Pharmacology

PDQ* SERIES
ACKERMANN
PDQ PHYSIOLOGY
BAKER, MURRAY
PDQ BIOCHEMISTRY
CORMACK
PDQ HISTOLOGY
DAVIDSON
PDQ MEDICAL GENETICS

KERN
PDQ HEMATOLOGY
McKIBBON
PDQ EVIDENCE-BASED PRINCIPLES AND PRACTICE

NORMAN, STREINER
PDQ STATISTICS, 2/e

STREINER, NORMAN
PDQ EPIDEMIOLOGY, 2/e
PDQ (Pretty Darned Quick)
PDQ
PHARMACOLOGY
GORDON E. JOHNSON, PhD
Professor Emeritus
Department of Pharmacology
University of Saskatchewan
Saskatoon, Saskatchewan
SECOND EDITION
2002
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2002 Gordon E. Johnson
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Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and drug dosages, is in accord with the accepted
standard and practice at the time of publication. However, since research and regulation constantly change clinical standards, the reader is urged to check the product information sheet
included in the package of each drug, which includes recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs.
Writing the dedication for a book is never easy,

particularly for a married man with six children. You know that each
and everyone of them will be looking in this space to make sure that his or
her name is here. So, to maintain our happy home, and pay all my
political debts, I dedicate this book to:
Mary-Jane (wife, mother, and benevolent dictator)
Dorothy
Ian
Warren
Louise
Ted
and
Becky
However, the story does not end here, for I
must also dedicate this book to the cascade of grandchildren
who have tumbled into our lives. For it is to these 12 products of
biotechnology that I owe my greatest debt. Thus, to Christina, Angela,
Gillian, Megan, Kelsey, Sarah, Vanessa, Victoria, Renee, Graham
(finally a boy!), Trevor, and Ryan, I dedicate this text. Who knows
what drugs we may have by the time they are in a
position to write their own books.
Preface
P
harmacology can be a most difficult subject to master. There

appears to be so much to learn. Students can not be blamed if, overcome
with the detail of individual drugs, they miss the basic concepts underlying
the use of an entire group of agents. We encourage students to view our subject from a distance first, thus allowing an understanding of the basic principles of drug therapy before they commit to memory the properties of one
drug after another. This is much easier said than done. It is hard to stand
back and view the whole lake, if you are just learning to swim and are being
swamped by each new swell. This book is intended to help beleaguered students, in danger of becoming phagocytosed by facts, rise above the field
of battle and take a global view of complex topics. Only then can they return
to the detail that is so important in correct drug use.
PDQ Pharmacology, is a small book. It is not intended to stand on its
own. Rather, it is meant to complement a good general pharmacology text.
Several excellent texts have been cited in this book. By the same token, this
book should not be used as a substitute for a good undergraduate course
in pharmacology.
If PDQ Pharmacology, is not intended to replace a recognized text or
substitute for a course in pharmacology, how then should it be used? First,
it can provide a valuable learning aid during the time the course is being
taught. Filled with figures and tables selected to illustrate important principles of drug action, it will assist students to grasp the concepts that
underlie groups of drugs before they are asked to concentrate on the properties unique to each agent. PDQ Pharmacology, can also assist students in
reviewing pharmacology. In those last frantic hours prior to an examination, when students wish to review the entire course or require a rapid
answer to an individual problem, PDQ Pharmacology, will fill the current
void.
Gordon E. Johnson, PhD
March, 2002
Contents
Part 1 Principles of Medical Pharmacology, 1
1
2
Drug Absorption, Distribution, and Elimination, 1

Pharmacodynamics: How Drugs Work, 13
Part 2 Autonomic Pharmacology, 18
3
4
5
6
7
Introduction to Autonomic Pharmacology, 18

Cholinergic and Anticholinergic Drugs, 27
Adrenergic Drugs (Sympathomimetics), 37
Antiadrenergic Drugs (Sympatholytics), 50
Neuromuscular Blocking Drugs, 62
Part 3 Cardiovascular and Renal Pharmacology, 64
8
9
10
11
12
13
Drugs for the Treatment of Congestive Heart Failure, 64

Drugs for the Treatment of Cardiac Arrhythmias, 76
Antianginal Drugs, 90
Antihypertensive Drugs, 97
Drugs for the Treatment of Hypotension and Shock, 107
Diuretics, 111
Part 4 Drugs and the Blood, 118
14
15
Antihyperlipidemic Drugs, 118

Anticoagulant and Antiplatelet Drugs, Fibrinolytic Agents,
and Vitamin K, 126
Part 5 Endocrine Pharmacology, 138
16
17
Drugs and the Thyroid, 138

Drugs for the Treatment of Diabetes Mellitus, 143
viii
18
19
CONTENTS
Adrenal Corticosteroids, 151

Sex Hormones, 158
Part 6 Psychopharmacology, 168
20
21
22
Antipsychotic Drugs, 168

Drugs for Mood Disorders, 175
Anxiolytics and Hypnotics, 184
Part 7 Drugs for the Treatment of Neurologic

Disorders, 193
23
24
Drugs for the Treatment of Epilepsy, 193

Antiparkinsonian Drugs, 203
Part 8 Drugs to Alleviate Pain, 211
25
26
27
28
29
30
31
32
33
34
35
Analgesics, 211
Antiarthritic and Antigout Drugs, 221
Antimigraine Drugs, 229
Beta Lactam Antibiotics, 233
Macrolide Antibiotics, 248
Aminoglycoside Antibiotics, 252
Fluoroquinolone Antibiotics, 256
Miscellaneous Antibiotics and Antibacterials, 259
Drugs for Systemic Fungal Infections, 271
Drugs for the Treatment of Viral Infections, 277
Anticancer Drugs (Antineoplastic Drugs), 289
Index, 299
Part 1
Principles of Medical
Pharmacology
Drug Absorption, Distribution,

and Elimination
CHARACTERISTICS OF DRUG MOVEMENT ACROSS
MEMBRANES
Drugs are Dissolved in Body Fluids
Most drugs are either weak acids or weak bases. When dissolved in body fluids, they exist in both the ionized and nonionized forms. The ionized form
is usually water soluble, or lipid insoluble, and does not diffuse readily
throughout the body. The nonionized form is usually less water soluble and
more lipid soluble. It is more likely to diffuse across lipid membranes
(Figure 11).
Figure 11 Diffusion of a drug across a lipid membrane. (After Johnson GE, Osis M, Hannah
KJ. Pharmacology. In: Nursing Practice. Toronto (ON): W.B. Saunders, 1998.)
PDQ PHARMACOLOGY
Ratio of C i /C n Drug Molecules

The ratio of ionized/nonionized (Ci/Cn) drug molecules depends on the pH
of the environment and the pKa of the drug in question.
Acids
eg,
HA
H+ + A
Cn
Ci
Salicylic Acid
Salicylate
When the pKa of the drug = the pH of the media, then Ci = Cn.
Raising the pH has the effect of removing H+ and driving the reaction to the
right, therefore, increasing Ci. Lowering the pH has the effect of adding H+
and driving the reaction to the left, therefore, increasing Cn.
Example:
Salicylic acid has a pKa of ~3.

At a pH of 3, Cn = Ci
At a pH < 3, Cn > Ci
At a pH > 3, Ci > Cn
Question: Would you expect salicylic acid to be mainly ionized or nonionized in the stomach pH of 1?
Answer:
Nonionized.
Bases
HB+
Ci
eg,
Morphine Sulfate
H+ + B
Cn
Morphine
When the pKa of the drug = the pH of the media, then Ci = Cn.
Raising the pH has the effect of removing H+ and driving the reaction to the
right, therefore, increasing Cn. Lowering the pH has the effect of adding H+
and driving the reaction to the left, therefore, increasing Ci.
Example:
Morphine has a pKa of ~ 8.

At a pH of 8, Cn = Ci
At a pH < 8, Ci > Cn
At a pH > 8, Cn > Ci
Question: Would you expect morphine to be mainly ionized or nonionized in the stomach pH of 1?
Answer:
Ionized.
Chapter 1
Drug Absorption, Distribution, and Elimination
OVERVIEW OF ABSORPTION, DISTRIBUTION, AND

ELIMINATION OF DRUGS IN THE BODY (FIGURE 12)
Figure 12 Characteristics of drug movement across membranes. (After Morgan JP. Alcohol
and drug abuse, curriculum guide for pharmacology faculty. Rockville, MD: U.S. Department of
Health and Human Services, 1985:3.)
ROUTES OF DRUG ADMINISTRATION

Sublingual
Drugs are absorbed through the oral mucosa. May be useful if a drug
1. irritates the stomach,
2. is destroyed in the stomach, or
3. is inactivated during its first pass through the liver.
Only an appropriate method of administration for a drug that
1. dissolves rapidly in saliva,
2. does not irritate the oral mucosa, and
3. is lipophilic.
PDQ PHARMACOLOGY
Oral
1. Drugs are absorbed from the stomach and the duodenum.
2. Drug absorption is better from the duodenum because of its larger
absorbing surface.
3. The stomach can absorb acidic drugs and weakly basic drugs.
For a drug to be absorbed from the stomach or the duodenum, it must
1. be dissolved in the gastrointestinal (GI) tract,
2. have at least 1 molecule in 500 nonionized, and
3. have nonionized molecules with sufficient lipid solubility to pass
through the GI mucosa.
Rectal
Drugs are administered rectally for a systemic effect if
1.
2.
3.
4.
they are irritating to the stomach,

the patient is nauseated,
the patient is too young or old to take the drug orally, or
a sustained effect is desired (of less value today because of the development of sophisticated sustained-release oral and topical products).
Drugs are also administered rectally for a local effect, such as the treatment
of proctitis or hemorrhoids.
Parenteral
Intravenous immediate effect, danger of overdose.
Intramuscular if the drug is dissolved in an aqueous media, absorption occurs rapidly; if the drug is administered as a suspension, absorption is prolonged.
Subcutaneous absorption is almost as rapid as the intramuscular
injection of a drug dissolved in an aqueous preparation.
Inhalation
For a systemic effect effect starts immediately.
For a local effect acts on the bronchioles.
Chapter 1
DRUG DISTRIBUTION IN THE BODY

Initially
Drugs are carried in largest amounts to the most richly perfused tissues,
such as the adrenals, brain, heart, lungs, kidneys, and muscles.
Later
Drugs then undergo redistribution within the body, being retained in tissues for which they have affinity, for example, in fat for lipophilic drugs
(Figure 13).
Plasma Protein Albumin
Drug molecules may be bound to plasma proteins in the bloodstream,
usually albumin. While bound to plasma proteins, drug molecules are
inactive because they cannot leave the vascular system and enter the tissues. Once the level of free drug in the plasma falls, bound drug molecules
diffuse off the plasma proteins in order to maintain a constant bound/free
ratio (Figure 14).
Blood-Brain Barrier
Brain capillary endothelial cells have no pores to allow diffusion. In addition, glial connective tissue is attached to the basement membrane of cap-
Figure 13 Time distribution of thiopental in a dog. Note the high levels found initially in the
liver and the muscle, and the subsequent redistribution to fat. (After Brodie BB. Distribution and
fate of drugs: therapeutic implications. In: Binns TB, ed. Absorption and distribution of drugs.
Edinburgh: E and S Livingston, 1964:246.)
PDQ PHARMACOLOGY
Figure 14 Schematic representation of the diffusion of a drug, which is 98% bound to plasma
protein, across a capillary. (After Johnson GE, Osis M, Hannah KJ. Pharmacology. In: Nursing
Practice. Toronto (ON): W.B. Saunders, 1998.)
illary endothelium. Together, these structural modifications are called the

blood-brain barrier. Ionized molecules cannot enter the brain. Nonionized
molecules, not bound to plasma proteins, enter the brain easily (Figure 15)
because they are lipid soluble and can pass through the blood-brain barrier.
Placental Transfer Of Drugs
The mature placenta contains a network of maternal blood sinuses that
interface with villi that carry the fetal capillaries. Drugs cross the placenta
primarily by simple diffusion. Lipid-soluble, nonionized drugs readily enter
the fetal blood from the maternal circulation. Placental transfer occurs less
readily with drugs possessing a high degree of dissociation or low lipid solubility. The view that the placenta is a barrier to drugs is not correct. The
fetus is, to at least some extent, exposed to essentially all drugs taken by the
mother (Figure 16).
Chapter 1
Figure 15 Blood-brain barrier. (After Morgan JP. Alcohol and drug abuse, curriculum guide
for pharmacology faculty. Rockville, MD: U.S. Department of Health and Human Services,
1985:3.)
DRUG ELIMINATION
Renal Excretion
Drugs are filtered, secreted, and reabsorbed by the kidneys (Figure 17).
Filtration: All drugs not bound to plasma proteins are filtered.
Secretion: Some acidic and basic drugs are secreted. This is an active
process with transport maxima. Drugs that are secreted usually have short
half-lives.
Reabsorption: Drug reabsorption from the renal tubules depends on the
percentage of the drug in the nonionized form. Nonionized drug molecules
are usually reabsorbed into the systemic circulation. Ionized molecules are
not reabsorbed.
Metabolism
Kidneys cannot eliminate lipophilic drug molecules. Lipophilic drugs must
first be transformed into ionized, or water-soluble, molecules before the kidney can excrete them. This process is referred to as drug metabolism.
Although drug metabolism can occur in most tissues, the liver is the major
organ involved in this process. Drug metabolism should not be equated with
Figure 16 Drug distribution in a model of the maternal-placental-fetal unit. (After Mirkin BL. Drug distribution in pregnancy. In: Boreus L, ed. Fetal pharmacology. New
York: Raven Press, 1972:22.)
8
PDQ PHARMACOLOGY
Chapter 1
Figure 17 Diagrammatic representation of the excretion of drugs by the kidney. (After Brodie
BB. Distribution and fate of drugs: therapeutic implications. In: Binns TB, ed. Absorption and
distribution of drugs. Edinburgh: E and S Livingston, 1964:201.)
drug inactivation. Although most molecules are inactivated by metabolism,

some are activated, and others undergo no change in activity.
Drug metabolism frequently occurs in two separate stages or phases.
Drug
Phase I
Introduction of a
polar group
Conjugation of the
Phase II
polar group
Phase I Metabolic Reactions

Phase I involves putting a handle (eg, hydroxyl, amine, or carboxyl group)
on the drug molecule. If the parent drug already possesses one of these reactive groups, it can be directly conjugated.
10
PDQ PHARMACOLOGY
Phase I reactions involve oxidation, reduction, or hydrolysis of the drug

molecules, with oxidation being the most common reaction. Oxidation
reactions are catalyzed by the mixed-function oxidase enzyme system,
which is mainly found on the smooth endoplasmic reticulum of cells. This
enzyme system consists of three distinct components: cytochrome c reductase (cytochrome P-450 reductase), cytochrome P-450, and a phospholipid.
The mixed-function oxidase enzyme system can catalyze a variety of different types of reactions. These include
Aromatic ring hydroxylation

Side-chain hydroxylation
N-dealkylation
O-dealkylation
S-dealkylation
Sulfoxidation
Desulfuration
Deamination
Dehalogenation
If the primary metabolite is sufficiently polar, the kidney can excrete it.
If this metabolite is still sufficiently lipophilic to be reabsorbed following
glomerular filtration, it will be subject to the second phase of drug metabolism, in which the handle is conjugated.
Phase II Metabolic Reactions
Phase II consists of conjugating either the drug or its oxidized metabolite.
Conjugation usually involves attaching the conjugating chemical to
hydroxyl, amine, or carboxyl group on the parent drug or its primary
metabolite formed during phase I. Common conjugating chemicals include
glucuronic acid (glucuronide conjugates),
sulfuric acid (sulfate conjugates), and
glycine (glycine conjugates).
Conjugated metabolites are usually eliminated rapidly by the kidneys.
Figures 18 and 19 depict the two phases of drug metabolism.
FREQUENTLY USED PHARMACOKINETIC EXPRESSIONS

Bioavailability
Bioavailability refers to the amount of administered drug that reaches the
systemic circulation. Two factors can reduce bioavailability: poor absorption and extensive rapid metabolism as the drug passes through the liver or
intestine before it reaches the systemic circulation (first-pass metabolism).
Chapter 1
Phase I
11
Phase II
Figure 18 Two phases of drug metabolism. (After Gram TE. Metabolism of drugs. In: Craig
CR, Stitzel RE, eds. Modern pharmacology. Boston: Little, Brown, 1994:37.)
Figure 19 Summary of drug metabolism and elimination.
Clearance
Clearance refers to the plasma volume cleared of drug over a given period
of time by the kidney (renal clearance), by liver metabolism (hepatic
clearance), in the bile (biliary clearance), or by all organs and processes
combined (total body clearance). A drug that is rapidly removed by an
12
PDQ PHARMACOLOGY
organ will have a high clearance value. For example, the renal clearance of
penicillin G approximates total renal blood flow because the drug is filtered
and secreted and not reabsorbed. Therefore, its renal clearance value
exceeds 600 mL/minute. A drug that is filtered by the kidney, but not
secreted or reabsorbed, will have a renal clearance value that approximates
the glomerular filtration rate of 120 mL/minute. If, on the other hand, a
drug is extensively reabsorbed into the systemic circulation as it passes
down the renal tubules, its clearance value will be much lower than the
glomerular filtration rate.
Half-Life
Half-life (t1/2) is the time it takes for the plasma concentration, or the
amount of drug in the body, to be reduced by 50%. Half-life is expressed in
minutes or hours.
Steady State
Drugs are often administered on a regular basis for long periods of time.
During the first few doses of a drug its concentration in the body usually
increases. Eventually, however, the level of the drug in the body stops
increasing and reaches a steady concentration. At this point, the amount of
drug being absorbed equals the amount being eliminated. This is referred
to as steady state.
2
Pharmacodynamics: How
Drugs Work
DRUG EFFECTS MEDIATED THROUGH DRUG RECEPTORS
Importance to Drug Therapy
Most drugs act in the body by either stimulating or blocking drug receptors. The combination of the drug with the receptor results in a molecular
change in the receptor that triggers a chain of events leading to a response
within the cell.
Description of a Drug Receptor
A receptor is any cellular macromolecule to which a drug binds to initiate
its effects. Although the exact nature of each receptor is not known, it is recognized that each type of receptor shows amazing specificity for the drug
or drugs with which it binds.
Agonists
Agonists are chemicals, such as drugs, that interact with a receptor and initiate a cellular reaction. They possess affinity for a receptor, and once
attached to the receptor demonstrate intrinsic activity. A cholinergic drug,
for example, stimulates muscarinic receptors (see Chapter 4) because it has
both affinity for these receptors and intrinsic activity.
Antagonists
Antagonists have affinity for a receptor, but lack intrinsic activity; therefore,
they do not stimulate the receptor. During the time the antagonist occupies
13
14
PDQ PHARMACOLOGY
the receptor, the drug will block any other chemical from binding to and
stimulating the receptor. An anticholinergic, for example, prevents acetylcholine from stimulating muscarinic receptors (see Chapter 4).
Specificity of Drug Receptors
The affinity of a drug for its receptor depends on its chemical structure.
Changing the structure of a drug, even slightly, can increase or decrease its
affinity for a receptor and significantly modify its pharmacologic effect. For
example, epinephrine (see Chapter 5) has affinity for beta2 receptors and
causes dilation of bronchioles. The structure of norepinephrine differs
from epinephrine only in that the methyl group on epinephrine is replaced
by hydrogen on norepinephrine. As a result of this change, norepinephrine
has no affinity for beta2 receptors and will not dilate bronchioles.
Effect of Agonists and Antagonists on Drug Receptor Density
Chronic drug therapy can affect receptor density. Long-term treatment with
an agonist reduces the number of drug receptors. This is called downregulation, tissue tolerance, or desensitization. When this occurs, the effects
of the drug diminish. An example of this type of drug-receptor interaction
is seen when asthmatic patients receive constant therapy with a beta2 agonist (see Chapter 5) to dilate their bronchioles. As therapy continues, the
effect of the drug decreases because of a reduced density of beta2 receptors.
Chronic therapy with an antagonist increases the density of drug receptors (up-regulation). For example, long-term treatment with a beta blocker
(see Chapter 6) causes an up-regulation of beta receptors. If the beta
blocker is suddenly stopped, patients can experience cardiac dysrhythmias
through increased sympathetic stimulation of these receptors due to their
greater abundance.
DOSE-RESPONSE RELATIONSHIPS
Potency and Intrinsic Activity Of Agonists
The magnitude of a drug response is believed to be a function of the concentration of the drug-receptor complex. Generally, the higher the concentration of the drug at the receptor site, the greater its effect. This occurs
up to the point when all receptors have been occupied and a maximum
response has been elicited. Increasing the dose of drug administered above
this level, and its corresponding concentration at the receptor site, will not
result in a further increase in effect.
Figure 21 illustrates the mean dose-response curves of three hypothetical drugs.
Chapter 2
Pharmacodynamics: How Drugs Work
15
Figure 21 Idealized dose-response curves of three agonists (a,b,c) that increase heart rate,
but differ in potency, maximum effect, or both. Dashed lines indicate 50% of maximum
response (horizontal) and individual ED50 values (vertical). (After Fleming WW. Mechanisms of
drug action. In: Craig CR, Stitzel RE, eds. Modern pharmacology. Boston: Little, Brown, 1994:15.)
Drugs a and b produce the same maximum effect or response, which is

an increase in heart rate of 80 beats per minute. However, the fact that the
dose-response curve for drug a lies to the left of the curve for drug b indicates that drug a is more potent. The ratio of the potencies for drugs a and
b can be calculated on the basis of their respective ED50 values. ED50, is the
dose that produces 50% of the maximum response. In the example depicted
in Figure 21, the difference in potency between a and b is quantified by the
following ratio:
ED50b/ED50a.
Thus, drug a is 10 times more potent than drug b (3/0.3).

Drug c has a maximum effect that is lower than that of either drug a or
drug b. Drug c is said to have a lower intrinsic activity than the other two
drugs. Drugs a and b are full agonists with an intrinsic activity of 1; drug c
is called a partial agonist and has an intrinsic activity of 0.5 because its
maximum effect is half the maximum effect of a or b. The potency of drug
c, however, is the same as that of drug b, because both drugs have the same
ED50 (3 g/kg).
Therapeutically, it is important not to equate greater potency of a drug
with therapeutic superiority as long as it produces the same maximum
16
PDQ PHARMACOLOGY
effect, because one can simply increase the dose of a less potent drug to
obtain the identical response observed with a more potent one.
Competitive Antagonism
Competitive antagonism is the most frequently encountered type of drug
antagonism in clinical practice. Examples of drugs that exhibit this type of
antagonism include antihistamines, H2-antagonists, beta blockers, and anticholinergics. For these drugs, and many others like them, the antagonist
competes with the agonist for the same site on the receptor but unlike the
agonist, it does not induce a response on binding because the antagonist
has little or no efficacy. For most competitive antagonists, the bond formed
with the receptor is loose, and the antagonism is reversible. In this situation, the antagonism increases as the concentration of the antagonist is
increased. Conversely, the antagonism can be overcome if the concentration
of the agonist is increased. Figure 22 depicts the idealized dose-response
curves of an agonist in the absence and presence of increasing doses of an
equilibrium-competitive antagonist. In this figure, the increasing presence
of the antagonist has shifted the dose-response curves of the agonist to the
right. Any level of response is still possible, but greater amounts of the agonist are required to achieve it.
It must be pointed out, however, that the continual shift of the curve to
the right, with no change in maximum response as the dose of the antagonist is increased, assumes that very large amounts of the agonist can be
delivered to the receptor site. This is usually impossible if the agonist is a
Figure 22 Idealized dose-response curves of an agonist in the absence (a) and the presence
(b, c, d) of increasing doses of an equilibrium-competitive antagonist. (After Fleming WW. Mechanisms of drug action. In: Craig CR, Stitzel RE, eds. Modern pharmacology. Boston: Little, Brown,
1994:17.)
Chapter 2
Pharmacodynamics: How Drugs Work
17
naturally occurring chemical, such as acetylcholine, epinephrine, or histamine because in this situation, the supply of the agonist is limited. As a
result, increasing the concentration of the antagonist at the receptor site will
ultimately block the effects of the endogenous agonist.
DRUG EFFECTS NOT MEDIATED THROUGH RECEPTORS

Not all drugs depend on receptors to produce their effects. Antacids, for
example, simply depend on neutralizing gastric acid. Cathartics, which work
by either irritating the bowel or by drawing water from the blood into the
feces by osmosis, also act independent of receptors. It will become apparent throughout the remainder of this book which drug effects depend on
drug-receptor interactions and which do not.
Part 2
Autonomic
Pharmacology
Introduction to Autonomic
Pharmacology
FUNCTIONS OF THE AUTONOMIC NERVOUS SYSTEM
The autonomic nervous system (Figure 31) is composed of the sympathetic and parasympathetic divisions. It functions to innervate
1. smooth muscle,
2. cardiac muscle, and
3. exocrine glands.
It also regulates
1.
2.
3.
4.
5.
6.
heart rate,
blood pressure,
sweat, salivary, and gastric secretions,
pupil diameter and eye accommodation,
gastrointestinal motility, and
diameter of the bronchioles.
DIVISIONS OF THE AUTONOMIC NERVOUS SYSTEM

Common Characteristics of Sympathetic and Parasympathetic
Divisions
Each parasympathetic and sympathetic nerve
originates in the central nervous system (CNS),
has its activity controlled and integrated by the brain, and
contains a preganglionic neuron, whose cell of origin lies within the
CNS, and a postganglionic neuron, whose cell of origin lies within a
18
Chapter 3
Introduction to Autonomic Pharmacology
19
Figure 31 Overview of the functions of the sympathetic and parasympathetic divisions of

the autonomic nervous system. (Drawing by Ted Johnson.)
ACh = acetylcholine; Decr = decrease; E = epinephrine; GI = gastrointestinal; Incr = increase;
NE = norepinephrine.
Chapter 3
20
ganglion outside the CNS. The pre- and postganglionic neurons synapse
at a ganglion.
Parasympathetic Division
1. Most preganglionic fibers originate in the midbrain or medulla oblongata of the brain.
2. Ganglia are found close to, or within, innervated organs.
3. A few preganglionic nerves leave the CNS in the sacral portion of the
spinal cord. These fibers also synapse with postganglionic nerves close
to, or within, the innervated organs.
4. The parasympathetic nervous system carries on many of the mundane
day-to-day functions:
(a) Flow of saliva
(b) Peristalsis
(c) Constriction of pupils
(d) Accommodation for near vision
Sympathetic Division
1. Sympathetic preganglionic fibers begin in the intermediolateral
columns of the spinal cord and extend from the first thoracic to the second or third lumbar segments.
2. Once outside the spinal cord, preganglionic fibers synapse with postganglionic nerves at ganglia located in three areas of the body:
(a) Paravertebral ganglia, which lie on each side of the vertebral column
(b) Prevertebral ganglia (ie, celiac, superior mesenteric, inferior mesenteric, and aorticorenal ganglia) in the abdominal cavity
(c) Terminal ganglia near the urinary bladder and rectum
3. Stimulation of the sympathetic nervous system prepares the body to
meet stress in the following ways:
(a) Increasing heart rate
(b) Elevating cardiac output
(c) Stimulating intermediary metabolism
(d) Dilating bronchioles
(e) Redistributing blood from the GI tract to the skeletal muscles
Chapter 3
21
NEUROTRANSMITTERS
Chemical Transmission of Impulses
Ganglia
Acetylcholine is the neurotransmitter at all autonomic ganglia. Released by
preganglionic nerve endings, acetylcholine stimulates nicotinic receptors
on the postganglionic neurons (Figure 32).
Parasympathetic Nerve Endings
Acetylcholine is also the neurotransmitter at all parasympathetic nerve endings. Following its release, acetylcholine stimulates muscarinic receptors on
the innervated tissue.
Figure 32 Chemical transmission of nerve impulses. ACH = Acetylcholine; NE = norepi-
nephrine; E = Epinephrine; N = nicotinic receptors; M = Muscarinic receptors; 1 = alpha1 receptors; = beta1 or beta2 receptors. (After Johnson GE, Osis M, Hannah KJ. Pharmacology and
the nursing practice. 4th ed. Toronto: WB Saunders, 1998:258260.)
Chapter 3
22
Sympathetic Nerve Endings

Norepinephrine (noradrenaline) is the neurotransmitter released from
most sympathetic postganglionic neurons. Once released, it stimulates
alpha1 receptors on blood vessels to cause vasoconstriction, or beta1 receptors in the heart to increase both heart rate and force of contraction.
Acetylcholine is the neurotransmitter released by a few sympathetic postganglionic nerves (eg, sympathetic innervation of the sweat glands), where
it stimulates muscarinic receptors.
Adrenal Medulla
Epinephrine (adrenaline) is an emergency hormone released by the adrenal medullae. It increases heart rate by stimulating cardiac beta1 receptors
and dilates the bronchioles by stimulating beta2 receptors. Adrenaline
redistributes blood in the body, shunting it from the peritoneal area to the
skeletal muscles. It does this by stimulating alpha1 receptors on visceral vessels and beta2 receptors on vessels in skeletal muscle.
Synthesis and Inactivation of Neurotransmitters

Acetylcholine
Synthesized within nerves from acetylcoenzyme A and choline by the
enzyme choline acetylase (Figure 33), acetylcholine is stored in vesicles
within the nerve until released. The enzyme acetylcholine esterase, also
formed within the nerve, rapidly inactivates acetylcholine (Figure 34).
Norepinephrine and Epinephrine
The synthesis of norepinephrine and epinephrine is presented in Figure 35.
The rate-limiting step in the synthesis of norepinephrine and epinephrine
is the conversion of tyrosine to dopa (dihydroxyphenylalanine), the precursor of dopamine. Epinephrine, norepinephrine, and dopamine are often
called catecholamines. In the noradrenergic neurons, the end product is
norepinephrine. In the adrenal medulla, the synthesis is carried one step
further. An enzyme found in the adrenal medulla, phenylethanolamine-Nmethyltransferase, converts norepinephrine to epinephrine. The human
adrenal medulla contains approximately four times as much epinephrine as
norepinephrine. The absence of phenylethanolamine-N-methyltransferase
in noradrenergic neurons accounts for the absence of significant amounts
of epinephrine in noradrenergic neurons.
The final step in the synthesis of norepinephrine, the conversion of
dopamine to norepinephrine, takes place within intraneuronal storage
vesicles. Norepinephrine is released from noradrenergic nerve endings by
Chapter 3
23
Figure 33 Synthesis of acetylcholine. After Johnson GE, Osis M, Hannah KJ. Pharmacology
and the nursing practice. 4th ed. Toronto: WB Saunders, 1998:258260.
Figure 34 Inactivation of acetylcholine. After Johnson GE, Osis M, Hannah KJ. Pharmacology and the nursing practice. 4th ed. Toronto: WB Saunders, 1998:258260.
Chapter 3
24
Figure 3-5 Synthesis of norepinephrine and epinephrine. After Johnson GE, Osis M, Hannah
KJ. Pharmacology and the nursing practice. 4th ed. Toronto: WB Saunders, 1998:258260.
action potentials through exocytosis. The norepinephrine contents of entire

vesicles are emptied into the synaptic region, where they may interact with
adrenergic receptors.
Norepinephrine is removed from the area of the synapse and receptors by
reuptake into the secreting neuron. Neuronal reuptake is the most
important mechanism for terminating the action of released norepinephrine. Following neuronal reuptake, norepinephrine is either stored
in vesicles or inactivated by mitochondrial monoamine oxidase (MAO);
diffusion from the synapse into the circulation and ultimate enzymatic
destruction in the liver by MAO or catechol-O-methyltransferase
(COMT); and
Chapter 3
25
active transport of the catecholamine into effector cells (extraneuronal

uptake), followed by enzymatic inactivation by COMT.
Figure 36 summarizes these processes.
AUTONOMIC RECEPTORS
Cholinergic Receptors
Nicotinic Receptors (so-called because the effects of nicotine in ganglia
and on skeletal muscle mimic the actions of acetylcholine)
Found in all autonomic ganglia. Nicotinic receptors are also found on skeletal muscle. However, nicotinic receptors in ganglia are not identical to those
on skeletal muscle. Nicotinic receptors in ganglia can be blocked competitively by ganglionic blockers. Ganglionic blockers do not block nicotinic
receptors on skeletal muscle; rather, these receptors are blocked by neuromuscular blockers (eg, tubocurarine).
Muscarinic Receptors (so-called because the effects of muscarine on
receptors innervated by parasympathetic postganglionic nerves and sympathetic cholinergic nerves mimic the actions of acetylcholine on these
receptors)
Found in smooth muscle, cardiac muscle, and exocrine glands innervated
by parasympathetic nerves. They are involved in the constriction of bronchioles, slowing of heart rate, increase in GI motility, and secretion of salivary, gastric, and bronchiolar glands. They are also found in sweat glands
innervated by the sympathetic nervous system. Muscarinic receptors are
also located in the brain. Several subtypes of muscarinic receptors have been
detected:
M1 receptors are found in various secretory glands.
M2 receptors predominate in the myocardium and also appear to be
found in smooth muscle.
M3 and M4 receptors are located in smooth muscle and secretory glands.
All subtypes are found in the CNS.
Adrenergic Receptors
Alpha1 Postsynaptic
Found on smooth muscle innervated by sympathetic nerves. Important
functions include vasoconstriction of precapillary resistance vessels (arterioles) and capacitance vessels (veins).
Chapter 3
26
Figure 36 Synthesis, storage, release and inactivation of norepinephrine. MAO = monoamine

oxidase; COMT = catechol-O-methyltransferase; NE = norepinephrine. (After Fleming WW. Introduction to the autonomic nervous system. In: Craig CR, Stitzel RE, eds. Modern Pharmacology.
Boston: Little, Brown, 1994;108.)
Alpha2 Presynaptic
Found on adrenergic nerve terminals. They are responsible for reducing the
release of norepinephrine from sympathetic nerves.
Beta1 Postsynaptic
Found on postsynaptic effector cells, especially in the heart. They are
responsible for the sympathetically mediated increase in heart rate and force
of contraction. They are also found on fat cells where they are responsible
for the sympathetically mediated increase in lipolysis. Beta1 receptors also
mediate the release of renin.
Beta2 Postsynaptic
Found on bronchioles, where they mediate sympathetic bronchodilation.
They are located on precapillary resistance vessels (arterioles) in skeletal
muscle where they mediate vasodilation. Beta2 receptors relax the bladder
and decrease intestinal motility.
4
Cholinergic and
Anticholinergic Drugs
CHOLINERGIC DRUGS (Figure 41)
Drugs Directly Stimulating Cholinergic Receptors
Rationale for Directly Acting Cholinergics
Acetylcholine has little value as a drug because
it is rapidly metabolized by acetylcholinesterase and serum cholinesterase,
and
it stimulates both muscarinic and nicotinic receptors.
Directly acting cholinergics have partially overcome these limitations. These
drugs
are resistant to cholinesterase hydrolysis and have a longer duration of
action than acetylcholine, and
show some selectivity for muscarinic receptors. However, only bethanechol appears to completely lack nicotinic agonist effects (Table 41).
General Uses for Directly Acting Cholinergics

In the Eye
Carbachol and pilocarpine are instilled in the eye to stimulate circular muscles in the iris to produce miosis. This action increases the drainage of the
aqueous humor through the canals of Schlemm and lowers intraocular
pressure in glaucoma. Carbachol and pilocarpine can also produce hyperemia and aching eyes and head. Refer to Figure 42 and Table 42 for a
review of the autonomic pharmacology of the eye.
27
28
PDQ PHARMACOLOGY
Figure 41 Diagrammatic representation of the types of drugs affecting the parasympathetic

nervous system. (Drawing by Ted Johnson.)
Systemically
Carbachol and bethanechol stimulate muscarinic receptors in the bladder
and intestinal tract. They are used to treat postoperative intestinal atony,
postoperative urinary retention, and neurogenic atony of the bladder. Stimulation of muscarinic receptors in the heart can be used to treat paroxysmal tachycardia. The systemic administration of these drugs also increases
gastric acid secretion, constricts bronchioles, increases salivary and sweat
secretion, and dilates blood vessels. Adverse effects include sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, bronchospasm, cardiac arrest, and circulatory collapse.
Chapter 4
29
Cholinergic and Anticholinergic Drugs
Table 41
Comparative Pharmacologic Properties of Some Directly

Acting Cholinergics
SusceptMuscarinic Effects
ibility to
cholin- Cardio- GI and
esterases vascular Bladder
Eye
Chemical
Acetylcholine
Sweat
Nicotinic
Effects
+++
++
++
++
Carbachol
+++
++
+++
Bethanechol
+++
++
Pilocarpine
++
+++
++
Cholinesterase Inhibitors (Anticholinesterases)

Cholinesterase inhibitors potentiate and prolong the effects of acetylcholine
released by neurons at
neuromuscular junctions,
adrenal medullae,
autonomic ganglia,
cholinergic synapses of the autonomic nervous system (ie, postganglionic parasympathetic nerves and a few postganglionic sympathetic
nerves), and
cholinergic synapses in the central nervous system.
Table 43 summarizes the effects of cholinesterase inhibitors.
Table 42
Summary of Autonomic Innervation of the Eye

Part of
the Eye
Iris
Ciliary
Body
Innervation
Parasympathetic to
circular muscle
Sympathetic to
longitudinal
muscle
Parasympathetic to
circular muscle
Receptors
Muscarinic
Alpha1
Muscarinic
Effects
Constriction of
pupil (miosis)
Dilation of pupil
(mydriasis)
Constriction of
sphincter permitting
accommodation
30
PDQ PHARMACOLOGY
Figure 42 Autonomic innervation of the eye. (After Johnson GE, Osis M, Hannah KJ. Pharmacology and the nursing practice. 4th ed. Toronto: WB Saunders, 1998:265.)
Anticholinesterase drugs can be divided into:

Reversible cholinesterase inhibitors:
Carbamates (neostigmine, pyridostigmine, physostigmine, ambenonium, and demecarium), and
Quaternary nitrogen compounds (edrophonium)
and
Irreversible cholinesterase inhibitors:
Phosphates (echothiophate), and
Fluorophosphates (isoflurophate)
Figures 43 and 44 provide the structures of reversible and irreversible
cholinesterase inhibitors.
Mechanism of Action of Reversible Cholinesterase Inhibitors

(Figure 45)
Carbamates
O
R2-N-C-O-R
Bind to the esteratic site on the cholinesterase molecule preventing acetylcholine from attaching to the enzyme.
Chapter 4
31
Table 43
Effects of Cholinesterase Inhibitors

Body Organ
Effect of Cholinesterase Inhibitor
Skin
Increased sweat
Eye
Lacrimation, miosis, blurred vision, spasm of accommodation
Digestive tract
Salivation; increased gastric, pancreatic and intestinal

secretions; increased gut tone and motility (abdominal
cramps, vomiting, diarrhea, and defecation)
Urinary tract
Urinary frequency and incontinence
Respiratory tract
Increased bronchial secretions, bronchoconstriction, weakness

or paralysis of respiratory muscles
Skeletal muscle
Fasciculations, weakness, depolarizing block and paralysis
Cardiovascular
system
Bradycardia (due to muscarinic effects), decreased cardiac

output, hypotension
These may be counterbalanced by ganglionic stimulation at the
adrenal medullae and the release of increased amounts of
adrenaline
Central nervous
system
Tremor, anxiety, restlessness, disrupted concentration and

memory, confusion, sleep disturbances, desynchronization of
electroencephalogram, convulsions, coma, circulatory
and respiratory depression
Quaternary Nitrogen Drugs

R-N+-(R)3
Attach to the anionic site on the cholinesterase molecule, preventing acetylcholine from binding to this site.
General Uses for Reversible Cholinesterase Inhibitors

In the Eye
Physostigmine and demecarium are instilled in the eye to produce miosis
and increase drainage of the aqueous humor in the treatment of glaucoma.
Systemically
Neostigmine is used to increase muscarinic stimulation in the intestine and
bladder in the prophylaxis or treatment of intestinal atony and urinary
retention. It is also used to reverse the effects of competitive neuromuscular
Figure 43 Representatives of reversible cholinesterase inhibitors.
32
PDQ PHARMACOLOGY
Chapter 4
33
Figure 44 Representatives of irreversible cholinesterase inhibitors
blockers (see Chapter 7). Along with pyridostigmine and ambenonium,

neostigmine is also used to increase stimulation of nicotinic receptors in the
treatment of myasthenia gravis.
Mechanism of Action of Irreversible Cholinesterase Inhibitors

Phosphates or Fluorophosphates
Irreversible inhibitors of cholinesterase phosphorylate the esteratic site on
the cholinesterase molecule. The phosphorylated enzyme is a stable complex. Recovery from the effects of an irreversible inhibitor usually depends
on the synthesis of new cholinesterase molecules (Figure 46).
General Uses for Irreversible Cholinesterase Inhibitors

In the Eye
Instilled in the eye, these drugs produce marked miosis. They are used when
other miotics fail to decrease the intraocular pressure in glaucoma. Because
they are also absorbed into the systemic circulation, irreversible
cholinesterase inhibitors may also produce systemic cholinergic stimulation. Other adverse effects include cataracts, spasm of accommodation, and
cysts of the iris.
ANTICHOLINERGIC DRUGS (See Figure 41)

Mechanism of Action
Anticholinergic drugs competitively block muscarinic receptors, inhibiting
all parasympathetic functions and sympathetic cholinergic activity (eg,
sweat).
Figure 47 provides the chemical structures of several anticholinergics.
These drugs compete with acetylcholine for muscarinic receptors because
34
PDQ PHARMACOLOGY
Figure 45 Interaction of acetylcholine, edrophonium, and neostigmine with the

cholinesterase molecule, demonstrating how the latter two chemicals prevent the attachment
of acetylcholine to the enzyme.
Chapter 4
35
Figure 46 Interaction of isoflurophate with a cholinesterase molecule.
the intra-atomic distance between the esteratic group and the nitrogen on
each anticholinergic is the same as on acetylcholine.
General Uses for Anticholinergic Drugs

In the Eye
Anticholinergics, such as homatropine, eucatropine, cyclopentolate, and
tropicamide, block muscarinic receptors on the circular muscle of the iris.
As a result, sympathetic stimulation of the alpha1 receptors on the longitudinal muscles of the iris can act unopposed by cholinergic stimulation and
dilate the pupil (mydriasis). Anticholinergics also block muscarinic receptors on the ciliary body and inhibit accommodation for near vision (cycloplegia). Anticholinergics are used for intraocular examination, intraocular
surgery, estimation of errors of refraction, and as a provocative test for
angle-closure glaucoma.
Systemically
Anticholinergics reduce muscarinic stimulation throughout the body. They
are used for blocking bronchiolar secretion, which aids in anesthesia;
inhibiting GI secretion and activity, which may facilitate the treatment of
peptic ulcers and irritable bowel syndrome; and decreasing vagal tone to the
heart, which can be of value in carotid sinus syndrome. The adverse effects
of systemically administered anticholinergics include mydriasis, cyclople-
36
PDQ PHARMACOLOGY
Figure 47 Structures of acetylcholine and several anticholinergics, showing structural similarity between acetylcholine and atropine.
gia, dryness of the mouth, flushing, tachycardia, irritability, thirst, fever,

ataxia, confusion, somnolence, hallucinations, and delirium.
GANGLIONIC BLOCKERS (See Figure 41)

Mechanism of Action
Ganglionic blockers competitively inhibit acetylcholine from stimulating
nicotinic receptors in sympathetic and parasympathetic ganglia. Examples
of ganglionic blocking drugs include hexamethonium, mecamylamine,
chorisondamine, and trimethaphan.
Uses
Ganglionic blockers are rarely used in medicine because they inhibit all
autonomic functions. Their effects include hypotension, tachycardia, dryness of the mouth and skin, constipation, and cycloplegia.
5
Adrenergic Drugs
(Sympathomimetics)
P
rior to beginning this chapter, it would be beneficial to review the

synthesis and inactivation of norepinephrine and epinephrine (see Figures
35 and 36), as well as the functions of alpha and beta receptors (pages 26
and 27 and Figure 51).
Adrenergic drugs may act
directly by stimulating adrenergic receptors, or
indirectly by releasing norepinephrine from sympathetic neurons (Figure 52).
DIRECTLY ACTING ADRENERGICS

May Stimulate
1.
2.
3.
4.
Alpha1 (1)-adrenergic receptors

Beta ()-adrenergic receptors
1- and -adrenergic receptors
Dopamine receptors
Figure 53 presents the structure of epinephrine, norepinephrine,

dopamine, and isoproterenol. The first two demand immediate attention
because most adrenergic drugs are designed to mimic the properties of
one, or both, of these naturally occurring compounds. Table 51 and Figure 54 compare the activities of epinephrine and norepinephrine.
37
38
PDQ PHARMACOLOGY
Figure 51 Actions mediated by adrenergic receptors. (Drawing by Ted Johnson.)

NE = norepinephrine; GI = gastrointestinal.
DIFFERENCES BETWEEN EPINEPHRINE AND NOREPINEPHRINE

Epinephrine: Emergency Hormone Secreted in Stress
1. Increases cardiac output (CO) (1)
2. Redistributes blood from viscera to skeletal muscles by constricting precapillary resistance vessels (arterioles) in the abdomen (1) and dilating precapillary resistance vessels in skeletal muscles (2)
3. Maintains venous return by constricting capacitance vessels (veins) (1)
4. Dilates bronchioles (2)
Norepinephrine: Sympathetic Neurotransmitter Responsible for Routine
Cardiovascular Control
1. Increases heart rate (1) when released by cardiac accelerator nerves
Chapter 5
Adrenergic Drugs (Sympathomimetics)
39
Figure 52 Classification of adrenergic drugs.
2. Decreases heart rate when infused because the increase in peripheral

resistance reflexly stimulates the vagus, overcoming the direct 1 stimulation produced by norepinephrine
3. Maintains peripheral resistance by constricting precapillary resistance
vessels (1)
4. Maintains venous return and prevents orthostatic hypotension by constricting capacitance vessels (1)
Figure 53 Structures of norepinephrine, epinephrine, dopamine, and isoproterenol.
Decreases heart rate. The

Increases peripheral
direct 1-receptor stimularesistance, due to
tion on the heart is more
1-receptor stimulation
than counterbalanced by
of arterioles (precapillary
reflex vagal bradycardia,
resistance vessels)
resulting from an increase
in peripheral resistance
by 1-receptor stimulation
of the arterioles
Norepinephrine
Venous Return
Bronchioles
Increases venous return

due to 1-stimulation of
the veins (capacitance
vessels)
No major effect
Decreases peripheral
Increases venous return due Dilates bronchioles, due
resistance. Stimulates
to 1-receptor stimulation
to 2 -receptor stimulation
1-receptors on arterioles
of the veins (capacitance
in the abdomen, and
vessels)
2-receptors on arterioles
in skeletal muscle, with
the latter effect being
greater
Increases both heart rate

and force of contraction;
a 1-mediated effect
Peripheral
Resistance
Epinephrine
Heart Rate and

Force of
Contraction
Comparison of the Actions of Infused Epinephrine and Norepinephrine
Table 51
40
PDQ PHARMACOLOGY
Chapter 5
41
Figure 54 Comparison of the effects of infused norepinephrine, epinephrine, and isoproterenol on pulse rate, blood pressure, and peripheral resistance. (After Allwood MJ, Cobbold
AE, Ginsburg J. Peripheral vascular effects of noradrenaline, isopropylnoradrenaline and
dopamine. Br Med Bull 1963; 19:132.)
1. 1-, 1-, and 2- Receptor Agonists (Epinephrine/Adrenaline)

Effect on Blood Vessels and Vascular Resistance
Constrict arterioles (precapillary resistance vessels) in skin, mucous membranes, kidneys, and splanchnic beds (1-receptors).
Dilate arterioles in skeletal muscles (2-receptors).
Small doses reduce total peripheral resistance (TPR) because the decrease
in PR in skeletal muscles exceeds the increase in PR in cutaneous and
mucous membranes, kidneys, and splanchnic area.
Large doses increase TPR due to a generalized 1 stimulation.
Increase venous return due to 1 stimulation of veins (capacitance vessels).
Effect on the Heart
Increase cardiac contractility (1-receptors).
42
PDQ PHARMACOLOGY
Increase heart rate (1), unless an increase in TPR from high doses reflexly
slows the heart.
Increase stroke volume and cardiac output.
Effect on Blood Pressure
Ranges from no change to a moderate increase in mean pressure with low
doses.
Increase systolic pressure. Decrease diastolic pressure with low doses and
increase diastolic pressure with higher doses.
Effect on the Bronchioles
Dilate bronchioles (2-receptors).
Effect on the Eye
Mydriasis (1-receptors on the radial muscles of the iris).
Epinephrine decreases intraocular pressure in glaucoma by increasing
drainage of aqueous humor, possibly due to vasodilation of conjunctival
blood vessels.
Additional Effects
Decrease in GI motility and tone (2-receptor stimulation).
Relaxation of uterus (2-receptor stimulation).
Relaxation of urinary bladder (2-receptor stimulation).
Increase in lipolysis (1-receptors) and glycogenolysis (2-receptor stimulation).
Uses
Epinephrine is used to
treat bronchospasm,
treat hypersensitivity reactions,
prolong action of local anesthetics,
treat cardiac arrest, and
treat open-angle glaucoma.
Adverse Effects
Anxiety, fear, tenseness, restlessness, headache, tremor, weakness, dizziness,
pallor, respiratory difficulty, palpitations.
Chapter 5
43
2. 1-Receptor Agonists (Norepinephrine/Noradrenaline/

Levarterenol, Methoxamine, and Phenylephrine)
Effect on Blood Vessels and Vascular Resistance
Constrict arterioles (precapillary resistance vessels) in skin, mucous membranes, skeletal muscles, kidneys, and splanchnic beds.
Increase TPR.
Increase venous tone.
Effect on the Heart
Decrease heart rate as a result of an increase in TPR and reflex vagal stimulation.
Effect on Blood Pressure
Increase in mean, diastolic, and systolic pressures.
No change in pulse pressure.
Additional Effects
Mydriasis, due to stimulation of radial muscles of the iris.
Uses
(a) Systemic (all of the above drugs) (a) maintenance of blood pressure
(BP) in acute hypotensive states, (b) surgical and nonsurgical trauma, (c)
central vasomotor depression, and (d) hemorrhage.
Phenylephrine in nose vasoconstriction and decongestion in the common cold; treatment of vasomotor and allergic rhinitis and sinusitis.
Phenylephrine in eye relief of conjunctivitis; production of mydriasis
during refraction, ophthalmic examination, or diagnostic procedures.
Adverse Effects
Systemicbradycardia, ventricular extrasystoles and tachycardia (from
phenylephrine), headache, local necrosis.
Phenylephrine in nose or eyeburning, stinging, dryness of mucosa, palpitations, tachycardia, arrhythmias, increase in BP, headache, blurred vision,
central nervous system (CNS) depression.
44
PDQ PHARMACOLOGY
3. -Receptor Agonists
Beta-adrenergic drugs may be divided into the following groups (Figure 55):
1-, 2- Receptor agonists (isoproterenol)
1-Receptor agonists (dobutamine)
2-Receptoragonists used to dilate bronchioles (albuterol/salbutamol,
fenoterol, salmeterol, terbutaline)
2-Receptor agonists used to dilate peripheral arterioles (nylidrin)
2-Receptor agonists used to decrease both the frequency and intensity
of uterine contractions (ritodrine)
A. 1-, 2-Receptor Agonists (Isoproterenol)

Effect on the Heart
Increase heart rate and force of contraction (a 1-mediated effect).
Effect on the Bronchioles
Dilate bronchioles (a 2-mediated effect).
Effect on Blood Vessels
Dilate blood vessels (a 2-mediated effect).
Uses
Isoproterenol is used to
treat low cardiac output,
dilate bronchioles, and
treat asthma.
Figure 55 Classification of -agonists.
Chapter 5
45
Adverse Effects
Refractory bronchospasm, palpitations, tachycardia, cardiac arrhythmias,
cardiac arrest, hypotension, headache, nausea, tremor, insomnia.
B. 1-Receptor Agonists (Dobutamine)

Effect on the Heart
Increases both heart rate and force of contraction, with a greater effect on
contractile force.
Effect on Renal Vessels
Does not stimulate dopamine receptors on renal vasculature, and, therefore,
it does not dilate renal vessels.
Uses
Is used to treat cardiac decompensation due to depressed contractility
from organic heart disease or surgical procedures. The major advantage of
dobutamine over other sympathomimetics is that it increases cardiac output with a minimal effect on heart rate.
Adverse Effects
Tachycardia, angina, cardiac arrhythmias, headache, hypertension, nausea,
vomiting.
C. 2-Receptor Agonist Bronchodilators (Albuterol/Salbutamol,

Fenoterol, Salmeterol, Terbutaline)
Actions
Dilate bronchioles.
Increase forced expiratory volume in one second (FEV1).
Increase forced expiratory flow (FEF).
Produce tachycardia in higher doses.
Uses
Relief of bronchospasm.
Treatment of chronic bronchitis.
Treatment of bronchopulmonary disorders in which bronchospasm is a
complicating factor.
46
PDQ PHARMACOLOGY
Adverse Effects
Headache, dizziness, nausea, tremor, palpitations.
Advantages over Nonselective -Receptor Agonists, such as

Isoproterenol
Greater Selectivity For Beta2 Receptors
These drugs are more selective in their ability to preferentially stimulate
2-receptors. Nonselective -agonists, such as isoproterenol, stimulate both
1- and 2-receptors. As a result, nonselective beta agonists increase heart
rate, while they dilate bronchioles. In normal therapeutic doses, selective 2agonists dilate bronchioles, while producing little tachycardia (Figure 56).
Oral Effectiveness
Isoproterenol is not effective orally. Most 2-agonists can be given orally or
by inhalation.
Figure 56 Comparison of isoproterenol (isoprenaline) and salbutamol/albuterol demonstrating the significant increase in FEV1 with minimal effects on heart rate with the latter compound when lower doses are used. (After Paterson JW. Human pharmacology: comparison of
intravenous isoprenaline and salbutamol in salbutamol in asthmatic patients. Postgrad Med J
1971; 47(March Suppl.):39.)
Chapter 5
47
Longer Duration of Action

Isoproterenol has a short duration of action (approximately 2 to 3 hours).
The 2-agonists have longer durations of action and are more convenient
for the patient.
D. 2-Vasodilators (Nylidrin)
Actions
Nylidrin stimulates 2-receptors and produces peripheral vasodilatation of
arteries and arterioles in skeletal muscle. It also has positive inotropic
effects, reflecting some 1-stimulation.
Uses
Possible benefit in the treatment of peripheral vascular disease.
Adverse Effects
Trembling, nervousness, weakness, nausea, vomiting, dizziness, palpitations,
postural hypotension.
E. 2-Uterine Relaxants (Ritodrine)

Actions
Ritodrine stimulates 2-receptors to decrease both the frequency and intensity of uterine contractions. To a lesser degree, ritodrine stimulates 1-receptors, resulting in a dose-related tachycardia.
Uses
Management of preterm labor (ie, > 20 and < 37 weeks gestation) in suitable patients who have intact amniotic membranes, cervical dilatation up
to 4 cm, and less than 80% cervical effacement.
Adverse Effects
Result mainly from -receptor adrenergic stimulation. These include:
tachycardia; increase in systolic and decrease in diastolic pressure; rise in
blood glucose, insulin, and free fatty acids; and a decrease in serum potassium. Ritodrine can also cause palpitations, tremor, nausea, vomiting,
hyperglycemia, headaches, nervousness, anxiety, malaise, chest pains and
tightness, and erythema. Fetal tachycardia, neonatal hypoglycemia, and
hypocalcemia have been reported. Fetus can also be affected by maternal
ketoacidosis.
48
PDQ PHARMACOLOGY
4. Dopamine Agonists (Dopamine)

Actions
Stimulates specific dopamine receptors.
Stimulates 1- and 1-receptors.
Releases norepinephrine from adrenergic nerves endings.
Produces a dose-dependent cardiovascular response:
Low doses of dopamine dilate the renal, mesenteric, coronary, and
intracerebral vascular beds, with little effect on the heart. The vasodilatation is mediated by specific dopamine receptors.
Stimulation of D1-receptors on blood vessels, and certain other
peripheral sites, results in vasodilation, natriuresis, and diuresis.
Stimulation of D2-receptors on ganglia, the adrenal cortex, and
within the cardiovascular centers of the CNS produces hypotension,
bradycardia, and renal vasodilatation.
Moderately higher doses of dopamine increase the rate and contractile
force of the heart and increase cardiac output. This action is mediated
by stimulation of 1-receptors and the release of norepinephrine.
Dopamine increases the force of contraction more than heart rate. As
a result, it produces a smaller increase in oxygen demand by the heart
than do drugs, such as isoproterenol, that only stimulate -receptors.
Higher doses of dopamine stimulate the heart and cause an 1-receptormediated vasoconstriction in most vascular beds.
Still higher doses of dopamine can constrict the renal and mesenteric
beds.
Uses
Treatment of cardiogenic shock, which may be due to myocardial infarction
or congestive heart failure.
Treatment of septic shock.
Dopamine has the advantage of increasing cardiac output, while dilating
renal blood vessels and improving blood flow to the kidneys.
Adverse Effects
Tachycardia, angina pectoris, cardiac arrhythmias, headache, hypertension, nausea, vomiting, constriction of renal vessels (produced by high
doses).
Chapter 5
49
INDIRECTLY ACTING ADRENERGICS (EPHEDRINE)

