noncancer end points are also of concern. Recent work
associates cryptorchidism and hypospadias in newborns with
maternal adipose levels of chlordane metabolites. These residues
are also linked to testicular cancer.
2. Environmental toxicology—The organochlorine pesti-
cides are considered persistent chemicals. Degradation is quite
slow when compared with other pesticides, and bioaccumula-
tion, particularly in aquatic ecosystems, is well documented.
Their mobility in soil depends on the composition of the soil;
the presence of organic matter favors the adsorption of these
chemicals onto the soil particles, whereas adsorption is poor in
sandy soils. Once adsorbed, they do not readily desorb. These
compounds induce significant abnormalities in the endocrine
balance of sensitive animal and bird species, in addition to their
adverse impact on humans. Since the early 1960s, when Rachel
Carson’s work and subsequent book, Silent Spring, brought
attention to the issue, the organochlorine pesticides have been
recognized as pernicious environmental toxins. Their use is
banned in most jurisdictions.
Organophosphorus Pesticides
These agents, some of which are listed in Table 56–3, are used to
combat a large variety of pests. They are useful pesticides when in
direct contact with insects or when used as plant systemics, where
the agent is translocated within the plant and exerts its effects on
insects that feed on the plant. The many varieties currently in use
are applied by spray techniques including hand, tractor, and aerial
methods. They are often spread widely by wind and weather and
are subject to widespread drift. The organophosphate pesticides
are based on compounds such as soman, sarin, and tabun, which
were developed for use as war gases. Some of the less toxic organo-
phosphorus compounds are used in human and veterinary medi-
cine as local or systemic antiparasitics (see Chapters 7 and 53).
The compounds are absorbed by the skin as well as by the
respiratory and gastrointestinal tracts. Biotransformation is rapid,
particularly when compared with the rates observed with the chlo-
rinated hydrocarbon pesticides. Storm and collaborators reviewed
current and suggested human inhalation occupational exposure
limits for 30 organophosphate pesticides (see References).
TABLE 56–3  Organophosphorus pesticides.
Compound Toxicity Rating1 ADI2
Azinphos-methyl 5 0.005
Chlorfenvinphos — 0.002
Diazinon 4 0.002
Dichlorvos — 0.004
Dimethoate 4 0.01
Fenitrothion — 0.005
Malathion 4 0.02
Parathion 6 0.005
Parathion-methyl 5 0.02
Trichlorfon 4 0.01
1
Toxicity rating: Probable human oral lethal dosage for class 4 = 50–500 mg/kg, class 5 =
5–50 mg/kg, and class 6 = ≤5 mg/kg, ;—, data not found. (See Gosselin et al, 1984.)
2
ADI, acceptable daily intake (mg/kg/d).
1. Human toxicology—In mammals as well as insects, the
major effect of these agents is inhibition of acetylcholinesterase
through phosphorylation of the esteratic site. The signs and symp-
toms that characterize acute intoxication are due to inhibition of
this enzyme and accumulation of acetylcholine; some of the agents
also possess direct cholinergic activity. Specific treatment with
antidotes and useful antagonists is available. In addition, pretreat-
ment with physostigmine and other short-acting compounds may
provide protection against these pesticides or their war gas analogs
if used in timely fashion. These effects and their treatment are
described in Chapters 7 and 8 of this book. Altered neurologic and
cognitive functions, as well as psychological symptoms of variable
duration, have been associated with exposure to these pesticides.
Furthermore, there is some indication of an association of low
arylesterase activity with neurologic symptom complexes in Gulf
War veterans.
In addition to—and independently of—inhibition of acetyl-
cholinesterase, some of these agents are capable of phosphorylating
another enzyme present in neural tissue, the so-called neuropathy
target esterase (NTE). This results in progressive demyelination
of the longest nerves. Associated with paralysis and axonal degen-
eration, this lesion is sometimes called organophosphorus ester-
induced delayed polyneuropathy (OPIDP). Delayed central and
autonomic neuropathy may occur in some poisoned patients.
Hens are particularly sensitive to these properties and have proved
very useful for studying the pathogenesis of the lesion and for
identifying potentially neurotoxic organophosphorus derivatives.
There is no specific treatment for NTE toxicity.
In humans, progressive chronic axonal neurotoxicity has been
observed with triorthocresyl phosphate (TOCP), a noninsecti-
cidal organophosphorus compound. It is also thought to occur
with the pesticides dichlorvos, trichlorfon, leptophos, methami-
dophos, mipafox, trichloronat, and others. The polyneuropathy
usually begins as burning and tingling sensations, particularly in
the feet, with motor weakness occurring a few days later. Sensory
and motor difficulties may extend to the legs and hands. Gait is
1012    SECTION IX Toxicology

affected, and ataxia may be present. Central nervous system and for the organophosphorus pesticides. However, as described in
autonomic changes may develop still later. There is no specific Chapters 7 and 8, the binding is relatively weak, dissociation
treatment for this form of delayed neurotoxicity. The long-term occurs after minutes to hours, and clinical effects are of shorter
prognosis of NTE inhibition is highly variable. Reports of this duration than those observed with organophosphorus com-
type of neuropathy (and other toxicities) in pesticide manufactur- pounds. Spontaneous reactivation of cholinesterase is more rapid
ing workers and in agricultural pesticide applicators have been after inhibition by the carbamates. The therapeutic index, the
published (see References). ratio of the doses that cause severe toxicity or death to those that
Recent clinical observation has also defined an intermediate result in minor intoxication, is larger with carbamates than with
syndrome in severely organophosphate-poisoned patients. This the organophosphorus agents. Although the clinical approach to
syndrome is characterized by neuromuscular transmission failure, carbamate poisoning is similar to that for organophosphates, the
and cardiac failure more typical of nicotinic than muscarinic use of pralidoxime is not recommended.
poisoning. Progressive neuromuscular failure leads to weakness of The carbamates are considered to be nonpersistent pesticides.
the respiratory muscles and eventually to death. The physiologic They exert only a small impact on the environment.
abnormalities are complex but involve a progressive decrement
in neuromuscular junction transmission efficiency. Patients who
develop this intermediate syndrome are at great risk of cardiore- Botanical Pesticides
spiratory failure and may require mechanical ventilation. Because Pesticides derived from natural sources include nicotine, rote-
organophosphorus poisoning frequently occurs in less developed none, and pyrethrum. Nicotine is obtained from the dried leaves
parts of the world where medical resources are very limited, the of Nicotiana tabacum and N rustica. It is rapidly absorbed from
development of the intermediate syndrome is frequently a lethal mucosal surfaces; the free alkaloid, but not the salt, is readily
complication. It is not effectively treated with the usual manage- absorbed from the skin. Nicotine reacts with the acetylcholine
ment protocol for organophosphate pesticide poisoning. receptor of the postsynaptic membrane (sympathetic and para-
sympathetic ganglia, neuromuscular junction), resulting in depo-
2. Environmental toxicology—Organophosphorus pesticides larization of the membrane. Toxic doses cause stimulation rapidly
are not considered to be persistent pesticides. They are relatively followed by blockade of transmission. These actions are described
unstable and break down in the environment as a result of hydro- in Chapter 7. Treatment is directed toward maintenance of vital
lysis and photolysis. As a class they are considered to have a small signs and suppression of convulsions. Nicotine analogs (neonic-
permanent impact on the environment, in spite of their acute otinoids) have been developed for use as agricultural pesticides
effects on organisms. and have been accused of a role in bee colony collapse.
Rotenone (Figure 56–1) is obtained from Derris elliptica,
Carbamate Pesticides D mallaccensis, Lonchocarpus utilis, and L urucu. The oral inges-
tion of rotenone produces gastrointestinal irritation. Conjunctivi-
These compounds (Table 56–4) inhibit acetylcholinesterase by
tis, dermatitis, pharyngitis, and rhinitis can also occur. Treatment
carbamoylation of the esteratic site. Thus, they possess the toxic
is symptomatic.
properties associated with inhibition of this enzyme as described
Pyrethrum consists of six known insecticidal esters: pyrethrin I
(Figure 56–1), pyrethrin II, cinerin I, cinerin II, jasmolin I, and
TABLE 56–4  Carbamate pesticides. jasmolin II. Synthetic pyrethroids account for an increasing per-
centage of worldwide pesticide usage. Pyrethrum may be absorbed
Compound Toxicity Rating1 ADI2 after inhalation or ingestion. When absorbed in sufficient quanti-
Aldicarb 6 0.005 ties, the major site of toxic action is the CNS; excitation, con-
vulsions, and tetanic paralysis can occur. Voltage-gated sodium,
Aminocarb 5 —
calcium, and chloride channels are considered targets, as well as
Carbaryl 4 0.01
peripheral-type benzodiazepine receptors. Treatment of exposure
Carbofuran 5 0.01 is usually directed at management of symptoms. Anticonvulsants
Dimetan 4 — are not consistently effective. The chloride channel agonist, iver-
Dimetilan 4 — mectin is of use, as are pentobarbital and mephenesin. The pyre-
Isolan 5 — throids are highly irritating to the eyes, skin, and respiratory tree.
They may cause irritant asthma and, potentially, reactive airways
Methomyl 5 —
dysfunction syndrome (RADS) and even anaphylaxis. The most
Propoxur 4 0.02
common injuries reported in humans result from their allergenic
Pyramat 4 — and irritant effects on the airways and skin. Cutaneous paresthe-
Pyrolan 5 — sias have been observed in workers spraying synthetic pyrethroids.
Zectran 5 — The use of persistent synthetic pyrethroids to exterminate insects
1
Toxicity rating: Probable human oral lethal dosage for class 4 = 50−500 mg/kg, class
on aircraft has caused respiratory and skin problems as well as
5 = 5−50 mg/kg, and class 6 = ≤ 5 mg/kg. (See Gosselin et al, 1984.) some neurologic complaints in flight attendants and other aircraft
2
ADI, acceptable daily intake (mg/kg/d), data not found. workers. Severe occupational exposures to synthetic pyrethroids in
 CHAPTER 56  Introduction to Toxicology: Occupational & Environmental     1013

CI O CI
+ + –
H3C N N CH3 2CI

CI O CI

Paraquat dichloride 2,3,7,8-Tetrachlorodibenzodioxin (TCDD)

CI C CI O CH2 COOH

CCI3 CI

Dichlorodiphenyltrichloroethane (DDT)

O CH3 CI
H3C
2,4-Dichlorophenoxyacetic acid (2,4-D)
O
O
H

O CH2 COOH
O
O O CI
H

CH2
H C CI
CH3 CI
Rotenone 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T)

H3C CH3 O

CH2 CH CH CH CH2
H COO O O
H3C
C NH P OH
CH3
C C H H
HO CH2 CH2 OH
H3C H
Pyrethrin I Glyphosate

FIGURE 56–1  Chemical structures of selected herbicides and pesticides.

China resulted in marked effects on the CNS, including convul-
sions. Other previously unreported toxic manifestations have been
observed in pyrethrin-exposed individuals.
HERBICIDES
Chlorophenoxy Herbicides
2,4-Dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophen-
oxyacetic acid (2,4,5-T), and their salts and esters have been
used as herbicides for the destruction of weeds (Figure 56–1).
These compounds are of relatively low acute human toxicity.
However, despite their low acute hazard, they cause serious long-
term human and environmental toxicity. 2,4-D remains in wide
commercial and domestic use for lawn weed control. 2,4,5-T had
similar uses but was infamously incorporated into Agent Orange,
used as a defoliant during the Vietnam conflict. Agent Orange was
contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (a potent
animal carcinogen and likely human carcinogen) and other toxic,
persistent, and undesirable polychlorinated compounds. When
this toxicity was discovered, the US Department of Agriculture
canceled the domestic pesticide registrations for trichlorophenoxy
herbicides, and these compounds are no longer used. However,
other, less thoroughly studied compounds, eg, chlorinated xan-
thenes, are present in both the dichlorophenoxy and trichlorophe-
noxy herbicides (see below).
In humans, 2,4-D in large doses can cause coma and gener-
alized muscle hypotonia. Rarely, muscle weakness and marked
hypotonia may persist for several weeks. In laboratory animals,
signs of liver and kidney dysfunction have also been reported with
chlorphenoxy herbicides. Several epidemiologic studies performed
by the U.S. National Cancer Institute confirmed the causal link
between 2,4-D and non-Hodgkin’s lymphoma. Evidence for a
causal link to soft tissue sarcoma, however, is considered equivocal.
1014    SECTION IX Toxicology

The dichlorophenoxy and related herbicides have been Bipyridyl Herbicides

found to contain and to generate dimethylnitrosamine
Paraquat is the most important agent of this class (Figure 56–1).
(N-nitrosodimethylamine; NDMA), a potent human carcino-
Its mechanism of action is said to be similar in plants and animals
gen, during environmental transformation as well as non-
and involves single-electron reduction of the herbicide to free radi-
chlorine water disinfection. Studies by Environment Canada
cal species. Ingestion (accidental or suicidal) is among the most
and others have questioned the use of this compound because
serious and potentially lethal pesticide poisonings. Many serious
of water contamination. Studies of related nitrosamine-forming
exposures take place in developing countries where limited treat-
herbicidal compounds have raised questions about the suitability
ment resources are available. Paraquat accumulates slowly in the
of these compounds for general weed control. Because of the
lung by an active process and causes lung edema, alveolitis, and
extremely high economic value of herbicides to the agricultural
progressive fibrosis. It probably inhibits superoxide dismutase,
community, however, long-term decisions on their use have been
resulting in intracellular free-radical oxygen toxicity.
delayed.
In humans, the first signs and symptoms after oral exposure
are hematemesis and bloody stools. Within a few days, however,
Glyphosate delayed toxicity occurs, with respiratory distress and the develop-
ment of congestive hemorrhagic pulmonary edema accompanied
Glyphosate (N-[phosphonomethyl] glycine, Figure 56–1), the
by widespread cellular proliferation. During the acute period,
principle ingredient in Roundup, is now the most widely used
oxygen should be used cautiously to combat dyspnea or cyanosis,
herbicide in the world. It functions as a contact herbicide and
because it may aggravate the pulmonary lesions. Hepatic, renal, or
is absorbed through the leaves and roots of plants. It is generally
myocardial involvement may develop. The interval between inges-
formulated with surfactant to enhance its intended effect on nox-
tion and death may be several weeks.
ious plants. Because it is nonselective, it may damage important
Because of the delayed pulmonary toxicity, prompt immo-
crops and desirable ornamental plants even when used as directed.
bilization of the paraquat to prevent absorption is important.
Therefore, genetically modified plants such as soybean, corn,
Adsorbents (eg, activated charcoal, Fuller’s earth) are routinely
and cotton that are glyphosate-resistant have been developed and
given to bind the paraquat and minimize its absorption. Gastric
patented. They are widely grown throughout the world. Almost
lavage is not recommended as it may promote aspiration from the
all soybean crops and many corn crops grown today are of the
stomach into the lungs. Once the paraquat is absorbed, treatment
glyphosate-resistant type. These genetically modified (GMO)
is successful in less than 50% of cases. Monitoring of plasma and
crops are grown from patented seeds and have great economic
urine paraquat concentrations is useful for prognostic assessment.
value to growers, contributing to the food supply in a meaningful
Computed tomography scanning has also been used to follow
way. However, in some jurisdictions their use is highly controver-
the pulmonary lesions as they develop and to help with prog-
sial. While there is no evidence that the modified crops are toxic
nosis. The pulmonary proliferative phase begins 1–2 weeks after
or dangerous to humans or animals, the long-term agricultural
paraquat ingestion. Although a few reports indicate some success
impact of widespread use of glyphosate herbicides on resistant
with dialysis, hemodialysis and hemoperfusion rarely change the
crops remains to be determined. Additionally, the impact of effec-
clinical course. Many approaches have been used to slow or stop
tive weed elimination on the food supply and habitat of critical
the progressive pulmonary fibrosis. Immunosuppression using
insect species, eg, bees, and some migrating birds has been a source
corticosteroids and cyclophosphamide is widely practiced, but
of increasing concern.
evidence for efficacy is weak. Antioxidants such as acetylcysteine
Because of the widespread availability and use of this herbi-
and salicylate might be beneficial through free radical-scavenging,
cide, glyphosate-surfactant poisonings are common. Many of the
anti-inflammatory, and nuclear factor kappa-B inhibitory actions.
observed ingestions and reports of poisoning are from developing
However, there are no published human trials. The case fatality
countries, where suicide by pesticide is common. Many injuries
rate is high in all centers despite large variations in treatment.
are minor, but some serious and lethal poisonings have been
Patients require prolonged observation and treatment for respi-
reported. Glyphosate is a significant eye and skin irritant. When
ratory and renal insufficiency if they survive the acute stage of
ingested it can cause mild to moderate esophageal erosion. It also
poisoning.
causes aspiration pneumonia and renal failure. There have been
some reports of teratogenic outcomes in workers who handle and
apply glyphosate, but the epidemiologic evidence is not clear. ENVIRONMENTAL POLLUTANTS
There is a growing literature on management of acute glyphosate
poisoning. Treatment is symptomatic and no specific protocol is
Polychlorinated & Polybrominated
indicated. Hemodialysis has been used with success in cases of
renal failure. Biphenyls
Although glyphosate seems to have little persistence and lower Highly halogenated biphenyl compounds, which have desirable
toxicity than other herbicides, the commercial formulations often properties for insulation, fire retardancy, and many other uses,
contain surfactants and other active compounds that complicate were manufactured in large quantities during the mid-20th century.
the toxicity of the product. Some of the toxic effects are related to The quantities produced and the almost universal dispersion of
the surfactant material. the materials in which they were incorporated have produced
 CHAPTER 56  Introduction to Toxicology: Occupational & Environmental     1015
an enormous environmental problem. Both chlorinated and
brominated biphenyls are environmentally dangerous and signifi-
cantly toxic, and are now banned from use.
The polychlorinated biphenyls (PCBs, coplanar biphenyls)
were used as dielectric and heat transfer fluids, lubricating oils,
plasticizers, wax extenders, and flame retardants. Their industrial
use and manufacture in the USA were terminated by 1977. The
chlorinated products used commercially were actually mixtures of
PCB isomers and homologs containing 12–68% chlorine. These
chemicals are very stable, highly lipophilic, poorly metabolized,
and very resistant to environmental degradation; thus they bioac-
cumulate in food chains.
Food is the major source of PCB residues in humans. Accumu-
lation of PCB in fish species led Canada and the USA to restrict
commercial fishing and to limit consumption of fish from the
Great Lakes of North America (see Box: Bioaccumulation & Bio-
magnification, earlier). In addition, large industrial site contami-
nation, illegal dumping, migration from hazardous waste sites and
other large-scale sources, and widespread use of PCBs in electrical
transformers has led to multiple localized areas of contamination
and human exposure. Leakage of transformer dielectric fluids in
neighborhoods and backyards has caused significant numbers of
serious but highly localized PCB exposure events.
There are numerous reports of large population exposures to
PCBs. A serious exposure to PCBs—lasting several months—
occurred in Japan in 1968 as a result of cooking oil contamination
with PCB-containing transfer medium (Yusho disease). A similar
outbreak called Yucheng disease occurred at about the same time
in Taiwan. Effects on the fetus and on the development of the
offspring of poisoned women were reported. It is now known that
the contaminated cooking oil contained not only PCBs but also
polychlorinated dibenzofurans (PCDFs) and polychlorinated qua-
terphenyls (PCQs). It is likely that the effects initially attributed
to the PCBs were actually caused by a mixture of contaminants.
Workers occupationally exposed to PCBs develop dermatologic
problems that include chloracne, folliculitis, erythema, dry-
ness, rash, hyperkeratosis, and hyperpigmentation. Some hepatic
abnormalities have been found in PCB poisoning, and plasma
triglycerides are elevated.
Information about the effects of PCBs on reproduction and
development is accumulating. The halogenated pesticides are
potent endocrine disrupters and there is widespread concern
about the persistent estrogenic effect of these chemicals. Adverse
reproductive impacts of PCBs have been found in many animal
studies. Direct teratogenic effects in humans have yet to be estab-
lished: studies in workers and in the general population exposed to
moderate or to very high levels of PCBs have not been conclusive.
Some adverse behavioral effects in infants have been reported.
An association between prenatal exposure to PCBs and deficits
in childhood intellectual function was described for children
born to mothers who had eaten large quantities of contaminated
fish. Epidemiologic studies have established increases in various
cancers including melanoma, breast, pancreatic, and thyroid
cancers. These findings and animal studies provided a sufficient
basis for the IARC to classify some co-planar PCBs as class 1,
carcinogenic to humans, in volume 100 of the IARC monographs.
A comprehensive EPA fact sheet on PCBs may be found at https://
www.epa.gov/pcbs.
The polybrominated biphenyls (PBBs) and their ethers
(PBDEs) share many of the toxic and environmentally damag-
ing persistent qualities of PCBs. They were introduced as fire
retardants in the 1950s and have been used in massive quantities
since that time. The biphenyls are no longer produced and may
no longer be used, but the biphenyl ethers remain in use as fire
retardants in plastics for bedding and in automobile upholstery.
PBB fire retardant contamination has been extensive in the
Great Lakes region, resulting in large exposure to the population.
PBBs are considered IARC class 2a: probable human carcino-
gens. PBDEs are not classified. An EPA technical fact sheet on
PBB and PBDEs may be found at http://www2.epa.gov/fedfac/
technical-fact-sheet-polybrominated-diphenyl-ethers-pbdes-and-
polybrominated-biphenyls-pbbs.
The polychlorinated dibenzo-p-dioxins (PCDDs), or
dioxins, are a group of halogenated congeners of which tetra-
chlorodibenzodioxin (TCDD) has been the most carefully stud-
ied. There is a large group of dioxin-like compounds, including
polychlorinated dibenzofurans (PCDFs) and coplanar
biphenyls. While PCBs were used commercially, PCDDs and
PCDFs are unwanted byproducts that appear in the environ-
ment and in manufactured products as contaminants because
of improperly controlled combustion processes. They are also
produced when unexpected heating to temperatures over 600°C
occurs as in lightning strikes or electrical fires in PCB-containing
transformers. Like PCBs, these chemicals are very stable and
highly lipophilic. They are poorly metabolized and very resistant
to environmental degradation. Several significant environmen-
tal contamination episodes involving dioxins and furans from
industrial sites have occurred. Recent publications have demon-
strated an elevated incidence of subsequent chronic diseases (eg,
diabetes, metabolic syndrome, and obesity) in exposed persons.
Laboratory studies of the blood concentrations of TCDD and
its metabolites have provided insight into the persistence and
metabolism of the contaminants.
In laboratory animals, TCDD has produced a variety of toxic
effects. Wasting syndrome (severe weight loss accompanied by
reduction of muscle mass and adipose tissue), thymic atrophy,
epidermal changes, hepatotoxicity, immunotoxicity, effects on
reproduction and development, teratogenicity, and carcinogenic-
ity have been produced. The effects observed in workers involved
in the manufacture of 2,4,5-T (and therefore presumably exposed
to TCDD) consisted of contact dermatitis and chloracne. In
severely TCDD-intoxicated patients, discrete chloracne may be
the only manifestation.
The presence of TCDD in 2,4,5-T, commercially known as
Silvex, was believed to be responsible for other human toxicities
associated with the herbicide. There is epidemiologic evidence
for an association between occupational exposure to the phenoxy
herbicides and an excess incidence of non-Hodgkin’s lymphoma.
The TCDD contaminant in these herbicides seems to play a role
in a number of cancers such as soft tissue sarcomas, lung cancer,
Hodgkin’s lymphomas, and others. TCDD is considered an IARC
class 1, known human carcinogen. Other halogenated compounds
1016    SECTION IX Toxicology
of this type are not currently classifiable as to carcinogenicity; they
are listed as IARC class 3.
Perfluorinated Compounds (PFCs)
Fluorinated hydrocarbon chemicals have been of commercial
interest since the mid-20th century. Their uses have included
coolant materials in air conditioning systems; artificial oxygen-
carrying substances in experimental clinical studies; and heat-,
stain-, and stick-resistant coatings for cookware, fabrics, and
other materials. The fluorocarbons were produced in very large
quantities and have become widespread in the environment.
When it later became apparent that migration of lower molecular
weight fluorocarbons to the troposphere had a deleterious effect
on the protective ozone layer, they were banned from use. The
higher molecular weight, more highly fluorinated compounds,
now called perfluorinated substances (eg, Teflon), have remained
in broad use. Like the heavily chlorinated and brominated hydro-
carbons, their commercial usefulness has been complicated by
a recognition of adverse environmental and suspected human
toxic impacts that resemble some of the adverse qualities of
the other halogenated hydrocarbons. A useful reference is the
Centers for Disease Control and Prevention (CDC) fact sheet
on PFCs. It is found at https://www.cdc.gov/biomonitoring/pdf/
PFCs_FactSheet.pdf.
1. Human toxicology—Concerns about the toxicology of
PFCs have centered on their estrogenic properties and accumula-
tion and persistence in humans. Human exposure to perfluoro
compounds takes place through ingestion and inhalation. Since
these compounds enter the food chain and water sources and are
persistent, ingestion of contaminated food and water products is
a major source of human accumulation. The human half-life of
PFOA is estimated to be about 3 years. As a persistent chemical
and an endocrine disrupter, it is likely that it has some long-term
adverse impact on reproductive function, cellular proliferation,
and other cellular homeostatic mechanisms. Several PFCs (but
not perfluoro compounds derived from PFOA) have been found
to act as proliferators of breast cancer cells. However, a large epi-
demiologic study recently demonstrated a statistically significant
association between high and very high serum PFOA levels in
workers and kidney cancer, and possibly prostate cancer, ovarian
cancer, and non-Hodgkin’s lymphoma. There also may be mod-
est associations with cholesterol elevation and uric acid abnor-
malities. Finally, an acute pulmonary disorder, polymer fume
fever, is caused by the pyrolysis of PFOA. Like metal fume fever,
seen in welders as a result of cadmium vaporization, polymer
fume fever has an acute onset several hours after exposure to the
vaporized PFOA and may cause severe respiratory distress. The
onset of constitutional symptoms, malaise, chills and fever, and
respiratory distress is characteristic of fume fevers. While poly-
mer fume fever is usually mild and self-limited, noncardiogenic
pulmonary edema has occurred. Whenever PFOA is heated
above 350–400°C, toxic fumes capable of causing polymer fume
fever are emitted. Overheated household cookware or burning of
coated fabrics present this risk.
Other human effects are not clearly defined, although animal
studies have shown toxic effects on immune, liver, and endocrine
function, and some increase in tumors and neonatal deaths. A
useful American Cancer Society fact sheet on the subject may be
found at https://www.cancer.org/cancer/cancer-causes/teflon-and-
perfluorooctanoic-acid-pfoa.html.
2. Environmental toxicology—Perfluoro compounds are per-
sistent environmental chemicals having a broad environmental
impact. PFOA and related compounds are now found widely
in water, soil, and many terrestrial and avian species. Aquatic
organisms have accumulated significant loads of PFCs. An
extensive risk assessment of the perfluoro chemicals has been
carried out by Environment Canada, and guidelines have been
developed for the management of PFOA and related compounds.
These may be found at http://www.ec.gc.ca/ese-ees/default.
asp?lang=En&n=451C95ED-1.
Endocrine Disruptors
As described above, the potential hazardous effects of some
chemicals in the environment are receiving considerable atten-
tion because of their estrogen-like or antiandrogenic properties.
Compounds that affect thyroid function are also of concern.
Since 1998, the process of prioritization, screening, and testing
of chemicals for such actions has been undergoing worldwide
development. These chemicals mimic, enhance, or inhibit a
hormonal action. They include a number of plant constituents
(phytoestrogens) and some mycoestrogens as well as industrial
chemicals, persistent organochlorine agents (eg, DDT), PCBs,
and brominated flame retardants. Concerns exist because of their
increasing contamination of the environment, the appearance of
bioaccumulation, and their potential for toxicity. In vitro assays
alone are unreliable for regulatory purposes, and animal stud-
ies are considered indispensable. Modified endocrine responses
in reptiles and marine invertebrates have been observed. In
humans, however, a causal relation between exposure to a spe-
cific environmental agent and an adverse health effect due to
endocrine modulation has not been fully established. Epidemio-
logic studies of populations exposed to higher concentrations
of endocrine-disrupting environmental chemicals are underway.
There are indications that breast and other reproductive cancers
are increased in these patients. Prudence dictates that exposure
to environmental chemicals that disrupt endocrine function
should be reduced.
Asbestos
Asbestos in many of its forms has been widely used in industry
for over 100 years. All forms of asbestos have been shown to cause
progressive fibrotic lung disease (asbestosis), lung cancer, and
mesothelioma. Every form of asbestos, including chrysotile asbes-
tos, causes an increase in lung cancer and mesothelioma. Lung
cancer occurs in people exposed at fiber concentrations well below
concentrations that produce asbestosis. Very large-scale studies of
insulation workers have shown that cigarette smoking and expo-
sure to radon daughters increase the incidence of asbestos-caused
 CHAPTER 56  Introduction to Toxicology: Occupational & Environmental     1017
lung cancer in a synergistic fashion. Asbestos exposure and smok-
ing is a very hazardous combination.
All forms of asbestos cause mesothelioma of the pleura or
peritoneum at very low doses. Other cancers (colon, laryngeal,
stomach, and perhaps even lymphoma) are increased in asbestos-
exposed patients. The mechanism for asbestos-caused cancer is
not yet delineated. Arguments that chrysotile asbestos does not
cause mesothelioma are contradicted by many epidemiologic stud-
ies of worker populations. Recognition that all forms of asbestos
are dangerous and carcinogenic has led many countries to ban all
uses of asbestos. Countries such as Canada, Zimbabwe, Russia,
Brazil, and others that still produce asbestos argue that asbestos
can be used safely with careful workplace environmental controls.
However, studies of industrial practice make the “safe use” of
asbestos highly improbable. Recent attempts to limit international
trade in asbestos have been thwarted by heavy pressure from the
asbestos industry and the producing countries. Information on
countries that currently ban asbestos and the International Ban
Asbestos movement may be found at http://ibasecretariat.org/
alpha_ban_list.php.
METALS
Occupational and environmental poisoning with metals, metal-
loids, and metal compounds is a major health problem. Toxic
metal exposure occurs in many industries, in the home, and
elsewhere in the nonoccupational environment. The classic metal
poisons (arsenic, lead, and mercury) continue to be widely used.
(Treatment of their toxicities is discussed in Chapter 57.) Occupa-
tional exposure and poisoning due to beryllium, cadmium, man-
ganese, and uranium are relatively new occupational problems. In
2016, cobalt and cobalt-releasing compounds were listed by the
National Institute of Environmental Health Sciences as “reason-
ably anticipated to be” human carcinogens.
Beryllium
Beryllium (Be) is a light alkaline metal that confers special prop-
erties on the alloys and ceramics in which it is incorporated.
Beryllium-copper alloys find use as components of computers, in
the encasement of the first stage of nuclear weapons, in devices
that require hardening such as missile ceramic nose cones, and in
heat shield tiles used in space vehicles. Because of the use of beryl-
lium in dental appliances, dentists and dental appliance makers
are often exposed to beryllium dust in toxic concentrations and
may develop beryllium disease.
Beryllium is highly toxic by inhalation and is classified by the
IARC as a class 1, known human carcinogen. Inhalation of beryl-
lium particles produces both acute beryllium disease and chronic
disease characterized by progressive pulmonary fibrosis. Skin
disease also develops in workers exposed to beryllium. The pul-
monary disease is called chronic beryllium disease (CBD) and is a
chronic granulomatous pulmonary fibrosis. In the 5–15% of the
population that is immunologically sensitive to beryllium, CBD is
the result of activation of an autoimmune attack on the skin and
lungs. The disease is progressive and may lead to severe disability,
cancer, and death. Although some treatment approaches to CBD
show promise, the prognosis is poor in most cases.
The current permissible exposure levels for beryllium of
0.01 mcg/m3 averaged over a 30-day period or 2 mcg/m3 over an
8-hour period are insufficiently protective to prevent CBD. Both
NIOSH and the ACGIH have recommended that the 8-hour PEL
and TLV be reduced to 0.05 mcg/m3. These recommendations have
not yet been implemented. Current OSHA information on beryl-
lium appears at https://www.osha.gov/SLTC/beryllium/index.html.
Environmental beryllium exposure is not generally thought to
be a hazard to human health except in the vicinity of industrial
sites where air, water, and soil pollution have occurred.
Cadmium
Cadmium (Cd) is a transition metal widely used in industry.
Workers are exposed to cadmium in the manufacture of nickel
cadmium batteries, pigments, low-melting-point eutectic materi-
als; in solder; in television phosphors; and in plating operations. It
is also used extensively in semiconductors and in plastics as a sta-
bilizer. Cadmium smelting is often done from residual dust from
lead smelting operations, and cadmium smelter workers often face
both lead and cadmium toxicity.
Cadmium is toxic by inhalation and by ingestion. When met-
als that have been plated with cadmium or welded with cadmium-
containing materials are vaporized by the heat of torches or
cutting implements, the fine dust and fumes released produce an
acute respiratory disorder called cadmium fume fever. This disor-
der, common in welders, is usually characterized by shaking chills,
cough, fever, and malaise. Although it may produce pneumonia, it
is usually transient. However, chronic exposure to cadmium dust
produces a far more serious progressive pulmonary fibrosis. Cad-
mium also causes severe kidney damage, including renal failure if
exposure continues. Cadmium is a human carcinogen and is listed
as a class 1, known human carcinogen by the IARC.
The current OSHA PEL for cadmium is 5 mcg/m3 but is
insufficiently protective of worker health. The OSHA cadmium
standard may be found at https://www.osha.gov/pls/oshaweb/
owadisp.show_document?p_table=STANDARDS&p_id=10036.
Nanomaterials
Nanomaterials are defined as any material, natural or manufac-
tured, that has at least one dimension that lies between 1 and 100
nanometers (nm) in size. The Stanford University Health and
Safety Department gives a more precise definition at https://ehs.
stanford.edu/topic/hazardous-materials/nanomaterials.
Nanomaterials have been of increasing commercial interest and
are now used for an extraordinary range of purposes. In the phar-
maceutical manufacturing industry, nanoparticles are being tested
and used to deliver cancer chemotherapeutic and other drugs.
Currently produced nanomaterials include gold, silver, cadmium,
germanium, ceramic, and aluminum oxide nanowires; carbon,
silicon, and germanium nanotubes; zinc oxide nanocrystals; gold
nanowafers; and copper oxide nanocubes. The increasing use of
nanomaterials has led to release of these nanoscale substances into
the workplace and the general environment. Because nanomaterials
1018    SECTION IX Toxicology
behave in unique patterns of chemical and physical reactivity, their
toxicology is often novel and there is insufficient information on
the likely human or environmental impact of dispersal of these
manufactured products in the environment. The University of
North Carolina laboratory safety and health manual outlines the
problems of working with nanomaterials in the laboratory and their
safe use at http://ehs.unc.edu/manuals/laboratory/chapter-18/.
1. Human toxicology—Inhalation, oral ingestion, dermal
absorption, and parenteral administration of nanomaterials have
been the sources of human exposure. Because of the unique physi-
cochemical properties of nanomaterials, their toxicity may be sim-
ilar to or very different from the larger, bulk materials encountered
in traditional toxicology studies. The nature of the exposure will
impact the likelihood that nanomaterials will reach target organs
or cells. Nanomaterials can cross cellular membranes, penetrate
nuclear material and genetic information, and may impact cel-
lular response at a nanoscale. Silica nanoparticles have been dem-
onstrated to produce kidney toxicity in humans, and zinc oxide
nanoparticles are toxic to human liver cells. Multiwalled carbon
nanotubes have been found to be cytotoxic in human lung cells.
Titanium dioxide nanoparticles that are widely used in sunscreens,
other cosmetics, pharmaceuticals, and many other products have
been noted to be toxic in the lungs and elsewhere.
2. Environmental toxicology—Nanomaterials can enter the
environment at all stages of their industrial life cycle, including
manufacturing, delivery, use, and disposal. When nanomaterials are
placed into waste streams they may enter water systems, or be car-
ried by wind or soils, and enter the food chain. An EPA fact sheet
on nanomaterials in the environment is available at https://www
.epa.gov/sites/production/files/2014-03/documents/ffrrofactsheet_
emergingcontaminant_nanomaterials_jan2014_final.pdf.
The increasing production of nanomaterials and their mul-
tiple uses has led to environmental contamination. Many species,
including bacteria, small mammals, and fish and other aquatic
organisms have been studied in laboratory assessments of nano-
material toxicity. The ecotoxicology of nanomaterials remains an
area of deep concern and ongoing research.
REFERENCES
Anonymous: Acute illnesses associated with insecticides used to control bed bug—
seven states, 2003-2010. MMWR 2011;60:1269.
Brandt A et al: The neonicotinoids thiacloprid, imidacloprid, and clothianidin
affect the immunocompetence of honey bees (Apis mellifera L.). J Insect
Physiol 2016;86:40.
Bräuner EV et al: A prospective study of organochlorines in adipose tissue and
risk of non-Hodgkin lymphoma. Environ Health Perspect 2012;120:105.
Buckley A et al: Hyperbaric oxygen for carbon monoxide poisoning: A systematic
review and critical analysis of the evidence. Toxicol Rev 2005;24:75.
Carlsen HK et al: Ozone is associated with cardiopulmonary and stroke emergency
hospital visits in Reykjavík, Iceland 2003–2009. Environ Health 2013;12:28.
Cattani D et al: Mechanisms underlying the neurotoxicity induced by glyphosate-
based herbicide in immature rat hippocampus. Involvement of glutamate
excitotoxicity. Toxicology 2014;320C:34.
Cha YS et al: Pyrethroid poisoning: Features and predictors of atypical presenta-
tions. Emerg Med J 2014;31:899.
Cummings KJ et al: A reconsideration of acute beryllium disease. Environ Health
Perspect 2009;117:1250.
Dockery DW et al: Effect of air pollution control on mortality and hospital admis-
sions in Ireland. Res Rep Health Eff Inst 2013;176:3.
Fanelli V et al: Acute respiratory distress syndrome: New definition, current and
future therapeutic options. J Thorac Dis 2013;5:326.
Fucic A et al: Environmental exposure to xenoestrogens and oestrogen related can-
cers: Reproductive system, breast, lung, kidney, pancreas, and brain. Environ
Health 2012;11(Suppl 1):S8.
Gawarammana IB, Buckley NA: Medical management of paraquat ingestion. Br J
Clin Pharmacol 2011;72:745.
Geusau A et al: Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication:
Clinical and laboratory effects. Environ Health Perspect 2001;109:865.
Gosselin RE, Smith RP, Hodge HC: Clinical Toxicology of Commercial Products,
5th ed. Williams & Wilkins, 1984.
Goyal P, Mishra D, Kumar A: Vehicular emission inventory of criteria pollutants
in Delhi. Springerplus 2013;2:216.
Haley RW et al: Association of low PON1 type Q (type A) arylesterase activity
with neurologic symptom complexes in Gulf War veterans. Toxicol Appl
Pharmacol 1999;157:227.
Hamm JI, Chen CY, Birnbaum LS: A mixture of dioxin, furans, and non-ortho
PCBs based upon consensus toxic equivalency factors produces dioxin-like
reproductive effects. Toxicol Sci 2003;74:182.
Hatch GE et al: Biomarkers of dose and effect of inhaled ozone in resting versus
exercising human subjects: Comparison with resting rats. Biomark Insights
2013;8:53.
Heinrich J et al: Long-term exposure to NO2 and PM10 and all-cause and cause-
specific mortality in a prospective cohort of women. Occup Environ Med
2013;70:179.
Jacobson JL, Jacobson SW: Association of prenatal exposure to an environmental
contaminant with intellectual function in childhood. J Toxicol Clin Toxicol
2002;40:467.
Järvholm B, Reuterwall C: A comparison of occupational and non-occupational
exposure to diesel exhausts and its consequences for studying health effects.
Occup Environ Med 2012;69:851.
Kao JW, Nanagas KA: Carbon monoxide poisoning. Emerg Med Clin North Am
2004;22:985.
Kelleher P, Pacheco K, Newman LS: Inorganic dust pneumonias: The metal-related
parenchymal disorders. Environ Health Perspect 2000;108(Suppl 4):685.
Lorenzoni PJ et al: An electrophysiological study of the intermediate syndrome of
organophosphate poisoning. J Clin Neurosci 2010;17:1217.
Lotti M, Moretto A: Organophosphate-induced delayed polyneuropathy. Toxicol
Rev 2005;24:37.
Mann A, Early GL: Acute respiratory distress syndrome. Mo Med 2012;109:371.
Maras M et al: Estrogen-like properties of fluorotelemer alcohols as revealed by
mcg-7 breast cancer cell proliferation. Environ Health Perspect 2006;114:100.
Mrema EJ et al: Persistent organochlorinated pesticides and mechanisms of their
toxicity. Toxicology 2013;307:74.
Nowack B et al: Analysis of the occupational, consumer and environmental expo-
sure to engineered nanomaterials used in 10 technology sectors. Nanotoxi-
cology 2013;7:1152.
Rappaport SM et al: Human benzene metabolism following occupational and
environmental exposures. Chem Biol Interact 2010;184:189.
Raub JA et al: Carbon monoxide poisoning—a public health perspective. Toxicol-
ogy 2000;145:1.
Ray DE, Fry JR: A reassessment of the neurotoxicity of pyrethroid insecticides.
Pharmacol Ther 2006;111:174.
Rusyn I et al: Trichloroethylene: Mechanistic, epidemiologic and other supporting
evidence of carcinogenic hazard. Pharmacol Ther 2014;141:55.
Sadasivaiah S, Tozan Y, Breman JG: Dichlorodiphenyltrichloroethane (DDT) for
indoor residual spraying in Africa: How can it be used for malaria control?
Am J Trop Med Hyg 2007;77(6 Suppl):249.
Sharifi S et al: Toxicity of nanomaterials. Chem Soc Rev 2012;41:2323.
Shusterman DJ: Polymer fume fever and other fluorocarbon pyrolysis-related
syndromes. Occup Med 1993;8:519.
Soderlund DM et al: Mechanisms of pyrethroid neurotoxicity: Implications for
cumulative risk assessment. Toxicology 2002;171:3.
St Hilaire S et al: Estrogen receptor positive breast cancers and their association
with environmental factors. Int J Health Geogr 2011;10:10.
 CHAPTER 56  Introduction to Toxicology: Occupational & Environmental     1019
Storm JE, Rozman KK, Doull J: Occupational exposure limits for 30 organophos-
phate pesticides based on inhibition of red blood cell acetylcholinesterase.
Toxicology 2000;150:1.
Trabert B et al: Maternal pregnancy levels of trans-nonachlor and oxychlordane
and prevalence of cryptorchidism and hypospadias in boys. Environ Health
Perspect 2012;120:478.
Vieira VM, et al: Perfluorooctanoic acid exposure and cancer outcomes in a
contaminated community: A geographic analysis. Environ Health Perspect
2013;121:318.
C ASE STUDY ANSWER
The child presents with classic signs (and history) of carbon
monoxide (CO) exposure. Pulse oximetry is unreliable in
CO poisoning, although newer instruments may distinguish
between carboxyhemoglobin (CO-Hgb) and oxyhemoglo-
bin. Institute the ABCDs of poisoning (see Chapter 58).
Immediate high-flow oxygen is mandatory and should be
administered via a tight-fitting face mask or endotracheal
catheter. A blood sample for blood gases and carboxyhemo-
globin content should be obtained. If the CO-Hgb is greater
Warheit DB: How to measure hazards/risks following exposures to nanoscale
or pigment-grade titanium dioxide particles. Toxicol Lett 2013;
220:193.
Warner M et al: Diabetes, metabolic syndrome, and obesity in relation to serum
dioxin concentrations: The Seveso women’s health study. Environ Health
Perspect 2013;121:906.
Wigfield YY, McLenaghan CC: Levels of N-nitrosodimethylamine in nitrogen
fertilizers/herbicide mixtures containing 2,4-D present as dimethylamine
salt. Bull Environ Contam Toxicol 1990;45:847.
than 50%, hyperbaric oxygen treatment (if available) may be
considered. The electrocardiogram should be continuously
monitored for arrhythmias. Anticonvulsant drugs may be
required if seizures occur. Neurologic damage due to CO
exposure may be subtle and long-lasting; the child should be
followed for years if necessary. The fetus is particularly sus-
ceptible to hypoxia, and if the mother is pregnant, her blood
gases and CO-Hgb should be measured. If the latter is high,
hyperbaric oxygen therapy should be considered.
 57
C H A P T E R
Heavy Metal Intoxication
& Chelators
Michael J. Kosnett, MD, MPH
C ASE STUDY
Following Sunday morning services, 27 people attended a
church social where coffee, baked goods, and sandwiches were
served. Within 15–60 minutes, 13 people developed vomiting
and abdominal discomfort, accompanied over the next several
hours by nonbloody diarrhea. Within 12 hours, seven of these
Some metals such as iron are essential for life, whereas others such
as lead are present in all organisms but serve no useful biologic
purpose. Some of the oldest diseases of humans can be traced to
heavy metal poisoning associated with metal mining, refining, and
use. Even with the present recognition of the hazards of heavy
metals, the incidence of intoxication remains significant, and the
need for preventive strategies and effective therapy remains high.
Toxic heavy metals interfere with the function of essential cations,
cause enzyme inhibition, generate oxidative stress, alter gene
expression, and perturb cell signaling. As a result, multisystem
signs and symptoms are a hallmark of heavy metal intoxication.
When intoxication occurs, chelator molecules (from chela
“claw”), or their in vivo biotransformation products, may be used
to bind the metal and facilitate its excretion from the body. Chela-
tor drugs are discussed in the second part of this chapter.
■■ TOXICOLOGY OF HEAVY
METALS
LEAD
Lead poisoning is one of the oldest occupational and environmental
diseases in the world. Despite its recognized hazards, lead continues
to have widespread commercial application, including production
1020
individuals were hospitalized with ongoing gastrointestinal
symptoms, hypotension, and anion gap metabolic acidosis.
Fluid resuscitation and pressors were accompanied by adequate
urine output. What diagnoses should be considered? What tests
should be conducted, and what therapy should be considered?
of storage batteries (nearly 90% of US consumption), ammunition,
metal alloys, solder, glass, plastics, pigments, and ceramics. Corro-
sion of lead plumbing in older buildings or supply lines may increase
the lead concentration of tap water. Environmental lead exposure,
ubiquitous by virtue of the anthropogenic distribution of lead to air,
water, and food, has declined considerably in the last three decades
as a result of the elimination of lead as an additive in gasoline, as
well as diminished contact with lead-based paint and other lead-
containing consumer products, such as lead solder in cans used as
food containers. Legislation in the United States in 2011 further
reduced the maximum permissible lead content of children’s prod-
ucts to 100 ppm. Lead continues to be used in some formulations of
aviation gasoline for piston-engine aircraft. The presence of lead in
certain folk medicines (eg, the Mexican remedies azarcon and greta,
and certain Ayurvedic preparations) and in cosmetics (eg, kohl
utilized around the eyes in certain African and Asian communities)
has contributed to lead exposure to children and adults. Although
public health measures, together with improved workplace condi-
tions, have decreased the incidence of serious overt lead poisoning,
there remains considerable concern over the effects of low-level
lead exposure. Extensive evidence indicates that low levels of lead
exposure may have subtle subclinical adverse effects on neurocogni-
tive function in children and may contribute to hypertension and
cardiovascular disease in adults. Lead serves no useful purpose in
the human body. In key target organs such as the developing central
 CHAPTER 57  Heavy Metal Intoxication & Chelators     1021

nervous system, no level of lead exposure has been shown to be
without deleterious effects.
Pharmacokinetics
Inorganic lead is slowly but consistently absorbed via the respira-
tory and gastrointestinal tracts. It is poorly absorbed through the
skin. Absorption of lead dust via the respiratory tract is the most
common cause of industrial poisoning. The intestinal tract is the
primary route of entry in nonindustrial exposure (Table 57–1).
Absorption via the gastrointestinal tract varies with the nature of
the lead compound, but in general, adults absorb about 10–15%
of the ingested amount, whereas young children absorb up to
50%. Low dietary calcium, iron deficiency, and ingestion on
an empty stomach all have been associated with increased lead
absorption.
Once absorbed from the respiratory or gastrointestinal tract,
lead enters the bloodstream, where approximately 99% is bound
to erythrocytes and 1% is present in the plasma. Lead is sub-
sequently distributed to soft tissues such as the bone marrow,
brain, kidney, liver, muscle, and gonads; then to the subperiosteal
surface of bone; and later to bone matrix. Lead also crosses the
placenta and poses a potential hazard to the fetus. The kinetics
of lead clearance from the body follows a multicompartment
model, composed predominantly of the blood and soft tissues,
with a half-life of 1–2 months; and the skeleton, with a half-
life of years to decades. Approximately 70% of the lead that is
eliminated appears in the urine, with lesser amounts excreted
through the bile, skin, hair, nails, sweat, and breast milk. The
fraction not undergoing prompt excretion, approximately half
of the absorbed lead, may be incorporated into the skeleton, the
repository of more than 90% of the body lead burden in most
adults. In patients with high bone lead burdens, slow release from
the skeleton may elevate blood lead concentrations for years after
exposure ceases, and pathologic high bone turnover states such as
hyperthyroidism or prolonged immobilization may result in frank
lead intoxication. Migration of retained lead bullet fragments
into a joint space or adjacent to bone has been associated with
the development of lead poisoning signs and symptoms years or
decades after an initial gunshot injury.
Pharmacodynamics
Lead exerts multisystemic toxic effects that are mediated by
multiple modes of action, including inhibition of enzymatic
function; interference with the action of essential cations, par-
ticularly calcium, iron, and zinc; generation of oxidative stress;
changes in gene expression; alterations in cell signaling; and
disruption of the integrity of membranes in cells and intracel-
lular organelles.

TABLE 57–1  Toxicology of selected arsenic, lead, and mercury compounds.

Form Major Route Key Aspects of Metabolism and
Entering Body of Absorption Distribution Major Clinical Effects Mechanism Elimination

Arsenic Inorganic Gastrointesti- Predominantly Cardiovascular: shock, Inhibits enzymes; Methylation. Renal
arsenic salts nal, respiratory soft tissues arrhythmias. CNS: interferes with oxida- (major); sweat and
(all mucosal (highest in liver, encephalopathy, periph- tive phosphorylation; feces (minor)
surfaces) kidney). Avidly eral neuropathy. Gastro- alters cell signaling,
bound in skin, enteritis; pancytopenia; gene expression
hair, nails cancer (many sites)
Lead Inorganic lead Gastrointesti- Soft tissues; CNS deficits; peripheral Inhibits enzymes; Renal (major); feces
oxides and salts nal, respiratory ­redistributed to neuropathy; anemia; interferes with essen- and breast milk
skeleton (>90% nephropathy; hyper- tial cations; alters (minor)
of adult body tension; reproductive membrane structure
­burden) toxicity
Organic (tetra- Skin, gastro- Soft tissues, Encephalopathy Hepatic dealkylation Urine and feces
ethyl lead) intestinal, ­especially liver, (fast) → ­trialkyl (major); sweat (minor)
respiratory CNS metabolites (slow) →
­dissociation to lead
Mercury Elemental Respiratory Soft tissues, CNS: tremor, behav- Inhibits enzymes; Elemental Hg
­mercury tract especially ioral (erethism); alters membranes c­ onverted to Hg2+.
kidney, CNS ­gingivo-stomatitis, Urine (major); feces
peripheral neuropathy; (minor)
acrodynia; pneumonitis
(high-dose)
Inorganic: Hg+ Gastrointes- Soft tissues, Acute renal tubular Inhibits enzymes; Urine
(less toxic); Hg2+ tinal, skin ­especially necrosis; gastroenteritis; alters membranes
(more toxic) (minor) kidney CNS effects (rare)
Organic: Gastrointesti- Soft tissues CNS effects, birth Inhibits enzymes; Deacylation. Fecal
alkyl, aryl nal, skin, respi- defects alters microtubules, (alkyl, major); urine
ratory (minor) neuronal structure (Hg2+ after deacyla-
tion, minor)
1022    SECTION IX Toxicology
A. Nervous System
The developing central nervous system of the fetus and young
child is the most sensitive target organ for lead’s toxic effect.
Epidemiologic studies suggest that blood lead concentrations
<5 mcg/dL may result in subclinical deficits in neurocognitive
function in lead-exposed young children, with no demonstrable
threshold or “no effect” level. The dose response between low blood
lead concentrations and cognitive function in young children is
nonlinear, such that the decrement in intelligence associated with
an increase in blood lead from <1–10 mcg/dL (6.2 IQ points)
exceeds that associated with a change from 10 to 30 mcg/dL
(3.0 IQ points).
Adults are less sensitive to the central nervous system (CNS)
effects of lead, but long-term exposure to blood lead concentra-
tions in the range of 10–30 mcg/dL may be associated with
subclinical effects on neurocognitive function. At blood lead
concentrations higher than 30 mcg/dL, behavioral and neuro-
cognitive signs or symptoms may gradually emerge, including
irritability, fatigue, decreased libido, anorexia, sleep disturbance,
impaired visual-motor coordination, and slowed reaction time.
Headache, arthralgias, and myalgias are also common com-
plaints. Tremor occurs but is less common. Lead encephalopathy,
usually occurring at blood lead concentrations higher than 100
mcg/dL, is typically accompanied by increased intracranial pres-
sure and may cause ataxia, stupor, coma, convulsions, and death.
Recent epidemiological studies suggest that lead may accentuate
an age-related decline in cognitive function in older adults. In
experimental animals, developmental lead exposure, possibly
acting through epigenetic mechanisms, has been associated with
increased expression of beta-amyloid, increased phosphorylated
tau protein, oxidative DNA damage, and Alzheimer’s-type
pathology in the aging brain. There is wide interindividual varia-
tion in the magnitude of lead exposure required to cause overt
lead-related signs and symptoms.
Overt peripheral neuropathy may appear after chronic high-
dose lead exposure, usually following months to years of blood
lead concentrations higher than 100 mcg/dL. Predominantly
motor in character, the neuropathy may present clinically with
painless weakness of the extensors, particularly in the upper
extremity, resulting in classic wrist-drop. Preclinical signs of
lead-induced peripheral nerve dysfunction may be detectable by
electrodiagnostic testing.
B. Blood
Lead can induce an anemia that may be either normocytic or
microcytic and hypochromic. Lead interferes with heme synthesis
by blocking the incorporation of iron into protoporphyrin IX
and by inhibiting the function of enzymes in the heme synthesis
pathway, including aminolevulinic acid dehydratase and fer-
rochelatase. Within 2–8 weeks after an elevation in blood lead
concentration (generally to 30–50 mcg/dL or greater), increases
in heme precursors, notably free erythrocyte protoporphyrin or
its zinc chelate, zinc protoporphyrin, may be detectable in whole
blood. Lead also contributes to anemia by increasing erythrocyte
membrane fragility and decreasing red cell survival time. Frank
hemolysis may occur with high exposure. Basophilic stippling on
the peripheral blood smear, thought to be a consequence of lead
inhibition of the enzyme 3′,5′-pyrimidine nucleotidase, is some-
times a suggestive—albeit insensitive and nonspecific—diagnostic
clue to the presence of lead intoxication.
C. Kidneys
Chronic high-dose lead exposure, usually associated with months
to years of blood lead concentrations >80 mcg/dL, may result in
renal interstitial fibrosis and nephrosclerosis. Lead nephropathy
may have a latency period of years. Lead may alter uric acid excre-
tion by the kidney, resulting in recurrent bouts of gouty arthritis
(“saturnine gout”). Acute high-dose lead exposure sometimes pro-
duces transient azotemia, possibly as a consequence of intrarenal
vasoconstriction. Studies conducted in general population samples
have documented an association between blood lead concentra-
tion and measures of renal function, including serum creatinine
and creatinine clearance. The presence of other risk factors for
renal insufficiency, including hypertension and diabetes, may
increase susceptibility to lead-induced renal dysfunction.
D. Reproductive Organs
High-dose lead exposure is a recognized risk factor for stillbirth
or spontaneous abortion. Epidemiologic studies of the impact of
low-level lead exposure on reproductive outcome such as low birth
weight, preterm delivery, or spontaneous abortion have yielded
mixed results. However, a well-designed nested case-control study
detected an odds ratio for spontaneous abortion of 1.8 (95%
CI 1.1–3.1) for every 5 mcg/dL increase in maternal blood lead
across an approximate range of 5–20 mcg/dL. Recent studies have
linked prenatal exposure to low levels of lead (eg, maternal blood
lead concentrations of 5–15 mcg/dL) to decrements in physical
and cognitive development assessed during the neonatal period
and early childhood. In males, blood lead concentrations higher
than 40 mcg/dL have been associated with diminished or aberrant
sperm production.
E. Gastrointestinal Tract
Moderate lead poisoning may cause loss of appetite, constipation,
and, less commonly, diarrhea. At high dosage, intermittent bouts
of severe colicky abdominal pain (“lead colic”) may occur. The
mechanism of lead colic is unclear but is believed to involve spas-
modic contraction of the smooth muscles of the intestinal wall,
mediated by alteration in synaptic transmission at the smooth
muscle-neuromuscular junction. In heavily exposed individuals
with poor dental hygiene, the reaction of circulating lead with sul-
fur ions released by microbial action may produce dark deposits of
lead sulfide at the gingival margin (“gingival lead lines”). Although
frequently mentioned as a diagnostic clue in the past, in recent
times this has been a relatively rare sign of lead exposure.
F. Cardiovascular System
Epidemiologic, experimental, and in vitro mechanistic data indi-
cate that lead exposure elevates blood pressure in experimental
animals and in susceptible humans. The pressor effect of lead may

be mediated by an interaction with calcium-mediated contraction
of vascular smooth muscle, as well as generation of oxidative stress
and an associated interference in nitric oxide signaling pathways.
In populations with environmental or occupational lead exposure,
blood lead concentration is linked with increases in systolic and
diastolic blood pressure. Studies of middle-aged and elderly men
and women have identified relatively low levels of lead exposure
sustained by the general population to be an independent risk
factor for hypertension. Lead exposure has also been associated
with prolongation of the QTc interval on the electrocardiogram.
Epidemiologic studies have linked chronic environmental lead
exposure associated with population blood lead concentrations
in the range of 10–25 mcg/dL to a significantly increased risk
of cardiovascular mortality. This is of considerable public health
concern because these concentrations were prevalent in the USA
prior to the 1980s. Although general population blood lead con-
centrations have since fallen considerably (see below), exposure
associated with blood lead in this range persists in occupational
settings worldwide.
Major Forms of Lead Intoxication
A. Inorganic Lead Poisoning (Table 57–1)
1. Acute—Acute inorganic lead poisoning is uncommon today.
It usually results from industrial inhalation of large quantities of
lead oxide fumes or, in small children, from ingestion of a large
oral dose of lead in the form of lead-based paint chips; small
objects, eg, toys coated or fabricated from lead; or contaminated
food or drink. The onset of severe symptoms usually requires
several days or weeks of recurrent exposure and manifests as signs
and symptoms of encephalopathy or colic. Evidence of hemolytic
anemia (or anemia with basophilic stippling if exposure has been
subacute) and elevated hepatic aminotransferases may be present.
The diagnosis of acute inorganic lead poisoning may be
difficult, and depending on the presenting symptoms, the
condition has sometimes been mistaken for appendicitis, peptic
ulcer, biliary colic, pancreatitis, or infectious meningitis. Subacute
presentation, featuring headache, fatigue, intermittent abdominal
cramps, myalgias, and arthralgias, has often been mistaken for a
flu-like viral illness. When there has been recent ingestion of lead-
containing paint chips, glazes, pellets, or weights, radiopacities
may be visible on abdominal radiographs.
2. Chronic—The patient with symptomatic chronic lead intoxi-
cation typically presents with multisystemic findings, including
complaints of anorexia, fatigue, and malaise; neurologic com-
plaints, including headache, difficulty in concentrating, and
irritability or depressed mood; weakness, arthralgias, or myalgias;
and gastrointestinal symptoms. Lead poisoning should be strongly
suspected in any patient presenting with headache, abdominal
pain, and anemia; and less commonly with motor neuropathy,
gout, and renal insufficiency. Chronic lead intoxication should
be considered in any child with neurocognitive deficits, growth
retardation, or developmental delay. It is important to recognize
that adverse effects of lead that are of considerable public health
significance, such as subclinical decrements in neurodevelopment
CHAPTER 57  Heavy Metal Intoxication & Chelators     1023
in children and hypertension in adults, are usually nonspecific and
may not come to medical attention.
The diagnosis of lead intoxication is best confirmed by measur-
ing lead in whole blood. Although this test reflects lead currently
circulating in blood and soft tissues and is not a reliable marker
of either recent or cumulative lead exposure, most patients with
lead-related disease have blood lead concentrations higher than
the normal range. Average background blood lead concentrations
in North America and Europe have declined by 90% in recent
decades, and the geometric mean blood lead concentration in the
United States in 2011–2012 was estimated to be 0.973 mcg/dL.
Though predominantly a research tool, the concentration of lead
in bone assessed by noninvasive K X-ray fluorescence measure-
ment of lead has been correlated with long-term cumulative lead
exposure, and its relationship to numerous lead-related disorders
is the subject of ongoing investigation. Measurement of lead
excretion in the urine after a single dose of a chelating agent
(sometimes called a “chelation challenge test”) primarily reflects
the lead content of soft tissues and may not be a reliable marker
of long-term lead exposure, remote past exposure, or skeletal
lead burden. Accordingly, this test is rarely indicated in clinical
practice. Because of the lag time associated with lead-induced
elevations in circulating heme precursors, the finding of a blood
lead concentration of 30 mcg/dL or more with no concurrent
increase in zinc protoporphyrin suggests that the lead exposure
was of recent onset.
B. Organolead Poisoning
Poisoning from organolead compounds is now very rare, in large
part because of the worldwide phase-out of tetraethyl and tetra-
methyl lead as antiknock additives in gasoline. However, organ-
olead compounds such as lead stearate or lead naphthenate are still
used in certain commercial processes. Because of their volatility or
lipid solubility, organolead compounds tend to be well absorbed
through either the respiratory tract or the skin. Organolead com-
pounds predominantly target the CNS, producing dose-depen-
dent effects that may include neurocognitive deficits, insomnia,
delirium, hallucinations, tremor, convulsions, and death.
Treatment
A. Inorganic Lead Poisoning
Treatment of inorganic lead poisoning involves immediate termi-
nation of exposure, supportive care, and the judicious use of che-
lation therapy. (Chelation is discussed later in this chapter.) Lead
encephalopathy is a medical emergency that requires intensive
supportive care. Cerebral edema may improve with corticosteroids
and mannitol or hypertonic saline, and anticonvulsants may be
required to treat seizures. Radiopacities on abdominal radiographs
may suggest the presence of retained lead objects requiring gas-
trointestinal decontamination. Adequate urine flow should be
maintained, but overhydration should be avoided. Intravenous
edetate calcium disodium (CaNa2EDTA) is administered at a
dosage of 1000–1500 mg/m2/d (approximately 30–50 mg/kg/d)
by continuous infusion for up to 5 days. Some clinicians advocate
1024    SECTION IX Toxicology

Prevention of Lead Poisoning: An Ongoing Effort

Exposure: Sources Examples of Preventive Measures

Home exposure: The US Consumer Product Safety
Commission adopted major restrictions on the use
of lead in residential house paint in 1977. Prior to
then, thousands of tons of lead pigments were
applied in millions of homes. The American Healthy
Homes Survey (2005–2006) estimated that 35% of
homes had some lead-based paint and 22% had
one or more lead-based paint hazards.
Workplace exposure: The US Occupational Health
and Safety Administration (OSHA) estimates that
more than 1.6 million workers are potentially
exposed to lead. State and federal OSHA programs
have established permissible exposure levels for
lead in workplace air, as well as medical surveillance
requirements for workers that may mandate peri-
odic blood lead monitoring.
Water: Lead may enter drinking water when service
pipes contain lead, especially when the water has
high acidity or low mineral content that corrodes
pipes and plumbing fixtures.
The US Environmental Protection Agency’s (EPA) Lead Renovation, Repair,
and Painting Rule requires that companies performing renovation, repair,
and painting projects that disturb lead-based paint in homes, child care
facilities, and preschools built before 1978 have their firm certified by EPA
(or an EPA-authorized state), use certified renovators who are trained by
EPA-approved training providers, and follow lead-safe work practices.
[https://www.epa.gov/lead/renovation-repair-and-painting-program]
Present OSHA rules regarding workplace lead exposure and medical
removal protection date from the late 1970s and no longer offer adequate
protection. The Occupational Lead Poisoning Prevention Program of the
California Department of Public Health offers up-to-date, health protec-
tive guidance.
[https://archive.cdph.ca.gov/programs/olppp/Pages/default.aspx]
Under EPA’s Lead and Copper Rule [https://www.epa.gov/dwreginfo/lead-
and-copper-rule], if more than 10% of tap water samples at sites likely to
have lead plumbing exceed the lead action level of 15 parts per billion,
water systems are required to institute corrosion control and other mea-
sures. The Safe Drinking Water Act, amended by the Reduction of Lead in
Drinking Water Act of 2011, sets limits on the lead content of new plumb-
ing materials for potable water.

Children: Because of normal mouthing behavior,
children are at special risk of exposure to lead
present in toys, jewelry, printed material, and
other consumer products.
[ https://www.epa.gov/dwstandardsregulations/
use-lead-free-pipes-fittings-fixtures-solder-and-flux-drinking-water]
The US Consumer Product Safety Commission has promulgated rules that
limit the amount of lead that can be present in children’s products.
[https://www.cpsc.gov/Business--Manufacturing/Business-Education/
Lead/Lead-in-Paint]

[https://www.cpsc.gov/Business--Manufacturing/Business-Education/
Lead/Total-Lead-Content]

Production of lead began 6000 years ago, and lead poisoning is one of the oldest known occupational illnesses. Worldwide, lead produc-
tion has doubled over the past two decades in part because of the growing demand for lead acid storage batteries. Efforts to prevent lead
poisoning from multiple industrial, commercial, and environmental sources remain an active focus of public health in the USA.

that chelation treatment for lead encephalopathy be initiated with
an intramuscular injection of dimercaprol, followed in 4 hours by
concurrent administration of dimercaprol and EDTA. Parenteral
chelation is limited to 5 or fewer days, at which time oral treat-
ment with another chelator, succimer (DMSA), may be insti-
tuted. In symptomatic lead intoxication without encephalopathy,
treatment may sometimes be initiated with succimer. The end
point for chelation is usually resolution of symptoms or return of
the blood lead concentration to the premorbid range. In patients
with chronic exposure, cessation of chelation may be followed by
an upward rebound in blood lead concentration as the lead re-
equilibrates from bone lead stores.
Although most clinicians support chelation for symptomatic
patients with elevated blood lead concentrations, the decision
to chelate asymptomatic subjects is more controversial. Since
1991, the Centers for Disease Control and Prevention (CDC)
has recommended chelation for all children with blood lead
concentrations of 45 mcg/dL or greater. However, a random-
ized, double-blind, placebo-controlled clinical trial of succimer
in children with blood lead concentrations between 25 and
44 mcg/dL found no benefit on neurocognitive function or
long-term blood lead reduction. Prophylactic use of chelating
agents in the workplace should never be a substitute for reduc-
tion or prevention of excessive exposure.

Management of elevated blood lead levels in children and
adults should include a conscientious effort to identify and
reduce all potential sources of future lead exposure. Many local,
state, or national governmental agencies maintain lead poisoning
prevention programs that can assist in case management. Blood
lead screening of family members or coworkers of a lead poison-
ing patient is often indicated to assess the scope of the exposure.
In 2012, the CDC adopted a new policy that defined as elevated
any childhood blood lead concentrations at or exceeding a refer-
ence value corresponding to the 97.5th percentile of quadrennial
reports of the National Health and Nutrition Examination Sur-
vey (NHANES). The blood lead reference value established in
2012 was 5 mcg/dL, and it is projected to decline in the future.
Because there is no blood lead concentration known to be devoid
of deleterious effects, the finding of a blood lead concentration
exceeding the reference value (ie, elevated in relation to the
general population) should prompt clinical and environmental
investigation (https://www.cdc.gov/nceh/lead/acclpp/final_doc-
ument_030712.pdf ). Although the US Occupational Safety
and Health Administration (OSHA) lead regulations introduced
in the late 1970s mandate that workers be removed from lead
exposure for blood lead levels higher than 50–60 mcg/dL,
an expert panel in 2007 recommended that removal be initi-
ated for a single blood lead level >30 mcg/dL or when two
successive blood lead levels measured over a 4-week interval
are 20 mcg/dL or greater (https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC1849937/pdf/ehp0115-000463.pdf ). The longer-
term goal should be for workers to maintain blood lead levels
<10 mcg/dL, and for pregnant women to avoid occupational
or avocational exposure that would result in blood lead levels
higher than 5 mcg/dL. Environmental Protection Agency (EPA)
regulations effective since 2010 require that contractors who
perform renovation, repair, and painting projects that disturb
lead-based paint in pre-1978 residences and child-occupied
facilities must be certified and must follow specific work prac-
tices to prevent lead contamination (see Box: Prevention of Lead
Poisoning: An Ongoing Effort).
B. Organic Lead Poisoning
Initial treatment consists of decontaminating the skin and pre-
venting further exposure. Treatment of seizures requires appropri-
ate use of anticonvulsants. Empiric chelation may be attempted if
high blood lead concentrations are present.
ARSENIC
Arsenic is a naturally occurring element in the earth’s crust with
a long history of use as a constituent of commercial and indus-
trial products, as a component in pharmaceuticals, and as an
agent of deliberate poisoning. Recent commercial applications
of arsenic include its use in the manufacture of semiconductors,
wood preservatives for industrial applications (eg, marine timbers
or utility poles), nonferrous alloys, glass, and the turf herbicide
monosodium methane arsonate (MSMA). The use of phenyl-
arsenic compounds as feed additives for poultry and swine was
terminated in the United States in 2015. In some regions of the
CHAPTER 57  Heavy Metal Intoxication & Chelators     1025
world, groundwater may contain high levels of arsenic that has
leached from natural mineral deposits. Arsenic in drinking water
in the Ganges delta of India and Bangladesh is now recognized
as one of the world’s most pressing environmental health prob-
lems. Environmental risk assessments have suggested that arsenic
migrating from coal combustion wastes (eg, coal ash) deposited
in unlined landfills may contaminate underlying groundwater.
Arsine, an arsenous hydride (AsH3) gas with potent hemolytic
effects, is manufactured predominantly for use in the semiconduc-
tor industry but may also be generated accidentally when arsenic-
containing ores or scrap gallium arsenide semiconductors come in
contact with acidic solutions.
It is of historical interest that Fowler’s solution, which contains
1% potassium arsenite, was widely used as a medicine for many
conditions from the eighteenth century through the mid-twentieth
century. Organic arsenicals were the first pharmaceutical
antimicrobials* and were widely used for the first half of the twen-
tieth century until supplanted by sulfonamides and other more
effective and less toxic agents.
Other organoarsenicals, most notably lewisite (dichloro-
[2-chlorovinyl]arsine), were developed in the early 20th century
as chemical warfare agents. Arsenic trioxide was reintroduced into
the United States Pharmacopeia in 2000 as an orphan drug for
the treatment of relapsed acute promyelocytic leukemia and is
finding expanded use in experimental cancer treatment protocols.
Melarsoprol, another trivalent arsenical, is used in the treatment of
advanced African trypanosomiasis (see Chapter 52).
Pharmacokinetics
Soluble arsenic compounds are well absorbed through the respira-
tory and gastrointestinal tracts (Table 57–1). Percutaneous absorp-
tion is limited but may be clinically significant after heavy exposure
to concentrated arsenic reagents. Most of the absorbed inorganic
arsenic undergoes methylation, mainly in the liver, to monomethyl-
arsonic acid and dimethylarsinic acid, which are excreted, along
with residual inorganic arsenic, in the urine. When chronic daily
absorption is <1000 mcg of soluble inorganic arsenic, approxi-
mately two thirds of the absorbed dose is excreted in the urine
within 2–3 days. After massive ingestions, the elimination half-life
is prolonged. Inhalation of arsenic compounds of low solubility may
result in prolonged retention in the lung and may not be reflected
by urinary arsenic excretion. Arsenic binds to sulfhydryl groups
present in keratinized tissue, and following cessation of exposure,
hair, nails, and skin may contain elevated levels after urine values
have returned to normal. However, arsenic in hair and nails as a
result of external deposition may be indistinguishable from that
incorporated after internal absorption.
Pharmacodynamics
Arsenic compounds are thought to exert their toxic effects by
several modes of action. Interference with enzyme function may
result from sulfhydryl group binding by trivalent arsenic or by
*
Paul Ehrlich’s “magic bullet” for syphilis (arsphenamine, Salvarsan) was
an arsenical.
1026    SECTION IX Toxicology
substitution for phosphate. Inorganic arsenic or its metabolites may
induce oxidative stress, alter gene expression, and interfere with cell
signal transduction. Although on a molar basis, inorganic trivalent
arsenic (As3+, arsenite) is generally two to ten times more acutely
toxic than inorganic pentavalent arsenic (As5+, arsenate), in vivo
interconversion is known to occur, and the full spectrum of arsenic
toxicity has occurred after sufficient exposure to either form. Recent
studies suggest that the trivalent form of the methylated metabolites
(eg, monomethylarsonous acid [MMAIII]) may be more toxic than
the inorganic parent compounds. Reduced efficiency in the meth-
ylation of MMA to dimethylarsonous acid (DMA), resulting in an
elevated percentage of MMA in the urine, has been associated with
an increased risk of chronic adverse effects. Arsenic methylation
requires S-adenosylmethionine, a universal methyl donor in the
body, and arsenic-associated perturbations in one-carbon metabo-
lism may underlie some arsenic-induced epigenetic effects such as
altered gene expression.
Arsine gas is oxidized in vivo and exerts a potent hemolytic effect
associated with alteration of ion flux across the erythrocyte mem-
brane; it also disrupts cellular respiration in other tissues. Arsenic is
a recognized human carcinogen and has been associated with cancer
of the lung, skin, and bladder. Marine organisms may contain large
amounts of a well-absorbed trimethylated organoarsenic, arseno-
betaine, as well as a variety of arsenosugars and arsenolipids. Arseno-
betaine exerts no known toxic effects when ingested by mammals
and is excreted in the urine unchanged; arsenosugars are partially
metabolized to dimethylarsinic acid. Thioarsenite compounds that
occur as minor metabolites of inorganic arsenic and methylated
arsenic compounds in vivo may contribute to toxicity.
Major Forms of Arsenic Intoxication
A. Acute Inorganic Arsenic Poisoning
Within minutes to hours after exposure to high doses (tens to
hundreds of milligrams) of soluble inorganic arsenic compounds,
many systems are affected. Initial gastrointestinal signs and symp-
toms include nausea, vomiting, diarrhea, and abdominal pain.
Diffuse capillary leak, combined with gastrointestinal fluid loss,
may result in hypotension, shock, and death. Cardiopulmonary
toxicity, including congestive cardiomyopathy, cardiogenic or
noncardiogenic pulmonary edema, and ventricular arrhythmias
(particularly in association with QTc prolongation on the electro-
cardiogram) may occur promptly or after a delay of several days.
Pancytopenia usually develops within 1 week, and basophilic stip-
pling of erythrocytes may be present soon after. Central nervous
system effects, including delirium, encephalopathy, and coma,
may occur within the first few days of intoxication. An ascending
sensorimotor peripheral neuropathy may begin to develop after a
delay of 2–6 weeks. This neuropathy may ultimately involve the
proximal musculature and result in neuromuscular respiratory
failure. Months after an acute poisoning, transverse white striae
(Aldrich-Mees lines) may be visible in the nails.
Acute inorganic arsenic poisoning should be considered in
an individual presenting with abrupt onset of gastroenteritis in
combination with hypotension and metabolic acidosis. Suspicion
should be further heightened when these initial findings are
followed by cardiac dysfunction, pancytopenia, and peripheral
neuropathy. The diagnosis may be confirmed by demonstration
of elevated amounts of inorganic arsenic and its metabolites in
the urine (typically in the range of several thousand micrograms
in the first 2–3 days after acute symptomatic poisoning). Arsenic
disappears rapidly from the blood, and except in anuric patients,
blood arsenic levels should not be used for diagnostic purposes.
Treatment is based on appropriate gut decontamination, intensive
supportive care, and prompt chelation with unithiol, 3–5 mg/kg
intravenously every 4–6 hours, or dimercaprol, 3–5 mg/kg intra-
muscularly every 4–6 hours. In animal studies, the efficacy of
chelation has been highest when it is administered within minutes
to hours after arsenic exposure; therefore, if diagnostic suspicion
is high, treatment should not be withheld for the several days to
weeks often required to obtain laboratory confirmation.
Succimer has also been effective in animal models and has a
higher therapeutic index than dimercaprol. However, because it
is available in the United States only for oral administration, its
use may not be advisable in the initial treatment of acute arsenic
poisoning, when severe gastroenteritis and splanchnic edema may
limit absorption by this route.
B. Chronic Inorganic Arsenic Poisoning
Chronic inorganic arsenic poisoning also results in multisys-
temic signs and symptoms. Overt noncarcinogenic effects may
be evident after chronic absorption of more than 0.01 mg/kg/d
(~500–1000 mcg/d in adults). The time to appearance of symp-
toms varies with dose and interindividual tolerance. Constitutional
symptoms of fatigue, weight loss, and weakness may be present,
along with anemia, nonspecific gastrointestinal complaints, and a
sensorimotor peripheral neuropathy, particularly featuring a stock-
ing glove pattern of dysesthesia. Skin changes—among the most
characteristic effects—typically develop after years of exposure and
include a “raindrop” pattern of hyperpigmentation, and hyperkera-
toses involving the hands and feet (Figure 57–1). Peripheral vas-
cular disease and noncirrhotic portal hypertension may also occur.
Epidemiologic studies suggest a possible link to hypertension, car-
diovascular disease mortality, diabetes, chronic nonmalignant respi-
ratory disease, and adverse reproductive outcomes. Cancer of the
lung, skin, bladder, and possibly other sites, including the kidney
and liver, may appear years after exposure to doses of arsenic that are
not high enough to elicit other acute or chronic effects. Some stud-
ies suggest that tobacco smoking may interact synergistically with
arsenic in increasing the risk of certain adverse health outcomes.
Administration of arsenite in cancer chemotherapy regimens,
often at a daily dose of 10–20 mg for weeks to a few months,
has been associated with prolongation of the QT interval on the
electrocardiogram and occasionally has resulted in malignant ven-
tricular arrhythmias such as torsades de pointes.
The diagnosis of chronic arsenic poisoning involves integra-
tion of the clinical findings with confirmation of exposure. The
urine concentration of the sum of inorganic arsenic and its pri-
mary metabolites MMA and DMA is <20 mcg/L in the general
population. High urine levels associated with overt adverse effects
may return to normal within days to weeks after exposure ceases.
Because it may contain large amounts of nontoxic organoarsenic

FIGURE 57–1  Dermatologic lesions associated with chronic
ingestion of arsenic in drinking water. (Photo courtesy of Dipankar
Chakraborti, PhD.)
such as arsenobetaine, or arsenosugars that are metabolized to
DMA, all seafood should be avoided for at least 3 days before
submission of a urine sample for diagnostic purposes. The arsenic
content of hair and nails (normally <1 ppm) may sometimes reveal
past elevated exposure, but results should be interpreted cautiously
in view of the potential for external contamination. Segmental
analysis of hair or nails using sensitive methods such as neutron
activation analysis or synchrotron radiation sources may some-
times have forensic value for investigation of the temporal pattern
of arsenic poisoning.
Management of chronic arsenic poisoning consists primar-
ily of termination of exposure and nonspecific supportive care.
Although empiric short-term oral chelation with unithiol or
succimer for symptomatic individuals with elevated urine arse-
nic concentrations may be considered, it has no proven benefit
beyond removal from exposure alone. Preliminary studies suggest
that dietary supplementation of folate—thought to be a cofactor
in arsenic methylation—might be of value in arsenic-exposed
individuals, particularly men, who are also deficient in folate.
C. Arsine Gas Poisoning
Arsine gas poisoning produces a distinctive pattern of intoxication
dominated by profound hemolytic effects. After a latent period that
CHAPTER 57  Heavy Metal Intoxication & Chelators     1027
may range from 2 to 24 hours postinhalation (depending on the
magnitude of exposure), massive intravascular hemolysis may occur.
Initial symptoms may include malaise, headache, dyspnea, weakness,
nausea, vomiting, abdominal pain, jaundice, and hemoglobinuria.
Oliguric renal failure, a consequence of hemoglobin deposition in the
renal tubules, often appears within 1–3 days. In massive exposures,
lethal effects on cellular respiration may occur before renal failure
develops. Urinary arsenic levels are elevated but are seldom available
to confirm the diagnosis during the critical period of illness. Intensive
supportive care—including exchange transfusion, vigorous hydration,
and, in the case of acute renal failure, hemodialysis—is the mainstay
of therapy. Currently available chelating agents have not been dem-
onstrated to be of clinical value in arsine poisoning.
MERCURY
Metallic mercury as “quicksilver”—the only metal that is liquid
under ordinary conditions—has attracted scholarly and scientific
interest from antiquity. The mining of mercury was early recog-
nized as being hazardous to health. As industrial use of mercury
became common during the last 200 years, new forms of toxicity
were recognized that were found to be associated with various
transformations of the metal. In the early 1950s, a mysterious
epidemic of birth defects and neurologic disease occurred in the
Japanese fishing village of Minamata. The causative agent was
determined to be methylmercury in contaminated seafood, traced
to industrial discharges into the bay from a nearby factory. In
addition to elemental mercury and alkylmercury (including meth-
ylmercury), other key mercurials include inorganic mercury salts
and aryl mercury compounds, each of which exerts a relatively
unique pattern of clinical toxicity.
Mercury is mined predominantly as HgS in cinnabar ore and
is then converted commercially to a variety of chemical forms.
Key industrial and commercial applications of mercury are found
in the electrolytic production of chlorine and caustic soda; the
manufacture of electrical equipment, thermometers, and other
instruments; fluorescent lamps; and dental amalgam. The wide-
spread use of elemental mercury in artisanal gold production is
a growing problem in many developing countries. Mercury use
in pharmaceuticals and in biocides has declined substantially in
recent years, but occasional use in antiseptics, folk medicines, and
cosmetic skin-lightening creams is still encountered. Thimerosal,
an organomercurial preservative that is metabolized in part to
ethylmercury, has been removed from almost all the vaccines in
which it was formerly present. Environmental releases of mercury
from the burning of fossil fuels, which contributes to the bioac-
cumulation of methylmercury in fish, remains a concern in some
regions of the world. Low-level exposure to mercury released from
dental amalgam fillings occurs, but systemic toxicity from this
source has not been established.
The United States banned the export of elemental mercury
in 2013. Once fully implemented, the international Minamata
Convention on Mercury, signed by 128 countries since 2013, will
result in a worldwide phase-out by 2020 of mercury in numer-
ous products including batteries, switches and relays, fluorescent
1028    SECTION IX Toxicology
lamps, pesticides, biocides and antiseptics, measuring instruments
(eg, thermometers, sphygmomanometers), and manufacturing
processes such as chloralkali production (by 2025)
Pharmacokinetics
The absorption of mercury varies considerably depending on the
chemical form of the metal. Elemental mercury is quite volatile
and can be absorbed from the lungs (Table 57–1). It is poorly
absorbed from the intact gastrointestinal tract. Inhaled mercury is
the primary source of occupational exposure. Organic short-chain
alkylmercury compounds are volatile and potentially harmful by
inhalation as well as by ingestion. Percutaneous absorption of
metallic mercury and inorganic mercury can be of clinical concern
following massive acute or long-term chronic exposure. Alkylmer-
cury compounds appear to be well absorbed through the skin, and
acute contact with a few drops of dimethylmercury has resulted in
severe, delayed toxicity. After absorption, mercury is distributed
to the tissues within a few hours, with the highest concentration
occurring in the kidney. Inorganic mercury is excreted through the
urine and feces. Excretion of inorganic mercury follows a multi-
compartment model: most is excreted within weeks to months,
but a fraction may be retained in the kidneys and brain for years.
After inhalation of elemental mercury vapor, urinary mercury
levels decline with a half-life of approximately 1–3 months.
Urine mercury concentration is <3 mcg/L in most individuals
without occupational exposure, and the median general popula-
tion urine mercury concentration in the 2011–2012 NHANES
was 0.324 mcg/L. Methylmercury, which has a blood and whole-
body half-life of approximately 50 days, undergoes biliary excre-
tion and enterohepatic circulation, with more than two thirds
eventually excreted in the feces. The geometric mean total blood
mercury concentration in the US population in the 2011–2012
NHANES was 0.703 mcg/L; the 95th percentile was 4.40 mcg/L
(~90% present as methylmercury). Mercury binds to sulfhydryl
groups in keratinized tissue, and as with lead and arsenic, traces
appear in the hair and nails. Mercury in hair has served as a valid
biomarker of methylmercury exposure over an interval of weeks to
months in epidemiologic studies.
Major Forms of Mercury Intoxication
Mercury interacts with sulfhydryl groups in vivo, inhibiting
enzymes and altering cell membranes. The pattern of clinical
intoxication from mercury depends to a great extent on the
chemical form of the metal and the route and severity of exposure.
A. Acute
Acute inhalation of elemental mercury vapors may cause
chemical pneumonitis and noncardiogenic pulmonary edema.
Acute gingivostomatitis may occur, and neurologic sequelae
(see following text) may also ensue. Acute ingestion of inor-
ganic mercury salts, such as mercuric chloride, can result in a
corrosive, potentially life-threatening hemorrhagic gastroenteri-
tis followed within hours to days by acute tubular necrosis and
oliguric renal failure.
B. Chronic
Chronic poisoning from inhalation of mercury vapor results
in a classic triad of tremor, neuropsychiatric disturbance, and
gingivostomatitis. The tremor usually begins as a fine intention
tremor of the hands, but the face may also be involved, and pro-
gression to choreiform movements of the limbs may occur. Neu-
ropsychiatric manifestations, including memory loss, fatigue,
insomnia, and anorexia, are common. There may be an insidious
change in mood to shyness, withdrawal, and depression along
with explosive anger or blushing (a behavioral pattern referred
to as erethism). Recent studies suggest that low-dose exposure
may produce subclinical neurologic effects. Gingivostomatitis,
sometimes accompanied by loosening of the teeth, may be
reported after high-dose exposure. Evidence of peripheral nerve
damage may be detected on electrodiagnostic testing, but overt
peripheral neuropathy is rare. Acrodynia is an uncommon idio-
syncratic reaction to subacute or chronic mercury exposure and
occurs mainly in children. It is characterized by painful erythema
of the extremities and may be associated with hypertension, dia-
phoresis, anorexia, insomnia, irritability or apathy, and a miliary
rash. Chronic exposure to inorganic mercury salts, sometimes via
topical application in cosmetic skin-lightening creams, has been
associated with neurological symptoms and renal toxicity in case
reports and case series.
Methylmercury intoxication affects mainly the CNS and
results in paresthesias, ataxia, hearing impairment, dysarthria, and
progressive constriction of the visual fields. Signs and symptoms
of methylmercury intoxication may first appear several weeks
or months after exposure begins. Methylmercury is a reproduc-
tive toxin. High-dose prenatal exposure to methylmercury may
produce mental retardation and a cerebral palsy-like syndrome
in the offspring. Low-level prenatal exposures to methylmercury
have been associated with a risk of subclinical neurodevelopmental
deficits.
A 2004 report by the Institute of Medicine’s Immunization
Safety Review Committee concluded that available evidence
favored rejection of a causal relation between thimerosal-containing
vaccines and autism. In like manner, a recent retrospective cohort
study conducted by the CDC did not support a causal association
between early prenatal or postnatal exposure to mercury from
thimerosal-containing vaccines and neuropsychological function-
ing later in childhood.
Dimethylmercury is a rarely encountered but extremely neu-
rotoxic form of organomercury that may be lethal in small
quantities.
The diagnosis of mercury intoxication involves integration of
the history and physical findings with confirmatory laboratory test-
ing or other evidence of exposure. In the absence of occupational
exposure, the urine mercury concentration is usually <5 mcg/L,
and whole blood mercury is <5 mcg/L. In 1990, the Biological
Exposure Index (BEI) Committee of the American Conference
of Governmental Industrial Hygienists (ACGIH) recommended
that workplace exposures should result in urinary mercury con-
centrations <35 mcg per gram of creatinine and end-of-work-week
whole blood mercury concentrations <15 mcg/L. To minimize the
risk of developmental neurotoxicity from methylmercury, the EPA
 CHAPTER 57  Heavy Metal Intoxication & Chelators     1029

and the US Food and Drug Administration (FDA) have advised A

O
O
pregnant women, women who might become pregnant, nursing
mothers, and young children to avoid consumption of fish with HO C C OH
high mercury levels (eg, swordfish) and to limit consumption of CH2 CH2
albacore tuna to 6 ounces a week, but to otherwise consume 8–12 N N
ounces of fish per week (see http://www.fda.gov/Food/Foodbor- CH2 CH2 CH2 CH2
neIllnessContaminants/Metals/ucm393070.htm).
Na O C C O Na

O O
Treatment
A. Acute Exposure
O O
In addition to intensive supportive care, prompt chelation with
B C O O C
oral or intravenous unithiol, intramuscular dimercaprol, or oral
succimer may be of value in diminishing nephrotoxicity after H2C Ca CH2
acute exposure to inorganic mercury salts. Vigorous hydration O N N O
may help to maintain urine output, but if acute renal failure
Na O C CH2 C C C C O Na
ensues, days to weeks of hemodialysis or hemodiafiltration in H2 H2 H2
conjunction with chelation may be necessary. Because the efficacy
of chelation declines with time since exposure, treatment should
not be delayed until the onset of oliguria or other major systemic C O
effects. O
O

O
O

O
B. Chronic Exposure
Unithiol and succimer increase urine mercury excretion follow- Pb
ing acute or chronic elemental mercury inhalation, but the impact N
of such treatment on clinical outcome is unknown. Dimercaprol

has been shown to redistribute mercury to the central nervous
system from other tissue sites, and since the brain is a key target
organ, dimercaprol should not be used in treatment of exposure to
elemental or organic mercury. Limited data suggest that succimer,
unithiol, and N-acetyl-l-cysteine (NAC) may enhance body clear-
ance of methylmercury.
■■ PHARMACOLOGY OF
CHELATORS
Chelating agents are drugs used to prevent or reverse the toxic
effects of a heavy metal on an enzyme or other cellular target, or to
accelerate the elimination of the metal from the body. By forming
a complex with the heavy metal, the chelating agent renders the
metal unavailable for toxic interactions with functional groups of
enzymes or other proteins, coenzymes, cellular nucleophiles, and
membranes. Chelating agents contain one or more coordinating
atoms, usually oxygen, sulfur, or nitrogen, which donate a pair of
electrons to a cationic metal ion to form one or more coordinate-
covalent bonds. Depending on the number of metal-ligand bonds,
the complex may be referred to as mono-, bi-, or polydentate.
Figure 57–2 depicts the hexadentate chelate formed by interac-
tion of edetate (ethylenediaminetetraacetate) with a metal atom,
such as lead.
In some cases, the metal-mobilizing effect of a therapeutic
chelating agent may not only enhance that metal’s excretion—a
desired effect—but may also redistribute some of the metal to
other vital organs. This has been demonstrated for dimercaprol,
N
O
O
FIGURE 57–2  Salt and chelate formation with edetate
(ethylenediaminetetraacetate, EDTA). A: In a solution of the
disodium salt of EDTA, the sodium and hydrogen ions are chemi-
cally and biologically available. B: In solutions of calcium disodium
edetate, calcium is bound by coordinate-covalent bonds with
nitrogens as well as by the usual ionic bonds. C: In the lead–edetate
chelate, lead is incorporated into five heterocyclic rings. (Adapted, with
permission, from Meyers FH, Jawetz E, Goldfien A: Review of Medical Pharmacology,
7th ed. Originally published by Lange Medical Publications. McGraw-Hill, 1980.
Copyright © The McGraw-Hill Companies, Inc.)
which redistributes mercury and arsenic to the brain while also
enhancing urinary mercury and arsenic excretion. Although
several chelating agents have the capacity to mobilize cadmium,
their tendency to redistribute cadmium to the kidney and increase
nephrotoxicity has negated their therapeutic value in cadmium
intoxication.
In addition to removing the target metal that is exerting toxic
effects on the body, some chelating agents may enhance excretion
of essential cations, such as zinc in the case of calcium EDTA
and diethylenetriaminepentaacetic acid (DTPA), and zinc and
copper in the case of succimer. No clinical significance of this
effect has been demonstrated, although some animal data suggest
the possibility of adverse developmental impact. If prolonged
1030    SECTION IX Toxicology

chelation during the prenatal period or early childhood period is
necessary, judicious supplementation of the diet with zinc might
be considered.
The longer the half-life of a metal in a particular organ, the
less effectively it will be removed by chelation. For example, in
the case of lead chelation with calcium EDTA or succimer, or of
plutonium chelation with DTPA, the metal is more effectively
removed from soft tissues than from bone, where incorporation
into bone matrix results in prolonged retention.
In most cases, the capacity of chelating agents to prevent or
reduce the adverse effects of toxic metals appears to be greatest
when such agents are administered very soon after an acute metal
exposure. Use of chelating agents days to weeks after an acute metal
exposure ends—or their use in the treatment of chronic metal
intoxication—may still be associated with increased metal excretion.
However, at that point, the capacity of such enhanced excretion to
mitigate the pathologic effect of the metal exposure may be reduced.
The most important chelating agents currently in use in the
USA are described below.
DIMERCAPROL
(2,3-DIMERCAPTOPROPANOL, BAL)
Dimercaprol (Figure 57–3), an oily, colorless liquid with a strong
mercaptan-like odor, was developed in Great Britain during
World War II as a therapeutic antidote against poisoning by the
H2N CONH CONH
(CH2)5 (CH2)2 (CH2)5 (CH2)2 (CH2)5
N C N C N C
O O O O O O
Fe3+
arsenic-containing warfare agent lewisite. It thus became known as
British anti-lewisite, or BAL. Because aqueous solutions of dimer-
caprol are unstable and oxidize readily, it is dispensed in 10%
solution in peanut oil and must be administered by intramuscular
injection, which is often painful.
In animal models, dimercaprol prevents and reverses arsenic-
induced inhibition of sulfhydryl-containing enzymes and, if
given soon after exposure, may protect against the lethal effects
of inorganic and organic arsenicals. Human data indicate that
it can increase the rate of excretion of arsenic and lead and may
offer therapeutic benefit in the treatment of acute intoxication by
arsenic, lead, and mercury.
Indications & Toxicity
Dimercaprol is FDA approved as single-agent treatment of acute
poisoning by arsenic and inorganic mercury and for the treatment of
severe lead poisoning when used in conjunction with edetate calcium
disodium (EDTA; see below). Although studies of its metabolism
in humans are limited, intramuscularly administered dimercaprol
appears to be readily absorbed, metabolized, and excreted by the
kidney within 4–8 hours. Animal models indicate that it may also
undergo biliary excretion, but the role of this excretory route in
humans and other details of its biotransformation are uncertain.
When used in therapeutic doses, dimercaprol is associated
with a high incidence of adverse effects, including hyperten-
sion, tachycardia, nausea, vomiting, lacrimation, salivation, fever
(particularly in children), and pain at the injection site. Its use
has also been associated with thrombocytopenia and increased
prothrombin time—factors that may limit intramuscular injec-
tion because of the risk of hematoma formation at the injection
CH3 site. Despite its protective effects in acutely intoxicated animals,
dimercaprol may redistribute arsenic and mercury to the central
nervous system, and it is not advocated for treatment of chronic
poisoning. Water-soluble analogs of dimercaprol—unithiol and
succimer—have higher therapeutic indices and have replaced
dimercaprol in many settings.

Ferroxamine
SUCCIMER (DIMERCAPTOSUCCINIC
COOH
ACID, DMSA)
H2C SH CH3 O
CH SH Succimer is a water-soluble analog of dimercaprol, and like that
HC SH CH SH H3C C CH C OH agent it has been shown in animal studies to prevent and reverse
H 2C OH SH NH2
metal-induced inhibition of sulfhydryl-containing enzymes and to
COOH
protect against the acute lethal effects of arsenic. In humans, treat-
Dimercaprol Succimer Penicillamine
(2, 3-dimercaptopropanol) (DMSA) ment with succimer is associated with an increase in urinary lead
excretion and a decrease in blood lead concentration. It may also
FIGURE 57–3  Chemical structures of several chelators. Ferrox- decrease the mercury content of the kidney, a key target organ of
amine (ferrioxamine) without the chelated iron is deferoxamine. It is inorganic mercury salts. In the USA, succimer is formulated exclu-
represented here to show the functional groups; the iron is actually
sively for oral use, but intravenous formulations have been used
held in a caged system. The structures of the in vivo metal-chelator
complexes for dimercaprol, succimer, penicillamine, and unithiol (see
successfully elsewhere. It is absorbed rapidly but somewhat vari-
text) are not known and may involve the formation of mixed disulfides ably after oral administration. Peak blood levels of succimer occur
with amino acids. (Adapted, with permission from Meyers FH, Jawetz E, Goldfien at approximately 3 hours. The drug binds in vivo to the amino
A: Review of Medical Pharmacology, 7th ed. Originally published by Lange Medical acid cysteine to form 1:1 and 1:2 mixed disulfides, possibly in the
Publications. McGraw-Hill, 1980. Copyright © The McGraw-Hill Companies, Inc.) kidney, and it may be these complexes that are the active chelating

moieties. Experimental data suggest that multidrug-resistance pro-
tein 2 (Mrp2), one of a group of transporter proteins involved in
the cellular excretion of xenobiotics, facilitates the renal excretion
of mercury compounds that are bound to the transformed suc-
cimer and to unithiol. The elimination half-time of transformed
succimer is approximately 2–4 hours.
Indications & Toxicity
Succimer is currently FDA approved for the treatment of chil-
dren with blood lead concentrations >45 mcg/dL, but it is also
commonly used in adults. The typical dosage is 10 mg/kg orally
three times a day. Oral administration of succimer is comparable
to parenteral EDTA in reducing blood lead concentration and
has supplanted EDTA in outpatient treatment of patients who
are capable of absorbing the oral drug. However, despite the
demonstrated capacity of both succimer and EDTA to enhance
lead elimination, their value in reversing established lead toxic-
ity or in otherwise improving therapeutic outcome has yet to
be established by a placebo-controlled clinical trial. In a recent
study in lead-exposed juvenile rats, high-dose succimer did
reduce lead-induced neurocognitive impairment when admin-
istered to animals with moderate- and high-dose lead exposure.
Conversely, when administered to the control group that was not
lead exposed, succimer was associated with a decrement in neu-
rocognitive performance. Based on its protective effects against
arsenic in animals and its ability to mobilize mercury from the
kidney, succimer has also been used in the treatment of arsenic
and mercury poisoning.
In limited clinical trials, succimer has been well tolerated.
It has a negligible impact on body stores of calcium, iron, and
magnesium. It induces a mild increase in urinary excretion of zinc
and, less consistently, copper. This effect on trace metal balance
has not been associated with overt adverse effects, but its long-
term impact on neurodevelopment is uncertain. Gastrointestinal
disturbances, including anorexia, nausea, vomiting, and diarrhea,
are the most common side effects, occurring in <10% of patients.
Rashes, sometimes requiring discontinuation of the medication,
have been reported in <5% of patients. Mild, reversible increases
in liver aminotransferases have been noted in <5% of patients,
and isolated cases of mild to moderate neutropenia have been
reported.
EDETATE CALCIUM DISODIUM
(ETHYLENEDIAMINETETRAACETIC
ACID, EDTA)
Ethylenediaminetetraacetic acid (Figure 57–2) is an efficient
chelator of many divalent and trivalent metals in vitro. To prevent
potentially life-threatening depletion of calcium, treatment of
metal intoxication should only be performed with the calcium
disodium salt form of EDTA (edetate calcium disodium).
EDTA penetrates cell membranes relatively poorly and there-
fore chelates extracellular metal ions much more effectively than
intracellular ions.
CHAPTER 57  Heavy Metal Intoxication & Chelators     1031
The highly polar ionic character of EDTA limits its oral
absorption. Moreover, oral administration may increase lead
absorption from the gut. Consequently, EDTA should be
administered by intravenous infusion. In patients with normal
renal function, EDTA is rapidly excreted by glomerular filtra-
tion, with 50% of an injected dose appearing in the urine within
1 hour. EDTA mobilizes lead from soft tissues, causing a marked
increase in urinary lead excretion and a corresponding decline in
blood lead concentration. In patients with renal insufficiency,
excretion of the drug—and its metal-mobilizing effects—may
be delayed.
Indications & Toxicity
Edetate calcium disodium is indicated chiefly for the chelation
of lead, but it may also have usefulness in poisoning by zinc,
manganese, and certain heavy radionuclides. A recent random-
ized, double-blind, placebo-controlled prospective trial of edetate
disodium (not edetate calcium disodium) observed a significant
decrease in cardiovascular events in a subgroup consisting of
diabetic patients with a prior history of myocardial infarction.
Further study is indicated to replicate the findings and explore
potential mechanisms of benefit.
Because the drug and the mobilized metals are excreted via
the urine, the drug is relatively contraindicated in anuric patients.
In such instances, the use of low doses of EDTA in combination
with high-flux hemodialysis or hemofiltration has been described.
Nephrotoxicity from EDTA has been reported, but in most cases
can be prevented by maintenance of adequate urine flow, avoid-
ance of excessive doses, and limitation of a treatment course to 5
or fewer consecutive days. EDTA may result in temporary zinc
depletion that is of uncertain clinical significance. Analogs of
EDTA, the calcium and zinc disodium salts of DTPA, pentetate,
have been used for removal (“decorporation”) of certain transura-
nic, rare earth, and transition metal radioisotopes, and in 2004
were approved by the FDA for treatment of contamination with
plutonium, americium, and curium.
UNITHIOL
(DIMERCAPTOPROPANESULFONIC
ACID, DMPS)
Unithiol, a dimercapto chelating agent that is a water-soluble
analog of dimercaprol, has been available in the official formu-
laries of Russia and other former Soviet countries since 1958
and in Germany since 1976. It has been legally available from
compounding pharmacies in the USA since 1999. Unithiol can
be administered orally and intravenously. Bioavailability by the
oral route is approximately 50%, with peak blood levels occur-
ring in approximately 4 hours. Over 80% of an intravenous dose
is excreted in the urine, mainly as cyclic DMPS sulfides. The
elimination half-time of total unithiol (parent drug and its trans-
formation products) is approximately 20 hours. Unithiol exhibits
protective effects against the toxic action of mercury and arsenic in
animal models, and it increases the excretion of mercury, arsenic,
1032    SECTION IX Toxicology
and lead in humans. Animal studies and a few case reports suggest
that unithiol may also have usefulness in the treatment of poison-
ing by bismuth compounds.
SH SH SO2H
CH2 CH CH2
Unithiol
Indications & Toxicity
Unithiol has no FDA-approved indications, but experimental
studies and its pharmacologic and pharmacodynamic profile
suggest that intravenous unithiol offers advantages over intra-
muscular dimercaprol or oral succimer in the initial treatment of
severe acute poisoning by inorganic mercury or arsenic. Aqueous
preparations of unithiol (usually 50 mg/mL in sterile water) can
be administered at a dosage of 3–5 mg/kg every 4 hours by slow
intravenous infusion over 20 minutes. If a few days of treatment
are accompanied by stabilization of the patient’s cardiovascular
and gastrointestinal status, it may be possible to change to oral
administration of 4–8 mg/kg every 6–8 hours. Oral unithiol may
also be considered as an alternative to oral succimer in the treat-
ment of lead intoxication. Intravenous unithiol in conjunction
with high flux hemodialysis or hemodiafiltration may be useful
in the treatment of patients with anuric renal failure caused by
mercury salts and bismuth.
Unithiol has been reported to have a low overall incidence of
adverse effects (<4%). Self-limited dermatologic reactions (drug
exanthems or urticaria) are the most commonly reported adverse
effects, although isolated cases of major allergic reactions, includ-
ing erythema multiforme and Stevens-Johnson syndrome, have
been reported. Because rapid intravenous infusion may cause
vasodilation and hypotension, unithiol should be infused slowly
over 15–20 minutes.
PENICILLAMINE (d-DIMETHLCYSTEINE)
Penicillamine (Figure 57–3) is a white, crystalline, water-soluble
derivative of penicillin. d-Penicillamine is less toxic than the
l-isomer and consequently is the preferred therapeutic form.
Penicillamine is readily absorbed from the gut and is resistant to
metabolic degradation.
Indications & Toxicity
Penicillamine is used chiefly for treatment of poisoning with
copper or to prevent copper accumulation, as in Wilson’s disease
(hepatolenticular degeneration). It is also used occasionally in
the treatment of severe rheumatoid arthritis (see Chapter 36). Its
ability to increase urinary excretion of lead and mercury had occa-
sioned its use in outpatient treatment for intoxication with these
metals, but succimer, with its stronger metal-mobilizing capacity
and lower adverse-effect profile, has generally replaced penicilla-
mine for these purposes.
Adverse effects have been seen in up to one third of patients
receiving penicillamine. Hypersensitivity reactions include rash,
pruritus, and drug fever, and the drug should be used with
extreme caution, if at all, in patients with a history of penicillin
allergy. Nephrotoxicity with proteinuria has also been reported,
and protracted use of the drug may result in renal insufficiency.
Pancytopenia has been associated with prolonged drug intake.
Pyridoxine deficiency is a frequent toxic effect of other forms
of the drug but is rarely seen with the d isomer. An acetylated
derivative, N-acetylpenicillamine, has been used experimentally
in mercury poisoning and may have superior metal-mobilizing
capacity, but it is not commercially available.
DEFEROXAMINE
Deferoxamine is isolated from Streptomyces pilosus. It binds iron
avidly (Figure 57–3) but binds essential trace metals poorly.
Furthermore, though competing for loosely bound iron in iron-
carrying proteins (hemosiderin and ferritin), it fails to compete
for biologically chelated iron, as in microsomal and mitochon-
drial cytochromes and hemoproteins. Consequently, it is the
parenteral chelator of choice for iron poisoning (see Chapters 33
and 58). Deferoxamine plus hemodialysis may also be use-
ful in the treatment of aluminum toxicity in renal failure.
Deferoxamine is poorly absorbed when administered orally
and may increase iron absorption when given by this route. It
should therefore be administered intramuscularly or, preferably,
intravenously. It is believed to be metabolized, but the pathways
are unknown. The iron-chelator complex is excreted in the urine,
often turning the urine an orange-red color.
Rapid intravenous administration may result in hypotension.
Adverse idiosyncratic responses such as flushing, abdominal discom-
fort, and rash have also been observed. Pulmonary complications
(eg, acute respiratory distress syndrome) have been reported in some
patients undergoing deferoxamine infusions lasting longer than
24 hours, and neurotoxicity and increased susceptibility to certain
infections (eg, with Yersinia enterocolitica) have been described after
long-term therapy of iron overload conditions (eg, thalassemia major).
DEFERASIROX & DEFERIPRONE
Deferasirox is a tridentate chelator with a high affinity for iron
and low affinity for other metals, eg, zinc and copper. It is orally
active and well absorbed. In the circulation, it binds iron, and the
complex is excreted in the bile. Deferasirox was approved by the
FDA in 2005 for the oral treatment of iron overload caused by
blood transfusions, a problem in the treatment of thalassemia and
myelodysplastic syndrome. More than 5 years of clinical experience
suggest that daily long-term usage is generally well tolerated, with
the most common adverse effects consisting of mild to moderate
gastrointestinal disturbances and skin rash. Monitoring of liver and
renal function has been advised because renal and liver impairment
and failure associated with deferasirox have been reported during
treatment of older adults with myelodysplastic syndromes.
Deferiprone, a bidentate iron chelator cleared predominantly
via the kidney, was approved by the FDA in 2011 as a second-line
oral chelator for patients with transfusional iron overload due to
 CHAPTER 57  Heavy Metal Intoxication & Chelators     1033

thalassemia. Compared to deferasirox, deferiprone appears to be P R E P A R A T I O N S

relatively more efficient in decreasing cardiac iron but less efficient A V A I L A B L E
in decreasing hepatic iron. Because neutropenia has occurred in
5–10% of patients, with agranulocytosis in approximately 1%,
GENERIC NAME AVAILABLE AS
regular hematologic monitoring is recommended.
Deferasirox Exjade, Jadenu
Magnetic resonance imaging has been increasingly used to
Deferiprone Ferriprox
evaluate cardiac and hepatic iron burden and to guide iron chelation
Deferoxamine Generic, Desferal
therapy. Regimens that combine iron-chelating agents have been
Dimercaprol BAL in Oil
used in cases when monotherapy has yielded suboptimal results.
Edetate calcium [calcium EDTA] Calcium Disodium Versenate
Penicillamine Cuprimine, Depen

PRUSSIAN BLUE (FERRIC Pentetate Calcium Trisodium Generic

HEXACYANOFERRATE)
Ferric hexacyanoferrate (insoluble Prussian blue) is a hydrated
crystalline compound in which Fe2+ and Fe3+ atoms are coordi-
nated with cyanide groups in a cubic lattice structure. Although
used as a dark blue commercial pigment for nearly 300 years, it
was only three decades ago that its potential usefulness as a phar-
maceutical chelator was recognized. Primarily by ion exchange,
and secondarily by mechanical trapping or adsorption, the com-
pound has high affinity for certain univalent cations, particularly
cesium and thallium. Used as an oral drug, insoluble Prussian blue
undergoes minimal gastrointestinal absorption (<1%). Because
the complexes it forms with cesium or thallium are nonabsorb-
able, oral administration of the chelator diminishes intestinal
absorption or interrupts enterohepatic and enteroenteric circula-
tion of these cations, thereby accelerating their elimination in
the feces. In clinical case series, the use of Prussian blue has been
associated with a decline in the biologic half-life (ie, in vivo reten-
tion) of radioactive cesium and thallium.
[calcium DTPA] and Pentetate Zinc
Trisodium [zinc DTPA]
Prussian Blue Radiogardase
Succimer Chemet, Succicaptal (in Europe)
Unithiol Dimaval
REFERENCES
Lead
Advisory Committee on Childhood Lead Poisoning Prevention of the Centers for
Disease Control and Prevention. Low Level Lead Exposure Harms Children:
A Renewed Call for Primary Prevention. CDC: Atlanta, GA. 2012. http://
www.cdc.gov/nceh/lead/ACCLPP/Final_Document_030712.pdf.
Brubaker CJ et al: The influence of age of lead exposure on adult gray matter
volume. Neurotoxicology 2010;31:259.
Burns MS et al: Implications of the new Centers for Disease Control and Preven-
tion blood lead reference value. Am J Publ Health 2014;104:e27.
Carlisle JC et al: A blood lead benchmark for assessing risks from childhood lead
exposure. J Environ Sci Health Part A 2009;44:1200.
Centers for Disease Control and Prevention (CDC): Guidelines for the Identification
and Management of Lead Exposure in Pregnant and Lactating Women. CDC,
2010. http://www.cdc.gov/nceh/lead/publications/LeadandPregnancy2010.pdf.

Indications & Toxicity
In 2003, the FDA approved Prussian blue for the treatment of
contamination with radioactive cesium (137Cs) and intoxication
with thallium salts. Approval was prompted by concern over
potential widespread human contamination with radioactive
cesium caused by terrorist use of a radioactive dispersal device
(“dirty bomb”). The drug is part of the Strategic National Stock-
pile of pharmaceuticals and medical material maintained by the
CDC (https://www.cdc.gov/phpr/stockpile/). (Note: Although
soluble forms of Prussian blue, such as potassium ferric hexacya-
noferrate, may have better utility in thallium poisoning, only the
insoluble form is currently available as a pharmaceutical.)
After exposure to 137Cs or thallium salts, the approved adult
dosage of Prussian blue is 3 g orally three times a day; the cor-
responding pediatric dosage (2–12 years of age) is 1 g orally three
times a day. Serial monitoring of urine and fecal radioactivity
(137Cs) and urinary thallium concentrations can guide the recom-
mended duration of therapy. Adjunctive supportive care for pos-
sible acute radiation illness (137Cs) or systemic thallium toxicity
should be instituted as needed.
Prussian blue has not been associated with significant adverse
effects. Constipation, which may occur in some cases, should be
treated with laxatives or increased dietary fiber.
Environmental Protection Agency. Integrated Science Assessment for Lead. EPA:
Research Triangle Park, NC. 2013. http://epa.gov/ncea/isa/lead.htm.
Kosnett MJ et al: Recommendations for medical management of adult lead expo-
sure. Environ Health Perspect 2007;115:463.
Lanphear BP et al: Low-level environmental lead exposure and children’s intellec-
tual development: An international pooled analysis. Environ Health Perspect
2005;113:894.
Weisskopf MG et al: Biased exposure-health effect estimates from selection in
cohort studies: are environmental studies at particular risk? Environ Health
Perspect 2015;123:1113. [Note: Study reports relationship between bone
lead concentration and cardiovascular mortality.]
Arsenic
Antonelli R et al: AS3MT, GSTO, and PNP polymorphisms: Impact on arse-
nic methylation and implications for disease susceptibility. Environ Res
2014;132:156.
Caldwell KL et al: Levels of urinary total and speciated arsenic in the US popula-
tion: National Health and Nutrition Examination Survey 2003–2004. J Exp
Sci Environ Epid 2009;19:59.
James KA et al: Association between lifetime exposure to inorganic arsenic in
drinking water and coronary heart disease in Colorado residents. Environ
Health Perspect 2015;123:128.
National Research Council: Critical Aspects of EPA’s IRIS Assessment of Inorganic
Arsenic: Interim Report. Washington, DC: The National Academies Press,
2013.
Naujokas MF et al: The broad scope of health effects from chronic arsenic
exposure: Update on a worldwide public health problem. Environ Health
Perspect 2013;121:295.
1034    SECTION IX Toxicology
Parvez F et al: A prospective study of respiratory symptoms associated with chronic
arsenic exposure in Bangladesh: Findings from the Health Effects of Arsenic
Longitudinal Study (HEALS). Thorax 2010;65:528.
Quansah R et al: Association of arsenic with adverse pregnancy outcomes/infant
mortality: A systematic review and meta-analysis. Environ Health Perspect
2015;123:412.
Mercury
Agency for Toxic Substances and Disease Registry (ATSDR): Action Levels
for Elemental Mercury Spills. ATSDR: Atlanta, GA 2012. http://www
.atsdr.cdc.gov/emergency_response/action_levels_for_elemental_mercury_
spills_2012.pdf.
Al-Saleh I: Potential health consequences of applying mercury-containing skin-
lightening creams during pregnancy and lactation periods Int J Hyg Environ
Health 2016;219:468.
Beasley DMG et al: Full recovery from a potentially lethal dose of mercuric chlo-
ride. J Med Toxicol 2014;10:40.
Bellinger DC et al: Dental amalgam restorations and children’s neuropsychologi-
cal function: The New England Children’s Amalgam Trial. Environ Health
Perspect 2007;115:440.
Environmental Protection Agency: What you need to know about mercury in
fish and shellfish. http://water.epa.gov/scitech/swguidance/fishshellfish/out-
reach/advice_index.cfm.
Franzblau A et al: Low-level mercury exposure and peripheral nerve function.
Neurotoxicology 2012;33:299.
Grandjean P et al: Adverse effects of methylmercury: Environmental health
research implications. Environ Health Perspect 2010;118:1137.
Hertz-Picciotto I et al: Blood mercury concentrations in CHARGE study children
with and without autism. Environ Health Perspect 2010;118:161.
C ASE STUDY ANSWER
Bacterial food poisoning is the most common cause of gas-
trointestinal signs and symptom appearing in a group of indi-
viduals within several hours of a common meal. Consumption
of food contaminated with preformed bacterial toxins such as
Staphylococcus or Bacillus cereus toxins can result in vomiting
after an incubation interval as short as 1–2 hours. However,
the onset of vomiting in some individuals within 15 minutes
and the progression to hypotension and metabolic acidosis in
several individuals are not typical for bacterial food poisoning
and are more suggestive of intoxication by certain toxic chemi-
cals or drugs, including inorganic arsenic and mercury salts
(eg, sodium arsenite or mercuric chloride). The absence of
hematemesis, bloody diarrhea, or renal insufficiency lowered
Mortensen ME: Total and methyl mercury in whole blood measured for the
first time in the U.S. population: NHANES 2011-2012. Environ Res
2014;134:257.
Yorifuji T et al: Long-term exposure to methylmercury and neurologic signs in
Minamata and neighboring communities. Epidemiology 2008;19:3.
Chelating Agents
Bradberry S, Vale A: A comparison of sodium calcium edetate (edetate calcium
disodium) and succimer (DMSA) in the treatment of inorganic lead poison-
ing. Clin Toxicol 2009;47:841.
Dargan PI et al: Case report: Severe mercuric sulphate poisoning treated with
2,3-dimercaptopropane-1-sulphonate and haemodiafiltration. Crit Care
2003;7:R1.
Escolar E et al: The effect of an EDTA-based chelation regimen on patients with
diabetes mellitus and prior myocardial infarction in the Trial to Assess Che-
lation Therapy (TACT). Circ Cardiovasc Qual Outcomes 2014;7(1):15.
Kosnett MJ: Chelation for heavy metals (arsenic, lead, and mercury): Protective or
perilous? Clin Pharmacol Ther 2010;88:412.
Kosnett MJ: The role of chelation in the treatment of arsenic and mercury poison-
ing. J Med Toxicol 2013;9:347.
Sheth S: Iron chelation: An update. Curr Opin Hematol 2014;21:179-185.
Thompson DF, Called ED: Soluble or insoluble Prussian blue for radiocesium and
thallium poisoning? Ann Pharmacother 2004;38:1509.
Thurtle N et al: Description of 3,180 courses of chelation with dimercapto-
succinic acid in children ≤ 5 y with severe lead poisoning in Zamfara,
Northern Nigeria: a retrospective analysis of programme data. PLOS Med
2014;11(10):e1001739.
the likelihood that inorganic mercury was responsible. An
epidemiologic investigation subsequently revealed that all
affected individuals had consumed the deliberately adulter-
ated coffee, which contained 6300 ppm of inorganic arsenic.
Analysis of urine for arsenic and mercury and stool and
emesis for bacterial pathogens would be reasonable initial
diagnostic tests. Pending test results, prompt empiric treat-
ment of this constellation of findings with the chelating agents
unithiol, succimer, or dimercaprol would be appropriate.
[Based on an actual incident, see: Gensheimer KF et al: Arse-
nic poisoning caused by intentional contamination of coffee at
a church gathering: An epidemiological approach to a forensic
investigation. J Forensic Sci 2010;55:1116].

Management of the
Poisoned Patient
Kent R. Olson, MD
C ASE STUDY
A 62-year-old woman with a history of depression is found in
her apartment in a lethargic state. An empty bottle of bupro-
pion is on the bedside table. In the emergency department,
she is unresponsive to verbal and painful stimuli. She has a
brief generalized seizure, followed by a respiratory arrest. The
emergency physician performs endotracheal intubation and
Over 1 million cases of acute poisoning occur in the USA each
year, although only a small number are fatal. Most deaths are due
to intentional suicidal overdose by an adolescent or adult. Child-
hood deaths due to accidental ingestion of a drug or toxic house-
hold product have been markedly reduced in the last 50 years as
a result of safety packaging and effective poisoning prevention
education.
Even with a serious exposure, poisoning is rarely fatal if the
victim receives prompt medical attention and good supportive
care. Careful management of respiratory failure, hypotension,
seizures, and thermoregulatory disturbances has resulted in
improved survival of patients who reach the hospital alive.
This chapter reviews the basic principles of poisoning,
initial management, and specialized treatment of poisoning,
including methods of increasing the elimination of drugs and
toxins.
■■ TOXICOKINETICS &
TOXICODYNAMICS
The term toxicokinetics denotes the absorption, distribution,
excretion, and metabolism of toxins, toxic doses of therapeutic
agents, and their metabolites. The term toxicodynamics is used to
58
C H A P T E R
administers a drug intravenously, followed by another sub-
stance via a nasogastric tube. The patient is admitted to the
intensive care unit for continued supportive care and recovers
the next morning. What drug might be used intravenously to
prevent further seizures? What substance is commonly used
to adsorb drugs still present in the gastrointestinal tract?
denote the injurious effects of these substances on body functions.
Although many similarities exist between the pharmacokinetics
and toxicokinetics of most substances, there are also important
differences. The same caution applies to pharmacodynamics and
toxicodynamics.
SPECIAL ASPECTS OF TOXICOKINETICS
Volume of Distribution
The volume of distribution (Vd) is defined as the apparent volume
into which a substance is distributed in the body (see Chapter 3).
A large Vd implies that the drug is not readily accessible to mea-
sures aimed at purifying the blood, such as hemodialysis. Exam-
ples of drugs with large volumes of distribution (>5 L/kg) include
antidepressants, antipsychotics, antimalarials, opioids, proprano-
lol, and verapamil. Drugs with a relatively small Vd (<1 L/kg)
include salicylate, ethanol, phenobarbital, lithium, valproic acid,
and phenytoin (see Table 3–1).
Clearance
Clearance is a measure of the volume of plasma that is cleared of
drug per unit time (see Chapter 3). The total clearance for most
1035
1036    SECTION IX Toxicology
drugs is the sum of clearances via excretion by the kidneys and
metabolism by the liver. In planning a detoxification strategy, it is
important to know the contribution of each organ to total clear-
ance. For example, if a drug is 95% cleared by liver metabolism
and only 5% cleared by renal excretion, even a dramatic increase
in urinary concentration of the drug will have little effect on
overall elimination.
Overdosage of a drug can alter the usual pharmacokinetic
processes, and this must be considered when applying kinetics to
poisoned patients. For example, dissolution of tablets or gastric
emptying time may be slowed so that absorption and peak toxic
effects are delayed. Drugs may injure the epithelial barrier of
the gastrointestinal tract and thereby increase absorption. If the
capacity of the liver to metabolize a drug is exceeded, the first-
pass effect will be reduced and more drug will be delivered to the
circulation. With a dramatic increase in the concentration of drug
in the blood, protein-binding capacity may be exceeded, resulting
in an increased fraction of free drug and greater toxic effect. At
normal dosage, most drugs are eliminated at a rate proportional
to the plasma concentration (first-order kinetics). If the plasma
concentration is very high and normal metabolism is saturated,
the rate of elimination may become fixed (zero-order kinetics).
This change in kinetics may markedly prolong the apparent serum
half-life and increase toxicity.
SPECIAL ASPECTS OF
TOXICODYNAMICS
The general dose-response principles described in Chapter 2 are
relevant when estimating the potential severity of an intoxication.
When considering quantal dose-response data, both the therapeu-
tic index and the overlap of therapeutic and toxic response curves
must be considered. For instance, two drugs may have the same
therapeutic index but unequal safe dosing ranges if the slopes of
their dose-response curves are not the same. For some drugs, eg,
sedative-hypnotics, the major toxic effect is a direct extension of
the therapeutic action, as shown by their graded dose-response
curve (see Figure 22–1). In the case of a drug with a linear dose-
response curve (drug A), lethal effects may occur at 10 times the
normal therapeutic dose. In contrast, a drug with a curve that
reaches a plateau (drug B) may not be lethal at 100 times the
normal dose.
For many drugs, at least part of the toxic effect may be differ-
ent from the therapeutic action. For example, intoxication with
drugs that have atropine-like effects (eg, tricyclic antidepressants)
reduces sweating, making it more difficult to dissipate heat. In
tricyclic antidepressant intoxication, there may also be increased
muscular activity or seizures; the body’s production of heat is thus
enhanced, and lethal hyperpyrexia may result. Overdoses of drugs
that depress the cardiovascular system, eg, β blockers or calcium
channel blockers, can profoundly alter not only cardiac function
but all functions that are dependent on blood flow. These include
renal and hepatic elimination of the toxin and that of any other
drugs that may be given.
■■ APPROACH TO THE POISONED
PATIENT
HOW DOES THE POISONED
PATIENT DIE?
An understanding of common mechanisms of death due to poi-
soning can help prepare the caregiver to treat patients effectively.
Many toxins depress the central nervous system (CNS), resulting
in obtundation or coma. Comatose patients frequently lose their
airway protective reflexes and their respiratory drive. Thus, they
may die as a result of airway obstruction by the flaccid tongue,
aspiration of gastric contents into the tracheobronchial tree, or
respiratory arrest. These are the most common causes of death
due to overdoses of narcotics and sedative-hypnotic drugs (eg,
barbiturates and alcohol).
Cardiovascular toxicity is also frequently encountered in
poisoning. Hypotension may be due to depression of cardiac
contractility; hypovolemia resulting from vomiting, diarrhea, or
fluid sequestration; peripheral vascular collapse due to blockade
of α-adrenoceptor-mediated vascular tone; or cardiac arrhythmias.
Hypothermia or hyperthermia due to exposure as well as the
temperature-dysregulating effects of many drugs can also produce
hypotension. Lethal arrhythmias such as ventricular tachycardia
and fibrillation can occur with overdoses of many cardioactive
drugs such as ephedrine, amphetamines, cocaine, digitalis, and
theophylline; and drugs not usually considered cardioactive,
such as tricyclic antidepressants, antihistamines, and some opioid
analogs.
Cellular hypoxia may occur despite adequate ventilation and
oxygen administration when poisoning is due to cyanide, hydro-
gen sulfide, carbon monoxide, and other poisons that interfere
with transport or utilization of oxygen. Such patients may not
be cyanotic, but cellular hypoxia is evident by the development
of tachycardia, hypotension, severe lactic acidosis, and signs of
ischemia on the electrocardiogram.
Seizures, muscular hyperactivity, and rigidity may result in
death. Seizures may cause pulmonary aspiration, hypoxia, and
brain damage. Hyperthermia may result from sustained muscular
hyperactivity and can lead to muscle breakdown and myoglobin-
uria, renal failure, lactic acidosis, and hyperkalemia. Drugs and
poisons that often cause seizures include antidepressants, isoniazid
(INH), diphenhydramine, cocaine, and amphetamines.
Other organ system damage may occur after poisoning and is
sometimes delayed in onset. Paraquat attacks lung tissue, result-
ing in pulmonary fibrosis, beginning several days after ingestion.
Massive hepatic necrosis due to poisoning by acetaminophen or
certain mushrooms results in hepatic encephalopathy and death
48–72 hours or longer after ingestion.
Finally, some patients may die before hospitalization because
the behavioral effects of the ingested drug may result in traumatic
injury. Intoxication with alcohol and other sedative-hypnotic
drugs is a common contributing factor to motor vehicle acci-
dents. Patients under the influence of hallucinogens such as

phencyclidine (PCP) or lysergic acid diethylamide (LSD) may
suffer trauma when they become combative or fall from a height.
■■ INITIAL MANAGEMENT OF THE
POISONED PATIENT
The initial management of a patient with coma, seizures, or
otherwise altered mental status should follow the same approach
regardless of the poison involved: supportive measures are the
basics (“ABCDs”) of poisoning treatment.
First, the airway should be cleared of vomitus or any other
obstruction and an oral airway or endotracheal tube inserted
if needed. For many patients, simple positioning in the lateral,
left-side-down position is sufficient to move the flaccid tongue
out of the airway. Breathing should be assessed by observation
and pulse oximetry and, if in doubt, by measuring arterial blood
gases. Patients with respiratory insufficiency should be intubated
and mechanically ventilated. The circulation should be assessed
by continuous monitoring of pulse rate, blood pressure, urinary
output, and evaluation of peripheral perfusion. An intravenous
line should be placed and blood drawn for serum glucose and
other routine determinations.
At this point, every patient with altered mental status should
receive a challenge with concentrated dextrose, unless a rapid
bedside blood glucose test demonstrates that the patient is not
hypoglycemic. Adults are given 25 g (50 mL of 50% dextrose
solution) intravenously, children 0.5 g/kg (2 mL/kg of 25%
dextrose). Hypoglycemic patients may appear to be intoxicated,
and there is no rapid and reliable way to distinguish them from
poisoned patients. Alcoholic or malnourished patients should also
receive 100 mg of thiamine intramuscularly or in the intravenous
infusion solution at this time to prevent Wernicke’s syndrome.
The opioid antagonist naloxone may be given in a dose of
0.4–2 mg intravenously. Naloxone reverses respiratory and CNS
depression due to all varieties of opioid drugs (see Chapter 31).
It is useful to remember that these drugs cause death primarily
by respiratory depression; therefore, if airway and breathing assis-
tance have already been instituted, naloxone may not be necessary.
Larger doses of naloxone may be needed for patients with overdose
involving propoxyphene, codeine, and some other opioids. The
benzodiazepine antagonist flumazenil (see Chapter 22) may be of
value in patients with suspected benzodiazepine overdose, but it
should not be used if there is a history of tricyclic antidepressant
overdose or a seizure disorder, as it can induce convulsions in such
patients.
History & Physical Examination
Once the essential initial ABCD interventions have been insti-
tuted, one can begin a more detailed evaluation to make a
specific diagnosis. This includes gathering any available history
and performing a toxicologically oriented physical examination.
Other causes of coma or seizures such as head trauma, menin-
gitis, or metabolic abnormalities should be sought and treated.
CHAPTER 58  Management of the Poisoned Patient     1037
Some common intoxications are described under Common Toxic
Syndromes.
A. History
Oral statements about the amount and even the type of drug
ingested in toxic emergencies may be unreliable. Even so, family
members, police, and fire department or paramedical personnel
should be asked to describe the environment in which the toxic
emergency occurred and should bring to the emergency depart-
ment any syringes, empty bottles, household products, or over-
the-counter medications in the immediate vicinity of the possibly
poisoned patient.
B. Physical Examination
A brief examination should be performed, emphasizing those
areas most likely to give clues to the toxicologic diagnosis. These
include vital signs, eyes and mouth, skin, abdomen, and nervous
system.
1. Vital signs—Careful evaluation of vital signs (blood pressure,
pulse, respirations, and temperature) is essential in all toxicologic
emergencies. Hypertension and tachycardia are typical with
amphetamines, cocaine, and antimuscarinic (anticholinergic)
drugs. Hypotension and bradycardia are characteristic features of
overdose with calcium channel blockers, β blockers, clonidine,
and sedative hypnotics. Hypotension with tachycardia is common
with tricyclic antidepressants, trazodone, quetiapine, vasodilators,
and β agonists. Rapid respirations are typical of salicylates, carbon
monoxide, and other toxins that produce metabolic acidosis or
cellular asphyxia. Hyperthermia may be associated with sympa-
thomimetics, anticholinergics, salicylates, and drugs producing
seizures or muscular rigidity. Hypothermia can be caused by any
CNS-depressant drug, especially when accompanied by exposure
to a cold environment.
2. Eyes—The eyes are a valuable source of toxicologic informa-
tion. Constriction of the pupils (miosis) is typical of opioids,
clonidine, phenothiazines, and cholinesterase inhibitors (eg,
organophosphate insecticides), and deep coma due to sedative
drugs. Dilation of the pupils (mydriasis) is common with amphet-
amines, cocaine, LSD, and atropine and other anticholinergic
drugs. Horizontal nystagmus is characteristic of intoxication with
phenytoin, alcohol, barbiturates, and other sedative drugs. The
presence of both vertical and horizontal nystagmus is strongly sug-
gestive of phencyclidine poisoning. Ptosis and ophthalmoplegia
are characteristic features of botulism.
3. Mouth—The mouth may show signs of burns due to cor-
rosive substances, or soot from smoke inhalation. Typical odors
of alcohol, hydrocarbon solvents, or ammonia may be noted.
Poisoning due to cyanide can be recognized by some examiners as
an odor like bitter almonds.
4. Skin—The skin often appears flushed, hot, and dry in poisoning
with atropine and other antimuscarinics. Excessive sweating occurs
with organophosphates, nicotine, and sympathomimetic drugs.
1038    SECTION IX Toxicology
Cyanosis may be caused by hypoxemia or by methemoglobinemia.
Icterus may suggest hepatic necrosis due to acetaminophen or
Amanita phalloides mushroom poisoning.
5. Abdomen—Abdominal examination may reveal ileus, which
is typical of poisoning with antimuscarinic, opioid, and sedative
drugs. Hyperactive bowel sounds, abdominal cramping, and
diarrhea are common in poisoning with organophosphates, iron,
arsenic, theophylline, A phalloides, and A muscaria.
6. Nervous system—A careful neurologic examination is essen-
tial. Focal seizures or motor deficits suggest a structural lesion
(eg, intracranial hemorrhage due to trauma) rather than toxic or
metabolic encephalopathy. Nystagmus, dysarthria, and ataxia are
typical of phenytoin, carbamazepine, alcohol, and other sedative
intoxication. Twitching and muscular hyperactivity are common
with atropine and other anticholinergic agents, and cocaine and
other sympathomimetic drugs. Muscular rigidity can be caused
by haloperidol and other antipsychotic agents, and by strychnine
or by tetanus. Generalized hypertonicity of muscles and lower
extremity clonus are typical of serotonin syndrome. Seizures are
often caused by overdose with antidepressants (especially tricyclic
antidepressants and bupropion [as in the case study]), cocaine,
amphetamines, theophylline, isoniazid, and diphenhydramine.
Flaccid coma with absent reflexes and even an isoelectric elec-
troencephalogram may be seen with deep coma due to sedative-
hypnotic or other CNS depressant intoxication and may be
mistaken for brain death.
Laboratory & Imaging Procedures
A. Arterial Blood Gases
Hypoventilation results in an elevated Pco2 (hypercapnia) and a
low Po2 (hypoxia). The Po2 may also be low in a patient with aspi-
ration pneumonia or drug-induced pulmonary edema. Poor tissue
oxygenation due to hypoxia, hypotension, or cyanide poisoning
will result in metabolic acidosis. The Po2 measures only oxygen
dissolved in the plasma and not total blood oxygen content or
oxyhemoglobin saturation and may appear normal in patients
with severe carbon monoxide poisoning. Pulse oximetry may also
give falsely normal results in carbon monoxide intoxication.
B. Electrolytes
Sodium, potassium, chloride, and bicarbonate should be measured.
The anion gap is then calculated by subtracting the measured
anions from cations:
Anion gap = (Na+ + K+) – (HCO3– + Cl–)
Normally, the sum of the cations exceeds the sum of the
anions by no more than 12–16 mEq/L (or 8–12 mEq/L if the
formula used for estimating the anion gap omits the potassium
level). A larger than expected anion gap is caused by the pres-
ence of unmeasured anions (lactate, etc) accompanying metabolic
acidosis. This may occur with numerous conditions, such as dia-
betic ketoacidosis, renal failure, or shock-induced lactic acidosis.
Drugs that may induce an elevated anion gap metabolic acidosis
TABLE 58–1  Examples of drug-induced anion gap
acidosis.
Type of Elevation
of the Anion Gap Agents
Organic acid Methanol, ethylene glycol, diethylene glycol,
metabolites oxoprolinuria (rare complication of
acetaminophen)
Lactic acidosis Cyanide, carbon monoxide, ibuprofen,
isoniazid, metformin, salicylates, valproic
acid; any drug-induced seizures, hypoxia, or
hypotension
Note: The normal anion gap calculated from (Na+ + K+) – (HCO3 + Cl−) is 12–16 mEq/L;
−
calculated from (Na+) – (HCO3− + Cl−), it is 8–12 mEq/L.
(Table 58–1) include aspirin, metformin, methanol, ethylene
glycol, isoniazid, and iron.
Alterations in the serum potassium level are hazardous because
they can result in cardiac arrhythmias. Drugs that may cause
hyperkalemia despite normal renal function include potassium
itself, β blockers, digitalis glycosides, potassium-sparing diuretics,
and fluoride. Drugs associated with hypokalemia include barium,
β agonists, caffeine, theophylline, and thiazide and loop diuretics.
C. Renal Function Tests
Some toxins have direct nephrotoxic effects; in other cases, renal
failure is due to shock or myoglobinuria. Blood urea nitrogen and
creatinine levels should be measured and urinalysis performed.
Elevated serum creatine kinase (CK) and myoglobin in the urine
suggest muscle necrosis due to seizures or muscular rigidity.
Oxalate crystals in large numbers in the urine suggest ethylene
glycol poisoning.
D. Serum Osmolality
The calculated serum osmolality is dependent mainly on the
serum sodium and glucose and the blood urea nitrogen and can
be estimated from the following formula:
Glucose (mg/dL) BUN (mg/dL)
2 × Na+ (mEq/L) + +
18 3
This calculated value is normally 280–290 mOsm/L. Ethanol
and other alcohols may contribute significantly to the measured
serum osmolality but, since they are not included in the calcula-
tion, cause an osmol gap:
Osmol gap = Measured osmolality – Calculated osmolality
Substances that are often associated with an abnormal osmol
gap include acetone, ethanol, ethylene glycol, isopropyl alcohol,
methanol, and propylene glycol.
E. Electrocardiogram
Widening of the QRS complex duration (to more than
100 milliseconds) is typical of overdose of tricyclic antidepressants
and other drugs that block the sodium channel in cardiac con-
ducting tissue (Figure 58–1). The QTc interval may be prolonged
in many poisonings, including antidepressants and antipsychotics,
 CHAPTER 58  Management of the Poisoned Patient     1039

A For example, determination of the acetaminophen level is useful

in assessing the need for antidotal therapy with acetylcysteine.
Serum levels of salicylate (aspirin), ethylene glycol, methanol, the-
ophylline, carbamazepine, lithium, valproic acid, and other drugs
B and poisons may indicate the need for hemodialysis (Table 58–2).

Decontamination
Decontamination procedures should be undertaken simultane-
C ously with initial stabilization, diagnostic assessment, and labora-
tory evaluation. Decontamination involves removing toxins from
the skin or gastrointestinal tract.

A. Skin
FIGURE 58–1  Changes in the electrocardiogram in tricyclic
antidepressant overdosage. A: Slowed intraventricular conduction
Contaminated clothing should be completely removed and
results in prolonged QRS interval (0.18 seconds; normal, 0.08 seconds). double-bagged to prevent illness in health care providers and for
B and C: Supraventricular tachycardia with progressive widening possible laboratory analysis. Wash contaminated skin with soap
of QRS complexes mimics ventricular tachycardia. (Reproduced, with and water.
permission, from Benowitz NL, Goldschlager N: Cardiac disturbances. In: Haddad LM,
Shannon MW, Winchester JF [editors]. Clinical Management of Poisoning and Drug B. Gastrointestinal Tract
Overdose, 3rd ed. WB Saunders, 1998. © Elsevier.) Controversy remains regarding the efficacy of gastrointestinal
decontamination, especially when treatment is initiated more than
1 hour after ingestion. For most ingestions, clinical toxicologists
lithium, and arsenic (see also https://www.crediblemeds.org/
recommend simple administration of activated charcoal to bind
everyone/composite-list-all-qtdrugs/). Variable atrioventricular
ingested poisons in the gut before they can be absorbed (as in
(AV) block and a variety of atrial and ventricular arrhythmias are
the case study). In unusual circumstances, gastric lavage or whole
common with poisoning by digoxin and other cardiac glycosides.
bowel irrigation may also be used.
Hypoxemia due to carbon monoxide poisoning may result in
ischemic changes on the electrocardiogram.

