Modern Pharmacology With Clinical Applications

The sixth edition of Modern Pharmacology With

Clinical Applications continues our commitment

to enlisting experts in pharmacology to provide

a textbook that is up-to-date and comprehensive. De￾signed to be used during a single semester, the book fo￾cuses on the clinical application of drugs within a con￾text of the major principles of pharmacology. It is meant

to serve students in medicine, osteopathy, dentistry,

pharmacy, and advanced nursing, as well as undergrad￾uate students.

SUMMARY OF FEATURES

This edition includes a number of new or updated fea￾tures that further enhance the appeal of the text.

Study Questions: Each chapter includes five to

seven examination questions (following the United

States Medical Licensing Examination guidelines) with

detailed answers to help students test their knowledge

of the covered material.

Case Studies: Appearing at the end of each chapter,

case studies present students with real-life examples of

clinical scenarios and require them to apply their

knowledge to solve the problem.

Refined Focus: In this edition, we chose to focus

more on drug classes rather than on individual drugs,

eliminate unnecessary detail such as chemical struc￾tures, and maintain emphasis on structure–activity rela￾tionships in drug action and development.

Updated Information: This edition also includes

new information from the clinic and the laboratory.

Emerging information has been added within chapters

and when appropriate (as in the case of herbal drugs

and erectile dysfunction), through the addition of new

chapters.

With these revisions, we hope we have provided a

book that is readable, up-to-date, comprehensive but

not exhaustive, and accurate—a text that supplies both

students and faculty with a clear introduction to mod￾ern pharmacotherapeutics.