Actions
Peripheral actions of ephedrine depend primarily on the release of norepinephrine from noradrenergic nerves. Ephedrine increases systolic and
diastolic blood pressure, the contractile force of the heart, and cardiac
output.
Ephedrine also directly stimulates 2-adrenergic receptors, accounting for
its bronchodilating effects.
Ephedrine crosses the blood-brain barrier and stimulates the CNS.
Uses
Treatment of nasal congestion and bronchial asthma.
Used in the eye as a mydriatic.
Adverse Effects
Similar to epinephrine.
6
Antiadrenergic Drugs
(Sympatholytics)
CLASSIFICATION OF ANTIADRENERGIC DRUGS (FIGURE 61)
Figure 61 Classification of antiadrenergic drugs.
50
Chapter 6
Antiadrenergic Drugs (Sympatholytics)
51
Sympathetic Depressant Drugs (Figure 62)

Depress the sympathetic nervous system by either
1.
2.
3.
4.
blocking adrenergic neurons (guanethidine),

interfering with norepinephrine storage (reserpine),
inhibiting the synthesis of norepinephrine (-methyltyrosine), or
preventing norepinephrine release within the CNS (clonidine, methyldopa).
Adrenergic Receptor Blockers (Figure 63)

Inhibit various aspects of sympathetic function by blocking either
1. 1-receptors,
2. -receptors, or
3. 1- and -receptors.
Figure 62 Mechanisms of action of sympathetic depressant drugs. (After Spector S, Pradhan SN. Drugs affecting catecholaminergic neurotransmisson. In: Pradhan SN, Maikel RP, Dutta
SN, eds. Pharmacology in medicine: principles and practice. Bethesda: SP Press International,
1986:103.)
Chapter 6
52
Figure 63 Action of alpha1 and beta blockers. (After Spector S, Pradhan SN. Drugs affecting catecholaminergic neurotransmission. In: Pradhan SN, Maikel RP, Dutta SN, eds. Pharmacology in medicine; principles and practice. Bethesda: SP Press International, 1986:103.)
SYMPATHETIC DEPRESSANT DRUGS

1. Adrenergic Neuron Blocking Drugs (Guanethidine)
Actions
Guanethidine accumulates in adrenergic neurons and disrupts the process
by which action potentials trigger the release of stored norepinephrine.
Guanethidine also reduces blood pressure. It dilates arterioles, decreasing peripheral resistance, and it also dilates veins, decreasing venous return
and reducing cardiac output.
Renal, splanchnic, and cerebral blood flow all fall in proportion to the
reduction in cardiac output.
Uses
Guanethidine is used in the treatment of essential hypertension.
Adverse Effects
Postural hypotension, weakness, fluid retention, heart failure in patients
with depressed myocardial function, diarrhea.
2. Drugs That Interfere with Norepinephrine Storage

(Reserpine)
Actions
Reserpine reduces the uptake of norepinephrine by intraneuronal vesicles.
Much of the norepinephrine released from adrenergic nerves is reabsorbed
by the neurons and stored in intraneuronal vesicles. Storage in these vesi-
Chapter 6
53
cles is essential to protect norepinephrine from monoamine oxidase metabolism. Because reserpine inhibits the uptake of norepinephrine by the
intraneuronal vesicles, much of the reabsorbed norepinephrine is metabolized within the nerve. As a result, norepinephrine levels within the sympathetic nerves fall and sympathetic transmission is reduced.
Reserpine
decreases blood pressure,

slows heart rate,
reduces cardiac output,
decreases venous return,
produces CNS depression,
increases gastrointestinal tone and motility, and
increases gastric acid secretion.
Uses
Reserpine is used to treat mild to moderate hypertension.
Adverse Effects
Depression, nightmares, abdominal cramps, diarrhea, flushing, nasal congestion, postural hypotension.
3. Drugs that Interfere with Norepinephrine Synthesis

(-Methyltyrosine/Metyrosine)
Actions
Metyrosine blocks the action of tyrosine hydroxylase and prevents the
conversion of tyrosine to dopa, the rate-limiting step in the synthesis of
the catecholamines dopamine, norepinephrine, and epinephrine (see
Chapter 3).
Uses
Metyrosine is useful for the preoperative treatment of pheochromocytoma
and for long-term therapy when surgery is not feasible.
Adverse Effects
Sedation, extrapyramidal effects, diarrhea, nasal congestion, dryness of
mouth.
Chapter 6
54
4. Centrally Acting Sympathetic Depressant Drugs

(-Methyldopa, Clonidine)
A. -Methyldopa
Actions
-Methyldopa rapidly enters the brain where it accumulates in noradrenergic nerves. Within noradrenergic nerves, -methyldopa is first converted
to -methyldopamine by dopa decarboxylase and then to -methylnorepinephrine by dopamine -oxidase (Figure 64). -Methylnorepinephrine
replaces norepinephrine within the central sympathetic neurons and is
released in place of norepinephrine by sympathetic stimulation. When
-methylnorepinephrine is released, it stimulates 2-adrenergic receptors
in the medulla oblongata to reduce subsequent central sympathetic outflow.
-Methyldopa also reduces blood pressure. In younger patients with
uncomplicated hypertension, it reduces vascular resistance without causing
much change in cardiac output. In older patients, -methyldopa may act
primarily by dilating veins, thereby reducing preload and cardiac output.
Uses
-Methyldopa is used to treat essential hypertension. Because plasma volume increases during prolonged treatment, -methyldopa is usually combined with a diuretic.
Adverse Effects
Sedation, headache, postural hypotension, bradycardia, edema, drug fever,
hepatic dysfunction, hemolytic anemia, impotence, lactation, nausea,
vomiting.
dopamine -oxidase
dopa decarboxylase
HO
HO
H NH2
C C COOH
H CH3
-Methyldopa
HO
HO
H H
C C NH2
H CH3
-Methyldopamine
HO
HO
H H
C C NH2
OH CH3
-Methylnorepinephrine
Figure 64 The metabolism of methyldopa in adrenergic neurons. a-Methylnorepinephrine

replaces norepinephrine in neurosecretory vesicles.
Chapter 6
55
B. Clonidine
Action
Clonidine stimulates 2-receptors in the medulla oblongata to decrease
sympathetic activity transmitted from the brain to the peripheral sympathetic nerves.
Clonidine reduces blood pressure by decreasing cardiac output. The
decrease in cardiac output is due to a reduction in heart rate and dilation
of the veins leading to a diminished venous return. Clonidine also dilates
arterioles, but its ability to lower blood pressure correlates better with a
decreased cardiac output than a reduced peripheral resistance.
Uses
Clonidine is used primarily to treat mild to moderate hypertension that has
not responded to a diuretic and is usually administered along with a
diuretic.
Adverse Effects
Sedation, dry mouth, edema, weight gain, and dizziness. Rebound hypertension if suddenly withdrawn.
ADRENERGIC RECEPTOR BLOCKERS

1. -Blockers
A. Nonselective -Blockers (Phentolamine, Tolazoline)
Actions
Phentolamine and tolazoline produce an equilibrium-competitive inhibition of the actions of catecholamines (epinephrine, norepinephrine, and
dopamine) on 1- and 2-receptors. Because these drugs block 2-adrenergic receptors, they increase the release of norepinephrine from sympathetic nerves. This leads to tachycardia as a result of increased 1-adrenergic receptor stimulation.
Uses
These drugs have limited clinical use because of the tachycardia and other
adverse effects they produce. Phentolamine is used to control blood pressure during surgery for pheochromocytoma and in the short-term control
of hypertension in patients with a pheochromocytoma.
Chapter 6
56
Adverse Effects
Postural hypotension, tachycardia, nasal congestion, nausea, vomiting,
diarrhea.
B. Selective 1-Adrenergic Blockers (Prazosin, Terazosin,

Doxazosin)
Actions
These drugs produce a selective equilibrium-competitive block of 1-adrenergic receptors. In normal clinical doses they do not block 2-receptors.
Because they block 1-receptors, these drugs dilate both arterioles and veins,
leading to a reduction in peripheral resistance and venous return.
Uses
These drugs are primarily used to treat hypertension.
They may also be used to treat benign prostatic hyperplasia. 1-Adrenergic receptors in the trigone muscle of the bladder and urethra contribute
to the resistance of urine outflow. Selective 1-adrenergic receptor blockers reduce this resistance in some patients with impaired bladder emptying
that has been caused by prostatic obstruction. They are effective in benign
prostatic hyperplasia because they relax smooth muscle in the bladder
neck, prostate capsules, and prostatic urethra.
Adverse Effects
Reflex tachycardia, postural hypotension, nasal congestion, gastrointestinal
hypermotility, inhibition of ejaculation, fluid retention, weakness, dizziness,
headache, lethargy.
2. -Blockers
Table 61 reviews the distribution of -receptors in the body and Table 62
compares the actions of the three groups of -blockers.
A. Nonselective -Adrenergic Blockers (Propranolol, Nadolol,

Timolol)
Actions
Nonselective -blockers competitively block both 1- and 2-adrenergic
receptors. As a result of these actions, nonselective -blockers
decrease heart rate,
decrease atrioventricular (AV) conduction,
Chapter 6
57
Table 61
Distribution of Beta Receptors

Organ
Receptor Type
Effects of Stimulation
Heart
Beta1
Beta1
Beta1
Increase in heart rate

Increase in cardiac contractility
Acceleration of AV conduction
Bronchioles
Beta2
Dilation
Arterioles
Beta2
Dilation
Kidney
Beta1
Release of renin
Metabolic
Beta2
Beta1
Increase in blood sugar

Increase in free fatty acids
AV = atrioventricular.
decrease myocardial contractility and cardiac output,

decrease blood pressure,
decrease renin release,
decrease FEV1 in asthmatic patients,
increase peripheral resistance, and
decrease blood sugar.
Uses
Nonselective -blockers are used to
treat essential hypertension,
manage angina pectoris,
treat supraventricular arrhythmias,
prevent migraine headaches (propranolol mechanism of action
unclear),
decrease the peripheral manifestations of hyperthyroidism,
reduce essential tremor (propranolol),
control blood pressure prior to surgery in patients with pheochromocytoma (used in combination with a nonselective -blocker), and
reduce intraocular pressure in glaucoma (timolol instilled in the eye
reduces the formation of aqueous humor mechanism of action
unclear).
Adverse Effects
Bronchoconstriction in asthmatics, increase in the hypoglycemic effects of
insulin, asystole, AV block, bradycardia, heart failure, nausea, vomiting, constipation, diarrhea, CNS depression, sleep disturbances, allergic reactions.
Decease release.
Decrease release.
Bronchoconstriction in asthmatics.
Prevent epinephrine from increasing

Little effect.
blood sugar. As a result, insulin produces
a greater and more prolonged fall in
blood sugar. Use with caution in diabetics
Renin Release
(1)
Bronchioles
(2)
Glucose
Metabolism
(2)
Reduce response to epinephrine because

partial agonist activity is not as potent
as endogenously-released epinephrine
Reduce capacity of asthmatics to dilate

bronchioles
Decrease release
May be a slight decrease because of

partial 2-agonist properties
Decrease both rate and force of

contraction. Produce less of a fall in
resting heart rate than non-selective or
cardioselective -blockers because of
their ISA
-Blockers with ISA:

Partial Agonist
-Blockers (Acebutolol,
Oxprenolol, Pindolol)
ISA = intrinsic sympathomimetic activity.
Little change because 2-receptors are

not blocked
Peripheral
Increase, due to the fact that 1-receptors
Resistance (2)
can act unopposed by 2-stimulation
Produce less bronchoconstriction

than non-selective -blockers but still
not recommended in asthmatics

contraction
Cardioselective
-Blockers (Acebutolol,
Atenolol, Betaxolol,
Esmolol, Metoprolol)

Heart Rate
and Force of
contraction
Contraction (1)
Non-Selective
-Blockers
(Propranolol, Nadolol,
Timolol)
Differences Between Groups of Beta Blockers
Table 62
Chapter 6
58
Chapter 6
59
B. Cardioselective -Adrenergic Blockers (Acebutolol, Atenolol,

Betaxolol, Esmolol, Metoprolol)
Actions
Cardioselective -blockers primarily block 1-receptors. Because they do
not block 2-receptors, these drugs are less likely to
prevent adrenergic dilation of the bronchioles,
increase peripheral resistance, and
potentiate the hypoglycemic actions of insulin.
Uses
Cardioselective -blockers are used to
treat essential hypertension,

prevent attacks of angina pectoris,
control ventricular arrhythmias in emergencies (esmolol),
reduce intraocular pressure in glaucoma (betaxolol instilled in the eye
reduces the formation of aqueous humormechanism of action is
unclear).
Adverse Effects
As for non-selective -adrenergic blockers, except they produce less bronchoconstriction, less effect on peripheral resistance, and less interaction
with insulin.
C. -Adrenergic Blockers with Intrinsic Sympathetic Activity (ISA):

Partial Agonist -Blockers (Acebutolol, Oxprenolol, Pindolol)
Actions
In contrast to the nonselective and cardioselective -blockers, which
attach to -receptors and block them, -blockers with ISA have affinity
for -receptors and, once attached, stimulate the receptors. However,
because they have less intrinsic sympathetic activity than either epinephrine or norepinephrine, the degree of -stimulation is reduced when acebutolol, oxprenolol, or pindolol occupies the receptor in place of the normal mediators, epinephrine and norepinephrine. These drugs are
sometimes called partial agonists, a term that reflects their limited ability
to stimulate adrenergic -receptors.
Acebutolol is listed under both cardioselective -blockers and -blockers with ISA because this drug is a partial agonist that affects only
1-receptors.
Chapter 6
60
-Blockers with ISA produce the same effects as nonselective -blockers,

except they
do not decrease resting heart rate to the same degree as nonselective blockers,
have less effect than nonselective -blockers on the bronchioles, and
produce a small decrease in peripheral resistance.
Uses
-Adrenergic blockers with ISA are used to
treat essential hypertension, and
prevent attacks of angina pectoris.
Adverse Effects
As for non-selective -blockers, except that they produce less bronchoconstriction and bradycardia.
3. 1- and -Blockers (Labetolol)

Action
Labetalol produces an equilibrium-competitive antagonism of 1- and
-receptors. It is 3 to 7 times more potent as a non-selective -blocker than
an 1-blocker. Labetalol is most appropriately thought of as a -blocker
with some 1-blocking properties.
Labetalols most important actions are exerted on the cardiovascular
system:
Labetalol combines the features of - and 1-blockade. When administered acutely, labetalol decreases peripheral vascular resistance (due to
1-blockade and direct vascular effects), without an increase in cardiac
rate and output (due to the -blockade, which prevents the reflex
increase in heart rate that is normally seen following a decrease in
peripheral resistance).
With prolonged therapy, the effects of -blockade become more pronounced and labetalol decreases the heart rate. Generally, however, the
decrease in heart rate is less pronounced than that seen after the administration of a -blocker, such as propranolol. Prolonged treatment with
labetalol also reduces vascular resistance and blood pressure.
Uses
Labetalol is used for
Chapter 6
61
the chronic treatment of essential hypertension, and

the preoperative management of patients with a pheochromocytoma.
Adverse Effects
Postural hypotension, gastrointestinal distress, tiredness, sexual dysfunction, and a tingling of the scalp due to 1-blockade.
Bronchospasm and congestive heart failure due to -blockade.
These latter effects occur with a lower frequency than those associated with
1-receptors.
7
Neuromuscular
Blocking Drugs
COMPETITIVE BLOCKERS (NONDEPOLARIZING BLOCKERS)
(TUBOCURARINE, ATRACURIUM, DOXACURIUM,
GALLAMINE, METOCURINE, MIVACURIUM, PANCURONIUM,
PIPERCURONIUM, ROCURONIUM, VECURONIUM)
Actions
These drugs competitively block nicotinic receptors on skeletal muscle, preventing acetylcholine, released from somatic nerves, from stimulating these
receptors.
Tubocurarine also releases histamine, resulting in bronchospasm,
hypotension, and excessive bronchial and salivary secretion.
Tubocurarine also releases heparin and this results in decreased blood
coagulability.
The actions of these drugs can be terminated by administering a
cholinesterase inhibitor, such as neostigmine. The resulting increased concentration of acetylcholine will overcome the competitive block of the nondepolarizing blocker.
Uses
Tubocurarine and the other competitive neuromuscular blockers are used
as adjuvant drugs in surgical anesthesia. Neuromuscular blockers relax
skeletal muscles and reduce the concentration of anesthetic required,
thereby decreasing the risk of cardiovascular and respiratory depression.
They are also used to prevent dislocations and fractures associated with electroconvulsive therapy and to control muscle spasms in tetanus.
62
Chapter 7 Neuromuscular Blocking Drugs
63
Adverse Effects
Prolonged apnea. Because it releases histamine, tubocurarine can produce
allergic responses, bronchospasm, excessive bronchial and salivary secretion, and hypotension.
DEPOLARIZING BLOCKERS (SUCCINYLCHOLINE)

Actions
Succinylcholine binds to acetylcholine nicotinic receptors on skeletal muscle to cause opening of ion channels, Na+ influx, and depolarization of the
muscle cell end-plate membrane in the same manner as acetylcholine.
However, succinylcholine has a longer duration of action than acetylcholine because it is metabolized more slowly. As a result of the relatively
slow metabolism of succinylcholine, the end-plate membrane remains
depolarized with the ion channels remaining open. Neuromuscular blockade during depolarization is called phase I block.
In the continued presence of succinylcholine, depolarization may
decrease so that Na+-channel inactivation is reduced or reversed and muscle excitability is restored. Despite this change, the neuromuscular block
continues. This condition is described as phase II block. The mechanism
for phase II block is not understood.
Succinylcholine is metabolized by pseudocholinesterase. In patients
with atypical pseudocholinesterase, succinylcholine is not metabolized rapidly and the drug has a prolonged duration of action.
Uses
Succinylcholine is used
as an adjunct to anesthesia, to induce skeletal muscle relaxation, and
to reduce the intensity of muscle contractions due to pharmacologically
or electrically induced convulsions.
Adverse Effects
Profound and prolonged muscle relaxation in patients with atypical
pseudocholinesterase, respiratory depression, bradycardia, tachycardia,
hypertension, hypotension, cardiac arrest, and arrhythmias.
Part 3 Cardiovascular and

Renal Pharmacology
Drugs for the Treatment of

Congestive Heart Failure
CONGESTIVE HEART FAILURE (CHF)
Heart Failure
Occurs following myocardial damage when the heart fails to pump enough
blood to meet the needs of the tissues.
Edema Formation (Figure 81)
Congestion, dyspnea, and edema result from a complex series of events that
occur when cardiac contractility falls.
Compensating Mechanisms in Heart Failure (Figure 82)
1. Increased heart size
2. Increased release of renin, with resulting increase in the synthesis of
angiotensin II and aldosterone
As a result:
angiotensin II constricts resistance vessels
aldosterone promotes salt and water retention
3. Increased sympathetic vasoconstriction
Consequences of Compensating Mechanisms
1. Increased systemic vascular resistance (afterload)
2. Increased blood volume
3. Increased venoconstriction (preload)
64
Chapter 8 Drugs for the Treatment of Congestive Heart Failure
65
Figure 81 Schematic diagram of the renal causes of edema formation in heart failure. (After
Young JB, Robert R. Heart failure. In: Dirks JH, Sutton RAL eds. Diuretics, physiology, pharmacology and clinical use. Philadelphia: W.B. Saunders, 1986:155.)
66
PDQ PHARMACOLOGY
Figure 82 Compensating mechanisms in heart failure. (After Bristol-Myers Squibb.)
DRUG TREATMENT OF CONGESTIVE HEART FAILURE

Purpose of Treatment
To increase cardiac output.
Means of Increasing Cardiac Output (Figure 83)
1. Decrease preload (diuretics and nitrates)
2. Reduce afterload [angiotensin converting enzyme (ACE) inhibitors,
hydralazine, and sodium nitroprusside]
3. Increase myocardial contractility (inotropic agents)
DRUGS THAT DECREASE PRELOAD

1. Diuretics
Actions
The pharmacologic actions of diuretics are presented in detail in Chapter 13.
These drugs, which include the thiazides, chlorthalidone, and loop
diuretics, increase sodium, chloride, and water excretion.
They decrease blood volume and lower cardiac filling pressure, thereby
reducing both pulmonary congestion and peripheral edema.
67
Figure 83 Use of diuretics, vasodilators and inotropic drugs to treat congestive heart failure. ACE= angiotensin converting enzyme. (Reproduced with permission of Bristol-Myers
Squibb.)
Uses
Diuretics are first-line agents for all grades of cardiac failure when sinus
rhythm is present.
They are usually sufficient to treat mild CHF.
For more severe CHF, diuretics are usually given with other drugs, such
as a vasodilator and/or digoxin.
When symptoms are mild, less potent diuretics, such as the thiazides or
chlorthalidone, may suffice.
In more severe cases, a loop diuretic, such as furosemide may be
required.
Potassium loss is a common problem with diuretics. This effect can be
reduced by combining these drugs with a potassium-sparing diuretic, such
as triamterene, amiloride, or spironolactone, or by adding a potassium
chloride preparation to the treatment regimen.
Adverse Effects
Hypovolemia, reduced renal perfusion, increased blood urea, hyponatremia, and hypokalemia. Mild to moderate hypokalemia can potentiate
digoxin toxicity. Other adverse effects include hyperglycemia, hypercalcemia, magnesium depletion, and hyperlipidemia.
68
PDQ PHARMACOLOGY
2. Nitrates
Actions
Nitrates dilate veins, thereby decreasing preload. This action accounts for
their major beneficial effect in CHF.
Nitrates also dilate arterioles (precapillary resistance vessels) to reduce
afterload.
Isosorbide dinitrate is the nitrate used most frequently.
Uses
May be added to diuretic therapy if a second drug is needed to further reduce
preload.
Adverse Effects
Headache and hypotension are the most common adverse effects.
DRUGS THAT DECREASE AFTERLOAD

1. Angiotensin Converting Enzyme (ACE) Inhibitors (Captopril,
Enalapril, Lisinopril)
Actions (Figures 84, 85, and 86)
By dilating precapillary resistance vessels (arterioles), ACE inhibitors reduce
the systemic vascular resistance. In the face of a reduced systemic vascular
Figure 84 Diagrammatic representation of the consequences of reducing the systemic vascular resistance (SVR) on the cardiac output (CO) of the normal heart and the heart in failure.
(After Bristol-Myers Squibb.)
69
Figure 85 Contribution of the renin-angiotensin-aldosterone system to congestive heart failure. SVR = systemic vascular resistance. (After Bristol-Myers Squibb.)
Figure 86 Effect of captopril on the renin-angiotensin-aldosterone system in congestive heart

failure. SVR = systemic vascular resistance. (After Bristol-Myers Squibb.)
70
PDQ PHARMACOLOGY
resistance, afterload falls and the heart in failure is more able to pump
blood; therefore, cardiac output increases.
Myocardial failure causes an increase in renin secretion by the kidneys.
Renin is converted to angiotensin I, which is, in turn, converted to
angiotensin II by the angiotensin converting enzyme. Angiotensin II has two
major effects:
It constricts blood vessels. Constricting arterioles increases systemic vascular resistance and afterload.
It increases aldosterone secretion, giving rise to sodium retention, volume expansion, and an increase in preload.
ACE inhibitors block the conversion of angiotensin I to angiotensin II,
thereby dilating arterioles and reducing afterload.
By lowering angiotensin II and reducing venoconstriction, ACE
inhibitors also decrease both right- and left-sided filling pressures (reduced
preload).
By decreasing aldosterone secretion, ACE inhibitors reduce blood volume, further contributing to a decrease in preload.
The consequences of these actions lead to an improvement in CHF.
Uses
ACE inhibitors are effective in treating chronic CHF. Blood pressure often
falls initially, but if the patient is not hypertensive, it usually returns to a
value not significantly below pretreatment levels.
ACE inhibitors are useful additions to diuretic therapy because they
reduce both the hyponatremia and urinary potassium loss.
If an ACE inhibitor is used, the patient should not receive a potassiumsparing diuretic or potassium supplement to prevent hyperkalemia.
The effects of ACE inhibitors depend on the patients salt balance.
Sodium depletion activates the renin-angiotensin system and increases
ACE inhibitor activity. Patients on high-dose diuretic therapy are most likely
to experience a severe fall in blood pressure after the first dose or doses of
an ACE inhibitor. Diuretics are often stopped a few days before starting low
doses of an ACE inhibitor to minimize the initial hypotensive effect of the
drug. After the patient has demonstrated the ability to tolerate these doses,
the physician can gradually increase the dose of the ACE inhibitor to meet
the patients needs.
Adverse Effects
Severe hypotension in volume depleted patients, modest deterioration in
renal function, proteinuria, neutropenia, alteration in taste (with captopril),
skin rash, cough, angioedema.
71
2. Hydralazine
Actions
Hydralazine effectively dilates precapillary resistance vessels (arterioles),
with minimal effect on the capacitance vessels (veins).
Its mechanism of action is not clear.
In heart failure, hydralazine reduces right and left ventricular afterload
by reducing systemic and pulmonary vascular resistance. These actions
result in an increase of forward stroke volume and a reduction in both ventricular systolic wall stress and regurgitant fraction in mitral insufficiency.
Because of the decrease in peripheral resistance, hydralazine can increase
heart rate (HR), raise the release of renin, the synthesis of angiotensin II,
and the secretion of aldosterone.
Hydralazine is inactivated by acetylation; therefore, slow acetylators
should receive lower doses.
Uses
Hydralazine has minimal effect on venous capacitance and therefore is most
effective when combined w ith venodilators, such as organic
nitrates.
Hydralazine reduces renal vascular resistance and increases renal blood
flow to a greater degree than most other vasodilators.
As a result of these actions, hydralazine may be the vasodilator of
choice in heart failure patients with renal dysfunction who cannot tolerate
an ACE inhibitor.
Adverse Effects
Headache, tachycardia, anorexia, dizziness, sweating.
3. Sodium Nitroprusside
Actions
Nitroprusside dilates both precapillary resistance and capacitance vessels,
thereby decreasing both afterload and preload, respectively.
Nitroprusside is one of the most effective afterload-reducing drugs
because of its effects on different vascular beds. Nitroprusside
decreases peripheral vascular resistance,

increases aortic wall compliance,
improves ventricular-vascular coupling, as well as cardiac output, and
dilates pulmonary arterioles and reduces right ventricular afterload.
72
PDQ PHARMACOLOGY
This combination of preload- and afterload-reducing effects improves

myocardial productivity by reducing wall stress, provided that blood pressure does not fall to the point of compromising diastolic coronary artery
flow, or to the point of activating a marked reflex increase in sympathetic
nervous system tone.
Uses
Nitroprusside is particularly effective in patients with congestive heart failure caused by mitral regurgitation or left-to-right shunts through a ventricular septal defect.
Adverse Effects
Flushing, headache, hypotension, nausea, vomiting, anorexia, muscle
spasms, hypoxia, methemoglobinemia, increased blood levels of thiocyanate
and cyanide.
DRUGS THAT INCREASE MYOCARDIAL CONTRACTILITY

(INOTROPIC DRUGS)
1. Digoxin
A. Mechanical Actions
Increased Myocardial Contractility
Digoxin improves myocardial contractility by increasing the intensity of the
interaction of actin and myosin filaments of the cardiac sarcomere. This
increased intensity is caused by an increase in the free calcium concentration in the vicinity of the contractile proteins during systole. Digoxin:
Inhibits membrane Na+, K+-ATPase transport function, causing accumulation of intracellular Na+. Elevated intracellular Na+ levels reduce
calcium expulsion from the myocardial cell by the Na+- Ca++ exchanger.
The resulting rise in intracellular calcium in the vicinity of the contractile proteins during systole increases myocardial contractility
Facilitates calcium entry into the myocardial cell through the voltagegated calcium channels of the membrane
Increases the release of calcium from intracellular storage sties on sarcoplasmic reticulum
Decreased Peripheral Resistance
Because of the improved performance of the heart, the need for increased
sympathetic stimulation of the precapillary resistance vessels is eliminated.
73
As a result of a reduction in norepinephrine release, the vessels dilate and

tissue perfusion improves.
Decreased Heart Rate and AV Conduction
Initially, prior to treatment, increased sympathetic stimulation increases
HR. Once myocardial performance improves under the influence of
digoxin, the need for increased sympathetic drive to the heart decreases.
Normal vagal tone returns and heart rate and atrioventricular (AV) conduction decrease.
B. Electrical Actions (Figure 87, Table 81)

Increased Automaticity
Digoxin increases spontaneous diastolic depolarization (see phase 4 in
Figure 87).
Decreased Conductivity
Digoxin decreases conductivity. This is reflected by a decrease in the rate of
rise and amplitude of the action potential.
Figure 87 Effects of digoxin on subsidiary pacemaker activity. (After Mason DT, Zelis R, et al.
Current concepts and treatment of digitalis toxicity. Am J Cadiol 1971;27:547.)
74
PDQ PHARMACOLOGY
Table 81
Summary of the Direct and Vagal-Mediated Effects of

Digoxin on Heart-Dominant Mechanisms
Area of Heart
SA Node
Atria
AV Conductivity
Purkinje
Automaticity
Conductivity
Refractory Period
Direct
Vagal
Direct
Direct
Increase
Decrease Decrease Decrease Decrease Increase

Decrease Increase Decrease Decrease
Decrease Decrease Decrease Decrease Increase
Decrease
Decrease
Increase
Increase
Vagal
Vagal
Dominant mechanisms in normal therapeutic doses are indicated in italics. AV = atrioventricular;

SA = sinoatrial.
Decreased Refractory Period

Digoxin shortens the duration of the action potential (see phases 1, 2, and
3 in Figure 87) and thus decreases the refractory period.
The overall effect of digoxin on the heart is a balance between its direct
actions (increased automoticity, decreased conductivity, and decreased refractory period) and the consequences of increased vagal activity (see Table 81).
Effects of Digoxin on Atrial Flutter
Digoxin often converts atrial flutter to atrial fibrillation. This is largely a result
of increased vagal stimulation. On atrial muscle, acetylcholine, released
from the vagus, increases conductivity and shortens the refractory period.
Effects of Digoxin On Ventricular Rate in Patients With Atrial Flutter
or Atrial Fibrillation
Despite the fact that digoxin often converts atrial flutter to fibrillation, the
ventricular rate usually slows because of the delay in AV conduction.
Pharmacokinetics of Digoxin
Given orally or intravenously

Absorption from tablets is 60 to 80%
Eliminated primarily by the kidneys
Half-life of 1.5 days in patients with normal renal function
Reduce dosage in proportion to decrease in creatinine clearance
Uses
Clearest indication is in patients with cardiac failure and atrial fibrillation
with uncontrolled ventricular response.
Its use in heart failure with normal sinus rhythm is controversial.
75
Adverse Effects
Sinus bradycardia
Paroxysmal or nonparoxysmal atrial tachycardia
Conversion of atrial flutter to atrial fibrillation
Increases automaticity in AV tissue, leading to junctional rhythms,
including tachycardia
Premature ventricular depolarizations (bigeminy, ventricular tachycardia, ventricular fibrillation)
Complete heart block
Anorexia, nausea, vomiting, abdominal discomfort, diarrhea
CNS effects headache, fatigue, malaise, drowsiness, blurred vision
Conditions which increase digoxins actions on the heart include
hypokalemia, hypothyroidism, age, and myocardial infarction.
2. Amrinone
Actions
Amrinone inhibits phosphodiesterase, thereby increasing the uptake of
Ca++ by myocardial cells.
This action may account for the ability of amrinone to increase myocardial contractility and dilate vascular smooth muscle.
Amrinone decreases both preload and afterload and reduces left and
right ventricular filling pressures and pulmonary capillary wedge pressure.
It improves resting and exercise hemodynamics, increases left ventricular ejection fraction, and improves ventricular capacity.
Uses
Amrinone is used in patients with severe CHF not adequately controlled by
digoxin, diuretics, antiarrhythmic drugs, or vasodilators.
It is also used in patients with refractory acute heart failure due to
myocardial infarction.
Adverse Effects
Thrombocytopenia, fever, and nephrogenic diabetes insipidus.
3. Dobutamine and Dopamine

Refer to Chapter 5 for information on these drugs.
9
Drugs for the Treatment
of Cardiac Arrhythmias
ETIOLOGY OF CARDIAC ARRHYTHMIAS
Cardiac Arrhythmias
Are caused by disorders of rate, rhythm, origin, or conduction within the
heart.
Cardiac Tachyarrhythmias
Are the result of disorders of
impulse formation,
impulse conduction, or
both.
DISORDERS OF IMPULSE FORMATION

The heart has many cells that have the potential to act as pacemakers.
These cells are referred to as latent pacemakers and are found in specialized conducting systems, such as the atrioventricular (AV) node, the
AV bundle, and the Purkinje network in the ventricles. These cells have
the property of automaticity because they can depolarize spontaneously.
Latent pacemakers have the potential to act as ectopic pacemakers.
Under normal circumstances, they do not function as pacemakers because
the sinoatrial (SA) node depolarizes more rapidly and serves as the site
for impulse formation. Once the SA node reaches its threshold, it sends
an electrical wave throughout the heart, depolarizing all latent pacemakers before they have a chance to act as sites of impulse conduction.
76
Chapter 9 Drugs for the Treatment of Cardiac Arrhythmias
77
If the normal SA pacemaker node is damaged, or if the rate of conduction of impulses from the SA node is reduced, formerly latent pacemakers may become ectopic pacemakers.
DISORDERS OF IMPULSE CONDUCTION

Disorders of impulse conduction are more often the cause of cardiac
arrhythmias than disorders of impulse formation.
AV blocks or bundle branch blocks cause arrhythmias.
Re-entry (Figure 91) can cause paroxysmal tachycardias and ventricular tachycardias. If a localized area of the heart is damaged by a
myocardial infarct, the transmission of impulses along a portion of a
normal conducting system may be blocked in one direction. In Figure
91, impulse transmission is blocked unidirectionally along pathway b.
As a result, the impulse that travels along a and c is allowed to come up
b in a retrograde manner and re-enter a in the manner shown. This
results in an extra heartbeat. If it happens at several sites, it can produce
severe tachyarrhythmias leading to fibrillation.
PHARMACOLOGIC APPROACHES TO TREATING

TACHYARRHYTHMIAS
Cardiac tachyarrhythmias may be treated by:
reducing the rate at which ectopic pacemakers depolarize, or
modifying the conduction defects that lead to re-entry. Re-entry mechanisms can be altered either by:
increasing the conductivity in the damaged tissue, or
further decreasing the conduction velocity, thereby converting a
undirectional block to a bidirectional one. A bidirectional block is
depicted in Figure 92.
Figure 91 The phenomenon of re-entry. (After Johnson GE, Osis M, Hannah KJ. Pharmacology in Nursing Practice. Toronto: W.B. Saunders, 1998.)
78
PDQ PHARMACOLOGY
Figure 92 Bidirectional block. (After Johnson GE, Osis M, Hannah KJ. Pharmacology in Nursing Practice. Toronto: W.B. Saunders, 1998.)
Class I (Blockers of Class II (-blockers) Class III (blockers of Class IV (blockers of

Fast Na+ channel)
K+ channels)
Ca++ channel)
IA (moderate block)
IB (weak block)
IC (pronounced block)
Figure 93 Classification of Antiarrhythmic Drugs
CLASSIFICATION OF ANTIARRHYTHMIC DRUGS

(FIGURE 93 AND TABLE 91)
Table 91
Classification of Antiarrhythmic Drugs

Antiarrhythmic
Class
Class IA
Representative
Drugs
Principal Pharmacologic Effects
Quinidine
Procainamide
Disopyramide
All Class I antiarrhythmic drugs (Class

IA, Class IB, and Class IC) reduce sodium
entry at the time the cell membrane rapidly
depolarizes (ie, they decrease the fast
inward sodium current). As a result, Class I
drugs decrease the rate of depolarization
Continued
79
Table 91
Classification of Antiarrhythmic DrugsContinued

Antiarrhythmic
Class
Representative
Drugs
In their presence, cells require a greater
(more negative) potential before they can
propagate an impulse to adjacent cells
(ie, they increase the threshold to impulse
propagation). Class I drugs also increase
the repolarization time, reduce conduction
velocity, prolong the effective refractory
period, and decrease automaticity.
Class IA drugs depress automaticity,
particularly at ectopic sites and slow
conduction and increase the refractoriness
of the atria, the His-Purkinje system,
accessory pathways, and the ventricles.
They have both direct and indirect
(anticholinergic) actions (Table 92).
Class IB
Lidocaine
Mexiletine
Phenytoin
Tocainide
For properties of all Class I antiarrhythmic drugs see comments above.

Class IB drugs depress automaticity and
reduce the duration of the refractory period
in the His-Purkinje system and the ventricles.
In therapeutic doses, they do not slow AV
nodal or intraventricular conduction, except
in diseased myocardium.
Class IC
Flecainide
Moricizine
Propafenone
For properties of all Class I antiarrhythmic drugs see comments above.

Flecainide and propafenone slow conduction
in the atria, AV node, ventricles, accessory
pathways, and particularly in the His-Purkinje
system. To a lesser extent, they also increase
atrial and ventricular refractoriness and
suppress sinus node automaticity.
Moricizine does not readily fit into any of
the subclasses of drugs that block sodium
channels and has proven difficult to
subclassify within the Class I antiarrhythmic
agents. It reduces the fast inward sodium
current of the action potential, prolongs
atria to His (AH) and His to ventricle (HV)
conduction times, and PR and QRS intervals.
Class II
Propranolol
Metoprolol
Nadolol
Class II antiarrhythmic drugs are

competitive -blockers. By blocking 1
receptors, these drugs reduce cardiac
Continued
80
PDQ PHARMACOLOGY
Table 91
Classification of Antiarrhythmic DrugsContinued

Antiarrhythmic
Class
Representative
Drugs
Acebutolol
Atenolol
Pindolol
Timolol
Sotalol
Esmolol
output, diminish myocardial oxygen

requirements, and prevent cardiac
arrhythmias, particularly those caused by
increased sympathetic activity (see Chapter 6).
The cardiac effects of 1-blockage include:
bradycardia
decreased contractility
increased AV conduction time
reduced automaticity
Class III
Amiodarone
Bretylium
Sotalol
Class III antiarrhythmic drugs inhibit

potassium repolarization.
Amiodarone increases refractoriness of the
sinus node, the atria, the AV node, the
ventricles, the His-Purkinje system, and the
accessory pathways; depresses sinus node
automaticity; and slows conduction in the
atria, the AV node, the His-Purkinje system,
and the ventricles.
Bretylium has two actions it directly
modifies the electrical properties of the myo
cardium, and it initially increases norepi
nephrine release and subsequently depresses
adrenergic neuronal transmission. The initial
release of norepinephrine increases auto
maticity. Subsequently, bretylium increases
the refractory period of the His-Purkinje
system and ventricles without slowing
conduction or depressing automaticity.
Sotalol is both a noncardioselective
-blocker and a drug with class III
antiarrhythmic properties that prolongs
atrial and ventricular refractoriness.
Class IV
Verapamil
Diltiazem
Class IV antiarrhythmic drugs are calcium

channel blockers, which selectively inhibit
the slow-channel calcium ion transport into
cardiac tissue. The pacemakers of the SA
node and the cells in the proximal region of
the AV node are depolarized primarily by the
calcium current. Blocking the calcium
channel has the effect of depressing AV
conduction, thereby reducing the ability of
the AV node to conduct supraventricular
impulses to the ventricle. The most important
electrocardiogram (ECG) change is a
prolongation of the PR interval.
81
CLASS IA ANTIARRHYTHMIC DRUGS

(QUINIDINE, PROCAINAMIDE, DISOPYRAMIDE)
Actions
Quinidine, procainamide, and disopyramide reduce the maximum rate of
depolarization. They
increase the threshold for excitation,
depress conduction velocity, and
prolong the effective refractory period
in the atrial, His-bundle, and ventricular conducting systems.
These drugs also exert a direct anticholinergic (atropine-like) effect on
the muscarinic receptors of the heart (see Chapter 4). A summary of the
effects of these drugs is presented in Table 92.
Uses and Adverse Effects
1. Quinidine
Used to treat both atrial and ventricular arrhythmias.
Has been used to maintain sinus rhythm after cardioversion in
supraventricular arrhythmias.
Table 92
Electrophysiologic Actions of Quinidine, Procainamide

and Disopyramide at Therapeutic Plasma Concentrations
Direct
Action
Indirect
AC* Action Net Effect
Sinus node depolarization
Decrease
Increase
No change
Atrial tissue
Conduction velocity
Effective refractory period
Decrease
Increase
Decrease
Increase
Decrease
Increase
AV node
Automaticity
Conduction velocity
Decrease
Decrease
Increase
Increase
Increase
Decrease
Increase/decrease
Increase/decrease
Decrease/increase
Decrease
Decrease
Increase
Tissue
His-Purkinje system ventricular muscle

Automaticity
Decrease
Conduction velocity
Decrease
Increase
(After Black SC, Lucchesi BR. Antiarrhythmic Drugs. In: Craig CR, Stitzel RE, eds. Modern
pharmacology. Boston: Little, Brown, 1994:285.)
*Anticholinergic
Dose-dependent effect (low dose/high dose)
82
PDQ PHARMACOLOGY
Often used with digoxin to treat atrial fibrillation. Because quinidine has
an atropinic action, it increases AV conduction. Digoxin, on the other
hand, decreases AV conduction. By combining the two drugs, the physician
can slow the atria with quinidine and reduce AV conduction with digoxin.
Quinidines toxicities are usually dose related.
At plasma concentrations above 8 g/mL, the direct depressant effects
on AV conduction appear and the QRS complex widens. As the concentration of drug rises, SA block or arrest, high-grade AV block, ventricular
arrhythmias, or asystole may occur.
The other adverse effects of quinidine include diarrhea, nausea and
vomiting, headache, vertigo, palpitations, tinnitus and visual disturbances.
GI symptoms are the most common. They occur even when the drug
concentrations in the plasma are low.
2. Procainamide
Possesses little atropinic action.
Has essentially the same therapeutic effects and clinical indications as
quinidine.
Used to treat atrial fibrillation and paroxysmal supraventricular tachycardia.
Should not be administered to patients with complete AV heart block
and is contraindicated in cases of second-degree and third-degree AV block
unless an electric pacemaker is operative.
May cause anorexia, nausea, vomiting, granulocytopenia, and a
reversible lupus erythematosus-like syndrome.
Both procainamide, and its active metabolite N-acetylprocainamide are
eliminated by the kidneys and will accumulate in patients with renal
impairment unless lower doses are given. Unless the serum concentrations
of procainamide can be measured, it is better not to use the drug in endstage renal failure.
3. Disopyramide
Has actions and uses similar to those of quinidine.
Eliminated by both hepatic metabolism and renal excretion, and therefore, dosage should be reduced in patients with liver or kidney impairment.
Contraindicated in the presence of shock, renal failure, severe intraventricular conduction defects, pre-existing second- and third-degree AV block
(if no pacemaker is present), and known hypersensitivity to the drug.
Should not be used in the presence of uncompensated or inadequately
compensated congestive heart failure because it can worsen the condition.
Severe hypotension occurring after disopyramide has been observed,
usually in patients with primary myocardial disease (cardiomyopathy),
and in patients with inadequately compensated CHF or advanced myocardial disease with low output states.
Other adverse effects include heart block, ventricular fibrillation, and
tachyarrhythmias.
83
Its anticholinergic effects are often marked, and the drug is contraindicated in most patients with glaucoma and in those with urinary
retention.
CLASS IB ANTIARRHYTHMIC DRUGS

(LIDOCAINE, MEXILETINE, PHENYTOIN, TOCAINIDE)
Actions
See Table 91.
1. Lidocaine
Used for the immediate control of ventricular premature extrasystoles
and ventricular tachycardia.
Also used for ventricular arrhythmias secondary to cardiac surgery, cardiac catheterization, acute myocardial infarction, and electrical conversion.
Major toxicities involve the CNS and the cardiovascular system (CVS).
Patients may experience drowsiness, paresthesias, muscle twitching, convulsion, coma, respiratory depression, and depressed myocardial contractility.
Rapidly metabolized and patients with hepatic insufficiency and those
over 70 age should, as a rule, receive 12 to 23 the usual loading dose and lower
than normal maintenance doses.
2. Mexiletine
Used to treat or prevent ventricular ectopy and tachycardia and to suppress ventricular arrhythmias in survivors of acute myocardial infarction
following therapy with lidocaine.
CVS toxicities include sinus bradycardia or tachycardia, atrial fibrillation, hypotension, dyspnea, ventricular tachyarrhythmias, including torsades de pointes.
Contraindicated in the presence of second- or third-degree AV block in
the absence of a pacemaker, and in cardiogenic shock.
Use with caution in patients with hypotension or CHF because of its
potential for depression of myocardial contractility.
Noncardiac adverse reactions include nausea, vomiting, malaise, dizziness, tremor, diplopia, paresthesias, confusion, and ataxia.
3. Phenytoin
Depresses spontaneous atrial and ventricular automaticity without
altering intraventricular conduction.
May also increase conduction through damaged Purkinje fibers.
Used mainly to reverse digitalis-induced arrhythmias.
Adverse effects include fatigue, dizziness, ataxia, nausea, vomiting, pruritus, and rashes.
84
PDQ PHARMACOLOGY
If given rapidly by intravenous (IV), it can slow the heart rate, depress
the myocardium, produce hypotension, reduce AV conduction, and, very
occasionally, cause cardiac arrest.
Contraindicated in sinus bradycardia, SA block, second- and thirddegree AV block, and Adams-Stokes syndrome.
4. Tocainide
Indicated only for the treatment of symptomatic ventricular arrhythmias in patients not responding to other therapy, or when other therapy was
not tolerated.
Use with caution in patients with heart failure or with minimal cardiac reserve because of the potential for aggravating the degree of heart
failure.
Nausea and tremor are the most common adverse effects. Other adverse
effects include dizziness, lightheadedness, confusion, anxiety, paresthesias,
hypotension, bradycardia, palpitations, chest pain, conduction disturbances, and left ventricular failure. There are also reports of hematologic
disorders, including leukopenia, agranulocytosis, bone marrow depression,
hypoplastic anemia, and thrombocytopenia.
CLASS IC ANTIARRHYTHMIC DRUGS

(FLECAINIDE, MORICIZINE, PROPAFENONE)
Actions
See Table 91.
1. Flecainide
Indicated for the treatment of documented ventricular arrhythmias,
such as sustained ventricular tachycardia, that are judged life-threatening.
Most serious adverse reactions are new or exacerbated ventricular
arrhythmias and new or worsened CHF.
Other adverse effects include blurred vision, dizziness, headache, nausea, fatigue, nervousness, tremor, and paresthesias.
2. Moricizine
In patients with impaired left ventricular function, moricizine has minimal
effects on measurements of cardiac performance, such as cardiac index, stroke
volume index, pulmonary capillary wedge pressure, and systemic or pulmonary vascular resistance or ejection fraction, either at rest or during exercise.
Used to suppress life-threatening ventricular arrhythmias.
CVS adverse effects include worsening of arrhythmias, conduction disturbances, and heart failure. Nausea and vomiting can also occur.
85
3. Propafenone
Used for suppression of the following ventricular arrhythmias when
they occur singly or in combination: episodes of ventricular tachycardia;
premature (ectopic) ventricular contractions, such as premature ventricular beats of unifocal or multifocal origin; couplets; and R on T phenomenon, when of sufficient severity to require treatment.
Adverse effects include worsening of CHF, AV and intraventricular
conduction disturbances, ventricular arrhythmias, nausea, diarrhea, constipation, paresthesias, and taste disturbances.
CLASS II ANTIARRHYTHMIC DRUGS

(BETA BLOCKERS)
Actions
See Table 91.
Uses and Adverse Effeccts
Beta blockers are best suited for catecholamine-induced arrhythmias.
Beta blockers can be used to treat:
Sinus tachycardia. First treat the underlying cause (eg, hyperpyrexia,
hypovolemia, etc)
Atrial fibrillation. Sinus rhythm is unlikely to be restored; however, the
beta blockade of the AV node will decrease the ventricular response to
the atrial tachyarrhythmia.
Atrial flutter or tachycardia. Beta blockers will reduce the ventricular
rate by inhibiting adrenergically mediated transmission through the
AV node.
Premature ventricular complexes. Effective in mitral valve prolapse,
hypertrophic cardiomyopathy, digitalis-related ectopic activity, as
well as ventricular complexes associated with exercise or induced by
ischemia.
Ventricular tachycardia. Most effective against arrhythmias associated
with digitalis toxicity and exercise, particularly if the latter is related to
ischemia.
Ventricular fibrillation. Postmyocardial infarct patients show increased
survival if treated with a -blocker. The beneficial effect may be related
to the decrease in heart rate and the anti-ischemic benefits from blocking the -receptors.
For adverse effects, refer to Chapter 6.
86
PDQ PHARMACOLOGY
CLASS III ANTIARRHYTHMIC DRUGS

(AMIODARONE, BRETYLIUM, SOTALOL)
Actions
See Table 91.
The importance of class III antiarrhythmic drugs is their effectiveness in
cases of intractable ventricular tachycardia and in reducing the likelihood
of developing ventricular fibrillation.
Class III drugs may prolong the action-potential duration sufficiently
to induce arrhythmias. This effect may relate to the ability of these drugs
to sufficiently reduce potassium ion conductance to lead to a marked prolongation in repolarization.
1. Amiodarone
The prominent effect seen after acute IV administration of amiodarone
is slow conduction and prolonged refractoriness of the AV node.
Amiodarone may also have a marked negative inotropic effect following acute IV administration.
Because of its toxicities, amiodarone is only indicated for the treatment
of patients with life-threatening cardiac arrhythmias (eg, ventricular tachycardia and ventricular fibrillation) that are refractory to other treatments.
Amiodarone is contraindicated in severe sinus node dysfunctions, sinus
bradycardia, and second- and third-degree AV block. It is also contraindicated in patients with episodes of bradycardia sufficient to cause syncope,
unless used in conjunction with a pacemaker.
Amiodarone can be a most toxic drug. The most serious and potentially
life-threatening adverse effects associated with its use are pulmonary fibrosis, aggravation of arrhythmias, and cirrhotic hepatitis.
Its effects on the CVS include myocardial depression, hypotension, SA
block, AV block, ventricular arrhythmias, fatal CHF, cardiogenic shock, and
cardiac arrest.
Other effects include headache, weakness, myalgia, tremor, ataxia,
paresthesias, depression, insomnia, nightmares, and hallucinations.
2. Bretylium
Bretylium suppresses ventricular fibrillation and ventricular arrhythmias. As a result, it may be of value as a last resort in life-threatening ventricular arrhythmias, principally ventricular tachycardia and fibrillation,
which are resistant to conventional antiarrhythmic drug therapy.
The major adverse effects of bretylium relate to its modification of
adrenergic function. The catecholamines released shortly after its injection
increase blood pressure and heart rate. This may be followed by the conse-
87
quences of a subsequent sympathetic block (peripheral vasodilatation and

profound, long-lasting hypotension).
The initial release of catecholamines may also cause anxiety, excitement,
flushing, substernal pressure sensation, headache, and angina pectoris.
Rapid IV administration may initiate nausea and vomiting.
3. Sotalol
Sotalol is approved for the treatment of documented life-threatening
ventricular arrhythmias, such as sustained ventricular tachycardia.
It may also be used for the treatment of patients with symptomatic ventricular arrhythmias.
Sotalol is contraindicated in patients with bronchial asthma, allergic
rhinitis, severe sinus node dysfunction, sinus bradycardia, second- and
third-degree AV block (unless a functioning pacemaker is present), and
congenital or acquired long QT syndrome. The drug is also contraindicated
in cardiogenic shock, severe or uncontrolled CHF, hypokalemia and anesthesia with agents that produce myocardial depression.
Adverse effects include those attributed to both beta blockade and
proarrhythmic actions. The proarrhythmic effects of the drug may lead to
ventricular fibrillation. For details on the adverse effects related to beta
blockade, refer to Chapter 6.
CLASS IV ANTIARRHYTHMIC DRUGS

(VERAPAMIL AND DILTIAZEM)
Actions
See Table 91.
1. Verapamil
IV administered verapamil can be used to treat paroxysmal supraventricular tachycardia (eg, atrial fibrillation or atrial flutter of recent onset
with rapid ventricular response).
Oral verapamil is indicated for the treatment of atrial fibrillation or flutter with rapid ventricular response not otherwise controlled with digoxin.
Oral verapamil is also indicated as follow-up treatment to injectable verapamil in paroxysmal supraventricular tachycardia.
Because of its potent AV nodal depressant activity, verapamil should be
used with caution, or not at all, in patients with AV nodal dysfunction,
including those taking digitalis.
Contraindications to the use of verapamil also include acute myocardial infarction, severe congestive heart failure (unless secondary to a
88
PDQ PHARMACOLOGY
supraventricular tachycardia amenable to verapamil therapy), cardiogenic

shock or severe hypotension, second- or third-degree AV block, sick sinus
syndrome (except in patients with a functioning artificial ventricular pacemaker), and marked bradycardia.
The most common adverse effect following IV administration is a transient and mild fall in blood pressure.
Oral verapamil almost invariably causes constipation. Nausea, vomiting, lightheadedness, headache, flushing, nervousness, rashes and pruritus
may also occur following oral treatment.
2. Diltiazem
The antiarrhythmic actions and uses of diltiazem are similar to those
of verapamil.
Injectable diltiazem is indicated for the temporary control of rapid ventricular rate during atrial flutter or atrial fibrillation.
The contraindications to the use of diltiazem and the adverse effects of
the drug are presented in Chapter 10.
MISCELLANEOUS ANTIARRHYTHMIC DRUGS

1. Digoxin
Actions
The actions of digoxin were presented in Chapter 8 (see Table 81 and
Figure 87).
Lengthens the AV nodal conduction time and functional refractory
period.
Slows the sinus rate when ventricular function is impaired because it
increases cardiac output, leading to a reduction in sympathetic stimulation.
Slows the ventricular response in patients with atrial fibrillation or flutter.
Because digoxin slows conduction over the AV node and increases the
refractory period of the AV node, fewer impulses originating in the atria are
able to invade the ventricular myocardium over the AV nodal pathway.
Thus, despite the continued presence of a supraventricular arrhythmia, the
ventricular rate will decrease, thereby improving cardiac hemodynamics.
Also used to treat AV nodal re-entrant tachycardia, and arrhythmias
associated with congestive heart failure.
The adverse effects of digoxin were presented in Chapter 8.
89
2. Adenosine
Actions
The electrophysiologic actions of adenosine on the AV node resemble those
of acetylcholine. Adenosine increases the effective refractory period and
depresses conductivity.
When injected by IV, adenosine slows AV nodal conduction and can
interrupt the re-entry pathways through the AV node.
Adenosine is indicated for the conversion of paroxysmal supraventricular
tachycardia (PSVT) to normal sinus rhythm, including PSVT with WolffParkinson-White syndrome.
Symptomatic adverse effects are common and include transient nausea,
metallic taste, dyspnea, chest pain, ventricular ectopy, headache, and flushing.
10
Antianginal Drugs
Angina Pectoris:
A syndrome of paroxysmal left-sided chest pain
Produced when the oxygen requirements of the heart exceed the oxygen supply
One of the most prominent and well-known symptoms of regional
myocardial ischemia
Caused most frequently by coronary artery disease
ANGINA CAUSED BY DISEASES OF CORONARY ARTERIES MAY

BE DIVIDED INTO STABLE ANGINA AND VARIANT ANGINA
Stable Angina
Also called typical, classic, or exertional angina. Caused by a reduction of
blood flow to a particular area of the heart as a result of atherosclerosis.
Brought on by conditions that increase myocardial oxygen consumption, such
as physical exertion, emotional stress, exposure to cold, or eating large meals.
Variant Angina
Also called vasospastic angina. Results from a coronary artery spasm.
Develops typically at rest rather than during physical exertion; it frequently
follows a diurnal rhythm, often occurring in the early morning. Not associated with an increased cardiac demand for oxygen, rather, the cause
appears to be a spasm of one or more of the coronary arteries.
Both spasm and atheroma may be present in varying degrees

Objectives of Drug Treatment
1. To stop an existing attack or prevent a new one from occurring
2. To increase the exercise capacity of the patient
90
Chapter 10
Antianginal Drugs
91
Means By Which These Objectives Can Be Reached

1. Increase the oxygen supply to the ischemic area(s) of the heart
2. Decrease the oxygen requirements of the heart muscle
For Stable Angina
The cause of the problem is a reduction in blood flow to an atherosclerotic
area of the heart because hardened vessels cannot dilate. It is easier to
decrease the myocardial oxygen requirements in stable angina than to
increase the oxygen supply to the heart.
For Variant Angina
The blood vessels are not atherosclerotic in variant angina and, therefore,
are able to dilate if treated with vasodilators. Thus, both nitrates and calcium channel blockers
prevent the arteriole from going into spasm, and
relax the arteriole that is in spasm.
Mechanisms of Action of Antianginal Drugs (Figure 101)
1. Reduce the heart rate (beta blockers)
2. Reduce preload (nitrates)
Reduction of Heart Rate

Beta Blockers
Reduction of Afterload
Vasodilators-Calcium Antagonists
(Nitrates)
Coronary Artery Vasodilation

Nitrates
Calcium Antagonists
Reduction of Preload
Nitrates
Reduction of Contractility
Beta Blockers
Calcium Antagonists
Figure 101 Mechanisms of action of anti-anginal drugs. (After Maclean D, Feely J. Calcium
antagonists, nitrates and new anti-anginal drugs. Br Med J 1983;266:1127.)
Chapter 10
Antianginal Drugs
92
3. Reduce contractility (beta blockers, Ca++-channel blockers)

4. Dilate coronary arteries (nitrates, Ca++-channel blockers)
5. Reduce afterload (Ca++-channel blockers)
DRUGS FOR THE TREATMENT OF ANGINA PECTORIS

