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From the authors of the field’s most trusted textbook, Katzung & Trevor’s Basic & Clinical Pharmacology, this full-color resource delivers a clear, concise review of fundamental concepts, backed by more than 800 questions and answers. The chapter-based approach facilitates use with course notes or larger texts.

•Concise discussion of the major concepts that underlie basic principles or specific drug groups in every chapter
•Full-color tables and figures (many new to this edition)
•Review questions followed by answers and explanations
•Two comprehensive 100-question practice exams, followed by answer keys and explanations for correct answers
•Diagrams that visually organize drug groups and concepts
•A list of high-yield terms and definitions you must know
•Skill Keeper Questions that prompt you to go back and review previous material to understand the link between topics
•A checklist of tasks you should be able to perform upon completion of the chapter
•Summary Tables that list the important drugs and include key information about their mechanism of action and effects, clinical uses, pharmacokinetics, drug interactions, and toxicities
•An Appendix of test-taking strategies for the highest score possible
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1 comment
Abdelazem Hassan Awad
Very nice and appreciate effort ?
31 March 2021 (17:47) 

Sie können die Buchrezension schreiben oder über Ihre Erfahrung berichten. Ihre Meinung über das gelesene Buch ist interessant für andere Leser. Unabhängig davon, ob Sie das Buch mögen oder nicht, kann Ihre ehrliche und ausführliche Beschreibung anderen Leuten beim Suchen von Büchern helfen.
a LANGE medical book

Katzung & Trevor’s

& Board Review
Twelfth Edition

Bertram G. Katzung, MD, PhD
Professor Emeritus of Pharmacology
Department of Cellular & Molecular Pharmacology
University of California, San Francisco

Marieke Kruidering-Hall, PhD

Professor & Academy Chair of Pharmacology Education
Department of Cellular & Molecular Pharmacology
University of California, San Francisco

Anthony J. Trevor, PhD

Professor Emeritus of Pharmacology and Toxicology
Department of Cellular & Molecular Pharmacology
University of California, San Francisco

New York Chicago San Francisco Athens London Madrid Mexico City
Milan New Delhi Singapore Sydney Toronto

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Preface  v







1. Introduction 1

16. H
 istamine, Serotonin, Drugs Used in
Obesity, & the Ergot Alkaloids 145

2. Pharmacodynamics 16

17. Vasoactive Peptides

3. Pharmacokinetics 26

19. Nitric Oxide, Donors, & Inhibitors 168

5. Pharmacogenomics 41

20. D
 rugs Used in Asthma & Chronic
Obstructive Pulmonary Disease 172





6.  Introduction to Autonomic Pharmacology 47
7.  Cholinoceptor-Activating
& Cholinesterase-Inhibiting Drugs 60
8.  Cholinoceptor Blockers & Cholinesterase
Regenerators 69

21. Introduction to CNS Pharmacology 181
22. Sedative-Hypnotic Drugs



24. Antiseizure Drugs 203

10. Adrenoceptor Blockers 85

25. General Anesthetics




23. Alcohols

9.   Sympathomimetics 76



18. Prostaglandins & Other Eicosanoids 161

4. Drug Metabolism 35




11. Drugs Used in Hypertension 93
12. D
 rugs Used in the Treatment of Angina
Pectoris 103
13. Drugs Used in Heart Failure 112
14. Antiarrhythmic Drugs 122
15. D
 iuretics & Other Drugs That Act on the
Kidney 134


26. Local Anesthetics 220
27. Skeletal Muscle Relaxants 225
28. D
 rugs Used in Parkinsonism &
Other Movement Disorders 233
29. Antipsychotic Agents & Lithium 241
30. Antidepressants


31. Opioid Analgesics & Antagonists 257
32. Drugs of Abuse 266

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47. Antimycobacterial Drugs 397


& GOUT 275
33. A
 gents Used in Cytopenias; Hematopoietic
Growth Factors 275

48. Antifungal Agents


49. Antiviral Agents 411
50. M
 iscellaneous Antimicrobial Agents &
Disinfectants, Antiseptics, & Sterilants 423
51. Clinical Use of Antimicrobial Agents 429

34. Drugs Used in Coagulation Disorders 284

52. Antiprotozoal Drugs

35. Agents Used in Dyslipidemia 296

53. C
 linical Pharmacology of the
Antihelminthic Drugs 444

36. N
 SAIDs, Acetaminophen, & Drugs Used in
Rheumatoid Arthritis & Gout 304




54. Cancer Chemotherapy


55. Immunopharmacology



37. Hypothalamic & Pituitary Hormones 315





38. Thyroid & Antithyroid Drugs 324

56. Environmental & Occupational Toxicology 477

39. A
 drenocorticosteroids & Adrenocortical
Antagonists 330

57. Heavy Metals

40. Gonadal Hormones & Inhibitors 337
41. P
 ancreatic Hormones, Antidiabetic Drugs,
& Glucagon 348


43. B
 eta-Lactam Antibiotics & Other Cell
Wall- & Membrane-Active Antibiotics 368
44. T
 etracyclines, Macrolides, Clindamycin,
Chloramphenicol, Streptogramins, &
Oxazolidinones 377
45. Aminoglycosides & Spectinomycin 385
46. Sulfonamides, Trimethoprim,
& Fluoroquinolones 390

Trevor_FM_p0i-vi.indd 4





60. D
 ietary Supplements & Herbal
Medications 507



58. Management of the Poisoned Patient 489

59. D
 rugs Used in Gastrointestinal
Disorders 497

42. A
 gents That Affect Bone Mineral
Homeostasis 357


61. I mportant Drug Interactions & Their
Mechanisms 512
Appendix I. S
 trategies for Improving Test
Performance 519
Appendix II. Key Words for Key Drugs 522
Appendix III. Examination 1


Appendix IV. Examination 2


Index  567

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This book is designed to help students review pharmacology
and to prepare for both regular course examinations and board
examinations. The twelfth edition has been revised to make
such preparation as active and efficient as possible. As with
earlier editions, rigorous standards of accuracy and currency
have been maintained in keeping with the book’s status as the
companion to the Basic & Clinical Pharmacology textbook. This
review book divides pharmacology into the topics used in most
courses and textbooks. Major introductory chapters (eg, autonomic pharmacology and CNS pharmacology) are included
for integration with relevant physiology and biochemistry. The
chapter-based approach facilitates use of this book in conjunction with course notes or a larger text. We recommend several
strategies to make reviewing more effective (Appendix I contains a summary of learning and test-taking strategies that most
students find useful).
First, each chapter has a short discussion of the major concepts that underlie its basic principles or the specific drug group,
accompanied by explanatory figures and tables. The figures
are in full color and some are new to this edition. Students
are advised to read the text thoroughly before they attempt to
answer the study questions at the end of each chapter. If a concept is found to be difficult or confusing, the student is advised
to consult a regular textbook such as Basic & Clinical Pharmacology, 14th edition.
Second, each drug-oriented chapter opens with an Overview
that organizes the group of drugs visually in diagrammatic form.
We recommend that students practice reproducing the overview
diagram from memory.
Third, a list of High-Yield Terms to Learn and their definitions is near the front of most chapters. Make sure that you are
able to define those terms.
Fourth, many chapters include a Skill Keeper question that
prompts the student to review previous material and to see links
between related topics. We suggest that students try to answer
Skill Keeper questions on their own before checking the answers
that are provided at the end of the chapter.
Fifth, each of the sixty-one chapters contains up to ten
sample questions followed by a set of answers with explanations. For most effective learning, you should take each set of
sample questions as if it were a real examination. After you have
answered every question, work through the answers. When you

are analyzing the answers, make sure that you understand why
each choice is either correct or incorrect.
Sixth, each chapter includes a Checklist of focused tasks
that you should be able to do once you have finished the
Seventh, most chapters end with a Summary Table that
lists the most important drugs and includes key information
concerning their mechanisms of action, effects, clinical uses,
pharmacokinetics, drug interactions, and toxicities.
Eighth, when preparing for a comprehensive examination,
you should review the strategies described in Appendix I if
you have not already done so. Then review the list of drugs in
Appendix II: Key Words for Key Drugs. Students are also
advised to check this appendix as they work through the chapters so they can begin to identify drugs out of the context of a
chapter that reviews a restricted set of drugs.
Ninth, after you have worked your way through most or
all of the chapters and have a good grasp of the Key Drugs,
you should take the comprehensive examinations, each of 100
questions, presented in Appendices III and IV. These examinations are followed by a list of answers, each with a short
explanation or rationale underlying the correct choice and
the numbers of the chapters in which more information can
be found if needed. We recommend that you take an entire
examination or a block of questions as if it were a real examination: commit to answers for the whole set before you check
the answers. As you work through the answers, make sure that
you understand why each answer is either correct or incorrect.
If you need to, return to the relevant chapters(s) to review the
text that covers key concepts and facts that form the basis for
the question.
We recommend that this book be used with a regular text.
Basic & Clinical Pharmacology, 14th edition (McGraw-Hill,
2018), follows the chapter sequence used here. However, this
review book is designed to complement any standard medical
pharmacology text. The student who completes and understands Pharmacology: Examination & Board Review will greatly
improve his or her performance and will have an excellent command of pharmacology.
Because it was developed in parallel with the textbook
Basic & Clinical Pharmacology, this review book represents the
authors’ interpretations of chapters written by contributors to


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vi    PREFACE

that text. We are grateful to those contributors, to our other
faculty colleagues, and to our students, who have taught us most
of what we know about teaching.
We very much appreciate the invaluable contributions to
this text afforded by the editorial team of Peter Boyle and
Michael Weitz. The authors also thank Katharine Katzung for

Trevor_FM_p0i-vi.indd 6

her excellent copyediting and proofreading contributions to
this edition.
Bertram G. KKatzung, MD, PhD
Marieke Kruidering-Hall, PhD
Anthony J. Trevor, PhD

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Pharmacology is the body of knowledge concerned with the
action of chemicals on biologic systems. Medical pharmacology is the area of pharmacology concerned with the use of
chemicals in the prevention, diagnosis, and treatment of disease,
especially in humans. Toxicology is the area of pharmacology
concerned with the undesirable effects of chemicals on biologic
systems. Pharmacokinetics describes the effects of the body on








drugs, eg, absorption, metabolism, excretion, etc. Pharmacodynamics denotes the actions of the drug on the body, such as
mechanism of action and therapeutic and toxic effects. The first
part of this chapter reviews the basic principles of pharmacokinetics and pharmacodynamics that will be applied in subsequent
chapters. The second part of the chapter reviews the discovery
and development of new drugs and the regulation of drugs.