Charles R. Craig

Robert E. Stitzel

Preface

I. GENERAL PRINCIPLES OF PHARMACOLOGY

1. Progress in Therapeutics 03

Robert E. Stitzel and Joseph J. McPhillips

2. Mechanisms of Drug Action 10

William W. Fleming

3. Drug Absorption and Distribution 20

Timothy S. Tracy

4. Metabolism and Excretion of Drugs 34

Timothy S. Tracy

5. Pharmacokinetics 48

Timothy S. Tracy

6. Drug Metabolism and Disposition in Pediatric and

Gerontological Stages of Life 56

Jeane McCarthy

7. Principles of Toxicology 63

Mary E. Davis and Mark J. Reasor

8. Contemporary Bioethical Issues in Pharmacology and

Pharmaceutical Research 73

Janet Fleetwood

II. DRUGS AFFECTING THE AUTONOMIC NERVOUS

SYSTEM

9. General Organization and Functions of the Nervous

System 83

William W. Fleming

10. Adrenomimetic Drugs 96

Tony J.-F. Lee and Robert E. Stitzel

11. Adrenoceptor Antagonists 109

David P. Westfall

12. Directly and Indirectly Acting

Cholinomimetics 121

William F. Wonderlin

13. Muscarinic Blocking Drugs 134

William F. Wonderlin

14. Ganglionic Blocking Drugs and Nicotine 141

Thomas C. Westfall

III. Drugs Affecting the Cardiovascular System

15. Pharmacologic Management of Chronic Heart

Failure 151

Mitchell S. Finkel and Humayun Mirza

16. Antiarrhythmic Drugs 160

Peter S. Fischbach and Benedict R. Lucchesi

17. Antianginal Drugs 196

Garrett J. Gross

18. The Renin–Angiotensin–Aldosterone System and Other

Vasoactive Substances 206

Lisa A. Cassis

19. Calcium Channel Blockers 218

Vijay C. Swamy and David J. Triggle

20. Antihypertensive Drugs 225

David P. Westfall

21. Diuretic Drugs 239

Peter A. Friedman and William O. Berndt

22. Anticoagulant, Antiplatelet, and Fibrinolytic

(Thrombolytic) Drugs 256

Jeffrey S. Fedan

23. Hypocholesterolemic Drugs and Coronary Heart

Disease 268

Richard J. Cenedella

IV. DRUGS AFFECTING THE CENTRAL NERVOUS

SYSTEM

24. Introduction to Central Nervous System

Pharmacology 281

Charles R. Craig

25. General Anesthesia: Intravenous and Inhalational

Agents 291

David J. Smith and Michael B. Howie

26. Opioid and Nonopioid Analgesics 310

Sandra P. Welch and Billy R. Martin

27. Local Anesthetics 336

J. David Haddox

28. Agents Affecting Neuromuscular

Transmission 338

Michael D. Miyamoto

29. Central Nervous System Stimulants 348

David A. Taylor

30. Sedative–Hypnotic and Anxiolytic Drugs 355

John W. Dailey

31. Drugs Used in Neurodegenerative Disorders 364

Patricia K. Sonsalla

32. Antiepileptic Drugs 374

Charles R. Craig

33. Drugs Used in Mood Disorders 385

Herbert E. Ward and Albert J. Azzaro

34. Antipsychotic Drugs 397

Stephen M. Lasley

35. Contemporary Drug Abuse 406

Billy R. Martin and William L. Dewey

V. THERAPEUTIC ASPECTS OF INFLAMMATORY

AND SELECTED OTHER CLINICAL DISORDERS

36. Antiinflammatory and Antirheumatic Drugs 423

Karen A. Woodfork and Knox Van Dyke

37. Drugs Used in Gout 441

Knox Van Dyke

Table of Contents

xi

38. Histamine and Histamine Antagonists 449

Knox Van Dyke and Karen A. Woodfork

39. Drugs Used in Asthma 458

Theodore J. Torphy and Douglas W. P. Hay

40. Drugs Used in Gastrointestinal Disorders 470

Lisa M. Gangarosa and Donald G. Seibert

41. Drugs Used in Dermatological Disorders 484

Eric L. Carter, Mary-Margaret Chren, and David R. Bickers

42. Drugs for the Control of Supragingival

Plaque 499

Angelo Mariotti and Arthur F. Hefti

VI. CHEMOTHERAPY

43. Introduction to Chemotherapy 509

Steven M. Belknap

44. Synthetic Organic Antimicrobials: Sulfonamides,

Trimethoprim, Nitrofurans, Quinolones,

Methenamine 515

Marcia A. Miller-Hjelle, Vijaya Somaraju, and J. Thomas Hjelle

45. -Lactam Antibiotics 526

James F. Graumlich

46. Aminoglycoside Antibiotics 538

Steven Belknap

47. Tetracyclines, Chloramphenicol, Macrolides, and

Lincosamides 544

Richard P. O’Connor

48. Bacitracin, Glycopeptide Antibiotics, and the

Polymyxins 552

Mir Abid Husain

49. Drugs Used in Tuberculosis and Leprosy 557

Vijaya Somaraju

50. Antiviral Drugs 567

Knox Van Dyke and Karen Woodfork

51. Therapy of Human Immunodeficiency Virus 584

Knox Van Dyke and Karen Woodfork

52. Antifungal Drugs 596

David C. Slagle

53. Antiprotozoal Drugs 606

Leonard William Scheibel

54. Anthelmintic Drugs 621

Mir Abid Husain and Leonard William Scheibel

55. The Rational Basis for Cancer

Chemotherapy 630

Branimir I. Sikic

56. Antineoplastic Agents 638

Branimir I. Sikic

57. Immunomodulating Drugs 657

Leonard J. Sauers

58. Gene Therapy 666

John S. Lazo and Jennifer Rubin Grandis

VII. DRUGS AFFECTING THE ENDOCRINE SYSTEM

59. Hypothalamic and Pituitary Gland

Hormones 677

Priscilla S. Dannies

60. Adrenocortical Hormones and Drugs Affecting the

Adrenal Cortex 686

Ronald P. Rubin

61. Estrogens, Progestins, and SERMs 704

Jeannine S. Strobl

62. Uterine Stimulants and Relaxants 716

Leo R. Brancazio and Robert E. Stitzel

63. Androgens, Antiandrogens, and Anabolic

Steroids 724

Frank L. Schwartz and Roman J. Miller

64. Drugs Used in the Treatment of Erectile

Dysfunction 735

John A. Thomas and Michael J. Thomas

65. Thyroid and Antithyroid Drugs 742

John Connors

66. Parathyroid Hormone, Calcitonin, Vitamin D, and Other

Compounds Related to Mineral Metabolism 754

Frank L. Schwartz

67. Insulin and Oral Drugs for Diabetes Mellitus 763

Michael J. Thomas and John A. Thomas

68. Vitamins 777

Suzanne Barone

69. Herbal Medicine 785

Gregory Juckett

Index

xii TABLE OF CONTENTS

I

1. Progress in Therapeutics 3

Robert E. Stitzel and Joseph J. McPhillips

2. Mechanisms of Drug Action 10

William W. Fleming

3. Drug Absorption and Distribution 20

Timothy S. Tracy

4. Metabolism and Excretion of Drugs ••

Timothy S. Tracy

5. Pharmacokinetics ••

Timothy S. Tracy

6. Drug Metabolism and Disposition in

Pediatric and Gerontological Stages

of Life ••

Jeane McCarthy

7. Principles of Toxicology ••

Mary E. Davis and Mark J. Reasor

8. Contemporary Bioethical Issues in

Pharmacology & Pharmaceutical

Research ••

Janet Fleetwood

1

SECTION

I

GENERAL PRINCIPLES

OF PHARMACOLOGY

3

Early in human history a natural bond formed be￾tween religion and the use of drugs. Those who became

most proficient in the use of drugs to treat disease were

the “mediators” between this world and the spirit

world, namely, the priests, shamans, holy persons,

witches, and soothsayers. Much of their power within

the community was derived from the cures that they

could effect with drugs. It was believed that the sick

were possessed by demons and that health could be re￾stored by identifying the demon and finding a way to

cast it out.

Originally, religion dominated its partnership with

therapeutics, and divine intervention was called upon

for every treatment. However, the use of drugs to effect

cures led to a profound change in both religious thought

and structure. As more became known about the effects

of drugs, the importance of divine intervention began to

recede, and the treatment of patients effectively became

a province of the priest rather than the gods whom the

priest served. This process lead to a growing under￾standing of the curative powers of natural products and

a decreasing reliance on supernatural intervention and

forever altered the relationship between humanity and

its gods. Furthermore, when the priests began to apply

the information learned from treating one patient to the

treatment of other patients, there was a recognition that

a regularity prevailed in the natural world independent

of supernatural whim or will. Therapeutics thus evolved

from its roots in magic to a foundation in experience.

