8 PART I Basic Principles
B. Other Distribution Models
A few drugs behave as if they are distributed to only 1 compart-
ment (eg, if they are restricted to the vascular compartment).
Others have more complex distributions that require more than
2 compartments for construction of accurate mathematical
models.
QUESTIONS
1. A 3-year-old is brought to the emergency department having
just ingested a large overdose of diphenhydramine, an anti-
histaminic drug. Diphenhydramine is a weak base with a p.K.
of 8.8. It is capable of entering most tissues, including the
brain. On physical examination, the heart rate is 100/min,
blood pressure 90/50 mm Hg, and respiratory rate 20/min.
Which of the following statements about this case of diphen-
hydramine overdose is most correct?
(A) Urinary excretion would be accelerated by administration
of NH 4Cl, an acidifying agent
(B) Urinary excretion would be accele rated by giving
NaHC0 3, an alkalinizing agent
(C) More of the drug would be ionized at blood pH than at
stomach pH
(D) Absorption of the drug would be faster from the stomach
than from the small intestine
(E) H emodialys is is the only effective therapy
2. Botulinum toxin is a large protein molecule. Its action on
cholinergic transmission depends on an intracellular action
within nerve endings. Which one of the following processes is
best suited for permeation of very large protein molecules
into cells?
(A) Aqueous diffusion
(B) Aqueous hydrolysis
(C) Endocytosis
(D) Lipid diffusion
(E) Special carrier transport
3. Which of the following terms describes the process by which
the amount of active drug in the body is reduced after admin-
istration but before entering the systemic circulation?
(A) Excretion
(B) First-order elimination
(C) First-pass effect
(D) Metabolism
(E) Pharmacokinetics
4. Ampicillin is a weak organic acid with a p.K. of 2.5. What
percentage of a given dose will be in the lipid-soluble form in
the duodenum at a pH of 4.5?
(A) About 1%
(B) About 10%
(C) About 50%
(D) About 90%
(E) About 99%
5. Which of the following statements best describes the process
by which the plasma concentration of a drug declines with
first-order kinetics?
(A) There is only 1 metabolic path for drug elimination
(B) The half-life is the same regardless of the plasma
concentration
(C) The drug is largely metabolized in the liver after oral
administration and has low bioavailability
(D) The rate of elimination is proportional to the rate of
administration at all times
(E) The drug is distributed to only I compartment outside
the vascular system
6. Which of the following statements is true regarding the
termination of drug action?
(A) Drugs must be excreted from the body to terminate their
action
(B) Metabolism of drugs always increases their water solubility
(C) Metabolism of drugs _always abolishes their pharmaco-
logic activity
(D) Hepatic metabolism and renal excretion are the 2 most
important mechanisms involved
(E) Distribution of a drug out of the bloodstream terminates
the drug's effects
7. Which statement about the distribution of drugs to specific
tissues is most correct?
(A) Distribution to an organ is independent of blood flow
(B) Distribution is independent of the solubility of the drug
in that tissue
(C) Distribution depends on the unbound drug concentra-
tion gradient between blood and the tissue
(D) Distribution is increased for drugs that are strongly
bound to plasma proteins
(E) Distribution has no effect on the half-life of the drug
8. Timolol is being considered for the treatment of glaucoma in
a 58-year-old patient. Except for previously reported elevated
intraocular pressure, the patient's history is unremarkable.
Vital signs include blood pressure 140/88 mm Hg; heart rate
76/bpm; respiratory rate 12/min. Body temperature (sublingual)
is 37.5°C. On examination, breath sounds are clear, no mur-
murs are heard, and there is no abdominal tenderness. Timolol
is a weak base of p.K. 9.2. Which of the following statements is
most correct?
(A) If given by the intravenous route, the concentration of
timolol in the aqueous humor (pH 7.8) will be lower
than the concentration in the duodenum (pH 5.5)
(B) When administered as eyedrops, the rate of absorption
into the eye will be slower if the drops are alkaline
(pH 8.0) than if they are acidic (pH 5.0)
(C) Excretion in the urine will be slower if urine pH is alkaline
(pH 8.0) than if the urine pH is acidic (pH 5.8)
(D) The proportion of timolol in the protonated form will be
approximately 10% at pH 8.2
(E) The proportion of timolol in the more lipid-soluble form
will be approximately 10% at pH 10.2
 CHAPTER 1 In troduction 9

9. T he pharmacokineri c principl e rhar is characteristic of the clearly wrong. C hoice D says (in effect) that the more ionized
eliminatio n o f ethano l and hi gh d oses of phenyroin and fo rm is absorbed fas ter, which is inco rrect. A and B are oppo-
as pirin is called sites because N H 4Cl is an acidifying salt and sodium bicar-
(A) Disrribu rion bonate an alkali nizing one. From the poinr of view of res t
(B) Excretion strategy, opposites always deserve careful attenrion and, in this
(C) Fi rst-pass effect case, encourage us to excl ude E, a distracter. Because an acid
(D) First-order elimination environmenr favors ionizatio n of a weak base, we should give
(E) Zero-order elimination NH 4C l. T he answer is A. Similar questions may be designed
aro und other comparrments, eg, prostatic and vaginal fluids,
10. T he set of p ropenies that characterize the effects of a drug on and breast milk (more acidic than blood) and cerebrospinal
rhe body is called flui d and aqueous humor (mo re alkali ne) . Note that clinical
(A) Disrribu rion managemenr of overdose involves many other considerations
(B) Permeation in addition to trapping the drug in urine; manipulation of
(C) Pharm acodynamics urine pH may be contraindicated for other reasons.
(D ) Pharm aco kinetics
(E) Proro nario n 2. Endocytosis is an imporranr mechanism fo r transporr of ve ry
large molecules across membranes. Aqueo us diffusion is rarely
11. A new drug was administered inrrave nously, and irs plasma used for transporr across cell mem branes. Li pid diffus ion and
levels were measured for several hours. A graph was prepared special carrier transporr are common for smaller molecules.
as shown below, with the plasma levels plon ed on a logarith- H yd rolysis has nothing to do with the mechanisms of perme-
mic ordinate and rime on a linear abscissa. Ir was concluded ation; rather, hydrolysis is one mechanism of drug metabolism.
that the drug has first-order kinetics. From rhis graph, what is T he answer is C.
the best estimate of the half-life? 3. "Firs t-pass effect" is the term given to elimination of a drug
before it enters the systemic circulatio n (ie, on irs fi rs t pass
th ro ugh the porral circulation and liver) . T he fi rst-pass effect
I is usually, but nor always, due to metabolism in the porral
I
I blood or the liver. T he answer is C.
I I I I I I I
32 -~---T--~---T---r--~---T--- 4. Ampicillin is an acid, so it is more ionized at alkaline pH and
1 I I I I I I
c I I I I I I I less ionized at acidic pH. T he Henderson-Hasselbalch equa-
0
I I I I I I
~ 16 1 --r--~---T---r--l---r--- tio n p redicts that the ratio changes fro m 50/50 at the pH
c
Q)
1
I I
I I
I
I
I
I
I
I
I
equal to the pi<, to 1/1 0 (proto nated/ unp roto nated) at 1 pH
{)
c 8 --~---L--~--- --L--~---L __ _ uni t mo re alkaline than the pi<, and 1/ 100 at 2 pH units
0 I I I I I I
{) I I I I I more alkal ine. For acids, the protonated form is the nonion-
Cll I I I I I I
E 4 --~---L--~---~---L--~---
ized , more lipid-soluble form. T he answer is A.
(/) 1 I I I I I I
Cll
c::: I I I I I I I 5. "First-order" means that the eliminatio n rate is proporrional
I I I I I I I
2 --~--- L --~---~---~--~---L---
to the concenrration perfusing the organ of elimination . T he
1 I I I I I I
I I I I I I I
half-life is a constant. T he rare of elimination is pro ponional
I I I I I I I to the rate of administration only at steady state. The order of
0 2 3 4 5 6 7 el im ination is independent of the number of comparrments
into which a drug distributes. T he answer is B.
Time (h)
6. Note the "trigger" words ("must," "always") in choices A and B.
All drugs that affect tissues other than the blood or vascular
endothelium act outside of the bloodstream or vascular com-
(A) 0.5 h parrmenr. T he answer is D .
(B) 1 h 7 . T his is a straightforward question of d isrribution concepts.
(C) 3 h There are no trigger words to give the answer away, but it can
(D) 4 h be deduced without much trouble. From the list of determi-
(E) 7 h nants of drug distribution give n previously, choice C is correct.
8. This question illustrates one of the techniques fo r saving time
in a board-rype examination. Because a great deal of informa-
ANSWERS tion is p rovided in the case description, it is easy to become dis-
tracted by possible abnormalities (eg, elevated blood pressure)
1. Questions that deal with acid-base (H enderson-Hasselbalch) that have nothing to do with the question (H enderson-
manipulations are common on examinations. Since absorp-
H asselbalch concepts). The best way to avo id such distractions
tion involves permeation across lipid membranes, we can
is to quickly scan the answers to focus on the inrent of the
(a t least in theory) treat an overdose by decreasing absorption
question. Weak bases are more protonated in an acidic envi-
fro m the gut and reabsorption from the tubular urine by
ronmenr because more protons (hydrogen ions) are available.
making the drug less lipid-soluble. Ionization attracts water In the protonated state, weak bases are ionized, polar, and less
molecules and decreases lipid solubi lity. Diphenhydramine is lipid-soluble. T herefore, less timolol is lipid-soluble and able to
a weak base, which means that it is mo re ionized (protonared)
diffuse back into the blood from the duodenum (pH 5.5) than
at acid pH than at basic pH. C hoice C suggests that the drug
is able to diffuse through the surface of the eye (pH 7.8). By
wo uld be mo re ionized at pH 7.4 than at pH 2.0, which is
the same reasoning, the drug diffuses fas ter if the eyedrops are
I0 PART I Basic Principles

alkaline than if they are acidic. Less drug diffuses back inro
the body from the urine if the urine pH is acidic than if
it is alkalin e, so excretion is fas ter in acidic urine. T he
answer is A.
9. T he excretion of most drugs follows fi rsr-order kinetics.
However, ethanol and, in higher doses, aspirin and phenyto in
follow zero-o rder kinetics; that is, their elimination rates
are constanr regardless of blood co ncentration . T h e
answer is E.
10. Definiti ons. Pharmacodynamics is the term given to drug
actions on the body. T he answer is C.
11. Drugs with fi rst-order kinetics have constanr half-lives, and
when rhe log of the concentration in a body compartment is
plotted versus rime, a straight line results. T he half-life is
defined as the rime required for rhe concentration to decrease
by 50%. As shown in the graph, the concentration decreased
from 16 units at 1 h to 8 units at 4 h and 4 units at 7 h; there-
fore the half-life is 4 h minus 1 h or 3 h. T he answer is C.

CHECKLIST

When you complete this chapter, you should be able to:

0 Define and describe the terms receptor and receptor site.
0 Distinguish between a competitive inhibitor and an allosteric inhibitor.
0 Predict the relative ease of permeation of a weak acid or base from a knowledge
of its pK., the pH of the medium, and the Henderson-Hasselbalch equation.
0 List and discuss the common routes of drug administration and excretion.
0 Draw graphs of the blood level versus time for drugs subject to zero-order
elimination and for drugs subject to first-order elimination . Label the axes
appropriately.

CHAPTER 1 Summary Table

Major Concept Description

Nature of drugs Drugs are chemicals that modify body functions.They may be ions, carbohydrates, lipids, or proteins.They vary in
size from lithium (MW 7) to proteins (MW ~ 50,000)

Drug permeation Most drugs are administered at a site distant from their target tissue.To reach the target, they must permeate
through both lipid and aqueous pathways. Movement of drugs occurs by means of aqueous diffusion, lipid
diffusion, transport by special carriers, or by exocytosis and endocytosis

Rate of diffusion Aqueous diffusion and lipid diffusion are predicted by Fick's law and are directly proportional to the concentration
gradient, area, and permeability coefficient and inversely proportional to the length or thickness of the diffusion path

Drug trapping Because the permeability coefficient of a weak base or weak acid varies with the pH according to the Henderson-
Hasselbalch equation, drugs may be trapped in a cellular compartment in which the pH is such as to reduce their
solubility in the barriers surrounding the compartment

Routes of administration Drugs are usually administered by one of the following routes of administration: oral, buccal, sublingual, topical,
transdermal, intravenous, subcutaneous, intramuscular, or rectal, or by inhalation

Drug distribution After absorption, drugs are distributed to different parts of the body depending on concentration gradient, blood
flow, solubility, and binding in the tissue

Drug elimination Drugs are eliminated by reducing their concentration or amount in the body.This occurs when the drug is
inactivated by metabolism or excreted from the body

Elimination kinetics The rate of elimination of drugs may be zero order (ie, constant regardless of concentration) or first order
(ie, proportional to the concentration)
 CHAPTER 2 Pharmacodynamics 17

TABLE 2-1 Examples of receptors that are coupled to their effectors by G proteins.

