MODERN
`PHARMACOLOGY S
`with Clinical Applications
`
`IPR2023-00512..
`
`SIXTH EDITION
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`Charles R. Craig - Robert E. Stitzel
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`CELGENE 2075
`CELGENE 2075
`‘APOTEX v. CELGENE
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

` wa
`
`—_
`THE LIBRARY
`
`THE UNIVERSITY
`OF TEXAS
`AT
`AUSTIN
`
`|
`
`seeratyeee
`
`

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`Pe knee cen
`
`

`

`MODERN
`
`EDITION
`
`EDITED BY
`
`Charles R. Craig, PhD
`PROFESSOR OF NEUROBIOLOGY AND ANATOMY
`West Virginia University School of Medicine
`Morgantown, West Virginia
`
`Robert E. Stitzel, PhD
`PROFESSOR AND ASSOCIATE CHAIRMAN OF BIOCHEMISTRY AND MOLECULAR PHARMACOLOGY
`West Virginia University School of Medicine
`Morgantown, West Virginia
`
`APa, LIPPINCOTTWILLIAMS &WILKINS
`
`
`A Wolters Kluwer Company
`Philadelphia - Baltimore +» New York « London
`Buenos Aires « Hong Kong + Sydney + Tokyo
`
`yy
`
`

`

`Editor: Betty Sun
`Managing Editor: Rebecca Kerins
`Marketing Manager: Joseph Schott
`Production Editor: Jennifer Ajello
`Designer: Doug Smock
`Compositor: Graphic World
`Printer: Quebecor World-Dubuque
`
`Copyright © 2004 Lippincott Williams & Wilkins
`
`351 West Camden Street
`Baltimore, MD 21201
`
`530 Walnut Street
`Philadelphia, PA 19106
`
`All rights reserved. This book is protected by copyright. No part of
`this book may be reproducedin any form or by any means,including
`photocopying,or utilized by any information storage and retrieval
`system without written permission from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability,
`negligence, or otherwise) for any injury resulting from any material
`contained herein. This publication contains information relating to
`generalprinciples of medical care that should not be construed as
`specific instructions for individual patients. Manufacturers’ product
`information and package inserts should be reviewed for currentin-
`formation, including contraindications, dosages, and precautions.
`
`04 05 06 07 08
`12345678910
`Printed in the United States ofAmerica
`
`Library of Congress Cataloging-in-Publication Data
`
`Modern pharmacology with clinical applications / edited by Charles
`R. Craig, Robert E.Stitzel—6th ed.
`p.;cm.
`Includes index.
`ISBN 0-7817-3762-1
`1. Clinical pharmacology.
`Robert E.
`[DNLM:
`1. Pharmacology. 2. Drug Therapy. QV 4 M6898
`2003]
`RM301.28.M63 2003
`615'.1—dce21
`
`I. Craig, Charles R.IL. Stitzel,
`
`The publishers have made every effort to trace the copyright holders
`for borrowed material. If they have inadvertently overlookedany, they
`will be pleased to makethe necessary arrangements atthefirst oppor-
`tunity.
`
`To purchase additional copies of this book, call our customerservice
`department at (800) 638-3030 or fax orders to (301) 824-7390.
`International customers should call (301) 714-2324.
`
`Visit Lippincott Williams & Wilkins on the Internet:
`http://www.LWW.com. Lippincott Williams & Wilkins customer
`service representatives are available from 8:30 am to 6:00 pm, EST.
`
`

`

`
`
`PREFACE
`
`Te 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 numberof new or updated fea-
`tures that further enhance the appealof thetext.
`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
`
`

`

` ACKNOWLEDGMENT
`
`are very pleased to dedicate this sixth edition to a new
`The editors began working together on Modern
`Pharmacology almost 25 years ago. We are grateful to—-generation of students, and to our grandchildren, Kaya
`be working togetherstill as colleagues and friends and—Seneca Stitzhal and Andrew, Megan, and Taylor Craig.
`
`

