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a LANGE medical book

Basic & Clinical

Pharmacology
Twelfth Edition

Edited by

Bertram G. Katzung, MD, PhD

Professor Emeritus
Department of Cellular & Molecular Pharmacology
University of California, San Francisco
Associate Editors
Susan B. Masters, PhD
Professor of Pharmacology & Academy Chair of Pharmacology Education
Department of Cellular & Molecular Pharmacology
University of California, San Francisco
Anthony J. Trevor, PhD
Professor Emeritus
Department of Cellular & Molecular Pharmacology
University of California, San Francisco

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Contents
Schedule of Controlled Drugs Inside Front Cover
Preface vii
Authors ix
Key Features xii

S E C T I O N I S E C T I O N III
BASIC PRINCIPLES 1 CARDIOVASCULAR-RENAL
DRUGS 169
1. Introduction
Bertram G. Katzung, MD, PhD 1 11. Antihypertensive Agents
Neal L. Benowitz, MD 169
2. Drug Receptors & Pharmacodynamics
Mark von Zastrow, MD, PhD 15 12. Vasodilators & the Treatment
of Angina Pectoris
3. Pharmacokinetics & Pharmacodynamics: Bertram G. Katzung, MD, PhD 193
Rational Dosing & the Time Course
of Drug Action 13. Drugs Used in Heart Failure
Nicholas H. G. Holford, MB, ChB, FRACP 37 Bertram G. Katzung, MD, PhD 211

4. Drug Biotransformation 14. Agents Used in Cardiac Arrhythmias

Maria Almira Correia, PhD 53 Joseph R. Hume, PhD, & Augustus O. Grant, MD,
PhD 227
5. Development & Regulation of Drugs
Bertram G. Katzung, MD, PhD 69 15. Diuretic Agents
Harlan E. Ives, MD, PhD 251
S E C T I O N II S E C T I O N IV
AUTONOMIC DRUGS 79
DRUGS WITH IMPORTANT ACTIONS
6. Introduction to Autonomic Pharmacology ON SMOOTH MUSCLE 273
Bertram G. Katzung, MD, PhD 79
16. Histamine, Serotonin, & the Ergot Alkaloids
7. Cholinoceptor-Activating & Bertram G. Katzung, MD, PhD 273
Cholinesterase-Inhibiting Drugs
Achilles J. Pappano, PhD 97 17. Vasoactive Peptides
Ian A. Reid, PhD 295
8. Cholinoceptor-Blocking Drugs
Achilles J. Pappano, PhD 115 18. The Eicosanoids: Prostaglandins,
Thromboxanes, Leukotrienes, &
9. Adrenoceptor Agonists & Related Compounds
Sympathomimetic Drugs Emer M. Smyth, PhD, & Garret A.
Italo Biaggioni, MD, & David Robertson, MD 129 FitzGerald, MD 313