F. Imaging Findings TABLE 58–2  Hemodialysis in drug overdose and

1
A plain film of the abdomen may be useful because some tab- poisoning.
lets, particularly iron and potassium, may be radiopaque. Chest Hemodialysis may be indicated depending on the severity of
radiographs may reveal aspiration pneumonia, hydrocarbon pneu- poisoning or the blood concentration:
monia, or pulmonary edema. When head trauma is suspected, a  Carbamazepine
computed tomography (CT) scan is recommended.
  Ethylene glycol

Toxicology Screening Tests  Lithium

 Methanol
It is a common misconception that a toxicology “screen” is the best
 Metformin
way to diagnose and manage an acute poisoning. Unfortunately,
rapid urine “drugs of abuse” screens are limited to a few classes  Phenobarbital
of drugs and are subject to many false-positive and false-negative  Salicylate
results, and more reliable comprehensive toxicology screening is  Theophylline
time-consuming and expensive and results of tests may not be avail-   Valproic acid
able for days. Moreover, many highly toxic drugs such as calcium Hemodialysis is ineffective or is not useful:
channel blockers, β blockers, and isoniazid are not included in
 Amphetamines
the screening process. The clinical examination of the patient and
selected routine laboratory tests are usually sufficient to generate a  Antidepressants
tentative diagnosis and an appropriate treatment plan. Although   Antipsychotic drugs
screening tests (so-called “drugs of abuse” panels) may be helpful in  Benzodiazepines
confirming a suspected intoxication, they should not delay needed   Calcium channel blockers
treatment. More formal, comprehensive screening may be necessary  Digoxin
in cases of suspected brain death (to rule out drugs as a cause of
  Metoprolol and propranolol
coma), child abuse, or as part of a postmortem examination.
When a specific antidote or other treatment is under  Opioids
consideration, quantitative laboratory testing may be indicated. 1
This listing is not comprehensive.
1040    SECTION IX Toxicology
1. Emesis—Emesis induced by ipecac syrup was previously used
to treat some childhood ingestions at home under telephone
supervision of a physician or poison control center personnel.
However, the risks involved with inappropriate use outweighed
the unproven benefits, and this treatment is no longer used in
the home or hospital. Other methods of inducing emesis such as
fingertip stimulation of the pharynx, salt water, and apomorphine
are ineffective or dangerous and should not be used.
2. Gastric lavage—If the patient is awake or if the airway is pro-
tected by an endotracheal tube, gastric lavage may be performed
using an orogastric or nasogastric tube—as large a tube as possible.
Lavage solutions (usually 0.9% saline) should be at body tempera-
ture to prevent hypothermia.
3. Activated charcoal—Owing to its large surface area, acti-
vated charcoal can adsorb many drugs and poisons. It is most
effective if given in a ratio of at least 10:1 of charcoal to estimated
dose of toxin by weight. Charcoal does not bind iron, lithium, or
potassium, and it binds alcohols and cyanide only poorly. It does
not appear to be useful in poisoning due to corrosive mineral acids
and alkali. Repeated doses of oral activated charcoal may enhance
systemic elimination of some drugs (including carbamazepine,
dapsone, and phenobarbital) by a mechanism referred to as “gut
dialysis,” although the clinical benefit is unproved.
4. Cathartics—Administration of a cathartic (laxative) agent
may hasten removal of toxins from the gastrointestinal tract and
reduce absorption, although no controlled studies have been
done. Whole bowel irrigation with a balanced polyethylene
glycol-electrolyte solution (GoLYTELY, CoLyte) can enhance gut
decontamination after ingestion of iron tablets, enteric-coated
medicines, illicit drug-filled packets, and foreign bodies. The solu-
tion is administered orally at 1–2 L/h (500 mL/h in children) for
several hours until the rectal effluent is clear.
Specific Antidotes
There is a popular misconception that there is an antidote for
every poison. Actually, selective antidotes are available for only a
few classes of toxins. The major antidotes and their characteristics
are listed in Table 58–3.
Methods of Enhancing Elimination of
Toxins
After appropriate diagnostic and decontamination procedures and
administration of antidotes, it is important to consider whether
measures for enhancing elimination, such as hemodialysis or uri-
nary alkalinization, can improve the clinical outcome. Table 58–2
lists intoxications for which dialysis may be beneficial.
A. Dialysis Procedures
1. Peritoneal dialysis—Although it is a relatively simple and
available technique, peritoneal dialysis is inefficient in removing
most drugs.
2. Hemodialysis—Hemodialysis is more efficient than perito-
neal dialysis and has been well studied. It assists in correction of
fluid and electrolyte imbalance and may also enhance removal of
toxic metabolites (eg, formic acid in methanol poisoning; oxalic
and glycolic acids in ethylene glycol poisoning). The efficiency
of both peritoneal dialysis and hemodialysis is a function of the
molecular weight, water solubility, protein binding, endogenous
clearance, and distribution in the body of the specific toxin.
Hemodialysis is especially useful in overdose cases in which
the precipitating drug can be removed and fluid and electro-
lyte imbalances are present and can be corrected (eg, salicylate
intoxication).
B. Forced Diuresis and Urinary pH Manipulation
Previously popular but of unproved value, forced diuresis may
cause volume overload and electrolyte abnormalities and is not
recommended. Renal elimination of a few toxins can be enhanced
by alteration of urinary pH. For example, urinary alkaliniza-
tion is useful in cases of salicylate overdose. Acidification may
increase the urine concentration of drugs such as phencyclidine
and amphetamines but is not advised because it may worsen renal
complications from rhabdomyolysis, which often accompanies the
intoxication.
■■ COMMON TOXIC SYNDROMES
ACETAMINOPHEN
Acetaminophen is one of the drugs commonly involved in suicide
attempts and accidental poisonings, both as the sole agent and
in combination with other drugs. Acute ingestion of more than
150–200 mg/kg (children) or 7 g total (adults) is considered
potentially toxic. A highly toxic metabolite is produced in the liver
(see Figure 4–5).
Initially, the patient is asymptomatic or has mild gastroin-
testinal upset (nausea, vomiting). After 24–36 hours, evidence
of liver injury appears, with elevated aminotransferase levels
and hypoprothrombinemia. Fulminant liver failure may ensue,
leading to metabolic acidosis, hypoglycemia, encephalopathy,
and death. Renal failure may also occur. With acute mas-
sive ingestion and very high serum levels, metabolic acidosis
can occur in the absence of liver failure. Rarely, acetamino-
phen ingestion can cause 5-oxoprolinuria due to glutathione
depletion.
The severity of poisoning is estimated from a serum acet-
aminophen concentration measurement. If the level is greater than
150 mg/L approximately 4 hours after ingestion, the patient is at
risk for liver injury. (Chronic alcoholics or patients taking drugs
that enhance P450 production of toxic metabolites may be at risk
with lower levels.) The antidote acetylcysteine acts as a glutathi-
one substitute, binding the toxic metabolite as it is produced. It
is most effective when given early and should be started within
8–10 hours if possible. Liver transplantation may be required for
patients with fulminant hepatic failure.
 CHAPTER 58  Management of the Poisoned Patient     1041

TABLE 58–3  Examples of specific antidotes.

Antidote Poison(s) Comments

Acetylcysteine Acetaminophen Best results if given within 8–10 hours of overdose. Follow liver function tests and
(Acetadote, acetaminophen blood levels. Acetadote is given intravenously; Mucomyst is given orally.
Mucomyst)
Atropine Anticholinesterase intoxication: An initial dose of 1–2 mg (for children, 0.05 mg/kg) is given IV, and if there is no response,
organophosphates, carbamates the dose is doubled every 10–15 minutes, with decreased wheezing and pulmonary
secretions as therapeutic end points.
Atropine Rapid-onset mushroom Useful for control of muscarinic symptoms. Note: Of no value in delayed-onset mushroom
poisoning with predominant poisoning.
muscarinic excess symptoms
Bicarbonate, Membrane-depressant 1–2 mEq/kg IV bolus usually reverses cardiotoxic effects (wide QRS, hypotension). Give
sodium cardiotoxic drugs (tricyclic cautiously in heart failure (avoid sodium overload).
antidepressants, quinidine, etc)
Calcium Fluoride; calcium channel Large doses may be needed in severe calcium channel blocker overdose. Start with
blockers 15 mg/kg IV.
Deferoxamine Iron salts If poisoning is severe, give 15 mg/kg/h IV. 100 mg of deferoxamine binds 8.5 mg of iron.

Digoxin antibodies Digoxin and related cardiac One vial binds 0.5 mg digoxin; indications include serious arrhythmias, hyperkalemia.
glycosides
Esmolol Theophylline, caffeine, Short-acting β blocker. Infuse 25–50 mcg/kg/min IV.
metaproterenol
Ethanol Methanol, ethylene glycol A loading dose is calculated so as to give a blood level of at least 100 mg/dL (42 g/70 kg in
adults). Fomepizole (see below) is easier to use.
Flumazenil Benzodiazepines Adult dose is 0.2 mg IV, repeated as necessary to a maximum of 3 mg. Do not give to
patients with seizures, benzodiazepine dependence, or tricyclic overdose.
Fomepizole Methanol, ethylene glycol More convenient than ethanol. Give 15 mg/kg; repeat every 12 hours.
Glucagon β blockers 5–10 mg IV bolus may reverse hypotension and bradycardia.
Hydroxocobalamin Cyanide Adult dose is 5 g IV over 15 minutes. Converts cyanide to cyanocobalamin (vitamin B12).
Naloxone Narcotic drugs, other opioid A specific antagonist of opioids; give 0.4–2 mg initially by IV, IM, or SC injection. Larger
derivatives doses may be needed to reverse the effects of overdose with propoxyphene, codeine, or
fentanyl derivatives. Duration of action (2–3 hours) may be significantly shorter than that
of the opioid being antagonized.
Oxygen Carbon monoxide Give 100% by high-flow nonrebreathing mask; use of hyperbaric chamber is controversial
but often recommended for severe poisoning.
Physostigmine Suggested for delirium caused Adult dose is 0.5–1 mg IV slowly. The effects are transient (30–60 minutes), and the lowest
by anticholinergic agents effective dose may be repeated when symptoms return. May cause bradycardia, increased
bronchial secretions, seizures. Have atropine ready to reverse excess effects. Do not use for
tricyclic antidepressant overdose.
Pralidoxime Organophosphate (OP) Adult dose is 1 g IV, which should be repeated every 3–4 hours as needed or preferably as
(2-PAM) cholinesterase inhibitors a constant infusion of 250–400 mg/h. Pediatric dose is approximately 250 mg. No proved
benefit in carbamate poisoning; uncertain benefit in established OP poisoning.

AMPHETAMINES & OTHER STIMULANTS
Stimulant drugs commonly abused in the USA include metham-
phetamine (“crank,” “crystal”), methylenedioxymethamphetamine
(MDMA, “ecstasy”), and cocaine (“crack”) as well as pharmaceu-
ticals such as pseudoephedrine (Sudafed) and ephedrine (as such
and in the herbal agent Ma-huang) (see Chapter 32). Caffeine is
often added to dietary supplements sold as “metabolic enhancers”
or “fat burners.” Newer synthetic analogs of amphetamines (often
sold on the street as “bath salts”) and synthetic agonists of the
endogenous cannabinoid receptors (sold as “research chemicals”
or “spice”) are becoming popular drugs of abuse.
At the doses usually used by stimulant abusers, euphoria and
wakefulness are accompanied by a sense of power and well-being.
At higher doses, restlessness, agitation, and acute psychosis may
occur, accompanied by hypertension and tachycardia. Prolonged
muscular hyperactivity or seizures may contribute to hyperther-
mia and rhabdomyolysis. Body temperatures as high as 42°C
(107.6°F) have been recorded. Hyperthermia can cause brain
damage, hypotension, coagulopathy, and renal failure.
Treatment for stimulant toxicity includes general supportive
measures as outlined earlier. There is no specific antidote. Seizures
and hyperthermia are the most dangerous manifestations and
must be treated aggressively. Seizures are usually managed with
1042    SECTION IX Toxicology
intravenous benzodiazepines (eg, lorazepam). Temperature is
reduced by removing clothing, spraying with tepid water, and
encouraging evaporative cooling with fanning. For very high body
temperatures (eg, >40–41°C [104–105.8°F]), neuromuscular
paralysis (eg, with vecuronium) is used to abolish muscle activity
quickly.
ANTICHOLINERGIC AGENTS
A large number of prescription and nonprescription drugs, as well
as a variety of plants and mushrooms, can inhibit the effects of
acetylcholine at muscarinic receptors. Some drugs used for other
purposes (eg, antihistamines) also have anticholinergic effects,
in addition to other potentially toxic actions. For example, anti-
histamines such as diphenhydramine can cause seizures; tricyclic
antidepressants, which have anticholinergic, quinidine-like, and
α-blocking effects, can cause severe cardiovascular toxicity.
The classic anticholinergic (technically, “antimuscarinic”) syn-
drome is remembered as “red as a beet” (skin flushed), “hot as a
hare” (hyperthermia), “dry as a bone” (dry mucous membranes,
no sweating), “blind as a bat” (blurred vision, cycloplegia),
and “mad as a hatter” (confusion, delirium). Patients usually
have sinus tachycardia, and the pupils are usually dilated (see
Chapter 8). Agitated delirium or coma may be present. Muscle
twitching is common, but seizures are unusual unless the patient
has ingested an antihistamine or a tricyclic antidepressant. Urinary
retention is common, especially in older men.
Treatment for anticholinergic syndrome is largely supportive.
Agitated patients may require sedation with a benzodiazepine or
an antipsychotic agent (eg, haloperidol or olanzapine). The spe-
cific antidote for peripheral and central anticholinergic syndrome
is physostigmine, which has a prompt and dramatic effect and
is especially useful for patients who are very agitated. Physostig-
mine is given in small intravenous doses (0.5–1 mg) with careful
monitoring, because it can cause bradycardia and seizures if given
too rapidly. Physostigmine should not be given to a patient with
serious tricyclic antidepressant overdose because it can aggravate
cardiotoxicity, resulting in heart block or asystole. Catheterization
may be needed to prevent excessive distention of the bladder.
ANTIDEPRESSANTS
Tricyclic antidepressants (eg, amitriptyline, desipramine, dox-
epin, many others; see Chapter 30) are among the most common
prescription drugs involved in life-threatening drug overdose.
Ingestion of more than 1 g of a tricyclic (or about 15–20 mg/kg)
is considered potentially lethal.
Tricyclic antidepressants are competitive antagonists at mus-
carinic cholinergic receptors, and anticholinergic findings (tachy-
cardia, dilated pupils, dry mouth) are common even at moderate
doses. Some tricyclics are also strong α blockers, which can lead
to vasodilation. Centrally mediated agitation and seizures may
be followed by depression and hypotension. Most important is
the fact that tricyclics inhibit the cardiac sodium channel, caus-
ing slowed conduction with a wide QRS interval and depressed
cardiac contractility. This cardiac toxicity may result in serious
arrhythmias (Figure 58–1), including ventricular conduction
block and ventricular tachycardia.
Treatment of tricyclic antidepressant overdose includes general
supportive care as outlined earlier. Endotracheal intubation and
assisted ventilation may be needed. Intravenous fluids are given
for hypotension, and dopamine or norepinephrine is added if
necessary. Many toxicologists recommend norepinephrine as
the initial drug of choice for tricyclic-induced hypotension. The
antidote for cardiac toxicity (manifested by a wide QRS complex)
is sodium bicarbonate: a bolus of 50–100 mEq (or 1–2 mEq/kg)
provides a rapid increase in extracellular sodium that helps over-
come sodium channel blockade. Although physostigmine does
effectively reverse anticholinergic signs, it can aggravate depression
of cardiac conduction and cause seizures and is not recommended.
Monoamine oxidase inhibitors (eg, tranylcypromine, phen-
elzine) are older antidepressants that are occasionally used for
resistant depression. They can cause severe hypertensive reactions
when interacting foods or drugs are taken (see Chapters 9 and
30), and they can interact with the selective serotonin reuptake
inhibitors (SSRIs).
Newer antidepressants (eg, fluoxetine, paroxetine, citalo-
pram, venlafaxine) are mostly SSRIs and are generally safer than
the tricyclic antidepressants and monoamine oxidase inhibitors,
although they can cause seizures. Bupropion (not an SSRI) has
caused seizures even in therapeutic doses. Some antidepressants
have been associated with QT prolongation and torsades de
pointes arrhythmia. SSRIs may interact with each other or espe-
cially with monoamine oxidase inhibitors to cause the serotonin
syndrome, characterized by agitation, muscle hyperactivity, and
hyperthermia (see Chapter 16).
ANTIPSYCHOTICS
Antipsychotic drugs include the older phenothiazines and butyro-
phenones, as well as newer so-called “atypical” drugs. All of these
can cause CNS depression, seizures, and hypotension. Some can
cause QT prolongation. The potent dopamine D2 blockers are
also associated with parkinsonian movement disorders (dystonic
reactions) and in rare cases with the neuroleptic malignant syn-
drome, characterized by “lead-pipe” rigidity, hyperthermia, and
autonomic instability (see Chapters 16 and 29).
ASPIRIN (SALICYLATE)
Salicylate poisoning (see Chapter 36) is a much less common
cause of childhood poisoning deaths since the introduction of
child-resistant containers and the reduced use of children’s aspirin.
It still accounts for numerous suicidal and accidental poisonings.
Acute ingestion of more than 200 mg/kg is likely to produce
intoxication. Poisoning can also result from chronic overmedica-
tion; this occurs most commonly in elderly patients using salicy-
lates for chronic pain who become confused about their dosing.
Poisoning causes uncoupling of oxidative phosphorylation and
disruption of normal cellular metabolism.

The first sign of salicylate toxicity is often hyperventilation
and respiratory alkalosis due to medullary stimulation. Metabolic
acidosis follows, and an increased anion gap results from accumu-
lation of lactate as well as excretion of bicarbonate by the kidney
to compensate for respiratory alkalosis. Arterial blood gas testing
often reveals a mixed respiratory alkalosis and metabolic acidosis.
Body temperature may be elevated owing to uncoupling of oxida-
tive phosphorylation. Severe hyperthermia may occur in serious
cases. Vomiting and hyperpnea as well as hyperthermia contrib-
ute to fluid loss and dehydration. With very severe poisoning,
profound metabolic acidosis, seizures, coma, pulmonary edema,
and cardiovascular collapse may occur. Absorption of salicylate
and signs of toxicity may be delayed after very large overdoses or
ingestion of enteric coated tablets.
General supportive care is essential. After massive aspirin inges-
tions (eg, more than 100 tablets), aggressive gut decontamination
is advisable, including gastric lavage, repeated doses of activated
charcoal, and consideration of whole bowel irrigation. Intrave-
nous fluids are used to replace fluid losses caused by tachypnea,
vomiting, and fever. For moderate intoxications, intravenous
sodium bicarbonate is given to alkalinize the urine and promote
salicylate excretion by trapping the salicylate in its ionized, polar
form. For severe poisoning (eg, patients with severe acidosis,
coma, and serum salicylate level >90–100 mg/dL), emergency
hemodialysis is performed to remove the salicylate more quickly
and restore acid-base balance and fluid status.
BETA BLOCKERS
In overdose, β blockers inhibit both β1 and β2 adrenoceptors;
selectivity, if any, is lost at high dosage. The most toxic β blocker
is propranolol. As little as two to three times the therapeutic dose
can cause serious toxicity. This may be because propranolol in
high doses may cause sodium channel-blocking effects similar to
those seen with tricyclic antidepressants, and it is lipophilic, allow-
ing it to enter the CNS (see Chapter 10).
Bradycardia and hypotension are the most common manifesta-
tions of toxicity. Agents with partial agonist activity (eg, pindolol)
can cause tachycardia and hypertension. Seizures and cardiac con-
duction block (wide QRS complex) may be seen with propranolol
overdose.
General supportive care should be provided as outlined earlier.
The usual measures used to raise the blood pressure and heart
rate, such as intravenous fluids, β-agonist drugs, and atropine, are
generally ineffective. Glucagon is a useful antidote that—like β
agonists—acts on cardiac cells to raise intracellular cAMP but does
so independent of β adrenoceptors. It can improve heart rate and
blood pressure when given in high doses (5–20 mg intravenously).
CALCIUM CHANNEL BLOCKERS
Calcium antagonists can cause serious toxicity or death with rela-
tively small overdoses. These channel blockers depress sinus node
automaticity and slow AV node conduction (see Chapter 12). They
also reduce cardiac output and blood pressure. Serious hypotension
CHAPTER 58  Management of the Poisoned Patient     1043
is mainly seen with nifedipine and related dihydropyridines, but
in severe overdose all of the listed cardiovascular effects can occur
with any of the calcium channel blockers.
Treatment requires general supportive care. Since most
ingested calcium antagonists are in sustained-release form,
it may be possible to expel them before they are completely
absorbed; initiate whole bowel irrigation and oral activated char-
coal as soon as possible, before calcium antagonist-induced ileus
intervenes. Calcium, given intravenously in doses of 2–10 g,
is a useful antidote for depressed cardiac contractility but less
effective for nodal block or peripheral vascular collapse. Other
treatments reported to be helpful in managing hypotension
associated with calcium channel blocker poisoning include high-
dose insulin (0.5–1 unit/kg/h) plus glucose supplementation
to maintain euglycemia; glucagon; veno-arterial extracorporeal
membrane oxygenation (ECMO-VA); and methylene blue. A
few case reports have suggested benefit from administration
of lipid emulsion (normally used as an intravenous dietary fat
supplement) for severe verapamil overdose.
CARBON MONOXIDE & OTHER TOXIC
GASES
Carbon monoxide (CO) is a colorless, odorless gas that is ubiq-
uitous because it is created whenever carbon-containing materials
are burned. Carbon monoxide poisoning is the leading cause of
death due to poisoning in the USA. Most cases occur in victims
of fires, but accidental and suicidal exposures are also common.
The diagnosis and treatment of carbon monoxide poisoning are
described in Chapter 56. Many other toxic gases are produced in
fires or released in industrial accidents (Table 58–4).
CHOLINESTERASE INHIBITORS
Organophosphate and carbamate cholinesterase inhibitors (see
Chapter 7) are widely used to kill insects and other pests. Most
cases of serious organophosphate or carbamate poisoning result
from intentional ingestion by a suicidal person, but poisoning
has also occurred at work (pesticide application or packaging) or,
rarely, as a result of food contamination or terrorist attack (eg,
release of the chemical warfare nerve agent sarin in the Tokyo
subway system in 1995).
Stimulation of muscarinic receptors causes abdominal cramps,
diarrhea, excessive salivation, sweating, urinary frequency, and
increased bronchial secretions (see Chapters 6 and 7). Stimulation
of nicotinic receptors causes generalized ganglionic activation,
which can lead to hypertension and either tachycardia or bradycar-
dia. Muscle twitching and fasciculations may progress to weakness
and respiratory muscle paralysis. CNS effects include agitation,
confusion, and seizures. The mnemonic DUMBELS (diarrhea,
urination, miosis and muscle weakness, bronchospasm, excitation,
lacrimation, and seizures, sweating, and salivation) helps recall
the common findings. Blood testing may be used to document
depressed activity of red blood cell (acetylcholinesterase) and
1044    SECTION IX Toxicology

TABLE 58–4  Characteristics of poisoning with some gases.

Gas Mechanism of Toxicity Clinical Features and Treatment

Irritant gases (eg, chlorine, Corrosive effect on upper and Cough, stridor, wheezing, pneumonia
ammonia, sulfur dioxide, lower airways
nitrogen oxides) Treatment: Humidified oxygen, bronchodilators

Carbon monoxide
Cyanide
Hydrogen sulfide
Oxidizing agents (eg,
nitrogen oxides)
Binds to hemoglobin, reducing
oxygen delivery to tissues
Binds to cytochrome, blocks
cellular oxygen use
Similar to cyanide
Can cause
methemoglobinemia
Headache, dizziness, nausea, vomiting, seizures, coma
Treatment: 100% oxygen; consider hyperbaric oxygen
Headache, nausea, vomiting, syncope, seizures, coma
Treatment: Conventional antidote kit consists of nitrites to induce methemoglobin-
emia (which binds cyanide) and thiosulfate (which hastens conversion of cyanide
to less toxic thiocyanate); a newer antidote kit (Cyanokit) consists of concentrated
hydroxocobalamin, which directly converts cyanide into cyanocobalamin
Similar to cyanide. Smell of rotten eggs
Treatment: No specific antidote; some authorities recommend the nitrite portion of
the conventional cyanide antidote kit.
Dyspnea, cyanosis (due to brown color of methemoglobin), syncope, seizures, coma
Treatment: Methylene blue (which hastens conversion back to normal hemoglobin)

plasma (butyrylcholinesterase) enzymes, which provide an indirect
estimate of synaptic cholinesterase activity.
General supportive care should be provided as outlined above.
Precautions should be taken to ensure that rescuers and health
care providers are not poisoned themselves by exposure to con-
taminated clothing or skin. This is especially critical for the most
potent substances such as parathion or nerve gas agents. Antidotal
treatment consists of atropine and pralidoxime (see Table 58–3).
Atropine is an effective competitive inhibitor at muscarinic sites
but has no effect at nicotinic sites. Pralidoxime given early enough
may be capable of restoring the cholinesterase activity and is
active at both muscarinic and nicotinic sites; however, studies are
conflicting regarding its effect on clinical outcome.
CYANIDE
Cyanide (CN–) salts and hydrogen cyanide (HCN) are highly
toxic chemicals used in chemical synthesis, as rodenticides (eg,
“gopher getter”), formerly as a method of execution, and as agents
of suicide or homicide. Hydrogen cyanide is formed from the
burning of plastics, wool, and many other synthetic and natural
products. Cyanide is also released after ingestion of various plants
(eg, cassava) and seeds (eg, apple, peach, and apricot).
Cyanide binds readily to cytochrome oxidase, inhibiting oxy-
gen utilization within the cell and leading to cellular hypoxia and
lactic acidosis. Symptoms of cyanide poisoning include shortness
of breath, agitation, and tachycardia followed by seizures, coma,
hypotension, and death. Severe metabolic acidosis is characteristic.
The venous oxygen content may be elevated because oxygen is not
being taken up by cells.
Treatment of cyanide poisoning includes rapid administration
of activated charcoal (although charcoal binds cyanide poorly, it
can reduce absorption) and general supportive care. The conven-
tional antidote kit available in the USA includes two forms of
nitrite (amyl nitrite and sodium nitrite) and sodium thiosulfate.
The nitrites induce methemoglobinemia, which binds CN–, creat-
ing the less toxic cyanomethemoglobin; thiosulfate is a cofactor in
the enzymatic conversion of CN– to the much less toxic thiocya-
nate (SCN–).
In 2006, the FDA approved a new cyanide antidote, a con-
centrated form of hydroxocobalamin, which is now available as
the Cyanokit (EMD Pharmaceuticals, Durham, North Carolina).
Hydroxocobalamin (one form of vitamin B12) combines rapidly
with CN– to form nontoxic cyanocobalamin (another form of
vitamin B12).
DIGOXIN
Digitalis and other cardiac glycosides and cardenolides are found
in many plants (see Chapter 13) and in the skin of some toads.
Toxicity may occur as a result of acute overdose or from accumula-
tion of digoxin in a patient with renal insufficiency or from taking
a drug that interferes with digoxin elimination. Patients receiving
long-term digoxin treatment are often also taking diuretics, which
can lead to electrolyte depletion (especially potassium).
Vomiting is common in patients with digitalis overdose.
Hyperkalemia may be caused by acute digitalis overdose or severe
poisoning, whereas hypokalemia may be present in patients as a
result of long-term diuretic treatment. (Digitalis does not cause
hypokalemia.) A variety of cardiac rhythm disturbances may
occur, including sinus bradycardia, AV block, atrial tachycardia
with block, accelerated junctional rhythm, premature ventricular
beats, bidirectional ventricular tachycardia, and other ventricular
arrhythmias.
General supportive care should be provided. Atropine is often
effective for bradycardia or AV block. The use of digoxin antibod-
ies (see Chapter 13) has revolutionized the treatment of digoxin
toxicity; they should be administered intravenously in the dosage

indicated in the package insert. Symptoms usually improve within
30–60 minutes after antibody administration. Digoxin antibodies
may also be tried in cases of poisoning by other cardiac glycosides
(eg, digitoxin, oleander), although larger doses may be needed due
to incomplete cross-reactivity.
ETHANOL & SEDATIVE-HYPNOTIC
DRUGS
Overdosage with ethanol and sedative-hypnotic drugs (eg, benzo-
diazepines, barbiturates, γ-hydroxybutyrate [GHB], carisoprodol
[Soma]; see Chapters 22 and 23) occurs frequently because of
their common availability and use.
Patients with ethanol or other sedative-hypnotic overdose may
be euphoric and rowdy (“drunk”) or in a state of stupor or coma
(“dead drunk”). Comatose patients often have depressed respiratory
drive. Depression of protective airway reflexes may result in pulmo-
nary aspiration of gastric contents, leading to pneumonia. Hypo-
thermia may be present because of environmental exposure and
depressed shivering. Ethanol blood levels greater than 300 mg/dL
usually cause deep coma, but regular users are often tolerant to
the effects of ethanol and may be ambulatory despite even higher
levels. Patients with GHB overdose are often deeply comatose for
3–4 hours and then awaken fully in a matter of minutes.
General supportive care should be provided. With careful
attention to protecting the airway (including endotracheal intuba-
tion) and assisting ventilation, most patients recover as the drug
effects wear off. Hypotension usually responds to intravenous
fluids, body warming if cold, and, if needed, dopamine. Patients
with isolated benzodiazepine overdose may awaken after intrave-
nous flumazenil, a benzodiazepine antagonist. However, this drug
is not widely used as empiric therapy for drug overdose because
it may precipitate seizures in patients who are addicted to benzo-
diazepines or who have ingested a convulsant drug (eg, a tricyclic
antidepressant). There are no antidotes for ethanol, barbiturates,
or most other sedative-hypnotics.
ETHYLENE GLYCOL & METHANOL
Ethylene glycol and methanol are alcohols that are important
toxins because of their metabolism to highly toxic organic acids
(see Chapter 23). They are capable of causing CNS depression
and a drunken state similar to ethanol overdose. In addition,
their products of metabolism—formic acid (from methanol) or
hippuric, oxalic, and glycolic acids (from ethylene glycol)—cause
a severe metabolic acidosis and can lead to coma and blindness
(in the case of formic acid) or renal failure (from oxalic acid and
glycolic acid). Initially, the patient appears drunk, but after a
delay of up to several hours, a severe anion gap metabolic acidosis
becomes apparent, accompanied by hyperventilation and altered
mental status. Patients with methanol poisoning may have visual
disturbances ranging from blurred vision to blindness.
Metabolism of ethylene glycol and methanol to their toxic
products can be blocked by inhibiting the enzyme alcohol
CHAPTER 58  Management of the Poisoned Patient     1045
dehydrogenase with a competing drug, such as fomepizole
(4-methylpyrazole). Ethanol is also an effective antidote, but it can
be difficult to achieve a safe and effective blood level.
IRON & OTHER METALS
Iron is widely used in over-the-counter vitamin preparations and
is a leading cause of childhood poisoning deaths. As few as 10–12
prenatal multivitamins with iron may cause serious illness in a
small child. Poisoning with other metals (lead, mercury, arsenic)
is also important, especially in industry. See Chapters 33, 56, and
57 for detailed discussions of poisoning by iron and other metals.
OPIOIDS
Opioids (opium, morphine, heroin, meperidine, methadone, etc)
are common drugs of abuse (see Chapters 31 and 32), and over-
dose is a common result of using the poorly standardized prepara-
tions sold on the street. See Chapter 31 for a detailed discussion
of opioid overdose and its treatment.
RATTLESNAKE ENVENOMATION
In the USA, rattlesnakes are the most common venomous reptiles.
Bites are rarely fatal, and 20% do not involve envenomation.
However, about 60% of bites cause significant morbidity due to
the destructive digestive enzymes found in the venom. Evidence of
rattlesnake envenomation includes severe pain, swelling, bruising,
hemorrhagic bleb formation, and obvious fang marks. Systemic
effects include nausea, vomiting, muscle fasciculations, tingling
and metallic taste in the mouth, shock, and systemic coagulopathy
with prolonged clotting time and reduced platelet count.
Studies have shown that emergency field remedies such as
incision and suction, tourniquets, and ice packs are far more
damaging than useful. Avoidance of unnecessary motion, on
the other hand, does help to limit the spread of the venom.
Definitive therapy relies on intravenous antivenom (also known as
antivenin), and this should be started as soon as possible.
THEOPHYLLINE
Although it has been largely replaced by inhaled β agonists, the-
ophylline continues to be used for the treatment of bronchospasm
by some patients with asthma and bronchitis (see Chapter 20). A
dose of 20–30 tablets can cause serious or fatal poisoning. Chronic
or subacute theophylline poisoning can also occur as a result of
accidental overmedication or use of a drug that interferes with
theophylline metabolism (eg, cimetidine, ciprofloxacin, erythro-
mycin; see Chapter 4). Caffeine produces similar toxic effects and
it is available in several “energy” supplements.
In addition to sinus tachycardia and tremor, vomiting is common
after overdose. Hypotension, tachycardia, hypokalemia, and hyper-
glycemia may occur, probably owing to β2-adrenergic activation.
1046    SECTION IX Toxicology
The cause of this activation is not fully understood, but the effects
can be ameliorated by β blockers (see below). Cardiac arrhythmias
include atrial tachycardias, premature ventricular contractions, and
ventricular tachycardia. In severe poisoning (eg, acute overdose
with serum level >100 mg/L), seizures often occur and are usually
resistant to common anticonvulsants. Toxicity may be delayed in
onset for many hours after ingestion of sustained-release tablet
formulations.
General supportive care should be provided. Aggressive gut
decontamination should be carried out using repeated doses of
activated charcoal and whole bowel irrigation. Propranolol or
other β blockers (eg, esmolol) are useful antidotes for β-mediated
C ASE STUDY ANSWER
Overdose of bupropion can cause seizures that are often
recurrent or prolonged. Drug-induced seizures are treated
with an intravenous benzodiazepine such as lorazepam or
diazepam. If this is not effective, phenobarbital or another
hypotension and tachycardia. Phenobarbital is preferred over
phenytoin for convulsions; most anticonvulsants are ineffective.
Hemodialysis is indicated for serum concentrations >100 mg/L
and for intractable seizures in patients with lower levels.
REFERENCES
Dart RD (editor): Medical Toxicology, 3rd ed. Lippincott Williams & Wilkins,
2004.
Goldfrank LR et al (editors): Goldfrank’s Toxicologic Emergencies, 10th ed.
McGraw-Hill, 2015.
Olson KR et al (editors): Poisoning & Drug Overdose, 6th ed. McGraw-Hill, 2011.
POISINDEX. (Revised Quarterly.) Thomson/Micromedex.
more potent central nervous system depressant may be used.
To prevent ingested drugs and poisons from being absorbed
systemically, a slurry of activated charcoal is often given
orally or by nasogastric tube.
 SECTION X  SPECIAL TOPICS
Special Aspects of
Perinatal & Pediatric
Pharmacology
Gideon Koren, MD, FRCPC, FACMT
The effects of drugs on the fetus and newborn infant are based
on the general principles set forth in Chapters 1–4 of this book.
However, the physiologic contexts in which these pharmacologic
laws operate are different in pregnant women and in rapidly
maturing infants. At present, the special pharmacokinetic fac-
tors operative in these patients are beginning to be understood,
whereas information regarding pharmacodynamic differences
(eg, receptor characteristics and responses) is still incomplete.
DRUG THERAPY IN PREGNANCY
Pharmacokinetics
Most drugs taken by pregnant women can cross the placenta and
expose the developing embryo and fetus to their pharmacologic
and teratogenic effects. Critical factors affecting placental drug
transfer and drug effects on the fetus include the following:
(1) the physicochemical properties of the drug; (2) the rate at
which the drug crosses the placenta and the amount of drug
reaching the fetus; (3) the duration of exposure to the drug;
(4) distribution characteristics in different fetal tissues; (5) the
stage of placental and fetal development at the time of exposure to
the drug; and (6) the effects of drugs used in combination.
59
C H A P T E R
A. Lipid Solubility
As is true also of other biologic membranes, drug passage across
the placenta is dependent on lipid solubility and the degree of
drug ionization. Lipophilic drugs tend to diffuse readily across the
placenta and enter the fetal circulation. For example, thiopental,
a drug commonly used for cesarean sections, crosses the placenta
almost immediately and can produce sedation or apnea in the
newborn infant. Highly ionized drugs such as succinylcholine
and tubocurarine, also used for cesarean sections, cross the pla-
centa slowly and achieve very low concentrations in the fetus.
Impermeability of the placenta to polar compounds is relative
rather than absolute. If high enough maternal-fetal concentration
gradients are achieved, polar compounds cross the placenta in
measurable amounts. Salicylate, which is almost completely ion-
ized at physiologic pH, crosses the placenta rapidly. This occurs
because the small amount of salicylate that is not ionized is highly
lipid-soluble.
B. Molecular Size and pH
The molecular weight of the drug also influences the rate of trans-
fer and the amount of drug transferred across the placenta. Drugs
with molecular weights of 250–500 can cross the placenta easily,
depending upon their lipid solubility and degree of ionization;
1047
1048    SECTION X  Special Topics
those with molecular weights of 500–1000 cross the placenta with
more difficulty; and those with molecular weights >1000 cross
very poorly. An important clinical application of this property
is the choice of heparin as an anticoagulant in pregnant women.
Because it is a very large (and polar) molecule, heparin is unable
to cross the placenta. Unlike warfarin, which is teratogenic and
should be avoided during the first trimester and even beyond
(as the brain continues to develop), heparin may be safely given
to pregnant women who need anticoagulation. Yet the placenta
contains drug transporters, which can carry larger molecules to
the fetus. For example, a variety of maternal antibodies cross the
placenta and may cause fetal morbidity, as in Rh incompatibility.
Starting in the second trimester of pregnancy, the placenta devel-
ops transporters that allow immunoglobulins to cross from the
mother to the fetus despite their large molecular size. This has
important clinical implications, because an increasing number
of biological drugs (eg, anti-tumor necrosis factor therapy) have
been shown to cross the placenta. In addition to the detection
of biologicals in cord blood, cases of severe neonatal neutropenia
and fetal dissemination of bacillus Calmette-Guérin (BCG) have
been reported. With an increasing number of infants exposed to
immunoglobulin biologicals in utero, there is a need to address the
challenges in vaccinating these infants.
Because maternal blood has a pH of 7.4, whereas the fetal
blood is 7.3, basic drugs with a pKa above 7.4 will be more ionized
in the fetal compartment, leading to ion trapping and, hence, to
higher fetal levels (see Chapter 1, Ionization of Weak Acids and
Weak Bases).
C. Placental Transporters
During the last decade, many drug transporters have been identi-
fied in the placenta, with increasing recognition of their effects
on drug transfer to the fetus. For example, the P-glycoprotein
transporter encoded by the MDR1 gene pumps back into the
maternal circulation a variety of drugs, including cancer drugs
(eg, vinblastine, doxorubicin) and other agents. Similarly, viral
protease inhibitors, which are substrates to P-glycoprotein, achieve
only low fetal concentrations—an effect that may increase the
risk of vertical HIV infection from the mother to the fetus. The
hypoglycemic drug glyburide has lower plasma levels in the fetus
as compared with the mother. Recent work has documented that
this agent is effluxed from the fetal circulation by the BCRP trans-
porter as well as by the MRP3 transporter located in the placental
brush border membrane. In addition, very high maternal protein
binding of glyburide (>98.8%) also contributes to lower fetal lev-
els as compared with maternal concentrations.
D. Protein Binding
The degree to which a drug is bound to plasma proteins (particu-
larly albumin) may also affect the rate of transfer and the amount
transferred. However, if a compound is very lipid-soluble (eg, some
anesthetic gases), it will not be affected greatly by protein binding.
Transfer of these more lipid-soluble drugs and their overall rates
of equilibration are more dependent on (and proportionate to)
placental blood flow. This is because very lipid-soluble drugs dif-
fuse across placental membranes so rapidly that their overall rates
of equilibration do not depend on the free drug concentrations
becoming equal on both sides. If a drug is poorly lipid-soluble
and is ionized, its transfer is slow and will probably be impeded by
its binding to maternal plasma proteins. Differential protein bind-
ing is also important since some drugs exhibit greater protein
binding in maternal plasma than in fetal plasma because of a lower
binding affinity of fetal proteins. This has been shown for sulfon-
amides, barbiturates, phenytoin, and local anesthetic agents.
E. Placental and Fetal Drug Metabolism
Two mechanisms help protect the fetus from drugs in the mater-
nal circulation: (1) The placenta itself plays a role both as a
semipermeable barrier and as a site of metabolism of some drugs
passing through it. Several different types of aromatic oxidation
reactions (eg, hydroxylation, N-dealkylation, demethylation) have
been shown to occur in placental tissue. Pentobarbital is oxidized
in this way. Conversely, it is possible that the metabolic capacity of
the placenta may lead to creation of toxic metabolites, and the pla-
centa may therefore augment toxicity (eg, ethanol, benzpyrenes).
(2) Because of the ability of the placenta to convert prednisolone
to the inactive prednisone, prednisolone can be used in pregnant
patients requiring corticosteroid treatment without the risk of
fetal exposure to an active corticosteroid. Drugs that have crossed
the placenta enter the fetal circulation via the umbilical vein.
About 40–60% of umbilical venous blood flow enters the fetal
liver; the remainder bypasses the liver and enters the general fetal
circulation. A drug that enters the liver may be partially metabo-
lized there before it enters the fetal circulation. In addition, a large
proportion of drug present in the umbilical artery (returning to
the placenta) may be shunted through the placenta back to the
umbilical vein and into the liver again. It should be noted that
metabolites of some drugs may be more active than the parent
compound and may affect the fetus adversely.
Pharmacodynamics
A. Maternal Drug Actions
The effects of drugs on the reproductive tissues (breast, uterus,
etc) of the pregnant woman are sometimes altered by the endo-
crine environment appropriate for the stage of pregnancy. Drug
effects on other maternal tissues (heart, lungs, kidneys, central
nervous system, etc) are not changed significantly by pregnancy,
although the physiologic context (cardiac output, renal blood
flow, etc) may be altered, requiring the use of drugs that are
not needed by the same woman when she is not pregnant. For
example, cardiac glycosides and diuretics may be needed for heart
failure precipitated by the increased cardiac workload of preg-
nancy, or insulin may be required for control of blood glucose in
pregnancy-induced diabetes.
B. Therapeutic Drug Actions in the Fetus
Fetal therapeutics is an emerging area in perinatal pharmacology.
This involves drug administration, mostly to the pregnant woman,
with the fetus as the target of the drug. At present, corticosteroids
are used to stimulate fetal lung maturation when preterm birth
is expected. Phenobarbital, when given to pregnant women near
 CHAPTER 59  Special Aspects of Perinatal & Pediatric Pharmacology      1049

term, can induce fetal hepatic enzymes responsible for the gluc-
uronidation of bilirubin, and the incidence of jaundice is lower
in newborns when mothers are given phenobarbital than when
phenobarbital is not used. Before phototherapy became the pre-
ferred mode of therapy for neonatal indirect hyperbilirubinemia,
phenobarbital was used for this indication. Administration of
phenobarbital to the mother was suggested recently as a means
of decreasing the risk of intracranial bleeding in preterm infants.
However, large randomized studies failed to confirm this effect.
Antiarrhythmic drugs have also been given to mothers for treat-
ment of fetal cardiac arrhythmias. Although their efficacy has not
yet been established by controlled studies, digoxin, flecainide, pro-
cainamide, verapamil, and other antiarrhythmic agents have been
shown to be effective in case series. Similarly, it has been shown
that maternal use of zidovudine and other HIV drugs substantially
decreases transmission of HIV from the mother to the fetus, and
use of combinations of three antiretroviral agents can eliminate
fetal infection almost entirely (see Chapter 49).
C. Predictable Toxic Drug Actions in the Fetus
Chronic use of opioids by the mother often produces dependence
in the fetus and newborn. This dependence may be manifested
after delivery as a neonatal withdrawal syndrome. A less well
understood fetal drug toxicity is caused by the use of angiotensin-
converting enzyme inhibitors during late pregnancy. These drugs
can result in significant and irreversible renal damage in the fetus
and are therefore contraindicated in pregnant women. Adverse
effects may also be delayed, as in the case of female fetuses exposed
to diethylstilbestrol, who may be at increased risk for adenocarci-
noma of the vagina after puberty.
D. Teratogenic Drug Actions
A single intrauterine exposure to a drug can affect the fetal struc-
tures undergoing rapid development at the time of exposure.
Thalidomide is an example of a drug that may profoundly affect
the development of the limbs after only brief exposure. This expo-
sure, however, must be at a critical time in the development of the
limbs. Thalidomide-induced phocomelia occurs during the fourth
through the seventh weeks of gestation because it is during this
time that the arms and legs develop (Figure 59–1).
1. Teratogenic mechanisms—The mechanisms by which dif-
ferent drugs produce teratogenic effects are poorly understood
and are probably multifactorial. For example, drugs may have a
direct effect on maternal tissues with secondary or indirect effects
on fetal tissues. Drugs may interfere with the passage of oxygen
or nutrients through the placenta and therefore have effects on
the most rapidly metabolizing tissues of the fetus. Finally, drugs
may have important direct actions on the processes of differen-
tiation in developing tissues. For example, vitamin A (retinol)

Embryonic period (weeks) Fetal period (weeks) Full term

1 2 3 4 5 6 7 8 9 16 20-38 38
Period of dividing Brain
zygote, implantation, Indicates common site of action of teratogen
and bilaminar embryo
CNS Palate
Eye Eye Teeth Ear
Heart Heart

Arm
Leg
External genitalia
Central nervous system

Heart

Arms

Eyes

Legs

Teeth

Palate

Usually not External genitalia

susceptible to
teratogen Ear

Physiologic defects and

Prenatal death Major morphologic abnormalities
minor morphologic abnormalities

FIGURE 59–1  Schematic diagram of critical periods of human development. (Reproduced, with permission, from Moore KL: The Developing Human:
Clinically Oriented Embryology, 4th ed. Saunders, 1988. © Elsevier.)
1050    SECTION X  Special Topics
has been shown to have important differentiation-directing
actions in normal tissues. Several vitamin A analogs (isotretinoin,
etretinate) are powerful teratogens, suggesting that they alter the
normal processes of differentiation. Finally, deficiency of a critical
substance appears to play a role in some types of abnormalities.
For example, folic acid supplementation during pregnancy appears
to reduce the incidence of neural tube defects (see Box, page 599).
Continued exposure to a teratogen may produce cumulative
effects or may affect several organs going through varying stages of
development. Chronic consumption of high doses of ethanol dur-
ing pregnancy, particularly during the first and second trimesters,
may result in the fetal alcohol spectrum disorder (see Chapter 23).
In this syndrome, the central nervous system, growth, and facial
development may be affected.
2. Defining a teratogen—To be considered teratogenic, a
candidate substance or process should (1) result in a character-
istic set of malformations, indicating selectivity for certain target
organs; (2) exert its effects at a particular stage of fetal develop-
ment, eg, during the limited time period of organogenesis of
the target organs (Figure 59–1); and (3) show a dose-dependent
incidence. Some drugs with known teratogenic or other adverse
effects in pregnancy are listed in Table 59–1. Teratogenic effects
are not limited only to major malformations, but also include
intrauterine growth restriction (eg, cigarette smoking), miscarriage
(eg, alcohol), stillbirth (eg, cigarette smoke), and neurocognitive
delay (eg, alcohol, valproic acid).
In addition to teratogenic drugs, teratogenicity can be induced
by a large group of infectious pathogens, including viruses such
as rubella, cytomegalovirus, herpes, and recently, Zika virus.
Similarly, numerous chemicals, such as heavy metals (eg, mercury,
lead) and environmental factors (eg, radiation, hyperthermia) can
damage the fetus. It is important to consider these nondrug factors
in the differential diagnosis of drug-induced adverse fetal effects.
The widely cited US Food and Drug Administration (FDA)
system for teratogenic potential (Table 59–2) has been an attempt
to quantify teratogenic risk from A (safe) to X (definite human
teratogenic risk). This system has been criticized as inaccurate
and impractical. For example, several drugs have been labeled “X”
despite extensive opposite human safety data (eg, oral contracep-
tives). Diazepam and other benzodiazepines are labeled as “D”
despite lack of positive evidence of human fetal risk. The FDA
has recently changed its system from the A, B, C grading system
to narrative statements that summarize evidence-based knowledge
about each drug in terms of fetal risk and safety.
3. Counseling women about teratogenic risk—Since the
thalidomide disaster, medicine has been practiced as if every drug
were a potential human teratogen when, in fact, fewer than 30
such drugs have been identified, with hundreds of agents proved
safe for the unborn. Owing to high levels of anxiety among
pregnant women—and because half of the pregnancies in North
America are unplanned—every year many thousands of women
need counseling about fetal exposure to drugs, chemicals, and
radiation. The ability of appropriate counseling to prevent unnec-
essary abortions has been documented. Clinicians who wish to
provide such counsel to pregnant women must ensure that their
information is up-to-date and evidence-based and that the woman
understands that the baseline teratogenic risk in pregnancy (ie,
the risk of a neonatal abnormality in the absence of any known
teratogenic exposure) is about 3%. It is also critical to address the
maternal-fetal risks of the untreated condition if a medication is
avoided. Recent studies show serious morbidity in women who
discontinued selective serotonin reuptake inhibitor therapy for
depression in pregnancy.
DRUG THERAPY IN INFANTS & CHILDREN
Physiologic processes that influence pharmacokinetic variables in
the infant change significantly in the first year of life, particularly
during the first few months. Therefore, special attention must be
paid to pharmacokinetics in this age group. Pharmacodynamic
differences between pediatric and other patients have not been
explored in great detail but are probably important for those spe-
cific target tissues that mature at birth or immediately thereafter
(eg, the ductus arteriosus).
Drug Absorption
Drug absorption in infants and children follows the same gen-
eral principles as in adults. Unique factors that influence drug
absorption include blood flow at the site of administration, as
determined by the physiologic status of the infant or child; and,
for orally administered drugs, gastrointestinal function, which
changes rapidly during the first few days after birth. Age after
birth also influences the regulation of drug absorption.
A. Blood Flow at the Site of Administration
Absorption after intramuscular or subcutaneous injection depends
mainly, in neonates as in adults, on the rate of blood flow to the
muscle or subcutaneous area injected. Physiologic conditions that
might reduce blood flow to these areas are cardiovascular shock,
vasoconstriction due to sympathomimetic agents, and heart failure.
However, sick preterm infants requiring intramuscular injections
may have very little muscle mass. This is further complicated
by diminished peripheral perfusion to these areas. In such cases,
absorption becomes irregular and difficult to predict, because the
drug may remain in the muscle and be absorbed more slowly than
expected. If perfusion suddenly improves, there can be a sudden
and unpredictable increase in the amount of drug entering the cir-
culation, resulting in high and potentially toxic concentrations of
drug. Examples of drugs especially hazardous in such situations are
cardiac glycosides, aminoglycoside antibiotics, and anticonvulsants.
B. Gastrointestinal Function
Significant biochemical and physiologic changes occur in the
neonatal gastrointestinal tract shortly after birth. In full-term
infants, gastric acid secretion begins soon after birth and increases
gradually over several hours. In preterm infants, the secretion of
gastric acid occurs more slowly, with the highest concentrations
appearing on the fourth day of life.
 CHAPTER 59  Special Aspects of Perinatal & Pediatric Pharmacology      1051

TABLE 59–1  Drugs with significant teratogenic or other adverse effects on the fetus.
Drug Trimester Effect

ACE inhibitors All, especially second Renal damage, hypocalvaria

and third
Aminopterin First Multiple gross anomalies
Amphetamines All Suspected abnormal developmental patterns, decreased school performance
Androgens Second and third Masculinization of female fetus
Antidepressants, tricyclic Third Neonatal withdrawal symptoms have been reported in a few cases with clomipramine,
desipramine, and imipramine
Barbiturates All Chronic use can lead to neonatal dependence.
Busulfan All Various congenital malformations; low birth weight
Carbamazepine First Neural tube defects
Chlorpropamide All Prolonged symptomatic neonatal hypoglycemia
Clomipramine Third Neonatal lethargy, hypotonia, cyanosis, hypothermia
Cocaine All Increased risk of spontaneous abortion, abruptio placentae, and premature labor; neonatal
cerebral infarction, abnormal development, and decreased school performance
Cyclophosphamide First Various congenital malformations
Cytarabine First, second Various congenital malformations
Diazepam All Chronic use may lead to neonatal dependence
Diethylstilbestrol All Vaginal adenosis, clear cell vaginal adenocarcinoma
Ethanol All Risk of fetal alcohol spectrum disorder
Etretinate All High risk of multiple congenital malformations
Heroin All Chronic use leads to neonatal abstinence syndrome
Iodide All Congenital goiter, hypothyroidism
Isotretinoin All Extremely high risk of central nervous system (CNS), face, ear, and other malformations
Lithium First, third Ebstein’s anomaly, neonatal toxicity after third trimester exposure
Methadone All Chronic use may lead to neonatal abstinence syndrome
Methotrexate First Multiple congenital malformations
Methylthiouracil All Hypothyroidism
Misoprostol First Möbius sequence
Mycophenolate mofetil First Major malformations of the face, limbs, and other organs
Organic solvents First Multiple malformations
Penicillamine First Cutis laxa, other congenital malformations
Phencyclidine All Abnormal neurologic examination, poor suck reflex and feeding
Phenytoin All Fetal hydantoin syndrome
Propylthiouracil All Congenital goiter
Serotonin reuptake Third Neonatal abstinence syndrome, persistent pulmonary hypertension of the newborn
inhibitors
Smoking (constituents of All Intrauterine growth restriction; prematurity; sudden infant death syndrome; perinatal
tobacco smoke) complications
Tamoxifen All Increased risk of spontaneous abortion or fetal damage
Tetracycline All Discoloration and defects of teeth and altered bone growth
Thalidomide First Phocomelia (shortened or absent long bones of the limbs) and many internal malformations
Trimethadione All Multiple congenital anomalies
Topiramate First Oral cleft
Valproic acid All Neural tube defects, cardiac and limb malformations; developmental delay; possibly autism
Warfarin First Hypoplastic nasal bridge, chondrodysplasia punctata
Second CNS malformations
Third Risk of bleeding. Discontinue use 1 month before delivery.
1052    SECTION X  Special Topics

TABLE 59–2  FDA teratogenic risk categories.1

Category Description

A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in late
trimesters), and the possibility of fetal harm appears remote.
B Either animal-reproduction studies have not demonstrated a fetal risk, but there are no controlled studies in pregnant women,
or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in
controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).
C Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no
controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential
benefit justifies the potential risk to the fetus.
D There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the
risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are
ineffective).
X Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human
experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is
contraindicated in women who are or may become pregnant.
1
This system has been changed as of 2014 by eliminating the A, B, C qualifications and replacing them with specific structured narratives for each drug.

Gastric emptying time is prolonged (up to 6 or 8 hours) in the Drug Distribution

first day or so after delivery. Therefore, drugs that are absorbed
As body composition changes with development, the distribu-
primarily in the stomach may be absorbed more completely than
tion volumes of drugs are also changed. The neonate has a higher
anticipated. In the case of drugs absorbed in the small intestine,
percentage of its body weight in the form of water (70–75%)
therapeutic effect may be delayed. Peristalsis in the neonate is
than does the adult (50–60%). Differences can also be observed
irregular and may be slow. The fraction of drug absorbed in the
between the full-term neonate (70% of body weight as water) and
small intestine may therefore be unpredictable; more than the
the small preterm neonate (85% of body weight as water). Simi-
usual amount of drug may be absorbed if peristalsis is slowed,
larly, extracellular water is 40% of body weight in the neonate,
and this could result in toxicity from an otherwise standard dose.
compared with 20% in the adult. Most neonates will experience
Table 59–3 summarizes data on oral bioavailability of various
diuresis in the first 24–48 hours of life. Since many drugs are
drugs in neonates compared with older children and adults. An
distributed throughout the extracellular water space, the size (vol-
increase in peristalsis, as in diarrheal conditions, tends to decrease
ume) of the extracellular water compartment may be important
the extent of absorption, because contact time with the large
in determining the concentration of drug at receptor sites. This is
absorptive surface of the intestine is decreased.
especially important for water-soluble drugs (such as aminoglyco-
Gastrointestinal enzyme activities tend to be lower in the
sides) and less crucial for lipid-soluble agents.
newborn than in the adult. Activities of α-amylase and other
Preterm infants have much less fat than full-term infants. Total
pancreatic enzymes in the duodenum are low in infants up to
body fat in preterm infants is about 1% of total body weight,
4 months of age. Neonates also have low concentrations of bile
compared with 15% in full-term neonates. Therefore, organs that
acids and lipase, which may decrease the absorption of lipid-
generally accumulate high concentrations of lipid-soluble drugs
soluble drugs.
in adults and older children may accumulate smaller amounts of
these agents in less mature infants.
Another major factor determining drug distribution is drug
TABLE 59–3  Oral drug absorption (bioavailability) of binding to plasma proteins. Albumin is the plasma protein with
various drugs in the neonate compared
with older children and adults. the greatest binding capacity. In general, protein binding of drugs
is reduced in the neonate, as seen with local anesthetic drugs,
Drug Oral Absorption diazepam, phenytoin, ampicillin, and phenobarbital. Therefore,
the concentration of free (unbound) drug in plasma is increased
Acetaminophen Decreased
initially. Because the free drug exerts the pharmacologic effect, this
Ampicillin Increased
can result in greater drug effect or toxicity despite a normal or even
Diazepam Normal low plasma concentration of total drug (bound plus unbound). As
Digoxin Normal an example, consider a therapeutic dose of a drug (eg, diazepam)
Penicillin G Increased given to a patient. The concentration of total drug in the plasma
Phenobarbital Decreased is 300 mcg/L. If the drug is 98% protein-bound in an older child
or adult, then 6 mcg/L is the concentration of free drug. Assume
Phenytoin Decreased
that this concentration of free drug produces the desired effect
Sulfonamides Normal
in the patient without producing toxicity. However, if this drug
 CHAPTER 59  Special Aspects of Perinatal & Pediatric Pharmacology      1053

is given to a preterm infant in a dosage adjusted for body weight neonatal and adult drug elimination half-lives can differ and how
and it produces a total drug concentration of 300 mcg/L—and the half-lives of phenobarbital and phenytoin decrease as the neo-
protein binding is only 90%—then the free drug concentration nate grows older. The process of maturation must be considered
will be 30 mcg/L, or five times higher. Although the higher free when administering drugs to this age group, especially in the case
concentration may result in faster elimination (see Chapter 3), this of drugs administered over long periods.
concentration may be quite toxic initially. Another consideration for the neonate is whether or not the
Some drugs compete with serum bilirubin for binding to mother was receiving drugs (eg, phenobarbital) that can induce
albumin. Drugs given to a neonate with jaundice can displace early maturation of fetal hepatic enzymes. In this case, the ability
bilirubin from albumin. Because of the greater permeability of the of the neonate to metabolize certain drugs will be greater than
neonatal blood-brain barrier, substantial amounts of bilirubin may expected, and one may see less therapeutic effect and lower plasma
enter the brain and cause kernicterus. This was in fact observed drug concentrations when the usual neonatal dose is given. Dur-
when sulfonamide antibiotics were given to preterm neonates as ing toddlerhood (12–36 months), the metabolic rate of many
prophylaxis against sepsis. Conversely, as the serum bilirubin rises drugs exceeds adult values, often necessitating larger doses per
for physiologic reasons or because of a blood group incompatibility, kilogram than later in life.
bilirubin can displace a drug from albumin and substantially raise
the free drug concentration. This may occur without altering the
total drug concentration and would result in greater therapeutic Drug Excretion
effect or toxicity at normal concentrations, as has been shown with The glomerular filtration rate is much lower in newborns than
phenytoin. in older infants, children, or adults, and this limitation per-
sists during the first few days of life. Calculated on the basis of
body surface area, glomerular filtration in the neonate is only
Drug Metabolism 30–40% of the adult value. The glomerular filtration rate is even
The metabolism of most drugs occurs in the liver (see Chapter 4). lower in neonates born before 34 weeks of gestation. Function
The drug-metabolizing activities of the cytochrome P450 super- improves substantially during the first week of life. At the end
family and the conjugating enzymes are substantially lower (50– of the first week, the glomerular filtration rate and renal plasma
70% of adult values) in early neonatal life than later. The point flow have increased 50% from the first day. By the end of the
in development at which enzymatic activity reaches adult levels third week, glomerular filtration is 50–60% of the adult value;
depends on the specific enzyme system in question. Glucuro- by 6–12 months, it reaches adult values (per unit surface area).
nide formation reaches adult values (per kilogram body weight) Subsequently, during toddlerhood, it exceeds adult values, often
between the third and fourth years of life. Because of the neonate’s necessitating larger doses per kilogram than in adults, as described
decreased ability to metabolize drugs, many drugs have slow clear- previously for drug-metabolic rate. Therefore, drugs that depend
ance rates and prolonged elimination half-lives in early life. If on renal function for elimination are cleared from the body very
drug doses and dosing schedules are not altered appropriately, this slowly in the first weeks of life.
immaturity predisposes the neonate to adverse effects from drugs Penicillins, for example, are cleared by preterm infants at 17%
that are metabolized by the liver. Table 59–4 demonstrates how of the adult rate based on comparable surface area and 34% of
the adult rate when adjusted for body weight. The dosage of
ampicillin for a neonate less than 7 days old is 50–100 mg/kg/d
TABLE 59–4  Comparison of elimination half-lives of in two doses at 12-hour intervals. The dosage for a neonate over
various drugs in neonates and adults. 7 days old is 100–200 mg/kg/d in three doses at 8-hour intervals.
A decreased rate of renal elimination in the neonate has also been
Neonates Adults observed with aminoglycoside antibiotics (kanamycin, gentami-
Drug Neonatal Age t½ (hours) t½ (hours)
cin, neomycin, and streptomycin). The dosage of gentamicin for a
Acetaminophen 2.2–5 0.9–2.2 neonate less than 7 days old is 5 mg/kg/d in two doses at 12-hour
Diazepam 25–100 40–50 intervals. The dosage for a neonate over 7 days old is 7.5 mg/
Digoxin 60–70 30–60 kg/d in three doses at 8-hour intervals. Total body clearance of
Phenobarbital 0–5 days 200 64–140 digoxin is directly dependent upon adequate renal function, and
accumulation of digoxin can occur when glomerular filtration is
5–15 days 100
decreased. Since renal function in a sick infant may not improve at
1–30 months 50
the predicted rate during the first weeks and months of life, appro-
Phenytoin 0–2 days 80 12–18 priate adjustments in dosage and dosing schedules may be very
3–14 days 18 difficult. In this situation, adjustments are best made on the basis
14–50 days 6 of plasma drug concentrations determined at intervals throughout
Salicylate 4.5–11 10–15 the course of therapy.
Although great focus is naturally concentrated on the neo-
Theophylline Neonate 13–26 5–10
nate, it is important to remember that toddlers may have shorter
Child 3–4
elimination half-lives of drugs than older children and adults,
1054    SECTION X  Special Topics
due probably to increased renal elimination and metabolism.
For example, the dose per kilogram of digoxin is much higher in
toddlers than in adults. The mechanisms for these developmental
changes are still poorly understood.
Special Pharmacodynamic Features in the
Neonate
The appropriate use of drugs has made possible the survival of
neonates with severe abnormalities who would otherwise die
within days or weeks after birth. For example, administration
of indomethacin (see Chapter 36) causes the rapid closure of a
patent ductus arteriosus, which would otherwise require surgi-
cal closure in an infant with a normal heart. Infusion of pros-
taglandin E1, on the other hand, causes the ductus to remain
open, which can be lifesaving in an infant with transposition
of the great vessels or tetralogy of Fallot (see Chapter 18). An
unexpected effect of such infusion has been described when the
drug caused antral hyperplasia with gastric outlet obstruction as
a clinical manifestation in 6 of 74 infants who received it. This
phenomenon appears to be dose-dependent. Neonates are also
more sensitive to the central depressant effects of opioids than
are older children and adults, necessitating extra caution when
they are exposed to some narcotics (eg, codeine) through breast
milk.
At birth, the function of drug transporters may be very low;
for example, P-glycoprotein, which pumps morphine from the
blood-brain barrier back to the systemic circulation. Low-level
function of P-glycoprotein at birth can explain why neonates
are substantially more sensitive than older children to the central
nervous system depressant effects of morphine.
PEDIATRIC DOSAGE FORMS &
ADHERENCE
The form in which a drug is manufactured and the way in
which the parent dispenses the drug to the child determine the
actual dose administered. Many drugs prepared for children
are in the form of elixirs or suspensions. Elixirs are alcoholic
solutions in which the drug molecules are dissolved and evenly
distributed. No shaking is required, and unless some of the
vehicle has evaporated, the first dose from the bottle and the last
dose should contain equivalent amounts of drug. Suspensions
contain undissolved particles of drug that must be distributed
throughout the vehicle by shaking. If shaking is not thorough
each time a dose is given, the first doses from the bottle may con-
tain less drug than the last doses, with the result that less than
the expected plasma concentration or effect of the drug may be
achieved early in the course of therapy. Conversely, toxicity may
occur late in the course of therapy, when it is not expected. This
uneven distribution is a potential cause of inefficacy or toxicity
in children taking phenytoin suspensions. It is thus essential
that the prescriber know the form in which the drug will be
dispensed and provide proper instructions to the pharmacist and
patient or parent.
Adherence (formerly called compliance) may be more difficult
to achieve in pediatric practice than otherwise, since it involves
not only the parent’s conscientious effort to follow directions but
also such practical matters as measuring errors, spilling, and spit-
ting out. For example, the measured volume of “teaspoons” can
vary from 2.5 to 7.8 mL. The parents should obtain a calibrated
medicine spoon or syringe from the pharmacy as these devices
improve the accuracy of dose measurements and simplify admin-
istration of drugs to children.
When evaluating adherence, it is often helpful to ask if an
attempt has been made to give a further dose after the child has
spilled half of what was offered. The parents may not always be
able to say with confidence how much of a dose the child actu-
ally received. The parents must be told whether or not to wake
the infant for its every-6-hour dose day or night. These matters
should be discussed and made clear, and no assumptions should
be made about what the parents may or may not do. Nonadher-
ence frequently occurs when antibiotics are prescribed to treat
otitis media or urinary tract infections and the child feels well after
4 or 5 days of therapy. The parents may not feel there is any reason
to continue giving the medicine even though it was prescribed
for 10 or 14 days. This common situation should be anticipated
so the parents can be told why it is important to continue giving
the medicine for the prescribed period even if the child seems to
be “cured.”
Practical and convenient dosage forms and dosing schedules
should be chosen to the extent possible. The easier it is to admin-
ister and take the medicine and the easier the dosing schedule is to
follow, the more likely it is that adherence will be achieved.
Consistent with their ability to comprehend and cooperate,
children should also be given some responsibility for their own
health care and for taking medications. This should be discussed
in appropriate terms both with the child and with the parents.
Possible adverse effects and drug interactions with over-the-
counter medicines or foods should also be discussed. Whenever a
drug does not achieve its therapeutic effect, the possibility of non-
adherence should be considered. There is ample evidence that in
such cases parents’ or children’s reports may be grossly inaccurate.
Random pill counts and measurement of serum concentrations
may help disclose nonadherence The use of computerized pill
containers, which record each lid opening, has been shown to be
very effective in measuring adherence.
Because many pediatric doses are calculated—eg, using body
weight—rather than simply read from a list, major dosing errors
may result from incorrect calculations. Typically, tenfold errors
due to incorrect placement of the decimal point have been
described. In the case of digoxin, for example, an intended dose
of 0.1 mL containing 5 mcg of drug, when replaced by 1.0 mL—
which is still a small volume—can result in a fatal overdose. Dif-
ferent strategies have been developed to prevent these potentially
fatal errors. For drugs with narrow therapeutic windows (eg,
digoxin, insulin, potassium), independent double-checking of
dose and volume calculations is widely practiced. A good rule for
avoiding such “decimal point” errors is to use a leading “0” plus
decimal point when dealing with doses less than “1” and to avoid
using a zero after a decimal point (see Chapter 65).
 CHAPTER 59  Special Aspects of Perinatal & Pediatric Pharmacology      1055

DRUG USE DURING LACTATION
Despite the fact that most drugs are excreted into breast milk in
amounts too small to adversely affect neonatal health, thousands
of women taking medications do not breast-feed because of
fears of harming the baby and misperception of risk. Unfortu-
nately, physicians often contribute to this bias. It is important to
remember that, compared with breast-feeding, formula feeding
is associated with higher infant morbidity and mortality in all
socioeconomic groups.
Most drugs administered to lactating women are detectable in
breast milk. Fortunately, the concentration of drugs achieved in
breast milk is usually low (Table 59–5). Therefore, the total amount
the infant would receive in a day is substantially less than what

TABLE 59–5  Drugs often used during lactation and possible effects on the nursing infant.
Drug Effect on Infant Comments

Amiodarone Significant Large amounts in milk; follow-up of thyroid function in the baby.
Ampicillin Minimal No significant adverse effects; possible occurrence of diarrhea or allergic sensitization.
Aspirin Minimal Occasional doses are safe.
Caffeine Minimal Caffeine intake in moderation is safe; concentration in breast milk is low.
Chloral hydrate Significant May cause drowsiness if infant is fed at peak concentration in milk.
Chloramphenicol Significant Concentrations too low to cause gray baby syndrome; possibility of bone marrow suppression
does exist; recommend not taking chloramphenicol while breast-feeding.
Chlorothiazide Minimal No adverse effects reported.
Chlorpromazine Minimal Appears insignificant.
Codeine Variable, based on Safe in most cases. Neonatal toxicity described when the mother is an ultra rapid 2D6 metabolizer,
genetic polymorphism producing substantially more morphine from codeine.
Dicumarol Minimal No adverse side effects reported; may wish to follow infant’s prothrombin time.
Digoxin Minimal Insignificant quantities enter breast milk.
Ethanol Moderate Moderate ingestion by mother unlikely to produce effects in infant; large amounts consumed by
mother can produce alcohol effects in infant.
Heroin Significant Enters breast milk and can prolong neonatal narcotic dependence.
Iodine (radioactive) Significant Enters milk in quantities sufficient to cause thyroid suppression in infant.
Isoniazid (INH) Minimal Milk concentrations equal maternal plasma concentrations. Possibility of pyridoxine deficiency
developing in the infant.
Kanamycin Minimal No adverse effects reported.
Lithium Variable In some cases—but not in others—large amounts enter breast milk.
Methadone Significant (See heroin.) Under close physician supervision, breast-feeding can be continued. Signs of opioid
withdrawal in the infant may occur if mother stops taking methadone or stops breast-feeding abruptly.
Oral contraceptives Minimal May suppress lactation in high doses.
Penicillin Minimal Very low concentrations in breast milk.
Phenobarbital Moderate Hypnotic doses can cause sedation in the infant.
Phenytoin Moderate Amounts entering breast milk are not sufficient to cause adverse effects in infant.
Prednisone Moderate Low maternal doses (5 mg/d) probably safe. Doses 2 or more times physiologic amounts
(>15 mg/d) should probably be avoided.
Propranolol Minimal Very small amounts enter breast milk.
Propylthiouracil Variable Rarely may suppress thyroid function in infant.
Radioactive nuclides Will expose baby to Ensure that mother’s system has cleared the radioactivity.
radioactivity
Spironolactone Minimal Very small amounts enter breast milk.
Tetracycline Moderate Possibility of permanent staining of developing teeth in the infant. Should be avoided during
lactation.
Theophylline Moderate Can enter breast milk in moderate quantities but not likely to produce significant effects.
Thyroxine Minimal No adverse effects in therapeutic doses.
Tolbutamide Minimal Low concentrations in breast milk.
Warfarin Minimal Very small quantities found in breast milk.
1056    SECTION X  Special Topics

would be considered a “therapeutic dose.” If the nursing mother Breast-feeding is contraindicated after large doses and should be
must take medications and the drug is a relatively safe one, she withheld for days to weeks after small doses. Similarly, breast-
should optimally take it 30–60 minutes after nursing and 3–4 hours feeding should be avoided in mothers receiving cancer chemo-
before the next feeding. In some cases this may allow time for drugs therapy or being treated with cytotoxic or immunomodulating
to be partially cleared from the mother’s blood, and the concentra- agents for collagen diseases such as lupus erythematosus or after
tions in breast milk will be relatively low. Most antibiotics taken by organ transplantation.
nursing mothers can be detected in breast milk. Tetracycline con-
centrations in breast milk are approximately 70% of maternal serum
concentrations and present a risk of permanent tooth staining in the PEDIATRIC DRUG DOSAGE
infant. Isoniazid rapidly reaches equilibrium between breast milk
Because of differences in pharmacokinetics in infants and chil-
and maternal blood. The concentrations achieved in breast milk are
dren, simple proportionate reduction in the adult dose may not
high enough so that signs of pyridoxine deficiency may occur in the
be adequate to determine a safe and effective pediatric dose. The
infant if the mother is not given pyridoxine supplements.
most reliable pediatric dose information is usually that provided
Most sedatives and hypnotics achieve concentrations in breast
by the manufacturer in the package insert. However, such infor-
milk sufficient to produce a pharmacologic effect in some infants.
mation is not available for the majority of products, even when
Barbiturates taken in hypnotic doses by the mother can produce
studies have been published in the medical literature, reflecting
lethargy, sedation, and poor suck reflexes in the infant. Chloral
the reluctance of manufacturers to label their products for chil-
hydrate can produce sedation if the infant is fed at peak milk
dren. Recently, the FDA has moved toward more explicit expecta-
concentrations. Diazepam can have a sedative effect on the nurs-
tions that manufacturers test their new products in infants and
ing infant, but, most importantly, its long half-life can result in
children. Still, most drugs in the common formularies, eg, Physi-
significant drug accumulation.
cians’ Desk Reference, are not specifically approved for children, in
Opioids such as heroin, methadone, and morphine enter breast
part because manufacturers often lack the economic incentive to
milk in quantities potentially sufficient to prolong the state of
evaluate drugs for use in the pediatric market.
neonatal narcotic dependence if the drug was taken chronically by
Most drugs approved for use in children have recommended
the mother during pregnancy. If conditions are well controlled and
pediatric doses, generally stated as milligrams per kilogram or per
there is a good relationship between the mother and the physician,
pound. In the absence of explicit pediatric dose recommendations,
an infant could be breast-fed while the mother is taking metha-
an approximation can be made by any of several methods based on
done. She should not, however, stop taking the drug abruptly; the
age, weight, or surface area. These rules are not precise and should
infant can be tapered off the methadone as the mother’s dose is
not be used if the manufacturer provides a pediatric dose. When
tapered. The infant should be watched for signs of narcotic with-
pediatric doses are calculated (either from one of the methods set
drawal. Although codeine has been believed to be safe, a case of
forth below or from a manufacturer’s dose), the pediatric dose
neonatal death from opioid toxicity revealed that the mother was
should never exceed the adult dose.
an ultra rapid metabolizer of cytochrome 2D6 substrates, produc-
The current epidemic proportions of childhood obesity calls
ing substantially higher amounts of morphine. Hence, polymor-
for a fresh and careful look at pediatric drug dosages. Studies in
phism in maternal drug metabolism may affect neonatal exposure
adults indicate that dosing based on per-kilogram body weight
and safety. A subsequent case-control study has shown that this
may constitute overdosing, because in obese subjects, drugs are
situation is not rare. The FDA has published a warning to lactating
distributed based on lean body weight.
mothers to exert extra caution while using painkillers containing
codeine. More recent research has also shown that blood-brain
barrier levels of P-glycoprotein are lower at birth, allowing more Surface Area, Age, & Weight
morphine to penetrate into the brain, than later in infancy and Calculations of dosage based on age or weight (see below)
childhood. This can explain sedation in breast-fed neonates even are conservative and tend to underestimate the required dose.
when there is no genetic variability in CYP2D6. Doses based on surface area (Table 59–6) are more likely to be
Minimal use of alcohol by the mother has not been reported to adequate.
harm nursing infants. Excessive amounts of alcohol, however, can Age (Young’s rule):
produce alcohol effects in the infant. Nicotine concentrations in
Age (years)
the breast milk of smoking mothers are low and do not produce Dose = Adult dose ×
Age + 12
effects in the infant. Very small amounts of caffeine are excreted
in the breast milk of coffee-drinking mothers.
Weight (somewhat more precise is Clark’s rule):
Lithium enters breast milk in concentrations equal to those in
maternal serum. Clearance of this drug is almost completely depen- Weight (kg)
Dose = Adult dose ×
dent upon renal elimination, and women who are receiving lithium 70
may expose the infant to relatively large amounts of the drug.
125
Radioactive substances such as iodinated I albumin and or
radioiodine can cause thyroid suppression in infants and may Weight (lb)
Dose = Adult dose ×
increase the risk of subsequent thyroid cancer as much as tenfold. 150
 CHAPTER 59  Special Aspects of Perinatal & Pediatric Pharmacology      1057

TABLE 59–6  Determination of drug dosage from Hansten PD, Horn JR: Drug Interactions, Analysis and Management. Facts &
Comparisons. [Quarterly.]
1
surface area.
International Liaison Committee on Resuscitation: The International Liaison
Committee on Resuscitation (ILCOR) consensus on science with treatment
Weight recommendations for pediatric and neonatal patients: pediatric basic and
Approximate Surface Percent of advanced life support. Pediatrics 2006;117:e955.
(kg) (lb) Age Area (m2) Adult Dose
Iqbal MM, Sohhan T, Mahmud SZ: The effects of lithium, valproic acid, and
3 6.6 Newborn 0.2 12 carbamazepine during pregnancy and lactation. J Toxicol Clin Toxicol
2001;39:381.
6 13.2 3 months 0.3 18 Ito S: Drug therapy for breast feeding women. N Engl J Med 2000;343:118.
10 22 1 year 0.45 28 Kearns GL et al: Developmental pharmacology—drug disposition, action and
therapy in infants and children. N Engl J Med 2003;349:1157.
20 44 5.5 years 0.8 48
Koren G: Medication Safety during Pregnancy and Breastfeeding; A Clinician’s Guide,
30 66 9 years 1 60 4th ed. McGraw-Hill, 2006.
40 88 12 years 1.3 78 Koren G, Nordeng H: Antidepressant use during pregnancy: The benefit-risk ratio.
Am J Obstet Gynecol 2012;207:157.
50 110 14 years 1.5 90
Koren G, Pastuszak A: Prevention of unnecessary pregnancy terminations by
60 132 Adult 1.7 102 counseling women on drug, chemical, and radiation exposure during the
first trimester. Teratology 1990;41:657.
70 154 Adult 1.76 103
Koren G, Pastuszak A, Ito E: Drugs in pregnancy. N Engl J Med 1998;
1
For example, if adult dose is 1 mg/kg, dose for 3-month-old infant would be 0.18 mg/kg 338:1128.
or 1.1 mg total. Koren G et al: Sex differences in the pharmacokinetics and bioequivalence of the
Reproduced, with permission, from Silver HK, Kempe CH, Bruyn HB: Handbook of delayed-release combination of doxylamine succinate-pyridoxine hydro-
Pediatrics, 14th ed. Originally published by Lange Medical Publications. © 1983 by the chloride: Implications for pharmacotherapy in pregnancy. J Clin Pharmacol
McGraw-Hill Companies, Inc. 2013;53:1268.
Madadi P et al: Pharmacogenetics of neonatal opioid toxicity following maternal
use of codeine during breastfeeding: A case control study. Clin Pharmacol
Despite these approximations, only by conducting studies in Ther 2009;85:31.
children can safe and effective doses for a given age group and Namouz-Haddad S, Koren G: Fetal pharmacotherapy 2: Fetal arrhythmia.
J Obstet Gynaecol Can 2013;35:1023.
condition be determined.
Pauwels S, Allegaert K: Therapeutic drug monitoring in neonates. Arch Dis Child
2016;101:377.
REFERENCES Peled N et al: Gastric-outlet obstruction induced by prostaglandin therapy in
Briggs GG, Freeman RK, Yaffe SJ: Drugs in Pregnancy and Lactation: A Refer- neonates. N Engl J Med 1992;327:505.
ence Guide to Fetal and Neonatal Risk, 10th ed. Wolters Kluwer/Lippincott SickKids Drug Handbook and Formulary 2015/2016. The Hospital for Sick
Williams & Wilkins, 2015. Children, Toronto.
de Wildt SN et al: Ontogeny of midazolam glucuronidation in preterm infants. Tetelbaum M et al: Back to basics: Understanding drugs in children: Pharmacoki-
Eur J Clin Pharmacol 2010;66:165. netic maturation. Pediatr Rev 2005;26:321.
Gavin PJ, Yogev R: The role of protease inhibitor therapy in children with HIV Van Lingen RA et al: The effects of analgesia in the vulnerable infant during the
infection. Paediatr Drugs 2002;4:581. perinatal period. Clin Perinatol 2002;29:511.
 60
C H A P T E R
Special Aspects of
Geriatric Pharmacology
Bertram G. Katzung, MD, PhD
C ASE STUDY
A 77-year-old man comes to your office at his wife’s insis-
tence. He has had documented moderate hypertension for
18 years but does not like to take his medications. He says
he has no real complaints, but his wife remarks that he has
become much more forgetful lately and has almost stopped
reading the newspaper and watching television. A Mini-
Mental State Examination reveals that he is oriented as to
name and place but is unable to give the month or year.
Society has traditionally classified everyone over 65 as “elderly,”
but most authorities consider the field of geriatrics to apply to
persons over 75—even though this too is an arbitrary definition.
Furthermore, chronologic age is only one determinant of the
changes pertinent to drug therapy that occur in older people. In
addition to the chronic diseases of adulthood, the elderly have an
increased incidence of many conditions, including Alzheimer’s
disease, Parkinson’s disease, and vascular dementia; stroke; visual
impairment, especially cataracts and macular degeneration; ath-
erosclerosis, coronary and peripheral vascular disease, and heart
failure; diabetes; arthritis, osteoporosis, and fractures; cancer; and
incontinence. As a result, the need for drug treatment is great
in this age group. And as the average life span approaches (and
in some countries, already exceeds) 80, this need will increase
dramatically.
When all confounders are accounted for, age itself is still the
strongest risk factor for cardiovascular and neurodegenerative dis-
eases and most forms of cancer. Research into the molecular basis
of aging has answered a few questions and opened many more. It
has long been known that caloric restriction alone can prolong the
life span of animals, including mammals. Some evidence suggests
1058
He cannot remember the names of his three adult children
or three random words (eg, tree, flag, chair) for more than
2 minutes. No cataracts are visible, but he is unable to read
standard newsprint without a powerful magnifier. Why
doesn’t he take his antihypertensive medications? What
therapeutic measures are available for the treatment of
Alzheimer’s disease? How might macular degeneration be
treated?
that calorically restricted mice also remain healthier for a longer
time. Drugs that mimic caloric restriction have been shown to
increase lifespan in the nematode Caenorhabditis elegans, as well
as other species, including mice. Metformin and rapamycin each
increase life span in these species when given alone and appear to
have synergistic effects when given together. Sirtuins, a class of
endogenous protein deacetylase enzymes, may be linked to life
span in some species, but activators (such as resveratrol) of certain
sirtuins have not been shown to prolong life in mice. Assuming
that safer alternatives to metformin or rapamycin can be found,
should everyone over the age of 40 or 60 years take such a drug?
Few would maintain that a simple increase in the years of life—life
span—is desirable unless accompanied by an increase in the years
of healthy life—“health span.” Provocative research suggests that
variables such as telomere length on chromosomes may predict
prospective life span and that proteins in the blood of young
animals may “rejuvenate” older animals, but these studies provide
no guidance regarding the current treatment of diseases in older
patients.
Important changes in responses to some drugs occur with
increasing age in many individuals. For other drugs, age-related
 CHAPTER 60  Special Aspects of Geriatric Pharmacology     1059

changes are minimal, especially in the “healthy old.” Drug usage
patterns also change as a result of the increasing incidence of
disease with age and the tendency to prescribe heavily for patients
in nursing homes. General changes in the lives of older people
have significant effects on the way drugs are used. Among these
changes with advancing age are the increased incidence of several
simultaneous diseases, nutritional problems, reduced financial
resources, and—in some patients—decreased dosing adherence
(also called compliance) for a variety of reasons. The health
practitioner should be aware of the changes in pharmacologic
responses that may occur in older people and should know how to
deal with these changes. Finally, dependent elders are sometimes
abused physically or financially by caregivers at home or in nurs-
ing homes, and the health practitioner should investigate abuse
as a cause of nonadherence, as well as bruises, dehydration, and
other morbidities.
PHARMACOLOGIC CHANGES
ASSOCIATED WITH AGING
In the general population, measurements of functional capacity
of most of the major organ systems show a decline beginning in
young adulthood and continuing throughout life. As shown in
Figure 60–1, there is no “middle-age plateau” but rather a linear
decrease beginning no later than age 45. However, these data
reflect the mean and do not apply to every person above a certain
age; approximately one third of healthy subjects have no age-
related decrease in, for example, creatinine clearance up to the age
of 75. Some of these changes result in altered pharmacokinetics.
100
90
80
Percent function remaining
For the pharmacologist and the clinician, the most important of
these is the decrease in renal function. Other changes and concur-
rent diseases may alter the pharmacodynamic characteristics of
particular drugs in certain patients.
Pharmacokinetic Changes
A. Absorption
There is little evidence of any major alteration in drug absorption
with age. However, conditions associated with age may alter the
rate at which some drugs are absorbed. Such conditions include
altered nutritional habits, greater consumption of nonprescription
drugs (eg, antacids and laxatives), and changes in gastric empty-
ing, which is often slower in older persons, especially in older
diabetics.
B. Distribution
Compared with young adults, the elderly have reduced lean body
mass, reduced body water, and increased fat as a percentage of
body mass. Some of these changes are shown in Table 60–1.
There is usually a decrease in serum albumin, which binds many
drugs, especially weak acids. There may be a concurrent increase
in serum orosomucoid (α-acid glycoprotein), a protein that binds
many basic drugs. Thus, the ratio of bound to free drug may be
significantly altered. As explained in Chapter 3, these changes
may alter the appropriate loading dose of a drug. However, since
both the clearance and the effects of drugs are related to the free
concentration, the steady-state effects of a maintenance dosage
regimen should not be altered by these factors alone. For example,
the loading dose of digoxin in an elderly patient with heart failure
should be reduced (if used at all) because of the decreased appar-
ent volume of distribution. The maintenance dose may have to be
Glomerular
reduced because of reduced clearance of the drug.
filtration
C. Metabolism
Cardiac
index The capacity of the liver to metabolize drugs declines with age for
some, but not all, drugs. Animal studies and some clinical stud-
ies have suggested that certain drugs are metabolized more slowly

70

60
TABLE 60–1  Some changes related to aging that
50 affect pharmacokinetics of drugs.

40 Young Adults Older Adults

Variable (20–30 years) (60–80 years)
Maximal
30 breathing Body water (% of body weight) 61 53
capacity
Lean body mass (% of body 19 12
20 weight)
Body fat (% of body weight) 26–33 (women) 38–45
30 40 50 60 70 80 90 18–20 (men) 36–38
Age (y) Serum albumin (g/dL) 4.7 3.8

FIGURE 60–1  Effect of age on some physiologic functions. Kidney weight (% of young 100 80
adult)
(Adapted, with permission, from Kohn RR: Principles of Mammalian Aging.
Copyright copy; 1978 by Prentice-Hall, Inc. Used by permission of Pearson Hepatic blood flow (% of young 100 55–60
Education, Inc.)
adult)
1060    SECTION X  Special Topics

TABLE 60–2  Effects of age on hepatic clearance of this change is marked prolongation of the half-life of many drugs,
some drugs. and the possibility of accumulation to toxic levels if dosage is not
reduced in size or frequency. Dosing recommendations for the
Age-Related Decrease in No Age-Related Difference elderly often include an allowance for reduced renal clearance. If
Hepatic Clearance Found Found
only the young adult dosage is known for a drug that requires renal
Alprazolam Ethanol clearance, a rough correction can be made by using the Cockcroft-
Barbiturates Isoniazid Gault formula to estimate the GFR and multiplying the recom-
Carbenoxolone Lidocaine mended young adult dosage by eGFR/100. The Cockcroft-Gault
formula is applicable to patients age 40 through 80:
Chlordiazepoxide Lorazepam
Chlormethiazole Nitrazepam Estimated creatinine clearance (mL/min)
Clobazam Oxazepam
(140 – Age) × (Weight in kg)
Desmethyldiazepam Prazosin =
72 × Serum creatinine in mg/dL
Diazepam Salicylate
Flurazepam Warfarin For women, the result should be multiplied by 0.85 (because
Imipramine of reduced muscle mass). It must be emphasized that this estimate
Meperidine
is, at best, a population estimate and may not apply to a particular
patient. If the patient has normal renal function (up to one third
Nortriptyline
of elderly patients), a dose corrected on the basis of this estimate
Phenylbutazone will be too low—but a low dose is initially desirable if one is
Propranolol uncertain of the renal function in any patient. Simple online
Quinidine, quinine calculators using the more modern MDRD (Modification of Diet
Theophylline in Renal Disease) formula are available, eg, http://nkdep.nih.gov/
Tolbutamide
lab-evaluation/gfr-calculators.shtml.
If a precise measure is needed, a standard 12- or 24-hour cre-
atinine clearance determination should be obtained. As indicated
above, nutritional changes alter pharmacokinetic parameters. A
in the elderly; some of these drugs are listed in Table 60–2. The patient who is severely dehydrated (not uncommon in patients
greatest changes are in phase I reactions, ie, those carried out by with stroke or other motor impairment) may have an additional
microsomal P450 systems. There are much smaller changes in marked reduction in renal drug clearance that is completely
the ability of the liver to carry out conjugation (phase II) reac- reversible by rehydration.
tions (see Chapter 4). Some of these changes may be caused by The lungs are important for the excretion of volatile drugs.
decreased liver blood flow (Table 60–1), an important variable in As a result of reduced respiratory capacity (Figure 60–1) and the
the clearance of drugs that have a high hepatic extraction ratio. increased prevalence of active pulmonary disease in the elderly,
In addition, there is a decline with age of the liver’s ability to the use of inhalation anesthesia is less common and intravenous
recover from injury, eg, that caused by alcohol or viral hepatitis. agents more common in this age group. (See Chapter 25.)
Therefore, a history of recent liver disease in an older person
should lead to caution in dosing with drugs that are cleared pri-
marily by the liver, even after apparently complete recovery from Pharmacodynamic Changes
the hepatic insult. Finally, malnutrition and diseases that affect It was long believed that geriatric patients were much more
hepatic function—eg, heart failure—are more common in the “sensitive” to the action of many drugs, implying a change in the
elderly. Heart failure may dramatically alter the ability of the liver pharmacodynamic interaction of the drugs with their receptors.
to metabolize drugs by reducing hepatic blood flow. Similarly, It is now recognized that many—perhaps most—of these appar-
severe nutritional deficiencies, which occur more often in old age, ent changes result from altered pharmacokinetics or diminished
may impair hepatic function. homeostatic responses. Clinical studies have supported the idea
that the elderly are more sensitive to some sedative-hypnotics and
D. Elimination analgesics. In addition, some data from animal studies suggest
Because the kidney is the major organ for clearance of drugs from actual changes with age in the characteristics or numbers of a
the body, the age-related decline of renal functional capacity is few receptors. The most extensive studies suggest a decrease in
very important. A decline in creatinine clearance (Clcr)—the usual responsiveness to β-adrenoceptor agonists. Other examples are
measure of estimated glomerular filtration rate (eGFR)—occurs discussed below.
in about two thirds of the population. It is important to note Important homeostatic control mechanisms appear to be
that this decline is not reflected in an equivalent rise in serum blunted in the elderly. Since homeostatic responses are often
creatinine because the production of creatinine is also reduced as significant contributors to the overall response to a drug, these
muscle mass declines with age; therefore, serum creatinine alone is physiologic alterations may change the pattern or intensity of
not an adequate measure of renal function. The practical result of drug response. In the cardiovascular system, the cardiac output

increment required by mild or moderate exercise is successfully
provided until at least age 75 (in individuals without obvious car-
diac disease), but the increase is the result primarily of increased
stroke volume in the elderly and not tachycardia, as in young
adults. Average blood pressure goes up with age (in most Western
countries), but the incidence of symptomatic orthostatic hypoten-
sion also increases markedly. It is thus particularly important to
check for orthostatic hypotension (>20 mm Hg drop in systolic
blood pressure on standing) on every visit. Similarly, the average
2-hour postprandial blood glucose level increases by about 1 mg/
dL for each year of age above 50. Temperature regulation is also
impaired, and hypothermia is poorly tolerated by the elderly.
Behavioral & Lifestyle Changes
Major changes in the conditions of daily life accompany the aging
process and have an impact on health. Some of these (eg, forget-
ting to take one’s pills) are the result of cognitive changes associ-
ated with vascular or other pathology. One of the most important
changes is the loss of a spouse. Others relate to economic stresses
associated with greatly reduced income and, frequently, increased
expenses due to illness.
■■ MAJOR DRUG GROUPS
CENTRAL NERVOUS SYSTEM DRUGS
Sedative-Hypnotics
The half-lives of many benzodiazepines and barbiturates increase
by 50–150% between ages 30 and 70. Much of this change occurs
during the decade from 60 to 70. For some of the benzodiazepines,
both the parent molecule and its metabolites (produced in the
liver) are pharmacologically active (see Chapter 22). The age-related
decline in renal function and liver disease, if present, both contribute
to the reduction in elimination of these compounds. In addition,
an increased volume of distribution has been reported for some
of these drugs. Lorazepam and oxazepam may be less affected by
these changes than the other benzodiazepines. In addition to these
pharmacokinetic factors, it is generally believed that the elderly vary
more in their sensitivity to the sedative-hypnotic drugs on a pharma-
codynamic basis as well. Among the toxicities of these drugs, ataxia
and other stability impairments lead to increased falls and fractures.
Analgesics
The opioid analgesics show variable changes in pharmacokinetics
with age. However, the elderly are often markedly more sensitive
to the respiratory effects of these agents because of age-related
changes in respiratory function. Therefore, this group of drugs
should be used with caution until the sensitivity of the particular
patient has been evaluated, and the patient should then be dosed
appropriately for full effect. Opioids are not as effective in chronic
pain syndromes as they are for acute pain, eg, fracture pain (see
Chapter 31). Unfortunately, studies show that opioids are consis-
tently underutilized in patients who require strong analgesics for
CHAPTER 60  Special Aspects of Geriatric Pharmacology     1061
chronic painful conditions such as cancer. Good pain manage-
ment plans are readily available (see Morrison, 2006; Rabow and
Pantilat, 2011).
Antipsychotic & Antidepressant Drugs
The traditional antipsychotic agents (phenothiazines and halo-
peridol) have been very heavily used (and often misused) in the
management of a variety of psychiatric conditions in the elderly.
There is no doubt that they are useful in the management of
schizophrenia in old age, and also in the treatment of some
symptoms associated with delirium, dementia, agitation, combat-
iveness, and a paranoid syndrome that occurs in some geriatric
patients (see Chapter 29). However, they are not fully satisfactory
in these geriatric conditions, and dosage should not be increased
on the assumption that full control is possible. There is no evi-
dence that these drugs have any beneficial effects in Alzheimer’s
dementia, and on theoretical grounds the antimuscarinic effects of
the phenothiazines might be expected to worsen memory impair-
ment and intellectual dysfunction (see below).
Much of the apparent improvement produced by these drugs in
agitated and combative patients may simply reflect their sedative
effects. When a sedative antipsychotic is desired, a phenothiazine
such as thioridazine is appropriate. If sedation is to be avoided,
haloperidol or a second generation (atypical) antipsychotic is more
appropriate. Haloperidol has increased extrapyramidal toxicity,
however, and should be avoided in patients with preexisting extra-
pyramidal disease. The phenothiazines, especially older drugs such
as chlorpromazine, often induce orthostatic hypotension because of
their α-adrenoceptor-blocking effects. They are even more prone to
do so in the elderly. Dosage of these drugs should usually be started
at a fraction of that used in young adults. The second generation
antipsychotic agents (clozapine, olanzapine, quetiapine, risperi-
done, aripiprazole) do not appear to be significantly superior to the
traditional agents although they have fewer autonomic adverse
effects. Evidence supporting the benefits of olanzapine is somewhat
stronger than that for the other second generation agents.
Lithium is often used in the treatment of mania in the aged.
Because it is cleared by the kidneys, dosages must be adjusted
appropriately and blood levels monitored. Concurrent use of
thiazide diuretics reduces the clearance of lithium and should be
accompanied by further reduction in dosage and more frequent
measurement of lithium blood levels.
Psychiatric depression is thought to be underdiagnosed and
undertreated in the elderly. The suicide rate in the over-65 age
group (twice the national average) supports this view. Unfor-
tunately, the apathy, flat affect, and social withdrawal of major
depression may be mistaken for senile dementia. Clinical evidence
suggests that the elderly are as responsive to antidepressants (of
all types) as younger patients but are more likely to experience
adverse effects. This factor along with the reduced clearance of
some of these drugs underlines the importance of careful dos-
ing and strict attention to the monitoring of toxic effects. Some
authorities prefer selective serotonin reuptake inhibitors (SSRIs)
to tricyclic antidepressants because the SSRIs have fewer auto-
nomic adverse effects. If a tricyclic is to be used, a drug with
1062    SECTION X  Special Topics
reduced antimuscarinic effects should be selected, eg, nortriptyline
or desipramine (see Table 30–2).
Drugs Used in Alzheimer’s Disease
Alzheimer’s disease (AD) is characterized by progressive memory
impairment, dementia, and cognitive dysfunction, and may lead
to a completely vegetative state, resulting in early death. Preva-
lence increases with age and may be as high as 20% in individuals
over 85, although long-term epidemiologic studies suggest that
the overall prevalence of dementia has decreased in the USA and
Europe over the last 15–30 years (see Langa 2017). The annual cost
of dementia in the United States is estimated at $150–$215 billion
annually. Both familial and sporadic forms have been identified.
Early onset of Alzheimer’s disease is associated with several gene
defects, including trisomy 21 (chromosome 21), a mutation of the
gene for presenilin-1 on chromosome 14, and an abnormal allele,
ε4, for the lipid-associated protein, ApoE, on chromosome 19.
Unlike the common forms (ApoE ε2 and ε3), the ε4 form strongly
correlates with the formation of amyloid β deposits (see below).
Pathologic changes include increased deposits of amyloid
beta (Aa) peptide in the cerebral cortex, which eventually forms
extracellular plaques and cerebral vascular lesions, and intra- and
interneuronal fibrillary tangles consisting of the tau protein
Aβ
ApoE4
Mitochondrion
Truncated E4
Impaired
synapse
Tau
Amyloid
plaque
Neurofibrillary
tangles
FIGURE 60–2  Some processes involved in Alzheimer’s disease. From the left: Mitochondrial dysfunction, possibly involving glucose utiliza-
tion; synthesis of protein tau and aggregation in filamentous tangles; synthesis of amyloid beta (Aβ) and secretion into the extracellular space,
where it may interfere with synaptic signaling and accumulates in plaques. (Reproduced, with permission, from Roberson ED, Mucke L: 100 years and count-
ing: Prospects for defeating Alzheimer’s disease. Science 2006;314:781. Reprinted with permission from AAAS.)
(Figure 60–2). There is a progressive loss of neurons, especially
cholinergic neurons, and thinning of the cortex. An inflamma-
tory process involving the NLRP3 inflammasome appears to
contribute to this pathology, and anti-inflammatory nonsteroidal
anti-inflammatory drugs (NSAIDs), eg, mefenamic acid, reverse
some of the markers of Alzheimer’s disease in animal models.
The loss of cholinergic neurons results in a marked decrease in
choline acetyltransferase and other markers of cholinergic activity.
Patients with Alzheimer’s disease are often exquisitely sensitive to
the central nervous system toxicities of drugs with antimuscarinic
effects. Some evidence implicates excess excitation by glutamate
as a contributor to neuronal death. In addition, abnormalities of
mitochondrial function may contribute to neuronal death.
Many methods of treatment of Alzheimer’s disease have been
explored (Table 60–3). Much attention has been focused on the
cholinomimetic drugs because of the evidence of loss of cholin-
ergic neurons noted earlier. Monoamine oxidase (MAO) type
B inhibition with selegiline (l-deprenyl) has been suggested to
have some beneficial effects. One drug that inhibits N-methyl-
d-aspartate (NMDA) glutamate receptors is available (see below),
and “ampakines,” substances that facilitate synaptic activity at
glutamate AMPA receptors, are under intense study. Some evi-
dence suggests that lipid-lowering statins are beneficial. So-called
cerebral vasodilators are ineffective.
Microglia
Neuron
Nucleus
Oligomers
Signaling
molecules
Neurite
 CHAPTER 60  Special Aspects of Geriatric Pharmacology     1063

TABLE 60–3  Some potential strategies for the Its modest efficacy in moderate-to-severe Alzheimer’s disease is similar
prevention or treatment of Alzheimer’s to or smaller than that of the cholinesterase inhibitors. In contrast,
disease. a small study of memantine in Alzheimer’s disease in persons with
Down syndrome found no benefit. However, this drug may be better
Therapy Comment tolerated and less toxic than the cholinesterase inhibitors. Combina-
Cholinesterase inhibitors Increase cholinergic activity; 4 drugs tion therapy with both memantine and one of the cholinesterase
approved inhibitors has produced mixed results. Memantine is available as
N-methyl-d-aspartate Inhibit glutamate excitotoxicity; Namenda in 5 and 10 mg oral tablets.
glutamate antagonists 1 drug approved Recent research has focused on amyloid beta, because the char-
Modifiers of glucose PPAR-γ agonists acteristic plaques consist mostly of this peptide. Unfortunately,
utilization two anti-amyloid antibodies, solanezumab and bapineuzumab,
Antilipid drugs Statins (off-label use) both failed to improve cognition or slow progression in recent
Retinoid X receptor Bexarotene transiently reduced Aβ in clinical trials. Verubecestat, an inhibitor of beta-site amyloid pre-
mice cursor protein cleaving enzyme (BACE1), reduces the production
NSAIDs Disappointing results with cyclooxy- of amyloid β. This drug showed safety in an early clinical trial,
genase (COX)-2 inhibitors but interest and longer-term phase 3 trials for efficacy are under way. Another
continues
effort suggests that the accumulation of filamentous tangles of tau
Anti-amyloid vaccines In clinical trials protein is a critical component of neuronal damage in Alzheimer’s
Anti-amyloid antibodies Bapineuzumab and solanezumab failed and several other neurodegenerative conditions. Accumulation of
clinical trials but did modify Aβ kinetics; tau appears to be associated with dissociation from microtubules
should treatment be started before
symptoms appear?
in neurons, which has stimulated interest in drugs that inhibit
microtubule disassembly, such as epothilone-D.
Inhibitors of Aβ synthesis γ-Secretase modulator studies in progress
Microtubule stabilizers Drugs that inhibit disassembly of
microtubules reduce accumulation of CARDIOVASCULAR DRUGS
tau protein tangles in mice
Anticytokine antibodies Anti-IL-12 and -23 antibodies reversed Antihypertensive Drugs
age-related cognitive decline and Aβ
accumulation in mice Blood pressure, especially systolic pressure, increases with age
Antioxidants Disappointing results in Western countries and in most cultures in which salt intake
Nerve growth factor One very small trial
is high. In women, the increase is more marked after age 50.
Although often ignored in the past, clinicians now believe that
PERK inhibitor Preliminary study in mice
GSK2606414
hypertension should be treated in the elderly. In fact, more aggres-
sive treatment of hypertension is one factor that may contribute to
Aβ, amyloid beta; IL, interleukin; PERK, protein kinase RNA-like ER kinase; PPAR-γ,
peroxisome proliferator-activated receptor-gamma.
the reported decline in the incidence of dementia.
The basic principles of therapy are not different in the geriatric
age group from those described in Chapter 11, but the usual cau-
Tacrine (tetrahydroaminoacridine, THA), a long-acting cho- tions regarding altered pharmacokinetics and blunted compensa-
linesterase inhibitor and muscarinic modulator, was the first tory mechanisms apply. Because of its safety, nondrug therapy
drug shown to have any benefit in Alzheimer’s disease. Because (weight reduction in the obese and moderate salt restriction)
of its hepatic toxicity, tacrine has been replaced in clinical use by should be encouraged. Thiazides are a reasonable first step in drug
newer cholinesterase inhibitors: donepezil, rivastigmine, and therapy. The hypokalemia, hyperglycemia, and hyperuricemia
galantamine. These agents are orally active, have adequate pen- caused by these agents are more relevant in the elderly because
etration into the central nervous system, and are much less toxic of the higher prevalence in these patients of arrhythmias, type
than tacrine. Although evidence for the benefit of cholinesterase 2 diabetes, and gout. Thus, use of low antihypertensive doses—
inhibitors (and memantine; see below) is statistically significant, rather than maximum diuretic doses—is important. Calcium
the amount of benefit is modest and does not prevent the progres- channel blockers are effective and safe if titrated to the appropriate
sion of the disease. The cholinesterase inhibitors cause significant response. They are especially useful in patients who also have ath-
adverse effects, including nausea and vomiting, diarrhea, and erosclerotic angina (see Chapter 12). Beta blockers are potentially
other peripheral cholinomimetic effects. These drugs should be hazardous in patients with obstructive airway disease and are con-
used with caution in patients receiving other drugs that inhibit sidered less useful than calcium channel blockers in older patients
cytochrome P450 enzymes (eg, ketoconazole, quinidine; see unless chronic heart failure is present. Angiotensin-converting
Chapter 4). Preparations available are listed in Chapter 7. enzyme inhibitors are also considered less useful in the elderly
Excitotoxic activation of glutamate transmission via NMDA unless heart failure or diabetes is present. The most powerful
receptors has been postulated to contribute to the pathophysiology of drugs, such as minoxidil, are rarely needed. Every patient receiving
Alzheimer’s disease. Memantine binds to NMDA receptor channels antihypertensive drugs should be checked regularly for orthostatic
in a use-dependent manner and produces a noncompetitive blockade. hypotension because of the danger of cerebral ischemia and falls.
1064    SECTION X  Special Topics

Positive Inotropic Agents vaccine should be given annually, tetanus toxoid every 10 years,
and pneumococcal and zoster vaccines once.
Heart failure is a common and particularly lethal disease in the
Since 1940, the antimicrobial drugs have contributed more to
elderly. Fear of this condition is one reason why physicians overuse
the prolongation of life than any other drug group because they
cardiac glycosides in this age group. The toxic effects of digoxin
can compensate to some extent for this deterioration in natural
are particularly dangerous in the geriatric population, since the
defenses. The basic principles of therapy of the elderly with these
elderly are more susceptible to arrhythmias. The clearance of
agents are no different from those applicable in younger patients
digoxin is usually decreased in the older age group, and although
and have been presented in Chapter 51. The major pharmacoki-
the volume of distribution is often decreased as well, the half-life
netic changes relate to decreased renal function; because most of
of this drug may be increased by 50% or more. Because the drug is
the β-lactam, aminoglycoside, and fluoroquinolone antibiotics
cleared mostly by the kidneys, renal function must be considered
are excreted by this route, important changes in half-life may be
in designing a dosage regimen. There is no evidence that there is
expected. This is particularly important in the case of the amino-
any increase in pharmacodynamic sensitivity to the therapeutic
glycosides, because they cause concentration- and time-dependent
effects of the cardiac glycosides; in fact, animal studies suggest a
toxicity in the kidney and in other organs. The half-lives of gen-
possible decrease in therapeutic sensitivity. On the other hand,
tamicin, kanamycin, and netilmicin are more than doubled. The
there is probably an increase in sensitivity to the toxic arrhythmo-
increase may be less marked for tobramycin.
genic actions. Hypokalemia, hypomagnesemia, hypoxemia (from
pulmonary disease), and coronary atherosclerosis all contribute
to the high incidence of digitalis-induced arrhythmias in geriatric ANTI-INFLAMMATORY DRUGS
patients. The less common toxicities of digitalis such as delirium,
visual changes, and endocrine abnormalities (see Chapter 13) also Osteoarthritis is a very common disease of the elderly. Rheuma-
occur more often in older than in younger patients. toid arthritis is less exclusively a geriatric problem, but the same
drug therapy is usually applicable to both types of disease. The
Antiarrhythmic Agents basic principles laid down in Chapter 36 and the properties of the
anti-inflammatory drugs described there apply fully here.
The treatment of arrhythmias in the elderly is particularly chal-
The nonsteroidal anti-inflammatory agents (NSAIDs) must be
lenging because of the lack of good hemodynamic reserve, the
used with special care in geriatric patients because they cause toxici-
frequency of electrolyte disturbances, and the high prevalence
ties to which the elderly are very susceptible. In the case of aspirin, the
of significant coronary disease. The clearances of quinidine and
most important of these is gastrointestinal irritation and bleeding. In
procainamide decrease and their half-lives increase with age. Diso-
the case of the newer NSAIDs, the most important is renal damage,
pyramide should probably be avoided in the geriatric population
which may be irreversible. Because they are cleared primarily by the
because its major toxicities—antimuscarinic action, leading to
kidneys, these drugs accumulate more rapidly in the geriatric patient
voiding problems in men; and negative inotropic cardiac effects,
and especially in the patient whose renal function is already compro-
leading to heart failure—are particularly undesirable in these
mised beyond the average range for his or her age. A vicious circle is
patients. The clearance of lidocaine appears to be little changed,
easily set up in which cumulation of the NSAID causes more renal
but the half-life is increased in the elderly. It is recommended
damage, which causes more cumulation. There is no evidence that
that the loading dose of this drug be reduced in geriatric patients
the cyclooxygenase (COX)-2 selective NSAIDs are safer with regard
because of their greater sensitivity to its toxic effects.
to renal function. Elderly patients receiving high doses of any NSAID
Recent evidence indicates that many patients with atrial
should be carefully monitored for changes in renal function.
fibrillation—a very common arrhythmia in the elderly—do as
Corticosteroids are extremely useful in elderly patients who
well with simple control of ventricular rate as with conversion
cannot tolerate full doses of NSAIDs. However, they consistently
to normal sinus rhythm. Measures (such as anticoagulant drugs)
cause a dose- and duration-related increase in osteoporosis, an
must be taken to reduce the risk of thromboembolism in chronic
especially hazardous toxic effect in the elderly. It is not certain
atrial fibrillation.
whether this drug-induced effect can be reduced by increased cal-
cium and vitamin D intake, but it would be prudent to consider
these agents (and bisphosphonates if osteoporosis is already pres-
ANTIMICROBIAL THERAPY
ent, see Qaseem reference) and to encourage frequent exercise in
Several age-related changes contribute to the high incidence of any patient taking corticosteroids.
infections in geriatric patients. A reduction in host defenses in
the elderly is manifested in the increase in both serious infections
and cancer. This may reflect an alteration in T-lymphocyte func-
OPHTHALMIC DRUGS
tion. In the lungs, a major age and tobacco-dependent decrease
in mucociliary clearance significantly increases susceptibility to Drugs Used in Glaucoma
infection. In the urinary tract, the incidence of serious infection Glaucoma is more common in the elderly, but its treatment does
is greatly increased by urinary retention and catheterization in not differ from that of glaucoma of earlier onset. Management of
men. Preventive immunizations should be maintained: influenza glaucoma is discussed in Chapter 10.

Macular Degeneration
Age-related macular degeneration (AMD) is the most common
cause of blindness in the elderly in the developed world. Two
forms of advanced AMD are recognized: the neovascular “wet”
form, which is associated with intrusion of new blood vessels
in the subretinal space, and a more common “dry” form, which
is not associated with abnormal vascularization. Although the
cause of AMD is not known, smoking is a documented risk fac-
tor, and oxidative stress has long been thought to play a role. On
this premise, antioxidants have been used to prevent or delay the
onset of AMD. Proprietary oral formulations of vitamins C and
E, β-carotene, zinc oxide, and cupric oxide are available. Some
include the carotenoids lutein and zeaxanthin, and omega-3
long-chain polyunsaturated fatty acids. Evidence for the efficacy
of these antioxidants is modest.
In advanced neovascular AMD, treatment has been moderately
successful. This form of AMD can now be treated with laser photo-
therapy or with antibodies against vascular endothelial growth fac-
tor (VEGF). Two antibodies are available—bevacizumab (Avastin,
used off-label) and ranibizumab (Lucentis)—as well as aflibercept
(Eylea, a decoy protein receptor that binds VEGF) and the oligo-
peptide pegaptanib (Macugen). Aflibercept is also approved for
the treatment of diabetic macular degeneration. These agents are
injected into the vitreous for local effect. Ranibizumab is extremely
expensive. Other agents that bind VEGF are under study.
■■ ADVERSE DRUG REACTIONS IN
THE ELDERLY
The relation between the number of drugs taken and the incidence
of adverse drug reactions (ADRs) has been well documented. In
long-term care facilities, in which a high percentage of the popu-
lation is elderly, the average number of prescriptions per patient
varies between 6 and 8. Studies have shown that the percentage
of patients with adverse reactions increases from about 10% when
a single drug is being taken to nearly 100% when 10 drugs are
taken. Thus, it may be expected that about half of patients in
long-term care facilities will have recognized or unrecognized
ADRs at some time. Patients living at home may see several differ-
ent practitioners for different conditions and accumulate multiple
prescriptions for drugs with overlapping actions. It is useful to
conduct a “brown bag” analysis in such patients. The brown bag
analysis consists of asking the patient to bring to the practitioner
a bag containing all the medications, supplements, vitamins, etc,
that he or she is currently taking. Some prescriptions will be found
to be duplicates, and others unnecessary. The total number of
medications taken can often be reduced by 30–50%.
The overall incidence of ADRs in geriatric patients is estimated
to be at least twice that in the younger population. Reasons for
this high incidence include errors in prescribing on the part of the
practitioners and errors in drug usage by the patient. Practitioner
errors sometimes occur because the physician does not appreci-
ate the importance of changes in pharmacokinetics with age and
age-related diseases. Some errors occur because the practitioner is
CHAPTER 60  Special Aspects of Geriatric Pharmacology     1065
unaware of incompatible drugs prescribed by other practitioners
for the same patient. For example, cimetidine, an H2-blocking
drug heavily prescribed (or recommended in its over-the-counter
form) to the elderly, causes a higher incidence of untoward effects
(eg, confusion, slurred speech) in the geriatric population than
in younger patients. It also inhibits the hepatic metabolism of
many drugs, including phenytoin, warfarin, β blockers, and other
agents. A patient who has been taking one of the latter agents
without untoward effect may develop markedly elevated blood
levels and severe toxicity if cimetidine is added to the regimen
without adjustment of dosage of the other drugs. Additional
examples of drugs that inhibit liver microsomal enzymes and lead
to adverse reactions are described in Chapters 4 and 66.
Patient errors may result from nonadherence for reasons
described below. In addition, they often result from use of non-
prescription drugs taken without the knowledge of the physician.
As noted in Chapters 63 and 64, many over-the-counter agents
and herbal medications contain “hidden ingredients” with potent
pharmacologic effects. For example, many antihistamines con-
tained in over-the-counter drugs have significant sedative effects
and are inherently more hazardous in patients with impaired
cognitive function. Similarly, their antimuscarinic action may pre-
cipitate urinary retention in geriatric men or glaucoma in patients
with a narrow anterior chamber angle. If the patient is also tak-
ing a metabolism inhibitor such as cimetidine, the probability
of an adverse reaction is greatly increased. A patient taking an
herbal medication containing gingko is more likely to experience
bleeding while taking low doses of aspirin.
■■ PRACTICAL ASPECTS OF
GERIATRIC PHARMACOLOGY
The quality of life in elderly patients can be greatly improved
and life span can be prolonged by the intelligent use of drugs.
However, the prescriber must recognize several practical obstacles
to compliance.
The expense of drugs can be a major disincentive in patients
receiving marginal retirement incomes who are not covered or
inadequately covered by health insurance. The prescriber must
be aware of the cost of the prescription and of cheaper alterna-
tive therapies. For example, the monthly cost of arthritis therapy
with newer NSAIDs may exceed $100, whereas that for generic
ibuprofen and naproxen, two older but equally effective NSAIDs,
about $20.
Nonadherence may result from forgetfulness or confusion,
especially if the patient has several prescriptions and different dos-
ing intervals. A survey carried out in 1986 showed that the popula-
tion over 65 years of age accounted for 32% of drugs prescribed in
the USA, although these patients represented only 11–12% of the
population at that time. Since the prescriptions are often written
by several different practitioners, there is usually no attempt to
design “integrated” regimens that use drugs with similar dosing
intervals for the several conditions being treated. Patients may
forget instructions regarding the need to complete a fixed dura-
tion of therapy when a course of anti-infective drug is being given.
1066    SECTION X  Special Topics
The disappearance of symptoms is often regarded as the best rea-
son to halt drug taking, especially if the prescription was expensive.
Nonadherence may also be deliberate. A decision not to take
a drug may be based on prior experience with it. There may
be excellent reasons for such “intelligent” noncompliance, and
the practitioner should try to elicit them. Such efforts may also
improve compliance with alternative drug regimens, because
enlisting the patient as a participant in therapeutic decisions
increases the motivation to succeed.
Some errors in drug taking are caused by physical disabilities.
Arthritis, tremor, and visual problems may all contribute. Liquid
medications that are to be measured “by the spoonful” are espe-
cially inappropriate for patients with any type of tremor or motor
disability. Use of a dosing syringe is essential in such cases. Because
of decreased production of saliva, older patients often have dif-
ficulty swallowing large tablets. “Childproof ” containers are often
“elder-proof ” if the patient has arthritis. Cataracts and macular
degeneration occur in a large number of patients over 70. There-
fore, labels on prescription bottles should be large enough for the
patient with diminished vision to read or should be color-coded
if the patient can see but can no longer read. Because of impaired
hearing, even carefully delivered instructions regarding drug use
may not be understood by the patient; written instructions may
be helpful.
Drug therapy has considerable potential for both helpful and
harmful effects in the geriatric patient. The balance may be tipped
in the right direction by adherence to a few principles:
1. Take a careful drug history. The disease to be treated may be
drug-induced, or drugs being taken may lead to interactions
with drugs to be prescribed.
2. Prescribe only for a specific and rational indication. Do not
prescribe omeprazole for “dyspepsia.” Expert guidelines are
published regularly by national organizations and websites such
as UpToDate.com.
3. Define the goal of drug therapy. Then start with small doses
and titrate to the response desired. Wait at least three half-lives
(adjusted for age) before increasing the dose. If the expected
response does not occur at the normal adult dosage, check
blood levels. If the expected response does not occur at the
appropriate blood level, switch to a different drug.
4. Maintain a high index of suspicion regarding drug reactions
and interactions. Know what other drugs the patient is taking,
including over-the-counter and botanical (herbal) drugs.
5. Simplify the regimen as much as possible. When multiple
drugs are prescribed, try to use drugs that can be taken at the
same time of day. Whenever possible, reduce the number of
drugs being taken.
REFERENCES
American College of Cardiology Foundation Task Force: ACCF/AHA 2011 Expert
consensus document on hypertension in the elderly. J Am Coll Cardiol
2011;57:2037.
American Geriatrics Society 2015 Beers Update Expert Panel: American Geriatrics
Society 2015 updated Beers criteria for potentially inappropriate medication
use in older adults. J Am Geriatr Soc 2015;63:2227.
Ancolli-Israel S, Ayalon L: Diagnosis and treatment of sleep disorders in older
adults. Am J Geriatr Psychiatry 2006;14:95.
Aronow WS: Drug treatment of systolic and diastolic heart failure in elderly
persons. J Gerontol A Biol Med Sci 2005;60:1597.
Blackburn EH, Epel ES, Liu J: Human telomere biology: A contributory and
interactive factor in aging, disease risks, and protection. Science 2015;
350:1193.
Calcado RT, Young NS: Telomere diseases. N Engl J Med 2009;361:2353.
Chatap G, Giraud K, Vincent JP: Atrial fibrillation in the elderly: Facts and
management. Drugs Aging 2002;19:819.
Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum
creatinine. Nephron 1976;16:31.
Dergal JM et al: Potential interactions between herbal medicines and conventional
drug therapies used by older adults attending a memory clinic. Drugs Aging
2002;19:879.
Docherty JR: Age-related changes in adrenergic neuroeffector transmission. Auton
Neurosci 2002;96:8.
Drugs for cognitive loss and dementia. Treat Guidel Med Lett 2013;11:95.
Epstein NU et al: Medication for Alzheimer’s disease and associated fall hazard:
A retrospective cohort study from the Alzheimer’s disease neuroimaging
initiative. Drugs Aging 2014;31:125.
Ferrari AU: Modifications of the cardiovascular system with aging. Am J Geriatr
Cardiol 2002;11:30.
Gandy S: Lifelong management of amyloid-beta metabolism to prevent Alzheimer’s
disease. N Engl J Med 2012;367:864.
Guarente L: Sirtuins, aging, and medicine. N Engl J Med 2011;364:2235.
Hubbard BP, Sinclair DA: Small molecule SIRT1 activators for the treatment of
aging and age-related diseases. Trends Pharmacol Sci 2014;35:146.
Jager RD, Mieler WF, Miller JW: Age-related macular degeneration. N Engl J Med
2008;358:2606.
Japp D et al: Mineralocorticoid receptor antagonists in elderly patients with
heart failure: a systematic review and meta-analysis. Age Ageing 2017;
46:18.
Kelly AS, Morrison RS: Palliative care for the seriously ill. N Engl J Med
2015;373:747.
Kennedy BK, Pennypacker JK: Drugs that modulate aging: the promising yet
difficult path ahead. Translat Res 2013;163:1.
Kirby J et al: A systematic review of the clinical and cost-effectiveness of meman-
tine in patients with moderately severe to severe Alzheimer’s disease. Drugs
Aging 2006;23:227.
Lachs MS, Pillemer KA: Elder abuse. N Engl J Med 2015;373:1947.
Lamming DW et al: Rapamycin-induced insulin resistance is mediated by
mTORC2 loss and uncoupled from longevity. Science 2012;335:1638.
Langa KM et al: A comparison of the prevalence of dementia in the United States
in 2000 and 2012. JAMA Intern Med 2017;177:51.
Levey AS et al: Using standardized serum creatinine values in the modification of
diet in renal disease study equation for estimating glomerular filtration rate.
Ann Int Med 2006;145:247.
Lipska KJ et al: Polypharmacy in the aging patient. A review of glycemic control in
older adults with type 2 diabetes. JAMA 2016;315:1034.
Mangoni AA: Cardiovascular drug therapy in elderly patients: Specific age-related
pharmacokinetic, pharmacodynamic and therapeutic considerations. Drugs
Aging 2005;22:913.
Moreno JA et al: Oral treatment targeting the unfolded protein response prevents
neurodegeneration and clinical disease in prion-infected mice. Sci Transl
Med 2013;5:206ra138.
Morrison LJ, Morrison RS: Palliative care and pain management. Med Clin N
Am 2006;90:983.
Palmer AM: Neuroprotective therapeutics for Alzheimer’s disease: Progress and
prospects. Trends Pharmacol Sci 2011;32:141.
Press D, Alexander M: Treatment of dementia. www.uptodate.com 2014;topic
5073.
Qaseem A et al: Treatment of low bone density or osteoporosis to prevent fractures
in men and women: a clinical practice guideline update from the American
College of Physicians. Ann Int Med 2017;doi: 10.7326/M15-1361.
Qato DM et al: Use of prescription and over-the-counter medications and
dietary supplements among older adults in the United States. JAMA
2008;300:2867.

Rabow MW, Pantilat SZ: Palliative care and pain management. In: Papadakis
MA, McPhee SJ, (editors): Current Medical Diagnosis & Treatment 2017,
McGraw-Hill, 2017.
Roberson ED, Mucke L: 100 years and counting: Prospects for defeating
Alzheimer’s disease. Science 2006;314:781.
Satizabal CL et al: Incidence of dementia over three decades in the Framingham
Heart Study. N Engl J Med 2016;374:523.
Sawhney R, Sehl M, Naeim A: Physiologic aspects of aging: Impact on cancer
management and decision making, part I. Cancer J 2005;11:449.
Staskin DR: Overactive bladder in the elderly: A guide to pharmacological
management. Drugs Aging 2005;22:1013.
C ASE STUDY ANSWER
This patient has several conditions that warrant careful treat-
ment. Hypertension is eminently treatable; the steps described
in Chapter 11 are appropriate and effective in the elderly as well
as in young patients. Patient education is critical in combating
his reluctance to take his medications. Alzheimer’s disease may
respond to one of the anticholinesterase agents (donepezil,
CHAPTER 60  Special Aspects of Geriatric Pharmacology     1067
Steinman MA, Hanlon JT: Managing medications in clinically complex elders.
JAMA 2010;304:1592.
Teixeira A et al: Management of acute heart failure in elderly patients. Arch
Cardiovasc Dis 2016;109:422.
Vaillaint GE: Aging Well. Little, Brown, 2002.
Vandenberghe R et al: Bapineuzumab for mild to moderate Alzheimer’s disease
in two global, randomized, phase 3 trials. Alzheimers Res Ther 2016;8:18.
Vik SA et al: Medication nonadherence and subsequent risk of hospitalisation and
mortality among older adults. Drugs Aging 2006;23:345.
Wright JT Jr et al: A randomized trial of intensive versus standard blood-pressure
control. N Engl J Med 2015;373:2103.
rivastigmine, galantamine). Alternatively, memantine may be
tried. Unfortunately, age-related macular degeneration (the
most likely cause of his visual difficulties) is not readily treated,
but the “wet” (neovascular) variety may respond well to one
of the drugs currently available (bevacizumab, ranibizumab,
pegaptanib). However, these therapies are expensive.
 61
C H A P T E R
Dermatologic
Pharmacology
Dirk B. Robertson, MD &
Howard I. Maibach, MD
C ASE STUDY
A 43-year-old woman presents with a complaint of worsen-
ing rosacea. She initially responded to once-daily topical
metronidazole 0.75% gel with excellent clearing of the
Diseases of the skin offer special opportunities to the clinician. In
particular, the topical administration route is especially appropri-
ate for skin diseases, although some dermatologic diseases respond
as well or better to drugs administered systemically.
The general pharmacokinetic principles governing the use of
drugs applied to the skin are the same as those involved in other
routes of administration (see Chapters 1 and 3). Although often
depicted as a simple three-layered structure, human skin is a
complex series of diffusion barriers (Figure 61–1). Quantitation
of the flux of drugs and drug vehicles through these barriers is the
basis for pharmacokinetic analysis of dermatologic therapy, and
techniques for making such measurements are rapidly increasing
in number and sensitivity.
Major variables that determine pharmacologic response to
drugs applied to the skin include the following:
1. Regional variation in drug penetration: For example, the
scrotum, face, axilla, and scalp are far more permeable than the
forearm and may require less drug for equivalent effect.
2. Concentration gradient: Increasing the concentration gradi-
ent increases the mass of drug transferred per unit time, just as
in the case of diffusion across other barriers (see Chapter 1).
Thus, resistance to topical corticosteroids can sometimes be
overcome by use of higher concentrations of drug.
3. Dosing schedule: Because of its physical properties, skin acts
as a reservoir for many drugs. As a result, the “local half-life”
may be long enough to permit once-daily application of drugs
1068
papulopustular component of her acne rosacea. Recently,
she has noted increasing persistent facial erythema. What
therapeutic options are available?
with short systemic half-lives. For example, once-daily applica-
tion of corticosteroids appears to be just as effective as multiple
applications in many conditions.
4. Vehicles and occlusion: An appropriate vehicle maximizes the
ability of the drug to penetrate the outer layers of the skin. In
addition, through their physical properties (moistening or dry-
ing effects), vehicles may themselves have important therapeu-
tic effects. Occlusion (application of a plastic wrap to hold the
drug and its vehicle in close contact with the skin) is extremely
effective in maximizing efficacy.
■■ REACTIONS TO
DERMATOLOGIC MEDICATIONS
Skin reacts to many systemic medications with a variety of
symptom-generating responses. In addition, some dermatologic
medications themselves cause skin reactions. The major types of
reactions are summarized in Table 61–1.
■■ DERMATOLOGIC VEHICLES
Topical medications usually consist of active ingredients incorpo-
rated in a vehicle that facilitates cutaneous application. Important
considerations in vehicle selection include solubility of the active
 CHAPTER 61  Dermatologic Pharmacology    1069

Vehicle Drug

Skin surface
Drug diffuses
through stratum
corneum

Stratum
Reservoir
corneum

Drug partitions into

stratum spinosum

Stratum
Metabolized ?
spinosum
Drug binds
to receptor

Drug partitions
into dermis

Basement
membrane Metabolized ?
zone Drug binds
to receptor

Drug partitions
into subcutaneous
tissue

Subcutaneous
Absorbed into bloodstream
fat

FIGURE 61–1  Schematic diagram of percutaneous absorption. (Redrawn from Orkin M, Maibach HI, Dahl MV: Dermatology. Appleton & Lange, 1991.)

agent in the vehicle; the rate of release of the agent from the
vehicle; the ability of the vehicle to hydrate the stratum corneum,
thus enhancing penetration; the stability of the therapeutic agent
in the vehicle; and interactions, chemical and physical, of the
vehicle, stratum corneum, and active agent.
Depending upon the vehicle, dermatologic formulations may
be classified as tinctures, wet dressings, lotions, gels, aerosols,
powders, pastes, creams, foams, and ointments. The ability of the
vehicle to retard evaporation from the surface of the skin increases
in this series, being least in tinctures and wet dressings and greatest
in ointments. In general, acute inflammation with oozing, vesicu-
lation, and crusting is best treated with drying preparations such
as tinctures, wet dressings, and lotions, whereas chronic inflamma-
tion with xerosis, scaling, and lichenification is best treated with
more lubricating preparations such as creams and ointments. Tinc-
tures, lotions, gels, foams, and aerosols are convenient for applica-
tion to the scalp and hairy areas. Emulsified vanishing-type creams
may be used in intertriginous areas without causing maceration.
Emulsifying agents provide homogeneous, stable preparations
when mixtures of immiscible liquids such as oil-in-water creams
1070    SECTION X  Special Topics

TABLE 61–1  Local cutaneous reactions to topical infections due to undetermined pathogens, and delayed microbial
medications. resistance to any single component antibiotic.

Reaction Type Mechanism Comment

Irritation Nonallergic Most common local reaction

BACITRACIN & GRAMICIDIN
Photoirritation Nonallergic Phototoxicity; usually requires Bacitracin and gramicidin are peptide antibiotics, active against
UVA exposure
Gram-positive organisms such as streptococci, pneumococci, and
Allergic contact Allergic Type IV delayed hypersensitivity staphylococci. In addition, most anaerobic cocci, neisseriae, tetanus
dermatitis
bacilli, and diphtheria bacilli are sensitive. Bacitracin is compounded
Photoallergic Allergic Type IV delayed hypersensitivity; in an ointment base alone or in combination with neomycin, poly-
contact dermatitis usually requires UVA exposure
myxin B, or both. The use of bacitracin in the anterior nares may
Immunologic Allergic IgE-mediated type I immediate
temporarily decrease colonization by pathogenic staphylococci.
contact urticaria hypersensitivity; may result in
anaphylaxis Microbial resistance may develop following prolonged use. Baci-
Nonimmunologic Nonallergic Most common contact
tracin-induced contact urticaria syndrome, including anaphylaxis,
contact urticaria urticaria; occurs without occurs rarely. Allergic contact dermatitis occurs frequently, and
prior sensitization immunologic allergic contact urticaria rarely. Bacitracin is poorly
absorbed through the skin, so systemic toxicity is rare.
Gramicidin is available only for topical use, in combination
are compounded. Some patients develop irritation from these agents. with other antibiotics such as neomycin, polymyxin, bacitracin,
Substituting a preparation that does not contain them or using one and nystatin. Systemic toxicity limits this drug to topical use. The
containing a lower concentration may resolve the problem. incidence of sensitization following topical application is exceed-
ingly low in therapeutic concentrations.

■■ ANTIBACTERIAL AGENTS MUPIROCIN

TOPICAL ANTIBACTERIAL
PREPARATIONS
Topical antibacterial agents may be useful in preventing infections
in clean wounds, in the early treatment of infected dermatoses and
wounds, in reducing colonization of the nares by staphylococci, in
axillary deodorization, and in the management of acne vulgaris.
Efficacy of antibiotics in these topical applications is not uniform.
The general pharmacology of the antimicrobial drugs is discussed
in Chapters 43–51.
Some topical anti-infectives contain corticosteroids in addition
to antibiotics. There is no convincing evidence that topical corti-
costeroids inhibit the antibacterial effect of antibiotics when the
two are incorporated in the same preparation. In the treatment of
secondarily infected dermatoses, which are usually colonized with
streptococci, staphylococci, or both, combination therapy may
prove superior to corticosteroid therapy alone. Antibiotic-cortico-
steroid combinations may be useful in treating diaper dermatitis,
otitis externa, and impetiginized eczema.
Selection of a particular antibiotic depends upon the diagnosis
and, when appropriate, in vitro culture and sensitivity studies
of clinical samples. The pathogens isolated from most infected
dermatoses are group A β-hemolytic streptococci, Staphylococcus
aureus, or both. The pathogens present in surgical wounds will
be those resident in the environment. Information about regional
patterns of drug resistance is therefore important in selecting a
therapeutic agent. Prepackaged topical antibacterial preparations
that contain multiple antibiotics are available in fixed dosages
well above the therapeutic threshold. These formulations offer the
advantages of efficacy in mixed infections, broader coverage for
Mupirocin (pseudomonic acid A) is structurally unrelated to
other currently available topical antibacterial agents. Most Gram-
positive aerobic bacteria, including methicillin-resistant S aureus
(MRSA), are sensitive to mupirocin (see Chapter 50). It is effec-
tive in the treatment of impetigo caused by S aureus and group A
β-hemolytic streptococci.
Intranasal mupirocin ointment for eliminating nasal carriage
of S aureus may be associated with irritation of mucous mem-
branes caused by the polyethylene glycol vehicle. Mupirocin is
not appreciably absorbed systemically after topical application to
intact skin.
RETAPAMULIN
Retapamulin (Altabax) is a semisynthetic pleromutilin derivative
effective in the treatment of uncomplicated superficial skin infec-
tion caused by group A β-hemolytic streptococci and S aureus,
excluding MRSA. Topical retapamulin 1% ointment is indicated
for use in adult and pediatric patients, 9 months or older, for the
treatment of impetigo. Recommended treatment regimen is twice-
daily application for 5 days. Retapamulin is well tolerated with
only occasional local irritation of the treatment site. Although
uncommon, allergic contact dermatitis has been reported.
POLYMYXIN B SULFATE
Polymyxin B is a peptide antibiotic effective against Gram-negative
organisms, including Pseudomonas aeruginosa, Escherichia coli,
Enterobacter, and Klebsiella. Most strains of Proteus and Serratia

are resistant, as are all Gram-positive organisms. Topical prepa-
rations may be compounded in either a solution or ointment
base. Numerous prepackaged antibiotic combinations contain
polymyxin B. Detectable serum concentrations are difficult to
achieve from topical application, but the total daily dose applied
to denuded skin or open wounds should not exceed 200 mg in
order to reduce the likelihood of neurotoxicity and nephrotoxic-
ity. Allergic contact dermatitis to topically applied polymyxin B
sulfate is uncommon.
NEOMYCIN & GENTAMICIN
Neomycin and gentamicin are aminoglycoside antibiotics active
against Gram-negative organisms, including E coli, Proteus,
Klebsiella, and Enterobacter. Gentamicin generally shows greater
activity against P aeruginosa than neomycin. Gentamicin is also
more active against staphylococci and group A β-hemolytic
streptococci. Widespread topical use of gentamicin, especially in a
hospital environment, should be avoided to slow the appearance
of gentamicin-resistant organisms.
Neomycin is available in numerous topical formulations,
alone and in combination with polymyxin, bacitracin, and other
antibiotics. It is also available as a sterile powder for topical use.
Gentamicin is available as an ointment or cream.
Topical application of neomycin rarely results in detectable
serum concentrations. However, in the case of gentamicin, serum
concentrations of 1–18 mcg/mL are possible if the drug is applied
in a water-miscible preparation to large areas of denuded skin, as
in burned patients. Both drugs are water-soluble and are excreted
primarily in the urine. Renal failure may permit the accumulation
of these antibiotics, with possible nephrotoxicity, neurotoxicity,
and ototoxicity.
Neomycin frequently causes allergic contact dermatitis, par-
ticularly if applied to eczematous dermatoses or if compounded in
an ointment vehicle. When sensitization occurs, cross-sensitivity
to streptomycin, kanamycin, paromomycin, and gentamicin is
possible.
TOPICAL ANTIBIOTICS IN ACNE
Systemic antibiotics traditionally used in the treatment of acne
vulgaris have been shown effective when applied topically. Cur-
rently, two antibiotics are used topically for this indication:
clindamycin phosphate and erythromycin base. Effectiveness of
topical therapy is less than that achieved by its oral administra-
tion. Therefore, topical therapy is generally suitable only in mild
to moderate cases of inflammatory acne.
Clindamycin
Clindamycin has in vitro activity against Propionibacterium
acnes; this has been postulated as the mechanism of its beneficial
effect in acne therapy. Approximately 10% of an applied dose
is absorbed, and rare cases of bloody diarrhea and pseudomem-
branous colitis have been reported following topical application.
CHAPTER 61  Dermatologic Pharmacology    1071
The hydroalcoholic vehicle and foam formulation (Evoclin)
may cause drying and irritation of the skin, with complaints
of burning and stinging. The water-based gel and lotion for-
mulations are well tolerated and less likely to cause irritation.
Allergic contact dermatitis is uncommon. Clindamycin is also
available in fixed-combination topical gels with benzoyl perox-
ide (Acanya, BenzaClin, Duac, Onexton) and with tretinoin
(Velitin, Ziana).
Erythromycin
In topical preparations, erythromycin base rather than a salt is
used to facilitate penetration. The mechanism of action of topi-
cal erythromycin in inflammatory acne vulgaris is unknown but
is presumed to be due to its inhibitory effects on P acnes. One
complication of topical therapy is the development of antibiotic-
resistant strains of organisms, including staphylococci. If this
occurs in association with a clinical infection, topical erythromy-
cin should be discontinued and appropriate systemic antibiotic
therapy started. Adverse local reactions to erythromycin solution
may include a burning sensation at application time and drying
and irritation of the skin. The topical water-based gel is less drying
and may be better tolerated. Allergic contact dermatitis is uncom-
mon. Erythromycin is also available in a fixed combination prepa-
ration with benzoyl peroxide (Benzamycin) for topical treatment
of acne vulgaris.
Metronidazole
Topical metronidazole is effective in rosacea treatment. The
mechanism of action is unknown, but it may relate to the inhibi-
tory effects of metronidazole on Demodex brevis; alternatively, the
drug may act as an anti-inflammatory agent by direct effect on
neutrophil cellular function. Oral metronidazole has been shown
to be a carcinogen in susceptible rodent species, and topical use
during pregnancy and by nursing mothers and children is there-
fore not recommended.
Adverse local effects of the water-based gel formulation
(MetroGel) include dryness, burning, and stinging. Less drying
formulations may be better tolerated (MetroCream, MetroLotion,
and Noritate cream). Caution should be exercised when applying
metronidazole near the eyes to avoid excessive tearing.
Ivermectin
Topical ivermectin is available as a 1% cream (Soolantra) for the
treatment of inflammatory lesions of rosacea. The mechanism
of action is unknown. Oral ivermectin has antiparasitic activity
against Demodex mites and possibly an anti-inflammatory effect.
Topical application is well tolerated with occasional complaints of
burning and irritation.
Sodium Sulfacetamide
Topical sulfacetamide is available alone as a 10% lotion (Klaron)
and as a 10% wash (Ovace), and in several preparations in com-
bination with sulfur for the treatment of acne vulgaris and acne
rosacea. The mechanism of action is thought to be inhibition of
1072    SECTION X  Special Topics
P acnes by competitive inhibition of p-aminobenzoic acid utili-
zation. Approximately 4% of topically applied sulfacetamide is
absorbed percutaneously, and its use is therefore contraindicated
in patients having a known hypersensitivity to sulfonamides.
Dapsone
Topical dapsone is available as a 5% and 7.5% gel (Aczone) for the
treatment of acne vulgaris. The mechanism of action is unknown.
Topical use in patients with glucose-6-phosphate dehydrogenase
(G6PD) deficiency has not been shown to cause clinically relevant
hemolysis or anemia, but a slight decrease in hemoglobin concen-
tration was noted in patients with G6PD deficiency, suggestive of
mild hemolysis. Cases of methemoglobinemia have been reported
in association with topical dapsone gel, and its use should be
avoided in patients with congenital or idiopathic methemoglo-
binemia. Adverse local side effects include mild dryness, redness,
oiliness, and skin peeling. Application of dapsone gel followed by
benzoyl peroxide may result in a temporary yellow discoloration
of the skin and hair.
■■ ANTIFUNGAL AGENTS
The treatment of superficial fungal infections caused by derma-
tophytic fungi may be accomplished (1) with topical antifungal
agents, eg, clotrimazole, efinaconazole, econazole, ketoconazole,
luliconazole, miconazole, oxiconazole, sertaconazole, sulconazole,
ciclopirox olamine, naftifine, terbinafine, butenafine, and tol-
naftate; or (2) with orally administered agents, ie, griseofulvin,
terbinafine, fluconazole, and itraconazole. Their mechanisms of
action are described in Chapter 48. Superficial infections caused
by Candida species may be treated with topical applications of
clotrimazole, miconazole, econazole, ketoconazole, oxiconazole,
ciclopirox olamine, nystatin, or amphotericin B.
TOPICAL ANTIFUNGAL
PREPARATIONS
TOPICAL AZOLE DERIVATIVES
The topical imidazoles, which include clotrimazole, econazole,
ketoconazole, luliconazole, miconazole, oxiconazole, sertacon-
azole, and sulconazole, have a wide range of activity against
dermatophytes (Epidermophyton, Microsporum, and Trichophyton)
and yeasts, including Candida albicans and Pityrosporum orbiculare
(see Chapter 48).
Miconazole (Monistat, Micatin) is available for topical appli-
cation as a cream or lotion and as vaginal cream or suppositories
for use in vulvovaginal candidiasis. Clotrimazole (Lotrimin,
Mycelex) is available for topical application to the skin as a cream
or lotion and as vaginal cream and tablets for use in vulvovaginal
candidiasis.
Efinaconazole (Jublia) is available as a 10% solution for
the treatment of onychomycosis of the toenails. Daily applica-
tion to affected toenails should be continued for 48 weeks.
Complete cure rates in clinical trials are between 15% and 18%.
Econazole (Spectazole) is available as a cream for topical applica-
tion. Oxiconazole (Oxistat) is available as a cream and lotion for
topical use. Ketoconazole (Nizoral) is available as a cream for
topical treatment of dermatophytosis and candidiasis and as a
shampoo or foam for the treatment of seborrheic dermatitis. Luli-
conazole (Luzu) is available as a cream. Sulconazole (Exelderm)
is available as a cream or solution. Sertaconazole (Ertaczo) is
available as a cream. Topical antifungal-corticosteroid fixed com-
binations have been introduced on the basis of providing more
rapid symptomatic improvement than an antifungal agent alone.
Clotrimazole-betamethasone dipropionate cream (Lotrisone) is
one such combination.
Once- or twice-daily application to the affected area will gen-
erally result in clearing of superficial dermatophyte infections in
2–3 weeks, although the medication should be continued until
eradication of the organism is confirmed. Paronychial and inter-
triginous candidiasis can be treated effectively by any of these
agents when applied three or four times daily. Seborrheic dermati-
tis should be treated with twice-daily applications of ketoconazole
until clinical clearing is obtained.
Adverse local reactions to the imidazoles may include stinging,
pruritus, erythema, and local irritation. Allergic contact dermatitis
is uncommon.
CICLOPIROX OLAMINE
Ciclopirox olamine is a synthetic broad-spectrum antimycotic
agent with inhibitory activity against dermatophytes, Candida
species, and P orbiculare. This agent inhibits the uptake of precur-
sors of macromolecular synthesis; the site of action is probably the
fungal cell membrane.
Pharmacokinetic studies indicate that 1–2% of the dose is
absorbed when applied as a solution on the back under an occlu-
sive dressing. Ciclopirox olamine is available as a 1% cream and
lotion (Loprox) for the topical treatment of dermatomycosis,
candidiasis, and tinea versicolor. The incidence of adverse reac-
tions has been low. Pruritus and worsening of clinical disease
have been reported. The potential for allergic contact dermatitis
is small.
Topical 8% ciclopirox olamine (Penlac nail lacquer) is approved
for the treatment of mild to moderate onychomycosis of finger-
nails and toenails. Although well tolerated with minimal side
effects, the complete cure rates in clinical trials are between 5.5%
and 8.5%.
TAVABOROLE
Tavaborole is the first oxaborole antifungal drug approved for
the treatment of toenail onychomycosis. Tavaborole blocks
fungal protein synthesis by inhibiting aminoacyl-transfer ribo-
nucleic acid synthetase. Tavaborole is available as a 5% solution
(Kerydin) that should be applied to the affected toenails once
daily for 48 weeks. Complete cure rates in clinical trials are
between 6.5% and 9.1%.