Receptor Types Coupling Protein Effector Effector Substrate Second Messenger Response Result
2
M 1, M 3,a 1 Gq Phospholipase C Membrane lipid s i IP 3, DAG i Ca + and protein
kinase activity

p, D, G, Adenylyl cyclase ATP i cAMP i ci +infl ux and

enzyme activity

<X2,M2 G; Adenylyl cyclase ATP J, cAMP J, ci +infl ux and enzyme

1'
activity; K+effl ux

this phenomenon . First, intracellular proteins may block access 2. Graded and quanta! dose-response curves are used for drug
of a G protein to the activated receptor molecule. For example, evaluation in the animal laboratory and in the clinic. Which
the molecule ~-arrestin has been shown to bind to an intracell ular of the following statements best describes quanta/ dose-
loop of the ~ adrenoceptor when the receptor is continuously response curves?
(A) More precisely quantitated than ordinary-graded dose-
activated. Beta-arrestin prevents access of the G ,-coupling
response curves
protein and thus desensitizes the tissue to further ~ agonist activa-
(B) Obtainable from the study of intact subjects but not from
tion within minutes. Removal of the ~ agonist results in removal isolated tissue preparations
of ~-arrestin and restoration of the full response after a few minutes (C) Used to determine the maximal efficacy of a drug
or hours. (D ) Used to determine the statistical variation {standard
Second, agonist-bound receptors may be internalized by deviation) of the maximal response to the drug
endocytosis, removing them from further exposure to extracellular {E) Used to determine the therapeutic index of a drug
molecules. The internalized receptor molecule may then be either 3 . The results shown in the graph below were obtained in a
reinserted into the membrane {eg, morphine receptors) or degraded comparison of drugs that increase the force of cardiac con-
{eg, ~ adrenoceptors, epidermal growth factor receptors). In some traction. Which of the following statements is correct?
cases, the internalization-reinsertion process may actual ly be neces-
sary for normal functioning of the receptor-effector system.
Third, continuous activation of the receptor-effector system
may lead to depletion of some essential substrate required for
downstream effects. For example, depletion of thiol co factors may
be responsib le for tolerance to nitroglycerin. In some cases, reple-
tion of the missing substrate {eg, by administration of glutathione)
can reverse the tolerance.
Long-term reductions in receptor number {downregulation)
may occur in response to continuous exposure to agonists. The
opposite change {upregulation) occurs when receptor activation
is blocked for prolonged periods {usually several days) by pharma-
cologic antagonists or by denervation.
Log dose

QUESTIONS {A) Drug A is most effective

(B) Drug B is least potent
1. A 55-year-old woman with heart failure is to be treated with
(C) Drug C is most potent
a diuretic drug. Drugs X and Y have the same mechanism of
{D )Drug B is more potent than drug C and more effective
diuretic action. Drug X in a dose of 5 mg produces the same
than drug A
magnitude of diuresis as 500 mg of drug Y. Which of the fo l-
(E) Drug A is more potent than drug B and more effective
lowing statements best describes these results?
than drug C
(A) Drug Y is less efficacious than drug X
(B) Drug X is about 100 times more potent than drug Y 4. In the absence of other drugs, pindolol causes an increase
{C) Toxicity of drug X is less than that of drug Y in heart rate by activating ~ adrenoceptors. In the presence
(D ) Drug X has a wider therapeutic window than drug Y of highly effective ~ stimulants, however, pindolol causes a
(E) Drug X will have a shorter duration of action than drug dose-dependent, reversible decrease in heart rate. Which of
Y because less of drug X is present over the time course of the following express ions best describes pindolol?
drug action (A) A chemical antagonist
{B) An irreversible antagonist
{C) A partial agonist
(D ) A physio logic antagonist
{E) A spare receptor agonist
18 PART I Basic Principles

5. Seve ral studies have indica ted that abo ut 90 o/o of 10. Which of the following provides information about the varia-
Padrenoceptors in the heart are spare receptors. Which of the tion in sensitivity to a drug within the population studied?
following statements about spare receptors is most correct? (A) Drug potency
(A) Spare receptors, in the absence of drug, are sequestered in (B) Graded dose-response curve
the cytoplasm (C) M aximal efficacy
(B) Spare receptors may be detected by finding that the (D) Quanta! dose-response curve
drug-receptor interactio n las ts longer than the intra- (E) T herapeutic index
cellular effect
(C) Spare receptors influence the maximal efficacy of the 11. Which of the following most accurately describes the trans-
drug-receptor system membrane signaling process involved in insulin hormone
(D) Spare receptors activate the effector machinery of the cell action?
without the need for a drug (A) Action on a membrane-spanning tyrosine kinase
(E) Spare receptors may be detected by the finding that the (B) Activation of a G protein, which activates or inhibits
EC 50 is smaller than the K.J for the ago nist adenylyl cyclase
(C) Diffusion across the membrane and binding to an intra-
6. Two cholesterol-lowering drugs, X andY, were studied in a large cellular receptor
group of patients, and the percentages of the group showing a (D) Diffusion of STAT molecules across the membrane
specific therapeutic effect (20o/o reduction in LDL cholesterol) (E) Opening of transmembrane ion channels
were determined. The results are shown in the following table.
12. Which of the following provides information about the
Drug Dose Percent Responding Percent Responding largest response a drug can produce, regardless of dose?
(mg) to Drug X to Drug Y (A) Drug potency
5 1 10 (B) Maximal efficacy
10 5 20 (C) Mechanism of receptor action
20 10 50 (D) T herapeutic index
50 50 70 (E) Therapeutic window
100 70 90
200 90 100 DIRECTIONS: 13-15. Each of the curves in the graph
below may be considered a concentration-effect curve or a
Which of the following statements about these results is correct? concentration-binding curve.
(A) D rug X is safer than drug Y
(B) Drug Y is more effective than drug X 13. Which of the curves in the graph describes the percentage of
(C) T he 2 drugs act on the same receptors binding of a large dose of full agonist to its receptors as the
(D) Drug X is less potent than drug Y concentration of a partial ago nist is increased from low to
(E) T he therapeutic index of drug Y is 10 very high levels?

7. Leukorrienes cause bronchoco nstriction (mediated at leuko-

triene recepto rs) in a patient with asthma. When albuterol
(acting at p adrenoceptors) is given to the patient during an Curve 1
as thma attack, bronchodilation usually results. Which of the 100
following expressions best describes the action of albuterol in
this situation?
E
(A) Chemical antagonist :::J
E
(B) No nco mpetitive antagonist ·x
(C) Partial agonist cc
E
(D) Pharmacologic antagonist 0 50
(E) Physiologic antagonist cQl
~
8. W hich of the following names best describes an antago nist Ql
c..
that interacts directly with the agonist and not at all, or only
incidentally, with the receptor?
(A) Chemical antagonist
(B) No nco mpetitive antago nist
Log dose
(C) Partial ago nist
(D) Pharmacologic antago nist
(E) Physiologic antagonist

9. Which of the followin g terms best describes a drug that (A) Curve 1
blocks the action of epinephri ne at its vascular a receptors (B) Curve 2
by occupying the epinephrine receptor-binding sites withou t (C) Curve 3
activating them ? (D) Curve 4
(A) Al losteric antagonist (E) Curve 5
(B) C hemical antagonist
(C) Inverse agonist
(D) Pharmacologic antagonist
(E) Physiologic antagonist

14. Which of the curves in the graph describes the percentage
effect observed when a large dose of full agonist is present
throughout the experiment and the concentration of a partial
agonist is increased from low to very high levels?
(A) Curve 1
(B) Curve 2
(C) Curve 3
(D) Curve 4
(E) Curve 5
15. Which of the curves in the graph describes the percentage of
binding of the partial agonist whose effect is shown by curve 4
if the system has many spare receptors?
(A) Curve 1
(B) Curve 2
(C) Curve 3
(D) Curve 4
(E) Curve 5
ANSWERS
1. No information IS given regarding the magnitude of the
maximum diuretic response to either drug. Similarly, no
information about toxicity is provided. The fact that a given
response is achieved with a smaller dose of drug X indicates
that X is more potent than Y in the ratio of 500:5. The
answer is B.
2. Graded (not quanta!) dose-response curves must be used to
determine maximum efficacy (maximum response). Quantal
dose-response curves show only the frequency of occurrence
of a specified response, which may be therapeutically effective
(ED) or roxie (TO). Dividing the TD 50 by the £0 50 (both
obtained from quantal dose-response curves) gives the thera-
peutic index. The answer is E.
3. Drug A produces 50% of its maximum effect at the lowest
dose and thus is the most potent; drug C is the least. Drug A
is less efficacious than drugs B and C. The answer is D.
4. Choices involving chemical or physiologic antagonism are
incorrect because pindolol is said to act at ~ receptors and to
block ~ stimulants. The drug effect is reversible, so choice B
is incorrect. "Spare receptor agonist" is a nonsense distracter.
The answer is C.
5. Altho ugh some types of receptors appear to be sequestered in
the cytoplasm under certain conditions, there is no difference
between "spare" and other receptors. Spare receptors may be
defined as those that are not needed for binding drug to
achieve the maximum effect. Spare receptors influence the
sensitivity of the system to an agonist because the statistical
probability of a drug-receptor interaction increases with the
total number of receptors. They do not alter the maximal effi-
cacy. If they do not bind an agon ist molecule, spare receptors
do not activate an effector molecule. EC 50 less than Kd is an
indication of the presence of spare receptors. The answer is E.
6. No information is presented regarding the safety of these
drugs. Similarly, no information on efficacy is presented; this
requires graded dose-response curves. Although both drugs
are said to be producing a therapeutic effect, no information
on their receptor mechanisms is given. Since no data on toxi-
city are available, the therapeutic index cannot be determined.
The answer is D because the £0 50 of drug Y (20 mg/d) is less
than that of drug X (50 mg/d).
CHAPTER 2 Pharmacodynamics 19
7. Because albuterol interacts with adrenoceptors and leukotriene
with leukotriene receptors, albuterol cannot be a pharmacologic
antagonist of leukotriene. Because the results of adrenoceptor
activation oppose the effects of leukotriene receptor activation,
albuterol must be a physiologic antagonist. The answer is E.
8. A chemical antagonist interacts directly (chemically) with the
agonist drug and not with a receptor. The answer is A.
9. A pharmacologic antagonist occupies the agonist receptor
sites without activating them. The answer is D.
10. Quantal dose-response curves provide information about the
statistical distribution of sensitivity to a drug. The answer is D.
11. Insulin and several other endogenous substances act at the
extracellular domain of a membrane-spanning tyrosine kinase
molecule whose catalytic site is on the cytoplasmic side. The
answer is A.
12. Maximal efficacy represents the largest response a drug can
produce. The answer is B.
13. The binding of a full agonist decreases as the concentration of
a partial agonist is increased to very high levels. As the partial
agonist displaces more and more of the fu ll agonist, the per-
centage of receptors that bind the full agonist drops to zero,
that is, curve 5. The answer is E.
14. Curve 1 describes the response of the system when a full
agonist is displaced by increasing concentrations of partial
agonist. This is because the increasing percentage of receptors
binding the partial agonist finally produce the maximum
effect typical of the partial agonist. The answer is A.
15. Partial agonists, like full agonists, bind 100% of their recep-
tors when present in a high-enough concentration. Therefore,
the binding curve (but not the effect curve) will go to 100% .
If the effect curve is curve 4 and many spare receptors are
present, the binding curve must be displaced to the right of
curve 4 (Kd > EC 50). Therefore, curve 3 fits the description
better than curve 2. The answer is C.
SKILL KEEPER ANSWER: ALLOSTERIC
ANTAGONISTS
Allosteric antagonists do not bind to the agonist receptor site,
they bind to some other region of the receptor molecule that
results in inhibition of the response to agonists (see Figure 1-7).
They do not prevent binding of the agonist. In contrast,
pharmacologic antagonists bind to the agonist site and prevent
access of the agonist. The difference can be detected experi-
mentally by evaluating competition between the binding of
radioisotopically labeled antagonist and the agonist. High
concentrations of agonist displace or prevent the binding of a
pharmacologic antagonist but not an allosteric antagonist.
26 PART I Basic Principles

rates are each 100 mg/d. Therefore, the corrected dosage in a 3. Despite your careful adherence to basic pharmacokinetic
patient with a creatinine clearance of 20 mL/min will be: principles, your patient on digoxin therapy has developed
mild digitalis toxicity. The plasma digoxin level is now
20 mUmin 4 ng/mL. Renal function is normal, and the plasma t 112 for
Dosage= 100 mg/d + 100 mg/d x mUm in digoxin in this patient is 1.5 days. How long should you
100 (7) withhold digoxin to reach a safer yet probably therapeutic
Dosage = 100 mg/d + 20 mg/d = 120 mg/d level of 1 ng/ mL?
(A) 1.5 days
(B) 2.5 days
Renal function is altered by age and many diseases. Because it
(C) 3 days
is important in the elimination of drugs, assessing renal function (D) 5 days
is important in estimating dosage in patients. The most important (E) 6 days
renal variable in drug elimination is glomerular filtration rate
(GFR) , and creatinine clearance (CLc,) is a conven ient approxi- 4. Verapamil and phenytoin are both eliminated from the
body by metabolism in the liver. Verapamil has a clearance of
mation of GFR. CLcr can be measured directly, but this requires
1.5 Llmin, approximately equal to liver blood flow, whereas
careful measurement of both serum creatinine concentration and phenytoin has a clearance of 0.1 L/min. When these com-
a timed total urine creatinine. A common shortcut that requires pounds are administered along with rifampin, a drug that
only the serum (or plasma) creatinine measurement (Sc,) is the use markedly increases hepatic drug-metabolizing enzymes, which
of an equation. One such equation in common use is the of the following is most likely?
Cockcroft-Gault equation: (A) The half-lives of both verapamil and phenytoin will be
markedly increased
CL ( L/ . ) = (140-Age) x body weight (kg) (B) (B) The clearance of both verapamil and phenytoin will be
cr m min 72xS markedly decreased
cr
(C) The clearance of verapamil will be unchanged, whereas
the clearance of phenytoin will be increased
The result is multiplied by 0.85 for females. A similar equation
(D) The half-life of phenytoin will be unchanged, whereas
for GFR is the MDRD equation: the half-life of verapamil will be increased
(E) The clearance of both drugs will be unchanged
GFR (ml/min/1.73 m 2 body surface area)
5. A 60-year-old man enters the hospital with a myocardial
= 175 x (0.742 iffemale) x( 1.212 if African American) (g) infarction and a severe ventricular arrhythmia. The anti-
s ~~ls4 x Ageo.2o3
arrhythmic drug chosen has a narrow therapeutic window:
The minimum toxic plasma concentration is 1. 5 rimes the
minimum therapeutic plasma concentration. The half-life is
6 h. It is essential to maintain the plasma concentration above
QUESTIONS the minimum therapeutic level to prevent a possibly lethal
arrhythmia. Which of the following would be the most
1-2. Mr Jones is admitted to the hospital with cough, shortness appropriate dosing regimen?
of breath, and fever. History, physical examination, and culture (A) Once a day
of the sputum lead to a diagnosis of pneumonia due to gram- (B) Twice a day
negative bacteria. The antib iotic tobramycin is ordered. T he (C) Three times a day
clearance and Vd of tobramycin in Mr Jones are 80 mL/min and (D) Four times a day
40 L, respectively. (E) Constant intravenous infusion
1. What maintenance dose should be administered intravenously
every 6 h to eventually obtain average steady-state plasma
concentrations of 4 mg/L?
(A) 0.32 mg
(B) 19.2 mg
(C)115mg
(D) 160 mg
(E) 230 mg

2. If you wish to give Mr Jones an intravenous loading dose to

achieve the therapeutic plasma concentration of 4 mg/L
rapidly, how much should be given?
(A) 0.1 mg
(B) 10 mg
(C) 115.2 mg
(D) 160 mg
(E) None of the above
 CHAPTER 3 Pharmacokinetics 27

6. A 50-year-old woman with metastatic breast cancer has
elected to participate in the trial of a new chemotherapeutic
agent. It is given by constant intravenous infusio n of 8 mg/h.
Plasma concentrations (Cp) are measured with the results
shown in the following table.
Time After Start of Plasma Concentration
Infusion (h) (mg/L)
0.8
2 1.3
4 2.0
9-10. A 74-year-old retired mechanic is admitted with a myocar-
dial infarction and a severe acute cardiac arrh ythmia. You decide
to give lidocaine to correct the arrhythmia.
9. A continuous intravenous infusion of lidocaine, 1.92 mg/min,
is started at 8 AM . The average pharmacokinetic parameters of
lidocaine are: Vd 77 L; clearance 640 mL!min; half- li fe
1.4 h. What is the expected steady-state plasma concentration?
(A) 40 mg/L
(B) 3.0 mg/L
(C) 0.025 mg/L
(D) 7.2 mg/L
(E) 3.46 mg/L