`

`
`
`CONTRIBUTING AUTHORS
`
`Albert J. Azzaro, PhD
`Chief Scientific Officer, Clinical Development
`Somerset Pharmaceuticals
`2202 North West Shore Blvd., Suite 450
`Tampa, FL 33607
`
`Suzanne Barone, PhD
`9710 Bellevue Drive
`Bethesda, MD 20814
`
`Steven M. Belknap, MD
`Associate Professor
`Department of Biomedical & Therapeutic Sciences
`University of Illinois College of Medicine at Peoria
`PO Box 1649
`Peoria, Ill 61656
`
`William O. Berndt, PhD
`Vice Chancellor, Academic Affairs
`Dean, Graduate Studies and Research
`Professor of Pharmacology
`University of Nebraska Medical Center
`986810 Nebraska Medical Center
`Omaha, NE 68198-6810
`
`David R. Bickers, MD
`Carl Truman Nelson Professor and Chairman
`Department of Dermatology
`College of Physicians & Surgeons of Columbia
`University
`New York, NY 10032
`
`Leo R. Brancazio, PhD
`Instructor, Division of Maternal/Fetal Medicine
`4010 Hospital South
`Duke University Medical Center
`Durham, NC 27710-3967
`
`Eric L. Carter, MD
`Assistant Clinical Professor of Dermatology
`Columbia University College of Physicians and
`Surgeons
`151 Ft. Washington Avenue
`New York, NY 10032
`Lisa A. Cassis, PhD
`Professor, Division of Pharmaceutical Sciences
`University of Kentucky, College of Pharmacy
`Lexington, KY 40536-0082
`Richard J. Cenedella, PhD
`Professor and Chairman, Department of Biochemistry
`Kirksville College of Osteopathic Medicine
`800 WestJefferson Street
`Kirksville, MO 63501
`
`Mary-Margaret Chren, MD
`Associate Professor in Residence
`University of California at San Francisco
`San Francisco VAMC 190
`4150 Clement Street
`San Francisco, CA 94121
`
`John M. Connors, PhD
`Associate Professor
`Department of Physiology and Pharmacology
`West Virginia University School of Medicine
`Morgantown, WV 26506-9229
`
`Charles R. Craig, PhD
`Director of West Virginia University Research
`Compliance
`Professor of Neurobiology and Anatomy
`West Virginia University School of Medicine
`Morgantown, WV 26506-9142
`
`John W. Dailey, PhD
`Professor Emeritus
`Departmentof Basic Science
`University of Illinois College of Medicine
`PO Box 1649
`Peoria, IL 61656
`
`Priscilla S. Dannies, PhD
`Professor of Pharmacology
`Department of Pharmacology School of Medicine
`Yale University
`333 Cedar Street
`New Haven, CT 06510
`
`MaryE. Davis, PhD
`Professor of Physiology and Pharmacology
`West Virginia University School of Medicine
`Morgantown, WV 26506-9229
`
`William L. Dewey, PhD
`Professor of Pharmacology and Toxicology
`Virginia Commonwealth University
`310 N. 12th Street
`PO Box 980613
`Richmond, VA 23219-0613
`
`Jeffrey S. Fedan, PhD
`Professor of Physiology and Pharmacology
`West Virginia University School of Medicine
`Research Pharmacologist
`National Institute for Occupational Safety and Health
`Morgantown, WV 26506
`
`

