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EDITION 4
James Olson, M.D., Ph.D.
aS Neer Oe
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Clinical Pharmacology Made Ridiculously Simple

James M. Olson, M.D., Ph.D.
MedMaster, Inc., Miami, FL @)

Clinical Pharmacology Made Ridiculously Simple aims

at providing general principles of pharmacology and is
not intended as a working guide to patient drug
administration. Please refer to the manufacturer’s
package insert for recommended drug dosage, undesir-
able effects, contraindications and drug interactions.
For Rose Olson
Copyright © 2015, 2014, 2011, 2006, 2003, 2001, 1997, 1994, 1992, 1991 by MedMaster, Inc.
All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a
retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying,
recording or otherwise, without written permission from the copyright owner.
ISBN 13: 978-1-935660-00-2
Made in the United States of America
Published by
MedMaster, Inc.
P.O. Box 640028
Miami, FL 33164
Special Thanks to:
The IIlustrators
Deb Haimes
Josh Worth
Nancy Ciliax
The Book Reviewers

Jang-Ho Cha, M.D., Ph.D.
Stephen Goldberg, M.D.
Joanne Finnorn, J.D.
The Chapter and Table Reviewers/Contributors

Rosemary Berardi, Pharm. D.
Anne Bournay, R.Ph.
Kevin Cassady, M.D.
Betty Chaffee, Pharm. D.
Tim Esser, M.D.
Marc Fischer, M.D.
Janet Gilsdorf, M.D.
Eric Hockstad, M.D. Contents
Roy Kulick, M.D.
Fred Lamb, M.D., Ph.D.
Lori Mangels, Ph.D.
Beverly Mitchell, M.D. Chapter 1 Principles of Pharmacology .........++0000000eeees 1
Charles Neal, M.D., Ph.D. Rational Therapeutics
Francis Pasely, M.D. Drug Administration
John Penney, M.D. ¢ Formulation
Anna Porcari, Pharm. D. ¢ Routes of Drug Administration
Rudy Roskos, M.D. ¢ Dosing Regimens
Anne Ruch, M.D. Pharmacokinetics
e Drug Absorption
Raymond Ruddon, M.D., Ph.D.
¢ Drug Distribution
Steve Silverman, M.D.
¢ Drug Metabolism
Helen Yun, Pharm. D., M.B.A. ¢ Drug Excretion
e Drug Clearance
Drug Actions
e Pharmacology at the Cellular Level
¢ Pharmacology at the Organism Level
¢ Pharmacology at the Population Level
Drug Interactions
Tolerance, Dependence and Withdrawal
The Patient Profile
Chapter 2 Peripheral Nervous System .........22000000200e 13

Sympathomimetics
e Direct Sympathomimetics
¢ Indirect & Mixed Agents
Adrenergic Blockers
¢ Central Anti-adrenergics
¢ Peripheral Presynaptic Anti-adrenergics
¢ Peripheral Postsynaptic Anti-adrenergics
Cholinomimetics
e Direct Cholinergic Agonists
¢ Cholinesterase Inhibitors
Cholinergic Antagonists
¢ Muscarinic Antagonists
¢ Ganglion Blockers
Neuromuscular Blockers Bacterial Cell Wall Inhibitors
e Neuromuscular Transmission and Blockade ¢ Penicillins (B-lactam drugs)
e Reversing Neuromuscular Blockade ¢ Cephalosporins
Local Anesthetics Intracellular Antibiotics
¢ Quinolones and DNA Inhibitors
Chapter 3 Central. N6rvOus SYSIOM 5 36 caa weeds
soles he we 34 e Sulfonamides and Antimetabolites
Neurotransmitters of the Brain ¢ Aminoglycosides
¢ Norepinephrine ¢ Protein Synthesis Inhibitors
¢ Dopamine The Enemies: Mycobacteria
e 5-Hydroxytryptamine (5-HT, Serotonin) The Enemies: Viruses
¢ Acetylcholine The Enemies: Fungi
¢ Gamma-amino butyric acid (GABA) The Enemies: Protozoans and Helminths
¢ Excitatory Amino Acids (EAA)
¢ The Opioids Chapter 8 Anticancer Drugs
¢ Other Neuropeptides
Principles of Cancer Chemotherapy
Antidepressants
¢ The cell cycle
Psychomotor Stimulants ¢ Resistance and Recurrence
Antipsychotic Drugs ¢ Toxicity of Anticancer Drugs
¢ Treatment of psychoses ¢ Combination therapy
¢ Undesirable Neurologic Effects Alkylating Agents
Antiemetics Antimetabolites
Anti-Parkinson Drugs Antibiotic Anticancer Agents
Central Analgesics Other Anticancer Agents
¢ The Opioid System
Hormonal and Other Immunomodulating Anticancer Agents
Anti-anxiety Agents
Hematopoietic Agents
Anticonvulsants
¢ Types of Seizures and Drugs of Choice
¢ Principles of Anticonvulsant Therapy Chapter 9 Anti-inflammatory and Immunomodulating Agents .- 136
General Anesthetics Prostaglandin Inhibitors
Antiarthritic Agents
Chapter 4 Cardiovascular and Hematology Drugs............. 59 Antigout Agents
Immunomodulating Agents
Heart Failure Drugs
¢ Acute Pumonary Edema Antihistamines
¢ Management of Shock
Antihypertensives Chapter10 Endocrine System
¢ Diuretics Anterior Pituitary Hormones
¢ Antiadrenergics Posterior Pituitary Hormones
¢ Vasodilators Other Hormones
Anti-anginal Agents Sex Hormones
Arrhythmias e Testosterone
Antiarrhythmic Agents e Anabolic Steroids
Lipid Lowering Agents e Estrogens
Anticoagulants, Antiplatelet agents and Thrombolytics e Progestins
¢ Oral Contraceptives
Chapter 5 ¢ Progestin Only “Minipills”
FIOSDIFALORY DIFUGS opi cia aya dev0 aan 'ySIME 87 ¢ Levonorgestrel Implants (Norplant®)
Obstructive Lung Disease Oxytocin and Other OB/Gyn Drugs
Treatment Options
Adrenal Hormones
¢ Glucocorticoids
Chapter 6 Gastrointestinal AgentS .........000ceceuunccaees 93 e Adrenocorticosteroid Hypersecretion
Antiulcer Drugs e Mineralocorticoids & Androgens
Antidiarrheals Thyroid Hormones
Drugs Used to Treat Constipation ¢ Hyperthyroidism (thyrotoxicosis)
¢ Hypothyroidism
Chapter 7 Pancreatic Hormones
ANU-INTECUVG AQCIIS: «is 2.0 scp tx. 0 tae gales beeps 99 e Diabetes Mellitus
Basic Strategies of Antimicrobial Therapy ¢ Insulin Replacement
The Enemies: Gram Positive Cocci ¢ Oral Hypoglycemic Drugs
The Enemies: Anaerobes
The Enemies: Gram-negative Pathogens
vi Vii
Preface
I developed the format of this book while teaching a review course in pharmacology to medical students who
were having difficulty with the standard course. The students stated that the concepts of pharmacology were
not difficult, but that they were overwhelmed by the quantity of material. They spent hours leafing through
pages, trying to identify subtle differences between drugs that have similar names, actions, pharmacokinetics
and side effects.
This guide organizes related drugs in tables. It allows the student to learn about a prototype drug and the
important ways that related drugs differ. The text that surrounds the tables emphasizes key issues pertaining to
therapeutic rationale, basic pharmacologic principles and clinical use of the drugs.
The book blends the essentials of basic pharmacology and clinical pharmacology so that the transition from
classroom to hospital is less abrupt. Students report that the book is most effective when lecture notes are written
directly on the tables and margins, providing a single, concise guide for finals and the National Boards. The
book can then be used during clinical training for a rapid review of the principles that guide rational prescribing
practices.
Clinical Pharmacology Made Ridiculously Simple contains the information required to perform well on the
National Boards and to answer most pharmacology questions asked during clinical rounds. It does not present
historical aspects of pharmacology, exhaustive lists of side effects and drug interactions, or other details that are
best found in traditional texts or formularies.
Digitized by the Internet Archive I welcome comments and suggestions for future editions.
In 2022 with funding from
Jim Olson, M.D., Ph.D.
Kahle/Austin Foundation Children’s Hospital/ University of Washington/Fred Hutchinson Cancer Center
1100 Fairview Ave N, Mailstop D4-110
Seattle, WA 98109
httos://archive.org/details/clinicaloharmacoO000olso_m3a2
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wastls Pitnii 4 Carel Sipe weer Rational Therapeutics Predict the actions, clinical uses, side effects, and
_ drug interactions of each drug based solely on its
_ _ There are thousands of drugs and hundreds of facts
mechanism of action. If you can predict these character-
7 — aa ae about each of them. It is unnecessary to memorize
many of these facts if one learns to predict the behavior
istics, you will only have to memorize those facts that
a0) cabana 8 aontelinags }Lame avenue dart fisole ital do not make intuitive sense.
of each drug based on a few facts and an understanding
= Rae ime naee | Finally, envision the course of events that would
of the principles of pharmacology.
aay. This chapter presents the basic principles of
occur as a drug enters the patient’s body. Continue
this practice each time you prescribe, dispense or
pharmacology upon which drug therapy is based.
administer drugs to a patient. Your patients will
As you read the chapter, try to apply the principles to
benefit if your clinical decisions are determined
a drug with which you are familiar, like aspirin. Refer
rationally and based on a foundation of basic
to this chapter often as you learn the drugs presented
pharmacology knowledge.
in the rest of the book. Try to learn the “story” of each
drug rather than isolated facts. The best way to
develop a story about a drug is to associate, ask,
and predict. Drug Administration
Associate each drug class with information that you e Formulation
already know about the drugs. Think of relatives or Clinically useful drugs are formulated by drug com-
ij friends who have taken medicine from the class of panies into preparations that can be administered
drugs you are studying. Remember what you have orally, intravenously, or by another route. The formula-
read or heard about the drugs. tion of a drug depends on the following factors:
Ask yourself why some drugs are administered as
shots and others as pills, why some drugs are taken ¢ The barriers that the drug is capable of passing.
four times daily and others only once, and why it is Intravenous drugs are injected directly into the blood
important for a health care provider to know the serum stream. In contrast, oral preparations must pass
concentration of some drugs but not of others. As you through the wall of the gastrointestinal tract and
read the following chapters, ask yourself “Why is blood vessel walls before entering the bloodstream.
this information important enough to be included e The setting in which the drug will be used. An
in this book?”. intravenous preparation might be appropriate for
a drug which is administered during surgery, but more accurate dose selection. Disadvantages include
would be inappropriate for home administration
of aspirin.
the need for strict asepsis, risk of infection, pain, and
local irritation.
Table 1.1 Influence of Dosing Regimen on Plasma Drug Levels
The urgency of the medical situation. The delay ¢ Intravenous (IV): Rapid onset of action because DOSING REGIMEN GRAPH OF PLASMA DRUG CONCENTRATION
before onset of action varies between preparations agent is injected directly into the blood stream. Single Dose
of the same drug. Emergency situations often call for Useful in emergencies and in patients that are
intravenous administration of agents which might unconscious. Insoluble drugs cannot be adminis- Plasma concentration of drug rises as the drug
normally be administered by another route. distributes to the bloodstream, then falls as the
tered intravenously. drug is distributed to tissues, metabolized,
¢ Stability of the drug. Drugs which are denatured ¢ Intramuscular (IM): Drug passes through capillary and excreted.
by acid are not good candidates for oral preparations walls to enter the blood stream. Rate of absorption
Drugs administered orally reach a peak plasma
because they may be destroyed in the stomach depends on formulation (oil-based preparations are concentration at a later time than drugs
(stomach pH = 2). absorbed slowly, aqueous preparations are absorbed administered intravenously. Oral agents must
First Pass Effect. Blood from the gastrointestinal rapidly). May be used for self-administration by be absorbed across Gl mucosa and capillary
tract passes through the liver before entering any trained patients. walls before entering the bloodstream.
Plasma
in
Concentration
Drug
c
other organs. During this first pass through the ¢ Subcutaneous (SubQ, SC): Drug is injected Le
liver, a fraction of the drug (in some cases nearly beneath the skin and permeates capillary wails
all) can be metabolized to an inactive or less to enter the blood stream. Absorption can be con- ontinuous Infusion (IV)
active derivative. The inactivation of some drugs trolled by drug formulation. Only nonirritating
is so great that the agents are useless when drugs can be used. Steady state (equilibrium) plasma drug @ 2X mg/hour
administered orally. concentration is reached after continuous
infusion for 4-5 half-lives.
¢ Dosing Regimens
Routes of Drug Administration Three common dosing regimens are compared in
Increasing the rate of infusion will not decrease
the time needed to reach steady state. © Xmg/hour
Routes of drug administration include: Table 1.1. The half-life is the amount of time required
Oral (PO): Most compatible with drugs that are for the plasma concentration of a drug to decrease by Increasing the rate of infusion will, however,
50% after discontinuance of the drug. The distribution increase the plasma drug concentration at
self-administered. Oral agents must be able to steady state.
withstand the acidic environment of the stomach half-life (t,,,«) reflects the rapid decline in plasma drug
Concentration
Drug
Plasma
in
and must permeate the gut lining before entering concentration as a dose of drug is distributed through-
15
the blood-stream. Absorption affected by gastric out the body. The elimination half-life (t,,,B) is often
emptying and intestinal motility. much slower, reflecting the metabolism and excretion
of the drug. Note that several half-lives pass before the Intermittent Dose
Sublingual: Good absorption through capillary bed
serum concentration of a drug reaches steady state. A drug must be administered for 4-5 half-lives
under tongue. Drugs are easily self-administered.
Thus in order to obtain values which reflect the steady before steady state (equilibrium) is reached.
Because the stomach is bypassed, acid-lability and
state, it is necessary to wait until the fourth or fifth half-
gut-permeability need not be considered. Peaks are the high points of fluctuation.
life of a drug before the peak, trough or plasma level is
Rectal (PR): Useful for unconscious or vomiting Toxic effects are most likely to be observed
measured. during peak drug concentrations.
patients or small children. Absorption is unreliable. Therapeutic levels of a drug can be obtained more
Inhalation: Generally rapid absorption. Some agents, rapidly by delivering a loading dose followed by Troughs are the low points of fluctuation.
marketed in devices which deliver metered doses, maintenance doses. A loading dose is an initial dose Lack of drug effect is most likely to occur
during troughs. For example, post-operative
are suitable for self-administration. of drug that is higher than subsequent doses for the pain is more likely to return just before a Plasma
in
Concentration
Drug
Topical: Useful for local delivery of agents, particu- purpose of achieving therapeutic drug concentrations second dose of morphine than midway
larly those which have toxic effects if administered in the serum rapidly. The loading dose is followed by between the first and second dose.
systemically. Used for most dermatologic, ophthal- maintenance doses, which are doses of drug that
mologic, nasal, vaginal, and otic preparations. maintain a steady state plasma concentration in the
therapeutic range. corresponds to the half-life of the drug (except when ¢ Drug-associated factors that influence absorption
¢ Transdermal: A few drugs can be formulated such
The dosing regimen (route, amount, and frequency) the drug binds irreversibly to its receptor) and is include ionization state, molecular weight, solubility
that a “patch” containing the drug is applied to the
of drug administration influences the onset and dependent on metabolism and excretion of the drug. (lipophilicity) and formulation (solution vs. tablet).
skin. The drug seeps out of the patch, through the
duration of drug action. Onset is the amount of time Small, nonionized, lipid-soluble drugs permeate
skin and into the capillary bed. Very convenient for
it takes a drug to begin working. Drugs administered plasma membranes most readily.
self-administration.
intravenously generally have a more rapid onset Pharmacokinetics
Patient-associated factors that influence drug
There are three drug administration techniques than drugs taken orally because oral agents must be e Drug Absorption absorption depend on the route of administration.
which have traditionally been labeled parenteral absorbed and pass through the gut before entering As a drug is distributed in the body, it comes in For example, the presence of food in the GI tract,
(“around the gastrointestinal tract”). Advantages the bloodstream. Duration is the length of time for contact with numerous membranes. Drugs pass some stomach acidity and blood flow to the GI tract
include more rapid and predictable absorption and which a drug is therapeutic. The duration usually membranes but not others. Table 1.2 compares four influence the absorption of oral medications.
drug transport mechanisms.
2 Principles of Pharmacology
Passive Diffusion Rapid for lipophilic, nonionic and small molecules.

Slow for hydrophilic, ionic, or large molecules.
Facilitated Diffusion Drugs bind to carrier by noncovalent mechanisms. Drug B displaces

Chemically similar drugs compete for carrier. 10% of Drug A
from albumin
Aqueous Channels Small hydrophilic drugs (<200 mw) diffuse along
concentration gradient by passing through aqueous
channels (pores).
Active Transport Identical to facilitated diffusion except that ATP

powers drug transport against concentration gradient.
e Drug Distribution The apparent volume of distribution (V,) is a Protein-bound

calculated value that describes the nature of drug ® @
The following factors influence drug distribution:
distribution. V, is the volume that would be required to Inactive)
Unbound Drug A Unbound Drug A
¢ Membrane permeability: In order to enter an contain the administered dose ifthat dose was evenly
(Active) ® (Active)
organ, a drug must permeate all membranes distributed at the concentration measured in plasma.
that separate the organ from the site of drug You could predict that a drug with V, = 3 liters is
administration. For example, benzodiazepines, distributed in plasma only (plasma volume = 3 liters), Figure 1.1 Consequence of drug displacement from albumin and other plasma proteins. Some drugs (e.g., “Drug A” in figure) are
which are very lipophilic, readily cross the gut whereas a drug with V, = 16 liters is likely distributed greater than 90% bound to plasma proteins. The “free” (unbound) drug molecules, but not the bound molecules, are available to act at receptors.
wall, capillary wall, and blood-brain barrier. In the figure, “Drug B” displaces only 5 molecules of “Drug A”, which more than triples the serum concentration offree (active) “Drug A”.
in extracellular water (extracellular water = 3 liters
This could be fatal if “Drug A” has a narrow margin of safety. Displacement of drugs which are less-highly protein bound is less significant.
Because of this, they distribute to the brain plasma plus 10-13 liters interstitial fluid). A drug with For example, if “Drug A” were 50% bound and 50% free, displacement of 10% of the bound fraction would increase the free fraction from 50%
rapidly and are useful for treating anxiety and V, > 46 liters is likely sequestered in a depot because to 55%. This small increment is unlikely to be clinically relevant.
convulsions. In contrast, some antibiotics are the body only contains 40-46 liters of fluid.
capable of passing from the gut into the blood
stream, but cannot pass into the brain. These increases the polarity of the drug. Drugs undergoing metabolized by P450. If a person hasn’t been
drugs cannot be used to treat infections in the
e Drug Metabolism Phase II conjugation reactions may have already drinking alcohol regularly, perhaps two drinks will
brain. Poor passage of some anticancer agents Drugs, chemicals, and toxins are all foreign to our undergone Phase I transformation. make him tipsy. If that same person were to consume
across the blood-brain barrier and the blood-testes bodies. Our body attempts to rid itself of foreign The liver microsomal drug oxidation/reduction two drinks daily for several weeks, it would likely
barrier results in relatively high rates of brain or chemicals, regardless of whether they are therapeutic system (The P450 system) is responsible for the take more than two drinks to achieve the same
testicular recurrences of some tumors. The blood- or harmful. Most drugs must be biotransformed, or metabolism of many drugs. Cytochrome P450 (so degree of intoxication. This occurs because the liver
placenta barrier prevents fetal exposure to some metabolized, before they can be excreted. In pharma- named because it maximally absorbs light at 450 nm) is enzymes have been induced, causing the alcohol to
drugs but allows passage of others. cology, the word “metabolism” often refers to the a family of isoenzymes located in the endoplasmic be metabolized more rapidly to an inactive form.
process of making a drug more polar and water solu- reticulum of the hepatocytes. Through an electron This same person would also metabolize any of a
Plasma protein binding (Fig. 1.1): The binding
ble. Although this often results in drug inactivation transport chain which uses NADPH as a proton carrier, multitude of drugs more rapidly once the enzymes
of drugs to plasma proteins, such as albumin,
and excretion, it is INCORRECT to assume that a a drug bound to cytochrome P450 can be oxidized or were induced, a common mechanism of drug
reduces the amount of “free” (that which is not
metabolite will be less active or more easily excreted reduced (Phase I Reaction). interaction. Therefore, a dose of such a drug that
protein bound) drug in the blood. “Free” drug was adequate a few months ago might have little or
than the parent drug. Cytochrome P450 can be induced (increased in
molecules, but not protein-bound molecules,
activity) by a number of drugs or chemicals. Induc- no effect following several weeks of increased
reach an equilibrium between the blood and tissues. alcohol consumption.
Metabolic reactions can transform... tion occurs in response to the presence of a chemical
Thus a decrease in free drug in the serum translates which is metabolized by P450 (more enzyme is
e an active drug into less-active or inactive forms.
to a decrease in drug which can enter a given organ. produced to handle the chemical load). Once the
e a PRODRUG (inactive or less-active drug) into a e Drug Excretion
¢ Depot storage: Lipophilic drugs, such as the seda- enzyme is induced, it will metabolize the “inducing
more active drug.
tive thiopental, accumulate in fat. These agents are agent” more rapidly. Because cytochrome P450 is not Some drugs are excreted from the body after they
released slowly from the fat stores. Thus, an obese Drug and toxin metabolism is divided into specific for the inducer, however, other drugs metab- have been metabolized to more polar congeners,
person might be sedated for a greater period of time “Phase I” and “Phase II” reactions (Figures 1.2A, 1.2B). olized by the induced enzyme will also be biotransformed while others are excreted “unchanged”. Most drugs,
than a lean person to whom the same dose of In Phase I Reactions (nonsynthetic), drugs are more rapidly. toxins, and metabolites are excreted in the urine.
thiopental had been administered. Calcium-binding oxidized or reduced to a more polar form. In Phase II Alcohol tolerance is a common example of Others are excreted in feces or expired air. Drugs that
drugs, such as the antibiotic tetracycline, accumulate Reactions (synthetic), a polar group, such as glu- P450 (microsomal enzyme) induction. Alcohol is are excreted in the feces may be concentrated in bile
in bone and teeth. tathione, is conjugated to the drug. This substantially
Phase | (nonsynthetic) Reactions Phase Il(Synthetic) Reactions
Catalyzed by specific enzymes rather than P4509
« Microsomal (P459) oxidation reactions
1. Hydroxylation 2. Dealkylation
con, MN
1. Glucuronide conjugation
O =e NADPH, 02
eee
microsomes
NADPH, O5
microsomes
¢ oH + UDPGA transferase
(drug) (donor)
glucurony}
C prOCeHeOe + UDP
3. Oxidation 4. Polarizing atom exchange 2. Ethereal sulfate conjugation

\NADPH,O, \ |
So__ —O a Ta OH + PAPS Sulfokinase € 080s + PAP
4 microsomes 7 microsomes (drug) (donor)
meee fi
- Microsomal (P459) reduction reactions 3. Acetylation
1. Azo-reduction
Acetyl i
R-K_)-N=CCHs + CoA
Opty SE Oem
R« NHz + CH3CO-CoA transferase
NADPH (drug) (donor)
microsomes
4. Transsulfuration (occurs In mitochondria)
2. Nitro-reduction CN + S,037 ——= CNS + SOs

NADPH NADPH NADPH
prNie glutamate glycine
microsomes microsomes microsomes
(removed) (removed)
5. Glutathione conjugation peas
glutathionase ) ) Acetylase
C pone + GSH— [X) —_—_—_—_—_—_—_———> a) CH S-SHp-- GHOOOH
- Nonmicrosomal oxidation and reduction reactions Acetyl-CoA
(drug) (donor)
1. Alcohol oxidation 2. Alcohol reduction
: | | Abbreviations of donors: UDPGA = uridine diphosphoglucuronic acid
PAPS = 3-phosphoadenosine 5' phosphosulfate
CH3CH2OH ne CH3CH20 aa + NADH + H* ——» Bab + NAD + H20
GSH = glutathione (g-glutamyl-cysteinyl-glycine)
OH H
Figure 1.2A Examples of Phase I metabolic reactions. Figure 1.2B Examples of Phase II metabolic reactions.
in the body retained the original concentration of OR

before entering the intestine. In some cases, these toxins are concentrated in the kidney, the organ is
drugs are reabsorbed into the portal bloodstream as frequently the site of chemical-induced toxicity. drug). “Clearance” is a calculated value that cannot Clearance = k-V,
they move through the intestines. This cycle, entero- | Undesirable symptoms in a patient with renal failure be directly measured in the body. It is measured in
hepatic circulation, can extend the duration of the may be due to drug accumulation rather than the liters per hour, but is often mistaken for “rate of Where k = elimination rate constant
elimination” which is reported as mg/hr. Clearance and V = apparent volume of distribution
drug in the body. disease process itself.
A number of processes occur in the kidney which values can be calculated for specific systems. For
affect the rate of drug excretion. The most important example, total clearance = renal clearance + Drug Actions
processes are glomerular filtration, tubular secretion, ¢ Drug Clearance metabolic clearance + all other clearance. Clearance
Most drugs bind to cellular receptors, where they
can be calculated several ways:
and tubular reabsorption. These processes are com- The term “clearance” refers to the volume of fluid initiate a series of biochemical reactions that alter the
pared in Table 1.3. Drug excretion mechanisms are that would be completely cleared of drug (per unit Elimination Rate (mg/hr) _ Liters cell’s physiology. In a given dose, some drug molecules
Clearance =
vulnerable to renal insults such as toxins, other drugs, _ time) if all the drug being excreted /metabolized were Drug Concentration (mg/L) hour find their target cells, while other molecules are being
or disease states. Because drugs, metabolites, and removed from that volume (and the remaining fluid
Table 1.3 Renal Processes thatInfluence Drug Excretion : 3. Assumed that drug binding to receptors repre- bound to receptors and drug that is free. A high-
sented only a fraction of available drug. affinity agonist or antagonist is less likely than a
PROCESS TRANSPORT ROUTE DRUGS TRANSPORTED — 4, Assumed that each receptor bound only low-affinity drug to dissociate from a receptor once
Diffusion Process. Small, Rate of filtration depends one drug. it is bound.
Glomerular Filtration Drugs pass from the blood
into the nephron by perfusing nonionic drugs pass more in part on blood pressure. Dissociation Constant (K,,): The dissociation
¢ Stephenson’s modified theory (generally accepted)
across the fenestrated readily. Drugs bound to constant is the measure of a drug’s affinity for a
capillaries of Bowmans plasma proteins cannot
1. Drug response depends on both the affinity of a
pass. drug for its receptors (defined below) and the drug’s given receptor. It is the concentration of drug
Capsule.
efficacy (defined in the next section). required in solution to achieve 50% occupancy of
Tubular Secretion Drugs secreted into the Active transport (drug Drugs may compete with 2. Described spare receptors. Proposed that maximal its receptors. Units are expressed in molar
nephron tubule from the carriers and energy). one another for the carrier.
Drugs which specifically A drug with a low margin
response can be achieved even if a fraction of concentration.
efferent arteriole.
bind to carriers of safety might reach toxic receptors (spare receptors) are unoccupied. ¢ Agonist: Drugs which alter the physiology of a cell
(transporters) are levels. Therapeutically, by binding to plasma membrane or intracellular
The following terminology refers only to events
transported. Size and drugs which compete for receptors. Usually, a number of receptors must be
charge are less transporters can be which occur at the cellular level:
occupied by agonists before a measurable change in
important. coadministered to increase
e Affinity: Affinity refers to the STRENGTH of cell function occurs. For example, a muscle cell does
plasma half-life.
binding between a drug and its receptor. The not depolarize simply because one molecule of
Tubular Reabsorption Drugs are reabsorbed into Diffusion Process. Small, Because ionic agents are number of cell receptors occupied by a drug is a acetylcholine binds to a nicotinic receptor and
the blood stream from the nonionic drugs pass poorly reabsorbed, drug function of an equilibrium between drug which is activates an ion channel.
nephron tubule. more readily. metabolites which are more
ionic than the parent drug will
be passed into the urine more
easily. Urinary pH can be
purposely altered to increase
the rate of drug excretion
(e.g., administration of
bicarbonate).
distributed, metabolized, and excreted. At the cellular e¢ Anormal cellular function is physically inhibited
site of action, drugs exert their primary actions. These (e.g., DNA synthesis, bacterial cell wall production,
actions are described in the following section. protein synthesis).
The actions of drugs are studied from a number of ¢ Acellular function is “turned on” (e.g., steroid pro-
different perspectives. Each perspective provides dif- motion of DNA transcription).
ferent information and uses different terminology. To
avoid confusion over terminology, the actions of drugs Very precise terminology is required when dis-
are presented in three sections: I) pharmacology at the cussing drug-receptor interactions. It is also important
cellular level, II) pharmacology at the organism level, to avoid substituting terms that describe drug actions
and III) pharmacology at the population level. at the organism or population level (e.g., potency,
efficacy, therapeutic index) for terms describing drug cAMP 3 Diacyl-
e Pharmacology at the Cellular Level actions at the receptor level (e.g., affinity). 3 glycerol
Drug Receptors: Receptors are generally proteins or The Receptor Theory of Drug Action: Langley Galo
glycoproteins that are present on the cell surface, on an and Ehrlich first proposed that drug actions were
organelle within the cell, or in the cytoplasm. There is a mediated by chemical receptors. In 1933, Clark devel- Protein
finite number of receptors in a given cell. Thus, receptor- oped the dose-response theory which stated that kinase C
mediated responses plateau upon (or before) receptor increased response to a drug depended on increased
saturation. When a drug binds to a receptor, one of the binding of drug to receptors. In 1956, Stephenson Figure 1.3 Examples of receptors and associated biochemical (second) messenger systems or ion channels. A). Receptors such as
presented a modified dose-response theory which is the beta-adrenergic receptor (B) are coupled with adenylate cyclase through a “G protein” (so named because it binds GTP). When an agonist
following actions is likely to occur (Fig. 1.3):
more widely accepted today. binds the receptor, the G protein signals adenylate cyclase to synthesize cyclic adenosine monophosphate (CAMP) which subsequently acts as
¢ Anion channel is opened or closed. an intracellular messenger. B). Receptors such as the muscarinic acetylcholine receptor (M) are coupled with a G protein that stimulates
phospholipase C. Phospholipase C catalyzes the breakdown of phosphatidyl inositol 5,5-bisphosphate (PIP) to produce inositol trisphosphate (IP ,)
¢ Biochemical messengers, often called second mes- ¢ Clark’s Theory and diacylglycerol (DAG). IP, may in turn stimulate other intracellular messengers, such as calcium or calmodulin and DAG stimulates protein
sengers, (CAMP, cGMP, Ca** , inositol phosphates) 1. Drug response is proportional to the number of kinase C. Protein kinase C acts by phosphorylating target proteins. C). Some receptors regulate ion channels in the plasma membrane. When the
are activated. The biochemical messenger initiates a receptors occupied. nicotinic receptor (N) is stimulated by acetylcholine, the channel opens and sodium ions pass into the cell. In the example of the nicotinic receptor,
series of chemical reactions within the cell, which 2. Assumed that all drug-receptor interactions were the drug receptor is a component of the proteins that form the ion channel. In other cases, a distinct receptor might be linked to the ion channel by
a G protein or other biochemical messengers.
transduce the signal stimulated by the drug. reversible.
¢ Strong Agonist: An agonist which causes maximal Chemicals that are produced in the body and exert
effects even though it may only occupy a small their actions through receptors (e.g., acetylcholine, ¢ Pharmacology at the Population Level phenobarbital, a potent inducer of isoenzyme
insulin) are termed endogenous ligands. CYP3A4 can produce a clinically significant drug
fraction of receptors on a cell. Before new drugs can be approved for marketing,
interaction with tacrolimus, a CYP3A4 isoenzyme
¢ Weak Agonist: An agonist which must be bound their efficacy and safety must be tested in animal and
substrate. Higher doses of tacrolimus and more
to many more receptors than a strong agonist to e Pharmacology at the Organism Level human population studies. Data derived from these
frequent drug monitoring may be required to keep
produce the same effect. studies are presented using the following terminology:
Many of the terms used in pharmacology were adequate serum concentrations of tacrolimus in
¢ Partial Agonist: A drug which fails to produce developed to reflect the observations made following ° EC,, (Effective Concentration 50%): The concentration the blood stream. An example of inhibition can be
maximal effects, even when all the receptors are administration of a drug to an experimental animal or of drug which induces a specified clinical effect in 50% described with the two drugs amiodarone and
occupied by the partial agonist. to a person. The following terms describe the actions of of the subjects to which the drug is administered. digoxin. Amiodarone is a potent inhibitor of isoen-
¢ Antagonist: Antagonists inhibit or block responses drugs on whole organisms. These terms are more likely ¢ LD,, (Lethal Dose 50%): The concentration of drug zymes CYP2C9 and CYP2D6. Because digoxin is
caused by agonists. to be used in a clinical setting than terms relating to which induces death in 50% of the subjects to which a substrate for one of these isoenzymes, amio-
Competitive Antagonist: Competes with agonists drug-receptor interactions. the drug is administered. darone may produce an increase in the digoxin
for receptors. During the time that a receptor is Efficacy: The degree to which a drug is able to induce serum level more than two-fold.
¢ Therapeutic Index: A measure of the safety of a
occupied by an antagonist, agonists cannot bind to maximal effects. If Drug A reduces blood pressure by drug. Calculated by dividing the LD,, by the ED,,. ¢ Plasma protein competition (Fig. 1.1): Drugs that bind
the receptor. The number of receptors appears 20 mm and Drug B reduces blood pressure by 10 mm, to plasma proteins may compete with other drugs for
then Drug A has greater efficacy than Drug B. In this Margin of Safety: The margin between therapeutic
unchanged because high doses of agonists will the protein binding sites. Displacement of a ‘Drug A’
and lethal doses of a drug.
compete for essentially all the receptors. The case, Drug A might be appropriate for treating hyper- from plasma proteins by ‘Drug B’ may increase the
agonists affinity, however, appears lower because tension that is refractory to Drug B. concentration of unbound ‘Drug A’ to toxic levels.
a higher dose of agonist is required, in the presence Potency: The amount of drug required to produce Drug Interactions ¢ Altered excretion: Drugs may act on the kidney to
of antagonist, to achieve receptor occupancy. 50% of the maximal response that the drug is capable Drugs may interact with one another according to reduce excretion of specific agents (e.g., probenecid
Because the antagonism can be overcome by high of inducing. For example, morphine and codeine are the following mechanisms: competes with sulfonamides for the same carrier,
doses of agonists, competitive antagonism is said both capable of relieving post-operative pain. A smaller increasing the risk of sulfonamide toxicity).
dose of morphine than codeine is required to achieve e Altered absorption: Drugs may inhibit absorption
to be surmountable.
this effect. Therefore, morphine is more potent than of other drugs across biologic membranes (e.g., Addition, synergism, potentiation or antagonism
¢ Noncompetitive Antagonist: Binds to a site other antiulcer agents that coat the stomach may decrease are the terms used to describe drug interactions. Table
codeine.
than the agonist-binding domain. Induces a confor- GI absorption of other drugs). 1.4 demonstrates the differences between the four types
“Potency” and “efficacy” have different meanings
mational change in the receptor such that the agonist of drug interactions.
and are used to describe different phenomenon. The e Altered metabolism: Clinically important drug
no longer “recognizes” the agonist-binding domain.
term “potency” is frequently used to compare drugs interactions can occur when the P450 isoenzymes
Even high doses of agonist cannot overcome this
antagonism. Thus it is considered to be insurmount-
within a chemical class, such as narcotic analgesics or (chemical cousins) are inhibited or induced. CYP is Tolerance, Dependence
corticosteroids. These drugs usually have similar the cytochrome nomenclature used to describe the
able. The number of agonist-binding sites appears to
maximal efficacy, if a high enough dose is given. human P450 isoenzyme followed by the family (an and Withdrawal
be reduced, but the affinity of agonist for the “unan-
“Efficacy” is more easily used to compare drugs Arabic number), followed by subfamily (a capital Tolerance represents a decreased response to a drug.
tagonized sites” remains unchanged.
with different mechanisms. For example, ketorolac letter), followed by the individual gene (an Arabic Clinically, it is seen when the dose of a drug must be
Irreversible Antagonist (Nonequilibrium (a nonsteroidal antiinflammatory drug) has equal number). Examples include CYP3A4, CYP1A2, and increased to achieve the same effect. Tolerance can be
competitive): Irreversible antagonists are also efficacy to morphine in controlling post-operative CYP2C9. Drugs and other substrates (such as metabolic (drug is metabolized more rapidly after
insurmountable. These agents compete with pain. Acetaminophen or aspirin have a lower efficacy smoking) can be inducers or inhibitors of the chronic use), cellular (decreased number of drug
agonists for the agonist-binding domain. In con- than either of the above drugs for controlling post- P450 isoenzymes. Other drugs can be substrates receptors, known as downregulation), or behavioral (an
trast to competitive antagonists, however, irre- operative pain. for the particular isoenzymes and thus can be alcoholic learns to hide the signs of drinking to avoid
versible antagonists combine permanently with Nothing can be said about the affinity of drugs candidates for drug interactions. For example, being caught by his colleagues).
the receptor. The rate of antagonism can be slowed based on their efficacy or potency. Affinity is a measure
by high concentrations of agonist. Once an irre- of the “strength” of binding between the drug and its
versible antagonist binds to a particular receptor, receptor and cannot be measured clinically. A low affin-
however, that receptor cannot be “reclaimed” by ity agonist might produce a response equal to or
an agonist. greater than that produced by a high affinity agonist.
Other forms of antagonism: In addition to pharmaco- Antagonists do not have efficacy, since they do not pro- YPE OF INTERACTION — MATHEMATICAL MODEL
logic antagonism, there are two other mechanisms by duce responses. Addition — The response elicited by combined drugs is EQUAL TO the combined teT=2
which a drug can inhibit or block the effects of an agonist: Graded dose-response curves: Graphs the magni- responses of the individual drugs.
tude of drug actions against the concentration (or dose)
¢ Physiological Antagonism: Two agonists, in unrelated of drug required to induce those actions. The curve Synergism — The response elicited by combined drugs is GREATER THAN the 1+1=3
reactions, cause opposite effects. The effects cancel combined responses of the individual drugs.
represents the effects and dose of a drug within an
one another. individual animal or tissue rather than in a population. O+1=2
Potentiation — A drug which has no effect enhances the effect of a second drug.
e Antagonism by Neutralization: Two drugs bind The receptor affinity, absorption, plasma protein bind-
to one another. When combined, both drugs are ing, distribution, metabolism, and excretion of a drug Antagonism — Drug inhibits the effect of another drug. Usually, the antagonist has 1+1=0
no inherent activity.
inactive. all affect the dose response curve.
|
17
Dependence occurs when a patient needs a drug to prescribed for pregnant or nursing women. Others
“function normally”. Clinically, it is detected when may be administered with caution.
cessation of a drug produces withdrawal symptoms. ¢ Smoking and drinking habits: Both smoking and
Dependence can be physical (chronic use of laxatives drinking induce P450 liver enzymes. This accelerates
leads to dependence on laxatives to have a normal the metabolism of a number of drugs. In some cases,
bowel movement) or may have a psychological compo- the result is lower-than-expected drug concentration,
nent (Do you HAVE to drink a cup of coffee to start leading to decreased therapeutic effectiveness. Pro-
your day?). drugs, however, might be metabolized to more active
Withdrawal occurs when a drug is no longer forms. In some cases, the active drug reaches toxic
administered to a dependent patient. The symptoms concentrations.
of withdrawal are often the opposite of the effects
¢ Liver or kidney disease: Dose reduction may be
achieved by the drug (cessation of antihypertensive
necessary in patients with liver or kidney dysfunc-
agents frequently causes severe hypertension and
tion. Failing kidneys excrete fewer drug metabolites.
reflex tachycardia). In some cases, such as with-
Failing livers metabolize drugs poorly compared to
drawal from morphine or alcohol, symptoms are
properly functioning livers. Liver and kidney failure
complex and may seem unrelated to drug effects.
are particularly common in the geriatric population.
Cross tolerance/cross dependence occurs when
tolerance or dependence develops to different drugs ¢ Pharmacogenetics: This is the most difficult assess-
which are chemically or mechanistically related. For ment in the patient profile. Briefly, there are genetic
Peripheral Nervous System

example, methadone relieves the symptoms of heroin differences between patients which affect the
withdrawal because patients develop cross dependence pharmacokinetics and actions of many drugs. For
to these two drugs. example, the half-life of phenytoin ranges from
10 hours in a “high hydroxylator” to 42 hours ina Co-authored by Anne Bournay, R.Ph.
“low hydroxylator” simply because the level of
The Patient Profile microsomal hydroxylation is lower in the latter
The Importance of the patient profile: Prescribing patient. A number of specific pharmacogenetic traits
drugs without consideration for the patient profile is The peripheral nervous system is divided into the neurons. Postsynaptic neurons subsequently transmit
have been described. Specific traits, associated mech-
substandard care. The patient profile includes each of autonomic and somatic nervous systems. The autonomic impulses to end organs (e.g., heart, stomach) by
anisms, and pharmacogenetic methodology are not
the following considerations: nervous system controls cardiac and smooth muscle releasing norepinephrine (sympathetic neurons) or
discussed in this introductory chapter.
contraction, and glandular secretion. The somatic ner- acetylcholine (parasympathetic neurons).
¢ Age: Drug metabolizing enzymes are often unde- e Drug interactions vous system supplies skeletal muscle during voluntary The catecholamines norepinephrine and
veloped in infants and depressed in the elderly. ¢ Psychosocial factors: Poor patient compliance is the movement and conducts sensory information, such as epinephrine transmit most impulses of the sympathetic
Because drugs are not metabolized as readily, they cause of many ‘drug failures’. Before prescribing a pain and touch. system. Upon release from presynaptic neurons, nore-
may accumulate to toxic concentrations. Pediatric medication, consider the cost, ease of administration, The autonomic nervous system is further divided into pinephrine diffuses across the synaptic cleft and binds
and geriatric dosing regimens are provided by and dose schedule of the drug. Also, assess the level the sympathetic and parasympathetic systems, which to postsynaptic adrenergic (a1, «2, 81 or 82) receptors.
most drug manufacturers. It is inappropriate to of patient responsibility. generally oppose one another. For example, the sympa- During times of stress, the adrenal gland releases
extrapolate adult doses to children. Instead, thetic system is generally catabolic, expending energy epinephrine (adrenaline) into the blood. Like nore-
pediatric dosing regimens are available for most In order to thoroughly evaluate the toxicity of a (the “fight or flight system”). It increases heart rate, pinephrine, circulating epinephrine is an agonist at
drugs and are usually adjusted according to patient drug, it is necessary to record the pre-drug status of the dilates bronchi, and decreases secretions, whereas the adrenergic (sympathetic) receptors. An exception to
weight or body surface area. patient for comparison. Particular attention should be parasympathetic system is anabolic, conserving energy. catecholamine neurotransmission in the sympathetic
Pregnancy status: Before prescribing drugs for a paid to the organs that are likely to be damaged by the e.g., it decreases heart rate, stimulates gastrointestinal system is the sweat glands. Acetylcholine, which is
woman of child-bearing age, it is essential to know drug. Particularly when administering drugs with a function (See Figs. 2.2 and 2.3 for a review of functions). often considered a parasympathetic transmitter,
whether there is any possibility that she is pregnant or narrow margin of safety, it is sometimes necessary to In the resting individual, the parasympathetic system conveys sympathetic signals to sweat glands.
whether she is nursing. Many drugs are not to be adjust dosage according to serum levels of the drug. dominates in most organs, resulting in a relatively slow Acetylcholine transmits all parasympathetic signals
heart beat, adequate secretions, and appropriate bowel to'end organs ;(heart, lungs, etc.) by binding to mus-
motility. In an individual under stress, however, the carinic (M) receptors. In addition, acetylcholine plays
sympathetic system dominates, diverting energy to three other important roles in neurotransmission.
functions which make a person fit to fight or flee
(e.g., improved oxygenation of tissues by bronchodila- ¢ Ganglionic transmission: Acetylcholine transmits
tion and increased cardiac output). both sympathetic and parasympathetic impulses from
Autonomic neurotransmission involves two neu- the preganglionic neurons in the brain and spinal
rons, the presynaptic and the postsynaptic neurons cord to nicotinic ganglionic (N -)receptors on post-
(Fig. 2.1)»Presynaptic neurons extend from the brain ganglionic neurons of the autonomic nervous
to autonomic ganglia where they transmit CNS signals system. This occurs in sympathetic ganglia, which are
to postsynaptic neurons by releasing acetylcholine into located along the spinal cord, and in parasympathetic
the synaptic cleft, which is the space between the two ganglia, which lie near the end organs. Because all
12 Principles of Pharmacology 13
0
Figure 2.1 Schematic of
Sympathetic @——~< autonomic and somatic
motor neurons. Presynaptic
PRE SYNAPTIC. NEURON
a et Le ee >
j
ACh (nicotinic) Norepinephrine (adrenergic) neurons are depicted with Tyrosine
solid cell bodies. Postsynpatic
Parasympathetic eo. —-_--- ~<

ACh (nicotinic)
()
ACh (muscarinic)
neurons are speckled. The
neurotransmitter released by the
presynaptic neuron and the type
of receptor it activates are listed
DOPA
below each synapse.
Somatic Motor (pe ll)
als
& Acetylcholine
ACh (nicotinic)
—
——s
=
~~
SSS
SSS
——
POSTSYNAPTIC NEVRON
POSTSYNAPTIC NEURON
Figure 2.4B Synthesis, release and degradation of acetylcholine.
Figure 2.4A Norepinephrine synthesis, release and degradation. 1). The enzyme choline acetyltransferase catalyzes the acetylation of
1). Norephinephrine is synthesized from the amino acid tyrosine. Tyro- choline by acetyl CoA to form acetylcholine. 2). Acetylcholine is stored in
sine is hydroxylated to dopa which is then decarboxylated to dopamine. storage vesicles. 3). Upon nerve stimulation, an action potential travels
2). Dopamine (empty squares) diffuses into synaptic vesicles where the down the neuron and causes calcium influx into the nerve terminal.
enzyme dopamine B-hydroxylase hydroxylates dopamine, forming Calcium influx causes the vesicles to fuse with plasma membrane and
norepinephrine (solid squares). 3). Upon nerve stimulation, calcium enters release acetylcholine. Acetylcholine diffuses through the synaptic cleft
Figure 2.2 The “Fight or Flight” response demonstrates the ability the presynaptic neuron and causes the synaptic vesicles to fuse with the and may bind to (4) Nm receptors (nicotinic receptors on muscle cells,
of the sympathetic nervous system to provide energy for vital functions. plasma membrane and release norepinephrine into the synaptic cleft. 4, 5, (5) Ng receptors (nicotinic receptors on ganglionic synapses of the auto-
Decreased pulmonary secretions and bronchodilation increase blood 6). Norepinephrine diffuses throughout the synaptic space and may bind nomic nervous system), (6) M1 muscarinic receptors, (7) M2 muscarinic
oxygenation. Increased heart rate and contractility improve cardiac to either a adrenergic receptors, B1 adrenergic receptors or B2 adrenergic receptors or (8) M3 muscarinic receptors. At least six muscarinic re-
output. Arteriolar constriction shunts blood from the skin and digestive Figure 2.3 The parasympathetic pig’s heart beats sluggishly receptors. Direct sympathomimetic drugs (adrenergic agonists) bind to ceptors have now been identified, of which M1, M2 and M3 receptors have
tract, whereas arterioles in the heart and skeletal muscle dilate to supply while his digestive tract hogs the energy. He’s drooling because of these receptors as well, without interacting with the presynaptic neuron. been most carefully studied (Table 2.5). 9). Acetylcholine is cleared from _
more blood to the latter organs. Glycogen and lipids break down and increased secretions. He needs to breath oxygen because his bronchioles 7). a2 adrenergic receptors are located on the presynaptic neuron in some the synaptic cleft by hydrolysis to choline, which is actively reabsorbed into
glucose is synthesized for energy. GI motility and secretions decrease and are constricted. He is defecating and urinating and he has an erection cases. Stimulation of a2 presynaptic receptors by norepinephrine inhibits the nerve terminal. 10). Acetylcholine breakdown products are recycled
urine is retained (because you can't fight a bear when you're urinating). (you'll have to picture this as none of these are drawn, for modesty). subsequent release of norepinephrine from the terminal. 8). The enzyme into acetylcholine.
(The sympathetic system, by the way, controls ejaculation). Notice how catechol-o-methyl transferase degrades catecholamines, such as nore-
tiny his pupils are compared to the scared boy in figure 2.2. pinephrine. 9). More commonly, excess norepinephrine is transported back
into the presynaptic neuron where it is (10) repackaged in storage vesicles
neurotransmitter, 4) the neurotransmitter diffuses across
or (11) degraded by mitochondrial monoamine oxidase. 12). Indirect the synaptic cleft and may bind to postsynaptic recep-
ganglionic transmission is cholinergic, drugs which ¢ Central neurotransmission: Acetylcholine is a neu- sympathomimetics are drugs that work by entering the presynaptic tors, 5) binding of neurotransmitter to receptor results
block ganglionic transmission (Table 2.8) inhibit either rotransmitter in the brain, acting predominantly via
terminal and displacing norepinephrine. in either opening of an ion channel or activation of a
sympathetic or parasympathetic signals, depending muscarinic receptors. “second messenger” such as cAMP or inositol phosphate,
on which system is predominant at the moment. First, consider the processes involved in neurotrans- 6) the resulting ion influx or second messenger activation
Before learning about specific drugs which modify mission (Fig. 2.4A and 2.4B): 1) the neurotransmitter is causes an action (e.g., depolarization) of the postsynaptic
Neuromuscular transmission: Acetylcholine, neurotransmission, it is helpful to consider how mes- synthesized from chemical precursors, 2) it is packaged cell. Neurotransmitter molecules which fail to bind to
released from neurons, causes muscle contraction sages are transmitted from one neuron to another and postsynaptic receptors are destroyed by degradative
into vesicles in the presynaptic terminal, 3) the presynap-
by binding to nicotinic muscle (N_,) receptors on the strategies available for enhancing or suppressing tic nerve is stimulated causing the synaptic vesicles to enzymes, are taken up into the presynaptic neuron to be
muscle cells, causing calcium influx (Fig. 2.1). neurotransmission. fuse with the synaptic membrane and release the recycled, or diffuse away from the synaptic cleft.
14 Peripheral Nervous System 15

Clinically useful agents which enhance neurotransmission Sympathomimetics The location of adrenergic receptors and the conse- are degradative enzymes which rapidly metabolize
include:
e Direct Sympathomimetics quences of their stimulation are outlined in Table 2.2. catecholamines and consequently shorten the duration
¢ Receptor agonists Catecholamines are chemicals which contain a of catecholamine effects. Despite their short duration
Endogenous sympathetic agonists (norepinephrine,
¢ Agents which induce neurotransmitter release catechol group and an amine. Catechol-O-methy] of action, catecholamines are used clinically to treat
epinephrine and dopamine) and other sympathomimetic
¢ Drugs which prevent transmitter degradation transferase (COMT) and monoamine oxidase (MAO) anaphylaxis, cardiac arrest, heart failure and shock
drugs are presented in Tables 2.1A and 2.1B. Direct
Catechol . Amine (Table 4.2B and associated text).
Clinically useful agents which suppress neurotransmission sympathetic agonists bind to a,, a,, B,, or B, adrenergic
Noncatecholamine adrenergic agonists (Table 2.1A)
include: receptors where they “turn on” second messengers a H ~ have longer serum half-lives than catecholamines,
(Fig. 2.5). The second messenger associated with each HO C—CH,-NH,
because they are not metabolized by MAO or COMT.
¢ Presynaptic nerve blockers receptor class mediates different effects. Thus the actions HO OH Most noncatecholamine sympathomimetics are B,-
¢ Receptor antagonists of each agonist depend on the class or classes of receptors
preferring agents which are marketed as bronchodila-
¢ Ganglion blockers to which it binds and the tissue location of the receptors. Norepinephrine tors (Table 2.1A) or uterine relaxants (Table 10.3).
Table 2. 1A Direct Sympathomimetics

FFECTS |
DRUG RECEPTOR» VASCULAR EFFECTS CARDIAC E OTHER EFFECTS
Catecholamines:
Epinephrine (Adrenalin) a and Bp Vasoconstriction (a1). Vasodilation All cardiac effects mediated by B1
Bronchodilation (8), Glycogenolysis and gluconeogenesis Gut relaxation (a, B2); bladder
(B2). Injected with local anesthetics: receptors: Increased heart rate;
vasoconstriction (a), and 82), lipolysis (81), predominant sphincter contraction (a); uterus
a1-mediated vasoconstriction contractility; conduction velocity; and
delays distribution of anesthetic automaticity of A-V node, HIS-Purkinje
decreased secretions (a). insulin release (a2) but also T contraction in non-pregnant
away from the site of injection. fibers and ventricles.
Used therapeutically as insulin release (2), T renin women (a1), uterus relaxation
bronchodilator (Table 5.1). secretion (81) in near-term women (82).
Norepinephrine a>B1>> B62 a1: INTENSE vasoconstriction leading Intense vasoconstriction causes reflex
(Levophed) to TT mean arterial pressure. (parasympathetic-mediated) slowing of
No 82 effects. Thus it Relatively weak J insulin release Endogenous transmitter
(vasoconstriction is unopposed the heart. This reflex bradycardia
cannot be used as a (a2), lipolysis (81). of the peripheral nervous
bronchodilator. system. Used only when
because drug fails to bind to B2 overwhelms the weak B1
intense vasoconstriction
receptors — which cause vasodilation cardiostimulatory effects.
is necessary (septic shock).
when stimulated).
Isoproterenol (Isuprel) Only 8 Intense vasodilation (82) Stimulates heart more than epinephrine
Clinically used to prevent T glycogenolysis and J tone and motility of gut. Metabolized by COMT,
reduces mean arterial pressure. due to direct effects and response to gluconeogenesis, hyperglycemia, Inhibits mast cell release.
bronchospasm. Most but it is a poor substrate
Doesn't bind to «1 receptors. decreased mean arterial pressure. potent bronchodilator hyperlipidemia. 7 insulin release. for monoamine oxidase.
Dobutamine (Dobutrex) B1>B2=a NO CHANGE in resistance Drug of choice to stimulate heart. Synthetic derivative of
because it has low affinity for Preserves the heart’s efficiency best. dopamine, but has no effect
a1 and B2. Minor change in heart rate. at dopamine receptors.
Dopamine (Intropin) Dopamine Low doses: constricts arterioles 81 effects: T contractility, T systolic In kidney, T glomerular Clinically used to treat
receptors and in sites other than the brain & pressure, less effect on rate than filtration rate, T blood flow, shock (underperfusion,
B1 adrenergic kidneys. Thus preserves flow to isoproterenol. Causes indirect release T Nat excretion. reflex vasoconstriction).
receptors these vital organs. At higher of norepinephrine which is offset by
doses, constricts all vessels. inhibition of norepinephrine release via
presynaptic dopamine receptors.
ee Ses AO et
Non
Phenylephrine Primarily a Intense vasoconstriction. J heart rate (reflex to T mean arterial Included in cold remedies as Used to treat paroxysmal
(Neo-Synephrine) T mean arterial pressure. pressure). Used Clinically to treat a nasal decongestant. atrial tachycardia. Reflex
paroxysmal supraventricular Decongestant effects due to J heart rate is maintained
tachycardia. nasal vasoconstriction. after drug is removed.
Methoxamine (Vasoxyl) i 73 oy ony
Metaproterenol (Alupent) Primarily B2. Vasodilation. Very few cardiac effects due to lack of Clinically used as a CNS-tremor Relax uterus in near term
affinity for 81 receptors. bronchodilator (Table 5.1). pregnant women.
“on “on
Albuterol (e.g., Ventolin) “oy
“oy
Bitolterol (Tornalate) “oy oy “oy

“on
CNS-tremor
“oy “oy
Terbutaline (Brethine) oy
“on
“oy “on
Salmeterol (Serevent) ony
“wn
“ny “oy
Pirbuterol (Maxair) “oy
“ny
“oy “oy
Levalbuterol (Xopenex) ony
“oy
Long-acting (Salmeterol)
See Table 5.1A for additonal bronchodilators

Exceptions include phenylephrine and methoxamine 4
which are potent «, vasopressors. Phenylephrine is Table 2.2 Location and Results of Stimulation of Adrenergic Receptors
marketed as nasal and ophthalmic decongestants. ALPHA -1 RECEPTORS ALPHA -2 RECEPTORS ALPHA -? RECEPTORS !
e Indirect & Mixed Agents Arterioles and Veins:

constriction
CNS Postsynaptic Terminals:
J sympathetic outflow from brain
Urinary Bladder Sphincter:
contraction (urine retention)
Indirect sympathomimetics cause norepinephrine re- Glands: CNS Presynaptic Terminals: Pregnant Uterus:
lease from presynaptic terminals, but do not bind to =
J secretions J norepinephrine release contraction
adrenergic receptors (Fig. 2.5, Table 2.1B). These drugs Eye: B Islet Cells of Pancreas: Penis:
enter the presynaptic terminal and displace stores of nore- constriction of radial muscle JL secretion ejaculation
pinephrine from storage vesicles. Mixed sympathomimet- Intestine:
ics displace norepinephrine from presynaptic terminals L motility
and bind to adrenergic receptors. (Fig. 2.5, Table 2.1B).
BETA -1 RECEPTORS BETA -2 RECEPTORS BETA -? RECEPTORS '
Figure 2.5 Direct, indirect and mixed actions of sympath- Heart: Trachea and Bronchioles: Eye:
omimetic drugs. TOP: Direct agents (open triangles) mimic T heart rate (SA node) relaxation relaxation of ciliary muscle (minimal
norepinephrine as agonists at adrenergic receptors without interacting T contractility effect)
T conduction velocity Pregnant/nonpregnant Uterus:
with the presynaptic neuron. The chemical structure of the drug T automaticity relaxation Urinary Bladder
determines its subclass specificity. MIDDLE: Indirect sympathomimetics relaxation of detrusor muscle (minimal
(striped) force epinephrine release from the presynaptic terminal (solid ED) Kidney:
T renin secretion
Arterioles (except in skin or
brain) and Veins ?:
effect).
triangles). Thus, these agents enhance the actions of endogenous
norepinephrine. Indirect agents do not bind to adrenergic receptors. dilation
a i
BOTTOM: Mixed sympathomimetics (speckled) induce the release of
norepinephrine and also bind to adrenergic receptors. Sympathetic ' Not yet determined which subclass of receptors is responsible for these actions.
neurotransmission is also enhanced by inhibition of the degradative ? Arterioles in skin and brain lack 8, receptors. In other areas of the body, the degree of sympathomimetic-induced vasoconstriction and/or vasodila-
enzyme, monoamine oxidase. Monoamine oxidase inhibitors are used to tion depends on the drug’s affinity for «, (vasoconstriction) or B, (vasodilation) receptors (Table 2.1A.).
treat depression (Table 3.1B).
‘DRUG =—_ VASCULAR EFFECTS __CARDIAC EFFECTS CNS EFFECTS CLINICAL USES UNDESIRABLE EFFECTS
Indirect Agents:
Amphetamine Vasoconstriction (due to T contraction (61). J heart Wakefulness, elation, | appetite, Stunts growth. Narcolepsy, hyperkinetic Hypertension, cerebral Treat toxicity by acidification
release of norepinephrine) rate (reflex to |mean improved simple motor tasks, syndrome of children, attention hemorrhage, convulsions, of urine (it is a weak base)
T mean arterial pressure. arterial pressure) euphoria. deficit disorder, Parkinson’s coma, confusion, anxiety, and administration of a
disease. hallucinations, fever, tremor, blockers or nitroprusside
restlessness. (for hypertension), and
antianxiety agents.
oo “oy “on
Methamphetamine cats oo
Mixed agents:
Ephedrine Vasoconstriction (a1)— Similar to epinephrine, but Clinically used to treat Bronchodilation (direct Asthma, nasal congestion, Less CNS toxicity than Longer duration, but less
T mean arterial pressure. no change in heart rate. narcolepsy. effect, remember that narcolepsy. Used as a amphetamine. potent than epinephrine.
norepinephrine doesn’t mydriatic (dilates pupil).
teases |
cause bronchodilation).
Hydroxy-amphetamine ie More CNS effects than ephedrine,

“oy
fewer CNS effects than amphetamine.
Mephentermine (Wyamine) aa Few CNS effects. Treatment of hypotension (pressor). Little CNS toxicity.
Phenyl-propanolamine Vasoconstriction. Anxiety, agitation, dizziness, Decongestant Over-the-counter oral Hypertension, anxiety, agitation,
hallucinations. decongestant dizziness, hallucinations.