1. Organic Nitrates (Nitroglycerin, Isosorbide Mononitrate,
and Isosorbide Dinitrate)
Actions
Organic nitrates stimulate nitrate receptors in the vascular endothelium to
increase intracellular cyclic guanosine monophosphate (GMP) formation.
The increase in cyclic GMP leads to vascular smooth muscle relaxation by
several mechanisms, including
an inhibition of calcium entry,
a decreased calcium release from intracellular stores, or
an increase in calcium extrusion.
As a result of these actions, organic nitrates dilate
veins (capacitance vessels):
to reduce venous return, thereby decreasing left ventricular volume and intramyocardial tension. These actions decrease myocardial oxygen requirements because the major factor controlling the
oxygen needs of the heart is the degree to which it is stretched as it
fills in diastole.
to increase oxygen delivery to the subendocardium. Blood flow to
the subendocardium occurs primarily in diastole. By reducing left
ventricular end-diastolic pressure, nitrates decrease extravascular
compression around the subendocardial vessels and favor a redistribution of coronary blood flow in this area.
arteries (conductance vessels) to improve regional blood flow to ischemic
areas.
arterioles (precapillary resistance vessels):
to decrease peripheral resistance (afterload), thereby reducing the
oxygen requirements of the myocardium.
to reflexly raise heart rate and increase myocardial oxygen
requirements. Fortunately, the increased oxygen demand created
by tachycardia is not sufficient to override the beneficial effects of
the nitrates which reduce the overall oxygen requirements of the
heart.
Chapter 10
Antianginal Drugs
93

Various nitrate preparations are available to terminate or prevent anginal
attacks. Oral nitroglycerin has an unpredictable effect, due to extensive
metabolism during its first pass through the liver in the portal circulation
(first-pass metabolism); therefore, other routes must be found for its
administration.
Sublingual nitroglycerin tablets, or nitroglycerin spray applied under or
on the tongue, are effective in stopping the pain of angina. If used immediately before an anticipated stress, they can also prevent an attack.
Topical nitroglycerin patches or ointment are rapidly absorbed through
the skin, circumvent first-pass metabolism, and prevent anginal attacks.
Because tolerance develops rapidly to the patches if they are applied on
a 24-hour basis, they should be applied for only 12 hours per day.
Buccal nitroglycerin contains nitroglycerin in an inert polymer matrix.
This formulation is absorbed through the membranes of the mouth,
begins to work promptly, and continues to be effective for a prolonged
period.
Isosorbide mononitrate and isosorbide dinitrate, taken orally, are used
to prevent anginal attacks.
Headache, due to vasodilatation of the blood vessels in the scalp, is the
most common adverse effect of all nitrates.
The other adverse effects are dizziness and weakness, due to postural
hypotension when nitrates dilate capacitance vessels.
Tolerance to nitrates develops if vessels are constantly exposed to them.
To forestall the development of tolerance, patients should not receive
nitrate therapy 24 hours a day.
2. Beta Blockers (Acebutolol, Atenolol, Metoprolol, Nadolol,

Propranolol, Timolol)
Actions
The pharmacology of these drugs was presented in Chapter 6.
Beta blockers reduce the oxygen requirements of the heart by decreasing heart rate and force of contraction.
Beta blockers form the mainstay of prophylactic treatment of chronic, stable angina pectoris.
They are often used with a sustained-release nitroglycerin product or
isosorbide mononitrate or dinitrate. The combination of a beta blocker with
Chapter 10
94
Antianginal Drugs
a nitrate is often more effective than either drug used alone. Furthermore,
beta blockers prevent the reflex tachycardia that often accompanies nitrate
therapy.
The adverse effects and contraindications of beta blockers can be found
in Chapter 6.
3. Calcium Channel Blockers/Calcium Entry Blockers (Diltiazem,

Felodipine, Isradipine, Nicardipine, Nifedipine, Verapamil)
Actions
Vasoconstriction depends on the entry of small amounts of calcium into the
vascular smooth muscle through the calcium channel. Calcium channel
blockers (calcium entry blockers) block the entry of calcium into the vascular muscle and prevent vasoconstriction.
All calcium channel blockers dilate coronary vessels, increasing the oxygen supply to patients with variant angina pectoris.
Calcium channel blockers differ, however, in other important respects.
These drugs can be divided into the following groups:
Diltiazem
The dihydropyridines (amlodipine, felodipine, isradipine, nifedipine,
and nicardipine)
Verapamil
Table 101 summaries the cardiovascular effects of these three groups
of calcium channel blockers.
Table 101
Cardiovascular Effects of Calcium Channel Blockers*

Blood pressure
Vasodilatation
Heart rate
Contractility
Coronary vascular resistance
Blood flow
Dihydropyridines
Diltiazem
Verapamil
+++
++
0/+
+++
++
+++
++
+/
0/
++
+ = increase; = decrease; 0 = no significant effect. The magnitude of the response is indicated

by the number of symbols.(After Swamy VC, Triggle DJ. Calcium Channel Blockers. In: Craig CR,
*Changes are those commonly seen following oral doses in the treatment of hypertension or
angina.
Stitzel RE, eds. Modern pharmacology. 4th ed. Boston: Little, Brown, 1994:251.)
Chapter 10
Antianginal Drugs
95
The dihydropyridines (amlodipine, felodipine, isradipine, nifedipine,

and nicardipine):
dilate arterioles, decrease peripheral resistance, reduce left ventricular
afterload, and decrease myocardial oxygen requirement;
increase heart rate in response to the fall in peripheral resistance. This
effect increases myocardial oxygen requirements, but is sufficiently offset by the other actions of these drugs; and
frequently do not depress myocardial contractility. All calcium channel
blockers directly depress myocardial contractility, but this effect is usually offset in the dihydropyridines by reflex sympathetic stimulation
triggered by the fall in peripheral resistance.
Verapamil:
is a potent myocardial depressant in isolated muscle preparations but
produces only mildly decreased contractility in patients with normal
cardiac function;
owes its major anti-anginal effect to peripheral vasodilatation, which
decreases afterload and reduces myocardial oxygen demand;
is also a potent inhibitor of coronary artery spasm and increases
myocardial oxygen delivery in patients with variant angina;
can produce mild bradycardia, increasing the time spent in diastole,
when most of the coronary perfusion occurs; and
does not produce the reflex tachycardia characteristic of the dihydropyridines because verapamils cardiodepressant effects counterbalance any reflex sympathetic stimulation produced by the decrease in
peripheral resistance.
Diltiazem:
is a less potent peripheral vasodilator than the dihydropyridines;
is a less potent negative inotrope and chronotrope than verapamil;
owes its antianginal effects to its ability to
relax the peripheral arterioles, thereby reducing afterload and myocardial oxygen requirements, and
dilate epicardial and subendocardial arteries and inhibit spontaneous coronary spasm, thus increasing oxygen delivery to heart
muscle; and
may also reduce resting heart rate (although generally less than verapamil), which will also increase the time for coronary perfusion.
Calcium channel blockers alleviate the symptoms of variant angina by decreasing the oxygen requirements of the heart and increasing oxygen supply.
Chapter 10
Antianginal Drugs
96
In stable angina pectoris, calcium channel blockers reduce myocardial

oxygen demand. They decrease the frequency of attacks, reduce nitrate
requirements, and improve exercise performance.
A calcium channel blocker may be indicated when nitrates are ineffective or poorly tolerated, or when beta blockers are contraindicated.
Compared to beta blockers, calcium channel blockers
are preferred in patients with bronchospastic disorders, and
may be better tolerated in patients with peripheral vascular disease,
severe hypertriglyceridemia, or unstable insulin-dependent diabetes
mellitus.
The most common adverse effects of the dihydropyridines result from
vasodilation. These include headache, flushing and heat sensation, peripheral edema, and hypotension.
Diltiazems most common adverse effects are nausea, swelling or edema,
arrhythmia (atrioventicular [AV] block, bradycardia, tachycardia, and sinus
arrest), headache, rash, and fatigue. Diltiazem should be avoided in patients
with sick sinus syndrome.
Adverse reactions to verapamil include bradycardia, transient asystole,
hypotension, development or worsening of heart failure, development of
rhythm disturbances (including AV block and ventricular dysrhythmias),
flushing, and peripheral and pulmonary edema. CNS effects include dizziness, headache, fatigue, excitation, vertigo, syncope, and tremor. Constipation, nausea, vomiting and other gastrointestinal complaints are the most
common adverse effects seen after oral administration.
11
Antihypertensive Drugs
FACTORS CONTROLLING BLOOD PRESSURE
1. Cardiac output
2. Peripheral resistance
ANTIHYPERTENSIVE DRUGS LOWER BLOOD PRESSURE BY

REDUCING CARDIAC OUTPUT OR DECREASING PERIPHERAL
RESISTANCE
1. Reducing cardiac output with drugs that
decrease heart rate and force of contraction (-blockers), or
diminish venous return (venodilators).
2. Decreasing peripheral resistance with drugs that
reduce renal reabsorption of salt and water (diuretics),
dilate arterioles (thiazide and thiazide-like diuretics and vasodilators), or
decrease sympathetic centers in the brain (central sympathetic
inhibitors).
Figure 111 depicts the sites of action of antihypertensive drugs.
DRUGS THAT REDUCE CARDIAC OUTPUT

1. Beta Blockers (Acebutolol, Atenolol, Metoprolol, Nadolol,
Pindolol, Propranolol, Oxprenolol)
Actions (see Chapter 6)
Decrease myocardial contractility and cardiac output.
97
98
PDQ PHARMACOLOGY
Adrenergic mechanisms in CNS

Affected by:
reserpine
methyldopa
clonidine
beta blockers?
-Adrenoceptor
Blocked by:
labetalol
prazosin
Cardiac output
Reduced by:
beta blockers
adrenergic
neuron
blockers
Adrenergic nerve
terminal
guanethidine
reserpine
Enzyme converting
angiotensin I
to angiotensin II
Blocked by:
captopril
enalapril
Renal renin release

Reduced by:
beta blockers
arteriole
Arteriolar smooth muscle
diazoxide
hydralazine
minoxidil
calcium channel blockers
ACE inhibitors
Angiotensin II receptor
antagonists
Renal tubules
thlazides, etc.
spironolactone
Figure 111 Sites of action of antihypertensive drugs. (After OBrien AJJ, Bulpitt CJ. Antihypertensive disease. In: Avery GS, ed. Drug Treatment. 4th ed. Sydney/Auckland: ADIS Press,
1997: 900.)
Reduce renin release, thereby decreasing the formation of angiotensin

II and the secretion of aldosterone.
May also reduce sympathetic stimulation within the brain.
Can be used in the first-line treatment of hypertension.
If a beta blocker alone proves inadequate, a diuretic may be added to the
treatment regimen.
When the combination of beta blocker and diuretic fails to reduce the
hypertension, a vasodilator is usually added as a third drug.
2. Venodilators (Guanethidine and Reserpine)

Reduce norepinephrine secretion in veins, thereby impairing venous return
and decreasing cardiac output.
Chapter 11
99
Decreased sympathetic stimulation of arterioles may also reduce peripheral resistance.

Guanethidine and reserpine are effective antihypertensive drugs, but adverse
effects limit their value. When used, these drugs are usually administered
with a diuretic, such as hydrochlorothiazide.
For adverse effects, see Chapter 6.
DRUGS THAT DECREASE PERIPHERAL RESISTANCE

1. Diuretics (Thiazides, Chlorthalidone, Metolazone, Furosemide)
Actions (see Chapter 13 and Figure 112)
Initially inhibit Na+, Cl-, and H2O reabsorption. As a result, plasma and
extracellular fluid (ECF) volumes shrink and cardiac output declines.
With chronic use, plasma volume returns to normal but peripheral
resistance decreases.
Vasodilatation is greater with the thiazides, chlorthalidone, and metolazone than with furosemide.
Diuretics are a first-line treatment for hypertension. Because thiazides,
chlorthalidone and metolazone dilate arterioles, they are usually preferred
Blood pressure
Fluid volume
Peripheral resistance
Institution of
diuretic therapy
Initial few
weeks
Months and
beyond
Figure 112 Hemodynamic changes responsible for the antihypertensive effects of diuretic
therapy. (After Kaplan NM. The therapy of hypertension. In: Kaplan NM, ed. Clinical Hypertension. 4th ed. Baltimore: Williams and Wilkins; 1986:180.)
100
PDQ PHARMACOLOGY
over furosemide, which does not dilate precapillary resistance vessels, and
is not as effective in lowering blood pressure.
If a second drug is necessary, a -blocker or an ACE inhibitor is frequently added to the diuretic therapy because:
Diuretics indirectly stimulate -adrenergic receptors in the kidney to
increase the release of renin. The newly released renin is converted first to
angiotensin I, which in turn gives rise to angiotensin II, a potent vasoconstrictor. Angiotensin II also releases the mineralocorticoid aldosterone. The
action of angiotensin II to constrict arterioles, and the effects of aldosterone
to retain salt and water, reduce the antihypertensive effects of diuretics.
A -blocker decreases the diuretic-induced increase in renin secretion,
thereby increasing the antihypertensive effect of therapy.
An ACE inhibitor inhibits the conversion of angiotensin I to angiotensin
II and reduces the consequences of a diuretic-induced increase in renin.
The adverse effects of diuretics are presented in Chapter 13.
2. Vasodilators
A. Angiotensin-Converting Enzyme Inhibitors (Benazepril, Captopril,
Cilazapril, Enalapril, Fosinopril, Lisinopril, Quinapril, Ramipril)
ACE inhibitors reduce the formation of angiotensin II, thereby decreasing
peripheral resistance. Refer to Figures 113 and 114.
Angiotensinogen
Renin
Angiotensin I
Converting
enzyme
Angiotensin II
Aldosterone
Sodium retention
Vasoconstriction
Blood pressure
Figure 113 Renin-angiotensin-aldosterone axis and blood pressure control. (After BristolMyers Squibb.)
Chapter 11
101
Angiotensinogen
Captopril
Renin
Angiotensin I
Converting
enzyme
Angiotensin II
Aldosterone
Sodium
ECF
Vasoconstriction
Blood pressure
Figure 114 Effect of captopril on the renin- angiotensin-aldosterone axis. (After Bristol-Myers
Squibb.)

ACE inhibitors are effective alone in treating hypertension.
ACE inhibitors produce fewer adverse effects than other antihypertensives. The alterations in blood chemistry, bradycardia, intermittent claudication, fatigue, cold extremities, and decrease in libido that may be produced by diuretics and -blockers are not experienced by patients taking
ACE inhibitors. However, ACE inhibitors are frequently more expensive
than diuretics or -blockers and this has often relegated them to secondline therapy.
ACE inhibitors may also be combined with a diuretic or a -blocker.
B. Angiotensin II Receptor Antagonists (Irbesartan, Losartan,

Valsartan)
Actions
These drugs block the binding of angiotensin II to type 1 angiotensin II
(AT-1) receptors in blood vessels and other tissues.
Angiotensin II receptor antagonists are used alone and in combination with
a diuretic for the treatment of hypertension.
Their adverse effects include dizziness and asthenia or fatigue.
102
PDQ PHARMACOLOGY
C. Calcium Channel Blockers (Amlodipine, Diltiazem, Felodipine,

Isradipine, Nicardipine, Nifedipine, and Verapamil)
These drugs dilate arterioles, decrease peripheral resistance, and lower systemic blood pressure.
Similar to ACE inhibitors, calcium channel blockers (CCBs) are effective
antihypertensives and not encumbered by many of the adverse effects commonly associated with the older drugs, such as diuretics, -blockers, and
central sympathetic inhibitors.
However, like ACE inhibitors, CCBs are also frequently more expensive
than diuretics or -blockers and are, therefore, used as second-line treatment of hypertension.
CCB therapy is usually added to initial treatment with a diuretic when
the latter agent is not satisfactory alone. Amlodipine, felodipine, isradipine,
nicardipine, and nifedipine are often used with a -blocker. However, verapamil and diltiazem have myocardial depressant effects and are not recommended in combination with beta blocker therapy.
The adverse effects of these drugs were presented in Chapter 10.
D. Hydralazine
Actions
Hydralazine relaxes arteriolar smooth muscles by activating guanylate
cyclase, resulting in the accumulation of cyclic guanosine monophosphate
(cGMP). The decrease in peripheral resistance increases heart rate and force
of contraction, plasma renin activity, and fluid retention.
Hepatic acetylation is the major route for the inactivation of hydralazine.
Patients can be divided into rapid acetylators and slow acetylators. During
chronic therapy, hydralazine will accumulate in the slow acetylators unless
lower doses are given.
The use of hydralazine alone to treat hypertension is limited because of
reflex tachycardia.
Hydralazine is often used together with a -blocker and a diuretic, with
the -blocker preventing tachycardia and the diuretic increasing salt and
water excretion.
Chapter 11
103
Hydralazine is contraindicated in patients with coronary artery disease,

mitral valvular rheumatic heart disease, and acute dissecting aneurysm of
the aorta.
Adverse effects include headache (due to vasodilatation), tachycardia,
anginal symptoms, edema, heart failure, anorexia, nausea, dizziness, and
sweating. The most serious effect is a lupus erythematosus-like syndrome,
most often seen in slow acetylators. These patients must receive lower
doses to prevent accumulation of toxic levels of hydralazine.
E. Alpha1-Adrenergic Blockers (Doxazosin, Prazosin, Terazosin)

These drugs selectively block 1-receptors and reduce peripheral resistance.
In contrast to hydralazine, selective 1-receptor blockers produce only
a small increase in heart rate and little change in cardiac output or plasma
renin levels.
These drugs are used to treat mild to moderate hypertension.
They are usually taken with a thiazide diuretic and/or other antihypertensive drugs.
F. Alpha1- and Beta- Receptor Blocker (Labetalol)

Labetalol blocks both 1- and -receptors. Although more potent as a
-blocker, labetalols antihypertensive effects are due primarily to 1-blockade,
resulting in decreased peripheral resistance.
The reflex bradycardia normally seen with arteriolar dilation is prevented by the partial beta block.
Labetalol is usually added to other therapeutic regimens, notably diuretic
therapy.
The adverse effects of labetalol were presented in Chapter 6.
104
PDQ PHARMACOLOGY
G. Diazoxide and Sodium Nitroprusside

Actions
Diazoxide primarily dilates arterioles. Sodium nitroprusside relaxes both
arterioles and veins.
Both drugs are given parenterally to treat hypertensive crises. In this situation, either drug may be lifesaving.
Both drugs are contraindicated in compensatory hypertension, such as
that associated with aortic coarctation of AV shunt.
3. Central Sympathetic Inhibitors

A. Clonidine
Clonidine stimulates 2-receptors in the brain to inhibit peripheral sympathetic activity. As a result of reduced sympathetic nervous system stimulation, arterioles and veins dilate. In addition, renin release falls.
Clonidine is a very potent antihypertensive. It may be used concomitantly
with other antihypertensive agents, such as diuretics or beta blockers.
B. -Methyldopa (Methyldopa)
-Methyldopa reduces central sympathetic activity, decreases total peripheral resistance, and reduces blood pressure. Cardiac output and blood flow
are usually maintained in younger patients. In older patients, -methyldopa
may act primarily by dilating veins, thereby reducing preload and cardiac
output.
a-Methyldopa is usually employed in a general treatment program in conjunction with a diuretic and/or other antihypertensive drugs. -Methyldopa
may also be used to treat hypertensive crises.
Chapter 11
105
PHARMACOLOGIC APPROACH TO THE TREATMENT OF

HYPERTENSION (TABLE 111)
Table 111
A Protocol for the Treatment of Hypertension with a Diastolic

Pressure of 90120 mm Hg
Step 0
Lifestyle modification, weight loss in the obese, sodium restriction
Step 1
Diuretic (hydrochlorothiazide) or -blocker
Step 2
Add a -blocker or diuretic as dictated by drug selected for Step 1

In place of a -blocker, an ACE inhibitor, angiotensin II receptor
antagonist, calcium channel blocker, 1-blocker, labetalol, or central
sympathetic inhibitor may be used
Step 3
Add a vasodilatory such as hydralazine, or 1-blocker to diuretic plus

-blocker therapy
RATIONALE FOR COMBINATION ANTIHYPERTENSIVE THERAPY

(TABLE 112)
Guiding Principle
Mild hypertension can often be treated with one antihypertensive. More
severe hypertension is often handled by the use of two or more drugs. Drugs
should be selected so that they complement each other mechanistically and
reduce the consequences of the physiological play-back mechanism evoked
by the other agent.
Table 112
Rationale for Combining Antihypertensive Drugs

Physiological PlayBack Mechanism
Appropriate Drugs to
Use in Combination
Diuretic
Increase in reninangiotensin-aldosterone
axis
-Blocker reduces renin

release and decreases cardiac
output
ACE Inhibitor reduces
formation of angiotensin II and
secretion of aldosterone
Angiotensin II Receptor
Antagonist blocks the
action of released angiotensin II
-Blocker
Decrease in renal perfusion Diuretic decreases blood

can increase blood volume volume
Continued
Drug
106
PDQ PHARMACOLOGY
Table 112
Rationale for Combining Antihypertensive DrugsContinued

Drug
Physiological PlayBack Mechanism
Appropriate Drugs to
Use in Combination
ACE Inhibitor,
Angiotensin II
Receptor
Antagonist,
Calcium
Channel
Blocker (CCB)
No direct play-back
Diuretic often combined with
mechanisms. ACE
ACE inhibitor or angiotensin II
inhibitors, angiotensin II
receptor antagonist (see above).
receptor antagonists, and
Adding a CCB to a diuretic
CCBs are often combined also increases the overall
with other drugs to affect antihypertensive effect
a greater fall in BP
-Blocker often combined
with ACE inhibitor, angiotensin II|
receptor antagonist, or CCB to
increase antihypertensive effect
Hydralazine,
Reflex tachycardia and

Diuretic reduces fluid retention.
increased myocardial
-Blocker reduces reflex
contractility with increased stimulation of the heart and
cardiac output. Increased decreases the release of renin
renin release results in
by the kidneys
angiotensin II-mediated
vasoconstriction and
aldosterone-mediated
fluid retention
Central
Sympathetic
Inhibitor
Decrease in peripheral
Diuretic increases sodium,
resistance may result in
chloride, and water excretion. In
an increased retention
addition, thiazides, chlorthalidone,
of sodium, chloride, and
and metolazone decrease
water
peripheral resistance
Adrenergic
Neuron
Blocker
Fall in cardiac output

Diuretic increases excretion
(secondary to reduced
of salt and water. In addition,
venous return), reduces
thiazides, chlorthalidone, and
renal perfusion, resulting
metolazone decrease peripheral
in sodium, chloride, and
resistance and this effect further
water retention
reduces blood pressure
12
Hypotension and Shock
SHOCK
Shock is a condition of acute peripheral circulatory failure. It can result
from the loss of circulating fluid. Therapy is aimed at correcting the hypoperfusion of vital organs. Hypovolemic shock is treated by volume replacement; bacteremic shock by intensive antibiotic therapy, corticosteroids, and
volume replacement. In addition, sympathomimetic drugs or vasodilators
(which either increase cardiac output, or alter peripheral resistance, or both)
may be appropriate.
TISSUE PERFUSION OF HEART, BRAIN, AND KIDNEYS

DURING HYPOTENSION AND SHOCK
Heart and Brain
The major factor regulating blood flow through the coronary and cerebral
vessels is the mean diastolic pressure. In the presence of hypotension,
myocardial and cerebral perfusion are compromised. In this situation, a
sympathomimetic drug that increases blood pressure will improve the perfusion of both the heart and brain. Sympathomimetics can be used without concern of constricting the blood vessels in these organs. The caliber
of these vessels is determined by the metabolic needs of the tissue, not by
stimulation of adrenergic receptors.
The heart and brain differ from each other with respect to their need
for oxygen.
Although the heart normally uses an aerobic metabolic pathway, it can
operate for a short time anaerobically.
The brain needs oxygen for its metabolism and is particularly susceptible to the consequences of acute hypotension and shock.
107
108
PDQ PHARMACOLOGY
Kidney
In contrast to the heart and brain, the kidney extracts only a relatively small
amount of the oxygen provided to it under resting conditions. This means
it can withstand, within limits, a reduction in blood flow by extracting a
higher percentage of the oxygen supplied.
However, sympathetic stimulation causes renal vasoconstriction. Adrenergic vasoconstrictors also reduce blood flow, possibly leading to renal
ischemia.
SYMPATHOMIMETICS
Sympathomimetics are used to improve tissue perfusion. They stimulate
1. 1-receptors, to increase venous return and peripheral resistance;
2. 1-receptors, to increase heart rate and cardiac output (if venous return
is adequate); or
3. dopamine receptors, to dilate the renal and splanchnic beds.
1. Epinephrine (Adrenaline)
Epinephrine stimulates 1-receptors in the heart to increase both heart rate
and force of contraction. In small doses, epinephrine stimulates
2-receptors on arterioles (precapillary resistance vessels) in skeletal
muscles to decrease peripheral resistance, and
1-receptors on veins to increase venous return.
Larger doses of epinephrine stimulate 1-receptors on arterioles throughout the body to produce a generalized vasoconstriction and an increase in
peripheral resistance.
Epinephrine also dilates bronchioles.
Epinephrine is the drug of choice to treat anaphylactic shock because it
antagonizes the effects of histamine, which constricts bronchioles and
dilates blood vessels.
By stimulating 2-receptors, epinephrine prevents or reverses histamine-induced bronchoconstriction.
By stimulating 1-receptors, epinephrine reverses histamine-induced
vasodilatation.
Chapter 12
Drugs for the Treatment of Hypotension and Shock
109
For the adverse effects of epinephrine, refer to Chapter 5.
2. Levarterenol (Norepinephrine and Noradrenaline)

Levarterenol stimulates 1-receptors, constricting both capacitance and precapillary resistance vessels (veins and arterioles). The resulting increase in
blood pressure activates the carotid sinus and aortic arch pressor receptors
to reflexly stimulate the vagus nerve. The result is a fall in heart rate and cardiac output.
Levarterenol is indicated for the maintenance of blood pressure in acute
hypotensive states, surgical and nonsurgical trauma, central vasomotor
depression, and hemorrhage.
3. Dobutamine and Dopamine

Refer to Chapter 5 for information on these drugs.
VASODILATORS
Vasodilators are used in patients with severe pump failure following acute
myocardial infarction and in individuals with refractory chronic congestive
heart failure. Vasodilators
1. increase cardiac output by reducing peripheral resistance (afterload
reduction),
2. relieve pulmonary congestion by increasing venous capacitance (preload reduction), and
3. limit the extent of ischemic damage by reducing myocardial oxygen
demand and increasing myocardial oxygen supply.
1. Sodium Nitroprusside
Nitroprusside dilates venous and arterial beds. Because it has a greater effect
on afterload than nitroglycerin, nitroprusside is more likely to increase cardiac output.
110
PDQ PHARMACOLOGY

Nitroprusside can be used to treat severe persistent pump failure in patients
with markedly reduced cardiac output and increased peripheral resistance.
Nitroprusside is particularly valuable in patients with severe acute
decompensated chronic congestive heart failure, refractory to digoxin and
diuretics.
Nitroprusside should not be used in the treatment of compensatory
hypertension, eg, AV shunt or coarctation of the aorta.
2. Intravenous Nitroglycerin
Actions
Nitroglycerin dilates both arterial and venous vessels, with a greater effect
on the venous side.
Intravenous (IV) nitroglycerin relieves pulmonary congestion, decreases
myocardial oxygen consumption, and reduces ST segment elevation.
IV nitroglycerin can be used to decrease myocardial ischemia and improve
hemodynamics in severe left ventricular dysfunction complicating acute
myocardial infarction.
Its primary use is in patients with recurrent ischemic pain, or in patients
with marked elevation of left ventricular filling pressure and pulmonary
edema.
Major adverse effects include symptomatic hypotension, reflex tachycardia, paradoxical increase of anginal pain, and palpitation.
Central nervous system effects include transient headache, weakness,
dizziness, apprehension, and restlessness.
Patients may also experience nausea, vomiting, abdominal pain, and
methemoglobinemia.
13
Diuretics
REABSORPTION OF SODIUM, CHLORIDE, AND WATER FROM
THE NEPHRON (FIGURE 131 AND TABLES 131 AND 132)
Proximal Convoluted Tubule
Distal Tubule
K
Na
PO4
Na, Cl
Glucose
H2 O
Amino Acids
HCO3
Pars Recta
ACTIVE TRANSPORT
Na
Cl
Na
Na
Cl
H 2O
Na
Cl
H2 O
PASSIVE TRANSPORT
Descending
Limb of
Henle
NaCl
H2 O
NaCl
Na
K
Cl
Cortical H
ADH H2O
Thick
Ascending
Limb of
Na
Henle
Aldo
Medullary
Thick
K
Ascending
Limb of
ADH H2O
Henle
Medullary
Thin
H
Ascending
Limb of
Henle
ADH H2O
Cortical
Collecting
Duct
Outer
Medullary
Collecting
Duct
Inner
Medullary
Collecting
Duct
Urea
Figure 131 The reabsorption of electrolytes and water from the nephron. ADH = antidiuretic
hormone. (After Jacobson HR, Kokko JR. Diuretics, sites and mechanisms of action. Ann Rev
Pharmacol Toxicol 1976; 16:201204.)
Table 131
Percent of Filtered Water and Sodium Remaining in

Different Segments of the Nephron
Segment of Nephron
End of proximal tubule
End of loop of henle
End of distal tubule
Excreted urine
% H2O Remaining
% Na+ Remaining
20
14
25
0.1 1
20
7
15
01
111
112
PDQ PHARMACOLOGY
Table 132
Reabsorption of Sodium, Chloride, Bicarbonate, and Water

and Secretion of Potassium and Hydrogen Ions in
Proximal
Tubule
Ascending Limb
of Loop of Henle Distal Tubule
Na+
Active
Passive; follows
Cl
Active, exchanged Active, exchanged

for K+ and H+.
for K+ and H+.
Aldosterone is
Aldosterone is
responsible for
responsible for the
the exchange of
exchange of K+ and
K+ and H+ for
H+ for Na+; CA
Na+; CA controls
controls an
an exchange of
exchange of H+
+
+
H for Na
for Na+
Cl
Passive,
follows
Na+
Active, taking
Na+ with it
1. Some Cl ions
1. Some Cl ions
are reabsorbed
are reabsorbed
passively with Na+. passively with Na+.
2. Other Cl ions
2. Other Cl ions
are retained in the are retained in the
tubular lumen to
tubular lumen to
electrically
electrically balance
balance K+ that
K+ that is secreted
is secreted in
in exchange for
exchange for rereabsorbed Na+ ions
absorbed Na+ ions
K+
H+
Secreted into
Secreted into
tubule in
tubule in exchange
exchange for Na+ for Na+
Secreted
into tubule
in exchange
for Na+, then
reabsorbed
CA involved
HCO3 Reabsorbed;
depends
on CA
H2O
Collecting Ducts
Passive;
follows
NA+
Secreted into
Secreted into
tubule in
tubule in exchange
exchange for Na+ for Na+
Reabsorbed;
depends on CA
Ascending limb
Passive; follows
is impermeable to Na+
H2O, which stays
in tubular lumen
CA = carbonic anhydrase; ADH = antidiuretic hormone.
Reabsorbed,
depends on CA
Passive; into
hypertonic medulla
in presence of
ADH
Chapter 13
Diuretics
113
FACTORS INFLUENCING THE REABSORPTION OF SODIUM

AND WATER IN THE NEPHRON
Carbonic Anhydrase
Carbonic anhydrase (CA) catalyzes the reaction:
H2O + CO2
H+ + HCO3
Carbonic anhydrase
provides H+ for exchange with Na+, and
promotes:
reabsorption of Na+, HCO3, and H+ in the proximal tubule,
secretion of H+ in the distal tubule and collecting duct, and
reabsorption of fixed base. HCO3 formed in the proximal tubule is
reabsorbed, retaining fixed base.
Inhibiting CA increases
HCO3 excretion,
urine pH, and
K+ excretion (in the absence of H+, more K+ is exchanged for Na+).
Aldosterone
Under the influence of aldosterone, Na+ in the distal tubule and collecting
duct is reabsorbed in exchange for K+ and H+, which are secreted into the
tubular lumen. Aldosterone antagonists block this exchange, increase Na+
excretion, and decrease the loss of K+ and H+ ions.
Antidiuretic Hormone
In the presence of antidiuretic hormone (ADH), collecting ducts are permeable to H2O, which is reabsorbed into the hypertonic medulla. In the
absence of ADH, water cannot be reabsorbed from collecting ducts and the
kidney excretes a dilute urine.
Impermeability of the Ascending Limb of the Loop of Henle to H2O
The inability of water to follow Na+ and Cl from the ascending limb of the
loop of Henle into the medulla of the kidney is essential to the formation
of a hypertonic medulla. It is the presence of a hypertonic medulla that facilitates the final concentration of urine when water in the collecting ducts is
drawn into the medulla. The hypertonic medulla also depends on the reabsorption of urea from the collecting ducts.
114
PDQ PHARMACOLOGY
SITE I
PROXIMAL
SITE IV
SITE III
DISTAL
Na+
filtrate
Na+
Na+
K+H+
Na+
TEX
COR
LLA
DU
ME
Na+
Na+
ASCENDING
LIMB
(water
impermeable)
SITE II
Figure 132 Sites of sodium reabsorption and diuretic action in the nephron. I = proximal
tubule; II = ascending limb of Henles loop; III = cortical diluting site; IV = distal Na+/K+H+
exchange site. (After Lant AF, Wilson GM. Modern diuretic therapy. Physiological basis and practical aspects. Excerpta Medica 1974:7.)
SITES OF ACTION OF DIURETICS WITHIN THE NEPHRON

(FIGURE 132 AND TABLE 133)
GROUPS OF DIURETICS
1. Thiazides, Chlorthalidone, and Metolazone
Actions
These drugs block Na+ and Cl reabsorption in the cortical diluting segment of
the loop of Henle (site III) and in the proximal section of the distal convoluted
tubule (site IV). Water is retained in the nephron because of the osmotic drawing power of Na+ and Cl. These drugs do not alter the hypertonicity of the renal
medulla or reduce the capacity of the nephron to concentrate urine in the collecting ducts. Because of increased Na+ arriving in the distal tubules and collecting ducts, more K+ is secreted in exchange. This can lead to hypokalemia.
Uses
These drugs are used as adjunct therapy in congestive heart failure, hepatic
cirrhosis, corticosteroid and estrogen therapy, and edema of renal origin.
Chapter 13
Diuretics
115
Table 133
Consequences of Reducing Sodium Reabsorption in

Site
Consequence
I = Proximal tubule
Although most of the glomerular filtrate is

reabsorbed in the proximal tubule, drugs which
impair salt and water reabsorption here have little
effect on urine production because salt and water
retained in the proximal tubule are reabsorbed in
the subsequent portions of the nephron
II = Ascending limb of
Henles loop
Loop diuretics inhibit sodium and chloride

reabsorption from site II, reduce the hypertonicity
of the medulla, and prevent the final concentration
of urine in the collecting ducts
III = Cortical diluting site
Drugs that block the reabsorption of sodium and

chloride at site III (cortical diluting segment)
produce a marked diuresis. They are not as potent
as loop diuretics because they do not modify the
hypertonicity of the renal medulla or the
concentrating ability of the collecting ducts
IV = Distal Na+/K+ H+
exchange site
Most of the salt and water filtered through the

glomeruli is reabsorbed before it reaches the distal
convoluted tubule. Drugs that work at site IV have
only limited effectiveness. Potassium-sparing
diuretics work in the distal tubules and collecting
ducts to reduce the secretion of K+ in exchange
for Na+
Also used in the treatment of hypertension (see Chapter 11).

Adverse Effects
Hypovolemia, hyponatremia, hypokalemia, hyperuricemia with attacks of
gout, hyperglycemia due to decreased insulin release.
2. Loop Diuretics (Furosemide, Ethacrynic Acid, Bumetanide)

Actions
Loop diuretics inhibit Cl- reabsorption in the ascending limb of the loop of
Henle in the renal medulla (site II). Na+ remains with Cl- in the tubular
lumen to maintain electrical neutrality. The resulting reduction in hypertonicity in the medulla impairs the urine-concentrating ability of the collecting ducts.
116
PDQ PHARMACOLOGY
Uses
Loop diuretics are used in the treatment of edema in patients with severe
edema or renal impairment in which thiazides, chlorthalidone, or metolazone are ineffective.
Also used in the treatment of hypertension; however, thiazides,
chlorthalidone, or metolazone are usually preferred because loop diuretics
do not dilate arterioles (see Chapter 11).
Adverse Effects
Electrolyte depletion, manifested as weakness, dizziness, lethargy, leg
cramps, sweating, bladder spasms, anorexia, or mental confusion.
Hyperuricemia and attacks of gout, Dermatitis, rashes, Vertigo, tinnitus, reversible deafness.
3. Potassium-Sparing Diuretics
A. Spironolactone
Actions
Spironolactone competitively blocks aldosterone receptors in the distal
convoluted tubule (site IV).
Uses
Spironolactone is used in the treatment of conditions of excessive aldosterone levels, primary aldosteronism, and cirrhosis. Treatment of congestive heart failure.
Combined with a thiazide diuretic, chlorthalidone, metolazone, or a
loop diuretic to prevent diuretic-induced hypokalemia.
Adverse Effects
Hyperkalemia, gynecomastia, nausea, cramping diarrhea.
B. Triamterene and Amiloride

Actions
Triamterene and amiloride act directly on tubular transport in the distal
convoluted tubules and collecting ducts to inhibit Na+ reabsorption and K+
secretion. Actions are independent of aldosterone.
Chapter 13
Diuretics
117
Uses
Triamterene and amiloride are used in the treatment of edema associated
with congestive heart failure, cirrhosis, nephrotic syndrome, steroid-induced
edema, and edema secondary to hyperaldosteronism.
Primary use of these drugs is with a thiazide diuretic, chlorthalidone, metolazone, or loop diuretic to reduce or prevent diuretic-induced
hypokalemia.
Adverse Effects
Hyperkalemia.
4. Osmotic Diuretics (Mannitol)

Actions
Osmotic diuretics are pharmacologically inert electrolytes. They are freely
filtered by the glomerulus and not reabsorbed. When excreted, they carry
an amount of water equivalent to their osmotic drawing power.
Uses
Mannitol is used to increase urine production when the glomerular filtration
rate (GFR) is acutely reduced. In this situation, loop diuretics cannot reduce
the reabsorbing capacity of the nephron sufficiently to increase urine flow.
Also used to reduce cerebrospinal fluid volume and pressure.
Adverse Effects
Increased extracellular fluid volume. Hypersensitivity reactions.
Part 4
Drugs and the Blood
14
Antihyperlipidemic Drugs
RATIONALE FOR LOWERING PLASMA LIPIDS
Myocardial Infarction
Caused by atherosclerosis. Is the most common cause of death in the Western world.
Three Factors Implicated in Atherosclerosis
1. Hypertension
2. Smoking
3. High plasma lipids
Rationale for Antihyperlipidemic Drugs
1. Antihyperlipidemic drugs reduce elevated plasma lipids
2. Decreasing plasma lipid levels reduces the risk of myocardial infarcts
CLASSIFICATION OF PLASMA LIPOPROTEINS (TABLE 141)

Table 141
Comparative Classification of Plamsa Lipoproteins

Ultracentrifugation
Electrophoresis
1. Chylomicrons, found near the top

of tube. Contain 8090%
triglycerides (TG)
Band that remains at the origin of

the electrophoresis plate
2. Very-low-density lipoproteins
(VLDL). Contain 5070% TG and
20% cholesterol
Prebeta band, moves slowly down

the electrophoresis plate
Continued
118
Chapter 14
119
Table 141
Comparative Classification of Plamsa LipoproteinsContinued

Ultracentrifugation
3. Low-density lipoproteins (LDL)
Responsible for 75% of
cholesterol found in plasma
Electrophoresis
= Beta band, moves farther down the
electrophoresis plate than the
prebeta band
4. High-density lipoproteins (HDL),

= Alpha lipoproteins, move farthest
found near bottom of tube. Contain
down the electrophoresis plate
about 20% cholesterol and 8% TG.
An inverse relationship exists
between HDL levels and incidence
of coronary heart disease in
subjects over age 50
ORIGINS OF PLASMA LIPOPROTEINS (FIGURE 141)

Chylomicrons
Formed in the intestines from food. They mainly contain triglycerides synthesized from fatty acids, with more than 12 carbons, and cholesterol. Once
absorbed into the lymph and transported to the plasma, chylomicrons are
acted on by lipoprotein lipase, an enzyme located at the endothelial surface
of capillary blood vessels. This enzyme releases triglycerides, which are subsequently stored as fat or converted to fatty acids. The remaining chylomicron remnant particles, rich in cholesterol of dietary origin, are bound and
internalized in liver cells, and then degraded by lysosomal enzymes. This
process delivers cholesterol of dietary origin to the liver.
VLDL
VLDL, containing 50 to 70% triglycerides and 20% cholesterol, are formed
in the liver from free fatty acids (FFA), cholesterol, and carbohydrate.
VLDL are stripped of some of their triglycerides by lipoprotein lipase and
converted to intermediate-density lipoproteins (IDL).
LDL
Formed from IDL as the latter lose triglycerides. LDL contain mainly cholesterol. They are removed from the circulation through binding with
plasma membrane B-100/E receptor (the LDL receptor) in the liver and
extrahepatic tissues. Most LDL appear to be removed by the liver. A deficiency of LDL-receptor activity results in type IIa hypercholesterolemia, also
known as familial hypercholesterolemia.
Chapter 14
dietary fat
Bile acids
and
Cholesterol
120
Liver
Gut
LCAT
Chylomicron
remnants
Extrahepatic
tissues
LPL
Chylomicrons
VLDL
IDL
LDL
HDL
FFA
Muscle and
Adipose tissue
Figure 141 Schematic overview of lipoprotein transport and turnover. VLDL = very-low-density lipoproteins; IDL = intermediate-density lipoproteins; LDL = low-density lipoproteins; HDL
= high-density lipoproteins; FFA = free fatty acids; LPL = lipoprotein lipase; LCAT = lecithin:cholesterol acyltransferase. (After Forster C. Hyerlipoproteinemia and antihyperlipidemic drugs. In:
Kalant H, Roschlau W, eds. Principles of Medical Pharmacology. 5th ed. Toronto: B.C. Decker,
1989:375385.)
HDL
The precursors of HDL (nascent HDL) are produced by the liver and converted to mature HDL in the circulation as a result of acquiring cholesterol
ester and apoproteins from other lipoproteins. HDL play a role in the
metabolism of chylomicrons and VLDL. HDL could also be important for
the transport of cholesterol out of peripheral tissues (including arterioles)
to the liver for disposal. This reverse cholesterol transport could be the basis
for the inverse correlation between coronary heart disease and plasma
HDL levels.
CAUSES OF HYPERLIPIDEMIAS
Hyperlipidemias may be of exogenous or endogenous origin (Table 142).
Chapter 14
121
Table 142
Causes of Hyperlipidemias
Exogenous
Hyperlipidemia
Exogenous hyperlipidemia results from the ingestion of a

meal high in fatty acids containing 12 or more carbons. The
chylomicrons formed are released into the circulation by the
intestinal lymphatics. Exogenous hyperlipidemia can be reduced
by eating food containing fatty acids having fewer than 12
carbons, because they are absorbed directly into the portal
circulation and carried to the liver
Endogenous
Hyperlipidemia
Endogenous hyperlipidemia results from an increase in the

synthesis of lipoproteins or a decrease in their rate of
removal from the plasma. Excessive hepatic triglyceride and
VLDL synthesis in the liver is the most common cause of
hypertriglyceridemia. Triglyceride synthesis is stimulated by
caloric excess, dietary carbohydrates, ethanol, estrogens,
and hyperinsulinism secondary to peripheral insulin
antagonism, such as is seen in obesity and corticosteroid
excess. Endogenous hypertriglyceridemia may also be genetic
in origin
Lipoprotein lipase is responsible for the removal of
triglycerides from VLDL and chylomicrons. A defect in
this enzyme is the most common cause of massive
hypertriglyceridemia. Both insulin and thyroxin are required
for the maintenance of lipoprotein lipase activity. Uncontrolled
diabetes mellitus and hypothyroidism are the leading causes
of severe hypertriglyceridemia. Treatment with insulin or
thyroid hormone reverses the condition
Endogenous hypercholesterolemia can result from
overproduction of cholesterol in the liver. This condition is
associated with obesity and genetic abnormalities and can
result in premature coronary heart disease
TREATMENT OF HYPERLIPIDEMIAS
Initial Non-Drug Treatment
Initial treatment for hyperlipidemia should include a specific diet, weight
reduction, and an exercise program. Patients with diabetes mellitus must
maintain good diabetic control. Drug therapy is often not recommended
until diet and exercise have been tried for two to three months. The institution of drug therapy should not mean that non-drug therapy be discontinued. Nonpharmacologic means of hyperlipidemia control must remain
an integral part of the treatment regimen.
Chapter 14
122
DRUG TREATMENT
1. Drugs Primarily Affecting VLDL
The Fibrates (Benzafibrate, Clofibrate, Fenofibrate, Gemfibrozil)
Actions
The mechanism of action of the fibrates has not been established, but likely
involves
catabolism of VLDL, as a result of increased lipoprotein and hepatic
triglyceride lipase activity; and
attenuation of triglyceride biosynthesis by acetyl-coenzyme A (CoA)
carboxylase inhibition.
Fibrates decrease both LDL and VLDL. However, because their major
action is to increase lipoprotein and hepatic triglyceride lipase, fibrates produce a greater reduction of VLDL.
Uses
Fibrates are used to treat patients with hypercholesterolemia of types
IIa (hyperbetalipoproteinemia), characterized by increased LDL, normal VLDL, and absence of chylomicrons; and
IIb (combined or mixed hyperlipidemia), characterized by increased
LDL, increased VLDL, and absence of chylomicrons.
Adverse Effects
Fibrates are generally well tolerated. Most common immediate adverse
effects are abdominal discomfort, epigastric fullness, nausea, and mild
diarrhea.
Fibrates may potentiate the effects of sulfonylurea hypoglycemics and
warfarin.
2. Drugs Primarily Affecting LDL

A. The Resins (Cholestyramine and Colestipol)
Actions
Cholestyramine and colestipol are nonabsorbed resins that sequester bile
acids in the intestine, preventing their absorption. The liver responds to the
lowered levels of bile acids by increasing the conversion of cholesterol to bile
Chapter 14
123
acids, thereby lowering cholesterol levels and increasing LDL-receptor

activity and apoprotein B catabolism.
Unfortunately, the decrease in LDL is partly offset by a compensatory
increase in cholesterol synthesis in the liver and intestine.
Uses
Cholestyramine and colestipol are used to treat hyperlipidemias characterized by an increase in beta lipoproteins or LDL.
They are used in situations where the increase is seen in LDL alone or
where the increase in LDL is accompanied by a rise in VLDL.
Adverse Effects
Cholestyramine and colestipols adverse effects include abdominal discomfort, bloating, nausea, dyspepsia, steatorrhea, and possibly either constipation or diarrhea.
Cholestyramine and colestipol bind to acidic drugs (including warfarin,
phenylbutazone, digoxin, thiazides, phenobarbital, and thyroid hormones)
in the GI tract, thereby decreasing their absorption.
Cholestyramine and colestipol also block the absorption of fat-soluble
vitamins and tetracycline antibiotics.
B. The Statins (Atorvastatin Fluvastatin, Lovastatin, Pravastatin,

Simvastatin)
Actions
The statins reduce LDL synthesis by inhibiting 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion
of HMG-CoA to mevalonate, which is an early and rate-limiting step in the
biosynthesis of cholesterol.
The statins also increase LDL catabolism, as a result of the induction of
LDL receptors.
They may also increase HDL levels.
Uses
The statins are used to reduce elevated cholesterol levels in patients with primary hypercholesterolemia of type IIa and IIb.
Adverse Effects
Most common complaints at the start of therapy are nausea, epigastric fullness, distension, constipation or loose bowel actions, and headache.
Chapter 14
124
Mild elevations in liver enzymes (transaminases) are common and

exceed the apparent safe level (3x the normal upper limit) in about 1.5% of
patients. Liver function should therefore be monitored every 4 to 6 weeks
during the first year of therapy and periodically thereafter.
A combination of muscle weakness and raised plasma creatine phosphokinase levels affects approximately 1 to 2 patients for every 1000 taking
statins. On rare occasions, this has been reported to progress to rhabdomyolysis and myoglobinuria. It is believed that the risk of myopathy is
greater when HMG-CoA reductase inhibitors are administered concurrently with cyclosporine, erythromycin, gemfibrozil, or nicotinic acid.
Cholestyramine and colestipol may decrease the bioavailability of
statins. If combined therapy is required, give the statin at least 1 hour before
or 4 hours after cholestyramine or colestipol.
3. Miscellaneous Drugs
A. Niacin (Nicotinic Acid)
Actions
Niacin reduces triglyceride synthesis, thereby decreasing hepatic secretion
of VLDL.
This action of niacin may be explained by its ability to inhibit lipolysis
in adipose tissue, which lowers FFA and decreases the hepatic synthesis of
triglycerides. This is because circulating FFA, derived almost totally from
adipose tissue, are the main source of fatty acids for the synthesis of triglycerides in the liver.
Since LDL is derived from VLDL, a reduction of plasma VLDL concentration can lead to a decrease in circulating levels of LDL, and thus of cholesterol.
Uses
Niacin is used effectively for the treatment of both hypercholesterolemias
and hypertriglyceridemias. Therefore, it has value in the treatment of type
IIb hyperlipoproteinemia, in which both VLDL and LDL are increased.
Niacin may also increase HDL.
Adverse Effects
The most common and annoying adverse reaction is the development of an
intense cutaneous flush and pruritus that severely limits compliance with
the drug. However, with continued use, these symptoms will disappear in
most patients.
Chapter 14
125
Gastrointestinal distress is often encountered with niacin therapy but

can be decreased by taking the drug with meals and using antacids.
More severe, but less frequent, side effects of niacin include abnormal
liver function tests, decreased glucose tolerance, glycosuria, hyperuricemia,
and jaundice.
Niacin is contraindicated in patients with hepatic dysfunction, active
peptic ulcers, or hyperuricemia. It should be used with caution in patients
with diabetes mellitus, since it can result in deterioration of blood glucose
control in noninsulin-dependent patients.
B. Probucol
Actions
The mechanism of action of probucol is not known, but may be related to
increased catabolism of LDL.
Probucol reduces total cholesterol and LDL-cholesterol concentrations without substantially affecting serum VLDL-cholesterol or triglyceride
levels.
Uses
Probucol is used in the treatment of patients with elevated LDL or combined hyperlipidemias.
Adverse Effects
Probucols adverse effects are diarrhea, flatulence, abdominal pain, and
nausea.
15
Anticoagulant and
Antiplatelet Drugs,
Fibrinolytic Agents,
and Vitamin K
THROMBI AND EMBOLI
Groups of Drugs Used in the Management of Thrombi and Emboli
1. Anticoagulants, which inhibit the formation of fibrin
2. Antiplatelet drugs, which reduce platelet adhesion and aggregation
3. Fibrinolytic and thrombolytic agents, which digest fibrin
Formation of Venous and Arterial Thrombi
Venous thrombi usually form in regions of slow or disturbed blood flow.
They begin as small deposits in either the valve cusp pockets or the venous
sinuses of the deep veins of the legs.
Coagulation of the blood plays a major role in the formation and
extension of venous thrombi.
Arterial thrombi are formed after damage to the endothelium of the
artery, which allows platelets to adhere to the vessel wall and serve as the
focus for thrombus formation (Figure 151). The adhesion of a few platelets
to the vessel wall is followed by the aggregation of increased numbers of
thrombocytes. Fibrin, formed by coagulation, subsequently encases the
platelets, giving rise to a platelet-fibrin plug. Because blood flow in the arteries is rapid, arterial thrombi stay close to vessel walls and have been termed
mural thrombi. A mural thrombus may either remain at its original site or
126
Chapter 15
Anticoagulant and Antiplatelet Drugs
127
Lesion
Platelet-fibrin
Mass
Platelet-fibrin Emboli
Figure 151 Diagrammatic representation of platelet adhesion in formation of arterial

emboli. (After Mustard JF, Packham MA. Platelets, thrombosis and drugs. Drugs 1975; 9:25.)
be sheared away by the rapid blood flow to locate in other parts of the body.
If it remains at its site of origin, the mural thrombus can serve as a focus
for further platelet aggregation. In that case, a platelet-fibrin plug may be
formed, which becomes incorporated into the vessel wall to produce
atherosclerosis-like lesions.
Anticoagulants
Used to prevent thrombus formation in the veins, where coagulation plays
an important role.
Antiplatelet Drugs
Used to stop microemboli from forming in the arteries and arterioles, where
platelet adhesion plays an important role.
Chapter 15
128
ANTICOAGULANT DRUGS
1. Heparin
Actions (Table 151 and Figure 152)
Works by means of a plasma cofactor, the heparin cofactor, or antithrombin III which neutralizes several activated clotting factors: XIIa, kallikrein,
XIa, IXa, Xa, IIA, and XIIIa.
Has an immediate but fleeting anticoagulant effect.
Decreases plasma turbidity by stimulating the release of a lipase from
capillary walls which breaks down chylomicrons and free fatty acids.
Uses
Prevents new clot formation and limits propagation of existing thrombi.
Effects are monitored by coagulation tests, such as whole blood clotting
time, thrombin time, or activated partial thromboplastin time (aPTT).
Table 151
Blood Clotting Factors

Factor
Common Synonyms
Factor
Common Synonyms
Fibrinogen
IX
Christmas factor, plasma

thromboplastin component (PTC)
I'
Fibrin monomer
Stuart factor
I"
Fibrin polymer
XI
Plasma thromboplastin antecedent

(PTA)
II
Prothrombin
XII
Hageman factor
III
Tissue thromboplastin
XIII
Fibrin-stabilizing factor (FSF)
HMW-K
High-molecular-weight kininogen,
Fitzgerald factor
++
IV
Calcium, Ca
Labile factor
Pre-K
Prekallikrein, Fletcher factor
VII
Proconvertin
Ka
Kallikrein
VIII
Antihemophilic
globulin (AHG)
PL
Platelet phospholipid
(After OReilly RA. Anticoagulant, antithrombotic, and thrombolytic drugs. In: Gilman AG,
Goodman LS, Rall TW, Murad F, eds. The pharmacological basis of therapeutics. 7th ed.
New York: MacMillan, 1985:1338.)
Chapter 15
129
Figure 152 Intrinsic and extrinsic systems of blood coagulation. (After OReilly RA. Anticoagulant, antithrombotic, and thrombolytic drugs. In: Gilman AG, Goodman LS, Rall TW, Murad
F, eds. The pharmacological basis of therapeutics. 7th ed. New York: MacMillan, 1985:1338.)
Adverse Effects
Hemorrhage, local irritation, mild pain or hematoma at site of injection,
hypersensitivity, osteoporosis, alopecia, thrombocytopenia, aldosterone
suppression.
2. Low-Molecular-Weight Heparins (Dalteparin, and Enoxaparin)

Actions
Derived from heparin by depolymerization, low-molecular-weight heparins
differ from unfractionated heparin in their high ratio of antifactor Xa to
antifactor IIa (antithrombin) activity, producing a more favourable ratio of
antithrombotic effect to bleeding risk.
Chapter 15
130
Have greater bioavailability than unfractionated heparin, permitting

fewer daily doses, more predictable plasma heparin concentrations, and
subcutaneous administration of fixed dosages without monitoring plasma
antifactor Xa activity or aPTT.
Uses
Used in prophylaxis of thromboembolic disorders (deep vein thrombosis)
and in surgery.
Compared to heparin, they have a reduced likelihood of causing hemorrhage.
Adverse Effects
Hemorrhage.
3. Oral Anticoagulants (Warfarin)