`

`Mitchell S. Finkel, MD
`Professor of Medicine and Biochemistry and Molecular
`Pharmacology
`West Virginia University School of Medicine
`Morgantown, WV 26506-9157
`
`Douglas W. P. Hay, PhD
`Associate Fellow, Department of Pulmonary
`Pharmacology
`SmithKline Beecham Pharmaceuticals
`King of Prussia, PA 19406-0639
`
`Peter S. Fischbach, MD
`Department of Pediatric & Communicable Diseases
`Division of Pediatric Cardiology
`F1310 Mott Children’s Hospital
`Ann Arbor, MI 48109-0204
`
`Janet Fleetwood, PhD
`Director, Medical Humanities Program
`Medical College of Pennsylvania
`3300 Henry Avenue
`Philadelphia, PA 19129
`
`Peter A. Friedman, PhD
`Professor of Pharmacology
`University of Pittsburgh School of Medicine
`Pittsburgh, PA 15261
`
`William W. Fleming, PhD
`Professor Emeritus
`Department of Physiology and Pharmacology
`West Virginia University School of Medicine
`Morgantown, WV 26506-9229
`
`Lisa M. Gangarosa, MD
`Assistant Professor
`Section of Gastroenterology
`C.B. 7080
`University of North Carolina
`Burnett-Womack Bldg., Room 724
`Chapel Hill, NC 27599
`
`Jennifer Rubin Grandis, M.D
`Associate Professor of Otolaryngology
`University of Pittsburgh School of Medicine
`Pittsburgh, PA 15261
`
`James F. Graumlich, MD
`Assistant Professor of Biomedical & Therapeutic
`Sciences
`University of Illinois College of Medicine
`One IJllini Drive, Box 1649
`Peoria, IL 61656-1649
`
`Garrett J. Gross, PhD
`Professor of Pharmacology & Toxicology
`Medical College of Wisconsin
`8701 Watertown Plank Road
`Milwaukee, WI 53226
`
`David Haddox, D.D.S., MD, F.A.C.P.M.
`Medical Director, Internal Analgesics
`Purdue Pharmaceuticals
`100 Connecticut Avenue
`Norwalk, CT 06850-3590
`
`Arthur F, Hefti, D.MD, P.D.
`Associate Dean
`Research and Graduate Studies
`Ohio State University College of Medicine and
`Dentistry
`305 W. 12th Ave.
`Columbus, OH 43210
`
`J. Thomas Hjelle, PhD
`Associate Professor of Pharmacology
`Department of Biomedical and Therapeutic Sciences
`University of Illinois College of Medicine at Peoria
`OneIllini Drive
`Peoria, IL 61605
`
`Michael B. Howie, MD
`Professor ofAnesthesia
`The Ohio State University College of Medicine
`Columbus, OH 43210
`
`Mir Abid Husain, MD
`Saint Francis Medical Center
`530 NE Glen Oak Avenue
`Peoria, IL 61637
`
`Gregory Juckett, MD
`Professor of Family Medicine
`West Virginia University Health Sciences Center
`Morgantown, WV 26506-9247
`
`Stephen M.Lasley, PhD
`Department of Biomedical & Therapeutic Sciences
`University of Illinois College of Medicine
`PO Box 1649
`Peoria, IL 61656-1649
`
`John S. Lazo, PhD
`Professor and Chair, Department of Pharmacology
`University of Pittsburgh School of Medicine
`E1340 Biomedical Sciences Tower
`Pittsburgh, PA 15261-0001
`
`Tony J.-F. Lee
`Professor of Pharmacology
`Southern Illinois University
`School of Medicine
`Springfield, IL 62794-9629 —
`
`Benedict R. Lucchesi, MD, PhD
`Professor of Pharmacology
`Department of Pharmacology
`University of Michigan Medical School
`1301 MSRB HI
`Ann Arbor, MI 48109-0632
`
`

`

`
`
`Contributing Authors ixIOOI—BhRt,
`
`Angelo Mariotti, D.D.S., PhD
`Chair, Department of Periodontology
`Ohio State University College of Medicine and
`Dentistry
`305 W. 12th Ave.
`Columbus, OH 43210
`
`Billy R. Martin, PhD
`Professor and Chair
`Department of Pharmacology & Toxicology
`Virginia Commonwealth University
`410 N. 12th St., 7th floor, Room 760
`PO Box 980613
`Richmond, VA 23298-0377
`
`Jeane McCarthy, MD
`Clinical Professor of Pediatrics
`University of South Florida
`All Children’s Hospital
`St. Petersburg, FL 33701
`
`Joseph J. McPhillips, PhD
`Retired, formerly Director of Clinical Research
`Boehringer Mannheim Pharmaceuticals Corp.
`Current address: 20611 Highland Hall Drive
`Montgomery Village, MD 20886-4024
`
`Marcia A. Miller-Hjelle, PhD
`Chief, Section of Medical Microbiology and Infectious
`Diseases
`Department of Biomedical and Therapeutic Sciences
`University of Illinois College of Medicine
`OneIllini Drive, Box 1649
`Peoria, IL 61656-1649
`
`Roman J. Miller, PhD
`Professor of Biology
`Eastern Mennonite College
`Harrisonburg, VA 22801
`
`Humayun Mirza, MD
`Interventional Fellow
`Section of Cardiology, Department of Medicine
`West Virginia University School of Medicine
`Morgantown, WV 26506-9157
`Michael D. Miyamoto, PhD
`Professor of Pharmacology
`East Tennessee State University College of Medicine
`Johnson City, TN 37614-0577
`Richard P. O’Connor, MD
`C/o Caterpillar Corporate Medical
`Caterpillar Inc.
`PO Box 600
`Mossville, IL 61552-0600
`Mark Reasor, PhD
`Professor ofPhysiology and Pharmacology
`WestVirginia University School of Medicine
`Morgantown, WV 26506-9229
`
`Ronald P. Rubin, PhD
`Professor and Chair
`Department of Pharmacology and Toxicology
`State University of New York at Buffalo
`School of Medicine
`102 Farber Hall
`Buffalo, NY 14214-3000
`
`Leonard J. Sauers, PhD, D.A.B.T.
`Director, Product Safety, Regulatory Affairs, &
`Analytical Sciences
`.
`The Procter & Gamble Company
`Ivorydale Technical Center
`5299 Spring Grove Avenue
`Cincinnati, OH 45217
`
`Leonard William Scheibel, MD
`Chief, Section of Clinical Pharmacology
`University of Illinois College of Medicine
`Department of Biomedical & Therapeutic Sciences
`PO Box 1649
`Peoria, IL 61656-1649
`
`Frank L. Schwartz, MD
`Associate Professor of Medicine
`West Virginia University School of Medicine
`Morgantown, WV 26506
`Medical Director, Diabetes Center
`Camden Clark Memorial Hospital
`Parkersburg, WV 26101
`
`Donald G. Seibert, MD
`Gastroenterology Associates of Southwest Virginia
`2012 Stephenson Ave SW
`Roanoke, VA 24014
`
`Branimir I. Sikic, MD, PhD
`Professor of Medicine (Oncology) and Clinical
`Pharmacology
`Stanford University Medical Center
`Stanford, CA 94305-5151
`
`David C. Slagle, MD
`Saint Francis Medical Center
`530 N. E. Glen Oak Avenue
`Peoria, IL 61637
`
`David J. Smith, PhD
`Professor of Biochemistry and Molecular
`Pharmacology
`WestVirginia University School of Medicine
`Morgantown, WV 26506-9142
`
`Vijaya Somaraju, MD
`Saint Francis Medical Center
`530 N. E. Glen Oak Avenue
`Peoria, IL 61637
`
`