Adrenergic Blockers brain by binding to a, adrenergic receptors. In contrast, Reserpine is long-acting, and the postsynaptic by an antagonist, the actions of catecholamines at a
methyldopa is metabolized in the presynaptic neuron neurons respond to the paucity of norepinephrine by adrenergic receptors (Table 2.2) are inhibited. Adrener-
Adrenergic neurotransmission can be blocked either to a-methyl norepinephrine. When released from the
by decreasing sympathetic outflow from the brain “upregulating” (increasing) the number of receptors gic blockers used to treat hypertension are presented in
presynaptic terminal, a-methylnorepinephrine acts as on the postsynaptic membrane. As a result, the post- greater detail in Table 4.3C.
(Table 2.3), suppressing norepinephrine release from
a potent a, agonist. synaptic terminal is supersensitive to direct sympath- The vasodilation induced by alpha-blockers may
presynaptic neurons (Table 2.3) or blocking postsynap-
The extent to which clonidine, guanabenz and omimetics. Consequently monoamine oxidase inhibitors result in orthostatic hypotension (blood pools in legs
tic adrenergic receptors (Table 2.4). methyldopa prevent norepinephrine release by binding (which prevent destruction of endogenous cate- when the patient is upright) and tachycardia which is
to presynaptic a, receptors is not known. cholamines such as norepinephrine and epinephrine) a B,-mediated sympathetic reflex to hypotension.
e Central Anti-adrenergics and direct sympathomimetics (Table 2.1A) should be Because a, receptors regulate norepinephrine release,
Alpha-2 (a,) adrenergic receptors inhibit sympathetic avoided in patients who have received reserpine. blockade of these receptors might result in hypersecre-
neurotransmission by two mechanisms. Postsynaptic a,
¢ Peripheral Presynaptic Anti-adrenergics
tion of norepinephrine.
receptors inhibit sympathetic neurons that exit the brain. Peripheral presynaptic anti-adrenergics inhibit
e Peripheral Postsynaptic Beta blockers: Nonspecific beta blockers (block
Alpha-2 receptors are also found on presynaptic nerve norepinephrine release from the presynaptic terminal.
terminals where they inhibit norepinephrine release. Guanadrel and reserpine deplete norepinephrine from Anti-adrenergics both 8, and B, receptors) have been used as first-step
antihypertensive agents. Because these agents block
Central anti-adrenergic drugs are commonly used presynaptic vesicles. As a result, guanadrel initially Alpha blockers: Alpha adrenergic antagonists com-
receptors as well as B, receptors, bronchospasm may
to treat hypertension (Table 4.3C). Clonidine and releases norepinephrine from the terminal causing a pete with endogenous catecholamines for binding at
occur. Newer agents are B,-specific and are not con-
guanabenz suppress sympathetic outflow from the transient increase in adrenergic transmission. a, and a, receptors. Because norepinephrine and
traindicated in asthmatic patients.
epinephrine cannot bind to a receptor that is occupied
Table 2.3 Presynaptic Adrenergic Nerve Blockers

DR _ BLOCKADEMECH =——S ACTIONS, UNDESIRABLE EFFECTS.
DOREY TPE te DERBOLENELGICs.
Clonidine Potent a2 AGONIST. J preganglionic sympathetic Orthostatic hypotension.
(Catapres) outflow from brain resulting in Sedation
J blood pressure. Rebound hypertension
—
“oy “on “on
Guanabenz
(Wytensin)
“on
Guanfacine is a
(Tenex)
Methyldopa Decarboxylated to a-methy! J preganglionic sympathetic Sedation, mild orthostatic Hypertension

(Aldomet) dopamine then B-hydroxy- output, rapidly J blood pressure— hypotension, dry mouth, fever,
lated to a-methylnorepinephrine, but sympathetic system can nasal stuffiness, Coombs
a potent a2 receptor agonist. respond with cardiac stimulation. positive RBCs, salt and water
Results in J sympathetic retention, rebound hypertension.
outflow from CNS.
Guanethidine Unknown initial effect. Later, By rapid IV infusion: J blood Inhibits ejaculation, diarrhea, Severe hypertension Seldom used
(Ismelin) JJ norepinephrine release, pressure, then transient orthostatic hypotension. With Renal hypertension
norepinephrine hypertension, then J arterial chronic use, get profound NE
concentration in nerve pressure if patient is standing. depletion and nerve toxicity.
terminals. Chronically, T GI motility, fluid retention.
sensitizes nerve to Orally: hypotension.
sympathomimetics.
ee
Guanadrel one io “oy
Hypertension
(Hylorel)
Bretylium a See guanethidine. Prolongs oy

Arrhythmias
(Bretylol) myocardial action potential.
Reserpine Depletes catecholamines and Gradual J mean arterial pressure Nightmares, depression, Hypertension No rebound effect because
serotonin in brain, adrenal, with bradycardia. Antihypertensive diarrhea, cramps, 7 risk of breast effects are long lasting.
and heart. Inhibits uptake of effects due to | cardiac output. cancer, peptic ulcers, Sometimes used for noncompliant
norepinephrine into presynaptic Tranquilization,sedation. parasympathetic predominance. patients because of long half-life.
vesicles.Chronically sensitizes
patient to sympathomimetics.
_—

Table 4 Adrenergic Antagonis
RECEPTOR
DRUG SPECIFICITY TYPE-OF BL OCKADE CLINICAL USES | _ UNDESIRABLE EFFECTS PHARMACOKINETICS NOTES
Phenoxy- CrKGl Irreversible alkylation of a Vasodilation («,). Blocks sympathetic outflow from Pheochromocytoma—to Postural hypotension (blood pooling), Slow onset, but long lasting Effects depend on degree
benzamine receptor. the brain and feedback inhibition of norepinephrine control hypertensive intense reflex tachycardia and force due to irreversible binding to of a adrenergic tone.
(Dibenzyline) release at a, receptors. Increases insulin release episodes. of contraction (enhanced by block of receptor.
NE feedback control at a,).
Arrhythmias, ischemia, sexual
dysfunction, nasal congestion.
Phentolamine CY OH Competitive Vasodilation Pheochromocytoma—to control Tachycardia, cardiac arrhythmias, Rapid onset, short half-life.
(Regitine) hypertensive episodes; dermal prolonged hypotensive episodes,
necrosis; pharmacological test nasal congestion, diarrhea.
for pheochromocytoma
Prazosin Selective a, ead Vasodilation Hypertension. No large reflex tachycardia; postural Tolerance not observed.
(Minipress) hypotension with first dose; less
sexual dysfunction.
Doxazosin Selective a, me Vasodilation Hypertension; benign prostatic No large reflex tachycardia; postural Greater effect on BP and HR
(Cardura) hyperplasia (relaxes smooth hypotension with first dose; less in the standing position.
Terazosin (Hytrin) muscles produced by blockade of sexual dysfunction.
a, in bladder neck and prostate.
“n
Alfuzosin (Uroxatral) Be ais Vasodilation Benign prostatic hyperplasia.
Tamsulosin (Flomax)
Labetalol (Trandate) a, By Bo - J BP (a, blockade) without reflex tachycardia Hypertension, IV for severe Further suppresses a failing heart; Oral completely absorbed, with Contraindicated in patients
(Normodyne) (B,, blockade). Conduction time and refractory hypertension. fatigue, impotence, diarrhea, peak levels in 1-2 hr and steady with asthma or bradycardia
period slightly prolonged. numbness, orthostatic hypotension. state in 3 days. Extensive 1st pass due to bronchoconstriction.
effect; |V peak occurs in 5 min.
Carvedilol (Coreg) Cha lShn (Cs a J cardiac output, exercise-induced tachycardia, Essential hypertension, congestive Hepatotoxic, postural hypotension, Well absorbed, extensive 1°‘ pass Contraindicated in patients
and reflex orthostatic tachycardia; Vasodilation, heart failure. hypoglycemia. effect, terminal elimination half-life with asthma due to
J peripheral vascular resistance with | BP 7-10 hrs, extensively metabolized. bronchoconstriction.
Propranolol (Inderal) Bas aK Heart: J inotropy, chronotropy, O, demand and conduction Hypertension, angina pectoris, Further suppresses a failing heart: Low bioavailability due to Contraindicated in patients
velocity. Arteries: compensatory vasoconstriction SVT, ventricular arrhythmias, CNS sedation and depression; significant 1%' pass effect; Readily with asthma due to
(dwindles over days) Kidney: J 6, mediated renin myocardial infarction, migraine rebound hypertension, impotence. enters CNS; Hall-life 3-5 hours; bronchoconstriction.
release, T Na* and H,O retention Liver: glycogenolysis prophylaxis, essential tremors Angina, myocardial infarction, Hepatically metabolized. 8 blockers should be weaned
and slows post-insulin recovery of glucose and other unlabeled uses. arrhythmias may occur if abruptly rather than abruptly withdrawn.
**no change in HR or contractility with pindolol. withdrawn.
“wn wn an
Carteolol (Cartrol) Hypertension Bradycardia, ventricular arrhythmias, Adjust dose for renal impairment. Has intrinsic sympathomimetic
dizziness, fatigue, hyperglycemia, activity; contraindicated in
hypoglycemia, impotence. bronchospasm.
“mn “n
Penbutolol (Levatol) Hypertension
“on
Sotalol (Betapace) Ventricular arrhythmias and Not metabolized. Contraindicated in asthma or
tachycardias. bronchospasm, long QT syndrome.
“n “n “n
Nadolol (Corgard) Hypertension; angina pectoris Fewer CNS effects than propranolol; Contraindicated in asthma or
longer half-life than propranolol. bronchospasm.
«“n «en “an “n

Timilol (Blocadren) Hypertension, myocardial infarction,
migraine prophylaxis: Ophthamologic
agent used to J intraocular pressure.
Pindolol (Visken) “oy “an «“»

Hypertension
wn
Has intrinsic sympathomimetic activity;
contraindicated in bronchospasm.
a
«n
Metoprolol (Lopressor) B, specific Compared to propranolol; less bronchospasm Hypertension, angina pectoris, Lower toxicity than propranolol; less Readily enter CNS.
in asthmatics, less inhibition of vasodilation myocardial infarction. likely to increase peripheral
and liver effects. resistance, cause bronchospasm,
or inhibit liver metabolism.
“n an «” “an
Atenolol (Tenormin) Hypertension See Table 4.2C
“n “n
Acebutolol (Sectral)
“” “on
Bisoprolol (Zebeta)
“on «on
Esmolol (Brevibloc)
Betaxolol (Kerlone)

and at the neuromuscular junction (N,,). Table 2.5 out-
Cholinomimetics from the choline esters and are not metabolized Like ganglion blockers, the action of nicotine at each
lines cholinergic actions at muscarinic receptors and
e Direct Cholinergic Agonists nicotinic receptors. by cholinesterases. visceral organ depends on whether the sympathetic or
Nicotine is among the most commonly used drugs. parasympathetic system is predominant at the time.
Acetylcholine is the neurotransmitter of the Choline esters are simply choline bound to an acetyl
Smokers become tolerant to and dependent on its effects.
parasympathetic nervous system, the neuromuscular derivative by an ester bond. The ester bond of acetyl- Choline
Nicotine stimulates the CNS, releases epinephrine from
junction, and autonomic ganglia. In addition, acetylcholine and related drugs is hydrolyzed by enzymes
adrenal glands, stimulates and then blocks receptors
in s
choline in the brain plays a role in memory formation, | known as cholinesterases (e.g., acetylcholinesterase). ganglia and at the neuromuscular junction. In the latter ‘
Choline esters are more or less sensitive to cholinesterase
motor skills and other important tasks.
Muscarinic receptors (M) mediate postganglionic deactivation depending on their chemical structure.
two cases, nicotine binds to the nicotinic receptor, causing
depolarization of the postsynaptic neuron. In contrast to
(CH)NCHCH*O-C'CHs
parasympathetic and CNS functions of acetylcholine, Cholinomimetic alkaloids are derived from plants
most agonists, however, nicotine remains at the receptor, %
whereas nicotinic receptors are found in ganglia (N,) by alkaline extraction. They are chemically distinct
preventing further stimulation of the occupied receptor. *<Ester bond
RECEPTOR :so| ORGAN = ‘2NDMESSENGERS — NOTES

Acetylcholine Muscarinic type 1 (M,) StOMaChimuae ein mere aera T acid pepsin in secretion
(Miochol-E) M, (GANQOn) 2. asc 2 aig ccs stimulation
Miosis in cataract surgery Peptic ulcer At M, receptors:
G-protein
M, (GNSH en anc che i eee neurotransmission
phosphatidyl inositol
M, SAiNOd6:s5.26ae. cicero T K* conduction, slow diastolic
depolarization, bradycardia
Coronary artery disease At M, receptors:
M, Atiatic. une See
ee J contractility, | conduction velocity, Hyperthyroidism (atrial T K* conduction (SA node),
J refractory period
fibrillation) J cAMP (atria and AV node),
M, PAV ENOGG wane israel eae slows conduction, AV block
T cGMP (other organs)
Asthma At M, receptors,
M, RUT siete ces hy carsales Jona gesaU oar bronchoconstriction, T secretion
phosphatidyl inositol
M, LE a el NR i T motility
M, BIACGE Mier ovNe auokne reatlckein
ees contract detruser, relax sphincter
Mechanical bladder At nicotinic receptor: opens
M, ASE! sosmeccocdacceoaede erection
obstruction sodium channel. Influx
M, Glands: BOr Oren a eee T secretion depolarizes cell.
M, EVON nama een ee Leer miosis, accommodation
Nicotinic Skeletal Muscle ............ contraction
Nicotinic Gariglion= aera as ae stimulation
Nicotinic GINISS AS aeper stn Geer eae eens neurotransmission
Choline Derivatives
Carbachol “wn “on on
on
Glaucoma. Applied Where constriction is Relatively resistant to
(Miostat) (Isopto
topically to the eye. undesirable cholinesterase degradation
Carbachol)
(long half-life)
Methacholine M,, M, and M,. Weak See M,, M,, and M, See M,, M,, and M, rows above. Diagnostic for bronchial airway Patients receiving B-blockers iG Short duration of action due to
(Provocholine) nicotinic agonist. rows above. cholinesterase degradation.
hyperreactivity without
clinically apparent asthma
Bethanechol M,, M, and M, and See M,, M,, and M, See M,, M,, and M, rows above. To induce evacuation of NON- Above plus bradycardia,
“on
Relatively specific for
(Urecholine) (Duvoid) nicotinic agonist. rows above. gastrointestinal tract and bladder.
obstructed bladder. To increase parkinsonism, epilepsy,
GI motility following surgery. hypotension, hypertension Resistant to cholinesterase.
Alkaloids
Cevimeline M,, M,, M,. See M,, M,, and M, See M,, M,, and M, rows above. Dry mouth associated
“wy
be Derived from a seed known as
rows above. with Sjogren's Syndrome. the betel nut
Pilocarpine (Pilocar) M,, M,, M,. Not nicotinic. See M,, M,, and M, rows See M,, M,, and M, rows above. Cystic Fibrosis sweat test,
“oy “on
(Isopto-Carpine) above. Sweat and salivary

Glaucoma (miotic),
glands particularly pronounced.
Xerostomia
a
Nicotine Nicotinic See nicotinic rows above See nicotinic rows above on
The drug initially used to characteriz
Smoking cessation aid
nicotinic pharmacologic responses

Cholinomimetics (co n t.) Once bound, these agents inactivate the enzyme by
: es phosphorylation. Regeneration of the enzyme may
Acetylcholine Cholinergic Antagonists
¢ Cholinesterase Inhibitors take over a week. >
9
oO
Cholinergic antagonists are classified as muscarinic
loa
blockers (Table 2.7), ganglion blockers, and neuromus-
ie Bauens of Seeuenoiiie ee ache ae Ha Cholinesterase inhibitors are used to treat dementia °
= cular blockers (Table 2.8). At therapeutic doses, mus-
See taeia ae een Oo Rese related to Alzheimer’s Disease, glaucoma and myasthe- 2
er = atts ig oe ce oe aa oe sen I a gravis. Cholinesterase inhibitors do not affect the ACH| ==> =
O
carinic antagonists do not bind to nicotinic receptors
n
_> and neuromuscular blockers (Nm antagonists) do
as - a ey eae Sheps Eee evening underlying pathology of Alzheimer’s, but increase oO
x not bind to muscarinic receptors. Most cholinergic
Sues peice ng) Heo eeOn. é cholinergic activity in the brain, which may reduce sed)
n
agonists, on the other hand, bind to both muscarinic
Cholinesterase inhibitors are classified by their symptoms. In glaucoma, aqueous humor production oO
and nicotinic receptors.
paaS ee oe ac uen exceeds outflow, resulting in increased intraocular
Muscarinic antagonists, ganglion blockers and
* The carbamyl ester inhibitors compete with acetyl. pressure. In the presence of cholinesterase inhibitor neuromuscular blockers are all competitive antagonists
choline for the active site of the enzyme. Acetyl- eye drops, acetylcholine causes constriction of the
Acetic Acid + Choline which can be overcome by adequate concentrations of
cholinesterase becomes carbamylated as it cleaves sphincter muscle which surrounds the iris. The iris is
cholinergic agonists.
the ester linkage. The carbamyl group prevents drawn away from the canal of Schlemm, enhancing
Figure 2.6 Acetylcholinesterase inhibitors (ACHI) prevent
acetylcholine from binding to the active site of outflow of aqueous humor.
acetylcholinesterase for a period of minutes to hours. Myasthenia gravisisan autoimmune disease
acetylcholine degradation by inhibiting the enzyme e Muscarinic Antagonists
acetylcholinesterase.
Upon decarbamylation, the enzyme regains its in which antibodies bind to nicotinic receptors at the neu- The prototype antimuscarinic agent is atropine,
ability to cleave acetylcholine. romuscular junction. Cholinesterase inhibitors prevent an alkaloid isolated from Atropa belladona (deadly
acetylcholine degradation, which increases the probabil- nightshade) and many other plants. Atropine
¢ Th anophosphorus inhibitors have very high
ss go re ea blocks the muscarinic actions of cholinergic agonists
affinity for the active site of aga olan aart Me
acetylcholinesterase. ity that remaining receptors will bind acetylcholine.
(Table 2.5). Its actions are dose dependent, occurring
approximately in the following order as the dose of
atropine 1s increased:
Table 2.6 Cholinesterase Inhibitors - : ee : 8 ¢ Decreased salivary & bronchial secretions
‘DRUG —_——sMECHANISM_—_—CLINICALUSES_——— PHARMACOKINETICS _ ¢ Decreased sweating (sympathetic controlled)

¢ Pupil dilation and tachycardia
Agents that act in the brain
e Inhibition of voiding (constriction of sphincter and
Galantamine Competitive, Mild to moderate dementia Crosses the blood relaxation of detrusor)
(Razadyne) reversible of Alzheimer’s disease. brain barrier.
cholinesterase ¢ Decreased GI motility
inhibitor. ¢ Decreased gastric secretions
Donepezil Other muscarinic antagonists resemble atropine,
(Aricept)
but differ slightly in potency and specificity for various
Rivastigmine organs. These are noted in table 2.7.
(Exelon) In addition, some antipsychotics, antihistamines,
antidepressants, and opioids have anticholinergic
Physostigmine Carbamyl (see text) Antidote for anticholinergic Crosses the blood effects. Patients receiving these agents should be told
IM/IV
overdose. brain barrier.
that dry mouth, tachycardia and constipation are
Agents that primarily act outside the brain
possible side effects.
Neostigmine Carbamy| Myasthenia gravis Ambenonium has more Belladonna poisoning occurs with the ingestion
PO (all) IM/IV (Neostigmine, of anticholinergic drugs or plants such as night-
(Prostigmine) prolonged action than others
Pyridostigmine)
shade, thorn-apple, Jimson weed, stinkweed or
Ambenonium devil’s apple. Poisoning can also occur in children re-
(Mytelase)
ceiving atropinic eye drops because of systemic
Pyridostigmine absorption.
(Mestinon) Symptoms include severe antimuscarinic effects
Topical agents used for glaucoma (Table 2.7), restlessness, headache, rapid and weak
pulse, blurred vision, hallucinations, ataxia,
Demecarium Carbamyl Glaucoma “burning” skin and possibly coma. Children are
(Humorsol) Eye drops
more susceptible to intoxication and death from
Echothiophate Organophosphorus Glaucoma i belladonna poisoning.
(Phospholine iodide) Eye drops Poisoning is treated with IV physostigmine (Table 2.6).
CNS excitement or convulsions may be treated with
benzodiazepines.
26 Peripheral Nervous System

ar
Cho linergic A ntago nists (co nt.) ganglia. Because of the complex and unpredictable Sympathetic and parasympathetic ganglia are clusters ganglia. Ganglion blockers therefore reduce the effects of
actions of these agents, they are seldom used clinically of synapses between the spinal cord and visceral organs _— whichever system is predominant. In the resting individ-
= Gang lion Blockers (Hexamethonium, mecamylamine). Trimethephan in which nerves from the brain connect with nerves ual, parasympathetic control dominates all organs
Ganglion blockers (Ng antagonists) block nicotinic is, however, occasionally used to treat hypertensive which innervate end organs. Acetylcholine is the neuro- _ except blood vessels and sweat glands. Thus, when
receptors in both sympathetic and parasympathetic crisis. transmitter in all sympathetic and parasympathetic ganglion blockers are administered to nonstressed
PHARMACOKINETICS
Alkaloids
Atropine Effects at M, receptors: Preanesthetic to prevent respiratory secretions, Dry mouth, urinary retention, tachycardia, CNS-driven Half life 2.5 hrs. Frequent dosing necessary, Contraindicated in
¢ Stomach-— J secretion of pepsin and acid treatment of parkinsonism, severe bradycardia, bradycardia (general increase in vagal tone). At high doses, Eliminated through the urine. asthma patients.
peptic ulcers, irritable bowel syndrome, mild CNS excitation (irritability, delerium etc.) followed by CNS
Effects at M, receptors: diarrhea, bladder spasms, enuresis, bronchospasm depression, possibly resulting in death. Contraindicated in
Heart—low dose—bradycardia (CNS-mediated) closed angle glaucoma!, open angle glaucoma, prostatic
Heart—high dose—tachycardia hypertrophy, heart disease, obstructive bowel disease.
CNS-— J memory and concentration
Lungs—bronchodilation, J secretion
Gl tract- J motility
Eye—cycloplegia, mydriasis, T outflow resistance
Effects at M, receptors:
® Glands—-J salivation and sweating
Scopolamine More potent at eye and glands than atropine, but less Prevention of motion sickness, nausea and vomiting; More CNS depression than atropine at low doses. Similar Transdermal preparation has fewer side effects. Contraindicated if
potent at heart, lungs and GI tract. inhibits excessive motility of the GI tract in irritable to atropine at high doses. hypersensitive to
colon syndrome, mild dysentery, diverticulitis. belladonna or barbiturates.
Homatropine Eye Mydriasis and cycloplegia for refraction and treatment Drowsiness, blurred vision, sensitivity to light, dryness Moderately long acting ophthalmic preparation.
(Isopto Homatropine) of uveal tract inflammation. of mouth, tachycardia, headache.
Synthetic-tertiary compounds:
Dicyclomine (Benty!) Nonspecific direct relaxant effect on smooth muscle; No Treatment of irritable bowel syndrome to decrease Tachycardia, headache, flushing, drowsiness, nervousness, Little or no antimuscarinic activity with no Contraindicated in infants
antimuscarinic activity and thus little effect on gastric acid secretion. motility of the bowel. dry mouth, constipation, urinary retention. effect on gastric acid secretion. <6 months old.
Oxybutynin (Ditropan) Direct antispasmodic effect on smooth muscle; no For relief of bladder spasms resulting in urinary “an
antinicotinic effects. leakage and incontinence. Decreased sweating, rash, decreased lacrimation, mydriasis,
1/5 of the anticholinergic effect of atropine with 4 to 10 times the cycloplegia.
antispasmodic activity.
Flavoxate (Urispas) Relaxes smooth muscle of bladder and also has direct effect Symptomatic relief of dysuria, urgency, nocturia, “n”
on muscle. suprapubic pain, frequency and incontinence that

may occur with cystitis, prostatitis, urethritis.
Tolterodine (Detrol) re Treatment of overactive bladder. Dry mouth, constipation, headache, dyspepsia, blurred vision. Reduce dose with liver impairment.
Trihexylphenldy! (Artane) Centrally acting; reduces akinesia, tremor, and rigidity by 20%; Adjunct treatment of parkinsonism; control of Tachycardia, hypotension, dry mouth, disorientation, constipation, More selective CNS activity than atropine.
may also reduce drooling. drug-induced extrapyramidal disorders. blurred vision, urinary retention, decreased sweating.
“” “» an
Biperiden (Akineton) “n
on “yy “n
Procyclidine (Kemadrin) an
“or
Benztropine (Cogentin) «n
Synthetic-quaternary compounds:
Propantheline (Pro-Banthine) Gl, Urinary, glands. Inhibits gastrointestinal mobility and gastric “n
Does not cross blood brain barrier; little CNS side
acid secretion. effects; little effect on pupil; longer duration of action.
Gl ain “”
Methscopolamine “on
bromide (Pamine)
“on “ny
Clidinium bromide (Quarzan) wn «“n
“n “on
Mepenzolate bromide (Cantil) “n “n
Glycopyrrolate (Robinul) Treatment of peptic ulcer; IV form used to decrease “os “n
salivary and tracheobronchial secretions and to

block cardiac inhibitory reflexes during induction of
anesthesia and intubation.
Tricyclic benzodiazepine
Pirenzepine (Gastrozepine) Selective antimuscarinic activity for gastric acid secretory cells; Treatment of ulcers comparable to cimetidine and Less side effects: dry mouth most common. 80% renal excretion; little drug found in brain. European agent. New drug
lesser effect on salivary secretion. ranitidine. application pending in United States.
ees

individuals, one would predict a shift from parasympa- contraction (fasciculations). Blockade is overcome by Other patterns of stimulation include sustained
thetic predominance to sympathetic predominance. high concentrations of agonist (ACh). Local Anesthetics
tetany and single stimulation. Patients who respond
¢ Depolarizing blockade occurs when an agonist to a sustained (5 second) 50 Hz stimulation are ready Local anesthetics are used to block pain conduction
by nerves. They are used for infiltration anesthesia,
Neuromuscular Blockers binds to the receptor (causing fasciculations) for extubation (patient will be able to cough, inspire
followed by slow dissociation of the agonist from the and raise head). Failure to elicit > 5% of normal twitch local nerve blocks, spinal nerve blocks and epidural
e Neuromuscular Transmission receptor. During the time that the agonist remains to a single 0.2 msec, 0.1 Hz stimulation indicates that
nerve blocks. The first local anesthetic was cocaine,
which has largely been replaced by synthetic agents.
and Blockade bound to the receptor, other agonist molecules the blockade is sufficient for intubation.
cannot stimulate the receptor. Mechanism of Action: Local anesthetics inhibit nerve
Action potentials trigger calcium influx and the sub- conduction by reducing the permeability of the neuronal
sequent release of acetylcholine (ACh) from presynap- Consequence of Blockade: Neuromuscular block- membrane to sodium. This prevents sodium influx
tic motor neurons. ACh diffuses across the membrane e Reversing Neuromuscular Blockade
ade causes paralysis of all muscles, including those of which is required for propagation of action potentials.
cleft and binds to nicotinic receptors on the muscle end Purpose & timing: Most patients are removed from
respiration. Intubation and ventilation equipment must Chemistry: Lidocaine and procaine are the prototype
plate. Nicotinic receptors have five subunits, two of the ventilator before leaving the surgery suite. Reversal
be prepared prior to injecting neuromuscular blockers. local anesthetics (Table 2.9). All local anesthetics are com-
which bind ACh. When both are occupied, the ion of neuromuscular blockade allows the patient to use
Reversing agents must be available. posed of a hydrophilic domain connected to a hydro-
channel (the core of the ring formed by the 5 subunits) Monitoring Neuromuscular Blockade: The periph-
the diaphragm and intercostal muscles to breathe. It is
phobic domain by an alkyl chain. The drugs are classified
opens, allowing Na* and Ca** influx and K* efflux. eral nerve stimulator is a device which delivers electrical essential that at least a single twitch is produced in
as amides or esters according to the type of bond
The simultaneous opening of many ion channels leads impulses to nerves by way of electrodes placed on
response to stimulation before an attempt is made to
between the hydrophobic domain and the alkyl chain.
to membrane depolarization and propagation of an the skin. The response to the stimulus (muscle twitch)
discontinue artificial ventilation.
action potential in the muscle cell. The action potential indicates the level of neuromuscular blockade. Pre-reversal: Atropine or glycopyrrolate (muscarinic
induces the excitation-contraction coupling mechanism In the operating room, the most useful stimulation
antagonists (Table 2.7) are often administered prior to
reversing agents to prevent bradycardia, salivation and CH3
which causes muscle contraction.
Neuromuscular blockade is classified as nondepolar-
pattern is the train of four. Four impulses are delivered
other muscarinic effects caused by the administration
S. JOHs
over two seconds: NEC] Ch = N.
izing or depolarizing: of cholinesterase inhibitors.
Response: What response means: , C,Hs
Reversal: Cholinesterase inhibitors inhibit acetyl-
¢ Nondepolarizing blockade occurs when pure antag- 1 twitch Sufficient relaxation w /nitrous-narcotic
choline degradation (Table 2.6). The resulting increased
CH; ~e
3 twitches Sufficient relaxation w /inhalation agents Amide bond
onists compete with agonists for nicotinic receptors. acetylcholine concentration competes with neuromus-
4th twitch > 75% of 1st Patient ready for extubation
Because antagonists lack activity, there is no muscle cular blockers, reversing the blockade. Lidocaine
Table 28 Neuromuscular Blockers (N,,Antagonists) —

ACTION | LINICAL USES : ONSET/DURATION ADVERSE EFFECTS ORDER OF PARALYSIS NOTES
Competitive Nondepolarizing
Vecuronium Competes with ACh at nicotinic Adjunct to anesthesia: muscle relaxant, eases Onset: 3-5 min.
(Norcuron) receptors. Does not activate intubation and ventilation, eases orthopedic Duration: 25—40 min. IV. Little dependence on kidney Usually cardiac stable, but induces 1. Small muscles Very little
receptor. Blockade can be manipulation, controls respiration during (<20%) for elimination; dosage severe tachycardia, bradycardia, (fingers, eyes). histamine release.
overcome by high concentration chest surgery. adjustment necessary in liver A-V block or CHF complications 2. Limbs, neck, trunk.
of agonists. impairment. in 1% of patients. 3. Intercostal muscles,
diaphragm.
Atracurium Ideal for patients with kidney and liver failure Onset: 3-5 min. “n
SSS |
IV. Metabolism: Hoffman Moderate histamine release Administer slowly to
Serer.
(Tracrium) (metabolized in blood). Duration: 20-45 min.
degradation (breaks ester (vasodilation, hypotension). avoid massive
linkage) in bloodstream. histamine release.
an
Cisatracurium Onset: 2-5 min. «n
(Nimbex) Duration: 20-60 min. IV. 80% Hoffman degradation. Bradycardia, hypotension
Pancuronium “” Also has vagolytic actions. Used when elevated heart rate is desired; Onset: 1-3 min.
(Pavulon) Adjunct to anesthesia, to facilitate mechanical Duration: 35-55 min. lV. Depends on kidney Vagolytic (T heart rate). “wn
Histamine release
ventilation and intubation (60-80%) for elimination; Renal is rare.
and liver impairment requires
dosage adjustments.
Rocuronium Minimal cardiovascular effect. Facilitate rapid sequence and routine intubation; Onset: 1-3 min.
(Zemuron) Facilitate mechanical ventilation Duration: 15-60 min. IV. Cleared by the liver. Transient hypotension and
hypertension
“on
Doxacurium Adjunct to anesthesia in long surgery Onset: 3-10 min. “» “on
“»
(Nuromax) cases; facilitate mechanical ventilation. Duration: 40-240 min.
Competitive Depolarizing
Succinylcholine Initial fasculations (depolarization), Ideal for intubation because of rapid onset and
aT
Onset: 30-60 sec, (IV).
(Anectine) then Phase | block (4 min block of short duration. Adjunct to anesthesia and Duration: 3-5 min. IM/IV. Diffuses away from T intraocular pressure (contraindicated: 1. Fasciculations in chest and Effects not reversed by
(Quelicin) voltage sensitive sodium channels). mechanical ventilation. endplate, hydrolyzed by plasma open eye wounds) and gastric pressure abdomen acetylcholinesterase
Then, Phase I! block (desensitize pseudocholinesterase and (caution: reflux during intubation), 2. Neck, arms, legs inhibitors. Numerous
receptor, lasts 20 min). acetylcholinesterase. dysrhythmias. Postoperative muscle 3. Facial, pharynx, larynx contraindications (e.g.,
Parasympathetic stimulation pain (myoglobin release and 4. Respiratory muscles hyperkalemia, burns,
(therapeutic dose), sympathetic hyperkalemia). May trigger malignant digoxin, myopathies,
stimulation (high dose). hyperthermia. pseudocholinesterase
deficiency, glaucoma). |

31
Bicarbonate as an adjunct in local anesthesia: Bicar- penetrated by local anesthetics than larger neurons. Consequences of IV injection: When injecting local
bonate may be added to local anesthetic preparations i ZOs The order of loss of nerve function is pain, temperature, anesthetics subcutaneously or intramuscularly, aspirate
to increase the percent of anesthetic in the nonionized Hn _- C-OCH,CH)-N’ touch, proprioception and skeletal muscle tone. prior to injection to decrease the likelihood of intravas-
form. This accelerates penetration of the nerve sheath. . s
s C,Hs Epinephrine as an adjunct in local anesthesia: cular injection. Systemic absorption can affect the
Once internalized, the drug re-equilibrates to the Ester Bond Vasoconstriction response to epinephrine causes local cardiovascular system and the CNS. IV injection is
cationic (active) form. hemostasis, inhibiting distribution of local anesthetic characterized by oral numbness, light headedness,
Preferential blockade of small nerve fibers: Pain Procaine away from the site of injection, decreasing systemic altered taste, or tinnitus. Epinephrine, if included in the
and temperature fibers (Ad and C fibers) are more easily absorption and prolonging duration of action. anesthetic preparation, will cause transient tachycardia.
‘Table
2.9 Local Anesthetics, Injectable’
MECHANISM/ACTIONS INDICATIONS __ _ PHARMACOKINETICS
Amides
Lidocaine lonized form of drug temporarily All types of injection and Drowsiness, dizziness, Rapid (< 1.5 min) Moderate (few hours) Metabolized by mixed function Most frequently used.
(Xylocaine) reduces the permeability of topical anesthesia, sedation, heart block, arrhythmias, Epidural (5-15 min) oxidases in liver. Some
neuronal membranes to sodium. arrhythmias (Table 4.7A), hypotension, myocardial metabolites are active.
Thus, action potentials cannot intracranial hypertension. depression. Excreted in the urine.
be generated or propagated.
Ropivacaine oy
For production of local or regional Anxiety Rapid (1—5 min) Moderate-long we:
(Naropin) anesthesia for surgery, post-op pain Epidural (15-30 min)
and obstetrical procedures.
“oy
Bupivacaine Local infiltration, lumbar, subarachnoid, Similar to lidocaine. IV Slow (5 min) Long (several hours) ee Used when long duration is desired.
(Marcaine) caudal, peripheral nerve, dental block. administration may induce Epidural (10—20 min)
(Sensorcaine) Long duration increases utility for ventricular arrhythmias.
epidural block during labor.
“oy
Mepivacaine Infiltration, nerve block, and epidural Less drowsiness and
Rapid Epidural Moderate me Use with caution in renal impairment.
(Carbocaine) anesthesia, dental infiltration. amnesia than lidocaine.
(5-15 min)
(Polocaine)
(lsocaine)
(a)
Prilocaine Local anesthesia by nerve block or See Lidocaine; methe- Rapid (<2 minutes) Short
(Citanest) infiltration in dental procedures. moglobinemia in large doses. Epidural (5-15 min)
Esters
ony
Procaine Low potency. Infiltration and spinal Low toxicity.
Rapid Epidural Short (15-60 min) Metabolized by plasma cholinesterase.
(Novocain) anesthesia.
(15-25) Metabolite, p-aminobenzoic acid
may cause hypersensitivity.
“oy
Chloroprocaine Low potency. Infiltration, nerve block, PERMANENT neural! damage
Moderate Epidural Short (830-90 min) Vy Preferred for those susceptible to 7
(Nesacaine) epidural anesthesia. may result from use of this
(5-15 min) malignant hyperthermia.
agent for spinal anesthesia.
“oy
Tetracaine High potency. Spinal anesthesia. Most toxic ester. “oy
Slow Epidural Moderate Motor blockade lasts longer than
(Pontocaine)
(20-30 min) sensory

33
The biochemical disturbance responsible for these ¢ Acetylcholine
two diseases is unknown.
The synthesis, release and degradation of acety|-
choline are presented in Figure 2.4B. Acetylcholine binds
¢ Dopamine to both muscarinic and nicotinic receptors throughout
Dopamine is synthesized from Dopa, the hydroxy- the brain. De MeN MINe ETmid acetylcholine
lated congener of the amino acid tyrosine (Fig. 2.4A). It neurotransmission are presented in Tables 2.5 to 2.9.
is degraded by monoamine oxidase A in the brain and A cholinergic antagonist is used in the treatment of
monoamine oxidase B outside the CNS and by Parkinson’s disease to correct the imbalance of acetyl-
catechol-O-methyl transferase (COMT). choline and dopamine neurotransmission created by the
Dopamine receptors are classified as D, or D, recep- degradation of dopaminergic nerves (Table 3.5). Rivastig-
tors. Both subtypes reside in numerous regions of the mine, a cholinergic drug, is used in the symptomatic treat-
brain. No specific D, agonists have been identified. ment of Alzheimer’s disease. Cholinergic or anti-cholinergic
Apomorphine is a D, agonist. Activation of either drugs are not otherwise used to treat CNS disorders.
subtype inhibits the rate of neuronal firing. Particularly
important dopaminergic pathways include 1) the ¢ Gamma-amino butyric acid (GABA)
nigrostriatal pathway (from substantia nigra to striatum),
2) neurons of the chemoreceptor trigger zone of the GABA is an inhibitory amino acid neurotransmitter
medulla, which controls vomiting, and 3) projections
of brain interneurons and other cerebral neurons. The
from the hypothalamus to the intermediate lobe of the enzyme glutamic acid decarboxylase catalyzes the
Central Nervous System pituitary, which are thought to regulate prolactin release.
Antipsychotic drugs (Tables 3.3A and 3.3B) inhibit
synthesis of GABA from glutamate. GABA is stored in
presynaptic vesicles and binds to either GABA-A or
GABA-B receptors upon release.
dopamine-stimulated adenylate cyclase (usually associ-
ated with D, receptor activation) and block D, dopamine GABA receptors reside on two subunits of a four-
receptors, suggesting that psychoses may result from over- subunit receptor complex that surrounds and regulates
Thousands of neuronal signals race through our taken-up into presynaptic neurons and metabolized a chloride ion channel. GABA activation of the receptor
into active neurotransmitter molecules, 3) drugs which stimulation of dopamine receptors. Another disorder,
brains each moment, controlling our breathing, move- induces chloride influx into the neuron. This hyperpo-
inhibit the enzymes that degrade neurotransmitters Parkinson's Disease, is caused by too little dopaminergic
ments, thoughts and emotions with admirable preci- larizes the neuron, making it more difficult to fire
and 4) agonists that act at postsynaptic receptors. input from the substantia nigra into the striatum. Loss of
sion. Neuronal circuits provide the basic “road map” when stimulated by excitatory neurotransmitters.
the nigrostriatal dopamine neurons results in a relative
for brain signals, and chemical neurotransmitters carry Benzodiazepines enhance the actions of GABA at
Because numerous pathways in the brain use the decrease in dopamine input (inhibitory) compared to
information from one neuron to another. Neurotrans- GABA-A receptors, but not GABA-B receptors.
same neurotransmitter, manipulating transmission in acetylcholine input (excitatory, Fig. 3.3).
mission in the brain parallels that in the autonomic Agents which enhance the actions of GABA such as
a diseased pathway simultaneously affects synapses As mentioned above, impaired monoamine neuro-
nervous system (Chapter 2), but utilizes several benzodiazepines and barbiturates are used to treat anx-
of normal neurons. For this reason, CNS drugs are transmission has been implicated in causing depression,
chemicals and peptides in addition to acetylcholine iety and seizures and assedativesor muscle relaxants.
notorious for causing a variety of side effects. attention deficit disorder and narcolepsy.
and norepinephrine. Neurotransmitters that have been
This chapter presents CNS agents according to dis-
most carefully studied are introduced below.
eases that are treated by neurotransmission modulators. e 5-Hydroxytryptamine e Excitatory Amino Acids (EAA)
Treatable neurotransmission diseases fall into two
General anesthetics are also included in this CNS drug (5-HT, Serotonin) Glutamate or a structurally-similar chemical is an
categories: those caused by too much neurotransmis-
chapter, but their mechanism of action does not appear aaa neurotransmitter in many areas of the brain.
sion and those caused by too little neurotransmission. The amino acid tryptophan is hydroxylated and
to be mediated by neurotransmitter receptors. Stimulation of EAA receptors increases cation
Too muchY neurotransmission may be due to: then decarboxylated ee AT Te neurons, 5-HT is
stored (in vesicles), released, taken up into presynaptic conductance, leading to depolarization, or stimulates
ea focusof hyperexcitable neurons that fire in the phosphatidy] inositol turnover.
absence of appropriate stimuli (e.g., seizure Neurotransmitters of the Brain neurons and either recycled or metabolized.
Excitatory amino acids such as glutamate are
disorders). Therapy is directed toward reducing 5-HT is released from inhibitory neurons originating
e Norepinephrine in the raphe nuclei of the pons and midbrain. 5-HT thought to be important in learning, memory and other
the automaticity of these cells. brain functions. Glutamate-induced excitotoxicity is
The synthesis, release and degradation of norepi- stimulates either 5-HT, or 5-HT, receptors which are
¢ too many neurotransmitter molecules binding to nephrine are presented in Figure 2.4A. Four classes distinguished by the specific antagonist ketanserin implicated in the pathogenesis of Alzheimer’s Disease,
postsynaptic receptors (possible explanation for of adrenergic receptors (a,, a, B, and B,) are presented (5-HT,-specific). The hallucinogenic drug, lysergic Huntington’s Disease, stroke, epilepsy and amy-
psychoses). Therapy includes administration of in Table 2.2. Pathways in the brain that utilize norepi- otrophic lateral sclerosis (ALS). Riluzole (Rilutek®),
acid diethylamide (LSD) is a potent agonist at both
antagonists which block postsynaptic receptors. nephrine have not been clearly identified. Drugs that protects neurons from glutamate toxicity in animals
receptor subtypes. In addition to its role as a neuro-
Rec be eee may be due to: mimic or modulate norepinephrine transmission are and minimally slows progression of ALS.
transmitter, 5-HT increases small intestine motility
¢ ‘foo few neurotransmitter molecules binding to presented in Tables 2.1 to 2.4. and modulates vasodilation. Ninety percent of the
e The Opioids
. See" SPAT RTORUNT OER og AmB AE —
postsynaptic receptors (e.g., depression, Parkinson’s A leading hypothesis suggests that depression is ody’s 5-HT is astored in enterochromaffin cells of0
vind ial th al FEST EC LIAN CANT leIIA:
disease). Several treatment strategies increase caused by impaired monoamine (e.g., norepine- e intestine. Endorphins, enkephalins and dynorphins are opiate
neurotransmission, including 1) drugs that cause phrine, dopamine, serotonin) neurotransmission. Depression, attention deficit disorder and headaches receptor agonists that are cleaved from a protein called
release of neurotransmitter stores from the presynaptic Drugs which induce monoamine release are have been attributed to serotonergic imbalances. Many pro-opiomelanocortin. Opiate receptors are located along
terminal, 2) neurotransmitter precursors that are indicated for attention deficit disorder and narcolepsy. serotonergic agents have been developed in the last the periaqueductal gray matter and other brain areas.
few years for the treatment of these diseases. Morphine and related drugs act at opiate receptors to
34 Central Nervous System 35
depression and mania carry the diagnosis of bipolar from depression may be due to postsynaptic receptor
relieve pain (Table 3.7A, 3.7B). In times of stress or Antidepressants affective disorder. downregulation (expression of fewer receptors at the
pain, endogenous peptides act at opiate receptors.
Major depression is characterized by intense sadness The biogenic amine hypothesis suggests that synaptic membrane) in response to elevated concentra-
or loss of interest in usual activities, accompanied by depression is due to paucity of norepinephrine, tions of biogenic amines that result during antidepres-
¢ Other Neuropeptides poor appetite, insomnia or hypersomnia, psychomotor dopamine, or serotonin neurotransmission in the brain sant therapy (Fig. 3.1). ,
In addition to the endogenous opiate peptides, agitation or retardation, decrease in sexual drive, whereas mania is caused by excessive monoamine
several other peptides function as neurotransmitters fatigue, feelings of worthlessness, decreased concentra- neurotransmission. The observation that antidepressants Psychomot or Stimulants
(e.g., substance P, vasoactive intestinal peptide). These tion, or thoughts of death or suicide.
agents are generally cleaved from larger peptide Mania, another affective disorder, is characterized increase the synaptic concentration ofthe monoamines Attention deficit disorder (ADD) in children is
circumstantially supports the biogenic amine hypothesis
precursors. They can assume a variety of three by elevated, expansive, or irritable mood, accompanied characterized by short attention span, restlessness,
(Tables 3.1A, 3.1B). Lack of correlation between the onset distractibility, impulsivity and emotional lability. Hyper-
dimensional shapes, making it difficult to assess the by increased activity, pressure of speech, flight of ideas,
chemistry of peptide-receptor interactions. For this
of drug action (hours) and clinical response (weeks) activity is sometimes associated. Amphetamine-like
grandiosity, decreased need for sleep, distractibility, or however, draws criticism to the theory. The latency of
reason, no chemical agonists (other than morphine) or involvement in activities that have high potential for drugs reduce these symptoms in >80% of affected
antagonists have been identified for peptide receptors. antidepressant effects prompted the suggestion that relief children (Table 3.2). Many treatment plans also involve
painful consequences. Patients that cycle between
a: able 3.1 Antidepressants

y
DRUG © _ MECHANISM/ACTIONS INDICATION
S DRUG INTERACTIONS
Tricyclic Antidepressants
LEO EEE Se
|aaandln ces
Generally Not yet clear. Most block reuptake Used to treat major depressive Anticholinergic effects, Well absorbed, widely Tolerance to anticholinergic Do not administer to patients with May shorten the cycle length
of monoamine neurotransmitters, episodes. Also enuresis, cardiotoxicity, sedation, distributed, highly bound to side effects may develop. monoamine oxidase inhibitors in between mania and depression
increasing synaptic levels of agoraphobia (fear of open orthostatic hypotension, mania, plasma proteins, half-lives Physical and psychic their system (potentiation may be in patients with bipolar disease.
the transmitter. Subsequent spaces) with panic attacks, hypomania, weight gain, range from 8 hrs to 90 hrs, dependence develops lethal). Other drugs which bind to Patients coming out of
downregulation (reduction in the obsessive compulsive neurosis, impotence, obstructive jaundice. metabolized more rapidly occasionally. Sudden plasma proteins may displace depression are at increased
number of receptors) of post- chronic pain, neuralgia, by children and more slowly withdrawal leads to TCADs. May potentiate effects of risk of committing suicide
synaptic receptors may be the true migraine headaches. by elderly patients. malaise, chills, coryza and other CNS depressants. Potentiate because they regain the energy
| mechanism of action (Fig. 3.1). muscle aches. actions of other anticholinergic drugs. to fulfill their ideations.
on
Amitriptyline i Often prescribed by Most severe anticholinergic effects. PO/IM. ou on
(Elavil) nonpsychiatrists for the Highly sedating. Half-life 30-45 hrs
disorders listed above.
Imipramine a Original TCAD. Prescribed less Less sedating than amitryptiline. Signi- PO/IM. See “generally” above.
“oy eo “ny
(Tofranil) often because of side effects. ficant anticholinergic effects.Has quinidine- Half-life 10-25 hrs
Enuresis in children. like action that may induce arrhythmias.
Doxepin a Commonly used for indications Very sedating, substantial PO “ow “oy “on “oy
(Sinequan) described above. anticholinergic effects.
Desipramine Use increasing because of fewer Less sedation, fewer anticholinergic effects. ony on “ny wn
(Norpramin) anticholinergic effects. Sudden death in children has occurred.
Nortriptyline oN Use increasing because there is Both anticholinergic and sedating. “on “om “oy ony
(Pamelor, Aventyl) a more clear relationship between Half-life 18-45 hrs

plasma levels and clinical
efficacy than other TCADs.
on
Amoxapine Depression. Moderate anticholinergic and sedative “oy ony “9
(Asendin) effects. Neuroleptic malignant syndrome. Shortest half-life 8 hrs
Protriptyline sae See generally Least sedation, some PO. Longest half-life (75— na aa
(Vivactil) anticholinergic effects. 90 hrs). Thus lower daily
dose than other tricyclics. N
Clomipramine “” Very effective serotonin- Obsessive compulsive disorder. Very sedating. See “Generally” above. oa ee
(Anafranil) uptake blocker. Half-life 20-35 hrs
“n
Core structure of tricyclic antidepressants
Trimipramine Depression Very sedating. Half-life 7-30 hrs fees
(Surmontil)
Monoamine Oxidase Inhibitors
Tranylcypromine Blocks metabolism of biogenic Used to treat depression if tricyclic Hepatotoxicity, excessive CNS ° PO. Binds irreversibly to MAO Low likelihood of abuse. Potentiate the effects of sympa- Amphetamine-like
(Parnate) amines (norepinephrine, antidepressants fail and when stimulation, orthostatic hypotension. causing pharmacologic effects thomimetics (including tyramine structure.
Isocarboxazid serotonin, dopamine) increasing electroconvulsive therapy fails or is Overdose may cause agitation, . for weeks. It is inactivated by present in dairy and yeast products,
(Marplan) the synaptic concentration of refused. Also used to treat narcolepsy, hallucinations, hyperreflexia, acetylation. Thus patients who are amphetamines in diet pills, and
Phenelzine these transmitters. Suppresses phobic/anxiety states and Parkinson’s hyperpyrexia, convulsions, altered genetically “slow acetylators” will sympathomimetics in cold remedies).
(Nardil) REM sleep. disease. blood pressure. have elevated serum levels.

TabiQe Antidepressants (continued) oo
‘DRUG = —- MECHANISM/ACTIONS~ “INDICATIONS SOKINETICS BUSE POTENTIAL — DRUG INTERACTIONS
‘SelectiveSE ae
Fluoxetine Selective serotonin reuptake Depression. Obsessive compulsive Drug discontinued in 15% of Half-life is 48-72 hrs, thus one Life-threatening reaction possible Increased suicide rate
(Prozac) inhibitor disorder, bulimia nervosa. patients due to nausea, headache, dose/day. Takes weeks to achieve with monoamine oxidase inhibitors reported in patients
nervousness, isomnia, anxiety or equilibrium blood levels. (MAOI) and with cisapride. Do not use taking fluoxetine.
diarrhea, altered platelet function; rash. within 2 weeks.
Sertraline ae Depression, obsessive compulsive Nausea, headache, diarrhea, dry PO. Once daily dosing. High MAOI interaction. Similar to fluoxetine.
(Zoloft) disorder, panic disorder. mouth, dizziness, insomnia, fatigue, plasma protein binding. Does not affect levels of other
impotence, altered platelet function. protein-bound drugs.
Fluvoxamine
on
Obsessive compulsive disorder. Nausea, dry mouth, asthenia. PO. Reduce dose with liver Contraindicated with cisapride.
(Luvox) dysfunction.
Paroxetine _ Depression, Obsessive compulsive Nausea, vomiting, somnolence, PO. Once daily dosing. Reduce as)
Cimetidine increases paroxetine.
(Paxil) disorder, panic disorder. insomnia, dizziness, agitation, anxiety, dose with hepatic/renal Paroxetine reduces phenytoin &
weakness, headache, abnormal insufficiency. digoxin and increases warfarin.
ejaculation, altered platelet function.
Citalopram Depression
(Celexa)
Escitalopram
(Lexapro)
Trazodone a Depression. Used by some to treat Rash, hypertension, tachycardia, PO. Well absorbed, extensively Substrate for cytochrome
(Desyrel) aggressive disorders and cocaine shortness of breath, many CNS effects metabolized. Effects seen in CYP206
withdrawal. reported, J appetite, priaprism. 1-3 weeks.
Serotonin-Norepinephrine
Uptake Inhibitors.
Nefazodone Inhibits uptake of serotonin Depression. “” Life-threatening hepatic failure PO. Twice daily. Reduce dose Increase effects of triazolam Contraindicated with
(Serzone) and norepinephrine. occurs rarely. Wiliver dysfunction. Extensively and alprazolam. cisapride or pimozide.
metabolized by liver.
Venlafaxine Inhibit serotonin and Depression, anxiety. Sustained hypertension PO. 2-3 doses/day. Reduce “” Substrate for cytochrome
(Effexor) norepinephrine uptake. photosensitivity. w/renal or hepatic problems. CYP2D6
Desvenlafaxine Active metabolite is
(Pristiq) O-desmethylvenlafaxine
“oy
Duloxetine Depression, diabetic neuropathic pain. Hepatotoxicity, sexual dysfunction PO Substrate CYP2D6 and 1A2.
(Cymbalta)
oy
Milnacipran Fibromyalgia, depression. Suicide risk, serotonin syndrome PO Contraindicated with monoamine
(Savella) hypertension oxidase inhibitors. Minimal CYP450
metabolism.
(a oy
Levomilnacipran on “om
(Fetzima)
Others
Maprotiline Mechanism unclear, blocks Equal in potency to tricyclic Fewer anticholinergic effects, may PO. Metabolized in liver, excreted Hepatic enzyme inhibiting and Tetracyclic structure.
(Ludiomil) reuptake of norepinephrine. antidepressants. induce blood dyscrasias. in the bile. inducing agents.
Mirtazapine Unknown Depression, anxiety associated Low anticholinergic effects, orthostatic PO; half-life 20-40 hrs; Extensively A substrate for cytochrome Tetracyclic structure.
(Remeron) with depression hypotension, sedation, agranulocytosis. metabolized by the liver. P450 2D6, 1A2, 3A4.
Alprazolam Benzodiazepine with anxiolytic Adjunct to tricyclic antidepressants for No anticholinergic effects. Does cause PO. 70% protein bound, half-life = Some argue that Alprazolam Few interactions. Additive with
(Xanax) activity. Mechanism of depression and panic attacks. sedation and lethargy. 11 hrs. More rapid onset than has high dependency/abuse other CNS depressants.
antidepressant effects unknown. tricyclic antidepressants. potential and a severe
withdrawal syndrome.
Bupropion Unknown mechanism. Depression, smoking cessation. Seizures, hepatotoxicity, agitation, PO. Active metabolites may Drugs which lower seizure threshold. Aminoketone
(Wellbutrin) anticholinergic effects, tremor, nausea, accumulate, worse w/liver or Bupropion induces P450 enzymes, structure.
vomiting, headaches. kidney disease. altering drug metabolism.

Figure 3.1 Possible mechanism of tricyclic Figure 3.2 Why are CNS stimulants prescribed to hyperki-
PROPOSED ACTION OF TCAs antidepressant action. Depression may be due toa netic children? “Stimulant” is perhaps a misnomer for the actions of
Presynaptic > Postsynaptic relative decrease in monoaminergic neurotransmission. amphetamine-like drugs. Although the drugs were first characterized
Terminal
> Membrane
In animal studies, tricyclic antidepressants initially with regard for their ability to stimulate CNSfunctions, the effects of
block re-uptake of monoamines, resulting in higher these drugs are actually very complex. In animal studies, amphetamines
neuro-transmitter concentrations in the synaptic accelerate behavior which is slow in the absence of drug and suppress
cleft. Over a period of time, the postsynaptic neuron rapid behavior patterns. It has been hypothesized that the sedative
responds to the chronic elevation of monoamines by effects of amphetamines in hyperkinetic children are due to inhibition
expressing fewer receptors on the postsynaptic of “fast-rate” behavior, and that amphetamine-induced acceleration of
Block >
membrane. Ifindeed clinical response is due to receptor “slow-rate” behavior in children with attention deficit disorder may
initial effect
downregulation, then the hypothesis that depression is account for improved learning and memory skills.
due to inadequate monoaminergic transmission would
chronic effect be unsatisfactory. It is unclear whether these mecha-
nisms are responsible for relieffrom depression in
Downregulation humans.
of postsynaptic
p> | receptors
Table 3.2 Psychomotor Stimulants _

DRUG = =~‘ MECHANISM/ACTIONS INDICATIONS =—sUUNDESIRABLE EFFECTS PHARMACOKINETICS. TOLERANCE/DEPENDENCE | _ DRUG INTERACTIONS
Amphetamine-like drugs
d-Amphetamine Releases biogenic amines (NE, Narcolepsy, attention CNS overstimulation, PO. Well absorbed, enters Often abused. Severe tolerance MAO inhibitors: hypertensive Overdose treatment:
(Adderall) dopamine, serotonin) from storage deficit disorder in restlessness, dizziness, CNS, excreted without and dependence. crisis, CNS overstimulation, Acidify urine. Give
Methylphenidate vesicles. CNS stimulant, decreases children. No longer insomnia, increased blood undergoing metabolism, Methamphetamine (“Speed”) Barbiturates: supraadditive chlorpromazine to
(Ritalin) appetite, improves ability of trained recommended for pressure, arrhythmia, half-life = 4-6 hrs. acts similarly, but is very mood elevation. Tricyclic treat CNS symptoms
Dexmethylphenidate — athletes and coordination and obesity. anorexia, psychotic Elimination is slowed by addictive and often abused. Antidepressants: potentiate and alpha-receptor
(Focalin) performance of fatigued subjects, episodes. alkalination of urine. CNS stimulation, inhibit meta- blocker to lower
increases blood pressure. bolism of amphetamine. blood pressure.
co “9
Lisdexamfetamine Pro-drug for d-Amphetamine. ve ai Metabolized to active form
(Vyvanse)
Pemoline (Cylert) Mild CNS stimulant. Actions similar Attention deficit disorder. Insomnia, anorexia, liver PO. 12 hour half-life allows Low abuse potential. Preferred
oo”
Onset of therapeutic
to d-amphetamine. dysfunction (usually once daily administration. drug in “addictive environment” actions begin after
reversible). or when parents are suspected of 3—4 weeks of
using or selling the above agents. treatment.
Methylated Xanthines
SI
Caffeine Adenosine receptor antagonist. Prolonged apnea in Insomnia, restlessness, PO/IM/IV. Rapid complete Tolerance and dependence likely. Oral contraceptives and 85 mg caffeine/cup
High dose: T Ca*+ permeability in pre-term infants anxiety neurosis, nausea, absorption. Cross placenta, Withdrawal may cause headache, cimetidine: inhibit coffee, 50 mg/cup of
sarcoplasmic reticulum and T cAMP (unlabeled use). Included tachycardia, diuresis. Liver metab. half-life = anxiety and muscle tension. metabolism. Smoking tea or cola
by inhibiting phosphodiesterase. in some over-the 3-7 hrs. enhances elimination.
Stimulates CNS, constricts cerebral counter analgesic
arterioles, induces diuresis, preps, particularly
stimulates heart, bronchodilates. headache remedies.
“on “oy
Theophylline Cellular mech like caffeine. Bronchial asthma. Apnea “” PO. half-life = 3.5 hrs Use decreasing due
More CNS stimulation than caffeine. and bradycardia in in children, 8.5 hrs in to toxicity and
Increased cardiac stimulation and premature infants adults. questionable
diuresis. More effective (unlabeled use). efficacy.
bronchodilator.
Norepinephrine uptake inhibitors
Atomoxetine Selectively inhibits Attention deficit disorder. Suicide risk, serious PO. Enters CNS. Low abuse potential MAO inhibitors (see
(Strattera) norepinephrine uptake. cardiovascular effects, heart amphetamine above)
rate increase

family counseling and/or psychotherapy. Therapy is Many people consume coffee or soft drinks, which con-
usually tailored around the school schedule, the goal tain caffeine, to maintain alertness and to stay awake.
Caffeine is psychologically addicting and tolerance
Antipsychotic Drugs months leading to impaired ability to maintain interper-
being to enhance school performance and encourage be- sonal relationships, a job, or daily living skills. Active
havior whichis stiitable for the classroom. Drug therapy develops to CNS and cardiovascular effects. Withdrawal e Treatment of psychoses psychosis often occurs only during a small portion of
is often discontinued during school vacations. often results in headaches. Psychotic Disorders are clinical syndromes charac- the patient’s life. Between psychotic episodes, the
The anorectic property (appetite suppression) of _ Theop ine lisa methylated xanthine which exem- terized by impaired sense of reality, disturbances of patient is often withdrawn and perhaps antisocial.
d-amphetamine may cause growth retardation. These plifies aclinically useful drug with a narrow margin of thought & emotion, hallucinations (often auditory- Widely accepted theories suggest that psychosis is
effects are less pronounced with other psychomotor safety. Theophylline is used to treat bronchial asthma “the voice tells me... ”), delusions (“I possess the due, at least in part, to excessive dopamine neurotrans-
stimulants. Insomnia and nervousness are common as well as apnea andbradycardiain premature infants. power to... ”), and confusion. The biochemical defects mission. This theory was originally based on the observa-
side effects of all psychomotor stimulants. Serum concentrations must be maintained between for these diseases have not been clearly elucidated. tion that all antipsychotic drugs blocked D, dopamine
Amongst the methylated xanthines (Table 3.2), caffeine 10 and 20 pg/ml because it is ineffective at lower The syndromes listed may represent several discrete receptors. More recently, investigators demonstrated that
is included in some analgesic preparations because of its concentrations and it produces undesirable effects at diseases which have similar clinical presentation. antipsychotic drugs inhibit dopamine-stimulated cAMP
CNS-stimulating =
and
<a
cerebrovascular-constricting effects. higher concentrations. Schizophrenia is a psychotic disorder in which the production. This action cannot easily be attributed to
Re rege EEO ONE
patient exhibits symptoms listed above for at least six receptor blockade because dopamine-stimulated cAMP
Table 3.3A Antipsychotic Drugs _

DRUG = —- MECHANISM/ACTIONS INDICATIONS
Phenothiazines
CE/DEPENDENCE DRUG INTERACTIONS
Chlorpromazine The actions of antipsychotic drugs are Psychoses, including mania, Acute dystonia (abnormal muscle
(Thorazine) complex. The ability of antipsychotics to acute idiopathic psychoses and tone), Parkinsonism, malignant
Thioridazine block D, dopamine receptors correlates acute episodes of syndrome, akathisia, tardive All PO. Chorpromazine and Not addicting. Some physical Chlorpromazine enhances These drugs are sometimes
(Mellaril) with their clinical efficacy. Animal studies schizophrenia; nausea and dyskinesia, jaundice, sedation, Perphenazine also IM/IV. dependence may occur. the effects of central called neuroleptics because they
Mesoridazine have shown that dopamine synthesis vomiting; hiccoughs. orthostatic hypotension, Tolerance develops to sedative depressants, sedatives, reduce initiative and interest in
(Serentil) and metabolism increase with acute anticholinergic effects, effects. Some cross tolerance, analgesics, antihistamines, the environment, alleviate aggressive
Fluphenazine treatment and receptor upregulation adrenergic blocking effects and but drugs are not easity alcohol and morphine. and impulsive behavior, and reduce
(Prolixin) occurs after a few weeks of antipsy- allergic reactions to the drug. substituted for one another. Increases respiratory spontaneous movement and complex
Perphenazine chotic administration. It is likely that Decreased release of Choreoathetosis may develop depression caused by behavior in animals. Generally
(Trilafon) these effects occur as a regulatory corticotropin and gonadotropins. upon abrupt withdrawal. meperidine. Inhibits actions antipsychotic drugs with more
Prochlorperazine response to the drug-induced decrease Increased prolactin secretion. of levodopa and dopamine anticholinergic effects produce fewer
(Compazine) in dopaminergic transmission. Fewer extrapyramidal symptoms and agonists. extrapyramidal side effects.
Trifluoperazine adrenergic blocking effects than chlor-
(Stelazine) promazine. More anticholinergic effects.
Retrograde ejaculation, decreased
testosterone, retinopathy.
Less orthostatic hypotension and
adrenergic blockade, but more
extrapyramidal signs.
Thioxanthenes
ony
Thiothixene (Navane) Psychoses. Less sedative and hypotensive effects
than chlorpromazine. oy on
PO/IM. Not recommended hg
for children under 12.
Atypical Antipsychotics (fewer extrapyramidal side effects, more effective for treating negative symptoms of schizophrenia)
Aripiprazole Partial agonist at dopamine D2 and Schizophrenia, mania, Headache, somnolence,

(Abilify) serotonin 5HT1A, receptor antagonist depression, autism. extrapyramidal disorder.
at 5HT2A receptor. PO. Well-absorbed. Many drug interactions.
Asenapine Unknown Psychosis, bipolar mania Somnolence, insomnia,

(Saphris) extrapyramidal disorder. “oy
Lurasidone PO. Rapidly absorbed.
(Latuda)
Ziprasidone Unknown. Possible Dopamine D2 Schizophrenia. Prolonged QT/QTe interval. Risk for
(Geodon) and Serotonin 5HT2 antagonist. arrhythmia and sudden death. Elderly
patients with dementia-related psychosis PO. Low risk of abuse Drugs that inhibit
face increased risk of death. Tardive CYP3A4 activity.
dyskinesia. Somnolence.
a
42 Central Nervous System

43
production is linked to D, rather than D, receptors and
antipsychotic drugs have low affinity for D, receptors.
¢ Parkinsonism: Symptoms include “pill-rolling” with
fingers, limb rigidity, shuffling gait, bradykinesia, and
Table 3.4 Antiemetic/Antivertigo Drugs
mask facies caused by dopamine receptor antagonism DRUG REMARKS |
e Undesirable Neurologic Effects in the nigrostriatal pathway. Symptoms develop Prochlorperazine Prochlorperazine, triflupromazine, chlorpromazine and trifluoperazine are phenothiazine antipsychotics which are described in
As described in the chapter introduction, dopamine within one month of initiating therapy. Parkinsonism (Compazine) Table 3.3. These agents control vomiting by blocking D, dopamine receptors in the chemoreceptor trigger zone (CTZ) of the brainstem.
is the neurotransmitter of numerous pathways in the is treated with drugs described in Table 3.5. Promethazine Both a D, dopamine antagonist and an H, histamine antagonist which is used to control motion sickness as well as nausea and vomiting.
(Phenergan) Particularly useful following surgery because it reduces anesthesia-related nausea, induces light sleep and reduces apprehension.
brain. Because antipsychotic drugs block all D, ¢ Malignant syndrome: This relatively rare, but some-
dopamine receptors, they suppress all D, receptor- times fatal syndrome is marked by catatonia, rigidity, Metoclopramide Dopamine (D,) antagonist which is particularly useful for reducing chemotherapy-induced nausea. Also used Clinically as a Gl stimulant
(Reglan) to improve gastric emptying. Risk of tardive dyskinesia.
mediated dopamine actions in the brain. Specific neu- stupor, fluctuating blood pressure, fever and
rologic side effects of antipsychotic drugs include: dysarthria. Antipsychotic drug must be discontinued Scopolamine This anticholinergic is available as a transdermal preparation to prevent motion sickness. Overdose may cause confusion, memory
(Transderm-Scop) alterations and other anticholinergic effects.
promptly! Malignant syndrome is treated with
¢ Acute dystonia: Patients may develop face, neck bromocriptine (dopamine agonist) or dantrolene Anticholinergics/ Diphenhydramine, dimenhydrinate and meclizine are antihistamines with anticholinergic effects. Anticholinergic drugs reduce motion
aes sickness as well as emesis.
and back spasms within a week of therapy initiation. (mechanism of action associated with reversing
Antiparkinsonian drugs reduce symptoms malignant syndrome is unknown), but not Ondansetron
(Zofran)
Blocks serotonin (5-HT,) receptors, but not dopamine receptors. Used to control chemotherapy-induced nausea. Remarkably more
effective than other agents in patients receiving chemotherapy.
(Table 3.5). antiparkinsonian agents. Granisetron (Kytril)
Dolastetron
(Anzemet)
Alosetron (Lotronex)
Palanosetron (Aloxi)
_TOLERANCE/DEPENDENCE DRUG INTERACTIONS NOTES
Miscellaneous
“oy
Molindone (Moban) Chemically unrelated to classes Psychoses. Few sedative or extrapyramidal effects, PO. Rapidly absorbed and
listed above, but similar actions. no hypotensive effects. Some metabolized. Actions last
anticholinergic effects. for 24—36 hours.
“on
Loxapine (Loxitane) “oy
Psychoses. Less sedative and hypotensive effects than PO. IM. Complete absorption,
chlorpromazine. Similar extrapyramidal extensive metabolism.
effects. Sedation lasts for up to 12 hours.
Clozapine (Clozaril) Antipsychotic mechanism unclear. Schizophrenia in those Very few extrapyramidal side effects PO. Rapid absorption, Abrupt withdrawal may Potentiates antihypertensive Therapy is
Blocks dopamine receptors as whom traditional (EPS). Potent antimuscarinic effects. extensive metabolism. induce psychosis. and anticholinergic agents. with held if
well as cholinergic, adrenergic, antipsychotics have failed Agranulocytosis in 2%. No tardive Displaces drugs from granulocyte count
serotonergic & histaminergic or have produced dyskinesia or increased prolactin plasma proteins. is <1500/mm°.
neurotransmission. intolerable side effects. release.
oy
Olanzapine (Zyprexa)
“on
Psychoses. “”- No agranulocytosis. PO Substrate for P450 isoenzyme CYP1A2
bo
ee Se Se EE EES
Quetiapine Higher affinity for 5 HT, receptors Psychoses. No anticholinergic effects, orthostatic PO; extensively metabolized Hepatic enzyme inducers and
(Seroquel) than D, receptors. hypotension, sedation; less EPS in the liver. inducers of P450 3A.
Haloperidol (Haldol) Similar to phenothiazines. Psychoses, Tourette’s Less sedation, anticholinergic effects, PO/IM/IV. Begin treatment Transient dyskinesias may Enhances actions of CNS depressants,
syndrome, severe and alpha-adrenergic blocking effects at low dose, individualize be caused by abrupt alcohol, & anticonvulsants. Decreases
behavioral problems in than chlorpromazine. Rarely dose for each patient. withdrawal. actions of amphetamines. Severe
children, hyperactive hypotension. Extrapyramidal side hypotension with alcohol, epinephrine,
children (short term), effects may be dramatic. antinypertensives. Antimuscarinics:
Huntington’s Disease. Increase intraocular pressure and
reduce haloperidol effects. Lithium:
encephalopathic syndrome.
Pimozide (Orap) Blocks dopamine receptors. Tourette's Syndrome. Extrapyramidal disorder, tardive PO. Serum level does not Withdraw slowly. Dyskinesia Lowers seizure threshold in patients
dyskinesia, sedation, headache, correlate with activity. may develop after abrupt taking seizure medications.
sensory changes, hypotension. withdrawal. Potentiates CNS depressants.
Risperidone Mechanism unknown. Binds as Psychosis. Extrapyramidal disorder, tardive PO. Metabolites active. Withdraw slowly. Metabolized by P450 enzyme that is Metabolism varies
(Risperdal) antagonist at serotonin, dopamine, dyskinesia, sedation, hyperkinesia, Reduce dose with liver or inhibited by many other drugs. genetically among
alpha adrenergic and H1 histamine somnolence, constipation. kidney dysfunction and patients.
receptors. in elderly patients.
Palilperidone Unknown. Possible Dopamine D2 Schizophrenia Prolonged QT/QTc interval. Elderly RO; Low risk of abuse. QT interval-prolonging drugs,
(Invega Sustenna) and Serotonin 5HT2 antagonist. patients with dementia-related psychosis Abiraterone, antihypertensives,
lloperidone face increased risk of death. Dizziness, CYP2D6 or CYP3A4 inhibitors.
(Fanapt) somnolence, tachycardia, orthostatic
hypotension

Table 22Drugs Used to Treat Parkinson’‘ Disease ;
-MECHANISM/ACTIONS- “INDICATIONS PHARMACOKINETICS | —_—DRUG INTERACTIONS
Levodopa Decarboxylated to dopamine (DA) in Parkinson’s disease. Nausea, vomiting due to stimulation
PO. Rapidly absorbed, half-life = Pyridoxine: may reduce effects of levodopa by stim- Rarely used without coadministration
(e.g., |-dopa) brain. Improves neurological, motor, of emetic center (tolerance develops
1-3 hrs. Less than 1% of levodopa ulating decarboxylation. Antipsychotic drugs: block of dopa decarboxylase inhibitors
and altered mood symptoms of to GI effects), modest orthostatic
penetrates CNS because of peripheral DA receptors. MAO inhibitors: cause buildup of sym- (carbidopa).
Parkinson’s Disease. hypotension, arrhythmias in older
decarboxylation. This is circumvented pathomimetic amines (withdraw 2 weeks before
patients, involuntary movements
by coadministration of carbidopa, administration of levodopa). Anticholinergic drugs:
(dose limiting), psychiatric
a dopa decarboxylase inhibitor. synergism with levodopa, may delay absorption by
disturbances, 7 sexual activity due to
slowing gastric emptying. Antidepressant drugs: 7
actions on hypothalamus.
orthostatic hypotension.
Carbidopa Diminishes decarboxylation of Used in conjunction with Reduces levodopa-induced nausea
PO. Pills contain fixed amounts of Has no pharmacological action
(Lodosyn) |-dopa in peripheral tissues. Improve levodopa for Parkinson’s and vomiting. Does not alleviate
carbidopa and levodopa (Sinemet). when given alone.
effect of I-dopa, decreased required disease. most side effects caused by levodopa.
dose of I|-dopa by about 75% Has no known toxicities when
administered alone.
Amantadine Releases DA from intact terminals. Less effective than I-dopa for Few side effects. At high doses may
PO. Must adjust dose with renal Anticholinergic agents: Enhance CNS Less effective than |-dopa, more
(Symmetrel) treating Parkinson’s Disease. induce hallucinations, confusion &
failure side effects. effective than anticholinergics. Also an
Also used to treat drug-induced nightmares.
antiviral drug (Table 7.11).
extrapyramidal reactions.
Ergot-derivative dopamine receptor agonists
Bromocriptine Powerful D, agonist. Parkinson’s disease, particu- More nausea, hallucinations,

(Parlodel) PO. Initiate at low dose and May be used with |-dopa/carbidopa
larly when tolerance develops confusion, and hypotension than
individualize. Rapid, partial
to |-dopa or when symptom l-dopa. Less dyskinesia. Nonspecific
absorption. Half-life = 1.5—3 hrs.
relief “swings” between doses. CNS arousal.
Also hyperprolactinemia,
adjunct in treatment of
pituitary tumors.
Nonergot-derivative dopamine receptor agonists
Rotigotine Dopamine receptor agonist. Parkinson’s Disease, Somnolence, hallucinations,

(Neupro) Transdermal patch Few interactions.
Restless leg syndrome. psychoses, hypotension, impulse
control deficits.
“oy
Pramipexole “oy oy
“oy
(Mirapex) PO
Ropinirole
(Requip)
Monamine oxidase inhibitors
Selegilene Irreversibly inhibits monoamine Parkinson’s disease as adjunct “oy
PO. Rapidly absorbed. Crosses blood Potentiates effects of sympathomimetics Slows progression of Parkinson’s
(Eldepryl) oxidase type B (but not type A). to levodopa and carbidopa.
brain barrier. Metabolized in liver. when used in conjunction with
Rasagiline Inhibits intracerebral metabolic
levodopa/carbidopa.
(Azilect) degradation of DA.
Catechol-O-methyltransferase (COMT) inhibitors
Entacapone
(Comtan)
Tolcapone
Selective, reversible COMT
inhibitor
oo
PO Drugs metabolized by COMT. MAO

inhibitors.
—
——__——_—
(Tasmar)
—
Anticholinergic drugs (also listed in Table 2.7)

oy
Trihexyphenidy| Antagonists at cholinergic receptors. “oy
“oy
(Artane) Lessen ACh:DA imbalance in PO
Biperiden (Akineton) striatum. Less effective than I-dopa
Procyclidine for tremor and other symptoms.
(Kemadrin)
Benztropine
(Cogentin)

47
¢ Akathisia: Motor restlessness occurring within two Sites that differ from nausea and vomiting. Serotonin (5-HT,) antagonists Cholinergic
(excitatory)
months of antipsychotic drug initiation. Decrease tricyclic antidepressants are potent antiemetics, particularly useful for STR IATUM S—
a,
dose or discontinue drug. Treat with benzodi- eg oe Tet chemotherapy-induced nausea. A few cholinergic
azepines or low-dose propranolol. S ! antagonists and histamine antagonists reduce emesis
¢ Tardive dyskinesia: Up to 20% of patients treated y and control motion sickness (Table 3.4). The neural
with antipsychotics for months to years (particularly N R, pathways influenced by these antagonists have not ‘ UBSTANTIA
phenothiazines and haloperidol) develop involun- ' been clearly identified. NIGRA Dopaminergic
{inhibitory)
tary movements of the face, trunk, and extremities R
(dyskinesia & choreoathetosis). Often non-reversible. Core structure of phenothiazines Figure 3.3 The symptoms of Parkinson's Disease are caused
Anti-Parkinson Drugs by degeneration of dopaminergic neurons in the nigrostriatal
Parkinson’s Disease affects a half million Americans. pathway. Inhibitory dopaminergic neurons which project from the
substantia nigra to the caudate and putamen are most affected.
Antiemetics Symptoms include tremor (pill-rolling) at rest,
Cholinergic input (excitatory) to the caudate and putamen appears to
bradykinesia (slow movements), and cogwheel
Dopamine stimulation of D, receptors in the be unaffected; thus the balance is tipped toward cholinergic input.
rigidity.
chemoreceptor trigger zone (CTZ) of the medulla
The disease is caused by decreased dopamine
mediates some forms of nausea and vomiting. Several
neurotransmission in the nigrostriatal pathway
antipsychotic agents antagonize D, receptors in the
secondary to degradation of dopaminergic neurons
CTZ, suppressing nausea and vomiting due to cancer
that project from the substantia nigra (black
chemotherapy agents and other drugs and radiation
substance) to the striatum (caudate and putamen).
therapy (Table 3.4). Dopamine antagonists are not the
Figures 3.3 and 3.4 outline the neuropathology of
only class of drugs employed to prevent or treat
Parkinson’s Disease. Treatment consists of either
| Table 3.6A Opioid Analgesics and Antagonists

DRUG MECHANISM/ACTIONS —_ INDICATIONS UNDESIRABLE EFFECTS _TOLERANCE/DEPENDENCE DRUG INTERACTIONS NOTES
Full Agonists
Morphine Opiate receptor agonist. Induces Severe pain which cannot Respiratory depression,
IM/PO/PR/SCI/IV, epidural, Tolerance develops to analgesic Enhances actions of other The analgesic actions of
analgesia, sedation, respiratory be alleviated by non- constipation, CNS disturbances,
intrathecal. Poorly absorbed, effects, but not to constipating effects. CNS depressants. Increases opioids are threefold. The
depression, nausea, vomiting, narcotic analgesics or orthostatic hypotension, cholestasis,
metabolized by conjugation High abuse potential. Withdrawal neuromuscular blocker-induced perception of pain is
vertigo, miosis, ADH release, Gl weaker narcotic nausea and vomiting with
w/glucuronic acid. 4—6 hr leads to insomnia, pain, increased respiratory depression. reduced (increased threshold),
effects (decreased propulsion analgesics. Drug of choice initial doses.
duration. GI activity, restlessness. Additive with drugs that cause the unpleasant psycho-
and secretions, tonic spasm). for treating severe pain
hypotension. logical response is reduced,
Increases tone in bile duct, of myocardial infarction.
and sleep is induced even in
bronchi, ureters, and bladder.
the presence of pain.
“oy “my
Levorphanol (Levo-dromoran) Moderate to severe pain. oy
Various. Better oral rid
Oxymorphone (Numorphone)
absorption than
Oxycodone (Oxycontin)
morphine.
Hydromorphone (Dilaudid)
Tramadol (Ultram)
Meperidine (Demerol) oe Also used to treat rigors Like morphine. Overdose causes
IM/SC/PO/IV. Shorter duration “” With MAO inhibitors, causes
such as those induced by convulsions due to excitatory
than morphine. Metabolite severe CNS excitation, respi-
amphotericin B. actions of metabolite.
is excitatory to CNS. ratory depression, or hypotension.
Methadone Full morphine-like actions, Detoxification of narcotic Similar to morphine.
IM/SC/PO. Excreted more Cross dependent with morphine Detoxification replaces
weaker sedative. addiction. Severe pain in
slowly than morphine (half- (basis for narcotic detoxification). heroin dependence with
hospitalized patients.
life = 25 h). Withdrawal Tolerance develops readily. methadone dependence.
symptoms are less intense, Less psychologically addicting Then slowly reducing
but prolonged. than morphine. methadone dose to zero.
Fentanyl! (Sublimaze) More potent than morphine. Preoperative medication Respiratory depression less likely.
IV. Rapid onset. Half-life = No tolerance or dependence when Transdermal, transmucosal
Respiratory depression less likely. | used in anesthesia. Muscle rigidity, mild bradycardia.
4h. Shorter duration than used as an anesthetic. preparation available for
morphine. chronic pain.
Sufentanil Most potent analgesic. Used in anesthesia. Little data available.
IV. Little data available.
Alfentanil See Fentanyl. wn “n
“on
/— IV. Fastest onset.
Remifentanil (Ultiva) cae a May cause chest wall rigidity if IV. ony
IV tubing must be changed
infused rapidly.
ey or cleared after remifentanil.