10. Adrenoceptor Antagonist Drugs 19. Nitric Oxide

David Robertson, MD, & Italo Biaggioni, MD 151 Samie R. Jaffrey, MD, PhD 331

iii
iv CONTENTS

20. Drugs Used in Asthma

Homer A. Boushey, MD 339
S E C T I O N VI
DRUGS USED TO TREAT DISEASES OF
S E C T I O N V THE BLOOD, INFLAMMATION,
DRUGS THAT ACT IN THE & GOUT 581
CENTRAL NERVOUS SYSTEM 359 33. Agents Used in Anemias; Hematopoietic
21. Introduction to the Pharmacology Growth Factors
Susan B. Masters, PhD 581
of CNS Drugs
Roger A. Nicoll, MD 359
34. Drugs Used in Disorders of Coagulation
James L. Zehnder, MD 601
22. Sedative-Hypnotic Drugs
Anthony J. Trevor, PhD, &
Walter L. Way, MD 373
35. Agents Used in Dyslipidemia
Mary J. Malloy, MD, & John P. Kane, MD, PhD 619
23. The Alcohols
Susan B. Masters, PhD 389
36. Nonsteroidal Anti-Inflammatory Drugs,
Disease-Modifying Antirheumatic Drugs,
24. Antiseizure Drugs Nonopioid Analgesics, & Drugs Used
Roger J. Porter, MD, & in Gout
Brian S. Meldrum, MB, PhD 403 Daniel E. Furst, MD, Robert W. Ulrich, PharmD, &
Shraddha Prakash, MD 635
25. General Anesthetics
Helge Eilers, MD, & Spencer Yost, MD 429 S E C T I O N VII
26. Local Anesthetics ENDOCRINE DRUGS 659
Kenneth Drasner, MD 449
37. Hypothalamic & Pituitary Hormones
27. Skeletal Muscle Relaxants Susan B. Masters, PhD, & Stephen M.
Marieke Kruidering-Hall, PhD, & Rosenthal, MD 659
Lundy Campbell, MD 465
38. Thyroid & Antithyroid Drugs
28. Pharmacologic Management of Parkinsonism Betty J. Dong, PharmD, FASHP, FCCP, & Francis S.
& Other Movement Disorders Greenspan, MD, FACP 681
Michael J. Aminoff, MD, DSc, FRCP 483
39. Adrenocorticosteroids & Adrenocortical
29. Antipsychotic Agents & Lithium Antagonists
Herbert Meltzer, MD, PhD 501 George P. Chrousos, MD 697

30. Antidepressant Agents 40. The Gonadal Hormones & Inhibitors

Charles DeBattista, MD 521 George P. Chrousos, MD 715

31. Opioid Analgesics & Antagonists 41. Pancreatic Hormones & Antidiabetic Drugs
Mark A. Schumacher, PhD, MD, Allan I. Martha S. Nolte Kennedy, MD 743
Basbaum, PhD, & Walter L. Way, MD 543
42. Agents That Affect Bone Mineral
32. Drugs of Abuse Homeostasis
Christian Lüscher, MD 565 Daniel D. Bikle, MD, PhD 769
 CONTENTS v

54. Cancer Chemotherapy

S E C T I O N VIII Edward Chu, MD, & Alan C. Sartorelli, PhD 949
CHEMOTHERAPEUTIC DRUGS 789
55. Immunopharmacology
43. Beta-Lactam & Other Cell Wall- & Douglas F. Lake, PhD, Adrienne D. Briggs, MD, &
Membrane-Active Antibiotics Emmanuel T. Akporiaye, PhD 977
Daniel H. Deck, PharmD, &
Lisa G. Winston, MD 790 S E C T I O N IX
44. Tetracyclines, Macrolides, Clindamycin, TOXICOLOGY 1001
Chloramphenicol, Streptogramins,
& Oxazolidinones 56. Introduction to Toxicology: Occupational
Daniel H. Deck, PharmD, & & Environmental
Lisa G. Winston, MD 809 Daniel T. Teitelbaum, MD 1001

45. Aminoglycosides & Spectinomycin 57. Heavy Metal Intoxication & Chelators
Daniel H. Deck, PharmD, & Michael J. Kosnett, MD, MPH 1013
Lisa G. Winston, MD 821
58. Management of the Poisoned Patient
46. Sulfonamides, Trimethoprim, Kent R. Olson, MD 1027
& Quinolones
Daniel H. Deck, PharmD, &
Lisa G. Winston, MD 831
S E C T I O N X
SPECIAL TOPICS 1039
47. Antimycobacterial Drugs
Daniel H. Deck, PharmD, & 59. Special Aspects of Perinatal &
Lisa G. Winston, MD 839 Pediatric Pharmacology
Gideon Koren, MD 1039
48. Antifungal Agents
Don Sheppard, MD, & 60. Special Aspects of Geriatric Pharmacology
Harry W. Lampiris, MD 849 Bertram G. Katzung, MD, PhD 1051

49. Antiviral Agents 61. Dermatologic Pharmacology

Sharon Safrin, MD 861 Dirk B. Robertson, MD, &
Howard I. Maibach, MD 1061
50. Miscellaneous Antimicrobial Agents;
Disinfectants, Antiseptics, & Sterilants 62. Drugs Used in the Treatment of
Daniel H. Deck, PharmD, & Gastrointestinal Diseases
Lisa G. Winston, MD 891 Kenneth R. McQuaid, MD 1081