ALLYLAMINES: NAFTIFINE &
TERBINAFINE
Naftifine hydrochloride and terbinafine (Lamisil) are allylamines
that are highly active against dermatophytes but less active against
yeasts. The antifungal activity derives from selective inhibition of
squalene epoxidase, a key enzyme for the synthesis of ergosterol
(see Figure 48–1).
They are available as 1% creams and other forms for the topi-
cal treatment of dermatophytosis, to be applied on a twice-daily
dosing schedule for 1–2 weeks. Adverse reactions include local
irritation, burning sensation, and erythema. Contact with mucous
membranes should be avoided.
BUTENAFINE
Butenafine hydrochloride (Mentax) is a benzylamine that is
structurally related to the allylamines. As with the allylamines,
butenafine inhibits the epoxidation of squalene, thus blocking
the synthesis of ergosterol, an essential component of fungal cell
membranes. Butenafine is available as a 1% cream to be applied
once daily for the treatment of superficial dermatophytosis.
TOLNAFTATE
Tolnaftate is a synthetic antifungal compound effective topi-
cally against dermatophyte infections caused by Epidermophyton,
Microsporum, and Trichophyton. It is also active against P orbiculare
but not against Candida.
Tolnaftate (Aftate, Tinactin) is available as a cream, solution,
powder, or powder aerosol for application twice daily to infected
areas. Recurrences following cessation of therapy are common,
and infections of the palms, soles, and nails are usually unrespon-
sive to tolnaftate alone. The powder or powder aerosol may be
used chronically following initial treatment in patients susceptible
to tinea infections. Tolnaftate is generally well tolerated and rarely
causes irritation or allergic contact dermatitis.
NYSTATIN & AMPHOTERICIN B
Nystatin and amphotericin B are useful in the topical therapy of
C albicans infections but ineffective against dermatophytes. Nystatin
is limited to topical treatment of cutaneous and mucosal candida
infections because of its narrow spectrum and negligible absorp-
tion from the gastrointestinal tract following oral administration.
Amphotericin B has a broader antifungal spectrum and is used
intravenously in the treatment of many systemic mycoses (see
Chapter 48) and to a lesser extent in the treatment of cutaneous
Candida infections.
The recommended dosage for topical preparations of nystatin
in treating paronychial and intertriginous candidiasis is applica-
tion two or three times a day. Oral candidiasis (thrush) is treated
by holding 5 mL (infants, 2 mL) of nystatin oral suspension in
the mouth for several minutes four times daily before swallowing.
CHAPTER 61  Dermatologic Pharmacology    1073
An alternative therapy for thrush is to retain a vaginal tablet in the
mouth until dissolved four times daily. Recurrent or recalcitrant
perianal, vaginal, vulvar, and diaper area candidiasis may respond
to oral nystatin, 0.5–1 million units in adults (100,000 units in
children) four times daily, in addition to local therapy. Vulvo-
vaginal candidiasis may be treated by insertion of 1 vaginal tablet
twice daily for 14 days, then nightly for an additional 14–21 days.
Amphotericin B (Fungizone) is available for topical use in
cream and lotion form. The recommended dosage in the treat-
ment of paronychial and intertriginous candidiasis is application
two to four times daily to the affected area.
Adverse effects associated with oral administration of nystatin
include mild nausea, diarrhea, and occasional vomiting. Topical
application is nonirritating, and allergic contact hypersensitivity
is exceedingly uncommon. Topical amphotericin B is well toler-
ated and only occasionally locally irritating. The drug may cause a
temporary yellow staining of the skin, especially when the cream
vehicle is used.
ORAL ANTIFUNGAL AGENTS
ORAL AZOLE DERIVATIVES
Azole derivatives currently available for oral treatment of candida
and dermatophyte infections include fluconazole (Diflucan) and
itraconazole (Sporanox). As discussed in Chapter 48, imidazole
derivatives act by affecting the permeability of the cell membrane
of sensitive cells through alterations of the biosynthesis of lipids,
especially sterols, in the fungal cell.
Fluconazole and itraconazole are effective in the therapy of
cutaneous infections caused by Epidermophyton, Microsporum,
and Trichophyton species as well as Candida. Tinea versicolor is
responsive to short courses of oral azoles.
Fluconazole is well absorbed following oral administration,
with a plasma half-life of 30 hours. In view of this long half-
life, daily doses of 100 mg are sufficient to treat mucocutaneous
candidiasis; alternate-day doses are sufficient for dermatophyte
infections. The plasma half-life of itraconazole is similar to that
of fluconazole, and detectable therapeutic concentrations remain
in the stratum corneum for up to 28 days following termina-
tion of therapy. Itraconazole is effective for the treatment of
onychomycosis in a dosage of 200 mg daily taken with food to
ensure maximum absorption for 3 consecutive months. Recent
reports of heart failure in patients receiving itraconazole for
onychomycosis have resulted in recommendations that it not
be given for treatment of onychomycosis in patients with ven-
tricular dysfunction. Additionally, routine evaluation of hepatic
function is recommended for patients receiving itraconazole for
onychomycosis.
Administration of oral azoles with midazolam or triazolam has
resulted in elevated plasma concentrations and may potentiate
and prolong hypnotic and sedative effects of these agents. Admin-
istration with HMG-CoA reductase inhibitors has been shown to
cause a significant risk of rhabdomyolysis. Therefore, administra-
tion of the oral azoles with midazolam, triazolam, or HMG-CoA
inhibitors is contraindicated.
1074    SECTION X  Special Topics
TERBINAFINE
Terbinafine (described above) is effective given orally for the treat-
ment of onychomycosis. Recommended oral dosage is 250 mg
daily for 6 weeks for fingernail infections and 12 weeks for toe-
nail infections. Patients receiving terbinafine for onychomycosis
should be monitored closely with periodic laboratory evaluations
for possible hepatic dysfunction. Rare cases of liver failure have
occurred with the use of oral terbinafine; therefore, its use is not
recommended in patients with chronic or active liver disease.
GRISEOFULVIN
Griseofulvin, effective orally against dermatophyte infections
caused by Epidermophyton, Microsporum, and Trichophyton, is
ineffective against Candida and P orbiculare. Griseofulvin’s mecha-
nism of antifungal action is not fully understood, but it is active
only against growing cells.
Following oral administration of 1 g of microsize griseofulvin,
drug can be detected in the stratum corneum 4–8 hours later.
Reducing the particle size of the medication greatly increases drug
absorption. Formulations that contain the smallest particle size are
labeled “ultramicrosize.” Ultramicrosize griseofulvin achieves bio-
equivalent plasma levels with half the dose of microsize drug. In
addition, solubilizing griseofulvin in polyethylene glycol enhances
absorption even further. Microsized griseofulvin is available as
250 mg and 500 mg tablets, and ultramicrosized drug as 125 mg,
165 mg, 250 mg, and 330 mg tablets and as 250 mg capsules.
The usual adult dosage of the microsize form of the drug is
500 mg daily in single or divided doses with meals; occasionally,
1 g/d is indicated in the treatment of recalcitrant infections. The
pediatric dosage is 10 mg/kg of body weight daily in single or
divided doses with meals. An oral suspension is available for use
in children.
Griseofulvin is most effective in treating tinea infections of
the scalp and glabrous (nonhairy) skin. In general, infections
of the scalp respond to treatment in 4–6 weeks, and infections of
glabrous skin will respond in 3–4 weeks. Dermatophyte infections
of the nails respond only to prolonged administration. Fingernails
may respond to 6 months of therapy, whereas toenails are recal-
citrant to treatment and may require 8–18 months of therapy;
relapse almost invariably occurs.
Adverse effects seen with griseofulvin therapy include head-
aches, nausea, vomiting, diarrhea, photosensitivity, peripheral
neuritis, and occasionally mental confusion. Griseofulvin is
derived from a Penicillium mold, and cross-sensitivity with peni-
cillin may occur. It is contraindicated in patients with porphyria
or hepatic failure or those who have had hypersensitivity reac-
tions to it in the past. Its safety in pregnant patients has not been
established. Leukopenia and proteinuria have occasionally been
reported. Therefore, in patients undergoing prolonged therapy,
routine evaluation of the hepatic, renal, and hematopoietic
systems is advisable. Coumarin anticoagulant activity may be
altered by griseofulvin, and anticoagulant dosage may require
adjustment.
■■ TOPICAL ANTIVIRAL AGENTS
ACYCLOVIR, VALACYCLOVIR,
PENCICLOVIR, & FAMCICLOVIR
Acyclovir, valacyclovir, penciclovir, and famciclovir are synthetic
guanine analogs with inhibitory activity against members of the
herpesvirus family, including herpes simplex types 1 and 2. Their
mechanism of action, indications, and oral use in the treatment of
cutaneous infections are discussed in Chapter 49.
Topical acyclovir (Zovirax) is available as a 5% ointment and
50 mg buccal tablet; topical penciclovir (Denavir), as a 1% cream
for the treatment of recurrent orolabial herpes simplex virus
infection in immunocompetent adults. Adverse local reactions to
acyclovir and penciclovir may include pruritus and mild pain with
transient stinging or burning.
■■ IMMUNOMODULATORS
IMIQUIMOD
Imiquimod is available as 5% cream (Aldara) for the treatment of
external genital and perianal warts in adults, actinic keratoses on
the face and scalp, and biopsy-proven primary superficial basal
cell carcinomas on the trunk, neck, and extremities. Creams with
lower concentrations of 2.5% and 3.75% (Zyclara) are available
for the treatment of face and scalp actinic keratoses. The mecha-
nism of its action is thought to be related to imiquimod’s ability to
stimulate peripheral mononuclear cells to release interferon alpha
and to stimulate macrophages to produce interleukins-1, -6, and
-8, and tumor necrosis factor-α (TNF-α).
Imiquimod should be applied to the wart tissue three times per
week and left on the skin for 6–10 hours prior to washing off with
mild soap and water. Treatment should be continued until eradi-
cation of the warts is accomplished, but not for more than a total
of 16 weeks. Recommended treatment of actinic keratoses consists
of twice-weekly applications of the 5% cream on the contiguous
area of involvement or nightly applications of the 2.5% or 3.75%
cream. The cream is removed after approximately 8 hours with
mild soap and water. Treatment of superficial basal cell carcinoma
consists of five-times-per-week application of 5% cream to the
tumor, including a 1 cm margin of surrounding skin, for a 6-week
course of therapy.
Percutaneous absorption is minimal, with less than 0.9%
absorbed following a single-dose application. Adverse effects con-
sist of local inflammatory reactions, including pruritus, erythema,
and superficial erosion.
TACROLIMUS & PIMECROLIMUS
Tacrolimus (Protopic) and pimecrolimus (Elidel) are macrolide
immunosuppressants that have been shown to be of significant
benefit in the treatment of atopic dermatitis. Both agents inhibit
T-lymphocyte activation and prevent the release of inflammatory

cytokines and mediators from mast cells in vitro after stimula-
tion by antigen-IgE complexes. Tacrolimus is available as 0.03%
and 0.1% ointments, and pimecrolimus is available as a 1%
cream. Both are indicated for short-term and intermittent long-
term therapy for mild to moderate atopic dermatitis. Tacrolimus
0.03% ointment and pimecrolimus 1% cream are approved for
use in children older than 2 years of age, although all strengths
are approved for adult use. Recommended dosing of both agents
is twice-daily application to affected skin until clearing is noted.
Neither medication should be used with occlusive dressings. The
most common side effect of both drugs is a burning sensation in
the applied area that improves with continued use. The US Food
and Drug Administration (FDA) mandates a black box warning
regarding the long-term safety of topical tacrolimus and pimecro-
limus because of animal tumorigenicity data.
■■ ECTOPARASITICIDES
PERMETHRIN
Permethrin is toxic to Pediculus humanus, Pthirus pubis, and
Sarcoptes scabiei. Less than 2% of an applied dose is absorbed per-
cutaneously. Residual drug persists up to 10 days following appli-
cation. Resistance to permethrin is becoming more widespread.
It is recommended that permethrin 1% cream rinse (Nix) be
applied undiluted to affected areas of pediculosis for 10 minutes
and then rinsed off with warm water. For the treatment of
scabies, a single application of 5% cream (Elimite, Acticin) is
applied to the body from the neck down, left on for 8–14 hours,
and then washed off. Adverse reactions to permethrin include
transient burning, stinging, and pruritus. Cross-sensitization to
pyrethrins or chrysanthemums has been alleged but inadequately
documented.
SPINOSAD
Spinosad (Natroba) suspension is approved for the topical treat-
ment of head lice in patients 4 years of age and older. Spinosad
is derived from the fermentation of a soil Actinomyces bacterium
and is toxic to P humanus with no appreciable absorption from
topical application. It is recommended that the 0.9% suspension
be applied to the hair and scalp for 10 minutes and then rinsed
out. A repeat treatment may be applied 1 week later if live lice
are present.
IVERMECTIN
Ivermectin (Sklice) 0.5% lotion is approved for head lice treat-
ment in patients 6 months of age and older. Ivermectin is toxic
to P humanus, resulting in paralysis and death of the parasite.
The pharmacology of ivermectin is discussed in Chapter 53. The
lotion should be applied to the hair and scalp and rinsed out after
10 minutes. Ivermectin is for single use only and should not be
repeated without health care provider recommendation.
CHAPTER 61  Dermatologic Pharmacology    1075
LINDANE (HEXACHLOROCYCLOHEXANE)
The gamma isomer of hexachlorocyclohexane was commonly
called gamma benzene hexachloride, a misnomer, since no ben-
zene ring is present in this compound. Percutaneous absorption
studies using a solution of lindane in acetone have shown that
almost 10% of a dose applied to the forearm is absorbed, to be
subsequently excreted in the urine over a 5-day period. After
absorption, lindane is concentrated in fatty tissues, including the
brain.
Lindane is available as a 1% shampoo or lotion. For pedicu-
losis capitis or pubis, 30 mL of shampoo is applied to dry hair
on the scalp or genital area for 4 minutes and then rinsed off.
No additional application is indicated unless living lice are
present 1 week after treatment. Then reapplication may be
required.
Recent concerns about the toxicity of lindane have altered
treatment guidelines for its use in scabies; the current recom-
mendation calls for a single 60 mL application to the entire body
from the neck down, left on for 8–12 hours, and then washed off.
Patients should be retreated only if active mites can be demon-
strated, and never within 1 week of initial treatment.
Concerns about neurotoxicity and hematotoxicity have resulted
in warnings that lindane should be used with caution in infants,
children, and pregnant women. The current USA package insert
recommends that it not be used as a scabicide in premature infants
and in patients with known seizure disorders. Local irritation may
occur, and contact with the eyes and mucous membranes should
be avoided.
CROTAMITON
Crotamiton, N-ethyl-o-crotonotoluidide, is a scabicide with some
antipruritic properties; its mechanism of action is not known.
Studies on percutaneous absorption have revealed detectable levels
of crotamiton in the urine following a single application on the
forearm.
Crotamiton (Eurax) is available as a 10% cream or lotion. Sug-
gested guidelines for scabies treatment call for two applications
to the entire body from the chin down at 24-hour intervals, with
a cleansing bath 48 hours after the last application. Crotamiton
is an effective agent that can be used as an alternative to lindane.
Allergic contact dermatitis and primary irritation may occur,
necessitating discontinuance of therapy. Application to acutely
inflamed skin or to the eyes or mucous membranes should be
avoided.
SULFUR
Sulfur has a long history as a scabicide. Although it is nonirritat-
ing, it has an unpleasant odor, is staining, and is thus disagreeable
to use. It has been replaced by more aesthetic and effective scabi-
cides in recent years, but it remains a possible alternative drug for
use in infants and pregnant women. The usual formulation is 5%
precipitated sulfur in petrolatum.
1076    SECTION X  Special Topics
MALATHION
Malathion is an organophosphate cholinesterase inhibitor that
is hydrolyzed and inactivated by plasma carboxylesterases much
faster in humans than in insects, thereby providing a therapeutic
advantage in treating pediculosis (see Chapter 7). Malathion is
available as a 0.5% lotion (Ovide) that should be applied to the
hair when dry; 4–6 hours later, the hair is combed to remove nits
and lice.
BENZYL ALCOHOL
Benzyl alcohol (Ulesfia) is available as a 5% lotion for the treat-
ment of head lice in patients older than 6 months. The lotion is
applied to dry hair and left on for 10 minutes prior to rinsing off
with water. Because the drug is not ovicidal, the treatment must be
repeated after 7 days. Eye irritation and allergic contact dermatitis
have been reported.
■■ AGENTS AFFECTING
PIGMENTATION
HYDROQUINONE, MONOBENZONE, &
MEQUINOL
Hydroquinone, monobenzone (Benoquin, the monobenzyl ether
of hydroquinone), and mequinol (the monomethyl ether of
hydroquinone) are used to reduce hyperpigmentation of the
skin. Topical hydroquinone and mequinol usually result in
temporary lightening, whereas monobenzone causes irreversible
depigmentation.
The mechanism of action of these compounds appears to
involve inhibition of the enzyme tyrosinase, thus interfering with
the biosynthesis of melanin. In addition, monobenzone may be
toxic to melanocytes, resulting in permanent loss of these cells.
Some percutaneous absorption of these compounds takes place,
because monobenzone may cause hypopigmentation at sites dis-
tant from the area of application. Both hydroquinone and mono-
benzone may cause local irritation. Allergic contact dermatitis to
these compounds can occur. Prescription combinations of hydro-
quinone, fluocinolone acetonide, and retinoic acid (Tri-Luma)
and mequinol and retinoic acid (Solagé) are more effective than
their individual components.
TRIOXSALEN & METHOXSALEN
Trioxsalen and methoxsalen are psoralens used for the repigmen-
tation of depigmented macules of vitiligo. With the development
of high-intensity long-wave ultraviolet fluorescent lamps, photo-
chemotherapy with oral methoxsalen for psoriasis and with oral
trioxsalen for vitiligo has been under intensive investigation.
Psoralens must be photoactivated by long-wavelength ultra-
violet light in the range of 320–400 nm (ultraviolet A [UVA]) to
produce a beneficial effect. Psoralens intercalate with DNA, and
with subsequent UVA irradiation, cyclobutane adducts are formed
with pyrimidine bases. Both monofunctional and bifunctional
adducts may be formed, the latter causing interstrand cross-
links. These DNA photoproducts may inhibit DNA synthesis.
The major long-term risks of psoralen photochemotherapy are
cataracts and skin cancer.
■■ SUNSCREENS
Topical medications useful in protecting against sunlight con-
tain either chemical compounds that absorb ultraviolet light,
called sunscreens, or opaque materials such as titanium diox-
ide that reflect light, called sunshades. The three classes of
chemical compounds most commonly used in sunscreens are
p-aminobenzoic acid (PABA) and its esters, the benzophenones,
and the dibenzoylmethanes.
Most sunscreen preparations are designed to absorb ultraviolet
light in the ultraviolet B (UVB) wavelength range from 280 to
320 nm, which is the range responsible for most of the erythema
and sunburn associated with sun exposure and tanning. Chronic
exposure to light in this range induces aging of the skin and pho-
tocarcinogenesis. Para-aminobenzoic acid and its esters are the
most effective available absorbers in the B region. Ultraviolet in
the longer UVA range, 320–400 nm, is also associated with skin
aging and cancer.
The benzophenones include oxybenzone, dioxybenzone, and
sulisobenzone. These compounds provide a broader spectrum of
absorption from 250 to 360 nm, but their effectiveness in the UVB
erythema range is less than that of PABA. The dibenzoylmethanes
include Parsol and Eusolex. These compounds absorb wavelengths
throughout the longer UVA range, with maximum absorption
at 360 nm. Patients particularly sensitive to UVA wavelengths
include individuals with polymorphous light eruption, cutaneous
lupus erythematosus, and drug-induced photosensitivity. In these
patients, dibenzoylmethane-containing sunscreen may provide
improved photoprotection. Ecamsule (Mexoryl) appears to pro-
vide greater UVA protection than the dibenzoylmethanes and is
less prone to photodegradation.
The sun protection factor (SPF) of a given sunscreen, a mea-
sure of its effectiveness in absorbing erythrogenic ultraviolet light,
is determined by measuring the minimal erythema dose with and
without the sunscreen in a group of normal people. The ratio
of the minimal erythema dose with sunscreen to the minimal
erythema dose without sunscreen is the SPF.
FDA regulations limit the claimed maximum SPF value on
sunscreen labels to 50+ because data are insufficient to show that
products with SPF values higher than 50 provide greater protection
for users. These regulations require that sunscreens labeled “broad
spectrum” pass a standard test comparing the amount of UVA
radiation protection in relation to the amount of UVB protection.
Broad spectrum sunscreens with SPF values of 15 or higher help
protect against not only sunburn, but also skin cancer and early
skin aging when used as directed. Sunscreens with an SPF value
between 2 and 14 can only claim that they help prevent sunburn.

In addition, products claiming to be water resistant must indicate
whether they remain effective for 40 minutes or 80 minutes while
swimming or sweating, based on standard testing. These regula-
tions are poorly enforced.
■■ ACNE PREPARATIONS
RETINOIC ACID & DERIVATIVES
Retinoic acid, also known as tretinoin or all-trans-retinoic acid, is
the acid form of vitamin A. It is an effective topical treatment for
acne vulgaris. Several analogs of vitamin A, eg, 13-cis-retinoic acid
(isotretinoin), have been shown to be effective in various dermato-
logic diseases when given orally. Vitamin A alcohol is the physio-
logic form of vitamin A. The topical therapeutic agent, retinoic
acid, is formed by the oxidation of the alcohol group, with all four
double bonds in the side chain in the trans configuration as shown.
H3C CH3
CH3 CH3
COOH
9 13
CH3
Retinoic acid
Retinoic acid is insoluble in water but soluble in many organic
solvents. Topically applied retinoic acid remains chiefly in the epi-
dermis, with less than 10% absorption into the circulation. The
small quantities of retinoic acid absorbed following topical appli-
cation are metabolized by the liver and excreted in bile and urine.
Retinoic acid has several effects on epithelial tissues. It sta-
bilizes lysosomes, increases ribonucleic acid polymerase activity,
increases prostaglandin E2, cAMP, and cGMP levels, and increases
the incorporation of thymidine into DNA. Its action in acne has
been attributed to decreased cohesion between epidermal cells and
increased epidermal cell turnover. This is thought to result in the
expulsion of open comedones and the transformation of closed
comedones into open ones.
Topical retinoic acid is applied initially in a concentration
sufficient to induce slight erythema with mild peeling. The con-
centration or frequency of application may be decreased if too
much irritation occurs. Topical retinoic acid should be applied to
dry skin only, and care should be taken to avoid contact with the
corners of the nose, eyes, mouth, and mucous membranes. During
the first 4–6 weeks of therapy, comedones not previously evident
may appear and give the impression that the acne has been aggra-
vated by the retinoic acid. However, with continued therapy, the
lesions will clear, and in 8–12 weeks optimal clinical improvement
should occur. A timed-release formulation of tretinoin containing
microspheres (Retin-A Micro) delivers the medication over time
and may be less irritating for sensitive patients.
The effects of tretinoin on keratinization and desquamation
offer benefits for patients with photo-damaged skin. Prolonged
use of tretinoin promotes dermal collagen synthesis, new blood
vessel formation, and thickening of the epidermis, which helps
CHAPTER 61  Dermatologic Pharmacology    1077
diminish fine lines and wrinkles. Specially formulated moistur-
izing 0.05% cream (Renova, Refissa) is marketed for this purpose.
The most common adverse effects of topical retinoic acid are
erythema and dryness that occur in the first few weeks of use, but
these can be expected to resolve with continued therapy. Animal
studies suggest that this drug may increase the tumorigenic poten-
tial of ultraviolet radiation. In light of this, patients using retinoic
acid should be advised to avoid or minimize sun exposure and
use a protective sunscreen. Allergic contact dermatitis to topical
retinoic acid is rare.
Adapalene (Differin) is a derivative of naphthoic acid that
resembles retinoic acid in structure and effects. It is available for
daily application as a 0.1% gel, cream, or lotion and a 0.3% gel.
The 0.1% gel has recently been approved by the FDA for over-
the-counter sale. Unlike tretinoin, adapalene is photochemically
stable and shows little decrease in efficacy when used in combina-
tion with benzoyl peroxide. Adapalene is less irritating than treti-
noin and is most effective in patients with mild to moderate acne
vulgaris. Adapalene is also available in a fixed-dose combination
gel with benzoyl peroxide (Epiduo, Epiduo Forte).
Tazarotene (Tazorac, Fabior) is an acetylenic retinoid available
as a 0.1% gel, cream, and foam for the treatment of mild to moder-
ately severe facial acne. Topical tazarotene should be used by women
of childbearing age only after contraceptive counseling. It is recom-
mended that tazarotene should not be used by pregnant women.
ISOTRETINOIN
Isotretinoin is a synthetic retinoid currently restricted to the oral
treatment of severe cystic acne that is recalcitrant to standard
therapies. The precise mechanism of action of isotretinoin in
cystic acne is not known, although it appears to act by inhibiting
sebaceous gland size and function. The drug is well absorbed, is
extensively bound to plasma albumin, and has an elimination
half-life of 10–20 hours. A lipid solubilized formulation, CIP-
isotretinoin (Absorica), has been approved that provides more
consistent absorption and can be taken with or without food.
Most patients with cystic acne respond to 1–2 mg/kg, given in
two divided doses daily for 4–5 months. If severe cystic acne per-
sists following this initial treatment, after a period of 2 months, a
second course of therapy may be initiated. Common adverse effects
resemble hypervitaminosis A and include dryness and itching of the
skin and mucous membranes. Less common side effects are head-
ache, corneal opacities, pseudotumor cerebri, inflammatory bowel
disease, anorexia, alopecia, and muscle and joint pains. These effects
are all reversible on discontinuance of therapy. Skeletal hyperostosis
has been observed in patients receiving isotretinoin with premature
closure of epiphyses noted in children treated with this medication.
Lipid abnormalities (triglycerides, high-density lipoproteins) are
frequent; their clinical relevance is unknown at present.
Teratogenicity is a significant risk in patients taking isotreti-
noin; therefore, the FDA mandates that women of childbearing
potential must use an effective form of contraception for at least
1 month before, throughout isotretinoin therapy, and for one or
more menstrual cycles following discontinuance of treatment.
1078    SECTION X  Special Topics
A negative serum pregnancy test must be obtained within 2 weeks
before starting therapy in these patients, and therapy should be
initiated only on the second or third day of the next normal men-
strual period. In the USA, health care professionals, pharmacists,
and patients must utilize the mandatory iPLEDGE registration
and follow-up system.
BENZOYL PEROXIDE
Benzoyl peroxide, an effective topical agent in acne vulgaris treat-
ment, penetrates the stratum corneum or follicular openings
unchanged and is converted metabolically to benzoic acid within
the epidermis and dermis. Less than 5% of an applied dose is
absorbed from the skin in an 8-hour period. It has been postulated
that the mechanism of action of benzoyl peroxide in acne is related
to its antimicrobial activity against P acnes and to its peeling and
comedolytic effects.
To decrease the likelihood of irritation, application should
be limited to a low concentration (2.5%) once daily for the first
week of therapy and increased in frequency and strength if the
preparation is well tolerated. Fixed-combination formulations of
5% benzoyl peroxide with 3% erythromycin base (Benzamycin)
or 1% clindamycin (BenzaClin, Duac); 3.75% benzoyl peroxide
with 1.2% clindamycin (Onexton); and 2.5% benzoyl peroxide
with 1.2% clindamycin (Acanya) or 0.1% adapalene (Epiduo)
appear to be more effective than individual agents alone.
Benzoyl peroxide is a potent contact sensitizer in experimental
studies, and this adverse effect may occur in up to 1% of acne
patients. Care should be taken to avoid contact with the eyes and
mucous membranes. Benzoyl peroxide is an oxidant and may
rarely cause bleaching of the hair or colored fabrics.
AZELAIC ACID
Azelaic acid is a straight-chain saturated dicarboxylic acid that
is effective in the treatment of acne vulgaris (Azelex) and acne
rosacea (Finacea, Finacea foam). Its mechanism of action has
not been fully determined, but preliminary studies demonstrate
antimicrobial activity against P acnes as well as in vitro inhibitory
effects on the conversion of testosterone to dihydrotestosterone.
Initial therapy is begun with once-daily applications of the 20%
cream, 15% gel, or 15% foam to the affected areas for 1 week and
twice-daily applications thereafter. Most patients experience mild
irritation with redness and dryness of the skin during the first
week of treatment. Clinical improvement is noted in 6–8 weeks
of continuous therapy.
BRIMONIDINE
Brimonidine (Mirvaso) is an α2-adrenergic agonist indicated for
the topical treatment of persistent facial erythema of rosacea in
adults 18 years of age or older. Daily topical application of bri-
monidine 0.33% gel may reduce erythema through direct vaso-
constriction. Exacerbation of facial erythema and flushing may
occur, ranging from 30 minutes to several hours after application.
Alpha2 agonists can lower blood pressure (see Chapter 11); there-
fore, brimonidine should be used with caution in patients with
severe, unstable, or uncontrolled cardiovascular disease.
■■ DRUGS FOR PSORIASIS
ACITRETIN
Acitretin (Soriatane), a metabolite of the aromatic retinoid etreti-
nate, is effective in the treatment of psoriasis, especially pustular
forms. It is given orally at a dosage of 25–50 mg/d. Adverse effects
attributable to acitretin therapy are similar to those seen with
isotretinoin and resemble hypervitaminosis A. Elevations in cho-
lesterol and triglycerides may be noted with acitretin, and hepato-
toxicity with liver enzyme elevations has been reported. Acitretin
is more teratogenic than isotretinoin in the animal species studied
to date, which is of special concern in view of the drug’s prolonged
elimination time (more than 3 months) after chronic administra-
tion. In cases where etretinate is formed by concomitant adminis-
tration of acitretin and ethanol, etretinate may be found in plasma
and subcutaneous fat for many years.
Acitretin must not be used by women who are pregnant or may
become pregnant while undergoing treatment or at any time for
at least 3 years after treatment is discontinued. Ethanol must be
strictly avoided during treatment with acitretin and for 2 months
after discontinuing therapy. Patients must not donate blood
during treatment and for 3 years after acitretin is stopped.
TAZAROTENE
Tazarotene (Tazorac) is a topical acetylenic retinoid prodrug that
is hydrolyzed to its active form by an esterase. The active metabo-
lite, tazarotenic acid, binds to retinoic acid receptors, resulting in
modified gene expression. The precise mechanism of action in
psoriasis is unknown but may relate to both anti-inflammatory
and antiproliferative actions. Tazarotene is absorbed percutane-
ously, and teratogenic systemic concentrations may be achieved if
applied to more than 20% of total body surface area. Women of
childbearing potential must therefore be advised of the risk prior
to initiating therapy, and adequate birth control measures must be
utilized while on therapy.
Treatment of psoriasis should be limited to once-daily applica-
tion of either 0.05% or 0.1% gel not to exceed 20% of total body
surface area. Adverse local effects include a burning or stinging
sensation (sensory irritation) and peeling, erythema, and localized
edema of the skin (irritant dermatitis). Potentiation of photosensi-
tizing medication may occur, and patients should be cautioned to
minimize sunlight exposure and to use sunscreens and protective
clothing.
CALCIPOTRIENE & CALCITRIOL
Calcipotriene (Dovonex, Sorilux) is a synthetic vitamin D3 deriva-
tive (available as a 0.005% cream, scalp lotion, and foam) that
is effective in the treatment of plaque-type psoriasis vulgaris of
 CHAPTER 61  Dermatologic Pharmacology    1079

TABLE 61–2  Biologic agents for psoriasis. APREMILAST

Biologic Agent Usual Adult Dosage Apremilast (Otezla) is an oral phosphodiesterase 4 (PDE4) inhibitor
Adalimumab—Humira 80 mg SC × 1, then 40 mg q2 weeks that is effective in treating moderate to severe plaque psoriasis. Selec-
Etanercept—Enbrel 50 mg SC twice/week × 12 weeks, then tive inhibition of PDE4 specific for cyclic adenosine monophos-
once/week phate (cAMP) results in increased intracellular cAMP levels. The
Infliximab—Remicade 5 mg/kg IV at 0, 2, and 6 weeks, then specific mechanism by which apremilast exerts its therapeutic effect
q8 weeks in psoriasis is not known. Initial dosage titration from day 1 to day
Ixekizumab—Taltz 160 mg at 0 weeks and 80 mg at 2, 4, 6, 8, 5, intended to reduce the gastrointestinal symptoms associated with
10, and 12 weeks, then q4 weeks starting therapy, is shown in Table 61–3. Following the 5-day titra-
Secukinumab—Cosentyx 300 mg SC at 0, 1, 2, 3, and 4 weeks, then tion, a maintenance dose of 30 mg twice daily is started on day 6.
q4 weeks Treatment with apremilast is associated with an increased inci-
Ustekinumab—Stelara Either 45 mg or 90 mg SC at 0 and 4 weeks, dence of depression. Patients should have their weight monitored
then q12 weeks (dose for psoriasis is regularly due to possible weight loss associated with therapy. Use
45 mg for patients weighing ≤100 kg and of cytochrome P450 enzyme inducers (see chapter 4) may result
90 mg for those weighing ≥100 kg)
in a loss of efficacy and is not recommended. Apremilast is gener-
ally well tolerated with mild gastrointestinal complaints occurring
early in the course of treatment that resolve with time.

moderate severity. Improvement of psoriasis is generally noted FUMARIC ACID ESTERS

following 2 weeks of therapy, with continued improvement for
up to 8 weeks of treatment. However, fewer than 10% of patients
demonstrate total clearing while on calcipotriene as single-agent
therapy. Adverse effects include burning, itching, and mild irri-
tation, with dryness and erythema of the treatment area. Care
should be taken to avoid facial contact, which may cause ocular
irritation. A once-daily two-compound ointment (Taclonex)
or foam (Enstilar) containing calcipotriene and betamethasone
dipropionate are available. This combination is more effective
than its individual ingredients and is well tolerated, with a safety
profile similar to betamethasone dipropionate.
Calcitriol (Vectical) contains 1,25-dihydroxycholecalciferol,
the hormonally active form of vitamin D3. Calcitriol 3 mcg/g
ointment is similar in efficacy to calcipotriene 0.005% ointment
for the treatment of plaque-type psoriasis on the body and is better
tolerated in intertriginous and sensitive areas of the skin. Clinical
studies show comparable safety data regarding adverse cutaneous
and systemic reactions between topical calcitriol and calcipotriene
ointment.
BIOLOGIC AGENTS
Biologic agents useful in treating adult patients with moderate
to severe chronic plaque psoriasis include the TNF-α inhibitors
adalimumab, etanercept, and infliximab, and the cytokine inhibi-
tors ixekizumab, secukinumab, and ustekinumab (Table 61–2).
The pharmacology of these agents is discussed in Chapters 36
and 55.
Fumaric acid esters (Fumaderm) are licensed in Germany for the oral
treatment of psoriasis. They are considered homeopathic treatment
in the USA and are not approved or regulated by the FDA for the
treatment of psoriasis. Dimethyl fumarate (Tecfidera) has recently
been approved by the FDA for treatment of multiple sclerosis. The
mechanism of action of dimethyl fumarate in psoriasis may be due
to immunomodulatory effects on lymphocytes and keratinocytes,
resulting in a shift away from a psoriatic cytokine profile. Note that
four cases of progressive multifocal leukoencephalopathy have been
reported in psoriasis patients treated with fumaric acid esters.
■■ ANTI-INFLAMMATORY AGENTS
TOPICAL CORTICOSTEROIDS
The remarkable efficacy of topical corticosteroids in the treatment of
inflammatory dermatoses was noted soon after the introduction of
hydrocortisone in 1952. Numerous analogs are now available that
offer extensive choices of potencies, concentrations, and vehicles.
The therapeutic effectiveness of topical corticosteroids is based pri-
marily on their anti-inflammatory activity. Definitive explanations
of the effects of corticosteroids on endogenous mediators of inflam-
mation await further experimental clarification. The antimitotic
effects of corticosteroids on human epidermis may account for an
additional mechanism of action in psoriasis and other dermatologic
diseases associated with increased cell turnover. The general pharma-
cology of these endocrine agents is discussed in Chapter 39.

TABLE 61–3  Apremilast dosage titration schedule.

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 & Thereafter

AM AM PM AM PM AM PM AM PM AM PM

10 mg 10 mg 10 mg 10 mg 20 mg 20 mg 20 mg 20 mg 30 mg 30 mg 30 mg
1080    SECTION X  Special Topics

Chemistry & Pharmacokinetics
The original topical glucocorticosteroid was hydrocortisone, the
natural glucocorticosteroid of the adrenal cortex. The 9α-fluoro
derivative of hydrocortisone was active topically, but its salt-
retaining properties made it undesirable even for topical use.
Prednisolone and methylprednisolone are as active topically
as hydrocortisone (Table 61–4). The 9α-fluorinated steroids
dexamethasone and betamethasone did not have any advantage
over hydrocortisone. However, triamcinolone and fluocinolone,
the acetonide derivatives of the fluorinated steroids, do have a
distinct efficacy advantage in topical therapy. Similarly, beta-
methasone is not very active topically, but attaching a 5-carbon
valerate chain to the 17-hydroxyl position results in a compound
over 300 times as active as hydrocortisone for topical use. Fluo-
cinonide is the 21-acetate derivative of fluocinolone acetonide;
the addition of the 21-acetate enhances the topical activity
about fivefold. Fluorination of the corticoid is not required for
high potency.
Corticosteroids are only minimally absorbed following applica-
tion to normal skin; for example, approximately 1% of a dose of
hydrocortisone solution applied to the ventral forearm is absorbed.
Long-term occlusion with an impermeable film such as plastic
wrap is an effective method of enhancing penetration, yielding
a tenfold increase in absorption. There is a marked regional ana-
tomic variation in corticosteroid penetration. Compared with the
absorption from the forearm, hydrocortisone is absorbed 0.14
times as well through the plantar foot arch, 0.83 times as well
through the palm, 3.5 times as well through the scalp, 6 times as
well through the forehead, 9 times as well through vulvar skin,
and 42 times as well through scrotal skin. Penetration is increased
severalfold in the inflamed skin of atopic dermatitis; and in severe
exfoliative diseases, such as erythrodermic psoriasis, there appears
to be little barrier to penetration.

TABLE 61–4   Relative efficacy of some topical corticosteroids in various formulations.

Concentration in Concentration in
Commonly Used Commonly Used
Preparations Drug Preparations Drug

Lowest efficacy Intermediate efficacy (continued)

0.25–2.5% Hydrocortisone 0.05% Fluticasone propionate (Cutivate)
0.25% Methylprednisolone acetate (Medrol) 0.05% Desonide (Desowen)
1
0.1% Dexamethasone (Decaderm) 0.025% Halcinonide1 (Halog)
1.0% Methylprednisolone acetate (Medrol) 0.05% Desoximetasone1 (Topicort L.P.)
0.5% Prednisolone (MetiDerm) 0.05% Flurandrenolide1 (Cordran)
0.2% Betamethasone1 (Celestone) 0.1% Triamcinolone acetonide1
Low efficacy 0.025% Fluocinolone acetonide1
1
0.01% Fluocinolone acetonide (Fluonid, Synalar) High efficacy
1
0.01% Betamethasone valerate (Valisone) 0.05% Fluocinonide1 (Lidex)
0.025% Fluorometholone1 (Oxylone) 0.05% Betamethasone dipropionate1 (Diprosone,
Maxivate)
0.05% Alclometasone dipropionate (Aclovate)
0.1% Amcinonide1 (Cyclocort)
0.025% Triamcinolone acetonide1 (Aristocort,
Kenalog, Triacet) 0.25% Desoximetasone1 (Topicort)
0.1% Clocortolone pivalate1 (Cloderm) 0.5% Triamcinolone acetonide1
0.03% Flumethasone pivalate1 (Locorten) 0.2% Fluocinolone acetonide1 (Synalar-HP)
Intermediate efficacy 0.05% Diflorasone diacetate1 (Florone, Maxiflor)
0.2% Hydrocortisone valerate (Westcort) 0.1% Halcinonide1 (Halog)
0.1% Mometasone furoate (Elocon) Highest efficacy
0.1% Hydrocortisone butyrate (Locoid) 0.05% Betamethasone dipropionate in optimized
vehicle (Diprolene)1
0.1% Hydrocortisone probutate (Pandel)
0.05% Diflorasone diacetate1 in optimized vehicle
0.025% Betamethasone benzoate1 (Uticort) (Psorcon)
0.025% Flurandrenolide1 (Cordran) 0.05% Halobetasol propionate1 (Ultravate)
1
0.1% Betamethasone valerate (Valisone) 0.05% Clobetasol propionate1 (Temovate)
0.1% Prednicarbate (Dermatop)
1
Fluorinated steroids.

Experimental studies on the percutaneous absorption of hydro-
cortisone fail to reveal a significant increase in absorption when
applied on a repetitive basis and a single daily application may be
effective in most conditions. Ointment bases tend to give better
activity to the corticosteroid than do cream or lotion vehicles.
Increasing the concentration of a corticosteroid increases the pen-
etration but not proportionately. For example, approximately 1%
of a 0.25% hydrocortisone solution is absorbed from the forearm.
A tenfold increase in concentration causes only a fourfold increase
in absorption. Solubility of the corticosteroid in the vehicle is a
significant determinant of the percutaneous absorption of a topi-
cal steroid. Marked increases in efficacy are noted when optimized
vehicles are used, as demonstrated by newer formulations of
betamethasone dipropionate and diflorasone diacetate.
Table 61–4 groups topical corticosteroid formulations accord-
ing to approximate relative efficacy. Table 61–5 lists major der-
matologic diseases in order of their responsiveness to these drugs.
TABLE 61–5  Dermatologic disorders responsive to
topical corticosteroids ranked in order
of sensitivity.
Very responsive
  Atopic dermatitis
  Seborrheic dermatitis
  Lichen simplex chronicus
  Pruritus ani
  Later phase of allergic contact dermatitis
  Later phase of irritant dermatitis
  Nummular eczematous dermatitis
  Stasis dermatitis
  Psoriasis, especially of genitalia and face
Less responsive
  Discoid lupus erythematosus
  Psoriasis of palms and soles
  Necrobiosis lipoidica diabeticorum
 Sarcoidosis
  Lichen striatus
 Pemphigus
  Familial benign pemphigus
 Pemphigoid
 Vitiligo
  Granuloma annulare
Least responsive: Intralesional injection required
 Keloids
  Hypertrophic scars
  Hypertrophic lichen planus
  Alopecia areata
  Acne cysts
  Prurigo nodularis
  Chondrodermatitis nodularis chronica helicis
CHAPTER 61  Dermatologic Pharmacology    1081
In the first group of diseases, low- to medium-efficacy corticoste-
roid preparations often produce clinical remission. In the second
group, it is often necessary to use high-efficacy preparations,
occlusion therapy, or both. Once a remission has been achieved,
every effort should be made to maintain the improvement with a
low-efficacy corticosteroid.
The limited penetration of topical corticosteroids can be
overcome in certain clinical circumstances by the intralesional
injection of relatively insoluble corticosteroids, eg, triamcinolone
acetonide, triamcinolone diacetate, triamcinolone hexacetonide,
and betamethasone acetate-phosphate. When these agents are
injected into the lesion, measurable amounts remain in place
and are gradually released for 3–4 weeks. This form of therapy is
often effective for the lesions listed in Table 61–5 that are gener-
ally unresponsive to topical corticosteroids. The dosage of the
triamcinolone salts should be limited to 1 mg per treatment site,
ie, 0.1 mL of 10 mg/mL suspension, to decrease the incidence of
local atrophy (see below).
Adverse Effects
All absorbable topical corticosteroids possess the potential to sup-
press the pituitary-adrenal axis (see Chapter 39). Although most
patients with pituitary-adrenal axis suppression demonstrate only
a laboratory test abnormality, cases of severely impaired stress
response can occur. Iatrogenic Cushing’s syndrome may occur as
a result of protracted use of topical corticosteroids in large quanti-
ties. Applying potent corticosteroids to extensive areas of the body
for prolonged periods, with or without occlusion, increases the
likelihood of systemic effects. Fewer of these factors are required to
produce adverse systemic effects in children, and growth retarda-
tion is of particular concern in the pediatric age group.
Adverse local effects of topical corticosteroids include the fol-
lowing: atrophy, which may present as depressed, shiny, often
wrinkled “cigarette paper”-appearing skin with prominent tel-
angiectases and a tendency to develop purpura and ecchymosis;
corticoid rosacea, with persistent erythema, telangiectatic vessels,
pustules, and papules in central facial distribution; perioral der-
matitis, steroid acne, alterations of cutaneous infections, hypopig-
mentation, and hypertrichosis; increased intraocular pressure;
and allergic contact dermatitis. The latter may be confirmed by
patch testing with high concentrations of corticosteroids, ie, 1%
in petrolatum, because topical corticosteroids are not irritating.
Screening for allergic contact dermatitis potential is performed
with tixocortol pivalate, budesonide, and hydrocortisone valerate
or butyrate. Topical corticosteroids are contraindicated in individ-
uals who demonstrate hypersensitivity to them. Some sensitized
subjects develop a generalized flare when dosed with adrenocorti-
cotropic hormone or oral prednisone. Systemic corticosteroid use
is discussed in Chapter 39.
CRISABOROLE
Crisaborole (Eucrisa) is a benzoxaborole, nonsteroidal, topi-
cal, anti-inflammatory PDE4 inhibitor approved as a 2% oint-
ment for the treatment of mild-to-moderate atopic dermatitis
1082    SECTION X  Special Topics
in patients 2 years of age and older. The most frequent adverse
effect is burning or stinging at the site of application. The specific
mechanism of action in atopic dermatitis is unknown. Long-term
safety in clinical application remains to be determined.
TAR COMPOUNDS
Tar preparations are used mainly in the treatment of psoriasis,
dermatitis, and lichen simplex chronicus. The phenolic constitu-
ents endow these compounds with antipruritic properties, making
them particularly valuable in the treatment of chronic lichenified
dermatitis. Acute dermatitis with vesiculation and oozing may be
irritated by even weak tar preparations, which should be avoided.
However, in the subacute and chronic stages of dermatitis and
psoriasis, these preparations are quite useful and offer an alterna-
tive to the use of topical corticosteroids.
The most common adverse reaction to coal tar compounds is
an irritant folliculitis, necessitating discontinuance of therapy to
the affected areas for a period of 3–5 days. Photoirritation and
allergic contact dermatitis may also occur. Tar preparations should
be avoided in patients who have previously exhibited sensitivity
to them.
■■ KERATOLYTIC & DESTRUCTIVE
AGENTS
SALICYLIC ACID
Salicylic acid has been extensively used in dermatologic therapy
as a keratolytic agent. The mechanism by which it produces its
keratolytic and other therapeutic effects is poorly understood.
The drug may solubilize cell surface proteins that keep the stra-
tum corneum intact, thereby resulting in desquamation of kera-
totic debris. Salicylic acid is keratolytic in concentrations of
3–6%. In concentrations greater than 6%, it can be destructive
to tissues.
COOH
OH
Salicylic acid
Salicylism and death have occurred following topical applica-
tion. In an adult, 1 g of a topically applied 6% salicylic acid prepa-
ration will raise the serum salicylate level not more than 0.5 mg/
dL of plasma; the threshold for toxicity is 30–50 mg/dL. Higher
serum levels are possible in children, who are therefore at a greater
risk for salicylism. In cases of severe intoxication, hemodialysis is
the treatment of choice (see Chapter 58). It is advisable to limit
both the total amount of salicylic acid applied and the frequency
of application. Urticarial, anaphylactic, and erythema multiforme
reactions may occur in patients who are allergic to salicylates.
Topical use may be associated with local irritation, acute inflam-
mation, and even ulceration with the use of high concentrations
of salicylic acid. Particular care must be exercised when using the
drug on the extremities of patients with diabetes or peripheral
vascular disease.
PROPYLENE GLYCOL
Propylene glycol is used extensively in topical preparations because
it is an excellent vehicle for organic compounds. It has been used
alone as a keratolytic agent in 40–70% concentrations, with
plastic occlusion, or in gel with 6% salicylic acid.
Only minimal amounts of a topically applied dose are absorbed
through normal stratum corneum. Percutaneously absorbed
propylene glycol is oxidized by the liver to lactic acid and pyru-
vic acid, with subsequent utilization in general body metabo-
lism. Approximately 12–45% of the absorbed agent is excreted
unchanged in the urine.
Propylene glycol is an effective keratolytic agent for the
removal of hyperkeratotic debris. It is also an effective humec-
tant and increases the water content of the stratum corneum.
The hygroscopic characteristics of propylene glycol may help it
to develop an osmotic gradient through the stratum corneum,
thereby increasing hydration of the outermost layers by drawing
water out from the inner layers of the skin.
Propylene glycol is used under polyethylene occlusion or with
6% salicylic acid for the treatment of ichthyosis, palmar and plan-
tar keratodermas, psoriasis, pityriasis rubra pilaris, keratosis pilaris,
and hypertrophic lichen planus.
In concentrations greater than 10%, propylene glycol may act
as an irritant in some patients; those with eczematous dermatitis
may be more sensitive. Allergic contact dermatitis occurs with
propylene glycol, and a 4% aqueous propylene glycol solution is
recommended for the purpose of patch testing.
UREA
Urea in a compatible cream vehicle or ointment base has a soften-
ing and moisturizing effect on the stratum corneum. It has the
ability to make creams and lotions feel less greasy, and this has
been utilized in dermatologic preparations to decrease the oily
feel of a preparation that otherwise might feel unpleasant. It is
a white crystalline powder with a slight ammonia odor when
moist.
Urea is absorbed percutaneously, although the amount
absorbed is minimal. It is distributed predominantly in the extra-
cellular space and excreted in urine. Urea is a natural product of
metabolism, and systemic toxicities with topical application do
not occur.
Urea increases the water content of the stratum corneum, pre-
sumably as a result of the hygroscopic characteristics of this natu-
rally occurring molecule. Urea is also keratolytic. The mechanism
of action appears to involve alterations in prekeratin and keratin,
leading to increased solubilization. In addition, urea may break
hydrogen bonds that keep the stratum corneum intact.

As a humectant, urea is used in concentrations of 2–20% in
creams and lotions. As a keratolytic agent, it is used in 20% con-
centration in diseases such as ichthyosis vulgaris, hyperkeratosis of
palms and soles, xerosis, and keratosis pilaris. Concentrations of
30–50% applied to the nail plate have been useful in softening the
nail prior to avulsion.
PODOPHYLLUM RESIN & PODOFILOX
Podophyllum resin, an alcoholic extract of Podophyllum peltatum,
commonly known as mandrake root or May apple, is used in the
treatment of condyloma acuminatum and other verrucae. It is a
mixture of podophyllotoxin, α and β peltatin, desoxypodophyl-
lotoxin, dehydropodophyllotoxin, and other compounds. It is
soluble in alcohol, ether, chloroform, and compound tincture of
benzoin.
Percutaneous absorption of podophyllum resin occurs, par-
ticularly in intertriginous areas and from applications to large
moist condylomas. It is soluble in lipids and therefore is distrib-
uted widely throughout the body, including the central nervous
system.
The major use of podophyllum resin is in the treatment of
condyloma acuminatum. Podophyllotoxin and its derivatives
are active cytotoxic agents with specific affinity for the micro-
tubule protein of the mitotic spindle. Normal assembly of the
spindle is prevented, and epidermal mitoses are arrested in
metaphase. A 25% concentration of podophyllum resin in com-
pound tincture of benzoin is recommended for the treatment
of condyloma acuminatum. Application should be restricted
to wart tissue only, to limit the total amount of medication
used and to prevent severe erosive changes in adjacent tissue.
In treating cases of large condylomas, it is advisable to limit
application to sections of the affected area to minimize systemic
absorption. The patient is instructed to wash off the prepara-
tion 2–3 hours after the initial application, because the irritant
reaction is variable. Depending on the individual patient’s reac-
tion, this period can be extended to 6–8 hours on subsequent
applications. If three to five applications have not resulted in
significant resolution, other methods of treatment should be
considered.
Toxic symptoms associated with excessively large applica-
tions include nausea, vomiting, alterations in sensorium, muscle
weakness, neuropathy with diminished tendon reflexes, coma,
and even death. Local irritation is common, and inadvertent
contact with the eye may cause severe conjunctivitis. Use during
pregnancy is contraindicated in view of possible cytotoxic effects
on the fetus.
Pure podophyllotoxin (podofilox) is approved for use as either
a 0.5% solution or gel (Condylox) for application by the patient
in the treatment of genital condylomas. The low concentration of
podofilox significantly reduces the potential for systemic toxicity.
Most men with penile warts may be treated with less than 70 μL
per application. At this dose, podofilox is not routinely detected
in the serum. Treatment is self-administered in treatment cycles of
twice-daily application for 3 consecutive days followed by a 4-day
CHAPTER 61  Dermatologic Pharmacology    1083
drug-free period. Local adverse effects include inflammation,
erosions, burning pain, and itching.
SINECATECHINS
Sinecatechins 15% ointment (Veregen) is a prescription botanical
drug product of a partially purified fraction of the water extract
of green tea leaves from Camellia sinensis containing a mixture of
catechins. Sinecatechins ointment is indicated for the topical treat-
ment of external genital and perianal warts in immunocompetent
patients 18 years and older. The mechanism of action is unknown.
Sinecatechins ointment should be applied three times daily to the
warts until complete clearance, not to exceed 16 weeks of therapy.
FLUOROURACIL
Fluorouracil is a fluorinated pyrimidine antimetabolite that
resembles uracil, with a fluorine atom substituted for the 5-methyl
group. Its systemic pharmacology is described in Chapter 54.
Fluorouracil is used topically for the treatment of multiple actinic
keratoses.
Approximately 6% of a topically applied dose is absorbed—an
amount insufficient to produce adverse systemic effects. Most of
the absorbed drug is metabolized and excreted as carbon dioxide,
urea, and α-fluoro-β-alanine. A small percentage is eliminated
unchanged in the urine. Fluorouracil inhibits thymidylate synthe-
tase activity, interfering with the synthesis of DNA and, to a lesser
extent, RNA. These effects are most marked in atypical, rapidly
proliferating cells.
Fluorouracil is available in multiple formulations containing
0.5%, 1%, 2%, 4%, and 5% concentrations (Carac, Efudex, Fluo-
roplex, Tolak). The response to treatment begins with erythema
and progresses through vesiculation, erosion, superficial ulcer-
ation, necrosis, and finally reepithelialization. Fluorouracil should
be continued until the inflammatory reaction reaches the stage of
ulceration and necrosis, usually in 3–4 weeks, at which time treat-
ment should be terminated. The healing process may continue for
1–2 months after therapy is discontinued. Local adverse reactions
may include pain, pruritus, a burning sensation, tenderness, and
residual postinflammatory hyperpigmentation. Excessive exposure
to sunlight during treatment may increase the intensity of the
reaction and should be avoided. Allergic contact dermatitis to
fluorouracil has been reported, and its use is contraindicated in
patients with known hypersensitivity.
INGENOL MEBUTATE
Ingenol mebutate (Picato) is derived from the sap of the Euphorbia
peplus plant and has recently been approved for the topical treat-
ment of actinic keratoses. The mechanism by which ingenol mebu-
tate induces keratinocyte cell death is unknown. For the treatment
of actinic keratoses on the face and scalp, the 0.015% gel should be
applied once daily for 3 consecutive days. For actinic keratoses on
the trunk and extremities, the 0.05% gel should be applied to the
1084    SECTION X  Special Topics
affected area daily for 2 consecutive days. Local skin reactions are
to be expected with crusting, swelling, vesiculation, and possible
ulceration. Caution must be taken to prevent eye exposure. Patients
must wash their hands well after applying the gel and avoid transfer
of the drug to the periocular area during and after application.
NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS
A topical 3% gel formulation of the nonsteroidal anti-inflamma-
tory drug diclofenac (Solaraze) has shown moderate effectiveness
in the treatment of actinic keratoses. The mechanism of action is
unknown. As with other NSAIDs, anaphylactoid reactions may
occur with diclofenac, and it should be given with caution to
patients with known aspirin hypersensitivity (see Chapter 36).
AMINOLEVULINIC ACID
Aminolevulinic acid (ALA) is an endogenous precursor of photo-
sensitizing porphyrin metabolites. When exogenous ALA is pro-
vided to the cell through topical applications, protoporphyrin IX
(PpIX) accumulates in the cell. When exposed to light of appro-
priate wavelength and energy, the accumulated PpIX produces a
photodynamic reaction resulting in the formation of cytotoxic
superoxide and hydroxyl radicals. Photosensitization of actinic
keratoses using ALA (Levulan Kerastick) and illumination with a
blue light photodynamic therapy illuminator (BLU-U) is the basis
for ALA photodynamic therapy.
Treatment consists of applying ALA 20% topical solution to
individual actinic keratoses followed by blue light photodynamic
illumination 14–18 hours later. Transient stinging or burning
at the treatment site occurs during the period of light exposure.
Patients must avoid exposure to sunlight or bright indoor lights
for at least 40 hours after ALA application. Redness, swelling, and
crusting of the actinic keratoses will occur and gradually resolve
over a 3- to 4-week time course. Allergic contact dermatitis to
methyl ester may occur.
■■ ANTIPRURITIC AGENTS
DOXEPIN
Topical doxepin hydrochloride 5% cream (Zonalon) may provide
significant antipruritic activity when utilized in the treatment
of pruritus associated with atopic dermatitis or lichen simplex
chronicus. The precise mechanism of action is unknown but may
relate to the potent H1- and H2-receptor antagonist properties of
dibenzoxepin tricyclic compounds. Percutaneous absorption is
variable and may result in significant drowsiness in some patients.
In view of the anticholinergic effect of doxepin, topical use is con-
traindicated in patients with untreated narrow-angle glaucoma or
a tendency to urinary retention.
Plasma levels of doxepin similar to those achieved during oral
therapy may be obtained with topical application; the usual drug
interactions associated with tricyclic antidepressants may occur.
Therefore, monoamine oxidase inhibitors must be discontinued
at least 2 weeks prior to the initiation of doxepin cream. Topical
application of the cream should be performed four times daily
for up to 8 days of therapy. The safety and efficacy of chronic
dosing have not been established. Adverse local effects include
marked burning and stinging of the treatment site, which may
necessitate discontinuation of the cream in some patients. Allergic
contact dermatitis appears to be frequent, and patients should be
monitored for symptoms of hypersensitivity.
PRAMOXINE
Pramoxine hydrochloride is a topical anesthetic that can provide
temporary relief from pruritus associated with mild eczematous
dermatoses. Pramoxine is available as a 1% cream, lotion, or gel
and in combination with hydrocortisone acetate. Application to the
affected area two to four times daily may provide short-term relief
of pruritus. Local adverse effects include transient burning and
stinging. Care should be exercised to avoid contact with the eyes.
■■ ANTISEBORRHEA AGENTS
Table 61–6 lists topical formulations for the treatment of sebor-
rheic dermatitis. These are of variable efficacy and may necessitate
concomitant treatment with topical corticosteroids for severe
cases.
■■ TRICHOGENIC &
ANTITRICHOGENIC AGENTS
MINOXIDIL
Topical minoxidil (Rogaine) is effective in reversing the pro-
gressive miniaturization of terminal scalp hairs associated
with androgenic alopecia. Vertex balding is more responsive
TABLE 61–6  Antiseborrhea agents.
Active Ingredient Typical Trade Name
Betamethasone valerate foam Luxiq
Chloroxine shampoo Capitrol
Coal tar shampoo Ionil-T, Pentrax, Theraplex-T, T-Gel
Fluocinolone acetonide FS Shampoo
shampoo
Ketoconazole shampoo and gel Nizoral, Xolegel
Selenium sulfide shampoo Selsun, Exsel
Zinc pyrithione shampoo DHS-Zinc, Theraplex-Z

to therapy than frontal balding. The mechanism of action
of minoxidil on hair follicles is unknown. Chronic dosing
studies have demonstrated that the effect of minoxidil is not
permanent, and cessation of treatment will lead to hair loss in
4–6 months. Percutaneous absorption of minoxidil in normal
scalp is minimal, but possible systemic effects on blood pres-
sure (see Chapter 11) should be monitored in patients with
cardiac disease.
FINASTERIDE
Finasteride (Propecia) is a 5α-reductase inhibitor that blocks the
conversion of testosterone to dihydrotestosterone (see Chapter 40),
the androgen responsible for androgenic alopecia in genetically
predisposed men. Oral finasteride, 1 mg/d, promotes hair growth
and prevents further hair loss in a significant proportion of men
with androgenic alopecia. Treatment for at least 3–6 months is
necessary to see increased hair growth or prevent further hair
loss. Continued treatment with finasteride is necessary to sustain
benefit. Reported adverse effects include decreased libido, ejacula-
tion disorders, and erectile dysfunction, which resolve in most
men who remain on therapy and in all men who discontinue
finasteride.
There are no data to support the use of finasteride in women
with androgenic alopecia. Pregnant women should not be exposed
to finasteride either by use or by handling crushed tablets because
of the risk of hypospadias developing in a male fetus.
BIMATOPROST
Bimatoprost (Latisse) is a prostaglandin analog available as a
0.03% ophthalmic solution to treat hypotrichosis of the eyelashes.
Mechanism of action is unknown. Treatment consists of nightly
application to the skin of the upper eyelid margins at the base of
the eyelashes using a separate disposable applicator for each eyelid.
Contact lenses should be removed prior to bimatoprost applica-
tion. Side effects include pruritus, conjunctival hyperemia, skin
pigmentation, and erythema of the eyelids. Although iris darken-
ing has not been reported with applications confined to the upper
eyelid skin, increased brown iris pigmentation, which is likely
to be permanent, has occurred when bimatoprost ophthalmic
solution was instilled onto the eye for glaucoma.
EFLORNITHINE
Eflornithine (Vaniqa) is an irreversible inhibitor of ornithine
decarboxylase, which catalyzes the rate-limiting step in the bio-
synthesis of polyamines. Polyamines are required for cell division
and differentiation, and inhibition of ornithine decarboxylase
affects the rate of hair growth. Topical eflornithine has been
shown effective in reducing facial hair growth in approximately
30% of women when applied twice daily for 6 months of therapy.
Hair growth was observed to return to pretreatment levels 8 weeks
CHAPTER 61  Dermatologic Pharmacology    1085
after discontinuation. Local adverse effects include stinging, burn-
ing, and folliculitis.
■■ ANTINEOPLASTIC AGENTS
The treatment of melanoma is discussed in Chapter 54.
Alitretinoin (Panretin) is a topical formulation of 9-cis-
retinoic acid that is approved for the treatment of cutaneous
lesions in patients with AIDS-related Kaposi’s sarcoma. Localized
reactions may include intense erythema, edema, and vesiculation
necessitating discontinuation of therapy. Patients who are apply-
ing alitretinoin should not concurrently use products containing
DEET, a common component of insect repellant products.
Bexarotene (Targretin), a member of a subclass of retinoids
that selectively binds and activates retinoid X receptor subtypes,
is available both in an oral formulation and as a topical gel for
the treatment of cutaneous T-cell lymphoma. Teratogenicity is
a significant risk for both systemic and topical treatment with
bexarotene, and women of childbearing potential must avoid
becoming pregnant throughout therapy and for at least 1 month
following discontinuation of the drug. Bexarotene may increase
levels of triglycerides and cholesterol; therefore, lipid levels must
be monitored during treatment.
Vismodegib (Erivedge) and sonidegib (Odomzo) are oral
hedgehog pathway inhibitors for the treatment of metastatic basal
cell carcinoma or locally advanced basal cell carcinoma in adults
who are not candidates for surgery or radiation. They are highly
effective in patients with basal cell nevus syndrome. The recom-
mended dosage of vismodegib is 150 mg daily and sonidegib is
200 mg daily. The most common adverse effects include dysgeusia
and ageusia, alopecia, fatigue, and muscle spasms.
Baseline serum creatine kinase and creatinine levels prior to
initiating therapy and during treatment may be indicated for
significant musculoskeletal symptoms.
Hedgehog pathway inhibitors are embryotoxic, fetotoxic, and
teratogenic in animals. Pregnancy status of females of reproductive
potential must be verified within 7 days prior to initiating therapy.
Exposure may occur through seminal fluid.
Vorinostat (Zolinza) and romidepsin (Istodax) are histone
deacetylase inhibitors that are approved for the treatment
of cutaneous T-cell lymphoma in patients with progressive,
persistent, or recurrent disease after prior systemic therapy.
Adverse effects include thrombocytopenia, anemia, and gas-
trointestinal disturbances. Pulmonary embolism, which has
occurred with vorinostat, has not been reported to date with
romidepsin.
■■ MISCELLANEOUS
MEDICATIONS
Drugs used primarily for other conditions may also find use as
oral therapeutic agents for dermatologic conditions. A few such
preparations are listed in Table 61–7.
1086    SECTION X  Special Topics

TABLE 61–7  Miscellaneous medications and the dermatologic conditions in which they are used.
Drug or Group Conditions For More Details, See:

Antihistamines Pruritus (any cause), urticarial Chapter 16

Antimalarials Lupus erythematosus, photosensitization Chapters 36, 52
Antimetabolites Pemphigus, pemphigoid Chapter 54
Becaplermin Diabetic neuropathic ulcers Chapter 41
Belimumab Systemic lupus erythematosus Chapters 36, 54
Capsaicin Postherpetic neuralgia Chapter 31
Corticosteroids Pemphigus, pemphigoid, lupus erythematosus, allergic contact Chapter 39
dermatoses, and certain other dermatoses
Cyclosporine Psoriasis Chapter 55
Dapsone Dermatitis herpetiformis, erythema elevatum diutinum, pemphigus, Chapter 47
pemphigoid, bullous lupus erythematosus
Denileukin diftitox Cutaneous T-cell lymphomas Chapters 54, 55
Drospirenone/ethinyl estradiol Moderate female acne Chapter 39
Mechlorethamine gel Cutaneous T-cell lymphoma Chapter 54
Methotrexate Psoriasis Chapter 54
Mycophenolate mofetil Bullous disease Chapters 54, 55
Thalidomide Erythema nodosum leprosum Chapters 54, 55

REFERENCES Agents Affecting Pigmentation

General
Bronaughs R, Maibach HI: Percutaneous Penetration: Principles and Practices,
4th ed. Taylor & Francis, 2005.
Lebwohl MG et al: Treatment of Skin Disease, 4th ed. Elsevier-Saunders, 2014.
Maibach HI, Gorouhi F: Evidence-Based Dermatology, 2nd ed. Peoples Medical
Publishing, 2012.
Wakelin S, Maibach HI, Archer CB: Systemic Drug Treatment in Dermatology,
2nd ed. CRC Press, 2015.
Wilhem, KP, Zhai H, Maibach HI: Marzulli & Maibach Dermatotoxicology, 8th ed.
Informa Healthcare, 2012.
Wolverton S: Comprehensive Dermatologic Drug Therapy, 2nd ed. Saunders, 2007.
Levitt J: The safety of hydroquinone. J Am Acad Dermatol 2007;57:854.
Stolk LML, Siddiqui AH: Biopharmaceutics, pharmacokinetics, and pharmacol-
ogy of psoralens. Gen Pharmacol 1988;19:649.
Retinoids & Other Acne Preparations
Shalita AR et al: Tazarotene gel is safe and effective in the treatment of acne vulgaris.
A multicenter, double-blind, vehicle-controlled study. Cutis 1999;63:349.
Thami GP, Sarkar R: Coal tar: Past, present and future. Clin Exp Dermatol
2002;27:99.
Tzellos T et al: Topical retinoids for the treatment of acne vulgaris. Cochrane
Database Syst Rev 2013;8:CD009470.

Antibacterial, Antifungal, & Antiviral Drugs Anti-Inflammatory Agents

Baddour LM: Skin abscesses, furuncles, and carbuncles. UpToDate 2014; topic
7656.
James WD: Clinical practice. Acne. N Engl J Med 2005;352:1463.
Ectoparasiticides
Leone PA: Scabies and pediculosis pubis: An update of treatment regimens and
general review. Clin Infect Dis 2007;44(Suppl 3):S153.
Brazzini B, Pimpinelli N: New and established topical corticosteroids in derma-
tology: Clinical pharmacology and therapeutic use. Am J Clin Dermatol
2002;3:47.
Williams JD, Griffiths CE: Cytokine blocking agents in dermatology. Clin Exp
Dermatol 2002;27:585.
Keratolytic & Destructive Agents
Bhutani T, Hong J, Koo J: Contemporary Diagnosis and Management of Psoriasis,
5th ed. Handbooks in Healthcare, 2011.
Samarasekera EJ et al: Topical therapies for the treatment of plaque psoriasis:
Systematic review and network meta-analyses. Br J Dermatol 2013;168:954.

C ASE STUDY ANSWER

Initiation of oral doxycycline therapy was discussed with the morning application of brimonidine 0.33% gel was added to
patient. She expressed concerns regarding possible adverse her treatment regimen. The patient noted prompt response
effects of prolonged systemic therapy. In light of this, daily with significant improvement of her facial redness.

Drugs Used in
the Treatment of
Gastrointestinal Diseases
Kenneth R. McQuaid, MD
C ASE STUDY
A 21-year-old woman comes with her parents to discuss
therapeutic options for her Crohn’s disease. She was diag-
nosed with Crohn’s disease 2 years ago, and it involves
her terminal ileum and proximal colon, as confirmed
by colonoscopy and small bowel radiography. She was
initially treated with mesalamine and budesonide with good
response, but over the last 2 months, she has had a relapse
of her symptoms. She is experiencing fatigue, cramping,
abdominal pains, and nonbloody diarrhea up to 10 times
daily, and she has had a 15-lb weight loss.
INTRODUCTION
Many of the drug groups discussed elsewhere in this book have
important applications in the treatment of diseases of the gastro-
intestinal tract and other organs. Other groups are used almost
exclusively for their effects on the gut; these are discussed in the
following text according to their therapeutic uses.
■■ DRUGS USED IN ACID-PEPTIC
DISEASES
Acid-peptic diseases include gastroesophageal reflux, peptic ulcer
(gastric and duodenal), and stress-related mucosal injury. In all
these conditions, mucosal erosions or ulceration arise when the
caustic effects of aggressive factors (acid, pepsin, bile) overwhelm
the defensive factors of the gastrointestinal mucosa (mucus and
62
C H A P T E R
She has no other significant medical or surgical his-
tory. Her current medications are mesalamine 2.4 g/d and
budesonide 9 mg/d. She appears thin and tired. Abdominal
examination reveals tenderness without guarding in the
right lower quadrant; no masses are palpable. On perianal
examination, there is no tenderness, fissure, or fistula.
Her laboratory data are notable for anemia and elevated
C-reactive protein. What are the options for immediate con-
trol of her symptoms and disease? What are the long-term
management options?
bicarbonate secretion, prostaglandins, blood flow, and the pro-
cesses of restitution and regeneration after cellular injury). Over
90% of peptic ulcers are caused by infection with the bacterium
Helicobacter pylori or by use of nonsteroidal anti-inflammatory
drugs (NSAIDs). Drugs used in the treatment of acid-peptic
disorders may be divided into two classes: agents that reduce
intragastric acidity and agents that promote mucosal defense.
AGENTS THAT REDUCE
INTRAGASTRIC ACIDITY
PHYSIOLOGY OF ACID SECRETION
The parietal cell contains receptors for gastrin (CCK-B), hista-
mine (H2), and acetylcholine (muscarinic, M3) (Figure 62–1).
When acetylcholine (from vagal postganglionic nerves) and gastrin
(released from antral G cells into the blood) bind to the parietal
1087
1088    SECTION X  Special Topics

Antrum of stomach Fundus of stomach

Vagus Fundic blood vessel

preganglionic
nerve

+ Gastrin

Vagus G/CCK-B-R
preganglionic +
M3-R
nerve

Histamine
ECL
cell
Antrum blood vessel

ACh Histamine

+ + + Gastrin

+
ACh-R M3-R H2-R G/CCK-B-R
GRP-R –
Gastrin
–
Parietal cell
Somatostatin-R Somatostatin

H+/K+
G cell D cell
ATPase
+ K+ K+

+ H+ H+ H+ H+
Dietary peptides Luminal acid H+ H+
Luminal acid
Lumen of antrum Lumen of fundus

FIGURE 62–1  Schematic model for physiologic control of hydrogen ion (acid) secretion by the parietal cells of the gastric fundic glands.
Parietal cells are stimulated to secrete acid (H+) by gastrin (acting on gastrin/CCK-B receptor), acetylcholine (M3 receptor), and histamine (H2
receptor). Acid is secreted across the parietal cell canalicular membrane by the H+/K+-ATPase proton pump into the gastric lumen. Gastrin is
secreted by antral G cells into blood vessels in response to intraluminal dietary peptides. Within the gastric body, gastrin passes from the blood
vessels into the submucosal tissue of the fundic glands, where it binds to gastrin-CCK-B receptors on parietal cells and enterochromaffin-like
(ECL) cells. The vagus nerve stimulates postganglionic neurons of the enteric nervous system to release acetylcholine (ACh), which binds to M3
receptors on parietal cells and ECL cells. Stimulation of ECL cells by gastrin (CCK-B receptor) or acetylcholine (M3 receptor) stimulates release of
histamine. Within the gastric antrum, vagal stimulation of postganglionic enteric neurons enhances gastrin release directly by stimulation of
antral G cells (through gastrin-releasing peptide, GRP) and indirectly by inhibition of somatostatin secretion from antral D cells. Acid secretion
must eventually be turned off. Antral D cells are stimulated to release somatostatin by the rise in intraluminal H+ concentration and by CCK that
is released into the bloodstream by duodenal I cells in response to proteins and fats (not shown). Binding of somatostatin to receptors on
adjacent antral G cells inhibits further gastrin release. ATPase, H+/K+-ATPase proton pump; CCK, cholecystokinin; M3-R, muscarinic receptors.

cell receptors, they cause an increase in cytosolic calcium, which in
turn stimulates protein kinases that stimulate acid secretion from
a H+/K+-ATPase (the proton pump) on the canalicular surface.
In close proximity to the parietal cells are gut endocrine cells
called enterochromaffin-like (ECL) cells. ECL cells also have
receptors for gastrin and acetylcholine, which stimulate histamine
release. Histamine binds to the H2 receptor on the parietal cell,
resulting in activation of adenylyl cyclase, which increases intra-
cellular cyclic adenosine monophosphate (cAMP) and activates
protein kinases that stimulate acid secretion by the H+/K+-ATPase.
In humans, it is believed that the major effect of gastrin upon acid
secretion is mediated indirectly through the release of histamine
from ECL cells rather than through direct parietal cell stimula-
tion. In contrast, acetylcholine provides potent direct parietal cell
stimulation.
ANTACIDS
Antacids have been used for centuries in the treatment of
patients with dyspepsia and acid-peptic disorders. They were the
mainstay of treatment for acid-peptic disorders until the advent
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1089

of H2–receptor antagonists and proton-pump inhibitors (PPIs).
They continue to be used commonly by patients as nonprescrip-
tion remedies for the treatment of intermittent heartburn and
dyspepsia.
Antacids are weak bases that react with gastric hydrochloric
acid to form a salt and water. Their principal mechanism of
action is reduction of intragastric acidity. After a meal, approxi-
mately 45 mEq/h of hydrochloric acid is secreted. A single dose of
156 mEq of antacid given 1 hour after a meal effectively neutral-
izes gastric acid for up to 2 hours. However, the acid-neutraliza-
tion capacity among different proprietary formulations of antacids
is highly variable, depending on their rate of dissolution (tablet
versus liquid), water solubility, rate of reaction with acid, and rate
of gastric emptying.
Sodium bicarbonate (eg, baking soda, Alka Seltzer) reacts
rapidly with hydrochloric acid (HCl) to produce carbon dioxide
and sodium chloride. Formation of carbon dioxide results in gas-
tric distention and belching. Unreacted alkali is readily absorbed,
potentially causing metabolic alkalosis when given in high doses
or to patients with renal insufficiency. Sodium chloride absorp-
tion may exacerbate fluid retention in patients with heart failure,
hypertension, and renal insufficiency. Calcium carbonate (eg,
Tums, Os-Cal) is less soluble and reacts more slowly than sodium
bicarbonate with HCl to form carbon dioxide and calcium chlo-
ride (CaCl2). Like sodium bicarbonate, calcium carbonate may
cause belching or metabolic alkalosis. Calcium carbonate is used
for a number of other indications apart from its antacid properties
(see Chapter 42). Excessive doses of either sodium bicarbonate or
calcium carbonate with calcium-containing dairy products can
lead to hypercalcemia, renal insufficiency, and metabolic alkalosis
(milk-alkali syndrome).
Formulations containing magnesium hydroxide or aluminum
hydroxide react slowly with HCl to form magnesium chloride or
aluminum chloride and water. Because no gas is generated, belch-
ing does not occur. Metabolic alkalosis is also uncommon because
of the efficiency of the neutralization reaction. Because unab-
sorbed magnesium salts may cause an osmotic diarrhea and alu-
minum salts may cause constipation, these agents are commonly
Both magnesium and aluminum are absorbed and excreted by the
kidneys. Hence, patients with renal insufficiency should not take
these agents long-term.
All antacids may affect the absorption of other medications by
binding the drug (reducing its absorption) or by increasing intra-
gastric pH so that the drug’s dissolution or solubility (especially
weakly basic or acidic drugs) is altered. Therefore, antacids should
not be given within 2 hours of doses of tetracyclines, fluoroquino-
lones, itraconazole, and iron.
H2-RECEPTOR ANTAGONISTS
From their introduction in the 1970s until the early 1990s,
H2-receptor antagonists (commonly referred to as H2 blockers)
were the most commonly prescribed drugs in the world (see
Clinical Uses). With the recognition of the role of H pylori in
ulcer disease (which may be treated with appropriate antibacterial
therapy) and the advent of PPIs, the use of prescription H2 blockers
has declined markedly.
Chemistry & Pharmacokinetics
Four H2 antagonists are in clinical use: cimetidine, ranitidine,
famotidine, and nizatidine. All four agents are rapidly absorbed
from the intestine. Cimetidine, ranitidine, and famotidine
undergo first-pass hepatic metabolism resulting in a bioavailability
of approximately 50%. Nizatidine has little first-pass metabolism.
The serum half-lives of the four agents range from 1.1 to 4 hours;
however, duration of action depends on the dose given
(Table 62–1). H2 antagonists are cleared by a combination of
hepatic metabolism, glomerular filtration, and renal tubular secre-
tion. Dose reduction is required in patients with moderate to
severe renal (and possibly severe hepatic) insufficiency. In the
elderly, there is a decline of up to 50% in drug clearance as well as
a significant reduction in volume of distribution.
CH3 CH2 CH2 NH C NH CH3
S CH2
HN N
HC C N

administered together in proprietary formulations (eg, Gelusil,

Maalox, Mylanta) to minimize the impact on bowel function. Cimetidine

TABLE 62–1  Clinical comparisons of H2-receptor blockers.

Dose to Achieve Usual Dose for Acute Usual Dose for Usual Dose for
>50% Acid Inhibition Duodenal or Gastric Gastroesophageal Prevention of Stress-
Drug Relative Potency for 10 Hours Ulcer Reflux Disease Related Bleeding

Cimetidine 1 400–800 mg 800 mg HS or 800 mg bid 50 mg/h continuous

400 mg bid infusion
Ranitidine 4–10 150 mg 300 mg HS or 150 mg bid 6.25 mg/h continuous
150 mg bid infusion or 50 mg IV
every 6–8 h
Nizatidine 4–10 150 mg 300 mg HS or 150 mg bid Not available
150 mg bid
Famotidine 20–50 20 mg 40 mg HS or 20 mg bid 20 mg bid 20 mg IV every 12 h
bid, twice daily; HS, bedtime.
1090    SECTION X  Special Topics

Pharmacodynamics Clinical Uses

The H2 antagonists exhibit competitive inhibition at the parietal
cell H2 receptor and suppress basal and meal-stimulated acid
secretion (Figure 62–2) in a linear, dose-dependent manner. They
are highly selective and do not affect H1 or H3 receptors (see
Chapter 16). The volume of gastric secretion and the concentra-
tion of pepsin are also reduced.
H2 antagonists reduce acid secretion stimulated by histamine
as well as by gastrin and cholinomimetic agents through two
mechanisms. First, histamine released from ECL cells by gastrin
or vagal stimulation is blocked from binding to the parietal cell H2
receptor. Second, direct stimulation of the parietal cell by gastrin
or acetylcholine has a diminished effect on acid secretion in the
presence of H2-receptor blockade.
The potencies of the four H2-receptor antagonists vary over
a 50-fold range (Table 62–1). When given in usual prescription
doses, however, all inhibit 60–70% of total 24-hour acid secre-
tion. H2 antagonists are especially effective at inhibiting nocturnal
acid secretion (which depends largely on histamine), but they
have a modest impact on meal-stimulated acid secretion (which
is stimulated by gastrin and acetylcholine as well as histamine).
Therefore, nocturnal and fasting intragastric pH is raised to 4–5,
but the impact on the daytime, meal-stimulated pH profile is less.
Recommended prescription doses maintain greater than 50% acid
inhibition for 10 hours; hence, these drugs are commonly given
twice daily. At doses available in over-the-counter formulations,
the duration of acid inhibition is 6–10 hours.
t
as
H2-receptor antagonists continue to be prescribed, but PPIs (see
below) are more commonly prescribed than H2 antagonists for
most clinical indications. The over-the-counter preparations of
the H2 antagonists are heavily used by the public.
1. Gastroesophageal reflux disease (GERD)—Patients with
infrequent heartburn or dyspepsia (fewer than three times per
week) may take either antacids or intermittent H2 antagonists.
Because antacids provide rapid acid neutralization, they afford
faster symptom relief than H2 antagonists. However, the effect
of antacids is short-lived (1–2 hours) compared with H2 antago-
nists (6–10 hours). H2 antagonists may be taken prophylactically
before meals in an effort to reduce the likelihood of heartburn.
Frequent heartburn is better treated with twice-daily H2 antago-
nists (Table 62–1) or PPIs. In patients with erosive esophagitis
(approximately 50% of patients with GERD), H2 antagonists
afford healing in less than 50% of patients; hence PPIs are
preferred because of their superior acid inhibition.
2. Peptic ulcer disease—PPIs have largely replaced H2 antago-
nists in the treatment of acute peptic ulcer disease. Nevertheless,
H2 antagonists are still sometimes used. Nocturnal acid suppres-
sion by H2 antagonists affords effective ulcer healing in most
patients with uncomplicated gastric and duodenal ulcers. Hence,
all the agents may be administered once daily at bedtime, result-
ing in ulcer healing rates >80–90% after 6–8 weeks of therapy.
ck

na
r
kf

ne

ts
ffe

nc
ea

gh
in
Co

Lu

Te
Br

Li

90
Median hourly acidity (mmol liter −1)

80 Acid (control)

70

60

50

40

30
H2 block
20

10 PPI

0900 1200 1500 1800 2100 2400 0300 0600 0800 hours
Time of day

FIGURE 62–2  Twenty-four-hour median intragastric acidity pretreatment (red) and after 1 month of treatment with either ranitidine,
150 mg twice daily (blue, H2 block), or omeprazole, 20 mg once daily (green, PPI). Note that H2-receptor antagonists have a marked effect
on nocturnal acid secretion but only a modest effect on meal-stimulated secretion. Proton-pump inhibitors (PPIs) markedly suppress meal-
stimulated and nocturnal acid secretion. (Data from Lanzon-Miller S et al: Twenty-four-hour intragastric acidity and plasma gastrin concentration before and during
treatment with either ranitidine or omeprazole. Aliment Pharmacol Ther 1987;1:239.)
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1091
For patients with ulcers caused by aspirin or other NSAIDs, the
NSAID should be discontinued. If the NSAID must be continued
for clinical reasons despite active ulceration, a PPI should be given
instead of an H2 antagonist to more reliably promote ulcer heal-
ing. For patients with acute peptic ulcers caused by H pylori, H2
antagonists no longer play a significant therapeutic role. H pylori
should be treated with a 10- to 14-day course of therapy including
a PPI and two or three antibiotics (see below).
3. Nonulcer dyspepsia—H2 antagonists are commonly used
as over-the-counter agents and prescription agents for treatment
of intermittent dyspepsia not caused by peptic ulcer. However,
benefit compared with placebo has never been convincingly
demonstrated.
4. Prevention of bleeding from stress-related gastritis—
Clinically important bleeding from upper gastrointestinal erosions
or ulcers occurs in 1–5% of critically ill patients as a result of
impaired mucosal defense mechanisms caused by poor perfusion.
Although most critically ill patients have normal or decreased acid
secretion, numerous studies have shown that agents that increase
intragastric pH (H2 antagonists or PPIs) reduce the incidence
of clinically significant bleeding and should be administered to
patients who are at high risk of gastrointestinal bleeding. How-
ever, the optimal agent is uncertain. For patients who are unable
to receive enteral medications, either intravenous H2 antago-
nists or PPIs may be administered. Continuous infusions of H2
antagonists are generally preferred to bolus infusions because they
achieve more consistent, sustained elevation of intragastric pH.
Adverse Effects
H2 antagonists are extremely safe drugs. Adverse effects occur in
less than 3% of patients and include diarrhea, headache, fatigue,
myalgias, and constipation. Some studies suggest that intravenous
H2 antagonists (or PPIs) may increase the risk of nosocomial
pneumonia in critically ill patients.
Mental status changes (confusion, hallucinations, agitation)
may occur with administration of intravenous H2 antagonists,
especially in patients in the intensive care unit who are elderly or
who have renal or hepatic dysfunction. These events may be more
common with cimetidine. Mental status changes rarely occur in
ambulatory patients.
Cimetidine inhibits binding of dihydrotestosterone to andro-
gen receptors, inhibits metabolism of estradiol, and increases
serum prolactin levels. When used long-term or in high doses, it
may cause gynecomastia or impotence in men and galactorrhea in
women. These effects are specific to cimetidine and do not occur
with the other H2 antagonists.
Although there are no known harmful effects on the fetus,
H2 antagonists cross the placenta. Therefore, they should not be
administered to pregnant women unless absolutely necessary. The
H2 antagonists are secreted into breast milk and may therefore
affect nursing infants.
H2 antagonists may rarely cause blood dyscrasias. Blockade
of cardiac H2 receptors may cause bradycardia, but this is rarely
of clinical significance. Rapid intravenous infusion may cause
bradycardia and hypotension through blockade of cardiac H2
receptors; therefore, intravenous infusions should be given over
30 minutes. H2 antagonists rarely cause reversible abnormalities
in liver chemistry.
Drug Interactions
Cimetidine interferes with several important hepatic cytochrome
P450 drug metabolism pathways, including those catalyzed by
CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (see Chapter 4).
Hence, the half-lives of drugs metabolized by these pathways may
be prolonged. Ranitidine binds 4–10 times less avidly than cimeti-
dine to cytochrome P450. Negligible CYP interaction occurs with
nizatidine and famotidine.
H2 antagonists compete with creatinine and certain drugs
(eg, procainamide) for renal tubular secretion. All of these agents
except famotidine inhibit gastric first-pass metabolism of ethanol,
especially in women. Although the importance of this is debated,
increased bioavailability of ethanol could lead to increased blood
ethanol levels.
PROTON-PUMP INHIBITORS (PPIs)
Since their introduction in the late 1980s, these efficacious acid
inhibitory agents have assumed the major role for the treatment
of acid-peptic disorders. PPIs are now among the most widely
prescribed drugs worldwide.
Chemistry & Pharmacokinetics
Six PPIs are available for clinical use: omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, and pantoprazole.
All are substituted benzimidazoles that resemble H2 antagonists in
structure (Figure 62–3) but have a completely different mecha-
nism of action. Omeprazole and lansoprazole are racemic mixtures
of R- and S-isomers. Esomeprazole is the S-isomer of omeprazole
and dexlansoprazole the R-isomer of lansoprazole. All are avail-
able in oral formulations. Esomeprazole and pantoprazole are also
available in intravenous formulations (Table 62–2).
PPIs are administered as inactive prodrugs. To protect the acid-
labile prodrug from rapid destruction within the gastric lumen,
oral products are formulated for delayed release as acid-resistant,
enteric-coated capsules or tablets. After passing through the
stomach into the alkaline intestinal lumen, the enteric coatings
dissolve and the prodrug is absorbed. For children or patients
with dysphagia or enteral feeding tubes, capsule formulations (but
not tablets) may be opened and the microgranules mixed with
apple or orange juice or mixed with soft foods (eg, applesauce).
Esomeprazole, omeprazole, and pantoprazole are also available as
oral suspensions. Lansoprazole is available as a tablet formulation
that disintegrates in the mouth, and rabeprazole is available in a
formulation that may be sprinkled on food. Omeprazole is also
available as a powder formulation (capsule or packet) that contains
sodium bicarbonate (1100–1680 mg NaHCO3; 304–460 mg of
sodium) to protect the naked (non-enteric-coated) drug from
acid degradation. When administered on an empty stomach by
1092    SECTION X  Special Topics

OCH3 OCH3

CH3 CH3 OCH3

N OCH3 N OCF2H

N CH2 S N CH2 S

O N O N

H H

Omeprazole Pantoprazole

O CH2 CF3

CH3 N N
H
CH2 S
N
CH2 CH2 N
CH2 S O
N
CH3 O CH2 O CH3 Na
O N

Lansoprazole Rabeprazole

FIGURE 62–3  Molecular structure of the proton-pump inhibitors: omeprazole, lansoprazole, pantoprazole, and the sodium salt of
rabeprazole. Omeprazole and esomeprazole have the same chemical structure (see text).

mouth or enteral tube, this “immediate-release” suspension results
in rapid omeprazole absorption (Tmax < 30 minutes) and onset of
acid inhibition.
The PPIs are lipophilic weak bases (pKa 4–5) and, after
intestinal absorption, diffuse readily across lipid membranes into
acidified compartments (eg, the parietal cell canaliculus). The
prodrug rapidly becomes protonated within the canaliculus and
is concentrated more than 1000-fold by Henderson-Hasselbalch
trapping (see Chapter 1). There, it rapidly undergoes a molecular
conversion to the active form, a reactive thiophilic sulfenamide
cation, which forms a covalent disulfide bond with the H+/K+-
ATPase, irreversibly inactivating the enzyme.
The pharmacokinetics of available PPIs are shown in
Table 62–2. Immediate-release omeprazole has a faster onset of
acid inhibition than other oral formulations. Although differences
in pharmacokinetic profiles may affect speed of onset and dura-
tion of acid inhibition in the first few days of therapy, they are
of little clinical importance with continued daily administration.
The bioavailability of all agents is decreased approximately 50%
by food; hence, the drugs should be administered on an empty
stomach. In a fasting state, only 10% of proton pumps are
actively secreting acid and susceptible to inhibition. PPIs should
be administered approximately 1 hour before a meal (usually
breakfast), so that the peak serum concentration coincides with
the maximal activity of proton-pump secretion. The drugs have a
short serum half-life of about 1.5 hours, but acid inhibition lasts
up to 24 hours owing to the irreversible inactivation of the proton
pump. At least 18 hours are required for synthesis of new H+/K+-
ATPase pump molecules. Because not all proton pumps are inac-
tivated with the first dose of medication, up to 3–4 days of daily
medication are required before the full acid-inhibiting potential is
reached. Similarly, after stopping the drug, it takes 3–4 days for
full acid secretion to return.
PPIs undergo rapid first-pass and systemic hepatic metabo-
lism and have negligible renal clearance. Dose reduction is not
needed for patients with renal insufficiency or mild to moderate

TABLE 62–2  Pharmacokinetics of proton pump inhibitors.

Usual Dosage for Peptic
Drug pKa Bioavailability (%) t1/2 (h) Tmax (h) Ulcer or GERD

Omeprazole 4 40–65 0.5–1.0 1–3 20–40 mg qd

Esomeprazole 4 >80 1.5 1.6 20–40 mg qd
Lansoprazole 4 >80 1.0–2.0 1.7 30 mg qd
Dexlansoprazole 4 NA 1.0–2.0 5.0 30–60 mg qd
Pantoprazole 3.9 77 1.0–1.9 2.5–4.0 40 mg qd
Rabeprazole 5 52 1.0–2.0 3.1 20 mg qd
GERD, gastroesophageal reflux disease; NA, data not available.
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1093
liver disease but should be considered in patients with severe liver
impairment. Although other proton pumps exist in the body,
the H+/K+-ATPase appears to exist only in the parietal cell and is
distinct structurally and functionally from other H+-transporting
enzymes.
The intravenous formulations of esomeprazole and pantopra-
zole have characteristics similar to those of the oral drugs. When
given to a fasting patient, they inactivate acid pumps that are
actively secreting, but they have no effect on pumps in quiescent,
nonsecreting vesicles. Because the half-life of a single injection of
the intravenous formulation is short, acid secretion returns several
hours later as pumps move from the tubulovesicles to the canalicu-
lar surface. Thus, to provide maximal inhibition during the first
24–48 hours of treatment, the intravenous formulations must be
given as a continuous infusion or as repeated bolus injections. The
optimal dosing of intravenous PPIs to achieve maximal blockade
in fasting patients is not yet established.
From a pharmacokinetic perspective, PPIs are ideal drugs: they
have a short serum half-life, they are concentrated and activated
near their site of action, and they have a long duration of action.
Pharmacodynamics
In contrast to H2 antagonists, PPIs inhibit both fasting and
meal-stimulated secretion because they block the final common
pathway of acid secretion, the proton pump. In standard doses,
PPIs inhibit 90–98% of 24-hour acid secretion (Figure 62–2).
When administered at equivalent doses, the different agents
show little difference in clinical efficacy. In a crossover study of
patients receiving long-term therapy with five PPIs, the mean
24-hour intragastric pH varied from 3.3 (pantoprazole, 40 mg)
to 4.0 (esomeprazole, 40 mg), and the mean number of hours the
pH was higher than 4 varied from 10.1 (pantoprazole, 40 mg)
to 14.0 (esomeprazole, 40 mg). Although dexlansoprazole has
a delayed-release formulation that results in a longer Tmax and
greater AUC than other PPIs, it appears comparable to other
agents in the ability to suppress acid secretion. This is because
acid suppression is more dependent upon irreversible inactiva-
tion of the proton pump than the pharmacokinetics of different
agents.
Clinical Uses
1. Gastroesophageal reflux disease—PPIs are the most
effective agents for the treatment of erosive reflux disease, esopha-
geal complications of reflux disease (peptic stricture or Barrett’s
esophagus), and extraesophageal manifestations of reflux disease.
Once-daily dosing provides effective symptom relief and tissue
healing in 85–90% of patients; up to 15% of patients require
twice-daily dosing.
GERD symptoms recur in over 80% of patients within
6 months after discontinuation of a PPI. For patients with erosive
esophagitis or esophageal complications, long-term daily mainte-
nance therapy with a full-dose or half-dose PPI is usually needed.
Many patients with nonerosive GERD may be treated success-
fully with intermittent courses of PPIs or H2 antagonists taken as
needed (“on demand”) for recurrent symptoms.
In current clinical practice, many patients with symptomatic
GERD are treated empirically with medications without prior
endoscopy, ie, without knowledge of whether the patient has
erosive or nonerosive reflux disease. Empiric treatment with PPIs
provides sustained symptomatic relief in 70–80% of patients,
compared with 50–60% with H2 antagonists. Because of recent
cost reductions, PPIs are used increasingly as first-line therapy for
patients with symptomatic GERD. Due to recent safety concerns,
however, initial empiric treatment with an H2 antagonist should
be considered.
Sustained acid suppression with twice-daily PPIs for at least
3 months is used to treat extraesophageal complications of reflux
disease (asthma, chronic cough, laryngitis, and noncardiac chest
pain).
2. Peptic ulcer disease—Compared with H2 antagonists, PPIs
afford more rapid symptom relief and faster ulcer healing for duo-
denal ulcers and, to a lesser extent, gastric ulcers. All the pump
inhibitors heal more than 90% of duodenal ulcers within 4 weeks
and a similar percentage of gastric ulcers within 6–8 weeks.
a. H pylori-associated ulcers—For H pylori-associated ulcers,
there are two therapeutic goals: to heal the ulcer and to eradicate
the organism. The most effective regimens for H pylori eradica-
tion are combinations of two antibiotics and a PPI. PPIs pro-
mote eradication of H pylori through several mechanisms: direct
antimicrobial properties (minor) and—by raising intragastric
pH—lowering the minimal inhibitory concentrations of antibiot-
ics against H pylori. Until recently, the most commonly recom-
mended treatment regimen consisted of a 14-day regimen of
“triple therapy”: a PPI twice daily; clarithromycin, 500 mg twice
daily; and either amoxicillin, 1 g twice daily, or metronidazole,
500 mg twice daily. Due to increasing treatment failures attribut-
able to rising clarithromycin resistance, “quadruple therapy” is
now recommended as first-line treatment for patients who likely
have clarithromycin resistance due to prior exposure or to resi-
dence in regions with high clarithromycin resistance. Two 14-day
treatment regimens currently are recommended. Each includes
a PPI twice daily with either: (a) bismuth subsalicylate 524 mg,
metronidazole 500 mg, and tetracycline 500 mg, all given four
times daily; or (b) amoxicillin 1 g, clarithromycin 500 mg, and
metronidazole 500 mg, all given twice daily. After completion of
antibiotic therapy, the PPI should be continued once daily for a
total of 4–6 weeks to ensure complete ulcer healing.
b. NSAID-associated ulcers—For patients with ulcers caused
by aspirin or other NSAIDs, either H2 antagonists or PPIs pro-
vide rapid ulcer healing so long as the NSAID is discontinued;
however, continued use of the NSAID impairs ulcer healing.
In patients with NSAID-induced ulcers who require continued
NSAID therapy, treatment with a PPI more reliably promotes
ulcer healing.
Asymptomatic peptic ulceration develops in 10–20% of people
taking frequent NSAIDs, and ulcer-related complications (bleed-
ing, perforation) develop in 1–2% of persons per year. PPIs taken
once daily are effective in reducing the incidence of ulcers and
ulcer complications in patients taking aspirin or other NSAIDs.
1094    SECTION X  Special Topics
c. Prevention of rebleeding from peptic ulcers—In patients
with acute gastrointestinal bleeding due to peptic ulcers, the risk
of rebleeding from ulcers that have a visible vessel or adherent
clot is increased. Rebleeding of this subset of high-risk ulcers is
reduced significantly with PPIs administered for 3–5 days either
as high-dose oral therapy (eg, omeprazole, 40 mg orally twice
daily) or as a continuous intravenous infusion. It is believed that
an intragastric pH higher than 6 may enhance coagulation and
platelet aggregation. The optimal dose of intravenous PPI needed
to achieve and maintain this level of near-complete acid inhibition
is unknown; however, initial bolus administration of esomeprazole
or pantoprazole (80 mg) followed by constant infusion (8 mg/h)
is commonly recommended.
3. Nonulcer dyspepsia—PPIs have modest efficacy for treat-
ment of nonulcer dyspepsia, benefiting 10–20% more patients
than placebo. Despite their use for this indication, superiority
to H2 antagonists (or even placebo) has not been conclusively
demonstrated.
4. Prevention of stress-related mucosal bleeding—As dis-
cussed previously (see H2-Receptor Antagonists), PPIs (given
orally, by nasogastric tube, or by intravenous infusions) may be
administered to reduce the risk of clinically significant stress-
related mucosal bleeding in critically ill patients. The only PPI
approved by the US Food and Drug Administration (FDA) for
this indication is an oral immediate-release omeprazole formula-
tion, which is administered by nasogastric tube twice daily on the
first day, then once daily. Although not FDA approved for this
indication, other PPI suspension formulations (esomeprazole,
omeprazole, pantoprazole) may also be used. For patients with
nasoenteric tubes, PPI suspensions may be preferred to intrave-
nous H2 antagonists or PPIs because of comparable efficacy, lower
cost, and ease of administration.
For patients without a nasoenteric tube or with significant
ileus, intravenous H2 antagonists are preferred to intravenous
PPIs because of their proven efficacy. Although PPIs are increas-
ingly used, there are no controlled trials demonstrating efficacy or
optimal dosing.
5. Gastrinoma and other hypersecretory conditions—
Patients with isolated gastrinomas are best treated with surgical
resection. In patients with metastatic or unresectable gastrinomas,
massive acid hypersecretion results in peptic ulceration, erosive
esophagitis, and malabsorption. With PPIs, excellent acid sup-
pression can be achieved in all patients. Dosage is titrated to
reduce basal acid output to less than 5–10 mEq/h. Typical doses
of omeprazole are 60–120 mg/d.
Adverse Effects
1. General—Although PPIs have been considered to be
extremely safe, a number of recent safety concerns have been
raised. As with most drugs, PPIs should be prescribed at the
lowest effective dose and the risks versus benefits of long-term
use carefully weighed. Diarrhea, headache, and abdominal pain
are reported in 1–5% of patients, although the frequency of
these events is only slightly increased compared with placebo.
In large observational studies, PPIs have been associated with
an increased risk of acute interstitial nephritis and chronic
kidney disease compared to nonusers or users of H2-receptor
antagonists. A mechanism by which kidney damage might occur
has not been determined. Some epidemiologic studies have
also detected an increased risk of dementia in long-term PPI
users, although causality has not been established. PPIs are not
teratogenic in animal models; however, safety during pregnancy
has not been established.
2. Nutrition—Acid is important in releasing vitamin B12 from
food. A minor reduction in oral cyanocobalamin absorption
occurs during proton-pump inhibition, potentially leading to
subnormal B12 levels with prolonged therapy. Acid also promotes
absorption of food-bound minerals (non-heme iron, insoluble cal-
cium salts, magnesium). Meta-analyses of cohort and case-control
studies have detected a modest increase in the risk of hip fracture
in patients taking long-term PPIs. Although a causal relation-
ship is unproven, PPIs may reduce calcium absorption or inhibit
osteoclast function. All PPIs carry an FDA-mandated warning of
a possible increased risk of hip, spine, and wrist fractures. Patients
who require long-term PPIs—especially those with risk factors
for osteoporosis—should have monitoring of bone density and
should be provided calcium supplements. Cases of severe, life-
threatening hypomagnesemia with secondary hypocalcemia due
to PPIs have been reported, possibly due to decreased intestinal
absorption.
3. Respiratory and enteric infections—Gastric acid is an
important barrier to colonization and infection of the stomach
and intestine from ingested bacteria. Increases in gastric bacte-
rial concentrations are detected in patients taking PPIs, which is
of unknown clinical significance. Some studies have reported an
increased risk of both community-acquired respiratory infections
and nosocomial pneumonia among patients taking PPIs.
There is a two- to threefold increased risk for hospital- and
community-acquired Clostridium difficile infection in patients
taking PPIs. There also is a small increased risk of other enteric
infections (eg, Salmonella, Shigella, Escherichia coli, Campylo-
bacter), which should be considered particularly when traveling in
underdeveloped countries.
4. Potential problems due to increased serum gastrin—
Gastrin levels are regulated by intragastric acidity. Acid suppres-
sion alters normal feedback inhibition so that median serum
gastrin levels rise 1.5- to twofold in patients taking PPIs. Although
gastrin levels remain within normal limits in most patients, they
exceed 500 pg/mL (normal, <100 pg/mL) in 3%. Upon stopping
the drug, the levels normalize within 4 weeks. The rise in serum
gastrin levels may stimulate hyperplasia of ECL and parietal cells,
which may cause transient rebound acid hypersecretion with
increased dyspepsia or heartburn after drug discontinuation,
which abate within 2–4 weeks after gastrin and acid secretion
normalize. In female rats given PPIs for prolonged periods, hyper-
gastrinemia caused gastric carcinoid tumors that developed in
areas of ECL hyperplasia. Although humans who take PPIs for a
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1095
long time also may exhibit ECL hyperplasia, carcinoid tumor for-
mation has not been documented. At present, routine monitoring
of serum gastrin levels is not recommended in patients receiving
prolonged PPI therapy.
5. Other potential problems due to decreased gastric
acidity—Among patients infected with H pylori, long-term
acid suppression leads to increased chronic inflammation in the
gastric body and decreased inflammation in the antrum. Con-
cerns have been raised that increased gastric inflammation may
accelerate gastric gland atrophy (atrophic gastritis) and intestinal
metaplasia—known risk factors for gastric adenocarcinoma. A
special FDA Gastrointestinal Advisory Committee concluded
that there is no evidence that prolonged PPI therapy produces
the kind of atrophic gastritis (multifocal atrophic gastritis) or
intestinal metaplasia that is associated with increased risk of
adenocarcinoma. Routine testing for H pylori is not recom-
mended in patients who require long-term PPI therapy. Long-
term PPI therapy is associated with the development of small
benign gastric fundic-gland polyps in a small number of patients,
which may disappear after stopping the drug and are of uncertain
clinical significance.
Drug Interactions
Decreased gastric acidity may alter absorption of drugs for which
intragastric acidity affects drug bioavailability, eg, ketoconazole,
itraconazole, digoxin, and atazanavir. All PPIs are metabolized by
hepatic P450 cytochromes, including CYP2C19 and CYP3A4.
Because of the short half-lives of PPIs, clinically significant drug
interactions are rare. Omeprazole may inhibit the metabolism of
clopidogrel, warfarin, diazepam, and phenytoin. Esomeprazole
also may decrease metabolism of diazepam. Lansoprazole may
enhance clearance of theophylline. Rabeprazole and pantoprazole
have no significant drug interactions.
The FDA has issued a warning about a potentially important
adverse interaction between clopidogrel and PPIs. Clopido-
grel is a prodrug that requires activation by the hepatic P450
CYP2C19 isoenzyme, which also is involved to varying degrees
in the metabolism of PPIs (especially omeprazole, esomeprazole,
lansoprazole, and dexlansoprazole). Thus, PPIs could reduce
clopidogrel activation (and its antiplatelet action) in some
patients. Several large retrospective studies have reported an
increased incidence of serious cardiovascular events in patients
taking clopidogrel and a PPI. In contrast, three smaller prospec-
tive randomized trials have not detected an increased risk. When
PPIs are prescribed to patients taking clopidogrel, agents with
minimal CYP2C19 inhibition (pantoprazole or rabeprazole)
may be preferred.
MUCOSAL PROTECTIVE AGENTS
The gastroduodenal mucosa has evolved a number of defense
mechanisms to protect itself against the noxious effects of acid
and pepsin. Both mucus and epithelial cell-cell tight junctions
restrict back diffusion of acid and pepsin. Epithelial bicarbon-
ate secretion establishes a pH gradient within the mucous layer
in which the pH ranges from 7 at the mucosal surface to 1–2
in the gastric lumen. Blood flow carries bicarbonate and vital
nutrients to surface cells. Areas of injured epithelium are quickly
repaired by restitution, a process in which migration of cells
from gland neck cells seals small erosions to reestablish intact
epithelium. Mucosal prostaglandins appear to be important in
stimulating mucus and bicarbonate secretion and mucosal blood
flow. A number of agents that potentiate these mucosal defense
mechanisms are available for the prevention and treatment of
acid-peptic disorders.
SUCRALFATE
Chemistry & Pharmacokinetics
Sucralfate is a salt of sucrose complexed to sulfated aluminum
hydroxide. In water or acidic solutions it forms a viscous, tena-
cious paste that binds selectively to ulcers or erosions for up to
6 hours. Sucralfate has limited solubility, breaking down into
sucrose sulfate (strongly negatively charged) and an aluminum
salt. Less than 3% of intact drug and aluminum is absorbed from
the intestinal tract; the remainder is excreted in the feces.
Pharmacodynamics
A variety of beneficial effects have been attributed to sucralfate,
but the precise mechanism of action is unclear. It is believed that
the negatively charged sucrose sulfate binds to positively charged
proteins in the base of ulcers or erosion, forming a physical bar-
rier that restricts further caustic damage and stimulates mucosal
prostaglandin and bicarbonate secretion.
Clinical Uses
Sucralfate is administered in a dosage of 1 g four times daily on an
empty stomach (at least 1 hour before meals). At present, its clini-
cal uses are limited. Sucralfate (administered as a slurry through
a nasogastric tube) reduces the incidence of clinically significant
upper gastrointestinal bleeding in critically ill patients hospitalized
in the intensive care unit, although it is slightly less effective than
intravenous H2 antagonists. Sucralfate is still used by many clini-
cians for prevention of stress-related bleeding because of concerns
that acid inhibitory therapies (antacids, H2 antagonists, and PPIs)
may increase the risk of nosocomial pneumonia.
Adverse Effects
Because it is not absorbed, sucralfate is virtually devoid of systemic
adverse effects. Constipation occurs in 2% of patients due to the
aluminum salt. Because a small amount of aluminum is absorbed,
it should not be used for prolonged periods in patients with renal
insufficiency.
Drug Interactions
Sucralfate may bind to other medications, impairing their
absorption.
1096    SECTION X  Special Topics
PROSTAGLANDIN ANALOGS
Chemistry & Pharmacokinetics
The human gastrointestinal mucosa synthesizes a number of pros-
taglandins (see Chapter 18); the primary ones are prostaglandins E
and F. Misoprostol, a methyl analog of PGE1, has been approved
for gastrointestinal conditions. After oral administration, it is
rapidly absorbed and metabolized to a metabolically active free
acid. The serum half-life is less than 30 minutes; hence, it must be
administered 3–4 times daily. It is excreted in the urine; however,
dose reduction is not needed in patients with renal insufficiency.
Misoprostol has both acid inhibitory and mucosal protective
properties. It is believed to stimulate mucus and bicarbonate secre-
tion and enhance mucosal blood flow. Misoprostol can reduce
the incidence of NSAID-induced ulcers to less than 3% and the
incidence of ulcer complications by 50%. It is approved for pre-
vention of NSAID-induced ulcers in high-risk patients; however,
misoprostol has never achieved widespread use owing to its high
adverse-effect profile and need for multiple daily dosing.
BISMUTH COMPOUNDS
Chemistry & Pharmacokinetics
Two bismuth compounds are available: bismuth subsalicylate, a
nonprescription formulation containing bismuth and salicylate,
and bismuth subcitrate potassium. In the USA, bismuth subci-
trate is available only as a combination prescription product that
also contains metronidazole and tetracycline for the treatment
of H pylori. Bismuth subsalicylate undergoes rapid dissociation
within the stomach, allowing absorption of salicylate. Over 99%
of the bismuth appears in the stool. Although minimal (<1%),
bismuth is absorbed; it is stored in many tissues and has slow renal
excretion. Salicylate (like aspirin) is readily absorbed and excreted
in the urine.
Pharmacodynamics
The precise mechanisms of action of bismuth are unknown.
Bismuth coats ulcers and erosions, creating a protective layer
against acid and pepsin. It may also stimulate prostaglandin,
mucus, and bicarbonate secretion. Bismuth subsalicylate reduces
stool frequency and liquidity in acute infectious diarrhea, due
to salicylate inhibition of intestinal prostaglandin and chloride
secretion. Bismuth has direct antimicrobial effects and binds
enterotoxins, accounting for its benefit in preventing and treating
traveler’s diarrhea. Bismuth compounds have direct antimicrobial
activity against H pylori.
Clinical Uses
Despite the lack of comparative trials, nonprescription bismuth
compounds (eg, Pepto-Bismol, Kaopectate) are widely used by
patients for the nonspecific treatment of dyspepsia and acute
diarrhea. Bismuth subsalicylate also is used for the prevention of
traveler’s diarrhea (30 mL or two tablets four times daily).
Bismuth compounds are used in four-drug regimens for the
eradication of H pylori infection (see earlier discussion of H pylori-
associated ulcers). One regimen consists of a PPI twice daily
combined with bismuth subsalicylate (two tablets; 262 mg each),
tetracycline (250–500 mg), and metronidazole (500 mg) four
times daily for 10–14 days. Another regimen consists of a PPI
twice daily combined with three capsules of a combination pre-
scription formulation (each capsule containing bismuth subcitrate
140 mg, metronidazole 125 mg, and tetracycline 125 mg) taken
four times daily for 10–14 days.
Adverse Effects
All bismuth formulations have excellent safety profiles. Bismuth
causes harmless blackening of the stool, which may be confused
with gastrointestinal bleeding. Liquid formulations may cause
harmless darkening of the tongue. Bismuth agents should be
used for short periods only and should be avoided in patients
with renal insufficiency. Prolonged usage of some bismuth
compounds may rarely lead to bismuth toxicity, resulting in
encephalopathy (ataxia, headaches, confusion, seizures). How-
ever, such toxicity is not reported with bismuth subsalicylate or
bismuth citrate. High dosages of bismuth subsalicylate may lead
to salicylate toxicity.
■■ DRUGS STIMULATING
GASTROINTESTINAL MOTILITY
Drugs that can selectively stimulate gut motor function
(prokinetic agents) have significant potential clinical useful-
ness. Agents that increase lower esophageal sphincter pressures
may be useful for GERD. Drugs that improve gastric emptying
may be helpful for gastroparesis and postsurgical gastric emp-
tying delay. Agents that stimulate the small intestine may be
beneficial for postoperative ileus or chronic intestinal pseudo-
obstruction. Finally, agents that enhance colonic transit may be
useful in the treatment of constipation. Unfortunately, only a
limited number of agents in this group are available for clinical
use at this time.
Physiology of the Enteric Nervous System
The enteric nervous system (see also Chapter 6) is composed of
interconnected networks of ganglion cells and nerve fibers mainly
located in the submucosa (submucosal plexus) and between the
circular and longitudinal muscle layers (myenteric plexus). These
networks give rise to nerve fibers that connect with the mucosa
and muscle. Although extrinsic sympathetic and parasympathetic
nerves project onto the submucosal and myenteric plexuses, the
enteric nervous system can independently regulate gastrointestinal
motility and secretion. Extrinsic primary afferent neurons project
via the dorsal root ganglia or vagus nerve to the central nervous
system (Figure 62–4). Release of serotonin (5-HT) from intestinal
mucosa enterochromaffin (EC) cells stimulates 5-HT3 receptors
on the extrinsic afferent nerves, stimulating nausea, vomiting, or
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1097
To CNS
ENS neuron
ACh, CGRP
5HT4R
Submucosal +
IPAN
Dorsal root
Tegaserod
or cranial
nerve afferent
5HT3R 5HTIPR
5HT
–
Alosetron
EC
Gut
lumen
Pressure,
other stimuli
FIGURE 62–4  Release of serotonin (5-HT) by enterochromaffin
(EC) cells from gut distention stimulates submucosal intrinsic
primary afferent neurons (IPANs) via 5-HT1P receptors and extrinsic
primary afferent neurons via 5-HT3 receptors (5-HT1PR, 5-HT3R).
Submucosal IPANs activate the enteric neurons responsible for
peristaltic and secretory reflex activity. Stimulation of 5-HT4
receptors (5-HT4R) on presynaptic terminals of IPANs enhances
release of acetylcholine (ACh) and calcitonin gene-related peptide
(CGRP), promoting reflex activity. CNS, central nervous system;
ENS, enteric nervous system. (Data from Gershon MD: Serotonin and its
implication for the management of irritable bowel syndrome. Rev Gastroenterol
Dis 2003;3[Suppl 2]:S25.)
abdominal pain. Serotonin also stimulates submucosal 5-HT1P
receptors of the intrinsic primary afferent nerves (IPANs), which
contain calcitonin gene-related peptide (CGRP) and acetylcholine
and project to myenteric plexus interneurons. 5-HT4 receptors
on the presynaptic terminals of the IPANs appear to enhance
release of CGRP or acetylcholine. The myenteric interneurons are
important in controlling the peristaltic reflex, promoting release
of excitatory mediators proximally and inhibitory mediators
distally. Motilin may stimulate excitatory neurons or muscle cells
directly. Dopamine acts as an inhibitory neurotransmitter in the
gastrointestinal tract, decreasing the intensity of esophageal and
gastric contractions.
Although there are at least 14 serotonin receptor subtypes,
5-HT drug development for gastrointestinal applications to date
has focused on 5-HT3-receptor antagonists and 5-HT4-receptor
agonists. These agents—which have effects on gastrointestinal
motility and visceral afferent sensation—are discussed under
Drugs Used in the Treatment of Irritable Bowel Syndrome and
Antiemetic Agents. Other drugs acting on 5-HT receptors are
discussed in Chapters 16, 29, and 30.
CHOLINOMIMETIC AGENTS
Cholinomimetic agonists such as bethanechol stimulate mus-
carinic M3 receptors on muscle cells and at myenteric plexus
synapses (see Chapter 7). Bethanechol was used in the past for
the treatment of GERD and gastroparesis. Owing to multiple
cholinergic effects and the advent of less toxic agents, it is now
seldom used. The acetylcholinesterase inhibitor neostigmine can
enhance gastric, small intestine, and colonic emptying. Intra-
venous neostigmine is used for the treatment of hospitalized
patients with acute large bowel distention (known as acute colonic
pseudo-obstruction or Ogilvie’s syndrome). Administration of
2 mg results in prompt colonic evacuation of flatus and feces
in the majority of patients. Cholinergic effects include excessive
salivation, nausea, vomiting, diarrhea, and bradycardia.
METOCLOPRAMIDE & DOMPERIDONE
Metoclopramide and domperidone are dopamine D2-receptor
antagonists. Within the gastrointestinal tract, activation of dopa-
mine receptors inhibits cholinergic smooth muscle stimulation;
blockade of this effect is believed to be the primary prokinetic
mechanism of action of these agents. These agents increase esoph-
ageal peristaltic amplitude, increase lower esophageal sphincter
pressure, and enhance gastric emptying but have no effect on
small intestine or colonic motility. Metoclopramide and dom-
peridone also block dopamine D2 receptors in the chemoreceptor
trigger zone of the medulla (area postrema), resulting in potent
antinausea and antiemetic action.
Clinical Uses
1. Gastroesophageal reflux disease—Metoclopramide is
available for clinical use in the USA; domperidone is available
in many other countries. These agents are sometimes used in
the treatment of symptomatic GERD but are not effective in
patients with erosive esophagitis. Because of the superior efficacy
and safety of antisecretory agents in the treatment of heartburn,
prokinetic agents are used mainly in combination with antisecre-
tory agents in patients with regurgitation or refractory heartburn.
2. Impaired gastric emptying—These agents are widely used
in the treatment of patients with delayed gastric emptying due
to postsurgical disorders (vagotomy, antrectomy) and diabetic
gastroparesis. Metoclopramide is sometimes administered in hos-
pitalized patients to promote advancement of nasoenteric feeding
tubes from the stomach into the duodenum.
3. Nonulcer dyspepsia—These agents lead to symptomatic
improvement in a small number of patients with chronic
dyspepsia.
1098    SECTION X  Special Topics
4. Prevention of vomiting—Because of their potent antiemetic
action, metoclopramide and domperidone are used for the preven-
tion and treatment of emesis.
5. Postpartum lactation stimulation—Domperidone is
sometimes recommended to promote postpartum lactation (see
also Adverse Effects).
Adverse Effects
The most common adverse effects of metoclopramide involve the
central nervous system. Restlessness, drowsiness, insomnia, anxiety,
and agitation occur in 10–20% of patients, especially the elderly.
Extrapyramidal effects (dystonias, akathisia, parkinsonian features)
due to central dopamine receptor blockade occur acutely in 25% of
patients given high doses and in 5% of patients receiving long-term
therapy. Tardive dyskinesia, sometimes irreversible, has developed
in patients treated for a prolonged period with metoclopramide.
For this reason, long-term use should be avoided unless absolutely
necessary, especially in the elderly. Elevated prolactin levels (caused
by both metoclopramide and domperidone) can cause galactor-
rhea, gynecomastia, impotence, and menstrual disorders.
Domperidone is extremely well tolerated. Because it does not
cross the blood-brain barrier to a significant degree, neuropsychi-
atric and extrapyramidal effects are rare.
MACROLIDES
Macrolide antibiotics such as erythromycin directly stimulate
motilin receptors on gastrointestinal smooth muscle and promote
the onset of a migrating motor complex. Intravenous erythromy-
cin (3 mg/kg) is beneficial in some patients with gastroparesis;
however, tolerance rapidly develops. It may be used in patients
with acute upper gastrointestinal hemorrhage to promote gastric
emptying of blood before endoscopy.
■■ LAXATIVES
The overwhelming majority of people do not need laxatives; yet
they are self-prescribed by a large portion of the population. For
most people, intermittent constipation is best prevented with a
high-fiber diet, adequate fluid intake, regular exercise, and the
heeding of nature’s call. Patients not responding to dietary changes
or fiber supplements should undergo medical evaluation before
initiating long-term laxative treatment. Laxatives may be classi-
fied by their major mechanism of action, but many work through
more than one mechanism.
BULK-FORMING LAXATIVES
Bulk-forming laxatives are indigestible, hydrophilic colloids that
absorb water, forming a bulky, emollient gel that distends the
colon and promotes peristalsis. Common preparations include
natural plant products (psyllium, methylcellulose) and synthetic
fibers (polycarbophil). Bacterial digestion of plant fibers within
the colon may lead to increased bloating and flatus.
STOOL SURFACTANT AGENTS
(SOFTENERS)
These agents soften stool material, permitting water and lipids to
penetrate. They may be administered orally or rectally. Common
agents include docusate (oral or enema) and glycerin suppository.
In hospitalized patients, docusate is commonly prescribed to prevent
constipation and minimize straining. Mineral oil is a clear, viscous
oil that lubricates fecal material, retarding water absorption from the
stool. It is used to prevent and treat fecal impaction in young chil-
dren and debilitated adults. It is not palatable but may be mixed with
juices. Aspiration can result in a severe lipid pneumonitis. Long-term
use can impair absorption of fat-soluble vitamins (A, D, E, K).
OSMOTIC LAXATIVES
The colon can neither concentrate nor dilute fecal fluid: fecal
water is isotonic throughout the colon. Osmotic laxatives are
soluble but nonabsorbable compounds that result in increased
stool liquidity due to an obligate increase in fecal fluid.
Nonabsorbable Sugars or Salts
These agents may be used for the treatment of acute constipation
or the prevention of chronic constipation. Magnesium hydroxide
(milk of magnesia) is a commonly used osmotic laxative. It
should not be used for prolonged periods in patients with renal
insufficiency due to the risk of hypermagnesemia. Sorbitol and
lactulose are nonabsorbable sugars that can be used to prevent
or treat chronic constipation. These sugars are metabolized by
colonic bacteria, producing severe flatus and cramps.
High doses of osmotically active agents produce prompt bowel
evacuation (purgation) within 1–3 hours. The rapid movement of
water into the distal small bowel and colon leads to a high volume
of liquid stool followed by bowel evacuation. Several purgatives
are available, which may be used for the treatment of acute con-
stipation or to cleanse the bowel prior to medical procedures (eg,
colonoscopy). These include magnesium citrate, sulfate solu-
tion, and a proprietary combination of magnesium oxide, sodium
picosulfate, and citrate (Prepopik). When taking these purgatives,
it is very important that patients maintain adequate hydration by
taking increased oral liquids to compensate for fecal fluid loss.
Sodium phosphate also is available—by prescription—as a tablet
formulation but is infrequently used due to the risk of hyper-
phosphatemia, hypocalcemia, hypernatremia, and hypokalemia.
Although these electrolyte abnormalities are clinically insignificant
in most patients, they may lead to cardiac arrhythmias or acute
renal failure due to tubular deposition of calcium phosphate
(nephrocalcinosis). Sodium phosphate preparations should not
be used in patients who are frail or elderly, have renal insuffi-
ciency, have significant cardiac disease, or are unable to maintain
adequate hydration during bowel preparation.
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1099
Balanced Polyethylene Glycol
Lavage solutions containing polyethylene glycol (PEG) are com-
monly used for complete colonic cleansing before gastrointestinal
endoscopic procedures. These balanced, isotonic solutions contain
an inert, nonabsorbable, osmotically active sugar (PEG) with
sodium sulfate, sodium chloride, sodium bicarbonate, and potas-
sium chloride. The solution is designed so that no significant
intravascular fluid or electrolyte shifts occur. Therefore, they are
safe for all patients. For optimal bowel cleansing, 1–2 L of solu-
tion should be ingested rapidly (over 1–2 hours) on the evening
before the procedure and again 4–6 hours before the procedure.
For treatment or prevention of chronic constipation, smaller doses
of PEG powder may be mixed with water or juices (17 g/8 oz) and
ingested daily. In contrast to sorbitol or lactulose, PEG does not
produce significant cramps or flatus.
STIMULANT LAXATIVES
Stimulant laxatives (cathartics) induce bowel movements through
a number of poorly understood mechanisms. These include direct
stimulation of the enteric nervous system and colonic electrolyte
and fluid secretion. There has been concern that long-term use of
cathartics could lead to dependence and destruction of the myen-
teric plexus, resulting in colonic atony and dilation. More recent
research suggests that long-term use of these agents probably is
safe in most patients. Cathartics may be required on a long-term
basis, especially in patients who are neurologically impaired and
in bed-bound patients in long-term care facilities.
Anthraquinone Derivatives
Aloe, senna, and cascara occur naturally in plants. These laxatives
are poorly absorbed and after hydrolysis in the colon, produce a
bowel movement in 6–12 hours when given orally and within
2 hours when given rectally. Chronic use leads to a characteristic
brown pigmentation of the colon known as “melanosis coli.”
There has been some concern that these agents may be carci-
nogenic, but epidemiologic studies do not suggest a relation to
colorectal cancer.
Diphenylmethane Derivatives
Bisacodyl is available in tablet and suppository formulations for
the treatment of acute and chronic constipation. It also is used
in conjunction with PEG solutions for colonic cleansing prior
to colonoscopy. It induces a bowel movement within 6–10 hours
when given orally and 30–60 minutes when taken rectally. It has
minimal systemic absorption and appears to be safe for acute and
long-term use.
CHLORIDE SECRETION ACTIVATORS
Lubiprostone is a prostanoic acid derivative labeled for use in
chronic constipation and irritable bowel syndrome (IBS) with pre-
dominant constipation. It acts by stimulating the type 2 chloride
channel (ClC-2) in the small intestine. This increases chloride-
rich fluid secretion into the intestine, which stimulates intestinal
motility and shortens intestinal transit time. Over 50% of patients
experience a bowel movement within 24 hours of taking one dose.
A dose of 24 mcg orally twice daily is the recommended dose for
treatment of chronic constipation. There appears to be no loss of
efficacy with long-term therapy. After discontinuation of the drug,
constipation may return to its pretreatment severity. Lubiprostone
has minimal systemic absorption but is designated category C for
pregnancy because of increased fetal loss in guinea pigs. Lubipro-
stone may cause nausea in up to 30% of patients due to delayed
gastric emptying.
Linaclotide and plecanatide are minimally absorbed, short
amino acid peptides that stimulate intestinal chloride secre-
tion through a different mechanism by binding to and acti-
vating guanylate cyclase-C on the luminal surface. This leads
to increased intracellular and extracellular cyclic guanosine
monophosphate (cGMP) with activation of the cystic fibrosis
transmembrane conductance regulator (CFTR), followed by
chloride-rich secretion and acceleration of intestinal transit.
Both agents are approved for the treatment of chronic constipa-
tion (linaclotide 145 mcg orally once daily; plecanatide 3 mg
orally once daily); linaclotide is also approved for the treatment
of irritable bowel syndrome with constipation (290 mcg orally
once daily). These agents result in an average increase of 1–2
bowel movements per week that usually occurs within the first
week of treatment. Upon discontinuation of the drug, bowel
movement frequency returns to normal within 1 week. The
most common side effect is diarrhea, which occurs in up to
20% of patients, with severe diarrhea in 2%. These drugs have
negligible absorption at standard doses. Both drugs are contra-
indicated in pediatric patients because of reports of increased
mortality in juvenile mice from dehydration. (Crofelemer is a
small molecule with the opposite effect: it is an inhibitor of the
CFTR channel and has recently been approved for the treatment
of HIV-drug-induced diarrhea.)
OPIOID RECEPTOR ANTAGONISTS
Acute and chronic therapy with opioids may cause constipation
by decreasing intestinal motility, which results in prolonged tran-
sit time and increased absorption of fecal water (see Chapter 31).
Use of opioids after surgery for treatment of pain as well as endog-
enous opioids also may prolong the duration of postoperative
ileus. These effects are mainly mediated through intestinal mu
(μ)-opioid receptors. Two selective antagonists of the μ-opioid
receptor are commercially available: methylnaltrexone bromide
and alvimopan. Because these agents do not readily cross the
blood-brain barrier, they inhibit peripheral μ-opioid receptors
without impacting analgesic effects within the central nervous
system. Methylnaltrexone is approved for the treatment of
opioid-induced constipation in patients receiving palliative care
for advanced illness who have had inadequate response to other
agents. It is administered as a subcutaneous injection (0.15 mg/
kg) every 2 days. Alvimopan is approved for short-term use to
1100    SECTION X  Special Topics
shorten the period of postoperative ileus in hospitalized patients
who have undergone small or large bowel resection. Alvimopan
(12 mg capsule) is administered orally within 5 hours before
surgery and twice daily after surgery until bowel function has
recovered, but for no more than 7 days. Because of possible cardio-
vascular toxicity, alvimopan currently is restricted to short-term
use in hospitalized patients only.
SEROTONIN 5-HT 4-RECEPTOR
AGONISTS
Stimulation of 5-HT4 receptors on the presynaptic terminal of
submucosal intrinsic primary afferent nerves enhances the release
of their neurotransmitters, including calcitonin gene-related pep-
tide, which stimulates second-order enteric neurons to promote
the peristaltic reflex (Figure 62–4). These enteric neurons stimu-
late proximal bowel contraction (via acetylcholine and substance P)
and distal bowel relaxation (via nitric oxide and vasoactive intes-
tinal peptide).
Tegaserod is a serotonin 5-HT4 partial agonist that has high
affinity for 5-HT4 receptors but no appreciable binding to 5-HT3
or dopamine receptors. Tegaserod was approved for the treatment
of patients with chronic constipation and IBS with predominant
constipation. It has since been withdrawn. Prucalopride is a
high-affinity 5-HT4 agonist that is available in Europe (but not
in the USA) for the treatment of chronic constipation in women.
In contrast to cisapride and tegaserod, it does not appear to have
significant affinities for either hERG K+ channels or 5-HT1B
receptors. In three 12-week clinical trials of patients with severe
chronic constipation, it resulted in a significant increase in bowel
movements compared with placebo. The long-term efficacy and
safety of this agent require further study.
■■ ANTIDIARRHEAL AGENTS
Antidiarrheal agents may be used safely in patients with mild to
moderate acute diarrhea. However, these agents should not be
used in patients with bloody diarrhea, high fever, or systemic
toxicity because of the risk of worsening the underlying condi-
tion. They should be discontinued in patients whose diarrhea is
worsening despite therapy. Antidiarrheals are also used to control
chronic diarrhea caused by such conditions as IBS or inflamma-
tory bowel disease (IBD).
OPIOID AGONISTS
As previously noted, opioids have significant constipating effects
(see Chapter 31). They increase colonic phasic segmenting activ-
ity through inhibition of presynaptic cholinergic nerves in the
submucosal and myenteric plexuses and lead to increased colonic
transit time and fecal water absorption. They also decrease mass
colonic movements and the gastrocolic reflex. Although all opi-
oids have antidiarrheal effects, central nervous system effects and
potential for addiction limit the usefulness of most.
Loperamide is a nonprescription opioid agonist that does not
cross the blood-brain barrier and has no analgesic properties or
potential for addiction. Tolerance to long-term use has not been
reported. It is typically administered in doses of 2 mg taken one
to four times daily. Diphenoxylate is a prescription opioid ago-
nist that has no analgesic properties in standard doses; however,
higher doses have central nervous system effects, and prolonged
use can lead to opioid dependence. Commercial preparations
commonly contain small amounts of atropine to discourage
overdosage (2.5 mg diphenoxylate with 0.025 mg atropine).
The anticholinergic properties of atropine may contribute to the
antidiarrheal action.
Eluxadoline is a prescription opioid agonist with high
affinity for the mu receptor (as well as low affinity for the
delta receptor). When taken orally, eluxadoline binds to
gut opioid receptors, resulting in slower colonic transit and
increased fecal fluid absorption. Eluxadoline is approved for
the treatment of patients with diarrhea-predominant IBS at a
dose of 75–100 mg twice daily. In two randomized placebo-
controlled trials, eluxadoline 100 mg twice daily led to sig-
nificant improvement in abdominal pain and diarrhea in 30%
of patients compared with 16% with placebo. Constipation
may occur in 8% of patients. Approximately 1% of patients
may experience sphincter of Oddi spasm (usually within the
first week of therapy) resulting in abdominal pain, pancreati-
tis, and/or elevated pancreatic or liver enzymes. Eluxadoline
should not be used in patients with a history of pancreatitis,
alcoholism, or known sphincter of Oddi disease. Caution is
advised in patients with prior cholecystectomy, in whom there
is up to a 5% risk of complications due to sphincter of Oddi
spasm. Eluxadoline 75 mg twice daily is recommended for
patients with prior cholecystectomy, mild to moderate liver
disease, or side effects at the higher dose.
COLLOIDAL BISMUTH COMPOUNDS
See the section under Mucosal Protective Agents in earlier text.
BILE SALT-BINDING RESINS
Conjugated bile salts are normally absorbed in the terminal ileum.
Disease of the terminal ileum (eg, Crohn’s disease) or surgical
resection leads to malabsorption of bile salts, which may cause
colonic secretory diarrhea. The bile salt-binding resins cholestyr-
amine, colestipol, or colesevelam, may decrease diarrhea caused
by excess fecal bile acids (see Chapter 35). These products come
in a variety of powder and pill formulations that may be taken
one to three times daily before meals. Adverse effects include
bloating, flatulence, constipation, and fecal impaction. In patients
with diminished circulating bile acid pools, further removal of
bile acids may lead to an exacerbation of fat malabsorption.
Cholestyramine and colestipol bind a number of drugs and reduce
their absorption; hence, they should not be given within 2 hours
of other drugs. Colesevelam does not appear to have significant
effects on absorption of other drugs.
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1101
OCTREOTIDE
Somatostatin is a 14-amino-acid peptide that is released in
the gastrointestinal tract and pancreas from paracrine cells,
D cells, and enteric nerves as well as from the hypothalamus
(see Chapter 37). Somatostatin is a key regulatory peptide that has
many physiologic effects:
1. It inhibits the secretion of numerous hormones and transmit-
ters, including gastrin, cholecystokinin, glucagon, growth
hormone, insulin, secretin, pancreatic polypeptide, vasoactive
intestinal peptide, and 5-HT.
2. It reduces intestinal fluid secretion and pancreatic secretion.
3. It slows gastrointestinal motility and inhibits gallbladder
contraction.
4. It reduces portal and splanchnic blood flow.
5. It inhibits secretion of some anterior pituitary hormones.
The clinical usefulness of somatostatin is limited by its short
half-life in the circulation (3 minutes) when it is administered by
intravenous injection. Octreotide is a synthetic octapeptide with
actions similar to somatostatin. When administered intravenously,
it has a serum half-life of 1.5 hours. It also may be administered
by subcutaneous injection, resulting in a 6- to 12-hour duration of
action. A longer-acting formulation is available for once-monthly
depot intramuscular injection.
Clinical Uses
1. Inhibition of endocrine tumor effects—Two gastrointesti-
nal neuroendocrine tumors (carcinoid, VIPoma) cause secretory
diarrhea and systemic symptoms such as flushing and wheezing.
For patients with advanced symptomatic tumors that cannot be
completely removed by surgery, octreotide decreases secretory
diarrhea and systemic symptoms through inhibition of hormonal
secretion and may slow tumor progression.
2. Other causes of diarrhea—Octreotide inhibits intestinal
secretion and has dose-related effects on bowel motility. In low
doses (50 mcg subcutaneously), it stimulates motility, whereas
at higher doses (eg, 100–250 mcg subcutaneously), it inhibits
motility. Octreotide is effective in higher doses for the treatment
of diarrhea due to vagotomy or dumping syndrome as well as for
diarrhea caused by short bowel syndrome or AIDS. Octreotide
has been used in low doses (50 mcg subcutaneously) to stimulate
small bowel motility in patients with small bowel bacterial over-
growth or intestinal pseudo-obstruction secondary to scleroderma.
3. Other uses—Because it inhibits pancreatic secretion, octreo-
tide may be of value in patients with pancreatic fistula. The role of
octreotide in the treatment of pituitary tumors (eg, acromegaly) is
discussed in Chapter 37. Octreotide is sometimes used in gastro-
intestinal bleeding (see below).
Adverse Effects
Impaired pancreatic secretion may cause steatorrhea, which can
lead to fat-soluble vitamin deficiency. Alterations in gastrointestinal
motility cause nausea, abdominal pain, flatulence, and diarrhea.
Because of inhibition of gallbladder contractility and alterations in
fat absorption, long-term use of octreotide can cause formation of
sludge or gallstones in over 50% of patients, which rarely results
in the development of acute cholecystitis. Because octreotide
alters the balance among insulin, glucagon, and growth hormone,
hyperglycemia or, less frequently, hypoglycemia (usually mild) can
occur. Prolonged treatment with octreotide may result in hypothy-
roidism. Octreotide also can cause bradycardia.
■■ DRUGS USED IN THE
TREATMENT OF IRRITABLE
BOWEL SYNDROME
IBS is an idiopathic chronic, relapsing disorder characterized by
abdominal discomfort (pain, bloating, distention, or cramps) in
association with alterations in bowel habits (diarrhea, constipa-
tion, or both). With episodes of abdominal pain or discomfort,
patients note a change in the frequency or consistency of their
bowel movements.
Pharmacologic therapies for IBS are directed at relieving
abdominal pain and discomfort and improving bowel function.
For patients with predominant diarrhea, antidiarrheal agents,
especially loperamide, are helpful in reducing stool frequency and
fecal urgency. For patients with predominant constipation, fiber
supplements may lead to softening of stools and reduced straining;
however, increased gas production may exacerbate bloating and
abdominal discomfort. Consequently, osmotic laxatives, espe-
cially milk of magnesia, are commonly used to soften stools and
promote increased stool frequency.
For chronic abdominal pain, low doses of tricyclic antidepres-
sants (eg, amitriptyline or desipramine, 10–50 mg/d) appear to
be helpful (see Chapter 30). At these doses, these agents have no
effect on mood but may alter central processing of visceral affer-
ent information. The anticholinergic properties of these agents
also may have effects on gastrointestinal motility and secretion,
reducing stool frequency and liquidity. Finally, tricyclic antide-
pressants may alter receptors for enteric neurotransmitters such as
serotonin, affecting visceral afferent sensation.
Several other agents are available that are specifically intended
for the treatment of IBS.
ANTISPASMODICS (ANTICHOLINERGICS)
Some agents are promoted as providing relief of abdominal pain
or discomfort through antispasmodic actions. However, small or
large bowel spasm has not been found to be an important cause
of symptoms in patients with IBS. Antispasmodics work primarily
through anticholinergic activities. Commonly used medications in
this class include dicyclomine and hyoscyamine (see Chapter 8).
These drugs inhibit muscarinic cholinergic receptors in the enteric
plexus and on smooth muscle. The efficacy of antispasmodics for
relief of abdominal symptoms has never been convincingly dem-
onstrated. At low doses, they have minimal autonomic effects.
1102    SECTION X  Special Topics

