Close Window Preface The eleventh edition of Basic & Clinical Pharmacology is a new book in two important ways. First, the addition of new Associate Editors to the editorial group has increased currency, depth, and breadth of coverage; second, conversion to fullcolor style has increased the clarity of presentation and total information content. At the same time, the overall organization has been improved and the educational content of previous editions has been expanded. As in prior editions, the book is designed to provide a comprehensive, authoritative, and readable pharmacology textbook for students in the health sciences. Frequent revision is necessary to keep pace with the rapid changes in pharmacology and therapeutics; the 2�3 year revision cycle of the printed text is among the best in the field and the availability of an online version provides even greater currency. In addition to the full-color illustrations, other new features have been introduced. The Case Study at the beginning of chapters and the Drug Summary Table at the end of chapters will make the learning process even more interesting and efficient. The book also offers special features that make it a useful reference for house officers and practicing clinicians. Information is organized according to the sequence used in many pharmacology courses and in integrated curricula: basic principles; autonomic drugs; cardiovascular-renal drugs; drugs with important actions on smooth muscle; central nervous system drugs; drugs used to treat inflammation, gout, and diseases of the blood; endocrine drugs; chemotherapeutic drugs; toxicology; and special topics. This sequence builds new information on a foundation of information already assimilated. For example, early presentation of autonomic nervous system pharmacology allows students to integrate the physiology and neuroscience they have learned elsewhere with the pharmacology they are learning and prepares them to understand the autonomic effects of other drugs. This is especially important for the cardiovascular and central nervous system drug groups. However, chapters can be used equally well in courses and curricula that present these topics in a different sequence. Within each chapter, emphasis is placed on discussion of drug groups and prototypes rather than offering repetitive detail about individual drugs. Selection of the subject matter and the order of its presentation are based on the accumulated experience of teaching this material to thousands of medical, pharmacy, dental, podiatry, nursing, and other health science students. Major features that make this book particularly useful in integrated curricula include sections that specifically address the clinical choice and use of drugs in patients and the monitoring of their effects�in other words, clinical pharmacology is an integral part of this text. Lists of the commercial preparations available, including trade and generic names and dosage formulations, are provided at the end of each chapter for easy reference by the house officer or practitioner writing a chart order or prescription. Significant revisions in this edition include: A Case Study is used to open many chapters, providing an introduction to the clinical applications of the drugs discussed. Explicit answers are provided at the end of some chapters but discussion of the concepts involved will be found in the text of all chapters. A Drug Summary Table is placed at the conclusion of most chapters; these provide a concise recapitulation of the most important drugs Many new illustrations in full color provide significantly more information about drug mechanisms and effects and help to clarify important concepts Major revisions of the chapters on sympathomimetic, sympathoplegic, antipsychotic, antidepressant, antidiabetic, anti-inflammatory, and antiviral drugs, prostaglandins, nitric oxide, hypothalamic and pituitary hormones, and immunopharmacology Continued expansion of the coverage of general concepts relating to newly discovered receptors, receptor mechanisms, and drug transporters Descriptions of important new drugs released through December 2008, including numerous new immunopharmacologic agents An important related educational resource is Katzung & Trevor's Pharmacology: Examination & Board Review, eighth edition (Trevor AJ, Katzung BG, & Masters SB: McGraw-Hill, 2008). This book provides a succinct review of pharmacology with over one thousand sample examination questions and answers. It is especially helpful to students preparing for board-type examinations. A more highly condensed source of information suitable for review purposes is USMLE Road Map: Pharmacology, second edition (Katzung BG, Trevor AJ: McGraw-Hill, 2006). This edition marks the 27th year of publication of Basic & Clinical Pharmacology. The widespread adoption of the first ten editions indicates that this book fills an important need. We believe that the eleventh edition will satisfy this need even more successfully. Spanish, Portuguese, Italian, French, Indonesian, Japanese, Korean, and Turkish translations are available. Translations into other languages are under way; the publisher may be contacted for further information. I wish to acknowledge the prior and continuing efforts of my contributing authors