Nature of drugs





of drugs in





Drug development & regulation

Safety &



Patents &
generic drugs


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2    PART I Basic Principles

Drugs in common use include inorganic ions, nonpeptide organic
molecules, small peptides and proteins, nucleic acids, lipids, and carbohydrates. Some are found in plants or animals, and others are partially
or completely synthetic. Many drugs found in nature are alkaloids,
which are molecules that have a basic (alkaline) pH in solution, usually
as a result of amine groups in their structure. Many biologically important endogenous molecules and exogenous drugs are optically active;
that is, they contain one or more asymmetric centers and can exist as
enantiomers. The enantiomers of optically active drugs usually differ,
sometimes more than 1000-fold, in their affinity for biologic receptor
sites. Furthermore, such enantiomers may be metabolized at different
rates in the body, with important clinical consequences.
A. Size and Molecular Weight
Drugs vary in size from molecular weight (MW) 7 (lithium)
to over MW 50,000 (thrombolytic enzymes, antibodies, other
proteins). Most drugs, however, have MWs between 100 and
1000. Drugs smaller than MW 100 are rarely sufficiently selective
in their actions, whereas drugs much larger than MW 1000 are
often poorly absorbed and poorly distributed in the body. Most
protein drugs (“biologicals”) are commercially produced in cell,
bacteria, or yeast cultures using recombinant DNA technology.
B. Drug-Receptor Bonds
Drugs bind to receptors with a variety of chemical bonds. These
include very strong covalent bonds (which usually result in irreversible action), somewhat weaker reversible electrostatic bonds

(eg, between a cation and an anion), and much weaker interactions (eg, hydrogen, van der Waals, and hydrophobic bonds).

A. Receptors
Drug actions are mediated through the effects of drug ligand
molecules on drug receptors in the body. Most receptors are large
regulatory molecules that influence important biochemical processes (eg, enzymes involved in glucose metabolism) or physiologic
processes (eg, ion channel receptors, neurotransmitter reuptake
transporters, and ion transporters).
If drug-receptor binding results in activation of the receptor
molecule, the drug is termed an agonist; if inhibition results,
the drug is considered an antagonist. Some drugs mimic agonist
molecules by inhibiting metabolic enzymes, eg, acetylcholinesterase
inhibitors. As suggested in Figure 1–1, a receptor molecule may
have several binding sites. Quantitation of the effects of drugreceptor interaction as a function of dose (or concentration) yields
dose-response curves that provide information about the nature of
the drug-receptor interaction. Dose-response phenomena are discussed in more detail in Chapter 2. A few drugs are enzymes themselves (eg, thrombolytic enzymes, pancreatic enzymes). These drugs
do not act on endogenous receptors but on substrate molecules.
B. Receptor and Inert Binding Sites
Because most ligand molecules are much smaller than their receptor molecules (discussed in the text that follows), specific regions

High-Yield Terms to Learn (continued)

Substances that act on biologic systems at the chemical (molecular) level and alter their functions

Drug receptors

The molecular components of the body with which drugs interact to bring about their effects

Distribution phase

The phase of drug movement from the site of administration into the tissues

Elimination phase

The phase of drug inactivation or removal from the body by metabolism or excretion

Endocytosis, exocytosis

Endocytosis: Absorption of material across a cell membrane by enclosing it in cell membrane material and pulling it into the cell, where it can be processed or released. Exocytosis: Expulsion of material from vesicles in the cell into the extracellular space


Movement of a molecule (eg, drug) through the biologic medium


The actions of a drug on the body, including receptor interactions, dose-response phenomena, and
mechanisms of therapeutic and toxic actions


The actions of the body on the drug, including absorption, distribution, metabolism, and elimination. Elimination of a drug may be achieved by metabolism or by excretion. Biodisposition is a term
sometimes used to describe the processes of metabolism and excretion


A specialized molecule, usually a protein, that carries a drug, transmitter, or other molecule across a
membrane in which it is not permeable, eg, Na+/K+ ATPase, serotonin reuptake transporter, etc


An effect on the inheritable characteristics of a cell or organism—a mutation in the DNA; usually
tested in microorganisms with the Ames test


An effect of inducing malignant characteristics


An effect on the in utero development of an organism resulting in abnormal structure or function;
not generally heritable

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CHAPTER 1 Introduction    3

High-Yield Terms to Learn (continued)

An inactive “dummy” medication made up to resemble the active investigational formulation as
much as possible but lacking therapeutic effect

Single-blind study

A clinical trial in which the investigators—but not the subjects—know which subjects are receiving
active drug and which are receiving placebos

Double-blind study

A clinical trial in which neither the subjects nor the investigators know which subjects are receiving
placebos; the code is held by a third party


Investigational New Drug Exemption; an application for FDA approval to carry out new drug trials in
humans; requires animal data


New Drug Application; seeks FDA approval to market a new drug for ordinary clinical use; requires
data from clinical trials as well as preclinical (animal) data

Phases 1, 2, and 3 of
clinical trials

Three parts of a clinical trial that are usually carried out before submitting an NDA to the FDA;
adaptive trials, combined two or more phases

Positive control

A known standard therapy, to be used in addition to placebo, to evaluate the superiority or inferiority of a new drug in relation to the other drugs available

Orphan drugs

Drugs developed for diseases in which the expected number of patients is small. Some countries
bestow certain commercial advantages on companies that develop drugs for uncommon diseases









A alone



Log Dose




Allosteric inhibitor

FIGURE 1–1 Potential mechanisms of drug interaction with a receptor. Possible effects resulting from these interactions are diagrammed
in the dose-response curves at the right. The traditional agonist (drug A)-receptor binding process results in the dose-response curve denoted
“A alone.” B is a pharmacologic antagonist drug that competes with the agonist for binding to the receptor site. The dose-response curve produced by increasing doses of A in the presence of a fixed concentration of B is indicated by the curve “A + B.” Drugs C and D act at different
sites on the receptor molecule; they are allosteric activators or inhibitors. Note that allosteric inhibitors do not compete with the agonist drug
for binding to the receptor, and they may bind reversibly or irreversibly. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical
Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 1–3.)

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4    PART I Basic Principles

of receptor molecules provide the local areas responsible for drug
binding. Such areas are termed receptor sites or recognition sites.
In addition, drugs bind to some nonregulatory molecules in the
body without producing a discernible effect. Such binding sites
are termed inert binding sites. In some compartments of the
body (eg, the plasma), inert binding sites play an important role
in buffering the concentration of a drug because bound drug does
not contribute directly to the concentration gradient that drives
diffusion. Albumin and orosomucoid (α1-acid glycoprotein) are 2
important plasma proteins with significant drug-binding capacity.

To produce useful therapeutic effects, most drugs must be
absorbed, distributed, and eliminated. Pharmacokinetic principles
make rational dosing possible by quantifying these processes.

The Movement of Drugs in the Body
To reach its receptors and bring about a biologic effect, a drug
molecule (eg, a benzodiazepine sedative) must travel from the site
of administration (eg, the gastrointestinal tract) to the site of action
(eg, the brain).
A. Permeation
Permeation is the movement of drug molecules into and within
the biologic environment. It involves several processes, the most
important of which include the following:
1. Aqueous diffusion—Aqueous diffusion is the movement of
molecules through the watery extracellular and intracellular spaces.
The membranes of most capillaries have small water-filled pores
that permit the aqueous diffusion of molecules up to the size of
small proteins between the blood and the extravascular space. This
is a passive process governed by Fick’s law (see later discussion).
The capillaries in the brain, testes, and some other organs lack
aqueous pores, and these tissues are less exposed to some drugs.
2. Lipid diffusion—Lipid diffusion is the passive movement of
molecules through lipid bilayer cell membranes and other lipid barriers. Like aqueous diffusion, this process is governed by Fick’s law.
3. Transport by special carriers—Drugs that do not readily
diffuse through membranes may be transported across barriers
by mechanisms that carry similar endogenous substances. A very
large number of such transporter molecules have been identified,
and many of these are important in the movement of drugs or as
targets of drug action. Unlike aqueous and lipid diffusion, carrier transport is not governed by Fick’s law and has a maximum
capacity, ie, is saturable. Important examples are transporters for
ions (eg, Na+/K+ ATPase), for neurotransmitters (eg, transporters for serotonin, norepinephrine), for metabolites (eg, glucose,
amino acids), and for foreign molecules (xenobiotics) such as
anticancer drugs.
After release, amine neurotransmitters (dopamine, norepinephrine, and serotonin) and some other transmitters are recycled

Trevor_Ch01_p001-p015.indd 4

into nerve endings by selective transport molecules. Selective
inhibitors for these transporters often have clinical value; for
example, several antidepressants act by inhibiting the transport of
amine neurotransmitters back into the nerve endings from which
they have been released or into nearby cells.
4. Endocytosis—Endocytosis occurs through binding of the
molecule to specialized components (receptors) on cell membranes, with subsequent internalization by infolding of that area of
the membrane. The contents of the resulting intracellular vesicle
are subsequently released into the cytoplasm of the cell. Endocytosis permits very large or very lipid-insoluble chemicals to enter
cells. For example, large molecules such as proteins may cross
cell membranes by endocytosis. Smaller, polar substances such
as vitamin B12 and iron combine with special proteins (B12 with
intrinsic factor and iron with transferrin), and the complexes enter
cells by this mechanism. Because the substance to be transported
must combine with a membrane receptor, endocytotic transport
can be quite selective. Exocytosis is the reverse process, that is, the
expulsion of material that is membrane-encapsulated inside the cell
out of the cell. Most neurotransmitters are released by exocytosis.
B. Fick’s Law of Diffusion
Fick’s law predicts the rate of movement of molecules across a
barrier. The concentration gradient (C1 – C2) and permeability
coefficient for the drug and the area and thickness of the barrier
membrane are used to compute the rate as follows:
Rate = C1 − C2 ×

Permeability coefficient
× Area


Thus, drug absorption into the blood is faster within organs
with large surface areas, such as the small intestine, than from
organs with smaller absorbing areas (the stomach). Furthermore,
drug absorption is faster from organs with thin membrane barriers
(eg, the lung) than from those with thick barriers (eg, the skin).
C. Water and Lipid Solubility of Drugs
1. Solubility—The aqueous solubility of a drug is often a function of the electrostatic charge (degree of ionization, polarity) of
the molecule, because water molecules behave as dipoles and are
attracted to charged drug molecules, forming an aqueous shell
around them. Conversely, the lipid solubility of a molecule is
inversely proportional to its charge.
Many drugs are weak bases or weak acids. For such molecules,
the pH of the medium determines the fraction of molecules
charged (ionized) versus uncharged (nonionized). If the pKa of
the drug and the pH of the medium are known, the fraction of
molecules in the ionized state can be predicted by means of the
Henderson-Hasselbalch equation:
 Protonated form 
log 
= pK a − pH
 Unprotonated form


“Protonated” means associated with a proton (a hydrogen ion);
this form of the equation applies to both acids and bases.