However, at higher doses they exhibit significant additional
anticholinergic effects, including dry mouth, visual disturbances,
urinary retention, and constipation. For these reasons, antispas-
modics are infrequently used.
SEROTONIN 5-HT3-RECEPTOR
ANTAGONISTS
5-HT3 receptors in the gastrointestinal tract activate visceral affer-
ent pain sensation via extrinsic sensory neurons from the gut to
the spinal cord and central nervous system. Inhibition of afferent
gastrointestinal 5-HT3 receptors may reduce unpleasant visceral
afferent sensation, including nausea, bloating, and pain. Blockade
of central 5-HT3 receptors also reduces the central response to vis-
ceral afferent stimulation. In addition, 5-HT3-receptor blockade
on the terminals of enteric cholinergic neurons inhibits colonic
motility, especially in the left colon, increasing total colonic transit
time.
Alosetron is a 5-HT3 antagonist that has been approved
for the treatment of patients with severe IBS with diarrhea
(Figure 62–5). Four other 5-HT3 antagonists (ondansetron,
granisetron, dolasetron, and palonosetron) have been approved
for the prevention and treatment of nausea and vomiting (see
Antiemetics); however, their efficacy in the treatment of IBS
has not been determined. The differences between these 5-HT3
antagonists that determine their pharmacodynamic effects have
not been well studied.
Pharmacokinetics & Pharmacodynamics
Alosetron is a highly potent and selective antagonist of the
5-HT3 receptor. It is rapidly absorbed from the gastrointestinal
tract with a bioavailability of 50–60% and has a plasma half-life
of 1.5 hours but a much longer duration of effect. It undergoes
extensive hepatic cytochrome P450 metabolism with renal excre-
tion of most metabolites. Alosetron binds with higher affinity
and dissociates more slowly from 5-HT3 receptors than other
5-HT3 antagonists, which may account for its long duration of
action.
Clinical Uses
Alosetron is approved for the treatment of women with
severe IBS in whom diarrhea is the predominant symptom

O
N
CH2
N
NH2
HO CH3
N

NH CH3

Serotonin Ondansetron

O NH N CH3

NH
NH N
N
CH3 NH
N CH3
CH3

NH Granisetron

Tegaserod O

O
CH3
O
N
NH O H
N
N
N
CH3 H
Alosetron Dolasetron

FIGURE 62–5  Chemical structure of serotonin; the 5-HT3 antagonists ondansetron, granisetron, dolasetron, and alosetron; and the 5-HT4
partial agonist tegaserod.
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1103
(“diarrhea-predominant IBS”). Its efficacy in men has not been
established. In a dosage of 1 mg once or twice daily, it reduces
IBS-related lower abdominal pain, cramps, urgency, and diarrhea.
Approximately 50–60% of patients report adequate relief of pain
and discomfort with alosetron compared with 30–40% of patients
treated with placebo. It also leads to a reduction in the mean
number of bowel movements per day and improvement in stool
consistency. Alosetron has not been evaluated for the treatment of
other causes of diarrhea.
Adverse Events
In contrast to the excellent safety profile of other 5-HT3-receptor
antagonists, alosetron is associated with rare but serious gastroin-
testinal toxicity. Constipation occurs in up to 30% of patients with
diarrhea-predominant IBS, requiring discontinuation of the drug
in 10%. Serious complications of constipation requiring hospital-
ization or surgery have occurred in 1 of every 1000 patients. Epi-
sodes of ischemic colitis—some fatal—have been reported in up to
3 per 1000 patients. Given the seriousness of these adverse events,
alosetron is restricted to women with severe diarrhea-predominant
IBS who have not responded to conventional therapies and who
have been educated about the relative risks and benefits.
Drug Interactions
Despite being metabolized by a number of CYP enzymes,
alosetron does not appear to have clinically significant interactions
with other drugs.
CHLORIDE CHANNEL ACTIVATORS
As discussed previously, lubiprostone is a prostanoic acid deriva-
tive that stimulates the type 2 chloride channel (ClC-2) in the
small intestine. Lubiprostone is approved for the treatment of
women with IBS with predominant constipation. Its efficacy for
men with IBS is unproven. The approved dose for IBS is 8 mcg
twice daily (compared with 24 mcg twice daily for chronic consti-
pation). In clinical trials, lubiprostone resulted in modest clinical
benefit—only 8% more patients than with placebo. Lubiprostone
is listed as category C for pregnancy and should be avoided in
women of child-bearing age.
Also discussed previously, linaclotide is a guanylyl cyclase-C
agonist that leads to activation of the CFTR in the small intes-
tine with stimulation of chloride-rich intestinal secretion. It is
approved for treatment of adults with IBS with constipation at an
approved dose of 290 mcg once daily (compared with 145 mcg
once daily for chronic constipation). In clinical trials, up to 25%
more patients treated with linaclotide than with placebo dem-
onstrated significant clinical improvement. Linaclotide is listed
as category C for pregnancy and is contraindicated for pediatric
patients.
Due to their high cost and lack of information about long-term
safety and efficacy, the role of these agents in the treatment of IBS
with constipation is uncertain. Neither agent has been compared
with other less expensive laxatives (eg, milk of magnesia).
■■ ANTIEMETIC AGENTS
Nausea and vomiting may be manifestations of a wide variety of
conditions, including adverse effects from medications; systemic
disorders or infections; pregnancy; vestibular dysfunction; central
nervous system infection or increased pressure; peritonitis; hepa-
tobiliary disorders; radiation or chemotherapy; and gastrointesti-
nal obstruction, dysmotility, or infections.
PATHOPHYSIOLOGY
The brainstem “vomiting center” is a loosely organized neuronal
region within the lateral medullary reticular formation and coor-
dinates the complex act of vomiting through interactions with
cranial nerves VIII and X and neural networks in the nucleus
tractus solitarius that control respiratory, salivatory, and vasomo-
tor centers. High concentrations of muscarinic M1, histamine H1,
neurokinin 1 (NK1), and serotonin 5-HT3 receptors have been
identified in the vomiting center (Figure 62–6).
There are four important sources of afferent input to the
vomiting center:
1. The “chemoreceptor trigger zone” or area postrema is located at
the caudal end of the fourth ventricle. This is outside the
blood-brain barrier and is accessible to emetogenic stimuli in
the blood or cerebrospinal fluid. The chemoreceptor trigger
zone is rich in dopamine D2 receptors and opioid receptors,
and possibly serotonin 5-HT3 receptors and NK1 receptors.
2. The vestibular system is important in motion sickness via
cranial nerve VIII. It is rich in muscarinic M1 and histamine H1
receptors.
3. Vagal and spinal afferent nerves from the gastrointestinal tract
are rich in 5-HT3 receptors. Irritation of the gastrointestinal
mucosa by chemotherapy, radiation therapy, distention, or
acute infectious gastroenteritis leads to release of mucosal sero-
tonin and activation of these receptors, which stimulate vagal
afferent input to the vomiting center and chemoreceptor
trigger zone.
4. The central nervous system plays a role in vomiting due to
psychiatric disorders, stress, and anticipatory vomiting prior to
cancer chemotherapy.
Identification of the different neurotransmitters involved with
emesis has allowed development of a diverse group of antiemetic
agents that have affinity for various receptors. Combinations of
antiemetic agents with different mechanisms of action are often
used, especially in patients with vomiting due to chemotherapeutic
agents.
SEROTONIN 5-HT3 ANTAGONISTS
Pharmacokinetics & Pharmacodynamics
Selective 5-HT3-receptor antagonists have potent antiemetic
properties that are mediated in part through central 5-HT3-
receptor blockade in the vomiting center and chemoreceptor
1104    SECTION X  Special Topics

Vestibular system

Central nervous system

Cortex
Thalamus
Hypothalamus H1 receptor?
Meninges M1 receptor

Fourth ventricle Chemoreceptor trigger zone

(area postrema)
Chemoreceptors
D2 receptor
Gastrointestinal tract and heart NK1 receptor?
(5-HT3 receptor)

Chemoreceptor
trigger zone
Vomiting center (nucleus of
tractus solitarius)
Cr H1 receptor
an Vomiting
ia l n er v M1 receptor
e IX or X center NK1 receptor?
(5-HT3 receptor)
Medulla oblongata
Mechanoreceptors
Chemoreceptors
5-HT3 receptor
Parasympathetic and
motor efferent activity

FIGURE 62–6  Neurologic pathways involved in pathogenesis of nausea and vomiting (see text). (Adapted, with permission, from Krakauer EL
et al: Case records of the Massachusetts General Hospital. N Engl J Med 2005;352:817. Copyright copy; 2005 Massachusetts Medical Society. Reprinted, with permission, from
Massachusetts Medical Society.)

trigger zone but mainly through blockade of peripheral 5-HT3 Clinical Uses
receptors on extrinsic intestinal vagal and spinal afferent nerves.
1. Chemotherapy-induced nausea and vomiting—5-HT3-
The antiemetic action of these agents is restricted to emesis
receptor antagonists are the primary agents for the prevention
attributable to vagal stimulation (eg, postoperative) and chemo-
of acute chemotherapy-induced nausea and emesis. When used
therapy; other emetic stimuli such as motion sickness are poorly
alone, these drugs have little or no efficacy for the prevention of
controlled.
delayed nausea and vomiting (ie, occurring >24 hours after che-
Four agents are available in the USA: ondansetron, granis-
motherapy). The drugs are most effective when given as a single
etron, dolasetron, and palonosetron. (Tropisetron is available
dose by intravenous injection 30 minutes prior to administration
outside the USA.) The first three agents (ondansetron, granis-
of chemotherapy in the following doses: ondansetron, 8 mg;
etron, and dolasetron, Figure 62–5) have a serum half-life of
granisetron, 1 mg; dolasetron, 100 mg; or palonosetron, 0.25 mg.
4–9 hours and may be administered once daily by oral or intrave-
A single oral dose given 1 hour before chemotherapy may be
nous routes. All three drugs have comparable efficacy and toler-
equally effective in the following regimens: ondansetron 8 mg
ability when administered at equipotent doses. Palonosetron is a
twice daily or 24 mg once; granisetron, 2 mg; dolasetron, 100 mg.
newer intravenous agent that has greater affinity for the 5-HT3
Although 5-HT3-receptor antagonists are effective as single agents
receptor and a long serum half-life of 40 hours. All four drugs
for the prevention of chemotherapy-induced nausea and vomit-
undergo extensive hepatic metabolism and are eliminated by renal
ing, their efficacy is enhanced by combination therapy with a
and hepatic excretion. However, dose reduction is not required in
corticosteroid (dexamethasone), NK1-receptor antagonist, and a
geriatric patients or patients with renal insufficiency. For patients
dopamine D2 antagonist (antipsychotics; see below).
with hepatic insufficiency, dose reduction may be required with
ondansetron. 2. Postoperative and postradiation nausea and
5-HT3-receptor antagonists do not inhibit dopamine or mus- vomiting—5-HT3-receptor antagonists are used to prevent or
carinic receptors. They do not have effects on esophageal or gastric treat postoperative nausea and vomiting. Because of adverse effects
motility but may slow colonic transit. and increased restrictions on the use of other antiemetic agents,
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1105
5-HT3-receptor antagonists are increasingly used for this indica-
tion. They are also effective in the prevention and treatment of
nausea and vomiting in patients undergoing radiation therapy to
the whole body or abdomen.
Adverse Effects
The 5-HT3-receptor antagonists are well-tolerated agents with
excellent safety profiles. The most commonly reported adverse
effects are headache, dizziness, and constipation. All four agents
cause a small but statistically significant prolongation of the QT
interval, but this is most pronounced with dolasetron. Although
cardiac arrhythmias have not been linked to dolasetron, it should
not be administered to patients with prolonged QT or in conjunc-
tion with other medications that may prolong the QT interval (see
Chapter 14). Serotonin syndrome has been reported in patients
taking 5-HT3-receptor antagonists in combination with other
serotonergic drugs (selective serotonin reuptake inhibitors [SSRIs]
and serotonin-norepinephrine reuptake inhibitors [SNRIs]; see
Chapter 30).
Drug Interactions
No significant drug interactions have been reported with 5-HT3-
receptor antagonists. All four agents undergo some metabolism
by the hepatic cytochrome P450 system, but they do not appear
to affect the metabolism of other drugs. However, other drugs
may reduce hepatic clearance of the 5-HT3-receptor antagonists,
altering their half-life.
CORTICOSTEROIDS
Corticosteroids (dexamethasone, methylprednisolone) have anti-
emetic properties, but the basis for these effects is unknown. The
pharmacology of this class of drugs is discussed in Chapter 39.
These agents appear to enhance the efficacy of 5-HT3-receptor
antagonists for prevention of acute and delayed nausea and
vomiting in patients receiving moderately to highly emetogenic
chemotherapy regimens. Although a number of corticosteroids
have been used, dexamethasone, 8–20 mg intravenously before
chemotherapy, followed by 8 mg/d orally for 2–4 days, is
commonly administered.
NEUROKININ RECEPTOR ANTAGONISTS
Neurokinin 1 (NK1)-receptor antagonists have antiemetic prop-
erties that are mediated through central blockade in the area
postrema. Aprepitant, netupitant, and rolapitant (all oral
formulations) are highly selective NK1-receptor antagonists that
cross the blood-brain barrier and occupy brain NK1 receptors.
They have no affinity for serotonin, dopamine, or corticosteroid
receptors. Netupitant (300 mg) is available only as a combina-
tion product with palonosetron (0.5 mg). Fosaprepitant is an
intravenous formulation that is converted within 30 minutes after
infusion to aprepitant.
Pharmacokinetics
The oral bioavailability of aprepitant is 65%, and the serum half-
life is 12 hours. Netupitant and rolapitant have longer half-lives
(90 and 180 hours, respectively), allowing single-dose administra-
tion. All three agents are metabolized by the liver, primarily by the
CYP3A4 pathway.
Clinical Uses
NK1-receptor antagonists are used in combination with 5-HT3-
receptor antagonists and corticosteroids for the prevention of acute
and delayed nausea and vomiting from highly emetogenic chemo-
therapeutic regimens. Combined therapy with an NK1-receptor
antagonist, a 5-HT3-receptor antagonist, and dexamethasone
prevents acute emesis in 80–90% of patients compared with less
than 70% of patients treated without an NK1 antagonist. Preven-
tion of delayed emesis occurs in more than 70% of patients receiv-
ing combined therapy versus 30–50% treated without an NK1
antagonist. Oral NK1-receptor antagonists may be administered as
follows: aprepitant 125 mg given 1 hour before chemotherapy, fol-
lowed by oral aprepitant 80 mg/d for 2 days after chemotherapy;
rolapitant 180 mg; or netupitant 300 mg/palonosetron 0.5 mg
given as a single dose 1–2 hours before chemotherapy. For patients
unable to tolerate oral therapy, intravenous fosaprepitant 115 mg
may be given as a single intravenous dose 1 hour before chemo-
therapy. The addition of the antipsychotic agent olanzapine 10 mg
on days 1–4 further decreases the incidence of acute and delayed
nausea and vomiting with highly emetogenic chemotherapeutic
regimens by 15–30%.
Adverse Effects & Drug Interactions
The NK1-receptor antagonists are well tolerated with a low
incidence of fatigue and dizziness. The drugs are metabolized by
CYP3A4 and may inhibit the metabolism of other drugs metabo-
lized by the CYP3A4 pathway. Several chemotherapeutic agents
are metabolized by CYP3A4, including docetaxel, paclitaxel, eto-
poside, irinotecan, imatinib, vinblastine, and vincristine. Drugs
that inhibit CYP3A4 metabolism may significantly increase apre-
pitant plasma levels (eg, ketoconazole, ciprofloxacin, clarithromy-
cin, nefazodone, ritonavir, nelfinavir, verapamil, and quinidine).
Aprepitant decreases the international normalized ratio (INR) in
patients taking warfarin.
ANTIPSYCHOTIC AGENTS
(PHENOTHIAZINES, BUTYROPHENONES,
& THIENOBENZODIAZEPINES)
Several classes of antipsychotic agents can be used for their anti-
emetic and sedative properties (see Chapter 29). The antiemetic
properties of phenothiazines are mediated through inhibition
of dopamine and muscarinic receptors. Sedative properties are
due to their antihistamine activity. The agents most com-
monly used as antiemetics are prochlorperazine, promethazine,
and thiethylperazine. The antiemetic properties of olanzapine
1106    SECTION X  Special Topics
(a thienobenzodiazepine) may be attributable to inhibition of
dopamine D2 and serotonin 5-HT1c and 5-HT3 receptors.
Antipsychotic butyrophenones also possess antiemetic proper-
ties due to their central dopaminergic blockade (see Chapter 29).
The main agent used is droperidol, which can be given by intra-
muscular or intravenous injection. In antiemetic doses, droperidol
is extremely sedating. Previously, it was used extensively for post-
operative nausea and vomiting, in conjunction with opiates and
benzodiazepines for sedation for surgical and endoscopic proce-
dures, for neuroleptanalgesia, and for induction and maintenance
of general anesthesia. Extrapyramidal effects and hypotension may
occur. Droperidol may prolong the QT interval, rarely resulting
in fatal episodes of ventricular tachycardia including torsades de
pointes. Therefore, droperidol should not be used in patients with
QT prolongation and should be used only in patients who have
not responded adequately to alternative agents.
SUBSTITUTED BENZAMIDES
Substituted benzamides include metoclopramide (discussed pre-
viously) and trimethobenzamide. Their primary mechanism of
antiemetic action is believed to be dopamine-receptor blockade.
Trimethobenzamide also has weak antihistaminic activity. For pre-
vention and treatment of nausea and vomiting, metoclopramide
may be given in the relatively high dosage of 10–20 mg orally
or intravenously every 6 hours. The usual dose of trimethoben-
zamide is 300 mg orally, or 200 mg by intramuscular injection.
The principal adverse effects of these central dopamine antago-
nists are extrapyramidal: restlessness, dystonias, and parkinsonian
symptoms.
H1 ANTIHISTAMINES &
ANTICHOLINERGIC DRUGS
The pharmacology of anticholinergic agents is discussed in
Chapter 8 and that of H1 antihistaminic agents in Chapter 16. As
single agents, these drugs have weak antiemetic activity, although
they are particularly useful for the prevention or treatment of
motion sickness. Their use may be limited by dizziness, seda-
tion, confusion, dry mouth, cycloplegia, and urinary retention.
Diphenhydramine and one of its salts, dimenhydrinate, are
first-generation histamine H1 antagonists that also have signifi-
cant anticholinergic properties. Because of its sedating properties,
diphenhydramine is commonly used in conjunction with other
antiemetics for treatment of emesis due to chemotherapy. Mecli-
zine is an H1 antihistaminic agent with minimal anticholinergic
properties that also causes less sedation. It is used for the pre-
vention of motion sickness and the treatment of vertigo due to
labyrinth dysfunction.
Hyoscine (scopolamine), a prototypic muscarinic receptor
antagonist, is one of the best agents for the prevention of motion
sickness. However, it has a very high incidence of anticholinergic
effects when given orally or parenterally. It is better tolerated as a
transdermal patch. Superiority to dimenhydrinate has not been
proved.
BENZODIAZEPINES
Benzodiazepines such as lorazepam or diazepam are used before
the initiation of chemotherapy to reduce anticipatory vomiting or
vomiting caused by anxiety. The pharmacology of these agents is
presented in Chapter 22.
CANNABINOIDS
Dronabinol is Δ9-tetrahydrocannabinol (THC), the major psy-
choactive chemical in marijuana (see Chapter 32). After oral
ingestion, the drug is almost completely absorbed but undergoes
significant first-pass hepatic metabolism. Its metabolites are
excreted slowly over days to weeks in the feces and urine. Like
crude marijuana, dronabinol is a psychoactive agent that is used
medically as an appetite stimulant and as an antiemetic, but the
mechanisms for these effects are not understood. Because of the
availability of more effective agents, dronabinol now is uncom-
monly used for the prevention of chemotherapy-induced nausea
and vomiting. Combination therapy with phenothiazines pro-
vides synergistic antiemetic action and appears to attenuate the
adverse effects of both agents. Dronabinol is usually administered
in a dosage of 5 mg/m2 just prior to chemotherapy and every
2–4 hours as needed. Adverse effects include euphoria, dysphoria,
sedation, hallucinations, dry mouth, and increased appetite. It has
some autonomic effects that may result in tachycardia, conjunc-
tival injection, and orthostatic hypotension. Dronabinol has no
significant drug-drug interactions but may potentiate the clinical
effects of other psychoactive agents.
Nabilone is a closely related THC analog that has been avail-
able in other countries and is now approved for use in the USA.
■■ DRUGS USED TO TREAT
INFLAMMATORY BOWEL DISEASE
(IBD)
IBD comprises two distinct disorders: ulcerative colitis and
Crohn’s disease. The etiology and pathogenesis of these disorders
remain unknown. For this reason, pharmacologic treatment of
inflammatory bowel disorders often involves drugs that belong
to different therapeutic classes and have different but nonspecific
mechanisms of anti-inflammatory action. Drugs used in IBD are
chosen on the basis of disease severity, responsiveness, and drug
toxicity (Figure 62–7).
AMINOSALICYLATES
Chemistry & Formulations
Drugs that contain 5-aminosalicylic acid (5-ASA) have been used
successfully for decades in the treatment of IBDs (Figure 62–8).
5-ASA differs from salicylic acid only by the addition of an amino
group at the 5 (meta) position. Aminosalicylates are believed to
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1107

Disease Responsiveness work topically (not systemically) in areas of diseased gastroin-

severity Therapy to therapy testinal mucosa. Up to 80% of unformulated, aqueous 5-ASA is
absorbed from the small intestine and does not reach the distal
Surgery
Natalizumab small bowel or colon in appreciable quantities. To overcome the
Severe Cyclosporine Refractory rapid absorption of 5-ASA from the proximal small intestine, a
TNF antagonists number of formulations have been designed to deliver 5-ASA to
Intravenous corticosteroids various distal segments of the small bowel or the colon. These
include sulfasalazine, olsalazine, balsalazide, and various forms
TNF antagonists
Oral corticosteroids of mesalamine.
Moderate
Methotrexate
Azathioprine / 6-Mercaptopurine 1. Azo compounds—Sulfasalazine, balsalazide, and olsala-
Budesonide (ileitis) zine contain 5-ASA bound by an azo (N=N) bond to an inert
Topical corticosteroids (proctitis) compound or to another 5-ASA molecule (Figure 62–8). In
Mild Antibiotics Responsive
sulfasalazine, 5-ASA is bound to sulfapyridine; in balsalazide,
5-Aminosalicylates
5-ASA is bound to 4-aminobenzoyl-β-alanine; and in olsalazine,
two 5-ASA molecules are bound together. The azo structure
FIGURE 62–7  Therapeutic pyramid approach to inflammatory markedly reduces absorption of the parent drug from the small
bowel diseases. Treatment choice is predicated on both the severity of intestine. In the terminal ileum and colon, resident bacteria cleave
the illness and the responsiveness to therapy. Agents at the bottom
the azo bond by means of an azoreductase enzyme, releasing the
of the pyramid are less efficacious but carry a lower risk of serious
active 5-ASA. Consequently, high concentrations of active drug
adverse effects. Drugs may be used alone or in various combinations.
Patients with mild disease may be treated with 5-aminosalicylates are made available in the terminal ileum or colon.
(with ulcerative colitis or Crohn’s colitis), topical corticosteroids
(ulcerative colitis), antibiotics (Crohn’s colitis or Crohn’s perianal 2. Mesalamine compounds—Other proprietary formulations
disease), or budesonide (Crohn’s ileitis). Patients with moderate have been designed that package 5-ASA itself in various ways
disease or patients who fail initial therapy for mild disease may to deliver it to different segments of the small or large bowel.
be treated with oral corticosteroids to promote disease remission; These 5-ASA formulations are known generically as mesalamine.
immunomodulators (azathioprine, mercaptopurine, methotrexate) Pentasa is a mesalamine formulation that contains timed-release
to promote or maintain disease remission; or anti-TNF antibodies.
microgranules that release 5-ASA throughout the small intestine
Patients with moderate disease who fail other therapies or patients
(Figure 62–9). Asacol and Apriso have 5-ASA coated in a pH-
with severe disease may require intravenous corticosteroids, anti-
TNF antibodies, or surgery. Natalizumab is reserved for patients with
sensitive resin that dissolves at pH 6–7 (the pH of the distal ileum
severe Crohn’s disease who have failed immunomodulators and TNF and proximal colon). Lialda also uses a pH-dependent resin that
antagonists. Cyclosporine is used primarily for patients with severe encases a multimatrix core. On dissolution of the pH-sensitive
ulcerative colitis who have failed a course of intravenous corticoste- resin in the colon, water slowly penetrates its hydrophilic and
roids. TNF, tumor necrosis factor. lipophilic core, leading to slow release of mesalamine throughout

COONa NaCOO COONa COOH

O
NaOOCCH2CH2NH C N=N OH HO N=N OH NHSO2 N=N OH
N

Balsalazide sodium Olsalazine Sulfasalazine

COOH

NH2 OH
NHSO2 NH2
N
5-Aminosalicylic acid (5-ASA)
Mesalamine Sulfapyridine

COOH

CH2CONH OH

5-Acetylaminosalicylic acid
(Ac-5-ASA)

FIGURE 62–8  Chemical structures and metabolism of aminosalicylates. Azo compounds (balsalazide, olsalazine, sulfasalazine) are
converted by bacterial azoreductase to 5-aminosalicylic acid (mesalamine), the active therapeutic moiety.
1108    SECTION X  Special Topics
Stomach Small Intestine
Jejunum Ileum
5-ASA delayed-release capsules (Pentasa)
5-ASA pH-dependent release (Asacol, Lialda)
FIGURE 62–9  Sites of 5-aminosalicylic acid (5-ASA) release from different formulations in the small and large intestines.
the colon. 5-ASA also may be delivered in high concentrations to
the rectum and sigmoid colon by means of enema formulations
(Rowasa) or suppositories (Canasa).
Pharmacokinetics & Pharmacodynamics
Although unformulated 5-ASA is readily absorbed from the small
intestine, absorption of 5-ASA from the colon is extremely low.
In contrast, approximately 20–30% of 5-ASA from current oral
mesalamine formulations is systemically absorbed in the small
intestine. Absorbed 5-ASA undergoes N-acetylation in the gut epi-
thelium and liver to a metabolite that does not possess significant
anti-inflammatory activity. The acetylated metabolite is excreted
by the kidneys.
Of the azo compounds, 10% of sulfasalazine and less than
1% of balsalazide are absorbed as native compounds. After azo-
reductase breakdown of sulfasalazine, over 85% of the carrier
molecule sulfapyridine is absorbed from the colon. Sulfapyridine
undergoes hepatic metabolism (including acetylation) followed
by renal excretion. By contrast, after azoreductase breakdown of
balsalazide, over 70% of the carrier peptide is recovered intact in
the feces and only a small amount of systemic absorption occurs.
The mechanism of action of 5-ASA is not certain. The pri-
mary action of salicylate and other NSAIDs is due to blockade of
prostaglandin synthesis by inhibition of cyclooxygenase. However,
the aminosalicylates have variable effects on prostaglandin produc-
tion. It is thought that 5-ASA modulates inflammatory mediators
derived from both the cyclooxygenase and lipoxygenase pathways.
Other potential mechanisms of action of the 5-ASA drugs relate
to their ability to interfere with the production of inflamma-
tory cytokines. 5-ASA inhibits the activity of nuclear factor-κB
(NF-κB), an important transcription factor for proinflammatory
cytokines. 5-ASA may also inhibit cellular functions of natural
killer cells, mucosal lymphocytes, and macrophages, and it may
scavenge reactive oxygen metabolites.
Clinical Uses
5-ASA drugs induce and maintain remission in ulcerative colitis
and are considered to be the first-line agents for treatment of mild
to moderate active ulcerative colitis. Their efficacy in Crohn’s
Colon
Proximal Distal Rectum
Sulfasalazine
Balsalazide
5-ASA enema (Rowasa)
5-ASA suppository (Canasa)
disease is unproven, although many clinicians use 5-ASA agents as
first-line therapy for mild to moderate disease involving the colon
or distal ileum.
The effectiveness of 5-ASA therapy depends in part on achiev-
ing high drug concentration at the site of active disease. Thus,
5-ASA suppositories or enemas are useful in patients with ulcer-
ative colitis or Crohn’s disease confined to the rectum (proctitis)
or distal colon (proctosigmoiditis). In patients with ulcerative
colitis or Crohn’s colitis that extends to the proximal colon, both
the azo compounds and mesalamine formulations are useful. For
the treatment of Crohn’s disease involving the small bowel, mesa-
lamine compounds, which release 5-ASA in the small intestine,
have a theoretic advantage over the azo compounds.
Adverse Effects
Sulfasalazine has a high incidence of adverse effects, most of
which are attributable to systemic effects of the sulfapyridine
molecule. Slow acetylators of sulfapyridine have more frequent
and more severe adverse effects than fast acetylators. Up to 40%
of patients cannot tolerate therapeutic doses of sulfasalazine. The
most common problems are dose-related and include nausea, gas-
trointestinal upset, headaches, arthralgias, myalgias, bone marrow
suppression, and malaise. Hypersensitivity to sulfapyridine (or,
rarely, 5-ASA) can result in fever, exfoliative dermatitis, pancre-
atitis, pneumonitis, hemolytic anemia, pericarditis, or hepatitis.
Sulfasalazine has also been associated with oligospermia, which
reverses upon discontinuation of the drug. Sulfasalazine impairs
folate absorption and processing; hence, dietary supplementation
with 1 mg/d folic acid is recommended.
In contrast to sulfasalazine, other aminosalicylate formula-
tions are well tolerated. In most clinical trials, the frequency of
drug adverse events is similar to that in patients treated with
placebo. For unclear reasons, olsalazine may stimulate a secretory
diarrhea—which should not be confused with active IBD—in
10% of patients. Rare hypersensitivity reactions may occur with all
aminosalicylates but are much less common than with sulfasalazine.
Careful studies have documented subtle changes indicative of renal
tubular damage in patients receiving high doses of aminosalicylates.
Rare cases of interstitial nephritis are reported, particularly in asso-
ciation with high doses of mesalamine formulations; this may be
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1109
attributable to the higher serum 5-ASA levels attained with these
drugs. Sulfasalazine and other aminosalicylates rarely cause worsen-
ing of colitis, which may be misinterpreted as refractory colitis.
GLUCOCORTICOIDS
Pharmacokinetics & Pharmacodynamics
In gastrointestinal practice, prednisone and prednisolone are
the most commonly used oral glucocorticoids. These drugs have
an intermediate duration of biologic activity allowing once-daily
dosing.
Hydrocortisone enemas, foam, or suppositories are used to
maximize colonic tissue effects and minimize systemic absorp-
tion via topical treatment of active IBD in the rectum and sig-
moid colon. Absorption of hydrocortisone is reduced with rectal
administration, although 15–30% of the administered dosage is
still absorbed.
Budesonide is a potent synthetic analog of prednisolone that
has high affinity for the glucocorticoid receptor but is subject to
rapid first-pass hepatic metabolism (in part by CYP3A4), result-
ing in low oral bioavailability. Two pH-controlled delayed-release
oral formulations of budesonide are available that release the drug
either in the distal ileum and colon (pH > 5.5, Entocort) or in the
colon (pH > 7, Uceris), where it is absorbed. The bioavailability
of controlled-release budesonide capsules is approximately 10%.
As in other tissues, glucocorticoids inhibit production of
inflammatory cytokines (tumor necrosis factor [TNF]-α, interleu-
kin [IL]-1) and chemokines (IL-8); reduce expression of inflam-
matory cell adhesion molecules; and inhibit gene transcription of
nitric oxide synthase, phospholipase A2, cyclooxygenase-2, and
NF-κB.
Clinical Uses
Glucocorticoids are commonly used in the treatment of patients
with moderate to severe active IBD. Active disease is commonly
treated with an initial oral dosage of 40–60 mg/d of prednisone
or prednisolone. Higher doses have not been shown to be more
efficacious but have significantly greater adverse effects. Once a
patient responds to initial therapy (usually within 1–2 weeks),
the dosage is tapered to minimize development of adverse
effects. In severely ill patients, the drugs are usually administered
intravenously.
For the treatment of IBD involving the rectum or sigmoid
colon, rectally administered glucocorticoids are preferred because
of their lower systemic absorption.
The oral controlled-release budesonide (9 mg/d) formulations
described above are used in the treatment of mild to moderate
Crohn’s disease involving the ileum and proximal colon (Ento-
cort) and ulcerative colitis (Uceris). They are slightly less effective
than prednisolone in achieving clinical remission but have signifi-
cantly less adverse systemic effects.
Corticosteroids are not useful for maintaining disease remis-
sion. Other medications such as aminosalicylates or immunosup-
pressive agents should be used for this purpose.
Adverse Effects
Oral controlled-release budesonide formulations are metabolized
extensively in the liver by CYP3A4. Potent inhibitors of CYP3A4
can increase budesonide plasma levels several-fold, increasing the
likelihood of adverse effects. General adverse effects of glucocorti-
coids are reviewed in Chapter 39.
PURINE ANALOGS: AZATHIOPRINE &
6-MERCAPTOPURINE
Pharmacokinetics & Pharmacodynamics
Azathioprine and 6-mercaptopurine (6-MP) are purine antime-
tabolites that have immunosuppressive properties (see Chapters 54
and 55).
The bioavailability of azathioprine (80%) is superior to 6-MP
(50%). After absorption, azathioprine is rapidly converted by a
nonenzymatic process to 6-MP. 6-Mercaptopurine subsequently
undergoes a complex biotransformation via competing catabolic
enzymes (xanthine oxidase and thiopurine methyltransferase)
that produce inactive metabolites and anabolic pathways that
produce active thioguanine nucleotides. Azathioprine and 6-MP
have a serum half-life of less than 2 hours; however, the active
6-thioguanine nucleotides are concentrated in cells resulting
in a prolonged half-life of days. The prolonged kinetics of
6-thioguanine nucleotide results in a median delay of 17 weeks
before onset of therapeutic benefit from oral azathioprine or
6-MP is observed in patients with IBD.
Clinical Uses
Azathioprine and 6-MP are important agents in the induction
and maintenance of remission of ulcerative colitis and Crohn’s
disease. Although the optimal dose is uncertain, most patients
with normal thiopurine-S-methyltransferase (TPMT) activity (see
below) are treated with 6-MP, 1–1.5 mg/kg/d, or azathioprine,
2–2.5 mg/kg/d. After 3–6 months of treatment, 50–60% of
patients with active disease achieve remission. These agents help
maintain remission in up to 80% of patients. Among patients
who depend on long-term glucocorticoid therapy to control active
disease, purine analogs allow dose reduction or elimination of
steroids in the majority.
Adverse Effects
Dose-related toxicities of azathioprine or 6-MP include nausea,
vomiting, bone marrow depression (leading to leukopenia, mac-
rocytosis, anemia, or thrombocytopenia), and hepatic toxicity.
Routine laboratory monitoring with complete blood count and
liver function tests is required in all patients. Leukopenia or
elevations in liver chemistries usually respond to medication dose
reduction. Severe leukopenia may predispose to opportunistic
infections; leukopenia may respond to therapy with granulocyte
stimulating factor. Catabolism of 6-MP by TPMT is low in 11%
and absent in 0.3% of the population, leading to increased pro-
duction of active 6-thioguanine metabolites and increased risk of
1110    SECTION X  Special Topics
bone marrow depression. TPMT levels can be measured before
initiating therapy. These drugs should not be administered to
patients with no TPMT activity and should be initiated at lower
doses in patients with intermediate activity. Hypersensitivity reac-
tions to azathioprine or 6-MP occur in 5% of patients. These
include fever, rash, pancreatitis, diarrhea, and hepatitis.
As with transplant recipients receiving long-term 6-MP or
azathioprine therapy, there appears to be an increased risk of lym-
phoma among patients with IBD, some of which may be related
to Epstein-Barr virus infection. The drugs are also associated with
an increased risk of nonmelanoma skin cancers. These drugs cross
the placenta; however, there are many reports of successful preg-
nancies in women taking these agents, and the risk of teratogenic-
ity appears to be small.
Drug Interactions
Allopurinol markedly reduces xanthine oxide catabolism of the
purine analogs, potentially increasing active 6-thioguanine nucle-
otides that may lead to severe leukopenia. Allopurinol should not
be given to patients taking 6-MP or azathioprine except in care-
fully monitored situations.
METHOTREXATE
Pharmacokinetics & Pharmacodynamics
Methotrexate is another antimetabolite that has beneficial effects
in a number of chronic inflammatory diseases, including Crohn’s
disease and rheumatoid arthritis (see Chapter 36), and in cancer
(see Chapter 54). Methotrexate may be given orally, subcutane-
ously, or intramuscularly. Reported oral bioavailability is 50–90%
at doses used in chronic inflammatory diseases. Intramuscular and
subcutaneous methotrexate exhibit nearly complete bioavailability.
The principal mechanism of action is inhibition of dihydrofolate
reductase, an enzyme important in the production of thymidine
and purines. At the high doses used for chemotherapy, methotrexate
inhibits cellular proliferation. However, at the low doses used in the
treatment of IBD (12–25 mg/wk), the antiproliferative effects may
not be evident. Methotrexate may interfere with the inflammatory
actions of IL-1. It may also stimulate increased release of adenosine,
an endogenous anti-inflammatory autacoid. Methotrexate may also
stimulate apoptosis and death of activated T lymphocytes.
Clinical Uses
Methotrexate is used to induce and maintain remission in patients
with Crohn’s disease. Its efficacy in ulcerative colitis is uncertain.
To induce remission, patients are treated with 15–25 mg of
methotrexate once weekly by subcutaneous injection. If a satisfac-
tory response is achieved within 8–12 weeks, the dose is reduced
to 15 mg/wk.
Adverse Effects
At higher dosage, methotrexate may cause bone marrow depres-
sion, megaloblastic anemia, alopecia, and mucositis. At the doses
used in the treatment of IBD, these events are uncommon but
warrant dose reduction if they do occur. Folate supplementa-
tion reduces the risk of these events without impairing the anti-
inflammatory action.
In patients with psoriasis treated with methotrexate, hepatic
damage is common; however, among patients with IBD and rheu-
matoid arthritis, the risk is significantly lower. Renal insufficiency
may increase risk of hepatic accumulation and toxicity.
ANTITUMOR NECROSIS FACTOR
THERAPY
Pharmacokinetics & Pharmacodynamics
A dysregulation of the helper T cell type 1 (Th1) response and regu-
latory T cells (Tregs) is present in IBD, especially Crohn’s disease.
One of the key proinflammatory cytokines in IBD is tumor necrosis
factor (TNF). TNF is produced by the innate immune system (eg,
dendritic cells, macrophages), the adaptive immune system (espe-
cially Th1 cells), and nonimmune cells (fibroblasts, smooth muscle
cells). TNF exists in two biologically active forms: soluble TNF
and membrane-bound TNF. The biologic activity of soluble and
membrane-bound TNF is mediated by binding to TNF receptors
(TNFR) that are present on some cells (especially Th1 cells, innate
immune cells, and fibroblasts). Binding of TNF to TNFR initially
activates components including NF-κB that stimulate transcrip-
tion, growth, and expansion. Biologic actions ascribed to TNFR
activation include release of proinflammatory cytokines from
macrophages, T-cell activation and proliferation, fibroblast col-
lagen production, up-regulation of endothelial adhesion molecules
responsible for leukocyte migration, and stimulation of hepatic
acute phase reactants. Activation of TNFR may later lead to apop-
tosis (programmed cell death) of activated cells.
Four monoclonal antibodies to human TNF are approved
for the treatment of IBD: infliximab, adalimumab, golimumab,
and certolizumab (Table 62–3). Infliximab, adalimumab, and
golimumab are antibodies of the IgG1 subclass. Certolizumab
is a recombinant antibody that contains an Fab fragment that is
conjugated to polyethylene glycol (PEG) but lacks an Fc portion.
The Fab portion of infliximab is a chimeric mouse-human anti-
body, but adalimumab, certolizumab, and golimumab are fully
humanized. Infliximab is administered as an intravenous infusion.
At therapeutic doses of 5–10 mg/kg, the half-life of infliximab
is approximately 8–10 days, resulting in plasma disappearance
of antibodies over 8–12 weeks. Adalimumab, golimumab, and
certolizumab are administered by subcutaneous injection. Their
half-lives are approximately 2 weeks.
All four agents bind to soluble and membrane-bound TNF
with high affinity, preventing the cytokine from binding to its
receptors. Binding of all three antibodies to membrane-bound
TNF also causes reverse signaling that suppresses cytokine release.
When infliximab, adalimumab, or golimumab bind to membrane-
bound TNF, the Fc portion of the human IgG1 region promotes
antibody-mediated apoptosis, complement activation, and cellular
cytotoxicity of activated T lymphocytes and macrophages. Certoli-
zumab, without an Fc portion, lacks these properties.
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1111

TABLE 62–3  Anti-TNF antibodies used in inflammatory bowel disease.

Infliximab Adalimumab Certolizumab Golimumab

Class Monoclonal antibody Monoclonal antibody Monoclonal antibody Monoclonal antibody

% Human 75% 100% 95% 100%
Structure IgG1 IgG1 Fab fragment attached IgG1
to PEG (lacks Fc portion)
Route of administration Intravenous Subcutaneous Subcutaneous Subcutaneous
Half-life 8–10 days 10–20 days 14 days 14 days
Neutralizes soluble TNF Yes Yes Yes Yes
Neutralizes membrane-bound TNF Yes Yes Yes Yes
Induces apoptosis of cells Yes Yes No Yes
expressing membrane-bound TNF
Complement-mediated cytotoxicity Yes Yes No Yes
of cells expressing membrane-
bound TNF
Induction dose 5 mg/kg at 0, 2, and 160 mg, 80 mg, and 400 mg at 0, 2, and 200 mg, 100 mg at 0,
6 weeks 40 mg at 0, 2, and 4 weeks 4 weeks 2 weeks
Maintenance dose 5 mg/kg every 8 weeks 40 mg every 2 weeks 400 mg every 4 weeks 100 mg every 4 weeks
TNF, tumor necrosis factor.

Clinical Uses
Infliximab, adalimumab, and certolizumab are approved for
the acute and chronic treatment of patients with moderate to
severe Crohn’s disease who have had an inadequate response to
conventional therapies. Infliximab, adalimumab, and golimumab
are approved for the acute and chronic treatment of moderate to
severe ulcerative colitis. With induction therapy, these approved
agents lead to symptomatic improvement in 60% and disease
remission in 30% of patients with moderate to severe Crohn’s
disease, including patients who have been dependent on gluco-
corticoids or who have not responded to 6-MP or methotrex-
ate. The median time to clinical response is 2 weeks. Induction
therapy is generally given as follows: infliximab 5 mg/kg intra-
venous infusion at 0, 2, and 6 weeks; adalimumab 160 mg (in
divided doses) initially and 80 mg subcutaneous injection at
2 weeks; and certolizumab 400 mg subcutaneous injection at 0, 2,
and 4 weeks. Patients who respond may be treated with chronic
maintenance therapy, as follows: infliximab 5 mg/kg intravenous
infusion every 8 weeks; adalimumab 40 mg subcutaneous injec-
tion every 2 weeks; certolizumab 400 mg subcutaneous injection
every 4 weeks. With chronic, regularly scheduled therapy, clinical
response is maintained in more than 60% of patients and disease
remission in 40%. However, one-third of patients eventually lose
response despite higher doses or more frequent injections. Loss
of response in many patients may be due to the development of
antibodies to the TNF antibody or to other mechanisms.
Infliximab is approved for the treatment of patients with mod-
erate to severe ulcerative colitis who have had inadequate response
to mesalamine or corticosteroids. After induction therapy of
5–10 mg/wk at 0, 2, and 6 weeks, 70% of patients have a clinical
response and one third achieve a clinical remission. With contin-
ued maintenance infusions every 8 weeks, approximately 50% of
patients have continued clinical response. Adalimumab and goli-
mumab also are approved for the treatment of moderate to severe
ulcerative colitis but appear to be less effective than intravenous
infliximab. After induction therapy, less than 55% of patients
have a clinical response and less than 20% achieve remission. The
reason why subcutaneous anti-TNF formulations are less effective
than intravenous infliximab is uncertain.
Adverse Effects
Serious adverse events occur in up to 6% of patients with anti-
TNF therapy. The most important adverse effect of these drugs is
infection due to suppression of the Th1 inflammatory response.
This may lead to serious infections such as bacterial sepsis,
tuberculosis, invasive fungal organisms, reactivation of hepatitis
B, listeriosis, and other opportunistic infections. Reactivation
of latent tuberculosis, with dissemination, has occurred. Before
administering anti-TNF therapy, all patients must undergo test-
ing with tuberculin skin tests or interferon gamma release assays.
Prophylactic therapy for tuberculosis is warranted for patients
with positive test results before beginning anti-TNF therapy.
More common but usually less serious infections include upper
respiratory infections (sinusitis, bronchitis, and pneumonia) and
cellulitis. The risk of serious infections is increased markedly in
patients taking concomitant corticosteroids.
Antibodies to the antibody (ATA) may develop with all four
agents. These antibodies may attenuate or eliminate the clini-
cal response and increase the likelihood of developing acute or
delayed infusion or injection reactions. Antibody formation is
much more likely in patients given episodic anti-TNF therapy
than regular scheduled injections. In patients on chronic main-
tenance therapy, the prevalence of ATA with infliximab is 10%,
with certolizumab 8%, and with adalimumab or golimumab 3%.
1112    SECTION X  Special Topics
Antibody development also is less likely in patients who receive
concomitant therapy with immunomodulators (ie, 6-MP or
methotrexate). Concomitant treatment with anti-TNF agents and
immunomodulators may increase the risk of lymphoma.
Infliximab intravenous infusions result in acute adverse infu-
sion reactions in up to 10% of patients, but discontinuation of
the infusion for severe reactions is required in less than 2%. Infu-
sion reactions are more common with the second or subsequent
infusions than with the first. Early mild reactions include fever,
headache, dizziness, urticaria, or mild cardiopulmonary symptoms
that include chest pain, dyspnea, or hemodynamic instability.
Reactions to subsequent infusions may be reduced with prophy-
lactic administration of acetaminophen, diphenhydramine, or
corticosteroids. Severe acute reactions include significant hypoten-
sion, shortness of breath, muscle spasms, and chest discomfort;
such reactions may require treatment with oxygen, epinephrine,
and corticosteroids.
A delayed serum sickness-like reaction may occur 1–2 weeks
after anti-TNF therapy in 1% of patients. These reactions consist
of myalgia, arthralgia, jaw tightness, fever, rash, urticaria, and
edema and usually require discontinuation of that agent. Positive
antinuclear antibodies and anti-double-stranded DNA develop
in a small number of patients. Development of a lupus-like
syndrome is rare and resolves after discontinuation of the drug.
Rare but serious adverse effects of all anti-TNF agents also
include severe hepatic reactions leading to acute hepatic failure,
demyelinating disorders, hematologic reactions, and new or wors-
ened congestive heart failure in patients with underlying heart
disease. Anti-TNF agents may cause a variety of psoriatic skin
rashes, which usually resolve after drug discontinuation.
Lymphoma appears to be increased in patients with untreated
IBD. Anti-TNF agents may further increase the risk of lymphoma
in this population, although the relative risk is uncertain. An
increased number of cases of hepatosplenic T-cell lymphoma, a
rare but usually fatal disease, have been noted in children and
young adults, virtually all of whom have been on combined
therapy with immunomodulators, anti-TNF agents, or corticoste-
roids. Anti-TNF agents may also be associated with an increased
risk of nonmelanoma skin cancers.
ANTI-INTEGRIN THERAPY
Integrins are a family of adhesion molecules on the surface of
leukocytes that may interact with another class of adhesion
molecules on the surface of the vascular endothelium known as
selectins, allowing circulating leukocytes to adhere to the vascular
endothelium and subsequently move through the vessel wall into
the tissue. Integrins consist of heterodimers that contain two sub-
units, alpha and beta. Two monoclonal antibodies directed against
integrins are available for the treatment of inflammatory bowel
disease: natalizumab and vedolizumab. Both are administered
intravenously. Natalizumab is a humanized IgG4 monoclonal anti-
body targeted only against the α4 subunit; thus, it blocks several
integrins on circulating inflammatory cells and prevents binding
to the vascular adhesion molecules and subsequent migration
into surrounding tissues, including the bowel and central nervous
system. Unfortunately, patients treated with natalizumab may
develop progressive multifocal leukoencephalopathy (PML) due
to central nervous system reactivation of a human polyomavirus
(JC virus), which is present in latent form in over 80% of adults.
Patients who are positive for JC virus antibody have a mean risk
of PML of 3.9 per 1000 patients; however, the risk is markedly
increased in patients treated for more than 24 months or receiving
other immunosuppressants.
Vedolizumab is a monoclonal antibody with activity directed
specifically against the α4/β7 integrin, thereby blocking interac-
tion of leukocytes with gut vascular endothelial cell adhesion
molecules. Because lymphocytes trafficking to the brain are unaf-
fected, the risk of reactivation of JC virus and PML is believed to
be extremely low. With the advent of vedolizumab, natalizumab
is almost never used for the treatment of IBD. Vedolizumab is
increasingly used as a second-line treatment for patients with
moderate to severe ulcerative colitis or Crohn’s disease who can-
not take anti-TNF agents due to side effects, lack of efficacy, or
loss of response. After intravenous induction therapy of 300 mg
at 0, 2, and 6 weeks, patients with a clinical response are treated
with intravenous maintenance therapy every 8 weeks. Vedoli-
zumab appears to have a very low incidence of serious side effects.
Neutralizing antibodies may develop in 2–10% of patients.
■■ PANCREATIC ENZYME
SUPPLEMENTS
Exocrine pancreatic insufficiency is most commonly caused by
cystic fibrosis, chronic pancreatitis, or pancreatic resection. When
secretion of pancreatic enzymes falls below 10% of normal, fat
and protein digestion is impaired and can lead to steatorrhea,
azotorrhea, vitamin malabsorption, and weight loss. Pancreatic
enzyme supplements, which contain a mixture of amylase, lipase,
and proteases, are the mainstay of treatment for pancreatic enzyme
insufficiency. Two major types of preparations in use are pancre-
atin and pancrelipase. Pancreatin is an alcohol-derived extract of
hog pancreas with relatively low concentrations of lipase and pro-
teolytic enzymes, whereas pancrelipase is an enriched preparation.
On a per-weight basis, pancrelipase has approximately 12 times
the lipolytic activity and more than 4 times the proteolytic activity
of pancreatin. Consequently, pancreatin is no longer in common
clinical use. Only pancrelipase is discussed here.
Pancrelipase is available worldwide in both non-enteric-coated
and enteric-coated preparations. Formulations are available in
sizes containing varying amounts of lipase, amylase, and prote-
ase. However, manufacturers’ listings of enzyme content do not
always reflect true enzymatic activity. Pancrelipase enzymes are
rapidly and permanently inactivated by gastric acids. Viokace is
a non-enteric-coated tablet that should be given concomitantly
with acid suppression therapy (PPI or H2 antagonist) to reduce
acid-mediated destruction within the stomach. Enteric-coated
formulations are more commonly used because they do not
require concomitant acid suppression therapy. At present, five
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1113
enteric-coasted, delayed-release formulations are approved for use
(Creon, Pancreaze, Zenpep, Ultresa, and Pertyze).
Pancrelipase preparations are administered with each meal
and snack. Enzyme activity may be listed in international units
(IU) or USP units. One IU is equal to 2–3 USP units. Dosing
should be individualized according to the age and weight of the
patient, the degree of pancreatic insufficiency, and the amount
of dietary fat intake. Therapy is initiated at a dose that provides
60,000–90,000 USP units (20,000–30,000 IU) of lipase activity
in the prandial and postprandial period—a level that is sufficient
to reduce steatorrhea to a clinically insignificant level in most
cases. Suboptimal response to enteric-coated formulations may be
due to poor mixing of granules with food or slow dissolution and
release of enzymes. Gradual increase of dose, change to a different
formulation, or addition of acid suppression therapy may improve
response. For patients with feeding tubes, microspheres may be
mixed with enteral feeding prior to administration.
Pancreatic enzyme supplements are well tolerated. The capsules
should be swallowed, not chewed, because pancreatic enzymes
may cause oropharyngeal mucositis. Excessive doses may cause
diarrhea and abdominal pain. The high purine content of pan-
creas extracts may lead to hyperuricosuria and renal stones. Several
cases of colonic strictures were reported in patients with cystic
fibrosis who received high doses of pancrelipase with high lipase
activity. These high-dose formulations have since been removed
from the market.
■■ GLUCAGON-LIKE PEPTIDE 2
ANALOG FOR SHORT-BOWEL
SYNDROME
Extensive surgical resection or disease of the small intestine may
result in short-bowel syndrome with malabsorption of nutrients
and fluids. Patients with less than 200 cm of small intestine (with
or without colon resection) usually are dependent on partial or
complete parenteral nutritional support to maintain hydration
and nutrition. Teduglutide is a glucagon-like peptide 2 analog
that binds to enteric neurons and endocrine cells, stimulating
release of a number of trophic hormones (including insulin-like
growth factor) that stimulate mucosal epithelial growth and
enhance fluid absorption. In clinical trials, 54% of patients treated
with teduglutide (0.05 mg/kg once daily by subcutaneous injec-
tion) reduced their need for parenteral support by at least 1 day/
wk compared with 23% treated with placebo. Teduglutide may be
associated with an increased risk of neoplasia, including colorectal
polyps.
■■ BILE ACID AGENTS
Ursodiol (ursodeoxycholic acid) is a naturally occurring bile
acid that makes up less than 5% of the circulating bile salt pool
in humans and a much higher percentage in bears. After oral
administration, it is absorbed, conjugated in the liver with glycine
or taurine, and excreted in the bile. Conjugated ursodiol under-
goes extensive enterohepatic recirculation. The serum half-life is
approximately 100 hours. With long-term daily administration,
ursodiol constitutes 30–50% of the circulating bile acid pool. A
small amount of unabsorbed conjugated or unconjugated urso-
diol passes into the colon, where it is either excreted or under-
goes dehydroxylation by colonic bacteria to lithocholic acid, a
substance with potential hepatic toxicity.
Pharmacodynamics
The solubility of cholesterol in bile is determined by the relative
proportions of bile acids, lecithin, and cholesterol. Although pro-
longed ursodiol therapy expands the bile acid pool, this does not
appear to be the principal mechanism of action for dissolution of
gallstones. Ursodiol decreases the cholesterol content of bile by
reducing hepatic cholesterol secretion. Ursodiol also appears to
stabilize hepatocyte canalicular membranes, possibly through a
reduction in the concentration of other endogenous bile acids or
through inhibition of immune-mediated hepatocyte destruction.
Clinical Use
Ursodiol is used for dissolution of small cholesterol gallstones in
patients with symptomatic gallbladder disease who refuse chole-
cystectomy or who are poor surgical candidates. At a dosage of
10 mg/kg/d orally for 12–24 months, dissolution occurs in up to
50% of patients with small (<5–10 mm) noncalcified gallstones.
It is also effective for the prevention of gallstones in obese patients
undergoing rapid weight loss therapy.
Ursodiol is also the first-line agent used for the treatment of
early primary biliary cirrhosis (PBC). As a nontoxic bile acid,
ursodiol is believed to reduce liver injury by replacement of
more toxic endogenous bile acids and through anti-inflammatory
effects. At a dose of 13–15 mg/kg/d, ursodiol improves liver
biochemical abnormalities, slows the rate of clinical and histo-
logic progression, reduces the need for liver transplantation, and
improves long-term survival. Approximately 35% of patients with
PBC do not respond to ursodiol.
Adverse Effects
Ursodiol is practically free of serious adverse effects. Bile salt-
induced diarrhea is uncommon. Unlike its predecessor, chenode-
oxycholate, ursodiol has not been associated with hepatotoxicity.
Obeticholic acid is a synthetic derivative of the naturally
occurring bile acid chenodeoxycholate. Like ursodiol, it is a non-
toxic bile acid and is believed to reduce liver injury by decreas-
ing hepatic concentrations of more toxic endogenous bile acids.
It also is a ligand for the nuclear farnesoid X receptor, which
modulates hepatic inflammation, fibrosis, gluconeogenesis, lipid
synthesis, and insulin sensitivity. Obeticholic acid was recently
approved for the treatment of PBC at a dose of 5–10 mg/d
orally in combination with ursodiol in patients who have had an
inadequate response to ursodiol monotherapy. In a randomized,
double-blind, placebo-controlled, 12-month trial, almost 50% of
patients treated with combination therapy had a clinical response
1114    SECTION X  Special Topics
compared with 10% treated with ursodiol alone. Obeticholic acid
causes severe pruritus in up to 25% of patients (especially at the
10 mg dose), leading to discontinuation in up to 10% of patients.
■■ DRUGS USED TO TREAT
VARICEAL HEMORRHAGE
Portal hypertension most commonly occurs as a consequence of
chronic liver disease. Portal hypertension is caused by increased
blood flow within the portal venous system and increased resis-
tance to portal flow within the liver. Splanchnic blood flow is
increased in patients with cirrhosis due to low arteriolar resis-
tance that is mediated by increased circulating vasodilators and
decreased vascular sensitivity to vasoconstrictors. Intrahepatic
vascular resistance is increased in cirrhosis due to fixed fibrosis
within the spaces of Disse and hepatic veins as well as reversible
vasoconstriction of hepatic sinusoids and venules. Among the con-
sequences of portal hypertension are ascites, hepatic encephalopa-
thy, and the development of portosystemic collaterals—especially
gastric or esophageal varices. Varices can rupture, leading to mas-
sive upper gastrointestinal bleeding.
Several drugs are available that reduce portal pressures. These
may be used in the short term for the treatment of active variceal
hemorrhage or long term to reduce the risk of hemorrhage.
SOMATOSTATIN & OCTREOTIDE
The pharmacology of octreotide is discussed above under Antidi-
arrheal Agents. In patients with cirrhosis and portal hypertension,
intravenous somatostatin (250 mcg/h) or octreotide (50 mcg/h)
reduces portal blood flow and variceal pressures; the mechanism
by which they do so is poorly understood. They do not appear to
induce direct contraction of vascular smooth muscle. Their activ-
ity may be mediated through inhibition of release of glucagon
and other gut peptides that alter mesenteric blood flow. Although
data from clinical trials are conflicting, these agents are probably
effective in promoting initial hemostasis from bleeding esophageal
varices. They are generally administered for 3–5 days.
VASOPRESSIN & TERLIPRESSIN
Vasopressin (antidiuretic hormone) is a polypeptide hormone
secreted by the hypothalamus and stored in the posterior pituitary.
Its pharmacology is discussed in Chapters 17 and 37. Although its
primary physiologic role is to maintain serum osmolality, it is also
a potent arterial vasoconstrictor. When administered intravenously
by continuous infusion, vasopressin causes splanchnic arterial
vasoconstriction that leads to reduced splanchnic perfusion and
lowered portal venous pressures. Before the advent of octreotide,
vasopressin was commonly used to treat acute variceal hemor-
rhage. However, because of its high adverse-effect profile, it is no
longer used for this purpose. In contrast, for patients with acute
gastrointestinal bleeding from small bowel or large bowel vascular
ectasias or diverticulosis, vasopressin may be infused—to promote
vasospasm—into one of the branches of the superior or inferior
mesenteric artery through an angiographically placed catheter.
Adverse effects with systemic vasopressin are common. Systemic
and peripheral vasoconstriction can lead to hypertension, myocar-
dial ischemia or infarction, or mesenteric infarction. These effects
may be reduced by coadministration of nitroglycerin, which may
further reduce portal venous pressures (by reducing portohepatic
vascular resistance) and may also reduce the coronary and periph-
eral vascular vasospasm caused by vasopressin. Other common
adverse effects are nausea, abdominal cramps, and diarrhea (due
to intestinal hyperactivity). Furthermore, the antidiuretic effects
of vasopressin promote retention of free water, which can lead to
hyponatremia, fluid retention, and pulmonary edema.
Terlipressin is a vasopressin analog that appears to have similar
efficacy to vasopressin with fewer adverse effects. Although this
agent is available in other countries, it has never been approved
for use in the USA.
BETA-RECEPTOR-BLOCKING DRUGS
The pharmacology of β-receptor-blocking agents is discussed in
Chapter 10. Beta-receptor antagonists reduce portal venous pres-
sures via a decrease in portal venous inflow. This decrease is due
to a decrease in cardiac output (β1 blockade) and to splanchnic
vasoconstriction (β2 blockade) caused by the unopposed effect
of systemic catecholamines on α receptors. Thus, nonselective
β blockers such as propranolol and nadolol are more effective than
selective β1 blockers in reducing portal pressures. Among patients
with cirrhosis and esophageal varices who have not previously
had an episode of variceal hemorrhage, the incidence of bleeding
among patients treated with nonselective β blockers is 15% com-
pared with 25% in control groups. Among patients with a history
of variceal hemorrhage, the likelihood of recurrent hemorrhage is
80% within 2 years. Nonselective β blockers significantly reduce
the rate of recurrent bleeding, although a reduction in mortality
is unproved.
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1115

SUMMARY  Drugs Used Primarily for Gastrointestinal Conditions

Clinical Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Applications Interactions

DRUGS USED IN ACID-PEPTIC DISEASES

  • Proton-pump Irreversible blockade of H+/ Long-lasting reduction of Peptic ulcer, Half-lives much shorter than duration of
+
inhibitors (PPIs), eg, K -ATPase pump in active stimulated and nocturnal gastroesophageal reflux action • low toxicity • reduction of
omeprazole, parietal cells of stomach acid secretion disease, erosive gastritis stomach acid may reduce absorption of
lansoprazole some drugs and increase that of others

  • H2-receptor blockers, eg, cimetidine: Effective reduction of nocturnal acid but less effective against stimulated secretion; very safe, available over the counter (OTC).
Cimetidine, but not other H2 blockers, is a weak antiandrogenic agent and a potent CYP enzyme inhibitor
  • Sucralfate: Polymerizes at site of tissue damage (ulcer bed) and protects against further damage; very insoluble with no systemic effects; must be given four times daily
  • Antacids: Popular OTC medication for symptomatic relief of heartburn; not as useful as PPI and H2 blockers in peptic diseases

DRUGS STIMULATING MOTILITY

  • Metoclopramide D2-receptor blocker • removes Increases gastric emptying Gastric paresis (eg, in Parkinsonian symptoms due to block of
inhibition of acetylcholine and intestinal motility diabetes) • antiemetic central nervous system (CNS) D2
neurons in enteric nervous (see below) receptors
system

  • Domperidone: Like metoclopramide, but less CNS effect; not available in USA
  • Cholinomimetics: Neostigmine often used for colonic pseudo-obstruction in hospitalized patients
  • Macrolides: Erythromycin useful in diabetic gastroparesis but tolerance develops

LAXATIVES

  • Magnesium Osmotic agents increase Usually causes evacuation Simple constipation; Magnesium may be absorbed and cause
hydroxide, other water content of stool within 4–6 h, sooner in bowel prep for toxicity in renal impairment
nonabsorbable salts large doses endoscopy (especially
and sugars polyethylene glycol
[PEG] solutions)

  • Bulk-forming laxatives: Methylcellulose, psyllium, etc: increase volume of colon contents, stimulate evacuation
  • Stimulants: senna, cascara; stimulate activity; may cause cramping
  • Stool surfactants: Docusate, mineral oil; lubricate stool, ease passage
  • Chloride channel activators: Lubiprostone, prostanoic acid derivative, stimulates chloride secretion into intestine, increasing fluid content; linaclotide, guanylyl cyclase-C
agonist, stimulates chloride secretion by CFTR
  • Opioid receptor antagonists: Alvimopan, methylnaltrexone; block intestinal μ-opioid receptors but do not enter CNS, so analgesia is maintained

ANTIDIARRHEAL DRUGS

  • Loperamide Activates μ-opioid receptors Slows motility in gut with Nonspecific, Mild cramping but little or no CNS
in enteric nervous system negligible CNS effects noninfectious diarrhea toxicity

  • Diphenoxylate: Similar to loperamide, but high doses can cause CNS opioid effects and toxicity
  • Colloidal bismuth compounds: Subsalicylate and citrate salts available. OTC preparations popular and have some value in travelers’ diarrhea due to adsorption of toxins
  • Kaolin + pectin: Adsorbent compounds available OTC in some countries

DRUGS FOR IRRITABLE BOWEL SYNDROME (IBS)

  • Alosetron 5-HT3 antagonist of high Reduces smooth muscle Approved for severe Rare but serious constipation • ischemic
potency and duration of activity in gut diarrhea-predominant colitis • infarction
binding IBS in women

  • Anticholinergics: Nonselective action on gut activity, usually associated with typical antimuscarinic toxicity
  • Chloride channel activator: Lubiprostone (see above); useful in constipation-predominant IBS in women; linaclotide (see above): useful in adults with constipation-
predominant IBS

(continued)
1116    SECTION X  Special Topics

Clinical Pharmacokinetics, Toxicities,

Subclass, Drug Mechanism of Action Effects Applications Interactions
ANTIEMETIC DRUGS

  • Ondansetron, other 5-HT3 blockade in gut and Extremely effective in First-line agents in Usually given IV but orally active in
5-HT3 antagonists CNS with shorter duration of preventing chemotherapy- cancer chemotherapy; prophylaxis • 4–9 h duration of action
binding than alosetron induced and postoperative also useful for postop • very low toxicity but may slow colonic
nausea and vomiting emesis transit

  • Aprepitant NK1-receptor blocker in CNS Interferes with vomiting Effective in reducing Given orally • IV fosaprepitant available
reflex • no effect on 5-HT, both early and delayed • fatigue, dizziness, diarrhea • CYP
dopamine, or steroid emesis in cancer interactions
receptors chemotherapy

  • Corticosteroids: Mechanism not known but useful in antiemetic IV cocktails

  • Antimuscarinics (scopolamine): Effective in emesis due to motion sickness; not other types
  • Antihistaminics: Moderate efficacy in motion sickness and chemotherapy-induced emesis
  • Phenothiazines: Act primarily through block of D2 and muscarinic receptors
  • Cannabinoids: Dronabinol is available for use in chemotherapy-induced nausea and vomiting, but is associated with CNS marijuana effects

DRUGS USED IN INFLAMMATORY BOWEL DISEASE (IBD)

  • 5-Aminosalicylates, Mechanism uncertain • may Topical therapeutic action Mild to moderately Sulfasalazine causes sulfonamide
eg, mesalamine in be inhibition of eicosanoid • systemic absorption may severe Crohn’s disease toxicity and may cause GI upset,
many formulations inflammatory mediators cause toxicity and ulcerative colitis myalgias, arthralgias, myelosuppression
  • Sulfasalazine • other aminosalicylates much less toxic

  • Purine analogs and Mechanism uncertain • may
antimetabolites, eg, promote apoptosis of
6-mercaptopurine, immune cells • Methotrexate
methotrexate blocks dihydrofolate
reductase
Generalized suppression of Moderately severe to GI upset, mucositis • myelosuppression
immune processes severe Crohn’s disease • purine analogs may cause
and ulcerative colitis hepatotoxicity, but rare with
methotrexate at the low doses used

  • Anti-TNF antibodies,
eg, infliximab, others
Bind tumor necrosis factor
and prevent it from binding to
its receptors
Suppression of several
aspects of immune
function, especially Th1
lymphocytes
Infliximab: Moderately Infusion reactions • reactivation of latent
severe to severe Crohn’s tuberculosis • increased risk of
disease and ulcerative dangerous systemic fungal and bacterial
colitis • others approved infections
in Crohn’s disease

  • Corticosteroids: Generalized anti-inflammatory effect; see Chapter 39

PANCREATIC SUPPLEMENTS

  • Pancrelipase Replacement enzymes from Improves digestion of Pancreatic insufficiency Taken with every meal • may increase
animal pancreatic extracts dietary fat, protein, and due to cystic fibrosis, incidence of gout
carbohydrate pancreatitis,
pancreatectomy

  • Pancreatin: Similar pancreatic extracts but much lower potency; rarely used

BILE ACID THERAPY FOR GALLSTONES AND PRIMARY BILIARY CIRRHOSIS

  • Ursodiol Reduces cholesterol secretion Dissolves gallstones Gallstones in patients May cause diarrhea
into bile and concentration of • reduces hepatic refusing or not eligible
endogenous hepatocyte bile inflammation and fibrosis for surgery • early
salts primary biliary cirrhosis

  • Obeticholic acid
Binds to hepatocyte nuclear
farnesoid X receptor
Reduces hepatic
inflammation and fibrosis
Treatment of primary Severe pruritus
biliary cirrhosis in
patients with
inadequate response to
ursodiol

DRUGS USED TO TREAT VARICEAL HEMORRHAGE

  • Octreotide Somatostatin analog May alter portal blood flow Patients with bleeding Reduced endocrine and exocrine
• mechanism not certain and variceal pressures varices or at high risk of pancreatic activity • other endocrine
repeat bleeding abnormalities • GI upset

  • Beta blockers: Reduce cardiac output and splanchnic blood flow; see Chapter 10
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1117

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

ANTACIDS Scopolamine Transderm Scop
*
Aluminum hydroxide gel Generic, AlternaGEL, others Trimethobenzamide Generic, Tigan, others
*
Calcium carbonate Generic, Tums, others SELECTED ANTI-INFLAMMATORY DRUGS USED IN
Combination aluminum hydroxide Generic, Maalox, Mylanta, GASTROINTESTINAL DISEASE (SEE ALSO CHAPTER 55)
and magnesium hydroxide Gaviscon, Gelusil, others Adalimumab Humira
preparations* Balsalazide Colazal
H 2 HISTAMINE RECEPTOR BLOCKERS Budesonide Entocort, Uceris
Cimetidine Generic, Tagamet, Tagamet HB* Certolizumab Cimzia
Famotidine Generic, Pepcid, Pepcid AC,* Golimumab Symponi
*
Pepcid Complete
Hydrocortisone Cortenema, Cortifoam,
Nizatidine Generic, Axid, Axid AR* Proctofoam–HC
Ranitidine Generic, Zantac, Zantac 75* Infliximab Remicade
SELECTED ANTICHOLINERGIC DRUGS Mesalamine 5-ASA
Atropine Generic  Oral: Asacol
Belladonna alkaloids tincture Generic  Rectal: Rowasa, Canasa
Dicyclomine Generic, Bentyl, others Methylprednisolone Medrol Enpack
Glycopyrrolate Generic, Robinul Olsalazine Dipentum
Hyoscyamine Anaspaz, Levsin, others Sulfasalazine Generic, Azulfidine
Scopolamine Generic, Transderm Scop Vedolizumab Entyvio
PROTON-PUMP INHIBITORS SELECTED ANTIDIARRHEAL DRUGS
Esomeprazole magnesium Nexium* Bismuth subsalicylate
*
Pepto-Bismol, others
Esomeprazole strontium   Difenoxin Motofen
Omeprazole Generic, Prilosec, Prilosec OTC* Diphenoxylate Generic, Lomotil, others
Omeprazole-sodium bicarbonate Zegerid Eluxadoline Viberzi
Lansoprazole Generic, Prevacid* Loperamide
*
Generic, Imodium
Dexlansoprazole Dexilant BULK-FORMING LAXATIVES *
Pantoprazole Generic, Protonix Methylcellulose Generic, Citrucel
Rabeprazole Generic, Aciphex Psyllium Generic, Serutan, Metamucil,
MUCOSAL PROTECTIVE AGENTS others
Sucralfate Generic, Carafate OTHER SELECTED LAXATIVE DRUGS
DIGESTIVE ENZYMES Alvimopan Entereg
*
Pancrelipase Creon, Pancrease, Zenpep, Bisacodyl Generic, Dulcolax, others
Pertyze, Ultresa Cascara sagrada* Generic
DRUGS FOR MOTILITY DISORDERS & SELECTED ANTIEMETICS Docusate* Generic, Colace, others
5-HT 3 -RECEPTOR ANTAGONISTS Lactulose Generic, Chronulac, Cephulac,
Alosetron Lotronex others
Dolasetron Anzemet Linaclotide Linzess
Granisetron Generic, Kytril Lubiprostone Amitiza
Ondansetron Generic, Zofran Magnesium hydroxide (milk of Generic
*
Palonosetron Aloxi magnesia, Epsom Salt)
OTHER MOTILITY AND ANTIEMETIC AGENTS Methylnaltrexone bromide Relistor
*
Aprepitant Emend Polycarbophil Equalactin, Mitrolan, FiberCon,
Fiber–Lax
Dronabinol Generic, Marinol
Polyethylene glycol electrolyte Co–Lyte, GoLYTELY, HalfLytely,
Fosaprepitant Emend, Emend IV solution Moviprep, others
Metoclopramide Generic, Reglan, others Senna
*
Senokot, ExoLax, others
Nabilone Cesamet Sodium Phosphate Fleets Phospho-soda, OsmoPrep,
Netupitant/palonosetron Akynzeo Visicol
Prochlorperazine Generic, Compazine DRUGS THAT DISSOLVE GALLSTONES
Promethazine Generic, Phenergan, others Obeticholic acid Ocaliva
Rolapitant Varubi Ursodiol Generic, Actigall, URSO
*
Over-the-counter formulations.
1118    SECTION X  Special Topics
REFERENCES
Acid-Peptic Diseases
Alshamsi F et al: Efficacy and safety of proton pump inhibitors for stress ulcer
prophylaxis in critically ill patients: A systematic review and meta-analysis of
randomized trials. Crit Care 2016;20:120.
Barletta JF et al: Stress ulcer prophylaxis. Crit Care Med 2016;44:1395.
Bredenoord AJ et al: Gastro-oesophageal reflux disease. Lancet 2013;
381(9881):1933.
Fallone CA et al: The Toronto Consensus for the treatment of Helicobacter pylori
infection in adults. Gastroenterology 2016;151:51.
Ford AC et al: Eradication therapy for peptic ulcer disease in Helicobacter pylori-
positive people. Cochrane Database Syst Rev 2016;4:CD003840.
Gerson L: Proton pump inhibitors and potential interactions with clopidogrel: An
update. Curr Gastroenterol Rep 2013;15:329.
Gomm W et al: Association of proton pump inhibitors with risk of dementia.
JAMA Neurol 2016;73:410.
Katz PO et al: Guidelines for the diagnosis and management of gastroesophageal
reflux disease. Am J Gastroenterol 2013;108:308.
Lazarus B et al: Proton pump inhibitor use and the risk of chronic kidney disease.
JAMA Intern Med 2016;176:238.
Malfertheiner P et al: Management of Helicobacter pylori infection—the Maastricht
IV/Florence Consensus report. Gut 2012;61:646.
Medlock S et al: Co-prescription of gastroprotective agents and their efficacy in
elderly patients taking nonsteroidal anti-inflammatory drugs: A systematic
review of observational studies. Clin Gastroenterol Hepatol 2013;11:1259.
Scheiman JM: The use of proton pump inhibitors in treating and preventing
NSAID-induced mucosal damage. Arthritis Res Ther 2013;15(Suppl 3):S5.
Schubert ML: Gastric secretion. Curr Opin Gastroenterol 2014;30:578.
Sigterman KE et al: Short-term treatment with proton pump inhibitors,
H2-receptor antagonists, and prokinetics for gastro-oesophageal reflux
disease-like symptoms and endoscopy negative reflux disease. Cochrane
Database Syst Rev 2013;5:CD002095.
Motility Disorders
Camilleri M et al: Clinical guideline: Management of gastroparesis. Am J Gastro-
enterol 2013;108:18.
Enweluzo C et al: Gastroparesis: A review of current and emerging treatment
options. Clin Exp Gastroenterol 2013;6:161.
Farmer AD: Diabetic gastroparesis: Pathophysiology, evaluation and management.
Br J Hosp Med 2012;73:451.
Laxatives
Bharucha AE et al: American Gastroenterological Association Medical Position
Statement on constipation. Gastroenterology 2013;144:211.
Brenner DM et al: Chronic constipation. Gastroenterol Clin North Am
2016;45:205.
Brock C et al: Opioid-induced bowel dysfunction: Pathophysiology and manage-
ment. Drugs 2012;72:1847.
Ford AC et al: Laxatives for chronic constipation in adults. BMJ 2012;345:e6168.
Johnson DA et al: Optimizing adequacy of bowel cleansing for colonoscopy:
Recommendations from the US Multisociety Task Force on Colorectal
Cancer. Gastroenterology 2014;147:903.
Kilgore TW et al: Bowel preparation with split-dose polyethylene glycol before
colonoscopy: A meta-analysis of randomized controlled trials. Gastrointest
Endosc 2011;73:1240.
Linaclotide (Linzess) for constipation. Med Lett Drugs Ther 2012;54:91.
Schey R et al: Lubiprostone for the treatment of adults with constipation and
irritable bowel syndrome. Dig Dis Sci 2011;56:1619.
Wald A: Constipation: Advances in diagnosis and treatment. JAMA 2016;315:185.
Antidiarrheal Agents
Camilleri M: Bile acid diarrhea: Prevalence, pathogenesis, and therapy. Gut Liver
2015;9:332.
Kent AJ: Pharmacologic management of diarrhea. Gastroenterol Clin N Am 2010;
39:496.
Li Z et al: Treatment of chronic diarrhea. Best Pract Clin Gastroenterol 2012;
26:677.
Drugs Used for Irritable Bowel Syndrome
Chang L et al: 2015 James W. Freston Topic Conference: A renaissance in
the understanding and management of irritable bowel syndrome. Clin
Gastroenterol Hepatol 2016;14:e77.
Chey WD et al: Linaclotide for irritable bowel syndrome with constipation: A
26-week randomized, double-blind, placebo-controlled trial to evaluate
efficacy and safety. Am J Gastroenterol 2012;107:1702.
Ford AC et al: American College of Gastroenterology monograph on the manage-
ment of irritable bowel syndrome and chronic idiopathic constipation. Am J
Gastroenterol 2014;109(Suppl 1):S2.
Lembo AJ et al: Eluxadoline for irritable bowel syndrome with diarrhea. N Engl J
Med 2016;374(3):242.
Vazquez RM et al: Linaclotide, a synthetic guanylate cyclase C agonist, for the
treatment of functional gastrointestinal disorders associated with constipa-
tion. Exp Rev Gastroenterol Hepatol 2011;5:301.
Antiemetic Agents
Basch E et al: Antiemetics: American Society of Clinical Oncology Clinical
Practice Guideline update. J Clin Oncol 2011;29:4189.
Ettinger DS et al: Antiemesis. J Natl Canc Comp Netw 2012;10:456.
Jordan K et al: Recent developments in the prevention of chemotherapy-induced
nausea and vomiting (CINV): A comprehensive review. Ann Oncol 2015;
26:1081.
Navarri R et al: Antiemetic prophylaxis for chemotherapy-induced nausea and
vomiting. N Engl J Med 2016;374:1356.
Navarri R et al: Olanzapine for the prevention of chemotherapy-induced nausea
and vomiting. N Engl J Med 2016;375:134.
Drugs Used for Inflammatory Bowel Disease
Bloomgren G et al: Risk of natalizumab-associated progressive multifocal leukoen-
cephalopathy. N Engl J Med 2012;366:20.
Bressler B et al: Clinical guidelines for the medical management of nonhospitalized
ulcerative colitis: The Toronto consensus. Gastroenterology 2015;148:1035.
Casteelle N et al: Trough concentrations of infliximab guide dosing for patients
with inflammatory bowel disease. Gastroenterology 2015;148:1320.
Cheifetz AS et al: Management of active Crohn disease. JAMA 2013;309:2150.
Ford AC et al: Efficacy of biological therapies in inflammatory bowel disease: A
systematic review and meta-analysis. Am J Gastroenterol 2011;106:644.
Ford A et al: Efficacy of oral vs. topical, or combined oral and topical
5-aminosalicylates in ulcerative colitis: A systematic review and meta-
analysis. Am J Gastroenterol 2012;107:167.
Ford A et al: Ulcerative colitis. BMJ 2013;346:f432.
Kotlyar DS et al: Risk of lymphoma in patients with inflammatory bowel disease
treated with azathioprine and 6-mercaptopurine: A meta-analysis. Clin
Gastroenterol Hepatol 2015;13:847.
Mosli MH et al: Vedolizumab for induction and maintenance of remission in
ulcerative colitis: A Cochrane systematic review and meta-analysis. Inflamm
Bowel Dis 2015;21:1151.
Ordas I: Ulcerative colitis. Lancet 2012;380:1606.
Pola S et al: Strategies for the care of adults hospitalized for active ulcerative colitis.
Clin Gastroenterol Hepatol 2012;10:1315.
Sandborn WJ et al: Adalimumab induces and maintains clinical remission in patients
with moderate-to-severe ulcerative colitis. Gastroenterology 2012;142:257.
Sandborn WJ et al: Subcutaneous golimumab induces clinical response and remis-
sion in patients with moderate to severe ulcerative colitis. Gastroenterology
2014;146:85.
Sandborn WJ et al: Subcutaneous golimumab maintains clinical response in patients
with moderate-to-severe ulcerative colitis. Gastroenterology 2014;146:96.
Sandborn WJ et al: Vedolizumab as induction and maintenance therapy for
Crohn’s disease. N Engl J Med 2013;369:711.
 CHAPTER 62  Drugs Used in the Treatment of Gastrointestinal Diseases     1119
Terdiman JP et al: American Gastroenterological Association Institute guide on the
use of thiopurines, methotrexate, and anti-TNF-alpha biologic drugs for the
induction and maintenance of remission in inflammatory Crohn’s disease.
Gastroenterology 2013;145:1459.
Pancreatic Enzyme Supplements
Forsmark C: Management of chronic pancreatitis. Gastroenterology 2013;
144:1282.
Whitcomb DC et al: Pancrelipase delayed-release capsules (CREON) for exocrine
pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery: A
double-blind randomized trial. Am J Gastroenterol 2010;105:2276.
Wier HA et al: Pancreatic enzyme supplementation. Curr Opin Pediatr 2011;23:541.
Bile Acids
Hempfling W, Dilger K, Beuers U: Systematic review: Ursodeoxycholic acid—
Adverse effects and drug interactions. Aliment Pharmacol Ther 2003;18:963.
C ASE STUDY ANSWER
The immediate goals of therapy are to improve this young
woman’s symptoms of abdominal pain, diarrhea, weight
loss, and fatigue. Equally important goals are to reduce the
intestinal inflammation in hopes of preventing progression
to intestinal stenosis, fistulization, and need for surgery. One
option now is to step up her therapy by giving her a slow,
tapering course of systemic corticosteroids (eg, prednisone)
for 8–12 weeks in order to quickly bring her symptoms and
inflammation under control while also initiating therapy
Hirschfield GM et al: Efficacy of obeticholic acid in patients with primary biliary
cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology
2015;148:751.
Drugs for Portal Hypertension
Ahmed ME: Treatment of portal hypertension. World J Gastroenterol 2012;
18:1166.
Garcia-Tsao G et al: Management of varices and variceal hemorrhage in cirrhosis.
N Engl J Med 2010;362:823.
Drugs for Short Bowel Syndrome
Buchman AL: Teduglutide and short bowel syndrome: Every night without
parenteral fluids is a good night. Gastroenterology 2012;143:1416.
Jeppesen PB et al: Teduglutide reduces need for parenteral support among
patients with short bowel syndrome with intestinal failure. Gastroenterology
2012;143:1473.
with an immunomodulator (eg, azathioprine or mercap-
topurine) in hopes of achieving long-term disease remis-
sion. If satisfactory disease control is not achieved within
3–6 months, therapy with an anti-TNF agent would then
be recommended. Alternatively, patients with moderate-
to-severe Crohn’s disease who have failed mesalamine may
be treated upfront with both an anti-TNF agent and immu-
nomodulators, which achieves higher remission rates than
either agent alone and may improve long-term outcomes.
 63
C H A P T E R
Therapeutic &
Toxic Potential of
Over-the-Counter Agents
Valerie B. Clinard, PharmD, &
Robin L. Corelli, PharmD
C ASE STUDY
KH, a 55-year-old woman, presents to the emergency
department with nausea, vomiting, and complaints of new-
onset flu symptoms over the past several days. Her past medical
history is significant for allergic rhinitis and chronic lower
back pain secondary to a work-related fall 2 years ago. Her
current medications include Norco 5/325 (hydrocodone 5 mg/
acetaminophen 325 mg per tablet; two tablets four times daily
for pain) and loratadine (10 mg daily). The patient also reported
recent use of several over-the-counter (OTC) medications over
the past 3 days to treat the new-onset flu symptoms, including
Alka-Seltzer Plus Severe Cold + Flu (two tablets every 4 hours
during the day) and Tylenol PM (two tablets at bedtime).
In the USA, medications are divided by law into two classes:
those restricted to sale by prescription only and those for which
directions for safe use by the public can be written. The latter
category constitutes the nonprescription, or over-the-counter
(OTC), medications. This category does not include supplements
(vitamins, minerals, herbals, and botanicals), which are subject
to different regulatory requirements (see Chapter 64, Dietary
Supplements & Herbal Medications). In 2016, the American
public spent approximately $34 billion on OTC products to self-
manage a wide variety of acute and chronic medical conditions.
It is apparent that many OTC medications are comparable
products advertised to consumers in ways that suggest signifi-
cant differences between them. For example, there are over 100
1120
Her social history is significant for alcohol use (three to four
glasses of wine/night). Her vital signs include the following:
temperature 99.8°F, blood pressure 132/64 mm Hg, pulse
78 bpm, and respiratory rate 15/min. On physical examination,
she had left upper abdominal tenderness with evidence of
hepatomegaly and mild scleral icterus. Laboratory data revealed
the following: alanine aminotransferase, 527 IU/L (normal
10–35 IU/L); aspartate aminotransferase, 425 IU/L (normal
< 35 IU/L); and bilirubin, 2.9 mg/dL (normal 0.1–0.3 mg/dL).
What medications do OTC cold and flu preparations typically
contain? Which of the OTC medications might have contrib-
uted to the patient’s current symptoms?
different systemic analgesic products, almost all of which contain
aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs
(NSAIDs) such as ibuprofen, or a combination of these agents as
primary ingredients. They are made different from one another
by the addition of questionable ingredients such as caffeine or
antihistamines; by brand names chosen to suggest a specific use
or strength (eg, “women’s,” “migraine,” “arthritis,” “maximum”);
or by special dosage formulations (eg, enteric-coated tablets, gel
tabs, liquids, orally disintegrating strips and tablets, sustained-
release products, powders, seltzers). Generally, a price is attached
to all of these features, and in most cases, a less expensive generic
product can be equally effective. It is probably safe to assume that
the public is generally overwhelmed and confused by the wide
 CHAPTER 63  Therapeutic & Toxic Potential of Over-the-Counter Agents     1121

array of products presented and will likely use those that are most
heavily advertised.
Since 1972, the US Food and Drug Administration (FDA) has
been engaged in a methodical review of OTC ingredients for both
safety and efficacy. There have been two major outcomes of this
review: (1) Ingredients designated as ineffective or unsafe for their
claimed therapeutic use are being eliminated from OTC product
formulations (eg, antimuscarinic agents have been eliminated
from OTC sleep aids; attapulgite and polycarbophil can no lon-
ger be marketed as OTC antidiarrheal products); and (2) agents
previously available by prescription only have been made available
for OTC use because they were judged by the review panel to
be generally safe and effective for consumer use without medical
supervision (Table 63–1). The prescription-to-OTC switch pro-
cess has significantly enhanced and expanded self-care options
for US consumers. More than 100 OTC active ingredients or
dosages are on the market today that were previously available
only by prescription. Other OTC ingredients previously avail-
able in low doses only are now available in original prescription
strength formulations (eg, ranitidine 150 mg, famotidine 20 mg).
Examples of other prescription medications with the potential for
future OTC reclassification include oral contraceptives, nicotine
replacement therapy (oral inhaler, nasal spray) for smoking cessa-
tion, proton-pump inhibitors (pantoprazole) for heartburn, and
second-generation nonsedating antihistamines (desloratadine) for
relief of allergy and cold symptoms. The prescription-to-OTC
reclassification process is both costly and rigorous, and only select
prescription medications are appropriate candidates for a switch
(eg, a consumer can self-diagnose and safely treat the condi-
tion). For example, the cholesterol-lowering agents lovastatin
and pravastatin were denied OTC status on the basis that these
agents could not be used safely and effectively in an OTC setting.
The nonprescription drug advisory committee believed that
diagnosis and ongoing management by a health care professional
was necessary for the management of hyperlipidemia, a chronic,
asymptomatic condition with potentially life-threatening conse-
quences. In a similar recommendation, oral acyclovir for OTC
use in the treatment of recurrent genital herpes was not approved
because of concerns about misdiagnosis and inappropriate use
leading to increased viral resistance.
There are three reasons why it is essential for clinicians to
be familiar with the OTC class of products. First, many OTC
medications are effective in treating common ailments, and it
is important to be able to help the patient select a safe, effective
product. Because health care insurance practices encourage clini-
cians to reduce costs, many providers will recommend effective
OTC treatments, since these medications are rarely paid for by
health plans. Second, many of the active ingredients contained
in OTC medications may worsen existing medical conditions or
interact with prescription medications (see Chapter 66, Impor-
tant Drug Interactions & Their Mechanisms). Finally, the misuse
or abuse of OTC products may actually produce significant
medical complications. Phenylpropanolamine, for example, a
sympathomimetic previously found in many cold, allergy, and
weight control products, was withdrawn from the US market
by the FDA based on reports that the drug increased the risk of
hemorrhagic stroke. Dextromethorphan, an antitussive found in
many cough and cold preparations, has been increasingly abused
in high doses (eg, >5–10 times the recommended antitussive dose)
by adolescents as a hallucinogen. Although severe complications
associated with dextromethorphan as a single agent in overdose
are uncommon, many dextromethorphan-containing products

TABLE 63–1  Selected agents switched from prescription to over-the-counter status by the US Food and Drug
Administration (2006–2017).

Year Ingredient
Ingredient Indication (Pharmacologic Category) First Switched Single-Ingredient Product Examples

Adapalene Acne (topical retinoid) 2016 Differin Gel

Budesonide Allergic rhinitis (topical glucocorticoid) 2015 Rhinocort Allergy Spray
Cetirizine Hay fever/upper respiratory allergies (antihistamine) 2007 Zyrtec
Esomeprazole Acid reducer (proton-pump inhibitor) 2014 Nexium 24 hour
Fexofenadine Hay fever/upper respiratory allergies (antihistamine) 2011 Allegra 12 hour, Allegra 24 hour
Fluticasone Allergic rhinitis (topical glucocorticoid) 2014 Flonase Allergy Relief, Flonase Sensimist
Allergy-Relief
Ketotifen Itchy eyes (ophthalmic antihistamine) 2006 Alaway, Zaditor
Lansoprazole Acid reducer (proton-pump inhibitor) 2009 Prevacid 24 hour
Levocetirizine Hay fever/upper respiratory allergies (antihistamine) 2017 Xyzal
Levonorgestrel Emergency contraceptive (progestin) 2006 Plan B One-Step
Orlistat Weight loss aid (lipase inhibitor) 2007 Alli
Oxybutynin Overactive bladder (transdermal anticholinergic) 2013 Oxytrol for Women
Polyethylene glycol Constipation (osmotic laxative) 2006 MiraLAX
Triamcinolone Allergic rhinitis (topical glucocorticoid) 2013 Nasacort Allergy 24 hour
1122    SECTION X  Special Topics

are formulated with other ingredients (acetaminophen, antihis-
tamines, and sympathomimetics) that can be fatal in overdose.
Loperamide is sometimes used in large doses to create an opioid-
like high or to self-treat opioid withdrawal symptoms. In large
doses, loperamide may cross the blood-brain barrier and cause
altered mental status and respiratory depression; additionally, lop-
eramide may induce ventricular arrhythmias in supratherapeutic
doses. Pseudoephedrine, a decongestant contained in numerous
OTC cold preparations, has been used in the illicit manufacture
of methamphetamine. A general awareness of these products and
their formulations will enable clinicians to more fully appreci-
ate the potential for OTC medication-related problems in their
patients.
Table 63–2 lists examples of OTC products that may be used
effectively to treat common medical problems. The selection
of one ingredient over another may be important in patients
with certain medical conditions or in patients taking other
medications. These are discussed in detail in other chapters.

TABLE 63–2  Ingredients of known efficacy for selected over-the-counter (OTC) classes.
Generic Name
OTC Category (Brand Example) Labeled Use Warnings Considerations

Acid reducers Cimetidine Relief and Avoid use: in children <12 years • To prevent symptoms, take 30–60 minutes
(H2 antagonists) (Tagamet HB) prevention of of age; if patient has trouble or before consuming food or beverages that
heartburn asso- pain swallowing food, vomiting cause heartburn.
Famotidine ciated with acid with blood, or bloody or black
(Pepcid AC) • Cimetidine may increase the serum
indigestion. stools; with other acid reducers; concentrations of theophylline, warfarin,
Ranitidine if symptoms include heartburn and phenytoin.
(Zantac 75, with lightheadedness, sweating,
Zantac 150) dizziness, or chest pain; for
treatment durations >14 days.
Adverse effects include: nausea,
agitation, headache, dizziness,
agitation, and gynecomastia
(cimetidine; rare).
Acid reducers Esomeprazole Treatment of Avoid use: in children <18 years • Not intended for immediate relief (products
(proton-pump (Nexium 24 hour) frequent heart- of age; if patient has trouble or take 1–4 days for full effect).
inhibitors [PPI]) burn (occurs pain swallowing food, vomiting • Take with water before eating in the
Lansoprazole 2 or more days with blood, or bloody or black
(Prevacid 24 hour) morning.
a week). stools; if symptoms include
heartburn with lightheaded- • Patients may repeat a 2-week course of
Omeprazole (Pri- therapy every 4 months.
losec OTC) ness, sweating, dizziness,
or chest pain; for treatment • PPI therapy can increase risk of Clostridium
durations >14 days. difficile-associated diarrhea and risk of
fracture.
Adverse effects include: head-
ache, abdominal pain, nausea, • Esomeprazole, lansoprazole, and
diarrhea, and flatulence. omeprazole may interact with warfarin,
clopidogrel, cilostazol, antifungal
medications, diazepam, digoxin, tacrolimus,
and HIV antiretrovirals.
Allergy Chlorpheniramine Temporary relief Avoid use: in children <2 years • Diphenhydramine is the most sedating
preparations (Chlor-Trimeton) of the following of age; in combination with antihistamine.
symptoms due other sedatives and alcohol • Consult product labeling before use in
Clemastine (Tavist to hay fever or as sedative effects may be
Allergy) children ages 2–11 years.
upper respiratory potentiated. Use caution when
allergies: driving or operating machinery. • First-generation antihistamines (chlorpheni-
Cetirizine (Zyrtec) ramine, clemastine, diphenhydramine) may
sneezing, runny
Diphenhydramine nose, itchy, Adverse effects include: drowsi- cause excitability in children.
(Benadryl Allergy) watery eyes, ness, dizziness, fatigue, nausea, • Second-generation antihistamines
itching of nose and urinary retention. (cetirizine, fexofenadine, levocetirizine,
Fexofenadine (Allegra
or throat. Antihistamines are contained loratadine) have minimal anticholinergic
12 hour, Allegra
in many OTC preparations in effects and are associated with lower
24 hour)
combination with analgesics, chances of sedation.
Levocetirizine (Xyzal) decongestants, and expectorants.
See the warnings section for
Loratadine (Alavert,
each formulation.
Claritin)

(continued)
 CHAPTER 63  Therapeutic & Toxic Potential of Over-the-Counter Agents     1123

TABLE 63–2  Ingredients of known efficacy for selected over-the-counter (OTC) classes. (Continued)
Generic Name
OTC Category (Brand Example) Labeled Use Warnings Considerations

Analgesics and Acetaminophen Temporary Acetaminophen Acetaminophen

antipyretics (Tylenol) reduction of Avoid use: in combination with
fever and tem- other drugs containing acet-
Nonsteroidal anti- porary relief of
inflammatory drugs aminophen; in patients drinking
minor aches, 3 or more alcoholic beverages
(NSAIDs) pains, and
daily due to an increased risk of
Aspirin (Ecotrin) headaches. severe liver damage.
Ibuprofen (Advil, Adverse effects include:
Motrin IB) drowsiness, hepatotoxicity
(dose related), nephrotoxicity
Naproxen (Aleve) (with chronic overdose), and
hypersensitivity reactions (rare).
Aspirin and other NSAIDs
Avoid use in patients with:
underlying gastrointestinal
bleeding disorders; heart failure;
renal insufficiency; hepatic
insufficiency; in children or
teenagers with chickenpox
or flu-like symptoms due to
an increased risk of Reye’s
syndrome (aspirin only).
Adverse effects include:
dyspepsia, nausea, gastric ulcer-
ation, duodenal ulceration, renal
insufficiency, hypersensitivity
reactions (rare), and tinnitus
(dose-related with aspirin).
• Maximum recommended adult dose for
OTC use is 3000 mg/24 h (4000 mg/24 h
under medical supervision).
• Many products may include
acetaminophen, which can lead to
unintentional overdose.
Aspirin and other NSAIDs
• Use can increase risk of severe
gastrointestinal hemorrhage in individuals:
age 60 or older; with peptic ulcer disease or
coagulation abnormalities; taking antico-
agulants, corticosteroids, or other NSAIDs;
who consume ≥3 alcoholic beverages daily;
who take the products for a longer time
than directed.
• Maximum recommended adult daily dose
for OTC use: aspirin (3900 mg); ibuprofen
(1200 mg); naproxen (660 mg).
• May reduce the effectiveness of medica-
tions used to treat high blood pressure.
• Long-term continuous use of ibuprofen
may increase the risk of myocardial
infarction and stroke.
• Frequent or regular use of ibuprofen may
interfere with the cardioprotective effect
of aspirin.

Antacids Aluminum hydroxide Temporary Avoid use in patients with: • Combinations of magnesium and
(generic only) relief of upset severe renal impairment aluminum hydroxide are less likely to cause
stomach with (aluminum- and sodium- constipation or diarrhea and offer high
Calcium carbonate heartburn, acid containing products); heart neutralizing capacity.
(Tums) indigestion, and failure or high blood pressure • With prolonged use, antacids may cause
Magnesium sour stomach. (sodium-containing products). “acid rebound” (paradoxical acid hyper-
hydroxide (Milk of Products secretory state associated with increased
containing Adverse effects include: diarrhea
Magnesia) (magnesium preparations) gastrin levels).
simethicone are
Sodium bicarbonate/ used for relief and constipation (aluminum • Antacids can significantly reduce the
citric acid (Alka- of bloating, preparations). absorption of many prescription drugs.
Seltzer Heartburn) pressure, or gas
symptoms.
Aluminum hydroxide/
magnesium
hydroxide/
simethicone
(Maalox, Mylanta)
Antidiarrheal Bismuth subsalicylate To control symp- Bismuth-containing products • Antidiarrheal agents should not be used
agents (Kaopectate, toms of diarrhea Avoid use in patients: taking if diarrhea occurs with fever >100°F or if
Pepto-Bismol) (including trav- salicylate products; with aller- blood or mucus present in stool.
eler’s diarrhea). gies to aspirin; with bleeding • Bismuth-containing products may be
Loperamide Bismuth-
(Imodium A-D) disorders; with peptic ulcer used as part of combination therapy for
containing disease; with bloody or black Helicobacter pylori eradication therapy.
products are also stool; in children or teenagers
used to relieve • Loperamide, a synthetic opioid, is not
with chickenpox or flu-like considered a controlled substance but
upset stomach symptoms due to an increased
symptoms is sometimes abused in high doses for
risk of Reye’s syndrome. euphoric opioid-like effects.
(indigestion,
heartburn,
nausea, gas,
belching).
(continued)
1124    SECTION X  Special Topics

TABLE 63–2  Ingredients of known efficacy for selected over-the-counter (OTC) classes. (Continued)
Generic Name
OTC Category (Brand Example) Labeled Use Warnings Considerations

Antidiarrheal Adverse effects include:

agents (cont.) fecal discoloration (black,
tarry), tongue discoloration
(darkening), and tinnitus (dose-
related and more likely when
coadministered with aspirin).
Loperamide
Avoid use in: children <12 years
of age; patients with bloody or
black stools.
Adverse effects include: abdom-
inal pain, nausea, constipation,
drowsiness, dizziness, and dry
mouth.
Antifungal Butenafine Relieves itching, For external use only. Avoid • For treatment of athlete’s foot, apply
preparations (Lotrimin Ultra) burning, scaling, contact with eyes, nose, mouth, product to spaces between toes and
(topical) chafing, and or other mucous membranes. change shoes and socks daily.
Clotrimazole discomfort asso- Avoid use: in children <2 years
(Lotrimin Antifungal) ciated with tinea of age (clotrimazole, micon-
Miconazole pedis (athlete’s azole, tolnaftate) or children
(Desenex, Lotrimin AF) foot), tinea cruris <12 years of age (butenafine,
(jock itch), and terbinafine).
Terbinafine tinea corporis
(Lamisil AT) (ringworm). Adverse effects include:
erythema, irritation, itching, and
Tolnaftate (Tinactin) burning.
Antifungal Clotrimazole Treatment of For vaginal use only. Avoid use: • Topical vaginal antifungals should only
preparations (Gyne-Lotrimin) vaginal yeast in children <12 years of age; if be used for treatment of recurrent
(vaginal) (candidiasis) patient has lower abdominal, vulvovaginal candidiasis in healthy,
Miconazole infections and back, or shoulder pain, or fever, nonpregnant women who were previously
(Monistat-1, for the relief of chills, nausea, vomiting, or foul- diagnosed by a clinician.
Monistat-3, external vulvar smelling vaginal discharge; in
Monistat-7, • Therapy should be discontinued if symp-
itching and irrita- combination with tampons, toms do not improve within 3 days or if
Vagistat-3) tion associated douches, spermicides, or other symptoms persist after 7 days of treatment.
Tioconazole with vaginal vaginal products.
yeast infections. • Vaginal products (7-day therapy preferred)
(Monistat-1 1-Day, Adverse effects include: vaginal can be used for treatment in pregnant
Vagistat-1) itching, burning, vaginal women.
soreness, and swelling. • Products with similar brand names may
contain different antifungal products; read
labels and instructions for use carefully.
• Condoms and diaphragms may be dam-
aged by the products and fail to prevent
pregnancy or sexually transmitted disease.
Antitussives Dextromethorphan Temporary relief Avoid use: in patients taking a • Dextromethorphan is a nonopioid
(Delsym, Robitussin of cough due to monoamine oxidase inhibitor congener of levorphanol without analgesic
Cough, Vicks 44) minor throat and (MAOI), or for 2 weeks after or addictive properties. Health care providers
bronchial irrita- discontinuation of an MAOI. should be alert for problems of abuse or
tion with the misuse.
common cold or Use with caution in patients
with a chronic cough that • Often used with antihistamines, decon-
inhaled irritants. gestants, and expectorants in combination
occurs with smoking, asthma,
and emphysema and in patients products.
with cough with production of • Notify provider if symptoms do not improve
mucus. in 7 days or are accompanied by fever, rash,
or persistent headache.
Adverse effects include:
confusion, excitement, irritability,
nervousness, and serotonin
syndrome (uncommon).

(continued)
 CHAPTER 63  Therapeutic & Toxic Potential of Over-the-Counter Agents     1125

TABLE 63–2  Ingredients of known efficacy for selected over-the-counter (OTC) classes. (Continued)
Generic Name
OTC Category (Brand Example) Labeled Use Warnings Considerations

Decongestants, Oxymetazoline (Afrin, Temporary relief Avoid use for >3 days. Use • Long-acting agents (oxymetazoline-
topical Mucinex Full Force, of nasal con- with caution in patients with: containing products) are generally
(intranasal) Vicks Sinex) gestion due to heart disease; high blood pres- preferred.
common cold, sure; thyroid disease; diabetes; • Topical decongestants should not exceed
Phenylephrine hay fever, upper trouble urinating due to an
(Neo-Synephrine) 3 days to prevent rebound nasal congestion
respiratory aller- enlarged prostate. (eg, worsening or recurrence of congestion
gies, or sinus symptoms).
congestion and Adverse effects include:
pressure. sneezing, burning, stinging,
dryness, and rhinorrhea.
Decongestants, Phenylephrine Temporary relief Avoid use: in patients taking an • May be found in combination with
systemic (Sudafed PE) of sinus conges- MAOI or for 2 weeks after stop- antihistamine, antitussives, expectorants,
tion and pres- ping the MAOI. Use with caution and analgesic products.
Pseudoephedrine sure. Temporarily in patients with heart disease;
(Sudafed) • Extended-release pseudoephedrine
relieves nasal high blood pressure; diabetes; products should not be used in children
congestion due thyroid disease; trouble urinat- <12 years of age.
to the common ing due to an enlarged prostate
cold, hay fever, gland. • Federal regulations established to discour-
or other upper age the illicit manufacture of metham-
respiratory Adverse effects include: arrhyth- phetamine specify that all drug products
allergies. mias, tachycardia, high blood containing pseudoephedrine must be
pressure, anxiety, headache, stored in locked cabinets or behind the
dizziness, tremor, and insomnia. pharmacy counter and can only be sold
in limited quantities to consumers after
they provide photo identification and are
entered into a registry.
Emergency Levonorgestrel To prevent preg- Avoid use in the case of known • Available only by prescription for women
contraceptive (Plan B One-Step) nancy following or suspected pregnancy. <17 years of age.
unprotected • Should be taken as soon as possible
intercourse or Adverse effects include: heavier
menstrual bleeding, nausea, within 72 hours after unprotected
possible contra- intercourse.
ceptive failure. lower abdominal pain, fatigue,
headache, dizziness, and breast • If vomiting occurs within 2 hours of taking
tenderness. the tablet, the dose may need to be
repeated.
• Use backup contraceptive after administra-
tion. Patients taking oral contraceptives
regularly should also use backup contra-
ception, such as condom, until next period
cycle starts.
Expectorants Guaifenesin Used to help Avoid use in children <2 years • The only OTC expectorant recognized as
(Mucinex) loosen phlegm of age. safe and effective by the FDA.
(mucus) and thin • Often used with antihistamines, decon-
bronchial secre- Adverse effects include: nausea,
vomiting, stomach pain, and gestants, and antitussives in combination
tions to make products.
cough more dizziness.
productive. • Administer with a large quantity of fluids
for best results.
• When used for self-care, do not use
extended-release tablets in children
<12 years of age.
Laxatives Bulk formers Temporary relief Bulk formers • The safest laxatives for chronic use include
Polycarbophil, of occasional Avoid use in patients with bulk formers and stool softeners.
psyllium, and constipation and difficulty swallowing. • The bulk formers in powder formulation
methylcellulose irregularity. must be taken with adequate fluid for
preparations Polyethylene glycol 3350 optimal effect and to avoid choking.
(Citrucel, Fibercon, Avoid use in patients with
Metamucil) kidney disease.

(continued)
1126    SECTION X  Special Topics

TABLE 63–2  Ingredients of known efficacy for selected over-the-counter (OTC) classes. (Continued)
Generic Name
OTC Category (Brand Example) Labeled Use Warnings Considerations

Laxatives (cont.) Hyperosmotics Adverse effects include: nausea,

Glycerin abdominal bloating, cramping,
(Fleet Glycerin and flatulence.
suppositories) Stool softeners
Polyethylene glycol Avoid use in patients taking
3350 (Miralax) mineral oil.
Stool softeners Stimulants
Docusate sodium Adverse effects include:
(Colace, Dulcolax) stomach discomfort, rectal
Docusate calcium burning, and mild cramps.
(Surfak)
Saline laxatives
Stimulant laxatives Do not use more than one
Bisacodyl (Dulcolax, enema in a 24-hour period.
Ex-Lax) Use with caution in patients
Senna (Senokot) on a sodium-restricted diet; in
patients with kidney disease.
Saline laxatives
Sodium phosphate All laxatives
(Fleet enema) Use with caution in patients
with a sudden change in bowel
habits that persist for 2 weeks;
in patients with abdominal pain,
nausea, or vomiting.
Overactive Oxybutynin Treatment of Avoid use in: men; women • Women should consult with their
bladder transdermal system overactive blad- <18 years of age; patients with physician about symptoms before using
treatment der for women symptoms of a urinary tract this product.
(Oxytrol for women) with symptoms infection (pain or burning when • Women who only experience accidental
of urge incon- urinating, blood in urine, unex- urine loss when coughing, sneezing, or
tinence and plained lower back pain, urine laughing may have stress incontinence;
urinary urgency that is cloudy or foul smelling). this product is not effective for this
and frequency condition.
for at least Adverse effects include:
3 months. sleepiness, dizziness, confusion, • The OTC patch formulation contains
dry mouth, constipation, and the same dosage as the prescription
blurred vision. product.
• One patch should be applied to abdomen,
hips, or buttocks every 4 days; alternating
sites.
Pediculicides Permethrin (Nix) Treatment For external use only. Avoid use: • Proper use requires careful inspection
(lice treatment) of head lice if allergic to ragweed; in children and thorough application of the products
Pyrethrins combined (permethrin- <2 years of age; near the eyes; (10 minutes) to the affected areas.
with piperonyl containing inside the nose, mouth, or
butoxide (RID) • Following application, lice and nits (eggs)
products); and vagina; on lice in eyebrows or should be removed with a fine-tooth
pubic and body eyelashes. comb.
lice (piperonyl
butoxide- Adverse effects include: itching • Kills live lice (neurotoxic), but is not effective
containing and redness at the application for eggs (nits). Therefore, repeat process in
products). sites. 7-10 days to kill newly hatched nits.
• Clothing, bed linens, and other items that
the infested person wore or used during
the 2 days before treatment should be
washed using the hot water (130°F) cycle
and dried using the high heat cycle.

(continued)
 CHAPTER 63  Therapeutic & Toxic Potential of Over-the-Counter Agents     1127

TABLE 63–2  Ingredients of known efficacy for selected over-the-counter (OTC) classes. (Continued)
Generic Name
OTC Category (Brand Example) Labeled Use Warnings Considerations

Sleep aids Diphenhydramine Reduces Avoid use in: children <12 years • Insomnia persisting for >2 weeks may
(Nytol, Sominex) difficulty in of age; combination with be a sign of a serious underlying medical
falling asleep. alcohol, other antihistamines, condition.
Doxylamine (Unisom) or sedatives; individuals with
angle-closure glaucoma; men
with trouble urinating due to
an enlarged prostate gland.
Use caution when driving or
operating machinery.
Adverse effects include:
dizziness, constipation, and dry
mouth.
Smoking Nicotine polacrilex Reduces with- Avoid use in: children • Nicotine replacement products in addition
cessation aids gum (Nicorette) drawal symp- <18 years of age; women who to behavioral support approximately
toms (including are pregnant or breastfeeding; double the long-term cessation rates
Nicotine polacrilex nicotine craving) individuals with temporoman- compared with placebo.
lozenge (Nicorette) associated dibular joint disease (gum only); • Nicotine replacement products can be
Nicotine transdermal with quitting individuals with allergies to used in combination to improve long-term
patch (Nicoderm CQ) smoking. adhesive tape (patch only). Use abstinence rates.
patch with caution in patients
with a history of dermatologic • The patch may aid in improved adherence
conditions (eczema, psoriasis, (once-daily dosing).
ectopic dermatitis). • Do not use lozenge if allergic to soya (soy
beans).
Gum
Adverse effects include: jaw
soreness, hiccups, dyspepsia,
throat and mouth irritation,
nausea, vomiting,
lightheadedness.
Lozenge
Adverse effects include: mouth
irritation, nausea, hiccups,
cough, heartburn, headache,
sore throat, dizziness.
Transdermal patch
Adverse effects include: local
skin reactions (erythema, itch-
ing, burning), headache, and
sleep disturbances (insomnia,
abnormal/vivid dreams).

The recommendations listed in Table 63–2 are based on the
efficacy of the ingredients and on the principles set forth in the
following paragraphs.
1. Select the product that is simplest in formulation; in general,
single-ingredient products are preferred. Combination products
may contain effective doses of some ingredients and subthera-
peutic doses of others. Furthermore, there may be differing
durations of action among the ingredients, and there is always
a possibility that the clinician or patient is unaware of the
presence of certain active ingredients in the product.
2. Select a product that contains a therapeutically effective dose.
3. Consumers and providers should carefully read the “Drug
Facts” label (Figure 63–1) to determine which ingredients are
appropriate based on the patient’s symptoms, underlying
health conditions, and whatever is known about the medica-
tions the patient is already taking. Many products with the
same brand name contain different ingredients that are
labeled for different uses. For example, multiple products
(with different active ingredients) carry the Allegra name,
including Allegra Allergy (fexofenadine), Allegra-D (fexofena-
dine and pseudoephedrine), and Allegra Anti-Itch Cream
(allantoin and diphenhydramine).
4. Recommend a generic product if one is available.
5. Be wary of claims of specific superiority over similar products.
6. For children, the dose, dosage form, and palatability of the
product are prime considerations.
1128    SECTION X  Special Topics

Certain ingredients in OTC products should be avoided or
used with caution in selected patients because they may exacer-
bate existing medical problems or interact with other medica-
tions the patient is taking. The presence of many of the more
potent OTC ingredients may be unexpectedly hidden in products
(Table 63–3). Although OTC medications have standardized
label formatting and content requirements (Figure 63–1), many
consumers do not carefully read or comprehend this informa-
tion. Lack of awareness of the ingredients in OTC products and
the belief by many patients and providers that OTC products
are ineffective and harmless may cause diagnostic confusion and
compromise therapeutic management. For example, innumerable
OTC products, including analgesics and allergy, cough, and cold
preparations, contain sympathomimetics. These agents should be
avoided or used cautiously by patients with type 1 diabetes and
patients with hypertension, angina, or hyperthyroidism. Aspirin
should not be used in children and adolescents for viral infections
(with or without fever) because of an increased risk of Reye’s syn-
drome. Aspirin and other NSAIDs should be avoided by individu-
als with active peptic ulcer disease, certain platelet disorders and
patients taking oral anticoagulants. Cimetidine, an H2 antagonist,
is a well-known inhibitor of hepatic drug metabolism and can
increase the blood levels and toxicity of agents such as phenytoin,
theophylline, and warfarin.
Overuse or misuse of OTC products may cause significant
medical problems. A prime example is rhinitis medicamentosa or
“rebound rhinitis,” a condition that manifests as nasal congestion
without rhinorrhea, associated with the regular use of topical
decongestant nasal sprays for more than 3 days. The improper
and long-term use of some antacids (eg, aluminum hydroxide)
may cause constipation and even impaction in the elderly, as
well as hypophosphatemia. Long-term laxative use can result in
abdominal cramping and fluid and electrolyte disturbances. A
condition known as laxative abuse syndrome is often observed in
women with anorexia nervosa. Insomnia, nervousness, and rest-
lessness can result from the use of sympathomimetics or caffeine
present in many OTC products (Table 63–3). The long-term
use of analgesics containing caffeine may trigger rebound head-
aches upon discontinuation. OTC products containing aspirin,
other salicylates, acetaminophen, ibuprofen, or naproxen may
increase the risk of hepatotoxicity and gastrointestinal hemor-
rhage in individuals who consume three or more alcoholic drinks
daily, and long-term use of these products has been associated
with interstitial nephritis. Acute ingestion of large amounts of

Drug Facts
Active ingredient (in each tablet) Purpose
Chlorpheniramine maleate 2 mg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Antihistamine
Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies:
Sneezing Runny nose Itchy, watery eyes Itchy throat

Warnings
Ask a doctor before use if you have
Glaucoma A breathing problem such as emphysema or chronic bronchitis
Trouble urinating due to an enlarged prostate gland
Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives
When using this product
You may get drowsy Avoid alcoholic drinks
Alcohol, sedatives, and tranquilizers may increase drowsiness
Be careful when driving a motor vehicle or operating machinery
Excitability may occur, especially in children
If pregnant or breast-feeding, ask a health professional before use.
Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control
Center right away.

Directions
Adults and children 12 years and over Take 2 tablets every 4 to 6 hours;
not more than 12 tablets in 24 hours
Children 6 years to under 12 years Take 1 tablet every 4 to 6 hours;
not more than 6 tablets in 24 hours
Children under 6 years Ask a doctor

Other information store at 20–25°C (68–77°F) Protect from excessive moisture

Inactive ingredients D&C yellow no. 10, lactose, magnesium stearate,

microcrystalline cellulose, pregelatinized starch

FIGURE 63–1  Typical FDA-required labeling for an over-the-counter antihistamine. The label must contain, in the following order: active
ingredient(s), including the amount in each dosage unit; purpose of product (pharmacologic action); use(s) for product (indication); specific
warnings, including when the product should not be used and pregnancy information; when the patient should seek care of a health care
provider; side effects and substances or activities to avoid; dosage instructions (when, how, and how often to take medication); and inactive
ingredients. Additional requirements include, but are not limited to, the following: type size must be large enough to be easily read, >6-point
font type for information in drug facts section; bullets must be solid square or circle 5-point type; and directions in table format for dosage
instructions when presented for three or more age groups or populations. Image from http://www.fda.gov/Drugs/ResourcesForYou/Consumers/
ucm143551.htm
 CHAPTER 63  Therapeutic & Toxic Potential of Over-the-Counter Agents     1129

TABLE 63–3  Hidden ingredients in over-the-counter (OTC) products.

Hidden Drug or Drug Class OTC Class Containing Drug Selected Product Examples

Alcohol (percent ethanol)
 
Antihistamines
 
 
Aspirin and other salicylates
 
 
 
Caffeine (mg/tablets or as
stated)
 
 
Local anesthetics (usually
benzocaine)
 
 
 
Sodium (mg/tablet or
as stated)
 
 
 
Sympathomimetics
(ephedrine, phenylephrine)
 
 
 
Cough syrups, cold preparations Theraflu Nighttime (10%); Vicks NyQuil Cold & Flu Liquid (10%); Vicks
NyQuil Cough (10%)
Mouthwashes Listerine (27%); Cepacol (14%)
Analgesics Advil PM; Excedrin PM; Goody’s PM Pain Relief Powder; Tylenol PM
Menstrual products Midol Complete; Pamprin
Sleep aids Nytol; Simply Sleep; Sominex; Unisom
Antacids Alka-Seltzer Original; Alka-Seltzer Extra Strength
Antidiarrheals Pepto-Bismol (bismuth subsalicylate); Kaopectate (bismuth subsalicylate)
Menstrual products Pamprin Max
Cold/allergy preparations Alka-Seltzer Plus Formulation: Cold; Cold and Cough; Night Cold
Analgesics Anacin Advanced Headache (65); Excedrin Extra Strength (65); Excedrin
Migraine (65); Goody’s Headache Relief Shot (65/60 mL)
Menstrual products Midol Complete (60); Pamprin Max (65)
Stimulants NoDoz Maximum Strength (200); Vivarin (200)
Antitussives/lozenges Cepacol Sore Throat Lozenges; Chloraseptic Sore Throat
Dermatologic preparations Bactine; Dermoplast; Solarcaine
Hemorrhoidal products Americaine Ointment; Tronolane
Toothache, cold sore, and teething Anbesol; Kank-A; Zilactin-B
products
Analgesics/antacids Alka-Seltzer Original Effervescent Tablet (567); Alka-Seltzer
  Extra Strength Effervescent Tablet (588); Alka-Seltzer Gold (309)
Cold/cough preparations Alka-Seltzer Plus Formulations: Day and Night Cold (416);
Cold & Cough (415); Severe Cold & Flu (416); Night Cold (474);
Cold Sparkling Original (476)
Laxatives Fleets Enema (4439 mg, of which 275–400 mg/enema is absorbed)
Analgesics Sine-Off; Tylenol Sinus
Asthma products Bronkaid; Primatene Tablets
Cold/cough/allergy preparations Advil Cold & Sinus; Alka-Seltzer Plus (many); Dimetapp (many); PediaCare
(many); Robitussin (many); Sudafed (many); Theraflu (many); Tylenol Cold
(many); Tylenol Allergy (many)
Hemorrhoidal products Preparation H (cream, ointment, suppository)

acetaminophen by adults or children can cause serious, and
often fatal, hepatotoxicity (see Chapter 4). Antihistamines may
cause sedation or drowsiness, especially when taken concurrently
with sedative-hypnotics, tranquilizers, alcohol, or other central
nervous system depressants.
Finally, use of OTC cough and cold preparations in the pedi-
atric population has been under scrutiny by the FDA based on a
lack of efficacy data in children less than 12 years of age and reports
of serious toxicity in children. Following a thorough review, the
FDA recommends that OTC cough and cold agents (eg, products
containing antitussives, expectorants, decongestants, and antihista-
mines) not be used in infants and children younger than 2 years
old due to serious and potentially life-threatening adverse events
associated with accidental overdose including arrhythmias, halluci-
nations, and encephalopathy. Drug information sources for OTC
products include the Handbook of Nonprescription Drugs, the most
comprehensive resource for OTC medications. It evaluates ingredi-
ents contained in major OTC drug classes and lists the ingredients
included in many OTC products. Facts and Comparisons eAnswers
is an online reference that is updated monthly; it provides detailed
OTC product information and patient counseling instructions.
Any health care provider who seeks more specific information
regarding OTC products may find useful the references listed
below.
1130    SECTION X  Special Topics
REFERENCES
Consumer Healthcare Products Association website: http://www.chpa.org/.
Handbook of Nonprescription Drugs, 18th ed. American Pharmacists Association,
2015.
Facts and Comparisons eAnswers (online). Wolters Kluwer Health, 2017.
C ASE STUDY ANSWER
Combination OTC “cold and flu” medications typically
contain analgesics (eg, acetaminophen, aspirin), antihistamines
(eg, chlorpheniramine, diphenhydramine), antitussives (eg,
dextromethorphan), expectorants (eg, guaifenesin), and nasal
decongestants (eg, phenylephrine, pseudoephedrine). KH’s
chronic prescription medications include a narcotic analgesic
combination product that provides 2600 mg of acetamino-
phen and 40 mg of hydrocodone. Over the past few days,
KH has added two different OTC acetaminophen-containing
products including Alka-Seltzer Plus Severe Cold + Flu
(650 mg acetaminophen/2 tablets) every 4 hours and Tylenol
PM (1000 mg acetaminophen/2 tablets) at bedtime. The clini-
cian should obtain a detailed medication history to determine
the actual total dose of acetaminophen consumed, but it is
likely that KH has ingested more than 6 g of acetaminophen
US Food and Drug Administration: Drug applications for over-the-counter drugs.
http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143551.
htm.
US National Library of Medicine: DailyMed. https://dailymed.nlm.nih.gov/
dailymed/index.cfm.
daily over the past 72 hours. This cumulative dosage, coupled
with KH’s chronic ethanol consumption (three to four glasses
of wine daily), significantly potentiates the risk for acet-
aminophen hepatotoxicity. In the USA, unintentional acet-
aminophen overdose is a leading cause of acute liver failure.
The warnings section on all OTC acetaminophen-containing
products clearly state that severe liver damage may occur when
consumers: (1) take dosages >4000 mg in 24 hours; (2) use
acetaminophen in combination with other drugs containing
acetaminophen; or (3) take acetaminophen and drink three or
more alcoholic beverages daily. Unfortunately, many consum-
ers do not carefully read OTC medication labels, and many
do not appreciate the amount of acetaminophen “hidden” in
combination prescription and OTC products.

Dietary Supplements &
*
Herbal Medications
Cathi E. Dennehy, PharmD, &
Candy Tsourounis, PharmD
C ASE STUDY
A 53-year-old woman with a history of knee osteoarthritis,
high cholesterol, type 2 diabetes, and hypertension presents
with new onset of hot flashes and a question about a dietary
supplement. She is obese (body mass index [BMI] 33), does
not exercise, and spends a good portion of her work day in a
seated position. She eats a low-sugar diet and regularly eats
packaged frozen meals for dinner because she doesn’t have
time to cook regularly. Her most recent laboratory values
include a low-density lipoprotein (LDL) cholesterol that is
above goal at 160 mg/dL (goal < 100 mg/dL) and a hemo-
globin A1c that is well controlled at 6%. Her blood pressure
The medical use of plants in their natural and unprocessed form
undoubtedly began when the first intelligent animals noticed that
certain food plants altered particular body functions. While there
is a great deal of historical information about the use of plant-
based supplements, there is also much unreliable information as a
result of unknown or poor-quality natural product formulations,
poorly designed clinical studies that do not account for random-
ization errors, confounders, and—most importantly—a placebo
effect that can contribute 30–50% of the observed response. Since
the literature surrounding dietary supplements is evolving, repu-
table evidence-based resources should be used to evaluate claims
and guide treatment decisions. An unbiased and regularly updated
compendium of basic and clinical information regarding botani-
cals is Natural Medicines by Therapeutic Research Center (see
References), which includes content review by an international,
*
The US Food and Drug Administration (FDA) recognizes “herbal
medication” and “botanical medication” as “dietary supplements.” For
the purposes of this chapter, they are identical.
64
C H A P T E R
is high at 160/100 mm Hg. Her prescription medications
include simvastatin, metformin, and benazepril. She also
takes over-the-counter ibuprofen for occasional knee pain
and a multivitamin supplement once daily. She has heard
good things about natural products and asks you if taking a
garlic supplement daily could help to bring her blood pres-
sure and cholesterol under control. She’s also very interested
in St. John’s wort after a friend told her that it helped allevi-
ate her hot flashes and could also help improve mood. How
should you advise her? Are there any supplements that could
increase bleeding risk if taken with ibuprofen?
multidisciplinary, collaborative review committee of experts.
The recommendations in this database are limited by the quality
of the existing research and the quality of the dietary supple-
ment used at the time of the report. As a result, all statements
regarding positive benefits should be regarded as preliminary,
and conclusions regarding safety should be considered tentative
at this time.
For legal purposes, “dietary supplements” are distinguished
from “prescription drugs” derived from plants (morphine, digi-
talis, atropine, etc) by virtue of being available without a pre-
scription and, unlike “over-the-counter medications,” are legally
considered dietary supplements rather than drugs. This distinc-
tion eliminates the need for proof of efficacy and safety prior
to marketing and also places the burden of proof on the FDA
to prove that a supplement is harmful before it can be removed
from the market or its use can be restricted. Furthermore,
marketed dietary supplements are not tested for dose-response
relationships or toxicity, and there is a lack of adequate testing
1131
1132    SECTION X  Special Topics
for mutagenicity, carcinogenicity, and teratogenicity. Although
manufacturers are prohibited from marketing unsafe or ineffec-
tive products, the FDA has met significant challenges from the
supplement industry largely due to the strong lobbying effort by
supplement manufacturers and the variability in interpretation of
the Dietary Supplement Health and Education Act (DSHEA).
The DSHEA defines dietary supplements as vitamins, minerals,
herbs or other botanicals, amino acids or dietary supplements
used to supplement the diet by increasing dietary intake, or con-
centrates, metabolites, constituents, extracts, or any combination
of these ingredients. For the purposes of this chapter, plant-based
substances and certain synthetic purified chemicals will be referred
to as dietary supplements. Among the purified chemicals, glucos-
amine, coenzyme Q10, and melatonin are of significant pharma-
cologic interest. Ephedrine, the active principle in Ma-huang, is
discussed in Chapter 9.
This chapter provides some historical perspective and describes
the evidence provided by randomized, double-blind, placebo-
controlled trials, meta-analyses, and systematic reviews involving
several of the most commonly used agents in this class. Health
care providers should adhere to the principles of “do no harm” but
also, because patients are strongly influenced by popular opinion
and media reports, be open to therapies that support “integrative
health” safely and responsibly. Unproven therapies that are mar-
keted as “alternatives” to conventional medicine should be viewed
with caution, but therapies that are supported by evidence-based
medicine and have been assessed for benefits and risks when used
in combination with conventional medicine can be viewed favor-
ably, especially if a patient expresses an interest in, and a desire to
utilize, dual treatment approaches.
HISTORICAL & REGULATORY FACTORS
Under the DSHEA, dietary supplements are not considered over-
the-counter drugs in the USA but rather food supplements used
for health maintenance. Legally, dietary supplements are intended
to supplement the diet, but consumers may use them in the
same fashion as drugs and even use them in place of drugs or in
combination with drugs.
In 1994, the US Congress, influenced by growing “consum-
erism” as well as strong manufacturer lobbying efforts, passed
the DSHEA. The DSHEA required the establishment of Good
Manufacturing Practice (GMP) standards for the supplement
industry; however, it was not until 2007 that the FDA issued
a final rule on the proposed GMP standards. This 13-year
delay allowed supplement manufacturers to self-regulate the
manufacturing process and resulted in many instances of adul-
teration, misbranding, and contamination. For example, a study
using DNA barcoding to confirm botanical content evaluated
44 botanicals containing 30 plant species and found product
substitutions in 32% of samples (see Newmaster reference).
Therefore, much of the criticism regarding the dietary supple-
ment industry involves problems with botanical misidentifica-
tion, a lack of product purity, and variations in potency and
purification, which continue to be problematic even with GMP
standards in place. When the new GMP standards are met,
dietary supplement manufacturers should be in compliance
with this legislation. However, the FDA has limited resources
to investigate and oversee compliance with manufacturing stan-
dards, particularly since many ingredient suppliers are based
overseas. Furthermore, the dietary supplement ingredient supply
chain is complex, and federal regulators are not able to inspect all
manufacturing facilities in a timely and efficient manner. Finally,
the financial incentive to maximize sales ($32 billion in supple-
ment sales in the USA in 2012) is very great, regardless of lack
of evidence of product safety or efficacy.
Because of the problems that resulted from self-regulation,
another law, the Dietary Supplement and Non-Prescription
Drug Consumer Protection Act, was approved in 2006. This law
requires manufacturers, packers, or distributors of supplements
to submit reports of serious adverse events to the FDA. Serious
adverse events are defined as death, a life-threatening event, hos-
pitalization, a persistent or significant disability or incapacity, con-
genital anomaly or birth defect, or an adverse event that requires
medical or surgical intervention to prevent such outcomes based
on reasonable medical judgment. These reports are intended to
identify trends in adverse effects and would help to alert the public
to safety issues.
CLINICAL ASPECTS OF THE USE OF
BOTANICALS
Many US consumers have embraced the use of dietary supple-
ments as a “natural” approach to their health care. Unfortunately,
misconceptions regarding safety and efficacy of the agents are
common, and the fact that a substance can be called “natural”
does not of course guarantee its safety. In fact, botanicals may be
inherently inert or toxic. If a manufacturer does not follow GMP,
this can also result in intentional or unintentional plant species
substitutions (eg, misidentification), adulteration with pharma-
ceuticals, or contamination.
Adverse effects have been documented for a variety of dietary
supplements; however, underreporting of adverse effects is likely
since consumers do not routinely report, and do not know how to
report an adverse effect if they suspect that the event was caused
by consumption of a supplement. Furthermore, chemical analysis
is rarely performed on the products involved, including those
products that are described in the literature as being linked to an
adverse event. This leads to confusion about whether the primary
ingredient or an adulterant caused the adverse effect. In some
cases, the chemical constituents of the herb can clearly lead to
toxicity. Some of the herbs that should be used cautiously or not
at all are listed in Table 64–1.
An important risk factor in the use of dietary supplements is
the lack of adequate testing for drug interactions. Since botanicals
may contain hundreds of active and inactive ingredients, it is very
difficult and costly to study potential drug interactions when they
are combined with other medications. This may present signifi-
cant risks to patients.
 CHAPTER 64  Dietary Supplements & Herbal Medications     1133

TABLE 64–1  Various supplements and some associated risks.