Actions
Prevents formation of new fibrin thrombi and reduces extension of already
formed clots, by competitively antagonizing vitamin K thereby preventing
hepatic synthesis of the biologically active forms of the vitamin Kdependent
clotting factors II, VII, IX, and X (indicated by circles in Figure 152).
Delayed onset of action. Effect not evident until the active factors
already present in blood are catabolized, ranging from 5 hours for factor VII
to 2 to 3 days for factor II.
Initially prolongs one-stage prothrombin time by depressing factor VII
levels.
Effects depend on reduction of all four vitamin Kdependent clotting
factors.
Uses
To treat acute deep vein thrombosis, rheumatic valve disease, and patients recovering from myocardial infarcts or suffering from cerebrovascular disease.
Effects controlled by prothrombin time (PT) are reported in terms of
an international normalized ratio (INR). The observed PT is corrected
depending on the reagent used in the testing. For most situations, the target INR is 2 to 3.
Adverse Effects
Hemorrhage. Drug interactions are common with warfarin. Consult an appropriate reference source for a list of the drugs that interact with warfarin.
Chapter 15
131
ANTIPLATELET DRUGS
1. Acetylsalicylic Acid (ASA, Aspirin)
Actions
Inhibits platelet aggregation by irreversibly inactivating cyclooxygenase, the
enzyme responsible for synthesis of the prostaglandin-like substance thromboxane A2 in platelets (Figure 153). Thromboxane A2 promotes platelet
aggregation.
Effects last for the lifetime of the platelet (7 to 10 days).
Uses
Given to reduce the risk of recurrent transient ischemic attacks (TIAs) or
stroke in patients who have had transient ischemia of the brain due to fibrin platelet emboli.
Used to decrease the adhesive properties of platelets in patients with diseased arteries, artificial blood vessel shunts and heart valves, and in patients
with spontaneous aggregation syndromes.
Administered in the prophylaxis of venous thromboembolism after
total hip replacement.
Figure 153 Conversion of arachidonic acid to prostaglandins. PG = prostaglandin; TX = thromboxane; H PETE = 12-L-hydroperoxy-5, 8, 10, 14, -eicosatetraenoic acid; HETE = 12-L-hydroxy5, 8, 10, 14 -eicosatetraenoic acid. (After Mustard JF. Prostaglandins in disease: modification
by acetylsalicylic acid. In: Barnett HJM, Hirsh J, Mustard JF, eds. Acetylsalicylic acid, new uses
for an old drug. New York: Raven Press, 1982:1.)
Chapter 15
132
Taken to reduce the risk of morbidity and death in patients who have
suffered a myocardial infarction.
Adverse Effects
Consult Chapter 25.
2. Sulfinpyrazone
Actions
Competitive inhibitor of cyclooxygenase.
Inhibits platelet adherence and the release reaction. In the release reaction, platelets change shape and undergo a complex secretory process
resulting in the release of adenosine disphosphate (ADP) from platelet granules and activation of platelet phospholipase A2 (see Figure 153).
Uses
Used in clinical states in which abnormal platelet behavior is a causative or
associated factor (amaurosis fugax [TIAs], thromboembolism associated
with vascular and cardiac prostheses, recurrent venous thrombosis, and
arteriovenous shunt thrombosis).
Approved for prophylactic use after myocardial infarction.
Adverse Effects
Gastric disturbances, skin rashes.
3. Dipyridamole
Actions and Uses
Decreases platelet adhesiveness to damaged endothelium. Inhibits phosphodiesterase and increases cyclic adenosine monophosphate (cAMP).
May also potentiate the effect of prostacyclin (PGI2), which stimulates
platelet adenyl cyclase.
These effects would prevent both platelet aggregation and the release
reactions.
However, dipyridamole itself neither prevents nor exerts a prophylactic effect on the incidence of death following myocardial infarction.
A beneficial effect may occur in combination with aspirin or when it
is combined prophylactically with warfarin in patients with artificial heart
valves.
Chapter 15
133
Adverse Effects
Headache, flushing, dizziness, weakness or syncope, skin rash, gastric irritation, abdominal cramping, emesis.
4. Ticlopidine
Actions
Causes a time- and dose-dependent inhibition of platelet aggregation and
release of platelet factors, as well as a prolongation of bleeding time.
Uses
Used to reduce the risk of first or recurrent stroke for patients who have
experienced at least one of the following events: complete thromboembolic
stroke, minor stroke, reversible ischemic neurological deficit, or transient
ischemic attack including transient monocular blindness.
Adverse Effects
Diarrhea, nausea. Diarrhea and gastrointestinal (GI) pain are most frequent.
Neutropenia has occurred in approximately 2% of patients.
Bleeding time is prolonged.
FIBRINOLYTIC DRUGS
1. Streptokinase
Actions
Activates plasminogen-plasmin system, giving rise to increased amounts of
plasmin, which lyses fibrin clots (Figure 154).
Uses
Used to treat pulmonary embolism, deep vein thrombosis and embolism,
arteriovenous cannula occlusion, and coronary artery thrombosis.
Adverse Effects
Hemorrhage. Aminocaproic acid is an antidote.
Because streptokinase depletes the blood of its normal store of plasminogen, spontaneous thrombosis can occur after the effects of streptokinase disappear. To prevent secondary clot formation, heparin should be
Chapter 15
134
Figure 154 Schematic representation of the fibrinolytic system. (After OReilly RA. Drugs
used in disorders of coagulation. In: Katzung BG, ed. Basic and clinical pharmacology. 5th ed.
Appleton & Lange, Norwalk: 1992:466.)
given immediately after the effects of streptokinase cease, followed by oral

anticoagulants for 7 days.
2. Urokinase
Action
Converts plasminogen to plasmin.
Uses
Treatment of pulmonary embolism and coronary artery thrombosis.
Chapter 15
135
Adverse Effects
Hemorrhage. Discontinue if there is bleeding and administer fresh whole
blood or fresh-frozen plasma. If these measures fail, the use of aminocaproic
acid is suggested.
3. Alteplase (Tissue Plasminogen Activator [TPA])

Actions
Binds to fibrin in a thrombus and converts the entrapped plasminogen to
plasmin.
The clot selectivity of TPA enables it to lyse clots without having a significant effect on circulating plasminogen.
Has a half-life of about 5 minutes, compared to about 23 minutes for
streptokinase.
Uses
Lysis of suspected occlusive coronary artery thrombi associated with evolving transmural myocardial infarction.
Reduces mortality associated with acute myocardial infarction (AMI).
Improves ventricular function following AMI and reduces incidence of congestive heart failure.
Adverse Effects
Hemorrhage.
FIBRINOLYTIC INHIBITORS: HEMOSTATIC AGENTS

1. Aminocaproic Acid
Actions
Inhibits fibrinolysis by competitively inhibiting the binding of plasminogen
and plasmin to fibrin.
Uses
To treat excessive bleeding resulting from systemic hyperfibrinolysis and
urinary fibrinolysis.
As an adjunct in replacement therapy in hemophiliac patients undergoing tooth extraction.
Chapter 15
136
Adverse Effects
Nausea, diarrhea, vomiting.
2. Aprotinin
Actions
Potent proteinase inhibitor, extracted from bovine lung tissue that has an
inhibitory action on plasmin activator. Also directly inhibits plasmin.
Uses
To treat patients with conditions caused by excessive fibrinolysis, which
occur during surgery (including open heart surgery and prosthetic surgery),
and pathologic obstetrical bleeding conditions, such as abruptio placentae.
Adverse Effects
Allergic reactions (such as flushing, tachycardia, itching, rash, and
urticaria), dyspnea, sweating, palpitations, nausea.
VITAMIN K1, VITAMIN K2, AND MENADIONE

Actions
Vitamin K is not a single chemical but a collection of structurally-related
substances that stimulate the hepatic synthesis of vitamin Kdependent
clotting factors. Collectively, they are often referred to simply as vitamin K.
Vitamin K1 (phytonadione) and vitamin K2 (menaquinone) are found
in plant leaves and vegetable oils and are synthesized in large quantities by
bacteria in the intestinal tract. Vitamins K1 and K2 are well absorbed from
the GI tract if bile salts are present. Vitamin K1 is also formulated for subcutaneous absorption.
Menadione (vitamin K3) is a synthetic chemical that does not require
bile for absorption. It is also available as a water-soluble salt, menadione
sodium bisulfite, for parenteral administration.
Menadiol tetrasodium diphosphate is another water-soluble salt of
menadione, intended for oral or parenteral administration.
Uses
To treat a deficiency resulting from the inadequate intake, absorption, or
utilization of vitamin K.
To antagonize the actions of oral anticoagulants.
Chapter 15
137
To treat newborns who have only 20 to 40% of adult levels of prothrombin. For the prophylaxis and treatment of hemorrhagic diseases of the newborn, the water-soluble vitamin K analogues are not as safe as phytonadione.
To reverse the hypoprothrombinemia resulting from the actions of
broad-spectrum antibiotics, which can kill vitamin K-producing bacteria in
the colon.
Adverse Effects
Temporary refractoriness to oral anticoagulant therapy.
An overdose of vitamin K in an infant can produce hemolytic anemia
or kernicterus.
Part 5
Endocrine
Pharmacology
16
Drugs and the Thyroid

Function of the Thyroid Gland
The thyroid synthesizes, stores, and secretes L-triiodothyronine (T3) and
L-thyroxine (T4).
To do this, the thyroid
actively extracts iodide from the plasma, and
oxidizes it to iodine before coupling the iodine to the amino acid tyrosine, forming either monoiodotyrosine or diiodotyrosine. T3 is formed
from one molecule each of monoiodotyrosine and diiodotyrosine. T4
is produced from two molecules of diiodotyrosine.
Once synthesized, T3 and T4 are
stored within the gland as thyroglobulin, and
released into the circulation following stimulation of the gland by the
thyroid-stimulating hormone (TSH). Some of the T4 released is subsequently converted to T3.
The activity of the thyroid gland is controlled by
the release of hypothalamic thyrotropic-releasing hormone, which in
turn
stimulates the secretion of pituitary TSH. TSH increases the synthesis
and secretion of T3 and T4.
A balance exists between secretion of TSH and the levels of T3 and T4.
An increase in plasma T3 and T4 decreases TSH secretion.
A decrease in plasma T3 and T4 increases TSH secretion.
Once secreted, T3 and T4 are highly bound to specific plasma proteins
called thyroid-binding globulin and thyroid-binding prealbumin. Only T3
and T4 not bound to these plasma proteins (free T3 and T4) enter body cells
to exert an effect. T3 produces a more rapid effect than T4 because it is less
bound to plasma proteins. Figure 161 presents the principal features of the
biosynthesis and metabolism of thyroid hormones.
138
Chapter 16
139
Figure 161 Principal features of the biosynthesis and metabolism of thyroid hormones. (After
Schimmer BP, George SR. Thyroid Hormones and Antithyroid Drugs. In: Kalant H, Roschlau W,
eds. Principles of Medical Pharmacology. 5th ed. Toronto: BC Decker, 1989:444450.)
Actions of T3 And T4
High-affinity binding sites for T3 and T4 exist in the nucleus, mitochondria,
and plasma membranes of the hormone-responsive tissues (pituitary, liver,
kidney, heart, skeletal muscle, lung, and intestine). T4 receptor affinity is 10
times lower than T3 affinity.
T3 and T4 increase tissue metabolic rate and mitochondrial protein synthesis. They also stimulate the cell membrane sodium pump. T3 and T4 are
necessary for the maturation and development of the central nervous and
skeletal systems. Thyroid deficiency in childhood results in cretinism, a condition characterized by growth failure and mental retardation.
HYPOTHYROIDISM
Hypothyroidism is characterized by low circulating levels of T3 and T4, or
rarely, tissue resistance to the thyroid hormones. Hypothyroidism can
result from pathology in
Chapter 16
140
the thyroid (primary hypothyroidism),

the pituitary (secondary hypothyroidism),
the hypothalamus (tertiary hypothyroidism), and
the peripheral tissues (generalized resistance to thyroid hormones, usually caused by a defect in the beta receptor for T4 and T3).
Symptoms of Hypothyroidism
Symptoms include fatigue, swelling of the hands and around the eyes, constipation, dry skin, and menstrual irregularities. When hypothyroidism is
severe, the patient may have a guttural voice, thickened boggy skin
(myxedema), slow mental processes, loss of body hair, intolerance to cold,
ascites, pericardial effusion, coma, and death.
Drugs for Hypothyroidism

L-Thyroxine (Levothyroxine)
Oral and injectable forms of L-thyroxine (T4) are the preferred treatment.
Converted in part to T3 in the body, T4 provides a reliable source of both
thyroid hormones.
L-Triiodothyronine (Liothyronine)
Liothyronine (T3) is 2.5 to 3.3 times more potent than T4 and its effects are
seen sooner. However, stabilization of a patient on T3 may be more difficult
because it is cleared faster than T4. Treatment with T4 provides a reliable
source of both T3 and T4.
Adverse Effects
An overdosage of either T3 or T4 can induce hyperthyroidism (eg, heat intolerance, weakness, fatigue, nervousness, insomnia, and tachycardia). For
drug interactions with T3 and T4 consult an appropriate reference source.
HYPERTHYROIDISM
Hyperthyroidism is a syndrome characterized by excessive production and
release of T3 and T4. The more common causes of hyperthyroidism are:
Graves disease (the most common cause of hyperthyroidism) caused
by the production of an antibody capable of stimulating the thyrotrophin
(TSH) receptor on the surface of the thyroid cells
Toxic adenoma a benign tumor of the thyroid capable of producing
excessive amounts of thyroid hormones
Chapter 16
141
Toxic multinodular goitre (found primarily in the elderly) a condition in which thyroid follicles autonomously produce excessive quantities of T3 and T4
Subacute thyroiditis results from the excessive release of T3 and T4
from an inflamed thyroid gland
Symptoms of Hyperthyroidism
These include heat intolerance, bruit over the thyroid, a hyperkinetic circulatory state (including a rapid heart rate and dysrhythmias), and dyspnea.
Unusual muscle fatigue, irritability, and the presence of eye signs, such as lid
lag, weakness of the extraocular muscle, and proptosis may also be seen.
Thyroid Storm
Thyroid storm is a rare medical emergency. It is characterized by thyrotoxicosis, with fever, tachycardia or tachyarrhythmias, and altered mental state.
Thyroid storm must be treated aggressively because its mortality is high.
Treatment includes
high doses of propylthiouracil (PTU) or methimazole (MMI),

IV sodium iodide or oral strong iodine solution,
beta blockers,
glucocorticoids, and
measures to ensure that hyperpyrexia, congestive heart failure, cardiac
arrhythmias, and dehydration are properly managed.
Drugs for Hyperthyroidism

1. Propylthiouracil and Methimazole
Actions
PTU and MMI prevent the formation of T3 and T4, by blocking the oxidative iodination of tyrosine. PTU also impairs the peripheral conversion of
T4 to T3.
Uses
PTU and MMI are used to prepare patients for thyroid surgery, to assist in
the management of patients in thyrotoxic crisis, and to treat chronic hyperthyroidism. Several weeks to months of treatment with PTU or MMI
restores euthyroidism in Graves patients.
Chapter 16
142
Adverse Effects
Important adverse effects include GI upset, mild elevation in liver enzymes,
and rash. Rare, but more serious, adverse effects include liver toxicity and
agranulocytosis.
Care must be taken in prescribing PTU or MMI during pregnancy
because these drugs cross the placenta and can cause fetal goitre and hypothyroidism. PTU is frequently preferred because of the unresolved contention
that MMI may cause the rare congenital complication, aplasia cutis.
Both PTU and MMI are contraindicated in nursing mothers.
2. Potassium Iodide, Sodium Iodide, and Strong Iodine Solution

Actions
Large doses of these drugs inhibit, at least temporarily, organic iodine formation and the production and release of T3 and T4. High doses may also
prevent the effects of TSH.
Uses
These products are used to prepare hyperthyroid patients for thyroidectomy.
Intravenous sodium iodide or oral strong iodine solution may also be
used with PTU or MMI to treat thyroid storm.
Adverse Effects
Unpleasant taste, burning of mouth, sore mouth and throat, hypersalivation, painful sialadenitis, acne and other rashes, productive cough,
angioedema with swelling of the larynx, dyspnea in sensitive individuals.
3. Beta Blockers (see Chapter 6)

Actions
Beta blockers are important adjuvant drugs because they reduce hyperthyroid symptoms caused by excessive beta adrenergic stimulation (eg, palpitations, tremor, and sweating). Beta blockers generally do not alter T4 levels. However, nonselective beta blockers, such as propranolol, may decrease
circulating T3 levels.
17
Diabetes Mellitus
DIABETES MELLITUS
Diabetes mellitus is a chronic metabolic disturbance that is characterized by fasting or postprandial hyperglycemia.
Diabetes mellitus is not a single entity. It is a heterogeneous syndrome
caused by an absolute or relative lack of insulin, resistance to the action
of insulin, or both.
When severe, diabetes mellitus affects carbohydrate, lipid, and protein
metabolism.
Severe long-term diabetes mellitus may lead to complications involving
small blood vessels (microangiopathy), large blood vessels (macroangiopathy), and nerve damage (neuropathy) that affect multiple organs
and systems.
DIAGNOSIS OF DIABETES MELLITUS

The diagnosis of diabetes mellitus is established by any of the following:
The presence of symptoms of diabetes plus a casual (random) plasma
glucose level 11.1 mmol/L.
A fasting plasma glucose level 7.0 mmol/L. This must be confirmed
by a second test on a subsequent day.
A plasma glucose level 11.1 mmol/L at 2 hours after a 75 g oral glucose tolerance test.
143
144
PDQ PHARMACOLOGY
GOALS OF THERAPY
To maintain the long-term health of the person affected with diabetes, therapy should
Control symptoms
Establish and maintain optimum metabolic control, while avoiding
hypoglycemia
Prevent, or minimize the risk of, complications
Achieve optimum control of comorbidities such as hypertension or dyslipidemia
CLASSIFICATION OF DIABETES MELLITUS

Type 1 diabetes mellitus (insulin-dependent diabetes mellitus, IDDM)
is due to beta cell destruction, usually leading to absolute insulin deficiency treated with insulin.
Type 2 diabetes mellitus (noninsulin-dependent diabetes mellitus,
NIDDM) ranges from predominant insulin resistance, with relative
insulin deficiency, to predominant insulin secretory defect, with insulin
resistance treated with oral agents and/or insulin.
Gestational diabetes mellitus is defined as onset or recognition of glucose intolerance in pregnancy treated with insulin.
Other specific types, including the genetic syndrome MODY (maturity-onset diabetes of youth), other genetic syndromes associated with
diabetes, pancreatic disease, infectious agents, other diseases leading to
carbohydrate intolerance, and drug-induced carbohydrate intolerance.
TARGETS FOR CONTROL

Control of blood glucose reduces the risk of long-term complications
in type 1 and type 2 diabetes; however, euglycemia is difficult to attain
and maintain. The main risk of tight control of blood glucose levels is
the increased risk of hypoglycemic episodes. Frequent hypoglycemia
may lead to hypoglycemia unawareness.
Control of serum lipids reduces the risk of cardiovascular events,
which are the main cause of morbidity and mortality in diabetes. Diabetes over age 30 is considered a very high risk for coronary artery disease. Therapy includes statins for elevated LDL-cholesterol and fibrates
for elevated triglyceride and/or low HDL-cholesterol (see Chapter 14).
Control of blood pressure (below 130/85 mm Hg) is an additional goal
of therapy. Diabetes, particularly type 2, is frequently associated with
hypertension.
Chapter 17
Drugs for the Treatment of Diabetes Mellitus
145
NON-DRUG TREATMENT OF TYPES 1 AND 2 DIABETES

MELLITUS
Nonpharmacologic therapy plays a pivotal role in the treatment of types 1
and 2 diabetes.
Type 1 diabetes must receive insulin immediately, along with non-drug
therapy.
In the absence of symptoms, type 2 diabetics usually receive nonpharmacologic therapy as the first step in treating the disease. Drug therapy
is instituted in type 2 asymptomatic diabetes only if nonpharmacologic
therapy fails to establish euglycemia.
Non-drug therapy can be found in standard texts on diabetes management. It includes:
Education, to make the patient a full participant in the diabetes
health care team
Nutritional management, designed to individualize the diet
Instruction in self-monitoring of glucose levels
A program of physical activity
Periodic reassessments to detect comorbidities and complications
DRUG TREATMENT OF TYPE 1 DIABETES MELLITUS

Insulin
Type 1 patients have little or no insulin in the pancreas.
These people usually experience an abrupt onset of symptoms, insulin
deficiency, and dependence on injected insulin to sustain life.
Human insulin should be started at the time of diagnosis. Table 171
presents commonly used human insulin preparations. For optimum
Table 171
Human Insulin and Analogues

Type of Insulin
Rapid-acting insulin lispro
Onset (h)
Peak (h)
Duration (h)
0.5 0.75
0.75 2.5
3.5 4.75
Short-acting regular insulin
0.5 1
0.75 4.5
5.0 7.5
Intermediate-acting NPH
12
4 12
12 24
Intermediate-acting Lente
24
7 15
12 24
Long-acting Ultralente
34
8 16
24 28
NPH = neutral protamine Hagedorn.

(After Boctor MA. Diabetes Mellitus. In: [editors names] eds. Therapeutic Choices. 3rd ed.
Ottawa: Canadian Pharmacist Association, 2000:613628.)
146
PDQ PHARMACOLOGY
control, regular insulin should be administered 20 to 30 minutes before

meals. Rapid-acting insulin may be more conveniently administered
shortly before eating.
Insulin Regimens For Type 1 Diabetics (Table 172)
Intensive treatment regimens control blood glucose more effectively than
conventional regimens and reduce the risk of long-term diabetic complications. Newly diagnosed type 1 diabetics, as well as type 1 diabetes who
Table 172
Insulin Regimens
Rapid or ShortActing Insulin
Intermediate or
Long-Acting Insulins Remarks
Conventional None
Once daily NPH or

Lente before breakfast
None
Twice daily NPH or
Lente at breakfast
and supper
Regular or insulin
NPH or Lente at
lispro at breakfast
breakfast and
and supper
supper
Regular or insulin
NPH or Lente at
lispro at breakfast
breakfast, Ultraand supper
lente at supper
Regular or insulin
NPH or Lente at
lispro at breakfast
breakfast, NPH or
and supper
Lente at bedtime
Intensive
Multidose
Insulin
Regimen
(MDI)
Regular or insulin
lispro before
each meal
Regular or insulin
lispro before
each meal
Intensive
Regular or insulin
continuous
lispro basal and
subcutaneous boluses as per
insulin
program
injection
Unlikely to achieve
control
Improved morning
levels
Most widely used
regimen; better
meal control
Ultralente more
likely to last until
next morning
More likely to last
until next morning
NPH, Lente, or Ultra

lente at supper or
bedtime
NPH, Lente or Ultra
lente twice daily
at breakfast and
supper or bedtime
Usually good
control, flexible
None
Most flexible, can

achieve even better
control than MDI;
most expensive;
diabetic ketoacidosis may
occur quickly with
discontinuation
Better suited for

people with
varying schedules
NPH = neutral protamine Hagedorn.

(After Boctor MA. Diabetes Mellitus. In: Gray J. eds. Therapeutic Choices. 3rd ed. Ottawa:
Canadian Pharmacists Association, 2000:613628.)
Chapter 17
147
have not achieved control on conventional therapy, should be offered an

intensive diabetes management option.
Adverse Effects of Insulin Therapy
Hypoglycemia is the most common adverse effect of insulin and occurs
most frequently in patients on tight diabetic control.
Mild hypoglycemia is manifested by adrenergic symptoms, such as
sweating, tremors, tachycardia, hunger, and general weakness. Treat with
an oral source of sugar.
Severe hypoglycemia requires assistance in its recognition and/or treatment. Neuroglycopenic symptoms, including confusion, altered behavior, and disorientation, can progress to seizures and coma, and prevent
the patient from treating the episode. If the patient is conscious, an oral
glucose preparation should be used. In unconscious patients, intramuscular or subcutaneous glucagon temporarily increases blood glucose
allowing for the intake of oral carbohydrate. Glucagon is not effective in
malnourished patients, or alcohol-induced hypoglycemia. Intravenous
dextrose is the treatment of choice under these circumstances.
Localized fat hypertrophy is most often the result of frequent reutilization of the same injection site.
Allergic reactions such as urticaria, angioedema rashes, and local erythema, are rare with human insulin.
Immune-mediated insulin resistance, due to production of antiinsulin antibodies, is rare with human insulin.
DRUG TREATMENT OF TYPE 2 DIABETES MELLITUS

All drugs presented below are used as adjuncts to diet and exercise in
asymptomatic type 2 diabetic patients whose diabetes cannot be controlled
satisfactorily by diet alone.
Drug treatment is warranted initially in symptomatic type 2 patients.
1. Drugs That Increase the Secretion of Insulin

A. Sulfonylureas (Acetohexamide, Chlorpropamide, Gliclazide,
Glyburide, Tolbutamide)
Actions
Sulfonylureas require the presence of insulin to be effective. They
1. stimulate the pancreatic release of insulin,
2. increase the action of insulin on the liver to decrease hepatic gluconeogenesis, and
148
PDQ PHARMACOLOGY
3. increase glucose utilization (Figure 171).

Adverse Effects
Severe hypoglycemia, nausea, epigastric fullness, heartburn, and allergic
skin reactions, such as pruritus, erythema, urticaria, and morbiliform or
maculopapular eruptions. For a list of the many drug interactions with sulfonylureas, consult a reference text.
B. Repaglinide
Actions
Repaglinide lowers blood glucose by stimulating the release of insulin.
Repaglinide is a short-acting drug, which is effective in regulating meal-
Oral Hypoglycemic Drugs

Agent
Oral Sulfonylurea
+ Insulin
Decreased Hepatic
Glucogenesis
Pancreas
Beta Cells
in Islets
Stimulated to
Put out
InsulinGrowth of
Beta Cells
Promoted
Increased
Insulin
Secretion
Decreased
Blood
Glucose
Increased
Glucose
Utilization
Muscle
Fat
Figure 171 Suggested actions of sulfonylurea drugs. (After Waife SO. Oral hypoglycemic
agents. In: Diabetes Mellitus. Indianapolis: Eli Lilly, 1980:123.)
Chapter 17
149
related glucose loads. Because of its short action, repaglinide should only
be taken with meals.
Adverse Effects
Hypoglycemia, especially if the meal is not taken, and weight gain.
2. Drugs that Increase Tissue Sensitivity to Insulin

A. Metformin
Actions
Metformin requires the presence of insulin to lower blood glucose. Metformin appears to increase the action of insulin in peripheral tissues but its
primary action is to reduce hepatic glucose output by inhibiting gluconeogenesis. It may also decrease plasma glucose by reducing the absorption of
glucose from the intestine. Used alone, metformin does not cause hypoglycemia, but it can potentiate the hypoglycemic effects of insulin and sulfonylureas.
Adverse Effects
Metallic taste in the mouth, epigastric discomfort, nausea, and vomiting. For
a list of the drug interactions with metformin consult a reference text.
B. Thiazolidinediones (Pioglitazone and Rosiglitazone)

Actions
Thiazolidinediones improve sensitivity to insulin in muscle and adipose tissue and inhibit hepatic gluconeogenesis. By decreasing insulin resistance,
thiazolidinediones improve glucose control, decrease hepatic glucose output, increase insulin-dependent glucose disposal in skeletal muscle, and
reduce circulating insulin levels. These drugs are used alone to treat type 2
diabetes, in patients not controlled by exercise and diet. Thiazolidinediones
are also used in combination with metformin and/or sulfonylureas, in type
2 diabetics who were not controlled with the original therapy.
Adverse Effects
Weight gain due to subcutaneous fat increases, and occasionally, water
retention.
150
PDQ PHARMACOLOGY
3. Drugs that Delay the Digestion of Complex Carbohydrates

(Acarbose)
Actions
Acarbose inhibits alpha-glucosidase in the brush border of the small intestine. Alpha-glucosidase is responsible for the hydrolysis of sucrose into
absorbable monosaccharides. By inhibiting this enzyme, acarbose delays
glucose absorption, reduces postprandial hyperglycemia, and decreases
glycosylated hemoglobin (HbA1C) in type 2 diabetes mellitus patients.
Adverse Effects
Flatulence, diarrhea, and abdominal pain.
4. Insulin
Insulin may be used alone in type 2 diabetics. It may also be used in combination with an oral agent in a nighttime insulin/daytime pill regimen.
Because of their underlying resistance to insulin, many type 2 diabetics
require higher doses of insulin.
18
Adrenal Corticosteroids
HORMONES SECRETED BY THE ADRENAL CORTEX
1. Glucocorticoids
2. Mineralocorticoids
3. Sex hormones (discussed in Chapter 19)
GLUCOCORTICOIDS
Synthesis and Secretion of Cortiosol (Figure 181)
Cortisol (hydrocortisone) is the major endogenous glucocorticoid. It is synthesized in, and secreted from, the adrenal cortex in response to the release
of adrenocorticotropic hormone (ACTH) from the pituitary. ACTH secretion is controlled by the release of corticotropin-releasing factor (CRF) from
the hypothalamus. High levels of glucocorticoids suppress CRF secretion,
thereby reducing ACTH release, and preventing cortisol secretion.
Mechanism of Action of Glucocorticoids (Figure 182 and Table 181)
Tissue selectivity for glucocorticoids depends on the presence of specific
corticosteroid receptors in the cytoplasm of the target cell. Glucocorticoids
pass from the blood into the cell and combine with the receptor. The
receptor-steroid complex then moves into the nucleus where it stimulates
new transcription of both messenger ribonucleic acid (mRNA) and (ribosomal) rRNA, a process essential to the physiologic/pharmacologic effects
of the glucocorticoids.
Metabolic Actions of Glucocorticoids (Figure 183)
1. Impair glucose utilization, while increasing its synthesis. Blood sugar
levels rise.
151
152
PDQ PHARMACOLOGY
Figure 181 Diagrammatic representation of hypothalamic-pituitary-adrenal axis. Pituitary

adrenocorticotropic hormone (ACTH) secretion is regulated by negative feedback effects of cortisol on the pituitary. Hypothalamic drive of ACTH release is mediated by corticotrophin-releasing factor (CRF). Cortisol inhibits pituitary response to CRF and may also inhibit the secretion of
CRF. (After Reichlin S. Current concepts of neural control of the pituitary gland: normal physiology and pathologic implications. Kalamazoo, (MI): Scope publications, The Upjohn Co, 1978:33.)
2. Stimulate fat and muscle catabolism, releasing FFA, glycerol, and amino
acids, increasing their levels in blood.
3. Increase gluconeogenesis.
4. Increase glucagon secretion, further accelerating hepatic glucose output.
5. Indirectly stimulate insulin release by increasing blood sugar. Direct
steroid actions on fat are counterbalanced, in part, by the effects
of insulin, which stimulates lipogenesis and inhibits lipolysis. The
result is a redistribution of fat. At sites where the actions of corticosteroids predominate, fat is lost; in areas where insulin dominates, fat
accumulates.
6. Reduce calcium absorption (by blocking actions of vitamin D) and increase calcium renal clearance. These actions can result in osteoporosis.
Chapter 18
153
Figure 182 Schematic representation of the mechanism of action of glucocorticoids.mRNA

= messenger ribonucleic acid; rRNA = ribosomal ribonucleicacid; DNA = deoxyribonucleic acid
(After Swartz SL, Dluhy RG. Corticosteroids. Clinical pharmacology and therapeutic use. Drugs
1978; 16:243.)
Anti-inflammatory and Immunosuppressive Action of Glucocorticoids

1. Potentiate vasoconstrictor effects of epinephrine and norepinephrine,
reducing blood flow, redness, and heat.
2. Decrease capillary permeability, reducing plasma loss into inflamed tissues, which decreases swelling.
3. Decrease mast cell accumulation at the site of inflammation, reducing
histamine release.
4. Reduce prostaglandin E2 (PGE2) synthesis, decreasing the pain-producing actions of histamine and bradykinin.
5. Reduce neutrophil migration to the inflammatory site(s).
6. Decrease T-lymphocyte levels in blood, reducing cell-mediated immunity.
Table 181
Presence of Glucocorticoid Receptors in Tissues

Tissues with Specific
Glucocorticoid Receptors
Brain
Lymphoid
tissue
Testes
Kidney
Stomach
Heart
Liver
Retina
Smooth
Fibroblasts
muscle
Lung
Intestine
Skeletal
muscle
Tissues with No Detectable,

or Low Glucocorticoid Receptors
Bladder
Prostate
SteroidSeminal
resistant
vesicle
fibroblasts
Steroid-resistant
lymphoid cells
Uterus
154
PDQ PHARMACOLOGY
Liver
Gluconeogensis
+
+
Enzyme +
Synthesis
Glucose
+
"ANABOLIC"
Glycogen
Energy
Supply
Muscle
Fatty
Acids
Glycerol
Amino
Acids
(Relative?)
Glucose
+
Skin
"CATABOLIC"
Lymphoid
Connective
Adipose
Figure 183 Glucocorticoid action on carbohydrate, lipid and protein metabolism. Arrows indicate the general flow of substrates in response to the catabolic and anabolic actions of the glucocorticoids when unopposed by secondary secretions of other hormones. + and signs indicate stimulation and inhibition, respectively. (After Baxter JD, Forsham PH. Tissue effects of
glucocorticoids. Am J Med 1972; 53:573589.)
7. Reduce fibrin deposition, capillary fibroblast proliferation, deposition

of collagen, and cicatrization.
Adverse Effects of Glucocorticoids
1.
2.
3.
4.
5.
Musculoskeletal myopathy, osteoporosis, fractures.

GI peptic ulceration, hemorrhage, perforation, pancreatitis.
CNS psychiatric disorders.
Eye glaucoma, cataracts.
Cardiovascular and renal hypertension, Na+ and water retention,
hypokalemic alkalosis.
Chapter 18
155
6. Metabolic precipitation of genetic diabetes mellitus, hyperosmolar

nonketotic coma, hyperlipidemia, centripetal obesity.
7. Endocrine growth failure, secondary amenorrhea, suppression of
hypothalamic-pituitary-adrenal system.
8. Inhibition of fibroblasts impaired wound healing, subcutaneous tissue atrophy.
9. Suppression of immune response superinfections.
SYNTHETIC GLUCOCORTICOIDS
Rationale Behind Synthetic Glucocorticoids (Table 182)
Cortisol possesses both significant glucocorticoid and mineralocorticoid
actions. Synthetic glucocorticoids have been synthesized with the aim of
accentuating glucocorticoid activity and reducing or abolishing mineralocorticoid properties. The anti-inflammatory effects of the various corticosteroids correlate with their relative glucocorticoid potencies. Because
synthetic corticosteroids are more potent glucocorticoids than cortisone
and cortisol (hydrocortisone), they are used in lower doses. Synthetic glu-
Table 182
Comparison of Corticosteroids
Drug
AntiEquivalent
Inflammatory Potency*
Potency*
(mg)
Sodium
Retaining
Potency
Biologic
Half-Life
(h)
Cortisol [A]
20
2+
812
Cortisone [A]
0.8
25
2+
812
Prednisone [B]
3.5
1+
1836
Prednisolone [B]
1+
1836
Methylprednisolone [B]
1836
Triamcinolone [B]
1836
Paramethasone [C]
10
3654
Betamethasone [C]
25
0.6
3654
Dexamethasone [C]
30
0.75
3654
*Potency is defined as mg for mg equivalence with cortisol.

[A] Short-acting corticosteroids; [B] Intermediate-acting corticosteroids; [C] Long-acting
corticosteroids
(Modified from Swartz SL, Dluhy RG. Corticosteroids. Clinical pharmacology and therapeutic use.
Drugs 1978; 16:238255.)
156
PDQ PHARMACOLOGY
cocorticoids also have longer half-lives than either cortisol or cortisone and
are given less frequently.
THERAPEUTIC USES FOR GLUCOCORTICOIDS

Replacement Therapy
Primary Adrenal Insufficiency
Both glucocorticoids and mineralocorticoids are administered in primary
adrenal insufficiency (Addisons Disease) because patients are deficient in
both cortisol and aldosterone.
Secondary Adrenal Insufficiency
Adrenal insufficiency secondary to pituitary insufficiency is characterized
by low levels of cortisol. Aldosterone secretion is normal. Cortisol can be
given daily with two-thirds of the dose in the morning and one-third
around 4 pm.
Congenital Adrenal Hyperplasia (Adrenogenital Syndrome)
This condition results from adrenal cortical enzyme deficiencies in the synthesis of cortisol. As a result of lower cortisol levels, ACTH secretion is
increased, elevating the synthesis and secretion of adrenal androgens. Evidence of the condition in the female is often seen at birth as masculinization of the external genitalia. Diagnosis of the adrenal genital syndrome in
males may not be made until later in infancy or in childhood. Treatment
involves administration of a glucocorticoid to suppress ACTH secretion. It
may also be necessary to administer a mineralocorticoid if a reduction in
both glucocorticoid and mineralocorticoid synthesis occurs. It is advisable
to give a larger dose of the glucocorticoid at bedtime to suppress the normal peak secretion of ACTH during the night.
Suppressive Therapy
Dosage Protocols
Short-term, high-dose is used for the treatment of emergencies, such as status asthmaticus and anaphylactic shock. This type of protocol has the least
likelihood of adverse effects.
Long-term, low-dose is often appropriate for many diseases, such as
asthma or arthritis.
Chapter 18
157
Long-term, high-dose is often required for severe conditions such as

autoimmune hemolytic anemia and temporal arteritis. This type of regimen
is most likely to cause adverse effects.
Alternate-day therapy is intended to minimize the consequences of
chronic glucocorticoid treatment. Start the patient on a daily dose until
relief is obtained. Then convert gradually to alternate-day treatment by doubling the daily dose and administering it as a single dose on alternate mornings. Use intermediate-acting steroids, such as prednisone, so that treatment
is effective for about 1.5 days, but still allows 0.5 days for the pituitaryadrenal responsiveness to return before the next dose.
Uses
Inflammatory diseases of the intestine, bronchioles, nose, eyes, ears, skin
and joints.
Allergic diseases used only in situations not adequately controlled by
less dangerous agents, such as antihistamines.
Rheumatic carditis, collagen vascular diseases, renal diseases, liver diseases, and shock.
MINERALOCORTICOIDS
Synthesis and Secretion of Aldosterone
Aldosterone is synthesized in the adrenal cortex. Secretion is increased by
stimulation of the renin-angiotensin system. Hyperkalemia increases and
hypokalemia decreases aldosterone secretion. During stress, ACTH may
stimulate aldosterone secretion. Increased levels of aldosterone are not
sustained by prolonged elevated ACTH secretion.
Actions of Mineralocorticoids
Mineralocorticoids increase Na+ reabsorption and K+ and H+ secretion in
the distal convoluted tubules and collecting ducts of the kidneys (see Chapter 13).
Adverse Effects of Mineralocorticoids
Mineralocorticoids increase salt and water retention and potassium loss.
Their effects include hypertension, edema, hypokalemia, cardiac enlargement, and congestive heart failure.
19
Sex Hormones
ESTROGENS
Naturally Occurring Estrogens
Estradiol secreted by the ovaries. The estrogen of greatest physiologic
significance.
Estrone also secreted by the ovaries.
Estriol a metabolic product of both estradiol and estrone.
Control of Estrogen Secretion
In females, follicle stimulating hormone (FSH) stimulates the ovaries to
produce ova and estrogens. Luteinizing hormone (LH) acts first, in concert
with FSH, to promote ovulation, and later alone to stimulate progesterone
and estrogen synthesis by the corpus luteum (Figure 191).
Actions
Tissue selectivity of estrogens is achieved by the presence of specific soluble
protein receptors found in the cytoplasm of sensitive cells. Estrogens pass
from the blood into the cell and combine with these receptors. Following
transfer of the receptor-estrogen complex into the nucleus, the estrogen
interacts with chromatin to produce the metabolic changes essential for
estrogen action. The principle behind the estrogen-receptor interaction is
similar to that previously described for corticosteroids (see Figure 182).
Estrogens are:
1. Essential for the development of the reproductive organs in the female.
They
increase mitotic activity and stratification of cells of the vaginal
epithelium and cause a proliferation of uterine cervical mucosa,
158
Chapter 19
Sex Hormones
159
Hypothalamus
LRH
Pituitary
Estrogen
LH
FSH
Estrogen
and
Progesterone
Ovary
Estrogen
Day
Estrogen and
Progesterone
14
28
Figure 191 Summary of endocrine changes during the menstrual cycle. The dashed arrows
indicate inhibitory effects and the sold lines stimulatory effects. (After The gonads: development and function of the reproductive system. In: Ganong WF Review of Medical Physiology.
11th ed. Los Altos: Lange, 1983:336.)
produce endometrial mitoses,

increase the height of the epithelium,
improve blood supply and capillary permeability of uterine vessels,
increase uterine water and electrolyte content, and
stimulate stromal development and ductal growth in the breasts.
2. Responsible for the accelerated growth phase in maturing females and

for closing the epiphyses of the long bones at puberty.
3. Partially responsible for the maintenance of normal skin and blood vessel structure.
4. Responsible for the decreased rate of bone resorption in females.
Pharmacokinetics
Oral estradiol is rapidly inactivated in the portal circulation during its first
pass through the liver. Injecting estradiol as either the benzoate, cypionate,
dipropionate, or valerate ester can circumvent this problem. Given this way,
estradiol has a long duration of action.
Ethinyl estradiol, mestranol, quinestrol, and diethylstilbestrol (among
others) are synthetic estrogens that are not rapidly inactivated by first-pass
metabolism.
Conjugated estrogens are a combination of the sodium salts of the sulfate esters of estrogenic substances, principally estrone and equilin. The
esters are similar to the type excreted by pregnant mares. The various
Chapter 19
Sex Hormones
160
preparations contain 50 to 65% estrone sodium sulfate and 20 to 35% equilin sodium sulfate. These products are effective orally, parenterally, and
vaginally.
17--Estradiol is also formulated as a skin patch.
Uses
Replacement Therapy
1. Treatment of the symptoms of menopause.
2. Prevention and treatment of postmenopausal osteoporosis.
Concern that estrogen treatment may increase the risk of breast and
uterine carcinoma has stopped many women from taking these
drugs.
Estrogen treatment can cause uterine bleeding, increase the risk for
venous thromboembolic events, produce cholelithiasis, cause
headaches, and result in pain and enlargement of the breasts.
Many women prefer other drugs such as the bisphosphonates for
the prevention and treatment of postmenopausal osteoporosis. Bisphosphonates, such as etidronate and alendronate, inhibit osteoclast-mediated bone resorption and are not encumbered by the toxicities of estrogens or the concerns that estrogen therapy may
increase the risk of breast or uterine cancer.
The selective estrogen receptor modulator, raloxifene (see below),
is also effective in preventing postmenopausal osteoporosis.
3. Used in conditions where the ovaries fail to develop:
In Turners syndrome, estrogen treatment produces breast enlargement and menses but does not cause the normal growth spurt or
ovarian maturation.
In hypopituitarism replacement therapy in girls, estrogens are administered together with thyroxine and adrenal cortical hormones.
Dysmenorrhea
Estrogens provide relief by inhibiting ovulation. Cyclic therapy with an
estrogen-containing oral contraceptive is often successful.
Endometriosis
Estrogen-containing oral contraceptives reduce FSH secretion and provide
symptomatic relief in 75 to 100% of cases of endometriosis-associated pain.
Alternatively, the androgen antagonist danazol, which prevents FSH
secretion, inhibits ovarian estrogen production, and causes atrophy of
endometrial deposits, is used to treat endometriosis-associated pain.
Chapter 19
Sex Hormones
161
Adverse Effects
Estrogens can produce nausea, vomiting, anorexia, diarrhea, breast tenderness,
weight gain due to edema, and hypertension. The effects of estrogens on blood
coagulation are discussed under Oral Contraceptives later in this chapter.
ANTIESTROGENS
1. Clomiphene
Actions
Clomiphene competes with estrogens for receptors. By blocking the
actions of endogenous estrogens, clomiphene prevents the normal feedback inhibition of FSH and LH secretion. Increased gonadotropin secretion leads to ovarian stimulation, ovulation, and sustained corpus luteum
formation.
Uses
Clomiphene is used to treat infertility due to anovulation. It is not effective
in women with ovarian or pituitary failure or with undeveloped ovaries.
Adverse Effects
Multiple pregnancy, birth defects, ovarian enlargement, liver dysfunction,
hot flashes, abdominal discomfort, visual blurring, spots or flashes, nausea,
vomiting, dizziness.
2. Tamoxifen
Actions
Competes with endogenous estrogens for receptors in target tissues, such
as breast and uterus. Produces regression of breast cancer in pre- and postmenopausal women.
Uses
Used to treat breast cancer in estrogen receptorpositive tumors.
Adverse Effects
Hot flashes, nausea, vomiting, vaginal bleeding and discharge.
Chapter 19
Sex Hormones
162
SELECTIVE ESTROGEN RECEPTOR MODULATOR (SERM)

Raloxifene
Actions
Raloxifene acts as an estrogen agonist in the skeleton, to increase bone mineral density in postmenopausal women, and on cholesterol metabolism,
to reduce LDL. Raloxifene has estrogen-antagonist effects on breast and
uterus. In contrast to estrogens, it does not appear to increase the risk of
uterine or breast cancer, or benign breast-related adverse events, such as
breast pain, breast enlargement, and fibrocystic disease. Raloxifene does not
appear to increase the risk of cardiovascular disease, myocardial infarction,
stroke, or any other major arterial cardiovascular event. Raloxifene may
increase the risk of venous thrombolytic events.
Uses
Raloxifene is used for the treatment and prevention of osteoporosis in postmenopausal women.
Adverse Effects
Vasodilatation and leg cramps are the most common adverse events.
PROGESTINS
Naturally Occurring Progestin
Progesterone is the naturally occurring progestin. Progesterone is synthesized and secreted by the corpus luteum and placenta (see Figure 191).
Actions
Progesterone works in association with estrogens its effects are only seen
in tissues previously stimulated by estrogens.
Both estrogens and progesterone are important in establishing a normal environment for the fertilized egg. Estrogens stimulate growth of sensitive tissue. Progesterone converts newly formed cells into secretory tissue,
for example:
Estrogens increase stromal and ductal development in breasts and
progesterone subsequently prepares the glands for lactation.
Progesterone reduces uterine motility and prepares the estrogen-stimulated endometrium for egg implantation and maintenance of gestation.
Chapter 19
Sex Hormones
163
Pharmacokinetics
Oral progesterone has little effect because it is rapidly inactivated during the
first pass through the liver. Intramuscular (IM) progesterone may be given
to circumvent first-pass metabolism. Medroxyprogesterone acetate is a synthetic progestin that can be IM injected or administered orally. Megestrol
acetate, norethindrone, norethindrone acetate, and norethynodrel are synthetic progestins that are not rapidly inactivated by first-pass metabolism and
can be given orally.
Uses
Progestin therapy is used to treat dysfunctional uterine bleeding. This condition often results from endometrial hyperplasia, produced by the continuous action of estradiol together with insufficient progesterone secretion
to maintain the endometrium.
Progestin therapy is also used with an estrogen to treat dysmenorrhea
and endometriosis.
Adverse Effects
Possible congenital malformation if administered early in pregnancy, breakthrough bleeding, intercyclic spotting, changes in menstrual flow, amenorrhea, changes in cervical erosion and secretion, breast tenderness, weight
gain, and edema.
ORAL CONTRACEPTIVES (OCs)

Types of Products
Oral contraceptives (OCs)contain either a combination of an estrogen plus
a progestin, or a progestin alone (Table 191).
Safety of Oral Contraceptives
Concern over the safety of OCs has centered on the estrogen component.
OCs increase the incidence of venous thromboembolism. This risk
may be reduced significantly by using low-dose estrogen preparations
( 50 g of estrogen).
The increased risk of MI in women over age 30 appears to be related to
estrogen dose. Decreasing the dose of estrogen to 35 g significantly
reduces MI risk. Risk of MI is higher in women > 35 years who smoke.
Chapter 19
Sex Hormones
164
Table 191
Contraceptive Products
Types of Products
Comments
Monophasic oral contraceptives

50 g estrogen
Taken at the same time each day from
EE or mestranol combined with
the 5th to the 26th day of each cycle,
ethynodiol, d-norgestrel, or
all estrogen-containing products
norethindrone
suppress ovulation. Bleeding occurs
3 or 4 days after stopping the tablets.
< 50 g estrogen
Day 1 is the first day of menstruation.
35 or 20 g EE combined with
desogestrel, ethynodiol acetate,
Concern over estrogen toxicity has
LN, norgestimate, NE or NE acetate
led to low-dose estrogen tablets.
Monophasic pills contain the same
ratio of estrogen to progestin in
each pill
Biphasic oral contraceptives
EE 35 g/NE 0.5 mg 10 d;
EE 35 g/NE 1 mg 11 d.
Triphasic oral contraceptives
Ratio of estrogen to progestin differs
on daily basis between products.
One product contains:
EE 35 g/NE 0.5 mg 7 d;
EE 35 g/NE 0.75 mg 7 d;
EE 35 g/NE 1 mg 7 d.
Progestin-only products
NE
Injectable products
Medroxyprogesterone acetate
Levonorgestrel implant
The biphasic and triphasic pills

provide a dosage pattern that more
closely approximates the estrogen-toprogestin ratios that occur during the
menstrual cycle. The purpose of
introducing the biphasic and triphasic
oral contraceptive products is to
decrease the incidence and severity
of drug-induced adverse effects,
such as breakthrough bleeding
Must be taken every day of the cycle
at the same time each day. Inhibits
secretion of pituitary gonadotropins,
preventing follicular maturation and
ovulation, as well as causing changes
in cervical mucus and endometrium
Somewhat less effective than
estrogen-containing products
A progestin than is extremely safe
and effective. Has prolonged effect.
Given every 3 months.
Progestin-containing rods are
implanted in the subcutaneous tissue
of the upper, inner arm. Efficacy close
to tubal ligation
Continued
Chapter 19
Sex Hormones
165
Table 191
Contraceptive ProductsContinued
Types of Products
Emergency postcoital contraception
EE 50 g/LN 0.25 mg
LN 0.75 mg
Comments
For both products, the 1st dose
should be taken as soon as possible
after unprotected intercourse, within
72 hours, followed by a 2nd dose
12 hours later
EE = ethinyl estradiol; NE = norethindrone; LN = nevonorgestrel; d = days
ANDROGENS
Naturally Occurring Androgens
Testosterone is the major androgen secreted by the testes. Pituitary LH and
FSH stimulate testosterone synthesis and secretion. The resultant increase
in plasma testosterone subsequently reduces LH and FSH release.
Actions
As for corticosteroids (see Figure 182). Tissue selectivity is achieved by the
presence of specific soluble protein receptors found in the cytoplasm of target cells. Testosterone passes from the blood into the cell and combines with
specific androgen receptors. Following transfer of the receptor-testosterone
complex into the nucleus, testosterone interacts with chromatin to produce
the metabolic changes essential for androgenic action. Testosterone, and the
other endogenous androgens
are responsible for the full morphologic and functional development of
the male reproductive tract, including the accessory glands and external genitalia;
determine the distribution and growth of hair on the face, body, and
pubes, and the initial recession of the male hairline;
enlarge the larynx and thicken the vocal cords;
increase protein anabolism and decrease catabolism; and
improve the ability of muscles to work, by increasing their number,
thickness, and tensile strength.
Chapter 19
Sex Hormones
166
Pharmacokinetics
Testosterone cannot be given orally, because it is rapidly inactivated during
its first pass through the liver. It must be IM injected as the propionate,
enanthate, or cypionate esters.
Methyltestosterone can be taken orally or sublingually. Other orallyeffective androgens are fluoxymesterone, mesterolone, oxandrolone, and
stanozolol.
Uses
Replacement Therapy
Used in patients with hypogonadism due to testicular failure.
Given at puberty to males with hypopituitarism.
Anemia
Used to stimulate erythropoiesis in patients with hypoplastic anemia, the
anemia of cancer, red cell aplasia, hemolytic anemias, and anemias related
to renal failure, lymphomas, leukemias, and myeloid metaplasias.
Cancer
Used for recurrent and metastatic carcinoma of the breast. The response
is much better in tumors containing estrogen receptors and/or progesterone
receptors.
Anabolic Effects
The androgens ethylestrenol, methylandrostenolone, and stanozolol
are used for their anabolic effects to help postoperative recovery and to
treat chronic debilitating disease.
Use in athletes cannot be condoned.
Adverse Effects
Women taking androgens experience menstrual irregularities. Masculinization can also be seen in females.
Seen first as acne, growth of facial hair, deepening of voice, and later as
the male pattern of baldness.
Marked development of the skeletal muscle and veins; hypertrophy of
the clitoris may subsequently ensue.
Salt and water retention because androgens increase renal Na+, Cl-, and
H2O reabsorption.
Androgens can cause biliary stasis, leading to jaundice and hepatic
andenocarcinoma.
Daily use of androgens can decrease FSH and LH in males, resulting in
impotence and azoospermia.
Chapter 19
Sex Hormones
167
ANTIANDROGENS
Finasteride
Actions
Finasteride is a competitive and specific inhibitor of 5-alpha-reductase, an
intracellular enzyme that metabolizes testosterone into the more potent
androgen, dihydrotestosterone.
Uses
Finasteride is used to treat symptomatic benign prostatic hyperplasia. It may
cause regression of the enlarged prostate and improve blood flow and the
symptoms associated with benign prostatic hyperplasia.
Adverse Effects
Finasteride is well tolerated. The most frequent reactions are impotence
(3.7%), decreased libido (3.3%), and decreased volume of ejaculate (2.8%).
Part 6 Psychopharmacology
20
Antipsychotic Drugs
TYPICAL OR TRADITIONAL ANTIPSYCHOTIC DRUGS
(TABLE 201)
Actions
Typical antipsychotic drugs block dopamine D2, histamine H1, muscarinic,
and alpha1-adrenergic receptors (Table 201, Figures 201 and 202).
Table 201
Typical and Atypical Antipsychotic Drugs

Typical Antipsychotics
Atypical Antipsychotic
1. Low-Potency Phenothiazines
Chlorpromazine
Mesoridazine
Promazine
Thioridazine
Clozapine
Olanzepine
Respiridone
2. Mid/High-Potency Phenothiazines
Fluphenazine
Fluspirilene
Perphenazine
Prochlorperazine
Pimozide
Trifluoperazine
3. Mid/High-Potency Thioxanthene
Thiothixene
4. Mid/High-Potency Butrophenone
Haloperidol
5. Mid/High-Potency Dibenzoxazepine
Loxapine
168
Chapter 20
Antipsychotic Drugs
169
dopamine
neuroleptic
drugs
dopamine
dopamine receptor blocked
Decreased
Intracellular
response
Figure 201 Dopamine-blocking actions of antipsychotic drugs. (After Neuroleptic Drugs in:
Lippincotts Illustrated Reviews. Eds Harvey RA, Champe PC. New York: Lippincott, 1992.)
Block of Dopamine (D2)-Receptors in the Brain by Typical Antipsychotics

accounts for their:
1. Antipsychotic actions. The block of D2-receptors in the mesolimbicmesocortical area of the brain is believed to play a major role in controlling the positive symptoms of schizophrenia (eg, irritability, hallucinations, and delusions).
2. Extrapyramidal effects. The parkinsonian effects, dystonic reactions,
akathisia, and tardive dyskinesia, result from a blockade of D2-receptors
in the nigrostriatal pathway.
3. Hypersecretion of prolactin. The hypersecretion of prolactin produced by typical antipsychotics is due to a block of D2-receptors in the
pituitary, which mediate the effects of the prolactin inhibitory factor.
Blocking D2-receptors increases prolactin release, which can result in
amenorrhea, infertility, and impotence.
4. Antiemetic actions. Stimulation of D2-receptors in the chemoreceptor
area of the medulla oblongata of the brain plays a pivotal role in the
nausea and vomiting produced by many drugs and chemicals. The
antiemetic action of many typical antipsychotics results from a block of
these receptors.
Block of Histamine1 (H1)-Receptors (Antihistaminic Effects)
Higher doses of phenothiazines, such as chlorpromazine, are more likely
to produce pronounced sedation. This is at least partly due to a block of
H1-receptors.
170
PDQ PHARMACOLOGY
Neuroleptic drugs
Particularly
thioridazine,
chlorpromazine
Particularly
droperidol,
chlorpromazine
cholinergic
(muscarinic)
receptor
All, but
particulary
haloperidol,
fluphenazine,
thiothixane
-adrenergic
receptor
dopamine
receptor
Particularly
promethazine,
chlorpromazine
serotonin
receptor
H1-histamine
receptor
GABA
receptor
Figure 202 Blocking actions of antipsychotic drugs. GABA = gamma-aminobutyric acid. (After
Neuroleptic Drugs in: Lippincotts Illustrated Reviews. Eds Harvey RA, Champe PC. New York:
Lippincott, 1992.)
Block of Muscarinic Receptors

The ability of typical antipsychotics to block muscarinic receptors in the
body (see Chapter 4) explains the dry mouth, constipation, urinary retention, and cycloplegia produced by these drugs.
Block of Alpha1-Adrenergic Receptors
By blocking 1-adrenergic receptors, some typical antipsychotics dilate
arterioles, decreasing peripheral resistance and blood pressure, and veins,
reducing venous return and causing orthostatic hypotension (see Chapter
6).
Uses
Psychoses are the major indications for these drugs. Antipsychotic drug
therapy is the most effective treatment for the acute-onset phase in schizophrenia or schizophreniform disorder. These drugs may also be very helpful in the prevention or recurrence of acute schizophrenic disturbances.
Typical antipsychotic drugs are less effective in the chronic phase of schizophrenia, particularly with such negative symptoms as anergia, low motivation, and flat affect. These drugs are also used to treat other psychoses,
including mania and paranoia. Despite differences in potency, all typical
antipsychotic drugs are equally effective in equivalent doses. The drug of
choice is usually the one the patient can best tolerate (see Adverse Effects
below).
Typical antipsychotic drugs are combined with lithium to treat the acute
manic episodes of bipolar affective disorders and to prevent recurrences.
Chapter 20
Antipsychotic Drugs
171
Organic mental syndromes, usually manifested as either delirium or

dementia, can be treated with typical antipsychotic drugs.
Nausea and vomiting resulting from the use of anticancer drugs, radiation,
estrogens, tetracyclines, and narcotics, and from uremia, can be treated with
typical antipsychotic drugs. Only thioridazine seems devoid of antiemetic
effects. Antipsychotics are not effective in controlling motion sickness.
Adverse Effects
CNS depression, which may be due to H1-receptor antagonism, is common
with all typical antipsychotics and pronounced after large doses of the lowpotency phenothiazines.
Anticholinergic effects can lead to mydriasis, cycloplegia, dry mouth,
retention or difficulty in urination, and constipation. Muscarinic block can
also cause a toxic confusional state.
Alpha1-adrenergic receptor blockade can cause orthostatic hypotension, impotence, and failure to ejaculate. Orthostatic hypotension is more
prevalent with the low-potency antipsychotics.
Inhibition of D2-pituitary receptors increases prolactin release, causing
amenorrhea, infertility, and impotence.
Hypersensitivity reactions include obstructive jaundice and blood
dyscrasias, manifested as leukopenia, leukocytosis, and eosinophilia.
Skin pigmentation, seen most often with chlorpromazine and other
low-potency drugs, is apparently the result of the accumulation of the
antipsychotic and its metabolites in the skin. Photosensitivity, most common with long-term chlorpromazine treatment, usually appears in the
form of hypersensitivity to the sun and severe sunburn.
Neuroleptic malignant syndrome is a rare, but serious, syndrome of
unknown cause. Its symptoms include tachycardia, sweating, rigidity, fevers,
fluctuations in blood pressure, seizure, or coma.
Extrapyramidal symptoms (EPS) are of great concern. Dopamine (DA)
and acetylcholine (Ach) are physiologic antagonists in the striatum of the
brain, with DA acting as an inhibitor and Ach as an excitatory neurotransmitter. Because typical antipsychotics block D2-receptors, they disturb the
normal balance between Ach and DA in the brain. As a result, the excitatory effects of Ach are seen unfettered by the inhibitory actions of DA. The
EPS of typical antipsychotics can be divided into the direct and indirect consequences of the D2 block (Table 202).
ATYPICAL ANTIPSYCHOTIC DRUGS