49
increasing dopamine neurotransmission or blocking prototype agonist is morphine, which is a potent anal-
cholinergic neurotransmission (Table 3.5, Fig. 3.4). gesic and sedative. Agonists with similar analgesic
effects (full agonists) are described in Table 3.6A and
partial agonists are described in Table 3.6B. Opioid
Central Analgesics agonists also reduce intestinal motility (antidiarrheals),
¢ The Opioid System reduce coughing (antitussives) and induce vomiting.
Nonanalgesic agonists used for these purposes are
Opium, derived from poppies, relieves pain and
listed in Table 3.6C.
induces euphoria by binding to “opiate receptors” in
Degeneration Patients on morphine and related agonists must be
the brain. These opioid drugs mimic the actions of
monitored for signs of CNS-mediated respiratory
three peptide families in the brain known as the
depression, which is the dose-limiting side effect of
NORMAL PARKINSON'S PARKINSON'S endorphins, the enkephalins, and the dynorphins.
opioid agonists.
+ L-DOPA These peptides, along with several nonopioid peptides
Principles that should be kept in mind when pre-
(MSH, ACTH, & lipotropin) are cleaved from the
scribing pain relievers include:
Figure 3.4 Synaptic view of Parkinson's Disease (PD) and therapy. Dopaminergic terminals decay in PD, leading to decreased protein precursors pro-opiomelanocortin (POMC),
dopamine (DA, solid triangles). L-dopa, an amino acid precursor of DA crosses the blood brain barrier, enters surviving DA terminals and is proenkephalin, and prodynorphin (Fig. 3.5). ¢ Narcotic analgesics should be employed only when
converted to DA. Increased DA neurotransmission partially restores the dopamine-acetylcholine neurotransmission balance. Three subtypes of receptors, mu, kappa and delta, pain cannot be relieved by non-narcotic analgesics
mediate the effects of opioid drugs and peptides. The (Chapter 9).
|Table ¢ee
a Cpe Analgesics and ertaaonics (cont.)
- MECHANISM/ACTIONS _ INDICATIONS = —_—sUNDESIRABLE EFFECTS NOTES |
WeakOe:
Codeine A prodrug: 10% of dose is Minor pain relief. Similar to morphine, but less intense PO/SC/IM. Rapid absorption, Low risk of abuse. Similar to morphine. Included in a number
converted to morphine. Actions Cough. at doses which relieve moderate half-life = 3 h. 10% demethylated of cough medicine
are due to morphine. Also an pain. At high doses, toxicity is as to form morphine, the rest is conju- preparations because
antitussive (Suppresses coughing). severe as with morphine. gated in liver and excreted in urine. of antitussive effects.
“on
Propoxphene Weak analgesic (less potent Relief of minor pain. Dizziness, sedation, nausea, PO. Well absorbed, Half meta- Low risk of abuse. Overdose often leads to
(e.g., Darvon) than aspirin). vomiting. Overdose causes bolized in first pass. death, particularly in patients
convulsions, CNS depression, Half-life = 15 h. with history of psychiatric
coma, death. disorders.
Mixed Agonist-antagonists—lower abuse potential
Pentazocine Similar to morphine, but less Moderate pain. Also used as Similar to morphine. IM/IV/SC. More rapid onset, Lower risk of abuse than morphine. To prevent IV abuse, it is
(Talwin) potent. Antagonized by naloxone, preoperative medication. shorter duration than Antagonist effects can induce mixed with naloxone. Taken
not by nalorphine. morphine. Well absorbed, withdrawal in narcotic addicts. orally, only pentazocine is
highly metabolized. absorbed. By IV however,
naloxone blocks pentazocine.
-
Nalbuphine (Nubain) “” Various. Abstinence syndrome upon Increase CNS depression Antagonist activity: -
Moderate to severe pain. Low incidence of respiratory
Dezocine Preoperative medicine, depression, sedation, dizziness, withdrawal. Lower abuse potential caused by CNS Bupromorphine > Butorphanol
Butorphanol than morphine. depressants. > Desocine = Nalbuphine
combination anesthesia. nausea, vomiting.
Buprenorphine > Pentazocine.
Pure Antagonists
Naloxone Surmountably blocks opioid Treatment of narcotic overdose. _ Induces narcotic withdrawal syndrome IV. Rapid onset, short half-life Induces abstinence syndrome in Reverses narcotic-induced
(Narcan) receptors. Has no effect in (aun): narcotic-dependent patients. depression.
Diagnostic agent (for evaluation (appetite loss, muscle contraction,
narcotic-free persons. of addiction) in methadone fever/chills, restlessness, cardiovascular
programs. To reduce postopera- and respiratory symptoms, nausea,
tive respiratory depression. vomiting, diarrhea.)
PO. Duration > 24 h. wm oy

Naltrexone Similar to naloxone, but longer “” Also indicated for treatment pa
(ReVia) duration. of alcoholism.

Pro-opiomelanocortin ¢ Abuse and street-sales of narcotic agents are com- Anti-anxiety Agents and Sedatives
mon. Monitor patients for drug-seeking behavior.
Barbiturates and benzodiazepines enhance the
¢ Remind patients that constipation is a likely side actions of the inhibitory neurotransmitter, gamma-
ACTH y -lipotropin y effect and that a stool softener may be necessary. aminobutyric acid (Fig 3.6, Tables 3.8A, 3.8B and 3.8C).
are ee Agents from both classes are effective sedative-
ames v Vicar Other Central Analgesics hypnotics (sleep-inducing agents), antianxiety agents,
and anticonvulsants (Table 3.9). Benzodiazepines are
Tramadol (Ultram®) is a weakly opiate synthetic
prescribed more often than barbiturates because they
analgesic that is indicated for moderate to severe pain.
SS cause fewer side effects.
B-MSH Tramadol and its primary metabolite bind to p-opioid
The non-barbiturate /non-benzodiazepine sedatives
receptors, but is only partially antagonized by nalox-
are not listed in a table. Zolpidem (Ambien), Chloral
one. It also reduces uptake of norepinephrine and
hydrate, paraldehyde, meprobamate and glutethimide
Figure 3.5 Cleavage of pro-opiomelanocortin (POMC) into B-endorphin and non-opioid peptides. POMC serves as a precursor (pro-) serotonin.
for the opiate peptide, B-endorphin (-opio-); for a-, B- and y-melanocyte-stimulating hormone (MSH, -melano-); for adrenocorticotrophic hormone cause sedation, but are neither benzodiazepines or bar-
Compared to other central analgesics, it produces biturates. Zolpidem acts through the GABA receptor
(ACTH, -cort-); and for a- and B- lipotropin (-in). Notice that the peptides are not located end-to-end, but that some of the smaller peptide sequences
less respiratory depression and histamine release than
are embedded in larger sequences (e.g., a-lipotropin, B-MSH and B-endorphin are contained within B-lipotropin). Two other protein precursors and its actions mimic benzodiazepines. It is used for
contain enkephalins and dynorphins. Proenkephalin contains seven met-enkephalin sequences (Tyr-Gly-Gly-Phe-Met). Prodynorphin contains opiates and less platelet toxicity than nonsteroidals. short-term treatment of insomnia. Chloral hydrate is
three leu-enkephalin sequences (Tyr-Gly-Gly-Phe-Leu) and the sequences for dynorphin A, Dynorphin B, a-neodymorphin and B-neoendorphin. Toxicity includes constipation, dizziness, nausea /
used for sedation in children. It is reduced in the body
vomiting, headache, pruritis. Tramadol-induce miosis
to trichloroethanol, a potent ethanol. Like ethyl alcohol,
may limit the utility of pupil examination in head the side effects of chloral hydrate include mucosal irri-
Rice
ble3.6C Nonanalgesic Uses of ee trauma patients. Tolerance, dependence, abuse are less
likely to develop with Tramadol than with opioids.
tation, light-headedness, malaise and ataxia. Paralde-
hyde, meprobamate and glutethimide are seldom used.
_ REMARKS
DiSReneayits Diphenoxylate is used to treat diarrhea. It is too insoluble to escape the GI tract. Like morphine,
it causes constipation, but diphenoxylate fails to produce analgesia. Antidiarrheal effects can
Table 3.8A Comparison of Benzodiazepines and Barbiturates
be blocked by narcotic antagonists (Table 3.6). BARBITURATES BENZODIAZEPINES
Dextromethorphan Dextromethorphan is the dextro- isomer of codeine. It is included in cough medicine because Mechanism/Actions: Bind to receptor adjacent to GABA Mechanism/Actions: Bind to benzodiazepine site on
of its centrally acting antitussive effects. Dextromethorphan actions are unaffected by narcotic receptor on chloride channels. Results in retention of neuronal GABA receptor complex. Enhances GABA-
antagonists. It causes little sedation or GI disturbances. GABA at its receptor causing increased flux of chloride mediated chloride influx (neuronal inhibition). At therapeutic
through the channel. Induces sedation, euphoria, other doses may also inhibit neurons by unknown mechanisms
Apomorphine Stimulates the chemoreceptor trigger zone, causing nausea and vomiting. These emetic mood alterations, hypnosis, “barbiturate” fast waves in which are unrelated to either GABA or chloride influx. Cause
EEG, respiratory depression. At high doses, may cause sedation, skeletal muscle relaxation, and “barbiturate” fast
effects are blocked by narcotic antagonists. Apomorphine has few other narcotic-like effects.
cardiovascular depression or death. waves on EEG. Also has anticonvulsant effects.
Indications: Clinical uses include treatment of epileptic Indications: Generally, benzodiazepines are used for
seizures and as a component of anesthesia. treatment of anxiety and neurotic states, nervous tension,
Benzodiazepines are usually preferred to barbiturates agitation, psychosomatic illness, delerium tremens. Also used
:Table 3.6D Selected Combination Products ( ontaining Narcotics for treatment of anxiety. Antipsychotics are preferred for for skeletal muscle relaxant, anticonvulsant, and sedative
properties. Diazepam is the benzodiazepine of choice for
treatment of neurotic states.
ACTIVE INGREDIENTS — muscle relaxation and intractable seizures.
Tylenol w/Codeine No. 3 30 mg. codeine phosphate and 325 mg. acetaminophen Undesirable effects: Drowsiness, clouding of consciousness, Undesirable Effects: Drowsiness, clouding of consciousness,
dysarthria, ataxia, “paradoxical” stimulation due to behavioral dysarthria, ataxia, behavioral disinhibition, dermatitis.
Tylenol w/Codeine No. 4 disinhibition, CNS depression to the point of coma and
60 mg. codeine phosphate and 300 mg. acetaminophen
lo respiratory arrest, laryngospasm.
Fiorinal w/Codeine No. 3 30 mg. codeine phosphate, 325 mg. aspirin, 40 mg. Pharmacokinetics: Primary difference between various
Pharmacokinetics: PO/PR/IM/IV. Well absorbed orally.
caffeine, 50 mg. butalbital Give IM only if patient can’t take orally. Give IV slowly benzodiazepine agonists are their pharmacokinetic properties
because of hypotension risk. Barbiturates vary markedly (Table 3.8C).
Vicodin 5 mg. hydrocodone bitartrate & 650 mg. acetaminophen in lipid solubility and plasma protein binding (Table 3.8B).
Barbiturates induce P450 enzymes in the liver which T
Opium and Belladonna* 60 mg. powdered opium and 15 mg. powdered Used for control metabolism of phenytoin, digitoxin, coumadin and others.
Suppositories’ (anticholinergic) belladonna extract of diarrhea. Ea
Tolerance/Dependence: Tolerance, metabolic dependence, Tolerance/Dependence: High dose, chronic therapy may
Percocet 5 mg. oxycodone and 325 mg. acetaminophen and psychologic dependence are likely. Dependence lead to dependence. Abrupt withdrawal may cause syndrome
eee presents much like chronic alcoholism. Upon withdrawal, that mimics alcohol withdrawal (convulsions, hyperthermia,
Percodan 4.5 mg. oxycodone HCl, 0.38 mg. oxycodone convulsions, hyperthermia, and delerium may be severe delerium). Cross tolerance and dependence occur.
terephthalate and 325 mg. aspirin enough to cause death.
Drug Interactions: Barbiturates as a class interact with Drug Interactions: Additive with alcohol.
Darvocet-N 100 100 mg. propoxyphene napsylate and 650 mg. acetaminophen
= over 40 other drugs. These interactions are largely due
to alteration of metabolizing enzymes in the liver or
Darvon-N W/A.S.A. 100 mg. propoxyphene napsylate and 325 mg. aspirin
interference with the absorption of other drugs.

53
Generalized seizures involve both hemispheres.
GABA
Receptor
Chloride lon They occur either as a result of hyperexcitability Table 3.8C Comparison of Benzodiazepines
throughout the brain or because an epileptic focus
Channel
spreads to both sides of the brain. By the latter mecha-
METABOLISM NOTES
Benzodiazepine Picrotoxin nism, focal seizures may become generalized. Long Acting
Receptor Receptor Diazepam (Valium) Most rapidly absorbed. Metabolized in liver to Indicated for anxiety disorders.
e Types of Seizures and Drugs of Choice active metabolites which prolong clinical duration
of action. Metabolized slowly by infants, elderly
¢ Partial Seizures: Simple partial seizures consist of a and patients with hepatic disease.
Barbiturate
single detectable motor, sensory or psychological dys-
Receptor Flurazepam (Dalmane) Active metabolites prolong duration of action. Commonly used for insomnia.
function which does not change during an episode. Quazepam (Doral)
Consciousness is retained throughout. Partial complex
seizures begin in a focal area, usually in the temporal Estazolam (Prosom) Metabolites are minimally active. Indicated for insomnia.
lobe or limbic cortex, and spread. Focal signs are often Clonazepam (Klonopin) yee Used primarily for anxiety disorders.
followed by automatisms (e.g., lip smacking, sweat-
ing) and dulled or lost consciousness. Effective drugs Chlorazepate (Tranxene) PRODRUG is hydrolyzed in stomach to active agent.
Figure 3.6. Schematic model of the GABA/Benzodiazepine/ include carbamazepine, phenytoin, clonazepam and Chlordiazepoxide (Librium) Longest duration of action. “n
Barbiturate receptor complex. The receptor complex surrounds a primidone. Valproic acid is sometimes added. Shorter Acting
chloride ion channel. Gamma-amino butyric acid (GABA) is an inhibitory
neurotransmitter. GABA binds to the receptor causing chloride influx. ¢ Absence Seizures (Petit mal): Generalized seizures
Midazolam (Versed) Short acting, water soluble compound. Used frequently in anesthesia.
The movement of chloride into the neuron hyperpolarizes the neuronal in children or teens which present as brief episodes Metabolites not active.
membrane, making it more difficult for excitatory neurotransmitters to of blank staring but no convulsions. Effective drugs
depolarize the cell. Benzodiazepines and barbiturates enhance the actions include ethosuximide, valproate, clonazepam and Alprazolam (Xanax) Metabolites not active. Has antidepressant actions as well as anxiolytic
of GABA, but fail to open the chloride channel in the absence of GABA. actions. Also used to treat panic attacks. Unlike
trimethadione. many benzodiazepines, alprazolam does not
cause daytime drowsiness.
¢ Generalized Tonic-Clonic Seizures (Grand mal):
Begin with prolonged contractions of muscles in exten- Lorazepam (Ativan) Metabolites not active. Useful for achieving rapid sedation of agitated
sion followed by cyanosis due to arrested breathing. patients. No daytime sedation.
ee |
Patients then experience whole-body clonic jerks. Oxazepam (Serax) Poorly absorbed, requires higher doses than Useful for treating elderly patients and patients
Anticonvulsants Treatment options include phenytoin, diazepam diazepam to achieve same effects. with liver dysfunction because it does not rely
on the liver for metabolism.
Seizures occur as a result of hyperactivity or hyper- carbamazepine, phenobarbital and primidone.
synchronicity of neurons in the brain. Focal seizures ¢ Status Epilepticus: Continuous series of seizures Temazepam (Restoril) Metabolites may be active.
involve a cluster of neurons and present with unilateral without reawakening. May cause permanent brain Triazolam (Halcion) Commonly used to sedate hospitalized patients.
symptoms. They are often due to structural abnormali- damage. Intravenous, diazepam, phenytoin or
ties such as scars, tumors or inflammation. phenobarbitol is recommended for treatment.
Table 3.88Comparison ofBarbiturates e Principles of Anticonvulsant Therapy in 1846 by a second-year medical student at
Massachusetts General Hospital. Ether has since
oRUGS = e Increase dose of suitable single agent until desired
been replaced by non-volatile agents.
effect is achieved or until toxicity prevents further
Long Acting Duration: 10-12 hours. Barbital is excreted primarily by the kidneys. Phenobarbital is metabolized Inhalation anesthetics do not appear to work
Phenobarbital by the P450 enzymes in the liver. Phenobarbital induces P450 enzymes, causing increased increase.
through a receptor mechanism and the mechanism
Mephobarbital metabolism of many drugs. Phenobarbital is used clinically as an anticonvulsant. ¢ Follow serum drug levels. of action remains a mystery. Theories suggesting
Short Acting Duration: 3-6 hours. Metabolized by P450 enzymes in liver. Amobarbital is sometimes ¢ Asecond drug may be added if maximal doses of that anesthetics work by altering the lipids in cell
Amobarbital administered by psychiatrists during analysis or therapy. Prior to some neurosurgical procedures the initial drug fail. The initial drug should then be membranes stem from the observation that the potency
Pentobarbital (e.g., temporal lobectomy for intractable seizures) amobarbital is injected unilaterally into the
Secobarbital carotid artery to determine the dominant hemisphere of the brain. tapered and discontinued. of anesthetics correlates extremely closely with the
e Abrupt discontinuance of an anticonvulsant may solubility of the drug in oil.
Ultra-short Acting Duration: <3 hours. These drugs are deposited in fat, then secondarily metabolized by the liver.
induce status epilepticus. Always taper doses. The measure of potency is the minimum
Thiopental
Methohexital alveolar concentration (MAC). MAC is the
¢ Inform female patients of association with birth defects.
Hexobarbital concentration of anesthetic that causes immobility
in 50% of subjects exposed to the agent at one
atmosphere. The MACs of commonly used
General Anesthetics anesthetics are:
“ Flumazenil (Romazicon) is a competitive antagonist at benzodiazepine receptors. Used clinically to reverse
Inhalation anesthetics are inert vapors used during
benzodiazepine sedation or overdose and as part of the treatment for hepatic encephalopathy. Resedation occurs e Halothane — 0.75
surgery to achieve sedation, muscle relaxation and
in about 10% of reversals. Seizures infrequently occur with reversal, usually following multi-drug overdose.
analgesia. The first anesthetic, ether, was introduced e Enflurane — 1.68

Barbiturate and benzodiazepines
|Dszepon(Valium) Enhances GABA-mediated chloride Status epilepticus. Rapid onset Drowsiness, clouding of |V/PO/PR. Rapid onset Additive with CNS depressants.
Lorazepam (Ativan) influx (Fig. 3.6). useful for stopping active seizures. consciousness, ataxia, other (IV <5 min). Metabolized in Many drugs inhibit metabolism of
Not used for chronic seizure control. signs of CNS depression. liver. Diazepam has longer half-life. diazepam.
Clonazepam
on
Alternative to ethosuximide or
“n PO. Additive with CNS depressants.
Clorazepate valproic acid for absence seizure.
Tiagabine (Gabitril) Blocks presynaptic GABA-uptake. Partial seizures. Dizziness, nervousness, tremor. PO. Titrate dose over 6—20 Cleared faster in patients taking
weeks until effective. other anticonvulsants.
Miscellaneous
Phenytoin Reduces sodium, calcium and potassium All types of seizures except Nystagmus, ataxia, other CNS PO/IV/IM. Therapeutic Many drugs alter metabolism
(Dilantin) currents across neuronal membranes. absence. disturbances, bone marrow serum level is 10—20 mcg/ml. and protein binding of phenytoin
Fosphenytoin Unclear which effects are responsible for suppression, gingival hyperplasia, Siow onset, long half-life. and vice-versa. Consult a
(Cerebyx) seizure prophylaxis. hepatotoxicity, G! disturbances. Metabolized in liver. comprehensive list of drug
IV administration may cause CNS interactions prior to changing
depression, severe hypotension, medications in patients on
arrhythmias, and hyperkinesis. phenytoin.
Carbamazepine Similar to phenytoin. Also has antidiuretic All types of seizures except Agranulocytosis or aplastic anemia PO. Induces its own Do not administer to patients
(Tegretol) effect. Chemical structure similar to absence. Trigeminal neuralgia, (monitor blood counts), vertigo, metabolism by stimulating with monoamine oxidase inhibitors
Oxcarbazepine tricyclic antidepressants. manic depression, schizophrenia nausea, vomiting. P450 enzymes in liver. (Table 3.1B) in their system
(Trileptal) that fails to respond to (potentiation may be lethal).
Eslicarbazepine antipsychotics.
(Aptiom)
aes |
Valproic Acid Mechanism unknown. Enhancement of All seizure types, particularly Severe/fatal hepatotoxicity, particularly PO/IV. Metabolized in liver, highly Additive with other anticonvulsants.
(Depakote) GABA neurotransmission postulated. disorders of combined seizure types. in small children, much less in adults protein bound, half-life longer in Levels decreased by aspirin and
Manic episodes in bipolar disorder. Thrombocytopenia, hyperammonemia. children and patients with liver damage. cimetidine.
Ethosuximide Mechanism unknown. Absence seizures. Nausea, vomiting, decreased appetite, PO. Metabolized in liver, not protein Ethosuximide increases phenytoin
(Zarontin) and weight loss. bound. Therapeutic level 40-100 mcg/ml. levels and decreases primidone.
Gabapentin Mechanism unknown. Related to GABA, Adjunctive treatment of partial Somnolence, ataxia, dizziness, other PO. Excreted unchanged by kidneys. Gabapentin absorption decreased
(Neurontin) but likely acts at distinct receptor. seizures. CNS effects. Reduce dose w/renal dysfunction. by antacids.
Lamotrigine Mechanism unclear. May stabilize Adult patients with partial seizures Dizziness, headache, nausea, ataxia, PO. Induces its own Reduce dose if patient is on
(Lamictal) neurons and affect glutamate/aspartate or Lennox-Gastaut Syndarome. somnolence, diplopia, blurred vision. metabolism. valproate. Other anticonvulsants
release. Life-threatening rash in children (1:50) may reduce serum levels.
and adults (1:1000).
Topiramate Mechanism unknown. May be related Partial onset seizures. Psychomotor slowing. Somnolence, PO. Excreted unchanged by Reduces levels (efficacy) of oral
(Topamax) to actions at GABA or kainate/AMPA ataxia, dizziness, speech impairment. kidneys. Reduce dose with contraceptives. Enhances CNS
receptors. renal impairment. depressants.
Zonisamide Mechanism unclear. May block sodium rey Elevated body temperature in some RO} Drugs that reduce liver enzymes
(Zonegran) channels or facilitate dopamine or serotonin. children. Agitation, irritability. T metabolism.
Rufinamide Inhibits sodium channel. Lennox-Gastaut Syndrome seizures. Central nervous system adverse effects. RO!
“ny
(Banzel)
Levetiracetam Unknown. Myoclonic, partial onset, primary Somnolence, dizziness, behavioral PO. Rapid absorption. May cause toxicity with
(Keppra) generalized. change. carbamezepine.
Pregabalin GABA receptor agonist. Neuropathic pain, seizures, Dizziness, somnolence, headache, PO. Minimal metabolism. ACE inhibitors, CNS depressants.
(Lyrica) fibromyalgia. blurred vision, weight gain.
Ethosuximide Mechanism unknown. Absence seizures. Nausea, vomiting, decreased PO. Metabolized in liver, not protein bound. Ethosuximide increases phenytoin
(Zarontin) appetite, and weight loss. Therapeutic level 40-100 mcg/ml. levels and decreases primidone.
Tiagabine GABA reuptake inhibitor. With other drugs for partial Dizziness, fatigue, weakness, PO. Well absorbed. Food Few interactions.
(Gabitril) and generalized seizures. irritability, anxiety, and confusion. slows absorption.
Lacosamide Enhances slow inactivation of With other drugs for partial seizures. Dizziness, nausea, vomiting. Few interactions.
PO. Well absorbed. Food does not
(Vimpat) voltage-gated sodium channels.
affect absorption.
Perampanel With other drugs for partial seizures. Dizziness, drowsiness, nausea. EO}
(Fycompa)
56 Central Nervous System oF

¢ Isoflurane — 1.15 vasoconstriction of the basilar artery and dura mater
e Nitrous oxide — 105.0 vessels. Pain relief occurs in 15 — 80% of patients.
Onset of relief is 10-120 minutes. Toxicity includes;
Note that the MAC of nitrous oxide is greater than dizziness, tingling, flushing, chest discomfort, weakness,
100%. This means that less than 50% of exposed neck pain, and marked hypertension.
subjects would be anesthetized even if 100% nitrous Propranolol and timolol are used to prevent onset of
oxide was administered. Thus nitrous oxide is a poor migraine headaches (Table 2.4).
anesthetic when used alone.
Migraine Headache Therapy

Sumatriptan (Imitrex®), naratriptan (Amerge),
rizatriptan (Maxalt), and zolmitriptan (Zomig) are
vascular 5HT, (serotonin) receptor agonists that cause
Table 3.10 General Anesthetics ee
Thiopental CNS: Sedation, hypnosis, CNS depression, decreased cerebral blood flow and metabolism (reduced
(Pentothal-see
Tables 3.8A and B)
intracranial pressure). CV: 10-20% drop in blood pressure. Resp: Apnea, bronchoconstriction.
Tox: Hypotension, tachycardia, resp depression, bronchospasm, anaphylaxis. Kinetics: |V. Onset
40 seconds, duration 30 minutes, drug released from fat stores may prolong anesthesia.
Cardiovascular and Hematology Drugs
——aee
Propofol CNS: More potent than thiopental. CV: Bradycardia, hypotension, decreased myocardial perfusion.
(Diprivan) Resp: Apnea. Tox: Pain on injection (use lidocaine first), CNS stimulation, severe cardiovascular
depression in elderly and hypovolemic patients. Kinetics: IV. Onset 1 min. Very rapidly cleared by In simple terms, ¢ Angina (chest pain) is the heart’s way of signalling
metabolism and tissue distribution. Constant infusion necessary to maintain anesthesia. that some of its cells are not getting enough oxygen
Etomidate CNS/CV/Resp: Similar to thiopental, less cardiovascular and respiratory depression. Tox: Myoclonus,
¢ The heart is a pump. (too little blood flow). Myocardial infarction
(Amidate) vomiting, adrenal insufficiency from chronic use. Kin: IV. Onset 1 min, Duration 3—5 min. ¢ It pumps blood through a system of blood vessels occurs when oxygen-starved areas of the heart
that has a limited volume capacity. begin dying.
Ketamine CNS: Dissociative (disconnected from surroundings) anesthesia, analgesia, increased intracranial
(Ketalar) pressure. CV: Increase or decrease in blood pressure, heart rate. Resp: Apnea, bronchodilation. e An electric conduction system maintains regular An understanding of the pathophysiology of each
Tox: Hallucinations (Adults > children), nightmares, increased secretions. Kinetics: |V/IM. Onset
30 sec, Duration 15 min.
rate and rhythm. disease and the therapeutic goals of each treatment
¢ Myocardial cells require oxygen. strategy will make learning the individual drugs
Volatile Organics CNS: Anesthesia, skeletal muscle relaxation. CV: Myocardial depression (*E > H > 1), decreased
-Halothane (H)* vascular resistance, sensitize heart to catecholamines (“H > E > |). Resp: Respiratory depression, much easier. Table 4.1, which follows, describes the
(Fluothane) bronchodilation (*H > E > 1). Tox: Malignant hyperthermia possible with all. Halothane associated with When heart function is considered in these terms, pharmacologic approach to treating heart malfunc-
-Enflurane (E)* hepatotoxicity and infrequent liver failure. Enflurane: nephrotoxicity Kinetics: Isoflurane is least heart malfunctions and therapeutic interventions can tions. Note that some drugs are used to treat several
(Ethrane) metabolized, lack of metabolites credited for hepatic & rena! safety. All stored in fat. Newer agents
-lsoflurane (I)* include Desflurane and Sevoflurane.
be predicted: malfunctions.
(Forane)
¢ Heart failure occurs when the heart can no longer
Nitrous Oxide CNS: 100% Nitrous oxide fails to induce anesthesia in >50% of people—usually used with other
agents. CV: When combined with halothane or enflurane, less hypotension at equivalent depth of
pump enough blood to meet the metabolic demands
anesthesia. Resp: Little effect. Tox: Transient hypoxia following use. Kinetics: Least soluble in blood. of the body. The most common cause is myocardial
Thus, excreted rapidly by expiration of unmetabolized gas. injury from ischemia, inflammation and chronic
hypertension.
"The molecular mechanism of action is unknown for most anesthetics. Agents often used with an anxiolytic (Table 3.8) and/or paralytic (Table 2.9).
Drugs are rapidly distributed, metabolized in the liver and excreted by the kidney unless noted. ¢ Hypertension develops when blood volume is
e Diuretics alone
————. great compared to the space available inside Diuretics reduce blood pressure and edema by
blood vessels. Mean arterial pressure is equal increasing urine production. All diuretics enhance
to cardiac output times peripheral resistance. water and sodium excretion, but the effect of diuretics
Increased heart rate, decreased vascular resistance on other salts depends on the mechanism of action
and myocardial contractility, enhance cardiac (Table 4.2A, Fig. 4.1).
output. Vasoconstriction elevates peripheral ¢ Thiazide diuretics inhibit sodium and chloride
resistance. reabsorption in the distal tubule, resulting in mild
¢ Arrhythmias occur when electrical signals become diuresis. Potassium supplements may be necessary
irregular. because of potassium-wasting effects.

og
Table 4.1B Strategies for ued Cardiovascular Disease (cont.)
THBRAREUTIC GOALS PHARMACOLOGIC STRATEGIES
Prototype drug listed, alternative drugs listed in following tables
Hypertension Heart Failure
Reduce workload. Diuretics decreases blood volume.
Natrecor (Nesiritide), a BNP (Brain Naturetic Peptide)

analog causes a naturesis, decreasing preload and
improving cardiac contractility.
Reduce volume overload Diuretics decrease blood volume by increasing the volume Captopril causes vasodilation.
of water excreted in the urine.
Atenolol (8 blocker) reduces heart rate and work load.
Reduce sympathetic outflow Clonidine is an agonist at a, receptors. Clonidine inhibits
from the brain further release of the sympathetic agonist, norepinephrine, Nitroglycerin reduces venous tone thereby decreasing
and inhibits sympathetic outflow from the brain. preload. (It also dilates coronary arteries, enhancing blood
delivery to the heart).
Block adrenergic receptors in the heart Atenolol is a 8, adrenergic receptor antagonist that reduces
heart rate and myocardial work. Hydralazine and Nitroprusside relax arterioles.
Dilate blood vessels Prazosin blocks «, adrenergic receptors, causing vasodilation. Improve myocardial contractility. Digoxin increases calcium influx into myocardial cells.
Nifedipine blocks calcium entry into smooth muscle cells Amrinone inhibits cAMP degradation (cAMP is a
of arterial walls, preventing contraction. biochemical messenger that stimulates the heart).
Hydralazine relaxes arterioles. Dobutamine increases cAMP production by stimulating B,

adrenergic receptors.
Captopril reduces production of angiotensin II,
causes vasodilation. Arrhythmias
Angina ¢ Stable Angina
Nitroglycerin reduces preload by venodilation.
Atenolol decreases myocardial work (81 antagonist)
Diltiazem decreases blood pressure through vasodilation,

by blocking calcium entry, and decreases heart rate, thereby
decreasing O, demand and consumption.
e Unstable Angina
Beta blockers reduce heart rate and myocardial work.
Aspirin prevents platelet aggregation in myocardial arteries.
Heparin inhibits clotting in myocardial arteries.

Restore synchronous myocardial contraction Several classes of agents described in Tables 4.7A & B.
Nitroglycerin reduces preload.
Vascular Occlusion
TK»
Eptifibatide or Tirofiban inhibit platelet aggregation.
Prevent coagulation Warfarin, heparin j
Reduce work of heart and improve
ome
tat
cardial circulation Direct thrombin inhibitors (bivalirudin)
ee
Myocardial Infarction Prevent platelet aggregation Aspirin
Thienopyridines (clopidogrel)
Reperfuse ischemic tissue Streptokinase converts plasminogen to plasmin. Plasmin GP IIb/Illa inhibitors (abciximab)
digests fibrin and fibrinogen, thus dissolving clots.
Destroy clots that have already formed tPA
Antianginal agents See above. Not nifedipine, which is
dangerous in setting of myocardial infarction.
60 Cardiovascular and Hematology Drugs 61

DStal cnvlude)
Www.Medicalstudyzone.com FH ouly Www.Medicalstudyzone.com
Amiloride Antihypertensives (cont.) - Antiadrenergics
Spironolactone Loop diuretics are more powerful than Andrenergic agonists increase blood pressure by
Triamterine thiazides and must be used cautiously stimulating the heart (B81 receptors) and/or constricting
to avoid dehydration. These agents peripheral blood vessels («1 receptors). In hypertensive
may cause hypokalemia, so potassium levels should patients, adrenergic effects can be suppressed by
Furosemide be followed closely. inhibiting release of adrenergic agonists or by antagoniz-
Ethacrynic Acid Potassium-sparing diuretics enhance sodium and ing adrenergic receptors (Table 4.2B & C).
Bumetanide water excretion while retaining potassium. These ¢ Presynaptic adrenergic release inhibitors are
Figure 4.1 Site of diuretic actions. Thiazide diuretics inhibit agents are marketed in combination with potassium-
sodium and chloride reabsorption in the distal tubule. Loop diuretics divided into “central” and “peripheral” antiadrener-
inhibit chloride reabsorption in the thick ascending loop of Henle.
wasted diuretics in order to minimize potassium gics (Table 4.2B). Central antiadrenergics prevent
Potassium sparing diuretics inhibit potassium secretion and influence imbalances. sympathetic (adrenergic) outflow from the brain
sodium excretion in the distal convoluted tubule. Mannitol osmotically Osmotic diuretics draw water into the urine, by activating inhibitory «2 receptors. By reducing
inhibits water and sodium reabsorption throughout the nephron.
without interfering with ion secretion or absorption sympathetic outflow, these agents encourage
in the kidney. “parasympathetic predominance”. Thus, the list of
Table 4.2A Antihypertensive Agents — Diuretics

MECHANISM/ACTIONS - INDICATIONS _ UNDESIRABLE EFFECTS — | -CONTRAINDICATIONS DRUG INTERACTIONS
_Thiazide Diuretics
Hydrocholorothiazide Inhibits sodium and chloride Ideal starting agent for hypertension, Hypokalemia, hyponatremia,hyperglycemia,
hyperuricemia,hypercalcemia, oliguria, PO. Absorbed rapidly, Pregnant women (unless clearly Increases toxicity of digitalis or lithium; There are many thiazide-like
(Oretic) reabsorption in the distal tubule. chronic edema, idiopathic hypercalcuria.
anuria, weakness, decreased placental flow, eliminated primarily as indicated for pathologic edema) hypokalemia with corticosteroids or diuretics which differ primarily
Loss of K*, Nat, and Cl- causes
sulfonamide allergy, GI distress. unchanged drug. Anuria. ACTH; orthostatic hypotension with in dosage requirements and
increase in urine output. Sodium
|
alcohol, barbiturates or with narcotics. duration. Consult a drug
loss results in GFR.
Decreases effects of vasopressors. index for these details.
Loop Diuretics
Furosemide Inhibits chloride reabsorption Preferred diuretic in patients with low Hyponatremia, hypokalemia, dehydration,
hypotension, hyperglycemia,hyperuricemia, PO/IV. 95% protein bound, Anuria, electrolyte depletion. Increases toxicity of ototoxic and Signs of hypochloremic alkalosis
(Lasix) in thick ascending loop of GFR and in hypertensive emergencies.
hypocalcemia, ototoxicity, sulfonamide allergy, eliminated unchanged nephrotoxic drugs and lithium. include tetany; increased
Henle. High loss of K* in Also, edema,pulmonary edema, and to
mobilize large volumes of fluid. Sometimes hypomagnesemia, hypochloremic alkalosis, by kidney. Probenecid and indomethacin inhibit bicarbonate, heart rate BUN, and
urine.
hypovolemia. diuretic effects of furosemide. Enhances hematocrit; decreased blood
used to reduce serum potassium levels.
effect of antihypertensive drugs. pressure, sodium, and skin turgor.
Ethacrynic Acid Orally for edema, IV for pulmonary edema. Most ototoxic, more GI distress,less “n
likely to cause alkalosis. Otherwise like Similar to furosemide. Ethacrynate sodium is used
(Ethacrynate)
furosemide. Narrower dose-response intravenously to treat acute
curve than furosemide. pulmonary edema.
Bumetanide Most potent. Orally for edema, IV for pulmonary edema. Similar to furosemide. Ototoxicity has not
(Bumex) been reported. Large doses may cause PO/IV. 95% absorbed, 95% as
severe myalgia. protein bound, half metabolized,
half-life = 1.5 hrs.
Potassium Sparing Diuretics
Amiloride Directly increases Na* excretion Used with other diuretics because HYPERkalemia, sodium or water depletion.
K*-sparing effects lessen hypokalemic Patients with diabetes mellitus may develop PO. Excreted unchanged in kidney, Severe hyperkalemia with potassium More rapid onset than
(Midamor) and decreases K* secretion in
distal convoluted tubule. effects. May correct metabolic alkalosis. glucose intolerance. 6 hr half-life. Can be used in supplements. Increased hyperkalemia spironolactone.
patients with hepatic insufficiency. with other K*-sparing diuretics.
Spironolactone Antagonist of aldosterone Used with thiazides for edema(in congestive As for amiloride. Also causes endocrine
PO. Metabolized extensively Anuria, substantial renal As for amiloride. Also increases The metabolite canrenone is
(e.g., Aldactone) faldosterone.causes.Na” heart failure),cirrhosis, and nephrotic imbalances (acne, oily skin, hirsutism,
in liver to an active metabolite. insufficiency, hyperkalemia. risk of digoxin toxicity and primarily responsible for the
Eplerenone €gtention). Also has actions syndrome. Also to treat or diagnose gynecomastia). Less gynecomastia
(Inspra) similar to amiloride. hyperaldosteronism. with eplerenone. Half-life = 1-1.5 days Avoid in diabetics. decreases vasopressor action actions of this drug.
(4-6 hr. For eplerenone) of norepinephrine.
Triamterene Directly inhibits Na* reab- Not used for hyperaldosteronism. May turn urine blue and decrease renal blood «n
(Dyrenium) sorption and secretion of K* Otherwise like spironalactone. flow. Otherwise like amiloride. PO. Rapidly absorbed, a Marketed in combination
highly metabolized, with thiazide diuretics.
and H* in collecting tubule.
rapidly excreted.
Carbonic Anhydrase Inhibitors
Acetazolamide Block carbonic anhydrase. Congestive heart failure. Acidosis, rash, or other hypersensitivity.
PO/IV. Hypersensitivity, acidosis, closed Cyclosporine, salicylates. Also used for open angle
angle glaucoma. glaucoma.
Osmotic Diuretic
Mannitol Osmotically inhibits sodium Acute renal failure, acute closed angle Headache, nausea, vomiting,chills, dizziness,
=
(e.g., Resectisol) and water reabsorption. glaucoma, brain edema, to remove IV. Heart failure, hypertension, Initially increases central venous
polydipsia,lethargy, confusion, and chest pain.
Initially increases plasma vol- overdoses of some drugs. pulmonary edema because of pressure, therefore may induce
ume and blood pressure. transient increase in blood pressure. heart failure in susceptible
patients.
62 Cardiovascular and Hematology Drugs

63
undesirable effects resembles the list of parasympa- occupation of §1 receptors prevents adrenergic to fall in blood pressure) will develop. Activated 82 endogenous vasoconstrictors or by activating a vasodi-
thetic actions (Fig 2.3). Peripheral antiadrenergics stimulation of the heart. receptors dilate large central arteries which provide a lation pathway (Tables 4.2D & 4.3). Examples of
prevent norepinephrine release from peripheral reservoir for blood. vasodilators include:
nerve terminals (e.g., those which terminate on the Selective «1 or B1 blockers are replacing nonspecific B
heart). These agents deplete norepinephrine stores blockers, because they produce fewer undesirable effects. ¢ Angiotensin converting enzyme (ACE) inhibitors
e Vasodilators suppress the synthesis of angiotensin II, a
in nerve terminals. Several 8 blockers have intrinsic sympathomimetic activ-
The previous table presented drugs that caused potent vasoconstrictor. In addition, ACE in-
¢ Alpha and beta blockers compete with endogenous ity (act as weak agonists at some adrenergic receptors).
vasodilation by blocking «1- mediated vasoconstriction. hibitors may induce production of vasodilators
agonists for adrenergic receptors. Antagonist occu- These drugs stimulate B2 receptors, which reduces the
Vasodilation can also be induced by inhibiting other in the body.
pation of a1 receptors inhibits vasoconstriction and likelihood that rebound hypertension (sympathetic reflex
Table 4.2BAntihypertensive
Agents — Presynaptic Adrenergic Release Inhibitors
MECHANISM/ACTIONS INDICATIONS | UNDESIRABLE EFFECTS AINDICATIONS _ DRUGINTERACTIONS NOTES
Central anti-adrenergics (See Table 2.3)
Clonidine (Catapres) Acts in brain as postsynaptic «2- Mild to moderate Rash, drowsiness, dry mouth, PO. Readily absorbed, 75% Hypersensitivity to clonidine. Tricyclinc antidepressants If blood pressure drop is too
adrenergic agonist causing hypertension. constipation, headache, bioavailability, eliminated reduce antihypertensive great, reflex renin production
reduction in sympathetic nervous impaired ejaculation. Rebound largely unchanged by kidney. effects. Alcohol, barbiturates may cause sodium and water
system activity (decreased heart hypertension if withdrawn abruptly. Must decrease dose and sedatives increase CNS retention. Diuretics may
rate, cardiac ouput and blood To limit toxicity, start with low dose w/renal insufficiency. depression. Concomitant counteract this.
pressure). Exact mechanism and increase slowly. withdrawal of B-blockers T
unknown. rebound hypertension.
et dap (Aldomet) As for clonidine. Also, synthesized As for clonidine. Dry mouth, sedations, slight PO/IV. Although 63% excreted If signs of heart failure (due Similar to clonidine. Antibodies to
to methylnorepinephrine which Used to treat orthostatic hypotension. Some unchanged by kidneys, it can to fluid retention as a result methyldopa may cause
acts as a weak sympathomimetic hypertension in patients experience impotence, be used in patients with renal of decreased renal blood hemolytic anemia
“false neurotransmitter” which pregnant women. psychic disturbances, nightmares, insufficiency. flow) occur, discontinue (fairly rare, but
decreases sympathetic outflow involuntary movements, or drug. Contraindicated in potentially lethal).
from the CNS. hepatotoxicity. those with liver dysfunction. Follow CBC.
Guanabenz (Wytensin) As for clonidine. Also depletes Mild to moderate Dry mouth, sedation, Rebound PO. Decrease dose with Similar to clonidine.
Guanfacine (Tenex) norepinephrine stores in peripheral hypertension. hypertension is observed less renal or hepatic dysfunction Thiazide diuretics increase
adrenergic nerve terminals. frequently. antihypertensive effects.
Peripheral anti-adrenergics (See Table 2.3)
Reserpine Partially depletes catecholamine Seldom used for “Parasympathetic predominence” PO. Well absorbed, Because of “parasympathetic Action of direct-acting DO NOT administer MAO
(e.g., Serpasil) stores in peripheral nervous system mild to moderate (bradycardia, diarrhea, catecholamines are sharply inhibitors and reserpine
extensively metabolized. predominance’,
and perhaps in the CNS. Decreases hypertension. bronchoconstriction, increased increased. Reduces
Plasma half-life is shorter contraindicated in patients within two weeks of each
total peripheral resistance, heart No longer secretions), decreased cardiac than therapeutic half-life, with congestive heart failure, effectiveness of mixed or other.
rate, and cardiac output. recommended for contractility and output, postural indirect sympathomimetics.
suggesting that drug may asthma, bronchitis, peptic
psychiatric disorders. hypotension (depletes be retained at its site of ulcer disease. Patients with Causes severe hypertension
norepinephrine inhibiting action. family history of depression. with MAO inhibitors.
vasoconstriction) peptic ulcers, Causes severe bradycardia,
sedation and suicidal depression, heart block or failure with
impaired ejaculation, gynecomastia. digitalis, quinidine,or beta
Low risk or rebound hypertension blockers. Potentiates action
because of long duration of action. of antihypertensive agents
or CNS-depressants.
Guanethidine Sequestered into adrenergic nerve Severe Initial increase in heart rate and PO. Incompletely absorbed, Patients with pheochromocy- Tricyclic antidepressants Because of long half-life,
endings. Initially releases hypertension when blood pressure (due to release inhibit uptake into neuron
>30% bioavailability, half toma will experience severe effects may persist up to two
norepinephrine (increase BP and other agents fail. of norepinephrine). Resting and eliminated unchanged, half hypertension. decreasing antihypertensive weeks after discontinuation.
HR). Then depletes norepinephrine Rarely used. orthostatic hypotension. Brady- as metabolites. Because of effects. Other interactions
from terminal and interferes with cardia, decreased cardiac output, very long half-life (5 days), similar to reserpine (above).
release.Reflex tachycardia is then dyspnea in COPD patients, severe
impossible because of depletion of maximal actions may not
nasal congestion. No depression develop for 2 weeks.
norepinephrine. (poor CNS penetration)
Guanadrel (Hylorel) Like guanethidine, but works Mild to moderate As for guanethidine, but less severe. on oy
faster, releases norepinephrine PO. Incompletely absorbed,

hypertension.
initially (transient increase in excreted unchanged (50%)
blood pressure), and has little and as metabolites (50%).
CNS activity. Shorter half-life (12 hrs) than
guanethidine.

65
Table 4.2C Antihypertensive Age nts
: DRUG MECHANISM/ACTIONS
-CONTRAIND. DRUG INTERACTIONS
a adrenergic Eniacentets (also described in Table 2.4)
Prazosin Peripheral alpha-1 adrenergic Hypertension and Hypotension (postural hypotension

on first dose is sudden and
PO. 50% bioavailability, >90% Phenobarbital shortens its Because of severe orthostatic
(Minipress) antagonist. Dilates both arteries hypertension with congestive
plasma protein bound, eliminated half-life. Enhances actions of hypotension, patients should be
Terazosin and veins. heart failure. severe). Sodium depletion (often
caused by diet or diuretic therapy
as unchanged drug and as other antihypertensives, may lying down and observed for at
(Hytrin) metabolites. Terazosin, Doxazosin,
in hypertensive patients) worsens produce severe hypotension. least two hours after initial
Doxazosin and Tamsulosin have longer half
the hypotensive episodes. Edema, doses.
(Cardura) lives than Prazosin, which permits
dry mouth, congestion, headache,
once daily dosing.
nightmares, sexual dysfunction
and lethargy may also be observed.
I a kn St
Mixed a and B antagonists
Labetalol Blocks a1, B1 and B2.Achieves Hypertension. Further suppresses failing heart.
Fatigue, impotence, diarrhea,
PO/IM/IV. Well absorbed, Contraindicated in Labetalol: Myocardial depression w/halothane. Blocks B-agonist
(e.g., Trandate) lower blood pressure (a1) without
high first pass metabolism, patients with asthma induced bronchodilation.
Carvedilol reflex tachycardia (81 blockade). numbness, orthostatic hypotension.
metabolized in liver. Reduce or bradycardia. Carvedilol: Increases effects/toxicity of
(Coreg)
Carvedilol dose w/renal or liver calcium entry blockers, clonidine, digoxin, insulin, antidiabetics.
dysfunction.
B adrenergic antagonists (also described in Table 2.4)
Atenolol Preferentially blocks 81 adrenergic Good starting therapy for Further suppresses failing heart.
PO. Long half-life allows once/ Severe diabetes, All 8 blockers may enhance
(Tenormin) receptors. Decreases heart rate mild to moderate hypertension CNS sedation and depression.
day dosing. Poor penetration bradycardia, partial effects of digoxin and lidocaine
Betaxolol and output and J renin release.
into brain (fewer CNS effects). heart block, severe
(Kerlone) Less bronchoconstriction than
Excreted unmetabolized. heart failure, asthma,
Carteolol agents which bind to 82 receptors
Decrease dose w/renal emphysema.
(Cartrol)
dysfunction.
Penbutolol
(Levatol)
Bisoprolol
(Zebeta)
oo
Metoprolol ee “oy
PO. Shorter half-life, metabolized Levels of metaprolol may be T

(Lopressor)
by liver, enters brain. by verapamil, cimetidine, or oral
contraceptives.
Acebutolol Has some intrinsic sympathomimetic oon
“on
PO. Moderate half-life, administered See Atenolol.
(Sectral) activity as well as 81 blocking activity.
once-twice/day.
Esmolol Similar to atenolol Cardiosuppression in acute
won
“on
IV. Short duration (half-life = 9 min)
won
Under investigation for use in
(Brevibloc) (no sympathomimetic activity) MI and unstable angina.
because it is metabolized by hypertensive emergencies.
erythrocyte esterase.
Propranolol Blocks both B1 and B2 adrenergic “on
Transient hypertension due to “oy
PO. Good CNS penetration (more Cimetidine increases serum Abrupt discontinuation may
(e.g., Inderal) receptors. Decreases heart rate antagonism of 82 receptors
severe side effects). concentration of propranolol. cause rebound hypertension and
and output and J renin release. (which dilate large arteries) and tachycardia. Increases risk of
Bronchoconstriction via antagonism reflex response to decreased cardiac
stroke, angina, arrhythmias,
of 82 receptors. output, bronchospasm, otherwise infarction.
like atenolol.
_—a
Nadolol oe on oy
“oo” “oy
(Corgard) PO. Poor CNS penetration. Decrease See atenolol.
dose w/renal dysfunction.
“oy wy
Timolol “wy “oy “oy
(Blokadren) PO. Longer half-life than propranolol
(it is not metabolized). Enters CNS,
but causes fewer side effects than
propranolol.
wy
Pindolol Has some intrinsic sympathomimetic Intrinsic sympathomimetic activity on
(Visken) activity as well as B1 and B2 PO. Metabolized by liver.
decreases likelihood of rebound
blocking activity. hypertension (by dilating large
arteries via B2) or bronchospasm

67
¢ Calcium entry blockers prevent calcium influx tract. Inhibition of propulsion by calcium channel calcium channel is particularly important in the calcium for contraction, calcium channel blockers
into the muscle cells of blood vessel walls. Smooth blockers causes constipation, a prevalent side effect S-A and A-V nodes. Blockade of these channels fail to affect skeletal muscle.
muscle relies on the influx of extracellular calcium of calcium channel blocker therapy. Cardiac muscle slows the heart. Skeletal muscle contraction is ¢ Direct Vasodilators relax smooth muscle cells which
for contraction. Blockade of the calcium influx pre- and conducting tissue rely on rapid influx of induced by rapid influx of sodium, which triggers surround blood vessels by a mechanism which is not
vents contraction, causing vasodilation. Smooth sodium and slow influx of calcium through the release of calcium from the sarcoplasmic reticu-
separate channels for contraction. The slow yet clear, but likely involves production of nitric
muscle is also responsible for propulsion in the GI lum. Because these cells do not require extracellular oxide by vascular endothelium.
Table 4. 2D Ar tihypertensive Agents - Vasodilato

rs
- MECHANISM/ACTIONS INDICATIONS UNDESIRABLE EFFECTS MACOKINETIC DRUG INTERACTIONS
Captopril (Capoten) Inhibits angiotensin converting Hypertension. Particularly useful All ACE inhibitors: First dose
PO. Prolonged duration in Pregnancy. May cause fetal Increased antihypertensive Often used in conjunction with
Lisinopril (e.g., Prinivil) enzyme (ACE) in the lung, which for high-renin hypertension. Preferred hypotension, dizziness,
patients with renal dysfunction. death or injury during second and hypotensive effects with a thiazide diuretic. Immediate
Enalapril (Vasotec) reduces synthesis of the drug for hypertensive patients proteinuria, rash, tachycardia,
Captopril requires 2-3 doses or third trimester. Bilateral diuretics, sympathetic blockers. cessation is indicated upon
Ramipril (Altase) vasoconstrictor, angiotensin II. with diabetic nephropathy because headache, cough.
per day, others one. renal artery stenosis. Increased serum potassium signs of potential angioedema
Benazepril (Lotensin) Suppresses aldosterone, glucose levels are not affected. Heart
with potassium-sparing diuretics. (swelling of face, lips, eyelids
Fosinopril (Monopril) resulting in natriuresis. failure — used with diuretics and
Decreased antihypertensive or difficulty breathing or
Qulnapril (Accupril) Potentiates other vasodilators digitalis. Myocardial infarction — Captopril infrequently causes
effects with indomethacin. swallowing).
Moexipril (Univasc) (e.g., bradykinin, prostaglandins). to enhance heart reperfusion. agranulocytosis or neutropenia.
Trandolapril (Mavik)
Perindopril (Aceon)
Angiotensin
|antagonists
Losartan (Cozaar) Antagonist at angiotensin II Hypertension Hypotension, dizziness.
PO. Metabolite is 40 times Pregnancy. Phenobarbital reduces level
Valsartan (Diavan) receptor of vascular muscle. more potent than parent. of Losartan and metabolites.
Irbesartan (Avapro)
Candesartan (Atacand)
Telmlsartan (Micardis)
Eprosartan (Teveten)
Olmesartan (Benicar)
Azilsartan (Edarbi)
Eplerenone (Inspra) Blocks binding of aldosterone Hypertension, congestive Hyperkalemia, nephrotoxicity.

PO. Once daily. Serum potassium Ketoconazole, itraconazole,
to mineralocorticoid receptor heart failure post-MI. > 5.5 mEg/L. Creatinine other CYP3A4 inhibitors.
clearance <30 ml/min.
Hydralazine Relaxes arterioles (not veins) inde- Moderate hypertension. May Reflex tachycardia, palpitations, fluid Potentiates other antihyper-
PO/IV/IM. Excreted unchanged Patients with ischemic Beta-blockers are usually used
(Apresoline) pendent of sympathetic interactions. be used in pregnant women retention, systemic lupus erythematosis- tensives. Reduces vasoconstriction concomitantly to reduce reflex
and as acetylated metabolites. heart disease.
Decreases blood pressure leading who are hypertensive. like syndrome. Chronic therapy may by sympathomimetic drugs. tachycardia. Diuretics are also
Rapid acetylators have lower
to reflex tachycardia and increased lead to peripheral neuritis (due to used adjunctively to reduce
plasma levels than slow
cardiac output. Directly increases interference with vitamin B6 sodium and water retention.
acetylators.
renal blood flow. metabolism in neural tissue).
Minoxidil hs Hypertension not controlled by other As for hydralazine. Also, cardiac muscle Duration = 24 hours, metabolized
“»
Causes profound othostatic Cardiac or pulmonary function
(Loniten) drugs. Marketed for male pattern lesions, pulmonary damage, hirsutism. hypotension in combination with impairment may require
by glucuronide conjugation.
baldness. guanethidine. cessation of drug.
Isoxsuprine (Vasodilan) Skeletal muscle vasodilator. Peripheral or cerebral vascular Dizziness, hypetension, tachycardia, Discontinue if rash develops.
PO
insufficiency. Gl distress.
Papaverine (e.g., Pavabid) Smooth muscle dilator. Mechanism Peripheral, cerebral and myocardial Tachycardia sedation, Gl distress, May inhibit Levodopa.
PO. Twice daily dosing
not defined. (with arrhythmias) ischemia. chronic hepatitis.
Epoprostenal (Flolan) Pulmonary and systemic arterial Primary pulmonary hypertension. Flushing, headache, GI distress, Continuous infusion IV. Requires Left ventricle-based congestive
vasodilation, J platelet aggregation. hypotension, jaw pain. pump for home use. heart failure.
Nitroprusside (Nipride) Converted to nitric oxide, which Continuous intravenous infusion Severe hypotension, cyanide toxicity, Dramatic changes in blood
Metabolized to cyanide and
induces cGMP. cGMP stimulates a used in hypertensive crisis. hepatotoxicity. pressure occur with small
cyanmethemoglobin inside red
phosphorylation/dephosphorylation infusion rate changes.
blood cells. Full effect within two
cascade. Relaxes smooth muscle by
dephosphorylating myosin.
minutes and rapid loss of effect
when infusion is discontinued.
Fenoldopam (Corlopam) Dopamine agonist (D, selective) Used in hypertensive emergencies. Dose-related fall in BP. Increase in lV. Continuous infusion Administer in ICU setting only.
heart rate.
Halflife = 5 min.

stable angina, but are effective antiplatelet agents.
Neutropenia is much less common in patients treated Table 4.4 Anti-anginal Agents — Nitrates @
with clopidogrel than patients treated with ticlopidine. DRUG _ SUMMARY |
Beta-blockers (Table 4.2C) reduce the frequency of
angina and increase treadmill time in patients with Nitroglycerin Actions: Dilates large myocardial arteries to increase blood supply to heart. Reduces cardiac preload by reducing
chronic angina. There is less evidence that beta- venous tone. This allows blood pooling in the periphery.
Indications: Most commonly used antianginal agent. Useful in treating all forms of angina. May be used immediately
blockers reduce death in this setting, unless the patient before exercise or stress to prevent ischemic episodes.
has had a previous infarction. Undesirable effects: Hypotension and rebound tachycardia, bradycardia, cerebral ischemia, contact dermatitis may
Calcium channel blockers (Table 4.3) are equally occur with transdermal preparation, aggravation of peripheral edema.
Pharmacokinetics: Sublingual: peak levels 1-2 min, duration = 30-60 min. IV: Onset by 2 min, duration 3—5 min.
effective as beta-blockers in reducing anginal symptoms Transdermal: peak levels at 30-60 min, duration = 1 day. Topical paste: Onset by 1 hour, duration = 2-12 hours.
Angina and Heart Failure in stable patients. Some studies have suggested a higher Once absorbed, liver rapidly metabolizes drug to inactive forrns. Tolerance may occur with continuous transdermal
adminstration.
cardiovascular event rate with short acting dihydropy-
Treatment of Stable Angina ridines (nifedipine) and these drugs should not be used
Drug Interactions: Alcohol, antihypertensive agents and vasodilators increase risk of orthostatic hypotension.
Aspirin reduces the rate of cardiovascular events by without a beta blocker. Calcium channel blockers are rec- Isosorbide Used for prophylaxis of angina. Not for acute attack. Sublingual: onset by 5 min, duration = 1-4 hours.
1/3 in patients with stable angina, and should be given ommended in patients with vasospastic angina. dinitrate Oral: onset = 30 min, duration = 4—6 hours (up to 8 hours with sustained release formula.)
(Isordil)
to all patients unless they have a clear contraindication. Similar to calcium channel blockers and beta block-
Patients with aspirin allergy should be placed on either ers, nitrates improve exercise tolerance, and time to ? Beta blockers (Table 4.2C) and calcium entry blockers (Table 4.3) are also used in the treatment of stable angina. Unstable angina is treated with
ticlopidine or clopidogrel. (Table 4.10). These drugs onset of angina in patients with exertional stable aspirin, heparin (Table 4.9, 4.10)
have not been specifically studied in patients with angina (Table 4.4). Nitrates are contraindicated in
nt bypertensheAnticongieas Agents — Calcium Ent y

MECHANISM/ACTIONS- | s DICATIONS UNDESIRABLE EFFECTS -CONTRAIND. DRUG INTERACTIONS NOTES
Verapamil Blocks calcium influx. Dilates peripheral Reduces frequency of Constipation, hypotension, PO/IV. Well absorbed, 80% Patient on IV B-blockers Beta blockers or digitalis: Increases Depolarization (leading to contraction)
(Isopten) arterioles, reducing afterload. Slows angina and the need for bradycardia, edema, congestive metabolized in first pass. 90% or digitalis. A-V node likelihood of bradycardia or A-V of vascular smooth muscle is
A-V node, prevents reentrant rhythms, nitrates. Drug of choice heart failure, A-V node block protein bound. Metabolites are block, sick sinus syndrome, blockade. Quinidine or prazosin: dependent on calcium entry.
protects myocardium during brief ischemia. for acute paroxysmal (rare), Gl upset, dizziness. active. Half-life is 5 hrs but may cardiogenic shock, heart Increases hypotension. Digoxin Vasodilation is induced by calcium
Has alpha-adrenergic blocking activity. supraventricular tachycardia. be up to 20 hrs in patients with failure, hypotension. levels are increased. Cimetidine entry blockers because they
Slows ventricular response cirrhosis. reduces verapamil clearance. inhibit calcium influx.
to atrial fibrillation. Calcium supplements may
Hypertension. inhibit actions of verapamil.
“oy
Diltiazem Less pronounced heart rate reduction. Reduces angina episodes. Edema, headache, dizziness, PO. 50% bioavailability after AV node block, sick sinus Beta-blockers and digoxin
(Cardizem) Reduces afterload by dilating peripheral Increases exercise tolerance asthenia, nausea, rash. oral dose. 75% protein bound, syndrome, hypotension, increase A-V conduction time.
arteries. Increases oxygen supply to in stable angina. Also used as half-life = 3 hrs, metabolites pulmonary congestion. Diltiazem increases propranolol
myocardium by preventing sympathetic- an antihypertensive. are active. Reduce dose in levels. Cimetidine and drugs
induced coronary artery spasm. patients with renal dysfunction. metabolized by P-450 increase
diltiazem levels.
Nifedipine More potent peripheral vasodilation. No longer used as single agent Myocardial infarction, peripheral PO/sublingual. Rapid, complete Hypotension. Betablockers increase risk Initial doses may exacerbate
(Procardia) Little depression of nodes. Fails to due to toxicity. edema, dizziness, nausea, absorption of sublingual dose. of severe hypotension, angina. Reduce dose in patients
dilate coronary arteries. Causes reflex transient hypotension, reflex 98%protein bound. Metabolites heart failure, and angina. with liver dysfunction.
increase in heart rate and output. tachycardia, pulmonary edema. are inactive, half-life = 3 hrs. Nifedipine increases effects
of oral anticoagulants.
Nicardipine Similar to nifedipine Chronic, stable angina. “” Fewer myocardial infarctions, PO/IV. Well absorbed. Reduce Severe aortic stenosis.
(Cardene) Hypertension. more palpitations. dose wi/liver-kidney dysfunction.
Isradipine Selectively inhibits vascular smooth muscle Angina, hypertension. Little tachycardia because of selective PO. Well abosorbed, high
(Dynacirc) contraction and S-A node conduction with actions. Headache, peripheral edema, first-pass metabolism.
little effect on heart contractility or A-V and flushing.
node conduction.
Felodipine Peripheral vasodilation, enhanced Hypertension. Peripheral edema, flushing, headache, Slow onset of action Increases digoxin levels.
(Plendil) myocardial contractility and output. dizziness. (2-5 hours).
Amlodipine Pie Hypertension, chronic stable Headache, edema, palpitations. PO. Slowest onset, longest Increases digoxin and beta Less acute hypotension due to
(Norvasc) angina, vasospastic angina. halflife. blocker effects. slow onset.
Nisoldipine Hypertension PO. Once daily.