7/13/18 6:00 PM

CHAPTER 1 Introduction    5

2. Ionization of weak acids and bases—Weak bases are
ionized—and therefore more polar and more water-soluble—when
they are protonated. Weak acids are not ionized—and so are less
water-soluble—when they are protonated.
The following equations summarize these points:
protonated weak
base (charged,
more water-soluble)
protonated weak
acid (uncharged,
more lipid-soluble)

+ H+
Unprotonated weak
base (uncharged,
more lipid-soluble)
+ H+
Unprotonated weak
acid (charged,
more water-soluble)


The Henderson-Hasselbalch relationship is clinically important when it is necessary to estimate or alter the partition of drugs
between compartments of differing pH. For example, most drugs
are freely filtered at the glomerulus, but lipid-soluble drugs can
be rapidly reabsorbed from the tubular urine. If a patient takes an
overdose of a weak acid drug, for example, aspirin, the excretion
of this drug is faster in alkaline urine. This is because a drug that is
a weak acid dissociates to its charged, polar form in alkaline solution, and this form cannot readily diffuse from the renal tubule
back into the blood; that is, the drug is trapped in the tubule.
Conversely, excretion of a weak base (eg, pyrimethamine, amphetamine) is faster in acidic urine (Figure 1–2).

Absorption of Drugs
A. Routes of Administration
Drugs usually enter the body at sites remote from the target tissue or organ and thus require transport by the circulation to the
intended site of action. To enter the bloodstream, a drug must
be absorbed from its site of administration (unless the drug has
been injected directly into the vascular compartment). The rate
and efficiency of absorption differ depending on a drug’s route of
administration as well as the drug’s physicochemical properties.
In fact, for some drugs, the amount absorbed may be only a small
fraction of the dose administered when given by certain routes.
The amount absorbed into the systemic circulation divided by the
amount of drug administered constitutes its bioavailability by
that route. Common routes of administration and some of their
features are listed in Table 1–1.

pH 7.4

pH 6.0


1.0 µM

Membranes of
the nephron


1.0 µM













0.4 µM

10.0 µM

1.4 µM total

11.0 µM total

FIGURE 1–2 The Henderson-Hasselbalch principle applied to
drug excretion in the urine. Because the nonionized, uncharged form
diffuses readily across the lipid barriers of the nephron, this form may
reach equal concentrations in the blood and urine; in contrast, the
ionized form does not diffuse as readily. Protonation occurs within
the blood and the urine according to the Henderson-Hasselbalch
equation. Pyrimethamine, a weak base of pKa 7.0, is used in this
example. At blood pH, only 0.4 μmol of the protonated species will
be present for each 1.0 μmol of the unprotonated form. The total
concentration in the blood will thus be 1.4 μmol/L if the concentration of the unprotonated form is 1.0 μmol/L. In the urine at pH 6.0,
10 μmol of the nondiffusible ionized form will be present for each
1.0 μmol of the unprotonated, diffusible form. Therefore, the total
urine concentration (11 μmol/L) may be almost 8 times higher than
the blood concentration.
concentration gradient is a major determinant of the rate of absorption. Drug concentration in the vehicle is particularly important in
the absorption of drugs applied topically.

Distribution of Drugs

B. Blood Flow
Blood flow influences absorption from intramuscular and subcutaneous sites and, in shock, from the gastrointestinal tract as well.
High blood flow maintains a high concentration gradient between
the drug depot and the blood and thus facilitates absorption.

A. Determinants of Distribution
1. Size of the organ—The size of the organ determines the concentration gradient between blood and the organ. For example,
skeletal muscle can take up a large amount of drug because the
concentration in the muscle tissue remains low (and the bloodtissue gradient high) even after relatively large amounts of drug
have been transferred; this occurs because skeletal muscle is a very
large organ. In contrast, because the brain is smaller, distribution
of a smaller amount of drug into it will raise the tissue concentration and reduce to zero the blood-tissue concentration gradient,
preventing further uptake of drug unless it is actively transported.

C. Concentration
The concentration of drug at the site of administration is important
in determining the concentration gradient relative to the blood
as noted previously. As indicated by Fick’s law (Equation 1), the

2. Blood flow—Blood flow to the tissue is an important determinant of the rate of uptake of drug, although blood flow may not
affect the amount of drug in the tissue at equilibrium. As a result,
well-perfused tissues (eg, brain, heart, kidneys, and splanchnic

Trevor_Ch01_p001-p015.indd 5

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6    PART I Basic Principles

TABLE 1–1 Common routes of drug administration.
Oral (swallowed)

Offers maximal convenience; absorption
is often slower. Subject to the first-pass
effect, in which a significant amount of the
agent is metabolized in the gut wall, portal
circulation, and liver before it reaches the
systemic circulation. Bioavailability may be
limited by the first pass effect.

Buccal and sublingual
(not swallowed)

Direct absorption into the systemic venous
circulation, bypassing the hepatic portal
circuit and first-pass metabolism.


Instantaneous and complete absorption (by
definition, bioavailability is 100%). Potentially more dangerous.


Often faster and more complete (higher bioavailability) than with oral administration.
Large volumes may be given if the drug is
not too irritating. First-pass metabolism is


Slower absorption than the intramuscular
route. First-pass metabolism is avoided.

Rectal (suppository)

The rectal route offers partial avoidance of
the first-pass effect. Larger amounts of drug
and drugs with unpleasant taste are better
administered rectally than by the buccal or
sublingual routes.


Route offers delivery closest to respiratory
tissues (eg, for asthma). Usually very rapid
absorption (eg, for anesthetic gases).


The topical route includes application to
the skin or to the mucous membrane of the
eye, ear, nose, throat, airway, or vagina for
local effect.


The transdermal route utilizes application to
the skin for systemic effect. Absorption usually occurs very slowly (because of the thickness of the skin), but the first-pass effect is

organs) usually achieve high tissue concentrations sooner than
poorly perfused tissues (eg, fat, bone).
3. Solubility—The solubility of a drug in tissue influences the
concentration of the drug in the extracellular fluid surrounding
the blood vessels. If the drug is very soluble in the cells, the concentration in the perivascular extracellular space will be lower and
diffusion from the vessel into the extravascular tissue space will be
facilitated. For example, some organs (such as the brain) have a
high lipid content and thus dissolve a high concentration of lipidsoluble agents rapidly.
4. Binding—Binding of a drug to macromolecules in the blood
or a tissue compartment tends to increase the drug’s concentration
in that compartment. For example, warfarin is strongly bound to
plasma albumin, which restricts warfarin’s diffusion out of the
vascular compartment. Conversely, chloroquine is strongly bound

Trevor_Ch01_p001-p015.indd 6

TABLE 1–2 Average values for some physical volumes
within the adult human body.

Volume (L/kg body weight)





Extracellular water


Total body water




to extravascular tissue proteins, which results in a marked reduction in the plasma concentration of chloroquine.
B. Apparent Volume of Distribution and Physical Volumes
The apparent volume of distribution (Vd) is an important pharmacokinetic parameter that reflects the above determinants of the
distribution of a drug in the body. Vd relates the amount of drug
in the body to the concentration in the plasma (Chapter 3). In
contrast, the physical volumes of various body compartments are
less important in pharmacokinetics (Table 1–2). However, obesity alters the ratios of total body water to body weight and fat to
total body weight, and this may be important when using highly
lipid-soluble drugs. A simple approximate rule for the aqueous
compartments of the normal body is as follows: 40% of total body
weight is intracellular water and 20% is extracellular water; thus,
water constitutes approximately 60% of body weight.

Metabolism of Drugs
Drug disposition is a term sometimes used to refer to metabolism and elimination of drugs. Some authorities use disposition
to denote distribution as well as metabolism and elimination.
Metabolism of a drug sometimes terminates its action, but other
effects of drug metabolism are also important. Some drugs when
given orally are metabolized before they enter the systemic circulation. This first-pass metabolism was referred to in Table 1–1 as
one cause of low bioavailability. Drug metabolism occurs primarily in the liver and is discussed in greater detail in Chapter 4.
A. Drug Metabolism as a Mechanism of Activation or
Termination of Drug Action
The action of many drugs (eg, sympathomimetics, phenothiazines) is terminated before they are excreted because they are
metabolized to biologically inactive derivatives. Conversion to an
inactive metabolite is a form of elimination.
In contrast, prodrugs (eg, levodopa, minoxidil) are inactive
as administered and must be metabolized in the body to become
active. Many drugs are active as administered and have active
metabolites as well (eg, morphine, some benzodiazepines).
B. Drug Elimination Without Metabolism
Some drugs (eg, lithium, many others) are not modified by the
body; they continue to act until they are excreted.

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CHAPTER 1 Introduction    7

5 units/h
2.5 units/h


Time (h)

Zero-order elimination
Plasma concentration

Plasma concentration

First-order elimination

2.5 units/h
elimination rate
2.5 units/h
2.5 units/h

Time (h)

FIGURE 1–3 Comparison of first-order and zero-order elimination. For drugs with first-order kinetics (left), rate of elimination (units
per hour) is proportional to concentration; this is the more common process. In the case of zero-order elimination (right), the rate is constant
and independent of concentration.