Clozapine, olanzapine, and risperidone are often referred to as atypical
antipsychotics because their pharmacologic and therapeutic effects differ
172
PDQ PHARMACOLOGY
Table 202
Extrapyramidal Effects of Traditional Antipsychotics

Direct Effects of the Block
of DA Receptors
Indirect Effect of the Block

of DA Receptors
Tardive dyskinesia occurs in

Parkinsonian effects involve a
10 to 40% of patients receiving
decrease or slowing of voluntary
long-term typical antipsychotic
movements associated with masked
drug therapy and is characterized
faces, tremor at rest, and a decrease in
by involuntary and lateral jaw
reciprocal arm movements when walking.
movements and fly-catching
Seen in about 13% of patients on typical
movements of the tongue.
antipsychotics, parkinsonian effects may
Choreiform-like movements,
appear as early as 5 days or as late as 1
characterized by quick, jerky,
month after treatment begins. Reducing
the dose of the antipsychotic or adding an purposeless movements of the
extremities, may also occur. Tardive
anticholinergic-antiparkinsonian drug (see
dyskinesia results indirectly from a
Chapter 24) decreases the severity of the
block of D2-receptors. The block of
syndrome
D2-receptors by these drugs
Dystonic reactions include facial
increases both the turnover and
grimacing, torticollis, oculogyric crisis,
stores of DA within nerve
difficulty in speech and swallowing, and
terminals. In time, the block of
uncoordinated, spastic movements of the
D2-receptors also results in the
body and limbs. Seen in 12% of patients
formation of new and
on typical antipsychotics, these effects
supersensitive D2-receptors.
usually appear 1 5 days after starting
Tardive dyskinesia results from the
treatment. Giving an anticholinergicoverstimulation of these new
antiparkinsonian drug decreases the
D2-receptors. Because tardive
severity of the syndrome
dyskinesia is caused by
overstimulation of new
Akathisia is the inability to sit quietly.
supersensitive D2-receptors and
Seen in 37% of patients treated with
not cholinergic predominance, it
typical antipsychotics, it is characterized
does not respond to
as restlessness, pacing, and insomnia. An
anticholinergic-antiparkinsonian
anticholinergic-antiparkinsonian drug
drugs. Tardive dyskinesia may
should reduce the symptoms
occur within the first year of
treatment or take considerably
longer to appear. The risk
increases with duration of
treatment and the use of
high-potency drugs
DA = dopamine.
Chapter 20
Antipsychotic Drugs
173
significantly from those of the typical or traditional antipsychotics. For

many patients, the atypical drugs provide relief previously not available with
the older drugs and cause less EPS than typical antipsychotics.
1. Clozapine
Actions
Clozapine differs from typical antipsychotics in its ability to block
dopamine4- (D4) receptors. This action presumably explains its antipsychotic
effects. Clozapine is a relatively poor D2-receptor blocker. It has the least
affinity of any antipsychotic drug for D2 receptors in the caudate nucleus, and
this probably accounts for the fact that it does not produce EPS.
Uses
Clozapine is effective in controlling both positive symptoms (eg, irritability, hallucinations, and delusions) and negative symptoms (eg, social disinterest or incompetence and poor personal hygiene) of schizophrenia and
other psychoses. Compared with other antipsychotics, clozapine appears to
be particularly useful in the treatment of severely disturbed, treatmentrefractory patients, in whom it has a 40 to 60% success rate. Clozapine may
also be effective in other unresponsive psychotic mood or schizoaffective
disorders. In addition, because of the very low risk of EPS with this drug, a
trial of clozapine is clearly indicated for patients in whom EPS (including
tardive dyskinesia) are severe and intolerable with other agents.
Adverse Effects
Agranulocytosis occurs in 1 to 2% of patients, usually in the first 6 months
of treatment. Although this reaction also occurs with other antipsychotics,
it is more prominent with clozapine. Clients must have a normal white
blood cell (WBC) and differential count prior to starting therapy. Subsequently, a WBC and differential count must be carried out weekly throughout treatment and for at least 4 weeks after stopping clozapine.
Other adverse effects include drowsiness or sedation (40%), hypersalivation (30%), tachycardia (25%; persistent in 10%), dizziness (20%), and
orthostatic hypotension (9%). Weight gain, transient fever, and seizures can
occur with clozapine.
2. Olanzapine
Actions
Olanzapine selectively inhibits mesolimbic dopaminergic pathways. Because
olanzapine does not inhibit nigrostriatal dopaminergic activity, its EPS are
174
PDQ PHARMACOLOGY
kept to a minimum. Olanzapines low incidence of side effects is also due

to its greater affinity for serotonin2A/5-hydroxytryptamine2A (5-HT2A)
receptors over D2-receptors.
Uses
Olanzapine appears to control the positive, negative, and affective (mood)
symptoms of schizophrenia. Olanzapine also demonstrates fewer EPS than
typical antipsychotics.
Adverse Effects
Somnolence appears to be the most frequent adverse effect (about 25% of
patients). Other possible adverse effects include dizziness, headache, agitation, and rhinitis.
3. Risperidone
Actions
Risperidone blocks both D2 and 5-HT2receptors. The balanced antagonism
of both types of receptors is the basis for risperidones superior therapeutic efficacy and reduced potential for inducing EPS.
Risperidone also inhibits 1-adrenergic receptors and H1-histaminergic
receptors. As a result of its inhibition of 1-receptors, risperidone can produce a dose-related fall in blood pressure and reflex tachycardia.
Risperidone changes sleep architecture by promoting deep slow-wave
sleep, thereby improving sleeping patterns. This effect is most likely due to
risperidones blockade of 5-HTreceptors.
Uses
Risperidone is used to manage both the positive and negative symptoms of
schizophrenia. Its ability to manage the negative symptoms is most significant and, along with its increased safety, serves to set risperidone apart from
the typical antipsychotics.
Adverse Effects
Asthenia, sedation, and difficulty in concentrating are the most common
adverse effects. Others include orthostatic hypotension, reflex tachycardia,
elevation of prolactin levels, weight gain, and sexual dysfunction. In patients
taking recommended doses of risperidone, the incidence of EPS is only
slightly higher than placebo.
21
Drugs for Mood Disorders
TREATMENT OF DEPRESSION
1. Tricyclic Antidepressants
Actions
Tricyclic antidepressants (TCAs) and maprotiline, a drug that is pharmacologically similar to TCAs, elevate mood; increase physical activity and the
activities of daily living; improve appetite and sleep patterns; and reduce
morbid preoccupation in 60 to 70% of patients with major depression
(Table 211). These effects often begin gradually (1 to 6 weeks). The means
by which these drugs increase mood is not clearly understood. The central
and peripheral actions of TCAs include
Table 211
Sedative and Anticholinergic Effects of Some Tricyclic

Antidepressants and Maprotiline
Name
Imipramine
Clomipramine
Desipramine
Amitriptyline
Nortriptyline
Doxepin
Protriptyline
Maprotiline
Sedation
Anticholinergic Effects
++
++
+
+++
++
+++
0
+++
++
++
+
+++
++
+++
++
+/0
0 = none; + = slight; ++ = moderate; +++ = high
175
176
PDQ PHARMACOLOGY
(a) Normal
monoamine
transmission
(b) Effect of
tricyclic
antidepressants
norepinephrine
serotonin
dopamine
response
Tricyclic
antidepressants
block reuptake of
neurotransmitter
norepinephrine
serotonin
dopamine
increased
response
Figure 211 Mechanism of action of tricyclic antidepressants. (After Harvey RA, Champe PC.
Lippincotts illustrated review: pharmacology. New York: J.P. Lippincott, 1992, p 120.)
A. Block of Neuronal Reuptake of Norepinephrine (NE) and/or

5-Hydroxytryptamine (Serotonin, 5-HT) in the Brain (Figure 211).
1. Inhibition of Reuptake
The ability of TCAs to inhibit NE and possibly 5-HT reuptake may account
for their therapeutic effects. Neuronal reuptake is the major physiologic
mechanism for removing NE and 5-HT from their receptors. If a drug
blocks neuronal reuptake, it raises the concentration of the neurotransmitter around receptors which increases the effect of the neurotransmitter.
2. Time Between Block of Reuptake and Relief of Depression
TCAs quickly inhibit NE and possibly 5-HT neuronal reuptake, but they
require 1 to 6 weeks to relieve depression. Obviously, blocking reuptake is
only the first step in modifying mood.
3. Down-Regulation of -Receptors
It is speculated that the block in NE neuronal reuptake leads to a downregulation or subsensitization of -adrenergic receptors. Down-regulation
of -receptors takes 2 or 3 weeks and correlates with relief of depression.
4. Summary of Sequence of TCA Effects on Central Nervous System
(CNS) NE
The antidepressant effects of TCAs may, at least partly, be attributed to the
following sequence of events:
Chapter 21
177
Inhibition of NE reuptake
Increase in synaptic concentrations of NE
Increase of neuronal NE release during normal rates of firing
Further increase in synaptic concentrations of NE
Desensitization of postsynaptic -receptors
5. Summary of Sequence of TCA Effects on CNS 5-HT

Some TCAs also inhibit 5-HT reuptake and this may lead to desensitization
of 5-HTreceptors.
B. Block of Alpha1 (1), Histamine1 (H1), and Muscarinic Receptors
TCAs block 1-adrenergic receptors, producing orthostatic hypotension;
H1-receptors, causing sedation; and muscarinic receptors, resulting in
blurred vision, dry mouth, decreased sweating, constipation, urinary retention, and delayed ejaculation. Table 211 summarizes the sedative (antihistaminic) and anticholinergic effects of TCAs.
Uses
TCAs are most effective in patients suffering from more severe depression,
particularly with greater vegetative disturbance and melancholia. Usually,
the more sedative drugs (amitriptyline and doxepin) are preferred for anxious or agitated depressives, while the less sedative drugs (protriptyline) are
better for patients with psychomotor withdrawal.
Adverse Effects
Cardiovascular (CV) effects orthostatic hypotension is the most common CV effect. Other effects seen with increasing doses are palpitations,
tachycardia, cardiac arrhythmias, and ECG abnormalities. Ventricular
arrhythmias, including fibrillation, can occur with large doses.
Anticholinergic effects see above.
CNS effects confusion can occur, especially in patients over age 40,
and particularly when used with drugs that also block muscarinic receptors.
Sedation is common. TCAs can produce tremors.
Weight gain can also occur with TCAs.
2. Selective Serotonin Reuptake Inhibitors (SSRIs) (Fluoxetine,

Fluvoxamine, Nefazodone, Paroxetine, Sertraline)
Actions
SSRIs selectively inhibit 5-HT neuronal reuptake, with little or no effect on
NE reuptake. SSRIs also take 1 to 6 weeks to relieve depression.
178
PDQ PHARMACOLOGY
Uses
SSRIs are used primarily in moderately and severely depressed out-patients.
They may be particularly useful
in patients with concurrent illness such as hypertension, coronary
artery disease, prostatic enlargement, or narrow-angle glaucoma;
in those who cannot tolerate the adverse effects of TCAs; and
in the elderly.
Adverse Effects
Headache, tremor, nausea, diarrhea, insomnia, agitation, and nervousness
are most frequent.
SSRIs may cause either agitation or sedation.
Because SSRIs do not have the anticholinergic, antihistaminic, or
1-receptor blocking activities of the TCAs, they are less likely to cause
orthostatic hypotension, tachycardia, delayed cardiac conduction, seizures,
blurred vision, or dry mouth.
Anorgasmia in both men and women and ejaculatory disturbances
appear more common with SSRIs than with TCAs.
SSRIs are much safer in an overdose than TCAs, which can cause lethal
cardiac toxicity.
3. Monoamine Oxidase Inhibitors (MAOIs) (Phenelzine,

Tranylcypromine, Moclobemide)
Actions
Monoamine oxidase (MAO) refers to a group of enzymes widely distributed
throughout the body that oxidatively deaminate and inactivate NE,
dopamine (DA) and 5-HT. MAOIs increase brain levels of NE, DA and 5HT (Figure 212). They probably relieve depression by this increase in brain
NE and/or 5-HT. Enzyme inhibition appears after a few doses; however, the
antidepressant effects of MAOIs take 2 to 4 weeks of treatment.
MAOs exists in the body as two isozymes, MAO-A and MAO-B, each
with selective substrate and inhibitor characteristics:
MAO-A preferentially metabolizes NE and 5-HT in the brain.

MAO-B metabolizes DA in the brain.
Inhibition of MAO-A, not MAO-B, is important to the antidepressant
actions of MAOIs.
Phenelzine and tranylcypromine inhibit both MAO-A and MAO-B.
Moclobemide inhibits only MAO-A.
Chapter 21
(a) Normal
monoamine
transmission
MAO inactivated
monoamines
(norepinephrine,
serotonin and
dopamine) that
leak from
vesicle
synaptic
vesicle
MAO
inactive
metabolites
norepinephrine
serotonin
dopamine
(b) Effect of
MAO inhibitors
MAO inhibitors
prevent
inactivation
of monoamines
within neuron,
causing excess
neurotransmitter
to diffuse into
synaptic space
response
179
synaptic
vesicle
MAO
inactive
metabolites
norepinephrine
serotonin
dopamine
increased response
Figure 212 Mechanism of action of MAOIs. (After Harvey RA, Champe PC. Lippincotts illustrated review: pharmacology. New York: J.P. Lippincott, 1992, p. 124.)
Uses
MAOIs are usually used only after other antidepressants have failed. Most
physicians consider other antidepressants more effective and less toxic
than phenelzine and tranylcypromine. Moclobemide appears to be as effective and as well tolerated as TCAs.
Adverse Effects
Phenelzine and tranylcypromine stimulate the CNS to produce tremors,
insomnia, and agitation. They also produce orthostatic hypotension, as well
as decreasing cholinergic stimulation, resulting in dry mouth, constipation,
difficulty in urination, delayed ejaculation, and impotence. A low incidence
of hepatotoxicity is also reported with these drugs. Acute overdosage with
phenelzine or tranylcypromine is a serious problem. Symptoms include
severe fever, agitation, hyperexcitable reflexes, hallucination, and increase
or decrease in blood pressure.
Moclobemide is well tolerated. The most common adverse effects are
dry mouth, dizziness, headache, somnolence, nausea, and insomnia.
Interaction of MAOIs with Food and Drugs
Tyramine is found in such foods as cheese, beer, wine, pickled herring, snails,
chicken liver, and coffee. It is normally metabolized rapidly by MAO-A in the
180
PDQ PHARMACOLOGY
cells of the intestinal wall and liver, and by MAO-B in the liver. Phenelzine
and tranylcypromine inhibit both MAO-A and MAO-B, increasing the circulating levels of tyramine, which enters sympathetic nerve endings and
releases NE. The resulting generalized vasoconstriction produces a hypertensive crisis. Death can occur from an intracranial hemorrhage.
Moclobemide is safer because tyramine can effectively compete with
moclobemide for intestinal and hepatic MAO-A. Moreover, liver MAO-B is
still available to inactivate any tyramine that is not metabolized by MAO-A
in the intestine or liver.
TCAs should not be used with MAOIs. By reducing both the reuptake
of NE and its enzymatic inactivation, their concomitant use can produce a
hyperpyretic crisis or severe convulsions.
MAOIs decrease the metabolism and increase the actions of a large
number of drugs, such as narcotics, barbiturates, many anesthetics, and
anticholinergics.
4. Miscellaneous Antidepressants
A. Trazodone
Actions
Like SSRIs, trazadone inhibits the neuronal reuptake of 5-HT. Trazadone
also stimulates the neuronal release of NE, and because of this action
chronic trazadone treatment leads to down-regulation (subsensitivity) of
-adrenergic receptors. This action may play a role in the antidepressant
effects of trazadone.
Trazadone is relatively free of antimuscarinic and CV adverse effects.
Uses
Trazadone is as effective as amitriptyline in both major and other subsets
of depressive disorders. Because of its sedative effect, trazadone is generally
more useful in depressive disorders associated with insomnia and anxiety.
Adverse Effects
Trazadone is generally well tolerated. Drowsiness is most common, and mild
nausea and vomiting occur less frequently. Trazadone can cause orthostatic hypotension for 4 to 6 hours after ingestion. This can be reduced by giving the drug with food.
Chapter 21
181
B. Venlafaxine
Actions
Venlafaxine is similar to TCAs because it inhibits NE and 5-HT uptake and
weakly inhibits DA uptake. In contrast to TCAs, venlafaxine has no affinity
for cholinergic, H1-, or 1-receptors.
Uses
Venlafaxine is an effective antidepressant.
Adverse Events
Venlafaxines adverse effects resemble those of SSRIs. Nausea, headache,
anxiety, anorexia, nervousness, sweating, dizziness, insomnia, and somnolence are the most common.
C. Bupropion
Actions
Bupropions mechanism of action is not known. Although it blocks the
reuptake of dopamine, this effect is seen only at higher doses than those
needed to relieve depression. Bupropion is a weak blocker of 5-HT and NE
reuptake, and it does not inhibit MAO.
Uses
Bupropion is used for the treatment of major depression. It appears to be
effective without causing the sedation, orthostatic hypotension, weight
gain, or sexual dysfunction associated with other antidepressants.
Bupropion is also used as a smoking cessation treatment in conjunction
with behavioral modification.
Adverse Effects
Bupropion is generally well tolerated and causes fewer anticholinergic,
sedative, or adverse sexual effects than TCAs. It does not cause weight gain
and does not affect cardiac conduction or produce orthostatic hypotension.
Agitation has been the most frequent reason for stopping the drug. Dry
mouth, headache, dizziness, insomnia, anorexia, weight loss, nausea, and
constipation have occurred.
182
PDQ PHARMACOLOGY
The main concern in using bupropion is the risk for seizures. These
occur more frequently at higher doses. Caution is used in patients with a
history of seizures or cranial trauma, during concurrent use with other
medications that may lower the seizure threshold, or when changes in
treatment regimens occur.
TREATMENT OF MANIC-DEPRESSIVE ILLNESS (BIPOLAR

DISORDER)
Lithium
Actions
Lithiums mechanism of action is not known. Lithium is a positively charged
ion, similar to sodium and potassium. It is unclear whether its therapeutic
effects have any relationship to the actions of sodium or potassium.
Therapeutic concentrations of lithium have no noticeable effects in normal individuals. Lithium differs from other psychotropic drugs in that it is
not a sedative, euphoriant, or depressant. It corrects sleep patterns in manic
patients but has no primary action on sleep itself, other than perhaps a small
decrease in rapid eye movement (REM) sleep.
Lithium carbonate is well absorbed from the intestine, producing sharp
peaks in serum concentrations. The use of a sustained-release lithium carbonate preparation can reduce the frequency of absorption-related side
effects.
Lithium is excreted by the kidney, with a half-life of 17 to 36 hours.
Lithium elimination is reduced in patients with renal impairment. Reducing sodium intake increases the renal reabsorption of lithium; therefore,
patients on lithium should not be given a low sodium diet.
Uses
Lithium carbonate is used to treat mania. Lithium requires 1 to 3 weeks of
treatment before it is effective. When mania is mild, lithium alone may suffice. In more severe cases, an antipsychotic drug, usually haloperidol or
chlorpromazine, is also given (see Chapter 20). After adequate serum levels of lithium have been reached, the antipsychotic may be carefully withdrawn. During the depressive phase, lithium may be combined with a TCA
or bupropion.
Prophylactic lithium treatment is considered the therapy of choice to
prevent recurrences of manic-depressive disorder.
Lithium is contraindicated in patients with significant CV or renal disease. It is also contraindicated in severely debilitated or dehydrated patients,
Chapter 21
183
and in patients with sodium depletion, brain damage, or those requiring low
sodium intake.
Adverse Effects
Lithium has a low therapeutic index and reaches toxic levels quickly.
Lithium serum levels should be measured frequently during stabilization
and routinely during maintenance. For many patients, serum concentrations of 0.6 to 0.7 mmol/L are effective and well tolerated. Mild to moderate toxic effects occur at 1.5 to 2.0 mmol/L and moderate to severe reactions
above 2.0 mmol/L.
Nausea, lethargy, and fatigue may occur in the first weeks of treatment,
even when serum concentrations are in the recommended range. Fine
tremor of the hand is common, especially during initial treatment. As the
concentration of lithium increases, the fine tremor may become coarse and
ataxia, dysarthria, loss of coordination, difficulty in concentration, and mild
disorientation may be established. Other signs of neurologic toxicity include
muscle twitching and fasciculations in the limbs, hands, and face, together
with nystagmus, dizziness, and visual disturbances. The signs of severe toxicity are restlessness, confusion, nystagmus, epileptic convulsion, delirium,
and eventually, coma and death.
Polyuria and polydipsia occur in 15 to 40% of patients. These do not
bother most patients. Toxic renal effects, including tubular lesions, interstitial fibrosis, and decreased creatinine clearance are uncommon but have
been reported following chronic lithium treatment. Lithium can also produce nephrogenic diabetes insipidus.
Lithium can cause euthyroid goitre, hypothyroidism, with or without
goitre, and abnormal endocrine test results.
22
Anxiolytics and Hypnotics
BENZODIAZEPINES
Actions
Benzodiazepines reduce anxiety by depressing the limbic system. The limbic system, composed of the septal region of the brain, the amygdala, the
hippocampus, and the hypothalamus, is important in determining an individuals emotional and autonomic response to situations.
Benzodiazepines depress the limbic system by facilitating the action of
-aminobutyric acid (GABA). Binding of GABA to its receptors inhibits the
formation of action potentials and depresses neuronal function. Benzodiazepines bind to specific, high-affinity sites on the cell membrane, which are
separate from, but adjacent to, the receptors for GABA. This binding of benzodiazepines to their receptors enhances the affinity of GABA receptors for
GABA. This results in greater depression of neuronal function.
Pharmacokinetics
Benzodiazepines are usually absorbed quickly and then metabolized. The
metabolic inter-relationship of the benzodiazepines is complex (Figure
221 and Table 221). Their half-lives range from 2 to 3 hours for triazolam to approximately 50 to 100 hours for diazepam and flurazepam. Chlordiazepoxide, ketazolam, and diazepam are active themselves and are also
metabolized to active compounds. The half-lives given for these drugs take
into account the duration of action of the metabolites, as well as the parent compounds.
Because benzodiazepines are often prescribed for prolonged periods of
time, their long-term pharmacokinetics are important. When a drug is taken
chronically, it requires about 5 half-lives to reach steady state. Therefore,
drugs with long half-lives, such as diazepam, require 2 to 3 weeks before they
184
Chapter 22
185
Figure 221 Benzodiazepine metabolism. (After Morgan JP. Alcohol and drug abuse. Curriculum guide for pharmacology faculty. Rockville, MD: U.S. Department of Health and Human
Services, 1985:44.)
reach plateau levels, and patients may not experience their full effects until
treatment has continued for this length of time. Other benzodiazepines with
shorter half-lives, such as oxazepam, reach plateau concentrations within
1 to 3 days and maximum effects are seen sooner.
Once treatment with a drug is stopped, it is eliminated from the body
in relation to its half-life. Thus, the effects of diazepam last long after the
drug is stopped. The actions of lorazepam, with a half-life of 12 to 15 hours,
disappear faster. The rapid elimination of a benzodiazepine from the body
following prolonged treatment can be a mixed blessing. Although the
patient may not be bothered with the hangover effects of the drug, rapid
elimination of the benzodiazepine often causes rebound excitation and a
request for another prescription. Patients on shorter-acting benzodiazepines
may be more likely to become dependent on these drugs.
Although metabolic inactivation is important in determining the duration of action of a benzodiazepine during long-term treatment, it is not
Chapter 22
186
Table 221
Properties of Some Benzodiazepines

Drug
Triazolam
Oxazepam
Temazepam
Bromazepam
Alprazolam
Lorazepam
Chlordiazepoxide
Nitrazepam
Clorazepate
Ketazolam
Diazepam
Flurazepam
Peak Time
of Effect (h)
Biological
Half-Life (h)
Therapeutic
Use*
2
1-4
0.8-1.4
1-4
1-2
1-6
2-4
2
1-2
?
1.5-2
1
2-3
4-13
8-10
12
6-20
12-15
20-24
26
48
50
50-100
50-100
Hypnotic
Anxiolytic
Hypnotic
Anxiolytic
Anxiolytic
Anxiolytic
Anxiolytic
Hypnotic
Anxiolytic
Anxiolytic
Anxiolytic
Hypnotic
*Refers to anxiolytic and hypnotic uses only.
Refers to half-life of drug plus active metabolites.
responsible for deciding how long the actions of benzodiazepine will last
during the initial days of treatment. Instead, the rate at which the drug diffuses out of the brain and into other body tissues is responsible for terminating its CNS effects. As most benzodiazepines diffuse from the brain into
other tissues at approximately the same rate following initial doses, all benzodiazepines should have approximately the same initial duration of action.
For example:
Triazolam is rapidly inactivated by metabolism and has a half-life of

2 to 3 hours.
Flurazepam is metabolized very rapidly to its active metabolite,
N-desalkylflurazepam, which is slowly inactivated and has a half-life of
50 to 100 hours.
Despite these differences, both drugs have approximately the same initial duration of action because triazolam and N-desalkylflurazepam diffuse out of the brain at about the same rate during the initial nights of
treatment.
If flurazepam is given for several nights, N-desalkylflurazepam levels

increase in blood and other tissues because it is slowly metabolized. With
higher blood levels, less N-desalkylflurazepam is less able to diffuse out of
the brain and its hypnotic effects last longer.
Because triazolam is rapidly metabolized, chronic treatment should not
lead to accumulation. As a result, triazolam should have a shorter duration
of action than flurazepam, when both drugs are given night after night.
Chapter 22
187
Figure 222 Early morning insomnia with triazolam and flurazepam. Patients were treated
nightly with 0.5 mg of triazolam or 30 mg of flurazepam. Early morning insomnia rate was measured during nights 16 to 18. (After Kales A, Soldatos CR, Bixler EO, Kales JC. Early morning
insomnia with rapidly eliminated benzodiazepines. Science 1983; 220:9597.)
The short half-life of triazolam means that patients on chronic triazolam may experience early morning insomnia (Figure 222). However, they
should not have significant daytime sedation. In contrast, patients on chronic
flurazepam experience daytime hangover, because significant amounts of
N-desalkylflurazepam remain in the brain during the waking hours.
Tolerance and Dependence
Tolerance develops to benzodiazepines. Figure 223 shows that patients
spent more time awake after 18 nights of treatment with triazolam than they
did after 7 nights. The percentage change in mean wake time for flurazepam did not change between week 1 and week 3 because the long halflife of N-desalkylflurazepam resulted in its accumulation in the brain,
minimizing the consequences of tissue tolerance.
Dependence to benzodiazepines is also common. Figure 224 demonstrates
Chapter 22
188
Figure 223 Change in percent mean wake time from control values during the first 6 hours
of night for triazolam- and flurazepam-treated patients. Patients were treated nightly with 0.5 mg
of triazolam or 30 mg of flurazepam. Percentage change in mean wake time was measured
during nights 5 to 7 and nights 16 to 18. (After Kales A, Soldatos CR, Bixler EO, Kales JC. Early
morning insomnia with rapidly eliminated benzodiazepines. Science 1983; 220:9597.)
the development of tolerance to triazolam between days 5 to 7 and 16

to 18, and
the appearance of rebound insomnia when patients stopped taking the
hypnotic.
Drugs with shorter half-lives are more likely to leave the patient with
rebound insomnia. This may lead to dependence on the drug and demands
for repeat prescription. The danger of drug dependence is greater with hypnotics having shorter half-lives.
Uses
Anxiety disorders, including panic and generalized anxiety, are the main uses
for benzodiazepines. These drugs may also be used for brief periods in stressrelated conditions, but this must be done with some caution. A benzodiazepine crutch to allay anxiety should be employed for shorter periods only.
Insomnia is the second major use for benzodiazepines. Ideally, a hypnotic should produce sleep quickly, work throughout the night, and have
no hangover effects. Although all hypnotics work quickly, short-acting
Chapter 22
189
Figure 224 Effect of triazolam on the induction and maintenance of sleep. Patients received
4 nights of placebo therapy prior to triazolam on day 4. Baseline data on Days 2 to 4. Day 5
was the first day of triazolam. Day 7 effects of triazolam on latency to sleep and total time
awake during days 5 to 7. Day 18 effect of triazolam on latency to sleep and total time awake
during days 16 to 18. Triazolam treatment was stopped after day 18. Day 21 effect of withdrawal from triazolam on day 19 to 21. (After Kales A, Sharf MB, Kales JD. Rebound insomnia:
a new clinical syndrome. Science 1978; 201:10391041.)
benzodiazepines are frequently not effective during the entire night, and
long-acting drugs leave patients with a morning hangover. Furthermore,
tolerance to these drugs develops rapidly, particularly when a short-acting
drug is used. Finally, many patients experience rebound insomnia when
short-acting benzodiazepines are stopped.
Adverse Effects
CNS depression (fatigue, drowsiness, and feelings of detachment) is the
major benzodiazepine adverse effect. Elderly patients are particularly prone
to headache, dizziness, ataxia, confusion, and disorientation. Psychological
impairment can occur. Physiologic dependence (characterized by anxiety,
agitation, restlessness, insomnia, and tension) following drug withdrawal
can also be seen. Although overdosage is common, few patients die. Unless
consumed with another CNS depressant or a narcotic, benzodiazepines
rarely kill.
Chapter 22
190
BENZODIAZEPINE ANTAGONIST
Flumazenil
Actions
Flumazenil specifically competes with benzodiazepines for their receptors,
thereby preventing these drugs from acting.
Uses
Intravenous flumazenil is used for the complete or partial reversal of the CNS
effects of benzodiazepines. It may be used in anesthesia, to terminate the
CNS effects of a benzodiazepine, and in intensive care, to manage overdosage. Flumazenils effects begin within 1 to 2 minutes of injection and peak
in 6 to 10 minutes. Because flumazenil has a half-life of about 1 hour and a
shorter duration of action than benzodiazepines, patients should be closely
monitored until all possible central benzodiazepine effects have subsided.
Adverse Effects
Flumazenil can cause nausea, dizziness, headache, blurred vision, increased
sweating and anxiety, and may provoke a panic attack in some patients. The
drug can cause convulsions in patients who are physically dependent on
benzodiazepines or who are taking them to control epilepsy.
NONBENZODIAZEPINE ANXIOLYTICS AND HYPNOTICS

1. Buspirone
Actions
Buspirones mechanism of action is not clear. Although buspirone shares some
of the antianxiety properties of benzodiazepines, it is not an anticonvulsant or
muscle relaxant and it does not bind to the benzodiazepine GABA receptor.
Uses
Buspirone is used for the short-term symptomatic relief of excessive anxiety in patients with generalized anxiety disorder.
Adverse Effects
The most common adverse reactions are dizziness, headache, drowsiness,
and nausea.
Chapter 22
191
2. Zopiclone
Actions
Zopiclone is a short-acting hypnotic. Zopiclone is rapidly absorbed and
extensively metabolized with a half-life of 5 hours.
Uses
Zopiclone is useful for the short-term management of insomnia characterized by difficulty in falling asleep and/or early morning awakenings.
Zopiclone reduces sleep latency and increases sleep duration. It produces
minimal morning residual effects and does not reduce daytime performance. Zopiclone causes either no, or only slight, psychomotor impairment.
Tolerance to zopiclone does not develop over eight weeks of therapy.
Rebound insomnia is not marked when patients stop zopiclone. Zopiclone
does not significantly affect sleep architecture. There is no evidence that
zopiclone produces drug dependence.
Adverse Effects
The adverse effects of zopiclone differ qualitatively from those of the various benzodiazepines. Bitter taste is the most common adverse reaction to
zopiclone. Severe drowsiness and/or impaired coordination are signs of
drug intolerance or excessive doses.
3. Barbiturates (Amobarbital, Butabarbital, Pentobarbital,

Secobarbital)
Actions
Barbiturates potentiate GABA-mediated inhibitory process in the CNS to
produce muscle relaxant, anticonvulsant, sedative, and hypnotic effects.
Barbiturates alter psychological functions, particularly complex tasks, and
especially fine points of judgement. Increasing doses lead to progressive
impairment of brain function, culminating with respiratory failure.
Uses
The availability of safer drugs (see above) has eliminated any need for the
continued use of barbiturates as anxiolytics (sedatives) or hypnotics.
Adverse Effects
CNS depression is the major adverse effect. Patients may experience drowsiness, confusion, or even psychosis. Other signs of CNS depression include
Chapter 22
192
nystagmus, dysarthria, and motor incoordination. The elderly are particularly at risk for ataxia and confusion. Paradoxic excitation may also occur.
Overdosage can cause respiratory failure.
4. Chloral Hydrate
Actions
Chloral hydrate works quickly and has a relatively short duration of action.
Uses
Chloral hydrate is frequently used as a hypnotic in pediatrics and geriatrics.
It is better suited for putting people to sleep than it is for keeping them
asleep.
Adverse Effects
Chloral hydrate produces gastric irritation. Because the drug depresses the
CNS, it produces all the effects consistent with depression of the brain. If
large doses are taken, death can occur as a result of respiratory failure.
Part 7
Drugs for the

Treatment of
Neurologic Disorders
23
Drugs for the Treatment

of Epilepsy
pilepsy is a symptom of excessive temporary neuronal

discharge due to intracranial or extracranial causes. It is characterized clinically by discrete episodes, which tend to be recurrent, in which there is a
disturbance of movement, sensation, behavior, perception and/or consciousness (Sutherland and Eadie).*
ETIOLOGIC AND SEIZURE PATTERN CLASSIFICATIONS OF
EPILEPSY (TABLES 231 AND 232)
Table 231
Etiologic Classification of Epilepsy

Primary Epilepsy
The cause is not known; thus it is
also called idiopathic epilepsy
Characterized by major (grand mal)
or minor seizures (petit mal,
myoclonic, and akinetic seizures)
Secondary Epilepsy
Also called symptomatic epilepsy,
secondary epilepsy can result from
either intracranial causes, such as
cerebral tumours, cerebrovascular
occlusive disease, or head injury; or
extracranial problems, such anoxia,
uremia, or eclampsia
*After Sutherland JM and Eadie MJ. The epilepsies: modern diagnosis and treatment. 3rd
ed. New York: Churchill Livingstone, 1980.
193
194
PDQ PHARMACOLOGY
Table 232
Seizure Pattern Classification of Epilepsy

Generalized Seizures
Bilateral symmetrical
seizures without local
onset, clinically:
(a) Absence seizures
(petit mal)
(b) Bilateral myoclonus
(c) Infantile spasms
(d) Clonic seizures
(e) Tonic seizures
(f) Tonic-clonic seizures
(grand mal)
(g) Akinetic seizures
Partial Seizures
Seizures beginning
locally with:
(a) Elementary
symptomatology,
Motor
Sensory
Autonomic
Compound
forms
(b) Complex
symptomatology,
Impaired
consciousness
Complex
hallucinations
Affective
symptoms
Automatism
(repetitive,
purposeless
behaviours)
(c) Partial seizures
becoming
generalized tonicclonic seizures.
Unclassified Seizures
Seizures that cannot be
classified because of
incomplete data
Classification suggested by the International League Against Epilepsy. (After Sutherland JM,
Eadie MJ. The epilepsies: modern diagnosis and treatment. 3rd ed. New York: Churchill
Livingstone, 1980.)
Symptoms of Epilepsy (Figure 231)

The symptoms of epilepsy depend on
1. the site of the epileptic focus, and
2. the degree to which it spreads.
Most antiepileptic drugs reduce the spread of the abnormal electrical
impulse.
CHOICE OF DRUG THERAPY

Choice of drug therapy is determined by the kinds of seizures experienced
(Table 233).
Chapter 23
Drugs for the Treatment of Epilepsy
195
Figure 231 Manifestations of partial (symptomatic, cortical) epilepsy. (After Sutherland JM,
Eadie MJ). The Epilepsies: Modern Diagnosis and Treatment. 3rd ed. New York: Churchill Livingstone, 1980:27.)
DRUGS EFFECTIVE AGAINST GENERALIZED TONIC-CLONIC

SEIZURES
1. Phenytoin
Actions and Pharmacokinetics
Phenytoin appears to prevent the spread of seizure activity in the cerebrum by reducing sodium transport across cell membranes. Phenytoin is
slowly absorbed from the GI tract. Elimination depends on hepatic metabolism. At low doses, the drug has a half-life of 24 hours. As the dosage
increases, the metabolic pathways for its inactivation become progressively
more saturated, and the half-life of phenytoin increases. Relatively small
increases in dose can produce significant increases in plasma concentrations and drug-related toxicity. Measuring phenytoin plasma levels is valuable in adjusting the dose. Plasma concentrations of phenytoin between
10 and 20 g/mL (39.6 79.2 mol/L) are often effective without causing undue toxicity.
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PDQ PHARMACOLOGY
Table 233
Choice of Drug Therapy Based on Seizures Experienced

Type of Seizure
Petit mal (absence) seizures are
relatively uncommon and begin in
childhood. Patients experience
recurrent, brief, sudden
interruptions of consciousness
without falling and have minimal
twitching around the face and eyes
Drug Therapy
Drugs of first choice are valproic acid,
sodium valproate, divalproex sodium,
or ethosuximide. Clonazepam is an
alternative drug
Corticosteroids or corticotrophin may stop

Myoclonic seizures are
these seizures and prevent mental
characterized by bilateral myoclonic
deterioration. If they fail, clonazepam,
jerks of the limbs, face and trunk
valproic acid, or nitrazepam may control
that, if severe, may throw the
the seizures, but are less likely to
patient to the ground. There may be
prevent mental deterioration
brief lapses of consciousness
Generalized tonic-clonic seizures
may be a manifestation of primary
generalized epilepsy or may occur
secondary to focal or myoclonic
seizures
Carbamazepine or phenytoin are first-line

drugs, with phenobarbital, primidone,
valproic acid, or sodium valproate
serving as second-line drugs
Gabapentin, lamotrigine, and vigabatrin
are newer adjuvant drugs. Phenobarbital is usually used for the prevention of febrile seizures in infants
Partial or focal epilepsy may

activate the deep central grey
matter to produce a secondary
generalized tonic-clonic seizure
Phenytoin and carbamazepine are firstline drugs. Phenobarbital and

primidone are second-line agents.
Gabapentin, lamotrigine, and
vigabatrin are newer adjuvant drugs
Status epilepticus exists when

Status epilepticus is usually treated with
seizures recur with increasing
IV diazepam. Alternatively, lorazepam,
frequency such that baseline
phenobarbital, or phenytoin can be
consciousness is not regained
administered by IV
between seizures. The patient is
considered to be in status epilepticus
when seizures last at least 30
minutes. Status epilepticus is a
medical emergency
IV = intravenous.
Uses
Phenytoin is used orally in adults to control generalized tonic-clonic and
psychomotor (grand mal and temporal lobe) seizures and to prevent and
treat seizures occurring during or following neurosurgery.
Chapter 23
197
Pediatric formulations are used for the control of generalized tonic-clonic

(grand mal) and complex partial (psychomotor and temporal lobe) seizures.
Parenteral phenytoin is used in the treatment of status epilepticus of the
grand mal type and the treatment of seizures occurring during or following neurosurgery.
Adverse Effects
Phenytoin can produce gastric irritation, nystagmus, ataxia, diplopia,
drowsiness, gum hypertrophy, hirsutism, immunologic abnormalities, skin
rashes, hyperglycemia, osteomalacia, lymphadenopathy, leukopenia, megaloblastic anemia, and teratogenicity.
2. Carbamazepine
Carbamazepine reduces the propagation of aberrant impulses in the brain.
It is absorbed slowly from the GI tract. Its half-life during chronic therapy
may range from 8 to over 24 hours. The drugs usual therapy range is 5 to
12 g/mL (21.150.8 mol/L); however, 15 to 17 g/mL (63.371.7 mol/L)
may be necessary in some patients.
Uses
Carbmazepines spectrum of activity is similar to phenytoins. It is a firstline drug for the treatment of generalized tonic-clonic seizures and partial
seizures with complex symptomatolgy.
Adverse Effects
Carbamazepine has a low incidence of adverse effects at normal dosages.
Most common adverse effects include gastric irritation, diplopia, and blurred
vision.
3. Phenobarbital
Phenobarbital is a CNS depressant that may act as an antiepileptic by
reducing sodium and potassium flux across cell membranes. Phenobarbital is a long-acting barbiturate with a half-life ranging from 60 to 120 hours
in adults. The plasma levels that are consistent with good effect and minimal toxicity fall between 15 to 25 g/mL (64.6107.7 mol/L).
198
PDQ PHARMACOLOGY
Uses
Phenobarbital remains popular for the treatment of tonic-clonic epilepsy,
focal seizures, and complex partial seizures. Phenobarbital is also used prophylactically in young children when febrile seizures are feared.
Adverse Effects
CNS depression is the major adverse effect of phenobarbital. Fortunately
tolerance to the CNS-depressive effects of phenobarbital occurs when the
drug is given chronically. Allergic rashes are reported in 1 to 2% of patients.
Prolonged therapy may be associated with folate deficiency, hypocalcemia,
and osteomalacia. Hypoprothrombinemia with hemorrhage has been
reported in babies delivered from mothers given phenobarbital. This can be
treated with vitamin K injections.
4. Primidone
Primidone is structurally similar to phenobarbital and has a similar spectrum of antiepileptic activity. Primidone is quickly absorbed and metabolized to phenobarbital and phenylethylmalonamide, both having antiepileptic activity. Because the half-life of primidone is 8 hours and the half-lives
of phenobarbital and phenylethylmalonamide are 60 to 120 hours and 24
to 48 hours, respectively, these metabolites accumulate in patients treated
with primidone. Effective plasma levels of primidone usually fall between
5 to 10 g/mL (22.945.8 mol/L). However, phenobarbital plasma levels
frequently can be used to guide dosage.
Uses
Primidone is useful in the prevention of grand mal and psychomotor
seizures. It may be used alone or in combination with other antiepileptics.
Adverse Effects
Primidone depresses the CNS and can cause sedation, vertigo, nystagmus,
ataxia, and diplopia. It can also cause nausea and vomiting. Although serious
adverse effects are not common, leukopenia, thrombocytopenia, systemic
lupus erythematosus, and lymphadenopathy have been reported. Similar to
phenobarbital, primidone may cause maculopapular and morbilliform rashes,
hemorrhage in the newborn, megaloblastic anemia, and osteomalacia.
Chapter 23
199
NEWER ADJUVANT DRUGS FOR THE TREATMENT OF

GENERALIZED TONIC-CLONIC SEIZURES
1. Gabapentin
Gabapentins mechanism of action is not known. Gabapentin is rapidly
absorbed after oral administration, with or without food, achieving maximum plasma concentrations in 2 to 3 hours. Gabapentin is not metabolized
and is almost completely excreted by the kidneys, with a half-life of 5 to 7
hours.
Uses
Gabapentin is used as an adjunct therapy for the management of patients
who are not satisfactorily controlled by conventional antiepileptic drugs.
Adverse Effects
Gabapentin appears to be well tolerated. Frequently transient mild to moderate somnolence, dizziness, ataxia, fatigue, and nystagmus have been the
most common adverse effects.
2. Lamotrigine
Lamotrigine may act by stabilizing neuronal voltage-dependent sodium
channels, thus reducing the presynaptic release of excitatory amino acids,
principally glutamate and aspartate, that are thought to play a role in the
generation and spread of epileptic seizures.
Lamotrigine is almost completely absorbed from the GI tract, either
with or without food. Plasma concentrations reach a peak in 1.5 to 5 hours.
The plasma half-life of a single dose is about 24 hours.
Uses
Lamotrigine is used as an adjunct therapy for the management of adult
patients who are not satisfactorily controlled by conventional therapy. It
may also be used as monotherapy in adults following withdrawal of concomitant antiepileptic drugs.
200
PDQ PHARMACOLOGY
Adverse Effects
Dizziness, diplopia, ataxia, blurred vision, nausea, vomiting, and rash have
been the common adverse effects when lamotrigine is added to other
antiepileptic drugs. Rash has occurred in about 10% of patients and caused
about 4% to stop taking the drug. Rarely, serious skin rashes, including
Stevens-Johnson syndrome and toxic epidermal necrolysis, have been
reported. Although the majority recover following drug withdrawal, some
patients experience irreversible scarring, and there have been rare cases of
associated death.
3. Vigabatrin
The antiepileptic action of vigabatrin has been attributed to its ability to
reversibly inhibit -aminobutyric acid transferase (GABA-T), the enzyme
responsible for the catabolism of the inhibitory neurotransmitter
-aminobutyric acid (GABA). The resulting increase in GABA is felt to
account for vigabatrins antiepileptic effects.
Vigabatrin is rapidly and almost completely absorbed from the GI
tract. Peak plasma concentrations occur within 1 to 2 hours. Vigabatrin is
eliminated primarily by renal excretion, with renal clearance of unchanged
drug accounting for about 60 to 70% of total clearance.
Uses
Vigabatrin is used for adjunctive management of epilepsy that is not satisfactorily controlled by conventional therapy.
Adverse Effects
Vigabatrin is generally well tolerated. Fatigue, headache, drowsiness, dizziness, depression, weight increase, agitation, tremor, abnormal vision, and
amnesia are the most frequent adverse effects.
DRUGS EFFECTIVE AGAINST ABSENCE SEIZURES

1. Ethosuximide
Pharmacokinetics and Uses
Ethosuximide is a first-line drug for the treatment of petit mal epilepsy.
With a half-life of 30 hours in children, ethosuximide requires 5 to 7 days
Chapter 23
201
of regular treatment to reach steady state. Therapeutic effects are usually

obtained with serum levels of 50 to 100 g/mL (354.2708.3 mol/L).
Adverse Effects
Gastric irritation is the most common adverse reaction. Other effects include
CNS depression and rashes. Eosinophilia is seen in about 10% of patients.
Pancytopenia and aplastic anemia have also occurred. Systemic lupus erythematosus and Stevens-Johnson syndrome have been rarely noted.
2. Valproic Acid, Sodium Valproate, Divalproex Sodium

Pharmacokinetics and Uses
Valproic acid, or sodium valproate, is used alone or adjunctively to treat
simple or complex absence seizures, including petit mal. It is also useful in
primary tonic-clonic generalized seizures. These drugs may also be used
adjunctively in patients with multiple seizure types, which include either
absence or tonic-clonic seizures.
Valproic acid and sodium valproate are rapidly absorbed from the GI tract.
With a half-life of 6 to 16 hours, they should be administered 3 or 4 times daily.
The therapeutic plasma window is 50 to 100 g/mL (347694 mol/L).
Divalproex sodium is a derivative of valproic acid. Provided in entericcoated tablets, it dissociates into valproic acid in the intestinal tract. The
drug may produce less gastric distress than valproic acid.
Adverse Effects
Anorexia, nausea, and vomiting are major deterrents to the use of valproic
acid. Taking the drug with food may help.
Minor elevations of serum glutamic oxaloacetic transaminase (SGOT)
and serum glutamic pyruvic transaminase (SGPT) and lactate dehydrogenase
(LDH) are frequent. Occasionally, laboratory tests also show increases in
serum bilirubin and abnormal changes in other liver function tests. These
results may reflect serious hepatotoxicity. Hepatic failure resulting in fatalities has occurred. Because children 2 years of age or younger have nearly a 20fold increase in risk of fatal hepatotoxicity, valproic acid should be used in this
age group with extreme caution and as the sole agent. Liver function tests
should be performed on patients receiving valproic acid prior to therapy and
at frequent intervals thereafter. Care should be observed when administering
valproic acid to patients with a prior history of hepatic disease.
Valproic acid may increase the incidence of congenital malformations
by 2- to 3-fold in the general population. The increase is largely associated
with specific defects (eg, congenital malformations of the heart, cleft lip
and/or palate, and neural tube defects).
202
PDQ PHARMACOLOGY
3. Clonazepam
Uses
Clonazepam is a benzodiazepine (see Chapter 22) that is used alone or as
an adjunct in the management of myoclonic and akinetic seizures and petit
mal variants.
Adverse Effects
Sedation and drowsiness are the main complaints. Ataxia may also be seen.
Alterations in behavior include aggressiveness, argumentativeness, hyperactivity, agitation, depression, euphoria, irritability, forgetfulness, and confusion.
MISCELLANEOUS ANTIEPILEPTICS
1. Clobazam
Uses
Clobazam is a benzodiazepine (see Chapter 22) that has been added to current
antiepileptic therapy in patients with refractory seizures. It appears to be a useful adjuvant medication in a variety of seizure types in adults and children.
Adverse Effects
Sedation, drowsiness, fatigue, and dizziness are most common. Ataxia,
insomnia, depression, behavioral changes and weight gain have also been
reported. Physical and psychological dependence have occurred.
2. Diazepam (See Chapter 22)

Uses
Intravenous diazepam is the recommended treatment for status epilepticus.
Repeated injections are required to maintain the high brain levels necessary
to terminate status epilepticus.
3. Lorazepam (See Chapter 22)

Uses
Lorazepam is a benzodiazepine. Given by IV, it is effective for the initial
treatment of status epilepticus. In this case, the patient must be observed
for signs of cardiorespiratory depression, especially when this drug is given
with other antiepileptics.
24
Antiparkinsonian Drugs
CHARACTERISTICS OF PARKINSONISM
Parkinsonism refers to two main disorders with similar clinical symptoms:
1. Paralysis agitans or idiopathic Parkinsons disease, which accounts for
90% of the cases, and
2. Secondary, or symptomatic parkinsonism, caused by previous infection with the virus of lethargic encephalitis.
Most Prominent Clinical Symptoms
Akinesia is difficulty in initiating movements or modifying ongoing motor
activity. The patient may show slowness and loss of dexterity, as well as
problems with speech, manual skills, and gait.
Tremor is seen at rest and usually disappears when the affected limb is
moved.
Rigidity is due to an abnormal increase in muscle tone, producing cogwheel resistance to passive movement of an extremity.
In addition, the patient may suffer from a stoop when standing or walking and a characteristic posturing of the hands and feet. Perspiration, excessive salivation, seborrhea, and difficulty in swallowing may also be seen.
ETIOLOGY OF PARKINSONISM
Role of Acetylcholine and Dopamine in the Basal Ganglia
The basal ganglia area of the brain is responsible for the smooth control of
skeletal muscle movement. It contains high concentrations of the neurotransmitters acetylcholine (ACh) and dopamine (DA). The two appear to
function as physiologic antagonists, with DA acting as an inhibitory neurotransmitter and ACh as an excitatory neurotransmitter. Normal control
203
204
PDQ PHARMACOLOGY
of muscle movements depends on a delicate balance between these two. In

patients with parkinsonism, this balance is destroyed, as the levels of DA in
the basal ganglia are reduced and ACh acts unopposed. Figure 241 presents the concentrations of DA in the caudate nucleus and putamen areas of
the basal ganglia. The depletion of DA can be correlated with the degree of
degeneration of the substantia nigra. In the presence of a DA deficiency, the
Figure 241 Concentrations of dopamine in the caudate nucleus and putamen at autopsy from
controls and patients afflicted with parkinsonism. (After data provided in Hornykiewicz O. Parkinsons disease: from brain homogenates to treatment. Fed Proc 1973; 32:183190.)
Chapter 24
205
normal balance between DA and ACh is disturbed, and cholinergic activity predominates (Figure 242).
DRUGS FOR THE TREATMENT OF PARKINSONISM

Given the decreased levels of DA in the basal ganglia of parkinsonian patients,
and the resulting cholinergic predominance, drug therapy is aimed at
A. stimulating DA receptors, and/or
B. blocking the cholinergic receptors in the basal ganglia.
1. Dopaminergic Drugs
A. Levodopa
Levodopa is the immediate precursor of DA. When administered, a small
portion of levodopa enters the brain and is converted to DA by the enzyme
dopa decarboxylase (refer to Chapter 3 for a review of dopamine synthesis). DA itself cannot be administered for the treatment of parkinsonism,
because it will not cross the blood-brain barrier.
ACh
DA
DA
ACh
b
Figure 242 Diagrammatic representation of the balance between dopaminergic and cholinergic mechanisms in the striatum. ACh = acetylcholine; DA = dopamine; A = normal state; B =
parkinsonism. (After Yahr MD. The treatment of parkinsonism. Med Clin North Am 1972;
56:13771382.)
206
PDQ PHARMACOLOGY
Orally administered levodopa is extensively metabolized in peripheral

tissues, with only a very small percentage being converted to DA in the brain
(Figure 243). As a result, very large doses of the drug must be administered
orally, accounting for the high incidence of levodopa-associated adverse
effects.
Uses
Levodopa, alone or in combination with a dopa decarboxylase inhibitor, is
the most useful drug for the treatment of Parkinsons disease. Although treatment may be started with an anticholinergic or amantadine, the disease usually progresses to the point where levodopa is required within one year.
The combination of levodopa and an anticholinergic may benefit
patients who are not adequately treated by either drug alone.
Levodopa is contraindicated in patients with parkinsonism secondary
to the use of antipsychotic drugs because it will reverse the therapeutic
benefits provided by phenothiazines and butyrophenones (see Chapter 20).
Levodopa
Levodopa +
Decarboxylase
Inhibitor
Brain
Brain
Heart
Heart
Kidneys
Kidneys
Liver
Liver
Stomach
Stomach
Levodopa
Levodopa
Dopamine
Dopamine
Figure 243 Diagrammatic representation of the peripheral decarboxylation of levodopa to

dopamine (A) and the inhibition of this by the administration of a decarboxylase inhibitor (B).
The concurrent administration of levodopa and a decarboxylase inhibitor decreases the amount
of levodopa required to elicit a therapeutic response in parkinsonism. (After Selby G. Treatment
of parkinsonism. Drugs 1976; 11:65.)
Chapter 24
207
Adverse Effects
Levodopa can produce anorexia, nausea, vomiting, or epigastric pain. It
may also produce mild postural hypotension and cardiac arrhythmias.
Abnormal involuntary movements (faciolingual tics, grimacing, head bobbing, and various rocking and rotating movements of the arms, legs, or
trunk) may also occur. Given to parkinsonian patients with impaired
memory or dementia, levodopa can stimulate the CNS, resulting in hallucinations, paranoia, mania, insomnia, and nightmares. It can also cause
depression. Levodopa can also stimulate the sexual interests of elderly
patients.
B. Levodopa plus a Dopa Decarboxylase Inhibitor (Carbidopa or

Benserazide)
Carbidopa and benserazide inhibit dopa decarboxylase. Because they do not
cross the blood-brain barrier, these drugs reduce only the peripheral metabolism of levodopa to DA (see Figure 243). The formation of dopamine in
the brain is not affected and a higher percentage of the administered levodopa is converted to DA in the brain. By using carbidopa or benserazide,
it is possible to administer lower doses of levodopa, thereby reducing its
peripheral adverse effects.
Products containing levodopa plus carbidopa and levodopa plus benserazide have replaced levodopa alone as the most useful treatment for parkinsonism. Because these products contain lower doses of levodopa, the incidence and severity of levodopa-induced adverse effects are reduced.
C. Levodopa/Dopa Decarboxylase Inhibitor, plus a Catechol-OMethyltransferase Inhibitor (Entacapone)

Actions
Entacapone is a reversible, specific, and mainly peripherally acting inhibitor
of catechol-O-methyltransferase (COMT) (see Chapter 3). COMT is
responsible for the O-methylation of levodopa. In the presence of a dopa
decarboxylase inhibitor, COMT becomes the major enzyme responsible for
the peripheral metabolism of levodopa, converting it to the inactive 3methoxy-4-hydroxy-l-phenylalanine (3-OMD). When administered with
levodopa and a dopa decarboxylase inhibitor, entacapone further decreases
the degradation of levodopa in the peripheral tissues. The ensuing sustained
208
PDQ PHARMACOLOGY
plasma levels of levodopa result in more constant dopaminergic stimulation

in the brain, further reducing the signs and symptoms of Parkinsons disease.
Uses
Entacapone is used as an adjunct to a levodopa/dopa decarboxylase inhibitor
for the treatment of the signs and symptoms of Parkinsons disease.
Adverse Effects
The most common adverse reaction to entacapone is diarrhea. Other
adverse effects include dyskinesia, abdominal pain, and nausea.
D. Direct Dopamine Agonist (Bromocriptine)

Actions and Uses
Bromocriptine directly stimulates brain dopamine D2-receptors. It is clinically useful as an adjunct to levodopa plus a dopa decarboxylase inhibitor
in the symptomatic management of selected patients with Parkinsons disease who experience dyskinesia or wearing-off reactions on long-term
levodopa therapy.
Adverse Effects
Bromocriptines adverse effects include nausea, vomiting, transient dizziness, abdominal pain, constipation, and blurred vision, with or without
diplopia. Digital vasospasm in response to cold, erythromelalgia, mental
disturbances, and dyskinesias may also be experienced. In higher doses,
bromocriptine can produce mental disturbance, including nightmares,
mild agitation, hallucinations, and paranoid delusions. These are more
common in the elderly.
E. Selective Monoamine Oxidase Type B (MAO-B) Inhibitor (Selegiline)

Actions
Selegiline may act by inhibiting MAO-B in the brain to reduce dopamine
metabolism and increase the amount of DA available to stimulate brain receptors. Selegiline may also block DA neuronal uptake and this effect would also
increase the amount of dopamine available to stimulate receptors.
Uses
Selegiline may be of value as an adjunct to levodopa (with or without a dopa
decarboxylase inhibitor) in the management of the signs and symptoms of
Parkinsons disease.
Chapter 24
209
Adverse Effects
The adverse effects of recommended doses of selegiline are those usually
associated with an excess of DA (see levodopa above). Hallucinations and
confusion have been seen with the combined use of selegiline and levodopa/carbidopa. Other adverse effects include nausea, depression, loss of
balance, insomnia, orthostatic hypotension, increased akinetic involuntary
movements, arrhythmia, bradykinesia, involuntary movements, chorea,
delusions, hypertension, angina, and syncope.
F. Dopamine-Releasing Drug (Amantadine)

Actions
Amantadine releases DA from the remaining intact dopaminergic nerves in
the basal ganglia. Although less effective than levodopa, amantadine produces a more rapid response and fewer adverse effects.
Uses
Amantadine is indicated for the treatment of Parkinsons syndrome. Unfortunately, the initial clinical improvements may not be sustained. Performance
deteriorates over 3 to 6 months. Therefore, amantadine is used most often
in combination with levodopa as it often improves the effects of the latter.
Amantadine is also used in the short-term management of druginduced extrapyramidal symptoms.
Adverse Effects
The more important adverse effects with amantadine are orthostatic
hypotensive episodes, congestive heart failure, depression, psychosis, and
urinary retention.
2. Central Anticholinergic Drugs (see Chapter 5)

(Trihexyphenidyl HCl, Benztropine Mesylate, Procyclidine
HCl, Biperiden HCl)
Actions and Uses
These drugs block central cholinergic receptors and reduce excessive cholinergic stimulation in basal ganglia. Classic anticholinergics, such as
atropine and hyoscine, also block cholinergic receptors in the brain. However, their profound peripheral adverse effects prevent them from being
used to treat parkinsonism. In contrast, the centrally acting anticholinergics have reduced peripheral effects, and accordingly decreased adverse
effects. Central anticholinergic drugs are used in patients at the early stage
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PDQ PHARMACOLOGY
of disease, for those with minor symptoms and in individuals who cannot
tolerate levodopa. They are also used in combination with levodopa. Central anticholinergics are also used to reduce drug-induced parkinsonism
(see Chapter 20).
Adverse Effects
The adverse effects of these drugs can mainly be attributed to a reduction
in peripheral cholinergic stimulation (see Chapter 5). Although more selective than atropine, these drugs can still produce cycloplegia, urinary retention, and constipation. Because of their mydriatic effects, they can precipitate an attack of acute-angle glaucoma in patients predisposed to angle
closure. The decrease in salivation that accompanies their use benefits the
patient who experiences sialorrhea. Confusion and excitement can occur
with large doses or in susceptible patients, such as elderly patients with
existing mental disorders and those taking other drugs with anticholinergic properties. Care must be taken in using anticholinergic drugs in patients
over the age of 70 or any individual with dementia.
Part 8
Drugs to Alleviate
Pain
25
Analgesics
NARCOTIC ANALGESICS (OPIOIDS)
General Properties of Narcotic Analgesics
Narcotic Receptors and the Mechanism of Action of Narcotic Analgesics
Opioids exert their analgesic activity by stimulating endogenous opioid
receptors. An excellent correlation exists between the in vivo potencies of
opioids and their in vitro affinities for opioid receptor binding sites. The
three major classes of opioid receptors in the CNS are:
1. (mu). Morphine, its congeners, and endogenous opioid peptides
produce supraspinal analgesia and euphoria by acting at 1-receptors,
which are localized at the anatomic sites important for pain. The
2-receptors, appear to be involved in the production of respiratory
depression and constipation. Narcotics also produce analgesia after
intrathecal or epidural administration. This analgesia is mediated by an
action at spinal -receptors.
2. (kappa) and (delta). The analgesic effects of both endogenous and
synthetic peptides are mediated by these receptors. In addition, opioid
agonist-antagonist analgesics, such as pentazocine, nalbuphine, and
butorphanol, relieve pain and cause sedation by acting on -receptors.
The dysphoric and psychotomimetic-like side effects observed after
higher doses of these drugs are produced by an action at -receptors.
Effects Common to Narcotic Analgesics
Most narcotic analgesics share common pharmacologic properties. These
are:
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PDQ PHARMACOLOGY
Euphoria must not be minimized because the analgesia produced by

narcotics depends to a great extent on the ability of narcotics to induce
a sense of well-being.
Drowsiness is a characteristic feature of stronger narcotics and plays a
role in their analgesic effects.
Respiratory depression occurs with even small doses, because narcotics
reduce the sensitivity of the brain stem respiratory centers to increases
in carbon dioxide (CO2) tension.
Nausea and vomiting may occur because narcotics stimulate the
chemoreceptor trigger zone in the medulla of the brain.
Miosis results from a stimulation of the autonomic segment of the
nucleus of the oculomotor nerve.
Constipation occurs with most narcotics. This is due to
1. a delayed emptying of the stomach as a result of constriction of the
pyloric sphincter and increased tone of the antral portion of the
stomach and duodenum;
2. a decrease in the propulsive contractions of the small intestine,
together with an increase in nonpropulsive contractions and an
increase in the tone of the colon; and
3. an increase in the tone of the anal sphincter.
Increased biliary tract pressure occurs with most narcotics. The symptoms range from epigastric distress to typical biliary colic.
Physiologic and psychological dependence develop during chronic
administration. If a dependent subject is suddenly deprived of a narcotic, physical withdrawal occurs quickly. The signs of physical withdrawal include autonomic hyperactivity, such as diarrhea, vomiting,
lacrimation, rhinorrhea, chills, and fever. Individuals may also suffer
from abdominal cramps, pain, and tremors. Psychological dependence
is evident when an individual who has been weaned off a narcotic still
feels a compulsion to take the drug.
Tolerance occurs to the analgesic, euphoric, and respiratory-depressant
effects of narcotics. If a narcotic is used daily over a prolonged period of
time, larger and larger doses must be given to maintain the same degree
of analgesia. Once a patient develops tolerance to one narcotic, he or she
will show tolerance to all other narcotics (cross-tolerance).
Pharmacokinetics
Narcotics are usually well absorbed from the GI tract, but they are often
extensively inactivated during their first pass through the liver (first-pass
effect). As a result, the oral dose of a narcotic is usually larger than the parenteral dose. Most narcotics are effective for 3 to 5 hours.
Chapter 25
Analgesics
213
Uses
The uses of narcotics include the treatment of:
severe pain, resulting from trauma, surgery, obstetrics, renal biliary

colic, and carcinoma;
dyspnea, produced by left-ventricular failure and pulmonary failure.
Because narcotics dilate veins, they reduce preload on the heart, thereby
decreasing dyspnea;
diarrhea. Loperamide is the preferred narcotic because it is very poorly
absorbed; and
cough. Narcotics depress the cough center in the medulla of the brain.
Codeine and hydrocodone are most frequently used.
Adverse Effects
The major adverse effects of narcotic analgesics are respiratory depression,
dependence, constipation, nausea, and vomiting. Because narcotics cause
hypoventilation and hypercapnia, they dilate cerebral blood vessels and
increase intracranial pressure. As a result, narcotics must be used very cautiously, if at all, in patients with head injuries, delirium tremens, and conditions in which intracranial pressure is increased.
Narcotics can cause hypotension and shock and they should be given
in lower doses, if at all, to patients in shock or those with decreased blood
volume.
The spasmogenic effect of narcotics on the urinary bladder can lead to
urinary retention in patients with prostatic hypertrophy or urethral
stricture.
Agonist-Antagonist Narcotic Analgesics

Actions, Uses, and Adverse Effects
Pentazocine, nalbuphine, and butorphanol are called agonist-antagonist
narcotics. In the presence of a narcotic agonist, they block many of the
actions of the narcotic. In the absence of a narcotic agonist, the agonistantagonist drugs produce analgesia. This action can be explained by the fact
that agonist-antagonist narcotics block -receptors, but stimulate -receptors.
These drugs are used to relieve pain in the same manner as the other narcotics. Because they block -receptors, agonist-antagonist narcotics must
not be administered to patients currently receiving an agonist narcotic.
These drugs have the same general adverse effects as narcotics. Particular
attention should be paid to the psychotomimetic effects of large doses of
pentazocine. See Table 251.
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PDQ PHARMACOLOGY
Table 251
Examples of Narcotic and Agonist-Antagonist Narcotic Drugs

Drug
Comments
Agonist Narcotics
Morphine
Prototype of strong analgesics. Relieves severe pain.