8 3.0
10. Your patient has been receiving lidocaine for 8 h, and the
arrhythmia is suppressed. H owever, there are som e signs
10 3.6 of toxicity. You decide to ob tain a plasma concentrati on
16 3.7 measurement. When the results come back, the plasm a
level is exactly twice what yo u expected. How should the
20 3.84 infusion rate be modified?
25 3.95 (A) C hanged to 0.48 mg/min
(B) C hanged to 0.96 mg/min
30 4.0 (C) H alted for 1.4 h and then restarted at 0.96 mg/min
40 4.0 (D ) Halted for 1.4 h and then restarted at 1.92 mg/min
(E) No change but the plas ma level should be measured again

11. A 63-year-old woman in the intensive care unit requires an

What conclusion can be drawn from these data? infusion of procainamide. Its half-life is 2 h. T he infusion is
(A) Volume of distribution is 30 L begun at 9 AM. At 1 PM on the same day, a blood sample is
(B) Clearance is 2 Llh taken; the drug concentration is found to be 3 mg/L. What
(C) Elimination follows zero-o rder kinetics is the probable steady-state drug concentration, for example,
(D ) H alf-life is 8 h after 12 or more hours of infusion?
(E) Doubling the rate of infusion wo uld result in a plasma (A) 3 mg/L
concentration of 16 mg/L at 40 h (B) 4 mg/L
(C) 6 mg/L
7. A city clinic is considerin g the substitution of generic drugs (D ) 9.9 mg/L
to save money. T he clinical pharmacologist is asked to advise (E) 15 mg/L
on the bioavailability of the generic products. Which of the
following statements is most correct? 12. A 30-year-old man is brought to the emergency department
(A) Bioavailabili ry is established by FDA regulatio n at 100% in a deep coma. Respiration is severely depressed and he has
for preparations for intramuscular injection pinpoint pupils. His friends state that he self-administered a
(B) Bioavailabili ry is 100% for oral preparations that are not large dose of morphine 6 h earlier. An immediate blood
metabolized in the liver anal ysis shows a morphine blood level of 0.25 mg/L. Assum-
(C) Bioavailabili ry is calculated fro m the peak concentration ing that the Vd of morphine in this patient is 200 L and the
of drug divided by the dose administered half-life is 3 h, how much morphine did the patient inj ect 6 h
(D) Bioavailabiliry is important because bioavailabiliry deter- earlier?
mines what percentage of the administered dose reaches (A) 25 mg
the systemic circulation (B) 50 mg
(E) Bioavailabili ry is equal to 1 (100%) only for drugs (C) 100 mg
administered by a parenteral route (D ) 200 mg
(E) Not enough data to predict
8. You are the only physician in a clinic that is cut off from the
outside world by violent storms and floodin g. A 19-year-old 13. A normal volunteer will receive a new drug in a phase 1 clinical
woman is brought to the clinic wi th severe asthmatic wheezing. trial. The clearance and Vd of the drug in this subject are
Because of the lack of other drugs, you decide to use intra- 1.386 Llh and 80 L, respectively. What is the predicted half-
venous theophylline for treatment. The pharmacokinetics of life of the drug in this subject?
theophylline include the following average parameters: Vd 35 L; (A) 83 h
CL 48 mL!min; half-life 8 h. If an intravenous infusion of theo- (B) 77 h
phylline is started at a rate of0.48 mg/min, how long would it (C) 58 h
take to reach 93.75% of the final steady-state concentration? (D ) 40 h
(A) Approximately 48 min (E) 0.02 h
(B) Approximately 7.4 h
(C) Approximately 8 h
(D ) Approximately 24 h
(E) Approximately 32 h
28 PART I Basic Principles

14. Gentamicin, an aminoglycoside antibiotic, is sometimes given ANSWERS

in intermittent intravenous bolus doses of 100 mg 3 times
a day to achieve target peak plasma concentrations of about 1. Maintenance dosage is a function of the target steady-state
5 mg/L. Gentamicin's clearance (normally 5.4 L/h/70 kg) is plasma level, bioavailabiliry, and clearance only:
almost entirely by glomerular filtration. Your patient, how- Rate in = Rate out at steady state
ever, is found to have a creatinine clearance one third of
normal. What should your modified dosage regimen for this Plasma level 55 x Clearance
patient be? Dosage = . . bT
8 1oava1 1a 11ty
(A) 20 mg 3 x/d
(B) 33 mg 3 x /d 4 mg/L x 0.08 U m in
(C) 72 mg 3 x/d
(D ) 100 mg 2 x/d 1.0
(E) 150 mg 2 x/d = 0.32 mg/ min
15-17. A new drug was studied in 20 healthy volunteers to deter- The arithmetic is correct to this point, so you might put down
mine basic pharmacokinetic parameters. A dose of 100 mg was "A" as the answer. Do not fall into this trap! Note that the
administered as an intravenous bolus to each volunteer, and blood drug is to be given at 6-h intervals:
samples were analyzed at intervals as shown in the graph below.
The average plasma concentrations at each time are shown by the = 0.32 mg/ min x 60 min/ h x 6 h
solid circles at 10 and 30 min and at 1, 2, 3, 4, 6, and 8 h after
administration. = 115 .2 mg/ dose every 6 h

20 The answer is C.
I I
15 --+
1
- ----·- ----r----
1
4--
I
---- 2. Loading dose is a function ofVd and target plasma concentration:
I I I
::I 10 --+------- ----+---
0, -~-~·----
Vd x Target concentration
.sc: 9 I Loading dose =--"----'--..,..---,-,-----
8 T Bioavailability
0 7 -t --- -+ ----
1
~ 6 T-- -
. d 40 L x 4 mg/ L
cQ) 5 - - l. _____ . J -
I
Load mg ose = = 160 mg
u
c: 4
_l. __ ~~J 1.0
0 I I
u I

"'E
(/)
3
The answer is D.
"'
0::: 2 T 3. Since the blood level for a drug with first-order kinetics drops
by 50% during each half- life, the level wi ll be 2 ng/mL after
1 1.5 days and 1 ng/mL after 3 days. After 3 days, you might
0 2 4 6 8 restart digoxin administration at a lower dosage. The answer
Time (h) is C.
4. Verapamil is metabolized so readily that only the rate of
15. The elimination half-life of the new drug is approximately delivery to the liver regulates its disappearance; that is, its
(A) 1.5 h elimination is blood flow- limited, not metabolism-limited.
(B) 2h Therefore, further increases in liver enzymes could not
(C) 4h increase its elimination. However, the rate of elimination of
(D ) 6h phenytoin is limited by its rate of metabolism since clearance
(E) 8h is much less than hepatic blood flow. Therefore, the clearance
of phenytoin can rise if some other agent causes an increase
16. The Vd of the new drug is approximately in liver enzymes. The answer is C.
(A) 0.05 L
(B) 0.1 L 5. From the description given, if the minimum therapeutic
plasma concentration of the hypothetical drug X is 100 units,
(C) 5 L
the minimum toxic concentration is 150 units. If a dose is
(D ) 10 L
(E) 20 L
given that brings the plasma concentration to 150 units, it will
fall to 75 units in 1 half-life (6 h). Because 75 units constitutes
17. The clearance of the new drug is approximately less than the minimum therapeutic concentration, a 6-h
(A) 0.43 L/h dosing interval (4 times/d) is too long. Thus, none of the
(B) 0.86 Llh intermittent dosing schedules listed would meet the require-
(C) 1.15 Llh ment of the question. However, a constant intravenous infusion
(D ) 2.3 L/h (which can be visualized as intermittent dosing at infinitely
(E) Too few data to answer short intervals) would be appropriate. The answer is E.

6. By inspection of the data in the table, it is clear that the
steady-state plasma concentration is approximately 4 mg/L.
According to the table, 50% of this concentration was reached
after 4 h of infusion. According to the constant infusion
principle (Figure 3-3), 1 half-life is required to reach one-half
of the final concentration; therefore, the half-life of the drug
is 4 h. Rearranging the equation for maintenance dosing
(dosing rate= CL X Cp), it can be determined that the clearance
(CL) =dosing rate/plasma concentration (Cp), or 2 L!h. The
volume of distribution (Vd) can be calculated from the half-
life equation (t 112 = 0.693 X Vd/CL) and is equal to 11.5 L.
This drug follows first-order kinetics, as indicated by the pro-
gressive approach to the steady-state plasma concentration.
The answer is B.
7. Oral bioavailability is calculated from the ratio of the area
under the curve after oral administration (AUC(Po)) to the
AUC after intravenous administration of the same dose
(AUC(lv); Figure 3-4), not from peak concentration measure-
ments. Many drugs given orally are incompletely absorbed or
metabolized in the gut; they will have a bioavailability of less
than 1.0 even if they are not metabolized in the liver. The
FDA cannot mandate a particular bioavailability by any
particular route, only that the bioavailability by that route
be reasonably constant among preparations. Some drugs have
a bioavailability ofless than 1.0 even when given transdermally
or intramuscularly. The answer is D.
8. The approach of the drug plasma concentration to steady-
state concentration during continuous infusion follows a
stereotypical curve (Figure 3-3) that rises rapidly at first and
gradually levels off. It reaches 50% of steady state at 1 half-life,
75% at 2 half-lives, 87.5% at 3, 93.75% at 4, and progres-
sively halves the difference between its current level and 100%
of steady state with each half-life. The answer is E, 32 h, or
4 half-lives.
9. The drug is being administered continuously and the steady-
state concentration (Cp, ) for a continuously administered
drug is given by the equation in question 1. Thus,
Dosage = Plasma level,, x Clearance
1.92 mg/min = Cp 55 x CL
Rearranging:
1.92 mg/min
Cp,, = CL
1.92 mg/min
Cp,, = 640 mllmin
Cp,, = 0.003 mg/ml or 3 mg/L
The answer is B.
10. If the half-life is 1.4 h, the plasma concentration should
approach steady state after 8 h (more than 4 half-lives). As
indicated in question 9, the steady-state concentration is a
function of dosage and clearance, not Vd. If the plasma level
is twice that predicted, the clearance in this patient must be
half the average value. To reduce the risk of toxicity, the
infusion should be halted until the concentration diminishes
(1 half-life) and then restarted at half of the previous rate.
The answer is C.
CHAPTER 3 Pharmacokinetics 29
11. According to the curve that relates plasma concentration to
infusion time (Figure 3-3), a drug reaches 50% of its final
steady-state concentration in 1 half-life, 75% in 2 half-lives,
etc. From 9 AM to 1 PM is 4 h, or 2 half-lives. Therefore, the
measured concentration at 1 PM is 75% of the steady-state
value (0.75 X Cp, ). The steady-state concentration is 3 mg/L
divided by 0.75, or 4 mg/L. T he answer is B.
12. According to the curve that relates the decline of plasma con-
centration to time as the drug is eliminated (Figure 3-3), the
plasma concentration of morphine was 4 times higher imme-
diately after administration than at the time of the measure-
ment, which occurred 6 h, or 2 half-lives, later. Therefore, the
initial plasma concentration was 1 mg/L. Since the amount in
the body at any time is equal to Vd X plasma concentration
(text Equation 1), the amount injected was 200 LX 1 mg/L,
or 200 mg. The answer is D.
13. Half-life can be estimated from
0.693 ( . )
t 112 = Vd--u:- text Equation 3
= 80 L X 0.693
1.386 L/h
1
= 80 L x L/h
2
= 40 h
The answer is D.
14. If the drug is cleared almost entirely by the kidney and
creatinine clearance is reduced to one third of normal, the
total daily dose should also be reduced to one third. The
answer is B.
15. We are asked to determine the elimination half-life of the
drug. The elimination phase of the graph of plasma concen-
tration follows a straight line on the semilogarithmic graph, so
we can conclude that the new drug follows first-order kinetics,
the first requirement for determining the half-life. The straight-
line portion of the graph shows a decline of 50% from the 2-h
point (4 mg/L) to the 8-h sample (2 mg/L). Therefore, the half-
life must be 8 minus 2 h, or 6 h. The answer is D, 6 h.
16. By definition, volume of distribution (Vd) is the amount of
drug in the body divided by the plasma concentration. To
determine the Vd, the drug must have reached equilibrium in
its diffusion into the Vd. Equilibrium is not reached until the
distribution phase is complete. Therefore, we cannot use any
of the data points precedibg the start of the elimination
phase. On the other hand, the only point at which we know
the amount of drug in the body with certainty is immediately
after administration, when the amount is equal to the dose
administered. This is the purpose of the extrapolated portion
of the straight line that extends to zero time. The dashed line
shows the plasma concentration curve that would have been
obtained if distribution were instantaneous. From the inter-
cept of the extrapolated line with the plasma concentration
axis, we see that the initial plasma concentration would have
been 5 mg/L. Therefore, Vd = 100 mg/5 mg/L, or 20 L. The
answer is E, 20 L.
30 PART I Basic Principles

17. By defi nition, clearance (CL) is equal to the rate of elimination

divided by the plasma concentration. However, we are not
given direct data for the rate of elimination. O n the other hand,
we have determined the half-life and the vdof the drug, so we
can calculate the clearance fro m the relationship t 112 = 0.693 X
vd -:- CL. Rearrangi ng this equation, CL =0.693 Xvd -:- t J/2 ·
Using the data from questions 16 and 17, we obtain 0.693 X
20 L -:- 6 h, or 2.3 Llh (approximately). T he answer is D.
SKILL KEEPER 1 ANSWER: ZERO-ORDER
ELIMINATION (SEE CHAPTER 1)
SKILL KEEPER 2 ANSWER: FIRST-PASS EFFECT
(SEE CHAPTER 1)
The oral route of administration entails passage of the drug
through the gastric and intestinal contents, the epithelium
and other tissues of the intestinal wall, the portal blood,
and the liver before it enters the systemic circulation for
distribution to the body. Metabolism by enzymes in any of
these tissues, expulsion by drug transporters, and excretion
into the bile all may contribute to the first-pass effect of
oral administration.

The 3 important drugs that follow zero-order rather than

first-order kinetics are ethanol, aspirin, and phenytoin.

CHECKLIST

When you complete this chapter, you should be able to:

0 Estimate the half-life of a drug based on its clearance and volume of distribution
or from a graph of its plasma concentration over time.
0 Calculate loading and maintenance dosage regimens for oral or intravenous
administration of a drug when given the following information: minimum therapeutic
concentration, oral bioavailability, clearance, and volume of distribution .
0 Calculate the dosage adjustment required for a patient with impaired renal function .

CHAPTER 3 Summary Table

Majo r Concept Description

Loading dose The dose required to achieve a specific plasma drug concentration level (Cp) with a single administration. Because
this requires filling the volume of distribution (Vd), the calculation uses the volume of distribution (Vd) equation as:
Loading dose= CP(target) x Vd and has units of mg

Maintenance dose The dose required for regular administration to maintain a target plasma level. Because this requires restoring the
amount of drug lost to elimination (clearance, CL). the calculation uses the clearance equation as:
Maintenance dose = CP(target) x CL and has units of mg per time

Half-life The half-life concept is useful not only in predicting the time course of falling drug levels after an administration, but
also in predicting the time course of increase in drug level when repeated administration is begun-see Figure 3-3.