Elimination of Drugs
Along with the dosage, the rate of elimination following the last
dose (disappearance of the active molecules from the site of action,
the bloodstream, and the body) determines the duration of action
for many drugs. Therefore, knowledge of the time course of concentration in plasma is one factor used in predicting the intensity
and duration of effect for most drugs. Note: Drug elimination
is not the same as drug excretion: A drug may be eliminated by
metabolism long before the modified molecules are excreted
from the body. For most drugs and their metabolites, excretion
is primarily by way of the kidney. Volatile anesthetic gases, a
major exception, are excreted primarily by the lungs. For drugs
with active metabolites (eg, diazepam), elimination of the parent
molecule by metabolism is not synonymous with termination of
action. For drugs that are not metabolized, excretion is the mode
of elimination. A small number of drugs combine irreversibly with
their receptors, so that disappearance from the bloodstream is not
equivalent to cessation of drug action: These drugs may have a very
prolonged action. For example, phenoxybenzamine, an irreversible
inhibitor of α adrenoceptors, is eliminated from the bloodstream
in less than 1 h after administration. The drug’s action, however,
lasts for 48 h, the time required for turnover of the receptors.
A. First-Order Elimination
The term first-order elimination indicates that the rate of elimination is proportional to the concentration (ie, the higher the concentration, the greater the amount of drug eliminated per unit time).
The result is that the drug’s concentration in plasma decreases
exponentially with time (Figure 1–3, left). Drugs with first-order
elimination have a characteristic half-life of elimination that is
constant regardless of the amount of drug in the body. The concentration of such a drug in the blood will decrease by 50% for every
half-life. Most drugs in clinical use demonstrate first-order kinetics.
B. Zero-Order Elimination
The term zero-order elimination implies that the rate of elimination is constant regardless of concentration (Figure 1–3, right).

Trevor_Ch01_p001-p015.indd 7

This occurs with drugs that saturate their elimination mechanisms
at concentrations of clinical interest. As a result, the concentrations of these drugs in plasma decrease in a linear fashion over
time. Such drugs do not have a constant half-life. This is typical
of ethanol (over most of its plasma concentration range) and of
phenytoin and aspirin at high therapeutic or toxic concentrations.

Pharmacokinetic Models
A. Multicompartment Distribution
After absorption into the circulation, many drugs undergo an
early distribution phase followed by a slower elimination phase.
Mathematically, this behavior can be simulated by means of a
“two-compartment model” as shown in Figure 1–4. The two
compartments consist of the blood and the extravascular tissues.
(Note that each phase is associated with a characteristic half-life:
t1/2α for the first phase, t1/2β for the second phase. Note also that
when concentration is plotted on a logarithmic axis, the elimination phase for a first-order drug is a straight line.)
B. Other Distribution Models
A few drugs behave as if they were distributed to only 1 compartment (eg, if they are restricted to the vascular compartment).
Others have more complex distributions that require more than 2
compartments for construction of accurate mathematical models.

The sale and use of drugs are regulated in most countries by
governmental agencies. In the United States, regulation is by the
Food and Drug Administration (FDA). New drugs are developed in industrial or academic laboratories. Before a new drug
can be approved for regular therapeutic use in humans, a series
of animal and experimental human studies (clinical trials) must
be carried out.

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8    PART I Basic Principles

Serum concentration (C) (µg/mL) (logarithmic scale)









Elimination phase









Time (h) (linear scale)

FIGURE 1–4 Serum concentration-time curve after administration of a drug as an intravenous bolus. This drug follows first-order kinetics
and appears to occupy 2 compartments. The initial curvilinear portion of the data represents the distribution phase, with drug equilibrating
between the blood compartment and the tissue compartment. The linear portion of the curve represents drug elimination. The elimination
half-life (t1/2β) can be extracted graphically as shown by measuring the time between any 2 plasma concentration points on the elimination
phase that differ by twofold. (See Chapter 3 for additional details.)

New drugs may emerge from a variety of sources. Some are
the result of identification of a new target for a disease. Rational
molecular design or screening is then used to find a molecule that
selectively alters the function of the target. New drugs may result
from the screening of hundreds of compounds against model diseases in animals. In contrast, many so-called “me-too” drugs are
the result of simple chemical alteration of the pharmacokinetic
properties of an original prototype agent.

Because society expects prescription drugs to be safe and effective, governments regulate the development and marketing of
new drugs. Current regulations in the USA require evidence of
relative safety (derived from acute and subacute toxicity testing
in animals) and probable therapeutic action (from the pharmacologic profile in animals) before human testing is permitted. Some
information about the pharmacokinetics of a compound is also
required before clinical evaluation is begun. Chronic toxicity test
results are generally not required, but testing must be underway
before human studies are started. The development of a new
drug and its pathway through various levels of testing and regulation are illustrated in Figure 1–5. The cost of development of a
new drug, including false starts and discarded molecules, may be

Trevor_Ch01_p001-p015.indd 8

greater than $500 million although the true cost is often hidden
by the manufacturer.

The animal testing of a specific drug that is required before human
studies can begin is a function of its proposed use and the urgency
of the application. Thus, a drug proposed for occasional topical use
requires less extensive testing than one destined for chronic systemic
Because of the urgent need, anticancer drugs and some antiviral drugs require less evidence of safety than do drugs used in
treatment of less threatening diseases. Urgently needed drugs are
often investigated and approved on an accelerated schedule.
A. Acute Toxicity
Acute toxicity studies are required for all new drugs. These studies
involve administration of incrementing doses of the agent up to
the lethal level in at least 2 species (eg, 1 rodent and 1 nonrodent).
B. Subacute and Chronic Toxicity
Subacute and chronic toxicity testing is required for most agents,
especially those intended for chronic use. Doses are selected
based on the results of acute tests. Tests are usually conducted

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CHAPTER 1 Introduction    9

In vitro


Clinical testing


Lead compound selectivity,


Years (average)

(Is it safe

Phase 1



(Does it
work in

Phase 2


Phase 3
(Does it work,
double blind?)

Phase 4

Drug metabolism, safety assessment
New Drug)

(New Drug

(Patent expires
20 years after filing
of application)

FIGURE 1–5 The development and testing process required to bring a new drug to market in the United States. Some requirements may
be different for drugs used in life-threatening diseases. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology,
12th ed. McGraw-Hill, 2012: Fig. 5–1.)
for 2–4 weeks (subacute) and 6–24 months (chronic), in at least
2 species.

TABLE 1–3 FDA ratings of drug safety in pregnancy.*

A. Pharmacologic Profile
The pharmacologic profile is a description of all the pharmacologic
effects of a drug (eg, effects on cardiovascular function, gastrointestinal activity, respiration, hepatic and renal function, endocrine
function, CNS). Both graded and quantal dose-response data are
B. Reproductive Toxicity
Reproductive toxicity testing involves the study of the fertility
effects of the candidate drug and its teratogenic and mutagenic
toxicity. Until 2015, the FDA had used a 5-level (A, B, C, D, X)
minimally descriptive scale to summarize information regarding the
safety of drugs in pregnancy (Table 1–3). For drugs submitted after
June 2015, the letter scale has been abolished in favor of a narrative description of the safety or hazards of each drug, and separate
categories are established for pregnancy, lactation, and for males
and females of reproductive potential. The new system is designated
the Pregnancy and Lactation Labeling Rule (PLLR) and is set
forth at https://www.fda.gov/Drugs/DevelopmentApprovalProcess/
DevelopmentResources/Labeling/ucm093307.htm. New labeling
for drugs approved after 2001 will be phased in. Teratogenesis can
be defined as the induction of developmental defects in the somatic
tissues of the fetus (eg, by exposure of the fetus to a chemical, infection, or radiation). Teratogenesis is studied by treating pregnant
female animals of at least 2 species at selected times during early
pregnancy when organogenesis is known to take place and by later
examining the fetuses or neonates for abnormalities. Examples

Trevor_Ch01_p001-p015.indd 9




Controlled studies in women fail to demonstrate a
risk to the fetus in the first trimester (and there is no
evidence of a risk in later trimesters), and the possibility of fetal harm appears remote


Either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies
in pregnant women, or animal reproduction studies
have shown an adverse effect (other than a decrease
in fertility) that was not confirmed in controlled
studies in women in the first trimester (and there is
no evidence of a risk in later trimesters)


Either studies in animals have revealed adverse effects
on the fetus (teratogenic or embryocidal or other) and
there are no controlled studies in women, or studies
in women and animals are not available. Drugs should
be given only when the potential benefit justifies the
potential risk to the fetus


There is positive evidence of human fetal risk, but
the benefits from use in pregnant women may be
acceptable despite the risk (eg, if the drug is needed
in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are


Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal
risk based on human experience or both, and the
risk of the use of the drug in pregnant women clearly
outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant


Because of lack of definitive evidence for many drugs, many experts consider the
A through X ranking system to be too simplistic and inaccurate; they prefer more
detailed narrative descriptions of evidence available for each drug in question. See
Pregnancy and Lactation Labeling Rule, text.