Given orally or parenterally
Oxymorphone
Administered by IV or rectally for moderate to severe

pain
Codeine
Used orally for mild to moderate pain, often with

non-narcotic analgesics
Oxycodone
Used with non-narcotic analgesics for moderate to

severe pain
Levorphanol
Used orally or parenterally for severe pain.
Meperidine
Used orally or parenterally for moderate to severe

pain
Propoxyphene
Used orally, often with non-narcotic analgesics, for

mild to moderate pain
Fentanyl, Sufentanil,
Alfentanil, and
Remifentanil
Administered by IV, for pain relief during surgery
Agonist-Antagonist Narcotics
Pentazocine
Given orally or parenterally for moderate pain
Butorphanol
Given parenterally for moderate to severe pain
Nalbuphine
Given parenterally for moderate to severe pain
IV = intravenous
NARCOTIC ANTAGONISTS (NALOXONE)

Actions, Uses and Adverse Effects
Narcotic antagonists, such as naloxone, competitively block opiate receptors. They produce few effects in patients who have not been treated with
an opioid, however, in patients previously treated with a narcotic, naxolone
reverses the effects of the narcotic. Narcotic antagonists are used to treat
narcotic overdoses or reverse the effects of a narcotic given during surgery.
Abrupt withdrawal of narcotic depression may result in nausea, vomiting,
sweating, tachycardia, increased BP, and tremors.
Chapter 25
Analgesics
215
NON-NARCOTIC ANALGESICS (ANALGESIC-ANTIPYRETICS)

1. Acetylsalicylic Acid (ASA) (Aspirin)
Actions (for the Antiplatelet and Antiarthritic Actions of ASA, Refer to
Chapters 15 and 26)
Analgesia Aspirin works both peripherally and within the brain to produce
analgesia. Peripherally, aspirin inhibits cyclooxygenase to reduce the formation of prostaglandin E2 (PGE2) in various organs and tissues (Figure
251). PGE2 sensitizes pain receptors to noxious substances, such as histamine and bradykinin. By reducing the synthesis of PGE2, aspirin diminishes
pain. Centrally, the drug acts in the hypothalamus to reduce pain perception. Since aspirin does not affect the cortex of the brain, analgesic doses do
not cause mental disturbance or drowsiness.
Antipyresis Therapeutic doses of aspirin lower elevated body temperatures. Toxic doses increase temperature. The antipyretic effects are due to
Figure 251 Inhibition of prostaglandin synthesis by aspirin. PG = prostaglandin; HETE =

hydroxyeicosatetaraenoic acid (After Mazel P. Analgesics-antipyretics. In: Pradhan SN, Maickel
RP, Dutta SN, ed. Pharmacology in Medicine. Bethesda, MD: SP Press International, 1986:224.)
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PDQ PHARMACOLOGY
aspirins action on the hypothalamus in the brain. In normal individuals,

the hypothalamus maintains body temperature within narrow limits by balancing heat production with heat loss. Aspirin lowers elevated temperature
by several means. In a person with a fever, aspirin dilates small blood vessels in the skin, thereby increasing heat loss by sweating. It also prevents the
temperature-elevating effects of leukocytic pyrogens, possibly by competing with pyrogens for receptor sites in the thermoregulatory centers of the
hypothalamus. Fever typically occurs from a disease state that increases
cytokine production. Cytokines, such interleukin-1 (IL-1) and tumor
necrosis factor, stimulate the synthesis of PGE2, which in turn increases
body temperature. Because aspirin inhibits cyclooxygenase, it may owe
some of the antipyretic effects to the resulting decrease in PGE2 synthesis.
Pharmacokinetics
Aspirin can be absorbed from the stomach, but its absorption proceeds faster
from the duodenum. Shortly after its absorption, aspirin is metabolized to
salicylic acid. Salicylic acid is then metabolized mainly in the liver to salicylic
acyl glucuronide, salicylic phenol glucuronide, salicyluric acid, and gentisic
acid (Figure 252). Salicyluric acid, a glycine conjugate, accounts for 75% of
the metabolites. The capacity of the liver to furnish enough glycine to inactivate salicylate is limited. If the daily dose of aspirin exceeds the capacity of
the liver to provide glycine, serum salicylate levels rise sharply and the
patient may become toxic. About 10% of the salicylate in the body is eliminated unchanged by the kidney. If the urine is alkalinized, this can be
increased 3- to 5-fold.
Uses
Aspirin is an effective analgesic and antipyretic for the relief of mild to moderate pain. Aspirin is more effective in the relief of skeletal muscle pain than
visceral pain and is often given to patients with headaches, neuralgias, myalgias, or primary spasmodic dysmenorrhea.
Because of concern over a possible correlation between the use of ASA
as an antipyretic in children with varicella or influenza virus infection and
the development of Reyes syndrome authorities advise that ASA not be
used in children, teenagers, or young adults with varicella or influenza.
Adverse Effects
Gastric irritation, ranging from discomfort to gastric ulceration and hemorrhage, is a common adverse effect of aspirin due to
its direct irritant effects on the gastric mucosa, and
Chapter 25
Analgesics
217
Figure 252 Metabolism of acetylsalicylic acid. * = 2 processes which proceed by easily saturable Michaelis-Menten kinetics. ASA acetylsalicylic acid, SA salicylic acid, GA gentisic acid, SAG salicylic acyl glucuronide, SPG salicylic phenol glucuronide, SU salicyluric
acid. (After Thiessen JJ. Pharmacokinetics of salicylates. In: Barnett HJM, Hirsch J, Mustard
JF, eds. Acetylsalicylic acid, new uses for an old drug. New York: Raven Press, 1982:53.)
its ability to inhibit prostaglandin formation. PGE2 promotes the secretion of protective gastric mucus. When its formation is blocked by ASA,
the secretion of mucous in the stomach falls and gastric damage occurs.
Enteric-coated tablets prevent the direct irritant effect of aspirin on the

gastric mucosa. However, enteric coating has no effect on the ability of
aspirin, delivered back to the stomach in the circulation, to inhibit cyclooxygenase and inhibit the formation of prostaglandins.
Hypoprothrombinemia can be produced by large doses of aspirin
because salicylate is a vitamin K antagonist. This effect is usually only significant in patients taking oral anticoagulants or suffering from liver disease.
Serious allergic reactions, including asthmatic attacks, can occur from
ASA use. Patients allergic to aspirin should not be given any nonsteroidal
anti-inflammatory drug (NSAID).
Large doses of aspirin can be very toxic. Beginning with tinnitus and
decreased hearing, the symptoms of acute poisoning can proceed to respiratory alkalosis. In response to the increased loss of CO2, renal excretion of
bicarbonate rises and systemic pH returns to normal, but at the cost of a
reduced bicarbonate reserve. If sufficient ASA is consumed, metabolic rate
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PDQ PHARMACOLOGY
increases and metabolic acidosis ensues. The final stage in salicylate intoxication is respiratory depression and death.
2. Other Cyclooxygenase Inhibitors

Diflunisal
Diflunisal is an orally effective nonsteroidal, analgesic, anti-inflammatory,
antipyretic drug that appears to act peripherally by inhibiting prostaglandin
synthesis. Diflunisal is indicated for the relief of mild to moderate pain
accompanied by inflammation. It is also used in the symptomatic relief of
osteoarthritis.
Ketorolac
Ketorolac is considered a nonsteroidal, anti-inflammatory, analgesic drug
that acts by reducing peripheral prostaglandin synthesis. Ketorolac is
administered orally or IM. At analgesic doses, it has minimal anti-inflammatory and antipyretic activity. Ketorolac is used to relieve pain. Its adverse
effects are similar to those of the other NSAIDs (see Chapter 26) and include
dyspepsia and GI pain.
Nonsteroidal Anti-inflammatory Drugs (see Chapter 26)
Like aspirin, NSAIDs inhibit the formation of the various prostaglandins.
As a result, NSAIDs can be used as analgesic-antipyretics. Drugs such as
ibuprofen, naproxen sodium, and fenoprofen are sold as analgesics. They are
effective in mild to moderate pain. Their pharmacology and adverse effects
are presented in Chapter 26.
3. Acetaminophen, Paracetamol
Actions
Acetaminophen is an analgesic and antipyretic. It does not have the antiinflammatory effects of aspirin. Acetaminophen does not affect platelet
aggregation or irritate the stomach.
Uses
Acetaminophen is indicated for the treatment of mild to moderate pain and
for the reduction of fever. The major use for the drug is as an analgesicantipyretic in patients who cannot tolerate aspirin (eg, patients who suffer
GI discomfort or are allergic to ASA). Acetaminophen should also be used
in place of aspirin in patients taking oral anticoagulants.
The drug is also valuable in relieving the pain of osteoarthritis.
Chapter 25
Analgesics
219
The connection between the use of ASA in children with varicella or

influenza virus infection and the development of Reyes syndrome has led
to the recommendation that acetaminophen, rather than ASA, be used in
these conditions.
Adverse Effects
Taken in recommended doses, acetaminophen is well tolerated. Hepatic
necrosis can occur if overdoses are taken. This toxicity results from a
change in the normal pathway of acetaminophen metabolism, which occurs
with high doses of the drug. Approximately 25% percent of the absorbed
dose of acetaminophen undergoes first-pass metabolism. The major
metabolites are sulfate and glucuronide conjugates (Figure 253). If large
doses (10 to 15 g) are taken, the capacity of the liver to form sulfate and glucuronide conjugates is exceeded. When this happens, acetaminophen
undergoes N-hydroxylation to form N-acetyl-benzoquinoneimine, a highly
reactive intermediate. This metabolite reacts with sulfhydryl groups in
proteins and glutathione. When hepatic glutathione is depleted by very large
doses of acetaminophen, reaction of this metabolite with hepatic proteins
is increased and liver necrosis occurs.
Figure 253 Pathways of acetaminophen metabolism. (After Mitchell JR, et al. Acetaminophen-induced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharm Therap 1974; 16:676684.)
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PDQ PHARMACOLOGY
Treatment of acetaminophen overdosage includes

1. gavaging the patient or inducing vomiting, and
2. administering N-acetylcysteine. This compound appears to protect the
liver by replenishing the stores of glutathione.
26
Antiarthritic and Antigout
Drugs
ANTIARTHRITIC DRUGS
1. First-Line Drugs
A. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Acetylsalicylic
Acid (ASA) (Aspirin), Diclofenac, Fenoprofen, Flurbiprofen,
Ibuprofen, Indomethacin, Ketoprofen, Naproxen, Piroxicam,
Sulindac, Tiaprofenic Acid, Tolmetin
Actions (see Figure 251)
NSAIDs inhibit cyclooxygenase, thereby reducing prostaglandin synthesis.
Specifically, they reduce the synthesis of prostaglandins PGE2 and PGF2.
These chemicals increase the activities of two endogenous mediators of
inflammation, histamine and bradykinin. In the face of reduced levels of
PGE2 and PGF2, the ability of histamine and bradykinin to dilate blood vessels, increase vascular permeability, and produce pain is reduced. Other
effects of NSAIDs that depend on their ability to inhibit prostaglandin formation include:
Analgesia PGE2 and PGF2 sensitize nerve endings to pain.

Antipyresis NSAIDs lower elevated body temperatures by dilating
the small vessels in the skin of the patient with a fever and increasing
heat loss. NSAIDs may also reduce heat production by reducing
prostaglandin formation in the hypothalamus. Prostaglandins are necessary for pyrogen-induced fever.
Gastric irritation NSAIDs irritate the stomach directly. They can
also damage the stomach after they are absorbed, due to an inhibition
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PDQ PHARMACOLOGY
of PGE2 and PGI2 synthesis in the gastric mucosa. PGE2 and PGI2
inhibit gastric acid secretion and promote the secretion of cytoprotective mucus in the intestine. By blocking the production of PGE2 and
PGI2, NSAIDs predispose the stomach to ulceration.
Reduce platelet aggregation Some NSAIDs inhibit platelet aggregation (see Chapter 15).
Decreased renal function PGE2 increases the renal excretion of
sodium, chloride, and water. Inhibition of its formation results in salt
and water reabsorption. Renal prostaglandins reduce the vasoconstriction produced by norepinephrine and angiotensin II. In patients
with reduced renal function, prostaglandins are important in maintaining renal flow. In these patients, NSAIDs can significantly reduce
renal function.
Uses
NSAIDs are used to provide relief from the symptoms of rheumatoid
arthritis, osteoarthritis, spondylitis, bursitis, and other forms of rheumatism
and musculoskeletal disorders.
NSAIDs are also used as analgesics (see Chapter 25).
Adverse Effects
NSAIDs can produce nausea, vomiting, diarrhea, gastritis, GI bleeding
and/or ulceration, tinnitus, vertigo, hearing loss, leukopenia, thrombocytopenia, purpura, urticaria, and angioedema.
They can also cause pruritus and skin eruptions, asthma, anaphylaxis,
reversible hepatotoxicity, mental confusion, drowsiness, sweating, and thirst.
B. Cyclooxygenase-2 (COX-2) Inhibitors (Celecoxib and Rofecoxib)

Two forms of cyclooxygenase exist (COX-1 and COX-2). COX-1 is constitutively expressed and enzymatically active in various tissues, including the
stomach, intestines, kidneys, and also in platelets. COX-1 is responsible for
prostaglandin-mediated normal physiologic functions such as cytoprotection and platelet aggregation, and is involved in renal function. Inhibition
of COX-1 has been associated with gastric damage and renal toxicity.
COX-2 is the inducible isoform of the enzyme that has been shown to be
up-regulated by proinflammatory stimuli. COX-2 has been postulated to be
primarily responsible for the synthesis of the prostanoid mediators of pain,
inflammation, and fever.
Chapter 26
Antiarthritic and Antigout Drugs
223
NSAIDs inhibit both COX-1 and COX-2. Therapeutic concentrations

of COX-2 inhibitors (celecoxib and rofecoxib) do not significantly inhibit
COX-1. These drugs produce their anti-inflammatory effects by inhibiting
COX-2, but because they do not significantly inhibit COX-1, they do not
produce the frequently severe gastric damage produced by NSAIDs.
2. Second-Line Drugs
A. Antimalarial Drugs (Chloroquine and Hydroxychloroquine)
Although their mechanism of action is not understood, both chloroquine
phosphate and hydroxychloroquine sulfate are used for rheumatoid arthritis, juvenile arthritis, and for the arthritic and skin manifestations of systemic lupus erythematosus.
The most common adverse effect is eye damage. This may involve
(1) corneal infiltration, which is reversible on stopping the drug, or
(2) retinopathy, which can lead to irreversible visual loss.
These drugs may also cause gastric intolerance.
B. Gold Compounds (Aurothioglucose and Gold Sodium Thiomalate

Administered Parenterally) (Auranofin Administered Orally)
Golds mechanism of action is not known. Gold has a delayed onset of
action. Treatment must be continued for at least a few months. These
drugs are useful and may even alter the course of arthritis in patients with
adult or juvenile rheumatoid arthritis, or psoriatic arthritis.
Gold compounds may produce rash, mucous membrane lesions, serious hematologic complications, and proteinuria. Auranofin can also cause
GI disturbances.
C. Penicillamine
Actions, Uses and Adverse Effects
Penicillamine may have an immunosuppressive action on T cells. It is as
effective as gold or azathioprine in treating rheumatoid arthritis but of little value in ankylosing spondylitis or psoriatic arthritis. Skin rashes and GI
disturbances are the most common adverse effects, but renal damage or
bone marrow depression are the major reasons for stopping the drug.
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PDQ PHARMACOLOGY
D. Azathioprine
Azathioprine is an immunosuppressant that should be used only in severe,
active, progressive rheumatoid arthritis that has failed to respond to conventional treatment. It should be given with NSAIDs; however, gold, antimalarials, and penicillamine should be stopped.
Azathioprine can cause nausea and vomiting, leukopenia, thrombocytopenia, and anemia. Complete blood counts, including platelet counts,
should be performed periodically.
E. Methotrexate
Methotrexate is a competitive inhibitor of folic acid reductase, but its
mechanism of action in rheumatoid arthritis is unknown. Usually, the
effects of methotrexate on articular swelling and tenderness in rheumatoid
arthritis can be seen as early as 3 to 6 weeks. It is indicated in the management of selected adults with severe, active, or definite rheumatoid arthritis
who have an insufficient response to, or were intolerant of, an adequate
trial of first-line therapy and usually a trial of a least one or more diseasemodifying antirheumatic drugs as well.
The most common adverse effects include nausea, stomatitis, GI discomfort, diarrhea, vomiting, and anorexia. Laboratory findings include elevation of liver enzymes and, occasionally, decreased WBC.
F. Adrenal Corticosteroids
Uses (see Chapter 18 for Actions and Adverse Effects)
Corticosteroids may be administered systemically when more conservative
measures fail or during the hiatus between the initiation of second-line
therapy and its onset of action in a patient whose condition cannot be controlled by rest, physical measures, analgesics, and NSAIDs.
Intra-articular therapy may be indicated for
1. the patient with otherwise well-controlled arthritis in whom a single
joint is particularly resistant,
2. the individual in whom one or two particularly active joints flare and
impede ambulation or physiotherapy, or
3. the patient with one active joint, in whom NSAIDs are contraindicated.
Chapter 26
225
G. Infliximab
Actions
Although the precise pathophysiology of rheumatoid arthritis (RA) remains
to be elucidated, it is believed to involve a T-cell-mediated immune response
that results in the release of the cytokines interleukin-1 (IL-1) and tumor
necrosis factor alpha (TNF). Infliximab is a recombinant chimeric humanmurine IgG monoclonal antibody that neutralizes TNF in the joints of RA
patients by binding specifically to both soluble and transmembrane TNF.
Uses
When added to methotrexate therapy, infliximab reduces the signs and
symptoms of moderate to severe rheumatoid arthritis. Infliximab appears
to be the only therapy, to date, that is effective in arresting and potentially
reversing the structural damage seen in severe RA patients.
Adverse Effects
From information to date, infliximab appears to be a safe medication. The
adverse effect profile is similar to that of placebo.
ANTIGOUT DRUGS
Etiology of Gout
Gout is a disorder of uric acid metabolism. The normal range for serum urate
concentrations is 3 to 8 mg/100 mL (190490 mmol/L). People with serum
urate concentrations in this range have little risk of gout. Individuals at high
risk have serum urate levels of 10 to 11 mg/100mL (610675 mmol/L). These
concentrations exceed the capacity of the blood fluids to hold urate in
solution, and, therefore, sodium urate crystals may deposit in a joint. When
neutrophils attempt to phagocytose the crystals, inflammation ensues and
the patient experiences gout (Figure 261).
Mechanism of Action of Antigout Drugs
Antigout drugs can act
(1) in the joint to reduce inflammation,
(2) in the tissues to decrease the production of uric acid, or
(3) in the kidneys to increase uric acid excretion.
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PDQ PHARMACOLOGY
Figure 261 Role of monosodium urate crystals and neutrophils in gout. (After Ryan GB, Majno
G. Inflammation. Kalamazoo, MI: Scope Productions. The Upjohn Co. 1974: 54.)
1. Drugs that Act in the Joint

A. Colchicine
Actions
Colchicine concentrates in neutrophils and decreases the release of chemotactic factors from the neutrophils, with the result that fewer neutrophils are
subsequently attracted to the affected joint.
Uses
Colchicine is effective in relieving the pain of acute attacks of gout, especially if therapy is begun early in the attack.
During the initial treatment with allopurinol or uricosurics, patients
often experience more attacks. Colchicine can be given at this time to reduce
the number of attacks.
Adverse Effects
Diarrhea, nausea, vomiting, and abdominal pain often occur. Large doses
can cause a burning sensation in the throat, bloody diarrhea, hematuria,
oliguria, CNS depression, and death.
B. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

The actions and adverse effects of these drugs have been presented earlier
in this chapter. NSAIDs have largely replaced colchicine for acute attacks
because of colchicines invariable tendency to produce GI upset. To be effective for gout, optimal doses of NSAIDs should be used promptly.
Chapter 26
227
2. Drugs that Reduce Uric Acid Synthesis

Allopurinol
Actions and Uses
Allopurinol and its major metabolite, oxypurinol, inhibit xanthine oxidase,
the enzyme response for the synthesis of uric acid. Both plasma and urine
uric acid levels fall within a few days to two weeks of starting treatment.
Allopurinol is used to treat chronic tophaceous gout.
Adverse Effects
Skin rashes, GI upset, hepatotoxicity, and fever are the most common
adverse effects of allopurinol.
Attacks of acute gout may occur more frequently during the first
months of treatment with allopurinol.
3. Drugs that Increase Renal Excretion of Uric Acid

(Uricosurics)
Probenecid
Actions
Uric acid undergoes filtration, reabsorption, and secretion in the nephron
as outlined below:
1. First, uric acid is filtered through the renal glomeruli.
2. Second, some of the filtered uric acid is reabsorbed back into the blood
from the proximal convoluted tubules.
3. Finally, uric acid is secreted from the blood into the renal tubules.
The amount of uric acid cleared in the urine is the result of:
filtration + secretion reabsorption
Probenecid decreases uric acid reabsorption. The resulting increase in
uric acid excretion reduces its plasma level. However, even high doses of
probenecid fail to prevent more than 50% of the filtered uric acid from
being reabsorbed.
Uses
Probenecid is used to treat hyperuricemia in all stages of gout and gouty
arthritis, except in an acute-presenting attack.
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PDQ PHARMACOLOGY
Adverse Effects
Probenecids adverse effects include headache, anorexia, nausea, vomiting,
urinary frequency, hypersensitivity reactions (dermatitis, pruritus, and
fever), sore gums, flushing dizziness, anemia, and anaphylactoid reactions.
Hemolytic anemia has been reported. This may be related to a genetic
glucose-6-phosphate dehydrogenase deficiency in red blood cells.
27
Antimigraine Drugs
M
igraine headaches are caused by dilation of the arteries of

the scalp, together with the release of 5-hydroxytryptamine (5-HT, serotonin), histamine, bradykinin, substance P, and prostaglandins that all sensitize pain receptors in the scalp vessel wall and adjoining tissue. Pulsation
in the scalp arteries, together with sensitization of pain receptors, leads to
the pain of migraine.
Rationale Behind Drug Therapy of Migraine Headaches
Drugs are used to:
1. prevent attacks (Note: The disparity in the mechanisms of action of
drugs used to prevent migraine headaches (see below) reflects our lack
of understanding of the multifactorial etiology of migraine headaches
and our willingness to try many types of drugs in an attempt to prevent
attacks.), and
2. terminate an attack, by producing analgesia or constricting the already
dilated vessels.
1. Drugs to Prevent Migraine Attacks

A. Beta Blockers (Propranolol)
Propranolol reduces the number of moderately severe migraine attacks in
more than 50% of cases. Propranolol is often ineffective in patients with
severe migraine. The adverse effects of propranolol were described in
Chapter 6.
229
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PDQ PHARMACOLOGY
B. Tricyclic Antidepressants (TCAs) (Amitriptyline)

TCAs (see Chapter 21) can prevent migraine in some patients and may be
given concurrently with other prophylactic agents. Their mechanism of
action in preventing migraine headaches is not clear. Amitriptyline has been
used most frequently. It appears to be an effective prophylactic in about 55
to 60% of migraine patients.
C. 5-Hydroxytryptamine (5-HT) Antagonists

1. Pizotyline
Pizotyline blocks 5-HT receptors but it is not clear whether this mechanism
explains the drugs ability to prevent migraine attacks. Approximately 33 to
66% of patients respond to the drug after 3 to 4 weeks of treatment. Its
adverse effects include CNS depression, increase in appetite, and weight
gain.
2. Methysergide
Methysergide is a 5-HT antagonist. It is not clear whether this action
explains, or is just coincidental to, its ability to prevent migraine attacks.
With a 70 to 80% success rate, methysergide is more effective than most
other drugs, but it is also more toxic. Its adverse effects have limited its use
to patients who do not respond to other drugs. Methysergide is indicated
in the prophylactic treatment of severe recurring vascular headaches that
occur at least once weekly, or in vascular headaches that are so severe or
uncontrollable that preventative therapy is indicated regardless of frequency. Methysergide has proven effective in reducing or eliminating the
pain and frequency of attacks of classic migraine, common migraine, and
cluster headache (histaminic cephalgia).
Adverse Effects
Methysergide may produce retroperitoneal fibrosis as well as fibrosis in the
pleura and heart valves. Because the risk of these adverse effects increases
with the length of treatment, methysergide should not be taken continuously for longer than 6 months. Other adverse effects include insomnia,
nausea, vomiting, heartburn, abdominal discomfort, and diarrhea.
Chapter 27
Antimigraine Drugs
231
D. Calcium Channel Blocker (Flunarizine)

Actions
Flunarizine is a calcium channel blocker that has no direct effects on the
heart. Migraine pathogenesis likely involves an initial decrease in cerebral
blood flow, leading to ischemia and hypoxia. Hypoxia, in turn, causes an
excessive influx of calcium into cells resulting in cerebral cellular dysfunction. By blocking calcium entry channels, flunarizine
inhibits the contraction of vascular smooth muscle mediated by the

entry of extravascular calcium, and
protects endothelial cells against damage from calcium overload and
brain cells from hypoxia.
Uses
Flunarizine prevents migraine attacks at least as well as the other drugs discussed in this chapter. Flunarizine is most beneficial for reducing migraine frequency. It appears to have less effect on the severity and duration of attacks.
Adverse Effects
Flunarizine is usually well tolerated. Its adverse effects include depression,
drowsiness, weight gain, headache, insomnia, nausea, gastric pain, and dry
mouth.
E. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

The pharmacology of NSAIDs was presented in Chapter 26. These drugs are
effective in both preventing and terminating migraine attacks.
2. Drugs to Treat Migraine Attacks

A. Analgesics
Analgesics, such as aspirin with codeine, may relieve migraine pain. They
are best taken early in the attack before pain has had an opportunity to
become established. Narcotics stronger than codeine are not recommended
because of the danger of dependence. NSAIDs can be quite effective in the
treatment of migraine attacks. The pharmacology and adverse effects of
these drugs were presented in Chapters 25 and 26.
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PDQ PHARMACOLOGY
B. Ergotamine and Dihydroergotamine

Actions
Ergotamine and dihydroergotamine are vasoconstrictors that reduce
migraine-induced vasodilatation. They should not be used in patients with
pre-existing vascular disease, such as atherosclerosis, hypertension, Raynauds phenomenon, and Buergers disease because of the risk of ischemia.
Uses
Ergotamine and dihydroergotamine abort migraine attacks. They should be
taken as soon as the patient feels an attack starting.
Adverse Effects
The major adverse effects of these drugs are generalized vasoconstriction
and stimulation of the vomiting center in the brain. Patients may experience nausea and vomiting, weakness in the legs, muscle pains in the extremities, numbness and tingling of fingers and toes, precordial distress and pain,
and transient tachycardia or bradycardia.
C. 5-Hydroxytryptamine1-Like Receptor Agonist (Sumatriptan)

Actions
Sumatriptan is a selective 5-HT1-like receptor agonist. The activation of
5-HT1 receptors located on intracranial blood vessels leads to vasoconstriction, which is believed to be correlated with the relief of migraine headaches.
Uses
Sumatriptan is indicated for the relief of migraine attacks, with or without
aura. The drug is contraindicated in patients with ischemic heart disease,
angina pectoris, previous myocardial infarction, and uncontrolled hypertension. Sumatriptan is also contraindicated in patients taking ergotamine-containing preparations.
Adverse Effects
The most common adverse effect of subcutaneous sumatriptan is transient
pain at the site of injection. Other side effects of oral or subcutaneous sumatriptan include sensations of tingling, heat, heaviness, pressure or tightness
in any part of the body, chest symptoms, flushing, dizziness, and feelings of
weakness.
28
Beta-Lactam Antibiotics
PENICILLINS AND CEPHALOSPORINS
Actions (Figures 281 to 285)
Bacterial cells are encased by both cell membranes and cell walls. The cell
wall lies on the outside of the bacterium and is essential to the survival of
the microbe. Bacterial cytoplasm is hypertonic. Without a rigid cell wall, the
cell membrane cannot withstand the internal hypertonic media. If the cell
wall is damaged, the high pressure within the bacterium causes the membrane to first bulge and finally to rupture, killing the bacterium.
In forming a cell wall, adjacent peptidoglycan strands are cross-linked,
giving the wall its strength. The transpeptidation reaction responsible for
cross-linking involves cleavage of the terminal alanine from the pentapeptide attached to N-acetylglucosamine. A cross-link is formed between the
lysine of one peptide chain to the first of the two D-alanines on another
peptide chain.
Penicillins and cephalosporins are structurally similar to the terminal
D-alanyl-D-alanine portion and, therefore, can compete for, and bind to, the
enzyme that catalyzes transpeptidation and cross-linking. As the old walls
gradually deteriorate and are not replaced by new material, they become
thinner. Eventually, they are not strong enough to support the cell membranes, which then rupture, killing the bacteria.
THE PENICILLINS
Antibacterial Spectra
Tables 281 and 282 present the properties and antibacterial spectra of the
three groups of penicillins.
233
234
PDQ PHARMACOLOGY
Figure 281 Structures of representative penicillins.

A = beta-lactam ring
B = thiazolidine ring
1 = site of action of penicillinase (beta-lactamase).
Chapter 28
235
Figure 282 Structures of representative cephalosporins. IV = intravenous; IM = intramuscular.
Figure 283 The chemical details of the transpeptidation reaction. (After Richmond MH.
Beta-lactam antibiotics, the background to their use as therapeutic agents. Frankfurt: Hoechst
Aktiegesellschaft; 1981.)
236
PDQ PHARMACOLOGY
Figure 284 Inhibition of transpeptidation by penicillins. (After Richmond MH. Beta-lactam

antibiotics, the background to their use as therapeutic agents. Frankfurt: Hoechst Aktiegesellschaft; 1981.)
Figure 285 The consequences of the interruption of peptidoglycan synthesis, such as is

caused by penicillins and cephalosporins. (After Richmond MH. Beta-lactam antibiotics, the
background to their use as therapeutic agents. Frankfurt: Hoechst Aktiegesellschaft; 1981.)
Chapter 28
237
Table 281
Properties of Some Commonly Used Penicillins

Type of
Penicillin
Stability
in Acid
Spectrum
of Action
Sensitivity to
Penicillinase
Admin.
Routes
Narrow-spectrum penicillins
Penicillin G
(Benzylpenicillin)
Poor
Narrow
Sensitive
Oral and
parenteral
Penicillin V
(Phenoxymethyl
penicillin)
Good
Narrow
Sensitive
Oral
Penicillinase-resistant penicillins
Methicillin
Poor
Narrow
Resistant
Parenteral
Cloxacillin
Good
Narrow
Resistant
Oral and
parenteral
Dicloxacillin
Good
Narrow
Resistant
Oral and
parenteral
Flucloxacillin
Good
Narrow
Resistant
Oral
Expanded-Spectrum Penicillins
Ampicillin
Fair
Broad
Sensitive
Oral and
parenteral
Amoxicillin
Good
Broad
Sensitive
Oral
Ticarcillin
Poor
Broad
Sensitive
Parenteral
Piperacillin
Poor
Broad
Sensitive
Parenteral
1. Narrow-spectrum penicillins
2. Penicillinase-resistant penicillins
3. Expanded-spectrum penicillins
To understand the need for the different groups of penicillins, one must
understand the limitations of penicillin G. Penicillin G:
1. is not stable in an acid media and is poorly absorbed from the GI tract,
2. is inactivated by penicillinase-producing staphylococci, and
3. has a narrow spectrum of activity.
To varying degrees, the newer penicillins overcome some of these shortcomings of penicillin G (see below).
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PDQ PHARMACOLOGY
Table 282
Antibacterial Spectra of the Various Penicillin Groups

Narrow-Spectrum
Penicillins
Expanded-Spectrum
Penicillins
Penicillin G
Cloxacillin
Ampicillin
Penicillin V
Dicloxacillin
Amoxicillin
(Penicillinase- (Penicillinase- Bacampicillin
Sensitive
Resistant
Pivampicillin
Penicillins)
Penicillins)
Staphylococcus
aureus
(pen sensitive)
Staphylococcus
aureus
(pen resistant)
Streptococcus
pyogenes
Streptococcus
pneumoniae
Enterococcus spp.
Clostridium
perfringens
Neisseria
gonorrhoeae
Neisseria
meningitidis
Haemophilus
influenzae
Escherichia coli
Klebsiella spp.
Proteus spp.
(indole negative)
Proteus spp.
(indole positive)
Serratia spp.
Salmonella spp.
Shigella spp.
Pseudomonas
aeruginosa
Bacteroides
fragilis
Other Bacteroides
spp.
Chlamydiae spp.
Mycobacteria
pneumoniae
+ = sensitive;
= resistant;
= some strains resistant.
Azlocillin
Mezlocillin
Piperacillin
Ticarcillin
+
+
+
+
+
Chapter 28
239
Pharmacokinetics of the Penicillins (Figure 286)

Absorption Most penicillins are destroyed, at least in part, by stomach acid.
About two-thirds of an oral dose of penicillin G is destroyed by gastric acid,
with only approximately one-third being absorbed. Penicillin G should be
administered parenterally.
Parenterally, penicillin G is available in three forms, which differ in their
absorption characteristics.
Intramuscular (IM) penicillin G produces peak blood levels within 15

minutes.
IM procaine penicillin G produces peak blood levels in 2 to 3 hours,
with concentrations falling to 0 in 24 hours.
IM benzathine penicillin G produces very low penicillin blood levels for
3 to 4 weeks.
Distribution All penicillins are distributed widely throughout the

body. Their passage into joint, ocular, and cerebral spinal fluids (CSF) is
poor in the absence of inflammation. In patients with inflamed meninges,
however, they will enter the CSF.
Elimination All penicillins are rapidly excreted by renal tubular secretion, with renal clearance values of approximately 600 mL/min and halflives of about 1 hour. Probenecid will reduce the renal tubular secretion of
penicillins and prolong their half-lives.
Penicillin G
Penicillin G is preferred for infections caused by frequently encountered
gram-positive bacteria and susceptible gram-negative cocci, with the exception of staphylococci and, in some cases, enterococci. Penicillin G is the drug
of choice for infections caused by certain gram-negative bacilli (eg, Spirillum minus, Streptobacillus moniliformis, Leptotrichia bucccalis), actinomycetes, and spirochetes.
Procaine penicillin G and benzathine penicillin G are used to treat
infections, such as early syphilis, late latent syphilis, and endocarditis due
to penicillin-sensitive streptococci, where prolonged blood levels are needed
and frequent dosing of aqueous penicillin G is undesirable. Procaine penicillin G or benzathine penicillin G should not be given when sustained high
concentrations of penicillin G are needed. Aqueous penicillin G should be
used in this case.
Penicillin V
Penicillin V is more stable than penicillin G in the acid medium of the stomach. As a result, it provides higher blood levels following ingestion. Its
absorption is not affected by food. Penicillin V is preferred over penicillin G
when oral treatment is indicated.
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PDQ PHARMACOLOGY
Figure 286 Schematic representation of the blood concentration of various forms of penicillin G plotted as a function of time after oral or IM administration. After Pratt WB. Chemotherapy of infections. New York: Oxford Press; 1977.
Narrow-Spectrum, Penicillinase-Resistant Penicillins (Methicillin,

Cloxacillin, Dicloxacillin, Flucloxacillin)
Within 5 to 6 years of the introduction of penicillin G and V, most strains
of Staphylococcus aureus had developed resistance (Figure 287) because of
their ability to secrete enzymes called penicillinases. Penicillinases are a subgroup of enzymes called beta-lactamases, which rupture the beta-lactam
ring of pencillins, thereby inactivating them (Figure 288). Bacteria produce
a variety of beta-lactamases. Only those beta lactamases that act selectively
on penicillin are referred to as penicillinases.
Methicillin, cloxacillin, dicloxacillin, and flucloxacillin are usually resistant to penicillinase secreted by S. aureus. Although they are active against
many penicillin Gsensitive bacteria, the penicillinase-resistant drugs are not
as effective as penicillin G or V against these bacteria. They should be used
primarily to treat staphylococcal infections and are considered to have a narrow spectrum of use. Resistant strains of staphylococci have emerged to this
entire group of drugs. These bacteria are commonly referred to as methicillinresistant staphylococci because methicillin was the first drug in this group
to be marketed. It is important to understand that the expression methicillin-resistant staphylococci means resistance to all penicillinase-resistant
Chapter 28
241
Figure 287 Emergence of penicillin-resistant strains of Staphylococcus aureus following

the widespread introduction of benzylpenicillin (penicillin G) for therapy. (After Richmond MH.
Beta-lactam antibiotics, the background to their use as therapeutic agents. Frankfurt: Hoechst
Aktiegesellschaft; 1981.)
penicillins. This resistance appears to be due to the production of altered

penicillin-binding proteins (PBPs) to which the penicillinase-resistant
penicillins are unable to bind. When methicillin-resistant strains of Staphylococcus aureus or S. epidermidis are known or suspected to be present, vancomycin is the drug of choice.
Expanded-Spectrum Penicillins
1. Aminopenicillins (Ampicillin, Amoxicillin, Bacampicillin, Pivampicillin)
Narrow-spectrum penicillins lack effect against gram-negative bacteria
because they cannot cross the outer membrane that surrounds the cell walls
of these bacteria. As a result, they cannot reach PBPs on the inner cell membrane to prevent cell wall formation. Aminopenicillins pass through the
pores in the outer membrane and reach PBPs on the inner cytoplasmic
membrane. These drugs are not resistant to penicillinase secreted by
S. aureus. They also should not be used to treat penicillin Gsensitive bacteria. The major advantage of the aminopenicillins over penicillin G or V
is their activity against most strains of Escherichia coli, Haemophilus influenzae, Proteus mirabilis, Salmonella, and Shigella.
242
PDQ PHARMACOLOGY
Figure 288 Effect of beta-lactamases on the penicillin nucleus. (After Drugs that weaken
the bacterial cell wall. 1: Penicillins. In: Lehne RA, Moore LA, Crosby LJ, Hamilton DB, editors.
Pharmacology for nursing Care. 2nd ed. Philadelphia: WB Saunders; 1994: pg 929.)
Amoxicillin is preferred over ampicillin for oral administration, because

it is more completely absorbed and less likely to cause diarrhea. Bacampicillin and pivampicillin are inactive esters of ampicillin. Once absorbed, they
are converted to ampicillin in the body.
2. Antipseudomonal Penicillins (Azlocillin, Mezlocillin, Piperacillin,
Ticarcillin)
Antipseudomonal penicillins are effective in higher concentrations against
most strains of Pseudomonas aeruginosa and indole-negative Proteus
species. However, their spectrum of activity also covers many other bacteria (see Table 282). They are usually used with an aminoglycoside antibiotic, such as gentamicin, tobramycin, amikacin, or netilmicin to treat
infections caused by Pseudomonas and Proteus. The inhibition of cell wall
synthesis by the penicillin permits better penetration of the cell wall by the
Chapter 28
243
aminoglycoside and more effective inhibition of protein synthesis by the

aminoglycoside.
3. Amidino Penicillin (Amdinocillin)
Amdinocillin (mecillinam) is active primarily against gram-negative
organisms and relatively ineffective against gram-positive organisms.
Amdinocillin pivoxal (pivmecillinam) is a prodrug of amdinocillin that is
converted to the microbiologically active amdinocillin (mecillinam) during
GI absorption. Pivmecillinam is used to treat acute and chronic urinary
tract infections caused by sensitive strains of E. coli, Klebsiella, Enterobacter, and Proteus species.
4. Penicillins Combined with a Beta-lactamase Inhibitor
By combining a drug that inhibits bacterial beta-lactamases with a penicillinase-sensitive penicillin, it is possible to expand the antimicrobial spectrum of the penicillin. Amoxicillin has been combined with the beta-lactamase inhibitor clavulanic acid. By inhibiting the beta-lactamases secreted
by some microorganisms, clavulanic acid protects amoxicillin from hydrolysis and enables it to act against microorganisms that would normally be
resistant to the antibiotic. Thus, clavulanic acid increases the spectrum of
activity of amoxicillin to include beta-lactamase-producing Haemophilus
influenzae, H. ducreyi, Neisseria gonorrhoeae, Staphylococcus aureus, and
Branhamella catarrhalis. Concentrations in the urine will inhibit many
strains of Escherichia coli, Klebsiella, Proteus, and Citrobacter.
Ampicillin has been combined with sulbactam, another beta-lactamase
inhibitor. Piperacillin plus tazobactam, and ticarcillin plus clavulanic acid are
other combinations of a penicillin plus a beta-lactamase inhibitor. The
addition of tazobactam or clavulanic acid to the respective antipseudomonal
penicillin extends the spectrum of the penicillin to include staphylococci
and a wide variety of anaerobes and gram-negative bacteria.
Adverse Effects
Allergic reactions (Table 283) are the major concern with the penicillins.
These may occur in 1 to 5% of patients. Patients allergic to one penicillin
should be considered allergic to all penicillins.
Given orally, the penicillins may produce GI upset, nausea, vomiting,
and diarrhea. Ampicillin is particularly notorious for the burning diarrhea
it causes. Amoxicillin is better tolerated.
244
PDQ PHARMACOLOGY
Table 283
Allergic Reactions to Penicillins

Immediate allergic reactions
(occur 230 minutes after
administration)
Urticaria
Flushing
Diffuse pruritus
Hypotension or shock
Laryngeal edema
Wheezing
Accelerated urticarial reactions

(171 hours)
Urticaria or pruritus
Wheezing or laryngeal edema
Local inflammatory reactions
Late allergic reactions (> 72 hours)
Morbilliform eruptions (occasionally

occur as early as 18 hours after
initiation of treatment)
Urticarial eruption
Erythematous eruptions
Recurrent urticaria and arthralgia
Local inflammatory reactions
Some relatively unusual late

reactions
Immunohemolytic anemia
Drug fever
Acute renal insufficiency
Thrombocytopenia
THE CEPHALOSPORINS
Based on their antibacterial spectra, cephalosporins may be classified as
first-, second-, and third-generation (Table 284) cephalosporins. They may
also be divided into orally and parenterally administered cephalosporins.
Injectable Cephalosporins
First-generation injectable cephalosporins are active against most grampositive and many gram-negative organisms (Table 285).
Second-generation injectable cephalosporins differ little from firstgeneration drugs with respect to their activity against gram-positive bacteria. They do have, however, lower minimal inhibitory concentrations (MICs)
against many gram-negative bacteria. This can be attributed to their:
Chapter 28
245
Table 284
Some Currently Available Cephalosporins

First Generation
Second Generation
Third Generation
Cephalothin
Cefamandole
Cefoperazone
Cephapirin
Cefuroxime
Cefotaxime
Cefazolin
Cefoxitin
Ceftazidime
Cephalexin*
Cefaclor*
Ceftizoxime
Cephradine*
Cefonicid
Ceftriaxone
Cefadroxil
Ceforanide
Cefixime*
*Orally active drugs
increased affinity for the penicillin-binding proteins (PBPs) of gramnegative bacteria,

increased ability to penetrate the gram-negative cell envelope, and
increased resistance to beta-lactamases produced by gram-negative
organisms.
Third-generation injectable cephalosporins are usually less active than

first-generation drugs against staphylococci, but have increased potency and
a wider spectrum of activity against clinically important gram-negative
bacteria when compared with first- and second-generation cephalosporins.
They show excellent activity against many aerobic gram-negative bacilli,
including Haemophilus influenzae and most of the Enterobacteriaceae,
including strains resistant to earlier-generation cephalosporins, penicillins,
and aminoglycosides. This activity is due to excellent beta-lactamase stability and their high affinity for PBPs.
Oral Effectiveness
First-generation oral cephalosporins are usually effective against Staphylococcus aureus, viridans streptococci, group A streptococci, Streptococcus
pneumoniae, Neisseria meningitidis, N. gonorrhoeae, Salmonella, Shigella,
Proteus mirabilis, and some strains of Escherichia coli.
Cefaclor (a second-generation oral cephalosporin) is equivalent to
first-generation drugs in activity against gram-positive cocci. It is active
against E. coli, Klebsiella pneumoniae, P. mirabilis, Shigella, Salmonella, and
H. influenzae. Cefuroxime axetil is an orally active prodrug of cefuroxime
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PDQ PHARMACOLOGY
Table 285
Antibacterial Spectrum of Cephalothin, a First-Generation