Therapeutic window The therapeutic window is much more useful as a clinical measure of drug safety and as a guide to dosage than the
older therapeutic index.The classic therapeutic index, Tl, determined from animal measures of therapeutically effec-
tive dosage and lethal dosage is inapplicable to human therapeutics, whereas the minimum therapeutic dosage
and the minimum toxic dosage is readily determined in clinical trials
 CHAPTER 4 Drug Metabolism 35

QUESTIONS 8. Which of the fo llowing dru gs is hydrolyzed by a plas ma

esterase that is abnormally low in activity in about 1 of every
1-2. You are planning to treat asthma in a 19-year-old patient with 25 00 humans?
recurrent, episodic attacks of bronchospasm with wheezing. You (A) Ethanol
are concerned about drug interactions caused by changes in drug (B) Procainamide
metabolism in this patient. (C) Rifampin
1. Drug metabolism in humans usually results in a product that is (D) Succinylcholine
(A) Less lipid soluble than the original dru g (E) T heophylline
(B) More likely to distribute intracellularly 9. Which of the following drugs, if used ch ronically, is most likely
(C) More likely to be reabsorbed by kidney tubules to increase the toxicity of acetaminophen?
(D) More lipid soluble than the original dru g (A) Cimetidine
(E) Less water soluble than the original d rug (B) Ethanol
2. If therapy with multiple drugs causes induction of drug (C) Ketoconazole
metabolism in your asthma patient, it will (D) Procainamide
(A) Be associated with increased smooth endoplasmic reticulum (E) Quinidine
(B) Be associated with increased ro ugh endoplasmic reticulum (F) Ri to navir
(C) Be associa ted with decreased enzymes in the soluble (G) Succinylcholine
cytoplas mic fraction (H) Verapamil
(D) Requ ire 3-4 mo nths to reach completion 10. Which of the following drugs has higher firs t-pass metabo-
(E) Be irreversible lism in men than in women?
3. Which of the following facto rs is likely to increase the duration (A) C imetidine
of action of a drug that is metabolized by CYP3A4 in the liver? (B) Ethanol
(A) Ch ro nic administratio n of phenobarbital before and (C) Ketoco nazole
during therapy with the drug in question (D) Procainamide
(B) Chronic therapy with cimetidine (E) Quinidine
(C) Displacement from tissue-binding sites by another drug (F) Ri to navir
(D) Increased cardiac output (G) Succinylcholine
(E) C hronic ad ministration of rifa mpin (H) Verapamil

4. Which of the following is a phase II drug-metabolizing reaction? 11. Which of the following drugs is an established inhibi tor of
(A) Acetylation P-glycoprotein (P-gp) drug transporters?
(B) D eamination (A) Cimetidine
(C) H yd rolysis (B) Ethanol
(D) O xidation (C) Ketoconazole
(E) Reduction (D) Procainamide
(E) Quinidine
5. Reports of cardiac arrhythmias caused by unusually high (F) Ritonavir
blood levels of 2 antihistamines, rerfenadine and astemizole, (G) Succinylcholine
led to their removal from the market. Which of the following (H) Verapamil
best explains these effects?
(A) Concomitant treatment with phenobarbital 12. Which of the followin g agents, when used in combination with
(B) Use of these drugs by smokers other anti-HN drugs, permits dose reductions?
(C) A genetic predisposition to metabolize succinylcholine (A) Cimetidine
slowly (B) Efavirenz
(D) Treatment of these patients with ketoconazole, an azole (C) Ketoconazole
antifungal agent (D) Procainamide
(E) Quinidine
6. Which of the following drugs is associated with slower meta- (F) Ritonavir
bolism in European Americans and African Americans than in (G) Succinylcholine
most Asians? (H) Verapamil
(A) Cimetidine
(B) Procainamide
(C) Propranolol ANSWERS
(D) Rifampin
(E) Succinylcholine 1. Biotransformation usually results in a product that is less lipid-
soluble. T his is needed to eliminate drugs that would otherwise
7. Which of the fo llowing drugs may inhibit the hepatic micro- be reabsorbed from the renal tubule. T he answer is A.
somal P450 respo nsible for warfarin metabolism ?
(A) Amiodaro ne 2. The smooth endoplasmic reticulum, which contains the mixed-
(B) Ethanol fun ction oxidase drug-metabolizing enzymes, is selectively
(C) Phenobarbital increased by inducers. T he answer is A.
(D) Procainamide 3. Phenobarbital and rifampin can induce drug-metabolizing
(E) Rifampin enzymes and thereby may reduce the duration of drug action.
36 PART I Basic Principles

Displacement of drug from tissue may transiently increase the
intensity of the effect but decreases the volume of distribution.
Cimetidine is recognized as an inhibitor ofP450 and may also
decrease hepatic blood flow under some circumstances. T he
answer is B.
4. Acetylation is a phase II conjugation reaction. The answer is A.
5. Treatment with phenobarbital and smoking are associated with
increased drug metabolism and lower, not higher, blood levels.
Ketoconazole, itraco nazole, erythromycin, and some substances
in grapefruit juice slow the metabolism of certain older non-
sedati ng antihistamines (Chapter 16). The answer is D.
6. Procainamide, like hydralazi ne and isoniazid, is metabolized
by N-acetylation, an enzymatic process that is slow in about
20% of Asians and in about 50% of European Americans and
African Americans. T he answer is B.
7 . Am iodarone is an important antiarrhythmic drug and has a
well-documented ability to inhibit the hepatic metabolism of
many drugs. T he answer is A.
8. Succinylcholine is normally hyd rolyzed quite rapidly by
plas ma cholinesterase (butyrylcholinesterase). T his enzyme is
abnormal in about 1 in 2500 of the human populatio n,
resulting in an unusually long duration of action of succinyl-
choline in these patients. T he answer is D.
9. Acetaminophen is normally eliminated by phase II conjugation
reactions. T he drug's toxicity is dependent on an oxidized reac-
tive metabolite produced by phase I oxidizing P450 enzymes.
Ethanol (and certain other drugs) induces P450 enzymes and
thus reduces the hepatotoxic dose. Alcoholic cirrhosis reduces
the hepatotoxic dose even more. T he answer is B.
10. Ethanol is subject to metabolism in the stomach as well as in
the liver. Independent of body weight and other factors, men
have greater gastric ethanol metabolism and thus a lower
ethanol bioavailability than wo men. T he answer is B.
11. Verapamil is an inhibitor of P-glycoprotein drug transporters
and has been used to enhance the cytotoxic actions of
methotrexate in cancer chemotherapy. The answer is H.
12. Ritonavir inhibits hepatic drug metabolism, and its use at
low doses in combination regimens has permitted dose
reductions of other HIV pro tease inhibito rs (eg, indinavir).
T he answer is F.

CHECKLIST

When you complete this chapter, you should be able to:

0 List the major phase I and phase II metabolic reactions.
0 Describe the mechanism of hepatic enzyme induction and list 3 drugs that are
known to cause it.
0 List 3 drugs that inhibit the metabolism of other drugs.
0 List 3 drugs for which there are well-defined, genetically determined differences
in metabolism.
0 Describe some of the effects of smoking, liver disease, and kidney disease on drug
elimination .
0 Describe the pathways by which acetaminophen is metabolized (1) to harmless products
if normal doses are taken and (2) to hepatotoxic products if an overdose is taken.

CHAPTER 4 Summary Table

Major Concept Description

Drug metabolism vs drug elimination
Termination of drug action requires either removal of the drug from the body (excretion)
or modification of the drug molecule (metabolism) so that it no longer has an effect. Both
methods constitute drug elimination, and both are very important in the clinical use of
drugs. Almost all drugs (or their metabolites) are eventually excreted, but for many,
excretion occurs only some time after they have been metabolized to inactive products

Induction and inhibition of drug metabolism A large number of drugs alter their own metabolism and the metabolism of other drugs
either by inducing the synthesis of larger amounts of the metabolizing enzymes (usually
P450 enzymes in the liver) or by inhibiting those enzymes. Some drugs both inhibit (acutely)
and induce (with chronic administration) drug metabolism

Toxic metabolism Some substances are metabolized to toxic molecules by drug-metabolizing enzymes.
Important examples include methyl alcohol, ethylene glycol, and, at high doses or in the
presence of liver disease, acetaminophen. See Figure 4-1 and Chapter 23
40 PART I Basic Principles

TABLE 5-2 Selected legislation pertaining to drugs in the United States.

Law Purpose and Effect

Pure Food and Drug Act of 1906 Prohibited mislabeling and adulteration of foods and drugs (but no requirement for
efficacy or safety)

Harrison Narcotics Act of 1914 Established regulations for the use of opium, opioids, and cocaine (marijuana added in 1937)

Food, Drug, and Cosmetics Act of 1938 Required that new drugs be tested for safety as well as purity

Kefauver-Harris Amendment (1962) Required proof of efficacy as well as safety for new drugs

Dietary Supplement and Health Amended the Food, Drug, and Cosmetics act of 1938 to establish standards for dietary
Education Act (1994) supplements but prohibited the FDA from applying drug efficacy and safety standards
to supplements

C. Phase 3 SKILL KEEPER: GRADED AND QUANTAL

A phase 3 trial usually consists of a large design involving many
patients (eg, 1000-5 000 or more, in many centers) and many
clinicians who are using the drug in the manner proposed for irs
ultimate general use (eg, in outpatients). Such studies usually
include placebo and positive controls in a double-blind crossover
design. T he goals are to explore further, under the conditions of
the proposed clinical use, the spectrum of beneficial actions of
DOSE-RESPONSE CURVES (SEE CHAPTER 2)
What type of dose-response curve is appropriate for the
determination of the therapeutic index of a new drug in mice?
What type of dose-response determination is needed for the
determination of the minimum effective dose and the maximal
efficacy of the drug in humans?

the new drug, to compare it with older therapies, and to discover

toxicities, if any, that occur so infrequently as to be undetectable
in phase 2 studies. Very large amo unts of data are collected and
these studies are usually very expensive.
If the drug successfully completes phase 3, an NDA is submit-
red to the FDA. If the NDA is approved, the drug can be mar-
keted and phase 4 begins.
D. Phase 4
Phase 4 represents the postmarkering surveillance phase of evalua-
tion, in which iris hoped that toxicities that occur very infrequently
will be detected and repo rted early enough to prevent major ther-
apeutic disasters. Manufacturers are required to infor~ the FDA
at regular intervals of all reported untoward drug reactions. Unlike
the first 3 phases, phase 4 has nor been rigidly regulated by the
FDA in the past. Because so many drugs have been found to be
unacceptably roxie on ly after they have been marketed, there is
considerable current interest in making phase 4 surveillance more
consistent, effective, and informative.
DRUG LEGISLATION
In the United Stares, many laws regulating drugs were passed dur-
ing the 20th century. Refer to Table 5-2 for a partial list of this
legislation.
ORPHAN DRUGS
An orphan drug is a drug for a rare disease (one affecting fewer
than 200,000 people in the United States). T he study of such
agents has often been neglected because the sales of an effective
agent for an uncommon ailment might nor pay the costs of devel-
opment. In the United Stares, current legislation provides for tax
relief and other incentives designed to encourage the development
of orphan drugs.

QUESTIONS
DRUG PATENTS & GENERIC DRUGS
1. Which of the following statements is most correct regarding
A patent application is usually submitted around the rime that a clinical trials of new drugs?
new drug enters animal resting. In the United Stares, approval of (A) Phase 1 involves the study of a small number of normal
the parent and completion of the NDA ap proval process give the volunteers by highly trained clinical pharmacologists
originator rhe right ro marker rhe drug without competition from (B) Phase 2 involves the use of the new drug in a large number
other firms for a period of 20 years from the parent approval dare. of patients (1000-5000) who have the disease to be treated
(C) Phase 3 involves the determination of the drug's therapeutic
After expiration of the parent, any company may apply to the
index by the cautious induction of toxicity
FDA for permission to marker a generic version of the same drug (D ) Phase 4 involves the derailed study of roxie effects that
if they demonstrate that their generic drug molecule is have been discovered in phase 3
bioequivalent (ie, meers certain requirements for content, purity, (E) Phase 2 requires the use of a positive control (a known
and bioavailability) to rhe original product. effective drug) and a placebo

2. Which of the following statements about animal resting of
potential new therapeutic agents is most correct?
(A) Extends at least 3 years to discover late toxicities
(B) Requires at least 1 primate species (eg, rhesus monkey)
(C) Requires the submission of histopathologic slides and
specimens to the FDA for evaluation by government
scientists
(D ) Has good predictability for drug allergy-type reactions
(E) May be abbreviated in the case of some very roxie agents
used in cancer
3. The "dominant lethal" rest involves the treatment of a male adult
animal with a chemical before mating; the pregnant female is
later examined for feral death and abnormalities. The dominant
lethal rest therefore is a rest of
(A) Teratogenicity
(B) Mutagenicity
(C) Carcinogenicity
(D ) Sperm viability
4. Which of the following would probably not be included in an
optimal phase 3 clinical trial of a new analgesic drug for mild
pain?
(A) A negative control (placebo)
(B) A positive control (current standard therapy)
(C) Double-blind protocol (in which neither the patient nor
immediate observers of the patient know which agent is
active)
(D ) A group of 1000-5000 subjects with a clinical condition
requiring analgesia
(E) Prior submission of an NDA (new drug application) to the
FDA
5. Which of the following statements about the resting of new
compounds for potential therapeutic use in the treatment of
hypertension is most correct?
(A) Animal tests cannot be used to predict the types of clinical
toxicities that may occur because there is no correlation
with human toxicity
(B) Human studies in normal individuals will be done before
the drug is used in individuals with hypertension
(C) The degree of risk must be assessed in at least 3 species of
animals, including 1 primate species
(D ) The animal therapeutic index must be known before trial
of the agents in humans
6. The Ames rest is a method for detecting
(A) Carcinogenesis in primates
(B) Carcinogenesis in rodents
(C) Mutagenesis in bacteria
(D ) Teratogenesis in any mammalian species
(E) Teratogenesis in primates
7. Which of the following statements about new drug development
is most correct?
(A) The original manufacturer is protected from generic com-
petition for 20 years after patent approval
(B) Food supplements and herbal (botanical) remedies are
subject to the same FDA regulation as ordinary drugs
(C) All new drugs must be studied in at least 1 primate species
before N DA submission
(D ) Orphan drugs are drugs that are no longer produced by
the original manufacturer
(E) Phase 4 (surveillance) is the most rigidly regulated phase of
clinical drug trials
CHAPTER 5 Drug Evaluation & Regulation 41
ANSWERS
1. Except for known roxie drugs (eg, cancer chemotherapy drugs),
phase 1 is carried our in 25-50 normal volunteers. Phase 2 is
carried our in several hundred patients with the disease. The
therapeutic index is rarely determined in any clinical trial.
Phase 4 is the general surveillance phase that follows general
marketing of the new drug. It is nor targeted at specific effects.
Positive controls and placebos are nor a rigid requirement of
any phase of clinical trials, although they are often used in
phase 2 and phase 3 studies. The answer is A.
2. Drugs proposed for short-term use may nor require long-term
chronic resting. For some drugs, no primates are used; for
other agents, only 1 species is used. The data from the rests,
nor the evidence itself, must be submitted to the FDA.
Prediction of human drug allergy from animal resting is nor
very reliable. The answer is E.
3. The description of the rest indicates that a chromosomal
change (passed from father to fetus) is the toxicity detected.
This is a mutation. The answer is B.
4. The first 4 items (A-D) are correct. An NDA cannot be
acted upon until the first 3 phases of clinical trials have been
completed. (The IND must be approved before clinical tri-
als can be conducted.) The answer is E.
5. Animal rests in a single species do nor always predict human
toxicities. However, when these rests are carried our in several
species, most acute toxicities that occur in humans also appear
in at least 1 animal species. According to current FDA rules,
the "degree of risk" must be determined in at least 2 species.
Use of primates is not always required. The therapeutic index
is nor required. Except for cancer chemotherapeutic agents and
antivirals used in AIDS, phase 1 clinical trials are always carried
our in normal subjects. The answer is B.
6. The Ames rest is carried our in Salmonella and detects mutations
in the bacterial DNA. Because mutagenic potential is associated
with carcinogenic risk for many chemicals, the Ames rest is often
used to claim that a particular agent may be a carcinogen.
However, the rest itself only detects mutations. The answer is C.
7. Food supplements and botanicals are much more loosely
regulated than conventional drugs. Primates are nor required
in any phase of new drug testing, although they are sometimes
used. Orphan drugs are those for which the anticipated patient
population is smaller than 200,000 patients in the United
Stares. Phase 4 surveillance is the most loosely regulated phase
of clinical trials. The answer is A.
SKILL KEEPER ANSWER: GRADED AND
QUANTAL DOSE-RESPONSE CURVES
(CHAPTER 2)
The therapeutic index is the ratio of the median toxic dose,
T050 or median lethal dose, LD50 to the effective dose in
half the population (ED5c), determined in a population of
subjects. Thus, quanta/ dose-response experiments are needed to
ascertain the therapeutic index. The minimum effective dose and
the maximal efficacy of a drug are determined by gradually
increasing the dose and noting the responses produced. Graded
dose-response experiments are needed for these measurements.
52 PART II Autonomic Drugs