51. Clinical Use of Antimicrobial Agents 63. Therapeutic & Toxic Potential of
Harry W. Lampiris, MD, & Daniel S. Maddix, Over-the-Counter Agents
PharmD 901 Robin L. Corelli, PharmD 1115
52. Antiprotozoal Drugs 64. Dietary Supplements & Herbal Medications
Philip J. Rosenthal, MD 915 Cathi E. Dennehy, PharmD, & Candy Tsourounis,
PharmD 1125
53. Clinical Pharmacology of the
Antihelminthic Drugs
Philip J. Rosenthal, MD 937
vi CONTENTS

65. Rational Prescribing & Prescription Writing Appendix: Vaccines, Immune Globulins,
Paul W. Lofholm, PharmD, & & Other Complex Biologic Products
Bertram G. Katzung, MD, PhD 1139 Harry W. Lampiris, MD, & Daniel S. Maddix,
PharmD 1163
66. Important Drug Interactions &
Their Mechanisms
John R. Horn, PharmD, FCCP 1149 Index 1171
Preface

The twelfth edition of Basic & Clinical Pharmacology continues trade and generic names and dosage formulations, are provided at
the important changes inaugurated in the eleventh edition, with the end of each chapter for easy reference by the house officer or
extensive use of full-color illustrations and expanded coverage of practitioner writing a chart order or prescription.
transporters, pharmacogenomics, and new drugs. Case studies
have been added to several chapters and answers to questions Significant revisions in this edition
posed in the case studies now appear at the end of each chapter. include:
As in prior editions, the book is designed to provide a compre-
hensive, authoritative, and readable pharmacology textbook for • In addition to the Case Studies used to open many chapters,
students in the health sciences. Frequent revision is necessary to Case Study Answers at the end of these chapters provide an
keep pace with the rapid changes in pharmacology and therapeu- introduction to the clinical applications of the drugs discussed.
tics; the 2–3 year revision cycle of the printed text is among the • A Drug Summary Table is placed at the conclusion of most
shortest in the field and the availability of an online version pro- chapters; these provide a concise recapitulation of the most
important drugs.
vides even greater currency. In addition to the full-color illustra-
tions, other new features have been introduced. The Case Study • Many new illustrations in full color provide significantly more
information about drug mechanisms and effects and help to
Answer section at the end of chapters will make the learning pro- clarify important concepts.
cess even more interesting and efficient. The book also offers • Major revisions of the chapters on sympathomimetic, sym-
special features that make it a useful reference for house officers pathoplegic, antipsychotic, antidepressant, antidiabetic, anti-
and practicing clinicians. inflammatory, and antiviral drugs, prostaglandins, nitric
Information is organized according to the sequence used in oxide, hypothalamic and pituitary hormones, and immuno-
many pharmacology courses and in integrated curricula: basic pharmacology.
principles; autonomic drugs; cardiovascular-renal drugs; drugs with • Continued expansion of the coverage of general concepts relat-
important actions on smooth muscle; central nervous system ing to newly discovered receptors, receptor mechanisms, and
drugs; drugs used to treat inflammation, gout, and diseases of the drug transporters.
blood; endocrine drugs; chemotherapeutic drugs; toxicology; and • Descriptions of important new drugs released through August
special topics. This sequence builds new information on a founda- 2011.
tion of information already assimilated. For example, early presen- An important related educational resource is Katzung &
tation of autonomic nervous system pharmacology allows students Trevor’s Pharmacology: Examination & Board Review, ninth edition
to integrate the physiology and neuroscience they have learned (Trevor AJ, Katzung BG, & Masters SB: McGraw-Hill, 2010).
elsewhere with the pharmacology they are learning and prepares This book provides a succinct review of pharmacology with over
them to understand the autonomic effects of other drugs. This is one thousand sample examination questions and answers. It is
especially important for the cardiovascular and central nervous especially helpful to students preparing for board-type examina-
system drug groups. However, chapters can be used equally well in tions. A more highly condensed source of information suitable
courses and curricula that present these topics in a different for review purposes is USMLE Road Map: Pharmacology, second
sequence. edition (Katzung BG, Trevor AJ: McGraw-Hill, 2006).
Within each chapter, emphasis is placed on discussion of drug This edition marks the 30th year of publication of Basic &
groups and prototypes rather than offering repetitive detail about Clinical Pharmacology. The widespread adoption of the first eleven
individual drugs. Selection of the subject matter and the order of editions indicates that this book fills an important need. We
its presentation are based on the accumulated experience of teach- believe that the twelfth edition will satisfy this need even more
ing this material to thousands of medical, pharmacy, dental, successfully. Spanish, Portuguese, Italian, French, Indonesian,
podiatry, nursing, and other health science students. Japanese, Korean, and Turkish translations are available.
Major features that make this book particularly useful in inte- Translations into other languages are under way; the publisher
grated curricula include sections that specifically address the clini- may be contacted for further information.
cal choice and use of drugs in patients and the monitoring of their I wish to acknowledge the prior and continuing efforts of my
effects—in other words, clinical pharmacology is an integral part of contributing authors and the major contributions of the staff at
this text. Lists of the commercial preparations available, including Lange Medical Publications, Appleton & Lange, and McGraw-Hill,