`

`Patricia K. Sonsalla, PhD
`Associate Professor of Neurology
`UMDNJ-RW Johnson Medical School
`675 Hoes Lane
`Piscataway, NJ 08854-5635
`
`Robert E.Stitzel, PhD
`Director of University Graduate Education
`Professor and Associate Chair
`Department of Biochemistry and Molecular
`Pharmacology
`West Virginia University School of Medicine
`Morgantown, WV 26506-9142
`
`Jeannine Strobl, PhD
`Professor of Biochemistry and Molecular
`Pharmacology
`WestVirginia University School of Medicine
`Morgantown, WV 26506-9142
`
`V. C. Swamy, PhD
`Chair, Biomedical Pharmacology
`School of Pharmacy
`State University of New York at Buffalo
`313 Hochstetter Hall
`Buffalo, NY 14260
`
`David A. Taylor, PhD
`Professor and Chair of Pharmacology
`East Carolina University School of Medicine
`Greenville, NC 27858-4353
`
`John A. Thomas, PhD
`219 Wood Shadow
`San Antonio, TX 78216-1633
`
`Michael J. Thomas, MD, PhD
`Associate Professor of Medicine, Division of
`Endocrinology
`University of North Carolina School of Medicine
`6101 Thurston Bowles, CB #7170
`Chapel Hill, NC 27599-7170
`
`Theodore J. Torphy, PhD
`Vice President and Director of Pharmacology
`Centocor, Inc.
`200 Great Valley Parkway
`Malvern, PA 19355
`
`Timothy S. Tracy, PhD
`Associate Professor of Basic Pharmaceutical Sciences
`West Virginia University School of Pharmacy
`Morgantown, WV 26506-9530
`
`David Triggle, PhD
`Dean, State University of New York at Buffalo
`School of Pharmacy
`126 Cooke
`Buffalo, NY 14260-0001
`
`Knox Van Dyke, PhD
`Professor of Biochemistry and Molecular
`Pharmacology
`West Virginia University School of Medicine
`Morgantown, WV 26506-9142
`
`Herbert E. Ward, MD
`Department of Psychiatry
`University of Florida
`PO Box 100256
`Gainesville, FL 32610-0256
`
`Sandra P. Welch, PhD
`Professor of Pharmacology & Toxicology’
`Virginia Commonwealth University
`PO Box 980613
`Richmond, VA 23298-0613
`
`David P. Westfall, PhD
`Professor of Pharmacology
`University of Nevada-Reno, MS318
`Reno, NV 89557-0046
`
`Thomas C. Westfall, PhD
`Professor and Chair
`Department of Pharmacology and Physiological
`Sciences
`St. Louis University School of Medicine
`1402 S. Grand Blvd.
`St. Louis, MO 63104-1083
`
`William F. Wonderlin, PhD
`Associate Professor of Biochemistry and Molecular
`Pharmacology
`West Virginia University School of Medicine
`Morgantown, WV 26506-9142
`
`Karen A. Woodfork, PhD
`Adjunct Associate Professor in Biochemistry and
`Molecular Pharmacology
`WestVirginia University School of Medicine
`Morgantown, WV 26506-9142
`
`