Canal of Schlemm

Ciliary epithelium (~)

Ciliary muscle (M)

FIGURE 6-5 Some pharmacologic targets in the eye. The diagram illustrates clinically important structures and their receptors. The heavy
arrow (blue) illustrates the flow of aqueous humor from its secretion by the ciliary epithelium to its drainage through the canal of
Schlemm. M, muscarinic receptor; a, alpha receptor; ~. beta receptor. (Modified and reproduced, with permission, from Katzung BG, editor:
Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 6-9.)

C. Complex Organ Control: The Eye QUESTIONS

T he eye contains multiple tissues with various functions, several of
1. T he victim of a severe accident is brought to the emergency
them under autonomic control (Figure 6- 5). The pupil, discussed
previously, is under reciprocal control by the SANS (via a receptors
on the pupillary dilator muscle) and the PANS (via muscarinic
receptors on the pupillary constrictor). T he ciliary muscle, which
controls accommodation, is under primary control of muscarinic
receptors innervated by the PANS, with insignificant contribu-
tions fro m the SANS. T he ciliary epithelium, on the other hand,
has important ~ receptors that have a permissive effect on aqueous
humor secretion. Each of these recepto rs is an important target of
drugs that are discussed in the following chapters.
department with marked hemodynamic instability. Which of
the following statements is most correct regarding the auto-
nomic regulation of blood pressure?
(A) Cardiac output is maintained constant at the expense of
other hemodynamic variables
(B) Reduction of blood press ure will result in reduced
aldosterone secretion
(C) Baroreceptor sensory nerve fi bers travel in the sympathetic
nerves
(D ) Stroke volume and mean arterial blood pressure are the
primary direct determinants of cardiac output
(E) Reduction in sensitivity of the sensory baro recepto r nerve
endings will cause an increase in sympathetic discharge

2. A 3-year-old child has swallowed the contents of 2 bottles of

a nasal decongestant whose primary ingredient is a potent,
selective a -adrenocepto r ago nist drug. Which of the follow-
ing is a sign of a-receptor activation that may occur in this
patient?
(A) Bronchodilation
(B) Cardioacceleration (tachycardia)
(C) Pupillary dilation (mydriasis)
(D ) Renin release
(E) Vasodilation
 CHAPTER 6 Introduction to Autonomic Pharmacology 53

3. Ms Green is a 60-year-old woman with poorly controlled 9. Nicotinic receptor sites do not include which one of the
hypertension of 170/110 mm Hg. She is to receive minoxidil. following sites?
Minoxidil is a powerful arteriolar vasodilator that does not (A) Bronchial smooth muscle
act on autonomic receptors. Which of the following effects (B) Adrenal medullary cells
will be observed if no other drugs are used? (C) Parasympathetic ganglia
(A) Tachycardia and increased cardiac contractility (D ) Skeletal muscle end plates
(B) Tachycardia and decreased cardiac output (E) Sympathetic ganglia
(C) Decreased mean arterial pressure and decreased cardiac
contractility 10. Several children at a summer camp were hospitalized with
(D ) Decreased mean arterial pressure and increased salt and symptoms thought to be due to ingestion of food containing
water excretion by the kidney botulinum toxin. Which one of the following signs or symp-
(E) No change in mean arterial pressure and decreased cardiac toms is consistent with the diagnosis of botulinum poisoning?
contractility (A) Bronchospasm
(B) Cycloplegia
4. Full activation of the sympathetic nervous system, as in the (C) Diarrhea
fight-or-flight reaction, may occur during maximal exercise. (D ) Skeletal muscle spasms
Which of the following effects is likely to occur? (E) Hyperventilation
(A) Bronchoconstriction
(B) Increased intestinal motility 11. Which one of the following is the neurotransmitter agent
(C) Decreased renal blood flow normally released in the sinoatrial node of the heart in response
(D ) Miosis to a blood pressure increase?
(E) Decreased heart rate (bradycardia) (A) Acetylcholine
(B) Dopamine
Questions 5-8. For these questions, use the accompanying (C) Epinephrine
diagram. Assume that the diagram can represent either the (D ) Glutamate
sympathetic or the parasympathetic system. (E) Norepinephrine

12-14. Assume that the diagram below represents a sympathetic

b
postganglionic nerve ending.

®
@
(£, Terminal

Spinal
cord

5. Which of the following drugs acts at site 3?

(A) Botulinum toxin
(B) Cocaine
(C) Reserpine
(D ) Tyramine
12. Which of the following blocks the carrier represented by "y"
6. Norepinephrine acts at which of the following sites in the
in the diagram?
diagram?
(A) Botulinum toxin
(A) Sites 1 and 2
(B) Cocaine
(B) Sites 3 and 4
(C) Guanethidine
(C) Sites 5 and 6
(D ) Hemicholinium
7. Atropine, a muscarinic receptor-blocking drug, is useful for (E) Reserpine
dilating the pupil and paralyzing accommodation. T hese
13. Which of the following blocks conversion of the intermediate
effects of atropine occur at which one of the following sites
"1" to "2" in the diagram?
on the diagram?
(A) Botulinum toxin
(A) Site 3
(B) Cocaine
(B) Site 4
(C) Metyrosine
(C) Site 5
(D ) Reserpine
(D ) Site 6
(E) Vesamicol
(E) Site 7
14. Which of the following inhibits the carrier denoted "z" in the
8. If the effector cell in the diagram is a thermoregulatory sweat
diagram?
gland, which of the following compounds is released from
(A) Cocaine
structure 5?
(B) Dopamine
(A) Acetylcholine
(C) Hemicholinium
(B) Dopamine
(D ) Reserpine
(C) Epinephrine
(E) Vesamicol
(D ) Norepinephrine
54 PART II Autonomic Drugs
IS. Which of the following drugs fac ilitates catecholamine trans-
mitter discharge fro m adrenergic nerve endin gs?
(A) Acetylcholine
(B) Amphetamine
(C) Botulinum toxin
(D ) Dopami ne
(E) Epineph rine
(F) Metyrosine
(G) No repinephrine
(H ) Reserpine
(I) Tetrodotoxin
(J) Vesamicol
ANSWERS
1. A decrease in barorecep to r sensitivity would decrease input to
the vaso moto r center, wh ich wo uld be interpreted by the
vasom otor center as a decrease in blood press ure. This would
lead to an increase in sympatheti c outflow. T he answer is E.
2. Mydriasis can be caused by contraction of the radial fib ers of
the iris; th ese smooth muscle cells have a recepto rs. All the
other respo nses are mediated by ~ adrenoceptors (Table 6-4).
T he answer is C.
3. Because of the compensatory responses, a dru g that di rectl y
decreases peri pheral vascular resistance will cause a reflex
increase in sym pathetic outflow, an increase in renin release,
and a decrease in parasympathetic outflow. As a result, heart
rate and cardi ac fo rce will increase. In addi t io n, salt and water
retention will occur. The answer is A.
4. Sympath etic discharge causes constriction of the renal resist-
ance vessels and a fall in renal blood flow. T his is the typ ical
response in severe exercise or hypotension. T he other effects
are parasympathomimetic actions. The answer is C.
S. Each of these agents has a diffe rent mechanism of action, yet
all but botulinum act on the sympathetic postganglio nic
nerve terminal (site 5). Site 3 is a cholinergic nerve ending.
T he answer is A.
6. Norepinephrine acts at postsynaptic a 1 adrenoceptors and at
presynaptic a 2 regulatory rece pto rs. It m ay be metabolized by
enzym es outs ide the synapse or transported back into the
nerve terminal . T he answer is C.
7. In the simplified diagram , the muscarinic receptors blocked by
atropine are located only at the smooth muscle effector cells and
postganglionic nerve terminals. T his type of receptor is also
fo und in ganglia, but higher concentrations of atropine are
required to block it. Blocki ng presynaptic muscarinic recepto rs
would not produce mydriasis and cycloplegia. T he answer is D.
8. The nerves innervating the thermoregulatory (eccrine) sweat
glands are sympathetic cholinergic nerves . T he answer is A.
9. Both types of ganglia and the skeletal muscle neuromuscular
junction have nicotinic cholinocepto rs, as does the adrenal
medulla (a modified form of sympathetic postganglionic neu-
ron tissue) . Bronchial smooth muscle contains muscarini c
cholinoceptors. T he answer is A.
IO. Botulinum toxi n impairs al l types of cholinergic transmission,
including transmission at ganglionic synapses and somati c
motor nerve endings. Botulinum toxin prevents discharge of
vesicular transmitter content from cholinergic nerve endin gs.
All of the signs listed except cycloplegia indicate increased
muscle co ntraction ; cycloplegia (paralys is of acco mmodati on)
res ults in blurred near vision. The answer is B.
II. Acetylcholine is the transmitter at parasympathetic nerve end-
ings innervating th e sinus node (nerve endings of the vagus
nerve). When blood press ure increases, the parasympath eti c
system is activated and h eart rate slows. T he answer is A.
I2. The vesicular carrier in th e di agram transpo rts dopamine and
norepinephrine into the vesicles for sto rage. It can be blocked
by reserpine. The answer is E.
I3. The intermediate " 1" in the diagram is tyrosine. It is con-
verted to DOPA ("2"). T his rate-l imiting step in cate-
cholamine synthesis can be inhibited by th e tyrosine analog
m etyrosine (see Figure 6-2). T he answer is C.
I4. T he reuptake carrier in sympathetic postganglionic nerve
endings can be blocked by cocaine or tricyclic antidepressants.
H em icholiniums and vesamicol block transporters in cholin-
ergic n erves. T he answer is A.
IS. Amphetam ine facilitates the discharge of catecholamine trans-
mi tters fro m sympathetic nerve end ings (Table 6-4). T he
answer is B.
SKILL KEEPER ANSWER: DRUG PERMEATION
(SEE CHAPTER 1)
Botulinum toxin is too large to cross membranes by means of
lipid or aqueous diffusion. It must bind to membrane receptors
and enter by endocytosis. Botulinum-binding receptors for
endocytosis are present on cholinergic neurons but not
adrenergic neurons.
 CHAPTER 7 Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs
enzyme. After initial hydrolysis, the phosphoric acid residue is
released over periods of days to weeks. Recovery is due in part to syn-
thesis of new enzyme.
C. Effects
By inhibiting cholinesterase, these agents cause an increase in the
concentration, half-life, and actions of acetylcholine in synapses
where acetylcholine is released physiologically. Therefore, the indirect
agents have muscarinic or nicotinic effects depending on which
organ system is under consideration. Cholinesterase inhibitors do
not have significant actions at uninnervated sites where acetylcholine
is not normally released {eg, vascular endothelial cells).
D. Clinical Use
The clinical applications of the indirect-acting cholinomimetics
are predictable from a consideration of the organs and the diseases
that benefit from an amplification of cholinergic activity. The
effects are summarized in the Drug Summary Table. Carbamates,
which include neostigmine, physostigmine, pyridostigmine,
and ambenonium, are used far more commonly in therapeutics
than are organophosphates. The treatment of myasthenia is espe-
cially important. {Because myasthenia has important autoimmune
aspects, treatment may also include thymectomy and immuno-
suppressant drugs.) Rivastigmine, a carbamate, and several
other cholinesterase inhibitors are used exclusively in Alzheimer's
disease. A portion of their action may be due to other, unknown
mechanisms. Their effects are significant but modest and tempo-
rary. However, lacking any better therapy, these drugs are frequently
used in this devastating condition. Some carbamates {eg, carbaryl)
are used in agriculture as insecticides. Two organophosphates used
in medicine are malathion {a scabicide), and metrifonate {an anti-
helminthic agent).
Edrophonium is used for the rapid reversal of nondepolarizing
neuromuscular blockade {Chapter 27), in the diagnosis of myas-
thenia, and in differentiating myasthenic crisis from cholinergic
crisis in patients with this disease. Because cholinergic crisis can
result in muscle weakness like that of myasthenic crisis, distin-
guishing the 2 conditions may be difficult. Administration of a
short-acting cholinomimetic, such as edrophonium, will improve
muscle strength in myasthenic crisis but weaken it in cholinergic
CflSIS.
E. Toxicity
In addition to their therapeutic uses, some indirect-acting agents
{especially organophosphates) have clinical importance because of
accidental exposures to toxic amounts of pesticides. The most
toxic of these drugs {eg, parathion) can be rapidly fatal if exposure
is not immediately recognized and treated. After standard protec-
tion of vital signs {see Chapter 58), the antidote of first choice is
the antimuscarinic agent atropine, but this drug has no effect on
the nicotinic signs of toxicity. Nicotinic toxicity is treated by
regenerating active cholinesterase. Immediately after binding to
cholinesterase, most organophosphate inhibitors can be removed
from the enzyme by the use of regenerator compounds such as
pralidoxime {see Chapter 8), and this may reverse both nicotinic
61
and muscarinic signs. If the enzyme-phosphate binding is allowed
to persist, however, aging {a further chemical change) occurs and
regenerator drugs can no longer remove the inhibitor. Treatment
is described in more detail in Chapter 8.
Because of their toxicity and short persistence in the environ-
ment, organophosphates are used extensively in agriculture as
insecticides and antihelminthic agents; examples are malathion
and parathion. Some of these agents {eg, malathion, dichlorvos)
are relatively safe in humans because they are metabolized rapidly
to inactive products in mammals {and birds) but not in insects.
Some are prodrugs {eg, malathion, parathion) and must be metab-
olized to the active product {malaoxon from malathion, paraoxon
from parathion) . The signs and symptoms of poisoning are the
same as those described for the direct-acting agents, with the fol-
lowing exceptions: vasodilation is a late and uncommon effect;
bradycardia is more common than tachycardia; CNS stimulation
is common with organophosphate and physostigmine overdosage
and includes convulsions, followed by respiratory and cardiovas-
cular depression. The spectrum of toxicity can be remembered
with the aid of the mnemonic DUMBBELSS {diarrhea, urination,
miosis, bronchoconstriction, bradycardia, excitation [of skeletal
muscle and CNS], lacrimation, and salivation and sweating).
QUESTIONS
1. A 30-year-old woman undergoes abdominal surgery. In spite
of minimal tissue damage, complete ileus {absence of bowel
motility) follows, and she complains of severe bloating. She
also finds it difficult to urinate. Mild cholinomimetic stimu-
lation with bethanechol or neostigmine is often effective in
relieving these complications of surgery. Neostigmine and
bethanechol in moderate doses have significantly different
effects on which one of the following?
{A) Gastric secretion
(B) Neuromuscular end plate
{C) Salivary glands
(D) Sweat glands
(E) Ureteral tone
2. Parathion has which one of the following characteristics?
{A) It is inactivated by conversion to paraoxon
{B) It is less toxic to humans than malathion
(C) It is more persistent in the environment than DDT
(D) It is poorly absorbed through skin and lungs
(E) If treated early, its toxicity may be partly reversed by
pralidoxime
3. Ms Brown has had myasthenia gravis for several years. She
reports to the emergency department complaining of rapid
onset of weakness of her hands, diplopia, and difficulty swal-
lowing. She may be suffering from a change in response to
her myasthenia therapy, that is, a cholinergic or a myasthenic
crisis. Which of the following is the best drug for distinguish-
ing between myasthenic crisis {insufficient therapy) and cholin-
ergic crisis {excessive therapy)?
{A) Atropine
{B) Edrophonium
(C) Physostigmine
{D) Pralidoxime
(E) Pyridostigmine
62 PART II Autonomic Drugs

