McGraw-Hill
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`McGraw-Hill
`A Division of TheMcGraw•Hi1lCompanies
`
`Goodman and Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 9/e
`Copyright OO 1996, 1990, 1985, 1980, 1975, 1970, 1965, 1955, 1941 by The McGraw-Hill Companies,
`Inc. All rights reserved. Printed in the United States of America. Except as pemutted under the United
`States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form
`or by any means, or stored in a data base or retrieval system, without the prior written percussion of
`the publisher.
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`34567890 DOWDOW 9
`
`ISBN 0-07-026266-7
`This book was set in Times Roman by York Graphic Services, Inc. The editors were Martin J.
`Wonsiewicz and Peter McCurdy; the production supervisors were Robert Laffler and Clare Stanley,
`and the cover designer was Marsha Cohen/Paralellogram. The index was prepared by Irving Conde
`Tullar.
`R.R. Donnelley and Sons Company was printer and binder.
`This book is printed on acid-tree paper.
`Library of Congress Cataloging-in-Publication Data
`Goodman & Gilman's The Piiarmacologicnl Bnsis of Therapeutics. —9th ed. /Joel G. Hardman,
`Alfred Goodman Gilman, Lee E. Limbird.
`p. cm.
`Includes bibliographical references and index.
`ISBN 0-07-026266-7 (hardcover)
`II. Gilman, Alfred.
`2. Chemotherapy. I. Goodman, Louis Sanford.
`1. Pharmacology.
`III. Hardman, Joel G. N Gilman, Alfred Goodman. V. Limbird, Lee E.
`2. Drug Therapy. QV 4 G6532 1995]
`[DNLM: 1. Pharmacology.
`RM300.G644 1995
`615' .7—dc20
`DNLM/DLC
`for Library of Congress
`
`95-36658
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`Page 2
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`S
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`i
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`S E C T I O N
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`I
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`GENERAL PRINCIPLES
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`INTRODUCTION
`Leslie Z. Benet
`
`In its entirety, pharmacology embraces the knowledge of the history, source, physical and
`chemical properties, compounding, biochemical and physiological effects, mechanisms of
`action, absorption, distribution, biotransformation and excretion, and therapeutic and other
`uses of drugs. Since a drug is broadly defined as any chemical agent that affects processes
`of living, the subject of pharmacology is obviously quite extensive.
`For the clinician and the student of health sciences, however, the scope of pharma-
`cology is less expansive than indicated by the above definitions. The clinician is interested
`primarily in drugs that are useful in the prevention, diagnosis, and treatment of human
`disease. Study of the pharmacology of these drugs can be reasonably limited to aspects
`that provide the basis for their rational clinical use. Secondarily, the clinician also is con-
`cerned with chemical agents that are not used in therapy but are commonly responsible
`for household and industrial poisoning as well as environmental pollution. Study of these
`substances is justifiably restricted to the general principles of prevention, recognition, and
`treatment of such toxicity or pollution. Finally, all health professionals share in the re-
`sponsibility to help resolve the continuing sociological problem of the abuse of drugs.
`The basic pharmacological concepts summarized in this section apply to the charac-
`terization, evaluation, and comparison of all drugs. A clear understanding and apprecia-
`tion of these principles is essential for the subsequent study of the individual drugs. The
`relationship between the dose of a drug given to a patient and the utility of that drug in
`treating the patient's disease is described by two basic areas of pharmacology: pharma-
`cokinetics and pharmacodynamics. Operationally, these terms may be defined as what the
`body does to the drug (pharmacokinetics) and what the drug does to the body (pharma-
`codynamics).
`Pharmacokinetics (Chapter 1) deals with the absorption, distribution, biotransfor-
`mation, and excretion of drugs. These factors, coupled with dosage, determine the con-
`centration of a drug at its sites of action and, hence, the intensity of its effects as a func-
`tion of time. Many basic principles of biochemistry and enzymology and the physical and
`chemical principles that govern the active and passive transfer and the distribution of sub-
`stances, both small molecules and protein drugs, across biological membranes are read-
`ily applied to the understanding of this important aspect of pharmacology.