(Sular)

blood pressure and inducing coronary vasodilation ischemic events in patients with vascular disease. Over 50,000 patients have been enrolled in studies
(Table 4.4). Although nitrates clearly reduce symptoms, Although neither thienopyridine has been studied designed to evaluate the effects of beta blockers during
there is no convincing evidence that they reduce mortal- specifically in unstable angina, they are accepted or after an infarction. The evidence overwhelmingly
ity or the rate of myocardial infarctions. Calcium channel substitutes for those patients that cannot take aspirin. suggests that beta blockers reduce death after myocardial
blockers must be considered as two classes: dihydropy- infarction, and these drugs should be given in all patients
ridines (i.e. nifedipine) and non-dihydropyridines with acute myocardial infarction who do not have clear
(i.e. diltiazem, Table 4.3). It is important to note that Adjunctive treatment of contraindications such as pulmonary edema, hypoten-
nifedipine can be hazardous in this setting, leading to a
higher rate of myocardial infarction or recurrent angina if
myocardial infarction sion, bradycardia, advanced heart block or asthma.
Angiotensin inhibitors (Table 4.2D) have been
given without a beta blocker. Non-dihydropyridine cal- Thrombolytic therapy reduces the relative risk of
convincingly shown to dramatically decrease death rates
cium channel blockers (i.e. diltiazem) can be safely used death by 20% if given within the first 12 hours of an acute
patients taking sildenafil (Viagra). Sildenafil potentiates in patients with reduced left ventricular dysfunction after
and may reduce the rate of death or recurrent myocardial infarction. There are several types of thrombolytic agents
the hypotensive effects of nitrates and increases the an infarction. These drugs also reduce death in all
infarction. This class of medicines is an excellent choice in available (Table 4.10). Accelerated dose alteplase reduced
risk of life threatening hypotension. patients after myocardial infarction but the relative risk
patients with absolute contraindications to beta blockers. mortality further than streptokinase in a very large study
The drugs discussed above have been tested in reduction of death is much less powerful. ACE inhibitors
Heparin has proven effective in the setting of unstable (GUSTO). Since then, other tissue plasminogen activators
combination, and combination therapy is more also reduce the rate of progression to heart failure. ACE
angina in many studies, reducing the rate of myocardial have been developed that are easier to dose. These drugs
effective than single drug therapy. inhibitors should be given in all patients presenting with
infarction or death by up to 35% when used in addition should only be used in the setting of ST elevation.
an acute myocardial infarction, unless they have
to aspirin (Table 4.9). Weight based protocols have . Thrombolysis is not effective when the patient’s ECG
Treatment of unstable angina become more popular in the wake of studies that have shows only ST depression or no diagnostic changes. In
contraindications such as renal failure, bilateral renal
insufficiency, hypotension, or angioedema due to
Rupture of an unstable plaque, and resulting throm- demonstrated their superiority over non weight based fact, there is evidence that thrombolysis is dangerous
previous ACE inhibitor use.
bus formation leads to unstable angina. Treatment is treatment. More recently, low molecular weight heparin in non-ST elevation ischemic syndromes.
Nitrate therapy has not consistently reduced death
targeted toward reducing myocardial demand, improv- (i.e. enoxaparin) has proven more effective than unfrac- Drugs that inhibit clot formation and extension
or recurrent infarction in these patients (Table 4.4). This
ing oxygen delivery, reducing coronary spasm, and tionated heparin in the setting of unstable angina. All include:
class of medications does reduce ischemic chest pain
halting thrombus formation. Heparin has been the low-molecular weight heparins are not equal. Other 1. Heparin or low molecular weight heparin and should be used for symptomatic patients.
primary anticoagulant. Recent trials have revealed LMWH’s have not proven superiority over heparin in Calcium-channel blockers do not reduce mortality
the importance of antiplatelet therapy. 2. IIfb/IlIla inhibitors (prevent platelets from sticking),
the setting of unstable angina. during or after acute myocardial infarction. Diltiazem
Oxygen therapy improves oxygen delivery in the Antiplatelet therapy has also been studied carefully. eg tirofiban, eptifibatide and abciximab
may reduce the rate of recurrent infarction after a non
subset of patients who are hypoxemic from CHF or Aspirin therapy has reduced the rate of recurrent 3. Aspirin
Q wave infarct, but any advantage over aspirin and
underlying lung disease. Morphine reduces the pain and ischemia, infarctions and death by more than 50%. Aspirin by itself reduces the risk of death from an beta blockers is not known. There may be an adverse
anxiety that can worsen symptoms in many patients. Two newer antiplatelets, derivatives of thienopy- infarction by 23%. It has an additive effect when used in effect of short acting dihydropyridines (nifedipine) and
Treating these symptoms can reduce the myocardial ridines, have recently been added (Table 4.10). combination with a thrombolytic medication. Aspirin these drugs should be avoided in this setting.
demand, reducing the total amount of ischemia. Ticlopidine (Ticlid) has been most extensively studied should always be used in the setting of an infarction Antiarrhythmic drugs have been studied in the set-
Medications that directly decrease cardiac workload in the field of ischemic cerebrovascular events, and unless the patient has evidence of an active gastrointesti- ting of acute infarctions. Class I and Class II drugs
are effective in unstable angina. Beta blockers reduce reduced the rate of vascular events compared to nal bleed, or a true allergy to aspirin. In the setting of an have increased the rate of death compared to placebo
ischemic burden by decreasing heart rate and blood pres- aspirin. It does carry an increased risk of neutropenia allergy, clopidogrel (Plavix) can be substituted for aspirin. when used to suppress ventricular ectopy after my-
sure (Table 4.2C). This class of medications may reduce and rarely can cause thromobotic thrombocytopenic Beta blockers (Table 4.2C) reduce chest pain, myocar- ocardial infarctions, especially in patients with reduced
further myocardial infarctions by 10-20%. Nitrates are purpura. Clopidogrel (Plavix) has been compared to dial wall stress and infarct size in the setting of an infarct. left ventricular function.
extremely effective in reducing symptoms by decreasing aspirin and was more effective in preventing recurrent
or stable congestive heartfailure/cardiomyopathy

MECH/ACTIONS UNDESIRABLE EFFECTS
Beta blockers Agents that preferentially Metaprolol is indicated for congestive CNS sedation and depression.
See Tables 2.4 & 4.2C Sinus bradycardia, severe heart See Tables 2.4 & 4.2C.
(Tables 2.4 & 4.2C) block B81 adrenergic receptors heart failure. Metaprolol, atenolol, Not indicated for acute or
decrease heart rate and output failure. Agents with b2 blocking
propranolol and timolol are indicated severe heart failure.
and reduce renin release. activity contraindicated in
for post-myocardial infarction patients.
Many are indicated for hypertension. asthma or COPD patients.
ACE inhibitors Reduces peripheral arterial Chronic congestive heart failure. See Table 4.2D
(Table 4.2D) See Table 4.2D. See Table 4.2D. See Table 4.2D.
resistance in hypertensive Mild to moderate hypertension.
ee
patients, by inhibiting angiotensin
converting enzyme (ACE).
Aldosterone inhibitors Aldosterone antagonist is a Congestive heart failure, cirrhosis, Hyperkalemia, sodium or water
(e.g. spironolactone, diuretic that reduces blood nephrotic syndrome. PO. Metabolized extensively in liver Anuria, renal insufficiency, Increases risk of digoxin The metabolite, canrenone,
depletion, endocrine imbalances. toxicity and decreases is primarily responsible for
eplerenone) volume (Table 4.2A). to active metabolite. Metabolite hyperkalemia, diabetes.
is 98% protein bound, therefore vasopressor action drug actions.
the halflife is 1-1.5 days. of norepinephrine.

73
venous return and ease breathing and (2) administering
Treatment consists of maintaining oxygenation, support- renal vessels (dopamine receptor-mediated) while
humidified oxygen to increase PaO,.
ing blood pressure and treating the metabolic acidosis if constricting vessels in other tissues. Norepinephrine
Drug therapy consists of (1) furosemide or
it is severe. The type of shock must be diagnosed so that and high-dose dopamine constrict all vessels including
bumetanide, potent diuretics which reduce vascular
the underlying problem can be treated. those of the kidney and brain. In addition, both of these
volume, leading to a shift of fluid from the lungs into
the vasculature; and (2) morphine, a venodilator which Vasopressors constrict blood vessels and improve agents improve cardiac function by stimulating B,
decreases preload and reduces anxiety through its
cardiac function by stimulating adrenergic receptors adrenergic receptors. Dopamine is more potent than
action on opiate receptors in the brain (Tables 4.3A & (Table 2.1). They are employed when intravenous fluids norepinephrine in this regard.
Heart Failure Drugs (cont.) 3.6A). Nitrates and/or bronchodilators may be added
alone fail to increase central venous pressure. Peripheral Dobutamine and isoproterenol are also used in
to reduce ischemic damage and improve ventilation,
vasoconstriction shunts blood to the heart and lungs. cardiogenic shock because they improve myocardial
e Acute Pulmonary Edema It may seem odd that vasoconstrictors are used to treat contractility. These agents are contraindicated when
Acute pulmonary edema usually accompanies left respectively (Tables 4.4 & 5.1).
a condition marked by poor tissue perfusion. Indeed, shock is due to hypovolemia rather than cardiac insuf-
heart failure. Successful treatment of pulmonary edema improvement in central venous pressure is frequently at ficiency, because they have no direct vasoconstrictor
reduces the risk of secondary right heart failure. Early e Management of Shock the expense of ischemic damage to peripheral tissues. effects (weak a, agonists). Dobutamine must be used
interventions in patients with pulmonary edema Shock is a potentially fatal condition in which tissues Low-dose dopamine is the preferred agent for with caution in patients with systolic blood pressure
include (1) sitting the patient upright to decrease are poorly perfused and, consequently, become ischemic. treating shock. At “renal doses”, dopamine dilates less than 100 because it can worsen hypotension.
Table 4.5B Other Heart Failure Drugs

‘DRUG MECHANISWACTIONS = INDICATIONS. UNDESIRABLE EFFECTS _ CONTRAINDICATIONS DRUGINTERACTIONS
Cardiac glycosides
Digoxin Inhibits Na*/K*-ATPase (sodium Heart failure, atrial fibrillation, Digitalis intoxication (See
(Lanoxin) pump) and 7 inward current of atrial flutter, paroxysmal text), bradycardia, AV or PO/IV. 36 hr half-life, 75% absorbed Ventricular fibrillation, Increased risk of toxicity with ECG effects: T wave
Cat*. Contraction enhanced by tachycardia. Also indicated SA node block, arrhyth- in Gl tract, slow distribution due to severe bradycardia, drugs that alter serum elec- diminished in amplitude or
T intracellular Ca**.T cardiac for hypoventilation, cardiogenic mias. Also anorexia, nausea, large apparent volume of distribution allergic reaction to trolytes (potassium- depleting inverted, P-R interval
output and J heart size, venous shock and thyrotoxic shock. vomiting, diarrhea, headache, (reduced in elderly), excreted cardiac glycosides. diuretics, corticosteroids, prolonged, Q-T interval
return, and blood volume. Causes Often a loading dose is fatigue, malaise, visual unchanged in urine (but does thiazide and loop diuretics, shortened. Tests for serum
diuresis by T renal perfusion. administered first to achieve disturbances, and gyneco- adjustment unnecessary w/renal amphotericin B, quinidine, digoxin levels may be altered
Slows ventricular rate in atrial therapeutic concentrations mastia. Increased peripheral dysfunction), 25% protein bound. amiodarone). Blockers of by electrolyte imbalance,
fibrillation or flutter by T sensitivity more rapidly. resistance may increase 8 adrenergic receptors, cal- renal impairment, age,
of AV nodes to vagal inhibition. the heart’s workload, cium channels, or acetyl- thyroid disease, other drugs,
T peripheral vascular resistance. worsening ischemic damage. cholinesterase increase risk or substances in the body
of complete AV block. Drugs which imitate dioxin in
which alter GI absorption radioimmunoassay.
may alter bioavailability.
Bipyridine derivatives
Milrinone Inhibits phosphodiesterase (the Added to digoxin therapy when Ventricular arrhythmias. Requires
(Primacor) enzyme that breaks down cAMP). heart failure persists despite constant ECG monitoring. IV. Well absorbed, short If cellular supplies of CAMP are
cAMP increases calcium uptake. digoxin. Has not been shown half-life (1.5 hrs). depleted, milrinone will not be
Increases contractility, stroke vol- to be effective in heart failure effective. Capable of increasing
ume, ejection fraction, and sinus rate. that lasts >48 hrs. myocardial contraction even
Decreases peripheral resistance. in the presence of B-adrenergic
antagonists.
Other agents
Dobutamine Beta, receptor-preferring To increase cardiac output in Tachycardia, hypotension, nausea,

(Dobutrex) adrenergic agonist. At moderate chronic heart failure. May be headache, palpitations, anginal lV. 2.4 min half-life. Continuous Hypersensitivity to None identified. Because of short half-life, |
dose, increases contractility used with afterload reducing symptoms, dyspnea, ventricular infusion is necessary to maintain dobutamine. Idiopathic can only be used for
without increasing heart rate or agents. Also used for arrhythmias. therapeutic effect. hypertrophic subaortic short-term therapy.
blood pressure. Minimal effect treatment of shock. stenosis.
on blood vessels.
oo”
Terazosin (Hytrin) Heart failure. Light headedness, fatigue, headache, on
Gl distress, nasal congestion, PO. All patients MUST start with 1 mg
tachycardia, edema. dose before bed, then increase dose
slowly if hypotension is not a problem.
Vasodilators Described in detail in Table 4.2D
fee
ae pet
Nesiritide (Natrecor) Brain Natriuretic Peptide analog. Heart failure. Hypotension
IV. Short half-life Cardiogenic shock.
issn
ceed IEISISIIIINSIIEIISIIIISSIISISSUEIIIEISNSSEIE Sl

75
beating too slowly (sinus bradycardia); 2) beating too Table 4.6B Arrhythmias (cont.)
fast (sinus or ventricular tachycardia, atrial or ventricu-
lar premature depolarization, atrial flutter); 3) beating
automatically without regard for impulses originating
CLASSIFICATION/PATHOLOGY ECG FINDINGS
Arrhythmias from the SA node (multifocal atrial tachycardia, atrial Arrhythmias Originating in the Atrium (cont.)
fibrillation, ventricular fibrillation), or 4) allowing
The following tables present arrhythmias based on Atrial Fibrillation: P waves can not be
impulses to travel along an accessory pathway to Multiple- ectopic foci of atrial discerned. Baseline is
the anatomical site of the underlying abnormality — areas of the heart which should not be depolarized at cells generate 350-450 irregular with unevenly-
atrial, ventricular or supraventricular impulses per minute. The spaced QRS complexes.
that particular moment (A-V reentry, Wolff-Parkinson- ventricle responds to an
(A-V junction) accessory pathway. Arrhythmias White syndrome). occasional impulse. Both
occur because one or more regions of the heart are 1) atrial and ventricular rhythm
are irregular.
«oft epee otal

THOLOGY oe
r a c ICATION/PS
Arrhythmias Originating in the Atrium Arrhythmias Involving the A-V Junction
Sinus Bradycardia: Slow, but regular rate on A-V Reentry: A-V node is Generally normal QRS
Increased parasympathetic rhythm strip. split into a pathway which complexes following normal P
4+—4—
(vagal) tone causes heart conducts toward the waves. The inverted P wave
ventricle and a pathway (retrograde atrial contraction)
pt
to beat at <60 beats per
minute. Depolarization which conducts the impulse is buried in the QRS. Rate is
BACK to the atrium. Reentry 150-250/minute.
originates from sinoatrial of the impulse into the atrium
node (hence the name causes the atrium and
sinus). ventricle to contract
simultaneously.
Sinus Tachycardia: Rapid, but regular rate on Wolff-Parkinson-White: Each P wave is followed
Increased sympathetic tone rhythm strip. A strip of conducting tissue (other rapidly by a QRS. A “delta
causes heart to race than the A-V node) connects wave” leads into the QRS.
ee eh
(100-160 beats per minute). the atrium and ventricle. Rate can exceed 300
a
Impulses reaching the ventricle beats/minute.
Depolarization originates
via the A-V node circle back { f |
from sinoatrial node. to the atrium via the accessory | /
pathway. Alternatively, the
circuit may be reversed.
Multifocal Atrial P waves are present, but are Arrhythmias Originating in the Ventricle
Tachycardia: morphologically different
Depolarization originates from one another. P-R Ventricular Premature Wide, tall QRS complexes which
from several atrial foci interval varies. Depolarization: are not associated with a P wave.
at irregular intervals. Spontaneous depolarization A prominent T wave often points
Yd
Rate is rapid (100—200 of ectopic focus in the in the opposite direction as the
beats per minute) and ventricle. Considered benign QRS complex.
irregular. if fewer than six per minute.
}
Premature Atrial Interruption of regular rhythm
Depolarization (PAT): by an early P wave. P wave Ventricular Wide QRS complexes with
Heart beats prematurely may be followed by a norma Tachycardia: Usually abnormal S-T segment and T
because a focus of atrial secondary to reentry circuit. wave deflections (opposite in
QRS if the SA node and
cells fires spontaneously Both A-V reentry and Wolff- direction to QRS). AV
ventricle have had time to dissociation and right bundle
Parkinson-White may
before the SA node is repolarize. branch block are often
progress to ventricular
ready to fire. associated.
WAVY
tachycardia.
Atrial Flutter: Atrial Series of 2—4 closely spaced

impulse reenters and P waves followed by a normal
depolarizes atrium. QRS complex.
Generates 250-350 Ventricular Fibrillation:
impulses per minute. Erratic discharge from many Completely erratic. Cannot
ectopic foci in the ventricle. distinguish normal waves or
The ventricle responds
Rate is 350—450 beats/min. complexes.
to every 2nd or 3rd
AY,
Rhythm is irregular.
impulse. Both atrial
and ventricular rhythm
are regular.
76 Cardiovascular and Hematology Drugs td

drugs influence cardiac conduction properties (usually
Antiarrhythmic Agents by modifying ion conductance) and may revert an
Class I drugs are Na+ channel blockers. Class Ia Figure 4.2 Example
of action potential in
50
drugs have little effect on SA node automaticity,
The sinoatrial node paces the heart by spontaneously abnormal rhythm to sinus rhythm. cardiac conducting cells.
depolarizing and stimulating the conducting nerves of while most other antiarrhythmics reduce SA node
An understanding of the mechanism by which Phase 0: Voltage-dependent
the atrium. The impulse rapidly spreads through the automaticity. Class Ia drugs slow conduction velocity Na* channel opens and rapid
action potentials are propagated through conducting and tend to be more effective than other classes in sodium influx depolarizes
atrium, causing myocardial cells of the atrium to cells facilitates learning about the mechanism of
contract in unison. The impulse reaches the atrioventric- prolonging the refractory period. No clear general- cell. Phase 1: Rapid phase -50
antiarrythmic action (Fig. 4.2). izations can be made of Class Ib agents. Class Ic of repolarization caused by
ular (A-V) node, which in turn transmits the conduction Antiarrhythmic drugs have been divided into four inactivation of Na* influx
signal to the His-Purkinje conduction pathway. The drugs slow conduction velocity most effectively. and the activation of a
classes to facilitate comparison and discussion. Since
His-Purkinje system carries the impulse to ventricular Class II drugs antagonize adrenergic receptors. transient outward K*
-100
the time the drugs were classified, however, it has current. Phase 2: Plateau
myocardial cells, causing a powerful contraction that become clear that drugs within each class may differ Class III agents tend to prolong repolarization. phase, characterized by low
propels blood throughout the body. significantly and cannot be substituted for one another. Class IV agents block slow inward (calcium driven) membrane conductance and the activation ofa slow inward Ca**
Interruption of this magnificent system, by the The original classification scheme (bold-face print) and current. current. Phase 3. Repolarization to resting potential results from
mechanisms described in Table 4.6, jeopardizes tissue other generalizations include: outward K* current. Phase 4. Outward K* current is deactivated
oxygenation and may lead to death. Antiarrythmic Automaticity is suppressed in ectopic foci by every and an inward Na+ current reduces transmembrane potential.
antiarrhythmic except bretylium.
Table 4. 7A Antiarrhythmic Drugs —

/DRUG -MECHANISM/ACTION INDICATIONS — a PHARMA LY
OKINETICS "DRUG INTERACTIONS NOTES

Class|
Quinidine Depresses automaticity of ectopic Multifocal atrial tachycardia, Torsades de pointes (recurrent, Prolongs QRS and QT PO best/IM painful/IV causes Phenobarbital and phenytoin increase
foci. Slows conduction velocity in premature atrial depolarization, temporary arrhythmia), increases intervals. hypotension. 90% protein bound. metabolism of quinidine. Quinidine
atria & His-Purkinje cells. Prolongs premature ventricular ventricle response to atrial Primarily metabolized in liver, increases plasma levels of digoxin,
refractory period throughout heart depolarization, atrial fibrillation tachyarrhythmia, nausea, vomiting, excreted by kidney. Adjust dose enhances vasodilator-induced
(except nodes) and accessory (these result from increased diarrhea, hypersensitivity, by monitoring plasma level. hypotension and potentiates
pathways. Has anticholinergic effects automaticity of ectopic foci), cinchonism, thrombocytopenic Extended duration formula allows warfarin.
which may actually enhance A-V and ventricular tachycardia. purpura. BID dosing.
conduction in patients with rapid
atrial depolarization.
Procainamide rout Premature atrial depolarization, Fewer Gl effects and weaker oy

PO/IM/IV. Low protein binding, No interaction with digoxin or
(e.g., Pronestyl) atrial fibrillation, Wolff-Parkinson- anticholinergic effects than otherwise like quinidine. The warfarin.
White, ventricular tachycardia, quinidine, but similar cardiac metabolite, N-acetylprocainamide
atrial flutter, premature toxicity. Lupus-like syndrome (NAPA) is active and toxic. NAPA
ventricular depolarization. and other hypersensitivity levels should be monitored.
reactions.
“oy
Disopyramide Premature atrial depolarization, Potent anticholinergic effects. “oy
PO only. 50% metabolized by No interaction with digoxin.
(e.g., Norpace) Atrial fibrillation, Ventricular Otherwise similar to quinidine. liver, 50% excreted unchanged.
tachycardia Must follow serum levels.
Lidocaine Depresses automaticity of ectopic Wolff-Parkinson-White, CNS: paresthesias, drowsiness, May shorten QT interval. IV, rarely IM. Rapidly metabolized Serum level increased by
(e.g., Xylocaine) foci, increases conduction velocity Ventricular tachycardia, confusion, restlessness (at low by liver (2 metabolites are active), drugs which reduce blood
of A-V node and His-Purkinje. Premature vent. depolarization, doses). At high doses, seizures flow to liver (8 blockers)
excreted by kidney.
Ventricular fibrillation. or disorientation. Cardiac and by cimetidine.
depression (if given by rapid IV),
arrhythmias.
Mexiletine Decreases automaticity of AV Premature vent. depolarization, May worsen arrhythmias, P450-inducing drugs (rifampin,
ECG changes not PO. Maintain dose <1.2 g/day
(Mexitil) node and ectopic foci. Prolongs Ventricular tachycardia (life- hepatotoxicity, rarely convulsions phenytoin) reduce half-life of
detectable. to reduce risk of CNS toxicity.
refractory period of His-Purkinje, threatening ventricular mexiletine.
Extensive metabolism in liver.
ventricle, and accessory pathway. arrhythmias).
Flecainide Reduces 1) automaticity of SA node Chronic therapy for atrial May worsen arrhythmias. Rarely Prolongs PR, QRS and QT. PO/IV. GI absorption varies Effects additive with other drugs Class Ic agents may
(Tambocor) & ectopic foci, 2) conduction velocity fibrillation. induces A-V block in patients with widely between patients. 10% which affect heart conduction. cause mortality in patients
throughout. Prolongs refractory period A-V conduction delay. of the population metabolizes Cimetidine increases half-life with structural heart
in His-Purkinje, ventricle, and accessory
the drug slowly (4 times slower of encainide. disease. Avoid in patients
pathways.
than remaining 90% of population.) with non-life-threatening
ventricular arrhythmias.
Propafenone Slows conduction throughout, prolongs Chronic or acute therapy for Nausea, dizziness, constipation, PO. 10% of the population, Propafenone increases plasma
(Rhythmol) atrial and ventricular refractory period, atrial fibrillation. altered taste sensation. May worsen metabolizes the drug slowly, levels of propranolol, digoxin
has weak 8 adrenergic and calcium- heart failure or arrhythmias. prolonging the half-life substantially. and warfarin. Cimetidine increases
entry blocking effects.
Titrate doses carefully. propafenone levels.
=

_ MECHANISM/ACTIONS | NACOKINETICS DRUG INTERACTIONS NOTES

Class Il
Propranolol 8 adrenergic receptor antagonist. J heart Sinus tachycardia, atrial flutter, Heart failure, depressed A-V Slow heart rate. Prolong PR PO/IV. 90% protein bound, Possibly fatal A-V node block
(Inderal) rate, contractility and automaticity. Prolongs atrial fibrillation, A-V reentry, conduction, bronchospasm, and QT interval. Metabolized by liver, excreted whencombined
with digitalis
A-V conduction time and refractoriness. Wolff-Parkinson-White hypotension. by kidney. *
Esmolol 81 adrenergic receptor-preferring na Less likely to cause bronchospasm IV. Metabolized by erythrocyte No significant interactions
(Kerlone) antagonist. Similar to propranolol than propranolol. Otherwise similar. esterase. Metabolite excreted with digoxin. ’
in action. renally. Serum levels unaffected
by liver or kidney failure.
Class III
Amiodarone Reduces potassium efflux. Reduces Effective inhibitor of ventricular Corneal deposits (reversible), hypo- Prolong PR, QRS and QT. PO/IV. Maximal response may take Increases serum levels of digoxin,
automaticity of SA node and ectopic foci, fibrillation, ventricular or hyperthyroidism (T4- like weeks. Serum levels correspond warfarin, flecainide.
reduces conduction velocity and increases tachycardia, Wolff-Parkinson- structure), photosensitivity, pulmonary poorly w/efficacy.
refractoriness. White, atrial fibrillation. fibrosis, bradycardia (rarely severe).
Sotalol (Betapace) Beta adrenergic blocker that slows Ventricular tachycardia. Arrhythmias. PO. Reduce dose with renal Increased risk of arrhythmias with
refractory period of Purkinje fibers & dysfunction. other antiarrhythmics.
heart muscle.
Class IV
Verapamil Reduces 1) Ca** entry into myocardial Multifocal atrial tachycardia, Sinus bradycardia, AV block, Slow heart rate, prolong PO/IV. Good GI absorption, but 80% Increases serum digoxin levels. Contraindicated in Wolff-
cells, 2) SA node and ectopic foci atrial flutter hypotension, GI upset, constipation. PR interval. is metabolized in first pass through Enhances A-V node suppression Parkinson-White (may
automaticity, 3) conduction and increases If infused rapidly into elderly patients, liver. Half-life increases up to of digoxin or propranolol - may induce potentially fatal
refractory period of AV node. may cause left ventricular failure. fourfold in cirrhotic patients. progress to A-V block. arrhythmia.)
Metabolites are active.
Unclassified
Digoxin Only drug which increases automaticity Atrial fibrillation, atrial flutter, See Table 4.2A. digitalis intoxication, Slows rate, prolongs PR PO/IV. 36 hour half-life excreted See Table 4.2A.
(Lanoxin) of ectopic pacemakers. Slows con- paroxysmal atrial tachycardia. arrhythmias, vomiting, headache, interval, shortens QT interval, unchanged in urine, 25% protein
duction velocity throughout. Complex visual distrurbances. Complete diminishes amplitude of T wave. bound.
actions on refractory period. heart block and accelerated
Increases parasympathetic tone. junctional rhythm.
Adenosine Decreases conduction velocity, prolongs Paroxysmal supraventricular Dyspnea, flushing, chest pain, Increases heart rate and IV. Rapidly (<30 seconds) Theophylline and other methylxan-
(Adenocard) refractory period and decreases tachyarrhythmias. arrhythmias. prolongs PR interval. deaminated in serum to thines antagonize adenosine.
automaticity in A-V node. active agent, inosine.

work that entangles blood cells and platelets.
Lipid-lowering Agents Drug therapy is generally reserved for patients who
fail to respond to diet or other measures described Several clotting factors require vitamin K for activa-
Thromboxane and some prostaglandins serve as
mediators of platelet aggregation. Antithrombotic
Lipoproteins are serum transport vehicles for lipids above. Lipid-lowering agents are described in Table 4.8. tion. Inhibition of vitamin K is therefore a pharmacologic agents inhibit prostaglandin and thromboxane synthe-
and triglycerides. There arelsc B858.08BREEDS: Strategies for reducing lipid levels included: 1) reduc- strategy for preventing coagulation (Table 4.9). The other sis (Table 4.10). Alternatively, prostaglandins that
which differ with respect to lipid and protein content, ing endogenous cholesterol synthesis, 2) enhancing clinically useful anticoagulation strategy involves inhibit platelet aggregation may be used to prevent
transport, function and mechanism of lipid delivery. cholesterol excretion, 3) inhibiting synthesis of lipopro- inactivating coagulation Factor III, which prevents thrombosis. Once a thrombus has formed, the only
They are named according to their size and density. teins, 4) enhancing degradation of lipoproteins. activation of the coagulation cascade from the extrinsic clinically-useful pharmacologic strategy involves
icr 3 that are Drugs that work by different mechanisms are some- pathway (Table 4.9). degrading fibrin with thrombolytic agents (Table 4.10).
absorbed through the intestine (exogenous pathway). times combined to achieve a greater reduction in
The other four lipoproteins form the endogenous trans- lipoproteins than possible by monodrug therapy.
port pathway that delivers cholesterol and’HIEIVerides All drugs are administered orally. Side effects
secreted by the liver. The four lipoproteins of the endoge-
Table 4.9 Anticoagula nts (see a Iso Table 4.10)

include GI distress and rash. Most agents potentiate
nous pathway are very low density lipoprotein (VLDL), oral anticoagulants. Statins may result in liver.and
intermediate density lipoprotein (IDL), low density leinj
lipoprotein (LDL) and high density lipoprotein (HDL). WARFARIN (COUMADIN)
Elevated lipoprotein concentration contributes to the
Mechanism/Action: Binds to antithrombin Ill. This complex Antagonize vitamin K. Interfere with the
formation of atherosclerotic plaques and in some cases Anticoagulants, Antiplatelet then binds to and inhibits activated synthesis of vitamin K-dependent clotting
pancreatitis. Treatment strategies focus first on diet.and
correction of underlying metabolic diseases. Diets that Agents, and Thrombolytics clotting factors (factor Xa). Larger
amounts inactivate thrombin and
factors (Il, VII, IX, X).
are low-inecholesteroband-saturated-animal-fats reduce Anticoagulants inhibit blood coagulation, clotting factors to prevent conversion
of fibrinogen to fibrin.
lipoprotein levels. In addition, overweight-patients antiplatelet agents prevent platelet aggregation,
should reduce their total caloric intake. Exercise and thrombolytic agents degrade clots that have Indications: Preventing postoperative deep vein Deep venous thrombosis, ischemic heart
imereases*serunrconcentrations’0f
HDL, which is asso- already formed. thrombosis and pulmonary embolism. disease (selected patients), rheumatic heart
ciated with reduced risk of coronary artery disease. Blood coagulation occurs as a “cascade” of prote- Maintaining extracorporeal circulation disease, pulmonary embolism. Lifelong use
during open heart surgery and renal in patients with artificial heart valves.
Secondary hyperlipidemia frequently subsides upon olytic factors are activated. Each factor is proteolyzed hemodialysis. Achieving immediate
treatment of the underlying metabolic disease or into an active protease. The newly-formed protease in anticoagulation.
cessation of aggravating factors. turn proteolyzes fibrin, which forms an insoluble net-
Undesirable Effects: Bleeding, hemorrhage, thrombocytopenia, Bleeding, necrosis, Gl upset.
hematoma or necrosis at injection site.
Pharmacokinetics: SubQ/IV. Only anticoagulant PO. Well absorbed rapidly, 99% plasma
‘Table 4,8pee Used to Treat LipidDisorders commonly used parenterally. Dose- protein bound, half-life = 37 hrs, metabolized
dependent kinetics. Metabolized in liver by liver.
: MECHANISM/A ONS INDICATIONS LIPID PROFILE EFFECTS to inactive products.
Cholestyramine Forms.insoluble-complex.with LDL > 190 mg/dl (160 J Cholesterol, LDL Drug Interactions: Risk of bleeding or hemorrhage is increased Urokinase and streptokinase increase risk of
(Questran) bile.salts,.excreted in feces. with 2 risk factors) T Triglycerides, VLDL, HDL with concomitant administration of aspirin, bleeding. Anticoagulation effects are
Colestipol (Colestid) Body compensates by provided that 6 month ibuprofen, anticoagulants/thrombolytics, increased by aspirin, phenylbutazone,
Colesevelam (Welchol) increasing LDL receptors and trial of low lipid diet dextran, phenylbutazone, indomethacin, oxyphenbutazone, disulfiram, cimetidine,
dipyridamole, several penicillins and sulfinpyrazone, metronidazole, trimethoprim-
oxidizing cholesterol to has failed.
cephalosporins, valproic acid, plicamycin, sulfamethoxazole, dextrothyroxine,
bile acids.
methimazole, propylthiouracil, probenecid, anabolic steroids, heparin, and many
hydroxychloroquine, chloroquine. Decreased others. Anticoagulation effects are
Lovastatin (Mevacor) Inhibit HMG-CoA reductase
“ny
J Cholesterol, LDL, VLDL, anticoagulation effect with digitalis, decreased by drugs which induce P-450
Pravastatin (Pravachol) 1 Is enzyme catalyzes triglyc. tetracyclines, antihistamines, nicotine. enzymes, rifampin, cholestryramine, high
Simvastatin (Zocor) the rate-limiting step in T HDL dose vitamin C or K.
Fluvastatin (Lescol) cholesterol synthesis.
Atorvastatin (Lipitor) Notes: Because of hemorrhage risk, check Prothrombin time should be monitored
Rosuvastatin (Crestor) hematocrit and test for blood in stool. carefully in patients taking warfarin. However,
Pitavastatin (Livalo)
= Administer with caution to menstruating
women, or patients with subacute bacterial
ecchymoses, hematuria, uterine and
intestinal bleeding, and other signs of
Gemfibrozil (Lopid) Inhibits VLDL synthesis, “oy
\ Cholest., triglyc., VLDL, endocarditis, severe hypotension, liver hemorrhage may occur even when
increases lipoprotein lipase IDL disease, or blood dyscrasias. Protamine prothrombin time is within normal range.
activity. Thus, reduces Lor T LDL T HDL sulfate inactivates heparin and can be used
triglyceride levels. as an antagonist if severe bleeding occurs.
Fenofibrate (Tricor) Unknown Hypertriglyceridemia + Cholesterol, Triglycerides Related drugs: Low molecular weight heparins [dalteparin (Fragmin), tinzaparin (Innohep)] and heparinoids
T LDL, HDL [enoxaparin (Lovenox)] are used for prophylaxis or treatment of deep venous thrombosis and
pulmonary emboli. Aldeparin and Enoxaparin also reduce risk of ischemia in unstable angina or
Ezetimibe (Zetia) Inhibits cholesterol GI absorption Hypercholesterolemia 1 LDL, T HDL, J triglyc. non-Q-wave myocardial infarction. These do not alter PT or PTT. Increase risk of spinal/epidural
hematoma following lumbar puncture. Lepirudin (Refludan), bivalirudin (Angiomax), and Argatroban
are direct thrombin inhibitors.
All drugs are administered orally. Side effects include GI distress and rash. Most agents potentiate oral anticoagulants.

Table 4.10 Antiplatelet and Thrombolyti ic Agents
and
Inhibitors (see also Table 4.9) ~~
: DRUG a _ MECHANISM/ACTIONS INDICATIONS DRUG INTERACTIONS

Tickgralor (Brilinta) Binds to the P2Y,, class of Reduce thromboses in Dyspnea, headache. PO. Aspirin reduces efficacy. Increased cardiac Ticagrelor binds ADP receptors
Prasugrel (Effient) adenosine diphosphate (ADP) acute coronary syndrome. Contraindicated in patients toxicity with digoxin. reversibly. Prasugrel is irreversible.
receptors on platelets. with history of brain hemorrhage.
aan |
Antiplatelet agents
ae
Aspirin Inhibits cyclooxygenase. Thus prevents Aspirin reduces risk of recurrent GI ulceration, Well absorbed primarily in upper small Increased risk of bleeding with anticoagulants.
Ibuprofen formation of thromboxane A, and transient ischemic attacks or bleeding, hemorrhage. intestine. Distributes to CNS. Metabolized Increased risk of GI ulceration with alcohol,
prostaglandins (which induce platelet stroke. Reduces risk of myocardial in liver, half-life = 15 min. corticosteroids, phenylbutazone, oxyphenbutazone.
aggregation). infarction in patients with unstable Decreases uricosurea effects of probenecid and
angina or prior infarction. Both sulfinpyrazone and diuretic effects of spironolactone.
used for antiinflammatory and Decreases absorption of tetracycline. Increases
analgesic purposes. plasma levels of methotrexate.
Clopidogrel (Plavix) Blocks platelet aggregation by inhibiting Reduction of atherosclerotic events. Similar to aspirin, PO. Metabolized to active drug. Increased bleeding risk with other antithrombotic Consider stopping prior to surgical
Ticlopidine (Ticlid) ADP receptor Neutropenia and rare agents. or dental procedures.
thrombotic thrombocytopenic
purpura with ticlopidine.
Cilostazol (Pletal) Inhibits phosphodiesterase III. Dilates Intermittent claudication. Headache, heart PO. Absorption increased by fatty meals. Levels increased by omeprazole, macrolides Contraindicated in patients with
lower extremity blood vessols. palpitations. diltiazem. congestive heart failure.
Dipyridamole Inhibits phosphodiesterase, increasing With warfarin, prevents emboli from May worsen angina. Pharmacokinetics are not well
(Persantine) cAMP levels to potentiate PGI, (platelet artificial valves. With aspirin, Dizziness, headache, established.
aggregation inhibitor). T levels of enhances lifespan of platelets in syncope, Gi
adenosine (a coronary artery vasodilator) patients with thrombotic disease. disturbances, rash.
Has few clinical effects alone.
Abciximab (ReoPro) Inhibit glycoprotein IIb/Illa, necessary Acute coronary syndrome. Bleeding. IV Increased bleeding risk with anti-coagulants. Contraindicated in cases of recent
Eptifibatide (Integrilin) molecule for platelet aggregation. bleeding.
Tirofiban (Aggrastat)
Thrombolytic agents:
Streptokinase Activates plasminogen to plasmin. To lyse thrombi in ischemic, but not Bleeding, In patients with antibodies against Enhances risk of bleeding caused by aspirin, Isolated from Group C
Plasmin digests fibrin and fibrinogen necrotic, coronary arteries after bruising. Rarely streptokinase (resulting from streptococcal heparin, or other anticoagulants. beta-hemolytic streptococci
forming degradation products. These infarction. Pulmonary embolism, immune oranaphylactic infections), half-life is 12 min. In others,
products also act as anticoagulants by deep venous thrombosis, occluded responses even through half-life = 83 min.
inhibiting the formation of fibrin. A-V cannula in dialysis patients, it is a foreign protein.
and peripheral artery thrombosis.
“oy “oy oy
Urokinase IV. Administered as infusion over Currently isolated from cultured
many hours. human renal cells. Very expensive.
Tissue plasminogen Binds to fibrin, then activates fibrin- To reperfuse coronary arteries that Hematoma at IV infusion. Half-life = 8 min. Metabolized
activator (TPA) bound plasminogen to plasmin. are occluded. catheterization site. by liver.
Alteplase (Activase) Recombinant forms of tissue Acute myocardial infarction (both). Bleeding. IV Contraindicated in cases of recent
Reteplase (Retavase) plasminogen activator. Ischemic stroke, pulmonary bleeding.
Tenecteplase (TNKase) embolism (Alteplase).
Direct Thrombin Inhibitors
Lepirudin (Refludan) Blocks circulating and clot-bound Alternative to heparin in heparin- Bleeding IV Enhanced risk of bleeding with other Derivative of the saliva of the
Argatraban thrombin induced thrombocytopenia antithrombotics medicinal leech Hirudo medicinalis
“on
Bivalirudin (Angiomax) Alternative to heparin in patients “on
undergoing coronary angioplasty.

oy
Desirudin (|privask) DVT prevention in hip “ny
SubQ. os
replacement.
“ow
Dabigatrin (Pradaxa) Prevent clots in patients with wy
BO} ned
atrial fibrillation.

PATHWAYS TO THROMBOSIS
AND SITES OF DRUG INTERVENTION
ENDOTHELIAL DAMAGE
Tissue Factor Collagen
!
ACTIVATION OF PLATELET ADHESION
CLOTTING CASCADE AND ACTIVATION
Respiratory Drugs
WARFARIN
Oxidized Reduced
form of _—» form of —» Prothrombin Thromboxane ADP
Obstructive Lung Disease degrade normal lung tissue leading to a loss of
Vitamin K Vitamin K if i THIENOPYRIDINES supportive lung tissue. Specific therapy to reverse
Bronchoconstriction, inflammation and loss of lung
or prevent proteolytic destruction of lungs is not
elasticity are the three most common processes that result
readily available.
in bronchial obstruction. Therapy for obstructive lung dis-
Guwih Factor Conformational change For diagnostic and treatment purposes, obstructive
ease is aimed at preventing or reversing these processes.
III > Xa ? of GP IIb/Illa receptors; lung disease is subclassified as either reactive airway
Bronchoconstriction results from the effects of
GP Ilb/Illa acetylcholine, histamine, and inflammatory mediators
disease or chronic obstructive lung disease (COPD).
Reactive Airway Disease (RAD, asthma): The
(HEPARIN, INHIBITORS released within the bronchial walls. The vagus nerve
trachea and bronchi of patients with reactive airway
releases acetylcholine in response to stimulation of
disease are particularly sensitive to stimulants such as
upper airway mucosa by irritants. Acetylcholine also
cigarette smoke, dust, cold air and allergens. Patients
DIRECT Thrombin PLATELET AGGREGATION triggers release of pulmonary secretions which further
reduce air flow by plugging airways. Sympathomimet-
present with wheezing, coughing and chest tightness.
Decreased oxygenation of the lungs secondary to
THROMBIN ics (adrenergic agonists, cholinergic antagonists),
tracheobronchial constriction, mucus production,
INHIBITORS methylated xanthines and corticosteroids reverse or
inflammation and edema cause these symptoms.
reduce bronchoconstriction (Tables 5.1A and 5.1B).
Therapeutic strategies are discussed below. Hospital-
Fibrinogen ————>__ Fibrin
|
Chronic Inflammation is caused by prolonged expo-
ization, oxygen supplementation, nebulized bronchodila-
sure to airway irritants such as pollution and cigarette
tor therapy, corticosteroid therapy and occasionally
smoke. Bronchiolar inflammation results in narrowed intubation are required for severe episodes.
airways, increased secretions, epithelial proliferation,
THROMBOLYTIC Chronic Obstructive Pulmonary Disease (COPD):
loss of ciliated epithelium and fibrosis. Corticosteroids Patients with chronic bronchitis and/or emphysema
AGENTS inhibit the inflammatory response, but their use is at experience chronic dyspnea as a result of airway
the expense of systemic side effects (Table 5.1B). obstruction and inflammation. COPD patients
THROMBUS Loss of lung elasticity results in terminal bronchiole complain of persistent cough and dyspnea on exertion.
enlargement, changes in lung compliance and the col- On physical examination, use of accessory respiratory
lapse of airways which are normally tethered open by muscles and expiratory wheezing are commonly noted.
surrounding lung tissue. It has been suggested that Expiratory wheezing is due in part to bronchiolar
Note: Thienopyridines: clopidogrel, ticlopidine; Glycoprotein (GP) IIb/llla inhibitors: abciximab, eptifibatide, tirofiban ; cigarette smoke stimulates proteases and inhibits collapse which traps air distal to the constricted site.
Low molecular weight heparin (LMWH): enoxaparin, fragmin; Direct thrombin inhibitors: bivalirudin, lepirudin,
argatroban; Thrombolytic agents: tPA, rPA, TNK-tPA; AT II] = Antithrombin Ill; Factor Xa = Activated Factor X; ADP = antiproteases. The relative abundance of proteases
Adenosine Diphosphate

Treatment Options B,-selective agents are preferred to nonselective ¢ Cromolyn is a prophylactic agent. It inhibits the ¢ Cholinergic Antagonists reduce bronchoconstriction
B-blockers because they are less likely to cause tachy- release of mediators from inflammatory cells, such and secretions caused by parasympathetic transmis-
The method of treatment depends on the severity cardia (mediated by B, receptors). These agents are
of the episode and the patient’s response to previous as mast cells. It is used exclusively in asthma. sion. Ipratroprium bromide is preferred for the
first line for prophylaxis and treatment of asthma. ° Methylxanthines increase cAMP and inhibit treatment of non-asthmatic COPD in adults and is
therapy. Therapeutic options include:
Corticosteroids decrease peribronchial inflamma- adenosine-induced bronchoconstriction. Oral a secondary drug in the treatment of asthma.
¢ Beta-adrenergic agonists bind to 8, receptors on tion. Inhaled steroids are recommended in conjunc- theophylline is used for outpatient management Most of these agents are administered by inhalation.
bronchial smooth muscle, causing an increase in the tion with beta agonists and cromolyn for asthma of asthma less frequently than in the past. An Consider improper administration of bronchodilators
biochemical messenger, cyclic AMP (cAMP). prophylaxis. Corticosteroid “bursts” (high doses for intravenous bolus of aminophylline, the water- as an explanation for therapeutic failure.
Increased levels of cAMP cause relaxation of a few days) are sometimes used when maintenance soluble salt of theophylline, produces therapeutic
bronchial muscle cells, resulting in bronchodilation. therapy fails to control asthma. serum levels faster than oral theophylline. Amino-
phyline is therefore used in acute management.
Table 5.1A Drugs Used in Bronchial Disorders —

|:DRUG . _ MECHANISM/ACTIONS “INDICATION
UG INTERACTIONS N
OTES
Adrenergic Bronchodilators
Albuterol 6, adrenergic receptor Drug of choice for treatment Though promoted as a B,-“selective” alnh: Ons < 15 m, Dur 3-4 h Bronchodilation severely
MAO inhibitors, tricyclic
(e.g., Ventolin, agonist-causes of acute asthma symptoms agonists, side effects parallel PO: Ons < 30 m, Dur 4-8 h. antidepressants and other reduced in hypoxic and
Proventil) bronchodilation. and to prevent exertion- “nonspecific” agonists (vasodilation, Time of onset and duration acidotic patients.
sympathomimetics enhance
induced asthma. tachycardia, CNS stimulation are most important points of sympathomimetic effects, Physician should be
(Table 2.1). Inhalation preparations distinction between these may induce toxicity. consulted if increased
have fewer side effects. drugs. B-blockers inhibit activity. frequency required for
symptomatic relief.
oy “om
Metaproterenol a Inh: Ons = 5 m, Dur 3-4 h “on “»
(e.g., Alupent) PO: Ons 15-30 m, Dur 4h
“oy wy “on
Terbutaline
SC: Ons 5-15 m, Dur 2-4 h oe High first pass
(e.g., Brethaire)
PO and Inh like albuterol. metabolism.
on
Formoterol “oy “ny
«n bee:
Inh: Ons < 5 m, Dur > 4h.
(e.g., Perforomist)
on “oy
Pirbuterol (Maxair) on
“on “oy “on
“oy “on “oy
Bitolterol (Tornalate) “on oy ony
“on “oy
Levalbuterol (Xopenex) “on
“on “on “on
“oy
Arformoterol (Brovana) “oy
oy “ny on
Salmeterol Long acting 8, > B, Chronic treatment of asthma Nasopharyngitis, headache, cough. wn
Inh: Ons 20 m, Dur 12h.
(Serevent) agonist. or bronchospasm in adults.
Twice a day dosing.
Not for acute exacerbations.
Epinephrine Adrenergic agonist causes Used emergently for severe Tachycardia, metabolic and GI SC/Inhalation. SC works Hypertension, es co
(e.g., Primatene Mist) bronchodilation (8, receptors,) bronchoconstriction/ abnormalities, CNS stimulation immediately. Short acting hyperthyroidism,
vasoconstriction (a1) and J vasodilation (anaphylaxis). (See Table 2.1). regardless of route of cerebrovascular
secretions (a1). More detail in
administration. insufficiency,
Table 2.1.
“ny glaucoma.
Ephedrine a6; B, oy
PO: Ons < 10 m, Dur 3-5 h er x
SC: Ons > 30 m, Dur<1h
IM: Ons 10-20 m, Dur < 1h
IV: immediate, short-acting
Isoproterenol B, and B, agonist. Like epinephrine, but
Inhalation/IV/sublingual. Tachycardia. Withdrawal may induce
(e.g., Isuprel) See Table 2.1. requires prescription.
reflex bronchoconstriction.
Anticholinergics
Ipratropium (Atrovent) Muscarinic antagonist. Bronchospasm associated Few systemic anticholinergic side Inhalation. Narrow angle glaucoma, Additive effect with Also marketed in
Aclidinium (Tudorza) Reverses acetylcholine- with COPD in adults. effects because it is a quaternary prostatic hypertrophy. adrenergic agonists. combination with albuterol.
Umeclidinium (Incruse) induced bronchoconstriction. ammonium compound which crosses
into systemic circulation poorly.
Tiotropium (Spiriva)
4 Abbreviations: Inh = Inhalation, SC = subcutaneous, Ons = onset, Dur = duration, m = minutes, h = hours.
88 Respiratory Drugs 89
DRUG DRUG INTERACTIONS NOTES

Bronchodilators — Methylxanthines
Theophylline The mechanism by which methylxanthines Used for maintenance Nausea, vomiting, headache,
PO/PR. Well absorbed, Patients with seizure Sympathomimetics T risk Warn patients: doubling
(e.g., Theo-Dur) dilate bronchioles is unknown. At toxic therapy in moderate to insomnia, tachycardia, dizziness,
liver metabolism, kidney disorder, cardiovascular of heart and CNS toxicity. a dose, even if one is
doses, these agents inhibit phospho- severe asthma. Slow neuromuscular irritability,
excretion. Dozens of disorder or peptic Cimetidine, oral contraceptives missed, is very
diesterase, the enzyme which breaks onset limits effectiveness seizures. Side effects are dose
related (T 7 risk when serum
standard and long-acting ulcer disease. and several antibiotics T dangerous. Intoxication
down cAMP (the second messenger in acute situations.
concentration >20 g/ml).
preparations available. half-life of theophylline — thus T may cause seizures.
that mediates adrenergic- induced Theophylline is being
toxicity. Phenobarbital Treat overdose with
bronchodilation). Methylxanthines replaced by ipratroprium Serum levels can be easily
and phenytoin induce ipecac, activated
block adenosine receptors which may bromide and/or monitored.
metabolism of theophylline, charcoal, and a cathartic.
account for CNS and cardiac stimulation. sympathomimetic agents
thus J half-life. Dehydration
Methylxanthines also induce diuresis for non-asthmatic COPD.
results from T diuresis with
by an unknown mechanism.
concurrent use of furosemide.
“ny
Aminophylline ts IV loading dose for severe, oy
IV/PO/PR. Increased Aminophylline is the water
acute bronchoconstriction.
solubility allows IV soluble salt of theophylline.
(Theophylline cannot be
administration. It is 79% theophylline.
administered IV.)
Corticosteroids
Systemic Decrease inflammation and edema Asthma which can Sodium/water retention and
PO/IV/IM. Steroids are adjunct agents
(Listed in in respiratory tract. Enhance activity not be controlled by subsequent cardiovascular
and should be discontinued
Table 10.2) of sympathomimetics in hypoxic and sympathomimetics problems, weakness,
as soon as possible.
acidotic states. (bronchodilators) alone. osteoporosis, peptic ulcers.
“oy “on
Beclomethasone Usually do not induce systemic
Inhalation. Rapid Treatment of status asthmaticus Inhalation agents must not
(e.g., Beclovent) toxicity. Actions primarily in lungs.
inactivation in lungs. (drug does not adequately be substituted for systemic
Budesonide Increases risk of oral Candida
relieve symptoms), patients steroids without first tapering
(Pulmicort) albicans infection (thrush).
w/systemic fungal infections. systemic steroids.
Fluticasone
(Flovent)
“wy oo on
Flunisolide “on “on oy
(Aerobid)
Mometasone
(Twisthaler)
Ciclesonide
(Zetonna)
“oy “on
Triamcinolone oy
on
(Azmacort)
Inflammatory Cell Stabilizers
Cromolyn (Intal) Prevents the release of inflammatory Prophylaxis of asthma Minimal side effects such as
Inhalation. Slow onset May allow patient to reduce
mediators (e.g., histamine) from mast attacks. Not useful throat irritation.
of action. Effective maintenance dose of
cells, macrophages, neutrophils against an ongoing
prophylaxis may require bronchodilators or
and eosinophils. attack.
several weeks of corticosteroids.
therapy.
7
Leukotriene Receptor Antagonists
Zafirlukast Competitive antagonist of leukotriene Prophylaxis and chronic Headache, Gl distress.

PO. Well absorbed. Peak Not indicated for reversal of Theophylline, erythromycin Efficacy similar to cromolyn.
(Accolate) D4 and E4 receptors. Inhibits asthma treatment. Increased respiratory infection levels in 3 hours. Inhibits bronchospasm in acute reduce Zafirlukast levels.
Montelukast bronchoconstriction and in older patients.
P450. asthma attacks. Phenobarbitol decreases
(Singulair) inflammation.
Montelukast.
Zileuton
(Zyflo)
Inhibits 5-lipoxygenase, an enzyme
required for leukotriene synthesis.
“oy
Headache, GI symptoms. Liver
enzyme elevation.
on “oy
Increases serum a
cae
theophylline level.
90 Respiratory Drugs
oT
Surfactant Infant respiratory distress syndrome (IRDS) is caused, in part, by surfactant deficiency.
(Exosurf, Survanta) Surfactant decreases surface tension in the lungs, permitting alveoli to open more readily.
Exosurf and Survanta are surfactant replacement products administered endotracheally
to reduce the incidence and severity of IRDS. Survanta is isolated from bovine lung and
supplemented to resemble natural surfactant. Exosurf is a synthetic surfactant analog.
Toxicity includes desaturation and bradycardia during administration and risk of pulmonary
hemorrhage.
N-Acetylcysteine Mucolytic agent reduces viscosity of mucous by cleaving protein complexes. Used in
(e.g., Mucomyst) patients with chronic bronchopulmonary disease.
Alpha,-Proteinase Patients with alpha1 antitrypsin deficiency develop pan acinar emphysema due to
Inhibitor degradation of elastin by neutrophil-produced elastase. Alpha,-Proteinase Inhibitor is
(Prolastin) purified from pooled human plasma and is administered intravenously each week. The
primary toxicity is fever.
Palivizumab A humanized monoclonal antibody targeted against respiratory syncytial virus (RSV).
(Synagis) It provides passive immunity for high risk infants (prematurity, bronchopulmonary dysplasia)
when given as monthly IM injections during winter and early spring months when RSV
Intranasal Steroids
infections are prevalent in the community.
Inhibit inflammatory cells in nasal mucosa. Reduce symptoms of rhinitis. May increase risk
Gastrointestinal Agents
Beclomethasone of thrush (oropharyngeal candida) and prevent healing of damaged nasal mucosa.
(e.g., Becanase)
Budesonide
(Rhinocort) Drugs for Stomach Disorders (nicotine relaxes the lower esophageal sphincter).
Ciclesonide
Nonmedical treatment includes elevation of the head
Helicobacter pylori is a bacterium that causes most
(Omnaris) of the bed, avoidance of eating before sleep, loose
cases of gastritis and duodenal ulcer disease. H. pylori
Flunisolide fitting clothing and surgical procedures that restore
(Nasalide) ulcers are in some cases precancerous. Prior to the
the competency of the lower esophageal sphincter.
Triamcinolone identification of H. pylori as a causitive agent, peptic
H, histamine-receptor antagonists are effective for
(Nasacort) ulcers were treated with agents that reduced or
short-term treatment of GERD (Table 6.1). Similarly,
Fluticasone neutralized gastric acid.
(Flonase) agents that increase the rate of gastric emptying, inhibit
Current practice utilizes at least two antibiotics with
Mometasone the proton pump of gastric parietal cells, form a protec-
(Nasonex) an antisecretory agent and/or bismuth. Although
tive coat in the stomach or augment endogenous
H. pylori is readily suppressed by a single antibiotic,
prostaglandins to promote bicarbonate and mucin
Antihistamines Presented in Table 9.7. monotherapy is suboptimal because it fails to eradicate
release are used for GERD, dysmotility, or stomach
the organism and leads to selection of resistant mucosa protection (Table 6.1).
organisms. Antibiotics typically used for H. pylori
Antacid salts, available over the counter (e.g.,
disease include amoxacillin, clarithromycin, TUMS), provide transient symptomatic relief of gastric
metronidazole or tetracycline. These are reviewed
acid irritation. Drugs which alter stomach or duodenal
in Chapter 7. pH frequently alter absorption of other oral drugs.
Antisecretory agents include proton pump Review potential drug interactions before prescribing.
inhibitors (e.g., omiprazole) and H2 histamine receptor
antagonists (e.g., ranitidine) which are described in
Table 6.1. These agents reduce gastric acid production Antidiarrheals
and promote mucosal healing. Bismuth reduces Diarrhea is usually caused by infection, toxins or
bacterial adherence to mucosal cells and damages drugs. Antidiarrheal agents are described in Table 6.2.
bacterial cell walls. It is also the active ingredient in Several of these drugs are sold over-the-counter and
Pepto-Bismol, an anti-diarrheal agent. are used more frequently than medically indicated.
Gastroesophageal Reflux Disease (GERD) and Viral or bacterial-induced diarrhea is usually
Dysmotility Reflux esophagitis is an inflammation of transient and requires primarily a clear liquid diet and
esophageal mucosa caused by reflux of acidic stomach increased fluid intake. Antimicrobial therapy may be
contents into the esophagus. The underlying defect is indicated by the presence of specific pathogens in the
usually an incompetent lower esophageal sphincter. stool or fecal leukocytes. Intravenous fluids may be
The disease is exacerbated by obesity and smoking required if dehydration occurs.
92 Respiratory Drugs 93
‘DRUG ©
Amoxacillin See chapter 7 H. pylori ulcers See chapter 7
Clarithromycin
Metronidazole
Tetracycline
H, Histamine Receptor Antagonists:

Cimetidine H, Histamine Receptor Duodenal/gastric ulcer, Well tolerated. Diarrhea, dizziness,
(Tagamet) Antagonist. hypersecretion of acid, GERD. rash, headache, confusion,
somnolence, decreased libido,
impotence, gynecomastia. Rarely,
blood dyscrasias, hepatotoxicity
and renal toxicity.
Ranitidine sides Similar to cimetidine. Possibly

(Zantac) less CNS and sexual disturbance
than cimetidine.
Famotidine
(Pepcid)
“on
Nizatidine (Axid) Duodenal ulcers, benign gastric ulcers.
Antacids
[esos
ee 2 ee ee ee
Aluminum Salts
ee
Neutralize gastric acid. Thus, Symptomatic relief of gastric

ee ee
Constipation, hypercalcemia, This PDF was created and uploaded by

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mucosal irritation is reduced. acid irritation. hypophosphatemia.
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Metoclopramide
(Reglan)
Increases rate of gastric
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Reflux esophagitis, gastroparesis,
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Diarrhea, constipation, drowsiness,
depression. Occasionally, extra-
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dopamine antagonism.
Omeprazole (Prilosec)
Lansoprazole (Prevacid)
Dexlansoprazole (Dexilant)
Inhibits H*/K* ATPase (proton
pump) of parietal cell. Thus,
reduces acid secretion.
Reflux esophagitis, duodenal
ulcers, hypersecretory states.
Few side effects. Constipation.
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Misoprostol (Cytotec) Increases HCO, and mucin Prevention of ulcers caused Abortion (uterine contraction), diarrhea,
release. Reduces acid secretion. by aspirin and other NSAIDS. abdominal pain, nausea, flatulence.
94 Gastrointestinal Agents
Parasitic infections are treated with agents Chronic diarrhea may be due to laxative abuse, lactose
described in Table 7.10. Antidiarrheal agents that intolerance, inflammatory bowel disease, malabsorption
decrease intestinal motility are contraindicated in syndromes, endocrine disorders, irritable bowel syn-
DRUG INTERACTIONS parasitic infections and some bacterial infections drome and other disorders. Treatment with nonspecific
See chapter 7 See chapter 7 See chapter 7 Effective therapy requires (e.g., shigellosis) because they suppress expulsion antidiarrheal agents such as those listed in Table 6.2 may
at least two antibiotics and of the organisms. mask an underlying disorder. Treatment of chronic
an antisecretory agent or
Drug or toxin-induced diarrhea is best treated by diarrhea should be aimed at correcting the cause of
bismuth.
discontinuing the causative agent when possible. diarrhea in addition to alleviating the symptoms.
l Infla Bowe Spiga

mmatory INDICATIONS
Use with caution in patients
rheaand
PO/IV/IM. Little plasma Increases concentration of antico-
Table 6.2 Antidiar

over 50 years old with kidney protein binding, little agulants, theophylline, lidocaine,
or liver failure. metabolism. phenytoin, benzodiazepines,
nifedipine, propranoloi, others
by inhibiting liver P450 enzymes.
DRUG MECHANISM/ACTIONS
Alters serum level of many other
drugs. Consult Drug Index. Opiates:
PO/IV. High first pass meta- Less inhibition of P450 Diphenoxylate Diphenoxylate is an agonist at opiate Diarrhea Few, minor side effects include
bolism, unchanged drug and metabolizing enzymes than and Atropine receptors in Gl tract and atropine constipation, abdominal and
metabolites excreted in urine. cimetidine. (Lomotil) blocks muscarinic receptors. Both bowel distention, nausea.
actions inhibit peristalsis.
PO. No P450 inhibition.
“on “on “on

Loperamide
PO. “on
(Imodium)
Adsorbents:
Osteomalacia (soft bones), PO. Binds and inactivates tetracycline, Magnesium antacids are
Bismuth Adsorbs toxins produced by bacteria Diarrhea. Prophylaxis for Impaction.
obstructive bowel disease, reduces absorption of warfarin, coadministered to prevent
constipation. digoxin, and other drugs. Increases constipation. Subsalicylate and other Gl irritants. traveler’s diarrhea.
risk of quinidine toxicity. (Pepto-Bismol) Large dose requirements
limit utility for long trips.
ow PO.
Decreases absorption of drugs
which are preferentially absorbed Kaolin/Pectin Adsorbant and protectant of Diarrhea. May * K* loss or interfere
at low pHs. Increases gastric (Kaopectate) questionabie efficacy. with absorption of drugs and
absorption of drugs normally nutrients.
absorbed in small intestine.
Cholestyramine Absorbs bile salts (which cause Diarrhea caused by Constipation.
“on
Diarrhea, \ renal function PO. Well absorbed, quickly Used with aluminum or (Questran) diarrhea) and C. difficile toxin. C.difficile or bile acids.
(result: hypermagnesemia) excreted by kidney calcium antacids to prevent
malabsorption syndrome. constipation. Others:
“on
Congestive heart failure, PO.
Anticholinergics Muscarinic agonists. Inhibit Diarrhea due to peptic Decrease memory and
hypertension.
Gl secretions and peristalsis. ulcer disease or irritable concentration, dry mouth,
bowel syndrome. urinary retention, tachycardia.
Corticosteroids Antiinflammatory agent. Ulcerative colitis, Crohn’s See Table 10.6.

PO. 3-5% absorbed. May interfere with absorption of other Use cautiously in dialysis disease, other inflammatory
drugs, especially fluoroquinoline patients. May increase bowel diseases.
antibiotics. aluminum concentration.
|Antibiotics See Antibacterial Agents, Chapter 7.
Elderly patients and children PO/IV/IM. Well absorbed, Sharply increases risk of hypertension
are more susceptible to 50% metabolized in liver, with MAO inhibitors. Increases Inflammatory Bowel Agents:
extrapyramidal effects. excreted in urine. toxicity of antipsychotics. Reduces
absorption of many drugs. Mesalamine Inflammatory bowel See drug monographs
(5-aminosalicylic acid) syndrome and/or ulcerative
PO. Acid labile capsule contains Inhibit cytochrome P450. Omeprazole
colitis (see drug monographs)
enteric-coated granules, interacts with warfarin, phenytoin
and diazepam.
and/or Crohn disease
short half-life (1-1.5 hr).
Olsalazine Anti inflammatory agents
(Dipentum)
Balsalazide
(Colazal)
Pregnancy. PO. Prodrug is de-esterified Misoprostol is a Sulfasalazine
to active acid. prostaglandin E analog. (Azulfadine)
95 96 Gastrointestinal Agents
Obesity Management to rule out treatable medical reasons for obesity Drugs Used to Treat Constipation Rectal administration of laxatives is preferred to oral
if there is a question of intestinal obstruction. Agents
(e.g., hypothyroidism) prior to initiating therapy. A variety of factors including low-fiber, diets, drugs
Lipase is an enzyme secreted by the pancreas. Lipase which stimulate peristalsis should be avoided when
breaks down fats so that they can be easily absorbed Orlistat should be accompanied by a balanced reduced (e.g., anticholinergics, antacids or narcotics), prolonged
calorie diet. Multivitamin supplements are recom- obstruction is possible.
by the intestines. Orlistat (Xenical) is a reversible lipase immobilization and abdominal surgery cause Laxative abuse is the most common complication of
inhibitor approved for management of patients with mended because vitamin absorption is decreased by constipation. laxative therapy. Chronic use of laxatives may lead to
the drug. Counsel patients to expect fatty/oily stool. Constipation in most nonhospitalized patients can
body mass index greater than 30 kg/m‘. It is essential dependence on such agents for normal bowel move-
be resolved by increasing the fiber content of their diet ments. Senna, in particular, is dangerous when used
or by supplementing the diet with bulk-forming chronically because it may damage nerves, resulting in
agents.
intestinal atony.
‘DRUG INTERACTIONS - NOTES

MECHANISM/ACTIONS UNDESIRABLEEF
Bulk Forming Agents
Parasitic or bacterial infections LO}: Potentiate CNS depressants.
accompanied by fever, Increases risk of hypertension Psyllium Nondigested plant cell wall Well tolerated. Flatulence, PO. Softens feces in 1-3 days.
obstructive jaundice. with MAO inhibitors. Increases (e.g., Metamucil) absorbs water into feces, impaction (if bolus is obstructed).
risk of paralytic ileus with thus softening the stool.
antimuscarinics.
“on “ny “on
Calcium polycarbophil
Parasitic or bacterial infections PO. None identified. Treat overdose with (e.g., Mitrolan)
w/ fever. naloxone.
Stimulant Laxatives and Cathartics

——4
Bisacodyl Increases water and electrolytes Continuous use may cause PO. Softens feces in 6-8 hrs.
Aspirin sensitivity. PO. Potentiates oral anticoagulants (e.g., Dulcolax) in feces and increases intestinal severe diarrhea.
and hypoglycemics, Reduces motility.
uricosuric effects of
probenecid and sulfinpyrazone. Cascara
“on “oy “om
Obstructive bowel lesions, RO: Decreases absorption of many Senna (Senokot) oon “oy
children under 3 years old. drugs.
a
Others
PO. Decreases absorption of Used primarily for its lipid
many drugs. lowering effects (Table 4.8). Saline solutions Mg** or Na* salts are poorly Precipitation or exacerbation PO. Watery excretion of bowel
(e.g., Milk of Magnesia) absorbed and thus draw water of cardiac, renal, convulsive contents in 1—3 hours.
into the lumen. High dose rids disorders or hypocalcemia.
bowel of parasites and empties
bowel preoperatively.
Closed angle glaucoma, Consult drug digest for Antacids interfere with Specific agents discussed
prostatic hypertrophy, specific agents. absorption. in Table 2.7. Metabolized in intestine to
Castor Oil Cramps, nausea. Chronic use PO. Watery excretion of bowel
heart disease, obstructive ricinoleate, a surfactant which must be avoided. Dehydration, contents in 1-3 hours.
bowel disease. decreases water and electrolyte electrolyte imbalances and
absorption and increases motility. nerve damage may develop.
See Table 10.6. PR. Administered as retention Corticosteroids discussed
enema. in Table 10.6. Polyethylene glycol Hyperosmolarity draws water Cramps nausea bloating. PO.
—
(MiraLax) into colon.
Glycerin Hyperosmolarity draws water PR. Evacuates colon within

into colon. 15 minutes.
“oy
Lactulose Cramps, flatulence, nausea, PO. Metabolized in intestine
See drug monographs Various See drug monographs See Chapter 9 for more (e.g., Chronulac) vomiting. to lactate which acts as a
details about anti- laxative osmotically and by
inflammatory drugs. lowering pH.
Mineral oil Lubricates feces and prevents Anal leakage and irritation, PO/PR.
absorption of water from feces. reduces vitamin absorption.
Aspiration pneumonitis may
develop with oral administration.
Docusate Improves penetration of water Diarrhea, abdominal cramps. PO/PR.