Injectable Cephalosporin
Microorganism
Sensitivity
Staphylococcus aureus (both

penicillin sensitive and
penicillin resistant)
High sensitivity, but some resistant strains
Streptococcus pyogenes
High sensitivity
Streptococcus pneumoniae
High sensitivity
Streptococcus (viridans group)
High sensitivity
Streptococcus faecalis
Some sensitivity, but many resistant strains
Clostridium perfringens
High sensitivity
Clostridium tetani
Very high sensitivity
Corynebacterium diphtheriae
Some sensitivity
Enterobacter cloacae
Resistant
Enterobacter aerogenes
Resistant
Escherichia coli
Moderate sensitivity, but many resistant strains
Haemophilus influenzae
Klebsiella pneumoniae
High sensitivity
Neisseria gonorrhoeae
Neisseria meningitidis
High sensitivity, but many resistant strains
Proteus mirabilis
Some sensitivity
Proteus morganii
Resistant
Proteus rettgeri
Resistant
Proteus vulgaris
Resistant
Pseudomonas aeruginosa
Resistant
Salmonella spp.
Shigella spp.
that is hydrolyzed by nonspecific esterases to release cefuroxime into the

blood stream.
Cefixime (a third-generation oral cephalosporin) is at least as active
as other oral cephalosporins against group A streptococci and pneumococci,
Chapter 28
247
but staphylococci, which are susceptible to other cephalosporins, are resistant to cefixime because the drug has a low affinity for a critical PBP.
Cefixime is highly active against Neisseria gonorrhoeae, Haemophilus
influenzae, and Moraxella catarrhalis, including beta-lactamase-producing
strains usually resistant to ampicillin, amoxicillin, and occasionally to cefaclor. Cefixime is more active than other cephalosporins against many gramnegative bacilli, including E. coli, Klebsiella, Proteus mirabilis, and Serratia
marcescens.
Resistance
Resistance can develop to cephalosporins by several means, including:
1. inactivation by bacteria beta-lactamases,
2. decreased permeability of the bacterial cells, which prevents the
cephalosporin from reaching the appropriate binding proteins, and
3. alterations in the penicillin-binding proteins that prevent the
cephalosporins from binding to them.
Clinically, beta-lactamase inactivation and, to a lesser extent, altered permeability are most important in gram-negative bacteria. The rapid development of resistance to supposedly beta-lactamase-stable third-generation
cephalosporins, particularly by species of Enterobacter, Serratia, and
Pseudomonas, is of increasing concern.
Adverse Effects
Cephalosporins are relatively safe drugs, but they can produce allergic
reactions in as many as 5% of patients. These include skin rash, urticaria,
fever, serum sickness, hemolytic anemia, and eosinophilia.
GI adverse effects include nausea, vomiting, and diarrhea. Overgrowth
of resistant organisms may occur after long-term cephalosporin administration. Patients receiving a third-generation cephalosporin should be
observed for enterococcal superinfection. Finally, third-generation
cephalosporins may suppress the GI microflora, resulting in decreased
vitamin K production and hypoprothrombinemia.
29
Macrolide Antibiotics
ERYTHROMYCIN, CLARITHROMYCIN, AZITHROMYCIN
Actions
Macrolide antibiotics inhibit bacterial protein synthesis by reversibly binding to the 50S ribosomal subunit and preventing elongation of the peptide
chain, most likely by interfering with the translocation step. Macrolides do
not bind to mammalian 50S ribosomes, and this partly accounts for their
selective toxicity.
Macrolides may be bacteriostatic or bactericidal, depending on the concentration of the drug, organism susceptibility, growth rate, and size of the
inoculum. Bacterial killing is favored by higher antibiotic concentrations,
lower bacterial density, and rapid growth.
Erythromycin
Erythromycin has an antibacterial spectrum similar to that of penicillin G.
It includes many strains of penicillin-resistant staphylococci, Streptococcus
pyogenes, Streptococcus pneumoniae, viridans streptococci, anaerobic streptococci, and many strains of Streptococcus faecalis. Erythromycin is also
effective against Corynebacterium diphtheriae, Propionibacterium acnes,
Clostridium tetani, Clostridium perfringens, Neisseria gonorrhoeae, Bordetella
pertussis, and some species of Brucella. Haemophilus influenzae is only
moderately sensitive to the drug. Oropharyngeal strains of Bacteroides are
usually sensitive to erythromycin. The drug is also effective against
Mycoplasma pneumoniae, Treponema pallidum, Legionella pneumophila,
and many species of Rickettsia and Chlamydia.
248
Chapter 29
249
Clarithromycin
Clarithromycin has an in vitro spectrum of activity that is similar to that
of erythromycin, but it is two- to fourfold more active against susceptible
streptococci and staphylococci. Gram-positive cocci resistant to erythromycin are resistant to clarithromycin as well. Clarithromycin is slightly more
active in vitro than erythromycin against certain pathogens responsible for
atypical pneumonias (ie, Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae).
Azithromycin
Azithromycin, unlike erythromycin and clarithromycin, inhibits some aerobic gram-negative bacilli. The majority of these bacilli, including the Enterobacteriaceae, are intrinsically resistant to erythromycin and clarithromycin
because the cell envelopes prevent passive diffusion of the antibiotic. Organisms that are moderately susceptible to azithromycin include most Salmonella,
Shigella and Aeromonas species, Escherichia coli, and Yersinia enterocolitica.
Azithromycin has excellent activity against Vibrio cholerea and species isolated
in patients with vaginitis, such as Gardnerella vaginalis and Mobiluncus.
Resistance
Bacteria with developed resistance to erythromycin are also resistant to
azithromycin and clarithromycin. Plasmid-mediated decreased binding of
macrolides to their target site accounts for nearly all the resistant strains isolated from patients.
Pharmacokinetics
Erythromycin
Erythromycin is not stable in the stomach; it must be protected from gastric juices. This can be achieved by using enteric-coated tablets or capsules,
or by preparing the drug as an acid-resistant ester, such as erythromycin
stearate, erythromycin ethylsuccinate, or erythromycin estolate, which are
hydrolyzed to erythromycin once absorbed. Once absorbed, erythromycin
diffuses well throughout the body. It enters most tissue compartments, with
the exception of the CSF. Erythromycin is concentrated in the liver and
excreted in the bile. Little erythromycin is eliminated in urine. Its half-life
ranges from 1 to more than 3 hours.
Clarithromycin
Clarithromycin is well absorbed from the GI tract, with or without food.
It is metabolized in the liver, and 30 to 40% of the administered dose can
250
PDQ PHARMACOLOGY
be recovered in the urine. Patients with a creatinine clearance 30 mL/min

may require a decreased dose. Clarithromycin penetrates well into both tissues and cells, including macrophages and polymorphonuclear leukocytes.
Clarithromycin is 65 to 70% bound to plasma proteins.
Azithromycin
Azithromycin is rapidly absorbed and distributed widely throughout the
body. Rapid movement of azithromycin from blood into tissue results in
significantly higher azithromycin concentrations in tissue than in plasma
(up to 50 times the maximum observed concentration in plasma). The
absolute bioavailability is approximately 37%. Following its absorption,
azithromycin is eliminated slowly from the body. Its half-life is 68 hours.
Elimination in the bile, metabolism in the liver, and possibly transintestinal elimination account for the clearance of azithromycin from the
body.
Uses
Erythromycin
Erythromycin is often used as a replacement for penicillin G or V in
patients who are allergic to these drugs. It can be used in the following
ways:
1. In the treatment of infections caused by group A streptococci, including tonsillitis, erysipelas, and scarlet fever
2. As a penicillin substitute in the chemoprophylaxis of streptococcal
infections
3. To treat pneumococcal infections
4. As a substitute for penicillin in the treatment of the acute illness or carrier
state of diphtheria and in the management of both early and late syphilis
5. In the treatment of Mycoplasma pneumoniae and Legionnaires disease
caused by Legionella pneumophila
6. To treat Chylamydia trachomatis infections in infants and children
7. In conjunction with sulfisoxazole to treat Haemophilus influenzaeinduced
otitis media in young children
8. In the treatment of acne vulgaris
Erythromycin can eradicate Propionibacterium acnes, the anaerobic
diphtheroid in pilosebaceous glands that secretes a variety of enzymes,
including hyaluronidase, which are capable of disrupting follicular epithelium and increasing inflammation.
Chapter 29
251
Clarithromycin
Clarithromycin is used to treat:
1. Pneumonia caused by Mycoplasma pneumoniae or Streptococcus
pneumoniae
2. Acute bacterial exacerbations of chronic bronchitis due to H. influenzae, Moraxella catarrhalis, or S. pneumoniae
3. Pharyngitis/tonsillitis due to Streptococcus pyogenes
4. Acute maxillary sinusitis due to S. pneumoniae in penicillin-allergic
patients
5. Uncomplicated skin and skin-structure infections due to S. aureus or
S. pyogenes
Azithromycin
Azithromycin is used in the following ways:
1. As an alternative antibiotic for the treatment of mild to moderate
pharyngitis/tonsillitis due to streptococcal species
2. To treat mild to moderate acute bacterial exacerbations of chronic
bronchitis due to H. influenzae, M. catarrhalis, or S. pneumoniae
3. In the treatment of pneumonia due to S. pneumoniae or H. influenzae
4. To treat uncomplicated skin and skin-structure infections due to
S. aureus, S. pyogenes or Streptococcus agalactiae
5. In the treatment of urethritis and cervicitis due to C. trachomatis
Adverse Effects
Erythromycin is well tolerated, except for its effects on the GI tract. Erythromycin causes GI upset with nausea, diarrhea, and abdominal pain.
Both clarithromycin and azithromycin are well tolerated. Neither drug
causes the high incidence of disabling nausea seen with erythromycin.
Reversible dose-related hearing loss has been reported with high doses (eg,
4 g/24 h) of both drugs used to treat Mycobacterium avium infections.
30
Aminoglycoside Antibiotics
AMIKACIN, GENTAMICIN, NETILMICIN, TOBRAMYCIN
Actions
Aminoglycoside antibiotics are a group of structurally related bactericidal
drugs. They derive their name from the fact that their structures contain at
least one sugar attached to one or more amino groups. Aminoglycosides
inhibit bacterial protein synthesis. They bind to the 30S ribosomal subunit
of streptococci to cause a misreading of the genetic code. The proteins
formed contain the wrong sequence of amino acids and have no biologic
value (nonsense proteins). Aminoglycosides block protein synthesis in
other bacteria by inhibiting amino acid translocation.
Antibacterial Spectrum
Aminoglycosides are principally used to treat infections caused by sensitive strains of Enterobacteriaceae, including Escherichia coli, Klebsiella,
Enterobacter, Serratia, and Proteus species. Amikacin, gentamicin,
netilmicin, and tobramycin are active against Pseudomonas aeruginosa.
They have only limited activity against most gram-positive bacteria. They
are active in vitro against certain species of streptococcus. Only minimal
activity is usually found against Streptococcus faecalis, S. pneumoniae, and
streptococci of the viridans group. Although aminoglycosides inhibit
staphylococci, safer drugs such as the penicillins or cephalosporins, are
usually used against these pathogens. Aminoglycosides have little activity
against anaerobic microorganisms or facultative bacteria under anaerobic
conditions.
Although the antibacterial spectra of amikacin, gentamicin, netilmicin,
and tobramycin show few qualitative differences, the various aerobic gram252
Chapter 30
253
negative bacilli vary in their susceptibility to the four drugs. Table 301
describes the differing sensitivities of six gram-negative bacilli to
tobramycin and gentamicin.
Resistance
Bacterial resistance can develop to the aminoglycosides. The major mechanism for the development of resistance involves enzymatic inactivation of
the antibiotics. Decreased uptake of the aminoglycoside by bacteria or alteration of bacterial ribosomal binding sites can also account for the development of resistance.
The aminoglycosides are inactivated by acetylation, adenylation, or
phosphorylation of critical binding sites. The prevalence of individual
aminoglycoside inactivating enzymes varies widely, both with respect to
geographic location and time. Thus, different patterns of aminoglycoside
resistance exist among countries, among hospitals in any country, district,
or city, and even among wards within a hospital. Therefore, established tests
of sensitivity should be used to determine bacterial susceptibility to a drug.
Pharmacokinetics
The aminoglycosides are very polar (water-soluble) drugs and cannot diffuse across gastrointestinal membranes. Less than 1% of an oral dose is
absorbed. Aminoglycosides are absorbed rapidly from IM injection sites,
with peak concentrations appearing within 1 hour.
Aminoglycosides do not diffuse readily across body membranes. For
example, concentrations of gentamicin in pleural and pericardial fluids are
Table 301
In Vitro Activity of Tobramycin and Gentamicin Against

Susceptible Gram-Negative Organisms
Number of
Strains
Tobramycin
(%)*
Gentamicin
(%)*
100
93
80
Enterobacter spp.
52
94
81
Proteus mirabilis
38
92
58
Proteus spp. (indole positive)
26
100
85
100
100
98
41
86
88
Escherichia coli
Klebsiella spp.
Serratia marcescens
*Percentage of isolates susceptible to 1.57 g/mL.
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PDQ PHARMACOLOGY
only one-quarter to one-half those in serum. Aminoglycoside levels in fetal

serum are 20 to 40% of those in maternal serum. Aminoglycosides do not
cross well into the CSF, even in the presence of inflammation.
Aminoglycosides are eliminated by renal excretion. Their half-lives of
2 to 3 hours in patients with normal kidney function are extended in
patients with renal impairment. Dosages must be decreased in the neonate
or adult with reduced renal function.
Uses
Gentamicin is still important in the treatment of many serious gramnegative bacillary infections (eg, caused by E. coli, Proteus mirabilis, indolepositive Proteus, Klebsiella, Enterobacter, and Serratia species and
Pseudomonas aeruginosa), although resistance to the drug is developing. Salmonella and Shigella species are often gentamicin-sensitive.
Gentamicin can be considered for the treatment of bacteremia, respiratory and urinary tract infections, infected wounds, and bone and softtissue infections, including peritonitis and burns complicated by sepsis.
Serious infections with P. aeruginosa may require gentamicin combined
with carbenicillin, ticarcillin, pipracillin, or ceftazidime. The combination
produces a synergistic effect with some strains and delays the emergence of
resistant organisms.
Gentamicin is also applied topically for use in the treatment of primary
and secondary infections caused by sensitive strains of streptococcus
(Group A beta-hemolytic, alpha-hemolytic), Staphylococcus aureus (coagulase-positive, coagulase-negative, and some penicillinase-producing
strains), and the gram-negative bacteria P. aeruginosa, Aerobacter aerogenes,
E. coli, Proteus vulgaris, and Klebsiella pneumoniae. Gentamicin may also be
used for ocular infections caused by S. aureus, P. aeruginosa, A. aerogenes,
E. coli, Proteus vulgaris, or K. pneumoniae.
Tobramycin has a similar antibacterial spectrum to that of gentamicin.
It is usually active against most strains of the following organisms in vitro
and in clinical infections: P. aeruginosa; Proteus species (indole positive and
indole-negative), including P. mirabilis, P. morganii, P. rettgeri, and P. vulgaris; E. coli; Klebsiella-Enterobacter-Serratia group; Citrobacter species;
Providencia species; and staphylococci, including S. aureus (coagulase positive and coagulase negative). Its minimum inhibitory concentration (MIC)
against P. aeruginosa is approximately one-quarter that of gentamicin.
Tobramycin is considered by many to be the aminoglycoside of choice for
P. aeruginosa infections, in which case it is combined with carbenicillin,
ticarcillin, piperacillin, or ceftazidime.
Tobramycin may be indicated for the treatment of the following infections when caused by susceptible organisms: septicemia, urinary tract
infections, lower respiratory tract infections, serious skin and soft-tissue
Chapter 30
255
infections, and CNS infections resistant to antibiotics usually considered

efficacious in such infections.
Like gentamicin, tobramycin can be used topically for ocular infections caused by S. aureus, P. aeruginosa, A. aerogenes, E. coli, P. vulgaris, or
K. pneumoniae.
Amikacin is indicated for the short-term treatment of serious infections
due to amikacin-susceptible strains of P. aeruginosa, E. coli, and S. aureus,
as well as Proteus, Klebsiella-Enterobacter-Serratia, Providencia, Salmonella,
and Citrobacter species. Among the aminoglycosides, amikacin has the
greatest resistance to bacterial aminoglycoside-inactivating enzymes.
Amikacin is often considered to be the drug of choice for the initial treatment of serious gram-negative bacillary infections in hospitals, where gentamicin resistance is a problem.
Netilmicin has a similar spectrum of activity to that of gentamicin and
tobramycin. However, because it is less sensitive to bacterial inactivation,
netilmicin is effective against some gentamicin-resistant and tobramycinresistant strains of Enterobacteriaceae. Netilmicin is indicated for the treatment of infections caused by susceptible strains of E. coli, Proteus (indole
negative and some indole positive), Klebsiella, Enterobacter, Citrobacter, and
Staphylococcus species.
Adverse Effects
Aminoglycosides accumulate in the perilymph of the inner ear, destroying
both the vestibular and cochlear sensory cells. The degree of permanent
damage correlates with the number of destroyed sensory hair cells in the
inner ear; this in turn relates to the concentration of the drug and length
of exposure. Patients experience tinnitus and hearing loss, dizziness, and
vertigo. Amikacin impairs auditory function preferentially, and gentamicin
is more likely to damage vestibular function. Tobramycin causes auditory
and vestibular damage with equal frequency. The diuretics ethacrynic acid
and furosemide potentiate aminoglycoside ototoxicity.
High concentrations of aminoglycosides accumulate in the renal cortex and urine. Five to 7 days of therapy can cause dose-dependent damage in the proximal tubular epithelium, particularly in elderly or debilitated patients or in individuals with pre-existing renal impairment. Serum
creatinine and blood urea nitrogen increase, and severe azotemia may
occur. Tobramycin and netilmicin are claimed to be less nephrotoxic
than the other aminoglycosides. Concomitant therapy with furosemide,
ethacrynic acid, cephalosporins, or methoxyflurane increases the risk of
the nephrotoxicity.
Rarely, aminoglycosides can reduce the release of acetylcholine from
motor nerve terminals and cause a neuromuscular blockade, leading to a
flaccid paralysis and respiratory failure.
31
Fluoroquinolone Antibiotics
CIPROFLOXACIN, ENOXACIN, LOMEFLOXACIN,
NORFLOXACIN, OFLOXACIN
Actions
Fluoroquinolones (Figure 311) inhibit DNA synthesis by a specific action
on DNA gyrase, the enzyme responsible for the unwinding and supercoiling of bacterial DNA within the bacterium before its replication.
Fluoroquinolones are effective against most aerobic, gram-negative, and
some gram-positive bacteria. The fluoroquinolones are highly active against
Enterobacteriaceae, including Escherichia coli, Klebsiella, Enterobacter, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia, Citrobacter, and Serratia. These drugs are active against Pseudomonas aeruginosa,
including strains that are resistant to other antibacterials.
The gram-negative coccobacilli Haemophilus influenzae and
Haemophilus ducreyi, and the gram-negative cocci Neisseria meningitidis,
Neisseria gonorrhoeae, and Moraxella catarrhalis, are highly susceptible to the
fluoroquinolones. The beta-lactamaseproducing strains of these organisms
are also susceptible.
The fluoroquinolones are active against some gram-positive bacteria,
although inhibitory concentrations generally are higher than for gram-negative bacteria. All of the fluoroquinolones are active against staphylococci
(Staphylococcus aureus, Staphylococcus epidermidis), including methicillinresistant strains.
Streptococci, including Streptococcus pyogenes (group A), Streptococcus
agaletiae (group B), Streptococcus pneumoniae, and viridans streptococci, are
usually highly susceptible.
256
Chapter 31
Fluoroquinolone Antibiotics
257
Figure 311 Chemical structures of fluoroquinolones. After AMA Drug Evaluations Subscriptions; 1993, 2:13. p. 8:2.
The fluoroquinolones are active in vitro against Legionella pneumophila.

Ciprofloxacin and ofloxacin are active against Mycobacterium tuberculosis
and certain atypical mycobacteria.
Resistance
Plasmid-mediated transferable resistance to the fluoroquinolones has been
reported. However, resistance can be caused by chromosomal mutations.
These involve alterations in DNA gyrase or changes in outer membrane proteins that affect bacterial membrane permeability.
Pharmacokinetics
The fluoroquinolones are rapidly, but variably absorbed following oral
administration. Oral bioavailability is approximately 40 to 50% for norfloxacin, 60 to 70% for ciprofloxacin, and 90 to 100% for enoxacin, lomefloxacin, and ofloxacin.
All the fluoroquinolones appear to distribute widely in body fluids and
tissues. They penetrate into blister fluid, bile, saliva, sputum, peritoneal
fluid, macrophages, polymorphonuclear neutrophils, lung, liver, kidney, gall
bladder, skeletal muscle, uterus, cervix, vagina, and bone. In the urine, all
the fluoroquinolones reach concentrations that exceed the MIC of most urinary tract pathogens for at least 12 hours.
In patients with inflamed meninges, ciprofloxacin and ofloxacin may
reach concentrations in the CSF that exceed the MIC90 for most gram-negative pathogens that cause bacterial meningitis, including Pseudomonas aeruginosa, Salmonella species, and other Enterobacteriaceae. However, the CSF lev-
258
PDQ PHARMACOLOGY
els of these drugs are not adequate to treat meningitis caused by staphylococci,
Streptococcus pneumoniae, group B streptococci, and Listeria monocytogenes.
Fluoroquinolones are eliminated by the liver, GI tract, and kidney. All
fluoroquinolones can be recovered in urine, and the drugs appear to be
cleared by both glomerular filtration and tubular secretion.
Uses
Fluoroquinolones are used to treat a wide range of infections.
Ciprofloxacin may be used for the treatment of patients with acute
bronchitis and acute pneumonia, urinary tract infections, skin and softtissue infections, bone and joint infections, and infectious diarrhea caused
by a wide range of susceptible organisms.
Enoxacin appears to be effective for complicated urinary tract infections. Single doses have been beneficial in uncomplicated urethral and
endocervical gonorrhea.
Lomefloxacin is used in acute exacerbations of chronic bronchitis of
mixed etiology that does not involve S. pneumoniae. It is also used in
uncomplicated and complicated infections of the upper and lower urinary
tract. Lomefloxacin appears to be effective in the treatment of acute and
chronic bacterial prostatitis, infectious diarrhea, bone and joint infections,
infections of the skin and skin structures, and sexually transmitted diseases
(eg, chancroid due to H. ducreyi).
Norfloxacin is indicated for the treatment of upper and lower urinary
tract infections (specifically complicated and uncomplicated cystitis),
pyelitis, and pyelonephritis caused by susceptible strains of E. coli, Klebsiella
pneumoniae, unspecified Klebsiella, unspecified Citrobacter, P. mirabilis, S.
aureus, Streptococcus faecalis, and P. aeruginosa.
Ofloxacin is used to treat lower respiratory tract infections, including
pneumonia, and acute exacerbations of chronic bronchitis due to H.
influenzae or S. pneumoniae. It is also used to treat uncomplicated cystitis
or complicated urinary tract infections due to E. coli, K. pneumoniae, or P.
mirabilis. Ofloxacin is used to treat prostatitis due to E. coli. Sexually transmitted disease due to N. gonorrhoeae and nongonococcal urethritis and cervicitis due to Chlamydia trachomatis can also be treated with ofloxacin.
Finally, ofloxacin can be used in mild to moderate skin and skin-structure
infections due to S. aureus and S. pyogenes.
Adverse Effects
The fluoroquinolones are well tolerated and rarely require discontinuation
because of adverse effects. Nausea, vomiting, and dizziness occur most
commonly. Abdominal pain, dyspepsia, flatulence, vomiting, diarrhea, and
stomatitis are also encountered. CNS adverse effects include malaise,
drowsiness, weakness, insomnia, restlessness, and agitation.
32
Miscellaneous Antibiotics
and Antibacterials
COTRIMOXAZOLE (TRIMETHOPRIM PLUS SULFAMETHOXAZOLE
Actions
Cotrimoxazole contains sulfamethoxazole plus trimethoprim.
Sulfamethoxazole (SMZ) is a sulfonamide drug, which inhibits bacterial folic acid synthesis. Humans absorb folic acid from food, but bacteria must synthesize the vitamin. Para-aminobenzoic acid (PABA) is an
essential component of folic acid. Sulfonamides, like SMZ (Figure
321), are structurally similar to PABA. By acting as competitive
antimetabolites of PABA, sulfonamides block PABAs incorporation
into folic acid (Figure 322), thereby preventing folic acid synthesis and
inducing bacteriostasis. Because humans can absorb folic acid from
food and bacteria must synthesize the vitamin, sulfonamides are selectively toxic to bacteria.
Trimethoprim (TMP) (see Figure 321) competitively inhibits bacterial dihydrofolate reductase, the enzyme responsible for converting
dihydrofolic acid to tetrahydrofolic acid, the active form of folic acid.
Cotrimoxazole is an effective combination, in which SMZ reduces
folic acid synthesis and TMP inhibits folic acid activation (Figure
323).
Cotrimoxazole has a broad spectrum of activity. All strains of Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus epidermidis, Streptococ-
259
260
PDQ PHARMACOLOGY
H
SO2
H2N
sulfamethoxazole
N
O
N
H2N
N
NH2
CH3
OCH3
OCH3
CH2
Trimethoprim
OCH3
Figure 321 Structures of sulfamethoxazole and trimethoprim.
cus pyogenes, viridans streptococci, Streptococcus faecalis, Escherichia coli,

Proteus mirabilis, Proteus morganii, Proteus rettgeri, Enterobacter species,
Pseudomonas psueudomallei, and Serratia species are inhibited by cotrimoxazole. Although many strains of Shigella and Salmonella remain sensitive to cotrimoxazole, others have developed resistance to it.
Resistance
Resistance can develop to cotrimoxazole. This may be either plasmid- or
chromosome-mediated. Clinically, the most important type of acquired
Figure 322 Mechanism of action of sulfonamides.
Chapter 32
Miscellaneous Antibiotics and Antibacterials
261
Figure 323 Mechanism of action of cotrimoxazole.
resistance to TMP results from the production of novel TMP-resistant dihydrofolate reductase. These dihydrofolate reductase enzymes are encoded on
transferable plasmids or transposons and confer on the bacteria a high-level
of resistance to TMP.
Pharmacokinetics
Both SMZ and TMP are well absorbed from the GI tract and distribute rapidly throughout the body, including the CSF. High concentrations of each
drug are found in the bile. The half-life of both drugs is approximately 10
hours. Although most of the TMP is eliminated unchanged in the urine,
approximately 85% of SMZ is inactivated prior to renal excretion.
Uses
Cotrimoxazole is used to treat a variety of systemic infections caused by
gram-positive and gram-negative organisms, including infections of the
upper and lower respiratory tract, urinary tract, genitourinary tract, gastrointestinal tract, and skin and soft tissues; Pneumocystis carinii infections;
and serious systemic infections, such as meningitis and septicemia caused
by susceptible organisms.
Adverse Effects
Nausea, anorexia, and vomiting are seen in 5 to 10% of patients taking sulfonamides. Hypersensitivity reactions to sulfonamides, beginning 10 to 12 days
after starting therapy or within hours in previously sensitized patients, can
cause generalized skin rashes, urticaria, photodermatitis, or drug fever. Blood
dyscrasias to sulfonamides are rare but they can be fatal. Acute or chronic
hemolytic anemia, developing within 2 to 7 days of starting sulfonamide ther-
262
PDQ PHARMACOLOGY
apy, or agranulocytosis, appearing between the second and sixth week of treatment, represent hypersensitivity reactions.
TMP has relatively few adverse effects. They include gastric distress
(nausea and vomiting), rash, itching, and very rarely, leukopenia, thrombocytopenia, and methemoglobinemia.
THE TETRACYCLINESTETRACYCLINE HCI,

OXYTETRACYCLINE, DEMECLOCYCLINE, DOXYCYCLINE,
METHACYCLINE, MINOCYCLINE
Actions
All tetracyclines have the same basic structure (Figure 324) and the same
bacteriostatic mechanism of action. Tetracyclines are concentrated within
sensitive gram-positive and gram-negative bacterial cells by an energydependent process. Once inside the bacteria, tetracyclines depress protein
synthesis by blocking the attachment of aminoacyl transfer RNA to the
acceptor site on the messenger RNA-ribosome complex. Binding of the
tetracycline antibiotic occurs primarily at the bacterial 30S ribosomal subunit.
The selective toxicity of tetracyclines for sensitive bacteria, and their
safety to the host, appears to depend partially on the energy-dependent
uptake of the antibiotics by bacterial, and not mammalian, cells.
Table 321 presents the antibacterial spectrum of the tetracyclines.
Resistance
Several species of bacteria have become increasingly resistant to the tetracyclines. Many enterobacteriaceae (eg, Shigella, Escherichia coli) and most
Pseudomonas aeruginosa are resistant. Many strains of staphylococci, streptococci, pneumococci, and Bacteroides are no longer susceptible. Emergence
of high-level tetracycline-resistant Neisseria gonorrhoeae strains is common
in some areas of the world.
Pharmacokinetics
Absorption from the GI tract ranges from 60 to 80% for oxytetracycline,
tetracycline, and demeclocycline and from 95 to 100% for minocycline and
doxycycline. Calcium, magnesium, and iron block tetracycline absorption.
Chapter 32
263
Figure 324 Structure of tetracycline, minocycline, and doxycycline.
Distribution in the body differs among the tetracyclines. Oxytetracycline, tetracycline, and minocycline are 35, 65, and 75% bound to the
plasma proteins, respectively. Methacycline, demeclocycline, and doxycycline are approximately 90% bound to plasma albumin. Tetracyclines distribute to varying degrees throughout the body. They cross the placenta but
have difficulty crossing the blood-brain barrier. Doxycycline and minocycline are more lipophilic and penetrate tissues and secretions better than the
other tetracyclines. Doxycycline diffuses well into endometrial, myometrial,
prostatic, and renal tissues.
Tetracyclines bind to calcium and are retained in bone and growing
teeth for long periods of time. Because they can damage developing teeth
and delay the development of long bones, tetracyclines are usually contraindicated during pregnancy and in patients under 8 to 10 years of age.
264
PDQ PHARMACOLOGY
Table 321
Sensitivities of Some Organisms to the Tetracyclines

Bacillus anthracis
Some sensitivity
Bacteroides spp.
Clostridium perfringens
Moderate sensitivity
Clostridium tetani
Escherichia coli
Haemophilus ducreyi
Haemophilus influenzae
Klebsiella pneumoniae
Listeria monocytogenes
Mycoplasma pneumoniae
High sensitivity
Neisseria gonorrhoeae
Neisseria meningitidis
Salmonella spp.
Shigella spp.
Staphylococcus aureus
(both penicillin sensitive
and penicillin resistant)
Some sensitivity, but tetracyclines not

recommended for treatment
Streptococcus pneumoniae
Moderate sensitivity, but some areas have many

resistant strains
Streptococcus pyogenes
Treponema pallidum
Sensitive; tetracycline is recommended in

penicillin-allergic patients
Elimination rates differ among the tetracyclines. The half-lives range

from 8 to 9 hours (for tetracycline HCl and oxytetracycline) to 16 to 18
hours (for minocycline and doxycycline). Renal excretion is the major
route of elimination. Minocycline has a low renal clearance, and less than
10% of a dose is recovered unchanged in urine. The drug undergoes enterohepatic circulation and may be metabolized to a considerable extent. Doxycycline elimination is independent of both renal and hepatic function. The
drug is excreted in the feces, largely as an inactive chelated product. Thus,
the dose of doxycycline does not require modification in patients with renal
or hepatic insufficiency.
Chapter 32
265
Uses
Despite their broad antibacterial spectrum, tetracyclines have relatively poor
activity against most pathogens and are rarely considered drugs of first
choice. They are considered first-line drugs for the treatment of Mycoplasma
pneumoniae, Rocky Mountain spotted fever, endemic typhus, Borrelia recurrentis (relapsing fever), chylamydial disease, nonspecific brucellosis, and
infections caused by Pasteurella. For most infections, tetracyclines are second- or third-line drugs, falling behind more effective agents.
Minocycline is frequently prescribed for the treatment of acne vulgaris.
By eradicating the anaerobe Propionibacterium acnes, minocycline reduces
the production of inflammatory fatty acids by the microbe and decreases
inflammatory acne. Minocycline is also used to treat rosacea. Exactly why
minocycline should be effective in rosacea is not known. However, its efficacy is probably unrelated to its antibacterial properties.
Adverse Effects
Tetracyclines can cause nausea, vomiting, epigastric burning, stomatitis, and
glossitis when given orally. Administered intravenously, they can produce
phlebitis. Tetracyclines can be hepatotoxic, particularly in patients with preexisting renal or hepatic insufficiency.
Tetracyclines can retard bone growth in the developing fetus if given to
pregnant women after the fourth month of gestation. They can also stain
teeth and retard growth if given to children under 8 years.
Photosensitivity, manifested mainly as abnormal sunburn reactions, is
particularly prevalent with demeclocycline. Minocycline produces vertigo
in a high percentage of patients.
Tetracyclines can produce superinfections. By suppressing the normal
bacterial flora, tetracyclines enable other bacteria, such as penicillinaseproducing staphylococci and Candida, to proliferate. Superinfections occur
in the oral, anogenital, and intestinal areas.
Tetracyclines can also lead to pseudomembranous colitis, secondary to
the overgrowth of Clostridium difficile.
VANCOMYCIN
Actions
Vancomycin inhibits cell wall synthesis in susceptible bacteria. However, it
is structurally and pharmacodynamically very different from beta-lactam
antibiotics, which also inhibit cell wall synthesis. Vancomycin does not bind
266
PDQ PHARMACOLOGY
to penicillin-binding proteins (PBPs) (see Chapter 28), but instead binds to

a different component of the cell wall to interfere with the elongation of the
peptidoglycan backbone of the wall. This specificity of action partly explains
the minimal resistance shown to vancomycin to date.
Vancomycin is only active against gram-positive bacteria. Because it cannot penetrate the outer membrane that surrounds gram-negative species,
vancomycin is ineffective in treating gram-negative infections. Vancomycin
is one of the most potent antibiotics against Staphylococcus aureus and
S. epidermidis, including methicillin- and cephalothin-resistant strains
(Chapter 28).
Streptococcus pyogenes and S. pneumoniae (including penicillin Gresistant strains) are highly susceptible to vancomycin. The drug usually inhibits
the growth of viridans streptococcus, Streptococcus bovis, Streptococcus
agalactiae (group B), and enterococci (eg, Enterobacter faecalis). However,
vancomycin may not be bactericidal against some strains of these species,
particularly the enterococci. Antibacterial synergism against enterococci is
usually obtained when vancomycin is combined with an aminoglycoside.
Gram-positive bacilli that are susceptible to vancomycin include
Clostridia (including C. difficile), Corynebacterium, Bacillus anthracis, Listeria monocytogenes, Actinomyces species, and lactobacilli.
Resistance
During the first 30 years of vancomycin use, the development of resistance
was not a serious clinical problem. In the last 10 years, however, some resistance has developed. In most cases, resistance to vancomycin is due to the
production of a new cell wall component that prevents the drug from binding to the wall. Resistance to vancomycin is reported for Enterococcus faecalis due to plasmid-mediated production of a protein that blocks vancomycin from binding to its normal receptor.
Pharmacokinetics
Vancomycin is not absorbed from the GI tract and is irritating if given by
IM injection. Therefore, vancomycin is administered by IV, except when it
is given orally for the treatment of Clostridium difficile, in which case the
intent is not to have the drug absorbed. Vancomycin is not metabolized. It
Chapter 32
267
is eliminated by glomerular filtration and its dosage is reduced in patients

with impaired renal function.
Uses
Vancomycin should be used only in serious gram-positive infections that
are not treatable with other antibiotics. It is recommended for serious
methicillin-sensitive staphylococcal infections in patients who cannot take
a penicillin or cephalosporin (eg, immediate-type hypersensitivitysee
Chapter 28) or who have not responded to these drugs.
Vancomycin is the drug of choice for serious infections caused by
methicillin-resistant S. aureus (MRSA) and coagulase-negative staphylococci, including methicillin-resistant S. epidermidis (MRSE). Often, the
addition of other drugs (eg, rifampicin, gentamicin) to a vancomycin regimen increases the rate of response.
Vancomycin with gentamicin or streptomycin (for susceptible strains)
is used for enterococcal endocarditis in penicillin-allergic patients. IV vancomycin is used for prophylaxis of infective endocarditis in high-risk
patients who are allergic to penicillins and are undergoing dental or certain
other surgical procedures.
Oral vancomycin is the drug of choice for the treatment of confirmed
antibiotic-associated pseudomembranous colitis caused by Clostridium
difficile.
Adverse Effects
Vancomycins most common adverse effect is called red neck or the redman syndrome. This is a nonimmunologic, dose-dependent, glycopeptideinduced anaphylactoid reaction, characterized by one or more of the
following:
Erythematous macular rash involving the face, neck, upper torso, back,
and arms
Flushing
Pruritus; pain and muscle spasm in the chest
Tachycardia
Hypotension
The exact mechanism of this reaction is unknown. It occurs coincident

with an increase in plasma histamine. Pretreatment with antihistamines is
effective in preventing this reaction.
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PDQ PHARMACOLOGY
NITROFURANTOIN
Actions
Nitrofurantoins mechanism of action is unclear. The drug inhibits a variety of enzyme systems in bacteria and is active against common urinary
pathogens.
Most strains of Escherichia coli are susceptible. About two-thirds of other
coliform strains are susceptible. Staphylococcus aureus, Staphylococcus saprophyticus, and enterococci (Enterococcus faecalis) are also susceptible.
Resistance
Susceptible bacteria do not readily develop resistance to nitrofurantoin during therapy.
Pharmacokinetics
Nitrofurantoin is well absorbed from the upper small intestine and is concentrated in the urine. Because nitrofurantoin is associated with a high incidence of GI irritation when it is absorbed quickly (see Adverse Effects
below), it is now formulated in large crystals that dissolve slowly and produce less GI intolerance.
Uses
Nitrofurantoin is used to treat urinary tract infections (eg, pyelonephritis,
pyelitis, cystitis) that are due to susceptible strains of E. coli, enterococci,
S. aureus, and certain susceptible strains of Klebsiella, Enterobacter, and Proteus species.
Adverse Effects
GI irritation is the most common adverse effect of nitrofurantoin. Symptoms include anorexia, nausea, and vomiting; diarrhea and abdominal pain
occur less frequently. These effects have been partially overcome by increasing the crystal size of the drug and delaying the rate at which nitrofurantoin is absorbed.
Nitrofurantoin can cause allergic reactions including rashes, urticaria,
angioneurotic edema, eosinophilia, and fever. Nitrofurantoin can also cause
an acute pulmonary reaction, characterized by fever, myalgia, dyspnea, pulmonary infiltration, and pleural effusion.
Chapter 32
269
Nitrofurantoin can also produce a second type of pulmonary reaction

involving pneumonic complications and characterized by shortness of
breath on exertion and cough.
A sensorimotor peripheral neuropathy has been associated with nitrofurantoin, and is seen most often in patients with impaired renal function.
Nitrofurantoin has also been reported to produce megaloblastic anemia
and cholestasis. In patients deficient in glucose-6-phosphate dehydrogenase,
the drug can produce hemolysis.
IMIPENEM PLUS CILASTATIN

Actions
Imipenem is a beta-lactam bactericidal antibiotic that inhibits cell wall synthesis in aerobic and anaerobic gram-positive and gram-negative bacteria.
It is metabolized to inactive potentially nephrotoxic derivatives by a dihydropeptidase enzyme located in the brush border of the proximal renal
tubules. Because of this, only very low concentrations of imipenem can be
found in the urine.
Cilastatin blocks the metabolism and inactivation of imipenem in the
kidney. By combining cilastatin with imipenem, it is possible to attain antibacterial concentrations of imipenem in the urine.
Imipenem has a wide spectrum of activity. Most aerobic and anaerobic
gram-positive and gram-negative species are susceptible. Imipenem owes
its activity to 3 major factors:
1. It readily penetrates the cell wall of gram-positive and gram-negative
bacteria.
2. It is highly resistant to the activity of most beta-lactamases, whether
they are of plasmid or chromosomal origin.
3. It preferentially binds to a critical penicillin-binding protein, PBP-2.
Uses
Neither imipenem nor cilastatin is appreciably absorbed from the GI tract;
therefore, they must be injected. The combination of imipenem and cilastatin is used to treat serious infections caused by sensitive bacteria.
Lower respiratory tract infections, urinary tract infections, intraabdominal and gynecologic infections, and septicemia caused by susceptible bacteria may be treated with imipenem plus cilastatin.
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Endocarditis caused by Staphylococcus aureus may also be treated with

the combination, as can bone, joint, and skin-structure infections produced
by susceptible bacteria.
Adverse Effects
The combination of imipenem and cilastatin is generally well tolerated. The
most common adverse effects include nausea, diarrhea, and vomiting.
However, imipenem plus cilastatin can produce severe allergic reactions.
Therefore, this combination should be administered with caution to any
patient who has demonstrated some form of allergy, particularly to structurally related drugs (eg, penicillins, cephalosporins). If an allergic reaction
occurs to imipenem plus cilastatin, stop the drug. Serious hypersensitivity
reactions may require epinephrine and other emergency measures.
33
Drugs for Systemic Fungal
Infections
Pharmacotherapy Of Systemic Fungal Infections
Systemic fungal infections constitute a major therapeutic problem and can
have a significant fatality rate. Systemic opportunistic infections occur
commonly in debilitated and immunosuppressed patients. The more
common infections include candidiasis, aspergillosis, cryptococcosis, and
phycomycosis.
The treatment of systemic fungal infections is unsatisfactory. Only a
limited number of drugs are presently available, and their use is often associated with severe adverse effects. Their use is further complicated by the
fact that patients with systemic mycotic infections may be seriously ill with
other diseases. Although antibiotics or antibacterials are sometimes used
to treat systemic mycotic infections (eg, penicillin G; erythromycin; a
cephalosporin, tetracycline, or clindamycin for actinomycosis; a sulfonamide, erythromycin, or tetracycline for nocardiosis), the number of fungal infections that respond to antibiotic/antibacterial therapy is limited.
Most systemic mycotic infections require treatment with drugs that were
specifically designed to interfere with various aspects of fungal metabolism. These drugs are presented below.
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PDQ PHARMACOLOGY
AMPHOTERICIN B
Actions
Amphotericin B owes its fungistatic activity to its ability to interact with
fungal membrane sterol ergosterol and increase membrane permeability.
Small molecules leak from sensitive fungal cells and amino acid uptake is
impaired. Amphotericin B does not affect bacteria, with the exception of
Mycoplasma, because bacterial cell membranes do not contain sterols.
Mammalian cells do contain sterols, and this partly explains amphotericin
Bs human toxicity.
Antifungal Spectrum
Amphotericin B has a broad spectrum of activity. It is effective against Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, and Sporothrix schenckii.
Pharmacokinetics
Because amphotericin B is poorly absorbed from the GI tract, it must be
administered by IV. Amphotericin B has an initial half-life of 24 hours.
However, because it is extensively stored in body tissues, the drug has a second half-life of 15 days. Although amphotericin B crosses the blood-brain
barrier, its concentration in the CSF is lower than its level in blood. Its major
route of excretion is extrarenal.
Uses
Amphotericin B is used to treat patients with progressive, potentially fatal
disseminated mycotic infections. It can be used to treat opportunistic infections in immunosuppressed patients caused by Candida, Cryptococcus, and
Torulopsis. Because amphotericin B does not diffuse well into the CSF,
intrathecal administration may be required for CNS infections.
Adverse Effects
Amphotericin B must be used with care. The most common early effect is
an acute febrile reaction beginning about 2 hours after starting the infusion
and peaking approximately 1 hour later.
Amphotericin B can produce a dose-dependent azotemia. Reversible
normocytic, normochromic anemia is common with prolonged therapy.
Hypersensitivity reactions are not usual. However, amphotericin B can
produce generalized pain, seizures, and anaphylactic shock. It can also
cause headache, fever, chills, anorexia, and vomiting.
Chapter 33
Drugs for Systemic Fungal Infections
273
FLUCYTOSINE
Actions
Flucytosine is a fungistatic structural analogue of cytosine, an essential component in body functions. Once taken up into fungal cells via cytosine permease, flucytosine is deaminated by fungal cytosine deaminase to form fluorouracil (5-FU) and fluorodeoxyuridine monophosphate. Fluorouracil is
incorporated into fungal RNA and inhibits protein synthesis.
Antifungal Spectrum
Flucytosine inhibits the growth of Cryptococcus neoformas, Candida albicans, Torulopsis glabrata, Sporothrix schenckii, Cladosporium species, and
Phialophora species, the fungi responsible for chromomycosis. Resistance
has been reported to flucytosine. This may reflect a deficiency in the
enzymes involved in the transport of the drug into the cytoplasm, or it may
be due to a compensatory ability of the organism to increase its rate of
pyrimidine synthesis.
Pharmacokinetics
Flucytosine is well absorbed and can be found in the serum 30 minutes after
oral administration. It is widely distributed in body fluids and readily crosses
the blood-brain barrier to enter the CSF. Because flucytosine is excreted primarily by the kidneys, its dosage schedule must be modified in patients with
impaired renal function. Flucytosine has a half-life of 3 to 5 hours.
Uses
Flucytosine is used to treat serious infections caused by susceptible strains
of Candida or Cryptococcus, or both. Flucytosine passes easily into the CSF
and enters the aqueous humor and bronchial secretions in concentrations
adequate to inhibit sensitive fungi. It has effectively treated septicemia,
endocarditis, and urinary tract infections caused by Candida, as well as
meningitis and pulmonary infections caused by Cryptococcus. Other uses for
flucytosine include the treatment of chromomycosis caused by Fonsecaea
pedrosoi, Cladosporium carrioni, and Phialophora verrucosa. Because resistance may develop during therapy, flucytosine is usually combined with
amphotericin B.
Adverse Effects
Flucytosines principal adverse effects are reversible neutropenia, together
with occasional thrombocytopenia. Flucytosine can also cause nausea,
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PDQ PHARMACOLOGY
eosinophilia, and skin rashes. It is also capable of producing reversible hepatic

dysfunction. Patients sometimes experience confusion, hallucinations,
headache, and vertigo. A few cases of irreversible bone marrow failure have
been reported. Flucytosines metabolite, fluorodeoxyuridine monophosphate,
(see Actions above) inhibits DNA synthesis and is probably responsible for
bone marrow depression. Patients with a limited bone marrow reserve, such
as individuals receiving cytotoxic drug treatment, may be prone to develop
hematologic adverse effects when treated with flucytosine.
3. AZOLE ANTIFUNGAL DRUGS

Fluconazole, Itraconazole, Ketoconazole
Actions
Fluconazole and itraconazole are called triazoles because they contain
three nitrogens in an azole ring.
Ketoconazole is classified as an imidazole because it contains two nitrogens in an azole ring.
All azole antifungal drugs bind to the heme iron of cytochrome P-450
and inhibit the demethylation of 14-alpha-methyl-sterols to ergosterol.
Ergosterol is the main sterol in the fungal cell membrane. Inhibiting its formation alters the permeability of the fungal cell membrane. Both fluconazole and itraconazole have greater specificity for fungal cytochrome P-450
than for the mammalian cytochrome. This may account for the relatively
low toxicity of the triazoles compared with the imidazoles.
Antifungal Spectra
Fluconazole has broad-spectrum activity and is effective in the treatment of aspergillosis, blastomycosis, candidiasis, cryptococcosis, and
histoplasmosis.
Itraconazole has an antifungal spectrum similar to that of ketoconazole
(see below), except that it is also active against Aspergillus species and
Sporothrix schenckii.
Ketoconazole is effective against a variety of fungi and yeasts, including Blastomyces dermatitidis, Candida, Coccidioides immitis, Histoplasma
capsulatum, and dermatophytes.
Pharmacokinetics
Fluconazole, with an oral bioavailability of over 90%, can be given orally
or by IV. Fluconazole penetrates all body tissues and fluids, and its apparent volume of distribution approximates that of the total body water. Its ter-
Chapter 33
Drugs for Systemic Fungal Infections
275
minal half-life is approximately 30 hours, allowing for once-daily dosing.

Because fluconazoles rate of elimination decreases as kidney function falls,
its dosage should be reduced in patients with renal impairment.
Itraconazoles oral absorption is variable and requires a low gastric pH.
Food enhances itraconazole absorption. The drug is concentrated in
lipophilic tissues. Itraconazole is metabolized by the liver and excreted in
the bile and has a plasma half-life of 30 to 35 hours after multiple doses.
Ketoconazole is well absorbed from the GI tract, but it is best absorbed
at low pH values. Drugs that increase gastric pH reduce ketoconazole
absorption. Ketoconazole is distributed widely throughout the tissues and
tissue fluids but does not reach therapeutic concentrations in the CNS
unless high doses are given. The drug is inactivated in the liver and excreted
in the bile and urine. Its plasma half-life is 8 hours.
Uses
Fluconazole is used to treat oropharyngeal and esophageal candidiasis. It is
also effective for the treatment of serious systemic candidal infections,
including urinary tract infections, peritonitis, and pneumonitis. Fluconazole
is also indicated for the treatment of cryptococcal meningitis. It is also used
to prevent cryptococcal meningitis recurrence in patients with AIDS. Oral
fluconazole has also been approved for the treatment of vaginal candidiasis.
Itraconazole is indicated for the treatment of the following infections
in normal, predisposed, or immunocompromised patients: invasive and
noninvasive pulmonary aspergillosis, oral/esophageal candidiasis, chronic
pulmonary histoplasmosis, cutaneous and lymphatic sporotrichosis, paracoccidioidomycosis, chromomycosis, and blastomycosis.
Ketoconazole is used to treat serious life-threatening systemic fungal
infections in normal, predisposed, or immunocompromised patients for
whom alternative therapy is considered inappropriate or has been unsuccessful. This includes systemic candidiasis, chronic mucocutaneous candidiasis, coccidioidomycosis and paracoccidioidomycosis, histoplasmosis,
and chromomycosis. Ketoconazole is not indicated in the treatment of CNS
fungal infections because it poorly penetrates the CNS.
Adverse Effects
Fluconazoles most serious adverse effects appear to be exfoliative skin disorders and hepatic necrosis. Immunocompromised patients (especially
those with AIDS) who develop rashes during treatment with fluconazole
should be monitored carefully. If lesions progress, fluconazole should be
stopped. Patients with baseline abnormal liver function tests, and those who
develop abnormal liver function tests during fluconazole therapy, should be
monitored for the development of more severe hepatic injury. Other adverse
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PDQ PHARMACOLOGY
effects of fluconazole include nausea, headache, skin rash, vomiting, abdominal pain, and diarrhea.
Itraconazoles most common adverse effects involve the GI tract,
including nausea. These are followed by dermatologic reactions (rash and
pruritus), headache, and effects involving the respiratory system. For therapy longer than 30 days, liver function should be monitored.
Ketoconazoles most common adverse effects are nausea and pruritus.
Patients may also experience headache, dizziness, abdominal pain, constipation, diarrhea, somnolence, and nervousness. Concern is greatest for possible hepatotoxic effects. Cases of fatal massive hepatic necrosis have been
reported and liver function should be monitored periodically. Ketoconazole
can block adrenal steroid synthesis. Approximately 10% of men experience
gynecomastia.
34
Viral Infections
Characteristics of Viruses and Difficulties in Developing Selective Antiviral Drugs
Viruses are among the simplest living organisms. Composed of a protein
coat and one or more strands of a linear or helical nucleic acid core, (either
DNA or RNA), a mature virus can exist outside a host cell and still retain
its infective properties. However, to reproduce, the virus must enter the host
cell, take over the cells mechanism for nucleic acid and protein synthesis,
and direct the host cell to make new viral particles. Viruses are essentially
intracellular parasites that utilize many of the biochemical mechanisms and
products of the host cell to sustain their viability. This makes it difficult to
find a drug that is selective for the virus that does not interfere with host
cell function.
This chapter will be divided into two parts:
Drugs for the treatment of AIDS

Drugs for the treatment of some other common viral infections
B. DRUGS FOR THE TREATMENT OF AIDS

Acquired immunodeficiency syndrome (AIDS) is caused by a retrovirus called
the human immunodeficiency virus (HIV). Retroviruses are a subgroup of RNA
viruses which, in order to replicate, must first reverse transcribe their RNA
genome into DNA. Once in the form of DNA, the viral genome is incorporated
into the host cell genome, allowing it to take full advantage of the host cells tran-
277
278
PDQ PHARMACOLOGY
scription/translation machinery for the purpose of replication. Anti-AIDS

drugs are used to:
1. attack the virus (anti-HIV drugs), or

2. to treat infections that have arisen as a result of the hosts reduced
immune response (supportive therapy).
1. Anti-HIV Drugs
Multiplication of HIV
HIV possesses an envelope glycoprotein (gp120) with a high affinity for the
CD4 receptor on host T-helper cells. As a result, the HIV binds to the T cell
and fuses with the lymphocyte surface membrane. Thereafter, the virus loses
its coat and releases its RNA core and reverse transcriptase enzyme into the
host cell cytoplasm (Figures 341 and 342). The HIV reverse transcriptase
copies the RNA message, producing a double-stranded proviral DNA, which
enters the host cell nucleus and becomes incorporated into the host chromosomal DNA. The incorporated viral DNA may remain dormant or, on activation, produce viral messenger RNA (mRNA). The viral mRNA codes for
proteins that are important in viral replication. Glycoproteins will then
envelop the RNA genome, resulting in the production of infectious viral particles. The completed viral particles are then released to infect other host cells.
Actions of Anti-HIV Drugs
Three classes of antiviral drugs are currently used to treat HIV infections:
Nucleoside and Nucleoside Analogue Reverse Transcriptase Inhibitors

(NRTIs)
Non-nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)
Protease Inhibitors (PIs)
Table 341 lists some currently available NRTIs, NNRTIs, and PIs.
Table 341
Currently Available Anti-HIV Drugs

NRTI
NNRTI
PI
Abacavir
Didanosine
Lamivudine
Stavudine
Zalcitabine
Zidovudine
Delaviridine
Efavirenz
Nevirapine
Indinavir
Nelfinavir
Ritonavir
Saquinavir
NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase

inhibitor; PI = protease inhibitor.
Chapter 34
Drugs for the Treatment of Viral Infections
Virus to cell infection

HIV
T Cell
279
Cell to cell infection

Infected cell
gp 120
CD4
Uninfected cell
Infected cell
soluble
CD4
Uninfected cell
Figure 341 HIV infective mechanism. Virus to cell infection (upper left): The gp120 knob-like
surface protein contacts the CD4 receptor on T lymphocytes or other cells. The virus fuses with
the cell and RNA is uncoated (middle left). If soluble CD4 molecules are present, they can bind
to the gp120 projections on the HIV and prevent infection of the host cell (lower left). Cell to
cell infection: Once a cell is infected, it can infect noninfected cells by fusion of processed surface gp120 with CD4 receptors of the uninfected cells (upper right). By fusion of infected and
multiple noninfected cells, a multinucleated giant cell can be produced (middle right). If soluble CD4 proteins exist, cell-to-cell fusion could be prevented (lower right). HIV = human
immunodeficiency virus; gp = glycoprotein; RNA = ribonucleic acid. (After Van Dyke K. Drugs
used in acquired immunodeficiency syndrome. In: Craig CR, Stitzel RE, editors. Modern pharmacology. 4th ed. New York: Little Brown; 1994.)
These drugs target two events in the HIV replication cycle:

1. Reverse transcription of the viral RNA into double-stranded proviral
DNA by the viral reverse transcriptase (NRTIs and NNRTIs)
2. Processing of the viral precursor protein by viral protease (ie, assembly
of the viral particles) (PIs)
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PDQ PHARMACOLOGY
HIV
T Cell
1 VIRUS
ATTACHES
gp120
REVERSE
2 TRANSCRIPTION
Double stranded region
CD4
Viron RNA
infective
plasmid
mRNA
3 TRANSCRIPTION
INTEGRATION
INTO HOST DNA
Viron RNA
Protein coat
4 TRANSLATION
AND ASSEMBLY
5 RELEASE
Glycoprotein
envelope
Figure 342 Steps that occur in viral infection and replication. Step 1: HIV infection of a T
cell. The gp120 viral knob attaches to a CD4 lymphocyte receptor. Step 2: HIV viral RNA produces a DNA copy using reverse transcriptase. The linear DNA has long terminal repeats at each
end that are complementary, and can participate in the formation of a partly double-stranded
DNA plasmid. This infective plasmid migrates into the nucleus of the host cell and integrates
into its DNA. Step 3: Transcription. At some point, host DNA, RNA, and protein synthesis is shut
off and viral RNA and protein synthesis is turned on, resulting in transcription of RNA. Step 4:
Translation. Translation into protein and assembly of viral particles surrounded by an envelope
glycoprotein now occur. Step 5: Release of the completed virus. HIV = human immunodeficiency
virus; gp = glycoprotein; RNA = ribonucleic acid; DNA = deoxyribonucleic acid. (After Van Dyke
K. Drugs used in acquired immunodeficiency syndrome. In: Craig CR, Stitzel RE, editors. Modern Pharmacology. 4th ed. New York: Little Brown; 1994.)
Uses
Anti-HIV drugs are used in combination in order to delay the development
of drug resistance.
Initial therapy for patients with a high viral load usually involves two
NRTIs plus a PI.
In patients who can comply with these regimens, dramatic reductions in viral load are seen.
The disadvantage of starting with a regimen that uses agents from
more than one class is that when drug failure eventually occurs,
resistance to several classes of drugs can exist, thereby limiting the
choices available for rescue therapy.
The alternative approach for initial therapy is using only NRTI drugs.
Chapter 34
281
This approach has the advantage of reserving the potent PI class or

the NNRTI class as key components for future therapy.
However, combinations containing three NRTI drugs have not been
as potent as regimens containing two NRTIs and one PI. As a result,
triple NRTI combinations have only been used as initial therapy in
patients who present with a low to moderate viral load.
Published data appear to demonstrate that replacing a PI with abacavir in combination with two other NRTIs (lamivudine and
zidovudine) does not result in a loss of clinical efficacy. This protocol could save a PI for the day when resistance to NRTI therapy
develops.
For patients with previous exposure to antiretroviral therapy, treatment should include:
the addition of at least two new agents, or
a switch to a completely new triple therapy that should ideally have no
overlapping resistance or toxicity with previously available therapy.
Adverse Effects
All anti-HIV drugs have the potential to produce severe adverse effects.
NRTIs frequently produce nausea, abdominal pain, diarrhea, headache,
insomnia, myalgia, and peripheral neuropathy. Hypersensitivity reactions
are a potential problem with some NRTIs.
NNRTIs can produce rash, nausea, fatigue, somnolence, headache, and
hepatotoxicity. Nevirapine has also been reported to produce StevensJohnson syndrome.
PIs can also produce diarrhea, abdominal discomfort, and nausea. It is
their ability to increase triglycerides, produce diabetes, and induce lipodystrophies that frequently causes the greatest concern because they can
alert others to the HIV status of the patient. Some PIs have also been
reported to produce allergic reactions, including urticaria, mild skin eruptions, bronchospasm, and angioedema. Hepatic transaminase elevations,
clinical hepatitis, and jaundice have also been reported with PIs.
Nephrolithiasis is an adverse effect of indinavir.
2. Supportive Therapy
People with AIDS are susceptible to opportunistic infections (ie, infections
that would not normally be found in patients with normal defence mechanisms). The appropriate use of antibiotics, antifungals, and antivirals can
significantly prolong life in HIV-infected individuals. Table 342 summarizes the management of selected HIV-associated infections.
Many of the drugs used as supportive therapy in AIDS patients are
described elsewhere. Three drugs not otherwise presented are summarized
here.
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PDQ PHARMACOLOGY
Foscarnet Sodium
Actions
Foscarnet inhibits the DNA polymerase of human herpes viruses and the
reverse transcriptase of HIV at a different site from nucleoside analogues,
such as ganciclovir, acyclovir, or zidovudine. In vitro, foscarnet inhibits
replication of cytomegalovirus (CMV), herpes simplex (HSV) 1 and 2, varicella zoster (VZV), and HIV at concentrations easily achieved with parenteral therapy.
Uses
Foscarnet is administered by IV to treat CMV retinitis in patients with
AIDS. It can also be used to treat ganciclovir-resistant CMV infections. Fos-
Table 342
Management of Selected HIV-Associated Infections

Infection
Treatment
Candida species
Mucosal candidal infections
Esophageal candidiasis
Severe discomfort or esophageal
disease requires systemic therapy
Thrush topical treatment

Nystatin suspension swished and
swallowed, or vaginal tablet, sucked
Clotrimazole vaginal tablet sucked or
clotrimazole troche
Vaginal infection
Miconazole or clotrimazole vaginal
cream or suppository
Systemic oral therapy
Fluconazole is first choice
Ketoconazole or itraconazole are
alternatives
Esophageal disease
Fluconazole or amphotericin B
Cryptococcus neoformans
Major cause of meningitis in later
stages of HIV infection (in 10% of
AIDS patients)
Ongoing prophylactic therapy
required after treatment of acute
infection
Induction therapy
Amphotericin B flucytosine for 2 weeks,
then completion of 12-week course with
fluconazole
Maintenance therapy
Fluconazole or amphotericin B weekly
Continued
Chapter 34
283
Table 342
Management of Selected HIV-Associated InfectionsContinued

Infection
Treatment
Cytomegalovirus (CMV)
Retinitis with visual disturbances
is most common manifestation
Enteritis, colitis, pneumonitis,
encephalitis, myelitis, and neuritis
can also occur
Prognosis is poor without therapy
Life-long maintenance therapy
required after initial therapy for
CMV retinitis
Induction therapy
Ganciclovir or foscarnet
Maintenance therapy
Ganciclovir or foscarnet
Mycobacterium avium complex (MAC)