Commercial Name,
Scientific Name,
Plant Parts Intended Use Toxic Agents, Effects Comments

Aconite Analgesic Alkaloid, cardiac and central nervous system Avoid

effects
Aconitum species
Aristolochic acid Traditional Chinese medicine; Carcinogen, nephrotoxicity Avoid
various uses
Aristolochia species
Black cohosh Menopausal symptoms Hepatotoxicity Avoid1
Cimicifuga racemosa
Borage Anti-inflammatory; diuretic Pyrrolizidine alkaloids, hepatotoxicity Avoid
Borago officinalis
Tops, leaves
Chaparral Anti-infective; antioxidant; Hepatotoxicity Avoid
anticancer
Larrea tridentata
Twigs, leaves
Coltsfoot Upper respiratory tract Pyrrolizidine alkaloids, hepatotoxicity Avoid ingestion of any parts of
infections plant; leaves may be used topi-
Tussilago farfara cally for anti-inflammatory effects
Leaves, flower for up to 4–6 weeks

Comfrey Internal digestive aid; topical Pyrrolizidine alkaloids, hepatotoxicity Avoid ingestion; topical use
for wound healing should be limited to 4–6 weeks
Symphytum species
Leaves and roots
Ephedra, Ma-huang Diet aid; stimulant; Central nervous system toxicity, cardiac Avoid in patients at risk for stroke,
bronchodilator toxicity myocardial infarction, arrhythmia,
Ephedra species hypertension, seizures, general
anxiety disorder
Germander Diet aid Hepatotoxicity Avoid
Teucrium chamaedrys
Leaves, tops
Gland-derived extracts Hormone replacement Risk of bacterial, viral, or prion transmission; Avoid
(thymus, adrenal, thyroid) variable hormone content
Human placenta derivatives Antirheumatic; Risk of bacterial, viral, or prion transmission Avoid
anti-inflammatory
Jin Bu Huan Analgesic; sedative Hepatotoxicity Avoid
Kava-kava Anxiety Hepatotoxicity Avoid
Pennyroyal Digestive aid; induction of Pulegone and pulegone metabolite, liver Avoid
menstrual flow; abortifacient failure, renal failure
Extract of Mentha pulegium
or Hedeoma pulegioides
Poke root Antirheumatic Hemorrhagic gastritis Avoid
Phytolacca americana
Royal jelly of Apis mellifera Tonic Bronchospasm, anaphylaxis Avoid in patients with chronic
(honeybee) allergies or respiratory diseases;
asthma, chronic obstructive
pulmonary disease, emphysema,
atopy
Sassafras Blood thinner Safrole oil, hepatocarcinogen in animals Avoid
Sassafras albidum root, bark
1
Cases of hepatotoxicity have occurred; these cases are rare given the widespread use of black cohosh.
1134    SECTION X  Special Topics
■■ BOTANICAL SUBSTANCES
ECHINACEA (ECHINACEA PURPUREA)
Chemistry
The three most widely used species of Echinacea are Echinacea
purpurea, E pallida, and E angustifolia. The chemical constitu-
ents include flavonoids, lipophilic constituents (eg, alkamides,
polyacetylenes), water-soluble polysaccharides, and water-soluble
caffeoyl conjugates (eg, echinacoside, cichoric acid, caffeic acid).
Within any marketed echinacea formulation, the relative amounts
of these components are dependent upon the species used, the
method of manufacture, and the plant parts used. E purpurea,
the purple coneflower, has been the most widely studied in
clinical trials. Although the active constituents of echinacea are
not completely known, cichoric acid from E purpurea and echi-
nacoside from E pallida and E angustifolia, as well as alkamides
and polysaccharides, are most often noted as having immune-
modulating properties. Most commercial formulations, however,
are not standardized for any particular constituent.
Pharmacologic Effects
1. Immune modulation—The effect of echinacea on the
immune system is controversial. In vivo human studies using
commercially marketed formulations of E purpurea have shown
increased phagocytosis, total circulating monocytes, neutrophils,
and natural killer cells, indicative of general immune modula-
tion. In vitro, a standardized ethanol extract of the aerial (above-
ground) parts of E purpurea, known as Echinaforce, inhibited the
rise in pro-inflammatory cytokines and interleukins-6 and -8, and
also inhibited mucin secretion caused by exposure to rhinovirus
type 1A in a 3D tissue model of human airway epithelium. This
type of model is intended to mimic what would be seen in vivo.
The extract had no effect on cytokine actions.
2. Anti-inflammatory effects—Certain echinacea constituents
have demonstrated anti-inflammatory properties in vitro. Inhibi-
tion of cyclooxygenase, 5-lipoxygenase, and hyaluronidase may be
involved. In animals, application of E purpurea prior to applica-
tion of a topical irritant reduced both paw and ear edema. Despite
these preclinical findings, randomized, controlled clinical trials
involving echinacea for wound healing have not been performed
in humans.
3. Antibacterial, antifungal, antiviral, and antioxidant
effects—In vitro studies have reported some antibacterial, anti-
fungal, antiviral, and antioxidant activity with echinacea constit-
uents. For example, Echinaforce demonstrated virucidal activity
(MIC100 < 1 mcg/mL) against influenza and herpes simplex
viruses and bactericidal activity against Streptococcus pyogenes,
Haemophilus influenzae, and Legionella pneumophila in human
bronchial cells. In vitro, Echinaforce inactivated both avian
influenza virus (H5N1, H7N7) and swine-origin influenza virus
(H1N1) at doses consistent with recommended oral consump-
tion. The extract blocked key steps (ie, viral hemagglutination
activity and neuraminidase activity in vitro) involved in early
virus replication and cellular entry. It was less effective against
intracellular virus. Newer in vitro research in human skin fibro-
blasts also suggests bactericidal activity and inhibition of secre-
tion of inflammatory cytokines produced by Propionibacterium
acnes with Echinaforce.
Clinical Trials
Echinacea is most often used to enhance immune function in
individuals who have colds and other respiratory tract infec-
tions. Two reviews have assessed the efficacy of echinacea for this
primary indication. A review by the Cochrane Collaboration
involved 24 randomized, double-blind trials with 33 comparisons
of echinacea mono-preparations, which are single-ingredient
echinacea preparations, and placebo. Trials were included if they
involved echinacea for cold treatment or prevention, where the
primary efficacy outcome was cold incidence in prevention trials
and duration of symptoms in treatment trials. Overall, the review
did not find significant evidence of benefit for echinacea (among
all species) in treating colds. Preparations made from the aerial
parts of E purpurea plants and prepared as alcoholic extracts or
pressed juices were discussed as possibly being preferred to other
formulations for cold treatment in adults, but still having a weak
overall treatment effect. In prevention trials, pooling results sug-
gested a small relative risk reduction of 10–20%, but no statisti-
cally significant benefit within individual trials.
A separate meta-analysis involving 14 randomized, placebo-
controlled trials of echinacea for cold treatment or prevention
was published in Lancet. In this review, echinacea decreased the
risk of developing clear signs and symptoms of a cold by 58%
and decreased symptom duration by 1.25 days. This review,
however, was confounded by the inclusion of four clinical trials
involving multi-ingredient echinacea preparations, as well as
three studies using rhinovirus inoculation versus natural cold
development.
Echinacea has been used investigationally to enhance hemato-
logic recovery following chemotherapy. It has also been used as an
adjunct in the treatment of urinary tract and vaginal fungal infec-
tions. These indications require further research before they can be
accepted in clinical practice. E purpurea is ineffective in treating
recurrent genital herpes.
Adverse Effects
Adverse effects with oral commercial formulations are minimal
and most often include unpleasant taste, gastrointestinal upset,
or allergic reactions (eg, rash). In one large clinical trial, pediatric
patients using an oral echinacea product were significantly more
likely to develop a rash than those taking placebo. In a small Nor-
wegian mother and child cohort study, 0.5% of women reported
taking any formulation of echinacea during early-stage (concep-
tion up to pregnancy week 17) or late-stage pregnancy and had no
adverse pregnancy outcomes compared to pregnant women who
did not use echinacea. Herbal supplements, and particularly those
made from alcoholic extracts, should only be used in pregnancy
 CHAPTER 64  Dietary Supplements & Herbal Medications     1135
and lactation after consultation with the primary health care
provider.
Drug Interactions & Precautions
Until the role of echinacea in immune modulation is better
defined, this agent should be avoided in patients with immune
deficiency disorders (eg, AIDS, cancer) or autoimmune disorders
(eg, multiple sclerosis, rheumatoid arthritis). Although there are no
well-documented herb-drug interactions for echinacea, in theory,
it should also be avoided in persons taking immunosuppressant
medications (eg, organ transplant recipients). Co-administration
of an echinacea product containing E purpurea and E angustifolia
root had no effect on warfarin pharmacodynamics, platelet aggre-
gation, or baseline clotting in healthy subjects. Human studies
have shown no effect of varied E purpurea preparations on the
pharmacokinetics of lopinavir, ritonavir, etravirine, and darunavir.
Dosage
It is recommended to follow the dosing on the package label, as
there may be variations in dose based on the procedure used in
product manufacture. Standardized preparations made from the
aerial parts of E purpurea (Echinaforce, Echinaguard) as an alco-
holic extract or fresh pressed juice may be preferred in adults for
common cold treatment if taken within the first 24 hours of cold
symptoms. It should not be used on a continuous basis for longer
than 10–14 days.
GARLIC (ALLIUM SATIVUM)
Chemistry
The pharmacologic activity of garlic involves a variety of organo-
sulfur compounds. Dried and powdered formulations contain
many of the compounds found in raw garlic and will usually be
standardized to allicin or alliin content. Allicin is responsible for
the characteristic odor of garlic, and alliin is its chemical precursor.
Dried powdered formulations are often enteric-coated to protect
the enzyme allinase (the enzyme that converts alliin to allicin)
from degradation by stomach acid. Aged garlic extract (AGE) has
also been studied in clinical trials but to a lesser degree than dried,
powdered garlic (GP). AGE contains no alliin or allicin and is
odor-free. Its primary constituents are water-soluble organosulfur
compounds, and packages may carry standardization to the
compound S-allylcysteine.
Pharmacologic Effects
1. Cardiovascular effects—In vitro, allicin and related
compounds inhibit HMG-CoA reductase, which is involved in
cholesterol biosynthesis (see Chapter 35), and exhibit antioxidant
properties. Several clinical trials have investigated the lipid-
lowering potential of garlic. The most recent meta-analysis (Ried
et al, 2013) involved 39 randomized, double-blind, placebo-
controlled trials with approximately 2300 patients. The inves-
tigators studied the effect of garlic mono-preparations on lipid
parameters and found a moderate and significant reduction in
both total serum cholesterol (–17 ±6 mg/dL) and LDL cholesterol
(–9 ±6 mg/dL) when garlic was taken for 2 or more months by
patients with elevated baseline cholesterol (>200 mg/dL). Sub-
group analysis showed a greater effect on cholesterol reduction
when AGE preparations were used than when GP preparations
were used. While the benefit of garlic in lowering total cholesterol
and LDL cholesterol is clinically relevant, optimal prescription
drug therapy is far more efficacious (see Chapter 35).
Clinical trials report antiplatelet effects (possibly through
inhibition of thromboxane synthesis or stimulation of nitric oxide
synthesis) following garlic ingestion. A majority of human studies
also suggest enhancement of fibrinolytic activity. These effects in
combination with antioxidant effects (eg, increased resistance to
LDL oxidation) and reductions in total cholesterol might be ben-
eficial in patients with atherosclerosis. A randomized, controlled
trial among persons with advanced coronary artery disease who
consumed GP for 4 years showed significant reductions in sec-
ondary markers (plaque accumulation in the carotid and femoral
arteries) as compared with patients on placebo, but primary end
points (death, stroke, myocardial infarction) were not assessed.
AGE preparations have similarly shown favorable effects in
three small (<100 patients) randomized, double-blind, placebo-
controlled trials in reducing coronary artery calcification (CAC)
progression over 1 year. All trials involved patients with known
coronary artery disease (CAD) or who were considered medium
to high risk for CAD at baseline.
Garlic constituents may affect blood vessel elasticity and blood
pressure. Several mechanisms have been proposed. Twenty placebo-
controlled studies using single-ingredient preparations of GP
(13 studies), AGE (5 studies), or other preparations (2 studies) were
included in a meta-analysis. Significant reductions in systolic blood
pressure (SBP) and diastolic blood pressure (DBP) were present
when all trials were considered. Benefits were most pronounced
in subjects with baseline hypertension (mean SBP reduction of
8.6 ±2.2 mm Hg and DBP reduction of 6.1 ±1.3 mm Hg), and
no significant effect was observed in subjects who had normal or
prehypertensive blood pressures (<140/90 mm Hg) at baseline. A
Cochrane review on the effect of garlic monotherapy for prevention
of cardiovascular morbidity and mortality in hypertensive patients
also identified a significant reduction in systolic and diastolic pres-
sure compared with placebo. A separate Cochrane review of the
effect of garlic on peripheral occlusive disease found insufficient
support for this indication.
2. Endocrine effects—The effect of garlic on glucose homeo-
stasis does not appear to be significant in persons with diabetes.
Certain organosulfur constituents in garlic, however, have demon-
strated hypoglycemic effects in nondiabetic animal models.
3. Antimicrobial effects—The antimicrobial effect of garlic
has not been extensively studied in clinical trials. Allicin has been
reported to have in vitro activity against some gram-positive
and gram-negative bacteria as well as fungi (Candida albicans),
protozoa (Entamoeba histolytica), and certain viruses. The primary
mechanism involves the inhibition of thiol-containing enzymes
1136    SECTION X  Special Topics
needed by these microbes. A Cochrane review studying the effect
of garlic on cold prevention and treatment found a significant
reduction in total number of colds using a garlic supplement
(with 180 mg allicin content) once daily for 12 weeks. Limited
conclusions can be drawn regarding the effects observed, however,
because only one trial met inclusion criteria. Given the availability
of safe and effective prescription antimicrobials, the usefulness of
garlic in this area appears limited.
4. Antineoplastic effects—In rodent studies, garlic inhibits
procarcinogens for colon, esophageal, lung, breast, and stomach
cancer, possibly by detoxification of carcinogens and reduced
carcinogen activation. Several epidemiologic case-control studies
demonstrate a reduced incidence of stomach, esophageal, and
colorectal cancers in persons with high dietary garlic consump-
tion. Current anticancer studies are focused on specific organosul-
fur garlic compounds in in vivo animal models of cancer and in
vitro effects on human cancer cell lines.
Adverse Effects
Following oral ingestion, adverse effects of garlic products may
include nausea (6%), hypotension (1.3%), allergy (1.1%), and
bleeding (rare). Breath and body odor have been reported with an
incidence of 20–40% at recommended doses using enteric-coated
powdered garlic formulations. Contact dermatitis may occur with
the handling of raw garlic.
Drug Interactions & Precautions
Because of reported antiplatelet effects, patients using anticlotting
medications (eg, warfarin, aspirin, ibuprofen) should use garlic
cautiously. Additional monitoring of blood pressure and signs
and symptoms of bleeding is warranted. Garlic may reduce the
bioavailability of saquinavir, an antiviral protease inhibitor, but it
does not appear to affect the bioavailability of ritonavir.
Dosage
Dried, powdered garlic products should be standardized to
contain 1.3% alliin (the allicin precursor) or have an allicin-
generating potential of 0.6%. Enteric-coated formulations are
recommended to minimize degradation of the active substances.
A daily dose of 600–900 mg/d of powdered garlic is most com-
mon. This is equivalent to one clove of raw garlic (2–4 g) per day.
A garlic bulb can contain up to 1.8% alliin. Doses of AGE most
often range from 600 to 1800 mg/d, but doses up to 7200 mg
daily have been safely used in clinical trials for up to 6 months.
GINKGO (GINKGO BILOBA)
Chemistry
Ginkgo biloba extract is prepared from the leaves of the ginkgo
tree. The most common formulation is prepared by concentrat-
ing 50 parts of the crude leaf to prepare one part of extract.
The active constituents in ginkgo are flavone glycosides and
terpenoids including ginkgolides A, B, C, and J, and bilobalide.
Pharmacologic Effects
1. Cardiovascular effects—In animal models and some
human studies, ginkgo has been shown to increase blood flow,
reduce blood viscosity, and promote vasodilation, thus enhanc-
ing tissue perfusion. Enhancement of endogenous nitric oxide
effects (see Chapter 19) and antagonism of platelet-activating
factor have been observed in animal models.
Ginkgo biloba has been studied for its effects on mild to
moderate occlusive peripheral arterial disease. Among 11 random-
ized, placebo-controlled studies involving 477 participants using
standardized ginkgo leaf extract (EGb761) for up to 6 months, a
nonsignificant trend toward improvements in pain-free walking
distance (increase of 64.5 meters) was observed (P = .06). The
authors concluded that the standardized extract lacked benefit for
this indication.
The Ginkgo Evaluation of Memory (GEM) study and the
recently published GuidAge study evaluated cardiovascular out-
comes as well as incidence and mean time to Alzheimer’s demen-
tia associated with the long-term use of ginkgo for 5–6 years
in approximately 3000 elderly (age ≥70) adults with normal
cognition or mild cognitive impairment. Daily use of 240 mg/d
EGb761 did not affect the incidence of hypertension or reduce
blood pressure among persons with hypertension or prehyperten-
sion. No significant effects in cardiovascular disease mortality,
ischemic stroke or events, or hemorrhagic stroke were observed.
2. Metabolic effects—Antioxidant and radical-scavenging prop-
erties have been observed for the flavonoid fraction of ginkgo as
well as some of the terpene constituents. In vitro, ginkgo has been
reported to have superoxide dismutase-like activity and superoxide
anion- and hydroxyl radical-scavenging properties. The flavonoid
fraction has also been observed to have antiapoptotic properties.
In some studies, it has also demonstrated a protective effect in lim-
iting free radical formation in animal models of ischemic injury
and in reducing markers of oxidative stress in patients undergoing
coronary artery bypass surgery.
3. Central nervous system effects—In aged animal models,
chronic administration of ginkgo for 3–4 weeks led to modifica-
tions in central nervous system receptors and neurotransmitters.
Receptor densities increased for muscarinic, α2, and 5-HT1a recep-
tors, and decreased for β adrenoceptors. Increased serum levels of
acetylcholine and norepinephrine and enhanced synaptosomal
reuptake of serotonin and dopamine have also been reported.
Additional possible effects include inhibition of amyloid-beta
fibril formation and protective effects of Egb761 on hippocampal
neurons against cell death induced by beta-amyloid.
Ginkgo has been used to treat cerebral insufficiency and
dementia of the Alzheimer type. The term cerebral insufficiency,
however, includes a variety of manifestations ranging from poor
concentration and confusion to anxiety and depression as well as
physical complaints such as hearing loss and headache. For this
 CHAPTER 64  Dietary Supplements & Herbal Medications     1137
reason, studies evaluating cerebral insufficiency tend to be more
inclusive and difficult to assess than trials evaluating dementia.
A meta-analysis of ginkgo for cognitive impairment or dementia
was performed by the Cochrane Collaboration. They reviewed 36
randomized, double-blind, placebo-controlled trials ranging in
length from 3 to 52 weeks. Significant improvements in cognition
and activities of daily living were observed at 12 but not 24 weeks.
Significant improvements in clinical global assessment however,
were observed at 24 but not 12 weeks. The authors concluded
that the effects of ginkgo in the treatment of cognitive impairment
and dementia were unpredictable and unlikely to be clinically
relevant. However, recent meta-analyses of randomized controlled
trials, 22–26 weeks in duration, using EGb761 that limited inclu-
sion criteria to patients with dementia of the Alzheimer type (in
eight studies), vascular or mixed dementia type (in six studies), or
dementia with neuropsychiatric features (in four studies) showed
favorable results. Significant improvements in cognition and
activities of daily living were observed for ginkgo compared to
placebo. Clinical global assessment of improvement also was sig-
nificantly improved when EGb761 doses of 240 mg/d were used,
but not doses of 120 mg/d. Because of the stricter inclusion crite-
ria used, the overall methodologic quality of the studies was higher
than that of the Cochrane review, when determining a benefit in
patients with dementia. This suggests that patients with a diagno-
sis of dementia are more likely to benefit than patients with more
mild cognitive impairment. In the GEM and GuidAge studies
that included persons with normal or mild cognitive impairment,
the effects of ginkgo as a prophylactic agent to prevent progression
to dementia were assessed. No benefit was observed with 5–6 years
of ginkgo treatment.
4. Miscellaneous effects—Ginkgo has been studied for its
effects in schizophrenia, tardive dyskinesia, allergic and asthmatic
bronchoconstriction, short-term memory in healthy, nonde-
mented adults, erectile dysfunction, tinnitus and hearing loss, and
macular degeneration. Preliminary data from eight randomized,
double-blind, placebo-controlled trials suggest that EGb761 can
significantly reduce the symptoms of chronic schizophrenia when
used in combination with standard treatment (eg, clozapine,
haloperidol, olanzapine). These trials were conducted in China, so
firm conclusions about benefit in a broader population are lack-
ing. There is insufficient evidence to warrant clinical use for the
other conditions listed.
Adverse Effects
Adverse effects of ginkgo have been reported with a frequency com-
parable to that of placebo. These include nausea, headache, stomach
upset, diarrhea, allergy, anxiety, and insomnia. A few case reports
noted bleeding complications in patients using ginkgo. In some of
these cases, the patients were also using either aspirin or warfarin.
Drug Interactions & Precautions
Ginkgo may have antiplatelet properties and should not be used
in combination with antiplatelet or anticoagulant medications.
Other single case reports noted virologic failure when ginkgo
was combined with efavirenz, sedation when combined with tra-
zodone, priapism when combined with risperidone, and seizure
when combined with valproic acid and phenytoin; all warrant
further pharmacokinetic studies before firm conclusions can be
drawn. Seizures have been reported as a toxic effect of ginkgo,
most likely related to seed contamination in the leaf formulations.
Uncooked ginkgo seeds are epileptogenic due to the presence of
ginkgotoxin. Ginkgo formulations should be avoided in individu-
als with preexisting seizure disorders.
Dosage
Ginkgo biloba dried leaf extract is usually standardized to contain
24% flavone glycosides and 6% terpene lactones. The daily dose
most commonly studied and associated with a benefit in clinical
trials of dementia is 240 mg daily of the dried extract in two divided
doses.
GINSENG
Chemistry
Ginseng may be derived from any of several species of the genus
Panax. Of these, crude preparations or extracts of Panax ginseng, the
Chinese or Korean variety, and P quinquefolium, the American vari-
ety, are most often available to consumers in the United States. The
active principles appear to be the triterpenoid saponin glycosides
called ginsenosides or panaxosides, of which there are approximately
30 different types. It is recommended that commercial P ginseng
formulations be standardized to contain 4–10% ginsenosides.
Other plant materials are commonly sold under the name
ginseng but are not from Panax species. These include Siberian
ginseng (Eleutherococcus senticosus) and Brazilian ginseng (Pfaffia
paniculata). Of these, Siberian ginseng may be more widely avail-
able in the USA. Siberian ginseng contains eleutherosides but no
ginsenosides. Currently, there is no recommended standardization
for eleutheroside content in Siberian ginseng products.
Pharmacologic Effects
An extensive literature exists on the potential pharmacologic
effects of ginsenosides. Unfortunately, the studies differ widely in
the species of Panax used, the ginsenosides studied, the degree of
purification applied to the extracts, the animal species studied, the
doses or concentrations involved, and the measurements used to
evaluate the responses. Reported beneficial pharmacologic effects
include modulation of immune function (induced mRNA expres-
sion for interleukins-2 and -1α, interferon-γ, and granulocyte-
macrophage colony-stimulating factor; activated B and T cells,
natural killer cells, and macrophages). Central nervous system
effects included increased proliferating ability of neural progeni-
tors and increased central levels of acetylcholine, serotonin, nor-
epinephrine, and dopamine in the cerebral cortex. Miscellaneous
effects included antioxidant activity; anti-inflammatory effects
(inhibited tumor necrosis factor-α, interleukin-1β, and vascu-
lar and intracellular cell adhesion molecules); antistress activity
1138    SECTION X  Special Topics
(ie, stimulated pituitary-adrenocortical system, agonist at glu-
cocorticoid receptor); analgesia (inhibited substance P); vaso-
regulatory effects (increased endothelial nitric oxide, inhibited
prostacyclin production); cardioprotective activity (reduced ven-
tricular remodeling and cardiac hypertrophy in animal models
of myocardial ischemia); antiplatelet activity; improved glucose
homeostasis (reduced cell death in pancreatic beta cells; increased
insulin release, number of insulin receptors, and insulin sensi-
tivity); and anticancer properties (reduced tumor angiogenesis,
increased tumor cell apoptosis). Such extensive claims naturally
evoke skepticism and require careful replication.
Clinical Trials
Ginseng is most often claimed to help improve physical and men-
tal performance or to function as an “adaptogen,” an agent that
helps the body to return to normal when exposed to stressful or
noxious stimuli. However, the clinical trials evaluating ginseng for
these indications have shown few, if any, benefits. Some random-
ized controlled trials evaluating “quality of life” and “cognition”
have claimed significant benefits in some subscale measures of
behavior, cognitive function, or quality of life but rarely in overall
composite scores using P ginseng. Better results have been observed
with P quinquefolium and P ginseng in lowering postprandial
glucose indices in subjects with and without diabetes. This was
the subject of a systematic review in which 15 studies (13 random-
ized and 2 nonrandomized) were evaluated. Nine of the studies
reported significant reductions in blood glucose. Some random-
ized, placebo-controlled trials have reported immunomodulating
benefits of P quinquefolium and P ginseng in preventing upper
respiratory tract infections. Use of ginseng for 2–4 months in
healthy seniors may reduce the risk of acquiring the common cold
as well as the duration of symptoms. Because of heterogeneity
in these trials, however, the findings are insufficient to warrant a
recommendation of ginseng for cold prevention. To assess effects
on cardiovascular health, a systematic review and meta-analysis
of 17 randomized controlled trials involving predominantly
P ginseng (12 studies) and P quinquefolium (5 studies) species in
persons with and without hypertension was performed. Over a
mean time period of 9 weeks, no significant effect was observed
of ginseng on SBP, DBP, and mean arterial pressure compared
with controls. Finally, two case-control studies and a cohort study
suggest a non-organ-specific cancer-preventive effect with long-
term administration of P ginseng. Significant benefits in some
cancer-related fatigue symptoms have been observed in both a
dose-finding study and a multisite, double-blind, randomized trial
using P quinquefolium, 2 g daily, versus placebo over a 2-month
period. In summary, the strongest support for use of P ginseng or
P quinquefolium currently relates to its effects in cold prevention,
lowering postprandial glucose, nonspecific cancer prevention, and
alleviating cancer-related fatigue.
Adverse Effects
Vaginal bleeding and mastalgia have been described in case
reports, suggesting possible estrogenic effects. Central nervous
system stimulation (eg, insomnia, nervousness) and hypertension
have been reported in patients using high doses (>3 g/d) of
P ginseng. Methylxanthines found in the ginseng plant may con-
tribute to this effect. Vasoregulatory effects have not been found
to be clinically significant.
Drug Interactions & Precautions
Irritability, sleeplessness, and manic behavior have been reported
in psychiatric patients using ginseng in combination with other
medications (phenelzine, lithium, neuroleptics). Ginseng should
be used cautiously in patients taking any psychiatric, estrogenic,
or hypoglycemic medications. Ginseng has antiplatelet properties
and should not be used in combination with warfarin. Cytokine
stimulation has been claimed for both P ginseng and P quinque-
folium in vitro and in animal models. In a randomized, double-
blind, placebo-controlled study, P ginseng significantly increased
natural killer cell activity versus placebo with 8 and 12 weeks
of use. Immunocompromised individuals, those taking immune
stimulants, and those with autoimmune disorders should use
ginseng products with caution.
Dosage
A dose of 1–2 g/d of the crude P ginseng root or its equivalent is
considered standard dosage. Two hundred milligrams of standard-
ized P ginseng extract are equivalent to 1 g of the crude root. The
trademarked preparation Ginsana has been used as a standardized
extract in some clinical trials and is available in the USA.
MILK THISTLE (SILYBUM MARIANUM)
Chemistry
The fruit and seeds of the milk thistle plant contain a lipophilic
mixture of flavonolignans known as silymarin. Silymarin comprises
2–3% of the dried herb and is composed of three primary isomers:
silybin (also known as silybinin or silibinin), silychristin (sili-
christin), and silydianin (silidianin). Silybin is the most prevalent
and potent of the three isomers and accounts for 50–70% of the
silymarin complex. Products should be standardized to contain
70–80% silymarin.
Pharmacologic Effects
1. Liver disease—In animal models, milk thistle purportedly
limits hepatic injury associated with a variety of toxins, including
Amanita mushrooms, galactosamine, carbon tetrachloride, acet-
aminophen, radiation, cold ischemia, and ethanol. In vitro studies
and some in vivo studies indicate that silymarin reduces lipid per-
oxidation, scavenges free radicals, and enhances glutathione and
superoxide dismutase levels. This may contribute to membrane
stabilization and reduce toxin entry.
Milk thistle appears to have anti-inflammatory properties. In
vitro, silybin strongly and noncompetitively inhibits lipoxygenase
activity and reduces leukotriene formation. Inhibition of leukocyte
migration has been observed in vivo and may be a factor when
acute inflammation is present. Silymarin inhibits nuclear factor
 CHAPTER 64  Dietary Supplements & Herbal Medications     1139
kappa B (NF-κB), an inflammatory response mediator. One of
the most unusual mechanisms claimed for milk thistle involves
an increase in RNA polymerase I activity in nonmalignant hepa-
tocytes but not in hepatoma or other malignant cell lines. By
increasing this enzyme’s activity, enhanced protein synthesis and
cellular regeneration might occur in healthy but not malignant
cells. In an animal model of cirrhosis, it reduced collagen accu-
mulation, and in an in vitro model it reduced expression of the
fibrogenic cytokine transforming growth factor-β. If confirmed,
milk thistle may have a role in the treatment of hepatic fibrosis.
In animal models, silymarin has a dose-dependent stimulatory
effect on bile flow that could be beneficial in cases of cholestasis.
To date, however, there is insufficient evidence to warrant the use
of milk thistle for these indications.
2. Chemotherapeutic effects—Preliminary in vitro and animal
studies of the effects of silymarin and silybinin have been carried
out with several cancer cell lines. In murine models of skin cancer,
silybinin and silymarin were said to reduce tumor initiation and
promotion. Induction of apoptosis has also been reported using
silymarin in a variety of malignant human cell lines (eg, mela-
noma, prostate, colon, leukemia cells, bladder transitional-cell
papilloma cells, cervical and hepatoma cells). Inhibition of cell
growth and proliferation by inducing a G1 cell cycle arrest has
also been claimed in cultured human breast and prostate cancer
cell lines. The use of milk thistle in the clinical treatment of can-
cer has not yet been adequately studied but preliminary trials in
patients undergoing chemotherapy show that it may improve liver
function (ie, reduced liver transaminase concentrations in blood).
There are insufficient data to support use in patients with cancer.
The antioxidant potential of milk thistle should be taken into con-
sideration prior to administration with chemotherapeutic agents
that may be affected by antioxidant compounds.
3. Lactation—Historically, milk thistle has been used by herbal-
ists and midwives to induce lactation in pregnant or postpartum
women. In female rats, milk thistle increases prolactin production.
As such, it is possible that it could have an effect on human breast
milk production. Clinical trial data are lacking, however, for this
indication, as are safety data on nursing mothers and infants.
Until further data become available, milk thistle should not be
used for this indication.
Clinical Trials
Oral milk thistle has been used to treat acute and chronic viral
hepatitis, alcoholic liver disease, and toxin-induced liver injury
in human patients. A systematic review of 13 randomized trials
involving 915 patients with alcoholic liver disease or hepatitis B
or C found no significant reductions in all-cause mortality, liver
histopathology, or complications of liver disease with 6 months of
use. A significant reduction in liver-related mortality was claimed
using the data from all the surveyed trials, but not when the
data were limited to trials of better design and controls. It was
concluded that the effects of oral milk thistle in improving liver
function or mortality from liver disease are currently poorly sub-
stantiated. A recent multicenter, double-blind, placebo-controlled
clinical trial in patients with hepatitis C refractory to interferon
treatment failed to show a benefit with 24 weeks of milk thistle,
420 mg/d and 700 mg/d, on reduction of serum alanine amino-
transferase levels. Milk thistle also had no effect on mean serum
hepatitis C virus (HCV) RNA levels at 24 weeks. In contrast, the
intravenous use of silybinin succinate has shown some benefit in
reducing HCV RNA levels and alanine aminotransferase levels in
patients with treatment-resistant hepatitis C infection. Prospective
pilot studies have also shown benefits with intravenous silybinin
before and after liver transplantation treatment in patients with
HCV cirrhosis. Potent antiviral activity was demonstrated with
significant reductions in HCV-RNA levels during treatment com-
pared to placebo or nontreated controls when given for at least
14 days before transplantation and 7 days after liver transplanta-
tion. HCV-RNA relapsed, however, after silibinin withdrawal.
This suggests that formulation and poor oral bioavailability may
influence treatment outcomes.
Although milk thistle has not been confirmed as an antidote
following acute exposure to liver toxins in humans, intrave-
nous silybinin is marketed and used in Europe (Legalon SIL)
as an antidote in Amanita phalloides mushroom poisoning.
This use is based on favorable outcomes reported in case-
control studies.
Adverse Effects
Milk thistle has rarely been reported to cause adverse effects
when used at recommended doses. In clinical trials, the inci-
dence of adverse effects (eg, gastrointestinal upset, dermatologic,
headaches) was comparable to that of placebo. At high doses
(>1500 mg), it can have a laxative effect caused by stimulation of
bile flow and secretion.
Drug Interactions, Precautions, & Dosage
Milk thistle does not significantly alter the pharmacokinetics
of other drugs transported by the P-glycoprotein transporter
or metabolized by cytochrome enzymes. In a recent review, the
impact of the herb was listed as “posing no risk for drug interac-
tions in humans.” Recommended oral dosage is 280–420 mg/d,
calculated as silybin, in three divided doses.
ST. JOHN’S WORT (HYPERICUM
PERFORATUM)
Chemistry
St. John’s wort, also known as hypericum, contains a variety of
constituents that might contribute to its claimed pharmacologic
activity in the treatment of depression. Hypericin, a marker of
standardization for currently marketed products, was thought to
be the primary antidepressant constituent. Recent attention has
focused on hyperforin, but a combination of several compounds is
probably involved. Commercial formulations are usually prepared
by soaking the dried chopped flowers in methanol to create a
hydroalcoholic extract that is then dried.
1140    SECTION X  Special Topics
Pharmacologic Effects
1. Antidepressant action—The hypericin fraction was initially
reported to have MAO-A and -B inhibitor properties. Later stud-
ies found that the concentration required for this inhibition was
higher than that achieved with recommended dosages. In vitro
studies using the commercially formulated hydroalcoholic extract
have shown inhibition of nerve terminal reuptake of serotonin,
norepinephrine, and dopamine. While the hypericin constitu-
ent did not show reuptake inhibition for any of these systems,
the hyperforin constituent did. Chronic administration of the
commercial extract has also been reported to significantly down-
regulate the expression of cortical β adrenoceptors and up-regulate
the expression of serotonin receptors (5-HT2) in a rodent model.
Other effects observed in vitro include sigma receptor binding
using the hypericin fraction and GABA receptor binding using
the commercial extract. Interleukin-6 production is also reduced
in the presence of the extract.
a. Clinical trials for depression—The most recent systematic
review and meta-analysis involved 29 randomized, double-blind,
controlled trials (18 compared St. John’s wort with placebo, 5 with
tricyclic antidepressants, and 12 with selective serotonin reuptake
inhibitors [SSRIs]). Only studies meeting defined classification
criteria for major depression were included. St. John’s wort was
reported to be more efficacious than placebo and equivalent to
prescription reference treatments including the SSRIs for mild to
moderate major depressive disorder but with fewer side effects.
Most trials used 900 mg/d of St. John’s wort for 4–12 weeks.
Depression severity was mild to moderate in 19 trials, moder-
ate to severe in 9 trials, and not stated in 1 trial. In a longer but
uncontrolled trial, the use of the herb for up to 52 weeks was
reported to reduce depression scores in patients with mild to mod-
erate major depression. These data and the mechanism of action
data reported above suggest a potential role for St. John’s wort in
relieving symptoms of mild to moderate major depression. Due
to the short study duration of these clinical trials, efficacy beyond
12 weeks still requires further study.
b. Other mood-related conditions—St. John’s wort has been
studied for several other indications related to mood, including
premenstrual dysphoric disorder, climacteric complaints, somato-
form disorders, and anxiety. For most of these indications, studies
are too few in number to draw any firm conclusions regarding
efficacy. Evidence for climacteric complaints was the subject of
a recent meta-analysis. Six trials were included where two used
mono-preparations of St. John’s wort and four used combinations
of St. John’s wort and black cohosh, Cimicifuga racemose (note
black cohosh warning in Table 64-1). St. John’s wort significantly
reduced hot flashes (severity, duration, and frequency) compared
to placebo when used for up to 16 weeks. Heterogeneity in
these trials limits drawing firm conclusions on efficacy for this
indication.
2. Antiviral and anticarcinogenic effects—The hypericin
constituent of St. John’s wort is photolabile and can be activated
by exposure to certain wavelengths of visible or ultraviolet A light.
Parenteral formulations of hypericin (photoactivated just before
administration) have been used investigationally to treat HIV
infection (given intravenously) and basal and squamous cell car-
cinoma (given by intralesional injection). In vitro, photoactivated
hypericin inhibits a variety of enveloped and nonenveloped viruses
as well as the growth of some neoplastic cells. Inhibition of protein
kinase C and inhibition of singlet oxygen radical generation have
been proposed as possible mechanisms. The latter could inhibit
cell growth or cause cell apoptosis. These studies were carried
out using the isolated hypericin constituent of St. John’s wort;
the usual hydroalcoholic extract of St. John’s wort has not been
studied for these indications and should not be recommended for
patients with viral illness or cancer.
Adverse Effects
Photosensitization is related to the hypericin and pseudohypericin
constituents in St. John’s wort. Consumers should be instructed
to wear sunscreen and eye protection while using this product
when exposed to the sun. Rarely, mild gastrointestinal symptoms,
fatigue, sedation, restlessness, dizziness, headache, and dry mouth
have been observed. Hypomania, mania, and autonomic arousal
have also been reported in patients using St. John’s wort. When
compared to SSRIs, St. John’s wort appears to be better tolerated
when used to support medical treatment of major depression.
Drug Interactions & Precautions
Inhibition of reuptake of various amine transmitters has been
highlighted as a potential mechanism of action for St. John’s
wort. Drugs with similar mechanisms (ie, antidepressants,
stimulants) should be used cautiously or avoided in patients
using St. John’s wort due to the risk of serotonin syndrome (see
Chapters 16 and 30). The hyperforin constituent of St. John’s
wort has been shown to activate the pregnane X receptor (PXR),
which ultimately leads to many drug interactions by inducing
hepatic CYP enzymes (3A4, 2C9, 1A2) and the P-glycoprotein
drug transporter. Another constituent, hypericin, which may not
be present in all commercial formulations, does not have any
effect on PXR, CYP, or P-glycoprotein. Case reports involving the
use of St. John’s wort have suggested the herb resulted in subthera-
peutic levels of numerous drugs, including digoxin, birth control
drugs (and subsequent pregnancy), cyclosporine, HIV protease
and nonnucleoside reverse transcriptase inhibitors, warfarin, irino-
tecan, theophylline, and anticonvulsants. Without knowing which
constituent is present in a St. John’s wort formulation, indiscrimi-
nate combined use with other medicines should be avoided.
Dosage
The most common commercial formulation of St. John’s wort is
the dried hydroalcoholic extract. Products should be standardized
to 2–5% hyperforin, although most still bear the older standard-
ized marker of 0.3% hypericin. The recommended dosing for
mild to moderate depression is 900 mg of the dried extract per day
in three divided doses. Onset of effect may take 2–4 weeks. Long-
term benefits beyond 12 weeks have not been studied.
 CHAPTER 64  Dietary Supplements & Herbal Medications     1141
SAW PALMETTO (SERENOA REPENS OR
SABAL SERRULATA)
Chemistry
The active constituents in saw palmetto berries are not well
defined. Phytosterols (eg, β-sitosterol), aliphatic alcohols, poly-
prenic compounds, and flavonoids are all present. Marketed
preparations are dried lipophilic extracts that are generally
standardized to contain 85–95% fatty acids and sterols.
Pharmacologic Effects
Saw palmetto is most often promoted for the treatment of benign
prostatic hyperplasia (BPH). Enzymatic conversion of testosterone
to dihydrotestosterone (DHT) by 5α-reductase is inhibited by
saw palmetto in vitro. Specifically, saw palmetto shows a noncom-
petitive inhibition of isoforms I and II of this enzyme, thereby
reducing DHT production. In vitro, saw palmetto also inhibits
the binding of DHT to androgen receptors. Additional effects
observed in vitro include inhibition of prostatic growth factors,
blockade of α1 adrenoceptors, and inhibition of inflammatory
mediators produced by the 5-lipoxygenase pathway.
The clinical pharmacology of saw palmetto in humans is not
well defined. One week of treatment in healthy volunteers failed
to influence 5α-reductase activity, DHT concentration, or testos-
terone concentration. Six months of treatment in patients with
BPH also failed to affect prostate-specific antigen (PSA) levels,
a marker that is typically reduced by enzymatic inhibition of
5α-reductase. In contrast, other researchers have reported a reduc-
tion in epidermal growth factor, DHT levels, and antagonist activ-
ity at the nuclear estrogen receptor in the prostate after 3 months
of treatment with saw palmetto in patients with BPH. Recent
reports suggest that daily saw palmetto, as compared to daily tam-
sulosin (see Chapter 10), has greater anti-inflammatory activity on
infiltrating prostatic cells in men with BPH-related lower urinary
tract symptoms at 3 months. The anti-inflammatory effects on
infiltrating prostatic cells may serve as a link between hormonal
changes and the remodeling process promoted by growth factors.
The anti-inflammatory effects of saw palmetto also raise questions
as to the value of early initiation of BPH therapy as well as the
value of early combination therapy with 5α-reductase inhibitors
(see Chapter 40).
Clinical Trials
The most recent review involved 32 randomized controlled trials
in 5666 men with symptoms consistent with BPH. Seventeen tri-
als compared saw palmetto monotherapy with placebo and found
no significant improvement in most urologic symptoms (eg,
international prostate symptom scores, peak flow, prostate size).
Adverse Effects
Adverse effects are reported with an incidence of 1–3%. The
most common include abdominal pain, nausea, diarrhea, fatigue,
headache, decreased libido, and rhinitis. Saw palmetto has been
associated with a few rare case reports of pancreatitis, liver dam-
age, and increased bleeding risk, but due to confounding factors,
causality remains uncertain. In comparison to tamsulosin and
finasteride, saw palmetto was claimed to be less likely to affect
sexual function (eg, ejaculation).
Drug Interactions, Precautions, & Dosage
No drug-drug interactions have been reported for saw palmetto.
Because saw palmetto has no effect on the PSA marker, it will
not interfere with prostate cancer screening using this test.
Recommended dosage of a standardized dried extract (containing
85–95% fatty acids and sterols) is 160 mg orally twice daily. The
lack of positive results as noted in the review of randomized con-
trolled studies cited above indicates that the use of saw palmetto
in prostate disease cannot be recommended.
■■ PURIFIED NUTRITIONAL
SUPPLEMENTS
COENZYME Q10
Coenzyme Q10, also known as CoQ, CoQ10, and ubiquinone, is
found in the mitochondria of many organs, including the heart,
kidney, liver, and skeletal muscle. After ingestion, the reduced
form of coenzyme Q10, ubiquinol, predominates in the systemic
circulation. Coenzyme Q10 is a potent antioxidant and has been
heavily promoted for this reason. It may have a role in maintain-
ing healthy muscle function, although the clinical significance of
this effect is unknown. Reduced serum levels have been reported
in Parkinson’s disease.
Clinical Uses
1. Hypertension—In clinical trials, small but significant reduc-
tions in systolic and diastolic blood pressure were reported after
8–10 weeks of coenzyme Q10 supplementation. The exact
mechanism is unknown but might be related to the antioxidant
and vasodilating properties of coenzyme Q10. In three random-
ized, placebo-controlled trials, coenzyme Q10 was reported
to significantly lower systolic and diastolic blood pressure by
11 mm Hg and 7 mm Hg, respectively, compared with no change
in the placebo groups. However, an exaggerated treatment effect
may have occurred as adequate randomization, blinding, and
concealment of allocation have been questioned for these studies.
Whether coenzyme Q10 can be used to lower blood pressure
remains unclear.
2. Heart failure—Low endogenous coenzyme Q10 levels have
been associated with worse heart failure outcomes, but this associa-
tion is likely because low levels are a marker for more advanced heart
failure, rather than a predictor of disease. Despite these findings,
coenzyme Q10 is often advocated to improve heart muscle function
in patients with heart failure. According to the most recent meta-
analysis, coenzyme Q10 was shown to improve ejection fraction
1142    SECTION X  Special Topics
by 3.7% when used short term (2–28 weeks). It is unclear whether
improvements in ejection fraction are applicable to all patients with
heart failure, including those receiving the current standard of care
for heart failure management. More research is required to assess
the role of coenzyme Q10 in heart failure and its impact on disease
severity, particularly with concomitant prescription medications.
3. Ischemic heart disease—The effects of coenzyme Q10 on
coronary artery disease and chronic stable angina are modest but
appear promising. A theoretical basis for such benefit could be meta-
bolic protection of the ischemic myocardium by reducing proinflam-
matory markers (including interleukin-6 and C-reactive protein)
that contribute to oxidative stress. Double-blind, placebo-controlled
trials have suggested that coenzyme Q10 supplementation improved
a number of clinical measures in patients with a history of acute
myocardial infarction (AMI). Improvements have been observed in
lipoprotein (a), high-density lipoprotein cholesterol, exercise toler-
ance, and time to development of ischemic changes on the electro-
cardiogram during stress tests. In addition, very small reductions in
cardiac deaths and rate of reinfarction in patients with previous AMI
have been reported (absolute risk reduction 1.5%).
4. Prevention of statin-induced myopathy—Statins reduce
cholesterol by inhibiting the HMG-CoA reductase enzyme (see
Chapter 35). This enzyme is also required for synthesis of coen-
zyme Q10. Initiating statin therapy has been shown to reduce
endogenous coenzyme Q10 levels, which may block steps in
muscle cell energy generation, possibly leading to statin-related
myopathy. It is unknown whether a reduction in intramuscular
coenzyme Q10 levels leads to statin myopathy or if the myopathy
causes cellular damage that reduces intramuscular coenzyme Q10
levels. A meta-analysis evaluating the effect of coenzyme Q10 on
statin-induced myopathy as measured by muscle pain and plasma
creatine kinase activity found that coenzyme Q10 supplementa-
tion (30 days to 3 months) did not demonstrate any benefit in
reducing myopathy. More information is needed to determine
which patients, if any, with statin-related myopathy might benefit
from coenzyme Q10 supplementation, especially as it relates to
the specific statin, the dose, and the duration of therapy.
Adverse Effects
Coenzyme Q10 is well tolerated, rarely leading to any adverse
effects at doses as high as 3000 mg/d. In clinical trials, gastrointes-
tinal upset, including diarrhea, nausea, heartburn, and anorexia,
has been reported with an incidence of less than 1%. Cases of
maculopapular rash and thrombocytopenia have very rarely been
observed. Other rare adverse effects include irritability, dizziness,
and headache.
Drug Interactions
Coenzyme Q10 shares a structural similarity with vitamin K, and
an interaction has been observed between coenzyme Q10 and
warfarin. Coenzyme Q10 supplements may decrease the effects
of warfarin therapy. This combination should be avoided or very
carefully monitored.
Dosage
As a dietary supplement, 30 mg/d of coenzyme Q10 is adequate
to replace low endogenous levels. For cardiac effects, typical dos-
ages are 100–600 mg/d given in two or three divided doses. These
doses increase endogenous levels to 2–3 mcg/mL (normal for
healthy adults, 0.7–1 mcg/mL).
GLUCOSAMINE
Glucosamine is found in human tissue, is a substrate for the pro-
duction of articular cartilage, and serves as a cartilage nutrient.
Glucosamine is commercially derived from crabs and other crusta-
ceans. As a dietary supplement, glucosamine is primarily used for
pain associated with knee osteoarthritis. Sulfate and hydrochloride
forms are available, but recent research has shown the hydrochlo-
ride form to be ineffective.
Pharmacologic Effects & Clinical Uses
Endogenous glucosamine is used for the production of glycosami-
noglycans and other proteoglycans in articular cartilage. In osteo-
arthritis, the rate of production of new cartilage is exceeded by
the rate of degradation of existing cartilage. Supplementation with
glucosamine is thought to increase the supply of the necessary
glycosaminoglycan building blocks, leading to better maintenance
and strengthening of existing cartilage.
Many clinical trials have been conducted on the effects of both
oral and intra-articular administration of glucosamine. Early stud-
ies reported significant improvements in overall mobility, range of
motion, and strength in patients with osteoarthritis. More recent
studies have reported mixed results, with both positive and nega-
tive outcomes. One of the largest and best-designed clinical trials,
which compared glucosamine, chondroitin sulfate, the combina-
tion, celecoxib, and placebo, found no benefit for glucosamine
therapy in mild to moderate disease. Unfortunately the investiga-
tors studied the glucosamine hydrochloride formulation, which
has been shown to be inferior to the sulfate formulation. The
formulation of glucosamine appears to play a critical role with
regard to efficacy, and this may be a factor contributing to the
variability observed across published studies. Research suggests
that use of a crystalline formulation of glucosamine sulfate leads
to less pain, functional improvements in knee osteoarthritis, and
an improvement in joint space narrowing at 3 years. Currently,
national orthopedic and rheumatic societies do not recommend
glucosamine for knee osteoarthritis primarily because of formula-
tion variability and study heterogeneity. More research is needed
to better define the ideal glucosamine formulation and patient
populations that stand to benefit from glucosamine sulfate.
Adverse Effects
Oral glucosamine sulfate is very well tolerated. In clinical trials,
mild diarrhea, abdominal cramping, and nausea were occasionally
reported. Cross-allergenicity in people with shellfish allergies is a
potential concern; however, this is unlikely if the formulation has
been properly manufactured and purified.
 CHAPTER 64  Dietary Supplements & Herbal Medications     1143
Drug Interactions & Precautions
Glucosamine sulfate may increase the international normalized
ratio (INR) in patients taking warfarin, increasing the risk for
bruising and bleeding. The mechanism is not well understood
and may be dose-related as increases in INR have occurred when
the glucosamine dose was increased. Until more is known, the
combination should be avoided or very carefully monitored.
Dosage
The oral dosage used most often in clinical trials is 500 mg three
times daily or 1500 mg once daily. Glucosamine does not have
direct analgesic effects, and improvements in function, if any, may
not be observed for 1–2 months.
MELATONIN
Melatonin, a serotonin derivative produced by the pineal gland
and some other tissues (see also Chapter 16), is believed to be
responsible for regulating sleep-wake cycles. Release coincides
with darkness; it typically begins around 9 pm and lasts until about
4 am. Melatonin release is suppressed by daylight. Melatonin has
also been studied for a number of other functions, including con-
traception, protection against endogenous oxidants, prevention
of aging, treatment of depression, HIV infection, and a variety of
cancers. Currently, melatonin is most often used to prevent jet lag
and to induce sleep.
Pharmacologic Effects & Clinical Uses
1. Jet lag—Jet lag, a disturbance of the sleep-wake cycle, occurs
when there is a disparity between the external time, ie, hours of
daylight or darkness, and the traveler’s endogenous circadian clock
(internal time). The internal time regulates not only daily sleep
rhythms but also body temperature and many metabolic systems.
The synchronization of the circadian clock relies on light as the
most potent “zeitgeber” (time giver).
Jet lag is especially common among frequent travelers and air-
plane cabin crews. Typical symptoms of jet lag may include daytime
drowsiness, insomnia, frequent awakenings, and gastrointestinal
upset. Clinical studies of melatonin have reported subjective reduc-
tion in daytime fatigue, improved mood, and a quicker recovery
time (return to normal sleep patterns, energy, and alertness). These
outcomes are also supported by a systematic review that showed
melatonin was better than placebo in helping patients fall asleep
faster and to sleep better at their destination. When traveling across
five or more time zones, jet lag symptoms are reduced when taking
melatonin close to the target bedtime (10 pm to midnight) at the
new destination. The benefit of melatonin is thought to be greater
as more time zones are crossed. In addition, melatonin appears
more effective for eastbound travel than for westward travel. Finally,
maximizing exposure to daylight on arrival at the new destination
can also aid in resetting the internal clock.
2. Insomnia—Melatonin has been studied in the treatment
of various sleep disorders, including insomnia and delayed
sleep-phase syndrome. It has been reported to improve sleep onset,
duration, and quality when administered to healthy volunteers,
suggesting a pharmacologic hypnotic effect. Melatonin has also
been shown to increase rapid eye movement (REM) sleep. These
observations have been applied to the development of ramelteon,
a prescription hypnotic that is an agonist at melatonin receptors
(see Chapter 22).
Clinical studies in patients with primary insomnia have shown
that oral melatonin supplementation may alter sleep architecture.
Melatonin appears effective in some patients who develop insom-
nia from β blockers. Subjective and objective improvements in
sleep quality and improvements in sleep onset and sleep duration
have been reported. Specifically, melatonin taken at the desired
bedtime, with bedroom lights off, has been shown to improve
morning alertness and quality of sleep as compared with placebo.
These effects have been observed in both young and older adults
(18–80 years of age). Interestingly, baseline endogenous melatonin
levels were not predictive of exogenous melatonin efficacy.
3. Pre- and postoperative anxiety in adults—Melatonin given
as a premedication has been shown to reduce preoperative anxiety
in adults. Melatonin may be as effective as midazolam in reducing
anxiety before a surgical procedure (measured 50–100 minutes after
administration). The effect of melatonin on postoperative anxiety in
adults is mixed, but studies support an overall reduction in anxiety
as compared to preoperative anxiety levels.
4. Female reproductive function—The presence of melato-
nin within the female reproductive system appears widespread in
mammals, and research suggests it plays a role in reducing oxida-
tive stress. Melatonin receptors have been identified in ovarian
granulosa cell membranes, and significant amounts of melatonin
have been detected in follicular fluid. Some studies suggest it
can be used as an adjunctive therapy in the treatment of infertil-
ity during in vitro fertilization by reducing oxidative stress and
thereby improving the quality of oocytes and embryos during
ovulation induction and egg retrieval. Melatonin requirements
increase during pregnancy, and researchers are evaluating the role
of melatonin in preeclampsia and neonatal neurologic morbidity.
Importantly, melatonin has been shown to lack teratogenic effects
when taken during pregnancy. Melatonin supplementation may
decrease prolactin release in women and therefore should be used
cautiously or not at all while nursing.
5. Male reproductive function—Melatonin receptors have
been identified on spermatozoa, suggesting melatonin may play
a role in sperm function. When melatonin was added to semen
samples, sperm motility was increased and early apoptosis was
inhibited. These findings suggest that melatonin may be impor-
tant in male fertility; however, more research is needed.
Adverse Effects
Melatonin appears to be well tolerated and is often used in prefer-
ence to over-the-counter “sleep-aid” drugs. Although melatonin is
associated with few adverse effects, some next-day drowsiness has
been reported as well as fatigue, dizziness, headache, and irritability.
1144    SECTION X  Special Topics
Transient depressive symptoms and dysphoria have been reported
rarely. Melatonin may affect blood pressure as both increases and
decreases in blood pressure have been observed. Careful monitor-
ing is recommended, particularly in patients initiating melatonin
therapy while taking antihypertensive medications.
Drug Interactions
Melatonin drug interactions have not been formally studied.
Various studies, however, suggest that melatonin concentrations
are altered by a variety of drugs, including nonsteroidal anti-
inflammatory drugs, antidepressants, β-adrenoceptor agonists and
antagonists, scopolamine, and sodium valproate. The relevance of
these effects is unknown. Melatonin is metabolized by CYP450 1A2
and may interact with other drugs that either inhibit or induce the
1A2 isoenzyme, including fluvoxamine. Melatonin may decrease
prothrombin time and may theoretically decrease the effects of
warfarin therapy. A dose-response relationship between the plasma
concentration of melatonin and coagulation activity has been sug-
gested according to one in vitro analysis. If combination therapy is
desired, careful monitoring is recommended especially if melatonin
is being used on a short-term basis. Melatonin may interact with
nifedipine, possibly leading to increased blood pressure and heart
rate. The exact mechanism is unknown.
Dosage
1. Jet lag—Daily doses of 0.5–5 mg appear to be equally effec-
tive for jet lag; however, the 5 mg dose resulted in a faster onset
of sleep and better sleep quality than lower doses. The immediate-
release formulation is preferred and should be given at the desired
sleep time (10 pm–midnight) upon arrival at the new destination
and for 1–3 nights after arrival. A dark room environment is
important when taking melatonin and when possible, room lights
should be turned off. The value of extended-release formulations
remains unknown, as evidence suggests the short-acting, high-
peak effect of the immediate-release formulation to be more effec-
tive. Exposure to daylight at the new time zone is also important
to regulate the sleep-wake cycle.
2. Insomnia—Doses of 0.3–10 mg of the immediate-release
formulation given orally once nightly have been used. The
lowest effective dose should be used first and may be repeated in
30 minutes up to a maximum of 10–20 mg. Sustained-release for-
mulations are effective and may be used but, as noted above, may
be inferior to immediate-release formulations. Sustained-release
formulations are also more costly.
REFERENCES
Agbabiaka TB et al: Serenoa repens (saw palmetto): A systematic review of adverse
events. Drug Saf 2009;32:637.
Ardjomand-Woelkart K, Bauer R: Review and assessment of safety data of orally
used echinacea preparations. Planta Med 2016;82:17.
Banach M et al: Effects of coenzyme Q10 on statin-induced myopathy: a meta-
analysis of randomized controlled trials. Mayo Clin Proc 2015;90:24.
Barnes J et al: Echinacea species (Echinacea angustifolia (DC.) Hell., Echinacea pallida
(Nutt.) Nutt., Echinacea purpurea (L.) Moench): A review of their chemistry,
pharmacology and clinical properties. Pharm Pharmacol 2005;57:929.
Barton DL et al: Wisconsin ginseng (Panax quinquefolius) to improve cancer
related fatigue: A randomized, double-blind trial, N7C2. J Natl Cancer Inst
2013;105:1230.
Birks J, Evans JG: Ginkgo biloba for cognitive impairment and dementia. Cochrane
Database Syst Rev 2009;1:CD003120.
Brzezinski A et al: Effects of exogenous melatonin on sleep: A meta-analysis. Sleep
Med Rev 2005;9:41.
Buck AC: Is there a scientific basis for the therapeutic effects of Serenoa repens in
benign prostatic hyperplasia? Mechanisms of action. J Urol 2004;172:1792.
Butterweck V, Schmidt M: St John’s wort: Role of active compounds for its mecha-
nism of action and efficacy. Wien Med Wochenschr 2007;157:356.
Capasso A: Antioxidant action and therapeutic efficacy of Allium sativum L.
Molecules 2013;18:690.
Chen X, Hong Y, Zheng P: Efficacy and safety of gingko biloba as an adjunct
therapy in chronic schizophrenia: A systematic review of randomized,
double-blind, placebo-controlled studies with meta-analysis. Psychiatry Res
2015;228:121.
Fotino AD, Thompson-Paul AM, Bazzano LA: Effect of coenzyme Q10 supple-
mentation on heart failure: A meta-analysis. Am J Clin Nutr 2013;97:268.
Franco OH et al: Use of plant-based therapies and menopausal symptoms. A
systematic review and meta-analysis. JAMA 2016;315:2554.
Fried MW et al: Effect of silymarin (milk thistle) on liver disease in patients with
chronic hepatitis C unsuccessfully treated with interferon therapy. JAMA
2012;308:274.
Garcia-Cazarin ML et al: Dietary supplement research portfolio at the NIH, 2009-
2011. J Nutri 2014;144:414.
Geller AI, et al: Emergency department visits for adverse events related to dietary
supplements. N Engl J Med 2015;373:1531.
Hansen MV, et al: Melatonin for pre- and postoperative anxiety in adults.
Cochrane Database Syst Rev 2015;4:CD009861.
Heitmann K et al: Pregnancy outcomes after prenatal exposure to echinacea:
The Norwegian mother and child cohort study. Eur J Clin Pharmacol
2016;72:623.
Herxheimer A, Petrie KJ: Melatonin for the prevention and treatment of jet lag.
Cochrane Database Syst Rev 2002;2:CD001520.
Ho MJ, Bellusci A, Wright JM: Blood pressure lowering efficacy of coenzyme Q10
for primary hypertension. Cochrane Database Syst Rev 2009;4:CD007435.
Hudson JB: Applications of phytomedicine Echinacea purpurea (Purple
Coneflower) in infectious diseases. J Biomed Biotechnol 2012;2012:769896.
Izzo AA et al: A critical approach to evaluating clinical efficacy, adverse effects, and
drug interactions of herbal remedies. Phytother Res 2016;30:4691.
Kang S, Min H: Ginseng, the immunity boost: Effects of Panax ginseng on the
immune system. J Ginseng Res 2012;36:354.
Kantor ED et al: Trends in dietary supplement use among US adults from
1999-2012. JAMA 2016;316:1464.
Karsch-Völk M et al: Echinacea for preventing and treating the common cold.
Cochrane Database Syst Rev 2014;2:CD000530.
Kim HJ, Kim P, Shin CY: A comprehensive review of the therapeutic and
pharmacologic effects of ginseng and ginsenosides in central nervous system.
J Ginseng Res 2013;37:8.
Komishono AM, et al: The effect of ginseng (genus Panax) on blood pressure: A
systematic review and meta-analysis of randomized controlled clinical trials.
J Hum Hypertension 2016;30:619.
Linde K et al: St. John’s wort for major depression. Cochrane Database Syst Rev
2008;4:CD000448.
Liu YR et al: Hypericum perforatum L. preparations for menopause: A meta-analysis
of efficacy and safety. Climacteric 2014;17:325.
Loguercio C, Festi D: Silybin and the liver: From basic research to clinical practice.
World J Gastroenterol 2011;17:2288.
Mastron JK et al: Silymarin and hepatocellular carcinoma: A systematic, compre-
hensive, and critical review. Anticancer Drugs 2015;26:475.
Mengs U, Pohl RT, Mitchell T: Legalon SIL: The antidote of choice in patients
with acute hepatotoxicity from amatoxin poisoning. Curr Pharmaceut
Biotechnol 2012;13:1964.
Natural Medicines. Therapeutic Research Center, Somerville, MA. Available from:
https://naturalmedicines.therapeuticresearch.com. Subscription required to view.
Newmaster SG et al: DNA barcoding detects contamination and substitution in
North American herbal products. BMC Med 2013;11:222.
 CHAPTER 64  Dietary Supplements & Herbal Medications     1145
Nicolai SP et al: Ginkgo biloba for intermittent claudication. Cochrane Database
Syst Rev 2013;6:CD006888.
Qaseem A et al: Nonpharmacologic versus pharmacologic treatment of adult
patients with major depressive disorder: A clinical practice guideline from
the American College of Physicians. Ann Intern Med 2016;164:350.
Rambaldi A et al: Milk thistle for alcoholic and/or hepatitis B or C virus liver
diseases. Cochrane Database Syst Rev 2007;4:CD003620.
Ried K: Garlic lowers blood pressure in hypertensive individuals, regulates serum
cholesterol, and stimulates immunity: An updated meta-analysis and review.
J Nutr 2016;146(suppl):389S.
Ried K, Toben C, Fakler P: Effect of garlic on serum lipids: An updated meta-
analysis. Nutr Rev 2013;71:282.
Scheer FAJL et al: Repeated melatonin supplementation improves sleep in hyper-
tensive patients treated with beta-blockers: A randomized controlled trial.
Sleep 2012;35:1395.
Schergis JL et al: Panax ginseng in randomized controlled trials: A systematic
review. Phytother Res 2013;27:949.
Seida JK, Durec T, Kuhle S: North American (Panax quinquefolius) and Asian
ginseng (Panax ginseng) preparations for prevention of the common cold in
healthy adults: A systematic review. Evid Based Complement Alternat Med
2011;2011:282151.
C ASE STUDY ANSWER
Garlic has shown significant benefits in lowering total choles-
terol, LDL, and systolic and diastolic blood pressure, but the
effects are moderate and unlikely to be large enough to lower
this patient’s values into the normal range. While this patient’s
diabetes is under control, her hypertension places her at risk
for microvascular complications of diabetes, thus making it
necessary to reevaluate her current medication adherence,
doses of benazepril for hypertension and simvastatin for hyper-
lipidemia, and duration of therapy. She would benefit from
meeting with a nutritionist because packaged frozen dinners
can be high in sodium, and this may be elevating her blood
pressure. Adding exercise to her weekly routine could also help
with weight control and overall cardiovascular health. The
data supporting benefits of St. John’s wort in patients with hot
Sharma M et al: Bactericidal and anti-inflammatory properties of a standardized
echinacea extract (Echinaforce): Dual actions against respiratory bacteria.
Phytomedicine 2010;17:563.
Sharma M et al: The efficacy of echinacea in a 3-D tissue model of human airway
epithelium. Phytother Res 2010;24:900.
Shi C et al: Ginkgo biloba extract in Alzheimer’s disease: From action mechanisms
to medical practice. Int J Mol Sci 2010;11:107.
Tacklind J et al: Serenoa repens for benign prostatic hyperplasia. Cochrane Database
Syst Rev 2012;12:CD001423.
Tan MS et al: Efficacy and adverse effects of ginkgo biloba for cognitive impair-
ment and dementia: a systematic review and meta-analysis. J Alzheimers Dis
2015;43:589.
Van Vijven JP et al: Symptomatic and chondroprotective treatment with collagen
derivatives in osteoarthritis: A systematic review. Osteoarthritis Cartilage
2012;20:809.
Vellas B et al: Long term use of standardized ginkgo biloba extract for the preven-
tion of Alzheimer’s disease (GuidAge): A randomized placebo-controlled
trial. Lancet Neurol 2012;11:836.
Wu D et al: Efficacies of different preparations of glucosamine for the treatment
of osteoarthritis: A meta-analysis of randomised, double-blind, placebo-
controlled trials. Int J Clin Pract 2013;67:585.
flashes are preliminary but show promise. Good data support
use of the herb to alleviate symptoms of mild to moderate
depression when used for up to 1 year. However, this patient is
not a good candidate for St. John’s wort (a cytochrome P450
1A2, 2C9, 3A4 inducer) because of her prescription drug use
and the potential for herb-drug interactions. Several dietary
supplements reviewed in this chapter (garlic, ginkgo, and gin-
seng) may have antiplatelet effects that could be additive with
ibuprofen. If this patient were also taking warfarin, additional
interactions could occur with coenzyme Q10 (vitamin K-like
structure), St. John’s wort, and melatonin (in vitro decreased
prothrombin time), leading to a decreased warfarin effect, or
with glucosamine (increased international normalized ratio),
leading to an increased warfarin effect.
 65
C H A P T E R
Rational Prescribing &
Prescription Writing
Paul W. Lofholm, PharmD, &
Bertram G. Katzung, MD, PhD
Once a patient with a clinical problem has been evaluated and a
diagnosis has been reached, the practitioner can often select from a
variety of therapeutic approaches. Medication, surgery, psychiatric
treatment, radiation, physical therapy, health education, counsel-
ing, further consultation (second opinions), and no therapy are
some of the options available. Of these options, drug therapy is
by far the one most frequently chosen. In most cases, this requires
the writing of a prescription. A written prescription is the pre-
scriber’s order to prepare or dispense a specific treatment—usually
medication—for a specific patient. When a patient comes for an
office visit, the physician or other authorized health professional
prescribes medications 67% of the time, and an average of one
prescription is written per office visit because more than one pre-
scription may be written at a single visit.
In this chapter, a plan for prescribing is presented. The physi-
cal form of the prescription, common prescribing errors, and legal
requirements that govern various features of the prescribing pro-
cess are then discussed. Finally, some of the social and economic
factors involved in prescribing and drug use are described.
RATIONAL PRESCRIBING
Like any other process in health care, writing a prescription should
be based on a series of rational steps as follows:
1. Make a specific diagnosis: Prescriptions based merely on a
desire to satisfy the patient’s psychological need for some type of
therapy are often unsatisfactory and may result in adverse effects.
A specific diagnosis, even if it is tentative, is required to move to
the next step. For example, in a patient with a probable diagnosis
of rheumatoid arthritis, the diagnosis and the reasoning underly-
ing it should be clear and should be shared with the patient.
2. Consider the pathophysiologic implications of the
diagnosis: If the disorder is well understood, the prescriber is
in a much better position to offer effective therapy.
1146
For example, increasing knowledge about the mediators of
inflammation makes possible more effective use of nonsteroidal
anti-inflammatory drugs (NSAIDs) and other agents used in
rheumatoid arthritis. The patient should be provided with the
appropriate level and amount of information about the patho-
physiology. Many pharmacies, websites, and disease-oriented
public and private agencies (eg, Arthritis Foundation, Ameri-
can Heart Association, American Cancer Society, etc) provide
information sheets suitable for patients.
3. Select a specific therapeutic objective: A therapeutic objective
should be chosen for each of the pathophysiologic processes
defined in the preceding step. In a patient with rheumatoid
arthritis, relief of pain by reduction of the inflammatory pro-
cess is one of the major therapeutic goals that identifies the
drug groups that should be considered. Arresting the course of
the disease process in rheumatoid arthritis is a different thera-
peutic goal, which might lead to consideration of additional
drug groups and prescriptions.
4. Select a drug of choice: One or more drug groups will be sug-
gested by each of the therapeutic goals specified in the preced-
ing step. Selection of a drug of choice from among these groups
follows from a consideration of the specific characteristics of
the patient and the clinical presentation, a selection process
that has been emphasized as part of “precision medicine.” For
certain drugs, characteristics such as age, other diseases, and
other drugs being taken (because of the risk of duplicative
therapy or drug-drug interactions) are extremely important in
determining the most suitable drug for management of the
present complaint. As the tools of precision medicine provide
more detailed information (eg, mutations of drug metabolizing
enzymes—pharmacogenomics), the selection process will
become more focused. In the example of the patient with
probable rheumatoid arthritis, it would be important to
know whether the patient has a history of aspirin intoler-
ance or ulcer disease, whether the cost of medication is an
 CHAPTER 65  Rational Prescribing & Prescription Writing     1147

especially important factor and the nature of the patient’s insur-

ance coverage, and whether there is a need for once-daily dos- 1 2

ing. Based on this information, a drug would probably be JOHN B. DOE, MD

selected from the NSAID group. If the patient does not have 1234 SOUTH NORTHEAST DR 3

WEST CITY, CA 94999

ulcer disease but does have a need for low-cost treatment, (234) 555 - 6789 4
ibuprofen or naproxen would be a rational choice.
5. Determine the appropriate dosing regimen: The dosing regi- FOR: 6 DATE:
5

men is determined primarily by the pharmacokinetics of the ADDRESS: 7

drug in that patient. If the patient is known to have disease of the
organs required for elimination of the drug selected, adjustment
of the average regimen is needed. For a drug such as ibuprofen, 8 9
(DRUG NAME AND STRENGTH)
which is eliminated mainly by the kidneys, renal function should (QUANTITY)
10
be assessed. If renal function is normal, the half-life of ibuprofen
(about 2 hours) requires administration three or four times daily. SIG: 11
The dose suggested in this book, drug handbooks, and the REFILL TIMES
manufacturer’s literature is 400–800 mg four times daily. OR
UNTIL 12
6. Devise a plan for monitoring the drug’s action and determine NO
CHILDPROOF 13
an end point for therapy: The prescriber should be able to CONTAINER

describe to the patient the kinds of drug effects that will be
monitored and in what way, including laboratory tests (if neces-
sary) and signs and symptoms that the patient should report. For
conditions that call for a limited course of therapy (eg, most
infections), the duration of therapy should be made clear so that
the patient does not stop taking the drug prematurely and under-
stands why the prescription probably need not be renewed. For
the patient with rheumatoid arthritis, the need for prolonged—
perhaps indefinite—therapy should be explained, including how
to obtain refills. The prescriber should also specify any changes
in the patient’s condition that would call for changes in therapy.
For example, in the patient with rheumatoid arthritis, develop-
ment of gastrointestinal bleeding would require an immediate
change in drug therapy and a prompt workup of the bleeding.
Major toxicities that require immediate attention should be
explained clearly to the patient.
7. Plan a program of patient education: The prescriber and
other members of the health team should be prepared to
repeat, extend, and reinforce the information transmitted to
the patient as often as necessary. The more toxic the drug
prescribed, the greater the importance of this educational pro-
gram. The importance of informing and involving the patient
in each of the above steps must be recognized, as shown by
experience with teratogenic drugs (see Chapter 59). Many
pharmacies routinely provide this type of information with
each prescription filled, but the prescriber must not assume
that this will occur.
WARNING:
15
14
, MD
AD1234567 16
STATE LICENSE NO. 17
FIGURE 65–1  Common form of outpatient prescription. Circled
numbers are explained in the text.
records environment, prescriptions are executed via electronic order
entry. The contents of that prescription are specified in the medical
staff rules by the hospital’s Pharmacy and Therapeutics Committee
or similar authority. The patient’s name is typed or written on the
form; the orders consist of the name and strength of the medication,
the dose, the route and frequency of administration, the date, other
pertinent information, and the signature of the prescriber. If the
duration of therapy or the number of doses is not specified (which
is often the case), the medication is continued until the prescriber
discontinues the order or until it is terminated as a matter of policy
routine, eg, a stop-order policy.
A typical chart order might be as follows:
3/12/16
10:30 a.m.
(1) Ampicillin 500 mg IV q6h 5 days
(2) Aspirin 0.6 g per rectum q6h prn temp over 101
[Signed] Janet B. Doe, MD
Thus, the elements of the hospital chart order are equivalent to
the central elements (5, 8–11, 15) of the outpatient prescription.

THE PRESCRIPTION
Although a prescription can be written on any piece of paper (as
long as all of the legal elements are present), it usually takes a
specific form. A typical printed prescription form for outpatients
is shown in Figure 65–1.
In the traditional hospital setting, drugs have been prescribed
on a particular page of the patient’s hospital chart called the physi-
cian’s order sheet (POS) or chart order. In the electronic medical
ELEMENTS OF THE PRESCRIPTION
The first four elements (see circled numerals in Figure 65–1) of
the outpatient prescription establish the identity of the prescriber:
name, license classification (ie, professional degree), address, and
office telephone number. Before dispensing a prescription, the
pharmacist must establish the prescriber’s bona fides and should be
able to contact the prescriber by telephone if any questions arise.
1148    SECTION X  Special Topics
Element [5] is the date on which the prescription was written. It
should be near the top of the prescription form or at the beginning
(left margin) of the chart order. Since the order has legal signifi-
cance and usually has some temporal relationship to the date of
the patient-prescriber interview, a pharmacist should refuse to fill
a prescription without verification by telephone if too much time
has elapsed since its writing.
Elements [6] and [7] identify the patient by name and address.
The patient’s name and full address should be clearly spelled out.
The body of the prescription contains the elements [8] to [11] that
specify the medication, the strength and quantity to be dispensed,
the dosage, and complete directions for use. When writing the drug
name (element [8]), either the brand name (proprietary name) or the
generic name (nonproprietary name) may be used. Reasons for using
one or the other are discussed below. The strength of the medication
[9] should be written in metric units. However, the prescriber should
be familiar with both systems now in use: metric and apothecary. For
practical purposes, the following approximate conversions are useful:
1 grain (gr) = 0.065 grams (g), often rounded to
60 milligrams (mg)
15 gr = 1 g
1 ounce (oz) by volume = 30 milliliters (mL)
1 teaspoonful (tsp) = 5 mL
1 tablespoonful (tbsp) = 15 mL
1 quart (qt) = 1000 mL
1 minim = 1 drop (gtt)
20 drops = 1 mL
2.2 pounds (lb) = 1 kilogram (kg)
The strength of a solution is usually expressed as the quantity
of solute in sufficient solvent to make 100 mL; for instance, 20%
potassium chloride solution is 20 grams of KCl per deciliter (g/dL)
of final solution. Both the concentration and the volume should
be explicitly written out.
The quantity of medication prescribed should reflect the antici-
pated duration of therapy, the cost, the need for continued contact
with the clinic or physician, the potential for abuse, and the poten-
tial for toxicity or overdose. Consideration should be given also to
the standard sizes in which the product is available and whether this
is the initial prescription of the drug or a repeat prescription or refill.
If 10 days of therapy are required to effectively cure a streptococcal
infection, an appropriate quantity for the full course should be pre-
scribed. Birth control pills are often prescribed for 1 year or until the
next examination is due; however, some patients may not be able
to afford a year’s supply at one time; therefore, a 3-month supply
might be ordered, with refill instructions to renew three times or
for 1 year (element [12]). Some third-party (insurance) plans limit
the amount of medicine that can be dispensed—often to only one
month’s supply. Finally, when first prescribing medications that are
to be used for the treatment of a chronic disease, the initial quan-
tity should be small, with refills for larger quantities. The purpose
of beginning treatment with a small quantity of drug is to reduce
the cost if the patient cannot tolerate it. Once it is determined
that intolerance is not a problem, a larger quantity purchased less
frequently is sometimes less expensive.
The directions for use (element [11]) must be both drug-specific
and patient-specific. The simpler the directions, the better; and the
fewer the number of doses (and drugs) per day, the better. Patient
noncompliance (also known as nonadherence, failure to adhere to
the drug regimen) is a major cause of treatment failure. To help
patients remember to take their medications, prescribers often give
an instruction that medications be taken at or around mealtimes
and at bedtime. However, it is important to inquire about the
patient’s eating habits and other lifestyle patterns, because many
patients do not eat three regularly spaced meals a day.
The instructions on how and when to take medications, the
duration of therapy, and the purpose of the medication must be
explained to each patient both by the prescriber and by the phar-
macist. (Neither should assume that the other will do it.) Further-
more, the drug name, the purpose for which it is given, and the
duration of therapy should be written on each label so that the
drug may be identified easily in case of overdose. An instruction to
“take as directed” may save the time it takes to write the orders out
but often leads to noncompliance, patient confusion, and medi-
cation error. The directions for use must be clear and concise to
prevent toxicity and to obtain the greatest benefits from therapy.
Although directions for use are no longer written in Latin,
many Latin apothecary abbreviations (and some others included
below) are still in use. Knowledge of these abbreviations is essential
for the dispensing pharmacist and often useful for the prescriber.
Some of the abbreviations still used are listed in Table 65–1.
Note: It is always safer to write out the direction without
abbreviating.
Elements [12] to [14] of the prescription include refill infor-
mation, waiver of the requirement for childproof containers,
and additional labeling instructions (eg, warnings such as “may
cause drowsiness,” “do not drink alcohol”). Pharmacists put the
name of the medication on the label unless directed otherwise by
the prescriber, and some medications have the name of the drug
stamped or imprinted on the tablet or capsule. Pharmacists must
place the expiration date for the drug on the label. If the patient
or prescriber does not request waiver of childproof containers,
the pharmacist or dispenser must place the medication in such a
container. Pharmacists may not refill a prescription medication
without authorization from the prescriber. Prescribers may grant
authorization to renew prescriptions at the time of writing the
prescription or over the telephone or electronically. Elements
[15] to [17] are the prescriber’s signature and other identifica-
tion data such as National Provider Identification (NPI), Drug
Enforcement Administration (DEA) number, or State License
number.
PRESCRIBING ERRORS
Unfortunately, prescribing errors are common. Several groups
provide online information regarding practices designed to reduce
or document such errors, eg, Institute for Safe Medication Prac-
tices (ISMP; http://www.ismp.org/) and National Coordinating
Council for Medication Error Reporting and Prevention Program
(MERP; http://www.nccmerp.org/about-medication-errors).
 CHAPTER 65  Rational Prescribing & Prescription Writing     1149

 TABLE 65–1  Abbreviations used in prescriptions and chart orders.

Abbreviation Explanation Abbreviation Explanation

ā before PO by mouth
ac before meals PR per rectum
agit shake, stir prn when needed
Aq water q every
Aq dest distilled water qam, om every morning
bid twice a day qd (do not use) every day (write “daily”)
c with qh, q1h every hour
cap capsule q2h, q3h, etc every 2 hours, every 3 hours, etc
D5W, D5W dextrose 5% in water qhs every night at bedtime
dil dissolve dilute qid four times a day
disp, dis dispense qod (do not use) every other day
elix elixir qs sufficient quantity
ext extract rept, repet may be repeated
g gram Rx take
gr grain s without
gtt drops SC, SQ subcutaneous
h hour sid (veterinary) once a day
hs at bedtime Sig, S label
IA intra-arterial sos if needed
IM intramuscular ss, ss one-half
IV intravenous stat at once
IVPB IV piggyback sup, supp suppository
kg kilogram susp suspension
mcg, μg (do not use) microgram (always write out “microgram”) tab tablet
mEq, meq milliequivalent tbsp, T (do not use) tablespoon (always write out “15 mL”)
mg milligram tid three times a day
no number Tr, tinct tincture
non rep do not repeat tsp (do not use) teaspoon (always write out “5 mL”)
OD right eye U (do not use) units (always write out “units”)
OS, OL left eye vag vaginal
OTC over-the-counter i, ii, iii, iv, etc one, two, three, four, etc
OU both eyes (do not use) dram (in fluid measure 3.7 mL)
p after (do not use) ounce (in fluid measure 29.6 mL)
pc after meals

All prescription orders should be legible, unambiguous, dated OMISSION OF INFORMATION

(and timed in the case of a chart order), and signed clearly for
optimal communication between prescriber, pharmacist, and
nurse. Furthermore, a good prescription or chart order should
contain sufficient information to permit the pharmacist or
nurse to discover possible errors before the drug is dispensed or
administered.
Certain types of prescribing errors are particularly common.
These include errors involving omission of needed information;
poor writing perhaps leading to errors of drug dose or timing; and
prescription of drugs that are inappropriate for the specific situation.
Errors of omission are common in hospital orders and may include
instructions to “resume pre-op meds,” which assumes that a full
and accurate record of the “pre-op meds” is available; “continue
present IV fluids,” which fails to state exactly what fluids are to be
given, in what volume, and over what time period; or “continue
eye drops,” which omits mention of which eye is to be treated
as well as the drug, concentration, and frequency of administra-
tion. Chart orders may also fail to discontinue a prior medication
when a new one is begun; may fail to state whether a regular or
1150    SECTION X  Special Topics
long-acting form is to be used; may fail to specify a strength or
notation for long-acting forms; or may authorize “as needed”
(prn) use that fails to state what conditions will justify the need.
POOR PRESCRIPTION WRITING
Poor prescription writing is traditionally exemplified by illegible
handwriting. However, other types of poor writing are common and
often more dangerous. One of the most important is the misplaced
or ambiguous decimal point. Thus “.1” is easily misread as “1,” a
tenfold overdose, if the decimal point is not unmistakably clear.
This danger is easily avoided by always preceding the decimal point
with a zero. On the other hand, appending an unnecessary zero
after a decimal point increases the risk of a tenfold overdose, because
“1.0 mg” is easily misread as “10 mg,” whereas “1 mg” is not. The
slash or virgule (“/”) was traditionally used as a substitute for a deci-
mal point. This should be abandoned because it is too easily misread
as the numeral “1.” Similarly, the abbreviation “U” for units should
never be used because “10 U” is easily misread as “100”; the word
“units” should always be written out. Doses in micrograms should
always have this unit written out because the abbreviated form
(“μg”) is very easily misread as “mg,” a 1000-fold overdose! Orders
for drugs specifying only the number of dosage units and not the
total dose required should not be filled if more than one size dosage
unit exists for that drug. For example, ordering “one ampule of furo-
semide” is unacceptable because furosemide is available in ampules
that contain 20, 40, or 100 mg of the drug. The abbreviation “OD”
should be used (if at all) only to mean “the right eye”; it has been
used for “every day” and has caused inappropriate administration
of drugs into the eye. Similarly, “Q.D.” or “QD” should not be
used because it is often read as “QID,” resulting in four daily doses
instead of one. Acronyms and abbreviations such as “ASA” (aspirin),
“5-ASA” (5-aminosalicylic acid), “6MP” (6-mercaptopurine), etc,
should not be used; drug names should be written out. Unclear
handwriting can be lethal when drugs with similar names but very
different effects are available, eg, acetazolamide and acetohexamide,
methotrexate and metolazone. In this situation, errors are best
avoided by noting the indication for the drug in the body of the
prescription, eg, “acetazolamide, for glaucoma.” Pharmacy and
Therapeutics committees have developed some additional princi-
ples to lessen errors, such as a High-Alert Medication list and using
a comma (in the USA) when the dose exceeds 999.
INAPPROPRIATE DRUG PRESCRIPTIONS
Prescribing an inappropriate drug for a particular patient often
results from failure to recognize contraindications imposed by
other diseases the patient may have, failure to obtain informa-
tion about other drugs the patient is taking (including over-the-
counter drugs), or failure to recognize possible physicochemical
incompatibilities between drugs that may react with each other.
Contraindications to drugs in the presence of other diseases or
pharmacokinetic characteristics are listed in the discussions of the
drugs described in this book. The manufacturer’s package insert
usually contains similar information. Many of the important drug
interactions are listed in Chapter 66 of this book as well as in
package inserts.
Physicochemical incompatibilities are of particular concern
when parenteral administration is planned. For example, certain
insulin preparations should not be mixed. Similarly, the simultane-
ous administration of antacids or products high in metal content
may compromise the absorption of many drugs in the intestine,
eg, tetracyclines. The package insert and the Handbook on Inject-
able Drugs (see References) are good sources for this information.
E-PRESCRIBING
Seventy percent of prescriptions in the USA are now E-prescribed.
Congress has passed legislation related to E-prescribing, including
Medicare Improvement for Patients and Providers Act (MIPPA)
and the Medicare and Medicaid Electronic Health Record Incen-
tive Program or the “meaningful use program.” E-prescribing
provides an electronic flow of information between the prescriber,
intermediary, pharmacy, and health plan. The health plan can
provide information on patient eligibility, formulary, benefits,
costs, and sometimes, a medication history. The prescriber selects
the medication, strength, dosage form, quantity, and directions
for use and the prescription is transmitted to the pharmacy
where the appropriate data fields are populated. The pharmacist
reviews the order and, if appropriate, dispenses the prescription.
The electronic system must be Health Insurance Portability and
Accountability Act (HIPAA)-compliant, and there is often a
business association agreement between the parties involved.
Prescribers can obtain decision support information such as
disease-drug and drug-drug interaction information or cost infor-
mation prior to prescribing as part of the health plan information.
Prescriptions can be clear in their writing, but pull-down drug lists
can create new errors. Prescription renewals can be processed elec-
tronically and drug misuse or abuse may be identifiable. Theoretically,
time to process prescription orders should be reduced and patients
would have their medication ready when they arrive at the pharmacy.
The DEA has issued rules for e-prescribing of controlled
substances. Currently, only registered prescribers can e-prescribe,
and there will be several independent identification proofing
sources required: a unique pin number, or retinal scan, or a finger
print. The objective is to prevent drug diversion. DEA regis-
trants, including pharmacies and physicians, can order controlled
drugs via computer using a specific form once they are certified
(Controlled Substances Ordering System, CSOS).
COMPLIANCE
Compliance (also called adherence) is the extent to which
patients follow treatment instructions. There are four types
of noncompliance leading to medication errors and increased
health care costs as given below:
1. The patient fails to obtain the medication. Some studies sug-
gest that one third of patients never have their prescriptions
filled. Patients usually leave the hospital without obtaining
 CHAPTER 65  Rational Prescribing & Prescription Writing     1151
their discharge medications because the hospital is not reim-
bursed for them by the insurer; others leave the hospital
without having their prehospitalization medications resumed.
In many cases, patients cannot afford the medications
prescribed.
2. The patient fails to take the medication as prescribed. Examples
include wrong dosage, wrong frequency of administration,
improper timing or sequencing of administration, wrong route
or technique of administration, or taking medication for the
wrong purpose. This usually results from inadequate communi-
cation between the patient, the prescriber, and the pharmacist.
3. The patient prematurely discontinues the medication. This can
occur, for instance, if the patient incorrectly assumes that the
medication is no longer needed because the bottle is empty or
symptomatic improvement has occurred.
4. The patient (or another person) takes medication inappropri-
ately. For example, the patient may share a medication with
others for any of several reasons.
Several factors encourage noncompliance. Some diseases cause
no symptoms (eg, hypertension); patients with these diseases
therefore have no symptoms to remind them to take their medica-
tions. Patients with painful conditions such as arthritis may con-
tinually change medications in the hope of finding a better one.
Characteristics of the therapy itself can limit the degree of com-
pliance; patients taking a drug once a day are much more likely
to be compliant than those taking a drug four times a day. Vari-
ous patient factors also play a role in compliance. Patients living
alone are much less likely to be compliant than married patients
of the same age. Packaging may also be a deterrent to compli-
ance—elderly arthritic patients often have difficulty opening their
medication containers. Lack of transportation as well as various
cultural or personal beliefs about medications are likewise barriers
to compliance. For example, some parents refuse to allow their
children to be vaccinated because of a misguided fear of autism.
Strategies for improving compliance include enhanced com-
munication between the patient and health care team members;
assessment of personal, social, and economic conditions (often
reflected in the patient’s lifestyle); development of a routine for
taking medications (eg, at mealtimes if the patient has regular
meals); provision of systems to assist taking medications (ie, con-
tainers that separate drug doses by day of the week, or medication
alarm clocks that remind patients to take their medications); and
mailing of refill reminders by the pharmacist to patients taking
drugs chronically. The patient who is likely to discontinue a medi-
cation because of a perceived drug-related problem should receive
instruction about how to monitor and understand the effects of
the medication. Compliance can often be improved by enlisting
the patient’s active participation in the treatment.
LEGAL FACTORS (USA)
The United States government recognizes two classes of drugs:
(1) over-the-counter (OTC) drugs and (2) those that require a pre-
scription from a licensed prescriber (Rx Only). OTC drugs are those
that can be safely self-administered by the layman for self-limiting
conditions and for which appropriate labels can be written for lay
comprehension (see Chapter 63). Half of all drug doses consumed
by the American public are OTC drugs. In 2014 in the USA,
$373.9 billion was spent on prescription drugs and $30.7 billion
was spent on OTC drugs, more than any other country.
Physicians, dentists, podiatrists, and veterinarians—and, in
many states, specialized pharmacists, nurses, physician’s assistants,
and optometrists—are granted authority to prescribe certain
drugs (those bearing the federal legend statement, “Rx Only”)
on the basis of their training in diagnosis and treatment (see
Box: Who May Prescribe?). Depending on the state, mid-level
practitioners may prescribe/furnish prescriptions. Pharmacists
are authorized to dispense prescriptions pursuant to a prescriber’s
order provided that the medication order is appropriate and
rational for the patient. Nurses are authorized to administer
medications to patients subject to a prescriber’s order.
Because of the multiplicity of third-party payers (health insurers)
and Medicare and Medicaid claimants, the concept of electronic
processing of prescriptions (“e-prescribing”) has become urgent.
(Further information about e-prescribing may be found at http://
www.cms.gov/Medicare/E-Health/Eprescribing/.) To further stan-
dardize electronic prescription transmission and billing, the Centers
for Medicare and Medicaid (CMS) issued regulations effective in
2008 requiring all US health care providers to obtain a National
Provider Identification (NPI) number. This 10-digit identifier is
issued by the National Plan and Provider Enumeration System
(NPPES) at https://NPPES.cms.hhs.gov. The purpose of the NPI
is to identify all health care transactions (and associated costs)
incurred by a particular practitioner with a single number.
In addition to a health care provider’s unique identification
number, some states require that prescriptions for controlled
substances be written on tamper-resistant security prescription
forms. The purpose of this legislation is to prevent forgeries and
to tighten the control of prescription order forms.
The concept of a “secure” prescription form was expanded by the
federal government in 2008 to all prescriptions written for Medicaid
patients. Any prescription for a Medicaid patient must be written
on a security form if the pharmacist is to be compensated for the
prescription service. In turn, the use of “triplicate” prescription forms
was eliminated and replaced with an online electronic transmission
system whereby orders for Schedule II, Schedule III, and Schedule IV
prescriptions are transmitted to a company that acts as a repository
for these transactions. In California, it is called the CURES program
(Controlled Substances Utilization Review and Evaluation System).
Prescribers are provided with a record of who prescribed which con-
trolled drug to which patient. Additional information about CURES
may be found at http://oag.ca.gov/cures-pdmp.
In the USA, prescription drugs are controlled by the US Food
and Drug Administration (FDA) as described in Chapter 1. The
federal legend statement as well as the package insert are part of
the packaging requirements for all prescription drugs. The pack-
age insert is the official brochure setting forth the indications,
contraindications, warnings, and dosing for the drug.
The prescriber, by writing and signing a prescription order,
controls who may obtain prescription drugs. The pharmacist may
1152    SECTION X  Special Topics

Who May Prescribe?

The right to prescribe drugs has traditionally been the respon-
sibility of the physician, dentist, podiatrist, or veterinarian.
Prescribing now includes—in a number of states and in varying
degrees—pharmacists, nurse practitioners, nurse midwives, phy-
sician’s assistants, and optometrists (see below; Table 65–2). In
the future, physical therapists may be licensed to prescribe drugs
relevant to their practice. The development of large health main-
tenance organizations has greatly strengthened this expansion
of prescribing rights because it offers these extremely powerful
economic bodies a way to reduce their expenses.
The primary organizations controlling the privilege of
prescribing in the USA are the state boards, under the pow-
ers delegated to them by the state legislatures. Many state
boards have attempted to reserve some measure of the primary
responsibility for prescribing to physicians by requiring that the
ancillary professional work with or under a physician according
to a specific protocol. In the state of California, this protocol
must include a statement of the training, supervision, and docu-
mentation requirements of the arrangement and must specify
referral requirements, limitations to the list of drugs that may be
prescribed (ie, a formulary), and a method of evaluation by the
supervising physician. The protocol must be in writing and must
be periodically updated.
The following rules govern prescribing by nonphysicians in
the various states at the time of this writing.
In almost all states, nurse practitioners (NPs) and physician
assistants (PAs) may prescribe with or without physician supervi-
sion depending on the state. Likewise, optometrists may prescribe
selected formulary drugs for ophthalmologic indications.
Pharmacists can initiate prescriptions in three states: Montana,
New Mexico, and North Carolina. They may practice with physicians
in collaborative drug therapy management (CDTM) programs in
47 states—all except New York, Maine, Oklahoma, and Alabama.
Pharmacists may prescribe controlled substances under physician
supervision in California, Massachusetts, Montana, New Mexico,
North Carolina, Ohio, and Washington.
New Mexico grants prescribing authority to medical
psychologists with advanced training.

purchase these drugs, but they may be dispensed only on the order
of a legally qualified prescriber. Thus, a prescription is actually
three things: the prescriber’s order in the patient’s chart, the
written order to which the pharmacist refers when dispensing,
and the patient’s medication container with a label affixed.
Whereas the US FDA controls the drugs and their labeling and
distribution, the state legislatures control who may prescribe drugs
through their licensing boards, eg, the Board of Medical Examin-
ers. Prescribers must pass examinations, pay fees, and—in the case
of some states and some professions—meet other requirements for

TABLE 65–2  Prescribing authority of certain allied health professionals in selected states.
Physician’s
State Pharmacists Nurse Practitioners Assistants Optometrists
1 2
California Yes, under protocol ; must be trained in clinical Yes Yes, under Yes; limited to certain drug classes
practice protocol1
2
Florida Yes, according to state formulary; protocol not Yes Yes2 Yes; limited to certain drug classes
required
2
Michigan Yes, under protocol; must be specially qualified by Yes Yes2 Yes; limited to certain drug classes
education, training, or experience
2
Mississippi Yes, under protocol in an institutional setting Yes, under narrowly No Yes; limited to certain drug classes
specified conditions
2
Nevada Yes, under protocol, within a licensed medical facility Yes Yes2 Yes; limited to certain drug classes
New Yes, under protocol, must be “pharmacist clinician” Yes; do not need Yes2 Yes; limited to certain drug classes
Mexico physician supervision
2
North Yes, under protocol in an institutional setting Yes; do not need Yes Yes; limited to certain drug classes
Dakota physician supervision
2
Oregon Yes, under guidelines set by the state board Yes; do not need Yes Yes; limited to certain drug classes
physician supervision
Texas Yes, under protocol set for a particular patient in an Yes; do not need Yes Yes; limited to certain drug classes
institutional setting physician supervision
2
Washington Yes, under guidelines set by the state board Yes; do not need Yes Yes; limited to certain drug classes
physician supervision
1
Under protocol; see Box: Who May Prescribe?
2
In collaboration with or under the supervision of a physician.
 CHAPTER 65  Rational Prescribing & Prescription Writing     1153
TABLE 65–3  Classification of controlled substances.
(See Inside Front Cover for examples.)
Potential
Schedule for Abuse Other Comments
I High No accepted medical use; lack of
accepted safety as drug.
II High Current accepted medical use. Abuse
may lead to psychological or physical
dependence.
III Less than I Current accepted medical use.
or II Moderate or low potential for physical
dependence and high potential for
psychological dependence.
IV Less than III Current accepted medical use. Limited
potential for dependence.
V Less than IV Current accepted medical use. Limited
dependence possible.
relicensure such as continuing education. If these requirements are
met, the prescriber is licensed to order dispensing of drugs.
The FDA Amendments Act of 2007 gave the FDA authority
to require a Risk Evaluation and Mitigation Strategy (REMS)
from manufacturers to ensure that the benefits of a drug or bio-
logical product outweigh its risks. The goal of this strategy is to
inform physicians of the emphasized risks and benefits. Further-
more, some drugs have “boxed warnings” to elucidate their risks
as part of FDA-mandated labeling.
The federal government and the states further impose special
restrictions on drugs according to their perceived potential for
abuse (Table 65–3). Such drugs include opioids, hallucinogens,
stimulants, depressants, and anabolic steroids. Special require-
ments must be met when these drugs are to be prescribed. The
Controlled Drug Act requires prescribers and dispensers to register
with the Drug Enforcement Agency (DEA), pay a fee, receive a
personal registration number, and keep records of all controlled
drugs prescribed or dispensed. Every time a controlled drug is
prescribed, a valid DEA number must appear on the prescrip-
tion. In the USA, there is an opioid epidemic with an increase in
overdoses. To combat this public health trend, prescriber educa-
tion, tracking of prescribing patterns, limitations on amounts
prescribed, and target education are being instituted.
Prescriptions for substances with a high potential for abuse
(Schedule II drugs) cannot be refilled without a new prescription.
However, multiple prescriptions for the same drug may be written
with instructions not to dispense before a certain date and up to
a total of 90 days. Prescriptions for Schedules III, IV, and V can
be refilled if ordered, but there is a five-refill maximum, and in no
case may the prescription be refilled after 6 months from the date
of writing. Schedule II drug orders may not be transmitted over
the telephone, and some states require a tamper-resistant security
prescription blank to reduce the chances for drug diversion.
These restrictive prescribing laws are intended to limit the
amount of drugs of abuse that are made available to the public.
Unfortunately, the inconvenience occasioned by these laws—
and an unwarranted fear by medical professionals themselves
regarding the risk of patient tolerance and addiction—continues
to hamper adequate treatment of patients with terminal condi-
tions. This has been shown to be particularly true in children and
elderly patients with cancer. There is no excuse for inadequate treat-
ment of pain in a terminal patient; not only is addiction irrelevant
in such a patient, it is actually uncommon in patients who are being
treated for pain (see Chapter 31). Unfortunately, the initiative
begun several years ago to manage pain more actively has led to
the overuse of opioids in patients with chronic pain, a condition
that does not respond well to these drugs. Chronic use of oxy-
codone, hydrocodone, and methadone has resulted in a marked
increase in habituation, overdoses, and deaths. As a result, most
professional authorities now advise limiting the use of any opioid
to acute pain only and the use of NSAIDs and other nonaddicting
therapies in chronic conditions.
Some states have recognized the underutilization of pain
medications in the treatment of pain associated with chronic and
terminal conditions. In California, upon receipt of a copy of the
order from the prescriber, eg, by fax, a pharmacist may write a pre-
scription for a Schedule II substance for a patient under hospice
care or living in a skilled nursing facility or in cases in which the
patient is expected to live less than 6 months, provided that the
prescriber countersigns the order (by fax); the word “exemption”
with regulatory code number is written on a typical prescription,
thus providing easier access for the terminally ill.
Labeled & Off-Label Uses of Drugs
In the USA, the FDA approves a drug only for the specific uses
proposed and documented by the manufacturer in its New Drug
Application (see Chapter 1). These approved (labeled) uses or indi-
cations are set forth in the package insert that accompanies the drug.
For a variety of reasons, these labeled indications may not include all
the conditions in which the drug might be useful. Therefore, a cli-
nician may wish to prescribe the agent for some other, unapproved
(off-label), clinical condition, often on the basis of adequate or even
compelling scientific evidence. Federal laws governing FDA regula-
tions and drug use place no restrictions on such unapproved use.*
Even if the patient suffers injury from the drug, its use for
an unlabeled purpose does not in itself constitute “malpractice.”
However, the courts may consider the package insert labeling as a
complete listing of the indications for which the drug is consid-
ered safe unless the clinician can show that other use is considered
safe by competent expert testimony.
Drug Safety Surveillance
Governmental drug-regulating agencies have responsibility for mon-
itoring drug safety. In the USA, the FDA-sponsored Med Watch
program collects data on safety and adverse drug effects (ADEs)
*
“Once a product has been approved for marketing, a physician may
prescribe it for uses or in treatment regimens or patient populations that
are not included in the approved labeling. Such ‘unapproved’ or, more
precisely, ‘unlabeled’ uses may be appropriate and rational in certain
circumstances, and may, in fact, reflect approaches to drug therapy that
have been extensively reported in medical literature.”–FDA Drug Bull
1982;12:4.
1154    SECTION X  Special Topics
through mandatory reporting by drug manufacturers and vol-
untary reporting by health care practitioners. Practitioners may
submit reports on any suspected adverse drug (or medical device)
effect using a simple form obtainable from http://www.fda.gov/
medwatch/index.html. The FDA is expected to use these data to
establish an adverse effect rate. It is not clear that the FDA has suf-
ficient resources at present to carry out this mandate, but they are
empowered to take further regulatory actions if deemed necessary.
A similar vaccine-reporting program is in place to monitor vaccine
safety (VAERS, vaccine adverse event reporting system). The FDA
homepage can be found at https://vaers.hhs.gov.
The FDA has also increased requirements for labeling on drugs
that carry special risks. Dispensers of medications are required to
distribute “Med Guides” to patients when these medications are
dispensed. These guides are generated by the manufacturers of the
medications. In addition, pharmacists often provide patient edu-
cational materials that describe the drug, its use, adverse effects,
storage requirements, methods of administration, what to do
when a dose is missed, and the potential need for ongoing therapy.
SOCIOECONOMIC FACTORS
The Cost of Prescriptions
Multiple factors are involved in the pricing of pharmaceuticals.
Research costs, marketing costs, production costs, shipping costs,
regulatory costs, and profit all contribute to a drug’s price. Insur-
ance companies pay for the drug because an extensive formulary
is mandated by regulations. Federal law and regulations require
Medicare Part D pharmacy and therapeutics committees to make
prescription drug coverage decisions based on scientific evidence
and standards of practice, and also to prevent discrimination in
a patient’s drug therapy. Because these companies are publicly
owned, the shareholders exert a strong influence to maximize
profits. While the cost to make the drug may be 20% (or less)
of the wholesale price, the aforementioned costs contribute to
the cost of the drug to the pharmacist or physician. Greed and
the excessive influence of shareholder funds (as opposed to the
interests of consumers) add another component of cost and have
sometimes resulted in startling increases in the price of long-
established drugs (which have no current development costs)
as well as newer ones. In the case of pyrimethamine, a simple
and long-established drug used for toxoplasmosis, the US price
increased from approximately $13/tablet to $750/tablet in 2015
when a new company acquired the rights to this drug. In 2016,
the price of the formulation of epinephrine most commonly used
for anaphylaxis (Epi-Pen) increased from $50 to $300 per single
dose, even though no changes were made in the drug, the vehicle,
or the injection unit.
A more complex situation applies to the pricing of new, com-
plex molecules that, unlike the above examples, required massive
research, development, and manufacturing investment, eg, the
new agents used for hepatitis B and C. These agents are extremely
expensive in the USA ($75,000–$120,000 for one course of treat-
ment), but the manufacturers justify the cost as being less than
the alternative (which is often a liver transplant). In fact, these
“specialty drugs” represent one third of the drug spending in the
USA.
Because the US Congress currently prohibits price negotiations
by the largest purchaser of drugs (Medicare), the public has no
protection from excessive pricing by manufacturers. Currently,
only the Veteran’s Administration and the largest private pharmacy
benefits manager (PBM) agencies are able to negotiate prices, and
as a result, drug expenses constitute a large and growing burden to
patients, Medicare, and private health insurers.
Generic Prescribing
Generic drug dispensing represents 10% of the total US drug
expense but 90% of the drugs dispensed. Prescribing by generic
name offers the pharmacist flexibility in selecting the particular
drug product to fill the order and offers the patient a potential
savings when there is price competition. For example, the brand
name of a popular sedative is Valium. The generic (public non-
proprietary) name of the same chemical substance adopted by
United States Adopted Names (USAN) and approved by the FDA
is diazepam. All diazepam drug products in the USA meet the
pharmaceutical standards expressed in the United States Pharma-
copeia (USP). However, there are several manufacturers, and prices
vary. For drugs in common use, the difference in cost between the
trade-named product and generic products varies from less than
twofold to more than 100-fold. For drugs with a limited market
(eg, pyrimethamine, Epi-Pen), the incentive for generic manufac-
turing and marketing is very low, so only one or two generics (or
none) may be available, and price competition is low or absent.
In most states and in most hospitals, pharmacists have the
option of supplying a generically equivalent drug product even if a
proprietary name has been specified in the order. If the prescriber
wants a particular brand of drug product dispensed, handwritten
instructions to “dispense as written” or words of similar meaning
are required. Some government-subsidized health care programs
and many third-party insurance payers require that pharmacists
dispense the cheapest generically equivalent product in the inven-
tory (generic substitution). However, the principles of drug prod-
uct selection by private pharmacists do not permit substituting
one therapeutic agent for another (therapeutic substitution); that
is, dispensing trichlormethiazide for hydrochlorothiazide would
not be permitted without the prescriber’s permission even though
these two diuretics may be considered pharmacodynamically
equivalent. Pharmacists within managed care organizations may
follow different policies; see below.
It cannot be assumed that every generic drug product is as
satisfactory as the trade-named product, although examples of
unsatisfactory generics are rare. Bioavailability—the effective
absorption of the drug product—varies between manufacturers
and sometimes between different lots of a drug produced by the
same manufacturer. Despite the evidence, many practitioners
avoid generic prescribing, thereby increasing medical costs. In the
case of a very small number of drugs, which usually have a low
therapeutic index, poor solubility, or a high ratio of inert ingredi-
ents to active drug content, a specific manufacturer’s product may
give more consistent results. In the case of life-threatening diseases,
 CHAPTER 65  Rational Prescribing & Prescription Writing     1155
the advantages of generic substitution may be outweighed by the
clinical urgency so that the prescription should be filled as written.
In an effort to codify bioequivalence information, the FDA
publishes Approved Drug Products with Therapeutic Equivalence
Evaluations, with monthly supplements, commonly called “the
Orange Book.” The book contains listings of multisource prod-
ucts in one of two categories: Products given a code beginning
with the letter “A” are considered bioequivalent to a reference
standard formulation of the same drug and to all other versions of
that product with a similar “A” coding. Products not considered
bioequivalent are coded “B.” Of the approximately 8000 products
currently listed, 90% are coded “A.” Additional code letters and
numerals are appended to the initial “A” or “B” and indicate the
approved route of administration and other variables.
Mandatory drug product selection on the basis of price is
common practice in the USA because third-party payers (insur-
ance companies, health maintenance organizations, etc) enforce
money-saving regulations. If outside a managed care organization,
the prescriber can sometimes override these controls by writing
“dispense as written” on a prescription that calls for a brand-
named product. However, in such cases, the patient may have to
pay the difference between the dispensed product and the cheaper
one.
Within most managed care organizations, formulary controls
have been put in place that force the selection of less expensive
medications whenever they are available. In a managed care envi-
ronment, the prescriber often selects the drug group rather than
a specific agent, and the pharmacist dispenses the formulary drug
REFERENCES
Aiken M, IMS Institute for Health Care Informatics: Medicines use and spend-
ing shifts: A review of the use of medicines in the U.S. in 2014. http://
www.imshealth.com/en/thought-leadership/quintilesims-institute/reports/
medicines-use-in-the-us-2014.
Allen L Jr: Remington’s The Science and Practice of Pharmacy, 22nd ed. Pharmaceuti-
cal Press, 2012.
American Pharmacists Association and The National Association of Chain Drug
Stores: MTM in Pharmacy Practice, Core Elements v. 2, 2008.
Bell D: A toolset for e-prescribing implementation. Rand Health, US AHRQ,
2011.
California Business and Professions Code, Chapter 9, Division 2, Pharmacy Law.
Department of Consumer Affairs, Sacramento, California, 2016.
Consumer Healthcare Products Association: OTC Retail Sales 1964-2015. http://
chpa.org/OTCRetailSales.aspx.
de Oliveira, DJ, Brummel AR, Miller DR: Medication therapy management:
10 years of experience in a large integrated health system. J Managed Care
Pharm 2010;3:185.
Department of Health and Human Services: About the (opioid) epidemic. https://
www.hhs.gov/opioids/about-the-epidemic/.
from that group. For example, if a prescriber in such an organiza-
tion decides that a patient needs a thiazide diuretic, the pharmacist
automatically dispenses the single thiazide diuretic carried on the
organization’s formulary. As noted below, the choice of drugs for the
organization’s formulary may change from time to time, depending
on negotiation of prices and rebates with different manufacturers.
Other Cost Factors
The private pharmacy bases its charges on the cost of the drug plus
a fee for providing a professional service. Each time a prescription
is dispensed, there is a fee. The prescriber controls the frequency of
filling prescriptions by authorizing refills and specifying the quan-
tity to be dispensed. However, for medications used for chronic
illnesses, the quantity covered by insurance may be limited to the
amount used in 1 month or 30 days. Thus, the prescriber can save
the patient money by prescribing standard sizes (so that drugs
do not have to be repackaged) and, when chronic treatment is
involved, by ordering the largest quantity consistent with safety,
expense, and third-party plan. Optimal prescribing for cost sav-
ings often involves consultation between the prescriber and the
pharmacist. Because of continuing increases in the wholesale
prices of drugs in the USA, prescription costs have risen dra-
matically over the past three decades, and with the passage of the
Affordable Care Act (ACA), prescription volume increased while
hospital services decreased.
Drug Enforcement Administration: Mid-Level Practitioners Authorized by State,
Title 21, Code of Federal Regulations, Section 1300.01 (b28), 5-24-16.
Gabriel MH: E-Prescribing Trends in the US, ONC Data Brief, 18, July, 2014.
Graber MA, Easton-Carr R: Poverty and pain: Ethics and the lack of opioid pain
medications in fixed-price, low-cost prescription plans. Ann Pharmacother
2008;42:1913.
Institute for Safe Medication Practices. http://www.ismp.org.
Jerome JB, Sagan P: The USAN nomenclature system. JAMA 1975;232:294.
Kesselheim AS, Avorn J, Sarpatwari JD: The high cost of prescription drugs in
the United States. Origins and prospects for reform. JAMA 2016;316:858.
Kesselheim AS et al: Clinical equivalence of generic and brand-name drugs used
in cardiovascular disease: A systematic review and meta-analysis. JAMA
2008;300:2514.
Levinson DR. Gaps in Oversight of Conflicts of Interest in Medicare Prescription
Drug Decisions, DHHS, Office of Inspector General, March, 2013. https://
oig.hhs.gov/oei/reports/oei-05-10-00450.pdf.
Schnipper JL et al: Role of pharmacist counseling in preventing adverse drug
events after hospitalization. Arch Intern Med 2006;166:565.
Trissel LA: Handbook on Injectable Drugs, 19th ed. American Society of Hospital
Pharmacists, 2016.
 66
C H A P T E R
Important Drug
Interactions & Their
Mechanisms
John R. Horn, PharmD, FCCP
One of the factors that can alter the response to drugs is the con-
current administration of other drugs. There are several mecha-
nisms by which drugs may interact, but most can be categorized
as pharmacokinetic (absorption, distribution, metabolism, excre-
tion), pharmacodynamic (additive, synergistic, or antagonistic
effects), or combined interactions. The general principles of
pharmacokinetics are discussed in Chapters 3 and 4; the general
principles of pharmacodynamics are discussed in Chapter 2.
Botanical medications (“herbals”) may interact with each other
or with conventional drugs. Unfortunately, botanicals are much
less well studied than other drugs, so information about their
interactions is scanty. Pharmacodynamic herbal interactions are
described in Chapter 64. Pharmacokinetic interactions that have
been documented (eg, St. John’s wort) are listed in Table 66–1.
Knowledge of the mechanism by which a given drug interac-
tion occurs is often clinically useful, since the mechanism may
influence both the time course and the methods of circumventing
the interaction. Some important drug interactions occur as a result
of two or more mechanisms.
■■ PREDICTABILITY OF DRUG
INTERACTIONS
The designations listed in Table 66–1 are used here to estimate
the predictability of the drug interactions. These estimates are
intended to indicate simply whether or not the interaction will
occur, and they do not always mean that the interaction is likely to
produce an adverse effect. Whether or not the interaction occurs
(precipitant drug produces a measurable change in the object drug
action) and produces an adverse effect depends on both patient-
and drug-specific factors. Patient factors can include intrinsic
drug clearance, genetics, gender, concurrent diseases, and diet.
1156
Drug-specific factors include dose, route of administration, drug
formulation, and the sequence of drug administration. The most
important factor that can mitigate the risk of patient harm is rec-
ognition by the prescriber of a potential interaction followed by
appropriate action.
PHARMACOKINETIC MECHANISMS
The gastrointestinal absorption of drugs may be affected by
concurrent use of other agents that (1) have a large surface
area upon which the drug can be adsorbed, (2) bind or chelate,
(3) alter gastric pH, (4) alter gastrointestinal motility, or
(5) affect transport proteins such as P-glycoprotein and organic
anion transporters. One must distinguish between effects on
absorption rate and effects on extent of absorption. A reduction
in only the absorption rate of a drug is seldom clinically impor-
tant, whereas a reduction in the extent of absorption is clinically
important if it results in subtherapeutic serum concentrations.
Similarly, an increase in the extent of absorption can lead to
adverse patient outcomes.
The mechanisms by which drug interactions alter drug
distribution include (1) competition for plasma protein binding,
(2) displacement from tissue binding sites, and (3) alterations in
local tissue barriers, eg, P-glycoprotein inhibition in the blood-
brain barrier. Although competition for plasma protein binding
can increase the free concentration (and thus the effect) of the
displaced drug in plasma, the increase will be transient owing to
a compensatory increase in drug disposition. The clinical impor-
tance of protein binding displacement has been overemphasized;
current evidence suggests that such interactions are unlikely to
result in adverse effects. Displacement from tissue binding sites
would tend to transiently increase the blood concentration of the
displaced drug. (Text continues on page 1171.)

TABLE 66–1  Important drug interactions.
Drug or Properties Promoting
Drug Group Drug Interaction
Acid-reducing Antacids may adsorb drugs in
agents gastrointestinal tract, thus reduc-
ing absorption. Some antacids (eg,
magnesium hydroxide with alumi-
num hydroxide) alkalinize the urine
somewhat, thus altering excretion
of drugs sensitive to urinary pH.
H2-antagonists and proton-pump
inhibitors can alter the absorption
of drugs requiring gastric acidity for
dissolution.
Alcohol Chronic alcoholism results in
enzyme induction. Acute alcoholic
intoxication tends to inhibit drug
metabolism (whether person is
alcoholic or not). Severe alcohol-
induced hepatic dysfunction may
inhibit ability to metabolize drugs.
Disulfiram-like reaction in the
presence of certain drugs. Additive
central nervous system depression
with other central nervous system
depressants.
Allopurinol Inhibits hepatic drug-metabolizing
enzymes. Febuxostat will also inhibit
the metabolism of azathioprine and
mercaptopurine.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
CHAPTER 66  Important Drug Interactions & Their Mechanisms     1157
Clinically Documented Interactions
Antivirals: [P] Decreased absorption of antivirals that require acid for dissolution
including atazanavir, fosamprenavir, indinavir, nelfinavir, rilpivirine.
Azole antifungals: [P] Reduced gastrointestinal absorption of itraconazole,
ketoconazole, and posaconazole due to increased gastric pH.
Digoxin: [NP] Decreased gastrointestinal absorption of digoxin.
Iron: [P] Decreased gastrointestinal absorption of iron with calcium-containing
antacids.
Kinase inhibitors: [P] Reduced gastrointestinal absorption of bosutinib, dabrafenib,
dasatinib, erlotinib, idelalisib, and lapatinib due to increased gastric pH.
Quinolones: [HP] Decreased gastrointestinal absorption of ciprofloxacin, norfloxacin,
and enoxacin (and probably other quinolones).
Rosuvastatin: [P] Decreased absorption of rosuvastatin.
Salicylates: [P] Increased renal clearance of salicylates due to increased urine pH;
occurs only with large doses of salicylates.
Tetracyclines: [HP] Decreased gastrointestinal absorption of tetracyclines.
Thyroxine: [NP] Reduced gastrointestinal absorption of thyroxine.
Acetaminophen: [NE] Increased formation of hepatotoxic acetaminophen metabolites
(in chronic alcoholics).
Acitretin: [P] Increased conversion of acitretin to etretinate (teratogenic).
Anticoagulants, oral: [NE] Increased hypoprothrombinemic effect with acute alcohol
intoxication.
Central nervous system depressants: [HP] Additive or synergistic central nervous
system depression.
Insulin: [NE] Acute alcohol intake may increase hypoglycemic effect of insulin
(especially in fasting patients).
Drugs that may produce a disulfiram-like reaction:
Cephalosporins: [NP] Disulfiram-like reactions are noted with cefamandole,
cefoperazone, cefotetan, and moxalactam.
Chloral hydrate: [NP] Mechanism not established.
Disulfiram: [HP] Inhibited aldehyde dehydrogenase.
Metronidazole: [NP] Mechanism not established.
Sulfonylureas: [NE] Chlorpropamide is most likely to produce a disulfiram-like
reaction; acute alcohol intake may increase hypoglycemic effect (especially in fasting
patients).
Anticoagulants, oral: [NP] Increased hypoprothrombinemic effect.
Azathioprine: [P] Decreased azathioprine detoxification resulting in increased
azathioprine toxicity.
Mercaptopurine: [P] Decreased mercaptopurine metabolism resulting in increased
mercaptopurine toxicity.
(continued )
1158    SECTION X  Special Topics
TABLE 66–1  Important drug interactions. (Continued)
Drug or Properties Promoting
Drug Group Drug Interaction
Anticoagulants, Susceptible to induction and
oral inhibition of CYP2C9 (warfarin),
CYP3A4 (apixaban, rivaroxaban),
and P-glycoprotein (apixaban,
dabigatran, edoxaban, rivaroxaban).
Warfarin highly bound to plasma
proteins. Anticoagulation response
altered by drugs that affect clotting
factor synthesis or catabolism.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
Clinically Documented Interactions
  Drugs that may increase anticoagulant effect:
Acetaminophen: [NE] Impaired synthesis of clotting factors at higher doses.
Amiodarone: [P] Inhibited anticoagulant elimination.
Anabolic steroids: [P] Altered clotting factor disposition?
Azole antifungals: [P] Ketoconazole, itraconazole, voriconazole, and posaconazole can
decrease apixaban, dabigatran, edoxaban, rivaroxaban, and perhaps warfarin elimination.
Cimetidine: [HP] Decreased warfarin metabolism.
Clopidogrel: [NP] Decreased warfarin metabolism and inhibits platelet function.
Disulfiram: [P] Decreased warfarin metabolism.
Efavirenz: [NP] Decreased warfarin metabolism.
Fluconazole: [P] Decreased warfarin metabolism.
Fluoxetine: [P] Decreased warfarin metabolism.
Gemfibrozil: [NE] Mechanism not established.
Lovastatin: [NP] Decreased warfarin metabolism.
Macrolide antibiotics: [NP] Clarithromycin and erythromycin inhibit the metabolism
of oral anticoagulants.
Metronidazole: [P] Decreased warfarin metabolism.
Miconazole: [NE] Decreased warfarin metabolism.
Nonsteroidal anti-inflammatory drugs (NSAIDs): [HP] Inhibition of platelet function,
gastric erosions; some agents increase hypoprothrombinemic response (unlikely with
diclofenac, ibuprofen, or naproxen).
Propafenone: [NE] Probably decreases anticoagulant elimination.
Quinidine: [NP] Additive hypoprothrombinemia, decreased apixaban, dabigatran,
edoxaban, rivaroxaban elimination.
Ritonavir: [P] Decreased apixaban, dabigatran, edoxaban, rivaroxaban elimination.
Salicylates: [HP] Platelet inhibition with aspirin but not with other salicylates; [P] large
doses have hypoprothrombinemic effect.
Simvastatin: [NP] Decreased warfarin metabolism.
Sulfinpyrazone: [NE] Inhibited warfarin metabolism.
Sulfonamides: [NE] Inhibited warfarin metabolism.
Trimethoprim-sulfamethoxazole: [P] Decreased warfarin metabolism.
Verapamil: [P] Decreased apixaban, dabigatran, edoxaban, rivaroxaban elimination.
See also Alcohol; Allopurinol.
  Drugs that may decrease anticoagulant effect:
Aminoglutethimide: [P] Increased metabolism of anticoagulant.
Barbiturates: [P] Increased metabolism of anticoagulant.
Bosentan: [P] Increased metabolism of anticoagulant.
Carbamazepine: [P] Increased elimination of anticoagulant.
Cholestyramine: [P] Reduced absorption of anticoagulant.
Nafcillin: [NE] Increased metabolism of anticoagulant.
(continued )

TABLE 66–1  Important drug interactions.
Drug or Properties Promoting
Drug Group Drug Interaction
Anticoagulants,
oral (cont.)
Antidepressants, Inhibition of transmitter uptake into
tricyclic and 5-HT and NE neurons. Antimuscarinic
heterocyclic effects may be additive with other
antimuscarinic drugs. Susceptible to
induction and inhibition of metabo-
lism via CYP2D6, CYP3A4, and other
CYP450 enzymes.
Azole Inhibition of CYP3A4
antifungals (itraconazole = ketoconazole >
posaconazole > voriconazole >
fluconazole). Inhibition of CYP2C9
(fluconazole, voriconazole).
Inhibition of P-glycoprotein
(itraconazole, ketoconazole,
posaconazole). Susceptible to
enzyme inducers (itraconazole,
ketoconazole, voriconazole).
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
CHAPTER 66  Important Drug Interactions & Their Mechanisms     1159
Clinically Documented Interactions
Phenytoin: [NE] Increased metabolism of anticoagulant. Anticoagulant effect may increase
transiently at start of phenytoin therapy due to protein-binding displacement of warfarin.
Primidone: [P] Increased metabolism of anticoagulant.
Rifabutin: [P] Increased elimination of anticoagulant.
Rifampin: [P] Increased elimination of anticoagulant.
St. John’s wort: [NE] Increased elimination of anticoagulant.
Tipranavir: [NP] Increased elimination of apixaban, dabigatran, edoxaban, rivaroxaban.
Amiodarone: [P] Decreased antidepressant metabolism. Expect similar interactions
with dronedarone.
Barbiturates: [P] Increased antidepressant metabolism.
Bupropion: [NE] Decreased antidepressant metabolism.
Carbamazepine: [NP] Enhanced metabolism of antidepressants.
Cimetidine: [P] Decreased antidepressant metabolism.
Clonidine: [P] Decreased clonidine antihypertensive effect.
Diphenhydramine: [P] Decreased metabolism of antidepressants metabolized by CYP2D6.
Guanadrel: [P] Decreased uptake of guanadrel into sites of action.
Haloperidol: [P] Decreased metabolism of antidepressants metabolized by CYP2D6.
Monoamine oxidase inhibitors (MAOIs): [NP] Some cases of excitation, hyperpyrexia,
mania, and convulsions, especially with serotonergic antidepressants such as clomipramine
and imipramine, but many patients have received combination without ill effects.
Quinidine: [NP] Decreased metabolism of antidepressants metabolized by CYP2D6.
Rifampin: [P] Increased antidepressant metabolism.
Selective serotonin reuptake inhibitors (SSRIs): [P] Fluoxetine and paroxetine inhibit
CYP2D6 and decrease metabolism of antidepressants metabolized by this enzyme
(eg, desipramine). Citalopram, sertraline, and fluvoxamine are only weak inhibitors
of CYP2D6, but fluvoxamine inhibits CYP1A2 and CYP3A4 and thus can inhibit the
metabolism of antidepressants metabolized by these enzymes.
Sympathomimetics: [P] Increased pressor response to norepinephrine, epinephrine,
and phenylephrine.
Terbinafine: [P] Decreased antidepressant metabolism.
Antivirals: [P] Decreased metabolism of amprenavir, atazanavir, boceprevir, daclatasvir,
darunavir, delavirdine, etravirine, fosamprenavir, indinavir, lopinavir, maraviroc,
nelfinavir, rilpivirine, ritonavir, saquinavir, and tipranavir.
Barbiturates: [P] Increased metabolism of itraconazole, ketoconazole, voriconazole.
Benzodiazepines: [P] Decreased metabolism of alprazolam, midazolam, triazolam.
Calcium channel blockers: [P] Decreased calcium channel blocker metabolism.
Carbamazepine: [P] Decreased carbamazepine metabolism. Potential increased
metabolism of itraconazole, ketoconazole, and voriconazole.
Cisapride: [NP] Decreased metabolism of cisapride.
Colchicine: [P] Decreased metabolism and transport of colchicine.
Cyclosporine: [P] Decreased elimination of cyclosporine.
Digoxin: [NE] Increased plasma concentrations of digoxin with itraconazole,
posaconazole, and ketoconazole.
(continued )
1160    SECTION X  Special Topics

TABLE 66–1  Important drug interactions.

Drug or Properties Promoting
Drug Group Drug Interaction Clinically Documented Interactions

Azole Eplerenone: [P] Decreased metabolism of eplerenone.

antifungals
(cont.)
Barbiturates Induction of hepatic microsomal
drug metabolizing enzymes and
P-glycoprotein. Additive central
nervous system depression with
other central nervous system
depressants.
Ergot alkaloids: [P] Decreased metabolism of ergot alkaloids.
HMG-CoA reductase inhibitors: [HP] Decreased metabolism of lovastatin, simvastatin,
and, to a lesser extent, atorvastatin.
Opioid analgesics: [P] Decreased elimination of alfentanil, fentanyl, methadone,
oxycodone, and sufentanil.
Quinidine: [P] Decreased metabolism of quinidine.
Phenytoin: [P] Decreased metabolism of phenytoin with fluconazole and probably
voriconazole.
Phosphodiesterase inhibitors: [P] Decreased metabolism of phosphodiesterase inhibitor.
Pimozide: [NE] Decreased pimozide metabolism.
Rifabutin: [P] Decreased rifabutin metabolism. Increased metabolism of itraconazole,
ketoconazole, and voriconazole.
Rifampin: [P] Increased metabolism of itraconazole, ketoconazole, and voriconazole.
Sirolimus: [P] Decreased elimination of sirolimus.
Tacrolimus: [P] Decreased elimination of tacrolimus.
See also Acid-Reducing Agents; Anticoagulants, oral.
Antivirals: Increased metabolism of antivirals amprenavir, atazanavir, boceprevir,
darunavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir,
simeprevir, and telaprevir with barbiturates.
Beta-adrenoceptor blockers: [P] Increased β-blocker metabolism.
Calcium channel blockers: [P] Increased calcium channel blocker metabolism.
Central nervous system depressants: [HP] Additive central nervous system depression.
Corticosteroids: [P] Increased corticosteroid metabolism.
Cyclosporine: [NE] Increased cyclosporine metabolism.
Doxycycline: [P] Increased doxycycline metabolism.
Estrogens: [P] Increased estrogen metabolism.
Kinase inhibitors: [P] Increased metabolism of axitinib, bosutinib, ceritinib, cabozantinib,
cobimetinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, ibrutinib, idelalisib, imatinib,
ixazomib, lapatinib, nilotinib, nintedanib, olaparib, osimertinib, palbociclib, pazopanib,
ponatinib, regorafenib, ruxolitinib, sunitinib, tofacitinib, vandetanib, vemurafenib.
Methadone: [NE] Increased methadone metabolism.
Opioid analgesics: [P] Increased elimination of alfentanil, fentanyl, methadone,
oxycodone, and sufentanil.
Phenothiazine: [P] Increased phenothiazine metabolism.
Phenytoin: [P] Increased phenytoin metabolism.
Quinidine: [P] Increased quinidine metabolism.
Sirolimus: [NE] Increased sirolimus metabolism.
Tacrolimus: [NE] Increased tacrolimus metabolism.
Theophylline: [NE] Increased theophylline metabolism.
Valproic acid: [P] Decreased phenobarbital metabolism.
See also Anticoagulants, oral; Antidepressants, tricyclic.

E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
(continued )

TABLE 66–1  Important drug interactions.
Drug or Properties Promoting
Drug Group Drug Interaction
Beta- Beta blockade (especially with
adrenoceptor noncardioselective agents such
blockers as propranolol) alters response to
sympathomimetics with β-agonist
activity (eg, epinephrine, albuterol).
Beta blockers that undergo
extensive first-pass metabolism
may be affected by drugs capable of
altering this process.
Bile acid- Resins may bind with orally adminis-
binding resins tered drugs in gastrointestinal tract.
Resins may bind in gastrointestinal
tract with drugs that undergo
enterohepatic circulation, even if
the latter are given parenterally.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
CHAPTER 66  Important Drug Interactions & Their Mechanisms     1161
Clinically Documented Interactions
  Drugs that may increase β-blocker effect:
Amiodarone: [P] Decreased metabolism of β blockers metabolized by CYP2D6
(timolol, propranolol, nebivolol, metoprolol, carvedilol). Enhanced effects on myocar-
dial conduction. Expect similar interactions with dronedarone.
Cimetidine: [P] Decreased metabolism of β blockers that are cleared primarily by the
liver, eg, propranolol. Less effect (if any) on those cleared by the kidneys, eg, atenolol,
nadolol.
Diphenhydramine: [P] Decreased metabolism of β blockers metabolized by CYP2D6
(timolol, propranolol, nebivolol, metoprolol, carvedilol).
Haloperidol: [P] Decreased metabolism of β blockers metabolized by CYP2D6 (timolol,
propranolol, nebivolol, metoprolol, carvedilol).
Quinidine: [P] Decreased metabolism of β blockers metabolized by CYP2D6 (timolol,
propranolol, nebivolol, metoprolol, carvedilol).
Selective serotonin reuptake inhibitors (SSRIs): [P] Fluoxetine and paroxetine
inhibit CYP2D6 and increase concentrations of timolol, propranolol, metoprolol,
carvedilol, and nebivolol.
Terbinafine: [P] Decreased metabolism of β blockers metabolized by CYP2D6 (timolol,
propranolol, nebivolol, metoprolol, carvedilol).
  Drugs that may decrease β-blocker effect:
Nonsteroidal anti-inflammatory drugs (NSAIDs): [P] Indomethacin reduces
antihypertensive response; other prostaglandin inhibitors probably also interact.
Effects of β blockers on other drugs:
Clonidine: [NE] Hypertensive reaction if clonidine is withdrawn; this is more likely to
occur with non-cardioselective beta blockers.
Insulin: [P] Inhibition of glucose recovery from hypoglycemia; inhibition of
symptoms of hypoglycemia (except sweating); increased blood pressure during
hypoglycemia.
Prazosin: [P] Increased hypotensive response to first dose of prazosin.
Sympathomimetics: [P] Increased pressor response to epinephrine (and possibly other
sympathomimetics); this is more likely to occur with noncardioselective β blockers.
See also Barbiturates; Theophylline.
Acetaminophen: [NE] Decreased gastrointestinal absorption of acetaminophen.
Digitalis glycosides: [NE] Decreased gastrointestinal absorption of digitoxin (possibly
also digoxin).
Furosemide: [P] Decreased gastrointestinal absorption of furosemide.
Methotrexate: [NE] Reduced gastrointestinal absorption of methotrexate.
Mycophenolate: [P] Reduced gastrointestinal absorption of mycophenolate.
Thiazide diuretics: [P] Reduced gastrointestinal absorption of thiazides.
Thyroid hormones: [P] Reduced thyroid absorption.
See also Anticoagulants, oral.
(continued )
1162    SECTION X  Special Topics
TABLE 66–1  Important drug interactions.
Drug or Properties Promoting
Drug Group Drug Interaction
Calcium channel Verapamil, diltiazem, and perhaps
blockers nicardipine inhibit hepatic drug-
metabolizing enzymes (CYP3A4)
and P-glycoprotein. Metabolism (via
CYP3A4) of diltiazem, felodipine,
nicardipine, nifedipine, verapamil,
and other calcium channel blockers
subject to induction and inhibition.
Carbamazepine Induction of hepatic microsomal
drug-metabolizing enzymes
and P-glycoprotein. Susceptible
to induction and inhibition of
metabolism, primarily by CYP3A4.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
Clinically Documented Interactions
Amiodarone: [P] Decreased metabolism of calcium channel blockers. Enhanced effects
on myocardial conduction with bepridil, diltiazem, and verapamil. Expect similar inter-
actions with dronedarone.
Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir,
indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the metabo-
lism of calcium channel blockers.
Boceprevir: [P] Decreased metabolism of calcium channel blockers.
Carbamazepine: [P] Decreased carbamazepine metabolism with diltiazem and
verapamil; possible increase in calcium channel blocker metabolism.
Cimetidine: [NP] Decreased metabolism of calcium channel blockers.
Colchicine: [P] Decreased colchicine elimination with diltiazem, nicardipine, and
verapamil.
Conivaptan: [P] Decreased metabolism of calcium channel blockers.
Cyclosporine: [P] Decreased cyclosporine elimination with diltiazem, nicardipine,
verapamil.
Digitalis glycosides: [P] Decreased elimination of digitalis glycoside with bepridil,
diltiazem and verapamil.
Kinase inhibitors: [P] Decreased metabolism of calcium channel blockers with
ceritinib, dasatinib, imatinib, idelalisib, and lapatinib. Decreased metabolism of kinase
inhibitors by diltiazem, nicardipine, and verapamil.
Macrolide antibiotics: [P] Clarithromycin and erythromycin inhibit the metabolism of
calcium channel blockers.
Phenytoin: [P] Increased metabolism of calcium channel blockers.
Rifampin: [P] Increased metabolism of calcium channel blockers.
Sirolimus: [P] Decreased sirolimus elimination with diltiazem, nicardipine, verapamil.
Statins: [P] Decreased atorvastatin, lovastatin, and simvastatin elimination with
diltiazem, nicardipine, verapamil.
Tacrolimus: [P] Decreased tacrolimus elimination with diltiazem, nicardipine,
verapamil.
Theophylline: [P] Decreased theophylline metabolism with diltiazem, nicardipine, and
verapamil.
See also Azole antifungals; Barbiturates.
Amiodarone: [P] Decreased metabolism of carbamazepine; increased metabolism of
amiodarone. Expect similar interactions with dronedarone.
Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir,
indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the
metabolism of carbamazepine. Increased metabolism of antivirals by carbamazepine.
Cimetidine: [P] Decreased carbamazepine metabolism.
Corticosteroids: [P] Increased corticosteroid metabolism.
Cyclosporine: [P] Increased cyclosporine metabolism and possible decreased
carbamazepine metabolism.
Danazol: [P] Decreased carbamazepine metabolism.
Digitalis glycosides: [P] Increased digoxin elimination.
Fluvoxamine: [NE] Decreased carbamazepine metabolism.
Estrogens: [P] Increased estrogen metabolism.
(continued )
 CHAPTER 66  Important Drug Interactions & Their Mechanisms     1163

TABLE 66–1  Important drug interactions.

Drug or Properties Promoting
Drug Group Drug Interaction Clinically Documented Interactions

Carbamazepine Haloperidol: [P] Increased haloperidol metabolism.

(cont.)
Cimetidine Inhibits hepatic microsomal drug-
metabolizing enzymes. (Ranitidine,
famotidine, and nizatidine do
not.) May inhibit the renal tubular
secretion of weak bases.
Cisapride Susceptible to induction and
inhibition of metabolism by
CYP3A4 inhibitors. High cisapride
serum concentrations can result in
ventricular arrhythmias.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
Isoniazid: [P] Decreased carbamazepine metabolism.
Kinase inhibitors: [P] Decreased metabolism of carbamazepine with ceritinib,
dasatinib, imatinib, idelalisib, and lapatinib. Increased metabolism of kinase inhibitors.
Macrolide antibiotics: [P] Clarithromycin and erythromycin inhibit the metabolism of
carbamazepine.
Nefazodone: [NE] Decreased carbamazepine metabolism.
Opioid analgesics: [P] Increased elimination of alfentanil, fentanyl, methadone,
oxycodone, and sufentanil.
Rifampin: [P] Increased carbamazepine metabolism.
Selective serotonin reuptake inhibitors (SSRIs): [NE] Fluoxetine and fluvoxamine
decrease carbamazepine metabolism.
Sirolimus: [P] Increased sirolimus metabolism.
St. John’s wort: [P] Increased carbamazepine metabolism.
Tacrolimus: [P] Increased tacrolimus metabolism.
Theophylline: [NE] Increased theophylline metabolism.
See also Anticoagulants, oral; Antidepressants, tricyclic; Azole antifungals; Calcium
channel blockers.
Antivirals: [P] Decreased metabolism of amprenavir, atazanavir, boceprevir, daclatasvir,
darunavir, delavirdine, etravirine, fosamprenavir, indinavir, lopinavir, maraviroc,
nelfinavir, rilpivirine, ritonavir, saquinavir, and tipranavir.
Benzodiazepines: [P] Decreased metabolism of alprazolam, chlordiazepoxide, diazepam,
halazepam, prazepam, and clorazepate but not oxazepam, lorazepam, or temazepam.
Carmustine: [NE] Increased bone marrow suppression.
Dofetilide: [NP] Decreased renal excretion of dofetilide.
Lidocaine: [P] Decreased metabolism of lidocaine.
Opioid analgesics: [P] Decreased elimination of alfentanil, fentanyl, methadone,
oxycodone, and sufentanil.
Phenytoin: [NE] Decreased phenytoin metabolism.
Procainamide: [P] Decreased renal excretion of procainamide.
Quinidine: [P] Decreased metabolism of quinidine.
Theophylline: [P] Decreased theophylline metabolism.
See also Anticoagulants, oral; Antidepressants, tricyclic; Azole antifungals;
β-Adrenoceptor blockers; Calcium channel blockers; Carbamazepine.
Amiodarone: [NP] Decreased cisapride metabolism. Expect similar interaction with
dronedarone.
Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir,
indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the metabolism
of cisapride.
Cobicistat: [P] Decreased metabolism of cisapride.
Conivaptan: [P] Decreased metabolism of cisapride.
Cyclosporine: [NE] Decreased metabolism of cisapride.
Kinase inhibitors: [P] Decreased metabolism of cisapride with ceritinib, dasatinib,
imatinib, idelalisib, and lapatinib.
(continued )
1164    SECTION X  Special Topics

TABLE 66–1  Important drug interactions.

Drug or Properties Promoting
Drug Group Drug Interaction Clinically Documented Interactions

Cisapride (cont.) Macrolide antibiotics: [P] Clarithromycin and erythromycin inhibit the metabolism of
cisapride.
Nefazodone: [NP] Decreased metabolism of cisapride by CYP3A4.
Ritonavir: [P] Decreased metabolism of cisapride.
Selective serotonin reuptake inhibitors (SSRIs): [NP] Fluvoxamine reduces cisapride
metabolism.
See also Azole antifungals.
Colchicine Susceptible to changes in CYP3A4 Amiodarone: [NP] Decreased colchicine metabolism and transport. Expect similar
metabolism and P-glycoprotein interactions with dronedarone.
transport.
Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir,
indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the metabolism
of colchicine.
Carbamazepine: [P] Increased metabolism of colchicine.
Cobicistat: [P] Decreased metabolism of colchicine.
Conivaptan: [P] Decreased metabolism of colchicine.
Cyclosporine: [P] Decreased colchicine elimination.
Kinase inhibitors: [P] Decreased metabolism of colchicine with ceritinib, dasatinib,
imatinib, idelalisib, and lapatinib.
Macrolide antibiotics: [P] Clarithromycin and erythromycin inhibit the metabolism of
colchicine.
Nefazodone: [NE] Decreased colchicine metabolism.
Rifampin: [P] Increased colchicine metabolism.
St. John’s wort: [NP] Increased colchicine metabolism.
See also Azole antifungals; Calcium channel blockers.
Cyclosporine Susceptible to induction and Aminoglycosides: [NE] Possible additive nephrotoxicity.
inhibition of elimination by CYP3A4
and P-glycoprotein. (Tacrolimus and Amphotericin B: [NE] Possible additive nephrotoxicity.
sirolimus appear to have similar Cidofovir: [NE] Possible additive nephrotoxicity.
interactions.)
  Drugs that may increase cyclosporine effect:
Amiodarone: [P] Decreased cyclosporine elimination. Expect similar interaction with
dronedarone.
Androgens: [NE] Increased serum cyclosporine concentration.
Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine,
fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir
inhibit the elimination of cyclosporine.
Cobicistat: [P] Decreased cyclosporine elimination.
Conivaptan: [P] Decreased cyclosporine elimination.
Kinase inhibitors: [P] Decreased metabolism of cyclosporine with ceritinib, dasatinib,
imatinib, idelalisib, and lapatinib. Cyclosporine reduces metabolism of kinase inhibitors.
Macrolide antibiotics: [P] Clarithromycin and erythromycin inhibit the elimination of
cyclosporine.
Nefazodone: [P] Decreased cyclosporine metabolism.
Quinupristin: [P] Decreased cyclosporine metabolism.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
(continued )
 CHAPTER 66  Important Drug Interactions & Their Mechanisms     1165

TABLE 66–1  Important drug interactions.