This was the cornerstone for the formation of a science￾based practice of medicine.

CONTRIBUTIONS OF MANY CULTURES

The ancient Chinese wrote extensively on medical

subjects. The Pen Tsao, for instance, was written about

2700 B.C. and contained classifications of individual me￾dicinal plants as well as compilations of plant mixtures

to be used for medical purposes. The Chinese doctrine

of signatures (like used to treat like) enables us to un￾derstand why medicines of animal origin were of such

great importance in the Chinese pharmacopoeia.

Ancient Egyptian medical papyri contain numerous

prescriptions. The largest and perhaps the most impor￾tant of these, the Ebers papyrus (1550 B.C.), contains

about 800 prescriptions quite similar to those written

today in that they have one or more active substances as

well as vehicles (animal fat for ointments; and water,

milk, wine, beer, or honey for liquids) for suspending or

dissolving the active drug.These prescriptions also com￾monly offer a brief statement of how the preparation is

to be prepared (mixed, pounded, boiled, strained, left

overnight in the dew) and how it is to be used (swal￾lowed, inhaled, gargled, applied externally, given as an

enema). Cathartics and purgatives were particularly in

vogue, since both patient and physician could tell al￾most immediately whether a result had been achieved.

It was reasoned that in causing the contents of the gas￾trointestinal tract to be forcibly ejected, one simultane￾ously drove out the disease-producing evil spirits that

had taken hold of the unfortunate patient.

The level of drug usage achieved by the Egyptians

undoubtedly had a great influence on Greek medicine

and literature. Observations on the medical effects of

Progress in Therapeutics 1 Robert E. Stitzel and Joseph J. McPhillips

various natural substances are found in both the Iliad

and the Odyssey. Battle wounds frequently were cov￾ered with powdered plant leaves or bark; their astrin￾gent and pain-reducing actions were derived from the

tannins they contained. It may have been mandrake

root (containing atropinelike substances that induce a

twilight sleep) that protected Ulysses from Circe. The

oriental hellebore, which contains the cardiotoxic

Veratrum alkaloids, was smeared on arrow tips to in￾crease their killing power.The fascination of the Greeks

with the toxic effects of various plant extracts led to an

increasing body of knowledge concerned primarily with

the poisonous aspects of drugs (the science of toxicol￾ogy). Plato’s description of the death of Socrates is an

accurate description of the toxicological properties of

the juice of the hemlock fruit. His description of the

paralysis of sensory and motor nerves, followed eventu￾ally by central nervous system depression and respira￾tory paralysis, precisely matches the known actions of

the potent hemlock alkaloid, coniine.

The Indian cultures of Central and South America,

although totally isolated from the Old World, developed

drug lore and usage in a fashion almost parallel with that

of the older civilization. The use of drugs played an inti￾mate part in the rites, religions, history, and knowledge of

the South American Indians. New World medicine also

was closely tied to religious thought, and Indian cultures

treated their patients with a blend of religious rituals and

herbal remedies. Incantations, charms, and appeals to

various deities were as important as the appropriate ap￾plication of poultices, decoctions, and infusions.

Early drug practitioners, both in Europe and South

America, gathered herbs, plants, animals, and minerals

and often blended them into a variety of foul-smelling

and ill-flavored concoctions. The fact that many of these

preparations were so distasteful led to an attempt to

improve on the “cosmetic” properties of these mixtures

to ensure that patients would actually use them.

Individuals who searched for improved product formu￾lations were largely responsible for the founding of the

disciplines of pharmacy (the science of preparing, com￾pounding, and dispensing medicines) and pharmacog￾nosy (the identification and preparation of crude drugs

from natural sources).

There has long been a tendency of some physicians

to prescribe large numbers of drugs where one or two

would be sufficient. We can trace the history of this

polypharmaceutical approach to Galen (A.D. 131–201),

who was considered the greatest European physician

after Hippocrates. Galen believed that drugs had cer￾tain essential properties, such as warmth, coldness, dry￾ness, or humidity, and that by using several drugs he

could combine these properties to adjust for deficien￾cies in the patient. Unfortunately, he often formulated

general rules and laws before sufficient factual informa￾tion was available to justify their formulations.

By the first century A.D. it was clear to both physi￾cian and protopharmacologist alike that there was

much variation to be found from one biological extract

to another, even when these were prepared by the same

individual. It was reasoned that to fashion a rational and

reproducible system of therapeutics and to study phar￾macological activity one had to obtain standardized and

uniform medicinal agents.

At the turn of the nineteenth century, methods be￾came available for the isolation of active principles from

crude drugs. The development of chemistry made it pos￾sible to isolate and synthesize chemically pure com￾pounds that would give reproducible biological results.

In 1806, Serturner (1783–1841) isolated the first pure ac￾tive principle when he purified morphine from the

opium poppy. Many other chemically pure active com￾pounds were soon obtained from crude drug prepara￾tions, including emetine by Pelletier (1788–1844) from

ipecacuanha root; quinine by Carentou (1795–1877)

from cinchona bark; strychnine by Magendie (1783–

1855) from nux vomica; and, in 1856, cocaine by Wohler

(1800–1882) from coca.