(e.g., Colace) and fat into feces. Increases absorption of mineral
oil (do not use with mineral oil).
97 98 Gastrointestinal Agents
Basic Strategies of Antimicrobial Empiric therapy should be changed to narrow-
spectrum, effective agent(s) when culture and
Therapy sensitivity results are available.
Sensitivity Determination: The sensitivity of
bacteria to various antibiotics is determined by
growing cultures in the presence of the antibiotics
of interest. The minimal inhibitory concentration
(MIC) is the concentration of antibiotic which prevents
growth of the culture. The minimal bactericidal
concentration (MBC) is the concentration that kills
99.9% of the inoculum. The serum bactericidal titer
is the dilution of patient’s serum (which contains
antibiotic molecules that haven’t been distributed to
other sites, bound to plasma proteins, metabolized,
or excreted) that is capable of killing the pathogen.
Figure 7.1 Selective toxicity of antibiotics. Bacterial cells differ This provides information on whether the con-
from normal human cells in that they have cell walls, structurally- centration of antibiotics in a given patient is
different ribosomes, and unique metabolic pathways. Antibiotics are high enough to be effective in body spaces (e.g.,
designed to exploit these differences so that bacteria, but not human joints, meninges) characterized by poor antibiotic
cells, are damaged.
permeability.
Anti-Infective Agents Keep your empiric therapy arsenal small: Antibi-
otic therapy often begins before the infectious agent is
Don’t harm innocent bystanders: The primary goal identified. Each practitioner should thoroughly under-
of antimicrobial therapy is to kill bacteria without stand a small number of antibiotics that are frequently
An ongoing war rages between the medical com- harming tissues of the host (Fig. 7.1). Antibiotics used for empiric therapy. The history, infection location
In addition to the mechanism of action, key issues to
munity and bacteria. Physicians utilize the latest consider when learning about antibiotics are: exploit the unique features of microbes (cell walls, and rapid identification tests described above provide
antibacterial weaponry, while bacteria have only different ribosomal structures, unique enzymes) ab- clues to the identity of the microbe. The following
personal protective gear and some basic strategies ¢ Chemistry: Subtle differences in chemical structure sent in eukaryotic cells. Drugs like penicillins have few statements summarize key points about drugs that are
for intercepting weapons. Nevertheless, because of can alter spectrum of activity, distribution in the side effects because they attack bacterial structures that frequently used for empiric therapy. If the presumed
their sheer number, ability to adapt, and unem- body, toxicity and likelihood of resistance. are absent in human cells. These agents have high se- organisms are:
barassed penchant for reproducing, bacteria often lective toxicity (i.e., good therapeutic index). In
¢ Spectrum of activity: It is useful to generalize “Drug ¢ Gram-positives: Nafcillin (IV) and dicloxacillin
have the upper hand. contrast, drugs like amphotericin, which attack less
A is generally effective against Gram-positives,” but (PO) provide excellent coverage of most Gram-
Effective antimicrobial therapy exploits the unique features in fungi, are toxic to human cells at
important exceptions must also be learned ” . . . but positives and are not destroyed by penicillinases.
differences between microbial and eukaryotic cells. therapeutic doses (poor selective toxicity).
it misses Enterococcus.” First generation cephalosporins (e.g., cephalexin,
Organisms that differ significantly from human cells Follow empiric therapy with focal therapy: The
e Mechanisms of microbial resistance to antibiotics and cefazolin) are effective against most skin and skin
are easier to selectively kill than those which have identity and drug-sensitivity of the infecting organism
ways to circumvent resistance. structure infections.
few unique properties. must be determined as rapidly as possible so that
¢ Toxicity: Learn the most common side effects as well rational therapy can be initiated. If the identity of the ¢ Gram-negatives: Third generation cephalosporins
When learning the anti-infective agents, it is useful are effective against many Gram-negatives and are
to group antimicrobials based on their mechanism of as the uncommon but severe. Uncommon, mild pathogen is unknown, empiric therapy (best guess) is
toxicities can be looked up in the future. initiated. The site of infection and Gram stain proper- not destroyed by cephalosporinases. They penetrate
action and their structure. The mechanism can
ties of the organism provide clues to its identity. Rapid the brain well. Cephalosporins and penicillins may
provide clues regarding a drug’s spectrum and ¢ Administration: Oral vs. parenteral, one vs. three
identification tests (e.g., latex agglutination) may fur- enhance the activity of aminoglycosides against
potential side effects. For example, gentamicin, an doses daily. These parameters affect patient compli-
ther confirm the identity. Local susceptibility reports Gram-negatives. The combination of “Amp & Gent”
aminoglycoside, gains access to bacteria by an ance, frequency of hospitalization and cost.
provide information on the susceptibility of pathogens (ampicillin and gentamicin) provides very good
oxygen-dependent pump and then binds to a ribo- e Distribution: Drugs must reach microbes to be
to antibiotics and allow a rational start to antibiotic coverage of both Gram-positives and Gram-
somal protein unique to bacteria. Based on this one effective. Know which drugs penetrate the blood brain
therapy. negatives. Trimethoprim-sulfamethoxazole
can predict the antibiotic will fail to enter anaerobic barrier, joint capsules, the eye, and abscess walls.
Cultures are the gold standard for identification (Bactrim/Septra) is active against most urinary
bacteria. In addition, one can see that by blocking Know which drugs fail to leave the gastrointestinal
of microbes. Unfortunately, several days may be tract infections. Amoxicillin is frequently used for
the energy dependent transport system or changing system and those that concentrate in the urinary tract.
required for growth and identification of the organism. otitis media and other bacterial upper respiratory
the ribosomal protein binding site, the bacteria devel- infections.
ops resistance to the drug. Finally, when taught that Following an introduction to therapeutic strategies False positive cultures occur when culture materials
renal tubule cells actively endocytose the drug during and commonly encountered microbes, this chapter become contaminated and when organisms are ¢ Pseudomonas: Ticarcillin or ceftazidime cover
excretion, one can predict that gentamicin might discusses antibacterial, antiviral, antifungal, and colonizing (but not infecting) the host. False negative most Gram-negatives, including Pseudomonas,
antiprotozoal drugs. cultures occur because of poor sampling technique, but fail to treat some Gram-positives. Imipenem
be nephrotoxic.
prior antibiotic therapy, and inappropriate culture and meropenem have good activity against
media or techniques. Pseudomonas.
99 100 Anti-Infective Agents

¢ Anaerobes: Metronidazole or clindamycin cover different mechanisms than to develop resistance to The Enemies: Gram Positive
most anaerobic bacteria. Mouth anaerobes are a single agent. Cocci
adequately covered by penicillin. ¢ To achieve synergy: The actions of some drugs make Background: Before the advent of penicillin, Gram-
¢ Mycoplasma: The macrolides (erythromycin, clar- other drugs more effective. The classic example is the positive cocci were responsible for most known
ithromycin, azithromycin) treat presumed Myco- combination of penicillins or cephalosporins with infections. Initially susceptible to basic penicillins,
plasma pneumonia, along with most other organisms aminoglycosides. Aminoglycosides work intra- Gram-positive bacteria have developed resistance
that cause community-acquired pneumonia. cellularly, but may have difficulty entering the cell. to basic penicillins and some strains may be resistant
¢ Systemic fungi: Amphotericin is the drug of choice Penicillins and cephalosporins prevent repair of to specialized penicillins.
for presumed fungemia. Systemic fungal infections holes in the bacterial cell wall, making it easier for Appearance: Blue & round by microscopy.
occur most frequently in patients that have been on aminoglycosides to enter. A peptidoglycan (polypeptide + sugar) cell wall
broad spectrum antibiotics that have destroyed their surrounds the bacteria. The impermeability of
endogenous bacteria, allowing fungal overgrowth. this wall (compared to Gram-negative bacteria) is res-
ponsible for the retention of blue dye during Gram
staining. Penicillins, cephalosporins, bacitracin,
vancomycin and cycloserine inhibit the synthesis of
the peptidoglycan wall.
Common Sites of Invasion: Staph aureus &
Staph epidermidis inhabit most people’s skin and
Needs are likely to infect wounds, surgical sites and
indwelling catheters (may cause infective endo-
Gyan il x carditis). Strep pneumoniae is often the cause of
jness
Popvlat ton Control is our BU community-acquired pneumonia and adult bacterial
meningitis. “Strep throat” is an infection caused by
Group A beta-hemolytic Streptococcus. If untreated,
Figure 7.3 Bacteriostatic drugs require an intact immune system it may elicit an immunologic reaction in the heart,
to eradicate an infection.
joints and other tissues, known as rheumatic
fever. Figure 7.4 Staph. and Strep. are protected by a crosslinked
Figure 7.2 Under the right circumstances, it may be necessary to Know which drugs kill and which drugs maim glycoprotein wall. Penicillin, cephalosporins, imipenem, aztreonam
initiate therapy with several antibiotic agents. and vancomycin prevent construction and repair of the wall.
(Fig. 7.3): Bactericidal antibiotics kill bacteria (cidal).
Bacteriostatic agents only inhibit bacterial proliferation
Sometimes you need more than one antibiotic while the host’s immune system does the killing. Bacte- The Enemies: Anaerobes Background: Common anaerobes include Bacteroides
ricidal agents are necessary for infections in patients fragilis, Clostridium difficile and Fusobacterium. C.
(Fig. 7.2): Quite often it is advantageous to use multiple
with defective immune systems (cancer, AIDS, dia- botulinum and C. tetani produce toxins responsible for
drugs to treat an infection. Examples include:
betes) and for overwhelming infections. Patients MUST botulism and tetanus, respectively. Metronidazole,
e Unknown microbe: If you haven't identified the take their full course of medication. Patient compliance chloramphenicol or clindamycin are effective against
Gram stain properties of an infectious agent, it is is often poor because it appears that their infection has anaerobic infections.
sometimes necessary to treat with antibiotics that subsided when in fact it is only suppressed. Appearance: Mixed Gram-positives and Gram-
cover a broad spectrum of microbes. Often a drug Get the drug to the site of infection: The brain, negatives compose most anaerobic infections.
that covers most gram positive organisms and a drug joints, testes, and eye are “protected” sites in the body. Infections are frequently encased in an abcess wall.
that covers gram negative bacteria are combined. An Few drugs penetrate the barriers that surround these Anaerobes produce foul-smelling gas.
agent that covers anaerobes or Pseudomonas may also sites. When treating infections at these sites, one must Common Sites of Invasion: Anaerobes colonize the
be desirable. Single drug therapy can then be insti- choose agents that penetrate the barriers and that are mouth, gastrointestinal tract and skin of all persons.
tuted when the organism is identified. active against the infecting organism. Similarly, abscess Infections develop when anaerobes penetrate poorly
¢ To prevent resistance: It is more difficult for walls form an effective barrier to antibiotics. Abscesses oxygenated tissues (e.g., the diabetic foot) or tissues
Figure 7.5 Anaerobic bacteria produce foul-smelling infections
bacteria to develop resistance to two drugs with must be incised and drained. that are normally sterile (e.g., peritoneum). When
that are typically encased in an abscess wall. Metronidazole,
chloramphenicol and clindamycin are used to treat anaerobic infections, broad spectrum antibiotics diminish normal bowel
which are typically composed of mixed Gram-positive and Gram- flora, C. difficile proliferates and releases a toxin that
negative organisms. causes pseudomembranous colitis.
102 Anti-Infective Agents

101
The mechanism of cell wall synthesis is demon- Chemistry: Penicillins, cephalosporins, monolac-
The Enemies: Gram-negative paired red spheres. Pseudomonas also has an extra-
strated in Figure 7.9. In brief, peptidoglycan chains tams (aztreonam) and carbapenems (imipenem) all
cellular polysaccharide slime layer and unipolar
Pathogens flagella. synthesized in the cytoplasm of bacteria are transferred have a beta-lactam ring in the center. Some of these
across the plasma membrane and linked to other are inactived if the ring is cleaved by B-lactamases
peptidoglycan chains. The result is a “chain-link” (Fig. 7.10, 7.11). Others (e.g., aztreonam, imipenem)
. Meningitis Mail wall that surrounds the bacteria.

Because human cells lack cell walls, they are generally
are resistant to B-lactamases.
Early penicillin was acid labile and could not be
unaffected by inhibitors of cell wall synthesis. This administered orally. It was ineffective against many
explains why penicillins and cephalosporins have few Gram-negative bacteria and was destroyed by B-
side effects. lactamases. Each of these limitations has been overcome
in newer penicillins due to alterations of the chemical
structure or the development of adjunct agents such as
Bactericidal Cell Wall Inhibitors probenicid and clavulanic acid. These advances are
Figure 7.7 Neisseria meningitides and N. gonorrhea are the only ¢ Penicillins (B-lactam drugs) diagrammed in figures 7.10, 7.11, and 7.12.
gram negatives that are susceptible to penicillin G and other narrow
Penicillin was first isolated from the Penicillium Clavulanic acid and probenicid potentiate the
spectrum penicillins, Ceftriaxone has now replaced penicillin as the
drug of choice for N. gonorrhea due to the emergence of penicillin- mold in 1928. It was effective against a variety of bacte- actions of penicillins and cephalosporins. Clavulanic
resistant strains. ria including most Gram-positive organisms. Excessive acid potentiates penicillins by binding to and
use of penicillin led to the development of bacterial inhibiting B-lactamase (Figure 7.11). Augmentin® is
Common sites of invasion: The enterics are respon- resistance (penicillinase production), rendering the trade name for amoxicillin and clavulanic acid,
sible for many urinary tract infections and aspiration the drug useless against many strains of bacteria. and Timentin® is the trade name for ticarcillin and
Figure 7.6 Gram negative bacteria. The glycoprotein wall of pneumonia due to the proximity of the gastrointestinal Nevertheless, it remains an inexpensive and well clavulanic acid. Probenicid acts by competing with
Gram negatives resembles that of Gram positives. In addition, Gram tract (their home) to the urethra and the lungs. Neisse- tolerated drug of choice for several infections. penicillin for the organic anion transport system, which
negatives wear a protective outer coat which is impermeable to
ria gonorrhea is responsible for sexually transmitted The pharmacokinetics, spectrum of activity and is the primary route of penicillin excretion (Fig. 7.12).
penicillin. Ampicillin and amoxicillin however, can penetrate the The result is higher serum levels of penicillin.
outer coat and destroy the cell wall. Gram-negatives cause meningitis, gonorthea. N. meningitidis and H. influenzae both clinical uses of penicillins are presented in Table 7.2.
pneumonia, bladder infections, otitis media and sinus infections. cause meningitis. H. influenzae more commonly
causes pneumonia, particularly in the elderly. Pseu- “Table 7.1 Bactericidal Drugs that Worl at the é ellWall:
domonas aeruginosa is sometimes responsible for hos- :
Background: Common Gram-negative pathogens pital acquired infections. Pseudomonal infections can “MECHA CLINICAL USE UNDESIRABLE EFFECTS ©
can be divided into four groups: 1) Enterics, consisting occur at any site, particularly in immunocompromised
NISM
of those organisms that normally inhabit the GI tract patients. If adequate moisture is available, Pseudomonas Penicillins and Inhibits crosslinking of cell wall See Table 7.2 and 7.3. Hypersensitivity. Rare nerve, liver or
(Escherichia, Shigella, Salmonella, Klebsiella, Enterobacter, Cephalosporins components. kidney toxicity.
may colonize any surface in the hospital (including
Serratia, Proteus, and others), 2) Haemophilus influenzae, workers) and is resistant to many disinfectants. Vancomycin Prevents transfer of cell wall precursor DOC!: Penicillin or methicillin-resistant Staph Thrombophlebitis, ototoxicity, nephrotoxicity.
3) Neisseria and 4) Pseudomonas. Although rarely a Dalbavancin from plasma membrane to cell wall. and Strep infections. Bacteriostatic against “Red Man Syndrome” when administered
Oritavancin Enterococcus. Oral: C. difficile colitis by rapid IV: tachycardia, flushing, paresthesias,
cause of hospital acquired (nosocomial) infections Telavancin hypotension, severe nephrotoxicity.
prior to the advent of antibiotics, the enterics are now
Bacitracin Inhibits recycling of the carrier which Gram-positive organisms infecting skin, Severe nephrotoxicity when administered
responsible for most nosocomial infections. Strains transports cell wall precursors across eye infections. intramuscularly.
resistant to many antibiotics have developed. the plasma membrane.
Appearance: Enterics and Haemophilus influenzae
Carbapenem
are red and elongated by microscopy (Fig. 7.6). The
plasma membrane of Gram-negative bacteria is Imipenem/ Inhibits crosslinking of cell wall DOC: Acinetobacter. Excellent coverage of Similar side effects as penicillins. Despite wide
Cilastatin components. most Gram-positives and Gram-negatives spectrum, imipenem rarely causes sterile
protected by an adjacent rigid peptidoglycan wall (Primaxin) (including those which produce B-lactamases) bowel. Perhaps due to iow concentration of
(site of action for penicillins, cephalosporins, etc.) Meropenem and P. aeruginosa. May find role in drug in bowel.
(Merrem) mixed infections.
which is encased by an outer membrane. Penicillins Ertapenem
must cross the outer membrane in order to act at the (Invanz)
Doripenem
inner cell wall. The outer membrane is made of Figure 7.8 Stella Pseudomonas shows off her slime coat and (Doribax)
lipopolysaccharides interrupted by transmembrane flagella, which distinguish her from the other gram negatives. She
can infect any site in the body and is relatively resistant to most
protein pores (which prohibit entry of most penicillins antibacterial agents. Tobramycin or ceftazidime are preferred agents
Pere
and cephalosporins). Broad spectrum penicillins for treating Pseudomonal infections. Aztreonam
“wn
Excellent coverage of Gram-negatives Similar side effects as penicillins
and third generation cephalosporins are more (Azactam) including P. aeruginosa. Not active against (hypersensitivity, seizures, hepatitis), Injection
Gram-positives. site pain, GI upset.
hydrophilic than previous drugs, allowing passage
through the selective pores. Even so, some Gram- Bactericidal Cell Wall Inhibitors Lipopeptides
negative strains are resistant to penicillins because The agents described in Table 7.1 kill bacteria by Daptomycin Depolarizes bacterial cell membrane. Skin infections caused by S. aureus, MRSA, Hepatotoxicity, diarrhea, rash.
they produce B-lactamases (penicillin-destroying preventing synthesis or repair of the cell wall. The cell (Cubilin) strep spectes, enterococcus (Vanco-sensitive).
enzymes) that are concentrated in the space between wall protects bacteria, which are hyperosmolar, and ' Abbreviation: DOC = Drug of Choice
the outer membrane and the cell wall. Neisseria are prevents them from absorbing water and exploding.
103 104 Anti-infective Agents

Figure 7.10 Penicillin Chemistry Penicillinases inactivate
Allergic Reactions: Penicillin penicillin by cleaving the B-lactam ring. In penicillinase-resistant O
reactions range from skin rashes to penicillins, a bulky chemical group prevents entry to the active site ll
anaphylactic shock. The more of penicillinase, but does not interfere with binding to the bacteria. R—C—NH—CH-cii CC oe
severe reactions are uncommon, Narrow spectrum penicillins are unable to pass through the outer i | CH;
but potentially life-threatening. “see
oe
membrane of Gram-negative bacteria. Broad spectrum penicillins are o=cz— N—- cH—COOH
more hydrophilic and are thus able to penetrate the aqueous pores
Some allergic reactions are of the outer membrane. a
mediated by IgE antibodies. Beta-lactam ring (site of Thiazolidine ring

Alternative antibiotics should be penicillinase action)
used in patients with a history of
reactions even though penicillin Penicillin
allergies are overreported. Skin
tests using penicilloylpolylysine
and penicillin degradation
products provide information Table 7.2 Penicillins — In Detail
about penicillin sensitivity in
patients with no history of peni- ‘DRUG MECHANISM SPECTRUM
_ cillin use. Virtually all patients Narrow Spectrum, Penicillinase-sensitive
who are truly allergic to one form
Penicillin G B-lactam binds penicillin binding proteins Gram-positive cocci. Nonresistant Staphylococcus and
of penicillin will be allergic to Procaine Pen G (similar structurally to pentapeptide’s alanine Neisseria. Streptococcus, N. meningitidis,
other penicillins. Benzathine terminus) and inhibits crosslinking of Most mouth anaerobes. B. anthracis, C. tetani, C, perfringens.
PenG bacterial cell wall components (Fig. 7.9) Not effective against Gram- Listeria. Syphilis.
Penicillin V negative aerobes or B-lactamase
producing organisms.
Group Il Narrow Spectrum, Penicillinase-resistant
Nafcillin Bulky side group protects the B-lactam ring Gram-positive cocci (including Penicillinase-producing Staphylococcus.
from penicillinases. Hydrophobic side group, R-lactamase producers).
however, inhibits antibiotic’s ability to penetrate Some streptococci.
gram negative bacteria via hydrophylic porins. Not effective against Gram-
negative aerobes.
See Tables 7.2 and 7.3 for specifics. Oxacillin “oy “nn “on
PO/IV. Poor absorption, poor CNS Be «nm cs

Dicloxacillin
penetration, excreted unchanged
by kidney. Group III Broad Spectrum, Aminopenicillins
Ampicillin Amino side group makes these agents Some Gram-negative and Gram- Listeria.
Marketed in combination with polymyxin
hydrophilic enough to penetrate the positive organisms. Not effective Enterococcus (if susceptible).
or neomycin as a topical agent.
pores in gram negative organisms. against B-lactamase-
producing organisms.
«“n
Amoxicillin ak Empiric therapy in otitis media, sinusitis,
(Amoxil) and pneumonia.
IM/IV. Imipenem is administered with
cilastatin (inactive), which inhibits renal Amoxicillin and ee Gram-negative and Gram-positive Moraxella (Brahnamella) catarrhalis
metabolism of imipenem. Renal failure Clavulanate Clavulanate inhibits penicillinases and B-lactamase-producing
oo and H. influenza.
requires dose reduction for both. (Augmentin) (Fig 7.11). organisms.
Extended Spectrum, Anti-Pseudomonas Penicillins

Figure 7.9 Bacterial cell wall synthesis. 1) Alanine molecules are added to a carbohydrate
tripeptide to forma “T” shaped cell wall precursor. This reaction is inhibited by D-cycloserine. 2) The Ticarcillin Side chain makes it more resistant to Gram-negative infections Pseudomonas
precursor is transported across the plasma membrane by a carrier. Vancomycin inhibits the transport B-lactamases from Gram-negative species (especially Pseudomonas) and
especially Pseudomonas species. aminopenicillin-resistant Proteus
process. 3) The transporter is recycled to the inside of the cell to carry other precursors. Bacitracin
infections. Less effective against
inhibits this step. 4) The precursor is linked to the existing cell wall structure by transpeptidase. Gram-positive penicillinase-
IM/IV. Wide distribution including joints, Penicillins, cephalosporins, imipenem and aztreonam inhibit the transpeptidase. Transpeptidase is producing organisms.
brain, and urine. Decrease dose with
renal failure.
one of several penicillin binding proteins and is not the only site of penicillin action.
| Piperacillin es Enterobacteria and Gram-positive cocci.
—
Piperacillin/ Extended spectrum penicillin combined As above plus piperacillin-resistant

IV Excreted by kidney. Tazobactam with beta lactamase inhibitor. Gram-negative and Gram-positive
penicillinase-producing organisms.

URINE BLOOD URINE
OCH3 O p BLOOD
QC—NH—CH-CH JS. 'C _,CHs ] 7 4CHs

—C—C—NH—CH—-CH Cy
Nemet teal, CH, | Be eewese:"
40cH, O=C—N—CH—COOH ¢
ny Soe Ne
nS Polar chain facilitates diffusion
‘
Bulky group prevents recognition through aqueous pores

of methicillin by penicillinases
Ampicillin
Methicillin
Figure 7.12 Probenicid potentiates the action of penicillins and cephaloporins by

competing
for excretion at the organic anion transport system (OATS) in the kidney. Probenicid
|. a .. Penicillin
SIDEEFFECTS %
Pen G IV/IM. Pen V PO (acid stable).

Procaine and benzathine prolong half-life.
Eliminated by organic acid transfer system
Hypersensitivity reactions (anapha-
laxis or hemolysis). Rare
neurologic toxicity (seizures) due
alosporins —In Detail ©
in kidney.
Probenicid competes at this transporter.
to inhibition of GABA neurotrans-
mission (B-lactam is structurally
_ MECHANISM SPECTRUM : PHARMACOKINETICS —
Can be used to increase penicillin half-life. similar to GABA). Neutropenia.
First Generation — Narrow Spectrum, sensitive to Beta Lactamase
Distributes to eyes, joints and brain if Nephrotoxicity.
meninges are inflamed. le
enicillinase Oral Drugs 8-lactam binds penicillin binding Gram-positive cocci except enterococci Fail to penetrate CSF, Penetrates bone
Cephalexin (Keflex) proteins. Inhibits cell wall synthesis and Methicillin Resistant Staph. aureus (especially cephazolin). IV drugs achieve
Cefadroxil and may in turn activate autolysins. (MRSA). adequate tissue and serum levels.
Bacteria develop resistance by reducing Some Gram-negative enterics Renal excretion of drug and metabolites
IV is preferred route because of low a
Parenteral Drugs drug permeability, mutating penicillin Not effective against unless noted.
absorption from PO/IM sites. Excreted by Severe thrombophlebitis.
Cefazolin (Kefzol) binding proteins and producing anaerobes Cephalothin only administered IV because
liver — high concentration in bile. Liver toxicity with elevated LFTs.
B-lactamase and cephalasporinases of pain with IM injection.
(clavulanate can circumvent Used for surgical prophylaxis and for
this problem). treating skin or soft tissue infections
Like penicillin. Coagulopathy, caused by Staph.or Strep.
interstitial nephritis.
SS
EeeSe Second Generation — Broader Gram-negative Activity
PO. en
Oral Drugs As above but more resistant to Gram-positive cocci (similar to first Fail to penetrate CSF cefuroxime achieves
Cefaclor (Ceclor) Beta-lactamase activity. generation). CSF levels but third generation agents
Cefprozil Extended Gram-negative activity (H. flu, preferred because of greater penetration
IV/IM/PO. Diarrhea. 7 Cefoxitin and Cefotetan Enterobacter, Proteus, Neisseria species). and more rapid sterilization.
Oral or Parenteral (cephamycins) are structurally None are effective against Pseudomonas. _—_ Eliminated by kidney.
Cefuroxime and pharmacologically related Used for otitis media, pharyngitis, and
(Ceftin) to the cephalosporins. sinus, skin, and respiratory infections.
Cefuroxime used as single dose therapy
PO. Diarrhea. Parenteral for N. gonorhea. cefuroxime is more
Cefoxitin effective than cefazolin in prophylaxis
Cefotetan against MRSA wound infections.
RO: Diarrhea.
Figure 7.11. Penicillinases and penicillinase-resistant Later Generation — Broad Spectrum, Resistant to Most Cephalosporinases
penicillins. Top: Penicillins destroy bacteria after binding to
Aa Sicitaiet “cats epsian Maal Aare penicillin binding proteins (PBPs). Middle: Penicillinases are Parenteral Similar mechanism to first generation Gram-negative bacilli (resistant to other Penetrates CSF (except
enzymes produced by bacteria that destroy penicillins by cleaving Ceftriaxone cephalosporins; however more resistant cephalosporins, penicillins, and cefoperazone and perhaps
IV the beta-lactam ring of the drug. Penicillins are “lured” into the (Rocephin) to Beta lactamase produced by aminoglycosides). cefixime).
active site because they are chemically similar to penicillin Cefotaxime Gram negative bacteria. Variable efficacy against Pseudomonads High levels of ceftriaxone and
Ceftazidime (Fortaz) (ceftazidime, cetipime, and cetoperazone cefoperazone excreted in bile.
binding proteins. Bottom: Clavulanic acid is a “decoy” drug that
Cefepime have best coverage). Remainder excreted renally.
enhances the activity of penicillins. Clavulanic acid binds to the Ceftaroline Gram positive cocci (including Serum half life — ceftriaxone >>
active sites of penicillinases rendering the enzyme inactive. Staphylococcus and nonenteric cefoperazone > ceftazidime.
Oral Streptococcus)
PO: “” Neutropenia and hematologic Ceftibuten
abnormalities. Cefpodoxime
Cefdinir
IV. Cefditorin

107
Bactericidal Cell Wall Inhibitors names Keflex (cephalexin), Ceclor (cefaclor) and
Suprax (cefixime) for 1st, 2nd and 3rd generation,
Table 7.4 DNA Inhibitors — Fluoroquinolones
and Iv ee
* Cephalosporins respectively. _ ACTIONS-SPECTRUM UNDESIRABLE EFFECTS _ PHARMACOKINETICS

Cephalosporins share with penicillins a common
Quinolones
mechanism, susceptibility to B-lactamases (penicillinases,
Antibiotics that Work
cephalosporinases) and similar side effects. Nalidixic acid Blocks a subunit of DNA Hypersensitivity reaction, nausea, PO. This pro-drug is hydroxylated
Like penicillins, the original “generation” of Inside the Cell (NegGram) gyrase. Bactericidal — prevents photosensivity, seizures, headache, to a bactericidal metabolite
supercoiling resulting in inhibition dizziness, skin tumors (in mice). which is concentrated in urine.
cephalosporins was most effective against Gram- Up to this point, we have discussed antibiotics that of DNA synthesis. Effective Displaces oral anticoagulants from Does not penetrate prostate.
positive organisms. Chemical modifications increased work outside of the bacteria or at its surface. Cell wall against enteric Gram-negative plasma proteins. Causes growth >90% plasma protein bound.
the effectiveness of subsequent generations against inhibitors cannot kill all types of bacteria because bacteria, but not Pseudomonas. plate arrest in animals — not
Gram-negatives and reduced their ability to fight recommended for children.
some lack cell walls. Other bacteria have unique struc-
Gram-positive infections. tures that resist the action or the accumulation of the Fluoroquinolones
Perhaps the greatest problem with cephalosporins cell wall inhibitors. Antibiotics that target other vital
is that their names sound alike. When learning the unique bacterial features are effective in eliminating Norfloxacin Disrupts DNA gyrase and Drug interactions. Cartilage PO. Reduced bioavailability.
(Noroxin) DNA topoisomerase activity. damage in animal studies. Renal elimination. Used
cephalosporins, concentrate on the commonly used these infections. primarily for prostatitis or
Good gram negative coverage. Hence, use in children has
agents first. Each generation has only one preferred These anti-microbials work within the bacteria been limited. urinary tract infections.
_ oral preparation, usually referred to by the trade and affect the genetic code or protein synthesis. The
Lomefloxacin Disrupts DNA gyrase and DNA
«cn
PO. Ciprofloxacin and ofloxacin
antibiotics target bacterial structures and enzymes
(Maxaquin) topoisomerase activity. Excellent are also available as IV. Good
(bacterial ribosomes, bacterial RNA polymerase, Ofloxacin gram negative, some gram tissue penetration except CSF.
DNA gyrase, dyhydrofolate reductase) that although (Floxin) positive. However, ofloxacin has good
unique to the bacteria, can share homology with host Ciprofloxacin CSF penetration. Renal elimination.
structures. These drugs, therefore, often have poorer (Cipro)
selective toxicity than the cell wall inhibitors. The Moxifloxacin Does not cover pseudomonas PO/IV. Reduce dose with renal
intrabacterial antibiotics have mechanisms of action (Avelox) aeruginosa. impairment.
Hypersensitivity reactions (anaphalaxis, Cross allergenicity between
serum sickness). Gl disturbances. cephalosporin and penicillins similar to those used to combat viral, protozoal, and
Gemifloxacin Indicated for acute bacterial PO. Reduce dose with renal
Rare neurologic toxicity (seizures, occurs in 10% to 15% of some fungal infections. (factive) exacerbation of chronic bronchitis impairment.
confusion) especially with Cefazolin. patients.
Hematologic abnormalities; (neutropenia, The disruption of a microbe’s genetic code and and mild-moderate pneumonia.
thrombocytopenia, anemia). the inhibition of DNA replication provide common a
Nephrotoxicity and hepatic enzyme Levofloxacin Disrupts DNA gyrase and DNA PO/IV. Renal elimination.
targets for anti-infectious agents. This can be done by
abnormalities. (Levaquin) topoisomerase activity. Sparfloxacin is PO only.
destroying the conformation of the DNA (quinolones / Excellent gram negative coverage Good tissue penetration.
fluoroquinolones), by introducing defective building and improved Staph coverage. All
blocks for DNA synthesis (ddI, ddC, griseofulvin) treat Legionella and Chlamydia
atypical pneumonia.
or by inhibiting enzymes or cofactors necessary for
Same as above. Cefotetan (a cephamycin) and DNA synthesis (sulfonamids, acyclovir, vidarabine). Others:
Cefaclor associated with high Cefpodoxime (an ester prodrug)
incidence of serum sickness reaction. have improved Gram-negative Drugs that target DNA frequently are mutagenic
coverage equivalent to many or carcinogenic because they can damage Metronidazole Enters bacteria or protozoan and Disulfiram-like reaction with alcohol PO/IV. Penetrates well into tissues
of the third generation (Flagyl) is activated by reduction of the (flushing, vomiting, headache). CNS and abcesses, empyemas and
cephalosporins. They are
eukaryotic DNA. nitro group. Activated intermediates disturbance (seizures, ataxia, CSF. Metabolism is through
sometimes grouped with the The fluoroquinolones are a growing class of antimi- bind DNA and inhibit its synthesis. dizziness), nausea, anorexia, glucuronidation. Majority of drug
third generation cephalosporins. crobial agents. The newer quinolones ((al)trovaflozacin, Cidal against obligate anaerobes bloating, cramping. is eliminated unmetabolized in
Cefotetan cefmetazole, and (Bacteroides, Clostridium, the urine.
cefoxitin cover Bacteroides sparfloxacin, and levofloxacin) have improved activity
Peptococcus) and Protozoans
and Clostridium spp. against gram positive organisms. This combined (Entamoeba histolytica,
with their excellent gram negative coverage and Trichomonas, Giardia)
a
SN a excellent tissue penetation, has broadened their list
Nitrofurantoin Mechanism unclear, may damage Nausea, vomiting (less so with PO. Reduced in liver, excreted
Same as first generation of indications to include skin and skin-structure,
cephalosporins.
(Macrodantin) DNA. Kills many urinary pathogens, macrocrystalline formulation), by kidney. Reduce dose if renal
bone and joint, gastrointestinal, and respiratory but not Pseudomonas, Klebsiella, hepatotoxicity, pulmonary fibrosis, compromised. Do not administer if
Ceftriaxone associated with acalculous
cholestasis and bilirubin displacement infections. Additionally, quinolones can be used for Proteus, Serratia, Acinetobacter. neuropathy. creatinine clearance <40 ml/min.
from albumin. Use cautiously in sexually transmitted diseases (gonorrhea and
neonates and avoid in jaundiced infants.
Chlamydia).
109 1710 Anti-infective Agents

Antimetabolites Pteridine + Para-amino benzoic acid (PABA) Table 7.6 Inhibitorsof Protein Synthesis. |
The antimetabolites described in Table 7.5 inhibit <@= Blocked by DRUG a a " MECHANIS _ RESISTAN E a
DNA, RNA and protein production by blocking the Sulfonamides
folate pathway. Tetrahydrofolate donates single carbon Aminoglycosides (Bactericidal)
Dihydropteroic Acid
molecules to the synthesis of purines, pyrimidines and Gentamicin Binds at the 30s/50s subunit interface Mutation of binding sites Aerobic and facultative Gram-
some amino acids (methionine, formyl-methionine Glutamate Tobramycin results in abnormal reading of mRNA Inhibition of transport and negative bacilli.
Kanamycin and defective bacterial proteins permeability of drug. Anaerobic bacteria are resistant
and serine). * Bacterial enzymatic because transport into bacteria
Streptomycin (Fig 7.14). Concentrated in bacterial
The sulfonamides are structurally similar to para- cytoplasm by energy (oxygen) inactivation of aminoglycoside. is oxygen dependent.
dependent protein transport.
amino benzoic acid (PABA). Sulfonamides compete
Dihydrofolic Acid
with PABA and prevent it from being incorporated into Amikacin es Has different enzyme resistance
“n
folate (Fig. 7.13). Trimethoprim prevents reduction of profile than gentamicin/tobramycin.
dihydrofolate (FAH,) to tetrahydrofolate (FAH,) by <@= Blocked by * Bacterial impermeability.
binding to and inhibiting dihydrofolate reductase Trimethoprim

Agents that bind to the 50s ribosomal subunit (Bacteristatic)
(Fig. 7.13). Human cells are spared from this reaction
Tetrahydrofolic Acid Chloramphenicol Reversibly binds 50s subunit R-tactors code for acetyl Excellent coverage of most Gram-
because trimethoprim has very low affinity for human (e.g., Chloromycetin) Preventing aminoacyl end of transferases which inactivate positives and Gram-negatives,
dihydrofolate reductase. tRNA from associating with the drug. including anaerobes.
peptidy! transferase (Fig 7.14).
The ability to achieve therapeutic levels of most
sulfonamides is limited by precipitation in urine. This Cofactors essential for synthesis
problem is circumvented by combining agents. Thera- of DNA, RNA or Proteins Linezolid (Zyvox) Binds to 50s subunit. Gram-positive organisms.
peutic doses of the combination can be achieved with Tedizolid (Sivextro)
nonprecipitating concentrations of individual drugs.
Figure 7.13 Sites ofAntimetabolite Action Macrolides
Erythromycin Prevents translocation of poly- Mutation of binding site by Bacteria lacking cell walls (mycoplasma,
(e.g., E.E.S.) peptide chain by binding to the methylation. legionella, chlamydia).
P site of the ribosomal 50s Most Gram positive aerobes. Gram
Sulfonamides and Other Antimetabolites subunit (Fig. 7.14). negative aerobes except Campylobacter,
Pasteurella, some H. influenza.
PECTRUM-USE UNDESIRABLE EFFECTS RESISTANCE-KINETICS Poor anaerobic agent.
Race
Sulfadiazine Covers both Gram-positives and Bone marrow depression, renal Bacteria which utilize exogenous Clarithromycin oe «n As above. Also Mycobacterium
Gram-negatives. toxicity, photosensitivity, hemolysis, folic acid are resistant to (Biaxin) avium intracellulare.
hepatotoxicity, hypersensitivity H. Flu and some anaerobes.
Used for treatment of uncomplicated sulfonamides.
urinary tract infections, nocardiasis, (fever/rash) Stevens-Johnson
chancroid, prophylaxis against Syndrome (serum sickness). PO. Readily penetrates CNS, Azi
zithromycin. “on “»
Similar to erythromycin and anaerobic
rheumatic fever. Combined with Kernicterus — sulfas compete joints, eye. (Zithromax) coverage similar to clarithromycin.
pyrimethamine for treatment of with bilirubin for albumin sites. Precipitates in acidic urine.
Toxoplasmosis. Sulfapyridine Resulting elevated free bilirubin Encourage fluids to prevent
used for Dermatitis herpetiformis. is deposited in brain nuclei. renal stone formation. Ketolides
Major metabolite is acetylated.
Telithromycin (Ketek) Binds to 50s subunit S. pneumoniae, H. influenza,
Sulfisoxazole “” Prophylaxis of recurrent otitis
“oy
“” Higher urine solubility than M. catarrhalis.
(Gantrisin) media and UTI. other sulfonamides.
Trimethoprim/ Enteric Gram-negatives (Proteus,

“oy
“” PO/IV. Intermediate urine Lincosamides
Sulfamethox- E. coli, Klebsiella, Enterobacter), solubility. High plasma protein
azole H. influenzae, Shigella, Serratia, binding. Clindamycin Binds to 50s ribosomal subunit Alteration of ribosome binding site. Covers Gram-positives and most
(Cleocin) and prevents chain elongation by Enzymatic inactivation of drug. anaerobes.
(TMP/SMZ, Salmonella, Pneumocystis carinil.
Lincomycin blocking transpeptidation (Fig. 7.14).
Cotrimoxazole, Inexpensive, effective choice for (Lincocin)
Septra, Bactrim) urinary tract infections, acute
otitis media, traveler’s diarrhea.
Used for Pneumocysitis carinii
prophylaxis/treatment in Agents that bind to the 30s ribosomal subunit (Bacteristatic)
immunocompromised hosts.
Tetracycline Inhibits protein synthesis. Binds to R-factor codes for proteins which Most Staphylococcus and Strepto-
Doxycycline 30s subunit blocking amino acid- transport drug out of cell. coccus strains, enterics, mycoplasma,
Minocycline linked tRNA from binding to the spirochetes, rickettsiae, Neisseria
Demeclocycline ‘A’ site of the ribosome (Fig. 7.14). gonorrhoeae.
Doxycycline approved for malaria
prophylaxis.
Tigecycline (Tygacil) aa Broad gram-negative and

positive activity.
112 Anti-infective Agents

INDICATIONS UNDESIRABLE EFFECTS PHARMACOKINETICS
DOC: Enterobacter, E. Coli, Nephrotoxicity (assoc. with high Slow IV or IM. Not distributed
K. pneumoniae, Proteus, troughs). Ototoxicity (assoc. with to CNS or eyes. Excreted
Serratia, Pseudomonas. high peaks). unchanged in kidney — reduce
dose with renal failure.
“on
Often reserved for Gram- “n
negative infections resistant

to other aminoglycosides.
DOC: Salmonella typhosa (typhoid Reversible bone marrow supres- PO/IV Crosses blood brain barrier. *Gray syndrome — toxic levels
fever), H. flu meningitis or sion (binds mitochondrial ribo- Conjugated with glucuronide in of drug in newborns unable to
epiglottitis. Some physicians/ somes 50s subunit in bone liver. Kidney excretion. Decrease conjugate drug. Symptoms:
institutions hesitate to use marrow) or irreversible dose with liver or kidney disease. abdominal distention, vomiting,
chloramphenicol due to risk of idiosyncratic aplastic anemia. Inhibits aminoglycoside transport pallid cyanosis, hypothermia,
aplastic anemia.) Gray syndrome (See Notes). into bacteria. collapse, death (40%).
DOC: Vancomycin resistant Synercid®-IV. Linezoild-IV/PO.

gram positive organisms.
Tetracycline
DOC: Mycoplasma pneumonia, GI upset. llosone prep may cause PO/IV (Erythromycin). Acid labile — Administer with caution in
neonate with Chlamydia cholestatic hepatitis. Injections take on empty stomach. patients with liver disease or
pneumonia, Pertussis. painful due to venodestruction. Concentrated in liver, excreted on medication metabolized
Dirythromycin used for Increases plasma level of many in bile (active). May pass by P-450 system.
upper respiratory infections drugs. Toxicity may result when through inflamed meninges. Prolonged QT and other
with M catarrhalis, coadministered w/ theophylline, Dirythromycin is a prodrug arrhythmias possible
S. pneumoniae. anticoagulants, carbamazepine. converted to erythromy-cylamine. if patient on terfenidine.
Figure 7.14 Sites of bacterial protein synthesis inhibition. Bacterial ribosomes exhibit sites that are distinct from human ribosomes. Gentamicin
Mycoplasma, Strep throat, Similar to Erythromycin Gl PO. Metabolized to active drug
by liver.
binds at the 30s/50s interface and interfers with mRNA reading. Chloramphenicol, erythromycin and clindamycin bind to the 50s subunit to prevent
upper respiratory infections upset (less frequently than
due to susceptible bacteria, erythromycin), headache. peptide chain elongation. Tetracycline binds to the 30s subunit which prevents tRNA from binding to the “A” site of the ribosome.
Staph. skiin infections.
Same as clarithromycin plus GI upset (less frequently than PO/IV. Take on empty stomach. Long
uncomplicated Chlamydia erythromycin), abdominal pain. half-life permits once daily dosing.
Protein Synthesis Inhibitors They have different molecular weight (70s vs. 80s), and
infections. Unmetabolized, excreted in bile.
bind antibiotics preferentially. The mitochondria within
Bacteria, like eukaryotic cells, must synthesize the eukaryotic cells contain similar ribosomes to the
proteins in order to survive. These proteins provide bacteria.
Bacterial exacerbation of Exacerbation of myasthenia PO. Once daily. structural integrity and enable bacterial energy produc- High exposure to some of these drugs can damaged
bronchitis, mild-moderate gravis. Hepatotoxicity. tion. Protein synthesis is critical to a micro-organism mammalian tissue by inhibiting this energy producing
pneumonia, sinusitis.
during replication when new structural proteins and organelle. Similarly, some of the drugs are less selective
enzymes are essential for progeny. Anti-microbials target for the bacterial ribosomes and can bind to the 80s
several steps in protein synthesis. Some of the drugs can eukaryotic ribosome and damage host tissue. Rapidly
Clindamycin is drug of choice for Abdominal cramps, diarrhea, Clindamycin: PO/IV. Hepatic and renal Normal gut bacteria are killed
severe anaerobic Gl infections. reversible elevation of liver excretion. Reduce dose with impaired by these drugs. C. difficile is kill but more often they only inhibit reproduction and dividing cells, (GI mucosa, skin, bone marrow) and cells
Also used for B. fragilis and enzymes and GI upset. liver function. Does not penetrate resistant and overgrowth/toxin rely on the immune system to kill the organism. The first in tissues exposed to higher levels of the drug (kidney,
Staph. infections. Pseudomembranous colitis seen CSF. Is actively transported into release may follow, causing
with any antibiotic but classically abcesses. pseudo-membranous colitis.
step in protein synthesis consists of copying the mRNA liver) manifest the greatest toxicities from these agents.
associated with clindamycin. code from a DNA blueprint. Rifampin inhibits RNA
Polymerase and destroys the code for protein synthesis
while the sulfonamides and anti-metabolities block Mycobacteria
Used for acne and chlamydial Gl distress, reversible nephrotoxicity, PO. Strong chelator — don’t give with Combinations with nystatin not cofactors necessary for RNA and protein synthesis. Tuberculosis (TB) and leprosy are the best known
infections. Also for Borrelia hepatotoxicity, photosensitivity, milk, antacid, Ca** or Fe+*. No CSF
penetration. Concentrated by liver,
effective. Use doxycycline in After the mRNA code is created it travels to the mycobacterial diseases. The development of antibiotics
Burgdorferi (Lyme Disease). dental staining (not used in pre- patients with renal disorders
pubertal children) increased enterohepatic circulation. Excreted (less nephrotoxic). cytoplasm where ribosomes translate the code into a changed tuberculosis from a debilitating / fatal illness to
intracranial pressure (rare). in urine and feces. polypeptide. Other anti-microbials (aminoglycosides, one that was readily controlled with oral medications.
chloramphenicol, erythromycin, tetracycline) target the The prevalence declined until the 1980s, but is now
Bacteria that are resistant to Nausea. IV only. actual factory (50s subunit of the 70s ribosome) that rapidly increasing, particularly among immunodefi-
tetracyclines, methicillin resistant
staph, vancomycin resistant enterococci.
synthesizes the protein from the mRNA (Fig 7.14). The cient individuals. The organisms are increasingly
bacterial ribosomes differ from mammalian ribosomes. resistant to multiple antimicrobials.

disease and may become fulminant in AIDS patients. Herpes Family Viruses cause genital and oral herpes,
Mycobacteria are rod-shaped bacilli that stain weakly growth rate reduces efficacy of antibiotics that prevent
Atypical mycobacteria are treated with combination Varicella (chicken pox), and uncommon but severe
gram positive. They are called “acid fast” bacilli because rapid synthesis of proteins and DNA, 2) the cell wall
chemotherapy or in some cases, surgery. Because drug infections like Herpes encephalitis. Acyclovir is treat-
they retain dye even when washed with acid alcohol. is not susceptible to classic cell wall inhibitors, 3) infec-
resistance is more common in nontuberculous ment of choice.
Mycobacteria infect mononuclear phagocytes, where tions may be walled off in tubercles which reduce
mycobacterial infections than in TB, the susceptibility Cytomegalovirus (CMV) is problematic in transplant
they may live for years as intracellular parasites. antibiotic penetration, 4) infections occur frequently in
of the microbe must be determined early. patients, AIDS patients and other immunosup-
Fulminant mycobacterial infections develop when the immunocompromised hosts which reduces the utility
host’s immune response is compromised. Thus patients of bacteriostatic antibiotics (rely on intact host pressed individuals. Intravenous ganciclovir therapy
for CMV infections requires careful monitoring for
with AIDS and alcohol addiction are particularly immunity). Antiviral Therapy granulocytopenia and thrombocytopenia.
susceptible. Treatment guidelines continue to be revised as
Viruses are obligate intracellular parasites com-
Tuberculosis often presents with pulmonary multi-drug resistance increases. Prophylactic treatment Influenza virus infections may be fatal in the elderly or
posed of either DNA or RNA wrapped in a protein
symptoms, but may involve lymph nodes, bones, is recommended for asymptomatic patients that immunocompromised. Amantadine prevents influenza
nucleocapsid. Some viruses produce a glycoprotein
skin, genitourinary tract and meninges. develop skin test positivity and for young (< 4 years) when used prophylactically and reduces the severity
envelope that surrounds the nucleocapsid.
Treatment consists of several drugs because resis- or immunocompromised patients that are exposed to of symptoms in infected individuals. Rimantidine is a
Viruses shed their capsid after invading a host
tance develops to single agent therapy. In addition to an infectious case of tuberculosis. related drug that has been approved for use in children.
cell. The host cell then synthesizes new viruses
the emergence of antibiotics resistance, treatment of Atypical (nontuberculous) mycobacteria: M. avium- Respiratory syncytial virus (RSV) causes bronchioli-
using the message encoded by the viral DNA
mycobacteria presents unique problems due to 1) slow intracellulare infects patients with chronic pulmonary tis in children. RSV usually resolves with supportive
or RNA.
Viral infections are diagnosed by clinical criteria, treatment. Ribavirin is recommended in children
culture, fluorescent antibody testing, polymerase who are at risk for cardiopulmonary complications.
chain reaction, or serology. Clinically important viral Human immunodeficiency virus (HIV) is discussed
UNDESIRABLE EFFECTS PHARMACOKINETICS infections include: on the next page.
Isoniazid Inhibits mycolic acid synthesis Peripheral neuropathies (can prevent PO. Widely distributed.
in wall of Mycobacterium by pretreating with pyridoxine), N-acetylated, thus, slow
tuberculosis. Bactericidal. hepatitis, hepatotoxicity. acetylators have greater
toxicity. Kidney excretion.
Rifampin Blocks B unit of bacterial RNA Secretions (urine, sweat) turn red. PO. Widely distributed —
Rifapentine polymerase. Stops bacterial Hepatitis (especially in alcoholics), penetrates CNS.
CLINICAL USE
RNA synthesis. flu symptoms.Induces P450 enzymes, Hepatic excretion.
Bactericidal. increasing the metabolism of oral
Acyclovir Metabolized by thymidine kinase and other enzymes to Herpes simplex | and II and Varicella
contraceptives and other drugs. (Zovirax) triphosphate analog which inhibits DNA polymerase and Zoster virus.
Valacyclovir incorporates into viral DNA. Binds to viral thymidine kinase with
Rifabutin Synthetic rifamycin with improved Similar to Rifampin PO. Wide distribution. Longer | (Valtrex) higher affinity than it binds to mammalian thymidine kinase.
activity against rifampin resistant duration of action.
strains of M. avium. (in vitro & Penciclovir a Topical HSV (coldsores).
mouse data). (Denavir)
Pyrizinamide Nicotinamide analog with unknown Hepatitis, Hyperuricemia with gouty PO. Widely distributed — Famciclovir Phosphorylated by viral thymidine kinase to penciclovir triphosphate Shortens duration of herpes zoster
(PZA) mechanism. Bactericidal. arthritis. Never used alone because penetrates CSF. Hepatic meta- (Famvir) which inhibits DNA polymerase in HSV. and genital herpes.
of rapid resistance. bolism with renal excretion.
Ganciclovir Metabolized by thymidine kinase and other enzymes to triphosphate Cytomegalovirus retinitis and severe
(Cytovene) form which inhibits DNA polymerase and incorporates into viral DNA. systemic CMV infections in immuno-
Streptomycin Inhibits protein synthesis Vestibular toxicity > nephrotoxicity IM. Widely distributed — does not
Valganciclovir Preferentially phosphorylated to active drug in CMV-infected compromised hosts.
Kanamycin by binding 30s/50s ribosome site. Rapid resistance by mutation of penetrate CSF. Poor intracellu- (Valcyte) mammalian cells.
Bactericidal ribosomal binding site. lar penetration. Renally
excreted. Foscarnet Analog of pyrophosphate. Competes for pyrophosphate site in viral, Cytomegalovirus retinitis in immuno-
(Foscavir) but not human, DNA polymerase and reverse transcriptase. compromised patients. Acyclovir-
Capreomycin Similar to above. Bactericidal Ototoxicity and nephrotoxicity. IM. Excreted renally. resistant HSV infections.
Para- Structurally related to Mono-like symptoms, severe Gl PO. Renal excretion of active aang Prevents virus from entering susceptible cells. Treatment/prophylaxis of influenza A
aminosalicylic sulfonamides — inhibits folate intolerance and Hypersensitivity metabolites. (e.g., Symmetrel) in the elderly and patients with
Acid (PAS) synthesis. Bacteriostatic lead to poor compliance. cardiopulmonary dysfunction.
|Rimantaine Analog of amantadine uncertain mechanism but appears to inhibit “” Approved for prophylaxis in children.
Ethambutol Inhibits mycolic acid synthesis in Reversible retrobulbar neuritis. Loss PO. Wide distribution. Reaches
(Flumadine) viral uncoating.
bacterial cell wall (mechanism of central vision. Patients must have 50% concentration in CNS.
not comfirmed) Bacteriostatic baseline ophthalmologic exam Concentrated in tubercles. Ribavirin Unknown mechanism. Hospitalized children with respiratory
prior to treatment. (Virazole)
peeioees syncytial virus (RSV) who are at risk
for cardiopulmonary complications.
Cycloserine D-alanine analog that inhibits Allergic dermatitis, CNS toxicity RO:
(Seromycin) cell wall synthesis. Bacteriostatic. Zanamivir Inhibits influenza virus neuraminidase. Treatment of influenza virus infection.
(Relenza)
Ethionamide Inhibits peptide synthesis. Depression, seizures, neuropathy. PO.
(Trecator) Oseltamivir Analog of adenosine monophosphate Influenza
(Tamiflu)
Quinolones See table 7.4 PO.

Antiretroviral Therapy targets are used. These multidrug “cocktails” are
Table 7.8B Antiviral Drugs — Hepatitis The greatest barrier to effective anti-HIV therapy
analagous to combination chemotherapy used for
cancer patients.
Hepatitis B Agents is the emergence of drug resistant strains. Human There are currently three categories of anti-HIV
Adefovir (Hepsera) Nucleoside analog to control (not cure) chronic hepatitis B. Hepatitis B infection may be exacerbated
immunodeficiency virus develops drug resistance by drugs: nucleoside analogs, non-nucleoside reverse
Telbivudine (Tyzeka) when drug is discontinued. HIV testing should be offered to all candidates prior to initiating drug to avoid mutating the enzymes that are targeted by antiviral transcriptase inhibitors and protease inhibitors
Entecavir (Baraclude) inducing HIV drug resistance in infected patients. Renal dysfunction associated with drug-induced agents. Retroviral reverse transcriptase has low (Table 7.8A). By combining medicines from all three
Tenofovir (Viread) nephrotoxicity. Lactic acidosis and liver damage are potentially severe side effects. transcription fidelity, so basepair substitutions are
: mechanistic categories into a single fixed-dose pill that
PegInterferon Induces immune activity against hepatitis B.
Alfa 2A (Pegasys)
cae Hee ei oe oh iste BO BGS is taken once a day, pharmaceutical companies have
pe econ michal pated ipo drug nciie made strides toward converting HIV into a chronic
Chronic Hepatitis C - Agents are used in combination. Please refer to hcvguidelines.org pocket pe pour ne are OG eae re illness. This is due to the fact that it is difficult for the
Sofosbuvir (Sovaldi) Nucleotide analog HCV NS5B polymerase inhibitor. Eatepo aminishing Dene pee HIV virus to simultaneously develop resistance to three
Baguee obras ies MOR oe rap ye seldom or more drugs and because patient compliance in tak-
Simeprevir (Olysio) HCV NS3/4A protease inhibitors.
Telaprevir (Incivek) ae pou ecating AIDS peueets, more one ce ing medicine is higher for once a day dosing compared
therapy is initiated, multiple agents with different viral to multiple drugs multiple times per day.
Ledipasvir/sofosbuvir Ledipasvir is a NSS5A inhibitor. Sold only in fixed dose combination with sofosbuvir.
(Harvoni)
Ombitasvir/paritaprevir/ Fixed dose combination for hepatitis C.

ritonavir copackaged with
dasabuvir (Viekira)
PegInterferon Alfa 2A Induces immune activity against hepatitis C.

(Pegasys) :Table 7.8C Antiviral Drugs - Retroviruses
PpRUG. :7 _ MECHANISM AND VIRAL:SELECTIVITY LINICAL USE
Maraviroc (Selzentry) Blocks CCRS5 receptors, blocks CCR5-tropic HIV CCR865-tropic HIV, as part of
from entering cells. combination therapy.
Raltegravir (Isentress) Blocks integrase, the enzyme that integrates viral HIV, as part of combination therapy.
UNDESIRABLE EFFECTS PHARMACOKINETICS

Dolutegravir (Tivicay)
Elvitegravir (Vitekta)
DNA into the host genome. Integrase is necessary
for viral replication.
Resistant strains produce Skin irritation and burning. Crystalline IV/PO. Administer slowly. CNS Valacyclovir has slightly Zidovudine (Retrovir) Nucleoside HIV Reverse Transcriptase Inhibitor. HIV in combination therapy
abnormal thymidine kinase nephropathy if drug is infused rapidly. level = 50% of serum level. better oral absorption. Emtricitabine (Emtriva) Zidovudine is used in the prevention
or DNA polymerase. Nausea, headache. Decrease dose with kidney Didanosine (Videx, DDI) of maternal-fetal transmission of HIV.
Lamivudine (Epivir)
dysfunction. Poor bioavailability.
Stavudine (Zerit)
Abacavir (Ziagen)
Topical Etravirine (Intelence)
Ritonavir (Norvir) Protease inhibitor. Protease is an enzyme necessary HIV in combination therapy.
Minimal toxicity. Headache. PO. Decrease dose with renal Indinavir (Crixivan) for cleaving the gag-pol precurser. Results in
dysfunction. Saquinavir (Invirase) immature virus formation.
Nelfinavir (Viracept)
Fosamprenavir (Lexiva)
Some resistant strains lack Granulocytopenia, anemia, IV/PO. Excreted unchanged in Do not coadminister zidovu-
Tenofovir (Viread)
thymidine kinase. Cannot thrombocytopenia. Renal dysfunction. urine. Decrease dose with renal dine (granulocytopenia) or Lopinavir/Ritonavir (Kaletra)
activate drug. dysfunction. imipenem-cilastatin Atazanavir (Reyataz)
(seizures). Tipranavir (Aptivus)
Darunavir (Prezista)
Because drug does not require Renal toxicity (frequent), seizures, IV. >80% excreted unchanged in Deposited in bone and teeth.
phosphorylation, it is active against hypocalcemia, fever, anemia, urine. CSF penetration variable. Hydrate patient during Nevirapine (Viramune) Non-nucleoside inhibitor of HIV reverse transcriptase. HIV. Never as monotherapy due
thymidine kinase-deficient strains. diarrhea, nausea, many others. Reduce dose with renal dysfunction. therapy to protect kidneys. Delavirdine (Recriptor) to rapid development of resistance.
Efavirenz (Sustiva)
Enfuvirtide (Fuzeon)
Depression, CNS toxicity, congestive PO. Excreted unmetabolized.
heart failure, orthostatic hypotension,
urinary retention.
Fewer CNS side effects, but still risk PO. Prolonged elimination w/renal or
hepatic dysfunction.
of seizures.
ea.
Decreased pulmonary function. Aerosol administration. Absorbed
Teratogenic in animal studies. systemically.
Minimal toxicity. Inhalation.

117
Table 7. 10A ntifun, yal Drugs:
INDICATIONS DRUG ~ . ACTION CLINICAL USE
Trimethoprim- Inhibits folate synthesis Oral dose form is drug of choice See Table 7.5. Polyenes
sulfamethoxazole pathway as demonstrated for PCP prophylaxis in immuno-
(TMP-SMZ) : in Figure 7.13. suppressed patients. IV form is Amphotericin B Disrupts the plasma membrane DOC: Systemic fungal infections, Poor therapeutic index (toxic at
(e.g., Bactrim, Septra) drug of choice for PCP infection. (Fungizone, of fungal cells. Amphotericin fungal meningitis, and fungal therapeutic dose). Fever/chills,
Abelcet, has greater affinity for ergosterol urinary tract infections. nephrotoxicity (reduce risk by
Pentamidine Unknown. Inhaled form frequently Ambisome) (component of fungal plasma hydrating patient), hypokalemia,
Nebulized form used as alternative
(Pentam) membrane) than for cholesterol nausea, headache,
PCP prophylaxis. IV form is an causes bronchospasm.
(mammalian). thrombophlebitis, anemia.
alternative for PCP treatment. Bronchodilators should
be readily available.
Dapsone Unknown Alternative for PCP prophylaxis.
Atovaquone Unknown Treatment for mild PCP in TMP- Nystatin e DOC: Intestinal Candida or Few adverse effects reported
(Mepron) SMZ-resistant patients. (e.g., Mycostatin) thrush (oral Candida). when administered orally.
iy » nA 2 ee
Azoles
Fluconazole Inhibits fungal cytochrome P-450 Systemic histoplasmosis, Nausea, headache, rash,
(Diflucan) enzymes. Damages plasma blastomycosis, coccidiomycosis vomiting, diarrhea.
membrane by inhibiting sterol (including meningitis), or
demethylation (an essential step sporotrichosis. Opportunistic
in the synthesis of plasma cryptococcosis, candidiasis.
membrane sterols). Candidal thrush, vaginitis,
_ PHARMACOKINETICS esophagitis.
Rash, hepatotoxicity. PO. Contraindicated in renal Itraconazole

“oy
Aspergillosis, histoplasmosis, Nausea, edema (rare), hepatitis.
function impaired
(Sporanex) blastomycosis, coccidiomycosis No gynecomastia or breast pain.
patients.
(not meningitis), sporotrichosis,
Dizziness, serious skin reactions. PO. paracoccidiomycosis. Local Tinea
or Candidal infections. Better than
ketoconozole for Sporothrix
aspergillus.
Mutations in reverse transcriptase Peripheral neuropathy, pancreatitis, PO. Metabolized in liver, excreted Limited utility as single
(e.g., conversion of methionine at diarrhea, headache, insomnia, in urine. Toxicity may be enhanced agent therapy because Clotrimazole Mechanism unknown. DOC: Candida, dermatophyte
codon 184 to either isoleucine vomiting, nausea, rash, abdominal by renal or hepatic dysfunction. of viral resistance.
(e.g., Lotrimin) infections of the skin. Vaginal
or valine.) pain. Zidovudine-myelosuppression.
candidiasis.
“oy
Miconazole Vaginal candidiasis, severe Phlebitis, pruritus, nausea, fever,
(Monistat) systemic fungal infections. rash, vomiting (if intravenous).
Mutations in protease sequence GI distress, headache, other neurologic PO. Metabolized P450 in liver. Potentially serious drug
reduce affinity of protease symptoms (e.g., weakness, anorexia, Reduce dose in patients with liver interactions due P450
dysfunction. Poor CNS penetration. enzyme competition.
Posaconazole Blocks synthesis of ergosterol Prevention of invasive Hypertension, hypotension, headache,
inhibitors. parasthesias). Indinavir associated
with increased risk of kidney stones. See package insert. (Noxafil) which is needed for fungal Aspertillus or Candida. rash, diarrhea, nausea, vomiting,
membranes. Oropharyngeal candidiasis hypokalemia.
resistant to itraconazole/
fluconazole.
Caspofungin Inhibits synthesis of beta Aspergillosis, candidemia, Hypotension, diarrhea, vomiting.