vii
viii CONTENTS
PREFACE

and of our editors for this edition, Donna Frassetto and Rachel Suggestions and comments about Basic & Clinical Pharmacology
D’Annucci Henriquez. I also wish to thank my wife, Alice Camp, are always welcome. They may be sent to me in care of the
for her expert proofreading contributions since the first edition. publisher.
This edition is dedicated to the memory of James Ransom,
PhD, the long-time Senior Editor at Lange Medical Publications, Bertram G. Katzung, MD, PhD
who provided major inspiration and invaluable guidance through San Francisco
the first eight editions of the book. Without him, this book would December, 2011
not exist.
Authors

Emmanuel T. Akporiaye, PhD Edward Chu, MD

Adjunct Professor, Oregon Health Sciences University, Professor of Medicine and Pharmacology & Chemical
Laboratory Chief, Earle A. Chiles Research Institute, Biology; Chief, Division of Hematology-Oncology, Deputy
Providence Cancer Center, Portland Director, University of Pittsburgh Cancer Institute,
University of Pittsburgh School of Medicine, Pittsburgh
Michael J. Aminoff, MD, DSc, FRCP
Professor, Department of Neurology, University of Robin L. Corelli, PharmD
California, San Francisco Clinical Professor, Department of Clinical Pharmacy,
School of Pharmacy, University of California, San
Allan I. Basbaum, PhD
Francisco
Professor and Chair, Department of Anatomy and
W.M. Keck Foundation Center for Integrative Maria Almira Correia, PhD
Neuroscience, University of California, San Francisco Professor of Pharmacology, Pharmaceutical Chemistry
and Biopharmaceutical Sciences, Department of Cellular
Neal L. Benowitz, MD
& Molecular Pharmacology, University of California,
Professor of Medicine and Bioengineering & Therapeutic
San Francisco
Science, University of California, San Francisco,
San Francisco Charles DeBattista, MD
Professor of Psychiatry and Behavioral Sciences, Stanford
Italo Biaggioni, MD
University School of Medicine, Stanford
Professor of Pharmacology, Vanderbilt University School
of Medicine, Nashville Daniel H. Deck, PharmD
Assistant Clinical Professor, School of Pharmacy,
Daniel D. Bikle, MD, PhD
University of California, San Francisco; Infectious
Professor of Medicine, Department of Medicine, and
Diseases Clinical Pharmacist, San Francisco General
Co-Director, Special Diagnostic and Treatment Unit,
Hospital
University of California, San Francisco, and Veterans
Affairs Medical Center, San Francisco Cathi E. Dennehy, PharmD
Professor, Department of Clinical Pharmacy, University of
Homer A. Boushey, MD
California, San Francisco School of Pharmacy
Chief, Asthma Clinical Research Center and Division of
Allergy & Immunology; Professor of Medicine, Betty J. Dong, PharmD, FASHP, FCCP
Department of Medicine, University of California, Professor of Clinical Pharmacy and Clinical Professor of
San Francisco Family and Community Medicine, Department of Clinical
Pharmacy and Department of Family and Community
Adrienne D. Briggs, MD
Medicine, Schools of Pharmacy and Medicine, University
Clinical Director, Bone Marrow Transplant Program,
of California, San Francisco
Banner Good Samaritan Hospital, Phoenix
Kenneth Drasner, MD
Lundy Campbell, MD
Profesor of Anesthesia and Perioperative Care, University
Professor, Department of Anesthesiology and
of California, San Francisco
Perioperative Medicine, University of California
San Francisco, School of Medicine, San Francisco Helge Eilers, MD
Professor of Anesthesia and Perioperative Care, University
George P. Chrousos, MD
of California, San Francisco
Professor & Chair, First Department of Pediatrics, Athens
University Medical School, Athens