Drug or Properties Promoting
Drug Group Drug Interaction Clinically Documented Interactions

Cyclosporine Statins: [NP] Decreased metabolism of atorvastatin, lovastatin, and simvastatin.

(cont.)
Digitalis Digoxin susceptible to alteration of
glycosides gastrointestinal absorption. Renal
and nonrenal excretion of digoxin
susceptible to inhibition. Digitalis
toxicity may be increased by drug-
induced electrolyte imbalance
(eg, hypokalemia).
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
Myopathy and rhabdomyolysis noted in patients taking statins and cyclosporine.
Drugs that may decrease cyclosporine effect:
Bosentan: [P] Increased cyclosporine elimination.
Dexamethasone: [NP] Increased cyclosporine metabolism.
Efavirenz: [P] Increased cyclosporine metabolism.
Etravirine: [NP] Increased cyclosporine metabolism.
Nevirapine: [NP] Increased cyclosporine metabolism.
Phenytoin: [P] Increased cyclosporine metabolism.
Rifabutin: [NP] Increased cyclosporine metabolism.
Rifampin: [P] Increased cyclosporine elimination.
St. John’s wort: [NP] Increased cyclosporine elimination.
See also Azole antifungals; Barbiturates; Calcium channel blockers; Carbamazepine.
  Drugs that may increase digitalis effect:
Amiodarone: [P] Increased digoxin plasma concentrations. Expect similar interaction
with dronedarone.
Antivirals: [P] Daclatasvir, indinavir, nelfinavir, paritaprevir, ritonavir, saquinavir, and
telaprevir reduce the elimination of digoxin.
Conivaptan: [P] Increased digoxin plasma concentrations.
Cyclosporine: [P] Increased digoxin plasma concentrations.
Macrolide antibiotics: [P] Azithromycin, clarithromycin, and erythromycin inhibit the
elimination of digoxin.
Potassium-depleting drugs: [P] Increases likelihood of digitalis toxicity.
Propafenone: [P] Increases digoxin plasma concentrations.
Quinidine: [HP] Increased digoxin plasma concentrations; displaces digoxin from tissue
binding sites.
Spironolactone: [NE] Increased digoxin plasma concentrations.
Tacrolimus: [P] Increased digoxin plasma concentrations.
Ticagrelor: [P] Increased digoxin plasma concentrations.
See also Azole antifungals; Calcium channel blockers.
  Drugs that may decrease digitalis effect:
Kaolin-pectin: [P] Decreased gastrointestinal digoxin absorption.
Rifampin: [NE] Increased metabolism of digitoxin and elimination of digoxin.
St. John’s wort: [NP] Increased digoxin elimination.
Sulfasalazine: [NE] Decreased gastrointestinal digoxin absorption.
See also Acid reducing agents; Bile acid-binding resins; Carbamazepine.
(continued )
1166    SECTION X  Special Topics

TABLE 66–1  Important drug interactions.

Drug or Properties Promoting
Drug Group Drug Interaction Clinically Documented Interactions

Disulfiram Inhibits CYP2C9. Inhibits aldehyde
dehydrogenase.
Estrogens Estrogen metabolism (CYP3A4)
susceptible to induction and
inhibition. Enterohepatic circulation
of estrogen may be interrupted by
alteration in bowel flora (eg, due to
antibiotics).
HMG-CoA Lovastatin, simvastatin, and, to
reductase a lesser extent, atorvastatin are
inhibitors susceptible to CYP3A4 inhibitors
(statins) and inducers; additive risk with
other drugs that can cause
myopathy.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
Benzodiazepines: [P] Decreased metabolism of chlordiazepoxide and diazepam but
not lorazepam and oxazepam.
Metronidazole: [NE] Confusion and psychoses reported in patients receiving this
combination; mechanisms unknown.
Phenytoin: [P] Decreased phenytoin metabolism.
See also Alcohol; Anticoagulants, oral.
Ampicillin: [NP] Interruption of enterohepatic circulation of estrogen; possible reduction
in oral contraceptive efficacy. Some other oral antibiotics may have a similar effect.
Bexarotene: [P] Increased estrogen metabolism, possible reduction in oral
contraceptive efficacy.
Bosentan: [NP] Enzyme induction leading to reduced estrogen effect.
Corticosteroids: [P] Decreased metabolism of corticosteroids leading to increased
corticosteroid effect. Dexamethasone may increase estrogen metabolism.
Efavirenz: [P] Increased estrogen metabolism, possible reduction in oral contraceptive
efficacy.
Griseofulvin: [NP] Increased estrogen metabolism, possible reduction in oral
contraceptive efficacy.
Nelfinavir: [P] Increased estrogen metabolism, possible reduction in oral contraceptive
efficacy.
Nevirapine: [NP] Increased estrogen metabolism, possible reduction in oral
contraceptive efficacy.
Phenytoin: [P] Increased estrogen metabolism; possible reduction in oral
contraceptive efficacy.
Primidone: [P] Increased estrogen metabolism; possible reduction in oral
contraceptive efficacy.
Rifabutin: [P] Increased estrogen metabolism; possible reduction in oral contraceptive
efficacy.
Rifampin: [P] Increased estrogen metabolism; possible reduction in oral contraceptive
efficacy.
St. John’s wort: [P] Increased estrogen metabolism; possible reduction in oral
contraceptive efficacy.
See also Barbiturates; Carbamazepine.
Amiodarone: [NP] Decreased atorvastatin, lovastatin, and simvastatin metabolism.
Expect similar interactions with dronedarone.
Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine,
fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir
inhibit the metabolism of atorvastatin, lovastatin, and simvastatin.
Bosentan: [P] Increased atorvastatin, lovastatin, and simvastatin metabolism.
Carbamazepine: [P] Increased atorvastatin, lovastatin, and simvastatin metabolism.
Clofibrate: [NP] Increased risk of myopathy.
Cobicistat: [P] Decreased metabolism of atorvastatin, lovastatin, and simvastatin.
Conivaptan: [P] Decreased metabolism of atorvastatin, lovastatin, and simvastatin.
Cyclosporine: [P] Decreased atorvastatin, lovastatin, rosuvastatin, pitavastatin, and
simvastatin elimination.
(continued )

TABLE 66–1  Important drug interactions.
Drug or Properties Promoting
Drug Group Drug Interaction
HMG-CoA  
reductase
inhibitors
(statins) (cont.)
Iron Binds with drugs in gastrointestinal
tract, reducing absorption.
Levodopa Levodopa degraded in gut prior to
reaching sites of absorption. Agents
that alter gastrointestinal motility
may alter degree of intraluminal
degradation. Antiparkinsonism
effect of levodopa susceptible to
inhibition by other drugs.
Lithium Renal lithium excretion sensitive
to changes in sodium balance.
(Sodium depletion tends to cause
lithium retention.) Susceptible to
drugs enhancing central nervous
system lithium toxicity.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
CHAPTER 66  Important Drug Interactions & Their Mechanisms     1167
Clinically Documented Interactions
Gemfibrozil: [NP] Increased plasma lovastatin and simvastatin and increased risk of
myopathy.
Kinase inhibitors: [P] Decreased metabolism of atorvastatin, lovastatin, and simvastatin
by ceritinib, dasatinib, imatinib, idelalisib, and lapatinib.
Macrolide antibiotics: [P] Clarithromycin and erythromycin inhibit the elimination of
statins.
Nefazodone: [NP] Decreased atorvastatin, lovastatin, and simvastatin metabolism.
Phenytoin: [P] Increased atorvastatin, lovastatin, and simvastatin metabolism.
Rifampin: [P] Increased atorvastatin, lovastatin, and simvastatin metabolism.
St. John’s wort: [NP] Increased atorvastatin, lovastatin, and simvastatin metabolism.
See also Azole antifungals; Calcium channel blockers; Cyclosporine.
Methyldopa: [NE] Decreased methyldopa absorption.
Mycophenolate: [P] Decreased mycophenolate absorption.
Quinolones: [P] Decreased absorption of ciprofloxacin and other quinolones.
Tetracyclines: [P] Decreased absorption of tetracyclines; decreased efficacy of iron.
Thyroid hormones: [P] Decreased thyroxine absorption.
See also Antacids.
Clonidine: [NE] Inhibited antiparkinsonism effect.
Haloperidol: [NP] Inhibited antiparkinsonism effect.
Metoclopramide: [NP] Inhibited antiparkinsonism effect.
Monoamine oxidase inhibitors (MAOIs): [P] Hypertensive reaction (carbidopa
prevents the interaction).
Papaverine: [NE] Inhibited antiparkinsonism effect.
Phenothiazines: [P] Inhibited antiparkinsonism effect.
Phenytoin: [NE] Inhibited antiparkinsonism effect.
Pyridoxine: [P] Inhibited antiparkinsonism effect (carbidopa prevents the
interaction).
ACE inhibitors (ACEIs): [NE] Reduce renal clearance of lithium; increase lithium
effect.
Angiotensin II receptor blockers (ARBs): [NE] Reduce renal clearance of lithium;
increase lithium effect.
Diuretics (especially thiazides): [P] Decreased excretion of lithium; furosemide
may be less likely to produce this effect than thiazide diuretics.
Haloperidol: [NP] Occasional cases of neurotoxicity in manic patients, especially with
large doses of one or both drugs.
Methyldopa: [NE] Increased likelihood of central nervous system lithium toxicity.
Nonsteroidal anti-inflammatory drugs (NSAIDs): [NE] Reduced renal lithium
excretion (except sulindac and salicylates).
Theophylline: [P] Increased renal excretion of lithium; reduced lithium effect.
(continued )
1168    SECTION X  Special Topics
TABLE 66–1  Important drug interactions.
Drug or Properties Promoting
Drug Group Drug Interaction
Macrolides The macrolides clarithromycin
and erythromycin are known to
inhibit CYP3A4 and P-glycoprotein.
Azithromycin does not appear to
inhibit CYP3A4 but is a modest
inhibitor of P-glycoprotein.
Monoamine Increased norepinephrine stored in
oxidase adrenergic neuron. Displacement
inhibitors of these stores by other drugs
(MAOIs) may produce acute hypertensive
response. MAOIs have intrinsic
hypoglycemic activity.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
Clinically Documented Interactions
Benzodiazepines: [P] Decreased metabolism of alprazolam, midazolam, triazolam.
Eplerenone: [P] Decreased metabolism of eplerenone.
Ergot alkaloids: [P] Decreased elimination of ergot alkaloids.
Kinase inhibitors: [P] Decreased metabolism of axitinib, bosutinib, ceritinib,
cabozantinib, cobimetinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, ibrutinib,
idelalisib, imatinib, ixazomib, lapatinib, nilotinib, nintedanib, olaparib, osimertinib,
palbociclib, pazopanib, ponatinib, regorafenib, ruxolitinib, sunitinib, tofacitinib,
vandetanib, and vemurafenib by clarithromycin and erythromycin.
Opioid analgesics: [P] Decreased elimination of alfentanil, fentanyl, methadone,
oxycodone, and sufentanil.
Phosphodiesterase inhibitors: [P] Decreased metabolism of phosphodiesterase
inhibitor.
Pimozide: [P] Increased pimozide concentrations.
Quinidine: [P] Increased serum quinidine concentrations.
Theophylline: [P] Decreased metabolism of theophylline.
See also Anticoagulants, oral; Calcium channel blockers; Carbamazepine; Cisapride;
Colchicine; Cyclosporine; Digitalis glycosides; HMG-CoA reductase inhibitors.
Anorexiants: [P] Hypertensive episodes due to release of stored norepinephrine
(benzphetamine, diethylpropion, mazindol, phendimetrazine, phentermine).
Antidiabetic agents: [P] Additive hypoglycemic effect.
Buspirone: [NE] Possible serotonin syndrome; avoid concurrent use.
Dextromethorphan: [NP] Severe reactions (hyperpyrexia, coma, death) have been
reported.
Guanethidine: [P] Reversal of the hypotensive action of guanethidine.
Mirtazapine: [NE] Possible serotonin syndrome; avoid concurrent use.
Nefazodone: [NP] Possible serotonin syndrome; avoid concurrent use.
Opioid analgesics: [NP] Some patients develop hypertension, rigidity, excitation;
meperidine more likely to interact than morphine; avoid concurrent use.
Phenylephrine: [P] Hypertensive episode, since phenylephrine is metabolized by
monoamine oxidase.
Selective serotonin reuptake inhibitors (SSRIs): [P] Fatalities have occurred
due to serotonin syndrome; contraindicated in patients taking MAOIs; avoid
concurrent use.
Sibutramine: [NE] Possible serotonin syndrome; avoid concurrent use.
Sympathomimetics (indirect-acting): [HP] Hypertensive episode due to release of
stored norepinephrine (amphetamines, ephedrine, isometheptene, phenylpropanol-
amine, pseudoephedrine).
Tramadol: [NP] Possible serotonin syndrome; avoid concurrent use.
Venlafaxine: [NP] Possible serotonin syndrome; avoid concurrent use.
See also Antidepressants, tricyclic and heterocyclic; Levodopa.
(continued )

TABLE 66–1  Important drug interactions.
Drug or Properties Promoting
Drug Group Drug Interaction
Nonsteroidal Prostaglandin inhibition may result
anti- in reduced renal sodium excretion,
inflammatory impaired resistance to hypertensive
drugs (NSAIDs) stimuli, and reduced renal lithium
excretion. Most NSAIDs inhibit
platelet function; may increase
likelihood of bleeding due to other
drugs that impair hemostasis.
Opioid Opioid analgesics that are
analgesics substrates of CYP3A4 (alfentanil,
fentanyl, oxycodone, sufentanil,
and to a lesser extent methadone)
are susceptible to inhibitors and
inducers. Methadone is primarily
metabolized by CYP2B6. Additive
central nervous system depression
with other central nervous system
depressants.
Phenytoin Induces hepatic microsomal
drug metabolism. Susceptible to
inhibition of metabolism by CYP2C9
and, to a lesser extent, CYP2C19.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
CHAPTER 66  Important Drug Interactions & Their Mechanisms     1169
Clinically Documented Interactions
ACE inhibitors (ACEIs): [P] Decreased antihypertensive response.
Angiotensin II receptor blockers (ARBs): [P] Decreased antihypertensive response.
Furosemide: [P] Decreased diuretic, natriuretic, and antihypertensive response to
furosemide.
Hydralazine: [NE] Decreased antihypertensive response to hydralazine.
Methotrexate: [NP] Possibly increased methotrexate toxicity (especially with
anticancer doses of methotrexate).
Selective serotonin reuptake inhibitors (SSRIs): [P] Increased risk of bleeding due to
platelet inhibition.
Thiazide diuretics: [P] Decreased diuretic, natriuretic, and antihypertensive response.
Triamterene: [NE] Decreased renal function noted with triamterene plus indomethacin
in both healthy subjects and patients.
See also Anticoagulants, oral; β-Adrenoceptor blockers; Lithium.
Amiodarone: [NP] Decreased CYP3A4-dependent opioid metabolism. Expect similar
interactions with dronedarone.
Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine,
fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir
inhibit the metabolism of CYP3A4-dependent opioids.
Boceprevir: [P] Decreased metabolism of CYP3A4-dependent opioids.
Bosentan: [P] Increased CYP3A4-dependent opioid metabolism.
Cobicistat: [P] Decreased metabolism of CYP3A4-dependent opioids.
Conivaptan: [P] Decreased metabolism of CYP3A4-dependent opioids.
Efavirenz: [P] Increased metabolism of CYP3A4-dependent opioids.
Kinase inhibitors: [P] Decreased metabolism of CYP3A4-dependent opioid by
ceritinib, dasatinib, imatinib, idelalisib, and lapatinib.
Nefazodone: [NP] Decreased CYP3A4-dependent opioid metabolism.
Nevirapine: [P] Increased metabolism of CYP3A4-dependent opioids.
Phenytoin: [P] Increased CYP3A4-dependent opioid metabolism.
Rifampin: [P] Increased CYP3A4-dependent opioid metabolism.
St. John’s wort: [NP] Increased CYP3A4-dependent opioid metabolism.
See also Azole antifungal agents; Barbiturates; Carbamazepine; Cimetidine; Macrolides;
Monoamine oxidase inhibitors.
  Drugs whose metabolism is stimulated by phenytoin:
Corticosteroids: [P] Decreased serum corticosteroid levels.
Doxycycline: [P] Decreased serum doxycycline levels.
Mexiletine: [NE] Decreased serum mexiletine levels.
Quinidine: [P] Decreased serum quinidine levels.
Theophylline: [NP] Decreased serum theophylline levels.
See also Calcium channel blockers; Cyclosporine; Estrogens; Opioid analgesics.
(continued )
1170    SECTION X  Special Topics

TABLE 66–1  Important drug interactions.

Drug or Properties Promoting
Drug Group Drug Interaction Clinically Documented Interactions

Phenytoin   Drugs that inhibit phenytoin metabolism:

(cont.)
Amiodarone: [P] Increased serum phenytoin concentration; possible reduction in
serum amiodarone concentration.
Capecitabine: [NE] Increased phenytoin plasma concentrations.
Chloramphenicol: [P] Increased phenytoin plasma concentrations.
Felbamate: [P] Increased phenytoin plasma concentrations.
Fluorouracil: [NE] Increased phenytoin plasma concentrations.
Fluvoxamine: [NP] Increased phenytoin plasma concentrations.
Isoniazid: [NP] Increased serum phenytoin; problem primarily with slow acetylators of
isoniazid.
Metronidazole: [NP] Increased phenytoin plasma concentrations.
Sulfamethoxazole: [P] Increased phenytoin plasma concentrations.
Ticlopidine: [NP] Increased phenytoin plasma concentrations.
See also Azole antifungals; Cimetidine; Disulfiram.
Drugs that enhance phenytoin metabolism:
Bosentan: [P] Decreased phenytoin plasma concentrations.
Carbamazepine: [P] Decreased phenytoin plasma concentrations.
Rifampin: [P] Decreased phenytoin plasma concentrations.
St. John’s wort: [P] Decreased phenytoin plasma concentrations.
See also Barbiturates.
Pimozide Susceptible to CYP3A4 inhibitors; Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir,
may exhibit additive effects with indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the
other agents that prolong QTc metabolism of pimozide.
interval.
Boceprevir: [P] Decreased metabolism of pimozide.
Cobicistat: [P] Decreased metabolism of pimozide.
Conivaptan: [P] Decreased metabolism of pimozide.
Kinase inhibitors: [P] Decreased metabolism of pimozide with ceritinib, dasatinib,
imatinib, idelalisib, and lapatinib.
Nefazodone: [NP] Decreased pimozide metabolism.
See also Azole antifungals; Cyclosporine; Macrolides.
Potassium- Additive effects with other agents ACE inhibitors (ACEIs): [NP] Additive hyperkalemic effect.
sparing diuret- increasing serum potassium con-
ics (amiloride, centration. Eplerenone is a substrate Angiotensin II receptor blockers (ARBs): [NP] Additive hyperkalemic effect.
eplerenone, for CYP3A4 and is susceptible to Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine,
spironolactone, inhibition and induction. May fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir
triamterene) alter renal excretion of substances inhibit the metabolism of eplerenone.
other than potassium (eg, digoxin,
hydrogen ions). Boceprevir: [P] Decreased metabolism of eplerenone.
Cobicistat: [P] Decreased metabolism of eplerenone.
Conivaptan: [P] Decreased metabolism of eplerenone.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
(continued )
 CHAPTER 66  Important Drug Interactions & Their Mechanisms     1171

TABLE 66–1  Important drug interactions.

Drug or Properties Promoting
Drug Group Drug Interaction Clinically Documented Interactions

Potassium-
sparing diuret-
ics (amiloride,
eplerenone,
spironolactone,
triamterene)
(cont.)
Probenecid Interference with renal excretion
of drugs that undergo active
tubular secretion, especially weak
acids. Inhibition of glucuronide
conjugation of other drugs.
Quinidine Substrate of CYP3A4. Inhibits
CYP2D6. Renal excretion susceptible
to changes in urine pH. Additive
effects with other agents that
prolong the QTc interval.
Quinolone Susceptible to inhibition of
antibiotics gastrointestinal absorption. Some
quinolones (ciprofloxacin, enoxacin)
inhibit CYP1A2, while ciprofloxacin
also inhibits CYP3A4.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
Kinase inhibitors: [P] Decreased metabolism of eplerenone with ceritinib, dasatinib,
imatinib, idelalisib, and lapatinib.
Potassium-sparing diuretics: [P] Additive hyperkalemic effect.
Potassium supplements: [P] Additive hyperkalemic effect; especially a problem in
presence of renal impairment.
See also Azole antifungals; Digitalis glycosides; Macrolides; Nonsteroidal anti-
inflammatory drugs.
Clofibrate: [P] Reduced glucuronide conjugation of clofibric acid.
Methotrexate: [P] Decreased renal methotrexate excretion; possible methotrexate
toxicity.
Pralatrexate: [P] Decreased renal pralatrexate excretion; possible pralatrexate toxicity.
Penicillin: [P] Decreased renal penicillin excretion.
Salicylates: [P] Decreased uricosuric effect of probenecid (interaction unlikely with
less than 1.5 g of salicylate daily).
Acetazolamide: [P] Decreased renal quinidine excretion due to increased urinary pH;
elevated serum quinidine.
Amiodarone: [NP] Increased serum quinidine levels; additive prolongation of QTc
interval.
Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine,
fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir
inhibit the metabolism of quinidine.
Boceprevir: [P] Decreased metabolism of quinidine.
Cobicistat: [P] Decreased metabolism of quinidine.
Conivaptan: [P] Decreased metabolism of quinidine.
Kaolin-pectin: [NE] Decreased gastrointestinal absorption of quinidine.
Kinase inhibitors: [P] Decreased metabolism of quinidine with ceritinib, dasatinib,
imatinib, idelalisib, and lapatinib.
Rifampin: [P] Increased quinidine metabolism.
Thioridazine: [NE] Decreased thioridazine metabolism; additive prolongation of QTc
interval.
See also Anticoagulants, oral; Antidepressants, tricyclic; Azole antifungals; Barbiturates;
Cimetidine; Digitalis glycosides; Macrolides; Phenytoin.
Caffeine: [P] Ciprofloxacin, enoxacin, and, to a lesser extent, norfloxacin inhibit caffeine
metabolism.
Frovatriptan: [P] Ciprofloxacin, enoxacin, and, to a lesser extent, norfloxacin inhibit
frovatriptan metabolism.
Ropinirole: [P] Ciprofloxacin, enoxacin, and, to a lesser extent, norfloxacin inhibit
ropinirole metabolism.
Sucralfate: [HP] Reduced gastrointestinal absorption of ciprofloxacin, norfloxacin, and
probably other quinolones.
Theophylline: [P] Ciprofloxacin, enoxacin, and, to a lesser extent, norfloxacin inhibit
theophylline metabolism.
(continued )
1172    SECTION X  Special Topics
TABLE 66–1  Important drug interactions.
Drug or Properties Promoting
Drug Group Drug Interaction
Quinolone
antibiotics
(cont.)
Rifampin Inducer (strong) of hepatic
microsomal drug-metabolizing
enzymes and P-glycoprotein.
Salicylates Interference with renal excretion of
drugs that undergo active tubular
secretion. Salicylate renal excretion
dependent on urinary pH when
large doses of salicylate used.
Aspirin (but not other salicylates)
interferes with platelet function.
Large doses of salicylates have
intrinsic hypoglycemic activity.
Selective SSRIs can lead to excessive serotonin
serotonin response when administered with
reuptake other serotonergic drugs (eg,
inhibitors MAOIs). Some SSRIs inhibit various
(SSRIs) cytochrome P450s including
CYP2D6, CYP1A2, CYP3A4, and
CYP2C19.
Theophylline Susceptible to induction and
inhibition of hepatic metabolism
by CYP1A2 and CYP3A4.
E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the
combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate
of predictability.
Clinically Documented Interactions
Tizanidine: [P] Ciprofloxacin, enoxacin, and, to a lesser extent, norfloxacin inhibit
tizanidine metabolism.
Zolmitriptan: [P] Ciprofloxacin, enoxacin, and, to a lesser extent, norfloxacin inhibit
zolmitriptan metabolism.
See also Acid-reducing agents; Anticoagulants, oral; Iron.
Corticosteroids: [P] Increased corticosteroid hepatic metabolism; reduced
corticosteroid effect.
Mexiletine: [NE] Increased mexiletine metabolism; reduced mexiletine effect.
Sulfonylurea hypoglycemics: [P] Increased hepatic metabolism of tolbutamide and
probably other sulfonylureas metabolized by the liver (including chlorpropamide).
Theophylline: [P] Increased theophylline metabolism.
See also Anticoagulants, oral; Antidepressants, tricyclic and heterocyclic; Azole
antifungals; Beta-adrenoceptor blockers; Calcium channel blockers; Cyclosporine;
Digitalis glycosides; Estrogens; HMG-CoA reductase inhibitors; Opioid analgesics;
Phenytoin; Quinidine.
Carbonic anhydrase inhibitors: [NE] Increased acetazolamide serum concentrations;
increase salicylate toxicity due to decreased blood pH.
Corticosteroids: [P] Increased salicylate elimination; possible additive toxic effect on
gastric mucosa.
Heparin: [NP] Increased bleeding tendency with aspirin, but probably not with other
salicylates.
Methotrexate: [P] Decreased renal methotrexate clearance; increases methotrexate
toxicity (primarily at anticancer doses).
Selective serotonin reuptake inhibitors (SSRIs): [P] Increased risk of bleeding due to
platelet inhibition.
Sulfinpyrazone: [HP] Decreased uricosuric effect of sulfinpyrazone (interaction unlikely
with less than 1.5 g of salicylate daily).
See also Acid-reducing agents; Anticoagulants, oral; Probenecid.
Codeine: [HP] Reduced analgesic effect due to inhibition of codeine metabolism to
morphine by fluoxetine and paroxetine.
Theophylline: [P] Decreased metabolism of theophylline by fluvoxamine-induced
inhibition of CYP1A2.
See also Anticoagulants, oral; Antidepressants, tricyclic and heterocyclic;
β-Adrenoceptor blockers; Carbamazepine; Cisapride; Colchicine; Cyclosporine;
HMG-CoA reductase inhibitors; Monoamine oxidase inhibitors; Nonsteroidal
anti-inflammatory drugs; Phenytoin; Pimozide; Salicylates.
Beta-adrenoceptor blockers: [NP] Decreased theophylline bronchodilation especially
with noncardioselective β blockers.
Smoking: [HP] Increased theophylline metabolism.
Tacrine: [NP] Decreased theophylline metabolism.
Ticlopidine: [NP] Decreased theophylline metabolism.
Zileuton: [NP] Decreased theophylline metabolism.
See also Barbiturates; Calcium channel blockers; Carbamazepine; Cimetidine; Lithium;
Macrolides; Phenytoin; Quinolones; Rifampin; Selective serotonin reuptake inhibitors.
 CHAPTER 66  Important Drug Interactions & Their Mechanisms     1173
The metabolism of drugs can be induced or inhibited by
concurrent therapy, and the importance of the effect varies from
negligible to dramatic. Drug metabolism primarily occurs in the
liver and the wall of the small intestine, but other sites include
plasma, lung, and kidney. Induction of cytochrome P450 isozymes
in the liver and small intestine can be caused by drugs such
as barbiturates, bosentan, carbamazepine, efavirenz, nevirapine,
phenytoin, primidone, rifampin, rifabutin, and St. John’s wort.
Enzyme inducers can also increase the activity of phase II metabo-
lism such as glucuronidation. Enzyme induction does not take
place quickly; maximal effects usually occur after 7–14 days and
require an equal or longer time to dissipate after the enzyme
inducer is stopped. Inhibition of metabolism generally takes place
more quickly than enzyme induction and may begin as soon as the
tissue concentration of the inhibitor is sufficient to cause reduced
enzyme activity. However, if the half-life of the affected (object)
drug is long, it may take a week or more (3–4 half-lives) to reach a
new steady-state serum concentration. Drugs that may inhibit the
cytochrome P450 metabolism of other drugs include amiodarone,
androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin,
clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydr-
amine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine,
fluvoxamine, furanocoumarins (substances in grapefruit juice),
indinavir, isoniazid, itraconazole, ketoconazole, metronidazole,
mexiletine, miconazole, omeprazole, paroxetine, quinidine, rito-
navir, sulfamethizole, sulfamethoxazole, verapamil, voriconazole,
zafirlukast, and zileuton.
The renal excretion of active drug can also be affected by con-
current drug therapy. The renal excretion of drugs that are weak
acids or weak bases may be influenced by other drugs that affect
urinary pH. This is due to changes in ionization of the object
drug, as described in Chapter 1 under Ionization of Weak Acids
and Weak Bases; the Henderson-Hasselbalch Equation. For some
drugs, active secretion into the renal tubules is an important elimi-
nation pathway. P-glycoprotein, organic anion transporters, and
organic cation transporters are involved in active tubular secretion
of some drugs, and inhibition of these transporters can inhibit
renal elimination with attendant increase in serum drug concen-
trations. Many drugs are partially eliminated by P-glycoprotein,
including digoxin, cyclosporine, dabigatran, colchicine, dauno-
rubicin, and tacrolimus. The plasma concentration of these drugs
can be increased by inhibitors of P-glycoprotein including amio-
darone, clarithromycin, erythromycin, ketoconazole, ritonavir,
and quinidine. To access over 200 brief reviews of specific drug
interactions visit http://www.hanstenandhorn.com/news.htm.
PHARMACODYNAMIC MECHANISMS
When drugs with similar pharmacologic effects are administered
concurrently, an additive or synergistic response is usually seen.
The two drugs may or may not act on the same receptor to
produce such effects. In theory, drugs acting on the same receptor
or process are usually additive, eg, benzodiazepines plus barbitu-
rates, until the receptor is saturated or the effect is maximal. How-
ever, two drugs competing for the same binding site may result in
less than an additive effect. Drugs acting on different receptors
or sequential processes may be synergistic, eg, nitrates plus silde-
nafil or sulfonamides plus trimethoprim. Conversely, drugs with
opposing pharmacologic effects may reduce the response to one
or both drugs. Pharmacodynamic drug interactions are relatively
common in clinical practice, but adverse effects can usually be
minimized if one understands the pharmacology of the drugs
involved. In this way, the interactions can be anticipated and
appropriate counter-measures taken.
COMBINED TOXICITY
The combined use of two or more drugs, each of which has toxic
effects on the same organ, can greatly increase the likelihood of
organ damage. For example, concurrent administration of two
nephrotoxic drugs can produce kidney damage, even though the
dose of either drug alone may be insufficient to produce toxicity.
Furthermore, some drugs can enhance the organ toxicity of
another drug, even though the enhancing drug has no intrinsic
toxic effect on that organ.
REFERENCES
Boobis A et al: Drug interactions. Drug Metab Rev 2009;41:486.
DeGorter MK et al: Drug transporters in drug efficacy and toxicity. Annu Rev
Pharmacol Toxicol 2012;52:249.
DuBuske LM: The role of P-glycoprotein and organic anion-transporting polypep-
tides in drug interactions. Drug Saf 2005;28:789.
Hansten PD, Horn JR: The Top 100 Drug Interactions. A Guide to Patient Manage-
ment. H&H Publications, 2016, www.hanstenandhorn.com.
Hillgren KM et al: Emerging transporters of clinical importance: An update
from the international transporter consortium. Clin Pharmacol Ther
2013;94:52.
Horn JR et al: Proposal for a new tool to evaluate drug interaction cases. Ann
Pharmacother 2007;41:674.
Hukkanen J: Induction of cytochrome P450 enzymes: A view on human in vivo
findings. Expert Rev Clin Pharmacol 2012;5:569.
Juurlink DN et al: Drug-drug interactions among elderly patients hospitalized for
drug toxicity. JAMA 2003;289:1652.
Leucuta SE, Vlase L: Pharmacokinetics and metabolic drug interactions. Curr Clin
Pharmacol 2006;1:5.
Meng Q, Lin K: Pharmacokinetic interactions between herbal medicines and
prescribed drugs: Focus on drug metabolic enzymes and transporters. Curr
Drug Metab 2014;15:791.
Pelkonen O et al: Inhibition and induction of human cytochrome P450 enzymes:
Current status. Arch Toxicol 2008;82:667.
Roberts JA, et al: The clinical relevance of plasma protein binding changes. Clin
Pharmacokinet 2013;52:1.
Thelen K, Dressman JB: Cytochrome P540-mediated metabolism in the human
gut wall. J Pharm Pharmacol 2009;61:541.
Zakeri-Milani P, Valzadeh H: Intestinal transporters: Enhanced absorption
through P-glycoprotein-related drug interactions. Expert Opin Drug Metab
Toxicol 2014;10:859.
Appendix: Vaccines, Immune
Globulins, & Other Complex
Biologic Products
Harry W. Lampiris, MD & Daniel S. Maddix, PharmD

Vaccines and related biologic products constitute an important PASSIVE IMMUNIZATION

group of agents that bridge the disciplines of microbiology, infec-
tious diseases, immunology, and immunopharmacology. A list Passive immunization consists of transfer of immunity to a host
of the most important preparations is provided here. The reader using preformed immunologic products. From a practical stand-
who requires more complete information is referred to the sources point, only immunoglobulins have been used for passive immuniza-
listed at the end of this appendix. tion, because passive administration of cellular components of the
immune system has been technically difficult and associated with
graft-versus-host reactions. Products of the cellular immune system
ACTIVE IMMUNIZATION (eg, interferons) have also been used in the therapy of a wide variety
of hematologic and infectious diseases (see Chapter 55).
Active immunization consists of the administration of antigen
Passive immunization with antibodies may be accomplished
to the host to induce formation of antibodies and cell-mediated
with either animal or human immunoglobulins in varying degrees
immunity. Immunization is practiced to induce protection against
of purity. These may contain relatively high titers of antibodies
many infectious agents and may utilize either inactivated (killed)
directed against a specific antigen or, as is true for pooled immune
materials or live attenuated agents (Table A–1). Desirable features
globulin, may simply contain antibodies found in most of the
of the ideal immunogen include complete prevention of disease,
population. Passive immunization is useful for (1) individuals
prevention of the carrier state, production of prolonged immunity
unable to form antibodies (eg, congenital agammaglobulinemia);
with a minimum of immunizations, absence of toxicity, and
(2) prevention of disease when time does not permit active immu-
suitability for mass immunization (eg, cheap and easy to admin-
nization (eg, postexposure); (3) for treatment of certain diseases
ister). Active immunization is generally preferable to passive
normally prevented by immunization (eg, tetanus); and (4) for
immunization—in most cases because higher antibody levels
treatment of conditions for which active immunization is unavail-
are sustained for longer periods of time, requiring less frequent
able or impractical (eg, snakebite).
immunization, and in some cases because of the development of
Complications from administration of human immunoglobu-
concurrent cell-mediated immunity. However, active immuniza-
lins are rare. The injections may be moderately painful, and rarely a
tion requires time to develop and is therefore generally inactive
sterile abscess may occur at the injection site. Transient hypotension and
at the time of a specific exposure (eg, for parenteral exposure to
pruritus occasionally occur with the administration of intravenous
hepatitis B, concurrent hepatitis B IgG [passive antibodies] and
immune globulin (IVIG) products, but generally are mild. Indi-
active immunization are given to prevent illness).
viduals with certain immunoglobulin deficiency states (IgA defi-
Current recommendations for routine active immunization of
ciency, etc) may occasionally develop (text continues on page 1177)
children are given in Table A–2.

1175
 TABLE A–1  Materials commonly used for active immunization in the United States.1

1176
Route of
Vaccine Type of Agent Administration Primary Immunization Booster2 Indications

Diphtheria Toxoids and Intramuscular See Table A–2 None For all children
tetanus acellular inactivated
pertussis (DTaP) bacterial
components
Haemophilus Bacterial Intramuscular One dose (see Table A–2 for Not 1. For all children
influenzae type b polysaccharide childhood schedule) recommended 2. Asplenia and other at-risk conditions
conjugate (Hib)3 conjugated to
protein
Hepatitis A Inactivated virus Intramuscular One dose (see Table A–2 for At 6–12 months 1. Travelers to hepatitis A endemic areas
childhood schedule) (administer for long-term 2. Men who have sex with men (MSM)
at least 2–4 weeks before travel to immunity
3. Injection or noninjection illicit drug users
endemic areas)
4. Chronic liver disease or clotting factor disorders
5. Persons with occupational risk for infection
6. Persons living in, or relocating to, endemic areas
7. Household and sexual contacts of individuals with acute hepatitis A
(with additional gamma globulin in select patients)
8. For all children
9. Unvaccinated persons who anticipate close personal contact with an
international adoptee during the first 60 days after arrival in the USA
from a country with high or intermediate endemicity
Hepatitis B Inactive viral Intramuscular Three doses at 0, 1, and 6 months Not routinely 1. For all infants
antigen, (subcutaneous (see Table A–2 for childhood recommended 2. Preadolescents, adolescents, and young adults
recombinant injection is schedule)
3. Persons with occupational, lifestyle, or environmental risk
acceptable
in individuals 4. Diabetic adults <60 years of age
with bleeding 5. Persons with end-stage renal disease, HIV, or chronic liver disease
disorders) 6. Postexposure prophylaxis
7. Household and sexual contacts of individuals with acute and chronic
hepatitis B
Human Virus-like particles Intramuscular Three doses at 0, 4–8, and None 1. HPV2, HPV4, or HPV9 for females between 9 and 26 years of age; HPV4
papillomavirus of the major capsid 24 weeks or HPV9 for males aged 9–21 years
(HPV)4 protein 2. MSM through age 26 years
3. Immunocompromised persons through age 26 years
Influenza, Inactivated virus or Intramuscular; One dose (Children <9 years who Yearly with 1. All adults >18 years
inactivated viral components an intradermal are receiving influenza vaccine current vaccine 2. All children aged 6 months to 18 years
vaccine is avail- for the first time should receive
able for adults two doses administered at least
aged 18–64 years; 4 weeks apart.)
a high-dose for-
mulation is an
option for adults
≥65 years
 Influenza, live Live virus Intranasal Split dose in each nostril. Children Yearly with Healthy persons aged 19–49 years who desire protection against
attenuated age 5–8 who are receiving influ- current vaccine influenza. May be substituted for inactivated vaccine in healthy
enza vaccine for the first time children 2–18 years except (1) asthmatics, and (2) those aged
should receive two doses 2–4 years with wheezing in the past year
administered 6–10 weeks apart
Measles- Live virus Subcutaneous See Table A–2 None 1. For all children
mumps-rubella 2. Adults born after 1956
(MMR)
Meningococcal Bacterial Intramuscular One dose Every 5 years if 1. All adolescents
conjugate polysaccharides there is continu- 2. Preferred over polysaccharide vaccine in persons aged 11–55 years
vaccine conjugated to ing high risk of
3. College freshman aged <22 years who live in dormitories
diphtheria toxoid exposure
4. Military recruits
5. Individuals with asplenia or complement deficiency (two-dose series)
6. Microbiologists who are routinely exposed to isolates of Neisseria
meningitidis
7. HIV-positive men who have sex with men
Meningococcal Bacterial Subcutaneous One dose Every 5 years if 1. Adult travelers >55 years to areas with hyperendemic or epidemic
polysaccharide polysaccharides there is continu- meningococcal disease
vaccine of serotypes ing high risk of
A/C/Y/W-135 exposure
Pneumococcal Bacterial Intramuscular or See Table A–2 None 1. For all children
conjugate polysaccharides subcutaneous 2. Adults with immunocompromising conditions, asplenia, cerebrospinal
vaccine conjugated to fluid leaks, or cochlear implants
protein
3. Adults ≥65 years who have not been vaccinated previously
Pneumococcal Bacterial Intramuscular or One dose Repeat after 1. Adults ≥65 years
polysaccharide polysaccharides of subcutaneous 5 years in 2. Persons at increased risk for pneumococcal disease or its complications
vaccine 23 serotypes patients at high
risk
Poliovirus Inactivated Subcutaneous See Table A–2 for childhood One-time booster 1. For all children
vaccine, viruses of all three schedule. Adults: Two doses dose for adults at 2. Previously unvaccinated adults at increased risk for occupational or
inactivated (IPV) serotypes 4–8 weeks apart, and a third dose increased risk of travel exposure to polioviruses
6–12 months after the second exposure
Rabies Inactivated virus Intramuscular Preexposure: Three doses at days Serologic testing 1. Preexposure prophylaxis in persons at risk for contact with rabies virus
0, 7, and 21 or 28 every 6 months 2. Postexposure prophylaxis (administer with rabies immune globulin in
to 2 years in per- previously unvaccinated individuals)
Postexposure: Four doses at days sons at high risk
0, 3, 7, and 14; immunosuppressed
patients should receive a 5th dose
at day 28
Rotavirus Live virus Oral See Table A–2 None For all infants
Tetanus- Toxoids Intramuscular Two doses 4–8 weeks apart, and a Every 10 years 1. All adults
diphtheria third dose 6–12 months after the 2. Postexposure prophylaxis if >5 years has passed since last dose
(Td or DT)5 second

(continued )

1177
 TABLE A–1  Materials commonly used for active immunization in the United States.1 (Continued)

1178
Route of
Vaccine Type of Agent Administration Primary Immunization Booster2 Indications

Tetanus, diph- Toxoids and inac- Intramuscular Substitute one dose of Tdap for Td None All adults; pregnant women should receive a dose with each
theria, pertussis tivated bacterial in all adults pregnancy (preferred during 27–36 weeks of gestation)
(Tdap) components
Typhoid, Ty21a Live bacteria Oral Four doses administered every Four doses every Risk of exposure to typhoid fever
oral other day 5 years
Typhoid, Bacterial Intramuscular One dose Every 2 years Risk of exposure to typhoid fever
Vi capsular polysaccharide
polysaccharide
Varicella Live virus Subcutaneous Two doses 4–8 weeks apart in Unknown 1. For all children
persons past their 13th birthday 2. Persons past their 13th birthday without a history of varicella infection
(see Table A–2 for childhood or immunization
schedule)
3. Postexposure prophylaxis in susceptible persons
Yellow fever Live virus Subcutaneous One dose 10 years to 10 days Every 10 years 1. Laboratory personnel who may be exposed to yellow fever virus
before travel 2. Travelers to areas where yellow fever occurs
Zoster Live virus Subcutaneous One dose None All adults ≥60 years of age
1
Dosages for the specific product, including variations for age, are best obtained from the manufacturer’s package insert.
2
One dose unless otherwise indicated.
3
Three Hib conjugate vaccines are available for use: (1) oligosaccharide conjugate Hib vaccine (HbOC), (2) polyribosylribitol phosphate-tetanus toxoid conjugate (PRP-T), and (3) Haemophilus influenzae type b conjugate vaccine
(meningococcal protein conjugate) (PRP-OMP).
4
Three HPV vaccines are available for use: (1) quadrivalent vaccine (HPV4) and (2) 9-valent vaccine (HPV9) for the prevention of cervical, vaginal, and vulvar cancers (in females) and genital warts (in males and females), and (3) bivalent
vaccine (HPV2) for the prevention of cervical cancers in females.
5
Td is tetanus and diphtheria toxoids for use in persons ≥7 years of age (contains less diphtheria toxoid than DPT and DT). DT is tetanus and diphtheria toxoids for use in persons <7 years of age (contains the same amount of diphtheria
toxoid as DPT).
 Appendix: Vaccines, Immune Globulins, & Other Complex Biologic Products     1179

TABLE A–2  Recommended routine childhood immunization schedule.

Age Immunization Comments

Birth to 2 months Hepatitis B vaccine (HBV) Infants born to seronegative mothers: Administration should begin prior
to hospital discharge, with the second dose administered at least 4 weeks
after the first dose.
Infants born to seropositive mothers: Should receive the first dose within
12 hours of birth (with hepatitis B immune globulin), the second dose at
1–2 months of age, and the third dose at 6–18 months of age.
2 months Diphtheria and tetanus toxoids and acellular
pertussis vaccine (DTaP), inactivated poliovirus
vaccine (IPV), Haemophilus influenzae type
b conjugate vaccine (Hib),1 pneumococcal
conjugate vaccine (PCV), rotavirus vaccine (RV)2
1–2 months HBV The second dose should be given at least 4 weeks after the first dose.
1 2
4 months DTaP, Hib, IPV, PCV, RV
6 months DTaP, Hib,1 PCV, RV2 The third dose of RV is only necessary if RV-5 is used for one or two of the
first two doses.
6–18 months HBV, IPV, influenza The third dose of HBV should be given at least 16 weeks after the first dose
and at least 8 weeks after the second dose, but not before age 24 weeks.
Influenza vaccine should be administered annually to children aged
6 months to 18 years. Live attenuated influenza vaccine cannot be
administered until age 2 years.
12–15 months Measles-mumps-rubella vaccine (MMR), Hib,1 The first dose of MMR may be administered at 6–11 months before depar-
PCV, varicella vaccine ture from the USA for international travel. These infants should receive two
additional doses at the usual interval. Children ≥12 months of age should
receive a second dose at least 4 weeks after the first dose before departure
from the USA for international travel.
15–18 months DTaP DTaP may be given as early as age 12 months if there has been at least
6 months since the third dose.
12–23 months Hepatitis A vaccine Two doses ≥6 months apart.
4–6 years DTaP IPV, MMR, varicella vaccine The second dose of MMR should be routinely administered at age
4–6 years but may be given during any visit if at least 4 weeks have elapsed
since administration of the first dose.
11–12 years Tetanus, diphtheria, pertussis (Tdap) vaccine, Three doses of HPV should be administered to females at 0, 1–2, and
human papillomavirus vaccine (HPV),3 6 months (may be started as early as age 9 years). HPV4 or HPV9 may be
meningococcal conjugate vaccine (MCV) administered to males aged 9–18 years to reduce the likelihood of devel-
oping genital warts. Administer one dose of Tdap to pregnant adolescents
during each pregnancy at 27–36 weeks of gestation. A booster dose of
MCV should be given at age 16 years.
1
Three Hib conjugate vaccines are available for use: (1) oligosaccharide conjugate Hib vaccine (HbOC), (2) polyribosylribitol phosphate-tetanus toxoid conjugate (PRP-T), and
(3) Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate) (PRP-OMP). Children immunized with PRP-OMP at 2 and 4 months of age do not require
a dose at 6 months of age. PRP-T should only be used for the booster dose in children aged 12–15 months.
2
Two RV vaccines are available for use: (1) RV-1 (Rotarix) monovalent live, oral, human attenuated rotavirus vaccine is approved for a two-dose series, and (2) RV-5 (RotaTeq) pentavalent
live, oral, human-bovine reassortant rotavirus vaccine is approved for a three-dose series.
3
Three HPV vaccines are available for use: (1) quadrivalent vaccine (HPV4) and (2) 9-valent vaccine (HPV9) for the prevention of cervical, vaginal, and vulvar cancers (in females)
and genital warts (in males and females), and (3) bivalent vaccine (HPV2) for the prevention of cervical cancers in females.
Adapted from MMWR Morb Mortal Wkly Rep 2013;62(Suppl 1).

hypersensitivity reactions to immune globulin that may limit
therapy. Conventional immune globulin contains aggregates of
IgG; it will cause severe reactions if given intravenously. However,
if the passively administered antibodies are derived from animal
sera, hypersensitivity reactions ranging from anaphylaxis to serum
sickness may occur. Highly purified immunoglobulins, especially
from rodents or lagomorphs, are the least likely to cause reactions.
To avoid anaphylactic reactions, tests for hypersensitivity to the
animal serum must be performed. If an alternative preparation
is not available and administration of the specific antibody is
deemed essential, desensitization can be carried out.
Antibodies derived from human serum not only avoid the risk
of hypersensitivity reactions but also have a much longer half-life
in humans (about 23 days for IgG antibodies) than those from
animal sources (5–7 days or less). Consequently, much smaller
doses of human antibody can be administered to provide thera-
peutic concentrations for several weeks. These advantages point to
the desirability of using human antibodies for passive protection
1180    SECTION X  Special Topics

TABLE A–3  Materials available for passive immunization.1

Indication Product Dosage Comments

Black widow Antivenin (Latrodectus One vial (6000 units) IV or IM. Some For persons with hypertensive cardiovascular disease
spider bite mactans), equine patients may require a repeat dose. or aged <16 or >60 years.
Bone marrow Immune globulin (intra- 500 mg/kg IV on days 7 and 2 prior to Prophylaxis to decrease the risk of infection, intersti-
transplantation venous [IV])2 transplantation and then once weekly tial pneumonia, and acute graft-versus-host disease
through day 90 after transplantation. in adults undergoing bone marrow transplantation.
Botulism Botulism antitoxin hep- Consult the CDC.3 Treatment of symptomatic botulism. Available from
tavalent equine, Types the CDC.3 Incidence of serum reactions is <1%.
A–G
Botulism immune 75 mg/kg IV. For the treatment of patients <1 year of age with
globulin (IV) infant botulism caused by toxin type A or B.
Chronic Immune globulin (IV)2 400 mg/kg IV every 3–4 weeks. Dosage CLL patients with hypogammaglobulinemia and a
lymphocytic should be adjusted upward if bacterial history of at least one serious bacterial infection.
leukemia (CLL) infections occur.
Cytomegalovi- Cytomegalovirus Consult the manufacturer’s dosing Prophylaxis of CMV infection in bone marrow, kidney,
rus (CMV) immune globulin (IV) recommendations. liver, lung, pancreas, and heart transplant recipients.
Diphtheria Diphtheria antitoxin, 20,000–100,000 units IV or IM Early treatment of respiratory diphtheria. Available
equine depending on the severity and duration from the CDC.3 Anaphylactic reactions in ≥7% of
of illness. adults and serum reactions in ≥5–10% of adults.
Hepatitis A Immune globulin (intra- Preexposure prophylaxis: 0.02 mL/kg Preexposure and postexposure hepatitis A
muscular [IM]) IM for anticipated risk of ≥3 months, prophylaxis. The availability of hepatitis A vac-
0.06 mL/kg for anticipated risk of cine has greatly reduced the need for preexposure
>3 months, repeated every 4–6 months prophylaxis. Patients >40 years should receive
for continued exposure. hepatitis A vaccine in addition to immune globulin
for postexposure prophylaxis
Postexposure: 0.02 mL/kg IM as soon as
possible after exposure up to 2 weeks.
Hepatitis B Hepatitis B immune 0.06 mL/kg IM as soon as possible after Postexposure prophylaxis in nonimmune persons
globulin (HBIG) exposure up to 1 week for percutaneous following percutaneous, mucosal, sexual, or perinatal
exposure or 2 weeks for sexual expo- exposure. Hepatitis B vaccine should also be
sure. 0.5 mL IM within 12 hours after administered.
birth for perinatal exposure.
HIV-infected Immune globulin (IV)2 400 mg/kg IV every 28 days. HIV-infected children with recurrent serious bacterial
children infections or hypogammaglobulinemia.
Idiopathic Immune globulin (IV)2 Consult the manufacturer’s dosing Response in children with ITP is greater than in
thrombocyto- recommendations for the specific adults. Corticosteroids are the treatment of choice in
penic purpura product being used. adults, except for severe pregnancy-associated ITP.
(ITP)
Kawasaki Immune globulin (IV)2 400 mg/kg IV daily for 4 consecutive Effective in the prevention of coronary aneurysms.
disease days within 4 days after the onset of For use in patients who meet strict criteria for
illness. A single dose of 2 g/kg IV over Kawasaki disease.
10 hours is also effective.
Measles Immune globulin (IM) Normal hosts: 0.25 mL/kg IM. Postexposure prophylaxis (within 6 days after
exposure) in nonimmune contacts of acute cases.
Immunocompromised hosts: 0.5 mL/kg
IM (maximum 15 mL for all patients).
Primary immu- Immune globulin (IV)2 Consult the manufacturer’s dosing Primary immunodeficiency disorders include specific
nodeficiency recommendations for the specific antibody deficiencies (eg, X-linked agammaglobulin-
disorders product being used. emia) and combined deficiencies (eg, severe
combined immunodeficiencies).
Rabies Rabies immune 20 IU/kg. The full dose should be Postexposure rabies prophylaxis in persons not
globulin infiltrated around the wound and any previously immunized with rabies vaccine. Must be
remaining volume should be given IM combined with rabies vaccine.
at an anatomic site distant from vaccine
administration.

(continued )
 Appendix: Vaccines, Immune Globulins, & Other Complex Biologic Products     1181

TABLE A–3  Materials available for passive immunization.1

Indication Product Dosage Comments

Respiratory syn- Palivizumab 15 mg/kg IM once prior to the For use in infants and children <24 months with
cytial virus (RSV) beginning of the RSV season and once chronic lung disease, hemodynamically significant
monthly until the end of the season. congenital heart disease, or a history of premature
birth (≥35 weeks of gestation).
Rubella Immune globulin (IM) 0.55 mL/kg IM. Nonimmune pregnant women exposed to rubella
who will not consider therapeutic abortion. Admin-
istration does not prevent rubella in the fetus of an
exposed mother.
Scorpion sting Scorpion Immune 3 vials IV over 10 minutes Use as soon as possible after scorpion sting
(Centruroides) F(ab)2
Snake bite Antivenin At least 3–5 vials (30–50 mL) IV initially Neutralizes venom of eastern coral snake and Texas
(coral snake) (Micrurus fulvius), within 4 hours after the bite. Additional coral snake. Serum sickness occurs in almost all
equine doses may be required. patients who receive >7 vials.
Snake bite Antivenin (Crotalidae) An initial dose of 4–6 vials should be For the management of minimal to moderate
(pit vipers) polyvalent immune infused intravenously over 1 hour. The North American crotalid envenomation.
Fab, ovine dose should be repeated if initial control
is not achieved. After initial control, 2
vials should be given every 6 hours for
up to three doses.
Tetanus Tetanus immune Postexposure prophylaxis: 250 units Treatment of tetanus and postexposure prophylaxis
globulin IM. For severe wounds or when there of nonclean, nonminor wounds in inadequately
has been a delay in administration, immunized persons (less than two doses of tetanus
500 units is recommended. toxoid or less than three doses if wound is >24 hours
old).
Treatment: 3000–6000 units IM.
Vaccinia Vaccinia immune Consult the CDC.3 Treatment of severe reactions to vaccinia vaccination,
globulin including eczema vaccinatum, vaccinia necrosum,
and ocular vaccinia. Available from the CDC.3
Varicella Varicella-zoster Weight (kg) Dose (units) Postexposure prophylaxis (preferably within
immune globulin 48 hours but no later than within 96 hours after
≥2 62.5 IM exposure) in susceptible immunocompromised hosts,
2.1–10 125 IM selected pregnant women, and perinatally exposed
newborns.
10.1–20 250 IM
20.1–30 375 IM
30.1–40 500 IM
≥40 625 IM
1
Passive immunotherapy or immunoprophylaxis should always be administered as soon as possible after exposure. Prior to the administration of animal sera, patients should be
questioned and tested for hypersensitivity.
2
See the following references for an analysis of additional uses of intravenously administered immune globulin: Ratko TA et al: Recommendations for off-label use of intravenously
administered immunoglobulin preparations. JAMA 1995;273:1865; and Feasby T et al: Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus
Med Rev 2007;21(2 Suppl 1)S57.
3
Centers for Disease Control and Prevention, 404-639-3670 during weekday business hours; 770-488-7100 during nights, weekends, and holidays (emergency requests only);
http://www.cdc.gov/laboratory/drugservice/formulary.html. Clinicians who suspect a diagnosis of botulism should immediately call their state health department’s 24-hour
emergency number.

whenever possible. Materials available for passive immunization
are summarized in Table A–3.
LEGAL LIABILITY FOR UNTOWARD
REACTIONS
It is the physician’s responsibility to inform the patient of the
risk of immunization and to use vaccines and antisera in an
appropriate manner. This may require skin testing to assess
the risk of an untoward reaction. Some of the risks previously
described are, however, currently unavoidable; on balance, the
patient and society are clearly better off accepting the risks for
routinely administered immunogens (eg, influenza and tetanus
vaccines).
Manufacturers should be held legally accountable for failure to
adhere to existing standards for production of biologicals. How-
ever, in the present litigious atmosphere of the USA, the filing of
large liability claims by the statistically inevitable victims of good
public health practice has caused many manufacturers to abandon
1182    SECTION X  Special Topics
efforts to develop and produce low-profit but medically valuable
therapeutic agents such as vaccines. Since the use and sale of these
products are subject to careful review and approval by govern-
ment bodies such as the Surgeon General’s Advisory Committee
on Immunization Practices and the US Food and Drug Admin-
istration, “strict product liability” (liability without fault) may be
an inappropriate legal standard to apply when rare reactions to
biologicals, produced and administered according to government
guidelines, are involved.
RECOMMENDED IMMUNIZATION OF
ADULTS FOR TRAVEL
Every adult, whether traveling or not, should be immunized
with tetanus toxoid and should also be fully immunized against
poliomyelitis, measles (for those born after 1956), and diphtheria.
In addition, every traveler must fulfill the immunization require-
ments of the health authorities of the countries to be visited. These
are listed in Health Information for International Travel, avail-
able from the Superintendent of Documents, US Government
Printing Office, Washington, DC 20402. A useful website is
http://wwwnc.cdc.gov/travel/. The Medical Letter on Drugs and
Therapeutics also offers periodically updated recommendations for
international travelers (see Treatment Guidelines from The Medical
Letter, 2012;10:45). Immunizations received in preparation for
travel should be recorded on the International Certificate of
Immunization. Note: Smallpox vaccination is not recommended
or required for travel in any country.
REFERENCES
Ada G: Vaccines and vaccination. N Engl J Med 2001;345:1042.
Advice for travelers. Med Lett Drugs Ther 2012;10:45.
Centers for Disease Control and Prevention websites: http://www.cdc.gov/
vaccines/ and http://wwwnc.cdc.gov/travel/.
Dennehy PH: Active immunization in the United States: Developments over the
past decade. Clin Micro Rev 2001;14:872.
Gardner P, Peter G: Vaccine recommendations: Challenges and controversies.
Infect Dis Clin North Am 2001;15:1.
Gardner P et al: Guidelines for quality standards for immunization. Clin Infect
Dis 2002;35:503.
General recommendations on immunization. Recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR Morb Mortal
Wkly Rep 2011;60(2):1.
Hill DR et al: The practice of travel medicine: Guidelines by the Infectious
Diseases Society of America. Clin Infect Dis 2006;43:1499.
Keller MA, Stiehm ER: Passive immunity in prevention and treatment of
infectious diseases. Clin Microbiol Rev 2000;13:602.
Kim DK, Bridges CB, Harriman KH: Advisory Committee on Immunization
Practices recommended immunization schedule for adults aged 19 years or
older—United States, 2016. MMWR Morb Mortal Wkly Rep 2016;65:88.
Pickering LK et al: Immunization programs for infants, children, adolescents,
and adults: Clinical practice guidelines by the Infectious Diseases Society of
America. Clin Infect Dis 2009;49:817.
Robinson CL: Advisory Committee on Immunization Practices recommended
immunization schedules for persons aged 0 through 18 years—United States,
2016. MMWR Morb Mortal Wkly Rep 2016;65:86.
Rubin LG et al: 2013 IDSA clinical practice guideline for vaccination of the
immunocompromised host. Clin Infect Dis 2014;58:309.
Zumula A et al: Travel medicine. Infect Dis Clin North Am 2012;26:575.
Index
Note: In this index, the letters “b,” “f  ,” and “t ” denote text box, figures, and tables, respectively.

A Acetohexamide, 758, 768t. See also azelaic acid, 1078

Abacavir Sulfonylureas benzoyl peroxide, 1078
description of, 870, 871t Acetylator, slow, 68 brimonidine, 1078
HLA polymorphisms in hypersensitivity Acetylcholine (ACh), 35, 372. isotretinoin, 1077–1078
reactions to, 80t, 83t, 83–84, 84f See also Neuromuscular retinoic acid derivatives, 1077
Abaloparatide, 775, 790t blocking drugs Aconite, 1133t
Abarelix, 678–679 in CNS, 374f, 376t, 378 Acquired immunodeficiency syndrome
Abatacept, 649–650, 994 functions of, 92t (AIDS), 984–985. See also
Abbreviations, prescriptions, and chart structure of, 109, 109f, 476f Human immunodeficiency
order, 1149t Acetylcholine-blocking drugs, 124, virus (HIV)
ABC (ATP-binding cassette) family, 8 for parkinsonism, 501t, Acromegaly
ABCG2, 83 501–502, 508t description of, 672
ABCG5 mutation, 631 Acetylcholinesterase (AChE) dopamine agonists for, 679–680
ABCG8 mutation, 631 cholinomimetics on, 108f, 109 Action potential-prolonging drugs
Abciximab, 621, 995 description of, 95, 372 (class 3), arrhythmia treated
Abiraterone Acetylcholinesterase inhibitors, 5, 120 with, 243–245, 251t
adrenocortical antagonist actions of, Acid, weak amiodarone, 239t, 240t, 243–244,
704f, 716–717 examples of, 10t 251t
antiandrogen actions of, 743, 745t ionization of, 9–10 dofetilide, 239t, 240t, 245, 251t
prostate cancer treated with, 972 Acidosis, metabolic dronedarone, 239t, 240t, 244, 251t
Abortion, eicosanoids for, 334 hyperchloremic ibutilide, 239t, 240t, 245, 251t
Abraxane, 963 from carbonic anhydrase inhibitors, preparations available, 252t
Absence seizures, 410 261 sotalol, 239t, 240t, 244–245, 251t
Absorption, 7 from potassium-sparing diuretics, Action potentials
extent of, 47, 47f, 47t 267 cardiac, sodium channels in, 231f,
percutaneous, 1069f Acid-peptic disease, 1087 231–232
rate of, 47f, 48 Acid-peptic disease drugs, 1087–1095, resting potentials on, 232–233,
on target concentration, 52 1115t 233f
Abstinence syndrome, 559 intragastric acidity-reducing agents, Activated charcoal, 1040
Abuse, drug, 575. See Drugs of abuse 1087–1095, 1115t Activated partial thromboplastin time
Acamprosate, 404, 406t, 407t acid secretion, 1087–1088, 1088f (aPTT, PTT), 612, 613
Acarbose, 761, 768t antacids, 1088–1089 Activated protein C, 624
Acceptable daily intake (ADI), 1004 H2-receptor antagonists, 1089–1091 Activator. See also Agonist; specific
Accumulation, drug, 46f, 46–47 proton-pump inhibitors, activators
Accumulation factor, 47 1091–1095 allosteric, 5, 6f
Acebutolol, 164t. See also b-receptor mucosal protective agents chloride channel, 1099, 1103
antagonist drugs bismuth compounds, 1096 tissue plasminogen, 611, 611f, 619
description of, 164t, 166, 170t mechanisms of, 1095 Active immunization
hypertension treated with, 183 prostaglandin analogs, 1096 childhood, recommended schedule for,
Acetaldehyde, 397f, 398 sucralfate, 1095 1175, 1179t
Acetaminophen, 659, 664t Acid reducers, OTC definition of, 1175
case study regarding, 56, 73 H2-antagonists, 1122t Activin
metabolism of, 64, 65f proton-pump inhibitors, 1122t in ovary, 732
in neonates, 1053t Acid-reducing agents, 1157t in testis, 740
poisoning management for, 65f, 1040, Acid secretion, gastrointestinal, Acute angle-closure glaucoma, 118
1041t 1087–1088, 1088f Acute colonic pseudo-obstruction, 1097
preparations available, 664t Acitretin, 1078 Acute coronary syndrome
Acetazolamide Aclidinium, 130, 354, 359 description of, 195
description of, 260–261, 270, 272t Acne preparations vasodilators for, 207–208
epilepsy treated with, 432 antibacterial, 1071–1072 Acute dystonic reactions, 522

1183
1184    Index
Acute heart failure, 223–224. See also Heart
failure
Acute kidney injury, 254, 275
Acute lymphoblastic leukemia (ALL), 969
Acute mountain sickness, 260–261
Acute myelogenous leukemia (AML), 969,
974, 977
Acute myocardial infarction
from female hormonal contraceptives,
735
thrombolytics for, 619, 619b
Acute renal failure
loop diuretics for, 263
from potassium-sparing diuretics, 267
Acyclovir
herpes simplex virus treated with, 865t,
866, 866f
topical dermatologic, 1074
varicella zoster virus treated with, 865t,
866, 866f
Adalimumab
description of, 993
inflammatory bowel disease treated with,
1110–1112, 1111t
psoriasis treated with, 1079
rheumatic disorders treated with,
652–654, 654f
Adapalene, 1077
Adaptive immune system, 979f, 979–980,
981f, 982f
Addiction, 575. See also Drugs of abuse
animal models of, 575
clinical pharmacology of, 587–588
definition of, 575
dopamine hypothesis of, 579b
dopamine transporter in, 576, 576f, 577t
as maladaptive learning, 577t, 578–580
nicotine, 583–584
opioid, 566
receptors in, 576
Gio protein-coupled, 576, 577f
ionotropic, 576, 577f, 577t
relapse in, 578
Addison’s disease, 709–710
Adefovir dipivoxil, 886
Adenohypophysis, 667, 668f
Adenosine
arrhythmia treated with, 239t, 240t,
246–247, 251t
in central nervous system, 380
on kidney, 259
vasodilator actions of, 206b
Adenosine deaminase (ADA) deficiency,
984
Adenosine diphosphate, 608
Adenosine triphosphate (ATP)
in central nervous system, 380
functions of, 92t
Adenylyl cyclase, 30, 139, 140f
Adherence (compliance), 1150–1151
Adjuvant chemotherapy, 950
Administration
alternative routes of, first-pass effect in,
47t, 48
rate of, 51
Ado-trastuzumab emtansine, 972, 993
Adrenal androgens, 715
Adrenal cortex, 303
Adrenal steroid inhibitors
mineralocorticoid antagonists, 265,
717
preparations available, 718t
synthesis inhibitors and glucocorticoid
antagonists, 715–717
Adrenergic fibers, 90f, 93
Adrenergic neuron-blocking agents
guanethidine, 181–182, 191t
reserpine, 179t, 182, 191t
Adrenergic neurons
cotransmitters in, 97–98
description of, 95, 96f–97f
Adrenergic transmission, 95–97,
96f–97f
Adrenoceptor, 98, 99t, 138–142
alpha, 138f, 139, 139t
beta, 139t, 139–140, 140f
biased agonists at, 141, 142b
definition of, 98
desensitization of, 141
dopamine, 139t, 140
polymorphisms of, 142
regulation of, 141
selectivity and affinities of, 141, 141t
structure of, 138, 138f
Adrenoceptor agonist drugs,
137–155, 154t. See also
Sympathomimetics
alpha-receptor antagonists, 156–162,
170t–171t.
beta-receptor antagonists, 162–170,
170t–171t.
thyroid, action of beta blockers 696
Adrenocortical antagonists, 715–717
abiraterone, 716–717
aminoglutethimide, 715, 716f
etomidate, 715
ketoconazole, 715, 716f
metyrapone, 716, 716f
mifepristone (RU-486), 717
mineralocorticoid antagonists, 717
mitotane, 716f, 717
preparations available, 718t
trilostane, 716
Adrenocortical insufficiency
acute, 710
chronic (Addison’s disease), 709–710
Adrenocorticosteroids, 703–715. See also
specific types
classification of, 703
corticosteroids, synthetic, 709–714.
See also Corticosteroids, synthetic
glucocorticoids, naturally occurring,
704–709. See also Glucocorti-
coids, naturally occurring
structures and properties of, 703, 704f
Adrenocorticotropic hormone (ACTH),
668f, 668–669, 669t
adrenocortical steroids versus, 713
diagnostic uses of, 670t
Adrenomedullin (AM), 315
Adverse drug event (ADE), 18
Adverse drug reaction (ADR), 18, 65
Adverse effects, 39
Afatinib, 968
Affordable Care Act (ACA), 1155
African trypanosomiasis drugs
antiprotozoal, 931–935, 932t–933t.
See also Antiprotozoal drugs
benznidazole, 933t, 934
eflornithine, 931t, 934
melarsoprol, 931t, 934
pentamidine, 931, 931t, 933
suramin, 931t, 934
Afterload, 215f, 216
Agatoxin, 370t
Age
in drug metabolism, 70
on physiologic function, 1059, 1059f
Age-related macular degeneration drugs
with Alzheimer’s and hypertension,
1058, 1067
in elderly, 1065
Aging
androgens and anabolic steroids for, 742
molecular basis of, 1058
pharmacology in, 1058–1067. See also
Geriatric pharmacology
Agitation, antipsychotics for, 519. See also
Antipsychotic agents
Agomelatine, 287b
Agonist, 5, 6f. See also specific types
biased, 141
at beta receptors, 142b
binding molecule inhibition by, 5
definition of, 3, 20
drugs as mediators of, 20
full, 5, 6f
inverse, 5–6, 7f
partial, 5–6, 6f, 24–25, 25f
receptor binding of, concentration-effect
curves and, 21–22, 22f
Agonist-antagonist property, mixed,
25, 25f
Agranulocytosis, 695

Air pollutants, 1006–1009
carbon monoxide, 1006–1007, 1007t
nitrogen oxides, 1007t, 1008
ozone and other oxides, 1007t,
1008–1009
permissible exposure limit values of,
1007t
sources of, 1006
sulfur dioxide, 1007, 1007t
Akathisia
antipsychotics as cause of, 522
tardive, 506
Akinesia, end-of-dose, 497
ALA photodynamic therapy, 1084
Albendazole, for helminths, 938–940, 939t
Albiglutide, 762, 769t
Albumin concentration, in protein
binding, 53
Albuterol, 154t. See also Sympathomimetics
asthma treated with, 351, 359, 362t
structure of, 350f
Alcohol(s), 396–408, 406t
antisepsis and disinfection uses of, 898,
898t
drug interactions with, 402, 1157t
ethanol (ethyl alcohol), 396–404.
See also Ethanol
ethylene glycol, 405–406, 406t
isopropyl alcohol, 405
methanol, 405, 405f, 406t
in OTC agents, 1129t
psychological dependence on, 400
Alcohol abuse, 396–397. See also Ethanol
ionotropic receptors in, 585
pharmacology of, 584–585
treatment of, 404, 406t, 407t, 585, 589t
Alcohol dehydrogenase inhibitor, for
methanol poisoning, 405, 406t
Alcohol dehydrogenase pathway, 397, 397f
Alcoholic liver disease, 400
Alcohol-use disorder, 396, 406t–407t.
See also Ethanol
Aldactazide, 266t
Aldactone, 266t
Aldehyde dehydrogenase (ALDH), 67t
Aldehydes, 900
Aldosterone, 703, 714–715
Aldosterone antagonists, 224t, 226t, 265
Aldosteronism, 710–711
Alemtuzumab, 991
Alendronate
bone metastases treated with, 789t
hypercalcemia treated with, 789t
osteoporosis treated with, 780b, 786,
789t
Paget’s disease of bone treated with, 789
Alfentanil, 555t, 567, 572t. See also Opioid
agonists
Alfuzosin, 160
Alirocumab, 638, 995
Aliskiren
heart failure treated with, 220
hypertension treated with, 192t, 193t
on renin-angiotensin system, 305
on vasoactive peptides, 316t
Alitretinoin, dermatologic, 1085
Alkaloids, cholinomimetic, 109, 110f.
See also specific types
Alkalosis, metabolic, 260–261
hypokalemic, 263, 265
Alkylating agents, 953–957
adverse effects of, 954
bendamustine, 956
dacarbazine, 956
mechanism of action of, 953–954,
954f
nitrosoureas, 953f, 954, 956
platinum analogs, 955t, 956–957
procarbazine, 955t, 956
resistance to, 954
structures of, 953, 953f
Allan-Herndon-Dudley syndrome, 690
Allele, 75t
Allele frequency, 75t
Allergic rhinitis, 283
Allergic rhinoconjunctivitis, 356, 362t
Allergy preparations, OTC, 1122t
Allium sativum, 1135–1136
Allopurinol, 71, 83
angina pectoris treated with, 207,
210t
drug interactions of, 1157t
gout treated with, 661–662, 662f
hypercalciuria treated with, 788
Allosteric activator, 5, 6f
Allosteric inhibitor, 5, 6f
Allosteric modulators, 21
negative, 5, 6f, 24
positive, 5, 6f, 24
Allylamines
dermatologic topical, 1073
terbinafine, 861t
topical antifungal, 860–861, 861t
Almorexant, 390b
Almotriptan, 291t, 296t
Aloe, 1099
Alogliptin, 763, 769t
Alosetron
chemical structure of, 1102f
irritable bowel syndrome treated with,
1102, 1102f
α1-acid glycoprotein concentration, 53
α1 adrenoceptor
activation of, 138, 138f
cardiovascular system activation by,
144–145, 146f, 146t, 147f
Index    1185
α adrenoreceptor
affinities of, 141, 141t
description of, 99, 99t, 138f, 139,
139t
α-adrenoreceptor antagonists, 156–162,
170t
alfuzosin, 160
chlorpromazine and haloperidol, 160
clinical pharmacology of, 160–162
α2 antagonist applications, 162
erectile dysfunction, 162
hypertension, chronic, 161
hypertensive emergencies, 161
peripheral vascular disease, 161
pheochromocytoma, 160–161, 161f
urinary obstruction, 161
doxazosin, 159, 159t
ergotamine and dihydroergotamine,
160
hypertension treated with, 184, 191t
indoramin, 160
labetalol and carvedilol, 160
mechanism of action in, 156–157
pharmacologic effects of
cardiovascular, 157, 158f
other, 157, 159
phenoxybenzamine, 159, 159t
phentolamine, 159, 159t
prazosin, 159, 159t
preparations available, 171t
silodosin, 160
structure and mechanism of action in,
158f
tamsulosin, 159t, 159–160
terazosin, 159, 159t
trazodone, 160
urapidil, 160
yohimbine, 160
α-amino-3-hydroxy-5-methylisoxazole-
4-propionic acid, 375
α-bungarotoxin, 370t
α-glucosidase inhibitors, 761, 768t
α-linolenic acids, 337
α-methyldopa, 154t. See also
Sympathomimetics
α1-selective adrenoceptor agonists, 154t
α2-selective adrenoceptor agonists, 149,
154t. See also Sympathomimetics,
direct-acting
α1-selective adrenoreceptor antagonists,
179t, 184, 193t
α2-selective adrenoreceptor antagonists,
162
α-synuclein, 493
Alprazolam, 384, 385t, 390, 393t. See also
Benzodiazepines
structure of, 382f
tremor treated with, 503
1186    Index
Alprostadil (PGE1), 323
erectile dysfunction treated with, 200b,
335
patent ductus arteriosus treated with, 335
structure of, 333f
Alteplase, 619
Alternative health care, 3
Altretamine, 955t
Aluminum hydroxide, 1089
Alveolar-venous partial pressure difference,
444–445, 445f
Alveolar ventilation, 443–444, 444f
Alvimopan
description of, 571, 572t
laxative action of, 1099–1100
Alzheimer’s disease, 1062f, 1062–1063,
1063t
drugs for
antipsychotics, 519. See also
Antipsychotic agents
in elderly, 1062f, 1062–1063, 1063t
tacrine, 120
epidemiology of, 1062
with hypertension and age-related
macular degeneration, 1058, 1067
mechanisms of, 1062, 1062f
prevention and treatment of,
1062–1063, 1063t
Amantadine
influenza treated with, 892
parkinsonism treated with, 501
Ambrisentan, 312, 313b, 317t. See also
Endothelin inhibitors
Amebiasis drugs, 928–931
diloxanide furoate, 929t, 930f, 930–931
emetine and dehydroemetine, 929t, 931
iodoquinol, 929t, 930, 930f
metronidazole and tinidazole, 929t,
929–930, 930f
paromomycin sulfate, 929t, 930f, 931
preparations available, 936t
Amenorrhea, 726, 735
American trypanosomiasis drugs
benznidazole, 934
nifurtimox, 933t, 934–935
Amides, 61t
Amikacin
description of, 827f, 831, 833t
tuberculosis treated with, 843t, 848
Amiloride
diuresis using, 265f, 265–267, 273t
drug interactions of, 1170t–1171t
Amine
primary, 9, 60t
quaternary, 9
reversible protonation of, 9
secondary, 9, 60t
tertiary, 9, 60t
Amine hypothesis, for depression, 533,
534–536, 535f
Amine oxidases, 61t
Amino acid neurotransmitters, CNS, 375.
See also specific types
GABA and glycine, 375–378, 376t
glutamate, 375, 376t, 377f
Aminocaproic acid (EACA)
coagulation disorders treated with, 611f,
623
fibrolysis treated with, 611, 611f
Aminoglutethimide, 715, 716f
Aminoglycosides, 826–832, 833t
adverse effects of, 829
amikacin, 827f, 831
clinical uses of, 829
gentamicin, 827f, 830–831
mechanism of action of, 826–827, 828f
mechanisms of resistance of, 827–828
neomycin and kanamycin, 831–832
netilmicin, 827f, 831
pharmacokinetics and once-daily dosing
of, 828–829
physical and chemical properties of,
826, 827f
preparations available, 833t
streptomycin, 827f, 829–830
tobramycin, 827f, 831
Aminolevulinic acid, for actinic keratoses,
1084
Aminopenicillins, 801. See also Penicillin(s)
Aminophylline, 352
Aminosalicylates, 1106–1109, 1107f, 1116t
adverse effects of, 1108–1109
chemistry and formulations of,
1106–1108, 1107f
clinical uses of, 1108
pharmacokinetics and pharmacodynamics
of, 1108
5-Aminosalicylic acid (5-ASA), 1106–1109,
1107f, 1116t
Aminosalicylic acid (PAS), 843t, 848
Amiodarone, 239t, 240t, 243–244, 251t
Amiodarone-induced thyrotoxicosis, 700
Amitriptyline
blocking effects of, 542t
dosing of, 546t
migraine headache prophylaxis using, 291
pharmacokinetics of, 540t
Amlodipine
angina pectoris treated with, 203t,
206. See also Calcium channel
blockers
hypertension treated with, 179t, 187
Ammonium compounds, quaternary,
899–900
Amnesia, 447b
Amobarbital, 393t. See also Barbiturates
Amodiaquine, 919f, 920t, 921
Amoxapine, 540t, 541, 542t, 546t, 549,
550t. See also Antidepressant
agents; Tetracyclic agents
Amoxicillin, rash from, 795, 814
AMPA, CNS, 375
AMPA receptors, CNS, 375
Amphetamines, 144f, 150. See also specific
types
abuse of, 577t, 581
biogenic amine binding in, 586f,
586–587
noradrenergic transmitter release by, 95
poisoning management for, 1041–1042
structure of, 144f
Amphotericin B, 853–854, 861t
adverse effects of, 855–856
antifungal activity and clinical uses of,
855
chemistry and pharmacokinetics of,
853–854, 854t
dermatologic topical, 1073
lipid formulations of, 854b, 854t
mechanisms of action and resistance to,
854–855, 855f
preparations available, 862t
AMP kinase activation, 638
Amplification, 35
Amylin, 747
Amyl nitrite, 198, 202t. See also Nitrates
and nitrites
Amyloid beta (Ab) peptide, 1062
Anabolic steroids, 740. See also Androgens
and anabolic steroids
abuse of, in sports, 742
preparations available, 741t, 745t
Anacetrapib, 638
Anakinra, 657, 994
Analgesia
in general anesthesia, 446
opioids for, 555t, 563. See also Opioid
agonists
Analgesics. See also Opioid(s); specific types
acetaminophen, 56, 64, 65f, 73, 659,
664t
disease-modifying antirheumatic drugs,
649–659, 664t
in elderly, 1061
gout agents, 659–663, 664t
ketorolac, 659
nonsteroidal anti-inflammatory drugs,
643–649, 645t, 664t
novel targets for, ion channels and, 560b
opioid agonists, 567–569, 572t. See also
Opioid agonists
OTC, 1123t
preparations available, 664t
tramadol, 659

Analytic epidemiologic studies, 15b
Anaphylaxis
histamine in, 281
sympathomimetics for, 152–153
Anastrozole, 739, 971
Andexanet alfa, 617
Androgen receptor inhibitors, 744f,
744–745, 745t
Androgen replacement therapy, in men,
741t, 741–742
Androgens
adrenal, 715
ovarian, 732
Androgens and anabolic steroids, 740–743.
See also specific types
adverse effects of, 742–743
clinical uses of
aging, 742
androgen replacement therapy, in
men, 741t, 741–742
androgen steroid and androgen abuse,
sports, 742
anemia, 742
growth stimulators, 742
gynecologic disorders, 742
osteoporosis, 742
protein anabolic agents, 742
contraindications and cautions with, 743
mechanism of action of, 741
metabolism of, 740–741
pharmacologic effects of, 741
physiologic effects of, 741
preparations of, 741, 741t, 745t
synthesis of, 704f, 722f, 740
synthetic steroids with androgenic and
anabolic action, 741, 741t
Androgen steroid abuse, in sports, 742
Androgen suppression, 743, 744f, 745t
Androstenedione
metabolism of, 740–741
synthesis of, 740
in women, 732
Anemia
iron-deficiency, 592–596, 593f, 594t
lead exposure as cause of, 1022
nutritional, 594t, 594–595, 605t–606t
pernicious, 598. See also Vitamin B12
deficiency
Anemia drugs, 591–600. See also specific
agents
androgens and anabolic steroids, 742
folic acid, 598–600, 599b, 599f
iron, 592–596, 593f, 594t
preparations available, 607t
vitamin B12, 596–598, 597f
Anesthesia
amnesia in, 447b
balanced, 440, 449
case study of, 459, 473
consciousness in, 447b
with hypertension and coronary artery
disease, 440
immobility in, 447b
minimum alveolar concentration in,
443t, 446, 447b
monitored anesthesia care in, 440, 441b
opioids for, 563–564
primary effects of, 440
sedation in, 441b
surgical, 446
Anesthetics, general, 440–458. See also
specific types
inhaled, 441–449
intravenous, 449–457
mechanism of action of, 440–441
preparations available, 458t
Anesthetics, inhaled, 441–449
pharmacodynamics of
cardiovascular effects, 447–448
cerebral effects, 446
renal and hepatic effects, 448
respiratory effects, 448
uterine smooth muscle effects, 448
pharmacokinetics of, 441–446
elimination in, 443t, 445–446
structures of, 443f
uptake and distribution in, 442–446,
443f–445f, 443t
potency of, 443t, 445, 447b
targets of, putative, 441, 442f
toxicity of, 448–449
volatile vs. gaseous, 441
Anesthetics, intravenous, 449–457
balanced anesthesia in, 440, 449
barbiturates, 442f, 450t, 451f, 453–454
benzodiazepines, 389, 451f, 454–455
current clinical practice in, 457
dexmedetomidine, 450t, 457
etomidate, 450f, 450t, 455
fospropofol, 452–453
fundamentals of, 449
ketamine, 450f, 450t, 456–457
opioid analgesics, 457
propofol, 450f, 450t, 450–452
sedative-hypnotics, 388–389
Anesthetics, local, 459–473
chemistry of, 459–461, 460f
clinical pharmacology of, 466–469
clinical block characteristics in,
466–467
injection sites for, 465, 466f
lipid resuscitation in, 469b
toxicity of, 463f, 467–469
commonly used, 460t, 462t, 469–471,
472t
articaine, 460t, 469–470
Index    1187
benzocaine, 460t, 470
bupivacaine, 460t, 462t, 470, 472t
chloroprocaine, 470, 472t
cocaine, 460t, 470, 472t
EMLA, 471
etidocaine, 470
levobupivacaine, 470
lidocaine, 460t, 462t, 471, 472t
mepivacaine, 460t, 462t, 471
prilocaine, 462t, 471, 472t
ropivacaine, 460t, 462t, 471, 472t
future developments in
reduced toxicity and greater selectivity
in, 471
sustained-release formulations in,
471
historical development of, 461b
in OTC agents, 1129t
pharmacodynamics of
mechanism of action in, 462f,
463–464
neuronal factors affecting block in,
465
structure-activity characteristics in,
464–465
pharmacokinetics of, 461–463
absorption in, 462, 463f
distribution in, 462–463
metabolism and excretion in,
462t, 463
structure and properties in,
460t, 462t
preparations available, 472t
Angina of effort, vasodilators for, 208,
208f, 209t
Angina pectoris, 194–197
definition of, 194
etiology of, 194
pathophysiology of, 195–196
coronary blood flow and myocardial
oxygen supply in, 195
myocardial oxygen demand in, 195,
195t
vascular tone in, 195t, 195–196,
196f, 197f
types of
classic, 194
effort, 194
unstable, 195
vasospastic, 194
variant
ergot alkaloids for diagnosis of,
295
nitrate effects in, 201
vasodilators for, 194–210, 209t–210t
Angioedema
description of, 284
hereditary, kinins in, 307
1188    Index

Angiotensin, 300–303 Antagonism magnesium, 247, 251t

biosynthesis of, 300–303, 302f
angiotensin I in, 302f, 302–303
converting enzyme in, 303
renin in, 300–301
renin release in, control of, 301–302,
302f
renin-angiotensin system inhibition by,
304–305
on renin release, 301
Angiotensin antagonists, 224t
Angiotensin-converting enzyme (ACE),
303
Angiotensin-converting enzyme inhibitors
(ACEIs). See also specific types
heart failure treated with, 212, 220,
224t, 227
chronic, 222
preparations available, 226t
hypertension treated with, 179t,
187–189, 192t, 193t
immediate effects of, 48–49, 49f
preparations available, 193t
on renin-angiotensin system, 304–305
on vasoactive peptides, 316t
Angiotensin I, 302f, 302–303
Angiotensin II
on adrenal cortex and kidney, 303
on blood pressure, 175, 303
on cell growth, 304
on central nervous system, 304
Angiotensin II inhibitors, for hypertension,
187–189
Angiotensin inhibitors, 176, 187–189
angiotensin-converting enzyme inhibitors,
179t, 187–189, 192t–193t
angiotensin receptor blockers, 179t, 189,
192t, 193t, 304–305
mechanisms and sites of action of, 187,
188f
Angiotensin receptor, 304
Angiotensin receptor blockers (ARBs)
heart failure treated with, 220, 224t
chronic, 222
preparations available, 226t
hypertension treated with, 179t, 189,
192t–193t
on renin-angiotensin system, 304–305
on vasoactive peptides, 316t
Anidulafungin, 859, 861t
Anion inhibitors, thyroid, 695
Anion overdose, 263
Anistreplase, 611f
Anorgasmia, 547
Antacids
drug interactions of, 1157t
OTC, 1123t
preparations available, 1117t
in antimicrobial drug, 912–913
chemical, 25
neutral, 6
physiologic, 25–26
Antagonist. See also specific types
chemical, 3
competitive, 23f, 23–24
definition of, 3, 20–21
irreversible, 23f, 24
noncompetitive, 23f, 24
pharmacologic, 5, 6f
Antagonist-precipitated withdrawal, 565
Anterior pituitary hormones, 668–680,
682t–684t. See also Pituitary
hormones, anterior
Anthelmintic drugs, 938–947
Anthracyclines, 962t, 964–965
Anthraquinone derivative laxatives, 1099
Antiandrogens, 743–745, 745t
receptor inhibitors, 744f, 744–745,
745t
steroid precursor conversion to andro-
gens in, inhibitors of, 743–744,
744f, 745t
steroid synthesis inhibitors, 743, 744f,
745t
Antiarrhythmic agents, 236–252. See also
specific agents
action potential-prolonging drugs
(class 3), 243–245, 251t
amiodarone, 239t, 240t, 243–245,
251t
dofetilide, 239t, 240t, 245, 251t
dronedarone, 239t, 240t, 244, 251t
ibutilide, 239t, 240t, 245, 251t
sotalol, 239t, 240t, 244–245, 251t
beta-adrenoceptor-blocking drugs
(class 2), 243, 251t
calcium channel-blocking drugs (class 4),
245–246, 251t
diltiazem, 239t, 240t, 246, 251t
verapamil, 239t, 240t, 245–246,
251t
chloride channel drugs, 248
classification and overview of, 237, 239t,
250t–251t
clinical use of
atrial fibrillation, 249b
benefits and risks in, 249
conduct of therapy in, 249
pretreatment evaluation in, 248–249
in elderly, 1064
mechanisms of action of, 233f, 236–239,
238f
miscellaneous
adenosine, 239t, 240t, 246–247, 251t
ivabradine, 247
potassium, 247, 251t
ranolazine, 247
preparations available, 251t
sodium channel-blocking drugs, class 1,
237–243, 239t, 240t, 251t
class 1A
disopyramide, 239t, 240t,
240–241, 250t
procainamide, 237–239, 239t,
240t, 250t
quinidine, 239t, 240, 240t, 250t
class 1B
lidocaine, 239t, 240t, 241f,
241–242, 250t
mexiletine, 239t, 240t, 242, 250t
class 1C
flecainide, 239t, 240t, 242, 251t
moricizine, 243, 251t
propafenone, 239t, 240t, 242–243,
251t
Antiatherogenesis, nitric oxide for,
342–343, 343f
Antibacterial agents, topical dermatologic
acne treated with
clindamycin, 1071
dapsone, 1072
erythromycin, 1071
metronidazole, 1071
sodium sulfacetamide, 1071–1072
bacitracin and gramicidin, 1070
fundamentals of, 1070
mupirocin, 1070
neomycin and gentamicin, 1071
polymyxin B sulfate, 1070–1071
retapamulin, 1070
Antibiotic resistance, 793
Antibiotics, 793. See also Antimicrobial
agents; specific antibiotic
antitumor
anthracyclines, 962t, 964–965
bleomycin, 962t, 965–966
mitomycin, 962t, 965
malaria treated with
clindamycin, 928
doxycycline, 920t, 927–928
spiramycin, 928
Antibodies
description of, 979, 980, 982f
immunosuppressive, 990–991
antilymphocyte and antithymocyte,
990
chimeric molecules, 990
development of, 990
hyperimmune immunoglobulins, 991
immune globulin intravenous,
990–991
Rh0(D) immune globulin, 991

Anticholinergic agents, 124. See also specific
agents
antiemetic properties of, 1106
irritable bowel syndrome treated with,
1101–1102
poisoning management for, 1041t, 1042
Anticoagulants, 611–618, 624t. See also
specific drugs
direct factor Xa inhibitors, oral, 616–617
direct thrombin inhibitors
oral, 618
parenteral, 617–618
indirect thrombin inhibitors, heparin,
612f, 612–616
oral, drug interactions of, 1158t–1159t
pharmacology of, basic, 614–617
warfarin and other coumarins, 614–616
Anticonvulsants, 389. See also Antiseizure
drugs
Antidepressant agents, 532–552, 549t–550t.
See also specific agents
chemistry and subgroups of, 536–539
5-HT2 receptor modulators, 538
monoamine oxidase inhibitors, 539
selective serotonin reuptake inhibitors,
536, 537f
serotonin-norepinephrine reuptake
inhibitors
selective serotonin-norepinephrine
reuptake inhibitors, 536–537
tricyclic antidepressants, 537, 538f
tetracyclics, 538–539, 539f
unicyclic, 538–539, 539f
clinical pharmacology of, 543–549
adverse effects of
5-HT receptor modulators, 547
MAO inhibitors, 547
SNRIs and tricyclic antidepressants,
547
SSRIs, 546–547
tetracyclic and unicyclic agents,
547
clinical indications in
anxiety disorders, 544
depression, 543–544
eating disorders, 545
other uses, 545
pain disorders, 544
premenstrual dysphoric disorder,
544
smoking cessation, 544
dosing of, 546, 546t
drug interactions in
5-HT receptor modulators,
548–549
MAO inhibitors, 549
SNRIs and tricyclic antidepressants,
548
SSRIs, 548, 548t
tetracyclic and unicyclic,
548t, 549
overdose in, 547–548
selection of, 545
drug interactions of
heterocyclic antidepressants, 1159t
tricyclic antidepressants, 1159t
in elderly, 542t, 1061–1062
indications for, 532
on NET, 95
non-depression uses of, 533
pathophysiology of depression and, 533f,
533–536, 535f
pharmacodynamics of, 541–543
5-HT receptor modulators, 542t, 543
MAO inhibitors, 542t, 543
SNRIs, 542, 542t
SSRIs, 541–542, 542t
tetracyclic and unicyclic agents, 542t,
543
tricyclic antidepressants, 542t,
542–543
pharmacokinetics of
5-HT receptor modulators,
540t, 541
MAO inhibitors, 540t, 541
SNRIs, 540, 540t
SSRIs, 539–540, 540t
tetracyclic and unicyclic agents, 540t,
541
tricyclic antidepressants, 540t, 541
poisoning with, 1041t, 1042
preparations available, 551t
prevalence of use of, 532
tricyclic. See Tricyclic antidepressants
[TCAs]
Antidiabetic agents, oral, 757–759,
768t–769t. See also specific agents
α-glucosidase inhibitors, 761, 768t
bromocriptine, 764, 769t
colesevelam hydrochloride, 764, 769t
drugs lowering glucose by tissue actions,
759–761
biguanides, 759–760, 768t
thiazolidinediones, 760–761, 768t
glucose absorption agents, 761
incretin mimics and action prolongers
dipeptidyl peptidase-4 inhibitors,
762–763, 769t
glucagon-like peptide-1 and, 762
glucagon-like peptide-1 receptor
agonists, 762, 769t
pramlintide, 764, 769t
sodium-glucose co-transporter 2
(SGLT2) inhibitors, 763–764,
769t
sulfonylurea receptor binders, 757–759
Index    1189
d-phenylalanine derivatives, 759,
768t
meglitinide analogs, 759, 768t
sulfonylureas, 757–759, 758t, 768t
Antidiarrheal agents
bile salt–binding resins, 1100
colloidal bismuth compounds, 1100
octreotide, 1101
opioid agonists, 1100
opioids for, 563
OTC, 1123t–1124t
use of, 1101, 1115t
Antidiuretic hormone (ADH), 268.
See Vasopressin
Antidotes, 1040, 1041t
Antiemetic agents, 1103–1106, 1116t
benzodiazepines, 1106
cannabinoids, 1106, 1116t
corticosteroids, 1105
H1 antihistamines and anticholinergic
drugs, 1106
mechanisms of action of, 1103, 1104f
neurokinin receptor antagonists, 1105
phenothiazines and butyrophenones,
1105–1106
serotonin 5-HT3-antagonists,
1103–1105, 1116t, 1117t
substituted benzamides, 1106
Antiepileptics, 409–439. See also
Antiseizure drugs
Antifolate drugs, 834–837. See also specific
drugs
DNA gyrase inhibitors, 837–840, 840t
methotrexate, 957, 958t
pemetrexed, 957–958, 958t
pralatrexate, 958–959
preparations available, 840t
sulfonamides, 834–836, 840t
trimethoprim and trimethoprim-
sulfamethoxazole mixtures,
836–837, 840t
Antifungal agents, 853–861, 861t, 862t.
See also specific types
Antifungal agents, dermatologic
oral
azole derivatives, 1073
griseofulvin, 1074
terbinafine, 1074
topical
allylamines, 1073
azole derivatives, 1073
butenafine, 1073
ciclopirox olamine, 1072
nystatin and amphotericin B, 1073
tolnaftate, 1073
Antifungal agents, OTC preparations
topical, 1124t
vaginal, 1124t
1190    Index

Antifungal agents, systemic, 853–860 case study of, 1058, 1067 amantadine and rimantadine, 892
allylamine, 861, 861t categories of, 175–176, 176f investigational, 892
amphotericin B, 853–854, 861t clinical pharmacology of, 189 oseltamivir and zanamivir, 891–892
azoles chronic hypertension, alpha-receptor Anti-integrin therapy, 1112
description of, 856–859, 861t antagonists, 161 Antilymphocyte globulin (ALT), 990
drug interactions of, 1159t–1160t hypertensive emergencies, 190–191 Antimetabolites, 957–961
echinocandins, 859–860, 861t outpatient therapy, 189–190 antifolates
flucytosine, 855f, 856, 861t diuretics, 175, 176–178, 191t methotrexate, 957, 958t
oral, for mucocutaneous infections mechanisms of action and pemetrexed, 957–958, 958t
griseofulvin, 860 hemodynamic effects of, 177 pralatrexate, 958–959
terbinafine, 860, 861t toxicity of, 178 deoxycytidine analogs
Antifungal agents, topical use of, 177–178, 179t cytarabine, 958t, 960
allylamines, 860–861, 861t in elderly, 1063 gemcitabine, 958t, 960
azoles, 860–861 ganglion-blocking agents, 181 development of, 957
nystatin, 860 hypertension and blood pressure fluoropyrimidines
Antigen-presenting cells (APCs), 979, 979f regulation by, 173–175, 174f, capecitabine, 958t, 959
Antihelminthics 175f. See also Hypertension 5-fluorouracil, 958t, 959
albendazole, 938–940, 939t preparations available, 193t purine antagonists
bithionol, 939t, 940 sites of action of, 175, 176f cladribine, 958t, 961
diethylcarbazine citrate, 939t, 940–941 sympathoplegics, 176, 176f, 178–182 fludarabine, 958t, 961
ivermectin, 939t, 941–942 adrenergic neuron-blocking agents 6-thiopurines, 958t, 960–961, 961f
mebendazole, 939t, 942 guanethidine, 181–182, 191t Antimicrobial agents, 793–916, 794f.
metrifonate, 939t, 943 reserpine, 179t, 182, 191t See also specific agents and types
niclosamide, 939t, 943 alpha-adrenoceptor blockers, other, development of, 904
oxamniquine, 939t, 943–944 184 drug combinations of
piperazine, 939t, 944 beta-adrenoceptor blocking agents, antagonism in, 912–913
praziquantel, 939t 179t, 182–183. See also rationale for, 912
preparations available, 939t, 946 b-receptor antagonist drugs synergism in, 912–913
pyrantel pamoate, 939t esmolol, 183 drug toxicity management for,
thiabendazole, 939t, 946 centrally acting, 179t, 179–180, 191t 907t–908t, 912
Antihepatitis agents, 884–891 clonidine, 179t, 179–181 in elderly, 1064
hepatitis B guanabenz and guanfacine, 180 empiric therapy with, 905–906,
adefovir dipivoxil, 886 methyldopa, 179, 179t 907t–909t
entecavir, 886 preparations of, 193t approach to, 905
fundamentals of, 884 vasodilators, 178f, 179t, 184–187, 192t choice of, 905–906
lamivudine, 886–887 calcium channel blockers, 179t, microbiology etiology in, 907t–908t
telbivudine, 887 186–187, 193t site of infection in, 909t
tenofovir, 887 diazoxide, 186, 192t etiologic agent and indications for, 905
hepatitis C, 887–891 direct, 176 infections of known etiology treated
fundamentals of, 887 fenoldopam, 186, 192t with, 906–911
polymerase inhibitors, 889 hydralazine, 179t, 184–185 misuse of, 793
protease inhibitors, 889, 890f mechanisms and sites of action of, Antimicrobial prophylaxis
simeprevir, 890–891 184, 184t nonsurgical, 914, 915t, 916
sofosbuvir, 889 minoxidil, 179t, 185 NRC wound classification criteria and,
ribavirin, 891 preparations available, 192t, 193t 914b
interferon alfa, 884t, 884–885, sodium nitroprusside, 185–186, surgical, 913–914, 914t
893t–894t 192t Antimuscarinic drugs, 124. See Muscarinic
Antihistamines, 281–285, 1129t Anti-IgE monoclonal antibodies, asthma receptor blockers (antagonists)
Antihypertensive agents, 173–193, treated with, 357, 360, 362t Antimycobacterial drugs, 842–852,
191t–192t. See also specific types Anti-IL-5 therapy, 357, 363t 851t
angiotensin inhibitors, 176, 187–189 Anti-inflammatory agents, 642. See also atypical mycobacteria, 849–850,
angiotensin-converting enzyme specific types 850t
inhibitors, 179t, 187–189, 192t, dermatologic, 1079–1082 leprosy
193t corticosteroids, topical, 1079–1081, clofazimine, 851
angiotensin receptor blockers, 179t, 1080t, 1081t dapsone and other sulfone, 850
189, 192t, 193t tar compounds, 1082 rifampin, 851, 851t
mechanisms and sites of action of, in elderly, 1064 tuberculosis, 842–849. See also
187, 188f Anti-influenza agents, 891–892 Tuberculosis drugs

Antineoplastic agents, 949. See
Chemotherapy; specific cancers
Antiplatelet agents, 619–620, 624t
aspirin, 619–620
cilostazol, 621
dipyridamole, 621
GP IIb/IIIa antagonists, 621
thienopyridines, 620
Antiprotozoal drugs, 917–937
African trypanosomiasis and other
protozoal infections, 932t–933t
amebiasis, 928–931
amphotericin, 932t, 935
benznidazole, 933t, 934
eflornithine, 931t, 934
malaria, 917–928
melarsoprol, 931t, 934
miltefosine, 935
nifurtimox, 933t, 934–935
nitazoxanide, 933–934
paromomycin, 932t, 935
pentamidine, 931, 932t, 933
preparations available, 936t
sodium stibogluconate, 930f, 932t, 933
suramin, 931t, 934
visceral leishmaniasis drug combinations,
935
Antipruritic agents
doxepin, 1084
pramoxine, 1084
Antipsychotic agents, 511–524, 528t–529t.
See also specific agents
atypical, 514f, 515, 515t
bipolar disorder agents, newer, 529t
butyrophenone derivatives, 514f, 515,
515t
clinical pharmacology of, 518–524
adverse reactions to, 518t, 521–523
benefits and limitations in,
523–524
dosage of, 521, 521t
drug choice in, 519–521, 520t
drug combinations in, 521
drug interactions in, 523
indications for
nonpsychiatric, 519
psychiatric, 518–519
maintenance treatment in, 521
overdoses of, 523
parenteral preparations of, 521
in elderly, 1061–1062
glutamatergic antipsychotics, 515–516
history of, 511–512
lithium and other mood stabilizers,
524–528, 529t
molindone, 514f, 515
pharmacodynamics of, 516–518
cardiovascular effects, 518
differences in, by drug, 515t,
517–518, 518t
dopamine receptors and their effects,
516–517, 517f
dopaminergic systems, 516
electroencephalographic effects, 518
endocrine effects, 518
psychological effects, 518
pharmacokinetics of, 516
phenothiazine derivative, 513f, 514–515,
515t
pimozide, 514f, 515
poisoning management for, 1042
preparations available, 529t
thioxanthene derivatives, 513f, 515, 515t
Antipyretics, OTC, 1123t
Antiretroviral agents, 870–884. See also
specific types
drug-drug interactions of two-drug com-
binations of, 877t
entry inhibitors, 882–883
fundamentals of, 870
integrase strand transfer inhibitors,
883–884
nonnucleoside reverse transcriptase
inhibitors, 876–879
nucleoside and nucleotide reverse
transcriptase inhibitors,
870–876, 871t–872t
in pregnancy, 879t
protease inhibitors, 879–882
Antiseborrhea agents, 1084, 1084t
Antiseizure drugs, 409–439, 433t,
435t–437t
chemistry of, 412f
clinical pharmacology of, 432–433, 433t
developmental, 435
development of, initial, 409–410, 412f
epilepsy treated with
acetazolamide, 432
benzodiazepines, 432, 437t
generalized seizures treated with,
428–430
ethosuximide, 428–429, 433t, 437t
phensuximide and methsuximide,
429f
valproic acid and sodium valproate,
426f, 426–427, 436t
molecular targets for
at excitatory, glutamatergic synapse,
412f
at inhibitory, GABAergic synapse,
412f
partial seizures and generalized tonic-
clonic seizures treated with,
413–421
carbamazepine, 413–417, 415f, 433t,
435t
Index    1191
eslicarbazepine, 417, 433t, 435t
ezogabine (retigabine), 421, 433t
felbamate, 425–426, 433t
gabapentin and pregabalin, 420, 433t,
436t
lacosamide, 417–418, 433t, 435t
lamotrigine, 422, 433t, 435t
levetiracetam, 422–423, 433t, 436t
mephenytoin, ethotoin, and
phenacemide, 419–420
oxcarbazepine, 417, 433t, 435t
perampanel, 423–424, 433t, 437t
phenobarbital, 424, 433t, 436t
phenytoin, 418f, 418–419, 419f,
433t, 435t
primidone, 424–425, 425f,
433t, 436t
retigabine, 421, 433t, 437t
rufinamide, 430, 433t, 436t
stiripentol, 431, 433t
tiagabine, 420–421, 433t, 437t
topiramate, 427–428, 433t, 436t
vigabatrin, 431, 433t, 437t
zonisamide, 428, 433t, 436t
pharmacokinetics of, 411–413, 412f
preparations available, 438t
structure of, 418f
toxicology of
suicidality in, 434
teratogenicity in, 434
withdrawal in, 434
Antisense oligonucleotides (ANOs), 2
Antisepsis, 898t
Antiseptics, 897. See Disinfectants and
antiseptics; specific types
Antispasmodics (anticholinergics),
1101–1102
Antithrombin (AT), 611, 612, 612f
Antithrombotics
description of, 621, 622t, 624t
nitric oxide, 342, 343f
Antithymocyte globulin (ATG), 990
Antithyroid drugs, 689–696, 701t
adrenoceptor-blocking agents, 696
anion inhibitors, 695
basic pharmacology of, 689–692
clinical pharmacology of,
696–700
Graves’ disease treated with, 698
hyperthyroidism, 698–699. See also
Hyperthyroidism
iodides, 695, 701t
nontoxic goiter, 700
preparations available, 701t
radioactive iodine, 695–696, 701t
thioamides, 693–695, 694f, 701t
thyroid neoplasms, 700
Antitrichogenic agents, 1084–1085
1192    Index
Antitumor antibiotics
anthracyclines, 962t, 964–965
bleomycin, 962t, 965–966
mitomycin, 962t, 965
Antitumor monoclonal antibodies,
991–992
Anti-tumor necrosis factor (anti-TNF)
therapy, 1110–1112, 1111t,
1116t
Antitussives
opioid, 570, 572t, 573t
OTC, 1124t
Antivenoms, 991
Antiviral agents, 863–894. See also specific
types
antihepatitis, 884t, 884–891
anti-influenza, 891–892
antiretroviral, 870–884
entry inhibitors, 882–883
fundamentals of, 870
integrase strand transfer inhibitors,
883–884
nonnucleoside reverse transcriptase
inhibitors, 876–879
nucleoside and nucleotide reverse
transcriptase inhibitors,
870–876, 871t–872t
protease inhibitors, 879–882
cytomegalovirus, 867–870
herpes simplex virus and varicella-zoster
virus, 864–867
history of, 863
imiquimod, 893
interferons, 892, 893t–894t
NS5A inhibitors, 888–889
NS5B RNA polymerase inhibitors, 889
palivizumab, 893
preparations available, 893t–894t
ribavirin, 893
topical, 1074
viral replication and, 863, 864f
Anxiety
benzodiazepines for, 544
performance, b-receptor antagonists for,
169
sedative-hypnotics for, 390–391
Apamin, 370t
Apis mellifera, 1133t
Apixaban, 617
Apo B-100 synthesis antisense inhibition,
638
Apocrine sweat glands, 148
Apolipoprotein B-100
description of, 626, 628f
familial ligand-defective, 629t, 630
Apomorphine (hydrochloride), 501, 508t
Apraclonidine, 154t. See also
Sympathomimetics
Apremilast, 1079, 1079t
Aprepitant, 314, 317t, 1105, 1116t. See also
Substance P, antagonists of
Apriso, 1107, 1107f
Aprotinin, 308, 624
Aquaporin-2 (AQP2), 258, 258f
Aquaretics, 267–268, 273t, 274t
Aqueous diffusion, 7–8, 8f
Arachidonic acid (AA), 321–322, 322f
dietary manipulation of metabolism of,
337
prostanoid mediators from, 643, 646f
Arcitumomab, 993
Area under the blood concentration-time
curve, 47, 47f
Area under the curve (AUC), 45
Argatroban, 617–618
Arginine vasopressin, 268. See Vasopressin;
Vasopressin receptor agonists
Aripiprazole. See also Antipsychotic agents
psychosis treated with, 514f, 515, 520t,
528t
tics treated with, 506
Aristolochic acid, 1133t
Arizona bark scorpion antivenom, 991
Aromatic hydrocarbons, 1009–1010
Aromatic (4)-hydroxylation, 68
Arrestins, 141
Arrhythmias, cardiac
alcohol ingestion as cause of, 401
beta-receptor antagonists for, 168
impulse conduction disturbances,
234–236
impulse formation disturbances, 233f,
233–234
mechanisms of, 233–236
molecular and genetic basis of, 234b,
235f, 235t, 237f
pathophysiology of, 228, 229f
treatment of
drugs in, 236–252
nonpharmacologic therapy in, 246b
Arsenic, 1025–1027
forms of intoxication with
acute inorganic, 1026
arsine gas, 1027
chronic inorganic, 1026–1027, 1027f
history and epidemiology of, 1025
pharmacodynamics of, 1025–1026
pharmacokinetics of, 1021t, 1025
Artemether, 922–923
Artemether-lumefantrine, 922t
Artemisinins, 919f, 920t, 922–923
Arterial dilators, 225t
Artesunate, 922–923
Artesunate-amodiaquine, 922t, 922–923
Artesunate-sulfadoxine-pyrimethamine,
922t, 922–923
Articaine, 460t, 469–470. See also
Anesthetics, local
Asacol, 1107, 1107f
Asbestos, 1016–1017
Ascariasis. See also Anthelmintic drugs
albendazole for, 938–940, 939t
mebendazole for, 942
piperazine for, 944
pyrantel pamoate for, 945–946
Asenapine, 515
Aspart, 768t. See also Insulin
Aspirin, 332, 645, 645t, 646f
antiplatelet effects of, 619–620
drug interactions of, 1172t
dysmenorrhea treated with, 335
heart attack and stroke prevention using,
335
inflammation treated with, 336
in OTC agents, 1129t
overdose of, 1, 19
peripheral artery disease and intermittent
claudication treated with, 209
poisoning management for, 1042–1043
Aspirin-exacerbated respiratory disease, 356
Astemizole, 284
Asthma
chronic obstructive pulmonary disorder
versus, 361
clinical features and severity of, 346–347
forms of, 347
pathogenesis of, 347–348, 348f
prevalence of, 346
respiratory infection on, 346, 365
subtypes of, 358
Asthma drugs, 346–365, 362t–363t.
See also specific drugs
anti-IgE monoclonal antibodies, 357,
362t
antimuscarinics, 353–354, 354f
asthma pathophysiology in, 347–348,
348f
clinical pharmacology of, 358–361
acute asthma management, 359
anti-IgE monoclonal antibody, 360
anti-inflammatory therapies, other,
360
bronchodilators, 359
corticosteroids, 359
leukotriene antagonists, 360
muscarinic antagonists, 359
corticosteroids
inhaled, 354–355, 362t
systemic, 354–355, 362t
cromolyn, 355–356, 362t
future directions in, 358
leukotriene antagonists, 356f, 356–357,
362t
methylxanthines, 352f, 352–353, 362t

nedocromil, 355–356, 362t
preparations available, 362t
preventive uses of, 360
sympathomimetics, 349–352, 350f, 362t
beta2-selective, 351
toxicities of, 351–352
Astrocytes, 368
AT1, 304
AT2, 304
Atazanavir, 74, 87, 871t, 879–880
Atenolol, 164t, 165, 170t. See also
b-receptor antagonist drugs
angina pectoris treated with, 210t
hypertension treated with, 179t, 183,
191t
structure of, 163f
Atezolizumab, 992
Atherogenesis
description of, 627
nitric oxide prophylaxis against,
342–343, 343f
Atherosclerosis, 209
Athetosis, 492, 505
Atomoxetine, 151
Atonic seizures, 430. See also Seizures
Atorvastatin, 632–634, 639t
Atosiban
description of, 681, 684t
preterm labor managed with, 206
Atovaquone, 919f, 926
Atovaquone-proguanil, 920t
Atracurium. See also Neuromuscular
blocking drugs
pharmacokinetics of, 477
properties of, 478t
structure of, 476f
Atrial fibrillation
antiarrhythmic agents for, 249b
electrocardiogram of, 236f
with left ventricular dysfunction, 228,
253
Atrial flutter, ECG of, 236f
Atrial natriuretic peptide (ANP)
description of, 34, 308–309, 309f
on kidney, 259
mechanism of action of, 28
Atrioventricular (AV) node, 228, 229f
Atropine, 124–129, 130t. See also
Muscarinic receptor blockers
actions of, 353
chemistry and pharmacokinetics in, 125,
125f
cholinergic poisoning treated with, 132
clinical pharmacology of, 130–133
discovery of, 353
elimination of, 125
intoxication with, 119
pharmacodynamics of, 125–129
pharmacology of, 124–129
structure of, 125, 125f
Autacoids, renal, 259
Autoclaving, 901
Autoimmune disorders, 996. See also specific
types
Autoimmune (type II) drug reactions,
982–983, 999
Autoimmunity, 984
Autologous stem cell transplantation,
G-CSF for, 603–604
Autonomic failure, pure, 137, 155
Autonomic motor nerves, 90f
Autonomic nervous system (ANS), 90–93
anatomy of, 90f, 90–93, 91f
enteric nervous system in, 91f, 91–92
ergotropic, 100
functions of, 89
on immune function, 89
parasympathetic division of, 90f, 90–91
somatic division of, 89
sympathetic division of, 90f, 90–91
trophotropic, 100
Autonomic pharmacology, 89–106. See also
specific agents
autonomic nervous system in, 90–93.
See also Autonomic nervous
system (ANS))
in eye, 105b, 105f
functional organization of, 100–103
cardiovascular function integration in,
100, 102f
central integration in, 91f, 100, 101t,
103
direct effects on organ systems of,
100, 101t
postsynaptic regulation in, 103, 103f
presynaptic regulation in, 100, 102t,
103
functions of, 89–90
neurotransmitter chemistry in, 90f,
93–98
adrenergic transmission in, 95–97,
96f–97f
cholinergic and noradrenergic fibers
in, 90f, 93
cholinergic transmission in, 93–95,
94f
cotransmitters in, 93
cotransmitters in cholinergic and
adrenergic nerves in, 97–98
nonadrenergic, noncholinergic neurons
in, 91f, 97
pharmacologic modification of
autonomic function in, 103,
104t, 105
receptors in, 98–99, 99t
Autonomic receptors, 98–99, 99t
Index    1193
Autonomic synapses, 93
Autonomic transmission, 103, 104t
Autoplex, 623
Autoreceptors, 100, 102t
Autosomal dominant hypophosphatemia,
787–788
Autosomal dominant polycystic kidney
disease, 268
Autosomal recessive hypercholesterolemia
(ARH), 631
Avastin, 1065
AV nodal block, 234–236, 235f
Axon, 368
Azapropazone, 649
Azathioprine
antirheumatic actions of, 650
immunosuppressive uses of, 988
inflammatory bowel disease treated with,
1109–1110
TPMT on metabolism of, 81
Azelaic acid, 1078
Azilsartan, 189
Azithromycin, 820, 824t
Azoles, 856–859, 861t
adverse effects of, 857–858
chemistry and pharmacokinetics of,
856–857, 857f, 858t
clinical uses of, 857–858
dermatologic
oral, 1073
topical, 1072
drug interactions of, 857–858,
1159t–1160t
fluconazole, 857f, 858, 858t
itraconazole, 857f, 858, 858t, 861t
ketoconazole, 857f, 858, 858t, 861t
mechanisms of action and resistance to,
857
posaconazole, 858t, 859
preparations available, 862t
topical, 860–861
voriconazole, 857f, 858t, 858–859
Azo reductions, 61t
Aztreonam, 806, 812t
B
B1 receptor antagonists, 307
B2 receptor agonists, 308
B2 receptor antagonists, 307–308
Babesiosis, 924
Bacillus subtilis, 811
Bacitracin, 811, 1070
Baclofen
for dependence and addiction, 588
spasmolytic actions of, 485–487, 486f,
489t
Bacterial cell wall, penicillins on, 797, 797f
Bacterial food poisoning, 1034
1194    Index

Bactericidal activity, 910, 910t Benzene hexachlorides, 1010t, 1010–1011, monobactams, 796f, 806, 812t
Bacteriostatic activity, 910, 910t 1013f penicillins, 795–801, 812t
Bagging, 585 Benznidazole, 933t, 934 preparations available, 813t
Balanced anesthesia, 440, 449 Benzocaine. See also Anesthetics, local Betamethasone, 706f, 709t. See also
Balanced polyethylene glycol, 1099 description of, 460t, 470, 472t Corticosteroids, synthetic
Ballismus, 492, 505 in OTC agents, 1129t b-receptor agonist drugs, 225t
Balsalazide, 1107, 1107f Benzodiazepines, 393t b-receptor antagonist drugs
Bambuterol, 351 abuse of, 577t angina pectoris treated with, 194,
Bapineuzumab, 1063 acute ethanol withdrawal managed with, 206–207, 210t
Barbiturates, 393t 406t, 585, 589t with nitrates, 208, 209t
anesthesia uses of, 442f, 450t, 451f, anesthesia uses of, 389, 451f, 454–455 arrhythmias treated with, 168, 243,
453–454 antagonists of, 390, 393t 250t, 251t
biotransformation of, 386 antiemetic properties of, 1106 choice of, 169
chemical classification of, 382, 383f anxiety managed with, 544 clinical pharmacology of, 167–169
clinical pharmacology of, 390t binding site ligands of, 387–388 cardiac arrhythmias, 168
dose-response curves for, 381, 382f biotransformation of, 383–386, 384f, cardiovascular disorders, other, 168
drug interactions of, 1160t 385t glaucoma, 168
neuropharmacology of, 386–387 chemical classification of, 381–383, 382f heart failure, 168
pharmacodynamics of, 386–389 clinical pharmacology of, 390t, 390–391 hypertension, 167
pharmacokinetics of disadvantages of, 390 hyperthyroidism, 168
absorption and distribution in, 386 dose-response curves for, 381, 382f ischemic heart disease, 167f, 167–168,
biodisposition in, factors in, 386 epilepsy managed with, 432, 437t 168f
excretion in, 386 flumazenil reversal of, 392 miscellaneous, 169
structure of, 383f ionotropic receptors in, 584 neurologic diseases, 168–169
Baroreceptor, renal, 301 pharmacodynamics of, 386–389 drug interactions of, 1161t
Baroreflex, postural, 175, 175f pharmacokinetics of heart failure treated with, 221
Bartter’s syndrome, 335 absorption and distribution in, 386 chronic, 222
Bases, weak biodisposition in, 386 dobutamine, 219
definition of, 9 excretion in, 386 preparations available, 226t
examples of, 10t structure of, 382f hypertension treated with, 179t,
ionization of, 9 Benzoic acid, 901 182–183, 192t
trapping of, 9, 11f Benzomorphans, 569 esmolol, 183
Basic research, 14b Benzophenones, 1076 labetalol, carvedilol, and nebivolol,
Basiliximab, 994 Benzoyl peroxide, 1078 183, 192t
Batrachotoxin, 370t Benztropine, 126f metoprolol and atenolol, 179t, 183
Bazedoxifene, 737f, 738 Benztropine mesylate, 501t, 508t nadolol, carteolol, betaxolol, and
BCNU (carmustine), 953f Benzyl alcohol, 1076 bisoprolol, 183
Beclomethasone (dipropionate), 355, 362t. Bepridil, 204. See also Calcium channel pindolol, acebutolol, and penbutolol,
See also Corticosteroids, inhaled blockers 183
(aerosol) Berinert. See also Kinin inhibitors propranolol, 179t, 182–183
Bedaquiline, 843t, 849 description of, 308, 317t hyperthyroidism treated with, 696, 698,
Beef tapeworms on vasoactive peptides, 317t 700, 701t
niclosamide for, 943 Beryllium, 1017 as inverse agonists, 162
praziquantel for, 944–945 b adrenoceptor, 139t, 139–140, 140f latanoprost and related agents, 337
Belimumab, 658, 994 affinities of, 141, 141t pharmacodynamics of, 162–165
Benazepril, 179t, 187 cardiovascular system activation by, 145, on cardiovascular system, 162–163,
Bendamustine, 955t 146f, 146t, 147 164f
Benign hereditary chorea, 505 b-arrestin, 32, 33f on eye, 164
Benign prostate hyperplasia (BPH) Beta blockers, 162. See b-receptor antagonist for glaucoma, 165b, 166t
alpha-receptor antagonists for, drugs metabolic and endocrine effects in,
159, 161 Beta-lactamase assay, 906 164–165
saw palmetto for, 1141 Beta-lactamase inhibitors, 806f, 806–807 non–beta-blockade effects in, 164t,
Benralizumab, 357, 363t Beta-lactam compounds, 795–807, 165
Benzalkonium chloride, 900 812t–813t. See also specific types on respiratory tract, 163–164
Benzamides, substituted, 1106 beta-lactamase inhibitors, 806f, 806–807 pharmacokinetics of, 162, 164t
Benzathine penicillin, 799. See also carbapenems, 796f, 807, 812t poisoning management for, 1041t, 1043
Penicillin(s) cephalosporins and cephamycins, 796f, preparations available, 171t
Benzene, 1009–1010 802–806, 812t hypertension treated with, 193t

structure of, 162, 163f
toxicity of, 169–170
types of, 164t, 165–167
variceal hemorrhage treated with, 1114
b-selective agonists, 141t, 149, 149f
b1-selective agonists, 99t, 141t, 149, 149f,
154t
b2-selective agonists, 154t, 362t
asthma treated with, 351
preparations available, 363t
structure of, 149f
b3-selective agonists, 154t
Betaxolol. See also b-receptor antagonist
drugs
description of, 164t, 166, 168, 170t
hypertension treated with, 183
Bethanechol, 109, 109f, 118, 122t
Bethanidine, 181
Bevacizumab, 966t, 968, 991–992, 1065
Bexarotene, dermatologic, 1085
Bezafibrate, 634
Bezold-Jarisch reflex, 287
Biased agonists, 141
at b receptors, 142b
BIBP3226, 318t. See also Neuropeptide Y
antagonists
Bicalutamide, 744, 972
Biguanides, 759–760, 768t
BIIE0246, 318t. See also Neuropeptide Y
antagonists
Bile acid–binding resins, 636–637, 639t
drug interactions of, 1161t
with ezetimibe, niacin, and reductase
inhibitors, 639
with fibric acid derivatives, 638
with HMG CoA reductase inhibitors,
639
with niacin, 639
Bile acid sequestrants
diabetes mellitus treated with, 764, 769t
dyslipidemia treated with, 639t
Bile acid therapy, for gallstones,
1113–1114, 1116t, 1117t
Bile salt–binding resins, 1100
Bimatoprost
glaucoma treated with, 337
ophthalmic, 1085
Binding sites, inert, 7
Binge drinking, 401
Bioaccumulation, 1006b
Bioavailability, 47–48
extent of absorption in, 47, 47f, 47t
first-pass elimination in, 47–48
rate of absorption in, 47f, 48
Biologic agents, for psoriasis, 1079
fumaric acid esters, 1079
TNF inhibitors, 1079
ustekinumab, 1079
Biological License Application (BLA), 17
Biologics, for inflammation, 643
Biomagnification, 1006b
Biotransformation, drug, 56–73
commensal gut microbiota in, 69–70
in drug disposition, 57, 57f
drug metabolism in
clinical relevance of, 64–72
to toxic products, 64–65, 65f
in liver, 57–58
liver P450 enzymes in, 59–61, 62t–63t
necessity for, 56–57
phase II reactions in, 57, 57f, 63, 64f, 64t
phase I reactions in
description of, 57, 57f
microsomal mixed function oxidase
system and, 58f, 58–59
Biperiden, 501t, 508t
Bipolar affective disorder
drugs for, 524–528
antipsychotics, 519
carbamazepine, 528, 529t
lamotrigine, 528, 529t
lithium, 524–528, 526, 529t
preparations available, 529t
valproic acid, 528, 529t
history of, 524
nature of, 524
pathophysiology of, 524
Bipyridines, 219, 225t
Bipyridyl herbicides, 1013f, 1014
Bisacodyl, 1099
Bismuth compounds, colloidal, 1100
Bismuth subcitrate potassium, 1096
Bismuth subsalicylate, 1096
Bisoprolol. See also b-receptor antagonist
drugs
heart failure treated with, 221, 222, 225t
hypertension treated with, 183
properties of, 164t
Bisphosphonates
bone homeostasis affected by, 779f,
779–781, 790t
bone metastases treated with, 789t
hypercalcemia treated with, 782, 789t
osteoporosis treated with, 780b, 786, 789t
Paget’s disease of bone treated with, 789
Bithionol, 939t, 940
Bitopertin, 515
Bivalirudin, 617–618
Black cohosh, 1133t
Blackwater fever, 924
Black widow spider bite, 1180t
Bleach, household, 899
Bleomycin, 962t, 965–966
Blepharospasm, 106
Blind designs, 14
Blood–brain barrier, 368–369
Index    1195
Blood clotting factors, 610t,
610–611, 611f
Blood concentration-time curve, 47, 47f
Blood:gas partition coefficient, 443t, 444,
444f
Blood glucose, self-monitoring of, 753
Blood pressure
angiotensin II on, 303
female hormonal contraceptives effect
on, 733
regulation of, 173–175
normal, 174f, 174–175
postural baroreflex in, 175, 175f
renal response to decreased blood
pressure in, 175
Blood schizonticides, 917, 918f
B lymphocytes, 950
Bond
covalent, 3–4
drug–receptor, 3–4
electrostatic, 3–4
hydrophobic, 3–4
Bone marrow transplantation
immune globulin, intravenous for, 1180t
immunosuppressive therapy for, 996
Bone mineral homeostasis
calcitonin in, 773, 774f
calcium and phosphate in, 772, 773f
1,25-dihydroxyvitamin D in, 773, 774f
Bone mineral homeostasis drugs, 772, 789t
clinical pharmacology of, 782–789
calcium levels in, abnormal serum
hypercalcemia, 782–783
hypocalcemia, 783–784
enteric oxaluria, 789
mineral-regulating hormone uses in,
784–788
chronic kidney disease, 785–786
hereditary vitamin D–resistant
rickets, 788
hyperparathyroidism, primary, 784
hypoparathyroidism, 784–785
idiopathic hypercalciuria, 788
intestinal osteodystrophy, 786
nephrotic syndrome, 788
nutritional rickets, 788
osteoporosis, 786–787, 787f
pseudovitamin D deficiency rickets,
788
vitamin D deficiency/insufficiency,
nutritional, 785
X-linked and autosomal dominant
hypophosphatemia, 787–788
Paget’s disease of bone, 788–789
phosphate levels in, abnormal serum
hyperphosphatemia, 784
hypophosphatemia, 784
presentation in, 782
1196    Index
Bone mineral homeostasis drugs (Cont.):
hormonal regulators, principal, 774–778
fibroblast growth factor 23, 777, 778t
parathyroid hormone, 774f, 774–775,
778t
PTH, FGF23, and vitamin D
interaction in, 777–778
vitamin D, 775–777, 776f, 777t, 778t
hormonal regulators, secondary
calcitonin, 778
estrogens, 779
glucocorticoids, 779
nonhormonal regulators, 779–782
bisphosphonates, 779f, 779–781, 789t
calcimimetics, 781
denosumab, 781
fluoride, 781
strontium ranelate, 782
thiazide diuretics, 781
pharmacology of, 772–773, 773f
preparations available, 790t
vitamin D in, 773, 774f, 789t
Bopindolol, 166, 170t. See also b-receptor
antagonist drugs
Borage, 1133t
Bortezomib, 966t, 971
Bosentan. See also Endothelin inhibitors
description of, 312, 313b, 317t
heart failure treated with, 220
Bosutinib, 966t, 967
Botanical pesticides, 1012–1013, 1013f
Botanicals, 1131. See Herbal medications
Botulinum toxin, 95
case study of, 89, 106
spasmolytic actions of, 487
Botulinum toxin A, 131
Botulism antitoxin heptavalent equine,
types A-G, 1180t
Botulism immune globulin, 1180t
Botulism toxin, 1180t
Bradycardic drugs, 207. See also specific
drugs
Brain cancer, 975
Brain-derived neurotrophic factor (BDNF),
533f, 533–534
Brain natriuretic peptide (BNP)
description of, 220, 308–309, 309f
on kidney, 259
Breakthrough bleeding, 734
Breakthroughs, drug, 11
Breast cancer
chemotherapy for
stage I & II, 971
stage III & IV, 972
from female hormonal contraceptives,
735
Breast cancer resistance protein (BCRP), 83
Breast-feeding, 1056
Brentuximab vedotin, 993
Brexpiprazole, 529t
Brimonidine, 154t, 1078. See also
Sympathomimetics
Brinzolamide, 260–261, 272t
Brivaracetam, 422–423, 436t
Brodalumab, 994
Bromocriptine, 154t, 294, 297t, 684t.
See also Ergot alkaloids;
Sympathomimetics
diabetes mellitus treated with, 764, 769t
as dopamine agonist, 679
hyperprolactinemia treated with, 295
Parkinson’s disease treated with, 498,
508t
Brompheniramine, 283t
Bronchial smooth muscle, 147
Bronchodilators, 359. See also specific types
Brugada syndrome, 234b
Brugia malayi, 941
Brugia timori, 941
Bucindolol, 166, 170t
Budesonide. See also Corticosteroids,
inhaled (aerosol)
asthma treated with, 355, 362t
inflammatory bowel disease treated with,
1109
Bulk-forming laxatives, 1098, 1117t
Bumetanide, for diuresis, 262t, 262–264,
273t
Bundle branch nodal block, 234–236, 235f
Bupivacaine, 460t, 462, 470, 472t. See also
Anesthetics, local
cardiotoxicity of
description of, 461b, 468
lipid resuscitation for reversal of, 449,
469b
historical development of, 461b
Buprenorphine
mixed receptor actions of, 568–569, 572t
opioid addiction managed with, 581,
588t
properties of, 555t
Bupropion
adverse effects in, 547
chemistry of, 538f, 538–539
depression treated with, 540t, 541, 542t,
550t
dosing, 546t
drug interactions in, 548t, 549
nicotine abuse treated with, 584
obesity managed with, 289b
pharmacodynamics of, 542t, 543
pharmacokinetics of, 540t, 541
poisoning/overdose of
seizure management in, 1035, 1047
treatment of, 1042
preparations available, 551t
Burimamide, 280
Buserelin, 676, 739
Buspirone, 288–289, 383, 394t. See also
Serotonin (5-HT) receptor
agonists
Busulfan, 953f, 955t. See also Alkylating
agents
Butabarbital, 393t
Butenafine, 1073
Butorphanol, 555t, 556, 569
Butoxamine, 167, 170t. See also b-receptor
antagonist drugs
Butyrophenone derivatives, 515, 515t,
529t
Butyrophenones, 511–524, 513f, 529t.
See also Antipsychotic agents
antiemetic properties of, 1105–1106
structure of, 513f
Butyrylcholinesterase, 69, 132
cholinesterase inhibitors on, 109
genetic polymorphisms in, 67t, 69
BZ site, GABAA receptor, 386
C
C1 esterase inhibitor, 307
C6, 133–134, 134f. See also Ganglion
blockers
Cabazitaxel, 963
Cabergoline. See also Dopamine agonists;
Ergot alkaloids
description of, 294, 679, 680f
hyperprolactinemia treated with, 295
Cadmium, 1017
Cadmium fume fever, 1017
Caffeine
asthma treated with, 352–353
in OTC agents, 1129t
structure of, 352f
Calcifediol, 775
Calcimar, 783
Calcimimetics
on bone homeostasis, 781
hyperparathyroidism treated with, 784
Calcineurin inhibitors
cyclosporine, 986
tacrolimus, 986
Calcipotriene, 789t. See also Vitamin D
for bone homeostasis, 775, 777t
psoriasis treated with, 1078–1079
Calcipotriol, 777t
Calcitonin
on bone homeostasis, 773, 774f, 778
hypercalcemia treated with, 782–783,
790t
osteoporosis treated with, 787, 790t
Paget’s disease of bone treated with, 789
Calcitonin gene-related peptide (CGRP),
92t, 290, 314–315, 318t