(Cancidas) (1,3)-D-glucan, which is esophageal candidiasis.
Rapid resistance develops due to Severe skin rash, fever, nausea, PO. Well absorbed. Nevirapine needed for fungal cell walls.
mutations in reverse transcriptase. headache. crosses placenta and has better
CNS penetration than Delavirdine. Micafungin has Candidemia, esophageal “oy
(Mycamine) candidiasis.
“on on
Anidulafungin “oy
(Eraxis)
Other
Terbinafine Inhibits squalene epoxidase, the Toenail infection due to Neutropenia, skin reactions ’
(Lamisil) critical enzyme that converts Trichphyton species. ophthalmic toxicity.
squalene to ergosterol in fungi.
Voriconazole Blocks fungal 14 a — lanosterol Aspergillosis, esophageal Visual disturbances, rash,

(Vfend) demethylation candidiasis, other fungal infections vomiting, hepatotoxicity,

Widespread resistance to antimalarial drugs compli-
Antifungal Therapy Anti-parasitic Therapy cates therapy. The drug of choice for the treatment of
Fungi exist in a yeast form and a mold form. The Table 7.10 presents agents used to treat parasites. malaria depends on the pattern of drug resistance in
yeast form reproduces by budding or spore formation Oral metronidazole is widely used for parasitic infec- the region where the patient was infected. Individuals
and the mold form grows by extending hyphae tions (e.g., Giardia). The intravenous preparation is traveling to endemic regions are encouraged to take
(branches). A history of travel is particularly important indicated for anaerobic bacterial infections. Lindane prophylactic antimalarial drugs.
Slow IV for systemic infections, Blood count, urinalysis, liver when fungal infection is suspected because most types is used for head lice.
intrathecal for meningitis, bladder enzymes, blood urea-
of fungi are endemic to specific regions.
irrigation for cystitis. Metabolism
poorly understood, no need to
reduce dose with renal
nitrogen, creatinine, &
electrolytes should be
checked before and during
Fungi are larger than bacteria and can usually be Table 7.10B Antiparasitic Drugs
dysfunction. teatment. Liposome-encased
visualized microscopically without stain, particularly
if nonfungal cells have been destroyed by 10% potas-
DRUG MECHANISM CLINICAL USE. INDESIRABLE EFFECTS —
amphotericin (Abelcet,
Ambisome) produces less sium hydroxide (KOH prep). Fungi are resistant to Metronidazole Activated nitro intermediates Protozoans: Entamoeba Seizures, ataxia, dizziness, nausea,
nephrotoxicity and infusion KOH because of their unique, rigid cell wall. Because (Flagyl) bind DNA and inhibit anaerobe histolytica, Trichomonas, Giardia. anorexia, bloating, cramping.
related toxicity. replication. Antiparasitic Anaerobes: Bacteroides, Disulfiram-like reaction.
human cells lack cell walls, antifungal therapy is mechanism unknown. Clostridium, Peptococcus.
PO. Negligable absorption, directed primarily at destroying the fungal cell wall.
fecal excretion. Also topical. Despite this apparent “selective” difference between Lindane Induces seizures in Scabies (Sarcoptes scabiel): Topical administration may lead to
(e.g., Kwell) ectoparasites. body, head, and pubic louse seizures, CNS disturbances, risk of
human and fungal cells, antifungal agents are (Pediculus capitis, P. corporis, arrhythmias. Skin irritant.
generally very toxic to human cells and should be Phthirus pubis).
PO/IV. Long half-life. Excellent No effects on testosterone used with caution.
penetration of CSF, eye, urine. synthesis. Circumvents Antihelminthic Drugs
Hepatic metabolism. Excellent need to use intrathecal Common Sites of Invasion: rit opens
bioavailability. amphotercin for Mebendazole Disrupts microtubules in worms. DOC or pinworm. Also effective Diarrhea, fever, GI pain. Highly
Coccidiomycosis meningitis. ¢ Candida most often infects the mouth (thrush) or the contagious, family members should be
against roundworms.
vagina, particularly in persons with impaired cell- treated.
mediated immunity. Thrush is generally treated
Praziquaniel Increases cell membrane Schistosome infections Minimal side effects. Patients may feel
PO/IV. Requires acidic evironment _No effect on testosterone, with nystatin “swish and swallow,” or clotrimazole
permeability causing loss of Single dose therapy is adequate. like they have flu.
for absorption. Accumulates over gluocorticoid synthesis. troches and vaginitis is usually treated with intracellular calcium. Results in
time, long half-life, poor CSF and miconazole. Systemic Candida infections occur in paralysis of worms and release
urine penetration, hepatic from host tissues.
metabolism. immunosuppressed patients and require intravenous
amphotericin B. Thiabendazole Unknown. Strongyloidiasis, multiple Flu symptoms, hepatotoxicity, anorexia,
parasite infection. CNS disturbances.
e Histoplasma capsulatum, Blastomyces dermatitidis,
Topical/PO (troches)/ Vaginal Coccidioides immitis and Aspergillus infections Ivermectin Helminthic glutamate-gated Strongyloides, Onchocerca Pruritis, rash, fever in onchocerciasis
cream and inserts. generally present as pneumonia which may (Stromectol) channel antagonist causes patients.
worm paralysis.
progress to systemic fungosis. Amphotericin B
|
Vaginal suppositories/vaginal has traditionally been the drug of choice for such Antimalarial Drugs
cream/topical/IV. systemic infections. Fluconazole and itraconazole =]
Chioroquine 4-aminoquinoline. Mechanism Prophylaxis or acute attacks. Dizziness, headache, irreversible retinal
PO/IV. Strong CYP3A4 inhibitor. are newer drugs that rival amphotericin B with Hydroxy- not clear. Erythrocytic forms of P. falciparum. damage, impaired accommodation,
regard to efficacy for some systemic fungal chloroquine Wide resistance of unknown Used in some auto-immune bullseye retina, hemolysis in G6PD-
infections. Amphotericin B requires intravenous (Plaquenil) mechanism. diseases (Lupus, Rheumatoid deficient patients.
infusion, but fluconazole and itraconazole are arthritis).
abailable in oral forms. Quinine Not Clear Chloroquine resistant P. falciparum. Cinchonism, curare-like effects, shock.
IV (slow infusion, not bolus). Increasing resistance in Little effect on sporozoites or MOST TOXIC antimalarial (Should only
¢ Cryptococcus neoformans may also present as pneu-
S.E. Asia. pre-erythrocytic stages. be used when other antimalarials fail).
monia, but more commonly presents as meningitis
on
in immunosuppressed individuals. Fluconazole Mefloquine Not Clear. Structural analog Active against multidrug resistant Well tolerated, benign sinus bradycardia
and flucytosine are the only antifungal agents that of quinine. malaria (including Chloroquine Single dose cures multidrug resistant
resistant P. falciparum.) P. falciparum malaria.
reach therapeutic concentrations in the brain. Of
the two, fluconazole is more effective against
on
Pyrimethamine Inhibits folate synthesis by Malaria prophyaxis. Erythrocytic Few, mild side effects. |
Cryptococcus. interfering with dihydrofolate form of P. falciparum. Used in
reductase. combination with sulfonamides or
Less resistance when used in sulfones for acute attacks.
combination with sulfonamides Combined with Sulfadiazine for
PO. Long half life. Good tissue Monitor blood counts. (Combination marketed as treating Toxoplasmosis.
penetration. Fansidar®).
(ee Mechanism unclear. Likely to Chloroquine resistant vivax Hemolysis in patients with G6PD-
IV for all indications except involve crosslinking of glutathione. malarias. deficiency.
esophogeal candidiasis (PO). Little resistance to drug by P. vivax More active against hepatic than
(8-aminoquinoline). erythrocytic forms of malaria.
121 122 Anti-Iinfective Agents

Principles of Cancer Chemotherapy
oul
Go
Figure 8.1 The cell cycle. Cells pass through four stages
Anticancer Drugs
of growth during each mitotic cycle. Cells that contain a double
complement of DNA (G, cells) divide during mitosis (M phase).
Following a “gap” (G, phase) cells may either differentiate and
remain out of the cycle for a long period of time (G, period) or begin
the process of DNA synthesis (S phase). Another gap (G,) follows.
Tumor cells are derived from normal cells in which (some, such as permanent cardiomyopathy from
proliferation is poorly controlled. Because tumor cells Adriamycin, are initially asymptomatic), to know how e Resistance and Recurrence multidrug resistance gene is likely one of
are similar to normal cells, it has been difficult to to treat neutropenic fever, and to effectively manage multiple genes that are induced to protect cells
If a tumor cell is to be killed by an anticancer drug,
develop anticancer agents which selectively kill tumor nausea and vomiting. from toxic insults.
1) the drug must reach the tumor cell, 2) the tumor cell
cells without harming normal tissues. must enter the phase of the cell cycle that is targeted
Most anticancer agents act by inhibiting cell ¢ Toxicity of Anticancer Drugs
proliferation. Generally this is achieved by either Principles of Cancer by the drug, and 3) the cell must not be resistant to
the drug. Erythropoietic and leukopoietic cells, cells lining
damaging DNA or preventing DNA repair. Essentially, Chemotherapy Cancer cells become resistant to anticancer the gastrointestinal tract, and hair follicle cells are
there are four ways in which most anticancer drugs
inhibit proliferation:
e The cell cycle agents through a variety of mechanisms including replaced at a much greater rate than most other non-
1) reduced uptake of drug into cell, 2) enhanced cancerous cells in the normal human. Because of the
Tumor cells are remarkably similar to noncancerous
¢ Crosslinking DNA. Prevents separation of DNA human cells. Thus, there are relatively few drug production of enzymes that repair damaged DNA, rapid growth rate of these cells, they are susceptible
strands. strategies for destroying tumor cells while sparing non- 3) production of chemically altered enzymes which to damage by anticancer drugs. Bone marrow sup-
¢ Linking alkyl groups to DNA bases. Inhibits repair neoplastic cells. Newer agents selectively target cancer are no longer recognized by drugs that inhibit pression, mucositis, and alopecia are predictable side
of DNA. cells by using monoclonal antibody technology. Neoplas- unaltered enzymes, 4) reduced transformation of effects of most anticancer agents. In addition, many
tic and normal cells differ primarily with regard to the prodrugs (inactive precursors) into cytotoxic agents drugs cause toxicity that is unrelated to cell growth
¢ Mimicking DNA bases, resulting in 1) incorporation and 5) enhanced transformation of toxic agents into
of drug into DNA or RNA, where it prevents repair number of cells undergoing cell division, and most anti- rate (Fig. 8.3).
cancer drugs act by killing cells that are dividing. The inactive metabolites.
or terminates the chain or 2) negative feedback on Some tumors become resistant to several classes
enzymes that synthesize or recycle purines. drugs accomplish this by interfering with DNA, RNA, ¢ Combination therapy
or protein synthesis or by inhibiting the formation of of antitumor agents, even if they have never been
e Intercalating between base pairs of DNA, disrupting exposed to some of these agents. This is called Chemotherapeutic regimens often consist of
microtubules in mitosis. Such agents are called cell cycle-
the triplicate codons or producing oxygen free multidrug resistance. Affected drugs include antibiotics, several agents which have different mechanisms of
specific agents because they exert their actions during
radicals which damage DNA. colchicine, the vinca alkaloids (vincristine & vinblas- action and minimize overlapping toxic effects. This
distinct phases of the cell cycle (Fig. 8.1). In general,
Hormonal anticancer drugs antagonize receptors, agents that interfere with DNA synthesis are S-phase tine) and epidophyllotoxins (VP-16). Cross-resistance affords multiple points of attack on the tumor cell
preventing endogenous growth-promoting hormones specific; those that interfere with microtubules disrupt among these agents is striking because they do not while sparing normal organs from the toxicity
from binding (Table 8.5). Other hormonal agents are mitosis and are called M-phase specific. share a common mechanism of action. produced by higher doses of a single drug. Most
agonists at receptors that, when activated, inhibit DNA alkylating agents damage tumor cells regard- Multidrug resistance is due to increased anticancer drugs cause bone marrow suppression.
tumor growth. less of whether the cell is actively dividing. Because expression of an energy-dependent membrane Bone marrow-sparing drugs (e.g., vincristine) are
In caring for patients on chemotherapy, it is essential of this property, these agents are called “cell cycle- glycoprotein “pump” which lowers the intracellular frequently included in combination regimens, if
to evaluate the patient for dose-limiting side effects nonspecific” drugs. concentration of chemotherapeutic agents. The the tumor is sensitive.
123 124 Anticancer Drugs

Alkylating Agents effect. Alkylating agents may cause secondary
tumors, even years after therapy. Important side
Alkylating agents were the first anticancer agents
effects are shown in Table 8.1 and Figure 8.3. Note
developed. They are chemically related to mustard gas
which drugs are used to treat CNS tumors, not
which was used in World War I.
because they are better agents, but because they
Alkylating agents are generally more effective
cross the blood brain barrier. Similarly, drugs that
against slow-growing tumors than other classes of
penetrate the blood-testis barrier are used to treat
antineoplastics because they are cell-cycle nonspecific.
testicular cancer. Figure 8.4 DNA alkylation. Normally, DNA strands are joined
Relatively few cells in slow-growing tumors are by hydrogen bonds and other weak forces which allow separation during
mitotically active during a given course of chemotherapy. cell division. Bifunctional alkylating agents (alkylating group on both
In contrast to most other agents, alkylator-induced ends) covalently bind double stranded DNA together, preventing DNA
damage to cancer cells accumulates even during Antimetabolites transcription. Bifunctional alkylation is more toxic than single strand
quiescent portions of the cell cycle. Antimetabolites are cell-cycle specific agents which alkylation because it is less easily repaired.
All alkylating agents are toxic to hematologic prevent synthesis of nucleotides or inhibit enzymes
cells. Thus, myelosuppression is a predictable side by mimicking nucleotides.
a 8.1 DNA Cee Ag,
MECHANISM TUMOR RESISTANCE 2
Photosensitivity: ems Mustards
ae 5-Fluorouracil
Mechlorethamine Not phase-specific. Kills slow- Binds to N7 of guanine. Crosslinks Decreased cellular uptake of drug
YX wl
growing tumors better than DNA by binding to both strands. and increased repair of drug-
i Lee ce. \
phase-specific drugs. induced DNA damage.
Stomatitis: Chlorambucil Not phase-specific “Bifunctional alkylating agent”. ‘aad

Methotrexate (Leukeran) Crosslinks DNA by binding to both
| strands.
Etoposide
Cytarabine Melphalan Not phase-specific ote es
(Phenylalanine
mustard, Alkeran)
Irreversible Cardiomyopathy: Cyclophosphamide Not phase-specific Metabolized to phosphoramide mustard, i
Adriamycin (Cytoxan) which is a DNA alkylating agent.
Pulmonary Toxicity; _~
Busulfan
Methotrexate Hepatotoxicity:
Bleomycin lfosfamide (lfex) Not phase-specific Alkylated metabolites of ifosfamide a
Methotrexate damage DNA.
Ulcers: Nitrosureas
Methotrexate
5-Fluorouracil Carmustine (BCNU) Not phase-specific Inhibit DNA synthesis by DNA alkylation me
Lomustine and protein carbamoylation.
Severe Emesis: Actinomycin D (CCNU)
Actinomycin D Corticosteroids
Streptozocin Not phase-specific ee a
Cisplatin
Renal Toxicity: (Zanosar)
Mechlorethamine
Streptozocin Cisplatin
Streptozocin Others:
Neurotoxicity: Busulfan (Myleran) Not phase-specific DNA alkylating agent. =

Vincristine
Vinblastine Hemorrhagic Cystitis:
Thiotepa Not phase-specific DNA alkylating agent. Also releases 7H
Bone Marrow Suppression: Cyclophosphamide ethylenimine radicals which disrupt DNA.
Most agents lfosfamide
Altretamine Unknown. Structurally similar to Not cross resistant with alkylating
(Hexalen) alkylating agents. agents.
No Marrow Suppression:
Bleomycin Temozolomide Methylation of guanine rich areas
Vincristine (Temodar) of DNA
Dacarbazine Alkylates DNA, blocks purine synthesis.

Delayed Marrow Suppression: (DTIC-Dome)
Carmustine (BCNU)
Procarbazine Induces free radical formation that induces
(Matulane) DNA strand breaks. May alkylate DNA.
Figure 8.3 Notable side effects of chemotherapeutic agents.
jen 126 Anticancer Drugs

the analogs are phosphorylated to nucleotides,
Methotrexate inhibits dihydrofolate reductase, an or by bypassing the folate pathway by adding then incorporated into DNA or RNA where they
enzyme which reduces dihydrofolate (FH,) to tetrahy- thymidine. Thymidine is converted directly to inhibit enzymes or result in faulty transcription
drofolate (FH,). Normally, the coenzyme FH , transfers thymidylate by thymidine kinase. Administration of
or translation. Nucleotide analogs also inhibit
a methyl group to dUMP, forming thymidylate, and these agents after methotrexate is called leucovorin
essential enzymes such as thymidylate synthetase.
is oxidized to FH, in the process. Methotrexate pre- or thymidine “rescue.” Leucovorin and thymidine
vents recycling of this cofactor. Because thymidylate is do not “rescue” tumor cells from methotrexate
necessary for DNA synthesis, methotrexate is toxic because they do not reach adequate concentration Miscellaneous Anticancer Agents Figure 8.5 Antimetabolites such as thioguanine are incorpo-
in the S-phase (synthesis). in tumor cells. Antibiotic Anticancer Agents (Table 8.3) are drugs rated into DNA where they inhibit repair or replication enzymes.
Methotrexate toxicity to normal cells is reduced Other antimetabolites used to treat cancer are isolated from the fungal species Streptomyces. These Thioguanine is phosphorylated to thio-GTP which mimics GTP. The
by supplying an alternative cofactor, leucovorin, either purine or pyrimidine analogs. In some cases, drugs are classified together solely by their origin. They exact mechanism by which thio-GTP inhibits enzymes is unknown.
The other purine and pyrimidine analogs work by similar mechanisms.
have different mechanisms, toxicities, pharmacokinetics
and indications. Therefore, it is not useful to simply
Table
8
ce .2 A ntimetabolites
INDICATIONS. PHASE_ MECHANISM TUMOR RESISTANCE —
Methotrexate S-phase. Also arrests Blocks folate reduction by inhibiting Decreased uptake, increased production
some cells in G1 phase, dihydrofolate reductase. Dihydrofolate of dihydrofolate reductase by gene
Injection site necrosis, IV. Rapid uptake, clearance, Hodgkins disease. preventing them from reductase (DHFR) reduces dihydrofolate amplification, altered forms of
nausea, vomiting, bone and action. entering S phase. to tetrahydrofolate, the coenzyme which dihydrofolate, which are not recognized
marrow suppression. is essential for the production of by methotrexate.
thymidylate.
Bone marrow suppression PO. Slower acting. Chronic lymphocytic leukemia
Drug is carcinogenic. May and ovarian carcinoma Purine Analogs
be mutagenic/teratogenic.
Mercaptopurine S-phase Mercaptopurine: Metabolized to Increased alkaline phosphatase
Drug induced leukemia. PO/IV. Multiple myeloma, ovarian (6-MP) 6-mercaptopurine ribose phosphate (degrades 6MPRP), decreased
Bone marrow suppression, carcinoma, breast cancer, Thioguanine (6MPRP), a false negative feedback sensitivity to feedback inhibition,
nausea, mucositis. neuroblastoma, sarcoma. (6-TG) inhibitor. decreased HGPRTase (the
Thioguanine: Metabolized to Thio-GTP metabolizing enzyme).
Hemorrhagic cystitis, bone PO/IV. This prodrug is Breast, testicular and other Hydrate well and give mesna
or Thio-dGTP which incorporates
marrow suppression, hydroxylated by the P450 solid tumors. Leukemia, to prevent hemorrhagic cystitis.
into DNA.
cardiotoxicity, nausea. system to a cytotoxic agent. lymphoma, neuroblastoma, Mesna is a drug that binds to
Also for immunosuppression toxic acrolein metabolite.
Cladribine Inhibits both DNA repair Metabolized intracellularly to 2-CdATP, High levels of deoxynucleotide
Hemorrhagic cystitis, bone IV. Prodrug is metabolized Germ cell testicular cancer,
“on (Leustatin) (non phase-specific) and which inhibits repair of single deaminase (diverts 2-CdATP
marrow suppression. to cytotoxic derivatives. others under investigation. DNA synthesis (S-phase). strand DNA. precursers into nontoxic pathway).
Incorporates into DNA of dividing cells. Low levels of enzymes that
synthesize 2-CdATP.
IV (carmustine), PO. Short

Pentostatin S-phase Inhibits adenosine deaminase
Bone marrow suppression Central nervous system tumors,
(nadir at 4-6 weeks), half life, crosses blood lymphomas, Hodgkin’s disease, (Nipent) causing increased dATP, which blocks
pulmonary toxicity. brain barrier. and melanoma. ribonucleotide reductase (essential for
DNA synthesis).
Renal toxicity, nausea, IV. Islet cell carcinoma of the
hepatotoxicity, diarrhea. pancreas. Fludarabine ae Metabolized to 2-fluoro-ara-ATP, which “oy
ET I a ee ee ee ed (Fludara) inhibits DNA polymerase, DNA primase

and ribonucleotide reductase.
Bone marrow suppression. PO. Chronic myelogenous leukemia. Pyrimidine Analogs:

Bone marrow transplant conditioning.
5-Fluorouracil S/G1 phase-specific Metabolized to fluoro-UMP which Decreased phosphorylation of prodrug
Bone marrow suppression. IV. Breast adenocarcinoma. Bone (5-FU) incorporates into RNA. Also metabolized to active form, increased intracellular
marrow transplant conditioning. Floxuridine to fluoro-dUMP which inhibits thymidylate catabolism (e.g., increased phosphatase
Capecitabine synthetase. Floxuridine and capecitabine activity), increased or altered target
Nausea, vomiting, PO. Palliative treatment of (Xeloda) are prodrugs to fluorouracil. enzyme.
neurotoxicity, leukopenia. ovarian cancer.
Cyiarabine S-phase-specific Metabolized to ara-CTP, which is “oy
Bone marrow suppression. PO. Food limits extent of Brain Tumor.

(Ara-C) incorporated into DNA. Acts as a chain
absorption.
terminator and inhibits DNA polymerase.
Gemcitabine S-phase Phosphorylation to dDFdCDP and dFdCTP

Prodrug that is rapidly metabolized Hodgkin’s lymphoma. (Gemzar) which inhibit ribonucleotide reductase.
Marrow suppression, mucositis,
to active form by liver microsomes. Also DNA strand terminator.
nausea, neurotoxicity.

learn a prototype drug for this class. The most com- tion. The result is DNA strand breaks which that dam- Table 8.3 Antibiotic Anticancer agents —
monly used antibiotics are Adriamycin, Actinomycin D, age the genome and ultimately lead to cell death.
mitomycin C and bleomycin. Kinase Inhibitors (Table 8.6) are typically designed S phase specific
Mitosis Inhibitors (Table 8.4) include agents that in- to block the catalytic domain of tyrosine kinases. Tyro- Dactinomycin (Actinomycin D) Intercalates between guanine bases of DNA. Also decreases RNA synthesis by blocking DNA-
terfere with the microtubules that form during mitotic sine kinases are often involved in activating oncogenic dependent RNA synthesis. IV agent used for Wilm’s, Ewings, rhabdomyosarcoma, and testicular tumors.
cell division. Microtubules are tubulin molecules that signaling cascades that initiate or maintain cancer. The
Doxorubicin (Adriamycin) Anthracycline chemical structure. Intercalate into DNA, decrease DNA and RNA synthesis, cause
polymerize to form the spindles that segregate dupli- success of imatinib (Gleevec) for treating chronic Daunorubicin (Daunomycin) DNA strand breaks via activity on topoisomerase ||. Most notable side effect is irreversible
cated chromosomes. The vinca alkaloids depolymerize myeloid leukemia led to intense and successful discov- Idarubicin cardiomyopathy. This risk is reduced by slow infusion and capping lifetime exposure. Also cause
microtubules. In contrast, the taxanes stabilize the tubu- ery efforts for other kinase targets. Rapid development Epirubicin radiation recall, in which previously irradiated skin/tissue becomes inflamed. IV agents are used in
combination with other agents for many types of cancer.
lin polymers so that they are unable to depolymerize, of resistance to these drugs is often problematic.
which is also necessary for cell division. Topoisomerase Immuno-oncology Agents (Table 8.7) include mono- G2/M phase specific
inhibitors block the enzyme that breaks and repairs clonal antibodies that induce cancer cell death through
Bleomycin Bithiazole rings intercalate into DNA strand. Drug oxidizes iron, which yields free radicals that
DNA strands as chromosomes unwind during duplica- complement fixation (e.g., rituximab); block activity of damage DNA. Most notable side effect is pulmonary fibrosis. Test doses are given prior to admin-
istration because of risk of anaphylactic reactions. Used in combination therapies because it is
less immunosuppressive than most cytotoxic agents. Indicated for testicular cancer, squamous
cell head and neck cancer, and lymphomas.
INDICATIONS : NOTES Not phase specific
Bone marrow suppression, PO/|V/intrathecal/intra-arterial. Acute lymphocytic leukemia, Leucovorin (formyl folate) Mitoxantrone (Novantrone) Inhibits DNA and RNA synthesis, causes DNA strand breaks, inhibits topoisomerase II. |V agent
mucositis, gastrointestinal Long retention in tissue, osteogenic sarcoma, lymphoma, can be administered after used for acute non-lymphocytic leukemia.
ulcers, nephrotoxicity, excreted unchanged in urine. breast, head, neck, small cell methotrexate to “rescue”
hepatotoxicity, nausea, Monitor serum levels. lung, choriocarcinoma, psoriasis, noncancerous cells. Leucovorin Plicamycin Blocks polymerase movement along DNA strand. Does not intercalate. Given as a slow IV infu-
diarrhea. rheumatoid arthritis. repletes reduced folate stores sion for metastatic testicular tumors.
in noncancerous cells.
Mitomycin C This is an lV prodrug that is metabolized to an alkylating and crosslinking agent. IV drug used for
adenocarcinoma of the stomach, colon, pancreatic and breast cancer along with squamous cell
head and neck carcinoma.
Bone marrow suppression, PO. Short half life, extensively Acute leukemia.
hepatotoxicity. metabolized.
Table 8.4 Mitosis Inhibitors and platinum containing agents

| Vinca Alkyloids
Bone marrow suppression, Administered by continuous Hairy cell leukemia, other Selective toxicity due to paucity Vincristine (Oncovin) M-phase-specific agent binds tubulin and depolarizes microtubules. Used for leukemia, lymphoma, and
infection, fatigue, nausea, IV infusion. leukemias/lymphomas. of deoxynucleotide deaminase some solid tumors. Toxicity includes neuropathy, constipation, jaw pain. Minimal bone marrow suppression.
headache, rash. in monocytes and lymphocytes.
Vinblastine Similar mechanism as vincristine. Less neuropathy and more marrow suppression.
Vinorelbine Similar mechanism. Used for non-small cell lung cancer, breast, ovarian, Hodgkins. Less neurotoxicity
Bone marrow suppression, IV. Poor CNS penetration. Hairy cell leukemia that is Combination with fludarabine is due to decreased affinity for nerve tubules.
nausea, vomiting, fever, Decrease dose with renal refractory to alpha-interferon. contraindicated due to fatal _—
rash, hepatotoxicity. dysfunction. pulmonary toxicity. Taxanes
Paclitaxel (Taxol) M-phase specific. Stabilizes microtubules and prevents depolymerization that is necessary for mitosis.
Bone marrow suppression, IV. Rapidly metabolized to B-cell chronic lymphocytic Used for metastatic ovarian carcinoma and breast cancer. Toxicity includes peripheral neuropathy, mar-
=a
nausea, vomiting, fever. active drug. leukemia. row suppression, myalgias, nausea, hypersensitivity reactions.
Albumin-bound By formulating Paclitaxel with albumin, toxicity-inducing solvents in Paclitaxel were removed which improved
Paclitaxel (Abraxane) the therapeutic index. Approved for metastatic breast cancer.
Nausea, vomiting, diarrhea, \V/PO/intra-arterial. Short Many solid tumors. Topically for Leucovorin can potentiate Docetaxel (Taxotere) Similar to Paclitaxel. Less peripheral neuropathy.
anorexia, ulcers, bone marrow half-life, extensive metabolism. solar keratosis and superficial 5-FU.
suppression, dermatitis, Floxuridine is administered carcinomas of the skin. Cabazitaxel (Jevtana) Similar to Paclitaxel. Improved penetration of the blood brain barrier compared to Paclitaxel.
photo-sensitivity. intra-arterially to tumor bed. Floxuridine: GI! adenocarcinoma.
Capecitabine: breast carcinoma. Topoisomerase Inhibitors
Bone marrow suppression, |\V. Metabolized in liver to Leukemia and lymphoma. Etoposide (VePesid) G2 Phase specific drug that interferes with topoisomerase, causing DNA strand breaks. Used for testic-
GI and oral mucositis, arauridine. Short half-life. Not used for solid tumors. ular and lung cancers. Causes marrow suppression, mucositis, nausea, and hypotension (associated
nausea, vomiting. with rapid infusion).
Conjunctivitis with high doses.
Teniposide (Vumon) Similar to Etoposide. Used for leukemia in children.
Nausea, bone marrow Pancreatic adenocarcinoma,
suppression, fever. lung carcinoma. Topotecan (Hycamptin) Interacts with topoisomerase |. Results in DNA strand breaks during replication. Used for lung and
ovarian carcinoma. Causes marrow suppression.

‘nase Inhibitors
Table 8.4 Mitosis Inhibitors and platinum containing agents (cont.)
Imatinib (Gleevec) BCR-ABL tyrosine kinase inhibitors. In certain cancers such as chronic myelogenous
lrinotecan (Camtosar) Similar to topotecan. Used for metastatic colon carcinoma. Causes severe diarrhea in some patients. Dasatinib (Sprycel) leukemia (CML), a translocation between chromosomes 9 and 22 creates a chimeric
Nilotinib (Tasigna) chromosome (Philadelphia chromosome, Ph+) with a novel fusion protein, called BCR-AbI
Epothilones at the junction. BCR-AbI is a tyrosine kinase that drives cancer. These kinase inhibitors
Bosutinib (Bosullif)
Ponatinib (Iclusig) inhibit kinases other than BCR-ABL to varying degrees, which influences both efficacy
Ixabepilone (Ixempra) Promotes tubulin polymerization. |V drug used for metastatic breast cancer that has failed anthracyline and side effects. Emergence of drug resistance is a problem for most kinase inhibitors.
and taxane therapy.
Platinum containing agents Gefitinib (Iressa) EGFR inhibitors. Bind to the tyrosine kinase extracellular domain of EGFR to block
Erlotinib (Tarceva) EGFR activity. These kinase inhibitors inhibit kinases other than EGFR to varying
Cisplatin (Platinol-AQ) Mechanism unclear. Indicated for metastatic testicular tumors, ovarian tumors, advanced bladder can- Lapatinib (Tykerb) degrees, which influences both efficacy and side effects.
cer and some central nervous system tumors. Causes irreversible ototoxicity and nephrotoxicity. IV Vandetanib (Caprelsa)
drug. Penetrates testes barrier and partially penetrates blood brain barrier.
*Sunitinib (Sutent) Vascular endothelial growth factor (VEGF) receptor inhibitors. These agents bind to the
Carboplatin (Paraplatin) Similar to cisplatin. Fewer side effects that cisplatin and approximately equal in efficacy for lung cancer *Sorafenib (Nexavar) VEGF receptor and block the tyrosine kinase activity that is required for generating new
and ovarian cancer. Less effective than cisplatin for germ cell tumors, bladder cancer, and head and *Axitinib (Inlyta) blood vessels that are needed for cancer mass growth. All of these agents inhibit kinases
neck cancer. other than VEGFR to varying degrees, which influences both efficacy and side effects.
*Cabozantinib (Cometriq)
Oxaliplatin (Eloxatin) Similar to cisplatin. Small but significant improvement in efficacy for advanced colorectal cancer, where
*Ponatinib (Iclusig)
it is used in combination therapy. *Regorafenib (Stivarga)
*Vendetanib (Capreisa)
*Pazopanib (Votrient)
Ziv-aflibercept (Zaltrap) Recombinant humanized protein that antagonizes VEGF-A, VEGF-B and placental
Table
8.5 Miscellaneous Cancer agents growth factor. Component of multi-drug regimen for colon cancer that is refractory to
front line therapy. Risk of severe bleeding, gastrointestinal perforation and delayed
wound healing due to on-target activity.
Vorinostat (Zolinza) Histone Deacetylase (HDAC) inhibitors. DNA is wrapped around histones and some cancers are
Belinostat (Beleodaq) caused or supported by genes that are abnormally expressed because of the interactions between Dabrafenib (Tafliniar) Multikinase inhibitors. These agents inhibit multiple kinases, which influences both
Romidepsin (lstodax) histones and DNA. HDAC inhibitors prevent HDACs from deacetylating histones, which changes the Trametinib (Mekinist) efficacy and side effects. Sometimes called “dirty” kinase inhibitors, these agents
expression level of many genes, some of which are integral to cancer growth. Vemurafenib (Zelboraf) were typically intentionally designed to block multiple signaling pathways that are all
Bortezomib (Velcade) Proteosome inhibitors. Proteins are degraded within cells by complexes of proteases in a structure
Crizotinib (Xalkori) important for cancer. Many of the signaling pathways are also important for noncancerous
Carfilzomib (Kyprolis) called the proteasome. Proteins are targeted to the proteasome by the addition of a ubiquitin group. Ibrutinib (Imbruvica) cells, so finding a therapeutic window in which the drugs kill cancer cells at doses that
The balance between protein production and protein degradation contributes to cellular homeostasis. Ruxolitinib (Jakafi) are well tolerated is challenging.
Certain cancer cells are particularly sensitive to disruption of this homeostasis by proteasome inhibitors. Afatinib (Gilotrif)
Administered by IV injection. Approved for lymphoma and multiple myeloma but not solid tumors. Ceritinib (Zykadia)
Idelalisib (Zydelig)
Arsenic trioxide (Trisenox) Induces degradation of the aberrant PML-retinoic acid receptor a fusion protein, which is likely involved Nintedanib (Ofev)
in efficacy for acute promyelocytic leukemia. Also interferes with multiple other cellular signaling path-
VEGEFR inhibitors marked with*
ways and induces apoptosis in a number of cancer cell types in vitro. ee
eee
Vismodegib (Erivedge) Sonic hedgehog (shh) pathway inhibitor. Blocks activity of the smoothened protein, which reduces shh Everolimus (Afinitor) Mammalian target of rapamycin (mTOR) inhibitors. The mTOR pathway is central to
activity. Indicated for basal cell carcinoma of the skin. Not effective for cancers that are driven by shh Temsirolimus (Torisel) multiple cancer causing or cancer promoting receptor tyrosine kinase pathways.
pathway activation that occurs downstream of the smoothened protein. May cause severe birth defects Used in renal cell carcinoma. Everolimus is also approved for tumors in patients with
if used by pregnant women. Tuberous Sclerosis, which involves overactivity of the mTOR pathway.
Asparaginase Not phase specific. Hydrolyzes L-asparagine to aspartate. Lack of asparagines kills tumor cells that Vemurafenib (Zelboraf) BRAF inhibitor used for melanoma with BRAFY®° mutation. Selectively inhibits
lack asparagines synthetase. Normal cells synthesize asparagine. mutated form compared to nonmutated form, which provides cancer specificity.
Side effects include rash, photosensitivity, alopecia, cutaneous squamous cell cancer,
Hydroxyurea S-phase specific agent that inhibits ribonucleotide reductases. Blocks deoxyribonucleotide synthesis.
Used for chronic granulocytic leukemia. Causes bone marrow suppression.
fatigue.
Mitotane Isomer of DDT (a pesticide that is now banned). Specifically kills adrenocortical cells. Is used for palliative Idelalisib (Zydelig) (CLL). Also used for relapsed follicular B-cell non-Hodgkin Lymphoma and Small
treatment of adrenocortical carcinoma. It is stored in fat and slowly released. Causes GI distress, Lymphocytic Lymphoma.
lethargy, weakness, and dizziness.
Tretinoin (Vesanoid) (Analog of retinoic acid (vitamin A) that induces maturation in acute promyelocytic
Tretinoin (Vesanoid) Analog of retinoic acid (vitamin A) that induces maturation in acute promyelocytic leukemia cells Isotretinoin (Accutane) leukemis cells and neuroblastoms. Toxicity incudes the retinoic acid syndrome
2
Isotretinoin (Accutane) and neuroblastoma. Toxicity includes the retinoic acid-syndrome (fever, dyspnea, pulmonary (fever, dyspnea, pulmonary infiltrates and effusions, fluid retention), transient
infiltrates and effusions, fluid retention), transient leukocytosis, pseudotumor cerebri. leukocytosis, pseudotumor cerebri.
Bexarotene (Targretin) Selectively binds and activates the retinoid X receptor subtypes (RXRa, RXRB, RXRY). These receptors
Portimer (Photofrin) A photosensitizing porphyrin that is toxic to cancer cells exposed to 630 nm light.
act as transcription factors that regulate gene expression that encode proteins involved in cellular differ-
entiation and proliferation. Used for refractory cutaneous T-cell lymphoma. Risk of severe birth defects. Preferentially retained in cancer cells after clearance from most normal tissues.
Light exposure induces a porphyrin excited state, which spin transfers to cxygen to
Porfimer (Photofrin) A photosensitizing porphyrin that is toxic to cancer cells exposed to 630 nm light. Preferentially retained form toxic oxygen free radicals. Indicated for palliation of esophageal cancers that
in cancer cells after clearance from most normal tissues. Light exposure induces a porphyrin excited occlude the airway.
state, which spin transfers to oxygen to form toxic oxygen free radicals. Indicated for palliation of
esophageal cancers that occlude the airway.

oncogenic proteins (e.g., cetuximab); or bind to the pro- Etoposide (VP-16) is a synthetic derivative of
Table 8.7 _Immuno-oncology Agents teins that are necessary for vascularization and growth epipodophyllotoxins. It appears to act by inhibiting
of solid tumors (e.g., bevacizumab). Some monoclonal topoisomerase, causing DNA strand breaks. VP-16
Monoclonal Antibodies antibody classes (anti CTLA-4, anti PD-1, anti PDL-1) is used to treat small and nonsmall lung cancer, tes-
were designed to “take the brakes off” the immune sys- ticular cancer, and non-Hodgkins lymphoma.
Rituximab (Rituxan) Monoclonal antibodies that block CD20, which is expressed on B-cell leukemias and
tem. For certain tumors, typically with many mutations, Mitotane is remarkable simply because it
Ofatumumab (Arzerra) lymphomas. Postulated to induce complement-dependent cytotoxicity. CD20 is also
Ibritumomab (Zevalin) present on normal B cells, but not normal B cell precursors. Therefore, patients normal tumor infiltrating lymphocytes have cancer killing preferentially accumulates in adrenocortical cells.
Obinutuzumab (Gazyva) B cell may be damaged by these antibodies causing transient immunodeficiency, but potential, but are negatively regulated by the CTLA-4 Although treatment is not curative, mitotane is used to
Tositumomab (Bexxar) are later replaced. and PD-1/PDL-1 pathwaysare negatively regulated... decrease symptoms caused by adrenal carcinoma.
[incomplete sentence?]. Blocking these targets with
Cetuximab (Erbitux) Blocks the epidermal growth factor receptor (EGFR, HER1) and prevents activating
therapeutic antibodies induces an anti-cancer immune
Panitumumab (Vectibix) ligands from binding to EGFR. Indicated for metastatic colon cancer patients. Does
response in a subset of patients.
Hormonal and Immunomodulating
not work in patients with mutant kras, so typically used in patients with wild type kras.
Recombinant human MAb that binds to EGFR and prevents ligand binding (similar to Anticancer Agents
Cetuximab). Indicated for EGFR-expressing colon cancer. Most anticancer hormones act as agonists that
Alemtuzumab (Campath)
—— ee
Other Anticancer Agents inhibit tumor cell growth or as antagonists that
Recombinant humanized MAB that binds to CD52, an antigen on B and T lymphocytes.
Approved for B-cell chronic lymphocytic leukemia. The vinca alkaloids, vincristine, vinblastine, and compete with endogenous growth promoting hor-
vinorelbine inhibit tumor growth by destroying mones. Adrenocorticosteroids inhibit multiple cell pro-
Ipilimumab (Yervoy) Monoclonal antibody that blocks the cytotoxic T lymphocyte antigen 4 (CTLA-4). microtubules which are essential for cell structure and cesses necessary for division. Leuprolide and Gosere-
CTLA-4 suppresses T cell activation, including tumor infiltrating lymphocytes (T cells that
have potential to recognize and kill cancer cells). Ipilimumab therefore augments T-cell ac-
mitosis. They differ in that vinblastine and vinorelbine lin act at the pituitary to reduce LH and FSH secretion.
tivation and proliferation. It is used for melanoma. Toxicities include immune mediated in- “blasts” bone marrow while vincristine spares marrow. LH and FSH promote growth of prostate cancer cells.
flammation of various tissues and organs. Vincristine however, causes peripheral neuropathy Estramustine relies on the estrogen moeity simply to
which is manifested by decreased reflexes, foot drop, target the other half of the drug, which is an alkylating
Pembrolizumab (Keytruda) Monoclonal antibodies that block programmed death ligand 1 (PDL-1) from binding to
weak fingers and decreased autonomic function. agent, into estrogen receptor-positive cells.
Nevolumab (Opdivo) PD-1 on activated T cells. PDL-1 binding to PD-1 normally causes the activated
T cell to become docile or die. PD-1 inhibitors therefore augment T-cell activation and
proliferation. It is used for melanoma. Toxicities include immune mediated inflammation
of various tissues and organs.
Traztuzimab (Herceptin)
Pertuzumab (Perjeta)
Recombinant humanized MAb that binds to the extracellular portion of the human epidermal
growth factor 2 (HER2) protein. Approved for breast cancers that over-express HER2.
Table 8.8 Hormonal and Immunomodulating Anticancer Agents —
eels: =)
Bevacizumab (Avastin) Monoclonal antibodies that inhibit vascular endothelial growth factor (VEGF) from binding to it’s
Ramucirumab (Cyramza) receptor (VEGFR). Because VEGF is necessary for new blood vessel formation, these Hormones
antibodies inhibit angiogenesis in tumors. Bevacizumab is used to treat brain, cervic, kidney,
lung, colon and rectal cancers. Ramucirumab is used to treat metastatic stomach cancer. Estrogen Estrogen receptor agonist which counteracts endogenous testosterone (testosterone enhances tumor growth) in
patients with prostate cancer.
Antibody-Drug Conjugates
|Progestin Progesterone receptor agonist used to treat endometrial carcinoma, metastatic renal carcinoma and breast cancer.
Mechanism of action unclear.
Brentuximab (Adcetris) Monoclonal antibody that delivers monomethy| auristatin E (MMAE) to cancer cells that [+
express CD30 (e.g., Hodgkins Lymphoma). The MMAE enters the cells and disrupts Tamoxifen Estrogen receptor antagonist. Prevents endogenous estrogens from stimulating tumor growth. Used to treat estrogen
microtubules, causing cell death. receptor-positive breast cancer in postmenopausal women. Increased risk of uterine cancer observed in women
treated with tamoxifen.
Ado-trastusumab emtansine Monoclonal antibody that delivers emtansine to cancer cells that express HER2 (e.g.,
breast cancer). Shown to provide benefit to HER2-positive breast cancer patients, Aromatase Non-steroidal aromatase inhibitor selectively reduces circulating estradiol levels for the treatment of advanced breast
(Kadcycla)
Inhibitor cancer (anastrazole and letrozole).
including those who previously failed Herceptin.
Androgen Testosterone receptor agonists active against some breast and renal cancers.
Other Immuno-oncology Agents
Flutamide Testosterone receptor antagonist which augments late effects of leuprolide and inhibits transient side effects caused
Thalidomide (Thalidomid) Thalidomide was originally removed from the market after use as an anti-emetic by initial leuprolide-induced LH and FSH secretion.
Lenalidomide (Revlimid) in pregnant women led to limb defects in newborn babies. With intensive safety
Pomalidomide (Pomalyst) precautions to avoid birth defects, it was approved for multiple myeloma patients. Abiraterone (Zytiga) Prodrug is converted in vivo to abiraterone, which inhibits androgen biosynthesis. The drug blocks CYP17, which is
expressed in testicular, adrenal and prostatic tumor tissues and is required for androgen biosynthesis. Abiraterone is
Thalidomide binds to and blocks the protein cereblon, which leads to immunomod- used with prednisone for treatment of castration-resistant (androgen antagonists no longer work) metastatic prostate
ulation, which is likely responsible for anti-cancer activity. Lenalidomide is used for anemia, cancer.
multiple myeloma, myelodysplastic syndrome in patients with 5q chromosome deletion.

Adrenocortico- Inhibit DNA and protein synthesis as well as mitosis. Used for acute lymphocytic leukemia, chronic lymphocytic
Pomalidomide is used for multiple myeloma. steroid leukemia, acute myelogenous leukemia, multiple myeloma, breast cancer, lymphoma.
Interferon Enhance activity of cytotoxic-T, natural killer cells and macrophages. Inhibit proliferation of tumor Leuprolide, Analog of gonadotropin releasing hormone (GNRH). Desensitizes GNRH receptors in pituitary, causing decreased
cells. Used for hairy cell leukemia, AIDS-related Kaposi’s sarcoma. Other uses under investigation. Goserelin release of gonadotropin. Results in decreased sex hormone release and is used for advanced prostate cancer. Initially
stimulates transient release of sex hormones (LH and FSH).
Levamisole Complex actions on immune system. Enhances depressed immune functions, including
Estramustine Estrogen agonist linked to alkylating agent. Drug uptake is enhanced in estrogen receptor-positive cells, causing
antibody production; T cell, macrophage, and monocyte activation. Used in conjunction (EmCyt) selective accumulation of alkylating agent in tumor cells. Used for prostate carcinoma.
with fluorouracil for advanced colon cancer following resection.

Leukemias and lymphomas are derived from immune has been introduced. Because they are identical or
cells, so it makes sense that agents which regulate divi- nearly identical to endogenous hematopoetic agents,
sion of immune cells might also affect tumor cell growth. there are relatively few side effects.
Interferons are protein products that were isolated from These agents are extremely expensive to develop
immune cells and are now produced using recombinant and produce. The investment has led to exciting new
DNA technology. Interferons induce a number of gene therapeutic interventions, however, which were
products in cells that are interferon receptor-positive. In impossible with conventional drug development
addition, they stimulate activity of certain immune cells, techniques. Recombinant DNA technology is now
some of which may act against tumor cells. being applied to numerous medical problems, particu-
larly those due to paucity of an endogenous substance
(e.g., insulin in diabetes mellitus).
Hematopoietic Agents The agents listed below reduce the need for blood
The agents listed in Table 8.9 differ from all the other transfusions in patients with chronic anemia, reduce the
drugs in this chapter. These are not chemicals, isolated incidence of life-threatening infections in patients with
from plants or synthesized in a lab. They are glycopro- low neutrophil counts, and improve the success of autol-
teins produced by cultured mammalian cells, into ogous bone marrow transplantation in cancer patients.
which the gene for erythropoietin, G-CSF or GM-CSF
Anti-inflammatory and
natopoetic Agents
_DESCRIPTION Immunomodulating Agents
Epoetin alpha Epoetin alpha is recombinant human erythropoetin. Erythropoetin, which is synthesized in the
(e.g., Epogen) kidney in response to hypoxia or anemia, stimulates erythropoiesis. Epoetin alpha is indicated for
anemia in patients with chronic renal failure, because these patients are unable to synthesize
Drugs presented in this chapter modulate inflamma- inhibiting or stimulating specific immune pathways.
erythropoetin to correct the anemia. Additional uses include correcting zidovudine (AZT)-induced
anemia in HIV-infected patients and chemotherapy-induced anemia in cancer patients. Several tion or other immune responses. Most of these agents Such agents permit exciting new therapeutic
weeks of therapy are required before the hematocrit levels rise, therefore, this drug cannot replace influence other cellular functions as well, and are dis- approaches to organ transplantation, hyper- and
transfusions for the acute treatment of severe anemia. Epoetin alpha should not be used in patients cussed in other chapters. The reason for the multitude of hypo-immune diseases and cancer.
with uncontrolled hypertension because the elevation in hematocrit may exacerbate hypertension. actions is that these agents generally interfere with pro- A third mechanism for treating inflammation
Filgrastim Filgrastim is human recombinant granulocyte colony stimulating factor (G-CSF), which induces | cesses that are vital to multiple biochemical pathways. involves antagonizing the effects of chemicals
(G-CSF) synthesis of neutrophils from progenitor cells. Indicated for replenishment of neutrophils in cancer A beautiful example of a drug with such pleiotropic released by immune cells. Histamine, released by
(Neupogen) patients treated with myelosuppressive anticancer agents. The goal is to prevent neutropenia, effects is aspirin. Aspirin reduces inflammation, lowers mast cells and basophils in response to antigens,
which is associated with life-threatening bacterial infections. In the past, neutropenia-associated the temperature of febrile patients, relieves moderate causes bronchial constriction and inflammation by
infection was the dose-limiting toxicity of many chemotherapeutic agents. Now, filgrastim permits the
development of chemotherapy protocols that include higher doses of myelosuppressive drugs. This pain and prevents blood clots. The biochemical mecha- binding to histamine receptors on bronchial cells.
will likely result in higher treatment success, but will also result in the development of toxicities that nism of these actions is inhibition of the enzyme, Antihistamines are antagonists which compete with
were previously rarely seen, because the toxicities are produced only at high doses. Filgrastim cyclooxygenase. Cyclooxygenase catalyzes the synthesis histamine for these receptors.
should not be used within 24 hours of the administration of anticancer drugs because the effect of of potent chemical messengers called prostaglandins, Like prostaglandins, histamine regulates numerous
cytotoxic agents on rapidly dividing myeloid cells is not clear. The theoretical concern that filgrastim
which regulate inflammation, body temperature, processes, including acid and pepsin secretion in the
might act as a growth factor for malignancies has not been substantiated clinically. Filgrastim is
indicated for the treatment of severe cyclic neutropenia and severe chronic neutropenia. The most analgesia, platelet aggregation and numerous other stomach, heart rate and vasodilation. Histamine antag-
frequent undesirable effect is medullary bone pain, likely due to rapid cell proliferation within | processes. onists which prevent acid and pepsin secretion are
the marrow. In producing inflammation, the role of clinically used to treat peptic ulcer disease (Table 6.1).
prostaglandins is to “call in” the immune system. Local
Sargramostim Sargramostim is human recombinant granulocyte-macrophage colony stimulating factor (GM-CSF).
(GM-CSF) It stimulates the proliferation of all lines of blood cells. It induces maturation of granulocytes and tissue infiltration by immune cells and the release of
(Leukine) macrophages, but not erythrocytes or megakaryocytes. Sargramostim also activates mature chemical mediators by such cells cause the symptoms Prostaglandin Inhibitors
granulocytes and macrophages. The principle indication is to accelerate bone marrow replenishment of inflammation (heat, redness, tenderness). Thus, a Until a few years ago, there were two ways to phar-
following autologous bone marrow transplantation. It is under investigation for the treatment of second mechanism for reducing inflammation involves macologically reduce inflammation. One approach was
several other myelosuppresive disorders. As with G-CSF, the possibility that GM-CSF might act as
a growth factor for some types of cancer has not been ruled out.
inhibiting immune functions. In the past, this was corticosteroids. The other was the chemically-diverse
accomplished using nonspecific immunosuppressants agents known as “non-steroidal anti-inflammatory
Oprelvekin Oprelvekin is a recombinant growth factor that stimulates platelet production. It is indicated for such as corticosteroids (presented in Chapter 10). drugs” or NSAIDs (Tables 9.1, 9.2 and 9.3).
(Interleukin II, maintaining platelet counts following chemotherapy. Clinical trials show limited efficacy. Toxicity Recent advances in immunology fueled the NSAIDs were used before their mechanism of action
Neumega) includes fluid retention, tachycardia and other cardiovascular reactions.
development of more selective agents, capable of was understood. Ample evidence indicates that
135 136 Anti-inflammatory and Immunomodulating Agents

NSAIDs act by preventing prostaglandin synthesis. anti-inflammatory agents (NSAIDS) are required to Table9.1 Acetaminophen andAspirin
They will likely be referred to as prostaglandin achieve therapeutic levels in the joint space. Of
synthesis inhibitors in the future. course toxicity to tissues other than joints is more
— MECHANISM/ACTIONS — INDICATIONS—
Prostaglandins are a family of potent arachidonic likely at high drug concentrations. Gastrointestinal Acetaminophen Mechanism not yet clear. Mild to moderate pain and Does not cause G/ upset or
acid metabolites, which modulate some components irritation and ulceration are likely to develop when (Tylenol) Weak inhibitor of prostaglandin fever. Preferred over aspirin in bleeding. Rash, occasionally with
of inflammation, body temperature, pain transmis- high-dose NSAIDs are employed unless anti-ulcer synthesis. Analgesic & antipyretic children because it is less likely fever. Overdose may cause
effects equal those of aspirin. to cause Reye’s Syndrome. severe hepatic necrosis leading
sion, platelet aggregation and a host of other actions. drugs are concurrently administered to prevent Anti-inflammatory effects much to coma and death.
They are not stored by cells, but are synthesized and gastroduodenal mucosa damage. weaker.
released on demand. Prostaglandins are rapidly
Nonsteroidal Inhibits cyclooxygenase (COX), an Symptomatic relief of minor Gl upset & bleeding, allergic
degraded, so their half-life is in the range of seconds
to minutes. Antiarthritic Agents anti-inflammatory
drugs (NSAIDs)
enzyme required for the synthesis
of prostaglandins (prostaglandins
pain, inflammation, fever, or
rheumatoid arthritis. Reduction
reactions. Increased risk of
Reye’s Syndrome in children.
Aspirin and other NSAIDs inhibit cyclooxygenase, Joint inflammation and tissue damage characterize mediate inflammation, fever & of stroke risk. Tinnitis.
a critical enzyme in prostaglandin synthesis. Because arthritis. Antiarthritic agents include prostaglandin pain). J inflammation and
pyrogen-induced fever. J pain
this enzyme plays a role in the synthesis of all inhibitors (Table 9.2), corticosteroids (Table 10.6), caused by injury or inflammation.
members of the prostaglandin family, NSAIDs tend other immunosuppressants (Table 9.3), and other Prevents platelet aggregation.
to inhibit all prostaglandin functions (Tables 9.1 antiarthritic agents (Table 9.3). The efficacy of
and 9.2). antiarthritic agents depends on the type of arthritis
being treated (Table 9.5).
The most important characteristics of antiarthritis
drugs are 1) ability to reduce inflammation,
2) ability to reach therapeutic concentrations in joint able 9.2 Nonsteroidal Anti-inflammatory A
capsules without reaching toxic levels in serum.
Drugs in Tables 9.2 and 9.3 are the primary
-LIKE DRUGS _ DISTINGUISHING PROPERTIES —
antiarthritic agents. Acetylsalicylic acid (aspirin) Reduces risk of myocardial infarction (MI) in patients with previous MI. Gastric irritation.
Nonsteroidal anti-inflammatory agents are used
Aspirin most frequently for arthritis. The major toxicity of these
Colecoxib Cox-2 inhibitor
(Acetylsalicylic Acid) drugs, when used at doses large enough to penetrate Diclofenac
joint capsules, is GI irritation and breakdown. Celecoxib ——
Diflunisal (Dolobid) Less likely to cause GI bleeding and tinnitis, but may cause acute interstitial nephritis.
(Celebrex®) and (now discontinued) rofecoxib (Vioxx®)
NHCOCH, are selective cyclooxygenase-2 inhibitors. Because Fenoprofen More potent than aspirin. Fewer Gl side effects, more genitourinary side effects (pain on urination, hematuria,
L
(Nalfon) nephropathy).
they do not inhibit cyclooxygenase-1, there are fewer
GI side effects at doses that are effective for arthritis. Ibuprofen (Advil, Motrin) Better tolerated than aspirin by most patients. Reduces diuretic effects of furosemide and may reduce
Antacids, H2 blockers, or prostaglandin analogs are effectiveness of several antihypertensive agents.
prescribed to prevent or reverse NSAID damage to Indomethacin (Indocin) Contraindicated in patients with GI lesions. May worsen pre-existing depression, epilepsy or Parkinson’s
OH GI mucosa (Table 6.1). disease. Most likely to be nephrotoxic. Also indicated to close patent ductus arteriosus in newborns.
Acetaminophen
ilsal
Ketoprogen
Antigout Agents Ketorolac (Toradol) The only parenteral nonsteroidal anti-inflammatory for pain relief. Initial clinical trials indicate that it is equal to
Sodium urate crystallizes in joints, inciting an narcotic analgesics for controlling postoperative pain. |V/IM/PO dosing forms available for short-term pain
management. No other indications.
Acetaminophen (e.g., Tylenol®) parallels aspirin inflammatory reaction called tophaceous gout.
with regard to its antipyretic (fever reducing) and Aspirin-like drugs may relieve the symptoms of Meclofenamate (Meclomen) Induces diarrhea in 10-35% of patients.
analgesic effects, yet it lacks anti-inflammatory and gout, but therapy is more often directed at lowering
Naproxen (Naprosyn) Better tolerated than aspirin.
antithrombotic actions. Because it produces less GI uric acid levels. Uric acid is a product of purine
irritation than aspirin, it was introduced as an aspirin metabolism. Strategies for reducing uric acid levels Olsalazine (Dipentum) Pro-drug is metabolized to 5-aminosalicylic acid. It is retained in the colon, making it effective against
substitute. Soon, acetaminophen was used in place of include inhibiting xanthine oxidase, the enzyme ulcerative colitis.
aspirin for fevers, analgesia and inflammation, even responsible of uric acid synthesis, and preventing Piroxicam (Feldene) In addition to inhibiting prostaglandin synthesis, piroxicam prevents neutrophil aggregation and release
though acetaminophen is a poor anti-inflammatory uric acid reabsorption from the urine. Antigout of lysosomal enzymes.
drug. This illustrates the hazard of equating similar drugs are described in Table 9.4. Sulindac (Clinoril) Fewer GI side effects than aspirin.
drugs with one another rather than learning important
differences.
a
PeL
Lae (Tolectin) Antiarthritic efficacy enhanced by concurrent administration of acetaminophen.
The use of aspirin-like drugs for arthritis illus- Immunomodulating Agents
trates one problem associated with selective drug Immunosuppressants help prevent rejection of
distribution. Many drugs fail to penetrate into joint transplanted organs and bone marrow, prevent
spaces. High doses of aspirin or other non-steroidal erythroblastosis fetalis (destruction of fetal blood

Table 9.4 Antigout Agents —
DRUG _ MECHANISM
NS PHARMACOKINETICS _ DRUG INTERACTIONS
Allopurinol Decreases uric acid levels Tophaceous gout, recurrent calcium May exacerbate gout attacks.
PO/PR. Readily absorbed, At high doses, acetaminophen (e.g., Zyloprim) by inhibiting xanthine oxidase, oxalate stones. Reduction of uric GI upset, hepatotoxicity, rash,
little plasma protein binding, may potentiate anticoagulants. the enzyme which converts acid in leukemia patients. Stevens-Johnson syndrome.
metabolized by liver, excreted hypoxanthine to xanthine
in urine and xanthine to uric acid.
Probenecid Inhibits renal reabsorption of Tophaceous gout. To enhance the May exacerbate gout attacks.
(e.g., Benemid) uric acid. duration of penicillin (Fig. 7.12) Otherwise well tolerated.
Bleeding disorders, peptic PO. Readily absorbed in Increased risk of bleeding with
ulcer disease. small intestine, enters brain. anticoagulants. Many drug
interactions. Sulfinpyrazone Inhibits renal reabsorption of Tophaceous gout & hyperuricemia. GI upset, hypersensitivity.
(Anturane) uric acid.
Colchicine Unclear, relief likely due to Gouty arthritis. GI upset (80%). Suspend
antiiflammatory properties. therapy upon onset of diarrhea.
Table 9.3 Rheumatoid Arthritis (RA) Drugs

Azothioprine (Imuran) Immune modulators. Each of these disease-modifying anti-rheumatic drugs inhibits
Cyclosporine (Sandimmune) the immune system, which can slow or stop progression of the disease process that
Leflunomide (Arava) causes rheumatoid arthritis. They may take up to six months to achieve full response.
Methotrexate (Rheumatrex) Often used with NSAIDs or glucocorticoids. Risks include infections caused by weakened
Tofacitinib (Xeljanz) immune system, anemia, thrombocytopenia, or toxicity to liver or kidney.
Abatacept (Orencia) Biologic response modifiers. These drugs target the immune response that leads to
Adalimumab (Humira) joint inflammation. They can slow progression or induce remission, but do not cure
Anakinra (Kineret) rheumatoid arthritis. They are typically given intravenously or by injection and often
Etanerept (Enbrel) taken in combination with methotrexate. Patient should be tested for tuberculosis,
Infliximab (Remicade) hepatitis B and C or other infections before starting and should not receive live
Rituximab (Rituxan) vaccines while on therapy. Dysmenorrhea Sunburn
Tendinitis/Bursitis Colitis
Ulcerative Rheumatoid
Arthritis Arthritis
Juvenile Spondylitis
Ankylosing Psoriatic
Osteoarthritis Arthritis Syndrome
Reiters
Golimumab (Simponi) Acetaminophen |
><
Pain
Moderate Xx irate mate x< phot aS Not indicated for arthritis, no
Certolizumab pegol (Cimzia) | anti-inflammatory actions.
Tocilizumab (Actemra) Nonsteroidal Anti-inflammatory Agents (Table 9.2)
Aspirin ORR Sy okealBoPEa Pra
|
*< x
Betamethasone (Celestone) Glucocorticoids. These steroids suppress the immune system and reduce
Prednisone (e.g., Teltasone) inflammation. Long-term use is associated with increased infection risk, avascular
necrosis of bones, skin thinning, and other serious side effects. For these reasons, Oxaprozin
Ibuprofen
Neeect OS Blerene lates nos] corm
glucocorticoids should primarily be used for acute exacerbations of RA.
Ketoprofen
Celecoxib (Celebrex) Non-steroidal anti-inflammatories. See Table 9.2. Naproxen
i
- E
Doclofenac (Voltaren) Fenoprofen
Ibuprofen (e.g., Motrin) Indomethacin
Sulindac
Acetaminophen (e.g., Tylenol) Analgesics. These agents reduce the pain experienced by patients with RA, but do Tolmetin x<
x<
[Piroxicrm |
I oe
Tramadol (Ultram) not affect the disease process.
Oxycodone (e.g., OxyContin)
Meclofenamate
(Tables 8.2 and 9.6)
x SS re ee x
Cyclophosphamide
Methotrexate
Kees bora as ial
é><
><]
<|
Corticosteroids (Table 10.6)
:
~OX
OK]
MK]
x
—- |
za

CONTRAINDICATIONS —_—KINETICS
Immunosuppressants
PO/PR. 80% absorbed.
Metabolized to oxipurinol Cyclosporine Inhibits T-Cell-mediated immunity by Agent of choice for Nephrotoxicity (presentation is
which is active and thus (Sandimmune, 1) J production of interleukin-II by activated preventing and treating similar to kidney rejection!),
extends the duration. Neoral) T-helper cells, 2) | the number of interleukin transplanted organ thromboembolism, neurotoxicity,
receptors on cytotoxic-T cells, 3) allowing rejection. Graft versus seizures, reversible hepatotoxicity,
proliferation of T-suppressor cells. host disease in bone hypertension.
Glomerular filtration rate PO. Highly metabolized, marrow transplant.
decreased by >50%. may accumulate with
repeated use. Tacrolimus Suppresses T-lymphocyte activity. Transplant organ rejection, Nephrotoxicity, neurotoxicity.
(FK 506, Prograf) Mechanism not clear. graft vs. host.
Glomerular filtration rate PO. Rapid complete
decreased by >50%. absorption, highly plasma Azathioprine Converted to 6-mercaptopurine ribose Prevention of organ GI distress, bone marrow
protein bound, primarily (Imuran) phosphate which inhibits purine synthesis. transplant rejection. depression, infections, mild
excreted unchanged. Because DNA & RNA synthesis requires leukopenia and thrombocytopenia.
proteins, all proliferating cells are inhibited
Debilitated patients w/renal, PO/IV. (B-cells, T-cells, nonimmune cells).
hepatic, cardiovascular or
GI disease. PRODRUG is converted by liver to an Drug of choice for Alopecia, GI distress, hemorrhagic
Cyclo-
phosphamide alkylating agent which crosslinks DNA. Wegener’s granulomatosis. cystitis of the bladder, bone marrow
(e.g., Cytoxan) Proliferation of B-cells is inhibited Also used for severe depression.
more than T-cells. May also attack rheumatoid arthritis &
immunocompetent lymphocytes to inhibit autoimmune blood
established immune responses. disorders.
cells by maternal antibody-mediated immunity) and other substances cause histamine release, including Lymphocyte Horse IgG antibodies which selectively Prevention of organ Fever, chills, leukopenia,
may reverse autoimmune diseases such as aplastic radiodiagnostic dyes, some antibiotics, kinins (chemi- immune-, suppress T-lymphocytes (cell-mediated transplant rejection, thrombocytopenia, skin reactions.
anemia. They work by a variety of mechanisms cals released by immune cells) and some venoms. anti-thymocyte- immunity) and humoral immunity. aplastic anemia. Less often: arthralgia, chest or back
globulin (Atgam) pain, dyspnea, vomiting, nausea,
(Table 9.6). Several synthetic histamine agonists are available for headache, night sweats.
Some immunosuppressants are not drugs, but are laboratory studies of histamine functions, but there
instead antibodies that are produced by non-human are virtually no clinical indications for histamine aren Immune Human immune globulin which prevents In Rho(D) negative mother Generally well tolerated.
Giobulin sensitization of Rho negative recipients to carrying Rho(D) positive
animals and are directed at human immune cells. receptor agonists.
(e.g., RhoGAM) Rho(D) positive blood. Theoretically binds to fetus or planning abortion.
Immunostimulants, primarily investigational at Histamine antagonists, on the other hand, are Rho(D) antigens, masking them from Goal: prevent erythroblastosis
this time, may be employed in the future for the among the most widely used drugs. The term “antihis- I antigen-sensitive immune cells. fetalis in future infants.
treatment of AIDS, other immunosuppressed states, tamines” generally refers to drugs which block H1
Interferon B Unknown. Binds to cell surface receptors Relapsing remitting multiple Flu-like illness, fever, headache,
cancer, and viral diseases. Interferons and inter- histamine receptors. These agents prevent bronchial 1b: (Betaseron) initiating several gene products. sclerosis. sweating, weakness, pain at
leukins are peptides released by immune cells in smooth muscle contraction and inhibit histamine- | ta: (Avonex) Reduces exacerbations. injection site, leukopenia.
the body (Table 9.6). induced vasodilation and increased capillary perme- “ony
Glatiramer Copolymer of L-alanine, L-glutamate, Transient post-injection reaction,
ability. Therefore, H1 antihistamines are particularly (Copaxone) L-lysine and L-tyrosine modifies immune transient chest pain.
useful for treating allergies. system by unknown mechanism.
Antihistamines H2 antagonists inhibit acid and pepsin secretion in
Corticosteroids (Tables 10.5 & 10.6), Nonsteroidal Anti-inflammatory Agents (Tables 9.1 & 9.2), Methotrexate (Table 8.2).
Ragweed pollen, bee stings and other antigens elicit the gastrointestinal tract and are used to treat peptic Basiliximab, Daclizumab, Muromonab-CD3, and Mycophenolate Mofetil are also used to prevent graft rejection in transplant settings.
immune responses ranging from mild wheezing to ulcer disease (Table 6.1).
potentially-fatal anaphylactic shock in sensitive indi- Both H1 and H2 histamine receptor antagonists act Immunostimulating Agents
viduals. Histamine, a chemical produced in many by competing with histamine that has been released. Levamisole Stimulates cell-mediated immunity. Colon cancer (Duke’s Dermatitis, agranulocytosis,
human tissues, mediates many of these responses. A second strategy for reducing histamine-induced (Ergamiso!) stage C), in conjunction GI distress, malaise.
Mast cells and basophils release histamine in response symptoms involves preventing histamine release from with fluorouracil.
to a variety of antigens. mast cells and basophils. Inhibitors of histamine release Interferons Enhance activity of cytotoxic-T, natural Hairy-cell leukemia, genital Fever, headache, myalgias.
Following release, histamine binds to either H1 or are available for prophylaxis against allergy and asthma killer cells, and macrophages. Inhibit warts, Kaposi’s sarcoma,
H2 histamine receptors causing a variety of effects symptoms (Table 9.7). proliferation of tumor cells and suppress chronic myelocytic leukemia.
graft-versus-host disease.
(listed in Table 9.8). In addition to allergens, several
Interleukin-2 Enhances production of T-cells and Under investigation for Hypotension, fever, chills, rigor.
gamma interferon. Activates natural killer effectiveness against AIDS,
and lymphokine activated killer cells. neoplasms, and viral diseases.

Table 9.7 Antihistamines :
MECHANISM —CLINICAL IN DICATIONS
DRUG TERACTIONS =
Release Inhibitor
Cromolyn Sodium (Nasalcrom) Inhibits release of Prophylaxis of bronchial asthma & Well tolerated. Local irritation,
Oral most common, but Synergistic nephrotoxicity with Cyclosporine does not inhibit antibody-mediated (B-cell) histamine from mast cells. seasonal allergic conjunctivitis. headache, unpleasant taste.
absorption is erratic. !V for amphotericin B, aminoglycosides & immunity. Therefore, transplant patients are not at significant
acute organ rejection. trimethoprim. Drugs which induce risk for microbial infections during cyclosporin therapy. Other Ethanolamines
Metabolized by liver. No dose liver metabolizing enzymes may drugs (corticosteroids), however, may suppress the patient’s
adjustment necessary with shorten half-life of cyclosporine. antimicrobial defenses. Diphenhydramine (Benadry|) H1 Receptor Type | allergies (allergic rhinitis & Sedative: VARIABLE
renal dysfunction. Clemastine (Tavist) Antagonist conjunctivitis, simple urticaria, pruritis, Anticholinergic: HIGH
Carbinoxamine (e.g., Clistin) angioedema). To induce sleep. GI upset: LOW
PO/IV. Absorption is erratic. Many drugs alter plasma Similar efficacy to cyclosporin. Occasionally effective in
concentration. Follow levels. patients that have failed a cyclosporin trial. Vice versa. Alkylamines
PO/IV. Prodrug is metabolized ALLOPURINOL inhibits xanthene 6-Mercaptopurine is an anticancer agent (Table 8.2). Chlorpheniramine (Chlortrimeton) “on
Sedative: LOW-MODERATE
to 6-mercaptopurine (6MP). oxidase activity, thus increasing Brompheniramine (Dimetane) Anticholinergic: MODERATE
6MP is converted to 6-thiouric serum azathioprine levels. Dexchlorpheniramine (Polaramine) Gl upset: LOW
acid by xanthine oxidase.
Renal excretion. Phenothiazine:
“n
PO. Must be hydroxylated by the Encourage patients taking cyclophosphamide to drink plenty Promethazine (Phenergan) Sedative: HIGH
P450 system to the active form of fluids and void often to prevent hemorrhagic cystitis. Anticholinergic: HIGH
of the drug.
Piperidines' & Piperazines?
«“
‘Cyproheptadine Type | allergies. Hydroxyzine is also Sedative: LOW-MODERATE
'Phenindamine (Nolahist) used for treatment of anxiety and Anticholinergic: MODERATE
'Desloratadine (Clarinex) pruritis. Meclizine is used for motion
IV. Must have filter in IV line to Anaphylaxis occurs in <1% of patients. An airway and *Hydroxyzine (Atarax) sickness and vertigo.
prevent insoluble material from appropriate drugs should be at the bedside during the course ?Meclizine (Antivert)
entering the bloodstream. of therapy. Often administered with steroids to reduce risk of
anaphylaxis. Nonsedating antihistamines
Loratadine (Claritin) Seasonal allergic rhinitis. Little or no sedation.