`

`
`
`GENERAL PRINCIPLES OF PHARMACOLOGY
`
`19.
`
`Caicium Channel Blockers
`
`218
`
`03
`
`. Progress in Therapeutics
`Robert E. Stitzel and Joseph J. McPhillips
`Mechanismsof Drug Action
`10
`William W. Fleming
`Drug Absorption and Distribution
`Timothy S. Tracy
`. Metabolism and Excretion of Drugs
`Timothy S. Tracy
`Pharmacokinetics
`
`48
`
`20
`
`34
`
`Timothy S. Tracy
`Drug Metabolism and Disposition in Pediatric and
`Gerontological Stagesof Life
`56
`Jeane McCarthy
`Principles of Toxicology
`Mary E. Davis and Mark J. Reasor
`Contemporary Bioethical Issues in Pharmacology and
`Pharmaceutical Research
`73
`Janet Fleetwood
`
`63
`
`DRUGS AFFECTING THE AUTONOMIC NERVOUS
`SYSTEM
`
`General Organization and Functions of the Nervous
`System
`83
`William W. Fleming
`96
`Adrenomimetic Drugs
`Tony J.-F. Lee and Robert E. Stitzel
`Adrenoceptor Antagonists
`David P Westfall
`
`109
`
`Directly and Indirectly Acting
`Cholinomimetics
`121
`William FE Wonderlin
`
`Muscarinic Blocking Drugs
`William F. Wonderlin
`
`134
`
`Ganglionic Blocking Drugs and Nicotine
`Thomas C. Westfall
`
`141
`
`Drugs Affecting the Cardiovascular System
`
`Pharmacologic Managementof Chronic Heart
`Failure
`151
`
`Mitchell S. Finkel and Humayun Mirza
`Antiarrhythmic Drugs
`160
`Peter S. Fischbach and Benedict R. Lucchesi
`
`Antianginal Drugs
`Garrett J. Gross
`
`196
`
`The Renin-Angiotensin—Aldosterone System and Other
`Vasoactive Substances
`206
`Lisa A. Cassis
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`UE.
`
`15.
`
`16.
`
`17.
`
`18.
`
`20.
`
`21.
`
`22.
`
`23.
`
`IV.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`31.
`
`32.
`
`33.
`
`34.
`
`35.
`
`Vijay C. Swamy and David J. Triggie
`Antihypertensive Drugs
`225
`David P Westfall
`
`239
`Diuretic Drugs
`Peter A. Friedman and William 0. Berndt
`
`Anticoagulant, Antipfatelet, and Fibrinolytic
`(Thrombolytic) Drugs
`256
`Jeffrey S. Fedan
`Hypocholesterolemic Drugs and Coronary Heart
`Disease
`268
`Richard J. Cenedella
`
`DRUGS AFFECTING THE CENTRAL NERVOUS
`SYSTEM
`
`Introduction to Central Nervous System
`Pharmacology
`281
`Charles R. Craig
`General Anesthesia: Intravenous and Inhalational
`
`291
`Agents
`David J. Smith and Michael B. Howie
`
`Opioid and Nonopioid Analgesics
`Sandra P Welch and Billy R. Martin
`Local Anesthetics
`330
`J. David Haddox
`
`Agents Affecting Neuromuscular
`Transmission
`338
`
`310
`
`Michael D. Miyamoto
`Central Nervous System Stimulants
`David A. Taylor
`Sedative—Hypnotic and Anxiolytic Drugs
`John W. Dailey
`Drugs Used in Neurodegenerative Disorders
`Patricia K. Sonsalla
`
`348
`
`355
`
`364
`
`374
`
`Antiepileptic Drugs
`Charles R. Craig
`Drugs Used in Mood Disorders
`Herbert E. Ward and Albert J. Azzaro
`
`385
`
`Antipsychotic Drugs
`Stephen M. Lasley
`Contemporary Drug Abuse
`Billy R. Martin and William L. Dewey
`
`397
`
`406
`
`THERAPEUTIC ASPECTS OF INFLAMMATORY
`AND SELECTED OTHER CLINICAL DISORDERS
`
`36.
`
`37.
`
`Antiinflammatory and Antirheumatic Drugs
`Karen A. Woodfork and Knox Van Dyke
`Drugs Used in Gout
`441
`Knox Van Dyke
`
`423
`
`