Calcitriol, 775
for bone homeostasis, 789t. See also
Vitamin D
chronic kidney disease treated with, 785
psoriasis treated with, 1078–1079
rickets treated with, 788
Calcium
for bone, 789t, 790t
on bone homeostasis, 773, 773f
enteric oxaluria treated with, 789
hyperphosphatemia treated with, 784
hypocalcemia treated with, 783–784
in membrane electrical activity,
229–230, 230f
Calcium abnormalities
hypercalcemia, 782–783
hypocalcemia, 783–784
Calcium carbonate, 1089
Calcium channel blockers
angina pectoris treated with, 194,
202–206, 210t
arrhythmia treated with, 245–246, 251t
diltiazem, 239t, 240t, 246, 251t
verapamil, 239t, 240t, 245–246, 251t
chemistry and pharmacokinetics of,
202–203, 203t
chronic heart failure treated with, 222
clinical use of, 206
discovery and history of, 202
drug interactions of, 1162t
hypertension treated with, 179t,
186–187, 193t
mechanism of action, 205
migraine headache prophylaxis using,
291
nitrates with, 208, 209t
pharmacodynamics of, 203t, 203–205
poisoning management for, 1041t, 1043
preparations available, 211t, 251t
smooth muscle contraction affected by,
196f, 197
toxicity of, 205
Calcium channels, voltage-activated, 203t
2+
Calcium ion (Ca )
description of, 30
as second messenger, 32–34, 34f
Calcium oxalate stones, 789
Calcium receptor agonists, 790t
hyperparathyroidism treated with, 784,
790t
preparations available, 790t
Calcium-sensing receptor (CaSR), 781
cAMP (cyclic adenosine-3′,5′-
monophosphate), 30, 302, 302f
Camptothecins, 962t, 964
Canagliflozin
description of, 261–262, 272t, 274t
diabetes mellitus treated with, 763, 769t
Canakinumab, 657, 994
Cancer. See also specific cancer
causes of, 948–949
chemotherapy for, 948–976. See
Chemotherapy
epidemiology of, 948
from female hormonal contraceptives,
735–736
treatment modalities for, 949–950
Candesartan
heart failure treated with, 224t
hypertension treated with, 189
on vasoactive peptides, 316t
Cannabinoid receptor inverse agonist, 589t
Cannabinoids, 577t, 581–582
antiemetic properties of, 1106, 1116t
Gio protein-coupled receptor activation
by, 577t, 581–582, 583f
Capacity-limited elimination, 45–46
Capacity-limited protein binding, 53
Capecitabine
description of, 958t, 959
dihydropyrimidine dehydrogenase on, 78
Capreomycin, 843t, 847
Capromab pendetide, 993
Capsaicin, 99, 372
Capsaicin receptors (TRPV1, TRPA1), 560b
Captopril
heart failure treated with, 220, 224t
hypertension treated with, 179t,
187–188, 192t
on renin-angiotensin system, 305
on vasoactive peptides, 316t
Carbachol, 109, 109f, 122t
Carbamate pesticides, 1012, 1012t
Carbamazepine, 529t
bipolar disorder treated with, 528, 529t
drug interactions of, 1162t–1163t
seizures treated with, 413–417, 415f,
433t, 438t
Carbamic acids, 115, 116f
Carbapenems, 796f, 807, 812t
Carbaryl, 115, 116f
Carbidopa, 495f, 508t. See also Parkinsonism
Carbidopa-levodopa, parkinsonism, 495,
495f, 508t
Carbimazole, 693–695, 694f
Carbinoxamine, 283t
Carbonic anhydrase inhibitors, 259–261,
260t, 272t, 274t, 432
Carbon monoxide
description of, 1006–1007, 1007t
poisoning, 1041t, 1043, 1044t
Carbonyl reductions, 61t
Carboplatin, 955t, 956–957
Carboprost tromethamine
abortion uses of, 334
structure of, 333f
Index    1197
Carboxypenicillins, 801. See also
Penicillin(s)
Carcinoid tumor, 292
Cardiac arrhythmias, 228–253.
See Arrhythmias, cardiac
Cardiac cell membrane, active, 230–232,
231f
Cardiac contractility
modulation therapy for chronic heart
failure on, 223
normal, control of, 213, 215
normal control of, 214f
Cardiac glycosides, 213. See also Digitalis;
Digoxin
drug interactions of, 1165t
heart failure treated with, 213, 217–220,
219f, 225t
Cardiac muscle
calcium channel blocker effects on,
204–205
sarcomere of, 213, 214f
Cardiac output, 174, 444
Cardiac performance, 216f, 216–217
Cardiac resynchronization, for chronic
heart failure, 223
Cardiac rhythm, 228–233
active cell membrane in, 230–232, 231f
ionic basis of membrane electrical
activity in, 229–230, 230f
nodes and conduction in, 228, 229f
potassium effects in, 231b
resting potentials on action potentials in,
232–233, 233f
Cardiovascular system
alcohol effects on, 398, 401
autonomic integration of, 100, 102f
cholinesterase inhibitors effect on, 118
contraceptives on, female hormonal, 734
histamine effects on, 279
kinins on, 306–307
lead exposure effects on, 1022–1023
methylxanthines effect on, 353
Cardioverter-defibrillator, implantable,
246b
Carfentanil, 568
Carfilzomib, 966t, 971
Cariprazine, 515, 529t
Carisoprodol, 488, 489t
Carmustine, 953f, 955t
Carperitide, 310. See also Natriuretic
peptides
heart failure treated with, 220
kidney effects of, 259
on vasoactive peptides, 317t
Carprofen, 649
Carrier molecules, special, 8, 8f
Carteolol, 164t, 166, 170t, 183. See also
b-receptor antagonist drugs
1198    Index
Carvedilol, 160, 164t, 166, 170t, 191t.
See also b-receptor antagonist
drugs
dissociation constants and enantiomers
of, 4, 4t
heart failure treated with, 221, 222, 225t
hypertension treated with, 183
Cascara, 1099
Case-control epidemiologic studies, 15b
Case reports, 14b
Case series, 14b
Case studies
acetaminophen safety, 56, 73
acute myelogenous leukemia, 977, 1001
alcohol poisoning, acute, 396, 408
amoxicillin, rash from, 795, 814
anesthesia, 440, 459, 473
antiseizure drugs, 409, 439
aspirin overdose, 1, 19
asthma, respiratory infection on, 346,
365
atazanavir, 74, 87
atrial fibrillation and left ventricular
dysfunction, 228, 253
autonomic failure, pure, 137, 155
bacterial food poisoning, 1034
blepharospasm, 106
botulinum toxin, 89, 106
bupropion overdose, seizure management
in, 1035, 1047
Clostridium difficile, 895, 903
cold medications, hypertension from,
1120, 1130
colorectal cancer stage III, chemotherapy
for, 948, 976
community-acquired pneumonia and
meningitis, cephalosporin and
vancomycin for, 795, 814
coronary artery disease, 194, 211
Crohn’s disease treatment, 1087, 1119
deep venous thrombosis, heparin for
pulmonary embolism from, 608,
625
digoxin, 41, 55
dihydropyrimidine dehydrogenase
enzyme deficiency, 976
diuretics, acute kidney injury from
chronic use of, 254, 275
drugs of abuse, 575, 589
eicosanoids, 321, 338
enalapril, 300
epilepsy (Seizures), 409, 439
falciparum malaria treatment, 917, 937
fluoxetine for depression, CYP450 and
pharmacodynamic interactions
of, 532, 552
food poisoning, 1034
growth hormone deficiency, 667, 686
heart failure, 212, 227
heterozygous familial
hypercholesterolemia, 626, 641
HIV and tuberculosis, antimycobacterial
drugs for, 842, 852
HIV plus HBV treatment, in alcoholic
smoker on methadone, 863, 894
hydrocortisone, 719
hypertension, 173, 193
with Alzheimer’s and age-related
macular degeneration, 1058, 1067
renin-angiotensin system suppression
for, 300, 320
insulin, 747, 771
marijuana, 575, 589
megaloblastic anemia, vitamin B12
deficiency, 591, 607
muscle relaxants, for emergency trauma
surgery, 491
opioids, 553, 574
organophosphate cholinesterase inhibitor
poisoning, 107, 123
osteoporosis, 772, 791
pheochromocytoma, 156, 172
propranolol, 20, 40
pulmonary hypertension, 321, 338
rheumatoid arthritis, 642, 666
schizophrenia, 511, 531
sleep problems, 381, 395
tetracyclines, 815, 825
tobramycin, 831, 833
toxicology, 1003
urinary frequency and incontinence after
prostatectomy, 124, 136
urinary tract infection, antibiotic choice
in, 834, 841
verapamil, 20, 40
Caspofungin, 859, 861t
Catatonic schizophrenia, antipsychotics
for, 518. See also Antipsychotic
agents
Catechol, 144f
Catecholamine receptors
agonists binding to, 139, 140f
structure of, 144f
Catecholamine reuptake inhibitors, 143f,
151
Catecholaminergic polymorphic ventricular
tachycardia, 234b
Catecholamines. See also specific types
biosynthesis of, 95, 97f
endogenous, 146f, 146t, 148–149
metabolism of, 96–97, 98f
Catechol-O-methyltransferase (COMT),
142–143
catecholamine metabolism by, 98f
inhibitors of, for parkinsonism, 500,
508t
Cathartics, for toxin elimination, 1040
Catumaxomab, 992
Causal prophylactic drugs, for malaria, 917
CB1 receptors, brain, 377t, 380
CD8 T lymphocytes, 979f, 980
Cefaclor, 802f
Cefadroxil, 802f
Cefazolin, 802f, 803t
Cefdinir, 802f
Cefepime, 802f, 803t
Cefotaxime, 802f, 803t
Cefotetan, 802f, 803t
Cefoxitin, 802f, 803t
Cefpodoxime, 802f
Cefprozil, 802f
Ceftaroline, 802f
Ceftazidime, 802f, 803t
Ceftazidime-avibactam, 803t
Ceftazidime-tazobactam, 803t
Ceftibuten, 802f
Ceftolozane R1, 802f
Ceftriaxone, 802f, 803t
Cefuroxime, 802f, 803t
Cefuroxime axetil, 804
Celecoxib, 645t, 647
Celiprolol, 164t, 166, 170t. See also
b-receptor antagonist drugs
Cell-mediated immunity, 979
Cell wall, bacterial, 797, 797f
Central integration, autonomic, 91f, 100,
101t, 103
Central nervous system (CNS), 89,
367–373
alcohol effects on, 398
angiotensin II on, 304
brain cellular organization in
hierarchical systems in, 373, 373f
nonspecific or diffuse neuronal
systems in, 373–374, 374f
contraceptives on, female hormonal, 733
fundamentals of, 368
ion channels and neurotransmitter
receptors in, 369f, 369–370, 370t
lead exposure effects on, 1022
methylxanthines effect on, 352–353
organization of
blood–brain barrier, 368–369
neuroglia, 368, 368f
neurons, 368, 368f
sites of drug action in, 371–373, 373f
sympathomimetics on, 148
synapses and synaptic potential in,
370–371, 371f
Central nervous system (CNS) drugs, in
elderly, 1061–1063
Alzheimer’s disease, 1062f, 1062–1063,
1063t
analgesics, 1061
 Index    1199

antipsychotics and antidepressants, Charcoal, activated, 1040 imatinib and other tyrosine kinase
1061–1062 Chart orders, 1147. See also Prescriptions inhibitors, 966t, 967
sedative-hypnotics, 1061 abbreviations in, 1149t leukemia, acute
Central nervous system (CNS) neurotrans- errors of omission in, 1149–1150 adult, 969
mitters, 375–380 Charybdotoxin, 370t childhood, 969
acetylcholine, 374f, 376t, 378 Chelators, 1029–1033. See also specific types leukemia, chronic
amino acid, 375–378 deferasirox, 1032–1033 lymphocytic, 970
GABA and glycine, 376t, 378 deferoxamine, 1032 myelogenous, 969–970
glutamate, 375, 376t, 377f dimercaprol, 1024, 1026, 1029, 1030, lymphoma
endocannabinoids, 377t, 379–380 1030f Hodgkin’s, 970
monoamine edetate calcium disodium, 1023, 1029f, non-Hodgkin’s, 970
dopamine, 374f, 376t, 378 1031 malignant melanoma, 974–975
histamine, 376t, 379 penicillamine, 1030f, 1032 multiple myeloma, 970–971
5-hydroxytryptamine, 374f, 376t, 379 pharmacology of, 1029f, 1029–1030 natural product drugs, 961–964, 962t
norepinephrine, 374f, 376t, 378–379 preparations available, 1033t camptothecins, 962t, 964
neuropeptides, 379 Prussian blue, 1033 epidophyllotoxins, 962t, 964
nitric oxide, 380 succimer, 1024, 1027, 1029, 1030f, taxanes and other anti-microtubule
opioid peptides, 377t 1030–1031 drugs, 962t, 963–964
orexins, 377t, 379 unithiol, 1026–1027, 1031–1032 vinca alkaloids, 961–962, 962t
purine, 380 Chemical antagonism, 25 neoadjuvant, 949–950
tachykinins, 377t Chemical antagonist, 3 ovarian cancer, 974
Cephalexin, 802f, 803t Chemical transmission, 89–90. See also primary, 949
Cephalosporins, 796f, 802–806, 812t Neurotransmitters prostate cancer, 972
adverse effects of, 806 Chemoattractant cytokines (chemokines), secondary malignancies, 975
chemistry and structure of, 796f, 802, 978 testicular cancer, 974
802f Chemokines, 978 Chemotherapy-induced nausea and
dosing of, 803t Chemoreceptor reflex, 287 vomiting, 1104, 1116t, 1117t
first-generation, 802f, 802–804, 803t Chemoreceptor trigger zone, 1103, 1104f Chemotherapy-induced neutropenia,
fourth-generation, 802f, 803t, 805–806 Chemotherapy, 948–976. See also specific G-CSF for, 603, 603f, 606t
methicillin-resistant staphylococci treated drugs Chimeric molecules, 990
with, 802f, 803t, 804–806 adjuvant, 950 Chirality, 4
preparations available, 813t alkylating agents, 953–957 Chloasma, 734
second-generation, 802f, 803t, 804 antimetabolites, 957–961. See also Chloral hydrate, 382, 383f
third-generation, 802f, 803t, 804–805 Antimetabolites Chlorambucil, 953, 953f, 955t. See also
Cephamycin, 802, 804 antitumor antibiotics Alkylating agents
Cerebral insufficiency, senile, 295 anthracyclines, 962t, 964–965 Chloramphenicol, 822–823, 824t
Cerebral vasospasm, 205 bleomycin, 962t, 965–966 Chlordiazepoxide, 72, 385t, 393t. See also
Certolizumab mitomycin, 962t, 965 Benzodiazepines
description of, 993 brain cancer, 975 acute ethanol withdrawal treated with,
inflammatory bowel disease treated with, breast cancer 406t
1110–1112, 1111t stage I & II, 971 structure of, 382f
rheumatic disorders treated with, 654f, stage III & IV, 972 Chlorhexidine, 898t, 898–899
654–655 cell cycle kinetics and anti-cancer effect Chloride channel
Cestodes, 944–945. See also Anthelmintic in, 950f, 950–952 CFTR, 248b
drugs clinical pharmacology of, 969–975 in cystic fibrosis, 248b
Cetirizine, 281, 283, 283t, 296t. See also dermatologic GABA receptor complex versatility in,
H1-receptor antagonists alitretinoin, 1085 386, 387f, 388b
CETP inhibition, 638 bexarotene, 1085 Chloride channel activators
Cetrorelix, 678–679 romidepsin, 1085 irritable bowel syndrome treated with,
Cetuximab, 966t, 967, 992 vismodegib, 1085 1103
Cevimeline, 119, 122t vorinostat, 1085 laxatives, 1099
CFTR gene, 248b dosage factors in, 952 Chloride channel drugs
CFTR mutations, 248b drug combinations in, 951–952 arrhythmias treated with, 248
cGMP, 302, 302f drug resistance in, 952 preparations available, 251t
-
Chagas disease fundamentals of, 969 Chloride (Cl ), 229–230, 230f
benznidazole for, 934 gastrointestinal cancers, 972–973 Chlorine, 899
nifurtimox for, 933t, 934–935 growth factor receptor inhibitors, 966t, 2-Chlorodeoxyadenosine (cladribine), 958t,
Chaparral, 1133t 967–969 961
1200    Index
Chlorophenothane (DDT), 1010t,
1010–1011, 1013f
Chlorophenoxy herbicides, 1013f,
1013–1014
Chloroprocaine, 470, 472t. See also
Anesthetics, local
Chloroquine, 650, 918–921, 920t
adverse effects of, 920–921
antimalarial action and resistance to,
918–919
chemistry and pharmacokinetics of,
918, 919f
clinical uses of
amebic liver abscess, 920
chemoprophylaxis, 919, 920t
treatment, 919, 920t
contraindications and cautions with, 921
malaria treated with, 918–921, 920t
Chlorothiazide, 264–265, 273t
Chlorotrianisene, 723, 723f. See also
Estrogen(s)
Chlorphenesin, 488, 489t
Chlorpheniramine, 282f, 283t, 296t.
See also H1-receptor antagonists
Chlorpromazine, 511, 513f. See also
Antipsychotic agents
description of, 160
psychosis treated with, 513f, 514–515,
515t, 520t, 528t
Chlorpropamide, 758, 768t. See also
Sulfonylureas
Chlorthalidone, 177, 264–265, 273t
Chlorzoxazone, 488
Cholecalciferol, 789t. See also Vitamin D
Cholecystokinin (CCK), 92t
Cholesterol
in cell membrane, 854
guidelines for, 629t
Cholesterol 7α-hydroxylase, 631
Cholesteryl esters, 626
Cholesteryl ester storage disease, 629t, 631
Cholestyramine
description of, 636–637, 640t
diarrhea treated with, 1100
Choline acetyltransferase (ChAT), 93, 94f
Choline esters
description of, 109, 109f, 110t
direct-acting, 122t
Cholinergic fibers, 90f, 93
Cholinergic junction, 93–95, 94f
Cholinergic nerves, 97–98
Cholinergic poisoning, 132–133
Cholinergic transmission, 93–95, 94f
Cholinesterase inhibitors
absorption, distribution, and metabolism
of, 115–117, 116f, 117t
Alzheimer’s disease treated with, 1063
chemical warfare use of, 121
durations of action of, 117t
intermediate-acting, 122t
mechanism of action of, 117
mode of action of, 94f, 108f, 109
pharmacodynamics of, 117–118
poisoning with
case study of, 107, 123
management of, 1041t, 1043–1044
short-acting, 122t
structure of, 115, 116f
therapeutic uses of, 117t
toxicity of, 120–121
Cholinesterase regenerators, 132–133,
135t, 136t
Choline transporter (CHT), 93, 94f
Cholinoceptor(s), 95, 98, 99t. See also
Muscarinic (M) receptors;
Nicotinic (N) receptor
definition of, 98
subtypes and characteristics of, 107–108,
108t
Cholinoceptor-blocking drugs, 124–134,
135t
ganglion-blocking drug pharmacology
in, 133–134
muscarinic receptor blockers,
124–129
clinical pharmacology of, 130–133
pharmacology of, 124–129
preparations available, 136t
subgroups of, 124
Cholinomimetics, 107–123. See also specific
types
classification of, 107
clinical pharmacology of, 118–121,
122t, 123t
clinical uses in
antimuscarinic drug intoxication,
119–120
CNS, 120
eye, 105f, 118
GI and urinary tracts, 118–119
heart, 119
neuromuscular junction, 111f, 119
mode of action of, 94f, 108f, 109
prokinetic activity of, 1097
spectrum of action of, 90f, 103f,
107–108, 108f, 108t
toxicity in
cholinesterase inhibitors, 120–121
muscarinic stimulants, direct-acting,
120
nicotinic stimulants, direct-acting,
120–121
Cholinomimetics, direct-acting, 109–115,
122t
chemistry and pharmacokinetics of, 109,
109f, 110f, 110t
mechanism of action in, 108t, 110–112,
111f
mode of action of, 94f, 108f, 109
organ system effects in, 112t, 112–115,
113f
cardiovascular system, 102f, 112t,
112–114, 113f
CNS, 114
eye, 112
gastrointestinal tract, 114
genitourinary tract, 114
neuromuscular junction, 108t, 111f,
115
PNS, 103f, 114
respiratory system, 114
secretory glands, 114
pharmacodynamics of, 108t, 110–115
preparations available, 123t
Cholinomimetics, indirect-acting,
115–118, 122t
chemistry and pharmacokinetics of,
115–117, 116f, 117t
mode of action of, 94f, 108f, 109
pharmacodynamics of, 112t, 117–118,
479f, 480f
preparations available, 123t
Cholinoreceptor stimulants, 107. See also
Cholinomimetics
CHOP, for non-Hodgkin’s lymphoma, 970
Chorea, 492
benign hereditary, 505
Huntington’s disease, 504f, 504–505,
508t
Choriogonadotropin alfa, 674
Christmas disease, 621, 622t
Chronic kidney disease, 785–786
Chronic lymphocytic leukemia (CLL)
description of, 970
immunization for, 1180t
Chronic myelogenous leukemia (CML),
969–970
Chronic obstructive pulmonary disorder
(COPD)
asthma versus, 361
exacerbations of, 361
muscarinic receptor blockers for,
126f, 130
b1-selective blockers for, 164
treatment of, 360–361
Chronic pancreatitis, 400
Chrousos syndrome, 710
Churg-Strauss syndrome, 357
Chylomicronemia, primary, 629t, 629–630
Chylomicrons, 627
Ciclesonide, 355
Ciclopirox olamine, dermatologic topical,
1072
Cidofovir, 868t, 869

Cigarette smoking, 120
Cilastatin, 807
Cilostazol
description of, 209, 621
peripheral artery disease and intermittent
claudication treated with, 209
Cimetidine, 1089. See also H2-receptor
antagonists
description of, 71, 296t, 1089–1091
drug interactions of, 1163t
Cinacalcet
on bone homeostasis, 781
hyperparathyroidism treated with, 784,
790t
Cinchonism, 924
Cinryze, 308, 317t. See also Kinin
inhibitors
Ciprofloxacin, 838–839
Circumventricular organs, 369
Cirrhosis, 271
Cisapride, 291, 1163t–1164t
Cisatracurium. See also Neuromuscular
blocking drugs
pharmacokinetics of, 477
properties of, 478t, 489t
Cisplatin, 955t, 956–957
Citalopram, 549t. See also Selective serotonin
reuptake inhibitors (SSRIs)
blocking effects of, 542t
dosing of, 546t
pharmacokinetics of, 540t
poisoning with, 1042
Cladribine, 958t, 961
Clarithromycin, 819f, 820, 824t
Classic angina, 194
Claudication, intermittent, 209, 211t
Clavulanic acid, 806f, 806–807
Clearance (CL), 42–46. See also specific
drugs
capacity-limited elimination in, 45–46
for drug concentration measurement
interpretation, 53
flow-dependent elimination in, 46
initial predictions of, 54
rate of elimination in, 45
revising individual estimates of, 54
on target concentration, 52
total systemic, 45
Clevidipine, 187
Clindamycin, 821–822, 824t
acne treated with, 1071
malaria treated with, 928
Clinical Pharmacogenetics Implementation
Consortium (CPIC), 74
Clinical trials, 15–17
confounding factors in, 14
controlled, 2
IND & NDA, 12f, 15–17
phase 1, 16
phase 2, 16
phase 3, 17
phase 4, 17
randomized controlled trails, 15b
Clobazam, 430, 432, 433t, 437t
CLOCK/BMAL-1, 706
Clofazimine, 843t, 851
Clomiphene, 737f, 738, 739–740
Clomipramine, 540t, 542t, 546t
Clonazepam, 393t. See also Benzodiazepines
restless legs syndrome treated with, 507
seizures treated with, 432, 433t, 437t
Clonidine. See also Sympathomimetics
description of, 149, 154t, 191t
hypertension treated with, 179t,
179–181
tics treated with, 506, 508t
withdrawal syndrome, 184
Clonorchiasis, 944
Clopidogrel
antiplatelet effects of, 620
CYP2C19 on metabolism of, 78, 79t
peripheral artery disease and intermittent
claudication treated with, 209
Clorazepate, 383, 385t, 393t, 432. See also
Benzodiazepines
Clostridium difficile, 895, 903
Clotrimazole, topical, 860
dermatologic, 1072
Clotting factors, 610t, 610–611, 611f
Clotting prevention agents, 624t
Clozapine, 514f, 515, 520t, 529t
Club drugs, 587
Coagulation
estrogens on, 725
mechanisms of, 608–609
Coagulation cascade, 609–611, 610f
fibrinolysis in, 611, 611f
fundamentals of, 608, 610t, 611f
tissue factor-VIIa complex in, 610–611,
611f
Coagulation disorder drugs, 608–625
anticoagulants, 611–618, 624t
antiplatelet agents, 619–620, 624t
aspirin, 619–620
cilostazol, 621
dipyridamole, 621
GP IIb/IIIa antagonists, 621
thienopyridines, 620
antithrombotics, 624t
factor VIIa, recombinant, 622t, 623,
624t
fibrinolytic inhibitors, 622t, 623, 624t
fibrinolytics, 611f, 618–619, 624t
plasma fractions, 621–623, 622t, 624t
vitamin K for bleeding disorders, 614f,
621, 622t
Index    1201
Cobalt, 1017
Cobimetinib, 975
Cocaine, 143f, 372, 460t, 470, 472t.
See also Anesthetics, local
abuse of, 577t, 581
biogenic amine binding in, 585–586,
586f
clinical uses of, 151
on dopamine transporter, 586, 586f
historical development of, 461b
on NET, 95
Coccidioides immitis, 862
Cockcroft-Gault formula, 1060
Codeine, 77, 568, 572t. See also Opioid
agonists
antitussive, 570, 572t
CYP2D6 activity on metabolism of,
77–80, 79t
Gio protein-coupled receptor activation
by, 581, 583f
properties of, 555t
Coding single nucleotide polymorphisms
(cSNPs), 75, 75t
Coenzyme Q10, 1141–1142
Cohort epidemiologic studies, 15b
Colchicine, 1164t
Cold-induced urticaria, 292
Cold medications, hypertension from,
1120, 1130
Colesevelam hydrochloride, 636–637, 640t
diabetes mellitus treated with, 764, 769t
diarrhea treated with, 1100
Colestipol
description of, 636–637, 640t
diarrhea treated with, 1100
Collecting tubule system, 255f, 257–259,
258f
Colloidal bismuth compounds, 1100
Colonic pseudo-obstruction, acute, 1097
Colony-stimulating factors, 600
Colorectal cancer
case study of, 948, 976
dihydropyrimidine dehydrogenase
enzyme deficiency on, 976
Coltsfoot, 1133t
Combined toxicity, of drug interactions,
1173
Comfrey, 1133t
Commensal gut microbiota, 69–70
Community-acquired pneumonia,
cephalosporin and vancomycin
for, 795, 814
Competitive antagonists, 23f, 23–24
Competitive inhibitor, 5, 6f
Complementary medicine, 3
Compliance (adherence), 1150–1151
Compound 21, 305, 316t
Compound 48/80, 278, 280
1202    Index
Compound optimization, 13
Concentration-dependent killing, 828, 910
Concentration-effect curves, receptor bind-
ing of agonists on, 21–22, 22f
Concentration measurements
clearance in, 53
dosing history in, 53
initial predictions in, 54
revising individual estimates of, 54
timing of samples for measurement of,
53–54
volume of distribution in, 54
on pharmacologic effects, 20, 21–26.
See also Dose, on pharmacologic
effects
Conductance, potassium on, 231b
Conduction, heart, 228, 229f
Conflicts of interest, 18
Confounding factors, 14
Congenital adrenal hyperplasia, 710
Conivaptan, 308, 682, 684t
diuresis using, 268–269, 273t
heart failure treated with, 224
on vasoactive peptides, 317t
Conjugates, drug, 63, 64f, 64t
Conn’s syndrome, 266
Consciousness, in anesthesia, 447b
Conscious sedation, 441b
Constipation, opioid-induced, 562
Constitutive activity, 5
Contact hypersensitivity, 983
Context-sensitive half-time, 451, 451f
Continuing medical education (CME), 18
Continuous subcutaneous insulin infusion
(CSII) devices, 756–757
Contraception, hormonal, 732–737
adverse effects of, 734–736
beneficial effects of, 737
clinical uses of, 734
contraindications and cautions with, 736
emergency, OTC, 1125t
mechanism of action of, 732
monophasic, biphasic, and triphasic, 732
pharmacologic effects of, 732–734
physiologic effects of, 728t, 729, 729f,
730t–731t
blood, 733
breast, 733
carbohydrate metabolism, 733
cardiovascular system, 734
CNS, 733
endocrine functions, 733
lipid metabolism, 733
liver, 733
ovary, 732–733
skin, 734
uterus, 733
postcoital contraceptives, 736t, 736–737
preparations of, 730t–731t, 732 clinical pharmacology of, 709–714
progestin-only contraception, 736 contraindications and cautions in, 713
types of, 732 diagnostic uses in, 711
Contractility, cardiac, 216, 216f drug selection and dosage in, 713–714
Controlled clinical trial, 2 fetal lung maturation, 711
Controlled ovarian stimulation mineralocorticoids
GnRH for, 677 aldosterone, 714–715
gonadotropins for, 674, 675f deoxycorticosterone, 714–715
Controlled substances, 1153, 1153t fludrocortisone, 715
Conus, 370b nonadrenal disorders, 711–712, 712t
Conversions, for prescriptions, 1148 pharmacodynamics of, 709, 709t
Converting enzyme, in angiotensin pharmacokinetics of, 706f, 709, 709t
biosynthesis, 303 preparations available, 718t
Convulsions, neuromuscular blockers for, 484 toxicity in, 712–713
Coplanar biphenyls, 1015 Corticotropin, 703
Copy number variations (CNVs), 75t Corticotropin-releasing hormone (CRH),
Coral snake antivenom, 1181t 669, 669t
Coral snake hyperimmune globulin, 991 Cortisol, 704–709, 718t. See also Glucocor-
Coronary artery disease (CAD) ticoids, naturally occurring
angina pectoris from, 194 Cortisone, 709t. See also Corticosteroids,
case study of, 194, 211 synthetic
with hyperlipidemia, 194, 211 Cost, prescription, 1154
hypertension and, anesthesia with, 440 Cotransmitters, 93
myxedema and, 697 autonomic, 93
treatment of, 207 in cholinergic and adrenergic nerves,
Coronary blood flow, 195 97–98
Coronary heart disease, 401 Coupling
Coronary steal, 206b definition of, 22
Corticosteroids receptor-effector, and spare receptors,
antiemetic properties of, 1105 22f, 22–23
asthma treated with, 354–355, 359, Covalent bonds, 3–4
362t, 363t COX-1, 323, 324f
on eicosanoid synthesis, 332 COX-2, 263, 323, 324f
in elderly, 1064 COX inhibitors
gout treated with, 663 Bartter’s syndrome treated with, 335
immunosuppressive uses of, 985t, ductus arteriosus delayed closure treated
985–986 with, 335
inhaled (aerosol), 354–355, 359, 362t, COX-2 inhibitors
363t adverse effects of, 643
rheumatoid arthritis treated with, azapropazone, 649
658–659 carprofen, 649
topical, 1079–1081, 1080t, 1081t celecoxib, 645t, 647
adverse effects of, 1081 diclofenac, 644f, 645t, 647
chemistry and pharmacokinetics of, diflunisal, 645t, 647
1080t, 1080–1081 etodolac, 645t, 647
dermatologic, 1079–1082, 1080t, flurbiprofen, 644f, 645t, 647
1081t ibuprofen, 644f, 645t, 647–648
Corticosteroids, synthetic indomethacin, 644f, 645t, 648
adrenal androgens, 715 ketoprofen, 645t, 648
adrenocortical hypo- and hyperfunction meclofenamate, 649
uses of meloxicam, 645t, 647
aldosteronism, 710–711 nabumetone, 644f, 645t, 648
Chrousos syndrome, 710 naproxen, 645t, 648
congenital adrenal hyperplasia, 710 nonselective, 647–648
Cushing’s syndrome, 710 oxaprozin, 645t, 648
adrenocortical insufficiency uses of piroxicam, 644f, 645t, 648
acute, 710 selective, 645t, 645–647
chronic (Addison’s disease), 709–710 sulindac, 645t, 648–649
 Index    1203

tenoxicam, 649 Cyclosporine (cyclosporin A, CSA), 887 D

tolmetin, 644f, 645t, 649 antirheumatic actions of, 651 D3, for bone homeostasis, 789t
C-peptide, 747–748 drug interactions of, 1164t–1165t Dabigatran etexilate mesylate, 618
Cretinism, 691, 696t immunosuppressive uses of, 986 Dabrafenib, 975
Crisaborole, 1081–1082 CYP1A2, 62t, 66t Dacarbazine, 955t, 956
Crofelemer, 248t, 252t, 1099 CYP2A6, 66t Daclatasvir, 888
Crohn’s disease CYP3A4, 67t, 384 Daclizumab, 994
helper T cell type 1 dysregulation in, CYP3A5, 64f, 67t, 68 Daglutril, 312, 317t
1110 CYP2B6, 62t, 64f, 66t, 69 Dalbavancin, 803t, 809–810, 812t
treatment of, 1087, 1119 CYP2C8, 66t Dalteparin, 612–616. See also Heparin
Cromolyn, 281 CYP2C9, 62t, 64f, 66t, 68 Danazol, 738–739
allergic rhinoconjunctivitis treated with, characteristics of, 77t Dantrolene
356 polygenic effects in, 80t, 85–86 malignant hyperthermia treated with,
asthma treated with, 355–356, 360, 362t CYP2C18, 62t 449, 488
Crossover design, 14 CYP2C19, 62t, 64f, 66t, 68, 76t, 78, 79t spasmolytic actions of, 486f, 487–488,
Cross-tolerance, 565 CYP2CB, 62t 489t
Crotalidae polyvalent immune Fab antive- CYP2D6, 62t, 64f, 66t–67t, 67, 75–78, Dapagliflozin, 261–262, 272t, 274t, 763
nom, 1181t 76t, 79t Dapsone, 850, 1072
Crotamiton, 1075 CYP2E1, 62t Daptomycin, 803t, 810, 810f, 812t
Cryoablation, for cardiac arrhythmias, 246b Cyproheptadine, 282, 283t, 291 Daratumumab, 992
Cryoprecipitate, 623 Cyproterenone, 744 Darbepoetin alfa, 601, 602t, 606t
Cryptosporidium parvum, nitazoxanide for, Cyproterenone acetate, 744–745 Darbufelone, 332
933 Cysticercosis, 944 Darifenacin, 131, 135t. See also Muscarinic
C-type natriuretic peptide (CNP) Cystic fibrosis receptor blockers
description of, 308–309, 309f chloride channels in, 248b Darunavir, 871t, 880
on kidney, 259 heart and, 248b Dasabuvir, 889
Cumulative effects, 49 Cystic fibrosis transmembrane regulator Dasatinib, 967
Cushing’s syndrome, 710 (CFTR), 24, 30 Data, missing, 15
Cutaneous larva migrans. See also Cytarabine (ara-C), for immunosuppression, Datura, 125. See also Atropine; Muscarinic
Antihelminthic drugs 958t, 960, 989 receptor blockers
albendazole for, 939t, 940 Cytisine, 584, 588t Daunorubicin, 962t, 964–965
thiabendazole for, 946 Cytochrome P450-derived metabolites, DDT (chlorophenothane), 1010t,
Cyanide, 200, 1041t, 1044, 1044t 331–332 1010–1011, 1013f
Cyanocobalamin, 596, 598, 606t Cytochrome P450 oxidoreductase Deamination, 60t
Cyclic adenosine monophosphate (cAMP) (POR, CYP), 60t–61t Debrisoquin, 67, 181
in bronchodilation, 349, 350f Cytokine receptors, 28–29, 29f Debrisoquin-sparteine oxidation, 65
description of, 32, 34, 34f Cytokines, 996, 997t, 998 Dechlorination, 61t
Cyclic AMP response element binding Cytomegalovirus (CMV), 867–870 Decongestants, OTC
protein (CREB), 578 cidofovir for, 868t, 869 systemic, 1125t
Cyclic guanosine monophosphate (cGMP), foscarnet for, 868t, 869 topical, 1125t
34, 343f fundamentals of, 867 Decontamination
Cyclizine, 283t ganciclovir for, 868, 868t description of, 898t
Cyclobenzaprine, 488, 489t valganciclovir for, 868t, 868–869 of poisoned patient, 1039–1040
Cyclodienes, 1010t, 1010–1011, 1013f Cytomegalovirus immune globulin, 1180t Deep brain stimulation (DBS), 588
Cyclooxygenases, 322–323, 324f Cytopenia agents, 591–607 Deep sedation, 441b. See also Anesthetics,
Cyclopentolate, 130t, 135t. See also anemia agents, 591–600, 605t–607t general
Muscarinic receptor blockers hematopoietic growth factors, 600–605, Deep venous thrombosis (DVT)
Cyclophosphamide, 953f, 954. See also 606t from female hormonal contraceptives,
Alkylating agents preparations available, 607t 735
antirheumatic actions of, 650–651 Cytotoxic agents, immunosuppressive pulmonary embolism caused by, 608,
clinical activity of, 955t azathioprine, 988 625
immunosuppressive uses of, 988 cyclophosphamide, 988 thrombolytics for, 619
metabolism of, 954, 954f hydroxychloroquine, 989 Deferasirox, 596, 605t, 1032–1033
Cycloplegia, from atropine, 127, 128f methotrexate, vincristine, and cytarabine, Deferoxamine, 1032
Cycloserine 989 iron overload treated with, 596, 605t
description of, 811 pentostatin, 989 iron toxicity treated with, 596
tuberculosis treated with, 843t, 847 pyrimidine synthesis inhibitors, 988–989 Definitive therapy, antimicrobial, 905
Cyclospasm, 105b vinblastine, 989 Degarelix, 678–679
1204    Index

Degree of spareness, 22f, 23 isotretinoin, 1077–1078 fluorouracil, 1083

Dehydroemetine, 929t, 931 retinoic acid derivatives, 1077 ingenol mebutate, 1083–1084
Dehydroepiandrosterone (DHEA), 740 antibacterial agents, topical NSAIDs, 1084
Dehydroepiandrosterone sulfate (DHEAS), bacitracin and gramicidin, 1070 podophyllum resin and podofilox,
740 fundamentals of, 1070 1083
Delavirdine, 871t, 877 mupirocin, 1070 propylene glycol, 1082
Delayed afterdepolarizations (DADs), 218, neomycin and gentamicin, 1071 salicylic acid, 1082
233, 233f polymyxin B sulfate, 1070–1071 sinecatechins, 1083
Delayed effects, 49 retapamulin, 1070 urea, 1082–1083
Delayed-type hypersensitivity (DTH), 983, antibacterial agents, topical acne melanoma agents, 1085
984f clindamycin, 1071 other agents, 1086t
Delirium tremens, 400 dapsone, 1072 percutaneous absorption in, 1068,
management of, 403 erythromycin, 1071 1069df
mortality rate for, 585 metronidazole, 1071 pharmacology response in, 1068
sedative-hypnotics for, 391 sodium sulfacetamide, 1071–1072 pigmentation agents, 1076–1077
Delta opioid receptors, 553, 554t antifungal agents, oral hydroquinone, monobenzone, and
Demeclocycline, 817 azole derivatives, 1073 mequinol, 1076
Dendrites, 368 griseofulvin, 1074 trioxsalen and methoxsalen, 1076
Denervation supersensitivity, 103 terbinafine, 1074 psoriasis drugs
Denileukin diftitox, 998 antifungal agents, topical acitretin, 1078
Denosumab, 995 allylamines, 1073 biologic agents, 1079
on bone homeostasis, 781 azole derivatives, 1072 fumaric acid esters, 1079
osteoporosis treated with, 775, 780b, butenafine, 1073 TNF inhibitors, 1079
787, 790t ciclopirox olamine, 1072 ustekinumab, 1079
Deoxycorticosterone (DOC), 714–715 nystatin and amphotericin B, 1073 calcipotriene and calcitriol,
Deoxycytidine analogs tolnaftate, 1073 1078–1079
cytarabine, 958t, 960 anti-inflammatory agents, 1079–1082 tazarotene, 1078
gemcitabine, 958t, 960 corticosteroids, topical, 1079–1081, sunscreens, 1076–1077
Dependence, physical, 389, 576–578 1080t, 1081t trichogenic and antitrichogenic agents
alcohol (ethanol), 396, 400 tar compounds, 1082 bimatoprost, 1085
benzodiazepine, 584 antineoplastic agents eflornithine, 1085
clinical pharmacology of, 587–588 alitretinoin, 1085 finasteride, 1085
definition of, 559, 575 bexarotene, 1085 minoxidil, 1084–1085
opioid, 559, 564–565, 566 romidepsin, 1085 Dermatologic vehicles, 1068–1070
sedative-hypnotics, 389–390 vismodegib, 1085 Desensitization, 32, 33f
on sedative-hypnotics, 391 vorinostat, 1085 of adrenoreceptors, 141
tolerance in, 576–578 antipruritic agents by G protein-coupled receptor kinases,
withdrawal, 576–578 doxepin, 1084 141
Depression pramoxine, 1084 heterologous, 141
acute bipolar, antipsychotics for, 519 antiseborrhea agents, 1084, 1084t homologous, 141
from female hormonal contraceptives, 735 antiviral agents, topical, 1074 membrane, by muscle relaxants, 479f,
major depressive disorder, 526, 532–536. dermatologic vehicles, 1068–1070 480
See also Major depressive disorder drug reactions, 1068, 1070t Desflurane, 441–449. See also Anesthetics,
(MDD) ectoparasiticides inhaled
pathophysiology of, 533–536 benzyl alcohol, 1076 properties of, 443t
integration of hypotheses on, 536 crotamiton, 1075 structure of, 443f
monoamine hypothesis in, 533, ivermectin, 1075 Design, rational drug, 4
534–536, 535f lindane, 1075 Desipramine, 537, 546t
neuroendocrine factors in, 536 malathion, 1076 Desloratadine, 281, 283t, 296t. See also
neurotrophic hypothesis in, 533f, permethrin, 1075 H1-receptor antagonists
533–534 spinosad, 1075 Desmethyldiazepam, 382f
recurrent, lithium for, 526 sulfur, 1075 Desmopressin
unipolar, antipsychotics for, 519 immunomodulators description of, 681–682, 684t
Dermatologic pharmacology, 1068–1086 imiquimod, 1074 diuresis using, 268
acne preparations tacrolimus and picrolimus, structure of, 681f
azelaic acid, 1078 1074–1075 Desmopressin acetate, 622, 622t
benzoyl peroxide, 1078 keratolytic and destructive agents Desogestrel, 728, 728t, 729f. See also
brimonidine, 1078 aminolevulinic acid, 1084 Progestins

Desoxycorticosterone acetate, 709t. See also
Corticosteroids, synthetic
Destructive agents, dermatologic, 1083.
See also Keratolytic and destruc-
tive agents
Desulfuration, 60t
Desvenlafaxine, 537, 546t, 550t.
See also Serotonin-norepinephrine
reuptake inhibitors (SNRIs)
Detemir, 768t. See also Insulin
Development and regulation, drug, 10–18
breakthroughs in, 11
drug discovery in, 11–13, 12f
drug screening in, 12–13
human evaluation in, 14–18
adverse drug reactions in, 18
clinical trials in
confounding factors in, 14–15
IND & NDA, 15–17
conflicts of interest in, 18
Food & Drug Administration in, 15
guidelines for, 14
legislation on, 15, 16t
orphan drugs and rare diseases in, 18
types of evidence in, 14b–15b
new drug development in, 11, 12f
safety and toxicity testing in, preclinical,
13, 13t
Dexamethasone, 709t, 1105. See also
Corticosteroids, synthetic
Dexamethasone suppression test, 711
Dexfenfluramine, 289
Dexlansoprazole, 1091–1095. See also
proton-pump inhibitors (PPIs)
Dexmedetomidine. See also
Sympathomimetics
anesthesia using, 450t, 457
description of, 149, 153, 154t
Dexrazoxane, 965
Dextromethorphan, 570, 572t
Diabetes insipidus
diuretics for, 272
nephrogenic
from ADH antagonists, 268–269
from lithium, 527
Diabetes mellitus
acute complications of, 767–768
chronic complications of, 768
complications of, 767–768
gestational, 752
hypoglycemia caused by, 767
treatment of
diet, 764
education used in, 764–765
glycemic control, 765, 765b
insulin, 747–749, 768t. See also
Insulin
nonpharmacologic, 764–765
oral antidiabetic agents, 757–764,
768t–769t. See also Antidiabetic
agents, oral
type 1, 751–752
type 2, 752
Diabetic ketoacidosis, 767
Diacetylmonoxime (DAM), 132
Diacylglycerol (DAG), 32, 34, 34f, 138f,
139, 139t
Dialysis, for poisoning, 1039t, 1040
Diarrhea, 1100–1101, 1123t–1124t.
See also Antidiarrheal agents
Diastereomers, 4, 4t
Diastolic heart failure, 212, 223
Diastolic hypertension, 174
Diazepam, 393t. See also Benzodiazepines
acute ethanol withdrawal treated with,
406t
in neonates, 1053t
pharmacokinetics of, 385t, 450t
seizures treated with, 432, 437t
spasmolytic actions of, 485, 489t
structure of, 382f
Diazoxide, 186, 192t
Dibenzomethanes, 1076
Dibucaine number, 478
2,4-Dichlorophenoxyacetic acid (2,4-D),
1013f, 1013–1014
Dichlorphenamide, 260t
Diclegis, 282, 296t. See also H1-receptor
antagonists
Diclofenac. See also Nonsteroidal anti-
inflammatory drugs (NSAIDs)
actinic keratoses treated with, 1084
description of, 644f, 645t, 647
Dicumarol, 614f
Dicyclomine
characteristics of, 135t
irritable bowel syndrome treated with,
1101
structure of, 126f
Didanosine, 871t, 874–875
Diet
diabetes mellitus managed with, 764
in drug metabolism, 70
Dietary Supplement Health and Education
Act (DSHEA), 1132
Dietary supplements, 3, 1141–1144
Diethylcarbazine citrate, 939t, 940–941
Diethylstilbestrol, 723, 723f. See also
Estrogen(s)
Difenoxin, 568. See also Opioid agonists
Diffusible second messengers, CNS, 369f,
370
Diffusion
aqueous, 7–8, 8f
lipid, 8, 8f
Diflunisal, 645t, 647
Index    1205
DiGeorge’s syndrome, 984
Digitalis, for heart failure, 217–219, 218t,
219f
chronic, 223
drug interactions of, 1165t
preparations available, 226t
Digitalis antibody, for heart failure, 226t
Digitalis glycosides, drug interactions of,
1165t
Digoxin, 41, 55
drug interactions of, 1165t
heart failure treated with, 223, 225t
mechanism of action of, 215
in neonates, 1053t
poisoning, 1041t, 1044–1045
toxicity of, 223
Digoxin immune fab, 223
Dihydroartemisinin, 922–923
Dihydroartemisinin-piperaquine, 922, 922t
Dihydrocodeine, 568. See also Opioid
agonists
Dihydroergotamine, 160
Dihydropyridines. See also Calcium channel
blockers; specific types
angina pectoris treated with, 202–206,
203t, 210t. See also Calcium
channel blockers
hypertension treated with, 179t, 187
Dihydropyrimidine dehydrogenase (DPD,
DPYD)
deficiency of, 976
pharmacogenomics of, 76t, 78, 79t, 81
Dihydrotestosterone, synthesis of, 740
Dihydroxyphenylalanine (DOPA), 495f
Dihydroxyphenylglycol (DHPG), 142
1,25-Dihydroxyvitamin D (1,25[OH]2D),
on bone homeostasis, 773, 774f
Diiodotyrosine (DIT), 688, 688f
Diloxanide furoate, 929t, 930f, 930–931
Diltiazem. See also Calcium channel
blockers
angina pectoris treated with, 202–206,
203t, 210t. See also Calcium
channel blockers, angina pectoris
treated with
arrhythmias treated with, 239t, 240t,
246, 251t
on double product, 208, 208f
hypertension treated with, 179t, 187,
191t
Dimenhydrinate, 283t, 284, 1106
Dimercaprol (2,3-dimercaptopropanol,
VAL), 1030, 1030f
arsenic poisoning treated with, 1026
lead poisoning treated with, 1024
mercury poisoning treated with, 1029
Dimercaptopropanesulfonic acid (DMPS),
1031–1032
1206    Index
Dimercaptosuccinic acid (DMSA),
1030–1031
Dimerization, 27
Dimethisterone, 728, 728t, 729f. See also
Progestins
Dimethylbenzene (xylene), 1010
Dimethyl fumarate (DFMF), 989
Dimethylmercury, 1028
Dinoprostone (PGE2, PGF2α), 323
abortion using, 334
labor induction using, 333f, 335
structure of, 333f
Dinutuximab, 992
Dioxins, 1015
Dipeptidyl peptidase-4 (DPP-4) inhibitors,
762–763, 769t
Diphenhydramine
antiemetic properties of, 1106
description of, 282f, 282–283, 283t,
296t. See also H1-receptor
antagonists
Diphenoxylate, 568, 1100. See also Opioid
agonists
Diphenylhydantoin, 418. See Phenytoin
Diphenylmethane derivative laxatives, 1099
Diphtheria vaccines
diphtheria antitoxin, equine, 1180t
diphtheria tetanus acellular pertussis
(DTaP), 1176t
tetanus, diphtheria, pertussis (Tdap),
1178t
tetanus-diphtheria (Td, DT), 1177t
Diphyllobothrium latum
niclosamide for, 943
praziquantel for, 944–945
Dipyridamole, 206b, 621
Direct-acting antiviral agents (DAAs), 887
Direct factor Xa inhibitors, 616–617
Direct thrombin inhibitors
oral, 618
parenteral, 617–618
Direct vasodilators, 176
Discontinuation syndrome, 547
Discovery, drug, 11–13, 12f
Disease-modifying antirheumatic drugs
(DMARDs), 649–659
abatacept, 649–650
azathioprine, 650
belimumab, 658
chloroquine and hydroxychloroquine,
650
combination therapy, 658
cyclophosphamide, 650–651
cyclosporine, 651
fundamentals of, 649
glucocorticoid drugs, 658–659
inflammation treated with, 643
interleukin-1 inhibitors
adverse effects of, 658 carbonic anhydrase inhibitors, 259–261,
anakinra, 657 260t, 272t
canakinumab, 657 clinical pharmacology of, 269–272
mechanism of action of, 657 edematous states, 269–270
rilonacept, 657–658 edema, idiopathic, 270–271
leflunomide, 651 general, 269–270
methotrexate, 651–652 heart failure, 270
mycophenolate mofetil, 652 hepatic cirrhosis, 271
preparations available, 664t kidney disease and renal failure,
rituximab, 652 270–271
sulfasalazine, 652–653 nonedematous states
tocilizumab, 653 diabetes insipidus, 272
tofacitinib, 656–657 hypercalcemia, 272
tumor necrosis factor-α blocking agents, hypertension, 271
653–656 nephrolithiasis, 271–272
adalimumab, 652–654, 654f combinations
adverse effects of, 655–656 loop and thiazide agents, 269
certolizumab, 654f, 654–655 potassium-sparing with loop or
etanercept, 654f, 655 thiazide diuretics, 269
golimumab, 654f, 655 potassium-sparing with proximal
infliximab, 654f, 655 tubule diuretics, 269
structures of, 654f fundamentals of, 254
Disinfectants and antiseptics, 897–901 heart failure treated with, 220, 224t, 227
alcohols, 898, 898t acute, 224
aldehydes, 900 chronic, 221–222
chlorhexidine, 898t, 898–899 preparations available, 226t
definitions of, 898t hypertension treated with, 175,
forms of, available, 902t 176–178, 179t, 191t
fundamentals of, 897–898 mechanisms of action and hemody-
halogens namic effects of, 177
chlorine, 899 toxicity of, 178
iodine, 899 use of, 177–178, 179t
iodophors, 899 kidney injury from, acute, 254, 275
phenolics, 899 loop, 191t, 262f, 262t, 262–264, 273t,
heavy metals, 901 274t
peroxygen compounds, 900–901 osmotic, 267–268, 273t, 274t
preservatives, 901 potassium-sparing, 191t, 265f, 265–267,
quaternary ammonium compounds, 266t, 273t
899 drug interactions of, 1170t–1171t
superoxidized water, 900 preparations available, 274t
Disinfection, 898t with proximal tubule diuretics, 269
Disopyramide, 239t, 240t, 240–241, 250t preparations available, 274t
Disseminated intravascular coagulation renal tubule transport and, 254–259.
(DIC), 611 See also Renal tubule transport
Distal convoluted tubule (DCT), 255f, mechanisms
257, 257f sodium glucose cotransporter 2 (SGLT2)
Distribution, drug, 7. See also specific drugs inhibitors, 261–262, 272t, 274t
drug interactions on, 1156 thiazide, 264–265. See also Thiazide
models of, 45f diuretics
Disulfiram Divalproex sodium, 426f, 426–427
alcoholism treated with, 404, 406t, 407t DNA guanine, 953
drug interactions of, 1166t DNA gyrase inhibitors, 837–840, 838f,
Diuresis, forced, 1040 838t, 840t
Diuretics, 191t, 254–275, 273t–274t Dobutamine, 141t, 149, 149f, 154t. See
antidiuretic hormone agonists, 268 also Sympathomimetics
antidiuretic hormone antagonists, for cardiac stress test, 152
268–269, 274t heart failure treated with, 219, 224, 225t
aquaretics, 267–268, 273t, 274t structure of, 149f

Docetaxel, 962t, 963
Docosahexaenoic acid, 324
Docosanol, 865t, 867
Docusate, 1098
Dofetilide, 239t, 240t, 245, 251t
Dolasetron
antiemetic properties of, 1104
chemical structure of, 1102f
Dolutegravir, 871t, 883
Domoic acid, 375
Domperidone, 1097–1098
Donepezil, 1063
Dopamine (DA), 494
biosynthesis of, 97f
in CNS, 374f, 376t, 378
in depression, 534, 535f
functions of, 92t, 149
heart failure treated with, 225t
acute, 224
hypothalamic, 669, 669t
metabolism of, 98f
in parkinsonism, 494, 494f
structure of, 144f
Dopamine agonists, 679–680
clinical pharmacology of
acromegaly, 679–680
hyperprolactinemia, 679, 680f
lactation, physiologic, 679
pharmacokinetics of, 679
preparations available, 685t
Dopamine hypothesis
of addiction, 579b
of schizophrenia, 512–513
Dopamine receptor
in addiction, 576, 579b
affinities of, 141, 141t
on cardiovascular system, 147
in CNS, 378
description of, 99, 99t, 139t, 140, 494,
516–517, 517f
effects of, 516–517, 517f
Dopamine receptor agonists, 154t
diabetes mellitus treated with, 764, 769t
dopamine1, 154t
dopamine2, 154t
Parkinson’s disease treated with, 151,
497–498, 497–499, 508t
adverse effects of, 499
bromocriptine, 498, 508t
mechanism of action of, 497–499,
498f
pergolide, 498
pharmacologic strategies for, 494, 498f
pramipexole, 498, 508t
ropinirole, 499, 508t
rotigotine, 499
prolactinemia treated with, 151
Dopamine receptor antagonists, 516
Dopaminergic neurons, 494, 494f
Dopamine system, mesolimbic, 575
Dopamine transporter (DAT, SLC6A3),
95b
in addiction, 575, 576f, 577t
cocaine on, 586, 586f
Doripenem, 803t, 807, 812t
Dorzolamide, 260–261, 272t
Dose. See also specific drugs
clinical response and, 36–40
in patients, 36–37
graded dose–response relations in,
36, 36f
quantal dose–effect curves in, 37,
37f
shape of dose–response curves in,
36, 36f
selectivity and beneficial vs. toxic
effects in, 39–40
variation in drug responsiveness in,
37–39
gene-based recommendations, 79t–80t
history of, for drug concentration
measurement interpretation, 53
loading, 45f, 50–51, 51f
maintenance, 50, 50b, 51f
on pharmacologic effects, 20, 21–26
chemical antagonism in, 25
competitive and irreversible
antagonists in, 23f, 23–24
concentration-effect curves and
receptor binding of agonists in,
21, 22f
partial agonists in, 24–25, 25f
physiologic antagonism in, 25–26
receptor-effector coupling and spare
receptors in, 22f, 22–23
surface area, age, and weight in calcula-
tion of, 1056–1057, 1057t
Dose axis, 36, 36f
Dose–concentration effect, 41, 42f
Dose–effect curves, quantal, 37, 37f
Dose escalation, 952
Dose–response curves
graded relations in, 36, 36f
shape of, 36, 36f
Double-burst stimulation, 481
Down-regulation, 28
Doxazosin. See also Adrenoceptor
antagonist drugs
description of, 159, 159t, 170t, 191t
hypertension treated with, 184
Doxepin, 546t, 1084
Doxercalciferol
for bone homeostasis, 775, 777t, 789t.
See also Vitamin D
chronic kidney disease treated with, 785
Doxorubicin, 962t, 964–965
Index    1207
Doxycycline, 824t, 920t, 927–928
Doxylamine, 282, 284, 296t. See also
H1-receptor antagonists
d-Phenylalanine derivatives, 759, 768t
Dravet’s syndrome, 410, 431, 435
Dronabinol
as cannabinoid agonist, 582
description of, 1106, 1116t
Dronedarone, 239t, 240t, 244, 251t
Droperidol, 1106
Drospirenone, 717
Drotrecogin alfa, 624
Droxidopa, 152
Drug action, duration of, 6–7
Drug–body interactions, 5–10
pharmacodynamic principles in, 5–7
agonists in, 5, 6f
agonists inhibiting binding molecules
in, 5
antagonists in, pharmacologic, 5, 6f
drug-receptor interaction types in, 5
duration of drug action in, 6–7
partial agonists and inverse agonists,
5–6, 6f
receptors and inert binding sites in, 7
pharmacokinetic principles in, 7–10
Fick’s law of diffusion in, 8–9
Henderson-Hasselbalch equation in, 9
permeation in, 7–9, 8f, 8t
Drug conjugates, 63, 64f, 64t
“Drug Facts” label, 1127, 1128f
Drug groups, 10
Drug interactions, 1156–1173,
1157t–1172t
from biotransformation, 58
combined toxicity in, 1173
in drug metabolism, 70–72, 71t
pharmacodynamic mechanisms of, 1173
predictability of, pharmacokinetic mech-
anisms in, 1156, 1173
Drug reactions
dermatologic, 1068, 1070t
H1-receptor antagonists, 284
hypersensitivity, 83t, 83–85, 84f
Drug–receptor bonds, 3–4
Drug-receptor interactions, 5
Drug responsiveness
idiosyncratic, 38
quantitative variations in, 38
variation in, 37–39
Drug safety surveillance, 1153–1154
Drug screening, 12–13
Drugs of abuse, 575–589, 588t–589t
biogenic amines, drugs binding to
transporters of, 585–586, 586f
amphetamines, 586f, 586–587
cocaine, 585–586, 586f
ecstasy (MDMA), 577t, 587
1208    Index
Drugs of abuse (Cont.):
case study of, 575, 589
classes of, 577t
clinical pharmacology of, 587–588
Gio protein-coupled receptors, drugs
activating, 581–583, 583f
cannabinoids, 577t, 581–582, 583f
gamma-hydroxybutyric acid, 577t,
582, 583f
LSD, mescaline, and psilocybin, 577t,
582–583
opioids, 577t, 581, 583f
ionotropic receptors, drugs mediating
effects via, 583–585
alcohol, 585
benzodiazepines, 584
inhalants, 585
ketamine and phencyclidine, 585
nicotine, 583–584
neurobiology of, 575–581
addiction in
dopamine hypothesis of, 579b
as maladaptive learning, 578–580
animal models of, 578b
dependence vs. addiction in, 575
dopamine reinforcement in, 575–576
nonaddictive, 577t, 580
tolerance, 576–578
withdrawal, 576–578
nonaddictive, 577t, 580
d-Tubocurarine, 475, 478t
Ductus arteriosus delayed closure, COX
inhibitors for, 335
Dulaglutide, 762, 769t
Duloxetine, 151, 537, 540, 540t, 546t,
550t. See also Serotonin-
norepinephrine reuptake
inhibitors (SNRIs
Dupilumab, 357, 363t
Duration
of drug action, 6–7
of exposure, 1005
Dutasteride, 744, 745t
Dyazide, 266t
Dynorphins, 554, 554t
Dyrenium, 266t
Dysbetalipoproteinemia, familial, 629t, 630
Dyskinesias
drug-induced, 506
from levodopa, 497
tardive, 506
antipsychotics as cause of, 522
Dyslipidemia, 626–641
atherogenesis from, 627
hypercholesterolemias, primary
ABCG5 and ABCG8 mutations, 631
autosomal recessive
hypercholesterolemia, 631
cholesterol 7α-hydroxylase, 631 malathion, 1076
cholesteryl ester storage disease, 629t, permethrin, 1075
631 spinosad, 1075
familial combined sulfur, 1075
hyperlipoproteinemia, 629t, 631 Eculizumab, 995
familial hypercholesterolemia, 629t, Edema
630, 631f estrogens on, 725
familial ligand-defective apolipoprotein histamine-induced, 280
B-100, 629t, 630 idiopathic, 270–271
HDL deficiency, 631f lithium as cause of, 527
Lp(a) hyperlipoproteinemia, 629t, 631 Edetate calcium disodium
PCSK9 mutations, 631 (ethylenediamine-tetraacetic acid,
hyperlipidemia drugs, 632–638, 640t. EDTA), 1023, 1029f, 1031
See also Hyperlipidemia drugs Edoxaban, 616–617
hyperlipoproteinemias, 627–632, 629t Edrophonium, 117, 122t
dietary management, 632 myasthenia gravis treated with, 119
pathophysiology of, 627–631 neuromuscular blockade reversal using,
hypertriglyceridemias, primary, 629t, 484
629–630 structure of, 115, 116f
lipid guidelines, 628, 629t Efavirenz, 871t, 877–878
lipoproteins in, 626 Effective dose, median (ED50), 37, 37f
Dysmenorrhea, 726 Efficacy
Dysmorphogenesis, 523, 527 intrinsic, 5
Dyspepsia, nonulcer maximal, 36, 36f
H2-receptor antagonists for, 1091 practical, 36
metoclopramide and domperidone for, Effort angina, 194
1097 Efinaconazole, 1072
proton-pump inhibitors for, 1094 Eflornithine
Dystonia, 492, 505 topical, 1085
acute, from antipsychotics, 522 trypanosomiasis and leishmaniasis
tardive, 505 treated with, 934
Eicosanoid receptors, 326–327, 327f, 328t
E Eicosanoids, 321–338
Early afterdepolarizations (EADs), 233, 233f arachidonic acid and other polyunsatu-
Ecallantide, 308, 317t. See also Kinin rated precursors, 321–322, 322f
inhibitors case study of, 321, 338
Ecamsule, in sunscreen, 1076 clinical pharmacology of, 333–337
Echinacea (Echinacea purpurea), blood, 335–336
1134–1136 cardiovascular system, 335–336
Echinocandins, 853 gastrointestinal system, 336
caspofungin, 859, 861t immune system, 336–337
preparations available, 862t renal system, 335
Echinococcus reproductive system
albendazole for, 939t, 940 female, 334–335
praziquantel for, 944–945 male, 335
Echothiophate, 115–116, 116f, 122t. respiratory system, 336
See also Organophosphate structures of, 333f
cholinesterase inhibitors dietary manipulation of metabolism of,
Econazole, 1072 337
Ecotoxicology, 1005 mechanisms and effects of, 326–332
Ecstasy (MDMA) in lipoxygenase and cytochrome P450-
acamprosate for dependence on, 589t derived metabolites, 331–332
description of, 577t, 587 prostaglandins and thromboxanes,
Ectoparasiticides 327–331
benzyl alcohol, 1076 receptor mechanisms in, 326–327,
crotamiton, 1075 327f, 328t
ivermectin, 1075 NSAIDs on synthesis of, 332
lindane, 1075 preparations available, 337t
 Index    1209

synthesis of, 323–326, 324f Enantiomers, 4, 4t asbestos, 1016–1017

epoxygenase products, 325–326
inhibition of, 332–333
isoeicosanoids, 326
lipoxygenase products, 323–325, 324f
prostaglandin endoperoxide synthase
products, 323, 324f
Elbasvir, 888
Eldecalcitol, 775, 777t, 780b
Elderly, 1058. See Geriatric pharmacology
Electrocardiogram, 236f, 1038
Electrochemical gradient, 231b
Electrophysiology, 228–233
Electrostatic bonds, 4
Eletriptan, 291t, 296t
Elimination, 7. See also Clearance (CL)
capacity-limited, 45–46
first-pass, 47–48
flow-dependent, 46
models of, 45f
rate of, 45
time course of, 46f
Elimination enhancement, for poisoned
patient
dialysis, 1039t, 1040
forced diuresis, 1040
urinary pH manipulation, 1040
Elixirs, 1054
Eloctate, 621
Elotuzumab, 992
Eltrombopag, 602t, 604–605, 606t
Eluxadoline, 1100
Elvitegravir, 871t, 883
Emergency contraceptives, 1125t
Emergency trauma surgery, muscle relaxant
for, 491
Emesis
pathophysiology of, 1103, 1104f
toxin elimination through, 1040
Emetine, 929t, 931
EMLA, 471. See also Anesthetics, local
Empagliflozin, 272t, 763
Empiric therapy, antimicrobial, 905–906,
907t–909t
approach to, 905
choice of, 905–906
microbiology etiology in, 907t–908t
site of infection in, 909t
Emtricitabine, 871t, 875
Enalapril. See also Angiotensin-converting
enzyme inhibitors (ACEIs)
case study of, 300
chronic heart failure treated with, 222,
224t
hypertension treated with, 187–188
immediate effects of, 48–49, 49f
on renin-angiotensin system, 305
on vasoactive peptides, 316t
Endocannabinoids, 372, 377t, 379–380
Endocrine disruptors, 1016
Endocrine glands, 307
Endocrine system. See also specific organs
and disorders
chemical transmission in, 90
dysfunction of, on drug metabolism, 72
Endocytosis, 8f, 9
End-of-dose akinesia, 497
Endogenous catecholamines, 146f, 146t,
148–149. See also specific types
Endogenous opioid peptides, 554, 554t
Endometriosis, 677
Endometrium, 724
Endorphins, 554, 554t
Endothelial-derived relaxing factor
(EDRF), 339
Endothelin inhibitors, 312
Endothelin receptors (ETA, ETB), 311
Endothelins, 311–312
actions of, 311f, 311–312
biosynthesis, structure, and clearance of,
311
physiologic and pathologic roles of, 312
Endothelium-derived hyperpolarizing
factors, 326
Endotracheal intubation, neuromuscular
blockers for, 484–485
Enflurane, 441–449. See also Anesthetics,
inhaled
properties of, 443t
structure of, 443f
Enfuvirtide, 872t, 882
Enkephalins, 92t, 554, 554t
Enoxacin, 838
Enoxaparin, 612–616. See also Heparin
Entacapone
parkinsonism treated with, 500, 508t
structure of, 495f
Entecavir, 886
Enteric nervous system (ENS), 91f, 91–92
nonadrenergic, noncholinergic neurons
in, 99
physiology of, 1096–1097, 1097f
Enteric oxaluria, 789
Enterochromaffin cells, 285
Enterochromaffin-like (ECL) cells, 1088,
1088f
Entresto, 222, 310
Entry inhibitors, 882–883
enfuvirtide, 872t, 882
fundamentals of, 882
maraviroc, 872t, 882–883
Environmental factors
cancer from, 948
in drug metabolism, 70
Environmental pollutants, 1014–1017
coplanar biphenyls, 1015
endocrine disruptors, 1016
perfluorinated compounds, 1016
polybrominated biphenyl esters, 1015
polybrominated biphenyls, 1015
polychlorinated biphenyls, 1014–1016
polychlorinated dibenzofurans, 1015
polychlorinated dibenzo-p-dioxins, 1015
Environmental toxicology, 1004–1005
Enzalutamide, 744
Enzyme(s), 21. See also specific enzymes
Enzyme genetic variations, 75–82
glucose 6-phosphate dehydrogenase,
81–82, 82t
phase I enzymes in, 75–78, 76t–77t,
79t–80t
phase II enzymes in, 76t, 79t, 81
Enzyme induction
in cytochrome P450 system, 59, 62t–63t
drugs in, 70, 71t
Enzyme inhibition
in cytochrome P450 system, 59–61,
62t–63t
drugs in, 71t, 71–72
Ephedra, 1133t
Ephedrine, 144f, 150
asthma treated with, 350–351
noradrenergic transmitter release by, 95
structure of, 144f
Epidemiologic studies
analytic, 15b
case-control, 15b
cohort, 15b
Epidermal growth factor (EGF), 27–28,
28f
Epidermal growth factor (EGF) receptor,
28, 28f
Epidermal growth factor receptor (EGFR)
inhibitors, 966t, 967–968
Epidophyllotoxins, 962t, 964
Epilepsy (Seizures)
case study on, 409, 439
drug development for, 409–410, 412f
drugs for
acetazolamide, 432
benzodiazepines, 432
seizures, 309–439. See also Antiseizure
drugs
status epilepticus, 432–433
prevalence of, 409
seizure classification in, 409, 410t
Epinephrine
biosynthesis of, 97f
cardiovascular responses to, 146t
functions of, 146f, 146t, 148
metabolism of, 96–97, 98f
structure of, 144f
1210    Index
Epinephrine reversal, 157
Epinephrine therapy
anaphylaxis treated with, 152–153
asthma treated with, 350, 362t
cardiac arrest treated with, 152
Epirubicin, 965
Epithelial Na channel (ENaC), 258, 258f
Eplerenone, 191t, 224t, 717. See also
Aldosterone antagonists; Diuretics
diuresis using, 265–267, 266t, 273t
drug interactions of, 1170t–1171t
heart failure treated with, 220
Epoetin alfa, 601–602, 602t, 606t
Epoprostenol (PGI2 analog), 324f
pulmonary hypertension treated with, 335
structure of, 333f
Epothilone-D, 1063
Epoxide hydrolases (EHs), 63, 64t
Epoxyeicosatrienoic acid (EET), 325, 332
e-prescribing, 1150–1151
Eprosartan
hypertension treated with, 189
on vasoactive peptides, 317t
Eptifibatide, 621
Equilenin, 723
Equilibrium potential, 229
Equilin, 723
Erectile dysfunction
alpha-receptor antagonists for, 162
drugs for, 200b, 211t
Erection, penile, 344
Erethism, 1028
Ergocalciferol, 789t. See also Vitamin D
Ergoline, 292
Ergonovine, 294–295, 297t. See also Ergot
alkaloids
Ergosterol, 854
Ergot alkaloids, 292–296, 297t–298t
accidental ingestion of, 292
applications of
hyperprolactinemia, 295
migraine, 295
postpartum hemorrhage, 295
senile cerebral insufficiency, 295
variant angina diagnosis, 295
chemistry and pharmacokinetics of,
292–293, 293t
origins of, 292
pharmacodynamics of, 293t, 293–295,
294f
preparations available, 297t–298t
Ergotamine, 160, 294–295, 297t
Ergotism, 292, 292b
Ergotropic nervous system, 100
Eribulin, 963–964
Erlotinib, 966t, 968
Errors, prescribing, 1148–1149
Ertapenem, 803t, 807, 812t
Erythema nodosum leprosum, 850
Erythromycin
acne treated with, 1071
description of, 819–820, 824t
prokinetic activity of, 1098
Erythropoietin (rHuEPO, EPO), 601–602,
602t, 606t, 997t
Escalation, dose, 952
Escitalopram, 540t, 542t, 546t, 549t.
See also Selective serotonin
reuptake inhibitors (SSRIs)
Eslicarbazepine (acetate), 417, 433t
Esmolol, 164t, 167. See also b-receptor
antagonist drugs
arrhythmias treated with, 239t–240t,
243, 251t
hypertension treated with, 183
Esomeprazole, 1091–1095. See also proton-
pump inhibitors (PPIs)
Esotropia, accommodative, 118
Essential tremor, 503
Estazolam, 393t. See also Benzodiazepines
Esters, 61t
Estradiol. See also Estrogen(s)
natural, 704f, 722, 723f
synthetic, 723, 723f
Estriol
natural, 704f, 722, 723f
synthetic, 723, 723f. See also Estrogen(s)
Estrogen(s), 722–727. See also specific types
adverse effects of, 726–727
on bone homeostasis, 779
clinical uses of
hypogonadism, primary, 725
ovulation suppression, 726
postmenopausal hormonal therapy,
725–726
contraindications to, 727
drug interactions of, 1166t
natural, 722f, 722–723
pharmacokinetics of, 723–724
physiologic effects of, 724–725
blood coagulation, 725
edema, 725
endometrial, 724
female maturation, 724
mechanism of action in, 707f, 724
metabolic and cardiovascular,
724–725
progesterone receptor synthesis,
725
stress system, 725
sympathetic nervous system, 725
preparations and dosages of, 724t, 727,
745t
synthetic, 723, 723f
types of, 722–723
Estrogen agonists, 737f, 737–738
Estrogen and progesterone inhibitors and
antagonists, 737–740
anastrozole, 739
danazol, 738–739
fadrozole, 739
fulvestrant, 739
GnRH and analogs, 739
letrozole, 739
mifepristone, 738
tamoxifen and related partial agonist
estrogens, 737f, 737–738
Estrogen receptors, 707f, 724
Estrogen response elements (EREs), 724
Estrone. See also Estrogen(s)
natural, 704f, 722, 723f
synthetic, 723, 723f
Eszopiclone, 382, 383f, 385t, 391, 394t.
See also Hypnotics
Etanercept
description of, 993
psoriasis treated with, 1079
rheumatic disorders treated with, 654f, 655
Ethacrynic acid, for diuresis, 262f, 262t,
262–264, 273t
Ethambutol, 842, 843t, 845–846, 851t
Ethanol, 382, 396–404, 406t. See also
Sedative-hypnotic drugs
alcohol use disorder, 396
drugs for, 406t, 407t
antisepsis and disinfection uses of, 898,
898t
clinical pharmacology of, 402–404
acute alcohol intoxication, 402–403
alcoholism, 404, 406t, 407t
alcohol withdrawal syndrome, 403,
403f, 406t, 407t, 585, 589t
dependence on, 396, 400
drug interactions, 402, 1157t
in OTC agents, 1129t
pharmacodynamics of, 398–402
in acute consumption, 398t, 398–399
alcohol-drug interactions in, 402
animal research on, 399b
chronic consumption, 399–402
cancer risk, 402
cardiovascular system, 401
endocrine system and electrolyte
balance, 401
fetal alcohol syndrome, 401
immune system, 402
liver and GI tract effects, 399–400
nervous system, 400–401
poisoning with, 396, 408, 1045
prevalence of use, 396
tolerance and dependence on, 396, 400
withdrawal syndrome management for, 403
drugs in, 406t, 407t, 585, 589t
time course of, 403f
 Index    1211

Ethinyl estradiol, 723f. See also Estrogen(s) Factor VII deficiency, 622t Ferrous sulfate, 595t, 605t
Ethionamide, 843t, 847 Factor VIIa, recombinant Ferumoxytol, 595, 605t
Ethosuximide, 428–429, 433t, 437t description of, 622t, 623, 624t Fesoterodine, 131. See also Muscarinic
Ethotoin, 419–420 warfarin reversal using, 616 receptor blockers
Ethyl alcohol, 382. See Ethanol Factor VIII deficiency, 621–623, 622t Fetal alcohol syndrome, 401
Ethylene glycol Factor IX deficiency, 621–623, 622t Fetal development, 1049, 1049f
description of, 405–406, 406t Factor Xa inhibitors, oral direct, 616–617 Fetal drug metabolism, 1048. See also
poisoning management for, 1041t, 1045 Factor XIII deficiency, 622t Pregnancy, pharmacology in
Ethylene oxide, 901 Fadrozole, 739 Fetal hemoglobin, 592b
Ethynodiol diacetate, 728t. See also Falciparum malaria treatment, 917, 937. Fexofenadine, 281, 282f, 283t, 296t.
Progestins See also Malaria drugs See also H1-receptor antagonists
Etidocaine, 470. See also Anesthetics, local Famciclovir Fibrates
Etidronate, 779f, 779–781 herpes simplex virus treated with, with bile-acid binding resins, 639
Etodolac, 645t, 647 865t, 867 description of, 634–635, 635f, 639t
Etomidate topical dermatologic, 1074 Fibric acid derivatives
anesthesia using, 450f, 450t, 455 varicella zoster simplex virus treated with bile-acid binding resins, 639
description of, 715 with, 865t, 867 description of, 634–635, 635f
Etoposide, 962t, 964 Familial combined hyperlipoproteinemia, Fibrinolysis, 611, 611f
Etravirine, 872t, 878 629t, 630, 631 Fibrinolytic inhibitors, 611f, 622t, 623,
Euphoria, 560 Familial combined hypertriglyceridemia, 624t
Eutectic mixture of local anesthetics 629t Fibrinolytics, 618–619, 624t
(EMLA), 471 Familial dysbetalipoproteinemia, 629t, 630 Fibroblast growth factor 23 (FGF23)
Everolimus, 986–987 Familial hypercholesterolemia, 629t, 630, bone homeostasis, 773, 773f, 777–778
Evidence, types of, 14b–15b 631f on gut, bone, and kidney, 778t
Evolocumab, 638, 995 Familial hypertriglyceridemia, 629t, 630 Fibroids, uterine, 677
Excitatory postsynaptic potential (EPSP), Familial ligand-defective apolipoprotein Fick’s law of diffusion, 8–9
35, 103, 103f, 371, 371f B-100, 629t, 630 Fidaxomicin, 896, 902t
Excitement, in general anesthesia, 446 Famotidine, 1089–1091. See also Filgrastim, 602t, 602–604, 603f, 606t
Exemestane, 739 H2-receptor antagonists Finasteride
Exenatide, 762, 769t Fansidar, 835, 926 antiandrogenic actions of, 743, 744f,
Exocrine glands, 307 Fasidotrilat, 310, 317t 745t
Exocrine pancreatic insufficiency, 1112 Fasudil, 313b dermatologic use of, 1085
Exocytosis, 8f, 9 angina pectoris treated with, 207, 210t Finerenone, 220, 266
Expectorants, 1125t pulmonary hypertension treated with, Fingolimod hydrochloride (FH), 989–990
Experimental physiology, 2 313b First-in-human studies, 14b
Exposure FDA, Food & Drug Administration, 15 First-pass effect
duration of, 1005 Febuxostat, 662–663 definition of, 58
intensity of, 1005 Feedback pathways, brain, 373 extraction ratio and, 48
quantity of, 1005 Feed-forward pathways, brain, 373 intestinal metabolism in, 58
routes of, 1005 FEIBA, 623 routes of administration in, alternative,
Expoxygenase products, 325–326 Felbamate, 425–426, 433t 48
Extensive metabolizer (EM), 68, 75t Felodipine First-pass elimination, 47–48
Extraction ratio (ER) angina pectoris treated with, 203t Fish tapeworms
first-pass effect and, 48 hypertension treated with, 187 niclosamide for, 943
formula for, 47 Female maturation, estrogens on, 724 praziquantel for, 944–945
Extrinsic factor, 596 Fenofibrate FK-binding protein (FKBP), 986
Eye description of, 634–635, 635f, 639t Flavin monooxygenase, 61t, 69
autonomic pharmacology of, 105b, 105f with reductase inhibitors, 639 Flecainide, 239t, 240t, 242, 251t
b receptors in, 148 Fenoldopam, 151, 154t, 186, 192t. See also Flexible regulation, 35
Ezetimibe, 637, 640t Sympathomimetics Flow-dependent elimination, 46
with bile-acid binding resins, niacin, and Fenoprofen, 645t Flucloxacillin, 83t, 84f, 84–85
reductase inhibitors, 639 Fentanyl. See also Opioid agonists Fluconazole
with reductase inhibitors, 639 description of, 555t, 567–568, 572t dermatologic, 1073
Ezogabine, 421, 433t, 437t transdermal, 564 description of, 857f, 858, 858t, 861t
Ferric carboxymaltose, 595, 605t Flucytosine, 855f, 856, 861t
F Ferric hexacyanoferrate, 1033 Fludarabine, 958t, 961
Factor V deficiency, 622t Ferrous fumarate, 595t, 605t Fludrocortisone, 709t, 715. See also
Factor V Leiden mutation, 611 Ferrous gluconate, 595t, 605t Corticosteroids, synthetic
1212    Index
Fluke infections
niclosamide for, 943
praziquantel for, 944–945
Flumazenil, 387, 390, 392, 393t. See also
Benzodiazepine antagonists
Flunarizine, 291
Flunisolide, 355, 362t. See also
Corticosteroids, inhaled (aerosol);
Corticosteroids, synthetic
Fluocinonide, 1080t
Fluoride, 781
Fluoropyrimidines
capecitabine, 958t, 959
5-fluorouracil, 958t, 959
Fluoroquinolones, 837–840, 840t
adverse effects of, 839–840
antibacterial activity of, 837–839, 838f,
838t
chemistry of, 836, 838f
clinical uses of, 839
mechanism of action of, 837
pharmacokinetics of, 838t, 839
preparations available, 840t
resistance of, 839
tuberculosis treated with, 848
5-Fluorouracil (5-FU), 958t, 959
actinic keratoses treated with, 1083
dihydropyrimidine dehydrogenase on,
78, 78t, 81
Fluoxetine
blocking effects of, 542t
depression treated with, 532, 549t, 552
dosing of, 546t
pharmacokinetics of, 540t
poisoning with, 1042
serotonergic action of, 291
Fluoxymesterone, 740–743, 741t. See also
Androgens and anabolic steroids
Fluphenazine
Huntington’s disease treated with, 505,
508t
psychosis treated with, 511–524, 513f,
520t, 528t. See also Antipsychotic
agents
Fluprednisolone, 709t. See also Corticoste-
roids, synthetic
Flurazepam. See also Benzodiazepines
description of, 382f, 393t
pharmacokinetics of, 385t
Flurbiprofen, 644f, 645t, 647. See also
Nonsteroidal anti-inflammatory
drugs (NSAIDs)
Flutamide, 744, 744f, 972
Fluticasone, 355, 362t. See also Corticoste-
roids, inhaled (aerosol)
Fluvastatin, 632–634, 639t
Fluvoxamine, 546t, 550t
Focal seizures, 410, 433
Folacin, 606t. See also Folic acid
Folate antagonists, 834–837. See also
specific types
DNA gyrase inhibitors, 837–840, 840t
preparations available, 840t
sulfonamides, 834–836, 840t
Folate deficiency, 594t, 599, 600
Folate synthesis inhibitors, 926
fansidar, 926
proguanil, 919f, 926
pyrimethamine, 919f, 926
sulfadoxine, 919f, 926
sulfadoxine-pyrimethamine, 920t
Folic acid, 598–600, 599b, 599f, 606t
chemistry of, 599, 599f
clinical pharmacology of, 600
in hematopoiesis, 591
pharmacodynamics of, 597f, 600
pharmacokinetics of, 597f, 599–600
preparations available, 607t
public health dilemma of, 599b
Folic acid deficiency, 599, 600, 606t
Follicles, 721
Follicle-simulating hormone (FSH), 668f,
668–669, 669t
chemistry and pharmacokinetics of, 674
in ovarian function, 720
pharmacodynamics of, 674
on testis, 740
Follitropin alfa, 674, 683t
Follitropin beta, 674, 683t
Fomepizole, 405, 406t
Fondaparinux, 612–616. See also Heparin
Food & Drug Administration (FDA)
description of, 15, 16t
on prescribing, 1151
Food poisoning, 1034
Forced diuresis, for poisoning, 1040
Formaldehyde, 900
Formalin, 900
Formoterol, 351, 362t
Fosamprenavir, 872t, 880
Fosaprepitant, 314, 317t, 1105. See also
Substance P, antagonists of
Foscarnet, 868t, 869
Fosfomycin, 810–811
Fosinopril, 187
Fosphenytoin, 418, 435t
Fospropofol, 452–453
Fowler’s solution, 1025
Fresh-frozen plasma, 616
Frovatriptan, 291t, 296t
Full agonists, 5, 6f
Fulvestrant, 739
Fumaric acid esters, 1079
Fungal meningitis, iatrogenic, 859b
Furanocoumarins, 72
Furosemide, 224t. See also Diuretics
diuresis using, 262f, 262t, 262–264,
273t
heart failure treated with, 221, 224
Fusion proteins, 93, 94f. See also specific
types
G
GABA, 378. See Gamma (γ)-aminobutyric
acid (GABA)
GABAA receptor, 386, 387f
GABAergic synapse, inhibitory, 412f
Gabapentin
analgesia using, 560b
restless legs syndrome treated with, 507
seizures treated with, 420, 433t, 436t
spasmolytic actions of, 487
tremor treated with, 503
GABA receptor agonists, 387
GABA receptor antagonists, 387
GABA receptor inverse agonists, 387
GABA receptors
chloride channel versatility of, 386, 387f,
388b
in CNS, 373, 378
heterogeneity and pharmacologic
selectivity of, 387b
in Huntington’s disease, 503
Galanin, 92t
Galantamine, 1063
Gallium nitrate, 783
Gallstones, bile acid therapy for,
1113–1114, 1116t, 1117t
Gametocides, malaria, 917
Gamma (γ)-aminobutyric acid (GABA)
in brain, 373
in CNS, 376t, 378
functions of, 92t
neuropharmacology of, 386–387
Gamma-delta T (γδT), 978
Gamma (γ)-hydroxybutyric acid (GHB),
577t, 582, 583f
Ganaxolone, 435
Ganciclovir, 868, 868t
Ganglion blockers. See also specific types
on cardiovascular response to
phenylephrine, 145, 147f
chemistry and pharmacokinetics of, 133,
134f
clinical applications of, 134, 135t
hypertension treated with, 181, 193t
pharmacodynamics of, 134
pharmacology of, 133–134
preparations available, 136t
toxicity of, 134, 135t
Ganirelix, 678–679, 683t
Gantacurium, 477. See also Neuromuscular
blocking drugs
Garlic (Allium sativum), 1135–1136, 1145

Gases, toxic, 1041t, 1043, 1044t
Gastric lavage, 1040
Gastrin (CCK-B) receptors, 1087–1088,
1088f
Gastrinoma, 1094
Gastrin-releasing peptide (GRP), 92t
Gastritis, stress-related
H2-receptor antagonists for, 1091
proton-pump inhibitors for, 1091
Gastroesophageal reflux disease (GERD)
H2-receptor antagonists for, 1090
metoclopramide for, 1097
proton-pump inhibitors for, 1093
Gastrointestinal cancers, chemotherapy for,
972–973
Gastrointestinal disease drugs, 1087–1119,
1115t–1116t. See also specific
drugs
acid-peptic diseases, 1087–1095, 1115t
antidiarrheals, 1100–1101, 1115t
antiemetics, 1103–1106, 1116t
bile acid therapy for gallstones,
1113–1114, 1116t
gastrointestinal motility stimulators,
1096–1098, 1115t
glucagon-like peptide 2 analog for short-
bowel syndrome, 1113
inflammatory bowel disease, 1106–1112,
1116t
irritable bowel syndrome, 1101–1103,
1115t
laxatives, 1098–1100, 1115t
pancreatic enzyme supplements,
1112–1113, 1116t
preparations available, 1117t
variceal hemorrhage, 1114, 1116t
Gastrointestinal motility
enteric nervous system in, 92, 1096–
1097, 1097f
stimulators of, 1096–1098, 1115t
cholinomimetic agents, 1097
macrolides, 1098
mechanism of action of, 1096–1097,
1097f
metoclopramide and domperidone,
1097–1098
preparations available, 1117t
Gastrointestinal tract
drug effects on, 1087
lead exposure effects on, 1022
methylxanthines effect on, 353
prostaglandins effect on, 327
thromboxanes effect on, 327
Gatifloxacin, 838
Gemcitabine, 958t, 960, 973
Gemfibrozil, 634–635, 635f, 639t
Gemifloxacin, 838
Gender, in drug metabolism, 69
“Gene-active” receptors, 27
General anesthetics, 440. See Anesthetics,
general
Generalized seizures. See also Antiseizure
drugs; Seizures
definition of, 410
drugs for, 426–430
divalproex sodium, 426f, 426–427
ethosuximide, 428–429, 433t, 437t
phensuximide and methsuximide,
429f
valproic acid, 426f, 426–427, 436t
Generalized tonic-clonic seizures, 413–421.
See also Antiseizure drugs;
Seizures
Generic prescribing, 1154–1155
Generic product, 17
Genetic factors, in drug metabolism, 65–69
pharmacogenetic testing in drug therapy,
69
phase I enzyme polymorphisms in,
65–69, 66t–67t, 68f, 76t, 79t
phase II enzyme polymorphisms in, 64f,
69
Genetic variations, in drug metabolism,
75–82
glucose 6-phosphate dehydrogenase,
81–82, 82t
phase I enzymes in, 75–78, 76t–77t,
79t–80t
phase II enzymes in, 76t, 79t, 81
Genitourinary system, 148
Genome-wide association (GWA) studies,
74
Gentamicin
description of, 827f, 830–831, 833t
topical dermatologic, 1071
Geriatric pharmacology, 1058–1067
adverse drug reactions, 1065
androgens and anabolic steroids, 742
anti-inflammatory drugs, 1064
antimicrobial therapy, 1064
cardiovascular drugs
antiarrhythmics, 1064
antihypertensives, 1063
positive inotropes, 1064
central nervous system drugs,
1061–1063
Alzheimer’s disease, 1062f,
1062–1063, 1063t
analgesics, 1061
antipsychotics and antidepressants,
542t, 1061–1062
sedative-hypnotics, 1061
drug taking errors from physical
disability in, 1066
expense of, 1065
fundamentals of, 1058–1059
Index    1213
nonadherence to, 1065
ophthalmic drugs
glaucoma, 1064
macular degeneration, age-related,
1065
pharmacologic changes, 1059f,
1059–1061
behavior and lifestyle, 1061
pharmacodynamics, 1060–1061
pharmacokinetics, 1059t,
1059–1060
principles for, 1065–1066
Germander, 1133t
Gestational diabetes mellitus, 752
Ghrelin, 747
Giardiasis, 933–934. See also Amebiasis
drugs
Gigantism, 672
Gilbert’s syndrome, 69
Gilles de la Tourette syndrome, 505. See
Tourette syndrome
Ginkgo (Ginkgo biloba), 1136–1137
Ginseng, 1137–1138
Gio protein-coupled receptors
in addiction, 576, 577f
drugs activating, 581–583, 583f
cannabinoids, 577t, 581–582, 583f
gamma-hydroxybutyric acid, 577t,
582, 583f
LSD, mescaline, and psilocybin, 577t,
582–583
Gland-derived extracts, 1133t
Glargine, 755, 769t. See also Insulin
Glatiramer acetate (GA), 989
Glaucoma drugs, 165b, 166t
cholinomimetics, 118
Glia, 368, 368f
Glicentin, 750
Gliclazide, 759, 769t. See also Sulfonylureas
Glimepiride, 759, 769t. See also
Sulfonylureas
Glipizide, 758–759, 769t. See also
Sulfonylureas
Glucagon, 165, 747, 749–751
Glucagon-like peptide-1 (GLP-1) receptor
agonists, 762, 769t
Glucagon-like peptide-1 (GLP-1), 762
Glucagon-like peptide-2 analog, for
short-bowel syndrome, 1113
Glucocorticoid antagonists, 715–717
Glucocorticoid receptor elements (GREs),
705
Glucocorticoid receptor (GR)
forms and interactions of, 705–707, 707f
genes for, 705
Glucocorticoid resistance, primary
generalized, corticosteroids for,
710
1214    Index
Glucocorticoids, 1001. See also
Corticosteroids
binding of, 27, 27f
on bone homeostasis, 779
gout treated with, 663
hypercalcemia treated with, 783
immunosuppressive uses of, 985t,
985–986
inflammation treated with, 643
inflammatory bowel disease treated with,
1109
rheumatoid arthritis treated with,
658–659
Glucocorticoids, naturally occurring,
704–709
pharmacodynamics of
anti-inflammatory and immunosup-
pressive, 708
catabolic and antianabolic, 708
mechanism of action in, 705–707,
707f
metabolic, 707–708
physiologic, 707
pharmacokinetics of, 704–705, 705f
biosynthetic pathways in, 704f
circadian secretion in, 705f
preparations available, 718t
structures of, 706f
Glucosamine, 1142–1143
Glucose
acute alcohol intoxication managed with,
403
blood, self-monitoring of, 753
Glucose absorption agents, 761
Glucose 6-phosphate dehydrogenase
(G6PD)
characteristics of, 77t
deficiency of, 82, 82t
pharmacogenomics of, 82, 82t
Glucose transporters, 749, 750t
Glulisine, 769t. See also Insulin
Glutamate
in brain, 373
in CNS, 375, 376t, 377f
in depression, 534–536
Glutamate hypothesis, of schizophrenia,
513
Glutamate receptor agonists, metabotropic,
516
Glutamatergic antipsychotics, 515–516
Glutamatergic synapse, excitatory, 412f
Glutaraldehyde, 900
Glutathione transferases (GSTs)
description of, 63, 64f, 64t
genetic polymorphisms in, 67t, 69
Glutethimide, 383f
Glyburide, 758, 769t. See also Sulfonylureas
Glycemic control, for diabetes mellitus,
765, 765b. See also Insulin
Glycerin suppository, 1098
Glycine
in brain, 373
in CNS, 376t, 378
spasmolytic actions of, 487
Glycopeptide antibiotics, 807–810, 812t
dalbavancin, 809–810, 812t
teicoplanin, 809, 812t
telavancin, 809, 812t
vancomycin, 807–809, 812t
Glycoprotein concentration, alpha1-acid, 53
Glycopyrrolate, 126f, 135t. See also Musca-
rinic receptor blockers
Glycosides, cardiac, 217. See also Digitalis;
Digoxin
drug interactions of, 1165t
heart failure treated with, 213, 217–220,
219f, 225t
Glyphosate, 1013f, 1014
GnRH receptor antagonists, 678–679
Goiter
nontoxic, 699
toxic multinodular, 699
toxic uninodular, 699
Golimumab
description of, 993
inflammatory bowel disease treated with,
1110–1112, 1111t
rheumatic disorders treated with, 654f,
655
Gompertzian model, 951
Gonadal hormones and inhibitors,
720–746
ovarian, 720–732, 745t
for contraception in women, 732–737
preparations available, 745t
testicular, 740–745
androgens and anabolic steroids,
740–743, 741t, 745t
androgen suppression, 743, 744f,
745t
antiandrogens, 743–745, 745t
male contraception, 745
preparations, 741, 741t, 745t
Gonadarche, 721
Gonadorelin, 676. See also
Gonadotropin-releasing hormone (GnRH),
669, 669t, 676–678, 739
actions of, 676
chemistry and pharmacokinetics of, 676
clinical pharmacology of, 677–678
in ovarian function, 720
pharmacodynamics of, 676–677
toxicity of, 678
uses of, 676
Gonadotropin-releasing hormone (GnRH)
agonists, 676–678
Gonadotropin-releasing hormone (GnRH)
analogs, 745
Gonadotropin-releasing hormone (GnRH)
antagonists, 678–679
Gonadotropins, 673–676
chemistry and pharmacokinetics of,
673–674
clinical pharmacology of, 674–675, 675f
pharmacodynamics of, 674
preparations available, 685t
toxicity and contraindications to, 676
Good Manufacturing Practice (GMP),
1132
Goserelin, 676, 972
Gossypol, 745
Gout
description of, 265, 659–660, 660f
drugs for, 659–663
allopurinol, 661–662, 662f
colchicine, 660f, 660–661
febuxostat, 662–663
glucocorticoids, 663
interleukin-1 inhibitors, 663
NSAIDs, 661
pegloticase, 663
preparations available, 664t
uricosuric agents, 660f, 661
G6PD, 77t, 82. See Glucose 6-phosphate
dehydrogenase (G6PD)
GP IIb/IIIa antagonists, 621
G protein-coupled receptor (GPCR), 30,
30f–31f, 31t
in addiction, 576, 577f, 577t
adrenoceptors as, 138, 138f
phosphorylation in regulation of, 32, 33f
G protein-coupled receptor kinases
(GRKs), 32, 33f, 141
G proteins, 30, 30f, 31f, 31t
Graded dose-response relations, 36, 36f
Gramicidin, 1070
Grand mal seizures, 413–421. See
Generalized tonic-clonic
seizures; Seizures
Granisetron
antiemetic properties of, 1104
chemical structure of, 1102f
Granulocyte colony-stimulating factor
(G-CSF), 602t, 602–604, 603f,
606t, 997t
Granulocyte macrophage colony-
stimulating factor (GM-CSF),
602t, 602–604, 603f, 606t,
997t, 998
Graves’ disease, 698. See also
Hyperthyroidism
neonatal, 700
Gray baby syndrome, 823
Grazoprevir, 890
Griseofulvin, 860
dermatologic, 1074
Groups, drug, 10

Growth factor receptor inhibitors, 966t,
967–969
bevacizumab, 966t, 968
cetuximab and panitumumab, 966t,
967–968
erlotinib, 966t, 968
pazopanib, 966t, 969
sorafenib, 966t, 969
sunitinib, 966t, 969
ziv-aflibercept, 966t, 968
Growth factors, hematopoietic, 600–605,
606t
Growth hormone (GH), 668f, 668–669,
669t, 682t
chemistry and pharmacokinetics of, 670
clinical pharmacology of, 671t
AIDS, 671
anti-aging, 671
growth hormone deficiency, 670–671
short bowel syndrome, 671
short-stature pediatric patients, 671
deficiency of, 667, 670–671, 686
pharmacodynamics of, 670
toxicity and contraindications to, 672
Growth hormone antagonists, 672–673
fundamentals of, 672
pegvisomant, 672
somatostatin analogs, 672f, 672–673
Growth hormone-releasing hormone
(GHRH), 669, 669t
Growth stimulators, 742
GSK1440115, 318t
Guanabenz, 149, 154t, 180. See also
Sympathomimetics
Guanadrel, 181, 191
Guanethidine, 181–182, 191t
Guanfacine, 149, 154t. See also
Sympathomimetics
hypertension treated with, 180
tics treated with, 506, 508t
Guedel’s signs, 446
Gut microbiota, commensal, 69–70
Gynecologic disorders, androgens and
anabolic steroids for, 742
Gynecomastia, 267
H by, 577t, 582–583, 583f
H1-receptor antagonists, 281–284, 296t
chemistry and pharmacokinetics of, 281,
282f, 283t
clinical pharmacology of, 283–284
pharmacodynamics of, 281–283, 283t
H2-receptor antagonists, 284–285, 296t,
1089–1091. See also specific types
adverse effects of, 1091
chemistry and pharmacokinetics of,
1089, 1089t
clinical comparisons of, 1089t
clinical uses of, 1090–1091
drug interactions of, 1091
OTC, 1122t
pharmacodynamics of, 1089t, 1090,
1090f
preparations available, 1117t
prevalence of use of, 1089
H3-receptor antagonists, 285
H4-receptor antagonists, 285
Haemophilus influenzae type b conjugate
(Hib) vaccine, 1176t
Hageman defect, 622t
Half-life (t1/2), 45f, 46, 46f
on target concentration, 52
Half-time, context-sensitive, 451, 451f
Halofantrine, 919f, 920t, 928
Halogenated aliphatic hydrocarbons, 1009
Halogens
chlorine, 899–900
iodine, 899
iodophors, 899
phenolics, 899
Haloperidol, 160
Huntington’s disease treated with, 505,
508t
psychosis treated with, 515, 515t, 520t,
529t
structure of, 513f, 515, 515t
tics treated with, 506, 508t
Halothane, 441–449. See also Anesthetics,
inhaled
properties of, 443t
structure of, 443f
Halothane hepatitis, 449
Hand-foot syndrome, 958
Hand hygiene, 897
Handle region peptide, 304
H1 antihistamines, 1106
Haplotypes, 75t, 142
Hardy-Weinberg equilibrium, 75t
Hashimoto’s thyroiditis
hypothyroidism from, 689, 696, 696t
nontoxic goiter from, 700
subacute thyroiditis from, 699
Hashish. See also Cannabinoids
description of, 582
Gio protein-coupled receptor activation
Hay fever, 283
Hazard, 1005
HDL deficiency, 631
Head lice treatment, OTC, 1126t
Heart block, 234–236, 235f
Heart failure, 212–217
acute, 223–224
angiotensin-converting enzyme,
212, 227
beta-receptor antagonists for, 168
cardiac contractility control, 213, 214f,
215
Index    1215
cardiac performance pathophysiology in,
216f, 216–217
chronic, 221t, 221–224
diastolic, 212, 222t, 223
diuretics for, 227, 270
nutritional supplements for, 1141
pathophysiology of, 215f, 215–216
signs and symptoms of, 215
systolic, 212, 222t
treatment of, 217–226, 224t–225t
ACE inhibitors and ARBs, 222
beta blockers and ion channel
blockers, 222
cardiac contractility modulation
therapy, 223
cardiac resynchronization, 223
digitalis, 223
non-inotropic
ACE inhibitors, 220
angiotensin receptor blockers, 220
beta-adrenoceptor blockers, 221
diuretics, 220
positive inotropes, 219–221
beta-adrenoceptor agonists, 219
bipyridines, 219
digitalis, 217–219, 218t, 219f, 226t
investigational, 219–220
istaroxime, 219
levosimendan, 219
omecamtiv mecarbil, 219–220
preparations available, 226t
sodium removal, 221–222
systolic vs. diastolic, 222t
therapies in, 212–213, 213t
vasodilators, 222
Heart rate, 216
Heavy metals, 901, 1020–1029
arsenic, 1021t, 1025–1027, 1027f
chelators for, 1029–1033, 1033t
lead, 1020–1025, 1021t
mercury, 1021t, 1027–1029
poisoning management for, 1045
Hedeoma pulegeoides extract, 1133t
Helminth infections, 938
drugs for, 938–947, 939t
Hematopoiesis, 591–592
Hematopoietic growth factors, 600–605,
606t
clinical uses of, 602t
endogenous, 591
erythropoietin, 601–602, 602t, 606t
fundamentals of, 600–601
megakaryocyte growth factors, 604–605,
606t
myeloid growth factors (G-CSF, GM-
CSF), 602t, 602–604, 603f, 606t
preparations available, 607t
Heme carrier protein 1 (HCP1), 593f
Hemochromatosis, 596
1216    Index

Hemodialysis, for poisoning, 1039t, 1040 Heroin. See also Opioid agonists HMG-CoA reductase, 628f
Hemoglobin A1c, 752–753 description of, 567 HMG-CoA reductase inhibitors
Hemophilia A, 621–623, 622t Gio protein-coupled receptor activation with bile-acid binding resins, 639
Hemophilia B, 621–623, 622t by, 581, 583f competitive, 632–634, 633f, 639t
Hemophilia C, 622t Herpes simplex virus (HSV), 864–867 drug interactions of, 1166t–1167t
Hemorrhage, postpartum, 295 acyclovir for, 865t, 866, 866f with ezetimibe, 639
Henbane, 125. See also Muscarinic receptor docosanol for, 865t, 867 with fenofibrate, 639
blockers famciclovir for, 865t, 867 with niacin, 639
Henderson-Hasselbalch equation penciclovir for, 865t, 866f, 867 sites of action of, 631f, 632–633
description of, 9 trifluridine for, 865t, 866f, 867 HMG-coenzyme A (CoA) reductase
for local anesthetics, 459 valacyclovir for, 865t, 866–867 inhibitors, OATP1B1 on, 83
Heparin, 612f, 612–616 valomaciclovir, 867 Homatropine, 130t, 135t. See also
administration and dosage of, 613–614 12(S)-HETE, 325, 331 Muscarinic receptor blockers
chemistry of, 612, 612f 12(R)-HETE, 331 Homeostatic responses, for cardiovascular
contraindications to, 613 20-HETE, 325, 332 function, 100, 102f
mechanism of action of, 612, 612f Heterodimers, 31 Homodimers, 31
monitoring of, 612 Heterologous desensitization, 141 Homologous desensitization, 141
pulmonary embolism treated with, case Heteroreceptors, 100, 102t Hookworms. See also Anthelmintic drugs
study of, 608, 625 Heterozygous familial hypercholesterolemia, albendazole for, 938–940, 939t
reversal of action of, 614 626, 641 mebendazole for, 942
toxicity of, 613 Hexachlorocyclohexane, 1075 Hormone replacement therapy (HRT).
Heparin-induced thrombocytopenia (HIT), Hexachlorophene, 899 See also Gonadal hormones and
613 Hexamethonium, 133–134, 134f. See also inhibitors, 720–746
Hepatic disease, 72. See also specific disease Ganglion blockers postmenopausal, estrogens for, 725–726
Hepatic encephalopathy, 261 High-density lipoprotein (HDL), 626, premature ovarian failure treated with,
Hepatitis 627–628, 628f 720
drugs for, 884t, 884–891. See also High-molecular-weight (HMW) heparin, Hormones
Antihepatitis agents 612f, 612–614. See also Heparin description of, 3. See also specific
halothane, 449 Hirsutism, 726, 734 hormones
Hepatitis A vaccine, 1176t Hirudin, 617 secretion of, catecholamines effect on,
Hepatitis B His-Purkinje system, 228, 229f 148
treatment of, 863, 894 Histamine and histamine agonists, 277–281 Horner’s syndrome, 153b
vaccine for, 1176t chemistry and pharmacokinetics of, 278 Host factors, in antimicrobial choice, 905
Hepatitis B immune globulin (HBIG), 1180t clinical uses of, 281 Household bleach, 899
Hepatitis C virus (HCV) life cycle, 887 in CNS, 376t, 379 5-HT3-antagonists, antiemetics,
Hepatocellular cancer, 973 history of, 278 1103–1105, 1116t, 1117t
Hepcidin, 592 pharmacodynamics of, 279–280 5-HT1D/1B agonists, 289–291, 290f, 291t
Hepoxilins, 325 storage and release of, 278 5-HT receptor modulators, 550t. See also
Herbal medications, 1131–1141, 1133t Histamine receptor antagonists, 281–285, Antidepressant agents
clinical aspects of, 1132 296t chemistry of, 538
echinacea, 1134–1136 H1-receptor, 281–284 clinical pharmacology of
garlic, 1135–1136 chemistry and pharmacokinetics of, adverse effects in, 547
ginkgo, 1136–1137 281, 282f, 283t drug interactions in, 548–549
ginseng, 1137–1138 clinical pharmacology of, 283–284 pharmacodynamics of, 542t, 543
historical and regulatory facts on, 1132 pharmacodynamics of, 281–283, 283t pharmacokinetics of, 540t, 541
history of, 1132 H2-receptor, 284–285 preparations available, 551t
literature on, 1131 H3- and H4-receptor, 285 Huffing, 585
milk thistle, 1138–1139 preparations available, 297t–298t Human chorionic gonadotropin (hCG)
saw palmetto, 1141 Histamine receptors chemistry and pharmacokinetics of, 674
St. John’s wort, 1139–1140 description of, 279t, 279–280 male infertility treated with, 675
toxicity of, 3 H2 parietal cell, 1087–1088, 1088f pharmacodynamics of, 674
Herbicides, 1013–1014 Histrelin, 676 properties of, 683t
bipyridyl (paraquat), 1013f, 1014 HIV, 870. See Human immunodeficiency Human immunodeficiency virus (HIV)
chlorophenoxy (2,4-D), 1013f, virus (HIV) AIDS from, 984–985
1013–1014 HLA polymorphisms in children, immune globulin
glyphosate, 1013f, 1014 in hypersensitivity reactions, 83t, 83–85, intravenous, 1180t
Hereditary angioedema, kinins in, 307 84f with HBV in alcoholic smoker on
Hereditary vitamin D–resistant rickets, 788 types of, 77t, 80t methadone, 863, 894

life cycle of, 870, 874f
retroviral agents in, 870–884. See also
Retroviral agents
with tuberculosis, antimycobacterial
drugs for, 842, 852
Human menopausal gonadotropin (hMG),
673–674. See also Gonadotropins
Human papillomavirus (HPV) vaccine,
1176t
Human placenta derivatives, 1133t
Humoral immunity, 979
Huntington’s disease, 504f, 504–505, 508t
Hydatid disease. See also Anthelmintic drugs
albendazole for, 939t, 940
praziquantel for, 944–945
Hydralazine
heart failure treated with, 222, 225t
hypertension treated with, 179t,
184–185, 191t
Hydrocarbons
aromatic, 1009–1010
halogenated aliphatic, 1009
inhalants, ionotropic receptors in, 585
Hydrochlorothiazide. See also Diuretics
description of, 191t, 224t, 264f,
264–265, 273t
hypercalciuria treated with, 788
Hydrocodone, 555t, 568, 572t. See also
Opioid agonists
Hydrocortisone
case study of, 719
natural, 704–709. See also Glucocorti-
coids, naturally occurring
preparations available, 718t
synthetic, 709t, 710
topical, 1079–1081, 1080t, 1081t
Hydroeicosatetraenoic acid. See HETE
Hydrogen cyanide, 1041t, 1044, 1044t
Hydrogen peroxide, 900–901
Hydrolyses, 61t
Hydromorphone, 555t, 567, 572t. See also
Opioid agonists
Hydrophobic bonds, 3–4
Hydroquinone, 1076
Hydroxocobalamin, 596, 598, 606t
Hydroxychloroquine
immunosuppressive uses of, 989
rheumatoid arthritis treated with, 650
5-Hydroxyindoleacetic acid, 286
Hydroxyprogesterone, 729f
Hydroxyprogesterone caproate, 728t. See
also Progestins
5-Hydroxytryptamine, 285–292
Hydroxyurea, 592b
Hydroxyzine, 283t, 383
Hymenolepis nana, 945
Hyoscine, 125. See also Muscarinic receptor
blockers
action of, 127, 128f
antiemetic properties of, 1106
Hyoscyamine. See also Atropine; Muscarinic
receptor blockers
description of, 125, 135t
irritable bowel syndrome treated with,
1101
Hyperalgesia, opioid-induced, 559
Hypercalcemia
description of, 782–783
diuretics for, 272
Hypercalciuria, idiopathic, 788
Hyperchloremic metabolic acidosis
carbonic anhydrase inhibitors as cause
of, 261
potassium-sparing diuretics as cause of,
267
Hypercholesterolemias, primary
ABCG5 and ABCG8 mutations, 631
autosomal recessive hypercholesterolemia,
631
cholesterol 7α-hydroxylase, 631
cholesteryl ester storage disease, 629t,
631
dietary management for, 632
familial combined hyperlipoproteinemia,
629t, 631
familial hypercholesterolemia, 629t, 630,
631f
familial ligand-defective apolipoprotein
B-100, 629t, 630
HDL deficiency, 631
Lp(a) hyperlipoproteinemia, 629t, 631
PCSK9, 631
Hyperglycemia
antipsychotics as cause of, 522
thiazide diuretics as cause of, 265
Hyperhidrosis, 133
Hypericum perforatum, 1139–1140
Hyperimmune immunoglobulins, 991
Hyperkalemia, 231b
loop diuretics for, 263
mannitol as cause of, 267–268
neuromuscular blockers as cause of, 483
potassium-sparing diuretics as cause of,
266–267
Hyperlipidemia, 627–632. See also
Hyperlipoproteinemias
antipsychotics as cause of, 522
coronary artery disease with, 194, 211
thiazide diuretics as cause of, 265
Hyperlipidemia drugs, 632–638, 640t
AMP kinase activation, 638
apo B-100 synthesis antisense inhibition,
638
bile acid-binding resins, 636–637, 640t
CETP inhibition, 638
combinations
Index    1217
fibric acid derivatives and bile-acid
binding resins, 639
HMG CoA reductase inhibitors and
bile-acid binding resins, 639
niacin and bile-acid binding resins,
639
niacin and reductase inhibitors, 639
reductase inhibitors and ezetimibe,
639
reductase inhibitors and fenofibrate,
639
resins, ezetimibe, niacin, and reductase
inhibitors, 639
use of, 638
fibric acid derivatives, 634–635, 635f
HMG-CoA reductase inhibitors, com-
petitive, 632–634, 633f, 639t
intestinal sterol absorption inhibitors,
637, 640t
microsomal triglyceride transfer protein
inhibitor, 638
niacin, 636, 640t
Hyperlipoproteinemias, 627–631, 629t
definition of, 626
dietary management, 632
pathophysiology of, 627–631, 628f
secondary, 631
Hypernatremia, 267–268
Hyperosmolar hyperglycemic syndrome
(HHS), 767–768
Hyperparathyroidism, primary, 784
Hyperphosphatemia, 784
Hyperprolactinemia
antipsychotics as cause of, 522
dopamine agonists for, 679, 680f
ergot alkaloids for, 295
Hyperreactive, 38
Hypersecretory conditions, proton-pump
inhibitors for, 1094
Hypersensitivity reactions, 38, 981–983,
983f
drug-induced, 83t, 83–85, 84f
type I, 982, 983f, 998–999
type II, 982–983, 999
type III, 952f, 983, 999–1000
type IV (delayed-type), 983, 984f
Hypertension
agents for, 173–193
alcohol consumption and, 401
b-receptor antagonists for, 167
carbonic anhydrase inhibitors for,
259–260
case study on, 173, 193
classification of, 173–174, 174t
coronary artery disease and, anesthesia
with, 440
diagnosis of, 173–174
diuretics for, 271
1218    Index

Hypertension (Cont.): pharmacodynamics of, 386–389 Ibutilide, 239t, 240t, 245, 251t
essential, 174 pharmacokinetics of Icatibant. See also Kinin inhibitors
etiology of, 174 absorption and distribution, 386 description of, 187, 307, 317t
malignant, 190 biodisposition, 386 on vasoactive peptides, 316t
nutritional supplements for, 1141 biotransformation, 385t, 386 Idarubicin, 962t, 965
portal, 1114 excretion, 386 Idarucizumab, 618
pulmonary Hypocalcemia, 783–784 Idelvion, 621
eicosanoids for, 335 Hypofibrinogenemia, 622t Idiopathic edema, 271
nitric oxide for, 344 Hypoglycemia, 767 Idiopathic hypercalciuria, 788
preparations available, 318t Hypoglycemic unawareness, 767 Idiopathic short stature, 671
treatment of, 313b Hypogonadism, primary, 725 Idiopathic thrombocytic purpura (ITP),
renin-angiotensin system suppression for, Hypokalemia, 231b, 270 1180t
300, 320 Hypokalemic metabolic acidosis Idiosyncratic drug response, 38
resistant, polypharmacy and, 177b from loop diuretics, 263 Idrocilamide, 487
risk factors for, 174 from thiazide diuretics, 265 IFNL3 (IL-28B), 77t, 80t, 85
secondary, 174 Hypomagnesemia, from loop diuretics, 263 Ifosfamide, 953. See also Alkylating agents
Hypertensive emergencies Hyponatremia IGF-I agonist, 672, 682t
alpha-receptor antagonists for, 161 from mannitol, 268 IL-28B, 77t, 80t, 85
description of, 190–191 from thiazide diuretics, 265 Iloprost (PGI2 analog), 324f
Hypertensive encephalopathy, 190 Hypoparathyroidism, 784–785 pulmonary hypertension treated with, 335
Hyperthermia, malignant, 288t Hypophosphatemia, 784 structure of, 333f
anesthetics as cause of, 449, 483 autosomal dominant, 787–788 Imatinib, 35, 966t, 967
131
dantrolene for, 449, 488 X-linked, 787–788 I-meta-iodobenzylguanidine (MIBG),
succinylcholine as cause of, 449, 483 Hyporeactive, 38 160
Hyperthermic syndromes, 288b, 288t Hypotension, renal response to, 175 Imidazoline receptor, clonidine binding to,
Hyperthyroidism, 698–699 Hypothalamic-pituitary-adrenal axis, 533 180
amiodarone-induced thyrotoxicosis, 700 Hypothalamic-pituitary endocrine system, Imipenem, 803t, 807, 812t
dermopathy, 699 667, 668f Imipramine, 537, 540t, 542t, 550t. See also
Graves’ disease, 698 Hypothalamic-pituitary-thyroid axis, Muscarinic receptor blockers;
neonatal, 700 689, 691f Tricyclic antidepressants (TCAs)
manifestations of, 694t Hypothalamus dosing of, 546t
ophthalmopathy, 699 description of, 667, 668f urinary disorders treated with, 132
subacute thyroiditis, 699 hormones and receptors of, 668f, Imiquimod, 893, 1074
subclinical, 700 668–670, 669t Immediate effects, 48–49, 49f
thyroid storm, 699 Hypothyroidism, 696–698 Immediate (type I) drug allergy, 982, 983f,
thyrotoxicosis in pregnancy, 700 congenital (cretinism), 691, 696t 998–999
toxic multinodular goiter, 699 drug-induced, 692t, 696t, 697–698 Immobility, in anesthesia, 447b
toxic uninodular goiter, 699 on drug metabolism, 72 Immune function, autonomic nervous
Hypertriglyceridemia etiology and pathogenesis of, 696, 696t system on, 89
familial, 629t, 630 management of, 696–698 Immune globulin (IM)
primary, 629t, 629–630 manifestations of, 691, 694t, 696 measles treated with, 1180t
chylomicronemia, primary, 629t, myxedema and coronary artery disease, rubella treated with, 1181t
629–630 697 Immune globulin intravenous (IGIV),
familial combined myxedema coma, 697 990–991
hyperlipoproteinemia, 630 pregnancy and, 697 bone marrow transplantation uses of,
familial combined subclinical, 697 1180t
hypertriglyceridemia, 629t chronic lymphocytic leukemia treated
familial dysbetalipoproteinemia, 629t, I with, 1180t
630 Ibandronate complications of, 1175
familial hypertriglyceridemia, 629t, 630 on bone homeostasis, 779–781, 789t hepatitis A treated with, 1180t
fundamentals of, 629 bone metastases and hypercalcemia hepatitis B treated with, 1180t
secondary, 629t treated with, 789t in HIV-infected children, 1180t
Hyperuricemia, 659–660 osteoporosis treated with, 786, 789t idiopathic thrombocytic purpura treated
from loop diuretics, 263 Ibritumomab tiuxetan, 993 with, 1180t
treatment of. See Gout Ibuprofen. See also Nonsteroidal anti- immunodeficiency disorders treated
Hypnotics, 381, 394t. See also Sedative- inflammatory drugs (NSAIDs) with, 1180t
hypnotic drugs; specific types description of, 644f, 645t, 647–648 Kawasaki disease treated with, 1180t
clinical pharmacology of, 390t on eicosanoid synthesis, 332 rabies treated with, 1180t

Immune response, 643
Immune system, 977–985
abnormal immune responses in,
981–985
autoimmunity, 984
hypersensitivity, 981–983, 983f
immunodeficiency, 984–985
genetic variations on function of, 83–85
drug-induced hypersensitivity reac-
tions, 83t, 83–85, 84f
IFNL3 (IL-28B), 77t, 80t, 85
normal immune responses in, 977–980
adaptive immune system, 979f,
979–980, 981f, 982f
innate immune system, 977–979
Immunization, 1175–1182. See also specific
vaccines
active, 1175, 1176t–1178t
passive, 1175, 1180t–1181t, 1181
routine childhood, recommended
schedule for, 1175, 1179t
for travelers, 1182
untoward reactions to, legal liability for,
1181–1182
Immunodeficiency. See also specific
immunodeficiency
description of, 984–985
primary disorders of, immune globulin
intravenous for, 1180t
Immunoglobulins
human, 1175, 1179
hyperimmune, 991
Immunomodulators, therapeutic, 996, 998
cytokines, 996, 997t, 998
dermatologic
imiquimod, 1074
tacrolimus and picrolimus,
1074–1075
Immunomodulatory derivatives of
thalidomide (IMiDs), 988
Immunopharmacology, 977–1001
immune system in, 977–985
immunologic drug reactions and drug
allergy, 998–1000
autoimmune (type II) drug reactions,
982–983, 999
immediate (type I) drug allergy, 982,
983f, 998–1000
serum sickness and vasculitis (type III)
reactions, 999–1000
types of, 998
immunomodulation therapy, 996–998
immunosuppressive therapy, 985–995
clinical uses of, 995–996
preparations available, 1000t
Immunosuppressive therapy, 985–995
calcineurin inhibitors
cyclosporine, 986
tacrolimus, 986
clinical uses of, 985t, 995–996
autoimmune disorders, 996
organ and bone marrow transplanta-
tion, 996
cytotoxic agents
azathioprine, 988
cyclophosphamide, 988
hydroxychloroquine, 989
methotrexate, vincristine, and
cytarabine, 989
pentostatin, 989
pyrimidine synthesis inhibitors,
988–989
vinblastine, 989
dimethyl fumarate, 989
fingolimod hydrochloride, 989–990
glatiramer acetate, 989
glucocorticoids, 985t, 985–986
immunosuppressive antibodies, 990–991
antilymphocyte and antithymocyte
antibodies, 990
chimeric molecules, 990
development of, 990
hyperimmune immunoglobulins, 991
immune globulin intravenous,
990–991
Rh0(D) immune globulin, 991
monoclonal antibodies, 991–995
abciximab, 995
antitumor, 991–992
delivering isotopics and toxins to
tumors, 993
denosumab, 995
eculizumab, 995
immunosuppressants and anti-
inflammatory agents, 993–995,
994f
palivizumab, 995
pegatinib, 995
ranibizumab, 995
raxibacumab, 995
mycophenolate mofetil, 987
proliferation signal inhibitors, 986–987
thalidomide, 987–988
Implantable cardioverter-defibrillator
(ICD), 246b
Inamrinone, 219, 225t
Incertohypothalamic pathway, 516
Incontinence, urinary, 124, 136
Incretin mimetics
dipeptidyl peptidase-4 inhibitors,
762–763, 769t
glucagon-like peptide-1 and, 762
glucagon-like peptide-1 receptor
agonists, 762
IND, 12f, 17
Indacaterol
Index    1219
asthma treated with, 351
chronic obstructive pulmonary disease
treated with, 152
Indinavir, 872t, 880–881
Indirect thrombin inhibitors, 612f,
612–614. See also Heparin
Indomethacin, 648. See also Nonsteroidal
anti-inflammatory drugs
(NSAIDs)
on eicosanoid synthesis, 332
structure and properties of, 644f, 645t
Indoramin, 160
Inert binding sites, 7
Infantile spasms, 410, 431. See also Seizures
Infant pharmacology, 1050–1054
Infertility drugs
female, gonadotropin-releasing hormone,
677
male
gonadotropin-releasing hormone, 677
hCG and hMG, 675
Inflammation, 977, 979f
aspirin for, 336
chronic, 643
kinins in, 307
NSAIDs for, 643
therapeutic strategies for, 643. See also
Analgesics
Inflammatory bowel disease (IBD),
1106–1112, 1116t. See also
specific agents
aminosalicylates for, 1106–1109, 1107f,
1116t
anti-integrin therapy for, 1112
antitumor necrosis factor therapy for,
1110–1112, 1111t
glucocorticoids for, 1109, 1116t
methotrexate for, 1110, 1116t
purine analogs for, 1109–1110, 1116t
therapeutic pyramid for, 1106, 1107f
Infliximab
inflammatory bowel disease treated with,
1110–1112, 1111t, 1116t
psoriasis treated with, 1079
rheumatic disorders treated with, 654f,
655
Influenza
drugs for, 891–892
amantadine and rimantadine, 892
investigational, 892
oseltamivir and zanamivir, 891–892
vaccines for
Haemophilus influenzae type b
conjugate (Hib), 1176t
inactivated, 1176t
live attenuated, 1177t
Ingenol mebutate, 1083–1084
Inhalants, ionotropic receptors in, 585
1220    Index

Inhibin rapid-acting, 754 Intestinal metabolism, in first-pass effect, 58

in ovary, 732 regimens for, 766 Intestinal osteodystrophy, 786
in testis, 740 regulation of release of, 758t Intestinal sterol absorption inhibitors, 637,
Inhibitors. See also Antagonist; specific types secretion of, 748, 749f 640t
acetylcholinesterase, 5 short-acting, 753–754 Intracellular receptors, for lipid-soluble
allosteric, 5, 6f types of, 754 agents, 27, 27f
competitive, 5, 6f tyrosine kinase receptors for, 28 Intraocular pressure, 165b, 267
suicide, 61 Insulin-like growth factor-I (IGF-I), Intraoperative floppy iris syndrome (IFIS),
Inhibitory postsynaptic potential (IPSP), 669 160
103, 103f, 371, 371f Insulin pumps, 756–757 Intravenous immunoglobulins (IGIV),
Innate immune system, 977–979 Insulin receptor, 748–749, 749f, 750t 990–991
Inositol-1,4,5-trisphosphate (IP3, InsP3), Insulin receptor substrates, 749 Intravenous lipid emulsion, 469b
33, 34f, 138f, 139, 139t Insulin resistance, 757, 771 Intrinsic efficacy, 5
Inotropes, positive Insulin secretagogues Intrinsic factor, 596
in elderly, 1064 meglitinide analogs, 759, 769t Intubation, endotracheal, 484–485
heart failure treated with, 219–221 sulfonylureas, 757–759, 769t. See also Inverse agonists
acute, 224 Sulfonylureas b-receptor antagonist drugs as, 162
beta-adrenoceptor agonists, 219 Integrase strand transfer inhibitors (INSIs), description of, 5–6, 7f, 23, 387
bipyridines, 219 883–884 Investigational New Drug (IND), 12f,
digitalis, 217–219, 218t, 219f, 226t dolutegravir, 871t, 883 15–17
investigational, 219–220 elvitegravir, 871t, 883 Iodide
istaroxime, 219 fundamentals of, 883 metabolism of, 687
levosimendan, 219 raltegravir, 872t, 884 organification of, 688, 688f
omecamtiv mecarbil, 219–220 Integrins, 1112 Iodides, 695, 701t
Insecticides Intensity of exposure, 1005 Iodine
organophosphates, 115–117, 116f Intention tremor, 504 bactericidal, 899
131
thiophosphates, 116f, 117 Intercalated cells, 258, 258f radioactive ( I, RAI), 695–696, 701t
Insertions/deletion (indel), 75t Interferon-α Iodism, 695
Insomnia description of, 996, 997t Iodophors, 899
melatonin for, 1143–1144 hepatitis treated with, 884t, 884–885, Iodoquinol, 929t, 930, 930f
OTC drugs for, 1127t 893t–894t Ion channels, 229. See also specific types
sedative-hypnotics for, 391 Interferon, pegylated in addiction, 576, 577f, 577t
Inspired concentration, 442–444 preparations available, 893t–894t in central nervous system, 369f,
Inspra, 266t with ribavirin, 80t, 85 369–370, 370b, 370t
Institutional review board (IRB), 16 Interferons, 996, 997t ligand-gated, 29f, 29–30, 35
Insulin, 747–749, 769t condylomata acuminata treated with, novel analgesic targets and, 560b
allergy to, 757 892 voltage-gated, 30
case study of, 747, 771 preparations available, 893t–894t, Ionization, of weak acids and bases, 9
chemistry of, 747–748 893–894 Ionization constants, 10t
circulating, 748 Interleukin-1 inhibitors Ionotropic receptors
degludec, 753t–754t, 755 adverse effects of, 658 in addiction, 576, 577f, 577t
degradation of, 748 anakinra, 657 drugs mediating effects via, 583–585.
delivery systems for canakinumab, 657 See also specific drugs
continuous subcutaneous infusion gout treated with, 663 alcohol, 585
devices, 756–757 mechanism of action of, 657 benzodiazepines, 584
portable pen injectors, 756 rheumatoid arthritis treated with, inhalants, 585
detemir, 753t–754t, 755 657–658 ketamine and phencyclidine, 584
diabetic ketoacidosis treated with, 767 rilonacept, 657–658 nicotine, 583–584
durations of action, 754 Interleukin-1α, 657 Ions, 229–230, 230f. See also specific ions
hyperosmolar hyperglycemic syndrome Interleukin-11 (IL-11), 604–605, 606t Ipecac syrup, 1040
treated with, 766 Interleukins, 997t Ipilimumab, 974, 992
immune resistance to, 757, 771 Intermediate-density lipoproteins (IDLs), Ipragliflozin, 261
inhaled, 757 626 Ipratropium (bromide). See also Muscarinic
intermediate-acting, 755–756 Intermittent claudication, 209, 211t receptor blockers (antagonists)
long-acting, 750t, 755–756 International normalized ratio (INR), 615 asthma treated with, 353–354
mixtures of insulins, 756 Interval reduction, in cancer chemotherapy, characteristics of, 135t
preparations available, 753t–754t, 952 chronic obstructive pulmonary disease
753–756 Intestinal flukes, 943 treated with, 130

Irbesartan
hypertension treated with, 189
on vasoactive peptides, 317t
Irinotecan
description of, 962t
UGT1A1 on metabolism of, 79t, 81
Iron, 592–596, 593f, 594t
clinical pharmacology of, 593f, 594–596
indications in, 594t, 594–595
oral iron therapy, 595, 595t
parental iron therapy, 595–596
toxicity of, 596
drug interactions of, 1167t
female hormonal contraceptives effect
on, 733
in hematopoiesis, 592
pharmacokinetics of, 592–594, 593f,
594t
pharmacology of, 592
poisoning management for, 1045
preparations available, 607t
toxicity of, clinical, 596, 606t
Iron-deficiency anemia, 592–596, 593f,
594t
Iron dextran, 595, 605t
Iron overload, 596, 605t
Iron sucrose complex, 595, 605t
Irreversible antagonists, 23f, 24
Irreversible cholinesterase inhibitors, 117
Irrigation, whole bowel, 596
Irritable bowel syndrome
description of, 1101–1102
drugs for, 1101–1103, 1115t
antispasmodics, 1101–1102
chloride channel activators, 1103
serotonin 5-HT3-receptor antagonists,
1102, 1102f, 1116t, 1117t
Isavuconazole, 859, 861t
Isavuconazonium sulfate, 859
Ischemic heart disease, 167f, 167–168, 168f
Islet amyloid, 769t
Islet amyloid polypeptide (IAPP) analogs,
747, 764, 769t
Isocarboxazid, 546t
Isoeicosanoids, 326
Isoflurane, 441–449. See also Anesthetics,
inhaled
properties of, 443t
structure of, 443f
Isolated systolic hypertension, 174
Isoniazid
phase II activation of, 57, 57f
tuberculosis treated with, 842–845,
843t, 851t
Isopropyl alcohol (isopropanol)
antisepsis and disinfection uses of, 898,
898t
ingestion of, 405
Isoprostanes, 326
Isoproterenol, 146f, 146t, 149. See also
Sympathomimetics, direct-acting
asthma treated with, 351, 362t
cardiovascular responses to, 146t
structure of, 144f, 350f
Isosorbide dinitrate
angina pectoris treated with, 198, 202t,
209t
heart failure treated with, 225t
Isosorbide dinitrate/hydralazine (BiDil),
222
Isosorbide mononitrate, 198, 202t, 209t.
See also Nitrates and nitrites
Isotretinoin, 1077–1078
Isoxazolyl penicillins, 801
Isradipine
angina pectoris treated with, 203t
hypertension treated with, 187
Istaroxime, for heart failure, 219
Itraconazole, 857f, 858, 858t, 861t
dermatologic, 1073
Ivabradine
angina pectoris treated with, 207, 210t
arrhythmia treated with, 247
chronic heart failure treated with, 222
Ivacaftor, 24, 248b, 252t
Ivermectin
ectoparasiticidal action of, 1075
helminths treated with, 939t, 941–942
Ixabepilone, 963
Ixekizumab, 994
J Kidney
JAK/STAT receptors, 667
Janus-kinase (JAK) family, 28–29, 29f
Jaw, osteonecrosis of, 780
Jet lag, 1143–1144
Jimson-weed, 125. See also Atropine;
Muscarinic receptor blockers
Jin Bu Huan, 1133t
Jod-Basedow phenomenon, 695
Jublia, 1072
Juxtaglomerular cells, 301
K from diuretics, 254, 275
Kainate receptors, CNS, 375
Kainic acid (KA), CNS, 375
Kallikrein-kinin system, 306f
description of, 306
drugs affecting, 307–308, 317t
Kallikreins, 306
Kanamycin, 831–832, 848
Kappa opioid receptors, 553, 554t
Kava-kava, 1133t
Kawasaki disease, 1180t
Kefauver-Harris Amendment, 15, 16t
Keratolytic and destructive agents
Index    1221
aminolevulinic acid, 1084
fluorouracil, 1083
ingenol mebutate, 1083–1084
NSAIDs, 1084
podophyllum resin and podofilox, 1083
propylene glycol, 1082
salicylic acid, 1082
sinecatechins, 1083
urea, 1082–1083
Ketamine
abuse of, 577t, 580
analgesic uses of, 560b
anesthesia uses of, 450f, 450t, 456–457,
535
depression treated with, 535–536
enantiomers of, 4
ionotropic receptors in, 585
Ketanserin, 292, 297t. See also Serotonin
(5-HT) receptor antagonists
Ketoacidosis, diabetic, 767
Ketoconazole, 1072
adrenocortical antagonist action of, 715,
716f
as antiandrogen, 743–745
as antifungal, 857f, 858, 858t, 861t
dermatologic, topical, 1072
topical, 861t
Ketolides, 820–821, 824t
Ketone bodies, 753
Ketones (inhalants), ionotropic receptors
in, 585
Ketoprofen, 645t, 648
Ketorolac, 659
angiotensin II on, 303
excretion from, manipulation of, 9, 11f
lead exposure effects on, 1022
methylxanthines effect on, 353
nephron segments and functions in,
256t
tubule transport mechanisms in,
254–259. See also Renal tubule
transport mechanisms
Kidney disease. See also specific types
chronic, 785–786
diuretics for, 270–271
Kidney stones
carbonic anhydrase inhibitors as cause
of, 261
potassium-sparing diuretics as cause of,
267
Kininase II, in angiotensin biosynthesis,
303
Kinin inhibitors, 307–308, 317t
preparations available, 318t
on vasoactive peptides, 316t
Kininogens, 306
1222    Index
Kinins, 306–307
biosynthesis of
kallikreins in, 306, 306f
kininogens in, 306, 306f
formation and metabolism of, 306, 306f
physiologic and pathologic effects of
on cardiovascular system, 306
on endocrine and exocrine glands, 307
in hereditary angioedema, 307
in inflammation and pain, 307
Kisspeptin, 720
Kleine-Levin syndrome, 261
L Leflunomide, 651, 988–989
Labeled uses of drugs, 1153
Labetalol, 160, 164t, 166, 170t. See also
b-receptor antagonist drugs
hypertension treated with, 183, 192t
structure of, 163f
Lacosamide, 417–418, 433t, 435t
Lactation
pharmacology of, 1055t, 1055–1056
physiologic, dopamine agonists for, 679
postpartum stimulation of, domperidone
for, 1098
Lactulose, 1098
Lamivudine
description of, 872t, 875
hepatitis B treated with, 886–887
Lamotrigine, 529t
bipolar disorder treated with,
528, 529t
seizures treated with, 416f, 422, 433t,
435t
Lanreotide, 673, 683t
Lansoprazole, 1091–1095. See also Proton-
pump inhibitors (PPIs)
Lanthanum carbonate, 784
Lapatinib, 972
Latanoprost (PGF2α derivative), 323, 327
Latrodectus mactans antivenom, equine,
1180t
Laxatives, 1098–1100, 1115t
bulk-forming, 1098
chloride channel activators, 1099
opioid receptor antagonists, 1099–1100
osmotic
balanced polyethylene glycol, 1099
nonabsorbable sugars or salts, 1098
OTC, 1125t–1126t
preparations available, 1117t
serotonin 5-HT4-receptor agonists,
1100
stimulant, 1099
stool surfactant agents, 1098
LCAT, 631
L-DOPA, 369
Lead compound, 13
Lead poisoning, 1020–1025 Leukotriene B4 (LTB4), 326, 332, 356
chelation for, 1030 Leukotriene C4 (LTC4), 324–325, 325f,
epidemiology of, 1020 332
inorganic, 1021t, 1023–1025 Leukotriene D4 (LTD4), 325f, 332
organolead, 1023, 1025 Leukotriene receptor antagonists
pharmacodynamics of, 1021–1023 asthma treated with, 336, 356f,
pharmacokinetics of, 1021, 1021t 356–357, 360, 362t
prevention of, 1024b preparations available, 363t
treatment of, 1025 Leuprolide, 676, 683t
Lebrikizumab, 358 Leuprolide agonists, 972
Lecithin:cholesterol acyltransferase (LCAT) Levetiracetam, 422–423, 433t, 436t
deficiency, 631 Levobunolol, 166. See also b-receptor
Ledipasvir, 888 antagonist drugs
Levobupivacaine, 460f, 470. See also
Left ventricular dysfunction, atrial Anesthetics, local
fibrillation with, 228, 253 Levodopa, 151, 494–497, 508t
Legislation, drug, 15, 16t adverse effects of, 495–497
Leiomyomata, uterine, 677 chemistry of, 494
Leishmaniasis drugs, 931–935, 932t–933t. clinical use of, 494–495
See also Antiprotozoal drugs contraindications to, 497
nitazoxanide, 933–934 drug holidays from, 497
pentamidine, 931, 933 drug interactions of, 497, 1167t
preparations available, 936t mechanism of action of, 494
sodium stibogluconate, 930f, 932t, 933 pharmacokinetics of, 494, 496f
visceral prolactinemia treated with, 151
amphotericin, 935 Levofloxacin, 838–839, 843t
drug combinations, 935 Levomethadone, 588t
miltefosine, 935 Levomilnacipran, 537, 540, 550t. See also
paromomycin, 935 Serotonin-norepinephrine
Lenalidomide reuptake inhibitors (SNRIs)
immunosuppressive uses of, 988 Levopropoxyphene, antitussive, 570, 572t
multiple myeloma treated with, 971 Levorphanol, 555t, 568. See also Opioid
Lennox-Gastaut syndrome, seizures agonists
associated with Levosimendan
clobazam for, 430 on calcium sensitivity, 213
description of, 410 heart failure treated with, 219, 224
felbamate for, 426 Levothyroxine (T4), 690–692, 701t, 702.
lamotrigine for, 422, 435t See also Thyroid drugs
rufinamide for, 430, 436t Lewisite, 1025
topiramate for, 427, 436t Lewy bodies, 493
Lenograstim, 602–603 Lialda, 1107
Lepirudin, 617 Licarbazepine, 417
Leprosy drugs Lice, 1126t
clofazimine, 851 Liddle’s syndrome, 266
dapsone and other sulfone, 850 Lidocaine, 460t, 462, 471, 472t. See also
rifampin, 851, 851t Anesthetics, local
Lethal dose arrhythmia treated with, 239t, 240t,
median (LD50), 13, 37, 37f 241f, 241–242, 250t
minimum, 13 historical development of, 461b
Letrozole, 739 on ion channels, 560b
Leukemia Ligand-gated channels
acute in central nervous system, 369f,
adult, 969 369–370
childhood, 969 description of, 29f, 29–30, 35
chronic Ligand-regulated transmembrane enzymes,
lymphocytic, 970 27–28, 28f
myelogenous, 969–970 Linaclotide, 1099, 1103
Leukotriene, 324f, 324–325 Linagliptin, 763, 769t

Lindane, 1075
Linezolid
description of, 823, 824t
tuberculosis treated with, 843t, 848–849
Linkage disequilibrium, 75t
Linoleic acids
on arachidonic acid metabolism, 337
description of, 324
Liothyronine (T3), 690–692, 701t. See also
Thyroid drugs
Lipid
blood levels of, guidelines, 628, 629t
diffusion of, 8, 8f
metabolism of, female hormonal
contraceptives on, 733
Lipid:aqueous partition coefficient, 8
Lipid resuscitation, 469b
Lipid-soluble agents, intracellular receptors
for, 27, 27f
Lipodystrophy, 757
Lipoprotein, 626
high-density, 626, 627–628, 628f
structure of, 627
synthesis and catabolism of, 627–628
types of, 626
very-low-density, 626, 627, 628f
Lipoprotein (a) (Lp[a]), 626–627
Lipoprotein disorders, 628–629, 629t
Lipoprotein lipase (LPL), 627
Liposomal irinotecan, 964
Lipoxins, 324, 331
Lipoxygenase (LOX), 323–325, 325f
effects of, 332
products of, 323–325, 325f
Liraglutide, 290t, 762, 769t
Lispo, 768t. See also Insulin
Lithium, 268, 524–528, 529t
acute major depression treated with, 526
adverse effects and complications of, 527
bipolar affective disorder treated with,
524, 526
in breast milk, 1056
clinical pharmacology of, 526–528
drug interactions, 527, 1167t
in elderly, 1061
maintenance treatment in, 526–527
monitoring treatment in, 526
overdoses of, 527–528
pharmacodynamics of, 524–526, 525f,
525t
pharmacokinetics of, 524, 524t
recurrent depression treated with, 526
schizoaffective disorder treated with, 526
schizophrenia treated with, 526
Liver
biotransformation in, 57–58
contraceptives on, female hormonal, 733
disease of. See also Hepatitis; specific types
on drug metabolism, 72, 72t
first-pass effect, 48
L-Norgestrel, 728t. See also Progestins
Loading dose, 50–51, 51f
Loa loa, 941
Lobeline, 109, 110f
Local circuit neurons, 373, 373f
Log-kill hypothesis, 950, 950f
Lomefloxacin, 838
Lomitapide, 638
Lomustine, 953f, 955t
Long QT syndrome
molecular and genetic basis of, 233f,
234b, 235t
torsade de pointes in, 234b, 237f
Long-term potentiation (LTP), 375
Loop diuretics, 191t, 224t, 262f, 262t,
262–264, 273t. See also Diuretics
kidney injury from, acute, 254, 275
with potassium-sparing diuretics, 269
preparations available, 274t
with thiazide diuretics, 269
Loop of Henle, 255f, 256–257, 257f, 263
Loperamide, 568, 1100. See also Opioid
agonists
Lopinavir, 872t, 881
Loratadine, 283t, 296t. See also H1-receptor
antagonists
Lorazepam, 393t. See also Benzodiazepines
delirium tremens treated with, 391
ethanol withdrawal treated with, 406t,
585, 589t
pharmacokinetics of, 385t, 450t
seizures treated with, 432, 437t
structure of, 382f
Lorcaserin
description of, 289, 296t
obesity treated with, 289b, 290t
Losartan. See also Angiotensin receptor
blockers (ARBs)
heart failure treated with, 220, 222, 224t
hypertension treated with, 179t, 189, 192t
on renin-angiotensin system, 305
Lovastatin, 632–634, 633f, 639t
Low-density lipoproteins (LDLs), 165,
626, 627, 628f
Low-molecular-weight (LMW) heparin,
612f, 612–614
5-LOX, 323, 325f
5-LOX-activating protein (FLAP), 324, 325f
Loxapine, 514f, 520t
5-LOX inhibitors, 332
Lp(a) hyperlipoproteinemia, 629t, 631
Lp(a) lipoprotein, 626–627
Lubiprostone, 1099, 1103
Lugol’s solution, 700, 701t
Lumacaftor, 30
Lumefantrine, 919f, 920t, 928
Index    1223
Lung cancer, 973–974
Lung maturation, fetal, corticosteroids for,
711
Lurasidone, 529t
Luteinizing hormone (LH), 668f, 668–669,
669t
chemistry and pharmacokinetics of, 674
diagnosis of responsiveness of, GnRH
in, 677
in ovarian function, 721
pharmacodynamics of, 674
Lutropin alfa, 674
Lymphoma
Hodgkin’s, 970
non-Hodgkin’s, 970
Lynestrenol, 728t. See also Progestins
Lysergic acid diethylamide (LSD). See also
Ergot alkaloids
description of, 294, 297t, 577t, 580
Gio protein-coupled receptor activation
by, 577t, 582–583
M
Macitentan, 312, 313b, 317t. See also
Endothelin inhibitors
Macrobid, 897
Macrolides, 818–821, 824t
azithromycin, 820, 824t
clarithromycin, 819f, 820, 824t
drug interactions of, 1168t
erythromycin, 819–820, 824t
ketolides, 820–821, 824t
preparations available, 825t
prokinetic activity of, 1098
Macrophage colony-stimulating factor, 997t
Macugen, 1065
Macula densa, on renin release, 301
Macular degeneration, age-related, 1058,
1065, 1067
Mafenide acetate, 836
Magnesium, 247, 251t
Magnesium citrate, 1098
Magnesium hydroxide, 1089, 1098
Ma-huang, 1133t
Maintenance dose, 50, 50b, 51f
Major depressive disorder (MDD),
532–536. See also Depression
characteristics of, 532
drugs for
antidepressants, 532–552, 549t–550t
lithium, 526
pathophysiology of, 533–536
integration of hypotheses on, 536
monoamine hypothesis in, 533,
534–536, 535f
neuroendocrine factors in, 536
neurotrophic hypothesis in, 533f,
533–534
1224    Index
Major histocompatibility complex (MHC)
molecules, 979f, 979–980
Malaoxon, 116f
Malaria drugs, 917–928
amodiaquine, 919f, 920t, 921
antibiotics
clindamycin, 927
doxycycline, 920t, 927–928
spiramycin, 928
artemisinin, 919f, 920t, 922–923
artesunate, 922–923
artesunate-amodiaquine, 922t,
922–923
artesunate-sulfadoxine-pyrimethamine,
922t, 922–923
atovaquone, 919f, 926
atovaquone-proguanil, 920t
case study on, 917, 937
chemical structure of, 919f
chemoprophylaxis and treatment of,
918, 920t–921t
chloroquine, 919f, 920t. See also
Chloroquine
classification of, 917
dihydroartemisinin-piperaquine, 922,
922t
folate synthesis inhibitors, 926
fansidar, 926
proguanil, 919f, 926
pyrimethamine, 919f, 926
sulfadoxine, 919f, 926
sulfadoxine-pyrimethamine, 920t
halofantrine, 919f, 920t, 928
lumefantrine, 919f, 920t, 928
major, 919f, 920t
malarone, 920t, 926
mefloquine, 919f, 924–925
piperaquine, 919f, 920t, 922, 922t
preparations available, 936t
primaquine, 919f, 920t, 925–926
quinidine, 923–924
quinine, 919f, 920t, 923–924
in travelers, 920t
for treatment, 922t
Malaria life cycle, 917, 918f
Malarone, 920t, 926
Malathion, 116f, 122t, 1076. See also
Organophosphate cholinesterase
inhibitors
Malignant hypertension, 190
Malignant hyperthermia, 288t
anesthetics as cause of, 449, 483
dantrolene for, 449, 488
succinylcholine as cause of, 449, 483
Malignant melanoma, 974–975
Managed care organizations, 1155
Manganese, 1017
Mannitol, 267, 273t, 274t
Maprotiline, 540t, 542t, 546t, 547, 549,
550t
Maraviroc, 872t, 882–883
Marfan syndrome, 305
Marijuana, 581–582
case study of, 575, 589
Gio protein-coupled receptor activation
by, 581, 582, 583f
Marinobufagenin, 217
Mast cell stabilizers, asthma treated with,
362t
Materia medica, 2
Maturation, female, estrogens on, 724
Maximal efficacy, 36f, 36–37
Maximal electroshock (MES) test, 409
Maximum effect, on target concentration,
52
Maxzide, 266t
MDMA
acamprosate for dependence on, 589t
description of, 587
Mean arterial pressure, 100, 102f
Measles, 1180t
Measles-mumps rubella (MMR) vaccine,
1177t
Mebendazole, 939t, 942
Mecamylamine, 133–134, 134f. See also
Ganglion blockers
Mecasermin, 672, 682t
Mechlorethamine, 953, 953f, 955t. See also
Alkylating agents
Meclinertant, 314, 318t. See also
Neurotensin antagonists
Meclizine, 283t, 1106
Meclofenamate, 649
Meclofenamic acid, 644f. See also
Nonsteroidal anti-inflammatory
drugs (NSAIDs)
Median effective dose (ED50), 37, 37f
Median lethal dose (LD50), 13, 37, 37f
Median toxic dose (TD50), 37, 37f
Medical pharmacology, 1
Medicare, 1154
Medroxalol, 166, 170t. See also b-receptor
antagonist drugs
Medroxyprogesterone (acetate), 728, 728t.
See also Progestins
clinical uses of, 731
structure of, 729f
Medullary depression, 446
Medullary-periventricular pathway, 516
Mefloquine, 919f, 924–925
Megakaryocyte growth factors, 604–605,
606t
Megaloblastic anemia, 591, 607
Megestrol acetate, 728, 728t. See also
Progestins
Meglitinide analogs, 759, 768t
Melagatran, 617
Melarsoprol, 934
Melatonin, 285f, 287b, 1143–1144
Melatonin receptor
agonists of, 394t
in sleep-wake cycle, 384b
Meloxicam, 645t, 647
Melphalan, 953f, 955t. See also Alkylating
agents
Memantine, 1063
Membrane-delimited pathways, CNS,
369f, 370
Membrane electrical activity, 229–230,
230f
Memory, 447b
Meningitis
cephalosporin and vancomycin for, 795,
814
iatrogenic fungal, 859b
Meningococcal vaccines
meningococcal conjugate, 1177t
meningococcal polysaccharide, 1177t
Menopause, 720
Menotropins, 673–674
Menstrual cycle, 720, 721f
Mentha pulegium extract, 1133t
Meperidine, 568, 572t. See also Opioid
agonists
Mephenytoin, 419–420
Mephobarbital, 393t. See also Barbiturates
Mepivacaine. See also Anesthetics, local
description of, 460t, 462, 471
Gio protein-coupled receptor activation
by, 581, 583f
Mepolizumab, 357, 363t, 994
Meprednisone, 709t. See also Corticoste-
roids, synthetic
Meprobamate, 383f, 392, 425f
Mequinol, 1076
Mercaptopurine, 71
6-Mercaptopurine (6-MP), 958t, 960–961,
961f
inflammatory bowel disease treated with,
1109–1110, 1116t
TPMT on metabolism of, 81
Mercurial diuretics, 262
Mercury, 1027–1029
acute exposure to, 1029
chronic exposure to, 1029
history and epidemiology of,
1027–1028
intoxication with, 1028–1029
pharmacokinetics of, 1021t, 1028
treatment of, 1029
Meropenem, 803t, 807, 812t
Mesalamine, 1107, 1116t
Mescaline, 582–583
Mesna, 988