ix
x AUTHORS

Garret A. FitzGerald, MD Michael J. Kosnett, MD, MPH

Chair, Department of Pharmacology; Director, Institute Associate Clinical Professor of Medicine, Division of
for Translational Medicine and Therapeutics, Perelman Clinical Pharmacology and Toxicology, University of
School of Medicine at the University of Pennsylvania, Colorado Health Sciences Center, Denver
Philadelphia
Marieke Kruidering-Hall, PhD
Daniel E. Furst, MD Associate Professor, Department of Cellular and
Carl M. Pearson Professor of Rheumatology, Director, Molecular Pharmacology, University of California, San
Rheumatology Clinical Research Center, Department of Francisco
Rheumatology, University of California, Los Angeles
Douglas F. Lake, PhD
Augustus O. Grant, MD, PhD Associate Professor, The Biodesign Institute, Arizona State
Professor of Medicine, Cardiovascular Division, Duke University, Tempe
University Medical Center, Durham
Harry W. Lampiris, MD
Francis S. Greenspan, MD, FACP Associate Professor of Medicine, University of California,
Clinical Professor of Medicine and Radiology and Chief, San Francisco
Thyroid Clinic, Division of Endocrinology, Department of
Paul W. Lofholm, PharmD
Medicine, University of California, San Francisco
Clinical Professor of Pharmacy, School of Pharmacy,
Nicholas H. G. Holford, MB, ChB, FRACP University of California, San Francisco
Professor, Department of Pharmacology and Clinical
Christian Lüscher, MD
Pharmacology, University of Auckland Medical School,
Departments of Basic and Clincial Neurosciences, Medical
Auckland
Faculty, University Hospital of Geneva,
John R. Horn, PharmD, FCCP Geneva, Switzerland
Professor of Pharmacy, School of Pharmacy, University of
Daniel S. Maddix, PharmD
Washington; Associate Director of Pharmacy Services,
Associate Clinical Professor of Pharmacy, University of
Department of Medicine, University of Washington
California, San Francisco
Medicine, Seattle
Howard I. Maibach, MD
Joseph R. Hume, PhD
Professor of Dermatology, Department of Dermatology,
Professor and Chairman, Department of Pharmacology;
University of California, San Francisco
Adjunct Professor, Department of Physiology and Cell
Biology, University of Nevada School of Medicine, Reno Mary J. Malloy, MD
Clinical Professor of Pediatrics and Medicine,
Harlan E. Ives, MD, PhD
Departments of Pediatrics and Medicine, Cardiovascular
Professor of Medicine, Department of Medicine,
Research Institute, University of California, San Francisco
University of California, San Francisco
Susan B. Masters, PhD
Samie R. Jaffrey, MD, PhD
Professor of Pharmacology & Academy Chair of
Associate Professor of Pharmacology, Department of
Pharmacology Education, Department of Cellular &
Pharmacology, Cornell University Weill Medical College,
Molecular Pharmacology, University of California,
New York City
San Francisco
John P. Kane, MD, PhD
Kenneth R. McQuaid, MD
Professor of Medicine, Department of Medicine; Professor
Professor of Clinical Medicine, University of California,
of Biochemistry and Biophysics; Associate Director,
San Francisco; Chief of Gastroenterology, San Francisco
Cardiovascular Research Institute, University of
Veterans Affairs Medical Center
California, San Francisco
Brian S. Meldrum, MB, PhD
Bertram G. Katzung, MD, PhD
Professor Emeritus, GKT School of Medicine,
Professor Emeritus, Department of Cellular & Molecular
Guy’s Campus, London
Pharmacology, University of California, San Francisco
Herbert Meltzer, MD, PhD
Gideon Koren, MD
Professor of Psychiatry and Pharmacology, Vanderbilt
Professor of Pediatrics, Pharmacology, Pharmacy,
University, Nashville
Medicine and Medical Genetics; Director, Motherisk
Program, University of Toronto Roger A. Nicoll, MD
Professor of Pharmacology and Physiology, Departments
of Cellular & Molecular Pharmacology and Physiology,
University of California, San Francisco
 AUTHORS xi