`The study of the biochemical and physiological e,~ects of drugs and their mechanisms
`of action is termed pharmacodynamics (Chapter 2). Pharmacodynamics borrows freely
`from both the subject matter and the experimental techniques of physiology, biochemistry,
`cellular and molecular biology, microbiology, immunology, genetics, and pathology. It is
`unique mainly in that attention is focused on the characteristics of drugs. As the name im-
`plies, the subject is a dynamic one. The student who attempts merely to memorize the
`pharmacodynamic properties of drugs is forgoing one of the best opportunities for corre-
`lating the entire field, of preclinical medicine. For example, the acrions and effects of the
`saluretic agents can be fully understood only in terms of the basic principles of renal phys-
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`SECTION I GENERAL PRINCIPLES
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`iology and of the. pathogenesis of edema. Conversely, great insight into normal and ab-
`normal renal physiology can be gained by the study of the pharmacokinetics and phar-
`macodynamics of the saluretic agents.
`The clinician is understandably interested mainly in the effects of drugs in human
`beings. This emphasis on clinical phnnnacology is justified, since the effects of drugs of-
`ten aze chazacterized by significant interspecies variation, and since they may be modi-
`fied further by disease. In addition, some drug effects, such as those on mood and be-
`havior, can be adequately studied only in human beings. However, technical, legal, and
`ethical considerations limit phannacological evaluation in human subjects, and the choice
`of drugs must be based in part on their phannacological evaluation in animals. Conse-
`quently, some knowledge of animal pharmacology and comparative pharmacology is help-
`ful in deciding the extent to which claims for a drug based upon studies in animals can
`be reasonably extrapolated to patients.
`Phnnnacothernpeutics (Chapter 3) deals with the use of drugs in the prevention and
`treatment of disease. Many drugs stimulate or depress biochemical or physiological func-
`tion in human beings in a sufficiently reproducible manner to provide relief of symptoms
`or, ideally, to alter favorably the course of disease. Conversely, chemotherapeutic agents
`are useful in therapy because they have only minimal effects on human beings but can
`destroy or eliminate pathogenic cells or organisms.
`Whether a drug is useful for therapy is crucially dependent upon its ability to pro-
`duce its desired effects only with tolerable undesired effects. Thus, from the standpoint
`of the clinician interested in the therapeutic uses of a drug, the selectivity of its effects is
`one of its most important characteristics. Drug therapy is rationally based upon the cor-
`relation of the actions and effects of drugs with the physiological, biochemical, micro-
`biological, immunological, and behavioral aspects of disease. In addition, disease may
`modify the pharmacokinetic properties of a drug by alteration of its absorption into the
`systemic circulation and/or its disposition.
`Toxicology (Chapter 4) is the aspect of pharmacology that deals with the adverse ef-
`fects of drugs. It is concerned not only with drugs used in therapy but also with the many
`other chemica?s that may be responsible for household, environmental, or industrial in-
`toxication. The adverse effects of the pharmacological agents employed in therapy are
`properly considered an integral part of their total pharmacology. The toxic effects of other
`chemicals is such an extensive subject that clinicians must usually confine their attention
`to the general principles applicable to the prevention, recognition, and treatment of drug
`poisonings of any cause.
`Traditionally, most drugs were small chemicals with molecular weights in the hun-
`dreds, as well as a few that were natural human or anunal hormones. Within the past
`decade, through advances in molecular and cellular biology, a number of protein and pep-
`tide drugs have been approved for clinical use. These therapies are designed to interact
`with a particular receptor or enzyme to ameliorate disease. Today we now consider the
`possibility of the drug directly replacing a diseased receptor (or gene) or of administer-
`ing agents that allow patients to make their own therapeutic protein through gene-based
`therapy (Chapter 5). The emergence of gene therapy is based on the assumption that the
`best treatment for generic diseases will be therapy that is directed to the mutant gene it-
`self. This requires a direct assault on mutant genes to replace or supplement defective ge-
`netic material with normal, functional genes. Pharmacokinetics of these new gene-based
`therapies, particularly delivery of the "drug" to its site of action or function, is a major
`hurdle for this new therapeutic modality. Gene therapy requires unique methods, many of
`which aze gene-based themselves through enhanced uptake of DNA expression vectors,
`to deliver a gene to its target cell.
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