4. A crop duster pilot has been accidentally exposed to a high 11. A 3-year-old child is admitted after taking a drug from her
concentration of a highly toxic agricultural organophosphate parents' medicine cabinet. The signs suggest that the drug is
insecticide. If untreated, the cause of death from such a an indirect-acting cholinomimetic with little or no CNS effect
poisoning wo uld probably be and a duration of action of about 2-4 h. Which of the following
(A) Cardiac arrhythmia is the most likely cause of these effects?
(B) Gastrointestinal bleeding (A) Acetylcholine
(C) Heart failure (B) Bethanechol
(D) Hypertension (C) Neostigmine
(E) Respiratory fai lure (D) Physostigmine
(E) Pilocarpine
S. Mr Green has just been diagnosed with myasthenia gravis. You
are considering different therapies for his disease. Pyridostigmine 12. Which one of the following agents is a prodrug that is much
and neostigmine may cause which one of the following? less toxic in mammals than in insects?
(A) Bronchodilation (A) Malathion
(B) Cycloplegia (B) Nicotine
(C) Diarrhea (C) Parathion
(D) Irreversible inhibition of acetylcholinesterase (D) Physostigmine
(E) Reduced gastric acid secretion (E) Varenicline

6. Parasympathetic nerve stimulatio n and a slow infusion of 13. Which one of the following is a direct-acting cholinomimetic
bethanechol will each: used for its mood-elevating action and as an insecticide?
(A) Cause ganglion cell depolarization (A) Bethanechol
(B) Cause skeletal muscle end plate depolarization (B) Neostigmine
(C) Cause vasodilation (C) Nicotine
(D) Increase bladder tone (D) Physostigmine
(E) Increase heart rate (E) Pilocarpine

7. Which one of the following receptors mediates the main effect
of pilocarpine in the smooth muscle of the bronchi?
(A) M 1
(B) M 2
(C) M3
(D) M 4
(E) M 5
8. In the comparison of bethanechol and pilocarpine, which one
of the following statements is correct?
(A) Both are hydrolyzed by acetylcholinesterase
(B) Both inhibit nicotinic receptors
(C) Both may decrease sweating
(D) Both may increase gastrointestinal motility
(E) Neither causes tachycardia
9. Actions and clinical uses of muscarinic cholinoceptor agonises
include which one of the following?
(A) Bronchodilation (asthma)
(B) Improved aqueous humor drainage (glaucoma)
(C) Decreased gastrointestinal motility (diarrhea)
(D) Decreased neuromuscular transmission and relaxation of
skeletal muscle (during surgical anesthesia)
(E) Increased sweating (fever)
10. Which of the following is a direct-acting cholinomimetic that
is lipid-soluble and is used to facilitate smoking cessation?
(A) Acetylcholine
(B) Berhanechol
(C) Neostigmine
(D) Physostigmine
(E) Varenicline
14. The Calabar plant is a native of Africa, and when its seed
(a bean) is ingested, it produces signs of an indirect-acting
cholinomimetic that readily enters the CNS . Which of the
following is most likely to be the active, toxic ingredient in
Calabar beans?
(A) Bethanechol
(B) Muscarine
(C) Neostigmine
(D) Nicotine
(E) Physostigmine
15. Which of the following is the primary second-messenger
process in the contraction of the ciliary muscle when focusing
on near objects?
(A) cAMP (cyclic adenosine monophosphate)
(B) DAG (diacylglycerol)
(C) Depolarizing influx of sodium ions via a channel
(D) IP 3 (inositol 1,4, 5-trisphosphate)
(E) NO (nitric oxide)
ANSWERS
1. Because neostigmine acts on the enzyme cholinesterase, which
is present at all cholinergic synapses, this drug increases acetyl-
choline effects at nicotinic junctions as well as muscarinic
ones. Bethanechol, on the other hand, is a direct-acting agent
that is selective for muscarinic receptors and ha~ no effect on
nicotinic junctions such as the skeletal muscle end plate. The
answer is B.
2. The "-thion" organophosphates (those containing the P=S
bond) are activated, not inactivated, by conversion to "-oxon"
(P=O) derivatives. They are less stable than halogenated
hydrocarbon insecticides of the DDT type; therefore, they are
less persistent in the environment. Parathion is more toxic
than malathion. It is very lipid-soluble and rapidly absorbed
through the lungs and skin. The answer is E.
 CHAPTER 7 Choli noceptor-Activating & Cholinesterase-Inhibiting Drugs 63

3. Any of the cholinesterase inhibitors (choices B, C, or E)
would effectively correct myasthenic crisis. H owever, because
cholinergic crisis (if that is what is causing the symptoms) would
be worsened by a cholinomimetic, we choose the shortest-acting
cholinesterase inhibitor, edrophonium. The answer is B.
4. Respi ratory failure, from neuromuscular paralysis or CNS
depression, is the most important cause of acute deaths in
cholinesterase inh ibitor toxicity. The answer is E.
5. Cholinesterase inhib ition is typically associated with increased
(never decreased) bowel activity. (Fortunately, many patients
become tolerant to this effect.) T he answer is C.
6. Choice (E) is not correct because the vagus slows the heart.
Parasympathetic nerve stimulation does not cause vasodilation
(most vessels do not receive parasympathetic innervation), so
choice (C) is incorrect. Ganglion cells and the end plate con-
tain nicotinic receptors, which are not affected by bethanechol,
a direct-acting muscarinic agonist. The answer is D.
7. Muscarin ic receptors M 1 through M 3 are mainly responsible
for the peripheral effects of cholinom imetics. M 3 is the sub-
type most directly involved in smooth muscle contraction.
T he answer is C.
8. Both bethanechol and pilocarpine may increase gastrointestinal
motility. Neither drug has nicotinic-blocking (or agonist) effects,
neither is significantly hydrolyzed by cholinesterase, and both
may cause sweating and tachycardia. The answer is D.
9. Muscarinic agonists cause accommodation and cyclospasm,
the opposite of paralysis of accommodation (cycloplegia). In
open-angle glaucoma, this res ul ts in increased outflow of
aqueous and decreased intraocular pressure. These agents may
cause bronchospasm but have no effect on neuromuscular
transmission. They may cause diarrhea and are not used in its
treatment. Muscarinic agonists may also cause swearing, but
drug-induced swearing is of no value in the treatment of fever.
The answer is B.
10. Varenicl ine is a lipid-soluble partial agonist at nicotinic recep-
tors and is used to reduce craving for tobacco in smokers. The
answer is E.
11. Neostigmine is the prototypical indirect-acting choli-
nomimetic; it is a quaternary (charged) substance with poor
lipid solubility; its d uration of action is about 2-4 h.
Physostigmi ne is sim ilar except for good lipid solubility and
significant CNS effects. The answer is C.
12. Malathion and parathion are prodrug insecticides, but
malathion is much less toxic than parathion in mammals
because mammals (and birds) readily metabolize malathion
(but not parathion) to inactive products. The answer is A.
13. Nicotine is a direct-acting cholinomimetic alkaloid with the
properties noted. The answer is C.
14. Physostigmine is a plant alkaloid and, like most such com-
pounds, is lipid-soluble and enters the CNS readily.
Bethanechol, m uscarine, and nicotine are direct-acting, and
neostigmine does not readily enter the CNS. The answer is E.
15. Cholinomimetics cause smooth muscle contraction mainly
through the release of intracell ular calcium. This release is
triggered by an increase in IP 3 acting o n receptors in the endo-
plasmic reticulum. The answer is D.
SKILL KEEPER ANSWER:
DRUG METABOLISM (SEE CHAPTER 4)
The esters acetylcholine and methacholine are hydrolyzed by
acetylcholinesterase. Hydrolytic drug metabolism reactions
are classified as phase I.

CHECKLIST

When you complete this chapter, you should be able to:

0 List the locations and types of acetylcholine receptors in the major organ systems
(CNS, autonomic ganglia, eye, heart, vessels, bronchi, gut, genitourinary tract,
skeletal muscle, exocrine glands).
0 Describe the second messengers involved and the effects of acetylcholine on the
major organs.
0 List the major clinical uses of cholinomimetic agon ists.
0 Describe the pharmacodynamic differences between direct-acting and indirect-acting
cholinomimetic agents.
0 Relate the different pharmacokinetic properties of the various choline esters and
cholinomimetic alkaloids to their chemical properties.
0 List the major signs and symptoms of (1) organophosphate insecticide poisoning
and (2) acute nicotine toxicity.
 CHAPTER 8 Cholinoceptor Blockers & Cholinesterase Rege nerators 71

QUESTIONS 7 . T he net changes induced by drug Y in these experiments are

shown in the fo llowing graph.
1-2. A 2-year-old child has been admitted to the emergency
department. An timuscarinic drug overdose is suspected .

1. Pro bable signs of atropine overdose include which one of the ~ +50
:::J
following? (/)
(/)
No Ganglion Muscarinic
Q)
(A) Gastrointestinal smooth m uscle cramping 0. blocker blocker blocker
{B) Increased heart rate '0
0
0
(C) Increased gastric secretion :0 y
y y
(D) Pupillary constriction .!: 0 r--1
L____J
{E) Urinary freq uency Q)
Ol
c
C1l
£
2. Which of the following is the most dangerous effect of {)
-
belladonna alkaloids in infants and toddlers? c
Q)
(A) Dehydration ~
-
Q)
(B) Hallucinations a.. - 50
(C) H ypertension
(D) Hyperthermia
(E) Intrave ntricular heart block