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10    PART I Basic Principles

of drugs known to have teratogenic effects include thalidomide,
isotretinoin, valproic acid, ethanol, glucocorticoids, warfarin, lithium, and androgens. Mutagenesis denotes induction of changes in
the genetic material of animals of any age and therefore induction
of heritable abnormalities. The Ames test, the standard in vitro test
for mutagenicity, uses a special strain of salmonella bacteria whose
growth depends on specific nutrients in the culture medium. Loss
of this dependence as a result of exposure to the test drug signals
a mutation. Many carcinogens (eg, aflatoxin, cancer chemotherapeutic drugs, and other agents that bind to DNA) have mutagenic
effects and test positive in the Ames test. The dominant lethal test
is an in vivo mutagenicity test carried out in mice. Male animals are
exposed to the test substance before mating. Abnormalities in the
results of subsequent mating (eg, loss of embryos, deformed fetuses)
signal a mutation in the male’s germ cells.
C. Carcinogenesis
Carcinogenesis is the induction of malignant characteristics in
cells. Carcinogenicity is difficult and expensive to study, and
the Ames test is often used to screen chemicals because there is
a moderately high degree of correlation between mutagenicity in
the Ames test and carcinogenicity in some animal tests, as previously noted. Agents with known carcinogenic effects include
coal tar, aflatoxin, dimethylnitrosamine and other nitrosamines,
urethane, vinyl chloride, and the polycyclic aromatic hydrocarbons in tobacco smoke (eg, benzo[a]pyrene) and other tobacco

Human testing of new drugs in the United States requires
approval by institutional committees that monitor the ethical
(informed consent, patient safety) and scientific aspects (study
design, statistical power) of the proposed tests. Such testing also
requires the prior approval by the FDA of an Investigational
New Drug (IND) Exemption application, which is submitted
by the developer to the FDA (Figure 1–5). The IND includes
all the preclinical data collected up to the time of submission
and the detailed proposal for clinical trials. The major clinical
testing process is usually divided into 3 phases that are carried out to provide information for a New Drug Application
(NDA). The NDA includes all the results of preclinical and
clinical testing and constitutes the request for FDA approval
of general marketing of the new agent for prescription use. A
fourth phase of study (the surveillance phase) follows NDA
approval. In particularly lethal conditions, the FDA may permit
carefully monitored treatment of patients before phases 2 and
3 are completed.
A. Phase 1
A phase 1 trial consists of careful evaluation of the dose-response
relationship and the pharmacokinetics of the new drug in a small
number of normal human volunteers (eg, 20–100). An exception is the phase 1 trials of cancer chemotherapeutic agents and

Trevor_Ch01_p001-p015.indd 10

other highly toxic drugs; these are carried out by administering
the agents to volunteer patients with the target disease. In phase
1 studies, the acute effects of the agent are studied over a broad
range of dosages, starting with one that produces no detectable
effect and progressing to one that produces either a significant
physiologic response or a very minor toxic effect.
B. Phase 2
A phase 2 trial involves evaluation of a drug in a moderate number
of sick patients (eg, 100–200) with the target disease. A placebo or
positive control drug is included in a single-blind or double-blind
design. The study is carried out under very carefully controlled
conditions, and patients are closely monitored, often in a hospital
research ward. The goal is to determine whether the agent has
the desired efficacy (ie, produces adequate therapeutic response)
at doses that are tolerated by sick patients. Detailed data are collected regarding the pharmacokinetics and pharmacodynamics of
the drug in this patient population.
C. Phase 3
A phase 3 trial usually involves many patients (eg, 1000–6000
or more, in many centers) and many clinicians who are using
the drug in the manner proposed for its ultimate general use (eg,
in outpatients). Such studies usually include placebo and positive controls in a double-blind crossover design. The goals are to
explore further, under the conditions of the proposed clinical use,
the spectrum of beneficial actions of the new drug, to compare it
with placebo (negative control) and older therapy (positive control), and to discover toxicities, if any, that occur so infrequently
as to be undetectable in phase 2 studies. Very large amounts of
data are collected and these studies are usually very expensive.
Unfortunately, relatively few phase 3 trials include the current
standard of care as a positive control.
If the drug successfully completes phase 3, an NDA is submitted to the FDA. If the NDA is approved, the drug can be marketed and phase 4 begins.
D. Phase 4
Phase 4 represents the postmarketing surveillance phase of
evaluation, in which it is hoped that toxicities that occur very
infrequently will be detected and reported early enough to prevent major therapeutic disasters. Manufacturers are required to
inform the FDA at regular intervals of all reported untoward drug
reactions. Unlike the first 3 phases, phase 4 has not been rigidly
regulated by the FDA in the past. Because so many drugs have
been found to be unacceptably toxic only after they have been
marketed, there is considerable current interest in making phase 4
surveillance more consistent, effective, and informative.
E. Adaptive Clinical Trials
Because the traditional 3-phase clinical trials are often prolonged
and expensive, a newer type of clinical trial is currently under
development. Adaptive trials are aimed at combining 2 or more of
the traditional phases and altering conditions, dosage, and targets
as the trial progresses, based on data being collected.

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CHAPTER 1 Introduction    11

A patent application is usually submitted around the time that a
new drug enters animal testing (Figure 1–5). In the United States,
approval of the patent and completion of the NDA approval
process give the originator the right to market the drug without
competition from other firms for a period of 10–14 years from the
NDA approval date. After expiration of the patent, any company
may apply to the FDA for permission to market a generic version
of the same drug if they demonstrate that their generic drug molecule is bioequivalent (ie, meets certain requirements for content,
purity, and bioavailability) to the original product.

Many laws regulating drugs in the United States were passed during the 20th century. Refer to Table 1–4 for a partial list of this

An orphan drug is a drug for a rare disease (in the United States,
defined as one affecting fewer than 200,000 people). The study of
such agents has often been neglected because profits from the sales
of an effective agent for an uncommon ailment might not pay the
costs of development. In the United States, current legislation
provides for tax relief and other incentives designed to encourage
the development of orphan drugs.

TABLE 1–4 Selected legislation pertaining to drugs
in the United States.

Purpose and Effect

Pure Food and Drug
Act of 1906

Prohibited mislabeling and adulteration of
foods and drugs (but no requirement for
efficacy or safety)

Harrison Narcotics Act
of 1914

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

Food, Drug, and Cosmetics Act of 1938

Required that new drugs be tested for
safety as well as purity

Amendment (1962)

Required proof of efficacy as well as safety
for new drugs

Dietary Supplement
and Health Education
Act (1994)

Amended the Food, Drug, and Cosmetics
Act of 1938 to establish standards for dietary
supplements but prohibited the FDA from
applying drug efficacy and safety standards
to supplements

Trevor_Ch01_p001-p015.indd 11

1. A 3-year-old is brought to the emergency department having just ingested a large overdose of chlorpropamide, an oral
antidiabetic drug. Chlorpropamide is a weak acid with
a pKa of 5.0. It is capable of entering most tissues. On
physical examination, the heart rate is 110/min, blood pressure 90/50 mm Hg, and respiratory rate 30/min. Which of
the following statements about this case of chlorpropamide
overdose is most correct?
(A) Urinary excretion would be accelerated by administration of NH4Cl, an acidifying agent
(B) Urinary excretion would be accelerated by giving
NaHCO3, an alkalinizing agent
(C) Less of the drug would be ionized at blood pH than at
stomach pH
(D) Absorption of the drug would be slower from the stomach than from the small intestine
2. Botulinum toxin is a large protein molecule. Its action on
cholinergic transmission depends on an intracellular action
within nerve endings. Which one of the following processes
is best suited for permeation of very large protein molecules
into cells?
(A) Aqueous diffusion
(B) Endocytosis
(C) First-pass effect
(D) Lipid diffusion
(E) Special carrier transport
3. A 12-year-old child has bacterial pharyngitis and is to receive
an oral antibiotic. She complains of a sore throat and pain
on swallowing. The tympanic membranes are slightly reddened bilaterally, but she does not complain of earache. Blood
pressure is 105/70 mm Hg, heart rate 100/min, temperature
37.8°C (100.1°F). Ampicillin is a weak organic acid with a pKa
of 2.5. What percentage of a given dose will be in the lipidsoluble form in the duodenum at a pH of 4.5?
(A) About 1%
(B) About 10%
(C) About 50%
(D) About 90%
(E) About 99%
4. Ampicillin is eliminated by first-order kinetics. Which of the
following statements best describes the process by which the
plasma concentration of this drug declines?
(A) There is only 1 metabolic path for drug elimination
(B) The half-life is the same regardless of the plasma
(C) The drug is largely metabolized in the liver after oral
administration and has low bioavailability
(D) The rate of elimination is proportional to the rate of
administration at all times
(E) The drug is distributed to only 1 compartment outside the
vascular system

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12    PART I Basic Principles

6. The pharmacokinetic process or property that distinguishes
the elimination of ethanol and high doses of phenytoin and
aspirin from the elimination of most other drugs is called
(A) Distribution
(B) Excretion
(C) First-pass effect
(D) First-order elimination
(E) Zero-order elimination
7. Which of the following statements about animal testing of
potential new therapeutic agents is most correct?
(A) Requires at least 3 years to discover late toxicities
(B) Requires at least 1 primate species (eg, rhesus monkey)
(C) Requires the submission of histopathologic slides and
specimens to the FDA for evaluation by government
(D) Has good predictability for drug allergy-type reactions
(E) May be abbreviated in the case of some very toxic agents
used in cancer
8. The “dominant lethal” test involves the treatment of a male
adult animal with a chemical before mating; the pregnant
female is later examined for fetal death and abnormalities.
The dominant lethal test therefore is a test of
(A) Teratogenicity
(B) Mutagenicity
(C) Carcinogenicity
(D) Sperm viability
9. In a phase 1 clinical trial, “Novexum,” a new drug, was administered intravenously to 25 volunteers, and blood samples
were taken for several hours. Several inactive metabolites
were found as well as declining concentrations of Novexum.
A graph was prepared as shown below, with the Novexum
plasma levels plotted on a logarithmic ordinate and time on a
linear abscissa. It was concluded that the drug has first-order
kinetics. From this graph, what is the best estimate of the
elimination half-life of Novexum?
(A) 0.5 h
(B) 1 h
(C) 3 h
(D) 4 h
(E) 7 h

Trevor_Ch01_p001-p015.indd 12

Plasma concentration

5. The pharmacokinetics of a new drug are under study in a
phase 1 clinical trial. Which statement about the distribution
of drugs to specific tissues is most correct?
(A) Distribution to an organ is independent of blood flow
(B) Distribution of a lipid-soluble drug will be to adipose
tissue initially
(C) Distribution into a tissue depends on the unbound drug
concentration gradient between blood and the tissue
(D) Distribution is increased for drugs that are strongly
bound to plasma proteins
(E) Distribution has no effect on the half-life of the drug









Time (h)