The isolation and use of pure substances allowed for

an analysis of what was to become one of the basic con￾cerns of pharmacology, that is, the quantitative study of

drug action. It was soon realized that drug action is pro￾duced along a continuum of effects, with low doses pro￾ducing a less but essentially similar effect on organs and

tissues as high doses. It also was noted that the appear￾ance of toxic effects of drugs was frequently a function

of the dose–response relationship.

Until the nineteenth century, the rapid development

of pharmacology as a distinct discipline was hindered by

the lack of sophisticated chemical methodology and by

limited knowledge of physiological mechanisms. The

significant advances made through laboratory studies of

animal physiology accomplished by early investigators

such as Françoise Magendie and Claude Bernard pro￾vided an environment conducive to the creation of sim￾ilar laboratories for the study of pharmacological phe￾nomena.

One of the first laboratories devoted almost exclu￾sively to drug research was established in Dorpat,

Estonia, in the late 1840s by Rudolph Bucheim (1820–

1879) (Fig. 1.1). The laboratory, built in Bucheim’s

home, was devoted to studying the actions of agents

such as cathartics, alcohol, chloroform, anthelmintics,

and heavy metals. Bucheim believed that “the investi￾gation of drugs . . . is a task for a pharmacologist and not

for a chemist or pharmacist, who until now have been

expected to do this.”

Although the availability of a laboratory devoted to

pharmacological investigations was important, much

more was required to raise this discipline to the same

prominent position occupied by other basic sciences; this

included the creation of chairs in pharmacology at other

4 I GENERAL PRINCIPLES OF PHARMACOLOGY

1 Progress in Therapeutics 5

academic institutions and the training of a sufficient num￾ber of talented investigators to occupy these positions.

The latter task was accomplished largely by Bucheim’s

pupil and successor at Dorpat, Oswald Schmiedeberg

(1838–1921), undoubtedly the most prominent pharma￾cologist of the nineteenth century (Fig. 1.1). In addition to

conducting his own outstanding research on the pharma￾cology of diuretics, emetics, cardiac glycosides, and so

forth, Schmiedeberg wrote an important medical text￾book and trained approximately 120 pupils from more

than 20 countries. Many of these new investigators either

started or developed laboratories devoted to experimen￾tal pharmacology in their own countries.

One of Schmiedeberg’s most outstanding students

was John Jacob Abel, who has been called the founder of

American pharmacology (Fig 1.1). Abel occupied the

chair of pharmacology first at the University of Michigan

and then at Johns Hopkins University. Among his most

important research accomplishments is an examination

of the chemistry and isolation of the active principles

from the adrenal medulla (a monobenzyl derivative of

epinephrine) and the pancreas (crystallization of in￾sulin). He also examined mushroom poisons, investigated

the chemotherapeutic actions of the arsenicals and anti￾monials, conducted studies on tetanus toxin, and de￾signed a model for an artificial kidney. In addition, Abel

founded the Journal of Experimental Medicine, the

Journal of Biological Chemistry, and the Journal of

Pharmacology and Experimental Therapeutics. His devo￾tion to pharmacological research, his enthusiasm for the

training of students in this new discipline, and his estab￾lishment of journals and scientific societies proved criti￾cal to the rise of experimental pharmacology in the

United States.

Pharmacology, as a separate and vital discipline, has

interests that distinguish it from the other basic sciences

and pharmacy. Its primary concern is not the cataloguing

of the biological effects that result from the administra￾tion of chemical substances but rather the dual aims of

(1) providing an understanding of normal and abnormal

human physiology and biochemistry through the appli￾cation of drugs as experimental tools and (2) applying to

clinical medicine the information gained from funda￾mental investigation and observation.

A report in the Status of Research in Pharmacology

has described some of the founding principles on which

the discipline is based and that distinguish pharmacol￾ogy from other fields of study. These principles include

the study of the following:

• The relationship between drug concentration

and biological response

• Drug action over time

• Factors affecting absorption, distribution, bind￾ing, metabolism, and elimination of chemicals

• Structure-activity relationships

• Biological changes that result from repeated

drug use: tolerance, addiction, adverse reactions,

altered rates of drug metabolism, and so forth

• Antagonism of the effects of one drug by an￾other

• The process of drug interaction with cellular

macromolecules (receptors) to alter physiolog￾ical function (i.e., receptor theory)

FIGURE 1.1

The three important figures in the early history of pharmacology are (left to right) Rudolf

Bucheim, Oswald Schmiedeberg, and John Jacob Abel. They not only created new laboratories

devoted to the laboratory investigation of drugs but also firmly established the new discipline

through the training of future faculty, the writing of textbooks, and the founding of scientific

journals and societies.

In the past 100 years there has been extraordinary

growth in medical knowledge. This expansion of infor￾mation has come about largely through the contribu￾tions of the biological sciences to medicine by a system￾atic approach to the understanding and treatment of

disease. The experimental method and technological

advances are the foundations upon which modern med￾icine is built.