Contraindicated in Rho(D) positive patients or in Rho(D) Fexofenadine (Allegra)
negative patients who have already developed anti-Rho(D) Cetirizine (Zyrtec)
antibodies. Azelastine (Astelin)
H2 Receptor Antagonists — Described in detail in Table 6.1
Subcutaneous injections. Efficacy and safety have not been established beyond two Cimetidine (Tagamet) H2 Receptor Duodenal/gastric ulcer, Well tolerated. Diarrhea, dizziness,
years. Patients develop antibodies against drug — unclear Ranitidine (Zantac) Antagonist hypersecretion of acid. headache.
whether efficacy is reduced in these patients. Famotidine (Pepcid)
Nizatidine (Axid)
Levocetirizine (Xyzal)
Subcutaneous. Daily injections. Induces IgG levels. Renal immune deposits noted in treated
animals. Long term immune effects of this synthetic antigen
are unknown.
INVESTIGATIONAL. May suppress immune system in some

BIOCHEMICAL MESSENGERS
cases. Clinical efficacy for treatment of various cancers is
being determined. H1 Lung Constrict bronchial smooth muscle Stimulate cyclic GMP
“oy
H1 Adrenal Medulla Stimulate catecholamine release
H1 Veins Constrict oy
“oy
H1 Capillaries Increase permeability
H1 Gastrointestinal Muscle Contract “oy
Heart Increase rate Stimulate cyclic AMP

Stomach Increase HCI and pepsin secretion “oy
Capillaries & arterioles Dilate Stimulate phosphatidyl inositol and T Na*

and Ca** permeability of membranes.
Heart Increase contractility “oy
Histamine-releasing cells Inhibit histamine release

PHARMACOKINETICS DRUG INTERACTIONS ~ NOTES
Nasal spray, oral. Poorly Requires 4—6 doses per day

A absorbed, not metabolized. to prevent reaction.
Anticholinergic activity may Duration: 4—6 hrs. Metabolized Slow onset prevents use in
aggravate bronchial asthma, in liver, excreted in kidney. anaphylaxis.
urinary retention, glaucoma. m
oe Duration: 4-25 hrs.
en Duration: 4—26 hrs.
Endocrine System
Endocrine glands release endogenous chemicals, called (Zoladex®) are indicated for endometriosis. Histrelin
hormones, into the bloodstream to regulate the function acetate (Supprelin®), nafarulin acetate (Synarel®) and
of target tissues. This chapter addresses endocrine func- leuprolide (Lupron Depot) are indicated for preco-
tions which are modified by clinically useful drugs. cious puberty. Gonadorelin (Lutrepulse®) is indicated
Concurrent use of erythromycin Don’t cross blood brain barrier. Potentially fatal arrhythmias with
(macrolide), ketoconazole, Rapid, extensive metabolism, erythromycin, ketoconazole, The pituitary gland regulates virtually every for primary hypothalamic amenorrhea.
itraconazole. high plasma protein binding. itraconazole. endocrine gland and is often called the “master gland.” Adrenal steroids: Corticotropin-releasing factor
It is divided anatomically and functionally into an (CRF), a hypothalamic releasing factor, stimulates
anterior and a posterior lobe. release of corticotropin (ACTH) from the pituitary
Use cimetidine with caution Little plasma protein binding, Cimetidine T levels of many drugs gland. ACTH stimulates the adrenal gland to
in >50 year olds w/kidney or little metabolism. (e.g., oral anticoagulants, theophylline, produce corticosteroid hormones (Tables 10.5-10.7).
liver failure. caffeine, phenytoin, phenobarbital,
benzodiazepines, propranolol) by Anterior Pituitary Hormones Cleavage of the precursor pro-opiomelanocortin
inhibiting liver P450 enzymes.
The hypothalamus secretes releasing and inhibitory (POMC) yields ACTH and another glycoprotein,
substances into the anterior pituitary vasculature, B-lipoprotein (Fig. 3.5). B-lipoprotein further con-
thereby regulating anterior pituitary function. Pituitary verts to the endogenous opioid peptide endorphin.
secretions are also controlled by feedback control via Likewise, melanocyte stimulating hormone (MSH)
circulating hormones. Endocrine systems influenced results from the cleavage of ACTH.
by the anterior pituitary are: Thyroid hormones: Thyroid stimulating hormone
¢ Sex Hormones: The pituitary glycoprotein hormones, (TSH), released by the pituitary gland, facilitates
luteinizing hormone (LH) and follicle stimulating hor- synthesis and release of thyroxine (T,) and triiodo-
mone (FSH), control sex steroid synthesis, spermato- thyronine (T,). TSH is a glycoprotein composed of
genesis, follicular development and menstruation. two chains, designated a and B. The a chain of
The hypothalamic peptide, gonadotropin-releasing TSH is identical to the a chain of FSH, LH and
hormone (GnRH), stimulates the release of both LH human chorionic gonadotropin (hCG). TSH release
and FSH from the pituitary. Circulating sex steroids is stimulated by thyrotropin-releasing factor (TRH),
inhibit the release of LH and FSH; inhibin, a peptide a hypothalamic peptide. Serum T3 and T4 are
synthesized in the gonads, selectively inhibits FSH. feedback inhibitors of TSH synthesis. They also
Synthetic GnRH agonists initially stimulate LH and act as TRH antagonists in the pituitary.
FSH secretion, then desensitize the pituitary, resulting Growth Hormone: Pituitary growth hormone
in decreased LH and FSH secretion. Nafarelin acetate (GH) is released by growing children in discrete
(Synarel®), leuprolide (Lupron®) and goserelin pulses, late in the sleep cycle. Hypothalamic growth
145 146 Endocrine System

presented in tables). PTH is an 84 amino acid chain Indications: Androgen deficiency (growth deficits,
hormone-releasing factor (GRF) stimulates GH and the and vasoconstricts blood vessels. It is released from secreted by the parathyroid glands in response to low impotence), delayed puberty in males, palliation
hormone somatostatin (SRIF) inhibits it. Somatostatin pituitary nerve terminals in response to hypotension. serum calcium. PTH induces bone resorption, which of breast cancer, postpartum breast pain and
is released from the hypothalamus, the gastrointestinal Vasopressin deficiency results in diabetes insipidus, liberates calcium into the bloodstream. These actions are engorgement.
tract and the pancreas. It acts as a neurotransmitter. a disorder which is remarkable for polyuria (excessive dependent on adequate serum concentrations of Undesirable Effects: Women - virilism (hirsutism),
Inadequate secretion of growth hormone results in urine production) and polydipsia (excessive thirst). 1,25-dihydroxy cholecalciferol (a derivative of vitamin menstrual irregularities. Men — prostatic hyperplasia or
dwarfism. Recombinant human growth hormone is Vasopressin (Pitressin®), lypressin (Diapid®) and D). Bone resorption is counterregulated by calcitonin, cancer, gynecomastia (high dose or with liver disease),
available by prescription (Somatrem®, Somatropin®). desmopressin (DDAVP, Stimate®) are synthetic analogs which inhibits osteoclasts (the cells which degrade bone). pattern baldness, reduced sperm count (negative feed-
Synthetic GH contains the 191 amino acid sequence of of arginine vasopressin used for treatment of diabetes PTH increases serum calcium levels by two other back). Both sexes — hypercalcemia, coagulopathies,
pituitary-derived GH. Both endogenous and synthetic insipidus (intranasal or intravenous). They act rapidly mechanisms. PTH increases the synthesis of the active sodium and water retention, hyperlipidemia,
GH induce skeletal and organ growth and promote and their antidiuretic actions persist for 8-20 hours. form of vitamin D, 1,25-dihyroxycholecalciferol, in the atherosclerosis, cholestatic hepatitis, liver cancer.
anabolic metabolism. Octreotide (Sandostatin®) is an Desmopressin is indicated for acute epistaxis kidney, which in turn stimulates production of calcium
analog of somatostatin, which inhibits growth hor- (intranasal) and GI hemorrhage (intravenous). It is binding protein. Calcium binding protein enhances cal-
mone. It is used clinically to treat acromegaly.
e Androgen Inhibitor
also used to maintain hemostasis during surgical cium phosphate absorption from the gut lumen. PTH
Finasteride (Proscar®, Propecia®), inhibits conversion
¢ Prolactin: Prolactin is an anterior pituitary hormone procedures in patients with hemophilia A and Von also inhibits renal calcium excretion, while promoting
of testosterone to 5a-dihydrotestosterone (DHT). It is
which induces milk secretion from the breasts of Willebrand’s disease. The mechanism of platelet phosphate excretion, causing a small increase in serum
lactating women. Nipple stimulation promotes function enhancement is unknown. indicated for benign prostatic hypertrophy and is being
calcium levels.
prolactin release and dopamine inhibits prolactin tested for prostatic cancer. At lower doses, it is indi-
¢ Oxytocin: The posterior pituitary also releases oxy- cated for male pattern baldness.
release. Cabergoline (Dostinex®) is indicated for
hyperprolactinemia
tocin, an octapeptide that differs from vasopressin by Sex Hormones
two amino acids. Oxytocin induces contractions in
the gravid uterus and promotes milk ejaculation e Androgens e Estrogens
Posterior Pituitary Hormones from the post-partum breast. Uterine relaxants and Mechanism: Induce transcription of target genes via
contractants are discussed in Table 10.3. OH intracellular receptors (Fig. 10.1).
The posterior pituitary stores and releases two
Indications: Contraception, atrophic vaginitis,
octapeptides, vasopressin and oxytocin, which are
osteoporosis, cardiovascular disease associated
synthesized in the supraoptic and paraventricular Other Hormones with menopause, hemorrhagic menstrual bleeding,
nuclei of the hypothalamus. Both polypeptides are
The pituitary does not control the endocrine pancreas failure of ovarian development, hirsutism, prostatic
carried to hypothalamic nerve endings in the posterior
or the parathyroid glands. The endocrine pancreas pro- cancer.
pituitary by the transport protein, neurophysin.
duces insulin, which regulates serum glucose levels. Undesirable Effects: Nausea (worse in morning,
¢ Vasopressin: Arginine vasopressin peptide (AVP, Pancreatic hormones are discussed on pages 153-155. tolerance develops), breast tenderness and edema,
Testosterone
antidiuretic hormone) promotes reabsorption of water Parathyroid hormone (PTH), vitamin D and calcitonin and gynecomastia. Increased risk of endometrial
in the distal tubules and collecting ducts of the kidney work in synchrony to regulate calcium homeostasis (not cancer.
Leydig cells in the testes produce testosterone Contraindications: Pregnancy (teratogenic), estrogen
(smaller amounts produced in ovaries of females) in dependent neoplasm, vaginal bleeding, liver impair-
Figure 10.1 Mechanism of response to LH stimulation. Testosterone is responsible ment, thromboembolic disorders.
Steroid hormone action. Steroid Cytoplasm
Nucleus
for male secondary sex characteristics and reproductive Pharmacokinetics: Most estrogens are well absorbed
hormones (S) penetrate plasma
membranes and bind to cytoplasmic capability. orally. They tend to be rapidly degraded by the liver
receptors (R). The steroid-receptor Actions: Enhances development and maintenance during their first pass from the gastrointestinal tract.
complex enters the nucleus and binds of male sex organs, sperm production, muscle mass, Metabolites include glucuronide and sulfide conjugates
to DNA, stimulating transcription of libido, and other secondary sex characteristics. of estradiol, estrone, and estriol.
target genes.
Testosterone cypionate IM. Long acting.
Testosterone enanthate
Testosterone propionate IM. Short acting. Useful for palliative treatment of breast cancer because therapy can be discontinued rapidly
if hypercalcemia develops.
Fluoxymesterone Short acting oral preparation is more convenient, but less effective than above preparations. Used to treat
hypogonadism which develops in adulthood.
PROTEIN
Methyltestosterone Similar to fluoxymesterone. Buccal form available.

are more effective in preventing pregnancy than any antidepressants. Oral contraceptives decrease the
OH progesterone fails to reach target tissues when adminis- other form of contraception and are more convenient effectiveness of oral anticoagulants, anticonvulsants,
tered orally. Synthetic progestins, in contrast, are not than many other forms. Nevertheless, the rate of preg- and oral hypoglycemic agents.
susceptible to first pass metabolism and can thus be nancy in women using oral contraceptives is higher
administered orally. than would be expected based on careful clinical trials. e Progestin Only “Minipills”
The most common reason for this is patient failure to
The mechanism is unclear but they probably act by
HO CH; take the pill at recommended dosing intervals.
altering the endometrium to prevent ovum implanta-
Dosing Regimen: Pills containing active steroids are
tion. Minipills are taken every day (there is no 7 day
Estradiol C=O taken for 21 days of the 28 day cycle. Placebos or iron
break in the cycle). Missed doses are treated as described
pills are taken the remaining 7 days to maintain a regi-
for combination products above, except alternate forms
e Progestins men of one pill per day. During the 7 days of nons-
of contraception are encouraged for two weeks after
teroid pills, patients experience withdrawal bleeding.
Mechanism: Induce synthesis of specific proteins via omission of two doses. Lack of estrogen may decrease
Mechanism of Action: Suppresses ovulation by
intracellular receptors (Fig. 10.1). side effects. Continued use may lead to amenorrhea and
feedback inhibition at the hypothalamus and pituitary.
Indications: Contraception, irregular or hemor- endometrial atrophy.
Estrogen suppresses FSH and progestin suppresses LH.
rhagic menstrual bleeding, endometrial carcinoma, Progesterone In addition, the steroids directly cause cervical mucosal
hypoventilation. e Levonorgestrel Implants (Norplant®)
thickening and render the endometrium “inhospitable”
Undesirable Effects: Masculinization with prolonged
for ovum implantation. Levonorgestrel implants are synthetic polymer
use, otherwise minimal toxicity. Undesirable effects of
e Oral Contraceptives Estrogen Component: ethinyl estradiol or mestranol. capsules embedded with levonorgestrel, a progestin.
oral contraceptives described on next page.
Progestin Component: norethindrone, ethynodiol, The capsules are implanted subcutaneously in women
Pharmacokinetics: Metabolized by liver to glu- Estrogen/Progestin Combinations: Oral contracep-
norethynodrel, norgestrel, or levonorgestrel. who choose this form of birth control. The capsules
curonide or sulfate conjugates. Most of initial dose tives which contain both estrogen and progestins are
Dosing Regimen: MONOPHASIC preparations — continuously release progestin to maintain low
is rapidly degraded by first pass metabolism, thus the most commonly used form of birth control. They
progestin dose is fixed through the cycle. BIPHASIC contraceptive serum progestin levels. Failure rates
and TRIPHASIC contraceptives were created with are similar to those of oral contraceptives. The most
the intention of more closely mimicking physiologic frequent side effects are prolonged, absent, or irregular
concentrations of progestins and to decrease side menstrual bleeding.
Table 10.2 Estrogens and Progestins effects by lowering the overall dose of progestins.
BIPHASIC pills have low dose progestin for 10 days,
‘UNIQUE PROPERTIES Oxytocin and Other OB/GYN Drugs
followed by 11 days at a higher dose. The concentration
Estrogens of progestin begins low in TRIPHASIC pills, then The posterior pituitary releases two hormones, oxy-
increases each 7 days through the 21 day cycle. Estro- tocin and vasopressin. Oxytocin induces contractions in
Estradiol Most potent endogenous estrogen secreted by the ovary. Transdermal/IM/PO. Reduces
gen concentration is fixed and unchanging in all three the gravid uterus and is therefore used when labor
(e.g., Estraderm) osteoporosis in postmenopausal women. Oral form metabolized to estrone (less active).
formulations. TRIPHASIC pills most closely resemble acceleration is desired. Because it is chemically similar
17-ethiny! estradiol High potency, not degraded during first pass metabolism (hepatic enzymes fail to recognize normal physiology and appear to be as effective as to vasopressin, oxytocin has antidiuretic effects and can
(e.g., Estinyl) this chemically altered estrogen). Used in combination with progestins for contraception. monophasic and biphasic formulations. cause fluid retention. Oxytocin, other uterine contrac-
Conjugated Sulfate esters of estrogenic substances. Less potent than estradiol. Oral, IV, or vaginal
Side effects: Improved formulation has dramatically tants, and uterine relaxants are listed in Table 10.3.
Estrogens (Premarin) preparations are effective. lowered the risk of side effects from birth control pills. Obstetricians administer methyl-ergonovine after
Most common side effects are nausea, vomiting, breast delivery to reduce uterine hemorrhage. This drug
Progestins tenderness, water retention, and weight gain. Less causes vasoconstriction, but more importantly causes
Progesterone IM only. Primarily used to treat menstrual disorders.
frequent but more serious side effects include increased tonic uterine contraction. The force of the muscle
(Progestaject) risk for thromboembolic episodes, hepatic adenomas, contraction impedes blood flow through the uterus
hemorrhagic stroke, myocardial infarction and which significantly reduces bleeding. The other uterine
Medroxyprogesterone PO/IM. Used for secondary amenorrhea and hormone-induced abnormal uterine bleeding. endometrial cancer. Smoking potentiates risk of contractants listed in Table 10.3 are used primarily for
(Depo-Provera) Intramuscular depot may have prolonged actions. Should be avoided in women who have
potential to become pregnant in the near future.
myocardial infarction 5-fold in women over 30. inducing abortion. Uterine relaxants known as tocolytic
Contraindications: History of thromboembolic agents are B2 adrenergic agonists which reduce con-
Megestrol Palliative chemotherapy for breast or endometrial cancer. Also used as an appetite stimulant. disorders, deep venous thrombosis, cerebral vascular tractions in patients with premature onset of labor
(e.g., Megace) disease, myocardial infarction, liver cancer, estrogen- (Table 10.3).
Norethindrone Potent oral agent. dependent cancer, breast cancer, undiagnosed Three pharmacologic strategies for treating infertil-
(e.g., Norlutin) abnormal genital bleeding, or suspected pregnancy. ity are presented in Table 10.4. Gonadorelin is synthetic
Drug Interactions: Contraceptive effects are decreased GnRH which stimulates FSH and LH production when
Estrogen Receptor Modulator |
when taken with ANTIBIOTICS (ampicillin, isoniazid, administered in pulses. Clomiphene is an antiestrogen
Raloxifene Binds to estrogen receptor and induces expression of genes that maintain bone density. neomycin, pen V, rifampin, sulfonamides, tetracycline) which causes FSH and LH release by reducing feed-
(Evista) Indicated for osteoporosis prevention. Is not an estrogen. Does not mimic estrogens in breast or CNS AGENTS (barbiturates, benzodiazepines, back inhibition by estrogen on the pituitary gland.
or uterus. phenytoin). Contraceptives increase the effects of corti- Menotropins are FSH and LH purified from the urine
costeroids and worsen side effects of tricyclic of postmenopausal women. All have greater than 50%

success rate in achieving ovulation and all carry the glucose tolerance, behavioral abnormalities), suppres-
| DRUG —
risk of inducing multiple pregnancies. sion of somatic growth, osteopenia and bone fractures. OTHER ACTI:
Uterine Contraction Stimulants
Adrenal Hormones CH,OH
Oxytocin T force and frequency of Contraction of myoepithelium Drug of choice to induce or
¢ Glucocorticoids C=O (e.g., Pitocin) uterine contractions. Most

pronounced in near-term
surrounding alveoli of
mammary gland. Antidiuretic
accelerate labor, to decrease
postpartum uterine bleeding.
HO --OH uterus. (vasopressin) effects. Stimulates milk ejection from
Cortisol is a glucocorticoid released by the adrenal breast (nasal spray).
gland which helps maintain homeostasis by regulating
numerous enzymes throughout the body. During Ergonovine Induce uterine smooth Blocks adrenergic receptors, To J uterine bleeding after
(Ergotrate Maleate) muscle contraction. causes vasoconstriction, abortion or parturition. NOT for
periods of stress, cortisol plays an important role in interacts with other receptors induction of labor.
increasing blood glucose levels and elevating blood (dopamine and tryptamine). J
lactation by J prolactin levels.
pressure. Clinically, cortisol and its derivatives are Cortisol
often used for their immunosuppressive properties. Methyl-ergonovine “on “n “on
They are also important for patients with adrenal (Methergine)

deficiencies. e Adrenocorticosteroid Hypersecretion Carboprost Synthetic prostaglandin Regulate smooth muscle tone, Abortion during 2nd trimester.
Synthesis: The limbic system ultimately controls Cushing’s Syndrome: State of excess glucocorticoids tromethamine which stimulates uterine coagulation, and body
cortisone production by regulating release of corti- (Prostin/15M) contraction. temperature.
caused by 1) overmedication with drugs listed above,
cotropin releasing hormone (CRH) from the hypothala- 2) adrenal hypersecretion due to tumor, or 3) excessive
mus via serotoninergic, dopaminergic and cholinergic ACTH release (pituitary adenoma or metastatic tumors). “on “
Dinoprostone Abortion during 2nd trimester. Also
neurons. CRH stimulates release of adrenocorticotrophic Results in osteoporosis, skin atrophy, abnormal fat (Prostin E2) used to “ripen” (soften) the cervix
hormone (ACTH) from the anterior pituitary. ACTH distribution, abnormal glucose tolerance, behavioral prior to induction of labor.
activates adenylate cyclase in the adrenal cortex. The abnormalities, euphoria. Primary Hyperaldosteronism:
resulting cAMP activates protein kinase which enhances Uterine Relaxants
Caused by adrenal adenoma which secretes aldosterone.
cholesterol esterase activity. Cholesterol esterase Results in hypertension, hypokalemia, metabolic alkalo- Terbutaline B, adrenergic receptor T glycogenolysis, tachycardia, Prolong gestation in premature
increases the amount of cholesterol available to mito- (e.g., Bricanyl) preferring agonist. | uterine gluconeogenesis, gut relaxation, labor cases.
sis, suppressed renin. Aminoglutethimide (Cytadren®) smooth muscle contraction in and vasodilation. J respiration
chondria, where cortisone is made from cholesterol. reduces synthesis of adrenal hormones by blocking near-term pregnant women. of mast cells and neutrophils.
ACTH also stimulates the conversion of cholesterol to conversion of cholesterol to A°-pregnenalone.
pregnenolone, the first step in steroid synthesis. “oo “ny “n
Ritodrine (Yutopar)
Transport to tissues: Cortisol is secreted into the e Mineralocorticoids & Androgens
blood stream where it is 90% bound to cortisol-binding
The preceding information focused primarily on Magnesium Decreases neuromuscular Premature onset of labor,
globulin (CBG) and albumin. Active cortisol (remaining Decreases uterine contraction.
glucocorticoids. Two other important classes of conduction, J acetylcholine pre-eclampsia, eclampsia.
10%) freely diffuses into cells where it exerts its actions release, vasodilation, respiratory
steroids, mineralocorticoids and androgens, are also
via intracellular receptors. CBG plays an important role depression at high doses.
produced by the adrenal glands.
in regulating cortisol delivery and clearance. Dexam-
Aldosterone is the primary mineralocorticoid. It
ethasone has low affinity for CBG. It is therefore more
retains sodium (and subsequently water) in the
potent pharmacologically because a greater fraction is
free in the bloodstream.
blood. It is stimulated in the renin-angiotensin Table
pathway.
Metabolism: In the liver, cortisol is converted to
Dehydroepiandrosterone and androstenedione are the DRUG
dihydro- and tetrahydro- derivatives which are subse-
principal androgens. They have little masculinizing effects
quently conjugated with glucuronic acid of sulfates. The Gonadorelin Gonadrenalin is synthetic human gonadotropin-releasing hormone (GnRH). Gonadorelin is
in men, but are metabolized to testosterone in women, (Lutrepulse) administered intravenously in pulses spaced 90 minutes apart. Like endogenous GnRH, the pulses
conjugates are water soluble and are rapidly excreted by
resulting in development of public hair and libido. of gonadrenalin stimulate FSH and LH release and result in ovulation in about 90% of women
the kidneys. Liver failure leads to decreased metabolism
who have been treated. The rate of multiple pregnancies was 12% in a small series. When
and decreased CBG synthesis. Thus greater amounts of administered continuously, rather than in pulses, GnRH analogs (Lupron®) suppress FSH and LH
unbound (active) cortisol is present in the blood. This production by acting as feedback inhibitors. Administered in this fashion, GnRH analogs are approved
leads to hypercortism. Likewise, renal failure increases Thyroid Hormones for the treatment of prostate cancer and endometriosis.
the half-life of cortisol. The thyroid gland synthesizes and releases T, (3,5,3'-
Clomiphene Clomiphene stimulates LH and FSH release by reducing negative-feedback by estrogen on the
Clinical Indications: Replacement therapy in adreno- triiodothyronine) and T, (thyroxine) which regulate (e.g., Clomid) pituitary. Increased LH and FSH levels induces ovulation and maintains functional corpus lutea. The
cortical insufficiency, salt-losing forms of congenital protein synthesis, regulate membrane-bound enzymes rate of multiple pregnancies is 8%. Abnormal ovarian enlargement occurs in 14% of patients and may
adrenal hyperplasia, autoimmune diseases, arthritis and stimulate mitochondrial oxidation. T, and T, also Cause pain.
(Table 10.5), asthma (Table 5.1), dermatitis, cancer regulate fetal and infant brain development and child-
Menotropins Menotropins are LH and FSH (purified from urine of postmenopausal women) which are administered
(Table 8.5) and sarcoidosis. hood growth. T, is more potent than T,,. (Pergonol) intramuscularly for 9-12 days and followed by an injection of chorionic gonadotropin. Multiple births
Undesirable Effects: Adrenal suppression (insuffi- T, and T, synthesis: The thyroid follicular cell occur in 20% of menotropin-induced pregnancies. Ovarian hyperstimulation, hemoperitoneum, febrile
ciency upon withdrawal), Cushing’s Syndrome (osteo- traps inorganic iodide and oxidizes it to iodine. Iodine reactions and arterial thromboembolism are the most frequent undesirable effects.
porosis, skin atrophy, central fat distribution, abnormal binds to tyrosine residues of thyroglobulin to form

DESIRABLE EFFECTS DRUG INTERACTIONS NOTES

Hydrocortisone PO/IV/IM/Top. Chemically identical to cortisol produced by adrenal glands. Preferred drug
(Solu-cortef) for replacement therapy. Has weak mineralocorticoid effects. Short acting.
1V/IM/nasal. Short Potential for uterine tetany or Potentiates hypertensive Synthetic oxytocin
half-life (8-5 min.). rupture, trauma to infant, post- effects of other drugs. May mimics the effects of Prednisone PO. Intermediate duration of action. Compared to hydrocortisone, glucocorticoid effects are
delivery uterine atony. Prolonged cause stroke/hemorrhage, endogenous oxytocin four times more potent and mineralocorticoid effects are half as potent. Drug of choice for
infusion (>24 h) may cause water fetal distress. which is released from maintenance therapy of severe asthma. Important agent in leukemia therapy.
intoxication (antidiuretic activity). the hypothalamus.
Serr cocre PO/IV/IM. Intermediate duration of action. Compared to hydrocortisone, glucocorticoid effects
Hypertension. May cause death si are five times more potent and mineralocorticoid effects are half as potent. Drug of choice
of infant if given prior to delivery.
Potentially fatal poisoning may
for treatment of acute asthmatic attacks (administered intravenously for this indication).
occur at normal doses in patients
sensitive to ergot alkaloids. Triamcinolone PO/IV/Top/Inh. Intermediate duration of action. Compared to hydrocortisone, glucocorticoid
(e.g., Aristocort) effects are thirty times more potent. No mineralocorticoid effects. “|
“on oy “oy
Dexamethasone PO/IV/IM/Inh. In addition to uses listed in text, it is used to reduce elevated intracranial
“on (Decadron) pressure. Few mineralocorticoid effects. Dexamethasone suppression test examines
IM. Short half-life. Mean Incomplete abortion. Nausea, 20% saline solution is
time to abortion is vomiting, fever. Uterine rupture, preferred for abortion.
whether the hypothalamus/pituitary can be suppressed by glucocorticoids. If the plasma
16 hours. perforation, inflammation, cramps, Consider alternatives cortisol level is <5 g/dl eight hours after receiving 1 gm of dexamethasone, Cushing’s
CNS, cardiovascular and for women with syndrome is ruled out.
respiratory complications. previous C-sections.
on “» “mw
Fludrocortisone PO. Halogenated derivative with potent mineralocorticoid effects. Only oral mineralocorticoid
PO/IM/IV/amniotically. (e.g., Florinef) replacement available. Inappropriate for use as an antiinflammatory agent.
Mean time to abortion is
10-15 hours.
IV/PO. Crosses placenta. Hypotension, tachycardia (reflex Corticosteroids 7 diabetogenic

and 81 stimulated), arrhythmia, effects.
pulmonary edema. Bradycardia, Inhalation anesthetics T
w/abrupt withdrawal. Nausea, hypotension.
headache, muscle tremor.
“on Mitotane Destroys adrenocortical cells. Used for paliiative treatment of metastatic
IV/PO. Similar to terbutaline. More severe
hypotension/tachycardia.
(Lysodren) adrenal! carcinoma.
IM/IV. If IM, onset = 1 hr, >8 mEq/L may cause depression of Additive with CNS depressants, Excess Ca** antago- Metyrapone Blocks 11B-hydroxylase activity, thus Under investigation for use in Cushing’s disease.
duration = 3.5 hrs. If IV, CNS, heart and reflexes. Flushing, potentiates neuromuscular nizes Mg** and is (Metopirone) inhibiting steroid synthesis.
onset = seconds, sweating, hypotension and flaccid blockers, 7 toxicity of digitalis. used to counteract CNS
duration = 30 min. paralysis may occur. and PNS depression. Aminoglutethamide Blocks conversion of cholesterol to Uses: Cushing’s disease; adjunct to irradiation in
(Cytadren) A®°-pregnenolone (the first step in preparing patients for adrenalectomy; treatment
steroid synthesis). of adrenal, breast, and ACTH-producing tumors.
Cyproheptadine Serotonin and cholinergic antagonist Experimental agent for treatment of ACTH
(Periactin) which may inhibit secretion of ACTH hypersecretion and Cushing’s disease.
from pituitary microadenoma cells.
nph, adipose, and connective tissue)
Spironolactone Antagonist of aldosterone, inhibits Treatment of hyperaldosteronism. Causes K*
Protein Metabolism: Carbohydrate Metabolism: Fat distribution: (Aldactone) Na* retention. retention. Diuretic actions are described in
Table 4.3A.
T catabolism T gluconeogenesis Redistribute fat toward truncal obesity
J anabolism J insulin binding to receptors
Electrolytes: Immune System: Blood cytology:

monoiodotyrosine (MIT) and diiodotyrosine (DIT). from degradation of T,. Thyroxine-binding globulin
T sodium retention 1 antibody production T erythropoesis
J inflammatory reaction T neutrophils Then, either two DIT molecules couple to form T, or (TBG) and prealbumin carry most T, and T, mole-
T potassium excretion
metabolic alkalosis J immunocompetent lymphocytes J lymphocytes MIT couples with DIT, forming T, (Fig. 10.2). T , pro- cules in the blood, protecting the hormones from
{ Gl calcium absorption { antigen processing duction exceeds T, production in the thyroid gland and degradation. Only free (unbound) T, and T, are
T, is converted to T, in the periphery. physiologically active. Feedback mechanisms at
Water: Brain: Gastrointestinal tract:
T, and T, release and transport: Thyroglobulin is the hypothalamus, pituitary gland and thyroid gland
T free water clearance J threshold for electrical excitation T acid and pepsin secretion proteolyzed from T, and T, and the hormones are inhibit or stimulate T, and T, production when free
thinning of mucus released into the circulation. Only 20% of circulating T, thyroid hormone levels are too high or too low,
is secreted by the thyroid. The remainder is derived respectively.

¢ Hyperthyroidism (thyrotoxicosis) Colloid
Clinical Features: Nervousness, weakness, heat
intolerance, sweating, weight loss, warm thin skin,
Thyroid Follicular Cell Drugs Used to Treat Hyperthyroidism
exophthalmos, loose stool. Known as Grave's disease
OD D> CS
when goiter and ocular signs are present.
(DIT) (mit) ODO @ Methimazole Inhibits transformation of Control hyperthyroidism until Temporary hypothyroidism (treat
Etiology: Thyroid-stimulating antibodies bind to TSH (Tapazole) inorganic iodine to organic surgery or'?' | therapy. Long term with thyroxine), agranulocytosis,
iodine. Thyroxine can’t be drug treatment to avoid surgery rash, hyperplastic thyroid. Not
receptors, causing release of thyroxin (current theory). given to women who are likely to
formed without organic iodine. or'3! | therapy. About half of
Lab Findings: Increased serum T, and T, levels and Also inhibits iodotyrosine patients will remain euthyroid become pregnant within 3 years.
increased radioiodide uptake. Thyroglobulin coupling. No clinical effects if drug is withdrawn after Damages thyroid of fetus.
a observed for several days. prolonged use.
Therapeutic Strategy: Control hyperthyroidism
Iodine
with drugs (propylthiouracil or methimazole) for one Propylthiouracil “” Also, blocks conversion of
on won
year, then, partial resection of thyroid gland. (PTU) T, to T, in peripheral tissues.

Thyroid Storm: Observed in hyperthyroid patients
lodine/iodide Inhibits release of thyroxine Adjunctive therapy used in Folliculitis, fever.
at the time of thyroidectomy (surgical trauma causes
instantaneous release of thyroid hormones) or in hyper- Iodide G9) > T3 from thyroid gland. Effects are
faster (1-3 days) but weaker
conjunction with drugs listed
above. Provides more rapid
thyroid patients in sepsis. Signs include high fever, irri- Blood than methimazole or PTU. relief in severely ill patients.
Useful for two weeks, then Used to devascularize thyroid
tability, delerium, tachycardia, vomiting, diarrhea and
gland adapts and resumes gland prior to thyroidectomy.
hypotension. Coma may develop. Treatment includes Figure 10.2 Synthesis of T,. Schematic drawing of T, synthesis thyroxine secretion.
IV glucose and saline, vitamin B, glucocorticoids. as described in the text. T, is formed by the coupling of one diiodinated
and one monoiodinated tyrosine on thyroglobulin. T, synthesis follows Drug which relieves symptoms of hyperthyroidism
the same pathways shown in the figure except that two diiodinated tyro-
e Hypothyroidism sine molecules couple to form T,. Abbreviations: DIT — diiodinated Propranolol 8 adrenergic receptor antagonist. Emergent preparation of CNS sedation and depression.
(Inderal) Suppresses tachycardia and hyperthyroid patients for surgery. Suppression of failing heart.
Clinical Features: Fatigue, weakness, cold intolerance, tyrosine, MIT — monoiodinated tyrosine, T3 — 3,5,3 -triiodothyronine,
other catecholamine effects. Thyrotoxicosis in pregnancy.
hoarseness, constipation, cold dough-like skin, thick TBG — thyroxin-binding globulin. Thyroid storm.
tongue, bradycardia, excessive menstrual bleeding,
anemia. Cretinism in childhood. Drugs Used to Treat Hypothyroidism
Etiology: 1) Primary hypothyroidism - surgery, loss, hyperglycemia, ketoacidosis, atherosclerosis, reti- Levothyroxine Replaces normal serum levels Drug of choice for hypothyroidism. No toxicity at replacement
radioiodine ablation, thyroiditis. 2) Secondary nal damage and kidney failure. Because the pancreatic (T4) of T, and T, (T, is converted conceniration. Overdose causes
hypothyroidism - hypofunction of pituitary or islet beta cells (which produce insulin) are damaged or
(Synthroid, into T3 by deiodination in the hyperthyroid effects (top of page).
Levothroid) periphery).
hypothalamus. destroyed, oral hypoglycemics cannot induce insulin
Lab Findings: Hypothyroid patients have low
release. Thus, patients require insulin injections.
concentrations of T, in their serum. The uptake of Noninsulin-dependent diabetes mellitus (NIDDM:
Liothyronine Replaces T,. Used in hypothyroid patients
“on
radioactive iodide is low because thyroid stores of (T3) who have difficulty absorbing
Type ID) is due to decreased release of insulin or (Cytomel) levothyroxine.
iodine are not being used to produce thyroid hor- decreased response of tissue to insulin (e.g., decreased
mones. The pituitary hormone, thyroid-stimulating number of insulin receptors) resulting in hyper-
hormone (TSH), is high in primary hypothyroidism Liotrix Replaces T, and T, When conversion of T, to T, is “ony
glycemia but not ketoacidosis. Treatment focuses on (T4 & T3) abnormally low (myxedema
and low in secondary hypothyroidism. diet and exercise, oral hypoglycemic drugs if diet fails, (e.g., Euthyroid) coma), liotrix may be more useful
Therapeutic Strategy: Replacement therapy with and insulin when all else fails. than levothyroxine.
purified or synthetic thyroid hormones (Table 10.8).
Myxedema Coma: Chronic, severe hypothyroidism
results in respiratory depression, hypothermia and e Insulin Replacement
Porcine insulin differs from human insulin by one
stupor. It is frequently fatal. Patients with insulin-dependent diabetes receive amino acid (terminal arginine). Bovine insulin is
subcutaneous insulin injections daily. The goal of the most immunogenic preparation. A typical
insulin therapy is to provide adequate glucose control
Pancreatic Hormones through each 24 hour period while minimizing the
dosing regimen consists of regular humulin
Muscle T glucose transport into cell with either lente or NPH two to three times per
Insulin is produced by pancreatic islet beta cells number of injections required to achieve that control. T glycogenesis
and is released in response to elevated serum glucose day before meals.
Repeated injections at the same site may result in T protein and triglyceride synthesis
concentrations. The principle actions of insulin are Insulin Toxicity: The most common undesirable
atrophy or hyperplasia at the injection site. Insulin
presented in Table 10.9. Each of these actions reduces Liver T glucose transport into cell effects of insulin administration are hypoglycemia
preparations of short, intermediate and long duration T glycogenesis
the plasma glucose concentration. and hypokalemia. Hypoglycemia is manifested by
are available (Table 10.10). T glucose utilization in Krebs cycle
T protein synthesis weakness, hunger, sweating, dizziness, tachycardia,
e Diabetes Mellitus
Human insulin (Humulin) is prepared by recombi-
nant DNA technology or is synthesized from porcine
Wes anxiety, tremor, headaches, mental disturbances and
Adipose T glucose transport into cell visual disturbances. Many of these symptoms are
Insulin-dependent diabetes mellitus (IDDM: insulin (enzymatic replacement of the terminal arginine T glycogenesis
with threonine). Human insulin is preferred to insulin caused by hypoglycemic release of epinephrine
Type 1) is due to an absolute deficiency of insulin T triglyceride synthesis
(epinephrine causes glycogenolysis, gluconeogenesis
which usually develops by age 15 and results in weight prepared from animals because it is less antigenic.

and lipolysis and inhibits insulin release). Remaining
symptoms are due to the brain being starved of its en-
ergy supply. ~
Hypokalemia develops because insulin drives Rapid-Acting

potassium from serum into cells. It is most often
encountered in patients with ketoacidosis when insulin Regular Insulin 0.5-1 5-8 Humulin R, Novolin R, Regular
PO. Excreted in urine. Therapy requires good = : lletin Il, Velosulin.
Adjust dose in patients patient compliance and therapy 1S instituted. Severe hypokalemia baie Prompt Insulin Zinc Suspension 1-2 12-16
with renal insufficiency. careful monitoring by health cardiac arrhythmias and neuromuscular disturbances.
Lispro Insulin Solution 0.25 6-8 Humalog.
professionals. Repeated injections at the same site may result in
Insulin glulisine 0.5-1.5 1-2.5 Apidra
atrophy or hyperplasia at the injection site.
Insulin-Drug Interactions: Many drugs alter blood Intermediate Acting
“n “wn glucose levels. Increased glucose renders diabetes 1-2 24-28 Humulin N, Novolin N.
Isophane Insulin Suspension
control difficult, even with insulin. Decreased blood
glucose levels may precipitate hypoglycemic episodes. Insulin Zinc Suspension 1-3 24-28 Humulin L, Lente Insulin, Lente
PO/JIV. IV administration lletin | and Il, Novolin L.
leads to more rapid e Agents which increase blood glucose levels include
Insulin glargine 1 24 Lantus
effect. antipsychotic drugs, diazoxide, adrenergic antago-
nists (also decrease insulin release) and thyroid Long Acting
supplements. Extended Insulin Zinc Suspension 4-8 >36 Humulin U Ultralente.
e Agents which decrease blood glucose levels include
alcohol, weight-reducing agents and catecholamine- Combination Product
depleting agents. Isophane Insulin Suspension 0.25-1 24 Novolin 70/30, Humulin 70/30
PO/IV. Some therapeutic actions and Insulin Injection Humulin 50/50
may be due to mechanisms
other than B-receptor
blockade. e Oral Hypoglycemic Drugs
Patients with noninsulin-dependent diabetes
mellitus (Type 2) who fail dietary control require oral
PO/IV. 70% absorbed, Treatment is life-long. hypoglycemic agents. The sulfonylureas described in
slow onset of action, Patients must not Table 10.11 sti fates li one ti
halflife = 1 week. discontinue replacement siatidlie eientsictes smseie ooo ae pete teen | enSEES Sulfonylureas
therapy when symptoms of beta cells and increase the sensitivity of tissues to the
Tolbutamide (Orinase) Stimulates insulin secretion by pancreatic beta cells and increases the sensitivity of tissues to the actions of insulin. May
hypothyroidism resolve. actions of insulin. Like insulin, the most frequent cause hypoglycemia. Patients who develop hypoglycemia while taking Chlorpropamide must be monitored carefully for
Tolazamide (Tolinase)
PO/IV. 100% absorbed, Because of short half-life, complication is hypoglycemia. Newer igus ations of Chlorpropamide (Diabinese) 3-5 days because of its long half-life (60-90 hours). Clinical trials revealed unexpected increased risk of cardiotoxicity
Glipizide (Glucotrol) when Tolbutamide was used for more than five years.
rapid onset of action, serum levels pulsate oral hypoglycemics reduce post-prandial sugar levels Glyburide (Micronase, Diabeta)
haiflife = several hours. according to dosing or increase the sensitivity of target tissues to insulin. Glimepiride (Amaryl)
aes 4 Nonsulfonylureas are less likely to cause hypo-
Nonsulfonylureas
PO. glycemia. Because diabetes damages kidneys and
livers, dose adjustments may be necessary. Patients Metformin (Glucophage) Reduces intestinal uptake and hepatic production of glucose. Increases sensitivity of tissues to insulin. Generally does
not cause hypoglycemia. May act synergistically with sulfonylureas. Rarely causes lactic acidosis, which is potentially
with NIDDM who fail dietary control and oral hypo- fatal (see warnings). More commonly causes gastrointestinal side effects.
glycemic agents progress to insulin-dependency. Miglitol (Glyset) Alpha glucoside inhibitor slows carbohydrate digestion resulting in lower serum glucose levels after meals. May be used
Acarbose (Precose) with sulfonylureas. Hypoglycemia unlikely when used as a single agent. Flatulance, diarrhea and abdominal pain are the
most frequent side effects.
Rosiglitazone (Avandia) Enhances response of target cells (e.g., liver, muscle) to endogenous insulin, perhaps by activating nuclear receptors
Pioglitazone (Actos) that increase transcription of glucose control genes. Because these require endogenous insulin, they should not be used
for Type | diabetes or diabetic ketoacidosis. Monitor liver function tests (LFTs). Discontinue drug if LFTs are greater than
3-times normal. May increase incidence of congestive heart failure and MI.
Repaglinide (Prandin) Blocks potassium channels in pancreatic beta cells, causing depolarization, calcium influx, and ultimately insulin secre-
tion. Thus reduces glucose levels through mechanism that requires intact beta cells. Used alone or with metformin for
type 2 diabetes that is diet refractory.
Nateglinide (Starlix) Stimulates insulin secretion from pancreas.

eS See
Dapagliflozin (Farxiga) Inhibits sodium-glucose transorter 2 (SGLT2), which reduces the amount of sugar absorbed by the body. Used for
Canagliflozin (Invokana) type || diabetes along with diet and exercise.
Empagliflozin (Jardiance)
Liraglutide (Victoza) Antagonizes glucagon-like peptide -1 (GLP-1), which increases the amount of insulin that the body produces. Used for
Exenatide (Bydureon) type II diabetes along with diet and exercise. Members of this drug class cause thyroid cancer in mice and it is not
Dulaglutide (Trulicity) known whether the same is true for humans.
Albiglutide (Tanzeum)
Pramlintide (Symlin Pen) This is an injectable medicine that slows digestion of food, which prevents blood sugar from rising rapidly after eating. It
is used in conjunction with insulin and may cause hypoglycemia when used in combination.

Bipyridine Derivatives «......:¢ 0... 74 Catv ediloleuey an dices 22, 66
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Cae ee 98 ClemmaRtING aabtatas rire cee esnes 144
PUCOZOMAIN IS ie Rig sie edie an 38, 55 IME ECG) eee EE ee 144 Bismuth Subsalicylate...... sa...06s6 96 CASpORING(fn an: 0x ans ck eee 120 Clanett os nares amici ssaq ee112
PRMUAGOR iis isAbani STOR OR 68 INTAZANAVED 6in OR SRACee 118 ESOP Oca oat os Aion yas abe oO 22, 66 Gastor Cilla restsccrtac ce eee 98 Chidinium Bronude s.0.. eies 2a wee 28
t2-Ethiny! Estradiole mien. fae ald149 PAL REP IAGE event ae ino. inna Moe ROE 84 71021400)
(6)Mepe ee,ae aa ee 22, 60, 61, 66 BiEOLEELO! ie toes aed oteycke nase 88 Gata LES ah acter sini glee SED 20, 64 LindamVci....cosa2. pervacaeneeas 112
peAminosalicylic Acid®.... mes hins 96 NiMmniEMOaltSemen eee oct eee 94 REBORN? smchcpireh
wm.i:84 Ga ween Oe 142 Binuglkinbrelin®” 46 an eaganaqane Mao 61, 84 Gone Aa ie sche eden ee 126 S1009|bell gr 138
OPH UMOFOUTACI uke aceHee
ant ween 128 MPO r iecek tap waka tes oe ae 88 INCI VON v.porcecorcRERK
AM Gk ODORS [5)PEELS 10OO eRe sore h 130 CRG sastinacis uaunaracce RES 108 CIP re bus pent ecee eae 144
DUE Th MOIR Sion Ge wenn ke 128 ANT eieNeKobinVes ) 5 Go asc dh oan one 46, 116 COMOX ELTIOS 6 Gretchen bee 40 leikeveevelifetil earn Wee eMe eran can + 22 GefaclOrisccsc.d0ocinencs ate 108 Clomid. 2. cone gece eee eee i52
5-Hydroxytryptamine............. Bo NM DEMONIMaskec kien ens ate aneeree ¢26 AtORVaStatilinnt ines 2os eee 82 BlOKaGren Ob rans cc Mayuga Ree: 66 Gefadroxdll: coegucocws oe ee 108 CoOmUIpnene ...onancsvowsee ee ome 152
BEGIN pcthirehipaats aera ei EN 128 INinNbisOmeosmaance eGeceeen oaeeen 120 PLOVAGUONG 6k aerate’ 119 BOGeZ
OM Dre omcyesis 2c oe 131 CTE WA0] lta Oates REE AIPM a Ps 2 108 ClOMIPTAMING 5s 6c 42s coe naw eee 36
ORI aN orssa steaks oahavs SL ER 128 PINT CLATCC tis us detaltadie. scene 58 AWACURIUM ease insane ee ee OU BOSULIPo MN ter on orca nae 132 (ler
KSig Ub ape ce eRe N RR EEC afinfo 108 CIOMAZEDOMNG.. tenance Aron Re 5o7 00
JN DVXGE AUC 8 5 ae a ed te 118 PATTING GETTER NNR ite dirsratacroronneecnc
ee iN PUPOPINE Ns Dannii anth anes 28 IBOSUILEAID er tacts bc ete, SRO 132 eH ATEOLI Mg ui seus enc ccas vo stucrea een ee 108 @lonidine® «ccna 20, 60, 64
INOMLECEPrensa liga SOR DES 139 PNT
OLA G Cacercenee teasrersrcens It se 62 MTOVeNtS ohh etic ee 88 [Bygeiquybbehanlond gaan eA codeas
yecon « 133 CAE DUNG soon. + a Ore ae ener 108 Clopidogrel, . 3204s 2ecoe cee 84, 61
ABODAO ic weak wioriys nee 61, 84 Aminoglutethamide ............. 154 USOT ®16-05 rh 56 SOL 106 Biren gre. hn oe ass a 88 Gefotarime: saeco. ee 108 Clorezenate... si.0o esos ones eee 56
PRDRICETAT ess cre ines cee 120 PARMO PRYING. sicesn nisin See 90 PAVIAINGIAS rs rorsie ore eke ee 158 BO aie rawr castes onal BPS 20 @GTOLCEAND, gcd duster ainc sino. 108 Clotrimazole: s iss.spagcenowe eee 120
EMELINE oN Wh 000 a noelPEON 42 PNINIO CATON E Yaivare hice Saree asset eR 80 AVAPIO"o50.ax54ns hae eee 68 ECE Ole rate Mien tise ANGE 20 (PSLOXIM acyaiernecinessir aane Oe 108 CIO ZANE oo sorecia nicnynies se a4
DITA leLON Gsm totsehnesolencnontece 134 PETRELLI ec. R owe wen Pee 36 (AV ASTIN Gis ane eA eee ee 133 Byer Oee, .ohoauwsag ues boo auun 22, 66 CRPPODONTING iene sus vovinm RatoaMe 108 Clozartl? wa: 5 inten eight. ae ...44
JEL DSN at en fe 130 AI GCIPING conned SAR 70 IAVElOXE Rican ee eee 110 ROO ube oieSiow sted SORE 152 OT TOLE a so is «5ees aioO 108 Codeite art. oS ndtiaa «nse: 50
ENCAT DOSER eee trsencdoxen nono en eee 158 NIN ODATD Ital e-sew soectusn.tencciae tones 54 AVERTVIC A «och coma Pee 36 rine ore een ee ce eee 84 Geftaroline tes ee eee 108 Cogentin® ocak pence ae 28, 46
ENGEOLALCE eee
itcss cine 90 FATVONA CII ea cacasncroton sel vars eee eee 94 AV ONOXCOHEA AD aan on ers ee 142 BEOIMOCI ING 5 ied cian ead ao ear 46 (CE TBVALGing (ee RAMEE cone oF 108 CONACE” oc no uss itgeuee nee 98
PCC CPHL rcisycir avs. pce nie Bayh 68 ETON
ADING ievars tease on ng os ERO 36 NSS nce eich ae os Se 94, 144 EYGRAORCHIFAINING «op oa sons view aie144 (Cite ob hs) oes Per EMREN) Sania 108 CMAN ot rive nk oa toa ee 96
INGEUEENNS® Ln, cos aN ee ae 131, 132 AMO XICIN ess cnet
een 106 NXTEIRIDY . arerec ys rccee eke eee 132 BLOMCMOGMATOLS wsrcoeiessucs
sues alee: 90 (GNSIGN ee aan panies ch, 7 108 COMCMCINE So.s6e aeons cee 140
Acer bitOrs esate: resorts 68 PATIO SPP ekescons cara eee 106 AZ ACAI & ecursnr.e ee 104 BLOMATAS Pe eee ERIN Sa oes 88 GeRiIaNONG 3 enw, op Ae 108 Colecodbh): ..0Pesese. .u. Sees 138
INGEDUtOLOl Maa ist ohiaiee tans Se 22, 66 ATIPREtAMING:o-n.cn veageclntoree
te ee 18 Azathioprine ’..iccadsimcatyoeeee 142 BUG ESOC Coe ate. oe eae: 90, 92 Gehuroxime Suc cee 108 Colesevelamirs ss. 25015 eepee> eee 82
BSCE) ME tsvsprens tebe vbrgiieovn tgEUR WO 68 PEN PHOTCHCIOUB ce oe ceeeaeenren 120 AZelaSTING? biccocto acess he Se ae 144 IBWIMeEATICON: Action’
ain eee 62 Cle TOKE aa hoyscnicine eaters ee 139 ColesGe”.....sin2.c.tore separ 82
MCCMMMNOPNEN inci raccweas « 138, 138 PEMPICUU sc occ tenaxecen s MO 106 ONCAll
<0)sean ER ea 46 BUM OXcm Mew eta <<.ce 62 GEIEGOXID oy cic esd ous ete 139 Colestipol 4.22 ,20.eeiaeeenee 82
Ncetazo laid @xcseiss scmarvaion seeaer eee 62 PATTNTTTTOMICR yeashe anssous eine enone eeu 61 AzilSartans: Geees eee GER nee 68 OW ACAING nies. 3.c.2 salt On ela ee GelestOmee vicci suuacencs cucentee ee 139 COMBI oo deine nnn keene eee 132
PRETVICNOUNG iiss 06 ee icacraiee
te 24, 35 (ANiatitannilSes s.sccvcnctouons
acnecce eet ee 36 AZithrOMY Clin <5 ata ee 112
URED OLONING) 5; cninouotee BA Re 50 Celexaee 6 Savact ee deer eee 38 COMIpaZINe as «on Aaea sen 42,45
Mcety salicylic Acid. sii... Satie 138 JANGORs GLI E22 a es a eR 139 AZimacore® 2222 cee cee eee 90 UDTODION. cares dieao no RAS ae 38 SPNAlEX 6 meni cna cciha Dee 108 Comisn® -. ccpxs Seurceses
SO 46
ERE INN EP kc. garavy iceSes RE 94 PRRCEO ROI 6 sa cktinswlioca
ates Aer 134 AZOUMOPTINe aac Has. wah cay 139 BUStilfatetetegssudarecacmceanwanuaee 126 Cephalosporins ......... 104, 108, 109 COPA aera esiseS 142
PNGITTINURET ts scvsvousid vorcwendcivdio
tsMTA ee 88 INTICCELG SRS duhnave winds tors ae 30 AZATCONAM cote Aone ede SORE ORM 104
DiH@EONANOD coy...ev acele alas 50 LEV Recnciss suarnd ane 56 Correo! Ae. Panne soo see ee 22, 66
ANGLER 5 re RS 139 PI OLIANG Bhs Scaaiwin corti eeROR 84 (Azultacdine®s ven eccrine 96 BYORI saeco a eco sph ee eth ex 158 Geritinib'. ven seen PO ery iey2 Corgatde oye cathen cake 22, 66
GIT
TOYS h(a oe 130 Angiotensin li Antagonists ........ 68 BACH PAGIN ciiicettcten
eases ee Ore 104
Aaucdalatun
gin o...avaaete.
ee eee om 120
CGabazitaxe lien te nists «nnn taastteha ote 130 Certolizumab Pegol.......
38. dene ew 139 Codopai’ s)0..2% abe nies Ae 68
PXGCEDU
AS COM onesoccemaaiarats tats oteem 84 IBeveinaboit’s «pase tenaccondanonc 111, 119
GapoZantinibia es iace cw onisee = 132 (@etInIZinCa ee ret see ee: 144 Cottimenazole® < ..o550 eee 111
EGEGG =FRY seteseee isaise doven ARNE 158 IAN TAGISH. eric ioncss wastosece ER 94 Balsalazide@n cos.dchos sneer 96
PCY CUVEE sh.sores storsresnraneeo
nes, «WR 116 PANTINGCOMNWALLSATNES casinos euneiors oe rn 56 Bane ence i-siento Serer 56
(SAO Cop epetebeas 5s cicsas eidiow ole Went 40 Cetuximab: a9 occu eee 133 Ce ead xg bean cee 68
ANGE
buen boneloy ne ores acecen inn ctionoe 139 ADIGE PTESSAMS o5..026:¢
5:00, Oe 35 Baraclide= =. .s ee ee 117
GalcimmiGarbomaters. sinc 9. nae: 94 @Meviine|liniesnccceusnays cee 24 ESO ncn ccna peo 82
NCGEELISS waponcne taenucorks nonce eee 133 AMIEIEEME TICS Ac stusxevenstevrxe
ore ae 48 Barbituratess..< fete on te ee 53
Calomm Entry Blockers ....c5. fe. 68 CuMOLOguINe.. 127. T.ncs ee 122 Cristvant® sc. x. 0350S eae 118
JAG IG(Sil ge ee een ee Aner 40 Antihypertensives 4.0 .itwes cee say 62 Bente Rs ee ee ee 126
Caicium Polycarbophil.....03
<0. 6055 98 Ghiorambucil.. 1. ceeCee 126 PTZ ORI oe ook ne oc 132
ING KEKONGUE 1 BOER ee eerPs 117 Antimalarial Drugs ...ucck eet. ze Becanase® Oyyeersncswien
eee eee 92
AE eePete co gn Fins sh eeied 133 Chloramphenicol: ..tjis.c.3 62tate 112 CEOMIGLYN ..65.c.we soca ee 89, 90
INACTOCATAS traced ee ea ae 80 Antiplatelet Agents «........ sakhipeates 84 Beclomethasones.)-..- eee ee 90, 92
(CA TIORE TE Sey eee ee ee cee 131 Chiorazepate: <4. Me ae. Beas 25) Gromolyn Sodium, «i... saoeee 144
INGEIOSINNC Mo artes anise cxaravoteadagy
Meee 80 PANHVELE i ickasnc acs Se ee 144 Beclovent2) cee cose eee 90 REAAG UOTE ope.
oess 2 erate 158 CLOrdIAZEPOXIE 6 5.56.6:wis'ciaiais Wee 55 CAE oo ricaccioaus
cee = Pa 104
Ado-Trastusumab Emtansine ..... 133 IANEUIPANCEN, oreo eee 140 Beleodaq ens atuvancaagee
ee 131 @ancidascw errs tcc cs 120 GhlOrOMmyCeRN Teac. cknde
seeRe 112 Cyclophosphamide.......... 126, 142
Adrenergic Bronchodilators........ 88 ANZEIGE is onsets SO 45 Ben OStat cc aiists-dehterc Mee 1st and esatttanie sts eid SOO 68 ILOKOPEOCAING cis5.4csracaucsh nie:eS e2 Cycloserine sitet bxw hw So ue 115
Adrenocorticosteroid ............ 134 CAO. AER: Vase CURES
ca eae a 158 Beria diy leas... tnectereacmiteeenen 144 (CEES oS cle oo ee renee aor rc 28 Chiorpheniramiine occ) aii (50 OE 144 Cyclosporine: ..«: dee aRSeage 139, 142
AAGEIN oh tranccc oteavchee
orden OES 130 RPOMOLP NING: ds... SRO Oe 52 Benazepril so iiss. een eee 68 CAPCeIADINe 6 i.) (aw acu sien SESE REM 128 Chlorpromazine: scr... sereicoeee 42 Cylert@ iss: oT ee eee 40
PG NS orcucs-cgesexennictors
6Sr 138 PNDEESOMME So cinccis-a.ce'n
De ere 68 jaYeiqlavoqucchi ene Ree er Re a 140 ee ntiniciicinc see 68 Chlorpropamide... os... eee 158 Cyinbalta®. 6. .i ac came
eee eee 38
[NCTODIAS Epa ae ee 90 AOI EE 6 tines -sndienn: 4 ARTO RE 56 Benicate—e dene Se ee ee 68 ACPO fe occiadin inae 2 see 132 Ghiortametontaaasee eee eee 144 Sy proheptadine=s....cc: Asker 144, 154
PEAT UO eft Oe nacezararotatsvdcac-o
0oO 182 DEV USS Betas ak-siniltlo RS 118 Bert yee beta, cera ener eee 28 tela SOP hie cena eee 132 Cholestyfamine s..¢00).. scat 82, 96 GCyramra® 4 oa, eee ee 133
PNET EOTCM pert neRarietcusoxcume
nerd oe ew (Ntae Go) a eee es ee eer eer 128 Benzathine PenG ............... 106 CAPLEOMYCID a 010,1,54, bdReh Bee Mls M5) Cholinesterase Inhibitors.......... 26 CARCI, is seein 3 cidsce ie 154
PCR
TAS CAR scented carson desininnns « SOME 84 INT ANAC Id. Leas csccc A 139 BenZodiaZepines sr 000s cars Sees De G70)
(0)0)| Ee ee 60, 61, 68 Gholinomilmetics dee sense eee 24 Gytarabine.....c. 2s cnehee
oo eee 128
INS CEOM SIE oie.cies die seiondine
oe 28, 46 PNTLOEMOtEIOly cucu eyes ects Ue 88 BENnZOpine sc 3cuais cS 28, 46 AAT
ALCO We Ses ss cess cS 94 Ghronulace ind woe eee 98 Cytomel ss cc0ks ates een 156
PD UCLA R sassinparseerteiot nserers iar9 tee 158 PRED AREA DAL Sonic setdvirnieheendl MARMOL 84 Detar Blockerssae see eee oe 60, 64 aE DACHOler. ner nes cca ee oe 24 Grclesomderen eect 90, 92 ytotee?”) os 258 fo ee ee 94
PANS ELLE LOM ota yan eononawsirsoxoeo oe ae he 88 INT COPE AME etecaste x ornorensibis <idoue OR 26 Beta-l Receptors: ..i..2:...atn
oe eee 19 Carbamazepine onc Aanhaeend eas 56 GilasStatinl ie ycaococioh
case ee 104 GytOV ENE onicee 116
INGE VEO} een tne eee 62, 154 PIUPUPEAZ
ONE os ciosronencaniece
©SRS 42 Beta=2 Receptors inseam eae oe 19 BAD APENEUR cagcicitin ois WHO ES LAG, Sew 104 GilOstaZolinwascosasteonaaucee
ee ee 84 RV AONE ces coca csidgue 126, 142
PNTOme ted cece dace ee 20, 64 INTISTOCOTED witonsedewic een 154 BetamethasOnes.a...04-ct eet 139 PeAIDIAO
DA conf dino 00 ies aaa 46 Gimetidines. sascha errr ee 94, 144 D-Amphetamine) << si<.0 ae 2ecaeRee 40
Aldosterone Receptor Antagonists . . . 68 Aromatase mini bitOreyeanaaenmcet ae 134 Betapace’ 224cin+.cent
ae ee 22, 80 Cantino xaniuinere 4. aemucee 144 GiiN Zale es... SER See 139 Dabratenib s.iek sates eee 132
AN ings VAbboneloy coe 6 ace ire to 0 blow cia 6 ANieteraie, Ihakopavelsy eee ae cee ae ous 6 not Betaserone eee eee eee ee 142 WEAR OCANE aks soya os xc SS 32 RTO hse nn Se Oe 110 Dacarbazine 2.5.4. eae 126
PATPEM tale Raseyonseneroread tok ene 48 (Ariane eaae es chavs ancaysvneyo I 28, 46 Betaxolol eer ficeeterna 22, 66 Carbonic Anhydrase Inhibitors. .... 62 CIpPOHOX ACI. jncitcsse
taaieini:spaos REO 110 DachNO MYCIN ois 2a sncie SAO 130
PN EUZ OSL eaters econo ee ee DP. PAT ZASTINAS Wa ayaecys cenrerccns
SRR eee 133 Bethanechiol c.c.3.4hen oe ee 24 CNDOPIAIN «Oe sas as «a OR Peee 131 Gisatracunivinirenseae
eee eter eee 30 Dalbavancins 2% hic: aay See 104
PALL Wey tec hessiaceesargsvers
ee 126 PSEA DING oir encstain tutes eine eee me 42 BevaciZuiab eerie arlene aie es Carboprost Tromethamine........ 152 CISD IAUUA sacetelots t sis wines eect 131 Dalmane i osc aend te scecee eee és
a torso ncnimnprovcizna
ord 144 INS OniGlithS esp ertenetere cn, oe 36 BEXatO lene peat ench nieces SIO 1Sil AT a. siiic tntmains anes DENDAEN 70 BPALOPLAIN ooiersincicwReencant
eee 38 Depa UO ZIG i oesiene nz nseliun a ae 158
PLS PEIN) sscisiedurysoneives
ans ee 140 PAS PABA UNASE iecstn scsesseaysrorornys
ohne 131 BexXatosecesantaenk ote een ee 133 (Chive nee co. eee 22, 66 Gitanestls. Aen. ee eee 32 Dapsone tic on vets sara 119
NI OSCEE
OL Mtr coesor teoranieo ee 45 aN Ug) pele ere 60, 61, 84 BUANaT Aan seats Teecaystalc evan te. G@antal Zoi ee caked eacgienc. ee 131 @Gladribine?ts ..reere see eer 128 Daptoniycin eee eee aeveiee 104
RSA Pa eeanstaeirseore
ysans 45 RS ELIRIN eE Pri cna echonotic SA 138 Bita ees reer eat 94 (SATTMTIS TING caso cucis. oreo d evn 126 @laninexe se tein uenceeee 144 SEUVEL 53) <n isescytetarah
dele Ne 118
ALpHal BIOCKELS odeciees.nnaenam
ene 64 INGAAS ee on re Bo ON BoB na bcc Fa© 144 DIDETICER, <p 3eN an onan 28, 46 GATE OLO ie aacyegtncnsusn
dee,cuciucitar eee 22, 66 Clarithrom
yin i ciccnsiiredehusienera 94,112 Darvacete ndnuchocacn eee 52
EAE Oo ee Pe. cE hee 22, 66 Claritin?’ 22 eeeeee 144 Darron. 22? Shi ee hee 50) 52
159 160 Index