10. A large pharmaceutical company has conducted extensive
animal testing of a new drug for the treatment of advanced
prostate cancer. The chief of research and development recommends that the company now submit an IND application
in order to start clinical trials. Which of the following statements is most correct regarding clinical trials of new drugs?
(A) Phase 1 involves the study of a small number of normal
volunteers by highly trained clinical pharmacologists
(B) Phase 2 involves the use of the new drug in a large
number of patients (1000–5000) who have the disease to be treated under conditions of proposed use
(eg, outpatients)
(C) Chronic animal toxicity studies must be complete and
reported in the IND
(D) Phase 4 involves the detailed study of toxic effects that
have been discovered in phase 3
(E) Phase 2 requires the use of a positive control (a known
effective drug) and a placebo
11. Which of the following would probably not be included in an
optimal phase 3 clinical trial of a new analgesic drug for mild
(A) A negative control (placebo)
(B) A positive control (current standard analgesic therapy)
(C) Double-blind protocol (in which neither the patient nor
immediate observers of the patient know which agent is
(D) A group of 1000–5000 subjects with a clinical condition
requiring analgesia
(E) Prior submission of an NDA (new drug application) to
the FDA
12. The Ames test is frequently carried out before clinical trials
are begun. The Ames test is a method that detects
(A) Carcinogenesis in primates
(B) Carcinogenesis in rodents
(C) Mutagenesis in bacteria
(D) Teratogenesis in any mammalian species
(E) Teratogenesis in primates

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CHAPTER 1 Introduction    13

13. Which of the following statements about new drug development is most correct?
(A) If the need is great, drugs that test positive for teratogenicity, mutagenicity, or carcinogenicity can be tested in
humans but the IND must specify safety measures to be
(B) Food supplements and herbal (botanical) remedies must
be shown to be effective for the target condition before
marketing is approved by the FDA
(C) All new drugs must be studied in at least 1 primate species before NDA submission
(D) Orphan drugs are drugs that are no longer produced by
the original manufacturer
(E) Phase 4 (surveillance) is the most rigidly regulated phase
of clinical drug trials


14. Which statement about the development of new drugs is
most correct?
(A) Because they may cause anaphylaxis, proteins cannot be
used as drugs
(B) Most drugs fall between 100 and 1000 in molecular
(C) Drugs for systemic action that are to be administered orally
should be highly water soluble and insoluble in lipids
(D) Water solubility is minimal in highly polarized (charged)
drug molecules




1. Questions that deal with acid-base (Henderson-Hasselbalch)
manipulations are common on examinations. Since absorption involves permeation across lipid membranes, we can in
theory treat an overdose by decreasing absorption from the
gut and reabsorption from the tubular urine by making the
drug less lipid-soluble. Ionization attracts water molecules and
decreases lipid solubility. Chlorpropamide is a weak acid,
which means that it is less ionized when protonated, ie, at
acid pH. Choice C suggests that the drug would be less ionized at pH 7.4 than at pH 2.0, which is clearly wrong for
weak acids. Choice D says (in effect) that the more ionized
form is absorbed faster, which is incorrect. A and B are opposites because NH4Cl is an acidifying salt and sodium bicarbonate an alkalinizing one. (From the point of view of test
strategy, opposites in a list of answers always deserve careful
attention.) Because an alkaline environment favors ionization of a weak acid, we should give bicarbonate. The answer
is B. Note that clinical management of overdose involves
many other considerations in addition to trapping the drug
in urine; manipulation of urine pH may be contraindicated
for other reasons.
2. Endocytosis is an important mechanism for transport of
very large molecules across membranes. Aqueous diffusion
is not involved in transport across the lipid barrier of cell
membranes. Lipid diffusion and special carrier transport
are common for smaller molecules. The first-pass effect has
nothing to do with the mechanisms of permeation; rather, it
denotes drug metabolism or excretion before absorption into
the systemic circulation. The answer is B.
3. U.S. Medical Licensing Examination (USMLE)-type questions often contain a lengthy clinical description in the
stem. One can often determine the relevance of the clinical
data by scanning the last sentence in the stem and the list

Trevor_Ch01_p001-p015.indd 13





of answers, see Appendix I. In this question, the emphasis is
clearly on pharmacokinetic principles. Ampicillin is an acid,
so it is more ionized at alkaline pH and less ionized at acidic
pH. The Henderson-Hasselbalch equation predicts that the
ratio changes from 50/50 at the pH equal to the pKa to 1/10
(protonated/unprotonated) at 1 pH unit more alkaline than
the pKa and 1/100 at 2 pH units more alkaline. For acids, the
protonated form is the nonionized, more lipid-soluble form.
The answer is A.
“First-order” means that the elimination rate is proportional
to the concentration perfusing the organ of elimination. The
half-life is a constant. The rate of elimination is proportional
to the rate of administration only at steady state. The order of
elimination is independent of the number of compartments
into which a drug distributes. The answer is B.
This is a straightforward question of pharmacokinetic distribution concepts. Choice B is incorrect because distribution
depends on blood flow as well as solubility in the tissue; thus
most drugs will initially distribute to high blood flow tissues
and only later to larger, low-flow tissues, even if they are
more soluble in them. From the list of determinants of drug
distribution given on pages 5–6, choice C is correct.
The excretion of most drugs follows first-order kinetics.
However, ethanol and, in higher doses, aspirin and phenytoin
follow zero-order kinetics; that is, their elimination rates are
constant regardless of blood concentration. The answer is E.
Drugs proposed for short-term use may not require longterm chronic testing. For some drugs, no primates are used;
for other agents, only 1 species is used. The data from the
tests, not the evidence itself, must be submitted to the FDA.
Prediction of human drug allergy from animal testing is useful but not definitive (see answer 12). Testing may be abbreviated for drugs for which there is urgent need; the answer is E.
The description of the test indicates that a chromosomal
change (passed from father to fetus) is the toxicity detected.
This is a mutation. The answer is B.
Drugs with first-order kinetics have constant half-lives, and
when the log of the concentration in a body compartment
is plotted versus time, a straight line results. The half-life
is defined as the time required for the concentration to
decrease by 50%. As shown in the graph, the concentration
of Novexum decreased from 16 units at 1 h to 8 units at 4 h
and 4 units at 7 h; therefore, the half-life is 7 h minus 4 h or
3 h. The answer is C.
Except for known toxic drugs (eg, cytotoxic cancer chemotherapy drugs), phase 1 is carried out in 25–50 normal
volunteers. Phase 2 is carried out in several hundred closely
monitored patients with the disease. Results of chronic toxicity studies in animals are required in the NDA and are usually
underway at the time of IND submission. However, they do
not have to be completed and reported in the IND. Phase 4
is the general surveillance phase that follows marketing of the
new drug. It is not targeted at specific effects. Positive controls and placebos are not a rigid requirement of any phase
of clinical trials, although placebos are often used in phase 2
and phase 3 studies. The answer is A.
The first 4 items (A–D) are correct; they would be included.
An NDA cannot be acted upon until the first 3 phases of clinical trials have been completed. (The IND must be approved
before clinical trials can be conducted.) The answer is E.

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14    PART I Basic Principles

12. The Ames test is carried out in Salmonella and detects mutations in the bacterial DNA. Because mutagenic potential is
associated with carcinogenic risk for many chemicals, a positive Ames test is often used to suggest that a particular agent
may be a carcinogen. However, the test itself only detects
mutations. The answer is C.
13. Food supplements and botanicals are much more loosely
regulated than conventional drugs; they are not required
to be shown effective before marketing. Primates are not
required in any phase of new drug testing, although they are
sometimes used. (Note the trigger word “all” in choice (C);
answers claiming “all…” are almost always wrong.) Orphan
drugs are those for which the anticipated patient population
is smaller than 200,000 patients in the United States. Phase 4

surveillance is the most loosely regulated phase of clinical
trials. Many drugs in current clinical use test positive for
teratogenicity, mutagenicity, or carcinogenicity. Such drugs
are usually labeled with warnings about these toxicities and,
in the case of teratogenicity, are labeled as contraindicated in
pregnancy. The answer is A.
14. Many peptide and protein drugs, eg, insulin, antibodies, are in
use; if identical or sufficiently similar to the human molecules,
anaphylaxis is uncommon. Most drugs do fall between 100
and 1000 in molecular weight. Drugs for systemic use should
be at least minimally water soluble (so they do not precipitate
in the intestine) and lipid soluble (so they can cross lipid barriers). Charged molecules attract a shell of water molecules,
making them more water soluble. The answer is B.

When you complete this chapter, you should be able to:
❑❑ Define and describe the terms receptor and receptor site.
❑❑ Distinguish between a competitive inhibitor and an allosteric inhibitor.
❑❑ Predict the relative ease of permeation of a weak acid or base from knowledge of its

pKa, the pH of the medium, and the Henderson-Hasselbalch equation.

❑❑ List and discuss the common routes of drug administration and excretion.
❑❑ Draw graphs of the blood level versus time for drugs subject to zero-order elimination

and for drugs subject to first-order elimination. Label the axes appropriately.

❑❑ Describe the major animal and clinical studies carried out in drug development.
❑❑ Describe the purpose of the Investigational New Drug (IND) Exemption and the New

Drug Application (NDA).

❑❑ Define carcinogenesis, mutagenesis, and teratogenesis.
❑❑ Describe the difference between the FDA regulations for ordinary drugs and those for

botanical remedies.