DRUG CONTROL AND DEVELOPMENT

Before the twentieth century, most government controls

were concerned not with drugs but with impure and

adulterated foods. Medicines were thought to pose

problems similar to those presented by foods. Efficacy

was questioned in two respects: adulteration of active

medicines by addition of inert fillers and false claims

made for the so-called patent (secret) medicines or nos￾trums. Indeed, much of the development of the science

of pharmacy in the nineteenth century was standardiz￾ing and improving prescription drugs.

A landmark in the control of drugs was the 1906

Pure Food and Drug Act. Food abuses, however, were

the primary target. Less than one quarter of the first

thousand decisions dealt with drugs, and of these, the

majority were concerned with patent medicines.

The 1906 law defined drug broadly and governed the

labeling but not the advertising of any substance used to

affect disease.This law gave the Pharmacopoeia and the

National Formulary equal recognition as authorities for

drug specifications. In the first contested criminal pros￾ecution under the law, action was taken against the

maker of a headache mixture bearing the beguiling

name of Cuforhedake-Brane-Fude. In 1912, Congress

passed an amendment to the Pure Food and Drug Act

that banned false and fraudulent therapeutic claims for

patent medicines.

Prescription drugs also were subject to control un￾der the 1906 law. In fact, until 1953 there was no fixed

legal boundary between prescription and nonprescrip￾tion medications. Prescription medications received a

lower priority, since food and patent medicine abuses

were judged to be the more urgent problems.

For the next 30 years, drug control was viewed pri￾marily as a problem of prohibiting the sale of dangerous

drugs and tightening regulations against misbranding.

Until the 1930s, new drugs posed little problem because

there were few of them.

MODERN DRUG LEGISLATION

The modern history of United States drug regulation

began with the Food, Drug and Cosmetic Act of 1938,

which superseded the 1906 Pure Food and Drug Act.

The 1938 act was viewed as a means of preventing the

marketing of untested, potentially harmful drugs. An

obscure provision of the 1938 act was destined to be the

starting point for some of the most potent controls the

Food and Drug Administration (FDA) now exercises in

the drug field. This provision allowed the prescription

drug to come under special control by requiring that it

carry the legend “Caution—to be used only by or on the

prescription of a physician.”

A major defect of the generally strong 1938 law was

its inadequate control of advertising. Regulations now

require that the “labeling on or within the package from

which the drug is to be dispensed” contain adequate in￾formation for the drug’s use; this requirement explains

the existence of the package insert. If the pharmaceuti￾cal manufacturer makes claims for its product beyond

those contained in an approved package insert, the

FDA may institute legal action against the deviations in

advertising.

The 1938 act required manufacturers to submit a

New Drug Application (NDA) to the FDA for its ap￾proval before the company was permitted to market a

new drug. Efficacy (proof of effectiveness) became a re￾quirement in 1962 with the Kefauver-Harris drug

amendments. These amendments established a require￾ment that drugs show “substantial evidence” of efficacy

before receiving NDA approval. Substantial evidence

was defined in the amendments as evidence consisting

of adequate and well-controlled investigations, includ￾ing clinical investigations, by experts qualified by scien￾tific training and experience to evaluate the effective￾ness of the drug, on the basis of which such experts

could fairly and responsibly conclude that the drug

would have the claimed effect under the conditions of

use named on the label.

Drug regulation in the United States is continuing to

evolve rapidly, both in promulgation of specific regula￾tions and in the way regulations are implemented (Table

1.1). The abolition of patent medicines is an outstanding

example, as is control over the accuracy of claims made

for drugs. Since the 1962 amendments, the advertising of

prescription drugs in the United States has been in￾creasingly controlled—to a greater extent than in most

other countries. All new drugs introduced since 1962

have some proof of efficacy. This is not to say that mis￾leading drug advertisements no longer exist; manufac￾turers still occasionally make unsubstantiated claims.

6 I GENERAL PRINCIPLES OF PHARMACOLOGY

Phase Purpose

I Establish safety

II Establish efficacy and dose

III Verify efficacy and detect adverse affects

IV Obtain additional data following approval

Phases of Clinical

Investigation

TABLE 1.1

1 Progress in Therapeutics 7

CLINICAL TESTING OF DRUGS

Experiments conducted on animals are essential to the

development of new chemicals for the management of

disease. The safety and efficacy of new drugs, however,

can be established only by adequate and well-controlled

studies on human subjects. Since findings in animals do

not always accurately predict the human response to

drugs, subjects who participate in clinical trials are put

at some degree of risk.The risk comes not only from the

potential toxicity of the new drug but also from possible

lack of efficacy, with the result that the condition under

treatment becomes worse. Since risk is involved, the pri￾mary consideration in any clinical trial should be the

welfare of the subject. As a consequence of unethical or

questionably ethical practices committed in the past,

most countries have established safeguards to protect

the rights and welfare of persons who participate in

clinical trials. Two of the safeguards that have been es￾tablished are the institutional review board (IRB) and

the requirement for informed consent.

The IRB, also known as the ethics committee or hu￾man subjects committee, originally was established to

protect people confined to hospitals, mental institutions,

nursing homes, and prisons who may be used as subjects

in clinical research. In the United States any institution

conducting clinical studies supported by federal funds is

required to have proposed studies reviewed and ap￾proved by an IRB.