`

`TABLE OF CONTENTS
`xii
`
`449
`
`470
`
`55. The Rational Basis for Cancer
`Chemotherapy
`630
`Branimir |. Sikic
`56. Antineoplastic Agents
`Branimir |. Sikic
`immunomodulating Drugs
`Leonard J. Sauers
`666
`58. Gene Therapy
`John §S. Lazo and Jennifer Rubin Grandis
`
`638
`
`657
`
`57.
`
`38. Histamine and Histamine Antagonists
`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
`Lisa M. Gangarosa and Donald G. Seibert
`484
`41. Drugs Used in Dermatological Disorders
`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
`Steven M. Belknap
`44. Synthetic Organic Antimicrobials: Sulfonamides,
`Trimethoprim, Nitrofurans, Quinolones,
`Methenamine
`515
`Marcia A. Miller-Hjelle, Vijaya Somaraju, and J. Thomas Helle
`45. B-Lactam Antibiotics
`526
`James F. Graumlich
`46. Aminoglycoside Antibiotics
`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
`Vijaya Somaraju
`567
`50. Antiviral Drugs
`Knox Van Dyke and Karen Woodfork
`51. Therapy of Human Immunodeficiency Virus
`Knox Van Dyke and Karen Woodfork
`52. Antifungal Drugs
`596
`David C. Slagle
`53. Antiprotozoal Drugs
`Leonard William Scheibel
`621
`54. Anthelmintic Drugs
`Mir Abid Husain and Leonard William Scheibel
`
`557
`
`509
`
`538
`
`584
`
`606
`
`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
`Jeannine S. Strobl
`62. Uterine Stimulants and Relaxants
`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
`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
`Michael J. Thomas and John A. Thomas
`68. Vitamins
`777
`Suzanne Barone
`69. Herbal Medicine
`Gregory Juckett
`Index
`
`763
`
`785
`
`704
`
`716
`
`742
`
`

`

`ClVeacla
`
`Pharmacokinetics is the description of the time course
`of a drug in the body, encompassing absorption,distri-
`bution, metabolism, and excretion. In simplest terms,it
`can be described as what the body does to the drug.
`Pharmacokinetic concepts are used during drug devel-
`opmentto determine the optimal formulationof a drug,
`dose (along with effect data), and dosing frequency. For
`drugs with a wide therapeutic index (difference be-
`tween the minimum effective dose and the minimum
`toxic dose), knowledge of the drug’s pharmacokinetic
`properties in that individual patient may not bepartic-
`ularly important. For example, nonsteroidal antiinflam-
`matory drugs, such as ibuprofen, have a wide therapeu-
`tic index, and thus knowledge of the pharmacokinetic
`parameters in a given individualis relatively unimpor-
`tant, since normal doses can vary from 400 to 3200 mg
`per day with no substantial difference in acute toxicity
`or effect. However, for drugs with a narrow therapeutic
`index, knowledge of that drug’s pharmacokinetic profile
`in an individual patient has paramount importance.
`If thereis little difference between the minimum ef-
`fective dose and the toxic dose, slight changes in a
`drug’s pharmacokinetic profile, or even simply in-
`terindividual differences, may require dosage adjust-
`ments to minimize toxicity or maximize efficacy. For ex-
`ample, the blood concentrations of the antiasthmatic
`drug theophylline must usually be maintained within
`the range of 10-20 pg/mL. At concentrations below
`this, patients may not obtain relief of symptoms, while
`concentrations above 20 wg/mL can result in serious
`toxicities, such as seizures, arrhythmias, and even death.
`Thus, a drug’s pharmacokinetic profile may have im-
`portantclinical significance beyond its use in drug de-
`velopment.
`
`48
`
`DRUG CONCENTRATION-TIME
`PROFILES AND BASIC
`PHARMACOKINETIC PARAMETERS
`The time course of a drug in the bodyis frequently rep-
`resented as a concentration-time profile in which the
`concentrations of a drug in the body are measured ana-
`lytically and the results plotted in semilogarithmic form
`against time. A representative profile of a drug given in-
`travenously is presented in Figure 5.1. Drug concentra-
`tions are measured in samples typically taken from the
`brachial vein, since this vein is readily accessible, since
`sampling results in minimal patient discomfort and
`since obtained valuesreflect the concentrations of drug
`in the bloodstream. Concentrations in the blood may
`not be identical to concentrations at the site of action,
`such as a receptor, but one hopesthey serve as a surro-
`gate that correlates in a proportional manner.
`Figure 5.1 showsthat for a drug givenintravenously,
`maximum concentrations are achieved almost instanta-
`neously, since absorption across membranesis not re-
`quired, though distributive processes may also occur
`(not depicted for the sake of simplicity). The concentra-
`tions of drug in the blood decline over time according to
`the elimination rate of that particular drug. More com-
`monly, drug is given via extravascular routes (e.g.,
`orally), so absorption and distribution must occur, and
`therefore it will take some time before maximum con-
`centrations are achieved.
`The blood concentration—time profile for a theoret-
`ical drug given extravascularly (e.g., orally) is shown in
`Figure 5.2. Some pharmacokinetic parameters, such as
`Conaxy Tmax, area under the curve, and half-life, can be es-
`timated by visual inspection or computation from a con-
`
`