CHAPTER 1 Summary Table (Continued)
Major Concept


Nature of drugs

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

Drug permeation

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

Rate of diffusion

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

Drug trapping

Because the permeability coefficient of a weak base or weak acid varies with the pH according to the HendersonHasselbalch equation, drugs may be trapped in a cellular compartment in which the pH is such as to reduce
their solubility in the barriers surrounding the compartment
(Continued )

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CHAPTER 1 Introduction    15

CHAPTER 1 Summary Table (Continued)
Major Concept


Routes of administration

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

Drug distribution

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

Drug elimination

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

Elimination kinetics

The rate of elimination of drugs may be zero order (ie, constant regardless of concentration) or first order
(ie, proportional to the concentration)

Drug safety and efficacy

Standards of safety and efficacy for drugs developed slowly during the 20th century and are still incomplete.
Because of heavy lobbying by manufacturers, these standards are still not applied to nutritional supplements
and many so-called botanical or herbal medications. A few of the relevant US laws are listed in Table 1–4

Preclinical drug testing

All new drugs undergo extensive preclinical testing in isolated tissue preparations and cell cultures, isolated
animal organ preparations, and intact animals. Experiments are carried out to determine the full range of toxic
and therapeutic effects. See Figure 1–5

Clinical drug trials

In the USA, all new drugs proposed for use in humans must undergo a series of tests in humans. These tests are
regulated by the FDA and may be accelerated or prolonged depending on the perceived clinical need and possible toxicities. The trials are often divided into 3 phases before marketing is allowed. See Figure 1–5

Trevor_Ch01_p001-p015.indd 15

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Pharmacodynamics deals with the effects of drugs on biologic
systems, whereas pharmacokinetics (Chapter 3) deals with
actions of the biologic system on the drug. The principles







of pharmacodynamics apply to all biologic systems, from
isolated receptors in the test tube to patients with specific



curves, spare

partial agonists,
biased agonists,
inverse agonists

Receptors are the specific molecules in a biologic system with which
drugs interact to produce changes in the function of the system.
Receptors must be selective in their ligand-binding characteristics
(so as to respond to appropriate chemical signals and not to meaningless ones). Receptors must also be modifiable when they bind
a drug molecule (so as to bring about a change in function). Many
receptors have been identified, purified, chemically characterized,
and cloned. Most are proteins; a few are other macromolecules such
as DNA. Some authorities consider enzymes as a separate category;
for the purposes of this book, enzymes that are affected by drugs are
considered receptors. The receptor site (also known as the recognition site) for a drug is the specific binding region of the receptor
macromolecule and has a relatively high and selective affinity for
the drug molecule. The interaction of a drug with its receptor is the
fundamental event that initiates the action of the drug, and many
drugs are classified on the basis of their primary receptor affinity.



single molecule may incorporate both the drug-binding site and the
effector mechanism. For example, a tyrosine kinase effector enzyme is
part of the insulin receptor molecule, and a sodium-potassium channel
is the effector part of the nicotinic acetylcholine receptor.

When the response of a particular receptor-effector system is measured against increasing concentrations of a drug, the graph of the
response versus the drug concentration or dose is called a graded
dose-response curve (Figure 2–1A). Plotting the same data on a
logarithmic concentration axis usually results in a sigmoid curve,
which simplifies the mathematical manipulation of the doseresponse data (Figure 2–1B). The efficacy (Emax) and potency
(EC50 or ED50) parameters are derived from these data. The
smaller the EC50 (or ED50), the greater the potency of the drug.



Effectors are molecules that translate the drug-receptor interaction into
a change in cellular activity. The best examples of effectors are enzymes
such as adenylyl cyclase. Some receptors are also effectors in that a

It is possible to measure the percentage of receptors bound by
a drug, and by plotting this percentage against the log of the
concentration of the drug, a dose-binding graph similar to the


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CHAPTER 2 Pharmacodynamics    17

High-Yield Terms to Learn

A molecule to which a drug binds to bring about a change in function of the biologic system

Inert binding molecule or site

A molecule to which a drug may bind without changing any function

Receptor site

Specific region of the receptor molecule to which the drug binds

Spare receptor

Receptor that does not bind drug when the drug concentration is sufficient to produce maximal
effect; present if Kd > EC50


Component of a system that accomplishes the biologic effect after the receptor is activated by an
agonist; often a channel, transporter, or enzyme molecule, may be part of the receptor molecule


A drug that activates its receptor upon binding

Biased agonist

An agonist that activates the same receptor as other drugs in its group but also causes additional
downstream effects that are not seen with other agonists in the group

Pharmacologic antagonist

A drug that binds to the receptor without activating it and thereby prevents activation by an agonist

Competitive antagonist

A pharmacologic antagonist that can be overcome by increasing the concentration of agonist

Irreversible antagonist

A pharmacologic antagonist that cannot be overcome by increasing agonist concentration

Physiologic antagonist

A drug that counters the effects of another by binding to a different receptor and causing opposing effects

Chemical antagonist

A drug that counters the effects of another by binding the agonist drug (not the receptor)

Allosteric agonist,

A drug that binds to a receptor molecule without interfering with normal agonist binding but
alters the response to the normal agonist

Partial agonist

A drug that binds to its receptor but produces a smaller effect (Emax) at full dosage than a full agonist

Constitutive activity

Activity of a receptor-effector system in the absence of an agonist ligand

Inverse agonist

A drug that binds to the non-active state of receptor molecules and decreases constitutive activity
(see text)

Graded dose-response curve

A graph of the increasing response to increasing drug concentration or dose

Quantal dose-response curve

A graph of the increasing fraction of a population that shows a specified response at progressively
increasing doses

EC50, ED50, TD50, etc

In graded dose-response curves, the concentration or dose that causes 50% of the maximal effect
or toxicity. In quantal dose-response curves, the concentration or dose that causes a specified
response in 50% of the population under study


The concentration of drug that binds 50% of the receptors in the system

Efficacy, maximal efficacy

The largest effect that can be achieved with a particular drug, regardless of dose, Emax


The amount or concentration of drug required to produce a specified effect, usually EC50 or ED50





Dose (linear scale)




Change in heart rate

Change in heart rate






Percent of
receptors bound




Dose (log scale)





Dose (log scale)

FIGURE 2–1 Graded dose-response and dose-binding graphs. (In isolated tissue preparations, concentration is usually used as the measure
of dose.) A. Relation between drug dose or concentration (abscissa) and drug effect (ordinate). When the dose axis is linear, a hyperbolic curve
is commonly obtained. B. Same data, logarithmic dose axis. The dose or concentration at which effect is half-maximal is denoted EC50, whereas
the maximal effect is Emax. C. If the percentage of receptors that bind drug is plotted against drug concentration, a similar curve is obtained, and
the concentration at which 50% of the receptors are bound is denoted Kd, and the maximal number of receptors bound is termed Bmax.

Trevor_Ch02_p016-p025.indd 17

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18    PART I Basic Principles

dose-response curve is obtained (Figure 2–1C). The concentration of drug required to bind 50% of the receptor sites is denoted
by the dissociation constant (Kd) and is a useful measure of the
affinity of a drug molecule for its binding site on the receptor
molecule. The smaller the Kd, the greater the affinity of the drug
for its receptor. If the number of binding sites on each receptor
molecule is known, it is possible to determine the total number of
receptors in the system from the Bmax.

When the minimum dose required to produce a specified response
is determined in each member of a population, the quantal doseresponse relationship is defined (Figure 2–2). For example, a blood
pressure-lowering drug might be studied by measuring the dose
required to lower the mean arterial pressure by 20 mm Hg in
100 hypertensive patients. When plotted as the percentage of
the population that shows this response at each dose versus the
log of the dose administered, a cumulative quantal dose-response
curve, usually sigmoid in shape, is obtained. The median effective dose (ED50), median toxic dose (TD50), and (in animals)
median lethal dose (LD50) are derived from experiments carried out in this manner. Because the magnitude of the specified
effect is arbitrarily determined, the ED50 determined by quantal
dose-response measurements has no direct relation to the ED50

Percent individuals responding


Cumulative percent
therapeutic effect

Cumulative percent
dead at each dose

determined from graded dose-response curves. Unlike the graded
dose-response determination, no attempt is made to determine
the maximal effect of the drug. Quantal dose-response data provide information about the variation in sensitivity to the drug in a
given population, and if the variation is small, the curve is steep.

Efficacy—often called maximal efficacy—is the greatest effect
(Emax) an agonist can produce if the dose is taken to the highest
tolerated level. Efficacy is determined mainly by the nature of the
drug and the receptor and its associated effector system. It can be
measured with a graded dose-response curve (Figure 2–1) but not
with a quantal dose-response curve. By definition, partial agonists
have lower maximal efficacy than full agonists (see later discussion).

Potency denotes the amount of drug needed to produce a specified
effect. In graded dose-response measurements, the effect usually
chosen is 50% of the maximal effect and the concentration or dose
causing this effect is called the EC50 or ED50 (Figure 2–1A and B).
Potency is determined mainly by the affinity of the receptor for
the drug and the number of receptors available. In quantal doseresponse measurements, ED50, TD50, and LD50 are also potency
variables (median effective, median toxic, and median lethal doses,
respectively, in the population studied). Thus, a measure of potency
can be specified using either graded or quantal dose-response curves
(eg, Figures 2–1 and 2–2, respectively), but the numbers obtained
are not identical and they have different meanings.


Percent requiring
dose to achieve
desired effect

1.25 2.5






Dose (mg)

dose for a
lethal effect

80 160 320 640

FIGURE 2–2 Quantal dose-response plots from a study of the
therapeutic and lethal effects of a new drug in mice. Shaded boxes
(and the accompanying bell-shaped curves) indicate the frequency
distribution of doses of drug required to produce a specified effect,
that is, the percentage of animals that required a particular dose to
exhibit the effect. The open boxes (and corresponding sigmoidal
curves) indicate the cumulative frequency distribution of responses,
which are lognormally distributed. (Modified and reproduced, with
permission, from Katzung BG, editor: Basic & Clinical Pharmacology,
12th ed. McGraw-Hill, 2012: Fig. 2–16.)

Trevor_Ch02_p016-p025.indd 18

Spare receptors are said to exist if the maximal drug response
(Emax) is obtained at less than 100% occupation of the receptors
(Bmax). In practice, the determination is usually made by comparing the concentration for 50% of maximal effect (EC50) with the
concentration for 50% of maximal binding (Kd). If the EC50 is
less than the Kd, spare receptors are said to exist (Figure 2–3).
This might result from 1 of 2 mechanisms. First, the duration
of the effector activation may be much greater than the duration
of the drug-receptor interaction. Second, the actual number of
receptors may exceed the number of effector molecules available.
The presence of spare receptors increases sensitivity to the agonist
because the likelihood of a drug-receptor interaction increases in
proportion to the number of receptors available. (For contrast,
the system depicted in Figure 2–1, panels B and C, does not have
spare receptors, since the EC50 and the Kd are equal.)