People who volunteer to be subjects in a drug study

have a right to know what can and will happen to them

if they participate (informed consent). The investigator

is responsible for ensuring that each subject receives a

full explanation, in easily understood terms, of the pur￾pose of the study, the procedures to be employed, the

nature of the substances being tested, and the potential

risks, benefits, and discomforts.

PHASES OF CLINICAL INVESTIGATION

The clinical development of new drugs usually takes

place in steps or phases conventionally described as

clinical pharmacology (phase I), clinical investigation

(phase II), clinical trials (phase III), and postmarketing

studies (phase IV). Table 1.1 summarizes the four

phases of clinical evaluation.

Phase I

When a drug is administered to humans for the first

time, the studies generally have been conducted in

healthy men between 18 and 45 years of age; this prac￾tice is coming under increasing scrutiny and criticism.

For certain types of drugs, such as antineoplastic agents,

it is not appropriate to use healthy subjects because the

risk of injury is too high. The purpose of phase I studies

is to establish the dose level at which signs of toxicity first

appear. The initial studies consist of administering a sin￾gle dose of the test drug and closely observing the sub￾ject in a hospital or clinical pharmacology unit with

emergency facilities. If no adverse reactions occur, the

dose is increased progressively until a predetermined

dose or serum level is reached or toxicity supervenes.

Phase I studies are usually confined to a group of 20 to

80 subjects. If no untoward effects result from single

doses, short-term multiple-dose studies are initiated.

Phase II

If the results of phase I studies show that it is reasonably

safe to continue, the new drug is administered to patients

for the first time. Ideally, these individuals should have no

medical problems other than the condition for which the

new drug is intended. Efforts are concentrated on evalu￾ating efficacy and on establishing an optimal dose range.

Therefore, dose–response studies are a critical part of

phase II studies. Monitoring subjects for adverse effects

is also an integral part of phase II trials. The number of

subjects in phase II studies is usually between 80 and 100.

Phase III

When an effective dose range has been established and

no serious adverse reactions have occurred, large num￾bers of subjects can be exposed to the drug. In phase III

studies the number of subjects may range from several

hundred to several thousand, depending on the drug.

The purpose of phase III studies is to verify the efficacy

of the drug and to detect effects that may not have sur￾faced in the phase I and II trials, during which exposure

to the drug was limited. A new drug application is sub￾mitted at the end of phase III. However, for drugs in￾tended to treat patients with life-threatening or severely

debilitating illnesses, especially when no satisfactory

therapy exists, the FDA has established procedures de￾signed to expedite development, evaluation, and mar￾keting of new therapies. In the majority of cases, the

procedure applies to drugs being developed for the

treatment of cancer and acquired immunodeficiency

syndrome (AIDS). Under this procedure, drugs can be

approved on the basis of phase II studies conducted in

a limited number of patients.

Phase IV

Controlled and uncontrolled studies often are con￾ducted after a drug is approved and marketed. Such

studies are intended to broaden the experience with the

drug and compare it with other drugs.

SPECIAL POPULATIONS

One of the goals of drug development is to provide suffi￾cient data to permit the safe and effective use of the drug.

ANSWERS

1. D. There is always some degree of risk in clinical

trials; the object is to minimize the risk to the pa￾tient. The primary consideration in any clinical trial

is the welfare of the subject. The safety of the drug

is one objective for certain clinical trials as is the ef￾ficacy of the drug in other trials.

2. A. Phase I studies are carried out in normal volun￾teers. The object of phase I studies is to determine

the dose level at which signs of toxicity first appear.

Phase II studies are carried out in patients in which

the drug is designed to be effective in. It is con￾ducted to determine efficacy and optimal dosage.

Phase III studies are a continuation of phase II, but

many more patients are involved. The purpose of

phase III studies is to verify efficacy established ear￾lier in phase II studies and to detect adverse effects

that may not have surfaced in earlier studies. Phase

IV studies are conducted when the drug has been

approved and is being marketed. The purpose of

these studies is to broaden the experience with the

drug and to compare the new drug with other

agents that are being used clinically.

3. C. John Jacob Abel occupied the first chair of a de￾partment of pharmacology in the United States.

This was at the University of Michigan. Abel subse￾quently left Michigan to chair the first department

of pharmacology at Johns Hopkins University.

Claude Bernard was an early French physiologist

and pharmacologist. Rudolph Bucheim established

one of the first pharmacology laboratories at the

University of Dorpat (Estonia). Oswald

Schmiedeberg is considered the founder of pharma￾cology. He trained approximately 120 pupils from

around the world, including the father of American

pharmacology, John Jacob Abel.

Therefore, the patient population that participates in

clinical trials should be representative of the patient pop￾ulation that will receive the drug when it is marketed. To

a varying extent, however, women, children, and patients

over 65 years of age have been underrepresented in clini￾cal trials of new drugs.The reasons for exclusion vary, but

the consequence is that prescribing information for these

patient populations is often deficient.