Isopto Homatropine®
HylorelPa tie xaos. aceance ere
64 ............. 28
CBee tha sett caer 2%, SS BR: 56
Masatinibiwcck oc Ce OR 132 DOXONUDICIN gerne
eee oak eee 130 PO IDOSIAG. 4i639 Biss 5a wink Sr semen 130 Galantamines.. acapien.«
oc scr ean 26 FAV AGE acs \ ee annette 22 [sopto-Carpine? s <4...
x.) mareeees 24
EIR OEELVICHN 5 oncsyn RE 130 TEORVEVCUING 5d casas woln ie 112 BivaViriite cies 8 aisle 1 2 ee ae 118 @anciclovinki-ee eerie cc ee ae 116 Hyltein sins os yc 66 Torco eee ee eco omnc ne 71
Be eee mary ox fusion Noe x Ewe a 118 PPCAUOING >aog. gacca ssh wodeona
tee 126 BUAU YI 300. bagourcase Seen 156 (Sane oul nee iN FAVRE Gee oa piv awn sx Bye 74 IsosotbideDinittaten: «aca. rae 71
Decadron.. 3c sos eee: dees 154 |EVOIE A LO a Bae aaa PR 158 BVOrOumUS..ceaacncecoden soe 132 eS OPE INE aa fasad shirk s+ ae eM 28 IllovanobanvovnVele) wanes ot 6 0 0.650. 133 ISGEHCHNOM a econ acs 1 ome Al
Delavirdines.c. 2. seven eee 118 DinlcOlaxe an oc nl Ae 98 EVistat se rc sa see ee 149 GVA eI how oats tcc es ws TM 133 weenie lacie cctateduartele
rene isye TSOthSEINOM oa soe oo wes oem ee 2
Demecatvumice «c+ eee. eee 26 UIOXECHNG nce as. aie ese eee 38 BXGlOnowet eit tones ee 26 Gehitintbmepes 00 oases: ces nce eee 132 IPPIPTOUEN “his ne viywine oe 2 eke oat 138 OXSUPTING) 6.06.003.40- ee eee 68
Deémeclocycline ....%s soca 112 PUVOIG wae cP os Soren
2. ane 24 EXenandes so cs oe aee te Ose eee 158 GEeIncitawlie we Seen os saeee 128 TCP ROSER ssc ateMayenne
nee teens 139 |) 2310 ea 2 70
EMOTCLOR pret criss nacics co >. ae 48 MO ACIEC A cess ano ogous a3. 2 70 BxOSttin ae oe orn ok ce RO eee 92 Gemitiorozills...c a6 aosss 46). 2 eee 82 TRUEOLOIWS os Sas ves awd eee Ole 84 ISOGANE RRS... che eee cee 131
OAV oe si ah Arad eee 116 Dy ema ao a as ce oe ee 62 BZetInIDe. cc morts oun sca ee 82 Genniloxacini sic Green add eeee 110 FOUR cambio raearanacbaree 132 Isuptel? peti tee. cs ca veies ee 88
WeDOR Oe pais Rein oy ere eae OO 56 Be ot peed each alae oe oS 112 BACtiVe® ta,e o0iceGabaene Lee 110 Geman meek coke hats Seer 128 Te ia dint nary divin. 132 TtaConaZOletanc kos ck eee 120
WeepO-F POVETE 5 singe co «SORA 149 FenOUNOp Mate 12x ic5 sn oes Se 26 BaINGICIOVITE enn pee nee 116 (GSritAmnGisen chcee 6 2's atese antes Seen Hie ASRCities a nant a eco a ele eee ee 130 IVeErmectint d...c¢sc.2
os foe eee 122
ROPRLANMING Sc sins(e's sors, va = ORT 36 PaO ors ee oe 68 Bamoucine ac. nee en: eee 94, 144 Gender: sethow sou cs ern snsdae Mees 42 Wdelaliisib Weacpcis eeu oni ae 132 biebepilonies.: a. ss nan eens e nde i338
IGS CITY fopna, siccs 5 sits.aarecin a eee 84 Blaine vcnan ssc he cate 118 BaMVil ea. on ee eee 116 CHGhit We sis cae os dhe ee 132 VLGIALLST UNAM « hetcvatvcrecte
tat aeons eee 132 pimpra® icc... ¢s+2s0en eee 131
Wesloratadine sca: oh ae cat ee 144 BEteXOTe 5a ie oe ee 38 Patdot toss tore Soe ae 4 Glatinamens, wccec oo 6p bim eateet 142 Keine oa oak cutace a owe See 126 Jap aie 2 ite cnn 4gee 132
Desvenlataxines ais, sc.cee nel 38 Ethientie trea here Leeee 84 Pendga.. ...ccecen
essen eee 158 (GIES ECe rn Fe cin 132 IM@STAINIG C12 acne ote cane ean eee 126 Vareliance®s...cos4.ssneeceee eee 158
PAE Sek shor © 1A bi eo 38 lava ee ere os eee. 5 7 eee 36 Reldences 2:5. Leen 2 eee ee 138 iis erecta
cs MIO 158 Het eer er bo sc alice ota 158 fevers ao oseedeen es oe 130
|B eG SA es ln ee Se MeN WR tr 28 BICepids cor essa te ceo re eee 46 PRlIOdIpING» 3:4 ¢0s sake ass eee 70 Glucocorticoids. asntsae
ae een 153 POpEMAONE sto. 2 cate i<etms See 44 Kadeyela? yo isa,2
2 ayers 133
Dexamethasone: .o1.-.
cs. mee 154 BIOKMaih 625 babe eek ack See 131 Fenotibtate. 50). 4.25 eae eee 82 RIOD C Si erycte d Ons MEGS 158 Ria tite ansctc csc ola. meee 132 Kaletra®es :..« ic eee ane 118
Dexchlorpheniramine............ 144 BIViCGLAVAN <2 crm on scien cin ee 118 Fenoldopam...5< 5.) +253 eee eee 68 G@lic oto er. Sek. 5 oe eee 158 limbiivicas mee sconcestees 1162 KanaRNYVCIN 2 sas rvk vasa atmn sheen 112
Pela. ak « scacucnece cmc heen 94 NONE ahi wh.fo tin Cie esl 134 Fenmoproren s .25.0.4
205 oes =«eine 138
IV DUI OMG e tes mle coc sin es we 158 ERE PEMEBIY «os vine toes ORO gee 104 KADARYIC 30.05% v.00 Soe eee AS
DEXIANSODTOZ OLE ee oc cae uel aN 94 Empagflo7inis «20:2 osc. «Meee 158 Fentanyl 504. chus a 5 ahs os ao alee 48 GRY COD VEL OlAC res. cisreicrsisi
was Weer 28 HIMOLAUNIINGS wieiere, asuecsseis; @OYon ernReee 36 Kaolin Rectin.... tasteoe 96
Dexmethylphenidate: . ...2iirnic.caw 40 Emenieitabine 2 acco «oer 118 Retziniae’: a.ct cco eee 38 Kaopectate®...... .. ei ota 96
CH Atte ed. 5 5 'd's) a 0 MERE 158 HMO GIT tas oo oes ron 96
Dextromethorphan .......... sistant: 52 Emiival ovccitte. teeta ees eee 118 Bexotenadine «.,.6 sacs oe eee 144
Reflexes tate cin ts onds ohne ween 108
Golmmumabeaascncal tenes) Soe 139 ANUBIS cteedeg sk eis g ose oxo 139
WEZOCIMC aces saeseas
d ae oe 50 PMAAPVlas cs nnn es.geen > pas ee 68 Filgrastim G-Csf, .4:24..%
>. sleen ee Igo
(Gonadoreltne.cancsieamuwes Does 152: IN UCLEAU ecole aoe tsidec oo eevee 142 etzoltwe® sso. cme ee eee 108
BATA hela a ws Pasi oven 6 158 Bnbrelesun cc acc tat ee cece ee 139 Biorinal®..c8/o0 ssht 5a: eee 52
Goserelinineerag Gotorttcvakena
oe 134 TMCEUSE SP cao ose eee sea i 88 Kemadtin® +. 3.nc hea eee 28
POTADUINESE caters ws one oie ne MRS 158 intl tirame:s so, «es be ns oleic On 58 BRIb062 cn cho eS ok eee 142
Gp lip (iia Inhibitors. 2. 2...
0. 6 61 ETTGlHAE Hee ts,cresscvs wsiccne pocecuae MAO 156 Kenradrin®) 4... «seayaaese enone 46
13)YS. asa Fs 68 Brttivintide:..csn.5.secses
cee cee 118 Blagyie a2 550 eee 110, 122
GEAMMODEAMNVEIN oi.wis wise ve a Pare ale112 ING@erAlee, . jcnawem ceo. eee 22 Hep pia? ite: s.r s0ssar saya See 56
PR AZEDADN «xis orais © ngs oo 4 bes oh 55,06 ERIACADONG «i155 65 dha ein anee ee 46 Rlavoxate:...05oatn
eee eee 28
(GrraniSemonn nascarons sae 45 NENG KEIRA oo a ee Enea 66 KRerloneg ooc.c.c Scicneti cle waco Ce Oe 22
Babenz Vee Yo cnc svn.ctas 2 /2) EINtECA Vee taiscee caclcorns Siete eee 117 Blecainide, visas 65 ss 2 on eee 78
GSilaMa ei rast aes alae 20 lad enalGAa Aarts incase ant See 80 Reétlone ese) itcsicn oo es Pee 66
DDTClOLCTACH etc. ors ond gen ca 138 [a12)0 Ss 18, 88 Plolanes 2 7 ck... cnet bi eee 68
(GmanabenZeirss.c tec nual ss ee 64 PIMCLANVAAy ete.cere ess waco 118 Kerlone® «sa. 50d5.20 sae eee 80
Wicloxacillinuswcrse nora eee 106 EDING DIG oaks sb aw oo ne see 88 Flomax®:-4.4) 252006. eee 22
IGV COMING wees iisa.o¥ ae snes 28 [ohotk U10)(ol) Ae ee aR RRP iy 130 Rlonasee fA 2 eee 92 (Gilamacheltee a neta uacsss bce 4 ese te 20 IRGC cick ches cacao
2 ee 138 KRetalareiice sc. ooabdun see 58
IDIGANOSINGceisn eee
ce ee 118 BINS cess i rs sack cs Re 118 Blorinet®. 22223) ee 154 tran ACEC We iy horde ar ee 64 Indomethacininaese ct: cease 138 NGtaIMINGHS. =.oidoo cance ders eee 58
BGMIGAN Siihs oo iv hak sarees ee 120 PDICTEHONG 6.0. cee ee eae on oe 62, 68 Blovente® oc. ii Sn. 2 eee ee 90 (GtranetniGinee-nccete: 6ogee rs ees 20 Ligudbbsahaaysoy Seana nee ene Meme es Face 139 Nétekeae io. 2 ieee oe 112
DAUAROD
AUR SRS ce eens meres coo 138 EPOCuAIDNAy scx .65. nee Sars 135 BLOXI OS he ovale ccteie WA elee 110 Gtanethicinepmae cerns Ske 64 lint aden a Poca vnc see 132 Netorola@. sxc: 05 0520026450, 138
PRON cc ccies 6 a ER wea we 61, 74, 80 BORE ieee airs vs bso ect eee 135 BIOXUTIGING, ares ocean eee 128 Giraniacine parr eeewescae 20 ES PA yt sp oiinse: Sn aeltenele
ee 62 eee 133
aI as bt hc eck eae 56 Foopcostetial ois sasoina se amollen 68 Fluconazole: a25cc ee ee 120 (Gwaniacine nee tres as GAT OR 64 | Oe eg ota ee rr Def 68 Nineret®awt,. escent
seo ee 139
ACN oscivet's onan & 5 one Re 48 POTOSATIAN 66:2ach se roan s 2 es 68 ELUcdrOCcOnisOone cere 154 alcionc eee eae ORs Sees 55 TS Ulli eee sorsistas also wae dee 158 Kiosopis .c60ss <<ensst
aac eee 55
BUH AZemiesrs
os oes ose 60, 70 UND AUGE oc 50+ ww is ene se 60, 84 Blumacdine® steer 116 JABIGLOIE «cee ei a ear 44 tall Secs eval ax ois sc 90 RW 8s oc inn enndhe cen eee 122
BTA OLAING ond eons5 6a or vin EE 144 BBARIS oars on ak oo mn) en 120 Blumvazenilt<. 2. scissor ee 54 Braloperidol 3. ccc ks a0 SRR A44 LE oi ie ren, ieee neuen Oe 84 KeyPrOlig? > te hed Se os on 131
EANODEOStONG ssrc.s ives alse He et 152 ETDIEUXC re nee ee eee 133 lunisolides. 07. eo eereee 90, 92 nal @thameuale oayeisguavs
crew Peelers 58 Imtelencecaameaaters craic aoe 118 Rett ieee ics nen Se cre 45
LTS 7i ai aa eee ne 96, 138 EeCamisOl g.45 05s e es vee aes 142 Flioroquinolones...c a5 ccs ae oe 110 TLAGVONI Meek civ css, Aare THY Tniterieromer warn cveccccton.
one oh eee 133 Pebapa® sec oust. csi 46
Diphenhydramiine. «<< <.20s1 Bale 144 BECOROVING 2 tn scan 6c udaan 6 SNORTED 152 Einothane® 2...)
ee eee 58 PAC POUAIL AND elias 4 okarsintcie ola eee 60 BRUTAL olga k yoo, Gott 6142 Labetalolicie.4 se. ee eee 22
TIpNeniOxXy Ate sc.
a 2a 2 52, 96 Ergotrate Maleate® .............. 152 BlUOXeHTe. Y6uaks So ie eee 38 PRE OOR ace aiiretsiss wscae 3.64 0 oSieern a 61 ERECRECKONSE A anrinta chee eee 142 abéetalolavuwes sca). 2 66
DOAt eter a & Seid ye, cn 58 ERD OU Oe css oie eveves Sa MUON 131 Fluoxymesterone ... .\.'. 00)... 148 FICO AEN iets, chon a 83 Interleukin i® «000. Soo 135 WaACOSATTNIG C= #4 42ers see 56
Dal ehig ts 10700) Ce eR eA 84 Erlotinibiden: «2 occu eae ore eee 182. Fluphenazinie . ivan. cot eee 42 Bis era ie ek sao 2 sen SEERA pid Intevl etakne2 Wer Wewscie
are 2 a ce 142 Pactoloseee = «<<a nes Sees 98
Direct Thrombin Inhibitors ........ 84 ETQDENGM, «2.6 ess gaccceeeaoe 104 FIGrAZepaMcetes |. set > oh ee 55 Diem 28 noice ven AO 135 imyannZ cer oats oo ee 104 Bamuctal®, cw: Sebel ae 56
PISOOV TANCE ',<5 2.0.09 5% snes teen 78 BEVEDTOUNV CIN «5.5.5.5 < + sareteinae
sige 112 Blitaimid@y..1os.0c cree eee 134 ISGRGIEAe., Ova ae Ane iC oytas Ce 126 hivega Sustenna®.......... bolero 44 Mamisieer® ck dace eee 120
DOC A) ce wi nial a eo = ON 28 ESCM AMODLAL ro He oan bhp 38 BIEICASONG ete neato eee 90, 92 RexObanbital een assess aera 54 invaraseea ene eae Bee ee 118 MamMiIviUcdine: <.c< a= cone eae 6 eee 118
DUE CS eo) cece onirccss noes = Oe Re 62 Eelicatbazepiv“... 5.15 60s i. Sees 56 Blisvastating. cose eee ee 82 PAOMIALLODING oo os <isniss oc.site 28 Invokana® sassee4.40:. eee 158 LAMOMIGING x 50.6005 5s0oan oa RE 56
|Dyolaysibaniiatsin eo eige pean aoine.o.. 61, 74 BSmOlOW oie nace so ee 22, 66, 80 LE VOXaIMiMesnels elena eee 38 PAO a ies odie ys ce: 158 Lodine/Modidea.. .h 0.4400
ee 156 PANOKIAOY is onc adi eons SE 74
IDO DUEEXS aia. 6 oat oa ono ee 74 FSOMODTAZ Ol’, a...+5042
+<saeMnroee 94 Bocalin® a. 5. Ges co eee eee 40 GLE TAD Payee coerce er a oc 139 Jpn Di 9.22515)...
0. 133 Ranoxime. .4o.cceuncetian cee 80
OCC taAX Ge ae nike sian «coed 130 PstazOlany cnn. aed oa) ee 55 Boranee 6 and ss Stee ee 58 Felt OLSO lS Peers a. 5 a easy ero 26 TSTAMOPIUIN js5.052156
Dysie vuln 88 PERSO PLaZOle ec. ccincne>acvageeree 94
DOClOLEMAG HS pi.5cisc reencics 2 ode eee 139 PSUnVle ct, oe cares 5 has eae 149 BOrinoterol.. ene ee ee 88 Ralcreel pee cas oiovys, Goi ad 158 PPV OSk OR Giictsi neces oget See 84 Lanter conic caie.deeea
uta See 158
IDOCUSALE heisn ea crs ar cer ee ee 98 EStraGeriniGa ees eee 149 Bottaz®. ¢ av eee wash one eee 108 PACARGOUE ain bana enn ey ee 130 Tb eSartantee ws cxascavconcaucs See 68 Dapatinibwane vied. ossusas
eee 132
IDOLASTCEEGTAG a chosercars cicutactsverec cin mete 45 EStraU 10linear teres hee cree ate 149 Fosamprenavit .s: .<..uca5 eee 118 SRA TIRO ei oin 5. xe Me Se 60 REC SaSIN. eee ie eee 182 TASER ARES <aiciw: non oan Re 62
Da] Obi ieee cere ener eee 138 EStramllUStinel sae 6 eee eae 134 FOSGArNet: « ciaie es on ae ee 116 [SAVE
i VA9 eA oO 61 LINO CE CAN F-bach asin yeas eee 1 atin OM Re acc atch ee ee 42
POC RTAVIES a.om 5.6 x oncbred ee ONS 118 BSOPOl, ccecsaa aac. pew ae 134, 148 HOScaVites -& roniee dete. eee 116 PAV AVALAZING os Weitere
ania nilolAa® 68 TSENEEESSoe aN ayaises,aotuees er 118 IbaXALIVES WARS ehocncuce ae eee 98
UNEP EZAL s,6.5.3 Tawa ewe, . Sk aa 26 BRANOTOD Ye ciace nove eo hla © be Oe OE 159 Fosinopril ¢.:..... 22 Ree aoe ees 68 Hydrocholorothiazide............. 62 Tstire lini eeeccancnee 20 Ledipasvir/Sofosbuvir........... 117
ODAC sc cs a. > 5% 2s a eee 85 Etiacrypater sors ssc as acces
MOMS 62 Fosphieny toi. .< 0. <wcieieee eee 56 FAY GLOCOTUSONE ccianesitit Hate 154 TSocaineSay.3 we ees cas. ee ee 32 Pehlunomide:|...5-.58A00. eee 139
PPA ra ops nes gee 55 Et AGry IMC ACI 05 s-s7 opheaynee
oea 62 Punpizone” 52... 2... 2: eae ee 120 Ply AEOUIGEDMOUE iux..00.0.4 noire tye 48 Isocatboxazidt....c..6 eee 36 Lenalidomidesien....046a ee 133;
Dori Daxce cnc orae ac ect Meee 104. BitratmbUtOleemcr can uen ae > tere 115 EtIrosemide.. eeeneane
cine eee 62 Hydroxy-Amphetamine........... 18 TSO fluUnaM eee weet cen 585 Le piney ccoxs.5. 58se-dcdotn ee 84
PCRIDENCIN ela Carsis9.2
16 ae ne or 104 EthiOnamiGde@seunimeier cee cenit 1 BUZEON © cen on:2.5% SEE eee ee 118 Hydro chloroquine......u.01.<<e 122 TSOINA ZA CR RRoara unde once ne 115 Lescolviikirtsnsc.cgese eee 82
WOXACULIMIN «an seein eee 30 Ethosuxtmider scent 56 PYCOMPa> Si cc tsb eae ee 56 TAGE ANES 6.35 asin ee 131 Isoproterenol ji.s0<70 02,seeeer 88 Grier Son. 5s.ksycexpeonn'vie st 126
IDOXAZOSUcews nc ascisic.e
aGaui ne 22, 66 thane cmeeeric cots atice oukcc eee 58 Gabateren css Bees can, See 35 BEV COX ZING eos, 3s: ave arnitalisecs 144 TSOP tettS es Siete ihore 58.92 acess aeRO 70 JES hiai i ge re 135
OKO OIG fore soe ee oss ag 5 a'sSR 36 BtOMmidater et, «cc: 5 eta 58 Gabapentin }..cc..
.ke mata ne eee 56 J
710) 2 MM Pe 20 sopto. Carbachol® «. 4... eee 24 Beuprolideics csv iinestiys
eo pe 134
162 Index
Wee otai ews tats iecea aun eeeee CUANZA
INE snc dc,-.5%n Stale eles 44 Petitostatlives ater cee ace ee eee 128
Magnesium Salts. icyo.e
ne Peet 94 MICOMAZOLG’. ca nuascre he ae nae Oe 120 ING EaVAIEe tever-ye echosancun
tc has Peon ee Olimesantan'.. i.4 <aelc cane ce eee 68 Rentothaloncee eee
eee eee 58
Bevalbuterolemee exces 88 INA TITUITO acct toesu dos wader ane nen neeee 62 WMicronase” wasseuke
soca cn tee 158 IN Crile ere husfae ca oo oo Olsalazinescs.c.wkinesacsi Meee 138 PERC” oocuiannt ox Po aes oes 144
ECV AI SOlGR Nee ek ne oie cee 133 NIA MOMUNES «i.aalew crc weenie 38 Nidamore? on. .0.cscecos
ene eee 62 INCOSUSTIC Rw asc.niecanwdicalerete
ainibvels Olsalazinets: tacte.taee acmc Pee 96 ROP oa ccus cree. meee 94
MeValnisOlenmenne+: en Scie ee 142 NFAT AVATOC teeta nescence
Ensee 118 MidaZOlam % 6 «cies ee PCAC RIN Ot, Aa 50 SAME culiralceiwts
CAE IST ose atecieirvue Rann sate 117 Pepto BNO” vanced 25> 5s eee 96
ReVequin watinenncweek see 110 IRAE
ANETO rsscco. avnvcnesae
Ae seeuhe ores 32 RUIGUIONS ccc sedawknn cose peek 158 INIGSIITET
CLO ioe ic evict coe moore Ombitasvir/Paritaprevir/Ritonavir... 117 PRLAIIOAUIEL 9 is end vse oo eee 56
EV OIGE Oe Cxicoh enc See 22 Bear planiccee Vitra
aks Celeteds 36 IIT
OLAREN ieccglis x Fm Senore con» oe,Oe 58 INesinittde® isa. = eee ee DOMEDYAZON? 3 g.v.cecies
<2 ona 7 eA 94 Percocet’... sss saw dep ne sO 52
REVATOL ot oS Soce Sake dedek sca 66 Matulanesc cnet cece wee 126 Milk Of Maenesia®.... .....
oxo we 98 CWMINATIS® Sounu vb oaeneadeeae
ome 92 Percodan® .... s.4 > 22> b> ene ay
Levenrecetamis.d.5.0su
ses eee 56 NVR th Gee ook aes yee 68 MEL
ACI DIAL oopces oa sy am oS INS ORENE es orsbesayo nce eissy ceee ONCOVINO wie eee aces eee 130 Pertoronist>. > «2. oe eee 88
Revo-Dromoran® 2.7.0. SLs 48 INIA ALES entiie ae scelce teen wie PRMD 88 IMGT ETON Cas su ortiees iste ereeee 74 INEUBEO Ge Naa Soda stem Swng OEE Ondansetron. oh ccasous
sso eee 45 Fern se sa 5.40 e ee 152
evocetinizine wn. sceedee. oe 144 AAX ACU © o.chs 2 aerks si AO 110 Min press? greg nase a0 ta aE 22 Neuromuscular Blockers ......... COIN ol.s oe 4s ees oo 133 Petiactine si; sea soos pro eee 154
PEVORODAS? Wk wat suk te See 46 Mebendazolenis.eaekenen eaten 122 Minipress®'_.; arse noe 66 INGUWEOMCINS eee aunec payee kotor aatree CIOS cor. vies 0s ony» ARR ae 35 Perindoor . .5.55%..5.5 salen 68
eV onloxacinny even.
eee eee 110 Mechlorethamine: ne ..0: .tescs
eee 126 Miniocycline\..dcaiieusscosn see 112 BETER CORON feieans enn. Sn w oe ne Podge 135 Ferjctd™., .<.':263>
0.00 aes 133
IN OVALA PING icc eic enh buen nde Gee
Bevomilnacipran a....55a de eens 38 MeGcIZING tia. Gakic chee eee 144 IMIMOXIGIL toss: Nieves a pete cars eee 68
INGVOlUIMADE Ae j-isis grea eee Oral Contraceptives ....is see abree. 149 Perphenazine |'s.\-% +- 42 eeenieeeee 42
Revorp nano i002). varie ae 48 Meclofenamateryn aa ote aera 138 IMiocholFBe =... .ccse pce eee 24 OAD cid vivid be «cua RI 44 Rersantine’> cc .¢ceek eee eee 84
INTeXaalie Sete A tesedes ced eee
eV OUTOId oe Kk ns 156 IMGclommet 6 ach Une eA anne 138 Mirostate 0. coe ee eee 24 Orencia-.... .. 2 ae 139 Rerttiziiriab! sy... & « ae ae 133
INSTT ee Se ee ie 5 oe:
Ferotnyroxdne 14>... 156 Medroxyprogesterone............ 149 Miralax® (vices on eee oe 98 Oper ss ocake twas eee 62 Phenelzine . 6 eos eee 36
INNCALCIIMINGs fatssg wieowe wd wine a OE
GKADIOS 25 on canes ies ST 38 MEHSCUING cna dh ne uke yee 122 WITAD OO oc. s «bx domo a ee 46 @nitiase. ccna aos ee 158 PRPRCICAN nae os do's nage en ee 144
INC OLUIRC Tete isons atts crd G ee
SOO | ee cs ed 118 See ees 149 NEITESZADING ws.ioienmne «leucine
areatenoeele 38
@ATAVANICIN 5c.0/ce Gans oacee OER 104 PRener gan” «iss oo ees 45
INSU IICS i.55.50, idee 4r0na AEROS
Letefa Vii] i ea hh aA teLU a 5) NIC ZESTIO! focus ovuin's vice eRe 149 IMISOPLOStOL. 6.5 in p'sbo dpe we 94 PheiindaMmine cece eee eee eee 144
INMGCIOING 15% dons oo 2 ee oad ROL Sel FAI eacrcaiyecuvare.cxe
tes ot 116
Mid OCain exc avs eats. eee tae 32 WICKIISES Wu eaten Se 132 Mitomycitt Co. '.55 Se cn oe + ee 130 Phenobarbital’... o-oo. ee. see 54
INGO GI WW yrs atefone cclls'chasse, ater @smotic Diuretic... ..6ec cee 62
Erdocainiotan a. tee. cette
Oe 78 Me ATS ei ccccne) coe ee 42 INGPORANG Tc.scscmck oe ce Re 131
PRISE efits BE ne oye denn oven WEAR @ ACI Niigia tues acccts co ao 5 106 PRENOXYDENZAMUNG . 2+ sway eee 22
COCHIN! 5 SGI A 112 Mel phialait/ ans sisiaetesae< eee 126 Mitotaneicckc ee cick © cee eee 154
AN PlStY vc sac «eden een Nk Phentolamin@:.........2
0 heels D2
EPERCORMY
CIs 5wistenis ts SEM Re 112 INIELIO (COPING x se yr a wn ae emer 152 Mitoxantrones 2c. sissies Sree 130
RDAZEOADN 1-0. can enatehiale stonves 55 Phenyl-Propanolamine............ 18
indantehs ie eee ee 122 Mepenzolate Bromide... -. /.52.0.4 28 Mitrolanes 2<4-..-6
a ee eee 98
ime ZOlicitm. th. seen
ee ete iP WEE DETICINE chen). son's or Oe Sen ee 48 Moban® hers chk onaeee 44
OXCALDAZEDING» 0.5.0.4 40» «mem 56 Phenylalanine Mustard® ......... 126
Viephentermines sick. css Wee eee 18
OVO, ck wp <0 0 ames oer 28 PRCOVIOU o> yar pe 2 eee 56
Brothyronine. 1320. owe
ues TI 156 MOexipril 25a. ys eee os seer 68
NMephobarbital, 1.0. ..% 4 eee 54 GPVCOGONE : ¢ nyinc feos x eeadeeRe: 139 Phosphotme lodide™.,.25
6 si vack 26
Tote Sis a ee
ee ee 156 IMskobogVekoraS Sag eedodgoamcostoacccs 42
Lipd=Lowering Agents:.'. 0... 20s 82 NIEPIVACAING 4% Vivik's hisx nics en Oo Mometasone: si: ... ese ee ee 90 Nitrogen Mustards ....0000¢.0. 50% RR COG OMG in pa Glew 6 ON ET 48 Phototrn®’.*4): see A See 131
PP UOL eee eS Lae Rha k AN 82 MERION! Pres eee.
eh lee 119 NMometaSONe sic ces eo ee ee 92 INTRO GEV COLE oi. 4555.0 6.5010.0 odie GCE COMUING cr ara neuieenunaea
HOLM 139 Biiotoitin®’ =o oe ee 132
Paraglutide™. 455% %4 5 WR 158 METCADtOPULINE: 4% c= Gy aes 128 IMonistat’s.6. aaeneee
oe eee 120 INTECO SEY COPIEL 8 rch ine 6 Gunce now « RE OX VINMOR PHONE: 5 sn0)y.0 ee UaREy 48 Bhysostigmine 2+ os As. - oan 26
lisdexam@fetamine. «=. acc...
fea 40 DASTOPEMEM. 0%feces 5. eo oR Oe 104 MGnODactainiy nce cee 104 INGIOGIY COIR ota. aise sw foe cee ORV IOI cipiniy buns + oe po SEES 152 Pilocat® ss. s). ee 24
BISINOPTU ee cds aes Pees 68 INTERFEMIOR eke cogs a ee 104 Monoclonal Antibodies .......... 133 CORD COTIT ...Naty Alda cade ac ibaxe Wares Gute aces cue ce ee 130 PHOCAPPUNE.. ne eso so es oc 24
0) Ce 158 INTESAIaTINITIC seen. ene oa eee 96 Monoprie. ui. 20 oe eee 68 PROD EUSSIOO i. 5 oiaieng 55 os ee gal’ Be Chitaxel pacar ese «sc oe o OG 130 Bit0Zid@ van. ioe ee ose seen ee 44
IRV OY A oe ae ey A 82 IMeSOridaZines anc ceee eee 42 Montéeluikast).4.c.. osc: a ae eee 90 PRTEPOPSRUSSICC aia... sis was Rta maatee RalanosemOteecn cones ee 45 Pindololks on... ee oe Ce oe
WocalVAMeSthetics:.eicica%
we oa so thee 31 INIESTIMNON® 24.5 cuca sick ae 26 INMFOL PEIN: o..:¢ orsyaim. 050 ee ene 48 POPUOSUEBAS 5 ie gaty ea Sy wimaisn Sine Meh PaIPeHONEY. 4 << o Kostuw ot eS 44 PindOlokn occ 5 so. s See ee 66
ROS VAN Obey
Gah tea Mae 46 INMISTANNTUCIS. 54 asa baie tn 98 Mottin one cathe tack Ae ee 138 Balivaztinntane ene ete eee 92 TIOCHIAZONG fo oan sisos 2 oe 158
FOI eOXACIN rion ee te 110 Metaproterenol 3.050555 kus. cee 88 Mottin® 2c cic osbe eee ee 139 BANE 6 5255 ses we bie wa a BAD WAIMCIOLS ers ee cas eee 36 Piperacilty jo. ...\26ee ce eee 106
OMOLL oe wees, pica he katie ee 96 INAGIECOMM CHING 6 Co dad aad one au ee aig oc 158 WikepelderGYeli, noua eaaodousaeucoone 110 PREM oo ees susie: ns a eatRLOND I RaImine cesar oe ee cee 28 Pisbuterol.. cc ccc feeds coe ee eee 88
IHOMNUStIMEE ner ht white awh ee oi LPS Methacholine:. 245 &.s... o.eaet 24 Mucomyst’>.35. 0) 2) tee eo ee 92 DO ANGE BB ts ees .cinsiare « eas Bs Rancunrontuiny - co.cc
eae ee 30 PIrenZepine.. 05s ascs oe Lene 28
Foniten care: oe unk ake i Se 68 Methadone shih wank na eee 48 Mycamine® x.intiaak ieee 120 Nonsteroidal Anti-Inflammatory amibuinnlnabs .cekesc
6see 133 TITOXICANY 5.6 Seaccg noe oe eee 138
LOOP Draretics <2 i.0hs ss SHOP ene 62 Methamphetamine «.:.... G.si.cee 18 Mycostatini® . 34.5 vaene oer 120 TEUCC rcs Sci aoe Aigo see PaRtOPTaZOle «ous SweUA eo 94 Pitavastatin.cc0aco0 no seer eee 82
Loperanide™, .44.vas
shops gh. ees 96 IMethergine’ ..e%.cktnvass Monee 152 Nivlerane no ine San toe eee 126 MOD AV LINC icsfis:ai0 5.5. 5 68 Pitocin’ S>s2s
as cds cn) eee 152
BOPId ere ee hehe bhees so ee 82 MethimaZoles..a aon eee ee 156 Miytelase? 25...
.«xo 26 MOLeEDINEPATING 6.2425.05.0:0 Poses Pata-Aminosalicylic Acids... 05/32 15 Plaque? 22 cna Adee eee ee ee 122
Lopinavir/Ritonavir............. 118 Methohexital, «ic. ck. Gke eee 54 N-Acetyleysteine:.«.°. .\.alts) emer 92 INOPEL RITIGTONG 5s. BRAS hd st or Patapiatin® docs aia ais > Sa Ue 131 Platinol-Ag® «:... < aakerden aes 131
POPUESSOR En kw ee aevhneaa
cle 22 Methomtexate ese eerie ee ee 128 INa aCitrate i:...2oencner can eres 94 IN OREO MAGI «oes Gaye eins Hole a sats Rarlodel@acacccs ces eo eee 46 Plavix’ .63k osc cs genes eee 84
Wapiessat 2c te eee e ih. ca eee 66 Methotrexate & .eeeee eee eee 139 INAGOIOIGSS Sepocncok ane seconee ote eee 22 BeCEN eesptecridare wie acai niesoes Rarnates ce secs. ee 36 Rlendile 3. 224. eek eee 70
WorataGginer. thnenk
tek ee kee oe 144 Methscopolamine Bromide ........ 28 Wadololanaunaeusce conten Sener 66 ENOUMOGVE. «25 Abe vaio esses eee Paroxetine: wjonises
Sa Pee 38 Pigtar. oss en sede ee 84
DOEAZEDANY 25.5 She sc sash Sine eee oe) Methyl-Ergonovime.<< 144.05... 152 IN@tcillint = icc barns ee 106 NGHGS47" oe eee aman fe IPASOL ete nrkca cus a ARR a ee TUS: PHeamyein .. <2 aes...) Se 130
POVAZE PAW tinal G22 ein nh « ee 56 Methyldopa uk 14.54 «atlch ott. eee 20 INalbUPHING:. 5 65. aewk oe eee 50 INOGOREE oyFacile ce odicne ddan en RAaVaAbId eas oes cee ona eee 68 Polaramine®™ 2.5.4.2: .5. eee 144
MEOSATtAn eee tase ae he wa be ee 68 MEIN YIdODAe as echt th 45a een 64 INalfone 2 co. ach eek One eee 138 Ria pEIMIN: vas saners -e Baviti] ONS coh adore ee 30 Polocame™. 3.037 222." sts eee o2
MEOECTISITICNE toh bettas un eee 68 Methylphenidate: ..ick
sae. sks toe 40 INalichixd GeAcide smiteeee 110 IOC
DEV TINE ec iiecesso bial oho oh IAN ree ene kee 38 Romalidomide > 4...
67 eae 133
MEO Lem egee eons Se ee ee ee 120 Methyltestosterone .............. 148 INGIOXONE 2 occas Sarees een ee 50 DNOEV ASO Rpg ligese ox cutinin wa oes MORSE PAZOP AND 2
6.0501.
9 See Bee 132 Pomalyst®: =. .3s.hcgsegs
er eee 133
WOMOREXC- TALL oe eee aoe 45 Metoclopramide: .14.c.ak oi.2eee 45 INGItNeXONGik, anh .ictone eh eee nee 50 ENG Sah acc. Gita Metis Gago a SORE Reg anys. cued ain o Se eee ae 117 Ponatinibe:.. 2. : ole ote eee 132
NOV aStAtiinn se hes See enldee
e 82 Mietoclopramide: G1.2e sev ee 94 INADLOSYIN® hss din 6 oan 138 Peginterferon Alfa 2a i siat seus sk need Ponatinibss*st2ckecuieee cae ie
POM AINE’. SESE Dede beth ee errr 44 Dictopirenie?s <4. 5440 ee 154 INAIDTOXEN: tise t aac ade ae oe eee 138 Rembrolizumab semen | meine: 16S Pontocaine” 2.4. ; 23 i085) 5 ee 32
Woilario. os e.8 Let 1h he aak ae 44 NACtOPrOlOl ei is beer ees Lee ap) INATOATICNS when alc ene ee 50 BemOlineii cau sions crs. 5.00) eee 40 RORMMEr ». Fach. stee eee ul
MEUGTOMIL: RE SES be E oh nwa ee 38 Metoprolol c2int6.% hank tee 66 INardiler on ccsnte h anachic keene ee 36 Ben HUtOlObs cisco cscs eres eee 22: Rortimer.: 72.52.3425.) 2 eee 132
PULASIAONe er wks oe
Re ee ee 42 Metronidazole i... on ees. eee 110 INGEODIN oe eh enter ais'20 Sail 32 Renbutololoece ascentre 66 Posaconazoles...\..2 12.00 nee 120
itrepulsesserras aes. ae 152 Metronidazole =... esi eee 1 INaSACOrte Be oe sce eee 92 PeNciclOVitio yyoneenies en eee 116 Potassium Sparing Diuretics ....... 62
EUV ONC RA hice eae Ce 38 Metronidazoleyneernntr ee torreon 94 INa@saleromoeann see oon 144 WRT PMOWS. a o.3 avin os 2 eee RenielllhiniG cc, ena a. eee eee 106 PYAGOKG on tne 6 tc one ia 84
Lymphocyte Immune WVIeLyTAPONG: 26.05tin
Pad be eNotes 154 INasalidee rcs 2 e5.. a8 nen eee 92 HUTOTMANCy: cue cafasersranyans
suet ee BenicilliniV <2. cone e cee cone 106 Pramipexole :..... -gasndgee Seaatee 46
Anti-Thymocyte Globulin ...... 142 INIGVACOL EAR oleh ek meee 82 INASONEXS pose cites este ecloetee eee 92 DAIL tess Sonica in aii gic SOON Renicilinisee. huss enero 104, 106 Rramillintid eames aes 158
ByItCay Sue Mees CR ERE . Ga ieee 56 IMXGHICHIICR ARE EeORT hehe chante 78 INategunid@..< + 0s 6.5 see eanees 158 @binutuzumabs. 2. oe. eee Rentain eee, on ge bees ec ee 119 Prandin’... 537 i Geek nae 158
LySGdfen tnd he. 3 154 WISE Wh Kink eS Ae sha eee: 78 INGIFECOR Uns eiia cect «kien eee 61 Rentamicdine er acces eee eee 119 Prastgrelscnaid«¢ oie sac ys Cee 84
Macrodantune een meenen are 110 Macatee. <4 54 tutes 1h RR 120 INatrecOnee as peek eek oa eee 74 RentaZOCine hc. oe 29 san. eres 50 Pravachol...) «in. ne eee 82
MACHESIUMAR TA A445 28 ceei ee 152 IMGarGliSce Anat hot Nee 68 INetazodonein..2c-- <p ee Be ee eee 38 RentOWarDitallscsascin
esses ce ere ee 54 Pravastatiniv, sasuceebes:
sc cee 82
163 164 Index

PAPO AN) ioc /vvithe son de eeee 122 MAT Za bie i<dwas ca acne 28 ROG DSi, 4:8 « e<s< Fu ms Sy OE 131 SULeMranilanrarcs ae-ossse stack eee 48 Tetpacveldine. 6.3. dda ons eee 94 IhepAgbvAlaNe Oper a hone ome oc.ts bon
BAZOSIfindeee sewn ae Cenc ee 22. ONGar ERAN es +58 hice hs ches eee 55 ROO MING 2 ios es 4s hen 46 AE ye 5 St esse avast 2.55 Si OTE 70 TevietenOi. wi cee ens oa ee 68 IME CAORSEr nee bo.cura cheeic Te
PE AZOSINGs,coeys creak 2s wate uke, SE 60 OvleliGinee OG cae ee 30 ROPIVACHING 6.505. ocu% u ce SOMONE Sultagdiazinew emai nee eee 111 halid onitd@ ty see eeeee 133 MIPEHINOWW ins he tis be eure ae ee
RraAZOSIMe oat cients cos ae 66 COOStVAI® | hss > oes ken Wee 82 ResigitaZ0nes ...% 6.50 4s ene 158 Sultasalaziness neon ose some 96 TH ahGomides.L.asasnecneoe eee 133 CHIN OM ta ncys sneer «bean eee
PHECOGE vic irsc.s'ee oeen os oN 158 @tlestrane ee ae cain ce ees eee 96 ROSUVastatllsg see scienee 82 SUNN PVTAZONG. ices.
ov+see 140 Mh eOs DUT es ks Glance wears 90 alam GimnOlOMe: vac nen oes) eee
Bredmisolones.:. nus eee ee 154 QueHSPING 545s vawk + radar ee dd ROP GUSERS 5 sjaco)d>5.vn a ee ome 46 SulhsGOre Vales « San onacincanoc.ocooc 111 Theophylline: .1i0<%
vies amas 40 ram CINOlONe: << .+> ++. eee
LeEGMISONG sec xyes ee 139 OUMIGINEG Ah paces, oe ee te 78 Reriinaninde:s, sae sek on eee Siudlinte
ee" oe ee eR a crs tre 138 TheophyNIMe cc css: 2204s POM 90 TAI COIOLONE? sci «lee ne eines
PECCMISOMER: i.) cis S-ssloncs OER 154 OUININ Ene 4 4. bo aise ak ee ee eD IRUgxOlitinibiee ane ceue os ees 132 SUING Dee te eum cnc Gee 132 Mina bengazoler once wees 0.y ee 122 MPIAINLETOTIES s.cc0.s-0.008aa aeons
PES RADANG 25a Geek a a4 0. SER 56 Ouinolones': is. <<. See ee eee 115 DAIMIECTORO IE 2c n.ancasee oe hot ae 88 ‘SLUICE UN: ach eR cn Pr 92 inazide Ditiretles 5.4...)
oa crete 62 Mita ZOlaiis ss cos ays eau ee
DMGUOARIENS bse iicaie cnwanda deun wns OR 149 WUMIApTib kos xitvenxMega oe eee 68 Sanicimnntinesser as ete ee eee 139 SUMO aatatieue seer ee ee 36 SPLEROPVTIGINGS 6.5 6 neea-t04 emo 61 COL! P.. sizic.cuniee teen eee
|
Esc ere. ro ee 94 Rabeprazoles ¢i2:+0%yss A 94 SANGIN Mm Une sone See 142 Suivantac, ekecethi
canst Teoh oe 92 TIVOGUEMING o5:5.0 02d cee tees 128 TMaperaZINe.. + i250 20s eee
TASCA cic en PE 118 RalOxitenek avis ayvac css atie eee 149 Sapte oy ss Kawnhews
4 eee 42 GAGE a ee I 118 PIG peiital: ood yin te,p008 aa Berens 54 Tchexylphenldy!... .0sc02<0 saowr
EBL OCAITO iat tok shen ee 62 RAMOS ANET tice cx cine x he Kes ean 118 SAQUINAVIT <0: 4 unter a ieeaeneeee 118 SUitentereeies ones cake ee ee 132 AMOPERAl «io saved sas: aw 0 RRC 58 Trihexyphenidy|.., 20.25.00 gees
ee SOG st bk hoo ee ee 94 Ragiprl) soca .18as ie avin s le Rien 68 SAPSTOMOStiNl «6654.45 20% oe ane 135 Ey MGR aii csecan'e « «0 MMCeROR 158 TOLIGAZIINCS sors Gets ac, 407 i sce coeee 42 hlatoi Seneca pdx e931 et ees
PAIANCGE” i hoa aw kts old 74 Ramucintimabsa.ea2 4. ee nee 133 Savellaece snnendhces na eee 38 Sy oui ac nrtinw = ence nee 116 I MOPODA 6 rc « 0in's.s' 0 te eae 126 ttl
017 <n ws: tr
Primaquineav ns WMNe Nae eee 122 RanitiGine yr. e272 see nr cee 144 SCOPOlAMNe so. vss’ oes ns ce eee 28 Siete ae ca kalehs:+ ee 46 MEVOXAMEREMES) «.. <.-arccnw usareeRRelee 42 Trimethoprim-Sulfamethoxazole . .
Rrimateneiviistoa meL eeeee 88 {chavo (ahhgletee ee CMe ereees ic cn! 94 SCOpOlaMINe .. i..%. 54 seve wae 45 OSes fi Sosans¥ 45, RR 92 MWROLAZING®. cies aoc sia s.r ae 42 Trimethoprim/Sulfamethoxazole . . .
TIER Bee isc oe ea RRR 104 Rasagilines ..0ts Alimsuls Pp See 46 Secobarbitall c.c.04 sdeec este eee 54 Ne EOL tects 8 otic wpe = aye 156 Thrombolytic Agents 84k DPIMUPTAMING cos. 2 26 one > aye eee
RGN 5b aweh ds deals
ROO 68 Razadyiie™ « ..iks sxx. es en4 cee 26 Serta Oe abc tide corsa. eee 22 WACHOMIIUS men aiis4 3,Sie cisnaes
Sn 142 PAC ADING)).c csr arts cr sas dT MOLD 56 SEROX OMe ook 5 wk Sie btn oe
eS Cee carne ows eu dates ew EN 38 Reehiptor? 24. inka nays <tc ae 118 Seciral ear wane i skin 66 Wiad Anes Pye a ooccevesns ocd wc ee 1182 TAG ROU, ilk oiegs « wee se 5-2 RR 56 NOOGEVE oeiacc 3 ie Vain ts oo bode eee
LO Banthiines asthe cee eee 28 RettiGane a4 <6 inmates ee 84 SESSION 4 did set bene 6 46 WAN cre
kus 2h. 2 SOR 144 TICAOTEIOR caine. selon s +25 sin, RE 84 Nit AORZAe sior.9:.65 «ors. oo. oc
Rrobenecidiha nse. ovtse Seoe 140 Re GtNGS orice sees cans cee ws SEIZANILY? 9 «nc sk tsesinee
tea eee 118 ENE Se a ce 94 Jticcerdeal
he RRs se 106 wasthialere es cesivnc.0 dssc3 + See
rocainamidet acs 6sen.os ask ee 78 Replat oss cxaann et cae tee ne 45 Senniaees...3.o bak wb lose ee ree 98 ‘TERINGAE ys eee eee 50 A cl lot Sos uci eho peer ayt 84 Dia ae cer cs 1s odes eee
BER OCAUNC He cise © Were mes en ane eI o2 Regie) ori: Hie Kaw ol ac 94 SEnOkOto a. eeccicin
swe 98 MAMI EOCOR o..ocais sav we > thse Le 78 DICIODIGUNE ois. oi ieicce naa net OOD 84
ProcainesPeniG, <o5 ga5sa sows 2 Re 106 Regotafemib ..4.s.0.0.0i.« es<6s 132 Sensorcaines sasha
ee eee 82 AIC SUS RS ep ee te 116 MUPECY CLINGS 26.65.55: «0:2 nin AaB ii
IBLROCAMDAZAMNE DE minian ical on. ones 126 Relenvacesoanwaruent ue Sa amouee 116 SEPTAT «5 shee wate cen eenee 111 ‘TETOINODSIIESRIS Sean peer oe eee es oc 134 MERINONO) eae 22 os:coresiad sotto sSuleutasaci-aie
oemee 22
BOC AIIAS oniauk xg wee He senw x 70 Remeron aas5.c he Ae Sen ee ee Oe 38 Septal syv.ac saeco echo na eae 119 HATS UILO STI eeee Ni cui ee veret icv SRA 22 BRIM OLOleetaye cra ineeairs Gassdcnioaso et eee 66
PIOGMONDEIAZING «xa sxwsinas oe >Soa 42 Remica dees seams tinyc ar eee 139 Setar bes gin Reva cee eee 515) Be rue UIT CE ete aye os cae os 158 AGRE OPI ois.50d soy a asta, Opa 88
ROC OTPCTAZING ise wen ns ts aces 45 Remutentaniltacnc emus one eres 48 Serentil® ...4.ccceetcas ea ee 42 LEE 5020) (SRR ae arm eR 156 ORAM AVAR |. 6 9.084 cay. eee 118
ProcVelidine os 4 gene sie ae ose eS 28 ROOPIOR iii var eave 84 Serevientoy cc Basan eee 88 WACO
RU A ieahts os ain) aiais echsiavate
De 132 ORDA yaks, to:cb hesitin eo Gee ee 60
PROC VENA ING a6 U286.45+5 sara »Ooh 46 REpACUNA Bes, 3 xix cine sown ome 158 SCHOMYEHS Few. cin og eae eee 115 TRO crete. ele85 ow «o's IER 131 MRO LUDA 9 cers coe see aoc es Ee 84
Ppotectaject ois dnc cans SOS 149 Requip® «WORMS RRO ee 46 Seroquel pc 2.5 Le eee 44 Ue a ee ee ore 132 Tissue Plasminogen Activator......
84 Wimechiaininiii: 3. 02 +,c nn Ae ee
BOR CSLOLOUC: » 5 8 sinsibi9 Fain. OO 149 IReSeGhisOlesea te eRe eee 62 Setpase sd.hagc tence sce ae 64 ASOD oe eile oid foiiecib's abn gE 46 SEAGAY is .ciaicvs owes s cain oh ae 118 Wnivase? oc: occ ee
POPES. aot nk eae 134 RESEPp ING: oda iakivwas
desde ae ean 20 Sertraline csi igiecacesen
eee ee 38 TASES 5 ee eee 144 AA URE a irs. hen ne 2g 119 Wrecholine®s 2:5... 01262550
PROC ESOS soe irs wok areca RO 148 INCSCNOING shi. coe 3.6W.iee.es wie 0ARON 64 Serzonee a. c.ae eee Ee 38 LEST SSS a eg eee 130 Hbrica SC pues ce ie aa or 8 csc EO 84 RISD AS” 0 eu cn gataee soe
Promlal’. ciel sane eyfoensso
eS 142 Restore: aesan.$ bo hcam eh ate 5D SIMEPIEVIE, «6S sw esha eevee 117 ETS oe A rh nSorenee 130 NfovelaAb
lant oyan a yurva ero eeurrere
ain taro te Loe) Wirokinas@ke.<.2 v2. ce Hee accor
TO aStiIncoeeee oo eee 92 Reta Vase isecek tere trde mac sre 84 Simponi®. .< cs ams o> ie ee 139 aZODA CALI paemieys hic clesena sc. ene 106 PPOLAGIULIUD ie icc reise oe 139 Wroxattral®. 2 ue einen eee
BEOWNINO Geer a hate ack sO 42 Reteplase icc. c44 ete sos snc ao ane 84 Simvastatinin. «.<stee- acne eee 82 PRC OL Clipe wieecie tetarsta a 112 bienframes 9c ates os, ecard eo os ee 36 WAlAGVEIOVIE 5oo. ssn ¢ cco ee
Rromethazinew tener 144 IRCHOVIL Be akk tome ehee eee 118 Sinequan® ;os sivas de eee 36 OR re Gia siais wan « AOE 56 Holazamud er. o. as.dc- amc nee Oe 158 MASCOT isn af 0a aie niaae en ae
Bromethazine: as. cuss. aoe tae 45 IREWAAS seaside eae 5 ee 50 Singulait® 2.) vse da eee 90 THENZINGIe dn Home ee eon ome metic a 104 MoliniatamiGege eevalacesns 6a, es 158 WALSANGICIOVIES 5. 20,5, ana.71
PORES 1 e Shace pee puedes 9 eC 8 IRevitmid® aes sere eee 133 SIVEXELO 2 ov nace poeee 112 He HOV Cite ye ccrnste tna eveac sicucvs esoheeNe 117 OCA ONG io. 6G. 5.5.5:6 0x ion an'e ee COME 46 Walaim@ stata oe esc cure ee
BIODAIENONG 64 pity 4:00 mes ER 78 Rev ataZ wie cisntvas sake See ee TR 118 SOfOSDUVIt suena eee 117 MS HENEODAV
CID sins armar tesa toate 12 OLESEN Caer rise os coke OR 138
PeOPAMUelEne sid iain. es AN Oek OG 28 Rhetmatiexcp eer nee eee 139 Solu-Corttef® sc..cnt
oe eee 154 HLTA SAntalncysieve iscsvaezuin!
21k OME eee 68 Wolinasetia- os esac c cs eee 158 Walproic Acid . 3.0...
«<2 eee
BOA
OLONS tas vert ececn:a4 sx 06.4 pe 58 RiniMOCOrte. hose eeeee 92 SOLALCNID icici ety atte) aeons 132 Weltas@mecern oes ls ecaance Oe 139 ‘Ike haqie\ab ot. area emo 66 8: 138 WalSartali as. 4 -s.c. oorsioes ae eee
PEOVOMP NENG isores pide we cine sce ROO 50 Rhod Immune Globulin.......... 142 Sotalol’. cxGececcteaitecsect nh 22 UGE VASCS ae a 55 HOlferoGdine:..... Seewthan matey ees 28 Voll ee
EtepranOlols). <i 8 ics. 14 STR 156 Rhoganirs soya. a22 tc vas eee 142 SOtal6l ss G coe senna 80 "Ss5 126 AINA” Gis Rabi oe 56 WERCORRYV
CIN: 5 5.«0/5 95a, 9:00
TOO CAIOIONS 6.52060) 504.3-5Fae 3:5AOR ae Rhythiniol? 9 gs0c60% +05 ee 78 Sovaldi®—sate ns 6 ee 117 emozolomiud eye. ole aoe eee 126 ROI ANALG 3 nu. cusp ae os See 56 Wand etani bo... oon «82h. ee
BLO PLANO. oie sans nd ee sane 66 (RGD ANGEITV ha cts a cee Ee ee ee 116 SPEae > ag a coente baw ee 88 WET SIPOMMMUS 0 «cys occ evara «cree « tvore IBY WOPOLCCEN 5826 os oo trod e's oo 130 Nasodalati® «. «hs san. ncn eee
EAOPIANOION s sague ewe 5 RRO 80 Ritab tititiceiate soconnnohon eo meee 115 SPIFONGlACtONe <2 ..05% 1. = 154 PENCE PASE scsi. << Gs: SONI TNT 84 OTAGO stan bucleestarcs eee 138
Prep yibiouradl), 05 5c soecea eae 156 INGEARADIN son's
oi kw WA RK SR Tee 115 DPILONOLACHONEN 2 hyn ous. eeeeee 62 ON Otis x cy ces « Oe 20 WIGTHISCLea yc cect tce Satine Aen is2 WaSOteCOs tec oe oe ee
NET@OS Ol cartes aisha es atk ee 55 IAP CONE: te cieakbanana
eee 115 SPO AEN ini 20 dopeuyhe eee eee 120 WO ayaa ec cima awed) oa 64 MOT Alae eee anoles. Neue see 88
BOSSES, oo. oi ..005 «0 SAI LO Rimantadine sree chee 116 Sptycel® yin. scvaace se eee 132 Wea DOSIGe rai: oka wen toa Oe 130 MOSILUIMOMAD sac cea cee 133
IELOSEIE ees aotie ninvon SOREN 152 IRISPORGOISs 1 4.40065 o-caiee oe eee 44 Stat lie es nyse de-scn ees oe Se 158 HLeTMOLOVMI ery cae enue eee 117 MODs eth) sss ace woss.04.)s SO 61 Meete InnibitorS a..04 90 ce ee een 132
KOS tin A O1I)owc ahve setceeeoistae ee i152: PaSPCHiGONe 54 nous Mame cen ye see 44 StaVULGINE™. Ausioseuenrc
coke eee 118 Het OLO WAT CHRIS iy ecas exas ase encase 118 PA aaitweid aetsa te os 5-5 versa 84 Veleada® onc5. cacao ee 131
ROLODUIXE § oh, Shoe mwcous are aeleene eee 94 Rattan) bey eee oh cence oe 40 Stelazinee in. cums cers cet eee 42 PRECIOUS eis oe bw sy vv vo vv. RON 22 iiaGti Tea irene: alobecsaci cio 30 els UR Aw sca cs oe ei 158
Prot iptyne si 0.4.05 +i0.< 2 vO 36 RUtOCING a, . 2 eee ce s Ses See 152 SiValede 4.44095
o-oee ye 432 OMOEIHIN: - eer oxen beeen tS 66 ARATE CHOllenese as, ode tiara stile opotie ee 139
BPG Ventilo merce sche, ae 88 RitOMavilinacsctc nao me eewoslotc
eee 118 Sirattera’ ss..<t senses ace.) eee 40 MET AZ OSIM We eke Abs meee cane 22 Hiv aGLOW rer Rek ead bacscusarde oni SCN 48
Pre VOChOline=saa. soe. sec en 24 RUGUXAN csc ess ae 133 Sireplokinase 55 faccecxan ss eee 60 METAZOSINS, <2 eee.a,ic)ities 4 oh 66 ivan ethint yes te estsciae ee 132
IBROZACS van fre cea old egyns OO 38 RAGAN heres cca eee ee ee 139 DiLEptOKINASe o.c./c o's«5 bscos-s oe 84 WEKAZOSIN jac Soe 4s ce 3c PR 74 SANG Ate eet acini oe DD Wenilaifaxines <tacc.21
aeeee eee
SUN ewes xo ood as Sonne 98 RittodiMnabys csc-naa se Mea bos 138) SHeplOmMycny, . sci. 265 05 eA 112 HERD IMA TTS. yep. G din cue. 10 > RE 120 ipatndatesery ei rectuckeciciecn
ware eae eee 66 Cit
2) iq ei |
Ucar Be aia seaesio eee 156 Rit ubaitiva Dee sue eae ecole Aan ee 139 SiePlOMVON 2.4.0 .00+0 5 aan 115 Be LILAC «ah ciate cc 152 eanidolaperll soisss.o sn acsiaje'se
SRE ORS 68 CRESS reese atktens dee Aiecceh rile
Rulimnicorteraae ase ose Ge 90 RAvashig mine: va aks 5 ees eee 26 SIFEPlOZOCIN § 0... aso a ee 126 MELD UitANIMNG <is,d.0ns<
3scers, a 88 Trangderm-Scop”... «2... saeieeremaes 45 WERS aU. <0.06 prels sia tes Se
PVD COSH EMME. 0644: 0.4100 « PREIS 26 ODI Ser weer ehBe eso e sci eee 28 Siromectolenanas a. See es 122 WESEOSLCTONE epavc «a2 oh aceon eee 148 iGaLXeNCaw a. seoei sino ee ee 55 Verapamil... ...'...2....¢4eeeReaeiens
Py iinethamune. as 305 ps5. daa ee 122 ROCEDH IN 65 4ux xu.x'sm WORcata 108 Sublimaze® ns sh.0Ger na 48 Hlietra Cali res ce.cseace kaa ae 32 cannyley promine as i <scas5ee See 36 Versed®
PYCIZIMAMUIAE 50.5 xs cuhnn ee see 115 ROGULOMTUMID «cies ybn onl ero 30 SUCCINVICHOMING <i0.<5 0 2 eee 30 NELEACY CIUIG).c« cae n s 2 SOREN 112 Mra7ZOGONE Re ohio cess eee 38
NENG ae tm Eeoe, coe Mee eI Pena oe 115 IROMAZ! CONS ana ana erences 54 Stteraltater cca casera crs tuesee 94
165 166 Index

RAPID LEARNING AND RETENTION THROUGH THE MEDMASTER SERIES:
A ute aaa te ogi Mee ge one ene TA EYVCHOINOU vastness ches es eyhan DO Ree ais + woine oisaaa ee eee 82
NHCOCIE oe ene a came al eae Somme vemine: . ordi fet eh Lb iS IGesonarir tiAMAL sa tA 90 CLINICAL NEUROANATOMY MADE RIDICULOUSLY SIMPLE, by S. Goldberg
NICER re oo Ma tben ieneta tone Veet! TOG. YNVACNSIN ote aetna bieag su aie ce ee fl ti yee Pee ee 133
MICEX pape naire heya ube Sy ttBd URE US ORANNS aos ak hein Alpedie atau is SU hea 612s eenRM nee ert 118 CLINICAL BIOCHEMISTRY MADE RIDICULOUSLY SIMPLE, by S. Goldberg
NRCRITO soe ech Metalic e ch akaay SE ARE OL ioe oe ten ors LOZ) F ZiMOvuditiet. tect teens wee 118 CLINICAL ANATOMY MADE RIDICULOUSLY SIMPLE, by S. Goldberg
WAR ate etek kite tlaahosrak ote BO MAAN AO) 42 its At Cane Ee BOal [IAilemtoner..2 <M ALi lieu ehs eeaes 90 CLINICAL PHYSIOLOGY MADE RIDICULOUSLY SIMPLE, by S. Goldberg
MINDIASONG,... 6 .a~ .erieato ae Baste 130 NANG aa. TF SOE Ay Gitte Ree Ve 55 PApTASIGONE: Actes ber a6 2 kas aias 42 CLINICAL MICROBIOLOGY MADE RIDICULOUSLY SIMPLE, by M. Gladwin and B. Trattler
MAINGY 1SULING Ban eto acnieued WEG dhawk aes ag NEA gia cca ee ch ety SO enwee TENPOUUGNG ape, a rua we era ahaa 112
WIDOSEIDUNG hea meee oc Mo en aise er 0m eeeloda ert Meee cae ee ee 125 SAV AtDercept, 4. neck oe oe te ae 132 CLINICAL PHARMACOLOGY MADE RIDICULOUSLY SIMPLE, by J.M. Olson
BNITRCEDL cate icunachin altho 118 -Xopetiotet Kae aces caer et ee BBt I PAbcorke. AeA. 2 ote die Rae oe 82 OPHTHALMOLOGY MADE RIDICULOUSLY SIMPLE, by S. Goldberg
ARAMIAUTIONS 50 5 Sow eds mem he ties 118° eeXylowaiie® tiio.o te ek del Tes 78 p paZotian tas SO Aa eee 45 PSYCHIATRY MADE RIDICULOUSLY SIMPLE, by W.V. Good and J. Nelson
MITAZ Ole asta etapa ay TG WX ZA os se e-25 atehs:se peae axeBar TAA ie oeCUTZOS oods, (erpetiinn pean a areal 131 CLINICAL PSYCHOPHARMACOLOGY MADE RIDICULOUSLY SIMPLE, by J. Preston and J. Johnson
NarOGC aac t cass tants wee’? Cee he Re EIN ON eave oor sing nals eee Lae te pal Co i seartme ofan eR lias Bry Sete > Ry 38
EROOULS earns anes tru noe 118° -Yutopar® ics.) ek a. Uo 152). Zonepran®l 2c, eas 04a ee 56 USMLE STEP 1 MADE RIDICULOUSLY SIMPLE, by A. Carl
VBKON WEE Ama nea aie hieee, 22°» ‘Zatirlukast’..... 26h dv-eraea aie O0f Te!Zonisamide: % Wii454.5 45 bee 56 USMLE STEP 2 MADE RIDICULOUSLY SIMPLE, by A. Carl
PARED gece oe teas Manavin ee 66 Zalttap?s.css) gent eicenwask Somers 1320 potZOVITAXS |pee es. antes tae eee 116 USMLE STEP 3 MADE RIDICULOUSLY SIMPLE, by A. Carl
NASIOC CRID i. ¢ Onno ated ue Sos TBM GATTIVAN ica we eaten on ee ss fo Fg RI gs ny PPA 132
eK a Rrra eed to anee Wee ASR <Zanocal”.. ete ee ek eee P26 EZ VEU c eae ene eee 132 BEHAVIORAL MEDICINE MADE RIDICULOUSLY SIMPLE, by F. Seitz and J. Carr
AE \era 2to ae Re DOIN Zatae: Mi SAod Addo Pee eon 144s RAGGA SA. OSS hte ae eee 90 ACID-BASE, FLUIDS, AND ELECTROLYTES MADE RIDICULOUSLY SIMPLE, by R. Preston
NOM ABOT SA verte ce drayciursdibnehvaniaaurs<s 139 SANA 3 eee es Cease Re 94-5 “Zykadia@ es:2518. 34see 132 THE FOUR-MINUTE NEUROLOGIC EXAM, by S. Goldberg
NOMCOMAZOIE naire Fd wae once a < G20" “Zarontin - Sosiaks cm cater ereee acne: DG a AVON cocci? csbetes shee a 140
MOMS AR ss eo ing oases: TSU) MZALOMUIS 8ox hrs noe eect ese BGT? AZVPIORAT wont ct cere ne ere 44
MEDICAL SPANISH MADE RIDICULOUSLY SIMPLE, by T. Espinoza-Abrams
Nottiengoetthe: 5 st. UR tthe 1SQI Zebetarns 2.2 avidly. ee Ae Dk MAARC? GL HGEN. SAN Set OT ee 144 CLINICAL ANATOMY AND PHYSIOLOGY FOR THE ANGRY HEALTH PROFESSIONAL, by J.V. Stewart
VOOR ai cac.so eenstee 8TS0Z OF Zebeta? ve1e1.13. 5. Faas tae: ee 66 we Zytiga® 2 ara eek tee ee 134 PREPARING FOR MEDICAL PRACTICE MADE RIDICULOUSLY SIMPLE, by D.M. Lichtstein
AWE ii 3sec aig penn eae CURES |2s SO me eRe eee 132 ZEON neo ein ae eyanete, es eS 112 MED’TOONS (260 humorous medical cartoons by the author) by S. Goldberg
RN ABE aM tae. retina uine ok Rolin yo Scant Gl. WUZeIDOl el raven ue tern nares 132
TLELON als eR eat tc eared 83. MeZemiGron’ } Was. teers ioe ote 30 CLINICAL RADIOLOGY MADE RIDICULOUSLY SIMPLE, by H. Ouellette
NCLEX-RN MADE RIDICULOUSLY SIMPLE, by A. Carl
THE PRACTITIONER'S POCKET PAL: ULTRA RAPID MEDICAL REFERENCE, by J. Hancock
ORGANIC CHEMISTRY MADE RIDICULOUSLY SIMPLE, by G.A. Davis
CLINICAL CARDIOLOGY MADE RIDICULOUSLY SIMPLE, by M.A. Chizner
PSYCHIATRY ROUNDS: PRACTICAL SOLUTIONS TO CLINICAL CHALLENGES, by N.A. Vaidya
and M.A. Taylor.
MEDMASTER'S MEDSEARCHER, by S. Goldberg
PATHOLOGY MADE RIDICULOUSLY SIMPLE, by A. Zaher
CLINICAL PATHOPHYSIOLOGY MADE RIDICULOUSLY SIMPLE, by A. Berkowitz
ATLAS OF MICROBIOLOGY, by S. Goldberg
ATLAS OF DERMATOLOGY, by S. Goldberg and B. Galitzer
ATLAS OF HUMAN DISEASES, by S. Goldberg
ORTHOPEDICS MADE RIDICULOUSLY SIMPLE, by P. Tétreault and H. Ouellette
ATLAS OF ORTHOPEDICS, by P. Tétreault, H. Ouellette, and S. Goldberg
ANATOMY OF THE SOUL, by S. Goldberg
IMMUNOLOGY MADE RIDICULOUSLY SIMPLE, by M. Mahmoudi
CLINICAL BIOSTATISTICS MADE RIDICULOUSLY SIMPLE, by A. Weaver and S. Goldberg
Try your bookstore. For further information and ordering send for the MedMaster catalog at MedMaster, P.O. Box 640028,
Miami FL 33164. Or see http://www.medmaster.net for current information. Email: mmbks@aol.com.
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Clinical Pharmacology Made Ridiculously Simple...
“Well organized and concise review of pharmacology. Excellent use of tables to compare different
agents within a given class of drugs. The narrative and graphics, including the comics, will make
this especially attractive to students as they review pharmacology.”
Joseph W. Cranston Jr., Ph.D.Director,

Department of Drugs
American Medical Association
“If you can only buy one textbook on pharmacology, make it this one. This book is excellent. It is
comprehensive, though concise and inexpensive . . . the organization is wonderful.”
Marc Colbeck
www.paramedicine.com
“The chart format for pharmacology makes both study and reference a snap. With such clinically
relevant material, I still carry my original ragged and torn copy to work with me every day.”
Scott Gibson M.D.

Emergency Medicine Physician
“Clinical Pharmacology Made Ridiculously Simple contains all the essentials of pharmacology,
without unnecessary detail, in a very readable format. An excellent source for Boards review.”
Debbie Overstreet
Medical Student
“The format is conducive to self-testing. The tables are complete, yet concise. The cartoons are
clever and strategically placed to reinforce concepts and enhance visual learning.”
Dan Swangard
Medical Student
“As a practicing physician, I found this to be an excellent quick review of pharmacology. It’s a
painless way to stay up to date in this rapidly changing field.”
Alan Gill M.D.

Family Physician
SBN-13: 978-1-935640-00-
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Clinical

Clinical Pharmacology Made Ridiculously Simple

MedMaster, Inc., Miami, FL @)

Clinical Pharmacology Made Ridiculously Simple aims

For Rose Olson

ISBN 13: 978-1-935660-00-2

Made in the United States of America

The Book Reviewers

The Chapter and Table Reviewers/Contributors

Chapter 2 Peripheral Nervous System .........22000000200e 13

' 1% Cumann b us ev iedokbemdee

Passive Diffusion Rapid for lipophilic, nonionic and small molecules.

Facilitated Diffusion Drugs bind to carrier by noncovalent mechanisms. Drug B displaces

Active Transport Identical to facilitated diffusion except that ATP

e Drug Distribution The apparent volume of distribution (V,) is a Protein-bound

3. Oxidation 4. Polarizing atom exchange 2. Ethereal sulfate conjugation

- Microsomal (P459) reduction reactions 3. Acetylation

4. Transsulfuration (occurs In mitochondria)

2. Nitro-reduction CN + S,037 ——= CNS + SOs

in the body retained the original concentration of OR

Peripheral Nervous System

Parasympathetic eo. —-_--- ~<

14 Peripheral Nervous System 15

Table 2. 1A Direct Sympathomimetics

Methoxamine (Vasoxyl) i 73 oy ony

Bitolterol (Tornalate) “oy oy “oy

16 Peripheral Nervous System 17

e Indirect & Mixed Agents Arterioles and Veins:

Hydroxy-amphetamine ie More CNS effects than ephedrine,

fewer CNS effects than amphetamine.

18 Peripheral Nervous System 19

Table 2.3 Presynaptic Adrenergic Nerve Blockers

Methyldopa Decarboxylated to a-methy! J preganglionic sympathetic Sedation, mild orthostatic Hypertension

Bretylium a See guanethidine. Prolongs oy

20 Peripheral Nervous System 21

«“n «en “an “n

Pindolol (Visken) “oy “an «“»

22 Peripheral Nervous System 23

RECEPTOR :so| ORGAN = ‘2NDMESSENGERS — NOTES

(Isopto-Carpine) above. Sweat and salivary

24 Peripheral Nervous System 25

‘DRUG —_——sMECHANISM_—_—CLINICALUSES_——— PHARMACOKINETICS _ ¢ Decreased sweating (sympathetic controlled)

26 Peripheral Nervous System

on muscle. suprapubic pain, frequency and incontinence that

Glycopyrrolate (Robinul) Treatment of peptic ulcer; IV form used to decrease “os “n

salivary and tracheobronchial secretions and to

28 Peripheral Nervous System 29

Table 28 Neuromuscular Blockers (N,,Antagonists) —

IV. Metabolism: Hoffman Moderate histamine release Administer slowly to

30 Peripheral Nervous System

32 Peripheral Nervous System

a: able 3.1 Antidepressants

(Sinequan) described above. anticholinergic effects.

(Norpramin) anticholinergic effects. Sudden death in children has occurred.

(Pamelor, Aventyl) a more clear relationship between Half-life 18-45 hrs

(Asendin) effects. Neuroleptic malignant syndrome. Shortest half-life 8 hrs

Monoamine Oxidase Inhibitors

36 Central Nervous System 37

38 Central Nervous System 39

Table 3.2 Psychomotor Stimulants _

Norepinephrine uptake inhibitors

40 Central Nervous System 41

Table 3.3A Antipsychotic Drugs _

Aripiprazole Partial agonist at dopamine D2 and Schizophrenia, mania, Headache, somnolence,