Current concepts of drug-receptor interactions consider the receptor
to have at least 2 states—active and inactive. In the absence of ligand,
a receptor might be fully active or completely inactive; alternatively,

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CHAPTER 2 Pharmacodynamics    19



Percent of maximum

Drug effect



Drug binding
Ri – D

Ra – D








Ra + Da
Full agonist


FIGURE 2–3 In a system with spare receptors, the EC50 is lower
than the Kd, indicating that to achieve 50% of maximal effect, less
than 50% of the receptors must be activated. Explanations for this
phenomenon are discussed in the text.
an equilibrium state might exist with some receptors in the activated
state and most in the inactive state (Ra + Ri; Figure 2–4). Many
receptor systems exhibit some activity in the absence of ligand,
suggesting that some fraction of the receptor pool is always in the
activated state. Activity in the absence of ligand is called constitutive activity. A full agonist is a drug capable of fully activating
the effector system when it binds to the receptors. In the model
system illustrated in Figure 2–4, a full agonist has high affinity for
the activated receptor conformation, and sufficiently high concentrations result in all the receptors achieving the activated state
(Ra – Da). A partial agonist produces less than the full effect, even
when it has saturated the receptors (Ra–Dpa + Ri–Dpa), presumably
by combining with both receptor conformations, but favoring
the active state. In the presence of a full agonist, a partial agonist
acts as an inhibitor. In this model, neutral antagonists bind with
equal affinity to the Ri and Ra states, preventing binding by an
agonist and preventing any deviation from the level of constitutive
activity. In contrast, inverse agonists have a higher affinity for the
inactive Ri state than for Ra and decrease or abolish any constitutive activity. Biased agonism denotes the ability of some agonists
in a group (eg, β-adrenoceptor ligands) to produce somewhat
different (biased) downstream effects despite activating the same
receptors. The mechanism of this effect is not understood but may
involve changes induced in the conformation of the receptor that
differ with different agonists.

A. Competitive and Irreversible Pharmacologic
Competitive antagonists are drugs that bind to, or very close to,
the agonist receptor site in a reversible way without activating
the effector system for that receptor. Neutral antagonists bind the
receptor without shifting the ratio of Ra to Ri (Figure 2–4). In
the presence of a competitive antagonist, the dose-response

Trevor_Ch02_p016-p025.indd 19


Dose (log scale)
Ra + Dpa
Partial agonist

Ra + Ri

Ra + Dant + Ri + Dant
Ri + Di

Inverse agonist

Log Dose

FIGURE 2–4 Upper: One model of drug-receptor interactions.
The receptor is able to assume 2 conformations, Ri and Ra. In the Ri
state, it is inactive and produces no effect, even when combined
with a drug (D) molecule. In the Ra state, it activates its effectors and
an effect is recorded, even in the absence of ligand. In the absence
of drug, the equilibrium between Ri and Ra determines the degree
of constitutive activity. Lower: A full agonist drug (Da) has a much
higher affinity for the Ra than for the Ri receptor conformation, and
a maximal effect is produced at sufficiently high drug concentration. A partial agonist drug (Dpa) has somewhat greater affinity for
the Ra than for the Ri conformation and produces less effect, even
at saturating concentrations. A neutral antagonist (Dant) binds with
equal affinity to both receptor conformations and prevents binding
of agonist. An inverse agonist (Di) binds much more avidly to the
Ri receptor conformation, prevents conversion to the Ra state, and
reduces constitutive activity. (Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology,
12th ed. McGraw-Hill, 2012: Fig. 1–4.)
curve for an agonist is shifted to higher doses (ie, horizontally to
the right on the dose axis), but the same maximal effect is reached
(Figure 2–5A). The agonist, if given in a high enough concentration, can displace the antagonist and fully activate the receptors.
In contrast, an irreversible antagonist causes a downward shift of
the maximum, with no shift of the curve on the dose axis unless
spare receptors are present (Figure 2–5B). Unlike the effects of
a competitive antagonist, the effects of an irreversible antagonist
cannot be overcome by adding more agonist. Competitive antagonists increase the ED50; irreversible antagonists do not (unless
spare receptors are present). A noncompetitive antagonist that
acts at an allosteric site on the receptor (see Figure 1–1) may bind
reversibly or irreversibly; a noncompetitive antagonist that acts at
the receptor site binds irreversibly.

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20    PART I Basic Principles





Agonist plus


Effect of


Percent of maximum

Percent of maximum


Effect of

plus irreversible






Agonist dose (log scale)






Agonist dose (log scale)

FIGURE 2–5 Agonist dose-response curves in the presence of competitive and irreversible antagonists. Note the use of a logarithmic
scale for drug concentration. A. A competitive antagonist has an effect illustrated by the shift of the agonist curve to the right. B. An irreversible
(or noncompetitive) antagonist shifts the agonist curve downward.
B. Physiologic Antagonists
A physiologic antagonist binds to a different receptor molecule,
producing an effect opposite to that produced by the drug it
antagonizes. Thus, it differs from a pharmacologic antagonist,
which interacts with the same receptor as the drug it inhibits.
Typical examples of physiologic antagonists are the antagonism of
the bronchoconstrictor action of histamine by epinephrine’s bronchodilator action and glucagon’s antagonism of the hypoglycemic
action of insulin.
C. Chemical Antagonists
A chemical antagonist interacts directly with the drug being
antagonized to remove it or to prevent it from binding to its
target. A chemical antagonist does not depend on interaction
with the agonist’s receptor (although such interaction may occur).
Common examples of chemical antagonists are dimercaprol, a
chelator of lead and some other toxic metals, and pralidoxime,
which combines avidly with the phosphorus in organophosphate
cholinesterase inhibitors.

Describe the difference between a pharmacologic antagonist
and an allosteric inhibitor. How could you differentiate these
two experimentally?

The therapeutic index is the ratio of the TD50 (or LD50) to the
ED50, determined from quantal dose-response curves. The therapeutic index represents an estimate of the safety of a drug, because

Trevor_Ch02_p016-p025.indd 20

a very safe drug might be expected to have a very large toxic dose
and a much smaller effective dose. For example, in Figure 2–2,
the ED50 is approximately 3 mg, and the LD50 is approximately
150 mg. The therapeutic index is therefore approximately 150/3,
or 50, in mice. Obviously, a full range of toxic doses cannot be
ethically studied in humans. Furthermore, factors such as the
varying slopes of dose-response curves make this estimate a poor
safety index even in animals.
The therapeutic window, a more clinically useful index of
safety, describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic
concentration or dose. For example, if the average minimum
therapeutic plasma concentration of theophylline is 8 mg/L and
toxic effects are observed at 18 mg/L, the therapeutic window is
8–18 mg/L. Both the therapeutic index and the therapeutic window depend on the specific therapeutic and toxic effects used in
the determination.

Once an agonist drug has bound to its receptor, some effector mechanism is activated. The receptor-effector system may be an enzyme
in the intracellular space (eg, cyclooxygenase, a target of nonsteroidal
anti-inflammatory drugs) or in the membrane or extracellular space
(eg, acetylcholinesterase). Neurotransmitter reuptake transporters
(eg, the serotonin transporter, SERT; and the dopamine transporter,
DAT) are receptors for many drugs, eg, antidepressants and cocaine.
Most antiarrhythmic drugs target voltage-activated ion channels in
the membrane for sodium, potassium, or calcium. For the largest
group of drug-receptor interactions, the drug is present in the extracellular space, whereas the effector mechanism resides inside the cell
and modifies some intracellular process. These classic drug-receptor
interactions involve signaling across the membrane. Five major types
of transmembrane-signaling mechanisms for receptor-effector systems have been defined (Figure 2–6, Table 2–1).

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CHAPTER 2 Pharmacodynamics    21




Ion Channel











FIGURE 2–6 Signaling mechanisms for drug effects. Five major cross-membrane signaling mechanisms are recognized: (1) transmembrane
diffusion of the drug to bind to an intracellular receptor; (2) transmembrane enzyme receptors, whose outer domain provides the receptor
function and inner domain provides the effector mechanism converting A to B; (3) transmembrane receptors that, after activation by an appropriate ligand, activate separate cytoplasmic tyrosine kinase molecules (JAKs), which phosphorylate STAT molecules that regulate transcription (Y, tyrosine; P, phosphate); (4) transmembrane channels that are gated open or closed by the binding of a drug to the receptor site; and
(5) G protein-coupled receptors, which use a coupling protein to activate a separate effector molecule. (Modified and reproduced, with permission,
from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 2–5.)

Receptors are dynamically regulated in number, location, and
interaction with other molecules. Changes can occur over short
times (seconds to minutes) and longer periods (days).
Frequent or continuous exposure to agonists often results in
short-term diminution of the response, sometimes called tachyphylaxis. Several mechanisms are responsible for this phenomenon.

First, intracellular molecules may block access of a G protein
to the activated receptor molecule. For example, the molecule
β-arrestin has been shown to bind to an intracellular loop of
the β adrenoceptor when the receptor is continuously activated.
Beta-arrestin prevents access of the Gs-coupling protein and thus
desensitizes the tissue to further β-agonist activation within minutes. Removal of the β agonist results in removal of β arrestin and
restoration of the full response after a few minutes or hours.

TABLE 2–1 Types of transmembrane signaling receptors.
Receptor Type


Intracellular, often steroid

Steroids, vitamin D, nitric oxide, and a few other highly membrane-permeant agents cross the membrane and
activate intracellular receptors. The effector molecule may be part of the receptor or separate.

Membrane-spanning receptoreffector enzymes

Insulin, epidermal growth factor, and similar agents bind to the extracellular domain of molecules that incorporate tyrosine kinase enzyme activity in their intracellular domains. Most of these receptors dimerize upon

Membrane receptors that bind
intracellular tyrosine kinase
enzymes (JAK-STAT receptors)

Many cytokines activate receptor molecules that bind separate intracellular tyrosine kinase enzymes (Janus
kinases, JAKs) that activate transcription regulators (signal transducers and activators of transcription, STATs)
that migrate to the nucleus to bring about the final effect.

Ligand-activated or modulated
membrane ion channels

Certain Na+/K+ channels are activated by drugs: acetylcholine activates nicotinic Na+/K+ channels, serotonin
activates 5-HT3 Na+/K+ channels. Benzodiazepines, barbiturates, and several other sedative hypnotics allosterically modulate GABA-activated Cl– channels; sympathomimetics modulate voltage-activated Ca2+ channels,
other drugs modulate voltage-activated K+ channels.

G-protein-coupled receptors

GPCRs consist of 7 transmembrane (7-TM) domain