`

`
`
` 5 Pharmacokinetics 49
`
`nation rate will generally exhibit a longer T,,,, and
`higher C,,,,. Once administered, a drug begins undergo-
`ing absorption, distribution, metabolism, and excretion
`all at once, not in a sequential fashion, such that all of
`these processes are involved in determining the shape
`of a concentration—time profile.
`Oneindicator of the overall exposure of a person to
`a drug is through the calculation of the area under the
`curve (AUC). As the name implies, AUC is the mathe-
`matically integrated area under the concentration-time
`curve and is most commonly calculated using the trape-
`zoidal rule of mathematics. In Figure 5.2, the AUCis
`represented by the shaded area. Though the shape of
`the concentration-time profile may affect the AUC for
`a drug, two drugs with entirely different concentra-
`tion—time profile shapes may have the same AUC.Itis,
`in fact, this property that makes calculating the AUC
`useful, because it can be used to assess the person’s
`overall exposure to a drug, even though the individual
`may have reached differentT,,,, and C,,,, values from
`those of other individuals. Furthermore, as will be dis-
`cussed shortly, AUC is also useful for calculating an-
`other pharmacokinetic parameter, clearance.
`An additional parameter that can be determined
`from a concentration-timeprofile is the half-life of the
`drug,thatis, the time it takes for half of the drug to be
`eliminated from the body. Half-life determination is
`very useful, since it can readily be used to evaluate how
`long a drug is expected to remain in the bodyafterter-
`mination of dosing, the time required for a drug to
`reach steady state (when the rate of drug entering the
`body is equal to the rate of drug leaving the body), and
`often the frequency of dosing. The following equationis
`used to calculate the half-life of a drug:
`
`0.693
`k .
`bi
`where t,,. is the half-life and k, is the elimination rate
`constant calculated from the slope of the declining por-
`tion of the concentration-timeprofile (Fig. 5.3). By def-
`inition, half-life denotes that 50% of the drug in the
`body at a given time will be eliminated over the calcu-
`lated period. However, this does not mean that the
`same amountof drugis eliminated each half-life. For ex-
`ample, Figure 5.3 showsthat duringthe first half-life pe-
`riod (0-5 hours) the drug concentration is reduced from
`100 pg/mL to 50 pg/mL. However, during the second
`half-life period (5-10 hours), even though the amount
`in the body is reduced by 50%, the concentrationfalls
`only from 50 wg/mL to 25 pg/mL (a reduction in con-
`centration of 25 wg/mL). This conceptis also illustrated
`in Table 5.1. It takes approximately five half-lives for
`97% of the drug to be eliminated from the body (re-
`gardless of the duration of the half-life). Thus, if one
`wished to switch a patient from one drug to another but
`not have both drugs present in substantial quantities,
`
`Intravenous Dosing
`
`Concentration
`
`(ug/ml)
`
`10
`
`15
`
`20
`
`25
`
`Hours
`
`FIGURE 5.1
`Concentration—-time profile for a hypothetical drug
`administered intravenously. Following intravenous dosing of
`a drug, blood concentrations of the drug reach a maximum
`almost immediately. Y-axis is logarithmic scale.
`
`centration—-time profile. C,,,, is defined as the maximum
`concentration achieved in the blood. In Figure 5.2, Cyrax
`can be estimated to be approximately 225 g/mL. The
`other pharmacokinetic parameter that can beeasily es-
`timated from a concentration—timeprofile is T,,,,,, or the
`time needed to reach maximum concentration.
`In
`Figure 5.2, the Tyax is estimated by visual inspection to
`be approximately 2 hours. The samedrug in a formula-
`tion that permits a faster rate of absorption would have
`a shorterT,,,,, and generally a higherC,,,,, than the for-
`mulation with slower absorptive properties. Likewise,
`all other things being equal, a drug with a slowerelimi-
`
`1000
`
`Cmax
`
`Extravascular Dosing
`f
`
`8 a
`
`2 100
`
`&2 §52
`
`oO
`oO
`
`10
`
`1
`
`Tmax
`
`Hours
`
`FIGURE 5.2
`Concentration-time profile for a hypothetical drug
`administered extravascularly. Cna,, maximum concentration
`achieved. Tn, time required to achieve maximum
`concentration. AUC = Area under the curve. Y-axis is on
`logarithmic scale.
`
`