Symptoms: fever, weight loss,
fatigue, and night sweats either
alone or with diarrhea, anemia,
lymphadenopathy, hepatitis
Multidrug regimens
Usually include clarithromycin or
azithromycin + ethambutol 13
additional drugs (such as rifampin or
rifabutin, ciprofloxacin, clofazimine, and
amikacin)
Pneumocystis carinii
Primary cause of pneumonia in
HIV-positive patients with CD4
< 200 cells/mm2
All patients at risk should receive
prophylaxis
Commonly presents as persistent
fever with progressive shortness
of breath and cough, often with
normal chest radiograph
Standard therapy
Cotrimoxazole, or pentamidine,
or dapsone + trimethoprim
Other therapies
Atovaquone, clindamycin + primaquine,
trimetrexate + folinic acid
Prednisone
Addition of prednisone in severe
PCP decreases morbidity and
side effects of cotrimoxazole
Toxoplasma gondii
Up to 50% of HIV-positive patients
with antibodies to this parasite will
develop toxoplasma encephalitis
as CD4 fall below 200 cells/mm3
Most commonly presents as fever
with focal neurologic signs
Standard Therapy
Pyrimethamine + folinic acid + sulfadiazine
Alternatives
Pyrimethamine + folinic acid +
(clindamycin or azithromycin), or
(clarithromycin, dapsone, or atovaquone)
Maintenance therapy
Pyrimethamine + sulfadiazine + folinic
acid, or pyrimethamine + clindamycin +
folinic acid
HIV = human immunodeficiency virus; PCP = Pneumocystis carinii pneumonia. After Gregson DB.
Opportunistic infections in HIV-positive patients. In: Therapeutic Choices, Canadian Pharmacists
Association. 3rd ed., 2000. p. 798809.
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PDQ PHARMACOLOGY
carnet appears to be the drug of choice for the treatment of acyclovir-resistant HSV and VZV infections.
Adverse Effects
Nephrotoxicity is the most common dose-limiting adverse effect of foscarnet. Foscarnet binds divalent metal ions, such as calcium. Metabolic abnormalities (eg, hypocalcemia, hypomagnesemia, hypophosphatemia), which
are all apparently related to this effect, occur commonly. Foscarnet can also
produce hypokalemia. High maintenance doses of foscarnet cause a
decrease in ionized calcium (with normal total serum calcium concentrations) that may cause neurologic and cardiac toxicity. Other adverse effects
include nausea, seizures, neutropenia, neuropathy, arrhythmia, nephrogenic
diabetes insipidus, and penile ulcers.
Ganciclovir
Ganciclovir is a synthetic nucleoside analogue that inhibits the replication
of herpes viruses. Ganciclovir is used to treat CMV retinitis in immunocompromised individuals, such as patients with AIDS, those with iatrogenic immunosuppression secondary to organ transplantation, or those
undergoing chemotherapy for neoplasia. Ganciclovirs most frequent
adverse effects involve the hematopoietic system (eg, neutropenia and
thrombocytopenia).
Pentamidine
Pneumocystis carinii pneumonia (PCP) occurs in approximately 80% of
AIDS patients and is a significant cause of death. Current therapies for PCP
are cotrimoxazole (Chapter 32) and parenteral pentamidine. Either therapy
is effective but adverse effects limit their potential. Pentamidine should be
given parenterally only in a hospital with facilities to monitor blood glucose,
blood counts, and renal and hepatic function. Fatalities due to severe
hypotension, hypoglycemia, and cardiac arrhythmias have been reported in
patients treated with parenteral pentamidine. Profound severe hypotension
may result after a single dose.
Aerosolized pentamidine isethionate once a month is effective in preventing recurrence of PCP in AIDS patients.
Chapter 34
285
DRUGS FOR THE TREATMENT OF SOME OTHER COMMON

VIRAL INFECTIONS
Acyclovir
Actions
Acyclovir is metabolized to acyclovir triphosphate, which inhibits DNA
polymerase and viral multiplication in herpes simplex types 1 and 2, varicella zoster, herpes simiae (B virus), and Epstein-Barr virus.
Uses
When injected, acyclovir is used to treat initial and recurrent mucosal and
cutaneous herpes simplex infections in immunocompromised adults and
children. Injectable acyclovir is also used for severe initial episodes of herpes simplex infections in patients who may not be immunocompromised.
Oral acyclovir may be used in the treatment of an initial episode of herpes genitalis and the suppression of unusually frequent recurrences of herpes genitalis.
Acyclovir is applied topically for management of initial episodes of genital herpes simplex infections. The topical preparation is also used for the
management of non-life-threatening cutaneous herpes simplex viral infections in immunocompromised patients.
Adverse Effects
Acyclovir appears to be a relatively safe drug, but a few patients have experienced delirium. A causal relationship to acyclovir has not been established.
Other reported adverse effects include inflammation and/or phlebitis at the
injection site, and diaphoresis, hematuria, hypotension, headache, and
nausea. Hives have been reported in some patients after acyclovir injection.
Oral acyclovir may produce nausea and vomiting, headache, diarrhea,
skin rash, vertigo, and arthralgia.
Topical acyclovir may produce discomfort.
Amantadine
Actions and Uses
Amantadine may inhibit penetration of influenza A viruses into the host
cell or reduce the uncoating of those viruses that do penetrate the cell.
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PDQ PHARMACOLOGY
Amantadine is used in the prevention and treatment of respiratory infections caused by influenza A virus strains. It may have its greatest value in
patients at high risk of developing influenza because of underlying disease,
such as the elderly in hospitals or nursing homes. Amantadine does not
interfere with immunization, and patients may receive amantadine while
waiting for the effects of immunization to develop. If used to treat an
influenza A virus infection, amantadine must be started within 48 hours
of the onset of symptoms.
Adverse Effects
Amantadine is generally well tolerated. The more important adverse effects
are orthostatic hypotensive episodes, congestive heart failure, depression,
psychosis, and urinary retention.
Idoxuridine
Actions and Uses
Idoxuridine is incorporated into viral DNA, destabilizing the nucleic acid
and altering viral protein synthesis. Ophthalmic idoxuridine is used topically to treat herpes simplex keratitis. Epithelial infections, especially initial
attacks, characterized by the presence of a dendritic figure, are highly
responsive to idoxuridine. Infections located in the stroma have shown a less
favorable response. In recurrent cases, idoxuridine will often control the
current episode of the viral infection, but scarring from previous infections
will not be corrected.
Adverse Effects
Idoxuridine can cause clouding of the cornea and small defects in the
corneal epithelium. It may also cause local irritation, itching, mild edema,
and photophobia.
Ribavirin
Actions and Uses
Ribavirin is active against the respiratory syncytial (RS) virus. Its mechanism of action is not known. Ribavirin is approved only for lower respiratory tract infections due to the RS virus. Ribavirin aerosol treatment must
be accompanied by (and does not replace) standard supportive respiratory
and fluid management for infants and children with severe respiratory tract
infections.
Chapter 34
287
Adverse Effects
Serious adverse effects that have occurred during ribavirin therapy have
included worsening of respiratory status, bacterial pneumonia, and pneumothorax. It is not clear whether these effects are related to the use of
ribavirin.
Trifluridine
Actions and Uses
Trifluridine is phosphorylated by a cellular thymidine kinase to its
nucleotide monophosphate. Trifluridine monophosphate and its metabolites inhibit the following DNA viruses: herpes simplex types 1 and 2, varicella zoster, adenovirus, and vaccinia virus. Trifluridine is approved for the
treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex viruses types 1 and 2.
Adverse Effects
The most common adverse effects are burning on instillation and superficial punctate keratitis.
Inhibitors of Influenza Virus Neuraminidase (Oseltamivir and

Zanamivir)
Actions and Uses
Oseltamivir and zanamivir are potent selective inhibitors of neuraminidase,
the influenza virus surface enzyme that aids the release of newly formed virus
particles from infected cells. Neuraminidase may also facilitate access of the
influenza virus through mucus to epithelial cell surfaces, enabling the virus
to infect other cells. By inhibiting the action of neuraminidase, oseltamivir and
zanamivir reduce the spread of influenza A and B viruses by suppressing the
release of infectious virions from the epithelial cells of the respiratory tract.
Oseltamivir is converted to its active metabolite oseltamivir carboxylate following oral administration. Oseltamivir is approved for the treatment of uncomplicated illness due to influenza infection in adults who have
been symptomatic for no more than 2 days.
Zanamivir is administered as a dry powder by oral inhalation, allowing high concentrations of the drug to act extracellularly to inhibit viral
neuraminidase. Zanamivir is approved for the treatment of uncomplicated
acute illness due to influenza virus in patients 12 years and older, who have
been symptomatic for no more than 2 days.
288
PDQ PHARMACOLOGY
Adverse Effects
Oseltamivirs most frequent adverse effects in clinical trials were nausea
and vomiting. Events were transient and generally occurred with first dosing.
Zanamivir is well tolerated when inhaled by young adults. In clinical
studies in young adults, the incidence of adverse effects reported was similar in the zanamivir and placebo groups.
35
Anticancer Drugs
(Antineoplastic Drugs)
GENERAL COMMENTS
Goal of Cancer Chemotherapy
The goal of cancer chemotherapy is to kill malignant tumor cells and spare
host cells. This is called selective toxicity. Selective toxicity forms the basis
of all antibiotic, antifungal, and antiviral therapy previously presented.
However, selective toxicity is relatively easy to achieve in anti-infective
therapy because mammalian cells and bacterial cells, for example, differ
markedly in their structure and metabolic processes. Selective chemotherapy is not, however, easy to achieve in cancer treatment because normal and
malignant cells often do not differ markedly. Therefore, it is virtually
impossible to kill large numbers of cancer cells without destroying at least
some normal cells.
Cells Killed by Anticancer Drugs
Anticancer drugs suppress all proliferating cells, both normal and neoplastic. This effect accounts for their major toxicities on such rapidly dividing
cells as bone marrow, GI and germinal epithelia, hair follicles, and lymphoid
organs. Thus, successful anticancer therapy is defined differently than successful anti-infective treatment. Successful antineoplastic treatment
depends on killing malignant tumor cells with doses of anticancer drugs
that allow recovery of normal proliferating cells. To understand how this can
be achieved, it is important to review the relationship of cellular growth
fraction to cancer chemotherapy.
289
290
PDQ PHARMACOLOGY
RELATIONSHIP OF GROWTH FRACTION TO SUCCESS OF

CHEMOTHERAPY
The Cell Cycle
Figure 351 presents the cell cycle. Every cell that divides passes through
specific phases before undergoing mitosis.
During the synthesis (S) phase, lasting from 6 to 50 hours, DNA synthesis increases and chromosomal material doubles.
Thereafter, the cell proceeds through the G2 phase, lasting about 6 hours,
during which time a series of biochemical events occur that prepare the
cell for mitosis.
After mitosis (the M phase), new cells enter the G1 phase. Depending
on the cells involved, G1 may last minutes or years.
Cell progressing through G1, S, G2. and mitosis are said to be in cycle.
Cells not actively dividing are said to be in the G0 phase.
Growth Fraction
Every tissue, whether normal or neoplastic, has a portion of its cells that are
not actively dividing. They can be found side by side with dividing cells. The
number of cells in cycle divided by the total number of cells in the tissue is
the growth fraction. The growth fraction does not remain constant. Larger
tumors have smaller growth fractions. If the size of the tumor is reduced,
daughter cells
G2
mitosis
DNA synthesis
G0
S
G1
nuclear trigger
interphase functions
(cell growth;
differentiation)
Figure 351 The cell cycle.
Chapter 35
Anticancer Drugs
291
either by surgery, radiation, or antineoplastic drugs, more resting cells

begin to cycle.
Cells in cycle
Resting cells
Relative Efficacy of Anticancer Drugs Against Cells in Cycle Versus Resting Cells
Anticancer drugs are more effective against proliferating cells than cells in
G0 because antineoplastic agents usually kill cells by disrupting either DNA
synthesis or mitosis, functions that occur only in proliferating cells. Thus,
as a general rule, antineoplastic drugs are much more toxic to tissues that
have a high growth fraction than to tissues whose growth fraction is low.
Solid tumors (eg, those of the lung, breast, stomach, colon, and rectum)
have a low growth fraction and often respond poorly to anticancer
drugs.
Disseminated tumors (eg, leukemias and lymphomas) have a high
growth fraction and generally respond well to antineoplastic drugs.
Combination Chemotherapy
Cancer chemotherapy that uses a combination of drugs is considerably
more effective than therapy with just one drug. The benefits of combination therapy are:
(a) suppression of drug resistance,
(b) enhancement of therapeutic effects, and
(c) reduced injury to normal cells.
If several drugs are selected with different mechanisms of action, drug
resistance occurs less frequently and more malignant cells are killed.
Because PDQ Pharmacology is a small book, intended to assist students grasp the concepts that underlie the use of groups of drugs, space
does not allow a discussion of the merits of the various combinations of
anticancer drugs used to treat each disease. Suffice it to say that most cancers are routinely treated with a combination or cocktail of several antineoplastics.
DRUG RESISTANCE
Explanations for Resistance to Anticancer Drugs
Some patients treated with cancer chemotherapy fail to respond from the
outset. In such patients, their cancers are resistant to drug therapy. Initial
292
PDQ PHARMACOLOGY
drug resistance can be explained by the fact that cancers are not composed
of homogeneous cells. Rather, human tumors contain various subpopulations of cells that differ genetically and structurally from one another
some are sensitive to a particular drug, others are not. Given the large number of cells present within most tumors at the time of diagnosis, it seems
likely that at least one resistant subpopulation will be present for each individual anticancer drug. Killing of the sensitive cells leads to the proliferation of the resistant. The use of combination chemotherapy, whereby all
cells in a tumor may respond to at least one drug, reduces the chance that
this form of drug resistance will develop.
Other patients initially respond, and subsequently relapse. For these
individuals, their cancers have developed resistance to chemotherapy. Figure 352 presents the major mechanisms of cellular resistance to anticancer
drugs.
Resistance to an anticancer drug can develop at its site of action. Resistance develops to methotrexate, for example, because of an alteration
in the structure of the target enzyme, dihydrofolate reductase, which
results in reduced drug affinity.
Tumor cells may become resistant to anticancer drugs because they
either fail to take up or retain sufficient drug. This type of resistance is
called multidrug resistance. It is the major form of resistance shown to
anthracyclines, vinca alkaloids, etoposide, paclitaxel, and dactinomycin.
Drug activation
(eg. kinases)
Enzyme targets
(eg. dihydrofolate reductase)
DNA repair
(topoisomerases)
Tubulins
Drug transport
(eg. P-glycoprotein)
Detoxification
(eg. glutathione transferases)
Figure 352 Cellular resistance to anticancer drugs. After Sikic BI. The rational basis for cancer chemotherapy. In: Craig CR, Stitzel RE, editors. Modern Pharmacology. 4th ed. Boston: Little Brown; 1994. p. 66372.
Chapter 35
Anticancer Drugs
293
Multidrug resistance results from the production of a high-molecularweight membrane protein called the P-glycoprotein, which acts to
increase the efflux of antineoplastic drugs out of the cells.
Resistance can develop to alkylating agents because of changes in cell
DNA repair capabilities, increases in thiol content (which serves as
alternative and benign targets of alklylation), decreases in cell permeability, and increases in glutathione transferase activity. The last phenomenon increases the cellular detoxification of alkylating agents.
Some drugs must be metabolically activated to function as anticancer
agents. These include the antimetabolites 6-fluorouracil and 6-mercaptopurine. These drugs may be ineffective if a tumor is lacking the
enzymes required for their activation. The reverse is also true. Some
drugs, such as cytarabine and bleomycin, can be metabolically inactivated by resistant tumors.
CLASSIFICATION OF ANTINEOPLASTIC DRUGS

1. Classification Based on Cell Cycle
Cell-Cycle Independent Antineoplastics
Antineoplastics are characterized as cell-cycle independent if they affect cells
during any phase of the cycle, including resting or G0 cells.
Cell-Cycle Dependent Antineoplastics
Anticancer drugs are considered to be cell-cycle dependent if they affect
only cells that are actively cycling at the time of exposure to the drug. Antineoplastics may also be phase dependent if one specific phase of the cycle
is the principle target of drug action. For example, the vinca alkaloids vinblastine, vincristine, vindesine, and vinorelbine block mitosis and are considered phase-dependent drugs.
2. Classification Based on Mechanism of Action or Source of

Drug (Table 351)
Alkylating Agents
By definition, alkylating agents introduce alkyl groups into nucleophilic
sites on other molecules. Their most important targets are the pyrimidine
and purine bases in DNA. These drugs interfere with RNA transcription,
thereby inhibiting cell growth and causing death. The degree to which each
drug can alkylate DNA correlates well with its cytotoxicity. This interaction
294
PDQ PHARMACOLOGY
Table 351
Classification of Antineoplastic Drugs According to

Mechanism of Action or Source of Drug
Classification
Drug
Alkylating agents
Busulphan, Carboplatin, Carmustine

(BCNU), Chlorambucil, Cisplatin, Cyclophosphamide, Dacarbazine, Ifosfamide,
Lomustine (CCNU), Mechlorethamine
HCl (Nitrogen Mustard), Melphalan,
Streptozocin, Thiotepa
Cladribine, Cytarabine (Cytosine
Arabinoside), Floxuridine, Fludarabine,
Fluorouracil (5-FU), Hydroxyurea,
Mercaptopurine (6-MP), Methotrexate
(Amethopterin), Thioguanine
Bleomycin, Dactinomycin (Actinomycin D),
Daunorubicin (Daunomycin),
Doxorubicin, Idarubicin, Mitomycin,
Pentostatin, Plicamycin (Mithramycin)
Docetaxel, Etoposide, Paclitaxel,
Teniposide, Vinblastine, Vincristine,
Vindesine, Vinorelbine
Aminoglutethimide, Buserelin,
Flutamide, Goserelin, Leuprolide,
Megestrol, Mitotane, Tamoxifen,
Testolactone
Asparaginase, Procarbazine
Antimetabolites
Antitumor antibiotics
Plant-derived products
Hormones and drugs that affect

hormone secretion or action
Miscellaneous antineoplastics
also accounts for the mutagenic and carcinogenic properties of the alkylating agents. By attaching to components of DNA molecules, alkylating
agents inhibit DNA replication and transcription, leading to cell death.
Antimetabolites
The antimetabolites listed in Table 351 are structurally similar to important chemicals in the body. These structural similarities allow antimetabolites to compete with normal body metabolites for vital enzymes. If an
antimetabolite replaces a normal metabolite on a vital enzyme, it blocks
reactions that are essential to cell function and life.
Methotrexate is similar in structure to dihydrofolate, a metabolite of

folic acid, and it competes with dihydrofolate for binding to the enzyme
dihydrofolate reductase. The reduction of dihydrofolate by dihydrofolate reductase is essential in the transfer of single carbon units that are
Chapter 35
Anticancer Drugs
295
necessary in DNA and purine synthesis. When methotrexate competes

successfully with dihydrofolate for binding sites on dihydrofolate reductase, it inhibits DNA and purine synthesis.
Cytosine, thymine, and uracil are pyrimidines. They are employed in the
biosynthesis of DNA and RNA. Cytarabine and 5-FU are two
antimetabolites of pyrimidines. Like all pyrimidine antimetabolites,
these drugs are metabolized into compounds that are structurally very
similar to pyrimidines. Because of this structural similarity, the drugs
can replace pyrimidines in key metabolic reactions and cause cell death.
Adenine, guanine, and hypoxanthine are purines. Purines, like pyrimidines, are used in the synthesis of DNA and RNA. Administering a
purine analogue, such as thioguanine, 6-MP, or fludarabine, blocks vital
metabolic functions and kills cells.
Antitumor Antibiotics
Bleomycin, dactinomycin, daunorubicin, doxorubicin, idarubicin, mitomycin, and plicamycin are cytotoxic compounds produced by microorganisms. These drugs produce their cytotoxic effects through direct interaction with DNA. Bleomycin, for example, binds to DNA and produces both
single- and double-strand breaks and fragmentation of DNA.
Plant-Derived Products
Several important antineoplastics are derived from plants.
The vinca alkaloids vinblastine, vincristine, vindesine, and vinorelbine

are either naturally occurring or semisynthetic products derived from
the Vinca rosea plant (periwinkle). They bind strongly to tubulin, a class
of proteins that form the mitotic spindle during cell division. They disrupt mitotic spindle formation during mitosis at the metaphase of the
cell cycle. Cell death results from an inability to segregate chromosomes.
Vinca alkaloids are usually regarded as M-phase specific in the cell cycle.
Paclitaxel is a naturally occurring chemical that is obtained from the yew
tree (genus Taxus). It binds specifically and reversibly to tubulin and stabilizes microtubules in the polymerized form. Stabilization of microtubules disrupts mitosis and kills cells.
Docetaxel is a semisynthetic anticancer drug that belongs to the taxoid
family. It is a mitotic spindle poison that increases the rate of microtubule assembly and inhibits the depolymerization of microtubules.
Etoposide is a semisynthetic derivative of podophyllotoxin that is produced in the roots of the American mandrake, or May apple. Its mechanism of action is poorly understood. However, it produces a singlestrand breakage of DNA. Etoposide is most lethal to cells in the S and
G2 phases of the cell cycle.
296
PDQ PHARMACOLOGY
Hormones and Drugs that Affect Hormones

Estrogens, progestins, androgens, and corticosteroids are used in the treatment of various cancers.
Estrogens are employed in the treatment of prostatic cancer and in the

management of five-year postmenopausal breast tumors.
Androgens are sometimes given to premenopausal patients with mammary cancer.
Progestins are used on occasion to treat kidney and endometrial carcinomas.
Corticosteroids, particularly prednisone, are administered in high doses
to patients with lymphomas and some other cancers.
The rationale behind the use of these drugs is the belief that some cancers are hormone dependent. For example, if a prostatic cancer is androgen
dependent, treatment with estrogens, together with castration, may be reasonable. The converse is also true. If breast cancer in premenopausal
patients is estrogen dependent, the use of androgens may make sense. Corticosteroids induce a regression of lymphoid tissue by causing a breakdown
of existing lymphocytes and inhibiting the production of new lymphocytes.
Tamoxifen competitively blocks estrogen receptors. Certain forms of

cancer, notably breast cancer in premenopausal women, often depend
on endogenous estrogens for growth. When given in high doses, tamoxifen prevents endogenous estrogens from stimulating their receptors
and significantly reduces cancer growth.
Flutamide inhibits androgen uptake and/or nuclear binding of androgen in target tissues. Flutamide is used in combination with luteinizing
hormonereleasing hormone (LHRH) agonist analogues (such as
leuprolide acetate) for the treatment of metastatic prostatic carcinoma.
Leuprolide and buserelin are synthetic derivatives of gonadotropin-releasing hormone (GnRH/LHRH). Chronic exposure of the pituitary to these
agents abolishes gonadotropin release and results in markedly decreased
estrogen and testosterone produced by the gonads. These drugs are used
for palliative treatment of patients with hormone-dependent advanced
carcinoma of the prostate. They are also useful in breast cancer.
Goserelin acetate is also a synthetic analogue of GnRH. Administered
chronically, goserelin inhibits gonadotropin production, resulting in
gonadal and accessory sex organ regression. Goserelin is approved for
the palliative treatment of patients with hormone-dependent advanced
carcinoma of the prostate.
Chapter 35
Anticancer Drugs
297
Miscellaneous Antineoplastics
Asparaginase is an enzyme extracted from cultures of Escherichia coli. It
converts asparagine to aspartic acid. Certain cancers are unable to make
asparagine and are dependent on the blood to bring them adequate
amounts of asparagine. In the absence of asparagine, because of its hydrolysis to aspartic acid by asparaginase, the cells cannot proliferate. Asparaginase is not toxic to normal cells, which have the ability to synthesize
asparagine.
Procarbazine is converted to an active metabolite in the liver of patients.
Following activation, it can cause chromosomal damage and suppress
DNA, RNA, and protein synthesis.
ADVERSE EFFECTS OF ANTINEOPLASTIC DRUGS

Antineoplastic drugs are cellular poisons that kill both malignant and normal cells. As previously stated, the selective toxicity seen with antibiotics
in which the drug preferentially attacks the microbe, leaving the host largely
unaffectedis not seen with antineoplastics. For example, a drug that
blocks DNA or RNA synthesis and/or function will damage both normal
and malignant cells. This is particularly true for cell-cycle independent
drugs. Cell-cycle dependent drugs will also damage both normal and neoplastic tissue, but these agents show a selectivity for tissues with the highest percentage of cells in cycle. This means that they can rapidly kill both
cancer cells and normal cells with a rapid turnover (eg, bone marrow, GI
tract, hair). They also damage the immune system, resulting in a fall in the
production of both T and B lymphocytes.
Particular Systems At Risk
The hematopoietic system is particularly at risk when antineoplastic
drugs are administered. Patients often show pancytopenia as the production of red cells, white cells, and platelets decreases. The decrease in
platelets predisposes patients to hemorrhage. A decrease in neutrophils,
together with the fall in B and T lymphocytes, places patients at risk of
infections.
The mucosal cells of hollow organs normally have a rapid rate of
turnover. By inhibiting cell duplication, antineoplastics damage the GI and
genitourinary (GU) tracts, leading to ulceration and bleeding.
Hair and nails are damaged by antineoplastics and alopecia and baldness are common adverse effects.
298
PDQ PHARMACOLOGY
Antineoplastics increase tissue breakdown, raising both the purine

load and the production of uric acid, possibly leading to kidney damage.
Some antineoplastics can produce significant nerve damage. Vinca
alkaloids do this by interfering with microtubular structures important to
nerve function.
Anticancer drugs often produce nausea and vomiting. These effects are
particularly pronounced with cisplatin.
Doxorubicin and daunomycin can cause cardiac arrhythmias and,
eventually, heart failure.
Procarbazine is metabolized to a monoamine oxidase inhibitor and can
produce the CNS effects characteristic of these drugs (see Chapter 21).
Patients should be warned to refrain from eating or drinking foods containing tyramine (eg, cheese, red wine).
Index
Note: Page numbers
followed by (t) indicate tables; those followed by (f) indicate
figures.
A
Abacavir, 278281,
278t
Acarbose, 150
ACE inhibitors. See
Angiotensinconverting enzyme
(ACE) inhibitors
Acebutolol, 5759,
58t, 7980t, 85,
9394
Acetaminophen,
218220, 219f
Acetohexamide,
147148
Acetylcholine
actions of, 21
inactivation of, 22,
23f
role in parkinsonism, 203205,
205f
synthesis of, 22, 23f
Acetylsalicylic acid
(ASA)
actions of, 131,
131f, 215216,
215f, 221222
adverse effects of,
216218
metabolism of, 217f

pharmacokinetics,
216
uses of, 131, 216
Acids, 2
Acyclovir, 285
Adenosine, 89
Adrenal corticosteroid(s). See Glucocorticoid(s);
Mineralocorticoids;
Sex hormones
Adrenal insufficiency,
156
Adrenaline. See
Epinephrine
Adrenergic drugs. See
also Epinephrine;
Norepinephrine
classifications of,
39f
directly acting, 37,
38f
indirectly acting, 49
structures of, 39f
Adrenergic receptor
blockers, 51, 5561
Adrenergic
receptor(s), 2526,
38f
Agonist(s), 1315, 15f
AIDS. See HIV/AIDS
Akathisia, from
antipsychotics, 172t
Albuterol/salbutamol,
4546
Aldosterone
effect on
reabsorption, 113
synthesis and
secretion of, 157
Alfentanil, 211214
Alkylating agents,
293294, 294t
Allopurinol, 227
Alpha and beta
blocker(s),
6061, 103
Alpha blockers
actions of, 51, 52f,
5556
combined with
other antihypertensive drugs,
105106t
for hypertension,
103
uses of, 5556
Alpha1 postsynaptic
receptors, 25, 38f
Alpha2 presynaptic
receptors, 26, 38f
Alpha-methyldopa,
54, 54f, 104
Alpha-methyltryosine, 51, 53
Alprazolam, 184189
Alteplase, 135
Amantadine, 209,
285286
Amdinocillin, 234f,
243
Amdinocillin pivoxal,
243
299
300
Amikacin, 252255
Amiloride, 116
Aminocaproic acid,
135136
Aminoglycosides
actions of, 252
adverse effects of,
255
antibacterial spectra of, 252253
pharmacokinetics,
253254
resistance to, 253
uses of, 254255
Aminopenicillins,
241242
Amiodarone, 80t, 86
Amitriptyline,
175177
Amlodipine, 95, 102
Amobarbital, 191192
Amoxicillin, 234f,
237t, 238t, 241242
Amphotericin B, 272
Ampicillin, 237t, 238t,
241242
Amrinone, 75
Analgesics
agonist-antagonist
narcotic, 213,
214t
for migraine
headaches, 231
narcotic, 211213,
214t
non-narcotic,
215220
Androgens, 165166
for cancer, 296
Anemia, 166
Angina pectoris, 9091
Angiotensin II receptor antagonists
combined with
105106t
for hypertension,
101
Angiotensin-converting enzyme (ACE)
inhibitors
actions of, 6870,
68f, 69f, 100f,
101f
adverse effects of,
70, 101
for CHF, 6870,
68f, 69f
combined with
105106t
for hypertension,
100101, 100f,
101f
uses of, 70, 100101
Antagonism,
competitive, 16, 16f
Antagonist(s), 13, 14
Anti-adrenergic
drugs, 5061. See
also Adrenergic
receptor blockers;
Sympathetic
depressant drugs
Antiandrogens, 167
Anti-anginal drugs,
9096, 91f
Antiarrhythmic drugs
class IA, 7879t,
8183, 81t
class IB, 79t, 8384
class IC, 79t, 8485
class II, 7980t, 85
class III, 80t, 8687
class IV, 80t, 8788

classification of, 78f
miscellaneous,
8889
Antiarthritic drugs,
221225
Antibiotics. See also
specific names
aminoglycoside,
252255
beta lactam,
233247
fluoroquinalone,
256258, 257f
macrolide, 248251
miscellaneous,
259270
tetracycline,
262265
Anticancer drugs
actions of, 289291
adverse effects of,
297298
classification of,
293297, 294t
resistance to,
291293, 292f
Anticholinergic drugs
adverse effects of,
210
chemical structure
of, 36f
mechanism of
action of, 3334,
209
for parkinsonism,
209210
uses of, 3536,
209210
Anticholinesterases,
2933. See also
Cholinesterase
inhibitors
Index
Anticoagulant drugs,
128130
Antidepressant drugs,
175182. See also
specific types
Antidiuretic hormone, 113
Antiepileptic drugs,
193202
Antiestrogens, 161
Antifungal drugs,
271276
Antigout drugs,
225228
Anti-HIV drugs,
278281, 278t
Antihyperlipidemic
drugs, 118125
Antihypertensive
drugs, 97106, 98f,
105106t, 105t
Antimalarial drugs,
for arthritis, 223
Antimetabolites, for
cancer, 294295,
294t
Antimigraine drugs,
229232
Antineoplastic drugs.
See Anticancer drugs
Antiparkinsonian
drugs, 203210
Antiplatelet drugs,
131132
Antipseudomonal
penicillins, 234f,
237t, 238t, 242243
Antipsychotic drugs
atypical, 168t,
171174
typical, 168171,
168t, 169f, 170f,
172t
Antitumor antibiotics, 294t, 295

Antiviral drugs,
277288
Anxiolytics, 184190
Aprotinin, 136
ASA. See Acetylsalicylic acid (ASA)
Asparaginase, 297
Aspirin. See Acetylsalicylic acid (ASA)
Atenolol
actions, 58t, 59, 80t,
85, 9394
adverse effects of, 59
for angina, 9394
for hypertension,
9798
uses of, 59, 98
Atorvastatin, 123124
Atracurium, 6263
Atropine, actions of,
3336
Auranofin, 223
Aurothioglucose, 223
Autonomic nervous
system
characteristics of, 18
of the eye, 29t, 30f
functions of, 18
parasympathetic
division of, 19f, 20
sympathetic division
of, 19f, 20
Autonomic neurotransmitters, 2122
Autonomic receptors,
2526
Azathioprine, 224
Azithromycin,
248251
Azlocillin, 238t,
242243
301
Azole antifungal
drugs, 274276
B
Bacampicillin, 238t,
241242
Barbiturates, 191192
Bases, 2
Benserazide, 207
Benzafibrate, 122
Benzapril, 100101
Benzodiazepine(s)
actions, 184
adverse effects of,
189190
antagonist, 190
metabolism, 185f
pharmacokinetics,
184187
properties of, 186t
tolerance and
dependence,
187188
uses of, 188189
Benztropine mesylate,
209210
Benzylpenicillin, 234f,
237t, 238t, 239
Beta agonists, 4447,
44f
Beta blockers
56, 59, 93, 98f,
142
adverse effects of,
57, 5960, 85
for angina, 9394
for arrhythmias,
7980t, 85
cardioselective, 59
combined with
other antihyper-
302
tensive drugs,
105106t
differences among,
58t
distribution of, 57t
for hypertension,
9798
for hyperthyroidism, 142
for migraine
headaches,
229230
non-selective,
5657
partial agonist,
5960
uses of, 57, 5960,
94, 98
Beta lactam antibiotics. See
Cephalosporins;
Penicillin(s)
Beta1 postsynaptic
receptors, 26, 38f
Beta2 postsynaptic
receptors, 26, 38f
Betaxolol, 58t, 59
Bioavailability, 10
Biperiden HCL,
209210
Bipolar disorders,
182183
Blood clotting factors,
128t, 129f
Blood-brain barrier,
56, 7f
Bretylium, 80t, 8687
Bromazepam,
184189
Bromocriptine, 208
Bronchodilators,
4547, 46f
Bumetanide, 115116
Bupropion, 181
Buserelin, 296
Buspirone, 190191
Butabarbital, 191192
Butorphanol, 213,
214t
Cefaclor, 245246,
245t
Cefadroxil, 245t
Cefamandole, 245t
Cefazolin, 245t
Cefixime, 245t,
246247
Cefoperazone, 245t
C
Ceforanide, 245t
Calcium channel
Cefotaxime, 245t
blockers
Cefoxitin, 245t
actions of, 9395,
Ceftazidime, 245t
94t, 102
Ceftizoxime, 245t
adverse effects of,
Ceftriaxone, 245t
96
Cefuroxime, 245t
for angina, 9496
Celecoxib, 222223
for cardiac arrhyth- Cell cycle, 290, 290f
mias, 80t, 8788
Cell-cycle dependent
cardiovascular
antineoplastics, 293
effects of, 94t
Cell-cycle independcombined with
ent antineoplastics,
other antihyper293
tensive drugs,
Central sympathetic
105106t
inhibitors, 104,
for hypertension,
105106t
102
Cephalexin, 246t
for migraine
Cephalosporins
headaches, 231
actions of, 233, 236f
uses of, 8788,
adverse effects of,
9596, 102
247
Calcium entry blockantibacterial specers. See Calcium
tra of, 244, 246t
channel blockers
currently available,
Candida species infec245t
tion, in HIV, 282t
injectable, 244245
Captopril, 6870,
oral effectiveness,
100101, 101f
245247
Carbamazepine, 197
resistance to, 247
Carbidopa, 207
structure of, 234f
Carbonic anhydrase,
Cephalothin, 246t
113
Cephapirin, 246t
Cardiac arrhythmias, Cephradine, 246t
7678
Chemotherapy
Index
combination, 291
principles of,
289291
resistance to,
291292, 292f
CHF. See Congestive
heart failure
Chloral hydrate, 192
Chlordiazepoxide,
184189
Chloroquine, 223
Chlorpropamide,
147148
Chlorthalidone,
99100, 114115
Cholestyramine,
122123
Cholinergic drugs,
2733
pharmacologic
properties of, 29t
types of, 28f
uses of, 2728
Cholinergic receptors,
25
Cholinesterase
inhibitors
effects of, 29, 31t
irreversible, 33, 33f,
35f
mechanisms of
action of, 3031,
33, 34f, 35f
reversible, 3031,
32f, 34f
uses of, 31, 33
Chylomicrons, 119
Cilastatin. See
Imipenem plus
cilastatin
Cilazapril, 100101
Ciprofloxacin,
256258, 257f
Clarithromycin,
248251
Clearance, 1112
Clobazam, 202
Clofibrate, 122
Clomiphene, 161
Clomipramine,
175177
Clonazepam, 202
Clonidine, 51, 55, 104
Clorazepate, 184189
Cloxacillin, 234f, 237t,
238t, 240241
Clozapine, 173
Coagulation, 128t,
129f
Codeine, 211214
Colchicine, 226
Colestipol, 122123
Congenital adrenal
hyperplasia, 156
Congestive heart failure (CHF)
causes of, 6465
compensating
mechanisms, 64,
66f
drug treatment of,
6675, 67f
edema formation
in, 65f
Cortisol. See
Glucocorticoid(s)
Cotrimoxazole
adverse effects of,
261262
antibacterial
spectrum,
259260
pharmacokinetics,
260f, 261, 261f
resistance to,
260261
303
structure of, 260

uses of, 261
Cryptococcus
neoformans
infections, in HIV,
282t
Cyclooxygenase-2
(COX-2) inhibitors,
222223
Cytomegalovirus
(CMV) infections,
in HIV, 282t
D
Dalteparin, 129130
Delaviridine,
278281, 278t
Demeclocycline. See
Tetracyclines
Depression. See
Antidepressant
drugs
Desipramine, 175177
Diabetes mellitus
diagnosis of,
143144
non-drug treatment, 145
type 1, 145147
type 2, 147150
Diazepam, 184187,
186t, 202
Diazoxide, 104
Diclofenac, 221222
Dicloxacillin, 237t,
238t, 240241
Didanosine, 278281,
278t
Diflunisal, 218
Digoxin, 7275, 88
electrical actions, 73f,
74t
304
Dihydroergotamine,
232
Dihydropyridines,
9496, 94t
Diltiazem
actions of, 80t,
8788, 94t, 95,
102
adverse effects of,
96, 102
uses of, 88, 9596,
102
Dipyridamole, 132
Disopyramide, 78t,
81t, 82
Diuretics
111f, 114f, 115t
adverse effects of,
67
combined with
other
antihypertensive
drugs, 105106t
loop, 115116
osmotic, 117
potassium-sparing,
116117
thiazides, 114115
uses of, 6667,
99100
Divalproex sodium,
201
Dobutamine, 45, 75,
109
Docetaxel, 295
Dopamine, 48, 75,
109
role in
parkinsonism,
203205, 204f,
205f
structure of, 39f
Dopamine agonist,
for parkinsonism,
208
Dopamine releasing
drug, for
parkinsonism, 209
Dopaminergic drugs,
for parkinsonism,
205209
Dose-response
relationships, 1417
Doxacurium, 6263
Doxazosin, 56, 103
Doxepin, 175177
Doxycycline. See
Tetracyclines
Drug absorption, 13
Drug administration,
routes of, 34
Drug distribution in
body, phases of,
56, 5f, 6f
Drug elimination,
710, 9f, 11f
Drug metabolism,
710, 9f, 11f
Drug receptors, 1314
Drug(s). See also specific names
adrenergic, 3749
analgesic, 211220
anti-adrenergic,
5061
anti-anginal, 9096,
91f
antiarrhythmic,
7880t, 7889,
78f
antiarthritic,
221225
anticancer, 289298
anticholinergic,
3336
anticoagulant,
128130
antidepressant,
175182
antiepileptic,
193202
antifungal, 271276
antigout, 225228
antihyperlipidemic,
118125
antihypertensive,
97106, 98f
antimalarial, for
arthritis, 223
antimigraine,
229232
antiparkinsonian,
203210
antipsychotic,
168174, 168t,
169f, 170f
antiviral, 277288
anxiolytic, 184190
cholinergic, 2733,
28f
for congestive
heart failure,
6675
for diabetes
mellitus, 145150
dopaminergic, for
parkinsonism,
205209
fibrinolytic,
133134, 134f
hemostatic agents,
135136
for HIV/AIDS,
277284
for
hyperlipidemias,
118125
hypnotic, 190192
Index
seizure pattern
classification of,
194t
symptoms of,
193194, 195f
Epinephrine
actions of, 22, 38,
4142, 108
compared with
norepinephrine,
3839, 40t, 41f
inactivation of, 22
structure of, 39f
synthesis of, 22, 24f
uses of, 42, 108
Ergotamine, 232
Erythromycin,
248251
Esmolol, 58t, 59, 80t,
85
Estrogens
actions of, 158159
adverse effects of,
E
161
for cancer, 296
Ectopic pacemakers,
control of secretion
7677
of, 158, 159f
Efavirenz, 278281,
pharmacokinetics
278t
of, 159160
Emboli, 126127, 127f
uses of, 160
Enalapril, 6870,
Ethacrynic acid,
100101
115116
Endometriosis, 160
Ethosuximide,
Enoxacin, 256258,
200201
257f
Enoxaparin, 129130 Etoposide, 295
Entacapone, 207208 Expanded-spectrum
penicillins, 234f,
Ephedrine, 49
237t, 238t, 241243
Epilepsy
Eye
choice of drug
autonomic
therapy for, 196t
innervation of,
etiologic classifica29t, 30f
tion of, 193t
for hypotension and
shock, 107110
inotropic, 7275
ionized, 12
for mood disorders,
175183
movement across
membranes, 13,
1f, 3f
neuromuscular
blocking, 6263
nonionized, 12
placental transfer
of, 6, 8f
renal excretion of, 7,
9f
in solution, 12
Dysmenorrhea, 160
Dystonic reactions,
172t
from antipsychotics,
172t
305
uses of anticholinergic drugs in,

3536
uses of
cholinesterase
inhibitors in, 31,
33
F
Felodipine, 94t,
9596, 102
Fenofibrate, 122
Fenoprofen, 221222
Fenoterol, 4546
Fentanyl, 211214
Fibrates, 122
Fibrinolytic drugs,
133135, 134f
Fibrinolytic
inhibitors, 135136
Finasteride, 167
Flecainide, 79t, 84
Flucloxacillin, 237t,
238t, 240241
Fluconazole, 274276
Flucytosine, 273274
Flumazenil, 190
Flunarizine, 231
Fluoroquinalones,
256258, 257f
Fluoxetine, 177178
Flurazepam, 184187,
186t, 187f, 188f
Flurbiprofren,
221222
Flutamide, 296
Fluvastatin, 123124
Fluvoxamine,
177178
Foscarnet sodium,
282284
Fosinopril, 100101
306
Furosemide
actions of, 99,
115116
adverse effects of,
116
uses, 99100,
115116
5-hydroxytryptamine1Glyburide, 147148
Gold compounds, 223
like receptor
Gold sodium
agonist, 232
thiomalate, 223
Hyperlipidemia
causes of, 120121,
Goserelin acetate,
121t
296
treatment of,
Gout, 225, 226f
121125
Growth fraction,
Hypertension,
290291
G
pharmacologic
Guanethidine, 51, 52,
Gabapentin, 199
approach to, 105t
9899
Gallamine, 6263
Hyperthyroidism,
Ganciclovir, 284
140142
H
Ganglionic blockers,
Hypnotics, 190192
36
Half-life, 12
Hypotension,
Gemfibrozil, 122
HDL, 120
107110
Hypothyroidism,
Gentamicin, 252255, Hemostatic agents,
139140
253t
135136
Glicazide, 147148
Heparin, 128129
Glucocorticoid(s)
low-molecular
I
actions of, 151153,
weight, 129130
154f
HIV/AIDS
Ibuprofen, 221222
adverse effects of,
drug treatment of,
Idoxuridine, 286
154155
277284
Imipenem plus
comparison of, 155t
mechanism of
cilastatin, 269270
dosage protocols,
infection, 279f,
Imipramine, 175177
156157
280f
Impulse conduction,
mechanisms of
supportive therapy
disorders of, 77, 77f
actions of, 151,
for, 281284
Indinavir, 278281,
153f, 153t, 154f
Hydralazine
278t
receptors in tissues, actions of, 71, 102
Indomethacin,
153t
adverse effects of,
221222
replacement
71, 103
Infliximab, 225
therapy, 156
combined with
Inhalation adminisuppressive therapy,
other
stration of drugs, 4
156157
antihypertensive Inotropic drugs, 67f,
synthesis and
drugs, 105106t
7275
secretion of, 151,
uses of, 71, 102
Insulin, 145147
Hydroxychloroquine,
152f
adverse effects of,
223
synthetic, 155156,
147
5-hydroxytryptamine
155t
drugs that increase
(5-HT) antagonists,
uses of, 156157,
secretion of,
147149
224
230
Index
drugs that increase

tissue sensitivity
to, 149
regimens, 146t
for type 2 diabetes,
150
types of, 145t
Intrinsic activity,
1415
Ionized drugs, 12
Irbesartan, 101
Isoproterenol, 4445,
46f
Isosorbide dinitrate,
9293
Isosorbide mononitrate, 9293
Isradipine, 9596, 102
Itraconazole, 274276
K
Ketazolam, 184189
Ketoconazole,
274276
Ketoprofen, 221222
Ketorolac, 218
Kidney(s). See also
Nephron
role in excretion of
drugs, 7, 9f
Levarterenol. See
Norepinephrine
Levodopa, 205208,
206f
Levorphanol, 211214
Levothyroxine, 140
Lidocaine, 79t, 83
Liothyronine, 140
Lisinopril, 6870,
100101
Lithium carbonate,
182183
Lomefloxacin,
256258, 257f, 258
Loop diuretics,
115116
Lorazepam, 184187,
186t, 202
Losartan, 101
Lovastatin, 123124
L-thyroxine, 140
L-triiodothyronine,
140
Macrolides
actions of, 248
adverse effects of,
251
antibacterial spectra of, 248249
pharmacokinetics,
L
249250
Labetalol, 6061, 103
resistance to, 249
uses of, 250251
Lamivudine, 278281,
Manic-depressive ill278t
ness, 182183
Lamotrigine, 199200
Latent pacemakers, 76 Mannitol, 117
LDL, 119
Maprotiline, 175177
drugs affecting,
Mecillinam. See
122124
Amdinocillin
Menadione, 136137
Leuprolide, 296
307
Menstrual cycle, 159f

Meperidine, 211214
Metabolism of drugs,
710
Metformin, 149
Methacycline. See
Tetracyclines
Methicillin, 237t,
238t, 240241
Methimazole (MMI),
141142
Methotrexate, for
arthritis, 224
Methoxamine, 43
Methyldopa, 51, 54,
54f, 104
Methyltyrosine, 51, 53
Methysergide, 230
Metocurine, 6263
Metolazone, 99100,
114
Metoprolol
actions of, 59,
7980t, 9394
uses of, 85, 9394,
9798
Metyrosine, 53
Mexiletine, 78t, 83
Mezlocillin, 238t,
242243
Migraine headaches,
229
Mineralocorticoids,
157
Minocycline. See
Tetracyclines
Mivacurium, 6263
Moclobemide,
178180
Monoamine oxidase
inhibitors
(MAOIs), 178180,
179f
308
Monoamine oxidase
type B (MAO-B)
inhibitors, 208209
Moricizine, 79t, 84
Morphine, 211214
Muscarinic receptors,
25
Mycobacterium avium
complex (MAC)
infections, in HIV,
282t
N
Nadolol
actions of, 5657,
58t, 7980t,
9394
adverse effects of,
57
uses of, 57, 85,
9394, 9798
Nalbuphine, 213, 214t
Naloxone, 214
Naproxen, 221222
Narcotic analgesics
adverse effects of,
213
agonist-antagonist,
213, 214t
effects of, 211212
mechanisms of
action, 211
pharmacokinetics,
212
uses of, 213
Narcotic antagonists,
214
Narrow-spectrum,
penicillinaseresistant pencillins,
234f, 237t, 238t,
240241
Nefazodone, 177178
Nelfinavir, 278281,
278t
Nephron
consequences of
reducing sodium
reabsorption,
115t
percentage of water
and sodium in,
111t
reabsorption from,
111f, 112t, 113,
114f
Netilmicin, 252255
Neuraminidase
inhibitors, 287288
Neuromuscular
blocking drugs,
6263
Neurotransmitters,
2124, 21f
Nevirapine, 278281,
278t
Niacin, 124125
Nicardipine, 9596,
102
Nicotinic acid. See
Niacin
Nicotinic receptors,
25
Nifedipine, 9596,
102
Nitrates
for angina pectoris,
9293
for congestive heart
failure, 68
Nitrazepam, 184189
Nitrofurantoin,
268269
Nitroglycerin, 9293,
110
NNRTIs, 278281
Nofloxacin, 256258
Nonionized drugs,
12
Non-narcotic analgesics, 215220
Non-nucleoside analogue reverse transcriptase inhibitors
(NNRTIs), 278281
Non-steroidal antiinflammatory drugs
(NSAIDs)
for arthritis,
221222
for gout, 226
for migraine
headaches, 231
for pain, 218
Noradrenaline. See
Norepinephrine
Norepinephrine
actions of, 22,
3839, 40t, 43,
109
adverse effects of,
43
compared with
epinephrine,
3839, 40t, 41f
inactivation of, 22,
26f
for shock, 109
structure of, 39f
synthesis of, 22, 24f,
26f
uses of, 43, 109
Norfloxacin, 256258
Nortriptyline, 175177
NRTIs, 278281
NSAIDs. See Nonsteroidal antiinflammatory drugs
Index
Nucleoside and
nucleoside analogue reverse transcriptase inhibitors
(NRTIs), 278281
Nylidrin, 47
Parkinsonian effects,
from antipsychotics, 172t
Parkinsonism,
203204
Paroxetine, 177178
Partial agonists, beta
blockers, 5960
O
Penicillamine, 223
Ofloxacin, 256258,
Penicillin G, 234f,
257f
237t, 238t, 239
Olanzapine, 173174 Penicillin V, 234f,
Opioids. See Narcotic
237t, 238t, 239
analgesics
Penicillin(s)
Oral administration
actions of, 233,
of drugs, 4
235f, 236f
Oral anticoagulants,
adverse effects of,
130
243
Oral contraceptives
allergic reactions to,
(OCs), 163,
244t
164165t
antibacterial specOrganic nitrates,
tra of, 238t
9293
combined with a
Oseltamivir, 287288
beta-lactamase
Osmotic diuretics, 117
inhibitor, 243
Oxazepam, 184189
expanded-specOxprenolol, 58t,
trum, 234f, 237t,
5960, 9798
238t, 241243
Oxycodone, 211214
narrow-spectrum,
Oxymorphone,
penicillinase211214
resistant, 234f,
Oxytetracycline. See
237t, 238t,
Tetracyclines
240241
pharmacokinetics
of, 239
P
properties of, 237t
Pacemakers, 7677
structure of, 234f
Paclitaxel, 295
Pentamidine, 284
Pancuronium, 6263 Pentazocine, 213, 214t
Paracetamol, 218220 Pentobarbital,
Parenteral
191192
administration of
Pharmacodynamics,
drugs, 4
1317
309
Phenelzine, 178180
Phenobarbital,
197198
Phenothiazines, 168t
Phentolamine, 5556
Phenylephrine, 43
Phenytoin
actions of, 79t, 83,
195
adverse effects of,
197
pharmacokinetics,
195
uses of, 8384,
196197
Pindolol, 58t, 5960,
80t, 85, 9798
Pioglitazone, 149
Piperacillin, 237t,
238t, 242243
Pipercuronium,
6263
Piroxicam, 221222
PIs. See Protease
inhibitors
Pivampicillin, 238t,
241242
Pivmecillinam. See
Amdinocillin
pivoxal
Pizotyline, 230
Placental transfer, 6,
8f
Plant-derived
antineoplastic
drugs, 295
Plasma lipoproteins
classification of,
118119t
origins of, 119120,
120f
rational for
lowering, 118
310
Plasma protein binding, albumin, 5

Pneumocystis carinii
infection, in HIV,
282t
Potassium iodide, 142
Potassium-sparing
diuretics, 116117
Potency, 15
Pravastatin, 123124
Prazosin, 56, 103
Prednisone, for cancer, 296
Primidone, 198
Probenecid, 227228
Probucol, 125
Procainamide, 78t,
8182, 81t
Procarbazine, 297
Procyclidine HCL,
209210
Progesterone, 162163
Progestins, 162163,
296
Propafenone, 84t, 85
Propoxyphene,
211214
Propranolol
actions of, 5657,
58t, 7980t, 9394
uses of, 57, 85,
9394, 9798,
229230
Propylthiouracil
(PTU), 141142
Protease inhibitors
(PIs), 278281
Protriptyline, 175177
Q
Quinapril, 100101
Quinidine, 78t, 8182,

81t
R
Raloxifene, 162
Ramipril, 100101
Receptors,
autonomic, 2526
Rectal administration
of drugs, 4
Remifantil, 211214
Renal excretion of
drugs, 7
Repaglinide, 148149
Reserpine, 51, 5253,
9899
Resins, 122123
Ribavirin, 286287
Risperidone, 174
Ritodrine, 47
Ritonavir, 278281,
278t
Rocuronium, 6263
Rofecoxib, 222223
Rosiglitazone, 149
S
Salbutamol, 4546
Salmeterol, 4546
Saquinavir, 278281,
278t
Secobarbital,
191192
Selective estrogen
receptor modulator
(SERM), 162
Selective serotonin
reuptake inhibitors
(SSRIs), 177178
Selegiline, 208209
Sertraline, 177178
Sex hormones,
158167, 296
Shock, 107110
Simvastatin, 123124
Sodium iodide, 142
Sodium nitroprusside, 7172, 104,
109110
Sodium valproate,
201
Sotalol, 80t, 87
Spironolactone, 116
Stable angina, 9091
Statins, 122123
Stavudine, 278281,
278t
Steady state, 12
Streptokinase,
133134
Strong iodine solution, 142
Sublingual
administration of
drugs, 3
Succinylcholine, 63
Sufentanil, 211214
Sulfinpyrazone, 132
Sulfonylureas,
147148, 148f
Sulindac, 221222
Sumatriptan, 232
Sympathetic depressant drugs, 5155,
51f
Sympatholytics. See
Anti-adrenergic
drugs
Sympathomimetics,
3749, 108109
T
Tamoxifen, 161, 296
Index
Tardive dyskinesia,
from antipsychotics,
172t
Temazepam, 184189
Terazosin, 56, 103
Terbutaline, 4546
Testosterone, 165166
Tetracycline HCL. See
Tetracyclines
Tetracyclines
actions of, 262
adverse effects of,
265
antibacterial
spectrum, 264t
pharmacokinetics,
262264
resistance to, 262
uses of, 265
Thiazides, 99100,
114115
Thiazolidinediones,
149
Thrombi, 126127
Thyroid gland,
138139
Thyroid hormones,
139f
Thyroid storm, 141
Tiaprofenic acid,
221222
Ticarcillin, 234f, 237t,
238t, 242243
Ticlopidine, 133
Timolol, 5657, 58t,
80t, 9394
Tissue plasminogen
activator (TPA), 135
Tobramycin, 252255,
253t
Tocainide, 79t, 84
Tolazoline, 5556
Tolbutamide, 147148
Tolmetin, 221222
Toxoplasma gondii, in
HIV, 282t
Tranylcypromine,
178180
Trazodone, 180
Triamterene, 116
Triazolam, 184187,
187f, 188f, 189f
Tricyclic
antidepressants,
175177, 175t, 176f,
230
Trifluridine, 287
Trihexyphenidyl
HCL, 209210
Trimethoprim plus
sulfamethoxazole
(TMP/SMZ). See
Cotrimoxazole
Tubocurarine, 6263
311
Variant angina,
9091
Vasodilators, 47, 67f,
100104, 109110
Vecuronium, 6263
Venlafaxine, 181
Venodilators, 9899
Verapamil
actions of, 80t,
9495, 94t, 102
adverse effects of,
88, 96
cardiovascular
effects of, 94t
uses of, 8788,
9596, 102
Vigabatrin, 200
Vinblastine, 295
Vinca alkaloids, 295
Vincristine, 295
Vindesine, 295
Vinorelbine, 295
Vitamin K, 136137
VLDL, 119
drugs affecting, 122
W
U
Urokinase, 134135
Uterine relaxants, 47
V
Valproic acid, 201
Valsartan, 101
Vancomycin,
265267
Warfarin, 130
Z
Zalcitabine, 278281,
278t
Zanamivir, 287288
Zidovudine, 278281,
278t
Zopiclone, 191

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PDQ* SERIES

PDQ MEDICAL GENETICS

PDQ EVIDENCE-BASED PRINCIPLES AND PRACTICE

PDQ STATISTICS, 2/e

PDQ EPIDEMIOLOGY, 2/e

PDQ (Pretty Darned Quick)

Singapore, Malaysia, Thailand,

Writing the dedication for a book is never easy,

harmacology can be a most difficult subject to master. There

Drug Absorption, Distribution, and Elimination, 1

Part 2 Autonomic Pharmacology, 18

Introduction to Autonomic Pharmacology, 18

Part 3 Cardiovascular and Renal Pharmacology, 64

Drugs for the Treatment of Congestive Heart Failure, 64

Part 4 Drugs and the Blood, 118

Antihyperlipidemic Drugs, 118

Part 5 Endocrine Pharmacology, 138

Drugs and the Thyroid, 138

Adrenal Corticosteroids, 151

Part 6 Psychopharmacology, 168

Antipsychotic Drugs, 168

Part 7 Drugs for the Treatment of Neurologic

Drugs for the Treatment of Epilepsy, 193

Part 8 Drugs to Alleviate Pain, 211

Drug Absorption, Distribution,

Ratio of C i /C n Drug Molecules

Salicylic acid has a pKa of ~3.

Morphine has a pKa of ~ 8.

Drug Absorption, Distribution, and Elimination

OVERVIEW OF ABSORPTION, DISTRIBUTION, AND

ROUTES OF DRUG ADMINISTRATION

they are irritating to the stomach,

Drug Absorption, Distribution, and Elimination

DRUG DISTRIBUTION IN THE BODY

illary endothelium. Together, these structural modifications are called the

Drug Absorption, Distribution, and Elimination

Drug Absorption, Distribution, and Elimination

drug inactivation. Although most molecules are inactivated by metabolism,

Phase I Metabolic Reactions

Phase I reactions involve oxidation, reduction, or hydrolysis of the drug

Aromatic ring hydroxylation

FREQUENTLY USED PHARMACOKINETIC EXPRESSIONS

Drug Absorption, Distribution, and Elimination

Figure 19 Summary of drug metabolism and elimination.

Pharmacodynamics: How Drugs Work

Drugs a and b produce the same maximum effect or response, which is

Thus, drug a is 10 times more potent than drug b (3/0.3).

Pharmacodynamics: How Drugs Work

DRUG EFFECTS NOT MEDIATED THROUGH RECEPTORS

DIVISIONS OF THE AUTONOMIC NERVOUS SYSTEM

Introduction to Autonomic Pharmacology

Figure 31 Overview of the functions of the sympathetic and parasympathetic divisions of

Introduction to Autonomic Pharmacology

Introduction to Autonomic Pharmacology

Figure 32 Chemical transmission of nerve impulses. ACH = Acetylcholine; NE = norepi-

Introduction to Autonomic Pharmacology

Sympathetic Nerve Endings

Synthesis and Inactivation of Neurotransmitters