ADVERSE REACTION SURVEILLANCE

Almost all drugs have adverse effects associated with

their use; these range in severity from mild inconven￾iences to severe morbidity and death. Some adverse ef￾fects are extensions of the drug’s pharmacological effect

and are predictable, for example, orthostatic hypoten￾sion with some antihypertensive agents, arrhythmias

with certain cardioactive drugs, and electrolyte imbal￾ance with diuretics. Other adverse effects are not pre￾dictable and may occur rarely or be delayed for months

or years before the association is recognized. Examples

of such reactions are aplastic anemia associated with

chloramphenicol and clear cell carcinoma of the uterus

in offspring of women treated with diethylstilbestrol

during pregnancy. Postmarketing surveillance programs

and adverse reaction reporting systems may detect such

events. The best defense against devastating adverse ac￾tions is still the vigilance and suspicion of the physician.

8 I GENERAL PRINCIPLES OF PHARMACOLOGY

Study Questions

1. The primary consideration in all clinical trials is to

(A) Determine the safety of the drug

(B) Determine the efficacy of the drug

(C) Ensure that there is no risk to the subject

(D) Provide for the welfare of the subject

2. To conduct reliable clinical trials with a potential

new drug, it is necessary to establish a dose level

that toxicity first appears. This is commonly deter￾mined in

(A) Phase I Studies

(B) Phase II Studies

(C) Phase III Studies

(D) Phase IV Studies

3. The history of pharmacology includes a long list of

heroes. The person considered to be the founder of

American pharmacology is

(A) Claude Bernard

(B) Rudolph Bucheim

(C) John Jacob Abel

(D) Oswald Schmeideberg

1 Progress in Therapeutics 9

SUPPLEMENTAL READING

Burks TF. Two hundred years of pharmacology: A mid￾point assessment. Proc West Pharmacol Soc

2000;43:95–103.

Guarino RA. (ed). New Drug Approval Process. New

York: Dekker, 1992.

Holmstead B and Liljestrand G. (eds.). Readings in

Pharmacology. New York: Macmillan, 1963.

Huang KC. The Pharmacology of Chinese Herbs. Boca

Raton, FL: CRC, 1993.

Lemberger L. Of mice and men: The extension of ani￾mal models to the clinical evaluation of new drugs.

Clin Pharmacol Ther 1986;40:599–603.

Muscholl E. The evolution of experimental pharmacol￾ogy as a biological science: The pioneering work of

Bucheim and Schmiedeberg. Brit J Pharmacol

1995;116:2155–2159.

O’Grady J and Joubert PH (eds.). Handbook of Phase

I/II Clinical Drug Trials. Boca Raton, FL: CRC,

1997.

Parascandola J. John J. Abel and the emergence of U.S.

pharmacology. Pharmaceut News 1995;2:911.

Spilker, B. Guide to Clinical Trials. New York: Raven,

1991.

10

RECEPTORS

A fundamental concept of pharmacology is that to ini￾tiate an effect in a cell, most drugs combine with some

molecular structure on the surface of or within the cell.

This molecular structure is called a receptor. The combi￾nation of the drug and the receptor results in a molecu￾lar change in the receptor, such as an altered configura￾tion or charge distribution, and thereby triggers a chain

of events leading to a response. This concept applies not

only to the action of drugs but also to the action of nat￾urally occurring substances, such as hormones and neu￾rotransmitters. Indeed, many drugs mimic the effects of

hormones or transmitters because they combine with

the same receptors as do these endogenous substances.

It is generally assumed that all receptors with which

drugs combine are receptors for neurotransmitters, hor￾mones, or other physiological substances. Thus, the dis￾covery of a specific receptor for a group of drugs can

lead to a search for previously unknown endogenous

substances that combine with those same receptors. For

example, evidence was found for the existence of en￾dogenous peptides with morphinelike activity. A series

of these peptides have since been identified and are col￾lectively termed endorphins and enkephalins (see

Chapter 26). It is now clear that drugs such as morphine

merely mimic endorphins or enkephalins by combining

with the same receptors.

DRUG RECEPTORS AND BIOLOGICAL

RESPONSES

Although the term receptor is convenient, one should

never lose sight of the fact that receptors are in actuality

molecular substances or macromolecules in tissues that

combine chemically with the drug. Since most drugs

have a considerable degree of selectivity in their actions,

it follows that the receptors with which they interact

must be equally unique.Thus,receptors will interact with

only a limited number of structurally related or comple￾mentary compounds.

The drug–receptor interaction can be better appreci￾ated through a specific example. The end-plate region of

a skeletal muscle fiber contains large numbers of recep￾tors having a high affinity for the transmitter acetyl￾choline. Each of these receptors, known as nicotinic re￾ceptors, is an integral part of a channel in the

postsynaptic membrane that controls the inward move￾ment of sodium ions (see Chapter 28). At rest, the post￾synaptic membrane is relatively impermeable to sodium.

Stimulation of the nerve leading to the muscle results in

the release of acetylcholine from the nerve fiber in the

region of the end plate.The acetylcholine combines with

the receptors and changes them so that channels are

opened and sodium flows inward. The more acetyl￾choline the end-plate region contains, the more recep￾tors are occupied and the more channels are open.When

the number of open channels reaches a critical value,

sodium enters rapidly enough to disturb the ionic bal￾ance of the membrane, resulting in local depolarization.