3. Which of the fo llowing pairs of drugs and properties is most D rug Y is probably a drug similar to
correct? (A) Acetylcholine
(A) Atropine: poorly absorbed after oral administration (B) Edrophonium
(B) Benztro pine: quaternary amine, poor CN S penetration (C) Hexamethonium
{C) Cyclopentolate: well absorbed into the eye (D) N icoti ne
(D) lpratro pium: well-absorbed, long elimination half-life {E) Pralidoxime
(E) Scopolamine: short duration of action when used as
8. A 30-year-old man has been treated with several auto nomi c
anti-motion sickness age nt
drugs for 4 weeks. H e is now admitted to the emergency
4. Which one of the following can be blocked by atropine? department showing signs of drug toxicity. W hich of the
{A) Decreased blood press ure caused by hexamethonium following signs would distin guish betwee n an overdose of a
(B) Increased blood pressure caused by nicotine ganglion blocker vers us a m uscarinic blocker?
{C) Increased skeletal muscle strength caused by neostigmine (A) Blurred vision
(D) Tachycardia caused by exercise {B) D ry mouth, constipation
(E) Tachycardia caused by infusion of acetylcholine (C) Mydriasis
(D) Postural hypotension
5. Which of the following best describes the mechanism of (E) Tachycardia
action of scopolamine?
{A) Allosteric antagonist at muscarinic receptors 9. W hich one of the following causes cyclospasm rather than
(B) Competi tive antago nist at muscarinic recepto rs cycloplegia (paralysis of acco mmodation) when used topically
(C) Irreversible antagonist at muscarinic receptors in the eye?
{D) Physiologic antagonist at muscarinic receptors (A) Atropine
{E) Reversible antagonist at nicotinic recepto rs (B) Cyclopentolate
{C) Physostigmine
6-7. Two new synthetic drugs {X and Y) are to be studied fo r their (D) Scopolami ne
cardiovascular effects. T he drugs are given to three anesthetized (E) Tropicamide
animals while the blood pressure is recorded. T he first animal has
received no pretreatment {control), the second has received an 10. You have been asked to consult in the treatment of an 80-year-
effective dose of a long-acting ganglion blocker, and the third has old woman. An antimuscarinic drug is being considered. Ordi-
received an effective dose of a long-acting muscarinic antago nist. nary doses of atropine may be hazardous in the elderly because
(A) Atrop ine can elevate intraocular pressure in patients with
6. Drug X caused a 50 mm H g rise in mean blood pressure in glaucoma
the control animal, no blood pressure change in the ganglion- {B) Atropine frequently causes ventricular arrhythmias
blocked animal, and a 75 mm mean blood pressure rise in {C) Urinary retention is often precipitated by atropine m
the atropine-pretreated animal. Drug X is probably a drug wo men
similar to {D) T he elderly are particularly pro ne to develop dangerous
(A) Acetylcholine hyperthermia when given atropine
{B) Atropine (E) Atropine often causes vasodilation and hypotension in
{C) Epinephrine the elderly
(D) H examethonium
(E) N icotine
72 PART II Autonomic Drugs
11. Accepted therapeutic indications for the use of antimuscarinic
drugs include all of the following except
(A) Atrial fibrillation
(B) Motion sickness
(C) Parkinson's disease
(D) Postoperative bladder spasm
(E) To antidote parathion poisoning
12. Which of the following is an expected effect of a therapeutic
dose of an antimuscarinic drug?
(A) Decreased cAMP (cyclic adenosine monophosphate} in
cardiac muscle
(B) Decreased DAG (diacylglycerol) in salivary gland tissue
(C) Increased IP 3 (inositol trisphosphate} in intestinal smooth
muscle
(D) Increased potassium efflux from smooth muscle
(E) Increased sodium influx into the skeletal muscle end plate
13. Which one of the following drugs causes vasodilation that
can be blocked by atropine?
(A) Benztropine
(B) Bethanechol
(C) Botulinum
(D) Cyclopentolate
(E) Edropho nium
(F) Neostigmine
(G) Pralidoxime
14. Which one of the following drugs has a very high affiniry for
the phosphorus atom in parathion and is often used to treat
life-threateni ng insecticide toxiciry?
(A) Atropine
(B) Benztropine
(C) Bethanechol
(D) Botulinum
(E) Cyclopentolate
(F) Neostigmine
(G) Pralidoxime
ANSWERS
1. Tachycardia is a characteristic atropine overdose effect.
Bradycardia is sometimes observed after small doses. The
answer is B.
2. Choices B, D, and E are all possible effects of the atropine
group. In infants, however, the most dangerous effect is hyper-
thermia. Deaths with body temperatures in excess of 42°C
have occurred after the use of atropine-containing eye drops in
children. The answer is D.
3. Atropine is very well absorbed. Scopolamine has a relatively
long duration of action, especially when used as an anti-
motion sickness transdermal patch. lpratropium is a quater-
nary amine (and therefore permanently charged} and poorly
absorbed from the airways. Benztropine is tertiary, lipid solu-
ble, and penetrates into the CNS well. Only C is correct.
4. Atropine blocks muscarinic receptors and inhibits parasympa-
thomimetic effects. Nicotine can induce both parasympath-
omimetic and sympathomimetic effects by virtue of its
ganglion-stimulating action. Hypertension and exercise-
induced tachycardia reflect sympathetic discharge and there-
fore would not be blocked by atropine. The answer is E.
5. All of the muscarinic blockers, including scopolamine, act as
reversible, competitive pharmacologic antagonists. Allosteric
inhibitors are often reversible, but because they do not bind
to the same site, they are not competitive with the agonist.
The answer is B.
6. Drug X causes an increase in blood pressure that is blocked by
a ganglion blocker but not by a muscarinic blocker. The pres-
sor response is actually increased by pretreatment with
atropi ne, a muscarinic blocker, suggesting that compensatory
vagal discharge might have blunted the full response. This
description fits a ganglion stimulant like nicotine but not
epinephrine, since epinephrine's pressor effects are produced
at a receptors, not in the ganglia. The answer is E.
7. Drug Y causes a decrease in blood pressure that is blocked
by a muscarinic blocker but not by a ganglion blocker.
Therefore, the depressor effect must be evoked at a site dis-
tal to the ganglia. In fact , the drop in blood pressure is
actually greater in the presence of ganglion blockade, sug-
gesting that compensatory sympathetic discharge might
have blunted the full depressor action of drug Y in the
untreated animal. The description fits a direct-acting mus-
carinic stimulant such as acetylcholine (given in high
dosage} . Indirect-acting cholinomimetics (cholinesterase
inhibitors} would not produce this pattern because the vas-
cular muscarinic receptors involved in the depressor
response are not innervated and are unresponsive to indi-
rectly acting agents. T he answer is A.
8. Both ganglion blockers and muscarinic blockers can cause
mydriasis, increase resting heart rate, blur vision, and cause
dry mouth and constipation, because these are determined
largely by parasympathetic tone. Postural hypotension, on the
other hand, is a sign of sympathetic blockade, which would
occur with ganglion blockers but not muscarinic blockers
(Chapter 6). The answer is D.
9. All antimuscarinic agents are, in theory, capable of causing
cycloplegia. (Ganglion blockers also cause cycloplegia.}
Physostigmine, on the other hand, is an indirect-acting
cholinomimetic and causes cyclospasm. The answer is C.
10. The elderly have a much higher incidence of glaucoma than
younger people (and may be unaware of the disease until late
in its course}. Antimuscarinic agents may increase intraocular
pressure in individuals with glaucoma. Elderly men (not
women} have a much higher probabiliry of developing urinary
retention-because they have a high incidence of prostatic
hyperplasia. Hypotensive and hyperthermic reactions to ordi-
nary doses of atropine are not common in the elderly. The
answer is A.
11. Atrial fibrillation and other arrhythmias are not responsive to
antimuscarinic agents. The answer is A.
12. Muscarinic M 1 and M 3 receptors mediate increases in IP 3 and
DAG in target tissues (intestine, salivary glands}. M 2 receptors
(heart) mediate a decrease in cAMP and an increase in
potassium permeabiliry. Antimuscarinic agents block these
effects. The answer is B.
13. Bethanechol (Chapter 7) causes vasodilation by activating
muscarinic receptors on the endothelium of blood vessels.
This effect can be blocked by atropine. The answer is B.
14. Pralidoxime has a very high affiniry for the phosphorus atom
in organophosphate insecticides. The answer is G.
80 PART II Autonomic Drugs

Long-acting oral symparhomimerics such as ephedrine are 3. A 65-year-old woman with long-standing diabetes mellitus is
sometimes used to improve urinary continence in the elderly and admitted to the ward from the emergency department, and
in children with enuresis. This action is mediated by a receptors you wish to examine her retinas for possible changes. Which of
the following drugs is a good choice when pupillary dilation-
in the trigone of the bladder and, in men, the smooth muscle of
but not cycloplegia-is desired?
the prostate. (A) Isoproterenol
(B) Norepinephrine
(C) Phenylephrine
TOXICITY (D) Pilocarpine
(E) Tropicamide

A. Catecholamines 4. A 30-year-old man is admitted to the emergency department

after taking a suicidal overdose of reserpine. His blood pressure
Because of their limited penetration into the brain, these drugs is 50/0 mm Hg and heart rate is 40 bpm. Which of the follow-
have lirrle CNS toxicity when given systemically. In the periphery, ing would be the most effective cardiovascular stimulant?
their adverse effects are extensions of their pharmacologic alpha or (A) Amphetamine
beta actions: excessive vasoconstriction, cardiac arrhythmias, (B) Clonidine
myocardial infarction , hemorrhagic stroke, and pulmonary edema (C) Cocaine
or hemorrhage. (D) Norepinephrine
(E) Tyramine

B. Other Sympathomimetics 5. When a moderate pressor dose of norepinephrine is given after

pretreatment with a large dose of atropine, which of the follow-
The phenylisopropylamines may produce mild to severe CNS ing is the most probable response to the norepinephrine?
toxicity, depending on dosage. In small doses, they induce nerv- (A) A decrease in heart rate caused by direct cardiac effect
ousness, anorexia, and insomnia; in higher doses, they may cause (B) A decrease in heart rate caused by indirect reflex effect
anxiety, aggressiveness, or paranoid behavior. Convulsions may (C) An increase in heart rate caused by direct cardiac action
occur. Peripherally acting agents have toxicities that are predictable (D) An increase in heart rate caused by indirect reflex action
(E) No change in heart rate
on the basis of the receptors they activate. Thus, a 1 agonisrs cause
hypertension, and ~ 1 agonists cause sinus tachycardia and serious 6. Which of the following drugs will prevent tachycardia evoked
arrhythmias. Beta 2 agonists cause skeletal muscle tremor. It is by isoproterenol?
important to note that none of these drugs is perfecrly selective; at (A) Atropine
high doses, ~ 1 -selecrive agents have ~ 2 actions and vice versa. (B) Hexamethonium
(C) Phentolamine (an a blocker)
Cocaine is of special importance as a drug of abuse: its major
(D) Physostigmine
toxicities include cardiac arrhythmias or infarction and convul- (E) Propranolol (a ~ blocker)
sions. A fatal outcome is more common with acute cocaine over-
dose than with any other sympathomimetic. 7-8. Your patient is to receive a selective ~ 2 -stimulant drug.
7. Beta2-selective stimulants are most common ly used in
(A) Angina due to coronary insufficiency
QUESTIONS (B) Asthma
(C) Chronic heart failure
1-2. A 7-year-old child with a previous history of bee sting allergy (D) Delayed or insufficienrly strong labor
is brought to the emergency department after being stung by (E) Raynaud's syndrome
3 bees.
8. In considering possible drug effects in this patient, you would
1. Which of the following are probable signs of the anaphylactic note that ~ 2 stimulants frequenrly cause
reaction to bee stings? (A) Direct stimulation of renin release
(A) Bronchodilation, tachycardia, hypertension, vomiting, (B) Hypoglycemia
diarrhea (C) Increased cGMP (cyclic guanine monophosphate) in mast
(B) Bronchospasm, tachycardia, hypotension cells
(C) Bronchodilarion, bradycardia, vomiting, diarrhea (D) Skeletal muscle tremor
(D) Bronchospasm, bradycardia, hypotension, diarrhea (E) Vasodilation in the skin
(E) Bronchodilarion, tachycardia, vomiting, diarrhea
9. Epinephrine causes a decrease in:
2. If this child has signs of anaphylaxis, what is the treatment of (A) cAMP (cyclic adenosine monophosphate) in heart muscle
choice? (B) Free fatty acids in blood
(A) Diphenhydramine (an antihistamine) (C) Glucose in blood
(B) Ephedrine (D) Lactate in blood
(C) Epinephrine (E) Triglycerides in fat cells
(D) Methylprednisolone (a corticosteroid)
(E) Phenylephrine
 CHAPTER 9 Sympathomimetics 81

10. Mr Green, a 54-year-old man, had a cardiac transplant ANSWERS

6 months ago. His current blood pressure is 120/70 mm Hg
and heart rate is 100 bpm. Which of the following drugs 1. Anaphylaxis is caused by the release of several mediamrs.
would have the least effect on Mr Green's heart rate? Leukotrienes and certain proteins are the most important of
(A) Albuterol these. They cause bronchospasm and laryngeal edema and
(B) Epinephrine marked vasodilation with severe hypotension. Tachycardia is a
(C) Isoproterenol common reflex response m the hypotension . Gastrointestinal
(D) Norep inephrine disturbance is not as common nor as dangerous. The answer is B.
(E) Phenylephrine 2. The treatment of anaphylaxis requires a powerful physiologic
11-12. Aumnomic drugs X and Y were given in moderate doses antagonist with the ability to cause bronchodilation (~ 2
as IV boluses m normal volunteers. The sysmlic and diasmlic effect), and vasoconstriction (a effect). Epinephrine is the
blood pressures changed as shown in the diagram below. most effective agent with these properties. Antihistamines and
corticosteroids are sometimes used as supplementary agents,
but the use of epinephrine is mandato ry. The answer is C.
3. Antimuscarinics (tropicamide) are mydriatic and cycloplegic;
Ol 200 a-sympathomimetic agonises are only mydriatic. Isoproterenol
I 180 X Y Systolic has negligible effects on the eye. Norepinephrine penetrates
~ ~
E 160 the conjunctiva poorly and would produce intense vasocon-
.s
Q)
140 Systolic
striction. Pilocarpine causes miosis. The answer is C.
:; 120
g) 100 4. A large overdose of reserpine causes marked depletion of
Q)

0.. 80 stored catecholamine transminer. The indirect-acting agents

"8 60 (amphetamines, cocaine, and tyramine) act through cate-
~ 40 cholamines in (o r released from) the nerve terminal and
20 Diastolic would therefore be ineffective in this patient. Clonidine acts
primarily on presynaptic nerve endings although it can acti-
vate a 2 receptors located elsewhere. Norepinephrine has the
necessary combination of direct action and a spectrum that
11 . Which of the following drugs most resembles drug X? includes a 1, a 2 , and ~ 1 effects. The answer is D.
(A) Atropine 5. The answer choices point m effects of norepinephrine (NE) on
(B) Bethanechol heart rate. What is the usual NE effect on heart rate? Recall that
(C) Epinephrine although NE has ~ 1 effects (and when released from sympa-
(D) Isoproterenol thetic nerves, increases rate), when given as a drug, its a-ago nist
(E) Norepinephrine effects in vessels, and the resulting increase in blood pressure,
12. Which of the following most resembles drug Y? result in a strong vagal reflex and bradycardia. This bradycardia
(A) Atropine is mediated by acetylcholine acting on muscarinic receptors in
(B) Bethanechol the sinus node. Atropine prevents the normal reflex bradycar-
(C) Epinephrine dia, since that requires integrity of muscarinic receptors. In the
(D) Isoproterenol presence of atropine, the direct ~ 1 action of norepinephrine on
(E) Norepinephrine the sinus node will be unmasked. The answer is C.
6. As in question 5, when considering questions that may
13. A new drug was given by subcutaneous injection to 25 involve reflex homeostatic responses, it helps to recall the
normal subjects in a phase 1 clinical trial. The cardiovas- pathway and recepmrs involved in the barocepmr reflex. In
cular effects are summarized in the table below. Which of the case of isoproterenol-induced tachycardia, a reflex is evoked
the following drugs does the new experimental agent most by the ~rmediated decrease in blood pressure. This reflex will
resemble? be processed by the vasomomr center and result in increased
sympathetic autonomic nervous system outflow m the sinus
Variable Control Peak Drug Effect node to increase heart rate. This reflex would be blocked by a
ganglion blocker such as hexamethonium. However, isopro-
Systolic BP (mm Hg) 116 144 terenol also causes tachycardia directly by activating the
Diastolic BP (mm Hg) 76 96 ~ recepmrs in the sinus node, an effect not blocked by gan-
glion blockers. Only a ~ blocker (propranolol) will prevent
Cardiac output (L/min) 5.4 4.7 both the reflex tachycardia and the direct tachycardia induced
Heart rate (beats/min) 71.2 54.3 by isoproterenol. The answer is E.
7. Beta agonises increase cardiac rate and force and increase
myocardial oxygen demand; they are generally contraindicated
(A) Atropine in angina. In chronic heart failure, the heart is already subject
(B) Epinephrine to excessive sympathetic drive. The absence of ~ 2 recepmrs in
(C) Isoproterenol the cutaneous vascular bed makes ~ agonises useless in condi-
(D) Phenylephrine tions involving reduced skin blood flow. Bronchiolar, and to a
(E) Physostigmine lesser extent, uterine smooth muscle are relaxed by ~ 2 agonises.
The answer is B.
82 PART II Autonomic Drugs