Mesolimbic dopamine system, 576, 576f,
579b
Mesolimbic-mesocortical pathway, 516
Mesothelioma, 1017
Mestranol, 723f. See also Estrogen(s)
Meta-analyses, 15b
Metabolic acidosis
hyperchloremic
from carbonic anhydrase inhibitors,
261
from potassium-sparing diuretics, 267
hypokalemic
from loop diuretics, 263
from thiazide diuretics, 265
Metabolic alkalosis
carbonic anhydrase inhibitors for,
260–261
diuretic-induced, 270
Metabolic syndrome, 289b
Metabolism, drug
clinical relevance of, 64–72
age and sex in, 70
commensal gut microbiota in, 69–70
diet and environmental factors in, 70
diseases on, 72, 72t
drug-drug interactions in, 70–72, 71t
drug-endogenous compound interac-
tions in, 72
drug interactions on, 1173
drugs enhancing, 70, 71t
drugs inhibiting, 71t, 72
genetic factors in, 65–69
phase I enzyme polymorphisms in,
65–69, 66t–67t, 68f
phase II enzyme polymorphisms in,
64f, 69
genetic variations in, 75–82
phase I enzymes, 74–81
phase II enzymes, 81
individual differences in, 65
to toxic products, 64–65, 65f
ultrarapid, 67
Metabolism, intermediate
adrenoceptors in, 148
sympathomimetics on, 148
Metabolizer
extensive, 68, 75t
poor, 67, 75t
ultrarapid, 67, 75t
Metabotropic glutamate receptor agonists,
516
Metabotropic (metabolic) receptors, CNS,
369f, 370
Metalloproteins, 340, 340f
Metals, heavy, 901, 1020–1029
arsenic, 1021t, 1025–1027, 1027f
chelators for, 1029–1033, 1033t. See also
Chelators
lead, 1020–1025, 1021t
mercury, 1021t, 1027–1029
poisoning management for, 1045
Metals, toxic
beryllium, 1017
cadmium, 1017
nanomaterials, 1017–1018
poisoning management for, 1045
Metaproterenol
asthma treated with, 351, 362t
structure of, 350f
Metastasis, 948
Metaxalone, 488
Metformin, 759–760, 768t, 1058
Methacholine, 109, 109f
Methadone, 555t, 556, 567, 572t, 581,
588t. See also Opioid agonists
Methallenestril, 723, 723f. See also
Estrogen(s)
Methamphetamine, 11f, 150. See also
Methylenedioxymethamphet-
amine (MDMA)
Methanol
description of, 405, 405f, 406t
poisoning management for, 1041t, 1045
Methazolamide, 260t
Methemoglobin, 199
Methenamine hippurate, 897, 902t
Methenamine mandelate, 897, 902t
Methicillin, 801
Methicillin-resistant staphylococci, cephalo-
sporins for, 802f, 803t, 804–806
Methimazole, 693–695, 694f, 701t, 702
Graves’ disease treated with, 698
thyroid storm treated with, 699
thyrotoxicosis in pregnancy treated with,
700
toxic multinodular goiter treated with,
699
Methocarbamol, 488, 489t
Methohexital, 450t
Methotrexate (MTX)
asthma treated with, 360
cancer treated with, 957, 958t
immunosuppressive uses of, 989
inflammatory bowel disease treated with,
1110, 1116t
rheumatoid arthritis treated with,
651–652
Methoxamine, 144f
Methoxsalen, 1076
Methoxy polyethylene glycol–epoetin beta,
601, 606t
Methsuximide, 429f
Methylbenzene (toluene), 1010
Methylcellulose, 1098
Methyldopa. See also Sympathomimetics,
direct-acting
Index    1225
description of, 149, 191t
hypertension treated with, 179t,
179–180
Methylenedioxymethamphetamine
(MDMA), 587, 589t
Methylmercury, 1028
Methylnaltrexone (bromide), 571, 572t,
1099
Methylphenidate, 150
Methylprednisolone, 709t. See also
Corticosteroids, synthetic
antiemetic properties of, 1105
asthma treated with, 355, 362t
Methyltestosterone, 740–743, 741t. See also
Androgens and anabolic steroids
Methylxanthine drugs. See also specific drugs
asthma treated with, 352f, 352–353,
362t
preparations available, 363t
Methysergide, 295
Metoclopramide, 1097–1098, 1106
Metolazone, 264f, 264t, 269, 273t
Metoprolol, 164t, 165, 170t, 191t. See also
b-receptor antagonist drugs
angina pectoris treated with, 210t. See also
b-receptor antagonist drugs
heart failure treated with, 221,
222, 225t
hypertension treated with, 179t, 183
structure of, 163f
Metrifonate, 939t, 943
Metronidazole, 895–896, 902t
acne treated with, 1071
amebiasis treated with, 929t, 929–930,
930f
Metyrapone, 716, 716f
Metyrosine, 95, 161, 171t
Mexiletine
arrhythmia treated with, 239t, 240t,
242, 250t
on ion channels, 560b
Mibefradil, 204. See also Calcium channel
blockers
Micafungin, 859, 861t
Miconazole, 1072
Microbiota, commensal gut, 69–70
Microglia, 368
Micro-RNAs (miRNAs), 2, 39
Microsomal drug oxidation, 58–59,
60t–61t
Microsomal ethanol-oxidizing system
(MEOS), 397f, 397–398
Microsomal mixed function oxidase system,
58f, 58–59
Microsomal triglyceride transfer protein
(MTP) inhibitor, 638
Microsomes, 58
Midamor, 266t
1226    Index

Midazolam, 393t. See also Benzodiazepines
anesthesia use of, 450f, 450t, 455
seizures treated with, 432
Midodrine, 149, 154t. See also
Sympathomimetics
Mifepristone (RU-486), 334, 717, 738
Miglitol, 761, 768t
Migraine headache
beta-receptor antagonists for, 168–169
ergot alkaloids for, 295
prophylaxis, 291
propranolol for, 168, 291
serotonin agonists for, 289–291, 290f,
291t
Milk of magnesia, 1098
Milk thistle (Silybum marianum),
1138–1139
Milnacipran, 151, 537, 540t, 546t, 550t.
See also Serotonin norepinephrine
reuptake inhibitors (SNRIs)
Milrinone, 219, 225t
Miltefosine, 935
Mineralocorticoid antagonists
drospirenone, 717
eplerenone, 717
spironolactone, 717
Mineralocorticoid receptor (MR)
forms and interactions of, 705–707, 707f
genes for, 705
Mineralocorticoids
aldosterone, 714–715
deoxycorticosterone, 714–715
fludrocortisone, 715
preparations available, 718t
Mineral oil, 1098
Minimal bactericidal concentration (MBC),
906
“Minimal change” nephropathy, 270
Minimum alveolar concentration (MAC),
443t, 446, 447b
Minimum inhibitory concentration (MIC),
797, 906
Minimum lethal dose, 13
Minocycline, 817, 824t
Minoxidil
hypertension treated with, 179t, 185, 191t
topical, 1084–1085
Miosis, 561
Mipomersen, 638
Mirabegron, 140, 154t, 289b. See also
Sympathomimetics
Mirtazapine, 540t, 541, 542t, 546t, 547,
549, 550t. See also Antidepres-
sant agents; Tetracyclic agents
Misoprostadil, 323
Misoprostol
abortion uses of, 334
gastric mucosa protection uses of, 1096
NSAID-induced peptic ulcer prophylaxis
using, 336
structure of, 333f
Missing data, 15
Mitiglinide, 768t
Mitomycin (mitomycin C), 962t, 965
Mitotane, 716f, 717
Mitoxantrone, 965
Mixed agonist-antagonist opioids, 553
Mixed function oxidases (MFOs), 58, 58f
Mixed lipemia, 630
MK-0557, 318t. See also Neuropeptide Y
antagonists
Modafinil, 150
Moduretic, 266t
Moexipril, 187
Molecular size, drug, 3
Molecular weights (MW), 3
Molindone
chemical structure of, 514f, 515
psychosis treated with, 515
Mometasone (furoate), 355, 709t. See also
Corticosteroids, synthetic
Monitored anesthesia care (MAC), 441b
Monoamine hypothesis, 533, 534–536,
535f
Monoamine neurotransmitters
dopamine, 374f, 376t, 378
histamine, 376t, 379
5-hydroxytryptamine, 374f, 376t, 379
norepinephrine, 374f, 376t, 378–379
Monoamine oxidase (MAO)
alpha carbon substitutions on, 143–144,
144f
catecholamine metabolism by, 98f
Monoamine oxidase inhibitors (MAOIs)
depression treated with, 550t
chemistry of, 539
clinical pharmacology of
adverse effects in, 547
drug interactions in, 549
pharmacodynamics of, 542t, 543
pharmacokinetics of, 540t, 541
preparations available, 551t
drug interactions of, 1168t
parkinsonism treated with, 498f,
499–500, 508t
poisoning with, treating, 1042
Monoamine transporters, 142, 143f
Monobactams, 796f, 806, 812t
Monobenzone, 1076
Monoclonal antibodies (MABs), 978,
991–995
abciximab, 995
antitumor, 991–992
delivering isotopes and toxins to tumors,
993
denosumab, 995
eculizumab, 995
immunosuppressants and anti-
inflammatory agents, 993–995,
994f
palivizumab, 995
pegatinib, 995
ranibizumab, 995
raxibacumab, 995
Monoiodotyrosine (MIT), 688, 688f
Monooxygenases, 58
Montelukast, 332. See also Leukotriene
receptor antagonists
asthma treated with, 336, 356–357,
360, 362t
structure of, 356f
Mood-stabilizing drugs, 524–528,
528t–529t
Moricizine, 239t, 243, 251t
“Morning after” contraception,
736, 736t
Morning sickness, H1-receptor antagonists
for, 274
Morphinans, 568, 569. See also Opioid
agonists
Morphine, 567. See also Opioid agonists
description of, 78, 555t, 567, 572t
Gio protein-coupled receptor activation
by, 581, 583f
Motility agents, 1096. See Gastrointestinal
motility, stimulators of
Motion sickness
H1-receptor antagonists for, 274
muscarinic receptor blockers for, 130
Movement disorders
athetosis and dystonia, 492, 505
ballismus, 505
benign hereditary chorea, 505
drug-induced dyskinesias, 506
functional circuitry of, 493f
Huntington’s disease, 504f, 504–505, 508t
Parkinsonism, 493–503. See also
Parkinsonism
restless legs syndrome, 506–507
tics, 493, 505–506, 508t
tremor, 492, 503–504
types of, 492–493
Wilson’s disease, 507
Moxifloxacin, 838, 843t
Moxonidine, 149. See also Sympathomi-
metics, direct-acting
MRP1 transporter, 8t
Mucosal protective agents, gastric
bismuth compounds, 1096
mechanisms of, 1095
prostaglandin analogs, 1096
sucralfate, 1095
Müllerian duct inhibitory factor, in testis,
740

Multicompartment pharmacokinetics,
45f, 46
Multidrug resistance-associated protein
(MRP) transporters, 8, 8t
Multidrug resistance (MDR) genes, 38
Multidrug resistance type 1 (MDR1)
transporter, 8, 8t
Multiple myeloma, 970–971
Mu opioid receptors, 553, 554t
Mupirocin, 896, 1070
Muscarine, 109, 110f
Muscarinic alkaloids, direct-acting, 122t
Muscarinic (M3) acetylcholine receptors,
parietal cell, 1087–1088, 1088f
Muscarinic (M) receptors, 98, 99t
M3 parietal cell, 1087–1088, 1088f
subtypes and characteristics of, 107–108,
108f, 108t
subtypes of, 124
Muscarinic receptor blockers (antagonists),
124–129
adverse effects of, 133
anticholinergic, 135t, 136t
applications of, 130–133
cardiovascular, 130–131
cholinergic poisoning, 132–133
CNS, 130
gastrointestinal, 131, 131t
ophthalmologic, 130, 130t
respiratory, 126f, 130
urinary, 131t, 131–132
asthma treated with, 353–354, 354f.
See also specific drugs
chemistry and pharmacokinetics of, 125,
125f, 126f
clinical pharmacology of, 130–133
clinical uses of, 353–354, 359
contraindications to, 133
discovery of, 353
mechanism of action, 125–127, 127t,
353, 354f
organ system effects in, 127–129
cardiovascular system, 94f, 111f,
127–129, 128f
CNS, 127
eye, 105f, 127, 128f
gastrointestinal tract, 127t, 129,
129f
genitourinary tract, 129, 129f
respiratory system, 129
sweat glands, 129
parkinsonism treated with, 501t, 508t
pharmacodynamics of, 125–129
preparations available, 363t
Muscarinic signaling, 110, 111f
Muscarinic stimulants, direct-acting, 120
Muscle relaxants
sedative-hypnotics, 389
skeletal, 474–491. See also specific types
neuromuscular blocking drugs,
474–475
preparations available, 490t
spasmolytic drugs, 485–487, 488t–489t
Mushroom poisoning
muscarinic receptor blockers for, 132
types of, 132–133
Myasthenia gravis
cholinesterase inhibitors for, 119
edrophonium for, 119
pathophysiology of, 119
Mycobacteria, 842
Mycobacterial drugs, 842–852, 851t.
See also Antimycobacterial drugs;
specific agents
Mycobacterium avium, 850t
Mycobacterium avium complex (MAC),
850, 850t
Mycobacterium intracellulare, 850, 850t
Mycobacterium kansasii, 850, 850t
Mycophenolate mofetil (MMF)
immunosuppressive uses of, 987
rheumatoid arthritis treated with, 652
Mydriasis, 127, 128f
Myeloid growth factors (G-CSF, GM-CSF),
602t, 602–604, 603f, 606t
Myenteric plexus, 91f, 92
Myocardial hypertrophy, 216
Myocardial infarction, acute
female hormonal contraceptives as cause
of, 735
thrombolytics for, 618–619, 619b
Myocardial oxygen demand, 195, 195t
Myocardial oxygen supply, 195
Myoclonic seizures, 410, 430
Myrcludex B, 887
Myxedema, 697
N Nature of drugs, 3–5
Nabilone, 582, 1106
Nabiximols, 582
Nabumetone, 644f, 645t, 648. See also
Nonsteroidal anti-inflammatory
drugs (NSAIDs)
N-acetylcysteine, 65, 73
N-acetyltransferases (NATs), 63, 64f, 67t
Na channels, epithelial, 258, 258f
+ -
Na /Cl cotransporter (NCC), 257, 257f
Nadolol, 162, 164t, 166, 170t, 183. See
also b-receptor antagonist drugs
NADPH-cytochrome P450 oxidoreductase
(POR), 58, 60t–61t
Nafarelin, 676, 739
Nafcillin, 799
Naftidrofuryl, 209
Naftifine, 861
+ +
Na /H exchanger (NHE3), 255, 256f
Index    1227
+ +
Na /K -ATPase, 229
in cardiac contractility, 213, 215
digitalis on, 217
+ + -
Na /K /2Cl cotransporter (NKCC2 or
NK2CL), 257, 257f
Nalbuphine, 555t, 556, 569, 572t
Nalmefene, 570, 572t
Naloxone, 570–571, 572t, 581, 588t, 659
Naltrexone, 289b, 570–571, 572t, 588t
alcoholism treated with, 404, 406t, 407t
dependence and addiction, 588
Naltrexone/bupropion, 290t
Nandrolone decanoate, 740–743, 741t.
See also Androgens and anabolic
steroids
Nanomaterials, toxic, 1017–1018
Nanoparticles, as drug vehicles, 7
Naproxen, 645t, 648
Naratriptan, 291t, 296t
Natalizumab, 995, 1112
Nateglinide, 759, 768t
National Health and Nutrition
Examination Survey (NHANES),
173
National Research Council wound
classification criteria, 914b
Natpara, 775, 784
Natriuretic peptides, 308–309
clinical role of, 310–311
heart failure treated with, 225t
on kidney, 259
pharmacodynamics and
pharmacokinetics of, 309
preparations available, 318t
synthesis and structure of, 308–309,
309f
on vasoactive peptides, 317t
Natural killer (NK) cells, 977, 978
Natural killer-T (NKT) cells, 977, 978
physical nature in, 3
rational drug design in, 4
reactivity and drug–receptor bonds in,
3–4
receptor nomenclature in, 4–5
shape in, 4
size in, 3
Nausea and vomiting
pathophysiology of, 1103, 1104f
of pregnancy, H1-receptor antagonists
for, 274
NAV receptors, 560b
NDA, 15–17, 17
Nebivolol, 164t, 166, 170t, 191t. See also
b-receptor antagonist drugs
heart failure treated with, 221, 222, 225t
hypertension treated with, 179t, 183
structure of, 163f
1228    Index
Necitumumab, 968, 992
Nedocromil, 281
allergic rhinoconjunctivitis treated with,
356, 362t
asthma treated with, 355–356, 360
Nefazodone, 538, 540t, 542t, 546t, 547,
550t. See also 5-HT receptor
modulators
Negative allosteric modulators, 24
Nelfinavir, 872t, 881
Neoadjuvant chemotherapy, 949–950
Neomycin
description of, 831–832, 833t
topical dermatologic, 1071
Neonicotinoids, 120
Neostigmine, 119, 122t
neuromuscular blockade reversal using,
483–484
prokinetic activity of, 1097
structure of, 115, 116f
Neovascular age-related macular
degeneration, 1065
Nephrogenic diabetes insipidus
ADH antagonists as cause of, 268–269
lithium as cause of, 527
Nephrolithiasis, diuretics for, 271–272
Nephron, 256t
Nephrotic syndrome, 788
Neprilysin, 309
Neprilysin inhibitors, 225t, 312
Nernst equation, 229
Nesiritide (BNP), 310. See also Natriuretic
peptides
heart failure treated with, 220, 225t
on kidney, 259
on vasoactive peptides, 317t
Netilmicin, 827f, 831
Neural tube defects, folic acid supplements
and, 599b
Neurocysticercosis. See also Antihelminthics
albendazole for, 939t, 940
praziquantel for, 944–945
Neuroglia, 368, 368f
Neurohypophysis, 667, 668f
Neurokinin A, 313
Neurokinin B, 313
Neurokinin receptor antagonists, 1105
Neuroleptanesthesia, 519
Neuroleptic malignant syndrome (NMS),
288b, 288t
antipsychotics as cause of, 523
dyskinesia in, 506
Neuromedin N, 314
Neuromuscular blocking drugs, 474–475,
488t–489t
cardiovascular effects, 481–482
chemistry of, 476, 476f, 477f
clinical pharmacology of, 480–485
depolarizing
mechanism of action, 478f–479f,
479t, 480
pharmacokinetics of, 477–478, 478t
disease and aging on neuromuscular
response, 484
drug interactions, 483
fundamentals of, 474
history of, 474
hyperkalemia, 483
intragastric pressure increase, 483
intraocular pressure increase, 483
mechanism of action of, 478f–479f,
478–480
muscle pain, 483
neuromuscular transmission assessment,
479f, 480–481
nondepolarizing
mechanism of action, 475f, 478f,
478–479, 479f, 479t
pharmacokinetics of, 476–477, 478t
normal neuromuscular function and,
474–475, 475f
pharmacokinetics of, 476–477
preparations available, 490t
reversal of nondepolarizing blockade in,
483
skeletal muscle paralysis, 480
uses of, 484–485
Neuromuscular function, 474–475, 475f
Neuronal systems, 373–374, 374f
Neurons, 368, 368f
local circuit, 373, 373f
relay (projection), 373, 373f
Neuropathy target esterase (NTE), 1011
Neuropeptides, CNS, 379
Neuropeptide Y antagonists, 318t
Neuropeptide Y (NPY), 92t, 315–316
Neurotensin, 314
Neurotensin agonists, 317t
Neurotensin antagonists, 318t
Neurotransmitter pathways, diffuse brain,
373–374, 374f
Neurotransmitter receptors, in central
nervous system, 369f, 369–370
Neurotransmitters, 90f, 93–98, 375–380
acetylcholine, 374f, 376t, 378
amino acid, 375–378
GABA and glycine, 376t, 378
glutamate, 375, 376t, 377f
autonomic
adrenergic transmission in, 95–97,
96f–97f
cholinergic and noradrenergic fibers
in, 90f, 93
cholinergic transmission in, 93–95,
94f
cotransmitters in, 93
cotransmitters in cholinergic and
adrenergic nerves in, 97–98
endocannabinoids, 377t, 379–380
monoamine
dopamine, 374f, 376t, 378
histamine, 376t, 379
5-hydroxytryptamine, 374f, 376t, 379
norepinephrine, 374f, 376t, 378–379
neuropeptides, 379
nitric oxide, 380
opioid peptides, 377t
orexins, 377t, 379
purine, 380
tachykinins, 377t
Neurotransmitter uptake carriers, 95b
Neurotrophic hypothesis, for depression,
533f, 533–534
Neutral antagonism, 6
Neutropenia
cancer chemotherapy-induced, G-CSF
for, 603, 603f, 606t
description of, 592
Nevirapine, 872t, 878
New Drug Application (NDA), 17
New drug development, 11, 12f
Niacin
with bile-acid binding resins, 639
dyslipidemia treated with, 639t
with ezetimibe, 639
with reductase inhibitors, 639
Niaspan, 636
Nicardipine
angina pectoris treated with, 202–206,
203t, 210t
hypertension treated with, 187
Niclosamide, 939t, 943
Nicorandil, 202
Nicotine, 122t
abuse of, 577t
analgesic uses of, 560b
ionotropic receptors in, 583–584
mechanism of action of, 583–584
in pesticides, 1012
prevalence of addiction to, 583
structure of, 109, 110f
toxicity, 120–121
treatment for, 584, 588t
Nicotinic acetylcholine receptor (nAChR)
description of, 475, 475f
mechanism of action of, 29f, 29–30
Nicotinic (N) receptor
agonists of
direct-acting, 122t
partial, in nicotine abuse, 584, 588t
description of, 98, 99t, 114
subtypes and characteristics of, 90f, 107,
108f, 108t
Nicotinic signaling, 110–112, 111f

Nicotinic stimulants, direct-acting,
120–121
Nifedipine. See also Calcium channel
blockers
angina pectoris treated with, 202–206,
210t
hypertension treated with, 187, 191t
Nifurtimox, 933t, 934–935
Nigrostriatal pathway, 516
Nilotinib, 967
Nilutamide, 744, 972
Nimodipine, 202–206, 210t. See also
Calcium channel blockers
Nirvanol, 420
Nisoldipine
angina pectoris treated with, 203t
hypertension treated with, 187
Nitazoxanide, 933–934
Nitrates and nitrites
angina pectoris treated with, 197–202,
202t, 209t
chemistry of, 197
clinical use of, 201–202, 202t
heart failure treated with, 222
inhalants, ionotropic receptors in, 585
mechanism of action of, 195, 197f
mechanisms of clinical effect of, 201,
201t
nitrates alone vs. with beta or calcium
channel blockers in, 208, 209t
as nitric oxide donors, 342
organic, 342
pharmacodynamics of
mechanism of action in smooth
muscle in, 197f, 198
organ system effects in, 198–200,
199f
pharmacokinetics of, 198
preparations available, 211t
tolerance to, 200–201
toxicity of
acute adverse effects in, 200
carcinogenicity of derivatives in, 201
Nitrazepam
seizures treated with, 432
structure of, 382f
Nitrendipine, 203t
Nitric oxide (NO), 34, 339–345, 345t
in CNS, 380
in disease
central nervous system, 344
infection and inflammation, 344
peripheral nervous system, 344
respiratory disorders, 344
septic shock, 343t, 343–344
vascular effects, 342–343, 343f
drugs increasing, mechanism of action
of, 197f
endogenous, discovery of, 339
functions of, 92t
inactivation of, 341
inhalation of, 342
isoforms of, 339, 340t
pharmacologic manipulation of
nitric oxide donors, 342
nitric oxide synthesis inhibitors,
341–342
preparations available, 345t
signaling mechanisms of, 339–341, 340f
metalloproteins in, 340, 340f
thiols in, 340–341
tyrosine nitration in, 341, 341t
synthesis of, 339–340, 340f
Nitric oxide donors, 342
Nitric oxide inhibitors, for septic shock,
343t, 343–344
Nitric oxide synthase (NOS), CNS, 380
Nitric oxide synthesis inhibitors, 341–342
Nitrites, 342. See also Nitrates and nitrites
Nitrofurantoin, 895–896, 902t
Nitrogen oxides, 341, 341t, 1007t, 1008
Nitroglycerin
angina pectoris treated with, 197–202,
202t, 209t
heart failure treated with, 224
mechanism of action of, 197f
Nitroprusside, 342
heart failure treated with, 224, 225t
hypertension treated with, 185–186,
192t
Nitro reductions, 61t
Nitrosothiols, 197f
Nitrosoureas, 953f, 954, 956
Nitrous oxide, 441–449. See also
Anesthetics, inhaled
properties of, 443t
structure of, 443f
Nitro-vasodilators, angina pectoris treated
with, 202
Nivolumab, 975, 992
Nizatidine, 1089–1091. See also
H2-receptor antagonists
Nizoral, 1072
NMDA, 375
NMDA antagonists
analgesic, ion channels and, 560b
as drugs of abuse, 580
NMDA receptor(s)
antagonists of
depression treated with, 535–536
ketamine and phencyclidine, 585
in central sensitization, 560b
in CNS, 375
N-methyl-d-aspartate, 375
No-effect dose, 13
Nonabsorbable sugars or salts, 1098
Index    1229
Nonadherence, in elderly, 1065–1066
Nonadrenergic, noncholinergic (NANC)
neurons, 99–100
Noncoding region polymorphism, 75t
Noncompetitive antagonist, 23f, 24
Nonnucleoside reverse transcriptase
inhibitors (NNRTIs), 876–879
delavirdine, 871t, 877
efavirenz, 871t, 877–878
etravirine, 871t, 878
fundamentals of, 874f, 876–877
nevirapine, 872t, 878
in pregnancy, 879t
rilpivirine, 872t, 878–879
Non-small cell lung cancer (NSCLC),
973–974
Nonsteroidal anti-inflammatory drugs
(NSAIDs), 643–649, 645t
adverse effects of, 645
aspirin (Salicylates), 645, 645t, 646f
chemistry and pharmacokinetics of, 643,
644f, 645t
choice of, 649
clinical uses of
dermatologic, 1084
dysmenorrhea, 335
gout, 661
inflammation, 643
COX-2 inhibitors, nonselective,
647–648
COX-2 inhibitors, selective, 645t,
645–647
celecoxib, 645t, 647
meloxicam, 645t, 647
drug interactions of, 1169t
on eicosanoid synthesis, 332
in elderly, 1064
nonacetylated salicylates, 645t
pharmacodynamics of, 643–645, 646f
preparations available, 664t
Nontoxic goiter, 700
Nonulcer dyspepsia drugs
H2-receptor antagonists, 1091
metoclopramide and domperidone,
1097–1098
proton-pump inhibitors, 1094
NOP receptor, 554
Noradrenergic fibers, 90f, 93
Noradrenergic junction, 96f
Norepinephrine (NE)
biosynthesis of, 97f
in CNS, 374f, 376t, 378–379
in depression, 534, 535f
dose-response curves to, 158f
functions of, 92t, 149
metabolism of, 96–97, 98f
on renin release, 301
structure of, 144f
1230    Index
Norepinephrine transporter (NET), 8t, 95,
95b, 96f, 97, 142, 143f
Norethindrone (acetate), 728t, 729f.
See also Progestins
Norethynodrel, 728t. See also Progestins
Norfloxacin, 838
Nortriptyline, 546t
Noscapine, 570
Notice of Claimed Investigational Exemption
for a New Drug (IND), 12f, 15
Novocain, 460f
NovoSeven, 623
N-Oxidation, 60t
NPH, 755, 768t. See also Insulin
NS3/4A inhibitors, 889–891, 890f
NS5A inhibitors, 888–889
NS5B RNA polymerase inhibitors, 889
NT79, 317t. See also Neurotensin agonists
N-terminal pro-brain natriuretic peptide,
216
NT69L, 317t. See also Neurotensin agonists
Nucleoside and nucleotide reverse tran-
scriptase inhibitors (NRTIs),
870–876, 871t–872t
abacavir, 870, 871t
didanosine, 871t, 874–875
emtricitabine, 871t, 875
fundamentals of, 870
lamivudine, 872t, 875
in pregnancy, 879t
stavudine, 873t, 875
tenofovir, 873t, 875–876
zidovudine, 873t, 876
Numeric rating scale (NRS), 562
Nutraceuticals, toxicity of, 3
Nutritional anemias, 594t, 594–595,
605t–606t. See also specific types
Nutritional rickets, 788
Nutritional supplements, purified,
1141–1144
coenzyme Q10, 1141–1142
glucosamine, 1142–1143
melatonin, 1143–1144
Nystatin, topical, 860
dermatologic, 1073
O analgesics, intravenous, 457
o-Benzyl-p-chlorophenol, 899
Obesity, 289b, 290t
Obeticholic acid, 1113–1114
Obidoxime, 132
Obiltoxaximab, 995
Obsessive-compulsive disorder, 544
Occupational toxicology, 1004
Octopamine, 97f
Octreotide, 672f, 673, 683t
diarrhea treated with, 1101
variceal hemorrhage treated with, 1114,
1116t
Odanacatib, 780b
Ofatumumab, 970, 992–993
Off-labeled uses of drugs, 1153
Ofloxacin, 838
Ogilvie’s syndrome, 1097
Olanzapine
Huntington’s disease treated with, 505
psychosis treated with, 515, 520t, 529t
structure of, 514f
Olcegepant, 315, 318t. See also Calcitonin
gene-related peptide
Oligodendrocytes, 368
Olmesartan
hypertension treated with, 189
on vasoactive peptides, 316t
Olodaterol, 152, 351
Olsalazine, 1107, 1107f
Omalizumab, 357, 360, 362t, 995
Omapatrilat, 310, 317t
Ombitasvir, 888–889
Omecamtiv mecarbil (CK-1827452)
on contractile proteins, 213
heart failure treated with, 219–220
Omega conotoxin, 370t
Omega-3 essential fatty acids, 337
Omega-6 essential fatty acids, 337
Omeprazole, 1091–1095. See also proton-
pump inhibitors (PPIs)
Omission, errors of, 1149–1150
Onchocerciasis, ivermectin for, 941–942
Oncogenes, 949
Ondansetron, 292, 297t. See also Serotonin
(5-HT) receptor antagonists
antiemetic properties of, 1104
chemical structure of, 1102f
On-off phenomenon, 497
o-Phenylphenol, 899
Ophthalmic drugs. See also specific types
in elderly
glaucoma, 1064
macular degeneration, age-related,
1065
Opioid(s), 553–554, 572t. See also Drugs
of abuse; specific types
abuse of, 577t
addiction, 566
in breast milk, 1056
case study of, 553, 574
classification and chemistry of, 553–554,
554t
clinical use of, 563–564
analgesia, 555t, 563
anesthesia, 563–564
buccal transmucosal, 564
diarrhea, 563
intranasal, 564
patient-controlled analgesia, 564
pulmonary edema, acute, 563
rectal suppositories, 564
shivering, 563
transdermal fentanyl patch, 564
in CNS, 377t
constipation caused by, 562
contraindications and cautions with, 566
dependence, 564–565, 566
drug interactions of, 566t, 566–567,
1169t
endogenous opioid peptides, 554, 554t
mechanism of action in, 557–559
cellular actions, 556, 557f
hyperalgesia, 559
receptor distribution and analgesia,
557f, 557–559, 559f
receptor types and physiologic effects,
554t, 555t, 556–557
tolerance and dependence, 559, 561t
mixed agonist-antagonist, 553
organ system effects, of morphine and
surrogates, 559–562
CNS, 559–562, 561t
peripheral, 560–561
overdosage, 566
pharmacodynamics of, 556–562
pharmacokinetics of, 554–556, 555t
poisoning management for, 1041t, 1045
preparations available, 573t
respiratory depression caused by, 561
source of, 553
tolerance, 561t, 564–565
toxicity and undesired effects of, 564t,
564–567
Opioid agonists, 567–569, 572t
diarrhea treated with, 1100
educating prescribers of, 569b
Gio protein-coupled receptor activation
by, 581, 583f
mild to moderate
phenanthrenes, 568, 572t
phenylheptylamines, 568
phenylpiperidines, 568
mixed receptor actions
benzomorphans, 569
morphinans, 569
phenanthrenes, 569, 572t
preparations available, 573t
strong
morphinans, 568
phenanthrenes, 567, 572t
phenylheptylamines, 567, 572t
phenylpiperidines, 568, 572t
tapentadol, 570, 572t
tramadol, 569–570, 572t
Opioid antagonists, 570–571, 572t, 581
laxative action of, 1099–1100
preparations available, 573t
Opioid antitussives, 570, 572t, 573t
Opioid-induced hyperalgesia, 559

Opioid peptides, endogenous, 554, 554t
Opioid receptors, 553, 554t
distribution of, on analgesia, 557f,
557–559, 559f
mechanism of action of, 554t, 555t, 556
Opisthorchiasis, 944
Oprelvekin, 604–605, 606t
Optimization, compound, 13
Oral antidiabetic agents, 757–764,
768t–769t
Oral contraceptives, 732–737
beneficial effects of, 737
physiologic effects of, 728t, 729, 729f,
730t–731t
Orexin receptor antagonists, 390b, 394t
Orexins, in CNS, 377t, 379
Organic anion transporter (OATP1B1),
82–83
Organochlorine pesticides, 1010t,
1010–1011, 1013f
Organophosphate cholinesterase inhibitors,
122t
absorption, distribution, and metabolism
of, 115–117
aging of, 117
pharmacodynamics of, 117–118
poisoning with, case study on, 107, 123
structure of, 115, 116f
Organophosphorus pesticides, 1011t,
1011–1012
Organ transplantation, immunosuppressive
therapy for, 996
Oritavancin, 803t
Orlistat, 289b, 290t
Oropharyngeal candidiasis, 355
Orphan Drug Amendment of 1983,
16t, 18
Orphan drugs, 18
Orphanin FQ, 554
Orphanin opioid-receptor-like subtype 1
(ORL1), 554
Orphan receptors, 21
Orphenadrine, 488, 489t, 501t, 508t
Ortho-phthalaldehyde (OPA), 900
Orthostatic hypotension, 157, 1061
Oseltamivir, 891–892
Osimertinib, 968, 974
Osmotic agents. See also specific agents
nature of, 3
preparations available, 274t
Osmotic diuretics, 267–268, 273t, 274t
Osmotic laxatives
balanced polyethylene glycol, 1099
nonabsorbable sugars or salts, 1098
Osteodystrophy, intestinal, 786
Osteonecrosis of the jaw, 780
Osteoporosis, 786–787, 787f
androgens and anabolic steroids for, 742
case study of, 772, 791
Index    1231
definition of, 786 contraindications for specific ingredients
epidemiology of, 786 in, 1128
treatment of, 780b, 786–787, 787f. decongestants
See also Bone mineral homeosta- systemic, 1125t
sis drugs topical, 1125t
Ouabain, 217 definition and classification of, 1120
Ovarian cancer, chemotherapy for, 974 emergency contraceptives, 1125t
Ovarian disturbances, 721–722 expectorants, 1125t
Ovarian hormones, 720–732. See also guidelines for, 1121
specific types hidden ingredients in, 1129t
androgens, 732 importance of physician familiarity with,
contraception, hormonal, in women, 1121
732–737 ingredients of, FDA safety and efficacy
estrogens, 722–727 review of, 1121
functions of, normal, 720–721 laxatives, 1125t–1126t
inhibin and activin, 732 overactive bladder treatment, 1126t
preparations available, 745t overuse or misuse of, 1121, 1128
progestins, 727–731 pediculicides (head lice), 1126t
relaxin, 732 selection of, 1121–1122
Ovarian hyperstimulation syndrome sleep aids, 1127t
(OHSS), 674, 676 smoking cessation aids, 1127t
Ovarian inhibitors use of, 1120
anastrozole, 739 Ovulation-inducing agents
danazol, 738–739 clomiphene, 739–740
estrogen and progesterone inhibitors and gonadotropins, 674–675, 675f
antagonists, 737–740 Ovulation-suppressing agents, 726
exemestane, 739 Oxaliplatin, 955t, 956–957
fadrozole, 739 Oxaluria, enteric, 789
fulvestrant, 739 Oxamniquine, 939t, 943–944
GnRH and analogs, 739 Oxandrolone, 740–743, 741t. See also
letrozole, 739 Androgens and anabolic steroids
mifepristone, 738 Oxazepam, 393t. See also Benzodiazepines
ovulation-inducing agents, 723f, ethanol withdrawal treated with, 585,
739–740 589t
tamoxifen and related partial agonist pharmacokinetics of, 385t
estrogens, 737f, 737–738 structure of, 382f
Ovarian stimulation, controlled Oxazolidinones, 823, 824t, 825t
GnRH for, 677 Oxcarbazepine, 417, 433t, 435t
gonadotropins for, 674, 675f Oxiconazole, 1072
Ovary, 720–722 Oxidation, drug, 58–59, 60t–61t
contraceptives on, female hormonal, Oxides, 1007t, 1008–1009
732–733 Oxistat, 1072
normal cycle of, 720–721, 721f Oxprenolol, 166, 170t. See also b-receptor
Overactive bladder, 1126t antagonist drugs
Overshoot phenomenon, 38 Oxybutynin, 131. See also Muscarinic
Over-the-counter agents, 1120–1130 receptor blockers
acid reducers Oxycodone. See also Opioid agonists
H2-antagonists, 1122t description of, 555t, 568, 572t
proton-pump inhibitors, 1122t Gio protein-coupled receptor activation
agents switched from prescription to by, 581, 583f
OTC status, 1121, 1121t Oxygen demand, myocardial, 195, 195t
allergy preparations, 1122t Oxygen supply, myocardial, 195
analgesics and antipyretics, 1123t Oxymetazoline, 149. See also
antacids, 1123t Sympathomimetics
antidiarrheal agents, 1123t–1124t Oxymetholone, 740–743, 741t. See also
antifungal preparations Androgens and anabolic steroids
topical, 1124t Oxymorphone, 555t, 567, 572t. See also
vaginal, 1124t Opioid agonists
antitussives, 1124t Oxytocin, 680–681, 681f, 684t
1232    Index
Oxytocin antagonist, 681, 684t
Ozone, 1007t, 1008–1009
P Parcopa, 495
Pacemaker cells, 229f
Paclitaxel, 962t, 963
Paget’s disease of bone, 788–789
Pain
kinins in, 307
treatment of. See Opioid(s), 553
Paliperidone, 515
Palivizumab
description of, 893, 995
respiratory syncytial virus treated with,
1181t
Palonosetron, antiemetic properties of,
1104
Palosuran, 316, 318t. See also Urotensin
antagonists
Pamidronate
on bone homeostasis, 779f, 779–781
hypercalcemia treated with, 782
osteoporosis, bone metastases, and
hypercalcemia treated with, 789t
Pancreas, endocrine, 747
Pancreatic enzyme supplements,
1112–1113, 1116t
Pancreatic hormones, 747–751
fundamentals of, 747
insulin, 747–749. See also Insulin
Pancreatic insufficiency, exocrine, 1112
Pancreatic peptide, 747
Pancreatic polypeptide (PP), 315
Pancreatin, 1112, 1116t
Pancrelipase, 1112, 1116t
Pancuronium. See also Neuromuscular
blocking drugs
description of, 119
properties of, 478t
structure of, 476f, 477f
Panitumumab, 966t, 967–968, 992
Pantoprazole, 1091–1095. See also proton-
pump inhibitors (PPIs)
Parabens, 901
Paracrine factors, 259
Paragonimiasis, 944
Paralytic ileus, 119
Paramethasone, 709t. See also
Corticosteroids, synthetic
Paraoxon, 116f
Paraquat, 1013f, 1014
Parasympathetic nervous system, 90f,
90–91
Parathion, 116f, 122t. See also Organophos-
phate cholinesterase inhibitors
Parathyroid hormone (PTH)
on bone mineral homeostasis, 774f,
774–775
deficiency of, 784
on gut, bone, and kidney, 778t
Paravertebral chains, 91
Paricalcitol. See also Vitamin D
for bone homeostasis, 775, 777t, 789t
chronic kidney disease treated with, 785
Paritaprevir, 890
Parkinsonism, 493–503
antipsychotics as cause of, 522
drug-induced, 503
drugs for, 502–503. See also specific drugs
acetylcholine-blocking drugs, 501t,
501–502, 508t
amantadine, 501
apomorphine, 501, 508t
catechol-O-methyltransferase
inhibitors, 500, 508t
dopamine receptor agonists, 497–499,
508t
levodopa, 494–497, 508t
monamine oxidase inhibitors, 495f,
498f, 499–500, 508t
functional circuitry of, 493f
gene therapy for, 502
neuroprotective therapy for, 502
nonmotor manifestation therapy in, 502
pathogenesis of, 493–494, 495f
surgical procedures for, 502
Parkinson’s disease, 127t, 130
Paromomycin (Sulfate), 831–832
amebiasis treated with, 929t, 930f, 931
trypanosomiasis and leishmaniasis
treated with, 932t, 935
Paroxetine, 540t, 542t, 549t. See also
Selective serotonin reuptake
inhibitors (SSRIs)
dosing of, 546t
poisoning with, treating, 1042
Partial agonists, 5–6, 6f, 24–25, 25f
Partial pressure, 442–444
Partial seizures, 413–421
Passive immunization, 1175, 1179,
1180t–1181t, 1181
Pasteurization, 898t
Patent, drug, 17
Patent ductus arteriosus, 335
Patient-controlled analgesia (PCA), 564
Pay to delay, 18
Pazopanib, 966t, 969
PB1046, 313
PCSK9 mutations, 631
PD149163, 317t. See also Neurotensin
agonists
PDE-5 inhibitors, for erectile dysfunction,
200b
Pediatric pharmacology, 1050–1054
absorption of drugs, 1050, 1052, 1052t
distribution of drugs, 1052–1053
dosage and dosage calculations in,
1056–1057, 1057t
dosage forms and compliance in, 1054
excretion of drugs, 1053–1054
metabolism of drugs, 1053
neonate pharmacodynamics in, 1054
placental and fetal drug metabolism in,
1048
Pediculicides, OTC, 1126t
Pefloxacin, 838
Pegademase, 984
Pegatinib, 995, 1065
Pegfilgrastim, 602–603, 606t
Pegloticase, 663
Pegvisomant, 672, 683t
Pegylated interferon. See also Interferons
preparations available, 893t–894t
with ribavirin, 80t, 85
Pelvic ganglia, 91
Pembrolizumab, 975, 992
Pemetrexed, 957–958, 958t
Penbutolol, 162, 164t, 166, 170t, 183.
See also b-receptor antagonist drugs
Penciclovir
herpes simplex virus treated with, 865t,
866f, 867
topical dermatologic, 1074
varicella zoster virus treated with, 865t,
866f, 867
Pendred syndrome (PDS), 687
Penicillamine (D-dimethylcysteine)
chelation uses of, 1030f, 1032
Wilson’s disease treated with, 507
Penicillin(s), 795–801, 812t, 1053
adverse reactions to, 801
chemistry and structure of, 795, 796f
classification of, 795–797, 796f
antistaphylococcal penicillins, 796,
796f
extended-spectrum penicillins, 796,
796f
penicillins, 795–797, 796f
units and formulation of, 797, 813t
clinical uses of
benzathine penicillin, 799
extended-spectrum penicillins, 801
fundamentals of, 800
penicillin G, 798
penicillin V, 800
procaine penicillin G, 799
staphylococcal beta lactamase–resistant
penicillins, 800–801
dosing and administration of, 799, 800t
mechanism of action of, 797, 797f–799f
pharmacokinetics of, 798–799
preparations available, 813t
resistance to, 797–798

Penicillin-binding protein (PBP), 797, 797f
Penicillin G, 798
Penicillin V, 800. See also Penicillin(s)
Pen injectors, portable insulin, 756
Pennyroyal, 1133t
Pentaerythritol tetranitrate, 202t
Pentamidine, 931, 932t, 933
Pentasa, 1107
Pentazocine, 555t, 569
Pentobarbital, 383f, 393t. See also
Barbiturates
Pentostatin, 989
Pentoxifylline
on blood viscosity, 353
peripheral artery disease and intermittent
claudication treated with, 209
P450 enzymes, 59–63
enzyme induction in, 59, 62t–63t
enzyme inhibition in, 59–61, 62t–63t
specific enzymes in, 59, 62t–63t, 64f
Peptic ulcer disease
H2-receptor antagonists for, 1090–1091
proton-pump inhibitors for, 1093–1094
Peptide YY (PYY), 315
Peptidyl dipeptidase, 303
Peracetic acid, 900–901
Perampanel, 411, 423–424, 433t, 437t
Percutaneous absorption, 1068, 1069df
Perfluorinated compounds (PFCs), 1016
Performance anxiety, 169
Pergolide. See also Dopamine receptor
agonists
description of, 294–295, 297t
Parkinson’s disease treated with, 498
Perhexiline, 210t
Perinatal pharmacology, 1047–1057. See
also Pregnancy, pharmacology in
Perindopril, 187
Peripheral artery disease (PAD), 209, 211t
Peripheral blood stem cells (PBSCs), 602
Peripheral nervous system (PNS), 89
Peripheral neuropathy, 1022
Peripheral synapses, 102t
Peripheral vascular disease, 161
Peripheral vascular resistance, 174
Peritoneal dialysis, 1039t, 1040
Permeation, 7–9, 8f, 8t
Permethrin, 1075
Permissible exposure limit values (PELs),
1007t
Pernicious anemia, 598. See also Vitamin
B12 deficiency
Peroxisome proliferator-activated receptor-
gamma (PPAR-g), 760
Peroxisome proliferator-activated receptor-
gamma (PPAR-g) ligands,
760–761
Peroxygen compounds, 900–901
Perphenazine, 513f, 514–515
Personalized medicine, 38, 74
Pertuzumab, 972, 992
Pesticides, 1010–1013
botanical, 1012–1013, 1013f
carbamate, 1012, 1012t
organochlorine, 1010t, 1010–1011, 1013f
organophosphorus, 1011t, 1011–1012
pFOX inhibitors, angina pectoris treated
with, 207
PGE1 analogs, 200b
PGI2 analogs, 324f, 335
P-glycoprotein transporter, 8
Pharmaceutical industry, 11
Pharmacodynamics. See also Receptor;
specific drugs
dose–effect in, 41, 42f
principles of, 5–7
agonists in, 5, 6f. See also Agonist
antagonists in, 5, 6f. See also
Antagonist
drug dose and clinical response in,
36–40
drug-receptor interaction types in, 5
duration of drug action in, 6–7
receptors and inert binding sites in, 7
of selected drugs, 43t–44t
of target concentration intervention, 52
Pharmacogenetics
definition of, 38
testing of, in drug therapy, 69
Pharmacogenomics, 74–87
definition of, 2, 74
enzyme genetic variations in, 75–82
future directions in, 86
glucose 6-phosphate dehydrogenase,
81–82, 82t
immune system function genetic
variations in, 83–85
drug-induced hypersensitivity
reactions, 83t, 83–85, 84f
IFNL3 (IL-28B), 77t, 80t, 85
phase I enzymes in, 75–78
phase II enzymes in, 81
polygenic effects in, CYP2C9 and
VKORC1, 77t, 80t, 85–86
terms in, 75t
transporter genetic variations in, 82–83
Pharmacokinetics, 41–48. See also specific
drugs
bioavailability in, 47f, 47t, 47–48
clearance in, 42–46. See also Clearance
(CL))
dose–concentration in, 41, 42f
drug accumulation in, 46f, 46–47
extraction ratio in
first-pass effect and, 48
formula for, 47
Index    1233
half-life in, 45f, 46, 46f
models of, 45f
multicompartment, 45f, 46
principles of, 7–10
Fick’s law of diffusion in, 8–9
Henderson-Hasselbalch equation in, 9
permeation in, 7–9, 8f, 8t
of selected drugs, 43t–44t
target concentration in, 43t–44t, 49–52
target concentration intervention in,
51–52
volume of distribution in, 42
Pharmacologic potency, 36, 36f
Pharmacologic profile, 12
Pharmacology
definition of, 1
history of, 2–3
major areas of study in, 1–2, 2f
medical, 1
principles of, 3–10. See also Principles,
pharmacology
Phase 1 clinical trials, 16
Phase 2 clinical trials, 16
Phase 3 clinical trials, 17
Phase 4 clinical trials, 17
Phase I enzyme pharmacogenomics, 75–78,
76t–77t, 79t–80t
CYP2C19, 76t, 78, 79t
CYP2D6, 75–78, 76t, 79t
dihydropyrimidine dehydrogenase, 76t,
78, 79t, 81
Phase I enzyme polymorphisms, 65–69,
66t–67t, 68f
Phase I reactions
description of, 57, 57f, 60t–61t
microsomal mixed function oxidase
system and, 58f, 58–59
Phase II enzyme pharmacogenomics, 76t,
79t, 81
thiopurine S-methyltransferase, 76t, 79t,
81
UGT1A1, 74, 76t, 79t, 81, 87
Phase II enzyme polymorphisms, in drug
metabolism, 69
Phase II reactions, 57, 57f, 63, 64f, 64t
Phenacemide, 419–420
Phenanthrenes, 567, 572t. See also Opioid
agonists
mild to moderate agonists, 568, 572t
mixed receptor analgesic actions, 569,
572t
Phencyclidine (PCP)
description of, 577t, 580
ionotropic receptors in, 585
Phenelzine, 539f, 540t, 546t, 550t.
See also Antidepressant agents;
Monoamine oxidase inhibitors
(MAOIs)
1234    Index
Phenindione, 614f
Phenobarbital, 393t. See also Barbiturates
in neonates, 1053t
seizures treated with, 424, 433t, 436t
structure of, 383f
teratogenicity of, 434
Phenol, 899
Phenolics, 899
Phenothiazines
antiemetic properties of, 1105–1106
derivatives of
chemical structure of, 513f, 514–515,
515t
psychosis treated with, 513f, 514–515,
515t
Phenoxybenzamine, 24, 157f, 159,
159t, 170t, 184, 291. See also
Adrenoceptor antagonist drugs
Phensuximide, 429f
Phentermine + topiramate, 289b, 290t
Phentolamine, 157f–158f, 159, 159t,
170t, 184. See also Adrenoceptor
antagonist drugs
Phenylbutazone, 644f. See also Nonsteroidal
anti-inflammatory drugs (NSAIDs)
Phenylephrine, 141t, 146f, 149, 154t.
See also Sympathomimetics
cardiovascular responses to, 146t
ganglion blockers on cardiovascular
response to, 145, 147f
structure of, 144f
Phenylethylamine, 144f. See also Catechol-
amines; Sympathomimetics
Phenylheptylamines. See also Opioid
agonists
mild to moderate, 568
strong, 567, 572t
Phenylpiperidines. See also Opioid agonists
mild to moderate, 568
strong, 568, 572t
Phenytoin
drug interactions of, 1169t–1170t
in neonates, 1053t
seizures treated with, 418f–419f,
418–419, 433t, 435t
Pheochromocytoma
alpha-receptor antagonists for, 160–161,
161f
case study of, 156, 172
Philanthotoxin, 370t
pH manipulation, urinary, 1040
Phocomelia, thalidomide-induced, 1049
Phosphate
abnormal serum hyperphosphatemia, 784
for bone, 790t
on bone homeostasis, 773, 773f
for hypercalcemia, 783
for hypophosphatemia, 784
Phosphate binders, for bone, 790t
3′-Phosphoadenosine 5′-phosphosulfate
(PAPS), 63, 64t
Phosphodiesterase inhibitors, 363t. See also
specific drugs
Phosphoinositides
description of, 32
as second messengers, 32–34, 34f
Phosphoinositide signaling pathway,
32–34, 34f
Phosphoramidon, 312
Phosphorylation, 32, 33f, 35
Physical dependence, 389, 575.
See Dependence, physical
Physical nature, of drugs, 3
Physician’s order sheet (POS), 1147
Physiologic antagonism, 25–26
Physiology, experimental, 2
Physostigmine, 122t
absorption of, 115
antimuscarinic intoxication reversal
using, 120
chemistry and pharmacokinetics of,
115–117
structure of, 115, 116f
Phytolacca americana, 1133t
Picrolimus, 1074–1075
Picrotoxin, 370t
Pigmentation agents, 1076
Pilocarpine, 109, 113, 122t
salivary secretion using, 119
structure of, 110f
Pimavanserin, 519
Pimozide
chemical structure of, 514f, 515
drug interactions of, 1170t
psychosis treated with, 515
tics treated with, 505, 508t
Pindolol, 164t, 166, 170t. See also
b-receptor antagonist drugs
hypertension treated with, 183
intrinsic efficacy of, 5
structure of, 163f
Pinworms. See also Antihelminthics
albendazole for, 938–940, 939t
mebendazole for, 942
pyrantel pamoate for, 945–946
Pioglitazone, 760, 768t
Pipecuronium, 477f. See also
Neuromuscular blocking drugs
Piperaquine, 919f, 920t, 922, 922t
Piperazine, 939t, 944
Pirbuterol, 351
Piroxicam, 644f, 645t, 648. See also
Nonsteroidal anti-inflammatory
drugs (NSAIDs)
Pitavastatin, 632–634, 639t
Pitolisant (BF2649), 279
Pituitary gland, 667, 668f
Pituitary hormones, anterior, 668–680,
682t–684t
classification of, 668f, 668–669
dopamine agonists, 679–680, 684t, 685t
fundamentals, 667
GnRH receptor antagonists, 678–679
gonadotropin-releasing hormone and
analogs, 676–678
actions of, 676
chemistry and pharmacokinetics of,
676
clinical pharmacology of, 677–678
pharmacodynamics of, 676–677
uses of, 676
gonadotropins, 673–676
chemistry and pharmacokinetics of,
673–674
clinical pharmacology of, 674–675,
675f
pharmacodynamics of, 674
preparations available, 685t
toxicity and contraindications to, 676
growth hormone, 670–672, 671t, 682t
growth hormone antagonists, 672–673
fundamentals of, 672
pegvisomant, 672
somatostatin analogs, 672f, 672–673
mecasermin, 672, 682t
preparations available, 685t
prolactin, 679
Pituitary hormones, for male contraception,
745
Pituitary hormones, posterior, 680–682,
684t
oxytocin, 680–681, 681f, 684t
oxytocin antagonist, 681
preparations available, 685t
structures of, 681f
vasopressin receptor agonists, 681–682,
684t, 685t
vasopressin receptor antagonists, 682,
684t, 685t
Pit viper antivenom, 1181t
Placebo response, 14
Placental drug metabolism, 1048. See also
Pregnancy, pharmacology in
Placental transporters, 1048
Plant systemics, 1011
Plasma fractions, 621–623, 622t, 624t
Plasma protein binding, 53, 53b
Plasmin, 611f
Plasminogen activator inhibitor (PAI), 611,
611f
Plasmodium life cycle, 917, 918f
Platelet-derived growth factor (PDGF), 27
Platelets, 329
Platinum analogs, 955t, 956–957

Plazomicin, 832
Plerixafor, 604, 606t
Plexus of Auerbach, 92
Plexus of Meissner, 92
Plicamycin, 788–789
Pneumococcal vaccines
pneumococcal conjugate, 1177t
pneumococcal polysaccharide, 1177t
Pneumocystis jiroveci, 925
Pneumocystosis, pentamidine for, 931, 933
Pneumonia, community-acquired, 795,
814
Podofilox, 1083
Podophyllum resin, 1083
Poisoned patient management, 1035–1046.
See also Toxicology; specific
poisons
epidemiology of, 1035
initial, 1037–1040
antidotes, specific, 1040, 1041t
decontamination, 1039–1040
ECG and imaging, 1038–1039, 1039f
elimination enhancement
dialysis, 1039t, 1040
forced diuresis, 1040
urinary pH manipulation, 1040
history and physical examination,
1037–1038
laboratory, 1038t, 1038–1039
toxicology screening tests, 1039,
1039t
mechanisms of death in, 1036–1037
toxicodynamics of, 1036
toxicokinetics of
clearance, 1035–1036
volume of distribution, 1035
toxic syndromes, 1040–1046
Poison ivy, 983
Poisons, 3, 1035. See also Toxicology
Poke root, 1133t
Poliovirus vaccine, inactivated (IPV), 1177t
Polybrominated biphenyl ethers (PBDEs),
1015
Polybrominated biphenyls (PBBs), 1015
Polycarbophil, 1098
Polychlorinated biphenyls (PCBs), 1006b,
1014–1016
Polychlorinated dibenzofurans (PCDFs),
1015
Polychlorinated dibenzo-p-dioxins
(PCDDs, dioxins), 1015
Polycystic kidney disease, autosomal
dominant, 268
Polyene macrolides, 853–854, 861t. See also
specific types
Polyethylene glycol-electrolyte solution, for
toxin elimination, 1040
Polyethylene glycol (PEG), balanced, 1099
Polygenic effects, CYP2C9 and VKORC1,
80t, 85–86
Polymerase inhibitors, 889
Polymer fume fever, 1016
Polymorphic ventricular tachycardia, 233f,
234b, 237f
Polymorphism, 75t
Polymyxin B sulfate, 1070–1071
Polymyxins, 896
Polypharmacy, 177b
Polyvinyl pyrrolidone (PVP), 899
Pomalidomide
immunosuppressive uses of, 988
multiple myeloma treated with, 971
Ponatinib, 967
Pontocaine, 460f
Poor metabolizer (PM), 67, 75t
Pork tapeworms
niclosamide for, 943
praziquantel for, 944–945
Portable pen injectors, insulin, 756
Portal hypertension, 1114
Posaconazole, 858t, 859, 861t
Positive allosteric modulators, 24
Positive chronotropic effect, 145
Positive dromotropic effect, 147
Positive inotropic effect, 147
Postantibiotic effect (PAE), 828, 910t,
910–911
Postantibiotic leukocyte enhancement
(PALE), 911
Postcoital contraceptives, 736t, 736–737
Posterior pituitary hormones, 680–682,
684t, 685t
Postmenopausal hormonal therapy, 725–726
Postoperative nausea and vomiting,
1104–1105, 1116t, 1117t
Postpartum hemorrhage, ergot alkaloids
for, 295
Postsynaptic regulation, autonomic, 103, 103f
Posttetanic facilitation, 481
Post-traumatic stress disorder (PTSD), 533,
536, 544
Postural baroreflex, 175, 175f
Potassium, arrhythmia treated with, 248,
251t
Potassium channels, 229
Potassium iodide, 695, 701t
+
Potassium ion (K )
on conductance, 231b
effects of, 231b
on electrochemical gradient, 231b
in membrane electrical activity,
229–230, 230f
Potassium perchlorate, 695
Potassium-sparing diuretics, 177, 265f,
265–267, 266t, 273t
combinations
Index    1235
with loop or thiazide diuretics, 269
with proximal tubule diuretics, 269
drug interactions of, 1170t–1171t
preparations available, 274t
Potassium wasting, from carbonic
anhydrase inhibitors, 261
Potency
definition of, 36
pharmacologic, 36, 36f
Povidone-iodine, 899
Practical efficacy, 36
Prader-Willi syndrome, 671
Pralatrexate, 958t, 958–959
Pralidoxime (PAM), 132, 135t
Pramipexole. See also Dopamine receptor
agonists
Parkinson’s disease treated with, 498, 508t
restless legs syndrome treated with, 507,
508t
Pramlintide, 764, 769t
Pramoxine, 1084
Pranlukast, 332
Prasugrel, 620
Pravastatin, 632–634, 639t
Praziquantel, 939t, 944–945
Prazosin, 159, 159t, 170t, 191t. See also
Adrenoceptor antagonist drugs
hypertension treated with, 179t, 184
structure of, 157f
Precision medicine, 38, 74
Preclinical safety and toxicity testing, 13, 13t
Precocious puberty, central, 678
Prednisolone, 709t. See also Corticosteroids
structure of, 706f
topical, 1079–1081, 1080t, 1081t
Prednisone, 709t. See also Corticosteroids
asthma treated with, 355, 362t
delayed-release, 658
topical, 1079–1081, 1080t, 1081t
Pregabalin
analgesic uses of, 560b
restless legs syndrome treated with, 507
seizures treated with, 420, 436t
Preganglionic parasympathetic fibers, 91
Pregnancy
hypothyroidism and, 697
lithium in, 527
multiple pregnancies in, 676
pharmacology in, 1047–1057
lactation pharmacology in, 1055t,
1055–1056
pharmacodynamics of, 1048–1050
pharmacokinetics of, 1047–1048
teratogens, 1049f, 1049–1050, 1051t,
1052t
toxic drug actions in fetus in, 1049
sedative-hypnotic drugs in, 383
thyrotoxicosis in, 700
1236    Index
Preload, 215f, 216
Premature depolarizations, 218
Premenstrual dysphoric disorder, 533
Prescribing, rational, 1148–1149
Prescribing authority, 1152t
Prescriptions, 1147f, 1148–1155
abbreviations in, 1149t
compliance in, 1150–1151
conversions for, 1148
elements of, 1147f, 1147–1148
e-prescribing in, 1150, 1151
errors in, 1148–1149
errors of omission in, 1149–1150
inappropriate drug prescriptions in,
1150
legal factors in, 1151–1154
controlled substances, 1153, 1153t
drug safety surveillance, 1153–1154
FDA, 1151
labeled and off-labeled uses, 1153
right to prescribe, 1151, 1152b
poor writing of, 1150
rational prescribing in, 1148–1149
security of, 1151
socioeconomic factors in
generic prescribing, 1154–1155
other cost factors, 1155
Preservatives, 901
Presynaptic regulation, autonomic, 100,
102t, 103
Prevertebral ganglia, 91
Prilocaine, 462, 471, 472t. See also
Anesthetics, local
Primaquine, 919f, 920t, 925–926
Primary amine, 9, 60t
Primary chemotherapy, 949
Primary generalized glucocorticoid
resistance, 710
Primidone
seizures treated with, 424–425, 425f,
433t, 436t
tremor treated with, 503
Principal cells, 258, 258f
Principles, pharmacology, 3–10
drug–body interactions in, 5–10
drug groups in, 10
nature of drugs in, 3–5
Prinzmetal angina, 194
Private pharmacy benefits manager, 1154
Probenecid, 660f, 661, 1171t
Procainamide, 237–239, 239t, 240t, 250t
Procaine, 460f, 461b, 472t
Procaine penicillin G, 799. See also
Penicillin(s)
Procarbazine, 955t, 956
Prochlorperazine, 1105–1106
Procyclidine, 501t, 508t
Prodrug, 7
Profile, pharmacologic, 12
Progabide, 487
Progesterone, 721f, 727–731
adverse effects of, 731
clinical uses of, 731
contraindications and cautions with, 731
diagnostic uses of, 731
pharmacokinetics of, 728
physiologic effects of, 729–731
Progesterone receptor synthesis, estrogens
in, 725
Progestin-only contraception, 736
Progestins, 727–731
adverse effects of, 731
clinical uses of, 731
contraindications and cautions with, 731
diagnostic uses of, 731
natural (progesterone), 721f, 727–728
pharmacokinetics of, 728
physiologic effects of, 729–731
synthetic, 728, 728t, 729, 729f,
730t–731t
Proguanil, 919f, 926
Proinsulin, 747
Proinsulin C, 748f
Projection neurons, 373, 373f
Prokinetic agents, 1096–1098, 1115t
cholinomimetic agents, 1097
macrolides, 1098
mechanism of action of, 1096–1097, 1097f
metoclopramide and domperidone,
1097–1098
preparations available, 1117t
Prolactin antagonist, 679. See Dopamine
agonists
Prolactin (PRL), 668, 668f, 669t, 679
Proliferation signal inhibitors, 986–987
Promethazine, 283t, 383, 1105–1106
Pro-opiomelanocortin, 703
Propafenone, 239t, 240t, 242–243, 251t
Propantheline, 126f
Prophylaxis, antimicrobial
nonsurgical, 914, 915t, 916
NRC wound classification criteria and,
914b
surgical, 913–914, 914t
Propiverine, 131. See also Muscarinic
receptor blockers
Propofol, for anesthesia, 450f, 450t,
450–452
Propoxyphene, 568. See also Opioid
agonists
Propranolol, 24, 164t, 165, 170t. See also
b-receptor antagonist drugs
angina pectoris treated with, 210t
arrhythmia treated with, 239t–240t,
243, 251t
case study on, 20, 40
hypertension treated with, 179t,
182–183, 191t
hyperthyroidism treated with, 696, 699,
700, 701t
migraine headache prophylaxis uses of,
168, 291
physiologic effects of, 38
structure of, 163f
tremor treated with, 503
Propylene glycol
as dermatologic vehicle, 1082
keratolytic actions of, 1082
Propylthiouracil (PTU)
description of, 693–695, 694f, 701t
thyrotoxicosis in pregnancy treated with,
700
Prorenin, 301
Prorenin receptors, 305
Prostacyclin (PGI2), 323
Prostaglandin(s)
effects of, 327–331
on kidney, 259
structures of, 333f
Prostaglandin analogs
gastric mucosa protection using, 1096
structures of, 333f
Prostaglandin endoperoxide synthase
products, 323, 324f
Prostaglandin F2α (PGF2α), 333f
Prostanoid biosynthesis, 323, 324f
Prostanoid mediators, from arachidonic
acid, 646f
Prostanoid receptors, 326–327, 327f, 328t
Prostate cancer
androgen suppression for, 743, 745t
chemotherapy for, 972
degarelix and abarelix for, 679
gonadotropin-releasing hormone agonists
for, 677–678
Prostatectomy, 124, 136
Protamine sulfate, 614
Protease inhibitors (PIs)
atazanavir, 871t, 879–880
darunavir, 871t, 880
fosamprenavir, 872t, 880
fundamentals of, 879
hepatitis C treated with, 889–891, 890f
human immunodeficiency virus treated
with, 879–882
indinavir, 872t, 880–881
lopinavir, 872t, 881
nelfinavir, 872t, 881
in pregnancy, 879t
ritonavir, 872t, 881
saquinavir, 872t, 881–882
simeprevir, 890–891
sofosbuvir, 889
tipranavir, 873t, 882
 Index    1237

131
Protein binding Pulmonary hypertension Radioactive iodine ( I, RAI), 695–696,
albumin concentration in, 53 case study of, 321, 338 701t
capacity-limited, 53 eicosanoids for, 335 Radiofrequency catheter ablation, 246b
factors in, 53 nitric oxide for, 344 Raloxifene
plasma, 53, 53b preparations available, 318t description of, 737f, 738
Protein C, 611 treatment of, 313b osteoporosis treated with, 780b, 787,
Protein S, 611 Purine analogs, 1109–1110, 1116t 790t
Protein tyrosine kinase, 27 Purine antagonists Raltegravir, 872t, 884
Prothrombin complex concentrates, 616 cladribine, 958t, 961 Ramelteon, 287b, 382, 384b, 394t. See also
Prothrombin deficiency, 622t fludarabine, 958t, 961 Melatonin receptor, agonists of
Prothrombin time (PT), 615 6-thiopurines, 958t, 960–961, 961f Ramipril, hypertension treated with, 187
Proton-pump inhibitors (PPIs), 1091–1095 Purines, in CNS, 380 Ramucirumab, 968, 993
adverse effects of, 1094–1095 “Purple glove syndrome,” 418 Randomization, 15b
chemistry and pharmacokinetics of, Pyrantel pamoate, 939t, 945–946 Randomized controlled trails (RCTs), 15b
1091–1093, 1092f, 1092t Pyrazinamide, 842, 843t, 846, 851t Ranibizumab, 995
clinical uses of, 1093–1094 Pyrethrum, 1012, 1013f Ranitidine, 1089–1091. See also
drug interactions of, 1095 Pyridostigmine, 122t H2-receptor antagonists
OTC, 1122t myasthenia gravis treated with, 119 RANK ligand (RANKL)
pharmacodynamics of, 1093 neuromuscular blockade reversal using, description of, 775
preparations available, 1117t 484 inhibitors of, for hyperparathyroidism,
Prototype drugs, 10 Pyrimethamine, 919f, 926 790t
Protriptyline, 546t Pyrimidine analog, 855f, 856, 861t Ranolazine
Proximal convoluted tubule (PCT), Pyrimidine synthesis inhibitors, 988–989 angina pectoris treated with, 207, 210t,
254–256, 255f Pyronaridine, 928 211t
Prucalopride, 1100 arrhythmia treated with, 247
Prussian blue, 1033 Q Rapamycin, 1058
Pseudocholinesterase, 69, 132. See Qinghaosu, 922–923 Rare disease treatment, 18
Butyrylcholinesterase (BCHE) Quantal dose–effect curves, 37, 37f Rasagiline, 500, 508t
Pseudoephedrine, 150 Quantity, of exposure, 1005 Rasburicase, 80t, 82
Pseudovitamin D deficiency rickets, 788 Quaternary amine, 9 Rate of administration, 51
Psilocybin Quaternary ammonium compounds, Rate of elimination, 45
description of, 577t 899–900 Rational drug design, 4
Gio protein-coupled receptor activation Quazepam, 393t. See also Benzodiazepines Rational prescribing, 1148–1149
by, 577t, 582–583 Quetiapine, 514f, 515, 520t, 529t Rattlesnake envenomation management,
Psoralens, 1076 “Quicksilver,” 1027 1045
Psoriasis Quinagolide, 679 Rattlesnake hyperimmune globulin, 991
acitretin for, 1078 Quinapril, 187 Raxibacumab, 995
alefacept for, 1079 Quinestrol, 723f. See also Estrogen(s) Reactive oxygen species (ROS), 63, 65
calcipotriene and calcitriol for, Quinidine Reactivity, drug, 3–4. See also specific drugs
1078–1079 arrhythmia treated with, 239t, 240, “Rebound rhinitis,” 1128
fumaric acid esters for, 1079 240t, 250t Reboxetine, 151
tazarotene for, 1078 drug interactions of, 1171t Receptor, 20–36. See also specific drugs and
TNF inhibitors for, 1079 malaria treated with, 923–924 receptors
ustekinumab for, 1079 Quinine, 919f, 920t, 923–924 in addiction, 576
Psychosis Quinolone antibiotics, 1171t–1172t as agonist and antagonist mediators,
drugs for, 511–524, 528t–529t Quinupristin-dalfopristin, 822, 20–21
nature of, 512 824t, 825t alterations in number or function of, 38
Psyllium, 1098 autonomic, 98–99, 99t
Pteroylglutamic acid, 606t. See also Folic acid R definition of, 3, 20
p-Tertiary amylphenol, 899 Rabbit syndrome, 506 drug concentration and response, 20,
PTSD, Posttraumatic stress disorder, 544 Rabeprazole, 1091–1095. See also Proton- 21–26
PU-14, 269 pump inhibitors (PPIs) drug concentration reaching, 38
Pulmonary disease, 72. See also specific Rabies drug development and, 35–36
disease immune globulin intravenous for, 1180t on drug dose and clinical response,
Pulmonary edema, acute, 563 vaccine for, 1177t 36–40. See also Dose, clinical
Pulmonary embolism Radiation, nausea and vomiting after, response and
heparin for, 608, 625 1104–1105, 1116t, 1117t in drug selectivity, 20
thrombolytics for, 619 Radical cure, 917 “gene-active,” 27
1238    Index

Receptor (Cont.): loop diuretics for, 263 idiosyncratic, 38

history of, 2 from potassium-sparing diuretics, 267 quantitative variations in, 38
inert binding sites in, 7 Renal potassium wasting, from carbonic variation in, 37–39
intracellular, for lipid-soluble agents, 27, anhydrase inhibitors, 261 Responsive neurostimulator, 411
27f Renal tubule transport mechanisms, Resting potential
macromolecular nature of, 21 254–259 on action potentials, 232–233, 233f
nomenclature for, 4–5 in collecting tubule system, 255f, of sodium channels, 233f
orphan, 21 257–259, 258f Restless legs syndrome, 506–507
response distal to, changes in compo- in distal convoluted tubule, 255f, 257, Rest tremor, 504
nents of, 38–39 257f Resynchronization, cardiac, 223
signaling mechanisms and drug action in loop of Henle, 255f, 256–257, 257f Retapamulin, 1070
in, 26–35 nephron segments and functions in, 256t Reteplase, 619
spare, and receptor-effector coupling, in proximal tubule, 254–256, 255f Retigabine, 411, 421, 433t, 437t
22f, 22–23 renal autacoids in, 259 Retinoic acid derivatives, 1077
types of, 21 Renin Retrograde signaling, 372
Receptor–drug interactions, 5 control of release of, 301–302, 302f Retrograde transmission, 90
Receptor-effector coupling, spare receptors description of, 300–301 Retroviral agents, 870–884
and, 22f, 22–23 Renin-angiotensin-aldosterone system drug-drug interactions of two-drug
Receptor ligand, endogenous, 38 in blood pressure regulation, 174 combinations of, 877t
Receptor recycling, opioid, 559 sites of action of drugs interfering with, entry inhibitors, 882–883
Receptor regulation, 32, 33f 187, 188f fundamentals of, 870
Receptor reserve, 22, 22f Renin-angiotensin system integrase strand transfer inhibitors,
Receptor tyrosine kinases inhibitors of, 304–305 883–884
description of, 27–28, 28f angiotensin-converting enzyme nonnucleoside reverse transcriptase
signaling function of, 27 inhibitors, 304–305 inhibitors, 876–879
Receptor uncoupling, opioid, 559 angiotensin receptor blockers, nucleoside and nucleotide reverse
Recombinant factor VIIa (rFVIIa), 616, 304–305 transcriptase inhibitors,
622t, 623, 624t prorenin receptors, 305 870–876, 871t–872t
Recombinant human insulin-like growth renin inhibitors, 302f, 305 in pregnancy, 879t
factor-binding protein-3 suppression of, hypertension treated protease inhibitors, 879–882
(rhIGFBP-3), 672 with, 300, 320 Reye’s syndrome, 1128
Red blood cells, 53 Renin inhibitors Rh0(D) immune globulin, 991
Red thrombi, 609 heart failure treated with, 220 Rheumatoid arthritis
Reductase inhibitors, 632. See HMG-CoA hypertension treated with, 192t description of, 649
reductase inhibitors preparations available, 318t treatment of, 642–659. See also
Reductions, 61t on renin-angiotensin system, 302f, 305 Analgesics; specific drugs
Red yeast rice, 634 on vasoactive peptides, 316t case study, 642, 666
Reentry, 234 Renshaw cells, 378 disease-modifying antirheumatic
Refractory period, 232–233, 233f Repaglinide, 759, 768t drugs, 649–659, 664t
Regadenoson, 206b Repinotan, 286 nonsteroidal anti-inflammatory drugs,
Regulation, drug, 10–18. See also Research. See also specific topics 643–649, 645t
Development and regulation, basic, 14b Rhinitis medicamentosa, 1128
drug translational, 12 Rho kinases (ROCK), 207
Regulation, flexible, 35 Reserpine, 285 rhPTH 1–84, 775, 790t
Regulatory proteins, as drug receptors, 21 Huntington’s disease treated with, 508t Rhythm, normal cardiac, 228–233
Relaxin, ovarian, 732 hypertension treated with, 179t, 182, Ribavirin
Relay neurons, 373, 373f 191t hepatitis C treated with, 891
Relcovaptan, 308, 317t. See also Vasopres- Resistance, antibiotic, 793 influenza A and B treated with, 893
sin receptor antagonists Reslizumab, 357, 363t, 994 Lassa fever and viral hemorrhagic fevers
Release inhibitors, histamine in, 281 Respiratory depressants, sedative-hypnotics, treated with, 893
Remifentanil, 555t, 567, 572t. See also 389 pegylated interferon with, 80t, 85
Opioid agonists Respiratory depression, opioid-induced, respiratory syncytial virus treated with,
Remodeling, cardiac, 216 561 893
“REM rebound,” 388 Respiratory syncytial virus (RSV), 1181t Rickets
Renal baroreceptor, on renin release, 301 Response axis, 36, 36f hereditary vitamin D–resistant, 788
Renal failure Response elements, 27 nutritional, 788
from ADH antagonists, 269 Response fluctuations, from levodopa, 497 pseudovitamin D deficiency, 788
diuretics for, 270–271 Responsiveness, drug Rifabutin, 843t, 849
 Index    1239

Rifampin Routes of exposure, 1005 nature of, 512

buspirone affected by, 385b Royal jelly, 1133t psychosocial and cognitive remediation
drug interactions of, 1172t Rubella, immune globulin for, 1181t for, 523
leprosy treated with, 851, 851t Rufinamide, 430, 433t, 436t serotonin hypothesis of, 512
tuberculosis treated with, 842, 843t, Rytary, 495 Sclerostin, 774f
845, 851t Scopolamine, 125, 130t, 135t, 284. See also
Rifapentine, 843t, 849 S Muscarinic receptor blockers
Right to prescribe, 1151, 1152b Sabal serrulata, 1141 action of, 127, 128f
Rilonacept, 657–658, 994 Sacubitril, 220, 222, 225t, 310 antiemetic properties of, 1106
Rilpivirine, 873, 878–879 S-adenosyl-l-methionine (SAMe), 63, 64t Scorpion antivenom, 991
Riluzole, 487 Safety testing, preclinical, 13, 13t Screening, drug, 12–13
Rimantadine, 892 Safinamide, 508t Sebelipase alfa, 631
Rimonabant Salbutamol, 154t, 351. See Albuterol Secobarbital, 383f, 393t. See also
cannabinoid dependence treated with, Salicylates, 645, 645t, 646f Barbiturates
588, 589t drug interactions of, 1172t Secondary amine, 9, 60t
obesity treated with, 289b in neonates, 1053t Second messengers, 32–34
Riociguat, 313b in OTC agents, 1129t cAMP, 32, 34, 34f
Risedronate poisoning management for, 1042–1043 cGMP, 34, 343f
on bone homeostasis, 779–781 Salicylic acid, 1082 diffusible, in central nervous system,
bone metastases treated with, 789t Salicylism, 1082 369f, 370
hypercalcemia treated with, 789t Saline diuresis, 782 phosphoinositides and calcium, 32–34, 34f
osteoporosis treated with, 780b, 786, 789t Salivary glands, 148 Secukinumab, 656, 994
Paget’s disease of bone treated with, 789 Salmeterol Sedation, 441b. See also Anesthetics, general
Risk, 1005 asthma treated with, 351, 362t conscious, 441b
Risk Evaluation and Mitigation Strategy structure of, 350f deep, 441b
(REMS), 1153 Salmon calcitonin, 778 Sedative-hypnotic drugs, 381–394, 394t
Risperidone, 514f, 515, 520t, 529t Salt restriction, dietary, 221–222 actions of, 381
Ritanserin, 292 Salts, nonabsorbable, 1098 adverse effects of, 392
Ritonavir, 872t, 881 Sampatrilat, 310, 317t buspirone, 288–289, 383, 385b, 394t
Rituximab, 993 Sanitization, 898t chemical classification of
chronic lymphocytic leukemia treated Saquinavir, 872t, 881–882 barbiturates, 382, 383f
with, 970 Saralasin, 38 benzodiazepines, 381, 382f
rheumatoid arthritis treated with, 652 Sarcomere, cardiac muscle, 213, 214f newer hypnotics, 382–383, 383f
2+
Rivaroxaban, 617 Sarcoplasmic endoplasmic reticulum Ca - clinical pharmacology of, 390t, 390–393
Rivastigmine, 1063 ATPase (SERCA) transporter, 213 anxiety states, 390–391
Rizatriptan, 291t, 296t Sarcoserine, 515 delirium tremens, 391
Rocuronium. See also Neuromuscular Sargramostim, 602, 602t, 606t dosages, 394t
blocking drugs Sarin, 116f, 122t. See also Organophos- other therapeutic uses, 391–392
properties of, 478t, 479t, 489t phate cholinesterase inhibitors sleep problems, 391
structure of, 477f Sassafras, 1133t withdrawal from physiologic
Roflumilast, 352, 361, 362t Saw palmetto (Serenoa repens, Sabal dependence, 393
Romidepsin, 1085 serrulata), 1141 dose-response curves for, 381, 382f
Romiplostim, 602t, 604–605, 606t Saxagliptin, 763, 769t in elderly, 1061
Romosozumab, 775, 780b Scavenger receptors, 626 hypnotic actions, 381
Ropinirole. See also Dopamine receptor Schild equation, 24 lethal dose of, 392
agonists Schistosoma haematobium, 943 overdose of, 392
Parkinson’s disease treated with, 499, 508t Schistosoma mansoni, 943–944 pharmacodynamics of, 386–389
restless legs syndrome treated with, 507, Schistosomiasis, 944 benzodiazepine binding site ligands in,
508t Schizoaffective disorders 387–388
Ropivacaine, 460t, 461b, 462, 471, 472t. antipsychotics for, 519 chloride channel GABA receptor
See also Anesthetics, local lithium for, 526 complex versatility in, 386, 387f,
Rosiglitazone, 760, 768t Schizonticides, 917–918, 918f 388b
Rosuvastatin, 83, 632–634, 639t Schizophrenia. See also Antipsychotic agents GABAA receptor molecular pharma-
Rotavirus vaccine, 1177t antipsychotics for, 518 cology in, 386, 387f
Rotenone, 1012, 1013f case study of, 511, 531 GABA receptor heterogeneity and
Rotigotine, 499. See also Dopamine dopamine hypothesis of, 512–513 pharmacologic selectivity in, 387b
receptor agonists glutamate hypothesis of, 513 neuropharmacology in, 386–387
Routes of administration, 47t, 48 lithium for, 526 organ level effects in, 388–389
1240    Index
Sedative-hypnotic drugs (Cont.):
pharmacokinetics of, 383–386
absorption and distribution, 383
biodisposition in, factors in, 386
biotransformation in
barbiturates, 386
benzodiazepines, 384f, 384–385,
385t
newer hypnotics, 385t, 386
excretion in, 386
poisoning management for, 1041t, 1045
in pregnancy, 383
preparations available, 394t
ramelteon, 382, 384b, 394t
sedative actions of, 381
tasimelteon, 382
tolerance and dependence on, 389–390
toxicology of
direct toxic actions, 392
drug interactions in, 393
drug response alterations in, 392–393
Sedative-hypnotics, 388
Sedatives, 381
Seizures, 409. See also Epilepsy (Seizures);
specific seizure
antipsychotics as cause of, 522
atonic, 430
case study on, 409, 439
classification of, 409, 410t
drugs for, 309–439
Selective estrogen receptor modulators
(SERMs), 724, 737, 737f
for bone, 790t
osteoporosis treated with, 780b, 786, 790t
preparations available, 790t
Selective serotonin reuptake inhibitors
(SSRIs), 546t, 549t. See also
Antidepressant agents
adverse effects in, 546–547
discontinuation syndrome associated
with, 547
dosing of, 546t
drug interactions in, 548, 548t, 1172t
pharmacodynamics of, 541–543, 542t
pharmacokinetics of, 539–540, 540t
preparations available, 551t
teratogenicity of, 547
Selectivity, drug
in beneficial vs. toxic effects, 39–40
definition of, 39
in structurally identical receptors, 27f, 35
Selegiline
depression treated with, 540t, 541, 546t,
550t
parkinsonism treated with, 498f, 499,
508t
structure of, 495f
Selepressin, 308
Selexipag, 313b
Self-monitoring of blood glucose, 753
Semustine, 953f
Senna, 1099
Sensitivity, target organ, on target
concentration, 52
Sensitization, opioid, 554
Sepsis, 343
Septic shock, 343t, 343–344
Sequential scheduling, in cancer
chemotherapy, 952
Serenoa repens, 1141
Serotonin (5-HT), 285–292
chemical structure of, 1102f
chemistry and pharmacokinetics of,
285f, 285–286
clinical pharmacology of, 288–289
in CNS, 374f, 376t, 379
in depression, 534, 535f
discovery of, 285
functions of, 92t
pharmacodynamics of, 286–288
in schizophrenia, 512
Serotonin (5-HT) receptor
in CNS, 379
description of, 286, 286t
Serotonin (5-HT) receptor agonists,
289–291, 296t, 394t
clinical pharmacology of, 288–289
migraine headaches and, 289–291, 290f,
291t
preparations available, 297t–298t
Serotonin 5-HT4 receptor agonists, 1100
Serotonin (5-HT) receptor antagonists,
291–292, 297t, 298t
Serotonin 5-HT3 receptor antagonists
antiemetic, 1103–1105, 1116t, 1117t
irritable bowel syndrome treated with,
1102, 1102f
Serotonin (5-HT) receptor modulators,
for depression, 550t. See also
Antidepressant agents
chemistry of, 538
clinical pharmacology of
adverse effects in, 547
drug interactions in, 548–549
pharmacodynamics of, 542t, 543
pharmacokinetics of, 540t, 541
preparations available, 551t
Serotonin-norepinephrine reuptake
inhibitors (SNRIs), 550t
chemistry of, 536
clinical pharmacology of
adverse effects in, 547
drug interactions in, 548
description of, 537
dosing of, 546t
pharmacodynamics of, 542, 542t
pharmacokinetics of, 540, 540t
preparations available, 551t
Serotonin syndrome, 288, 288b, 288t, 549,
1042
Serotonin transporter (SERT, SLC6A4)
description of, 95b
MDMA (ecstasy) on, 587
Sertaconazole, 1072
Sertindole, 515
Sertoli cells, 740
Sertraline, 540t, 542t, 546t, 549t. See also
Selective serotonin reuptake
inhibitors (SSRIs)
SERT transporter, 8t
Serum sickness drug reactions, 999–1000
Sevelamer, for hyperphosphatemia, 784
Sevoflurane, 441–449. See also Anesthetics,
inhaled
properties of, 443t
structure of, 443f
Sex (gender), in drug metabolism, 69
Shape, drug, 4
Shivering, opioids for, 563
Short-bowel syndrome, 1113
Sibutramine, 151, 289b
Sickle cell disease, hydroxyurea and, 592b
Sick sinus syndrome, 234b
Side effect, 39. See also Adverse drug event
(ADE)
Signaling mechanisms, drug action and,
26–35
cytokine receptors in, 28–29, 29f
G proteins and second messengers in,
30f, 30–32, 31f
G proteins in, 31t
interplay among, 34–35
intracellular receptors for lipid-soluble
agents in, 27, 27f
ligand- and voltage-gated channels in,
29f, 29–30
of ligand-regulated transmembrane
enzymes, 27–28, 28f
mechanisms of, transmembrane, 26, 26f
phosphorylation in, 35
receptor regulation in, 32, 33f
receptor tyrosine kinases in, 27–28, 28f
second messengers in
cAMP, 32, 34, 34f
cGMP, 34, 343f
phosphoinositides and calcium,
32–34, 34f
Sildenafil, 34, 200b
Silodosin, 160
Siltuximab, 994
Silver nitrate, 901
Silver sulfadiazine, 836, 901
Silybum marianum, 1138–1139
Simeprevir, 890–891
 Index    1241

Simvastatin, 632–634, 639t Sodium bicarbonate Somatic motor nerves, 90f

Sinecatechins, 1083 antacid actions of, 1089 Somatomedin C, 670
Single nucleotide polymorphism (SNP), aspirin overdose treated with, 1, 19 Somatostatin
69, 75t Sodium-calcium exchanger, 213, 230 description of, 669, 672f, 672–673, 747,
Single-twitch stimulation, 481 Sodium channel, 230 1101
Sinoatrial (SA) node, 127, 228, 229f antiarrhythmic state- and use-dependent variceal hemorrhage treated with,
Sinus rhythm, normal, 236f block of, 236, 238f 1114
Sirolimus, 986–987 in cardiac action potential, 231f, 231–232 Somatostatin analogs, 672f, 672–673
Sirtuins, 1058 resting potential of, 233f Somatotropin 668f, 668–669. See Growth
Sitagliptin, 762, 769t Sodium channel blockers hormone (GH)
Sitaxsentan, 312, 317t. See also Endothelin angina pectoris treated with, 207, 210t, Sonidegib, 1085
inhibitors 211t Sorafenib, 966t, 969
Size, of drugs, 3 arrhythmia treated with, 237–243, 239t, Sorbitol, 1098
Skeletal muscle 240t, 250t Sotalol
calcium channel blocker effects on, 205 class 1A arrhythmia treated with, 239t, 240t,
methylxanthines effect on, 353 disopyramide, 239t, 240t, 240–241, 243, 244–245, 251t
Skeletal muscle relaxants, 474–491. See also 250t properties of, 164t
specific types procainamide, 237–239, 239t, 240t, Sources of information, 18–19
neuromuscular blocking drugs, 250t Spareness, degree of, 22f, 23
474–475 quinidine, 239t, 240, 240t, 250t Spare receptors, 22, 22f
preparations available, 490t class 1B Spasmolytics, 485–487, 489t
spasmolytic drugs, 485–487, 489t lidocaine, 239t, 240t, 241f, 241–242, baclofen, 485–487, 486f, 489t
Skin, 1068. See Dermatologic pharmacology 250t botulinum toxin, 487
SLCO1B1 gene pharmacogenomics, 77t, mexiletine, 239t, 240t, 242, 250t dantrolene, 449, 486f, 487–488, 489t
80t, 82–83 class 1C diazepam, 485, 489t
Sleep aids, OTC, 1127t flecainide, 239t, 240t, 242, 251t gabapentin, 487
Sleep-enabling drugs, 390b moricizine, 243, 251t glycine, 487
Sleeping sickness, 931. See African propafenone, 239t, 240t, 242–243, idrocilamide, 487
trypanosomiasis 251t local muscle spasm treated with, 488
Sleep-wake cycle, melatonin receptors in, preparations available, 251t mechanisms of action of, 485, 486f
384b Sodium etidronate, for Paget’s disease of preparations available, 490t
Slow acetylator, 69 bone, 789 progabide, 487
SLV306, 316t Sodium ferric gluconate complex, for iron- riluzole, 487
Small interfering RNAs (SiRNAs), deficiency anemia, 595, 605t spasticity and, 485, 486f
therapeutic, 2 Sodium-glucose cotransporter 2 (SGLT2) tizanidine, 486f, 487
Smoking, 120, 583. See Nicotine description of, 256, 256f Spasticity, 485, 486f
Smoking cessation aids, OTC, 1127t inhibitors of, 261–262, 272t, 274t, Special carrier molecules, 8, 8f
Smooth muscle 763–764, 769t Spectazole, 1072
alcohol effects on, 398 Sodium hypochlorite, 899 Spectinomycin, 832–833, 833t
calcium channel blocker effects on, Sodium nitroprusside, 342 Spina bifida, 434
204 Sodium phosphate, 1098 Spinosad, 1075
contraction of, calcium channel blocking Sodium pump, 214f, 217, 230 Spiramycin, 928
drugs on, 196f, 197 Sodium removal, for chronic heart failure, Spironolactone, 191t, 224t, 717. See
methylxanthines effect on, 353 221–222 also Aldosterone antagonists;
prostaglandins effect on, 327 Sodium stibogluconate, 930f, 932t, 933 Diuretics
thromboxanes effect on, 327 Sodium sulfacetamide, 1071–1072 antiandrogen actions of, 745
SN-38, 964 Sodium thiosulfate, 199 diuresis uses of, 265f, 265–267, 273t
Snake bite treatment Sodium valproate, 426f, 426–427, 436t drug interactions of, 1170t–1171t
coral snake, 991, 1181t Sofosbuvir, 889 heart failure treated with, 220
rattlesnake, 991, 1045, 1181t Solanezumab, 1063 SR142948A, 314
SNAP-25, 95 Solid organ transplantation, 996 SRX251, 308, 317t. See also Vasopressin
Sniffing, 585 Solifenacin, 131, 135t. See also Muscarinic receptor antagonists
Social anxiety disorder, 544 receptor blockers SSR240612, 308
+
Sodium (Na ) Solvents, 1009–1010 St. Anthony’s fire, 292
dietary restriction of, 189 aromatic hydrocarbons, 1009–1010 St. John’s wort (Hypericum perforatum), 70,
in membrane electrical activity, halogenated aliphatic hydrocarbons, 1009 71t, 1139–1140
229–230, 230f Somatic division, of autonomic nervous Stable effort angina, 194, 211
in OTC agents, 1129t system, 89 Staccato, 435
1242    Index
Stage fright, b-receptor antagonists for, 169
Stalevo, 495, 500
Staphylococcal beta lactamase-resistant
penicillins, 800–801. See also
Penicillin(s)
Staphylococcus aureus, transpeptidation
reaction in, 798, 798f
State-dependent drug action, 236, 238f
Statins
description of, 632–634, 639t
OATP1B1 on metabolism of, 83
STATs (signal transducers and activators of
transcription), 29, 29f
Status epilepticus, 432–433
Stavudine, 873t, 875
Steam, 901
Stem cell transplantation, autologous,
603–604
Stereoisomerism, 4
Sterilants, 898t, 901
Sterilization, 898t
Sterilox, 900
Steroids, anabolic, 740–743, 745t. See also
Androgens and anabolic steroids
Steroid synthesis inhibitors, 743, 745t
Sterol absorption inhibitors, 637, 640t
Stevens-Johnson syndrome (SJS), 83, 83t
Stimulant laxatives, 1099
Stimulants, 144f, 150. See Amphetamines;
specific stimulant
Stiripentol, 431, 433t, 435
Stones (calculi)
calcium oxalate, 789
kidney
from carbonic anhydrase inhibitors,
261
from potassium-sparing diuretics, 267
Stool surfactant agents (Softeners), 1098
Strabismus, 118
Stratified medicine, 74
Streptococcus pneumoniae, 592b
Streptogramins, 822, 824t, 825t
Streptokinase, 611, 611f, 618–619
Streptomycin
description of, 827f, 829–830, 833t
tuberculosis treated with, 843t,
846–847, 851t
Stress-related gastritis, H2-receptor antago-
nists for, 1091
Stress-related mucosal bleeding, 1094
Strongyloidiasis
ivermectin for, 942
thiabendazole for, 946
Strontium, for bone, 790t
Strontium ranelate, 780b
on bone homeostasis, 782
osteoporosis treated with, 787
Structural proteins, as drug receptors, 21
Structure-activity relationship, 35
Strychnine, 370t
Stuart-Prower defect, 622t
Subarachnoid hemorrhage, 205
Submucous plexus, 91f, 92
Substance P
antagonists of, 317t, 318t
description of, 92t, 313–314
Substituted benzamides, 1106
Substrate stabilization, 59
Succimer (dimercaptosuccinic acid,
DMSA), 1030f, 1030–1031
arsenic poisoning treated with, 1027
lead poisoning treated with, 1024
mercury poisoning treated with, 1029
Succinylcholine, 488t
chemistry and structure of, 476, 476f
clinical pharmacology of
neuromuscular transmission assess-
ment in, 480–481
skeletal muscle paralysis in, 480
malignant hyperthermia from, 449, 483
mechanism of action of, 478f–479f,
479t, 480
pharmacokinetics of, 477–478, 478t
properties of, 478t, 479t, 488t
Sucralfate, 1095
Sufentanil, 555t, 567, 572t. See also Opioid
agonists
Sugammadex, 484
Sugars, nonabsorbable, 1098
Suicide inhibitors, 61
Sulbactam, 806f, 806–807
Sulconazole, 1072
Sulfacetamide, 836
Sulfadiazine, 835
Sulfadoxine, 835, 919f, 926
Sulfadoxine-pyrimethamine, 920t
Sulfamethoxazole, 835
Sulfasalazine
description of, 652–653, 835
inflammatory bowel disease treated with,
1107, 1107f, 1116t
Sulfate solution, 1098
Sulfinpyrazone, 660f, 661
Sulfonamides, 834–836, 840t
adverse reactions of, 836
chemistry of, 835f
clinical uses of, 835–836
mechanism of action and antimicrobial
activity of, 835f
pharmacokinetics of, 835
preparations available, 840t
resistance to, 835
trimethoprim and trimethoprim-
sulfamethoxazole mixtures of,
836–837, 840t
Sulfones, 850
Sulfonylurea receptor binding agents
d-phenylalanine derivatives, 759, 768t
meglitinide analogs, 759, 768t
sulfonylureas, 757–759, 758t, 768t
Sulfonylureas, 757–759, 768t
efficacy and safety of, 758
first-generation, 758, 768t
mechanism of action of, 757, 758t
second-generation, 758–759, 768t
Sulfotransferases (SULTs), 63, 64f, 64t
Sulfur, 1075
Sulfur dioxide, 1007, 1007t
Sulindac, 645t, 648–649
Sulpiride, 515
Sulthiame, 432
Sumatriptan, 289–291, 290f, 291t, 296t
Sunitinib, 966t, 969
Sun protection factor (SPF), 1076
Sunscreens, 1076–1077
Superoxidized water, 900
Supplements, dietary, 3, 1141–1144
coenzyme Q10, 1141–1142
definition of, 1132
glucosamine, 1142–1143
historical and regulatory facts on, 1132
melatonin, 1143–1144
regulation of, 1132
Suramin, 934
Surface area, in dosage calculations,
1056–1057, 1057t
Surgery, nausea and vomiting after,
1104–1105, 1116t, 1117t
Surgical anesthesia, 446
Susceptibility, organism, 906
Susceptibility testing, 906
Suspensions, 1054
Suvorexant, 390b, 391, 394t
Sweat glands, apocrine, 148
Sympathetic nervous system, 90f, 90–91
estrogens on, 725
functions of, 137
on renin release, 301
Sympathetic sacral outflow, 93
Sympathomimetics, 137–155, 154t, 191t
adrenoreceptors in, 138–142
alpha, 138f, 139, 139t
beta, 139t, 139–140, 140f
dopamine, 139t, 140
polymorphisms of, 142
potencies of, 138
regulation of, 141
selectivity and affinities of,
141, 141t
structure of, 138, 138f
asthma treated with, 349–352, 350f,
362t. See also specific drugs
beta2-selective, 351
preparations available, 363t

structures of, 350f
toxicities of, 351–352
chemistry of, medicinal, 142–155
clinical uses of, 151–153, 154t
additional, 153
anaphylaxis, 152–153
cardiovascular
cardiac, 152
hypotension, acute, 151
hypotension, chronic orthostatic,
152
shock, 151
vasoconstriction, local, 152
CNS, 153
genitourinary, 153
heart failure, 226t
ophthalmic, 153
pulmonary, 152
definition of, 137
direct-acting, 137–138, 141t, 144f, 146f,
149, 149f. See also specific types
endogenous catecholamines, 146f, 146t,
148–149
indirect-acting, 137–138, 150–151
amphetamine-like, 97f, 144f, 150
catecholamine reuptake inhibitors,
143f, 151
mixed, noradrenergic transmitter
release by, 95
mixed-acting sympathomimetics,
144f, 150
noradrenergic transmitter release by, 95
mixed-acting, 144f, 150
molecular pharmacology of, 138–142
norepinephrine transporter in, 142, 143f
organ system effects of
cardiovascular, 101t, 102f, 144–147,
146t
beta-receptor activation in, 145,
146f, 146t, 147
dopamine-receptor activation in, 147
α1-receptor activation in, 144–145,
146f, 146t, 147f
α2-receptor activation in, 145
noncardiac, 145t, 147–148
in OTC agents, 1129t
preparations available, 155t
specific drugs in, 148–151
structure in, 142–144, 143f
substitution on alpha carbon in,
143–144, 144f
substitution on amino group in, 143
substitution on benzene ring in,
142–143, 144f
substitution on beta carbon in, 144
types of, 154t
Sympathoplegics, 176, 176f, 178–182
adrenergic neuron-blocking agents, 191t
guanethidine, 181–182, 191t
reserpine, 179t, 182, 191t
adrenoceptor antagonist drugs,
156–172
α-adrenoceptor blockers, 184
b-adrenoceptor blockers, 179t, 182–183.
See also b-receptor antagonist
drugs
esmolol, 183
labetalol, carvedilol, and nebivolol,
183, 192t
metoprolol and atenolol, 179t, 183
nadolol, carteolol, betaxolol,
bisoprolol, 183
pindolol, acebutolol, and penbutolol,
183
propranolol, 179t, 182–183
centrally acting, 179t, 179–180, 191t
clonidine, 179t, 179–181
guanabenz and guanfacine, 180
methyldopa, 179t, 180
preparations of, 193t
ganglion-blocking agents, 181
prazosin, 179t
prazosin and, 184
Synapses
autonomic, 93
central nervous system, 370–371, 371f
peripheral, 102t
Synaptic potential, 370–371, 371f
Synaptic transmitters, 29–30. See also
Neurotransmitters
Synaptobrevin, 94
Synaptosomal nerve-associated proteins
(SNAPs), 90, 94f
Synaptotagmin, 95
Syndrome of inappropriate ADH secretion
(SIADH), 268
Synechia, 130
Synergism, in antimicrobial drug, 912–913
Synergistic killing, 828
Synergy studies, antimicrobial, 906
Synonymous SNPs, 75t
Syntaxin, 95
Synucleinopathy, 493
Systolic heart failure. See also Heart failure
description of, 212
diastolic heart failure versus, 222t
Systolic hypertension, 174
T Tavaborole, 1072
T3, 687, 690–692, 701t. See also Thyroid
drugs
biosynthesis of, 688, 688f
effects of, 691, 693f
in hypothalamic-pituitary-thyroid axis,
689, 691f
mechanism of action of, 690–691, 693f
Index    1243
peripheral metabolism of, 688, 689f
pharmacokinetics of, 689t, 690
T4, 687, 689t, 690–692, 701t. See also
Thyroid drugs
biosynthesis of, 688, 688f
contraceptives on, female hormonal, 733
effects of, 691, 693f
in hypothalamic-pituitary-thyroid axis,
689, 691f
mechanism of action of, 690–691, 693f
peripheral metabolism of, 688, 689f
pharmacokinetics of, 689t, 690
Tachykinins, 313, 377t. See also specific types
Tachyphylaxis, 38
Tacrine, 120, 1063
Tacrolimus (FK 506), 986, 1074–1075
Tadalafil, 200b
Taenia saginata
niclosamide for, 943
praziquantel for, 945
Taenia solium
niclosamide for, 943
praziquantel for, 945
Tamoxifen
breast cancer treated with, 971
description of, 35, 737f, 737–738
Tamsulosin, 157f, 159t, 159–160, 170t.
See also Adrenoceptor antagonist
drugs
Tangier disease, 631
Tapentadol, 570, 572t, 573t
Tapeworms
niclosamide for, 943
praziquantel for, 944–945
Tar compounds, dermatologic, 1082
Tardive akathisia, 506
Tardive dyskinesia, 506, 522
Tardive dystonia, 506
Target, drug, 10–11. See also specific drugs
Target concentration, 49, 51–52
drug examples of, 43t–44t
pharmacodynamic variables in, 52
pharmacokinetic variables in, 51–52
rational dosage regimen based on, 49–51
loading dose in, 50–51, 51f
maintenance dose in, 50, 50b, 51f
strategy in, 52b
TAS-102, 959–960
Tasimelteon, 287b, 382, 384b, 394t
Tau protein, 1062
Taxanes and other anti-microtubule drugs,
962t, 963–964
cabazitaxel, 963
docetaxel, 962t, 963
eribulin, 963–964
ixabepilone, 963
paclitaxel, 962t, 963
1244    Index

Tazarotene androgen suppression, 743, 744f, 745t
acne treated with, 1077 antiandrogens, 743–745, 745t
psoriasis treated with, 1078 contraception in men, chemical
Tazobactam, 806f, 806–807 cyproterenone acetate, 745
Tbo-filgrastim, 606t fundamentals of, 745
TCDD, 1013f, 1015 gossypol, 745
Tedizolid, 823 preparations available, 745t
Teduglutide, 1113 Testis, 740
Tegafur, 78, 79t Testosterone, 740–743
Tegaserod, 291 adverse effects of, 742–743
chemical structure of, 1102f clinical uses of, 741t, 741–742
laxative action of, 1100 contraindications and cautions with, 743
Teicoplanin, 809, 812t mechanism of action of, 741
Telavancin, 803t, 809, 812t metabolism of, 740
Telbivudine, 887 pharmacologic effects of, 741
Telcagepant, 315, 318t. See also Calcitonin physiologic effects of, 741
gene-related peptide preparations of, 741, 741t, 745t
Telithromycin, 820–821, 824t synthesis of, 704f, 722f, 740
Telmisartan synthetic steroids with androgenic and
hypertension treated with, 189 anabolic action, 741, 741t
on vasoactive peptides, 316t in women, 732
Temazepam, 385t, 393t. See also Testosterone cypionate, 740–743, 741t
Benzodiazepines Testosterone enanthate, 740–743, 741t
Temozolomide, 955t, 975 Tetanic stimulation, 479f, 481
Tendon xanthomas, 630 Tetanus immune globulin, 1181t
Tenecteplase, 619 Tetanus vaccines
Tenofovir tetanus, diphtheria, pertussis (Tdap),
description of, 873t, 875–876 1178t
hepatitis B treated with, 887 tetanus-diphtheria (Td, DT), 1177t
Tenoxicam, 649 Tetrabenazine, 505, 508t
Teratogens, 1051t. See also Pregnancy, Tetracaine, 460f, 461b, 472t
pharmacology in Tetrachlorodibenzodioxin (TCDD), 1013f,
definition of, 1050 1015
FDA risk categories for, 1052t Tetracyclic agents, 549t
Terazosin, 159, 159t, 170t, 184, 191t. chemistry of, 538–539, 539f
See also Adrenoceptor antagonist clinical pharmacology of
drugs adverse effects in, 547
Terbinafine drug interactions in, 548t, 549
dermatologic pharmacodynamics of, 542t, 543
oral, 1074 pharmacokinetics of, 540t, 541
topical, 1072 preparations available, 551t
description of, 861, 861t Tetracyclines, 815–818, 824t
Terbutaline adverse reactions to, 818
asthma treated with, 351, 362t antimicrobial activity of, 816, 816f
structure of, 149f, 350f case study of, 815, 825
Terfenadine, 284 clinical uses of, 817–818
Teriflunomide, 988–989 dosing of, 818
Teriparatide, 775, 780b, 787, 790t mechanism of action of, 816, 816f
Terlipressin, 308. See also Vasopressin pharmacokinetics of, 817
receptor agonists preparations available, 825t
variceal hemorrhage treated with, 1114 resistance to, 816–817
on vasoactive peptides, 317t structure and chemistry of, 815–816
Tertiary amine, 9, 60t Tetraethylammonium (TEA), 133–134,
Testicular cancer, 974 134f. See also Ganglion blockers
9
Testicular hormones, 740–745, 745t. Δ -Tetrahydrocannabinol (THC)
See also specific hormones for analgesia, on ion channels, 560b
androgens and anabolic steroids, Gio protein-coupled receptor activation
740–743, 741t, 745t by, 577t, 582, 583f
mechanism of action of, 380
rimonabant for dependence on, 588, 589t
Tetraiodothyronine (thyroxine, T4), 687.
See T4
Tetrathiomolybdate, 507
Tetrodotoxin, 370t, 464
Tezosentan, 220
Thalidomide, 15
erythema nodosum leprosum treated
with, 850
immunomodulatory derivatives of, 988
immunosuppressive uses of, 987–988
multiple myeloma treated with, 971
phocomelia caused by, 1049
T helper lymphocytes (TH1, TH2), 980
Theobromine
asthma treated with, 352–353
structure of, 352f
Theophylline. See also Methylxanthine
drugs
asthma treated with, 352f, 352–353,
362t
drug interactions of, 1172t
in neonates, 1053t
poisoning with, 1041t, 1045
structure of, 352f
Therapeutic index, 37
Therapeutic window, 37
Thiabendazole, 939t, 946
Thiamine
acute ethanol withdrawal treated with,
406t
alcohol withdrawal syndrome treated
with, 403
Wernicke-Korsakoff syndrome prophy-
laxis using, 403
Thiazide diuretics, 177, 224t, 264f,
264–265, 273t. See also Diuretics
on bone homeostasis, 781
chronic heart failure treated with, 221
heart failure treated with, 221
idiopathic hypercalciuria treated with,
788
with loop diuretics, 269
with potassium-sparing diuretics, 269
preparations available, 274t
Thiazolidinediones, 760–761, 768t
Thick ascending limb, 257, 257f
Thienopyridines, 620
Thiethylperazine, 1105–1106
Thimerosal, 901
Thioamides, 693–695, 694f, 701t
Thiocyanate, 199
6-Thioguanine (6-TG), 81, 958t, 960–961
Thiols, 340–341
Thiopental, 450f, 450t
Thiophosphate insecticides, 117
6-Thiopurines, 958t, 960–961, 961f

Thiopurine S-methyltransferase (TPMT)
characteristics of, 78t
genetic polymorphisms in, 67t, 69
pharmacogenomics of, 77t, 79t, 81
Thioridazine. See also Antipsychotic agents
description of, 511–524, 513f, 528t
psychosis treated with, 513f, 514–515,
520t. See also Antipsychotic
agents
Thiotepa, 953, 953f, 955t. See also
Alkylating agents
Thiothixene, 511–524, 513f, 515, 515t,
528t. See also Antipsychotic
agents
Thioxanthenes, 511–524, 513f, 528t. See
also Antipsychotic agents
derivatives of, 513f, 515, 515t
structure of, 513f
Thorn apple, 124. See also Atropine;
Muscarinic receptor blockers
Threshold limit values (TLVs), 1004
Thrombin, 609–610, 611f
Thrombin inhibitors
direct, 617–618
indirect, 612f, 612–614. See also Heparin
Thrombocytopenia, 592
Thrombolytics, 619, 619b
Thrombophlebitis, ascending, 619
Thrombopoietin (TPO), 604, 997t
Thrombosis, 342, 343f
Thromboxane A2 (TXA2), 259, 324, 329,
608, 619
Thromboxanes, 327–331
Thymidylate synthase (TS), 958
Thyroid drugs, 689–692, 701t. See also
Antithyroid drugs; specific drug
basic pharmacology of, 689–692
clinical pharmacology of, 696–698
hypothyroidism, 694t, 696t, 696–698
myxedema coma, 697
preparations available, 701t
Thyroid gland
abnormal stimulators of, 689
autoregulation of, 688f, 689
function of
on drug metabolism, 72
evaluation of, 688–689, 690t
iodide metabolism in, 687
Thyroid hormones, 689–692
biosynthesis of, 687–688, 688f
chemistry of, 689f, 689–690
effects of, 691, 692t
mechanism of action of, 690–691, 693f
metabolism of, peripheral, 688, 689f
pharmacokinetics of, 689t, 690, 692t
preparations of, 691–692
transport of, 688
Thyroid neoplasms, 700
Thyroid–pituitary relationships, 690, 691f
Thyroid-simulating hormone (TSH,
thyrotropin), 668f, 668–669,
670t
Thyroid storm, 699
Thyrotoxicosis
amiodarone-induced, 700
manifestations of, 691, 694t
in pregnancy, 700
Thyrotropin-releasing hormone (TRH),
669, 669t
Thyroxine, 687. See T4
Tiagabine, 420–421, 433t, 437t
Ticagrelor, 620
Ticlopidine, 620
Tics, 493, 505–506, 508t
Tigecycline, 817–818, 824t
Tiludronate
on bone homeostasis, 779–781
Paget’s disease of bone treated with, 789
Time course
of drug accumulation, 46f, 46–47
of drug effect, 48–49
cumulative, 49
delayed, 49
immediate, 48–49, 49f
of drug elimination, 46f
Time-dependent killing, 910
Timing of samples, for drug concentration
measurement, 53–54
Timolol, 163f, 164t, 166, 170t. See also
b-receptor antagonist drugs
Tinidazole
amebiasis treated with, 929t, 929–930,
930f
description of, 896, 902t
Tinzaparin, 612. See also Heparin
Tiotropium, 126f, 135t. See also Muscarinic
receptor blockers (antagonists)
chronic obstructive pulmonary disease
treated with, 130, 354, 359
structure of, 126f
Tipranavir, 873t, 882
Tiprolisant, 285
Tirofiban, 621
Tissue factor pathway inhibitor, 610
Tissue factor-VIIa complex, 610–611, 611f
Tissue plasminogen activator (t-PA), 611,
611f, 619
Tissue schizonticides, 917, 918f
Tizanidine. See also Sympathomimetics,
direct-acting
description of, 149, 153, 154t
spasmolytic actions of, 486f, 487, 489t
T-lymphocyte-associated antigen 4
(CTLA-4), 980
T lymphocytes, 979, 979f, 980, 981f
Tobramycin, 826, 827f, 831, 833, 833t
Index    1245
Tocilizumab, 653, 995
Tofacitinib, 656–657, 987
Tolazamide, 758, 768t. See also
Sulfonylureas
Tolbutamide, 758, 768t. See also
Sulfonylureas
Tolcapone, 500, 508t
Tolerance, 38, 576–578
alcohol (ethanol), 400
inducer, 71
nitrates and nitrites, 200–201
opioid, 559, 561t, 564–565
sedative-hypnotic drugs, 389–390
Tolmetin, 644f, 645t, 649. See also
Nonsteroidal anti-inflammatory
drugs (NSAIDs)
Tolnaftate, 1073
Tolterodine, 131, 135t. See also Muscarinic
receptor blockers
Toluene, 1010
Tolvaptan, 308, 317t, 682, 684t
diuresis uses of, 268–269, 273t
heart failure treated with, 224
Tonic-clonic seizures, generalized,
413–421. See also Antiseizure
drugs; Seizures
Topiramate
migraine headache prophylaxis using, 291
seizures treated with, 427–428, 433t, 436t
tremor treated with, 503
Topiramate + phentermine, 289b, 290t
Topotecan, 962t, 964
Torcetrapib, 638
Toremifene, 737, 737f
Torsade de pointes, 233f, 234b, 237f
Torsemide, 262t, 262–264, 273t
Total systemic clearance, 45
Tourette’s syndrome
antipsychotics for, 519
description of, 505–506, 508t
Toxaphenes, 1010t, 1010–1011, 1013f
Toxic dose, median (TD50), 37
Toxic effects, selectivity and, 39–40
Toxic epidermal necrosis (TEN), 83, 83t
Toxicity, 3, 13, 13t. See also specific drugs
Toxic multinodular goiter, 699
Toxicodynamics, 1035
Toxicokinetics, 1035
Toxicology, 1003–1019
air pollutants, 1006–1009
carbon monoxide, 1006–1007, 1007t
nitrogen oxides, 1007t, 1008
ozone and other oxides, 1007t,
1008–1009
permissible exposure limit values of,
1007t
sources of, 1006
sulfur dioxide, 1007, 1007t
1246    Index
Toxicology (Cont.):
bioaccumulation and biomagnification
in, 1006b
definition of, 1
ecotoxicology, 1005
environmental, 1004–1005
environmental pollutants, 1014–1017
asbestos, 1016–1017
coplanar biphenyls, 1015
endocrine disruptors, 1016
perfluorinated compounds (PFCs),
1016
polybrominated biphenyl ethers
(PBDEs), 1015
polybrominated biphenyls (PBBs),
1015
polychlorinated biphenyls (PCBs),
1014–1016
polychlorinated dibenzofurans
(PCDFs), 1015
polychlorinated dibenzo-p-dioxins
(PCDDs, dioxins), 1015
heavy metals, 901, 1020–1029. See also
Heavy metals
chelators for, 1029–1033, 1033t.
See also Chelators
herbicides, 1013–1014
bipyridyl (paraquat), 1013f, 1014
chlorophenoxy (2,4-D), 1013f,
1013–1014
glyphosate, 1013f, 1014
metals
beryllium, 1017
cadmium, 1017
nanomaterials, 1017–1018
occupational, 1004
pesticides, 1010–1013
botanical, 1012–1013, 1013f
carbamate, 1012, 1012t
organochlorine, 1010t, 1010–1011,
1013f
organophosphorus, 1011t, 1011–1012
poisoned patient management in,
1035–1046. See also Poisoned
patient management
solvents, 1009–1010
aromatic hydrocarbons, 1009–1010
halogenated aliphatic hydrocarbons,
1009
terminology of, 1005
Toxicology screening tests, 1039, 1039t
Toxic products, drug metabolism to,
64–65, 65f
Toxic syndromes, 1040–1046
acetaminophen, 65f, 1040, 1041t
amphetamines and other stimulants,
1041–1042
anticholinergic agents, 1041t, 1042
antidepressants, 1041t, 1042
antipsychotics, 1042
aspirin (Salicylate), 1042–1043
beta blockers, 1041t, 1043
calcium channel blockers, 1041t, 1043
carbon monoxide and other toxic gases,
1041t, 1043, 1044t
cholinesterase inhibitors, 1041t,
1043–1044
cyanide and hydrogen cyanide, 1041t,
1044, 1044t
digoxin, 1041t, 1044–1045
ethanol and sedative-hypnotic drugs,
1041t, 1045
ethylene glycol, 1041t, 1045
iron and other metals, 1045
methanol, 1041t, 1045
opioids, 1041t, 1045
rattlesnake envenomation, 1045
theophylline, 1041t, 1045
Toxic uninodular goiter, 699
Toxins, 3
Trademark, 17
Train-of-four (TOF) stimulation, 479f, 481
Tramadol, 569–570, 572t, 573t, 659
Trametinib, 975
Trandolapril, 187
Tranexamic acid, 623
Transcranial magnetic stimulation (TMS),
588
Transferases, 63, 64f, 64t. See also specific
types
Transforming growth factor-b (TGF-b),
27–28
Transient neurologic symptoms (TNS),
469
Translational research, 12
Transmembrane enzymes, ligand-regulated,
27–28, 28f
Transporter genetic variations, 82–83
Transporters
MDR1, 8, 8t
MRP1, 8t
multidrug resistance-associated protein,
8, 8t
SERT, 8t
types of, 8t
VMAT, 8t
Transport proteins, as drug receptors, 21
Tranylcypromine, for depression, 539f,
541, 546t, 549t
Trapping, drug, 9, 11f
Trastuzumab, 35, 971, 993
Trauma surgery, emergency, 474, 491
Travelers
immunization for, 1182
malaria prevention for, 920t
Travoprost, 337
Trazodone, 160, 538, 540t, 542t, 546t,
547, 549t. See also 5-HT
receptor modulators
Trematodes, 944–945. See also
Anthelmintic drugs
Tremor, 492, 503–504
beta-receptor antagonists for, 169
definition of, 492
essential, 503
intention, 504
from lithium, 527
rest, 504
Treprostinil, 324f, 335
Treprostinil sodium, 333f
Triamcinolone (acetonide), 709t. See also
Corticosteroids, synthetic
asthma treated with, 355
structure of, 706f
Triamterene
diuresis using, 262–267, 273t
drug interactions of, 1170t–1171t
Triazolam, 382f, 384, 385t, 389, 393t.
See also Benzodiazepines
Trichlorfon, 939t, 943
2,4,5-Trichlorophenoxyacetic acid
(2,4,5-T), 1013f, 1013–1014
Trichogenic and antitrichogenic agents
bimatoprost, 1085
eflornithine, 1085
finasteride, 1085
minoxidil, 1084–1085
Trichomoniasis, 929. See Amebiasis drugs
Trichostrongylus orientalis, 945–946
Trichuriasis. See also Anthelmintic drugs
albendazole for, 938–940, 939t
mebendazole for, 942
Tricyclic antidepressants (TCAs), 549t.
See also Antidepressant agents
chemistry of, 537, 538f
clinical pharmacology of
adverse effects in, 547
drug interactions in, 548, 1159t
intoxication with, 119
pharmacodynamics of, 542t, 542–543
pharmacokinetics of, 540t, 541
poisoning with, 1041t, 1042
preparations available, 551t
Trientine hydrochloride, 507
Triethylenemelamine, 953f
Trifluridine, 865t, 866f, 867
Trihexyphenidyl, 501t, 508t
Triiodothyronine (T3), 687, 690–692. See T3
Trilostane, 716
Trimetazidine, 207, 210t
Trimethadione, 429–430
Trimethaphan, 145
Trimethobenzamide, 1106
Trimethoprim, 836–837, 840t

Trimethoprim-sulfamethoxazole, 835–837,
840t
Trimipramine maleate, 546t
Triorthocresyl phosphate (TOCP), 121,
1011
Trioxsalen, 1076
Triptans, 289–291, 290f, 291t, 296t, 298t
Triptorelin, 676
1,4,5-Trisphosphate-diacylglycerol cascade,
215
Troglitazone, 761
Trophotropic nervous system, 100
Tropicamide, 126f, 130t, 135t. See also
Muscarinic receptor blockers
Tropisetron, antiemetic properties of, 1104
Trospium, 131, 135t. See also Muscarinic
receptor blockers
TRPA1, 560b
TRPV1, 560b
Trypanosomiasis drugs, 931–935,
932t–933t. See also Antiprotozoal
drugs
t-SNAREs, 95
Tuberculin hypersensitivity, 983
Tuberculosis
drug-susceptible, 844t
with HIV, antimycobacterial drugs for,
842, 852
Tuberculosis drugs, 842–849, 851t
ethambutol, 842, 843t, 845–846, 851t
isoniazid, 842–845, 843t, 851t
preparations available, 852t
pyrazinamide, 842, 843t, 846, 851t
rifampin, 842, 843t, 845, 851t
second-line, 846–849
aminosalicylic acid, 843t, 848
bedaquiline, 843t, 849
capreomycin, 843t, 847
cycloserine, 843t, 847
ethionamide, 843t, 847
fluoroquinolones, 848
kanamycin and amikacin, 843t, 848
linezolid, 848–849
rifabutin, 843t, 849
rifapentine, 843t, 849
streptomycin, 843t, 846–847, 851t
types and dosing of, 843t
Tuberoinfundibular system, 516
Tubocurarine, 475, 489t. See also
Neuromuscular blocking drugs
properties of, 478t
structure of, 476f
Tumor necrosis factor-α (TNF-α), 997t,
998
Tumor necrosis factor-α blockers, 653–656
adalimumab, 652–654, 654f
adverse effects of, 655–656
certolizumab, 654f, 654–655
etanercept, 654f, 655
golimumab, 654f, 655
infliximab, 654f, 655
for psoriasis, 1079
structures of, 654f
Tumor stem cells, 948
Tumor suppressor genes, in cancer, 949
Turner syndrome, growth hormone for,
671
Type I hypersensitivity, 982, 983f,
998–1000
Type II hypersensitivity, 982–983
Type III hypersensitivity, 983, 999–1000
Type IV hypersensitivity, 983, 984f
Typhoid vaccines
Ty21a, oral, 1178t
VI capsular polysaccharide, 1178t
Tyramine, 97f, 150, 150t
biosynthesis of, 97f
noradrenergic transmitter release by, 95
Tyrosine, 341, 341t
Tyrosine hydroxylase inhibitors, 171t
Tyrosine kinase inhibitors (TKIs), 966t,
967
Tyrosine kinase receptor, 27–28, 28f
U Urodilatin, 309
UGT1A1 pharmacogenomics, 74, 76t, 79t,
81, 87
Ularitide. See also Natriuretic peptides
heart failure treated with, 220
on kidney, 259
on vasoactive peptides, 317t
Ultrarapid metabolism, 67
Ultrarapid metabolizer (UM),
67, 75t
Umeclidinium, 130, 354
Unfractionated heparin (UFH), 612f,
612–614. See also Heparin
Unicyclic agents, for depression, 549t.
See also Antidepressant agents
chemistry of, 538–539, 539f
clinical pharmacology of
adverse effects in, 547
drug interactions in, 548t, 549
pharmacodynamics of, 542t, 543
pharmacokinetics of, 540t, 541
preparations available, 551t
Unipolar depression, antipsychotics for,
519. See also Antipsychotic
agents
Unithiol, 1031–1032
for arsenic poisoning
acute, 1026
chronic, 1027
for mercury poisoning
acute, 1029
chronic, 1029
Index    1247
Unstable angina, 195, 208–209
Urantide, 316
Urapidil, 160
Urea, 1082–1083
Urea transporter UT1, 259
Ureidopenicillins, 801. See also Penicillin(s)
Uric acid metabolism, 265
Uricosuric agents, 660f, 661
Uridine 5-diphosphate (UDP)-glucuronosyl
transferases (UGTs), 63, 64f, 64t,
67t, 69
Uridine 5′-diphosphoglucuronosyl transfer-
ase 1 (UGT1A1), 74, 76t, 79t,
81, 87
Urinary antiseptics, 902t
methenamine hippurate, 897, 902t
methenamine mandelate, 897, 902t
nitrofurantoin, 895–896, 902t
Urinary frequency, after prostatectomy,
124, 136
Urinary obstruction, alpha-receptor
antagonists for, 161
Urinary pH manipulation, for poisoning,
1040
Urinary retention, 118
Urinary tract infection, 834, 841
Urofollitropin, 674, 683t
Urokinase, 611, 618
Urotensin, 316
Urotensin antagonists, 318t
Ursodiol, 1113, 1116t
Urticaria, 278, 284
Use-dependent drug action, 236, 238f
Ustekinumab, 656, 995, 1079
Uterine leiomyomata (fibroids), 677
V
Vaccines, 1175–1182, 1176t–1179t.
See also Immunization; specific
types
routine childhood, recommended
schedule for, 1175, 1179t
Vaccinia immune globulin, 1181t
Vagus nerve
on cardiovascular function, 100
on immune function, 89
Vagus nerve stimulation (VNS), for
epilepsy, 411
Valacyclovir
herpes simplex virus treated with, 865t,
866–867
topical dermatologic, 1074
varicella zoster virus treated with, 865t,
866–867
Valganciclovir, 868t, 868–869
Valomaciclovir, 839
Valproate, 529t. See Valproic acid
1248    Index
Valproic acid, 529t
bipolar disorder treated with, 528, 529t
migraine headache prophylaxis using,
291
myoclonic seizures treated with, 430
seizures treated with, 426f, 426–427,
430, 433t, 436t
Valsartan, 310
heart failure treated with, 224t
hypertension treated with, 189
on renin-angiotensin system, 305
on vasoactive peptides, 316t
Vancomycin, 803t, 807–809, 812t
“Vaping,” 121
Vardenafil, 200b
Varenicline, 122t
nicotine abuse treated with,
584, 588t
smoking cessation using, 121
Variant, 75t
Variant angina, 194
ergot alkaloids for diagnosis of, 295
nitrate effects in, 201
Variceal hemorrhage drugs
beta-receptor blocking drugs, 1114
preparations available, 1117t
somatostatin and octreotide, 1114,
1116t
vasopressin and terlipressin, 1114
Varicella vaccine, 1178t
Varicella-zoster immune globulin,
1181t
Varicella-zoster virus (VZV) agents,
864–867
acyclovir, 865t, 866, 866f
docosanol, 865t, 867
famciclovir, 865t, 867
penciclovir, 865t, 866f, 867
trifluridine, 865t, 866f, 867
valacyclovir, 865t, 866–867
valomaciclovir, 867
varicella vaccine, 1178t
varicella-zoster immune globulin,
1181t
Vascular endothelial growth factor (VEGF),
968
Vascular smooth muscles, 198–199
Vascular tone, 195t, 195–196, 196f, 197f
Vasculitis (type III) drug reactions,
999–1000
Vasoactive intestinal peptide agonists,
317t
Vasoactive intestinal peptide (VIP), 92t,
312–313
Vasoactive peptides, 300–318, 317t
adrenomedullin, 315
angiotensin, 300–303
angiotensin II, 303–304
calcitonin gene-related peptide, Vasomera, 313
314–315 Vasopressin (antidiuretic hormone, ADH),
endothelins, 311–312 268, 308, 681–682, 684t
kinins, 306–307 blood pressure affected by, 175
natriuretic peptides, 308–309 diuresis using, 268
neuropeptide Y, 315–316 structures of, 681f
neurotensin, 314 variceal hemorrhage treated
preparations available, 318t with, 1114
substance P, 313–314 on vasoactive peptides, 317t
urotensin, 316 Vasopressin receptor, 308
vasoactive intestinal peptide, Vasopressin receptor agonists, 268, 308,
312–313 317t, 681–682, 684t
vasopressin, 308 preparations available, 685t
Vasodilators, angina pectoris treated with, on vasoactive peptides, 317t
194–210, 209t–210t. See also Vasopressin receptor antagonists
specific drug description of, 268, 273t, 308,
allopurinol, 207 682, 684t
beta blockers, 206–207, 210t preparations available, 318t,
calcium channel blockers, 202–206 685t
clinical pharmacology of Vasospastic angina, 194, 208
angina of effort, 208, 208f, 209t Vecuronium. See also Neuromuscular
nitrates alone vs. with beta or calcium blocking drugs
channel blockers, 208, 209t properties of, 478t, 489t
principles of, 207 structure of, 477f
unstable angina and acute coronary Vedolizumab, 995, 1112
syndromes, 208–209 Vehicles
vasospastic angina, 208 dermatologic, 1068–1086
with coronary artery disease and drug, 7
hyperlipidemia, 194, 211 Velpatasvir, 889
drug action in, 196–197 Vemurafenib, 975
fasudil, 207 Venlafaxine, 537, 540t, 542t, 549t.
ivabradine, 207 See also Serotonin-norepinephrine
newer drugs, 207t reuptake inhibitors (SNRIs)
nitrates and nitrites, 197–202, 202t, dosing of, 546t
210t poisoning with, 1042
nitro-vasodilators, other, 202 Venous thrombosis, 735
pFOX inhibitors, 207 Ventilation, alveolar, 443–444, 444f
preparations available, 211t Ventilation control, neuromuscular blockers
ranolazine, 207 for, 485
special, 206b Ventral tegmental area (VTA), in addiction,
Vasodilators, nitric oxide as, 342 576, 576f, 579b
Vasodilators, for heart failure, 220, 225t Ventricular fibrillation, 236f
acute, 224 Ventricular tachycardia
chronic, 222 ECG of, 236f
Vasodilators, hypertension treated with, polymorphic, in torsades de pointes with
178f, 179t, 184–187, long QT syndrome, 233f, 234b,
191t, 192t 237f
calcium channel blockers, 179t, Verapamil. See also Calcium channel
186–187, 193t blockers
diazoxide, 186, 192t angina pectoris treated with, 202–206,
direct, 176 203t, 210t. See also Calcium
fenoldopam, 186, 192t channel blockers, angina pectoris
hydralazine, 179t, 184–185 treated with
mechanisms and sites of action of, 184, arrhythmia treated with, 239t, 240t,
184t 245–246, 251t
minoxidil, 179t, 185 case study on, 20, 40
preparations available, 193t hypertension treated with, 179t, 187,
sodium nitroprusside, 185–186, 192t 191t

migraine headache prophylaxis using,
291
Vernakalant, 239t–240t, 247, 251t
Verubecestat, 1063
Very-low-density lipoproteins (VLDLs),
165, 626, 627, 628f
Vesamicol, 93
Vesicle-associated membrane proteins
(VAMPs), 93, 94f
Vesicle-associated transporter (VAT), 93,
94f
Vesicular acetylcholine transporter
(VAChT), 93
Vesicular glutamate transporter (VGLUT),
375
Vesicular monoamine transporter (VMAT),
95
Vesicular proteoglycan (VPG), 94
Vestibular disturbances, 274
Vigabatrin, 431, 433t, 437t
Vilanterol
asthma treated with, 351, 362t
chronic obstructive pulmonary disease
treated with, 152
Vilazodone, 540t, 541, 549
Vildagliptin, 763, 769t
Vinblastine
cancer treated with, 961–962, 962t
immunosuppressive uses of, 989
Vincristine
cancer treated with, 962t, 963
immunosuppressive uses of, 989
Vinorelbine, 962t, 963
Viruses, 863
cancer from, 948–949
replication of, 863, 864f
Vismodegib, 1085
Visual analog scale (VAS), 562
Vitamin B1, 403. See Thiamine
Vitamin B12 deficiency
description of, 594t, 596, 598
megaloblastic anemia from,
591, 607
Vitamin B12 therapy, for vitamin B12
deficiency, 596–598, 597f
chemistry of, 596
clinical pharmacology of, 594t, 598
cyanocobalamin, 596, 598, 606t
hydroxycobalamin, 596, 598, 606t
pharmacodynamics of,
596–598, 597f
pharmacokinetics of, 596
preparations available, 607t
Vitamin D
bone homeostasis and, 773, 774f,
775–777, 776f, 777t, 789t
chronic kidney disease treated with,
785–786
Index    1249
on gut, bone, and kidney, 778t drug interactions of, 616, 616t
hyperparathyroidism treated with, 784 mechanism of action of, 610t,
hypocalcemia treated with, 614–615, 615f
784 reversal of action of, 616
hypoparathyroidism treated with, 784 toxicity of, 615
intestinal osteodystrophy treated with, Water, superoxidized, 900
785 Weak acid
nutritional deficiency/insufficiency of, examples of, 10t
785 ionization of, 9–10
Vitamin D3 Wearing-off, 497
on bone homeostasis, 773, 776f Wernicke-Korsakoff syndrome,
vitamin D deficiency/insufficiency 400, 403
treated with, 785 West’s syndrome, 410, 431
Vitamin D2, for vitamin D deficiency/ White thrombi, 609
insufficiency, 785 Whole bowel irrigation, for iron toxicity,
Vitamin D preparations, 789t 596
chronic kidney disease treated with, Wilson’s disease, 507
785–786 Withdrawal, 576–578. See also specific
forms of, available, 790t substances
Vitamin K from alcohol, 403, 403f, 406t, 407t
bleeding disorders treated with, 614f, from opioids, 559
621 from sedative-hypnotics, 393
structure of, 621 Withdrawal syndrome, 559, 565, 575
Vitamin K1 Wolff-Chaikoff block, 689
structure of, 614f Wolff-Parkinson-White syndrome, 234
warfarin reversal using, 616 Wong-Baker scale, 562
Vitamin K epoxide reductase complex Worm infections, 938–947, 939t. See also
subunit 1 (VKORC1) Antihelminthics
alleles of, 77t Wuchereria bancrofti, 941
polygenic effects in, 79t, 85–86
VKORC1, 77t, 79t, 85–86 X
VMAT transporter, 8t Xanthine oxidase inhibitors, 83
Voglibose, 761, 768t Xanthines, 352f. See also Methylxanthine
Voltage-gated channels, 30, 369f, 369–370. drugs
See also specific types Xeljanz, 987
Volume of distribution (V), 42 Xenobiotics, 56
initial predictions of, 54 biotransformation of. See
revising individual estimates of, 54 Biotransformation, drug
on target concentration, 52 definition of, 3
Vomiting, 1103, 1104f X-linked agammaglobulinemia, 984
Vonicog alfa, 622 X-linked hypophosphatemia,
von Willebrand disease, 622t, 623 787–788
Voriconazole, 857f, 858t, Xylene, 1010
858–859, 861t
Vorinostat, dermatologic, 1085 Y
Vortioxetine, 540t, 542t, 547, 549, Yellow fever vaccine, 1178t
549t. See also 5-HT receptor Yervoy, 992
modulators YKP3089, 435
v-SNAREs, 94 Yohimbine, 160, 170t
W Z
Warfarin, 614–616 Zafirlukast, 332. See also Leukotriene
administration and dosage of, receptor antagonists
615–616 asthma treated with, 336,
chemistry and pharmacokinetics of, 356–357, 362t
614, 614f structure of, 356f
CYP2C9 and VKORC1 polymorphisms Zaleplon, 382, 383f, 385t, 389, 391, 394t.
on, 79t, 85–86 See also Hypnotics
1250    Index

Zanamivir, 891–892 Zinc acetate, 507 Zolmitriptan, 291t, 296t

Ziconotide, 560b, 573t Ziprasidone, 514f, 515, Zolpidem, 382, 383f, 385t, 391, 394t.
Zidovudine, 873t, 876 520t, 529t See also Hypnotics
Ziegler’s enzyme, 61t, 69 Ziv-aflibercept, 966t, 968 Zonisamide, 428, 428f, 433t, 436t
Zileuton, 332. See also Leukotriene receptor Zoledronate Zoster vaccine, 1178t
antagonists on bone homeostasis, 779–781 Zotepine, 515
asthma treated with, 336, bone metastases treated with, 789t
356–357, 362t hypercalcemia treated with, 782, 789t
structure of, 356f osteoporosis treated with, 786, 789t