`

`50°
`
`;
`
`| GENERAL PRINCIPLES OF PHARMACOLOGY
`
`100 -
`
`Slope = k, (elimination rate constant)
`
`
`
`
`
`5 hours
`
`10
`
`=Ob
`Si=
`g
`
`gS3
`
`g&oO
`O
`
`ADDITIONAL PHARMACOKINETIC
`PARAMETERS
`aee
`
`Bioavailability
`
`Bioavailability (designated as F) is defined as the frac.
`tion of the administered drug reaching the systemiccir-
`culation as intact drug. Bioavailability is highly depend-
`ent on both the route of administration and the drug
`formulation. For example, drugs that are given intra-
`venously exhibit a bioavailability of 1, since the entire ~
`dose reaches the systemic circulation as intact drug,
`However, for other routes of administration, this is not
`necessarily the case.
`Subcutaneous, intramuscular, oral, rectal, and other
`extravascular routes of administration require that the
`drug be absorbedfirst, which can reduce bioavailability,
`The drug also may be subject to metabolism prior to
`reaching the systemic circulation, again potentially re-
`ducing bioavailability. For example, when the B-blocking
`agent propranolol is given intravenously, F = 1, but
`whenit is given orally, F = ~0.2, suggesting that only ap-
`proximately 20% of the administered dose reaches the
`systemic circulation as intact drug.
`With respect to the effect of drug formulation on
`bioavailability, the drug digoxin provides a good exam-
`ple. Given orally as a solution, the bioavailability of
`digoxin approaches F = 1, suggesting essentially com-
`plete bioavailability and one that approachesthatof the
`intravenous formulation. Digoxin liquid capsules also
`exhibit F = ~1 whengivenorally and thus are also com-
`pletely available. However,for digoxin tablets, F = ~0.7,
`suggesting incomplete bioavailability, probably because
`of lack of absorption.
`Twotypes of bioavailability can be calculated, de-
`pending on the formulations available and the informa-
`tion required. The gold standardis a calculation of the
`absolute bioavailability of a given product compared to
`
`1 a
`0
`5
`10
`15
`20
`25
`Hours
`
`30
`
`FIGURE 5.3
`Elimination of a hypothetical drug with a haif-life of 5 hours.
`The drug concentration decreases by 50% every 5 hours
`(i.é.,2 = 5 hours). The slope of the line is the elimination
`rate (k.).
`
`the clinician must wait five half-lives (in this case, 25
`hours) before administering the second drug.It will also
`require five half-lives for a drug to reach steady state
`(see Pharmacokinetics of Single Versus Multiple
`Dosing, later in the chapter), again, independent of
`the duration of the half-life. Steady state is when the
`amount of drug entering the body is equal
`to the
`amount of drug being eliminated in a given period.
`Finally, it is a rule of thumb (though certainly not ab-
`solute) that drugs are generally dosed every half-life
`(with allowance for rounding to convenient intervals).
`Thus, the concept of half-life has considerable impor-
`tance for determining dosing frequency or adjusting
`dosesin a patient.
`
`E
`
`TABLE 5.1.
`
`Elimination Characteristics of a Drug with a 5-Hour Half-life
`
`Oa
`Percent of Original
`Concentration at
`Concentration at
`Period
`Concentration
`Beginning of Period?
`End of Period?
`(hours)
`100.00
`50.000
`0-5
`50.000
`50.00
`25.000
`5-10
`25.000
`25.00
`12.500
`10-15
`12.500
`12.50
`6.250
`15-20
`6.250
`‘
`6.25
`3.125
`20-25
`3.125
`Half ofthe concentration at the beginning of any period is eliminated during the period.Thus, each successive half-life removesless drug,but
`the concentration at the beginning of the period is reduced by 50% during the period.
`*Microgramspermilliliter.
`
`

`

`—_—
`
`5 Pharmacokinetics
`
`51
`
`the intravenous formulation (F = 1). The absolute
`bioavailability of a drug can be calculated as:
`_ DOSE, * (AUCo.0)other
`~ DOSCother * (AUC)iv
`
`where the route of administration is other than intra-
`venous (e.g., oral,