8. Tremor is a common ~ 2 effect. Blood vessels in the skin have
almost exclusively a (vasoconstrictor) receptors. Stimulation of
renin release is a ~ 1 effect. Beta2 agonises cause hyperglycemia.
The answer is D.
9. Epinephrine increases plasma-free farcy acids by activating
lipolysis of rriglycerides in far cells. The answer is E.
10. Heart transplantation involves the cutting of autonomic nerves
to the heart. As a result, autonomic nerve endings degenerate,
and cardiac transmitter stores are absent for 2 years or longer
after surgery. Therefore, indirect-acting symparhomimerics are
ineffective in changing heart rare. All the drugs listed are
direct-acting, and all bur phenylephrine have significant effects
on ~ receptors. Phenylephrine usually causes reflex bradycar-
dia, which requires intact vagal innervation. The answer is E.
(Note that denervarion may result in up-regulation of both ~ 1
and ~ 2 receptors so that direct-acting ~ agonises have a greater
than normal effect.)
11. The drug X dose caused a decrease in diastolic blood pressure
and lirrle change in systolic pressure. Thus, there was a large
increase in pulse pressure. The decrease in diastolic pressure
suggests rhar the drug decreased vascular resistance, rhar is, it
must have significant muscarinic or ~-agonist effects. The fact
that it also markedly increased pulse pressure suggests that it
strongly increased stroke volume, a ~-agonist effect. The drug
with these beta effects is isoproterenol (Figure 9-1). The
answer is D.
12. Drug Y caused a marked increase in diastolic pressure, sug-
gesting strong a vasoconstrictor effects. It also caused a small
increase in pulse pressure, suggesting some ~-agonist action.
An increase in stroke volume may also result from increased
venous return (an a-agonist effect) and stroke volume. The
drug that best marches this description in norepinephrine. The
answer is E.
13. The investigational agent caused a marked increase in
diasrolic pressure bur a small increase in pulse pressure
(from 40 to 48 mm Hg). T hese changes suggest a strong alpha
effect on vessels bur an increase in venous return and stroke
volume or a small ~-agonist action in the heart. The heart rare
decreased markedly, reflecting a baroreceptor reflex compen-
satory response. Note rhar rhe stroke volume increased slightly
(cardiac ourpur divided by heart rare-from 75.8 to 86.6 mL).
This is to be expected even in the absence of beta effects if
bradycardia causes increased diastolic filling rime. The drug
behaves most like a pure a agonist. T he answer is D.
SKILL KEEPER ANSWER: BLOOD PRESSURE
CONTROL MECHANISMS IN
PHEOCHROMOCYTOMA (SEE CHAPTER 6)
Because the control mechanisms that attempt to maintain
blood pressure constant are intact in patients with
pheochromocytoma (they are reset in patients with ordinary
hypertension), a number of compensatory changes are
observed in pheochromocytoma patients (see Figure 6-4).
These include reduced renin, angiotensin, and aldosterone
levels in the blood. With the reduced aldosterone effect on the
kidney, more salt and water are excreted, reducing blood
volume. Since the red cell mass is not affected, hematocrit is
often increased. If the tumor releases only norepinephrine,
a compensatory bradycardia may also be present, but most
patients release enough epinephrine to maintain heart rate at
a normal or even increased level.

CHECKLIST

When you complete this chapter, you should be able to:

0 Name a typical nonselective a agonist, a selective a 2 agonist, a nonselective
~agonist, a selective~~ agonist, selective ~ 2 agonists, an a,, a 2, ~ ~ agonist, and an a,,
a 2, ~ 1 , ~ 2 agonist.
0 List tissues that contain significant numbers of a, or a 2 receptors.
0 List tissues that contain significant numbers of~~ or ~ 2 receptors.
0 Describe the major organ system effects of a pure a agonist, a pure~ agonist, and a
mixed a and ~agonist.
0 Describe a clinical situation in which the effects of an indirect sympathomimetic
would differ from those of a direct agonist.
0 List the major clinical applications of the adrenoceptor agonists.
90 PART II Autonomic Drugs

QUESTIONS 6. Drug X had the effects shown in the table below.

1. Which of the following effects of epinephrine would be blocked In the Animal Receiving Heart Rate Response to Drug X Was
by phentolamine but not by metoprolol? J,
No pretreatment
{A) Cardiac stimulation
{B) Increase of cAMP {cyclic adenosine monophosphate) in Hexamethonium i
fat Atropine i
(C) Mydriasis
{D) Relaxation of bronchial smooth muscle Phenoxybenzamine i
{E) Relaxation of the uterus

2. Both phentolamine and phenoxybenzamine Drug X is probably a drug similar to

{A) Are inactive by the oral route (A) Acetylcholine
(B) Block both a and ~ receptors (B) Albuterol
{C) Cause hypertension {C) Edrophonium
{D) Cause tachycardia {D) Isoproterenol
(E) Induce vasospasm in large doses (E) Norepinephrine
3. Propranolol is not useful in the treatment of which one of the 7. Drug Y had the effects shown in the table below.
fo llowing?
{A) Angina
In the Animal Receiving Heart Rate Response to Drug Y Was
{B) Familial tremor
(C) Hypertension No pretreatment i
(D) Idiopathic hypertrophic subaortic cardiomyopathy
(E) Partial atrioventricular heart block Hexamethonium i
Atropine i
4. Adverse effects that limit the use of adrenoceptor blockers
include which one of the following? Phenoxybenzamine i
(A) Bronchoconstriction from a-blocking agents
{B) Heart fai lure exacerbation from ~ blockers
(C) Impaired blood sugar response with a blockers Drug Y is probably a drug similar to
{D) Increased intraocular pressure with ~ blockers {A) Acetylcholine
(E) Sleep disturbances from a-blocking drugs (B) Edropho nium
(C) Isoproterenol
5-8. Four new synthetic drugs {designated W, X, Y, and Z) are to {D) Norepinephrine
be studied for their cardiovascular effects. They are given to (E) Prazosin
4 anes thetized animals while the heart rate is reco rded. The first
animal has received no pretreatment ("control"); the second has 8. The results of the test of drug Z are shown in the graph.
received an effective dose of hexamethonium; the third has received
an effective dose of atropine; and the fourth has received an effec- Q)

tive dose of phenoxybenzamine. The net changes induced by the "§ No Hexa- Atropine Phenoxy-
1ij 100 pretreatment methonium benzamine
new drugs {not by the blocking drugs) are described in the fol- Q)
.<:::
z z
lowing questions. .!:
Q)
z
en
5. Drug W increased heart rate in the control animal, the c

atropine-pretreated animal, and the phenoxybenzamine- "'u

.<:::

pretreated animal. However, Drug W had no effect on heart

c
~-100
rate in the hexamethonium-pretreated animal. Drug W is ~
probably a drug similar to
{A) Acetylcholine
{B) Edrophonium Drug Z is probably a drug similar to
(C) Isoproterenol {A) Acetylcholine
(D) N icotine (B) Edrophonium
(E) Norepi nephrine (C) Isoproterenol
{D) Norepinephrine
(E) Pralidoxime

9. A traveler to your city visits you with a request for a renewal

of his prescription for phenoxybenzamine. While preparing
to telephone his physician, you recall that phenoxybenzamine
is not useful in which of the following?
(A) Carcinoid
{B) Essential hypertension
(C) Mastocytosis
(D) Pheochromocytoma
{E) Raynaud's phenomenon
 CHAPTER 10 Adrenoceptor Blockers 91

10. When given to a patient, phentolamine blocks which one of 15. A patient receiving a ~ blocker for chronic angina complains of
the following? sleep disturbances and loss of energy. She is probably receiving
(A) Bradycardia induced by phenylephrine (A) Arenolol
(B) Bronchodilarion induced by epinephrine (B) Esmolol
(C) Increased cardiac contractile force induced by norepinephrine (C) Laberalol
(D) Miosis induced by acetylcholine (D) Nadolol
(E) Vasodi lation induced by isoproterenol (E) Propranolol

11. Pretreatment with propranolol will block which one of the

following?
(A) Methacholine-induced tachycardia ANSWERS
(B) Nicotine-induced hypertension
1. Mydriasis caused by contraction of the pupillary dilator radial
(C) Norepinephrine-induced bradycardia
smooth muscle is mediated by a receptors. All the other
(D) Phenylephrine-induced mydriasis
(E) Pilocarpine-induced miosis effects listed are mediated by ~ receptors. The answer is C.
2. These a blockers cause hypotension and significant reflex
12. Your 75-year-old patient with angina and glaucoma is to receive tachycardia. They have no ~-blocking action and never cause
a ~-blocking drug. Which of the following statements is true vasospasm. The answer is D.
regarding ~-blocking drugs?
(A) Esmolol's pharmacokinetics are compatible with chronic 3. Atrioventricular block is an important contraindication to the
topical use use of ~ blockers. All of the other choices are valid indications
(B) Metoprolol blocks ~ 2 receptors selectively for ~ blockers. The answer is E.
(C) Nadolollacks ~ 2 -blocking action 4. Although chronic heart fai lure is often treated with~ blockers,
(D) Pindolol is a~ antagonist with high membrane-stabilizing acute heart failure can be precipitated by these drugs. Choices A,
(local anesthetic) activity C, and E reverse the correct pairing of receptor subtype
(E) Timolollacks the local anesthetic effects of propranolol (a versus ~) with effect. Choice D reverses the direction of
change of intraocular pressure. The answer is B.
13. A 56-year-old man has hypertension and an enlarged prostate,
which biopsy shows to be benign prostatic hyperplasia. Which of 5. In developing a strategy for this type of question, consider first
the following drugs would be the most appropriate initial therapy? the actions of the known blocking drugs. Hexamethonium
(A) Alburerol blocks reflexes as well as the direct action of nicotine. Atropine
(B) Atenolol wo uld block direct muscarinic effects of an unknown drug
(C) Metoprolol (if it had any) or reflex slowing of the heart mediated by the
(D) Prazosin vagus. Phenoxybenzamine blocks only a-receptor-mediated
(E) Timolol processes. If the response produced in the nonpretreared animal
is blocked or reversed by hexamethonium, it is probably a
14. A new drug was administered to an anesthetized animal with direct nicotinic effect or a reflex response to hypotension. In
the results shown here. A large dose of epinephrine (epi) was that case, consider all the receptors involved in mediating the
administered before and after the new agent for comparison. reflex. Drug W causes tachycardia that is prevented by gan-
Which of the following agents does the new drug most closely glion blockade. The only drug in the list of choices that causes
resemble? hypotension and tachycardia that is not blocked by atropine is
(A) Atenolol isoproterenol, and the tachycardia caused by isoproterenol is
(B) Atropine not blocked by ganglionic blockade. Thus, drug W must be
(C) Laberalol nicotine. Th!'= answer is D.
(D) Phenoxybenzamine 6. Drug X causes slowing of the heart rate, but this is converted
(E) Propranolol into tachycardia by hexamethonium and atropine, demon-
strating that the bradycardia is caused by reflex vagal dis-
charge. Phenoxybenzamine also reverses the bradycardia to
200 ----------- Newdru9 __________ _ tachycardia, suggesting that a receptors are needed to induce
Ci

JZ::
E~ ---- t __E~---------
I the reflex bradycardia and that X also has direct ~-agonist
_____
E
.s
!!!
~
(/)

!!!
100
~t ___ t___;_ ___ actions. The choices that evoke a vagal reflex bradycardia bur
can also cause direct tachycardia are limited; the answer is E.
7. Drug Y causes tachycardia that is not significantly influenced
by any of the blockers; therefore, drug Y must have a direct
c. ~-agonist effect on the heart. The answer is C.
'80
8. Drug Z causes tachycardia that is converted to bradycardia by
il5
0 hexamethonium and blocked completely by atropine. This
indicates that the tachycardia is a reflex evoked by vasodila-
tion. Drug Z causes bradycardia when the gangl ia are blocked,
indicati ng that it also has a direct muscarinic action on the
heart. T his is confirmed by the ab ility of atropine to block
both the tachycardia and the bradycardia. The answer is A.
92 PART II Autonomic Drugs

9. Phenoxybenzamine is not useful in essential hypertension 15. All but one of the drugs listed have relatively low lipid solu-
because it causes severe tachycardia and marked orthostatic bility and enter the CNS poorly. Esmolol is also unsuitable for
hypotension. T he drug is used in Raynaud's phenomenon, chronic angina, it is short-acting and given intravenously.
although efficacy in this application is controversial. The Propranolol is highly lipid soluble, enters the CN S. readily,
answer is B. and has numerous CNS effects, including sedation, sleep dis-
10. Phenylephrine, an a agonist, induces bradycardia through the turbances, and loss of energy or lassitude. T he answer is E.
baroreceptor reflex. Blockade of this drug's a-mediated vaso-
constrictor effect prevents the bradycardia. The answer is A.
11. The ~ blocker does not block the reflex vagal slowing induced
by hypertension caused by norepinephrine. Nicotine-induced Pindolol binding
hypertension and phenylephrine-induced mydriasis are mediated 100 /
by a receptors. Methacholine and pilocarpine are muscarinic
ago nists. Muscarinic ago nists cause vasodilation and evoke
compensatory tachycardia that is mediated by sympathetic
E
activation of ~ receptors in the sinus node. T he answer is A. :::J
E
·;;:
12. Esmolol is a sho rt-acting ~ blocker fo r parenteral use only. <1l
- Albuterol binding
Nadolol is a nonselective ~ blocker, and metop rolol is a ~~­ E 50
selective blocker. T imolol is useful in glaucoma because it does 0
not anesthetize the cornea. T he answer is E.
c
Ql
~
Ql
13. An a blocker is appropriate therapy in a man with both a..
hypertension and benign prostatic hyperplasia because both
condi tions involve contraction of smooth muscle containing
a receptors. T he answer is D. 0
14. T he new drug blocks both the a -mediated effects (increased 0 Very high
diastolic and mean arterial blood press ure) and ~-mediated Concentration of albuterol
action (increased cardiac fo rce) . In addition, it does not cause
epinephrine reversal. T herefore, the drug must have both a-
and ~- blocking effects. T he answer is C.

SKILL KEEPER ANSWER: PARTIAL AGONIST

ACTION (SEE CHAPTER 2)

Because pindolol is a partial agonist at~ receptors, the

concentration-response curve will show a bronchodi/ating
effect at zero albuterol concentration. As albuterol concentration
increases, the airway diameter also increases. The binding
curves will show pindolol binding starting at 100% of receptors
and going to zero as albuterol concentration increases, with
albuterol binding starting at zero and going to 700%.

CHECKLIST

When you complete this chapter, you should be able to:

0 Describe and compare the effects of an a blocker on the blood pressure and heart
rate responses to epinephrine, norepinephrine, and phenylephrine.
0 Compare the pharmacodynamics of propranolol, labetalol, metoprolol, and pindolol.
0 Compare the pharmacokinetics of propranolol, atenolol, esmolol, and nadolol.
0 Describe the clinical indications and toxicities of typical a and ~ blockers.