The local depolarization (end-plate potential) triggers

the activation of large numbers of voltage-dependent

sodium channels, causing the conducted depolarization

known as an action potential. The action potential leads

to the release of calcium from intracellular binding sites.

The calcium then interacts with the contractile proteins,

resulting in shortening of the muscle cell. The sequence

of events can be shown diagrammatically as follows:

Mechanisms of Drug Action 2 William W. Fleming

2 Mechanisms of Drug Action 11

Ach receptor → Na influx → action potential

→ increased free Ca → contraction

where Ach acetylcholine. The precise chain of events

following drug–receptor interaction depends on the

particular receptor and the particular type of cell. The

important concept at this stage of the discussion is that

specific receptive substances serve as triggers of cellular

reactions.

If we consider the sequence of events by which

acetylcholine brings about muscle contraction through

receptors, we can easily appreciate that foreign chemi￾cals (drugs) can be designed to interact with the same

process. Thus, such a drug would mimic the actions of

acetylcholine at the motor end plate; nicotine and car￾bamylcholine are two drugs that have such an effect.

Chemicals that interact with a receptor and thereby initi￾ate a cellular reaction are termed agonists. Thus, acetyl￾choline itself, as well as the drugs nicotine and car￾bamylcholine, are agonists for the receptors in the

skeletal muscle end plate.

On the other hand, if a chemical is somewhat less

similar to acetylcholine, it may interact with the recep￾tor but be unable to induce the exact molecular change

necessary to allow the inward movement of sodium. In

this instance the chemical does not cause contraction,

but because it occupies the receptor site, it prevents the

interaction of acetylcholine with its receptor. Such a

drug is termed an antagonist. An example of such a

compound is d-tubocurarine, an antagonist of acetyl￾choline at the end-plate receptors. Since it competes

with acetylcholine for its receptor and prevents acetyl￾choline from producing its characteristic effects, admin￾istration of d-tubocurarine results in muscle relaxation

by interfering with acetylcholine’s ability to induce and

maintain the contractile state of the muscle cells.

Historically, receptors have been identified through

recognition of the relative selectivity by which certain

exogenously administered drugs, neurotransmitters, or

hormones exert their pharmacological effects. By apply￾ing mathematical principles to dose–response relation￾ships, it became possible to estimate dissociation con￾stants for the interaction between specific receptors and

individual agonists or antagonists. Subsequently, meth￾ods were developed to measure the specific binding of

radioactively labeled drugs to receptor sites in tissues

and thereby determine not only the affinity of a drug for

its receptor, but also the density of receptors per cell.

In recent years much has been learned about the

chemical structure of certain receptors.The nicotinic re￾ceptor on skeletal muscle, for example, is known to be

composed of five subunits, each a glycoprotein weighing

40,000 to 65,000 daltons. These subunits are arranged as

interacting helices that penetrate the cell membrane

completely and surround a central pit that is a sodium

ion channel. The binding sites for acetylcholine (see

Chapter 12) and other agonists that mimic it are on one

of the subunits that project extracellularly from the cell

membrane. The binding of an agonist to these sites

changes the conformation of the glycoprotein so that

the side chains move away from the center of the chan￾nel, allowing sodium ions to enter the cell through the

channel. The glycoproteins that make up the nicotinic

receptor for acetylcholine serve as both the walls and

the gate of the ion channel. This arrangement repre￾sents one of the simpler mechanisms by which a recep￾tor may be coupled to a biological response.

SECOND-MESSENGER SYSTEMS

Many receptors are capable of initiating a chain of

events involving second messengers. Key factors in

many of these second-messenger systems are proteins

termed G proteins, short for guanine nucleotide–

binding proteins. G proteins have the capacity to bind

guanosine triphosphate (GTP) and hydrolyze it to

guanosine diphosphate (GDP).

G proteins couple the activation of several different

receptors to the next step in a chain of events. In a num￾ber of instances, the next step involves the enzyme

adenylyl cyclase. Many neurotransmitters, hormones,

and drugs can either stimulate or inhibit adenylyl cy￾clase through their interaction with different receptors;

these receptors are coupled to adenylate cyclase

through either a stimulatory (GS) or an inhibitory (G1)

G protein. During the coupling process, the binding and

subsequent hydrolysis of GTP to GDP provides the en￾ergy needed to terminate the coupling process.

The activation of adenylyl cyclase enables it to cat￾alyze the conversion of adenosine triphosphate (ATP)

to 35-cyclic adenosine monophosphate (cAMP), which

in turn can activate a number of enzymes known as ki￾nases. Each kinase phosphorylates a specific protein or

proteins. Such phosphorylation reactions are known to

be involved in the opening of some calcium channels as

well as in the activation of other enzymes. In this system,

the receptor is in the membrane with its binding site on

the outer surface. The G protein is totally within the

membrane while the adenylyl cyclase is within the mem￾brane but projects into the interior of the cell. The

cAMP is generated within the cell (see Figure 10.4).

Whether or not a particular agonist has any effect

on a particular cell depends initially on the presence or

absence of the appropriate receptor. However, the na￾ture of the response depends on these factors:

• Which G protein couples with the receptor

• Which kinase is activated

• Which proteins are accessible for the kinase to

phosphorylate