Martha S. Nolte Kennedy, MD Mark A. Schumacher, PhD, MD

Clinical Professor, Department of Medicine, University of Associate Professor, Department of Anesthesia and
California, San Francisco Perioperative Care, University of California, San Francisco
Kent R. Olson, MD Don Sheppard, MD
Clinical Professor, Departments of Medicine and Associate Professor, Departments of Microbiology and
Pharmacy, University of California, San Francisco; Immunology and Medicine, McGill University; Program
Medical Director, San Francisco Division, California Director, McGill Royal College Training Program in
Poison Control System Medical Microbiology and Infectious Diseases, Montreal
Achilles J. Pappano, PhD Emer M. Smyth, PhD
Professor Emeritus, Department of Cell Biology and Assistant Professor, Department of Pharmacology,
Calhoun Cardiology Center, University of Connecticut University of Pennsylvania School of Medicine, Philadelphia
Health Center, Farmington
Daniel T. Teitelbaum, MD
Roger J. Porter, MD Professor, University of Colorado School of Medicine,
Adjunct Professor of Neurology, University of Aurora, and Colorado School of Mines, Golden
Pennsylvania, Philadelphia; Adjunct Professor of
Anthony J. Trevor, PhD
Pharmacology, Uniformed Services University of the
Professor Emeritus, Department of Cellular & Molecular
Health Sciences, Bethesda
Pharmacology, University of California, San Francisco
Shraddha Prakash, MD
Candy Tsourounis, PharmD
Senior Fellow in Rheumatology, David Geffen School of
Professor of Clinical Pharmacy, Medication Outcomes
Medicine, University of California, Los Angeles
Center, University of California, San Francisco School of
Ian A. Reid, PhD Pharmacy
Professor Emeritus, Department of Physiology, University
Robert W. Ulrich, PharmD
of California, San Francisco
Senior Clinical Science Manager, Abbott Laboratories Inc.,
David Robertson, MD Covina, California
Elton Yates Professor of Medicine, Pharmacology and
Mark von Zastrow, MD, PhD
Neurology, Vanderbilt University; Director, Clinical &
Professor, Departments of Psychiatry and Cellular &
Translational Research Center, Vanderbilt Institute for
Molecular Pharmacology, University of California,
Clinical and Translational Research, Nashville
San Francisco
Dirk B. Robertson, MD
Walter L. Way, MD*
Professor of Clinical Dermatology, Department of
Professor Emeritus, Departments of Anesthesia and
Dermatology, Emory University School of Medicine,
Cellular & Molecular Pharmacology, University of
Atlanta
California, San Francisco
Philip J. Rosenthal, MD
Lisa G. Winston, MD
Professor of Medicine, University of California,
Associate Professor, Department of Medicine, Division of
San Francisco, San Francisco General Hospital
Infectious Diseases, University of California, San Francisco;
Stephen M. Rosenthal, MD Hospital Epidemiologist, San Francisco General Hospital
Professor of Pediatrics, Associate Program Director,
Spencer Yost, MD
Pediatric Endocrinology; Director, Pediatric Endocrine
Professor, Department of Anesthesia and Perioperative
Outpatient Services, University of California,
Care, University of California, San Francisco; Medical
San Francisco
Director, UCSF-Mt. Zion ICU, Chief of Anesthesia,
Sharon Safrin, MD UCSF-Mt. Zion Hospital
Associate Clinical Professor, Department of Medicine,
James L. Zehnder, MD
University of California, San Francisco; President,
Professor of Pathology and Medicine, Pathology Department,
Safrin Clinical Research
Stanford University School of Medicine, Stanford
Alan C. Sartorelli, PhD
Alfred Gilman Professor of Pharmacology, Department of
Pharmacology, Yale University School of Medicine,
New Haven ∗Deceased
xii
KEY FEATURES xiii
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