and the major contributions of the staff at Lange Medical Publications, Appleton & Lange, and more recently at McGraw-Hill, and of our editors, Alison Kelley and Donna Frassetto. I also wish to thank my wife, Alice Camp, for her expert proofreading contributions since the first edition. Special thanks and recognition are due James Ransom, PhD, the long-time Senior Editor at Lange Medical Publications, who provided major inspiration and invaluable guidance through the first eight editions of the book. Without him, this book would not exist. Suggestions and comments about Basic & Clinical Pharmacology are always welcome. They may be sent to me at the Department of Cellular & Molecular Pharmacology, P.O. Box 0450, University of California, San Francisco, CA 94143-0450. Bertram G. Katzung, MD, PhD San Francisco February, 2009 Close Window Copyright Information Basic & Clinical Pharmacology, Eleventh Edition Copyright © 2009 by The McGraw-Hill Companies, Inc. All rights reserved. Printed in China. Except as permitted 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 permission of the publisher. Previous editions copyright © 2007, 2004, 2001 by McGraw-Hill Companies, Inc.; copyright © 1998, 1995, 1992, 1989, 1987 by Appleton & Lange; copyright © 1984, 1982 by Lange Medical Publications ISBN 978-0-07-160405-5 Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. Close Window Contributors Editors 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 Authors Emmanuel T. Akporiaye, PhD Professor, Department of Microbiology and Immunology, University of Arizona Health Sciences Center, Tucson Michael J. Aminoff, MD, DSc, FRCP Professor, Department of Neurology, University of California, San Francisco Allan I. Basbaum, PhD Professor and Chair, Department of Anatomy and W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco Neal L. Benowitz, MD Professor of Medicine, Psychiatry, and Biopharmaceutical Sciences, University of California, San Francisco Barry A. Berkowitz, PhD Adjunct Professor, Northeastern University, Boston University; CEO and President, Cetek Corporation, Marlborough, Massachusetts Italo Biaggioni, MD Professor of Pharmacology, Vanderbilt University School of Medicine, Nashville Daniel D. Bikle, MD, PhD Professor of Medicine, Department of Medicine, and Co-Director, Special Diagnostic and Treatment Unit, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco Henry R. Bourne, MD Professor, Department of Cellular & Molecular Pharmacology, University of California, San Francisco Homer A. Boushey, MD Chief, Asthma Clinical Research Center and Division of Allergy & Immunology; Professor of Medicine, Department of Medicine, University of California, San Francisco Adrienne D. Briggs, MD Clinical Director, Bone Marrow Transplant Program, Banner Good Samaritan Hospital, Phoenix Henry F. Chambers, MD Professor of Medicine, University of California, San Francisco; Chief of Infectious Diseases, San Francisco General Hospital, San Francisco Kanu Chatterjee, MB, FRCP Ernest Gallo Distinguished Professor of Medicine, University of California, San Francisco George P. Chrousos, MD Professor & Chair, First Department of Pediatrics, Athens University Medical School, Athens Edward Chu, MD Professor of Medicine and Pharmacology; Director, VACT Cancer Center; Associate Director, Yale Cancer Center; Yale University School of Medicine, New Haven Robin L. Corelli, PharmD Associate Clinical Professor, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco Maria Almira Correia, PhD Professor of Pharmacology, Pharmaceutical Chemistry and Biopharmaceutical Sciences, Department of Cellular & Molecular Pharmacology, University of California, San Francisco Charles DeBattista, MD Professor of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford Daniel H. Deck, PharmD Assistant Clinical Professor, School of Pharmacy, University of California, San Francisco Cathi E. Dennehy, PharmD Associate Clinical Professor, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco Betty J. Dong, PharmD, FASHP, FCCP Professor of Clinical Pharmacy and Clinical Professor of Family and Community Medicine, Department of Clinical Pharmacy and Department of Family and Community Medicine, Schools of Pharmacy and Medicine, University of California, San Francisco Garret A. FitzGerald, MD Professor and Chair, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia Daniel E. Furst, MD Carl M. Pearson Professor of Rheumatology, Director, Rheumatology Clinical Research Center, Department of Rheumatology, University of California, Los Angeles Augustus O. Grant, MD, PhD Professor of Medicine, Cardiovascular Division, Duke University Medical Center, Durham Francis S. Greenspan, MD, FACP Clinical Professor of Medicine and Radiology and Chief, Thyroid Clinic, Division of Endocrinology, Department of Medicine, University of California, San Francisco Nicholas H. G. Holford, MB, ChB, FRACP Professor, Department of Pharmacology and Clinical Pharmacology, University of Auckland Medical School, Auckland John R. Horn, PharmD, FCCP Professor of Pharmacy, School of Pharmacy, University of Washington, Seattle Joseph R. Hume, PhD Professor and Chairman, Department of Pharmacology; Adjunct Professor, Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno Harlan E. Ives, MD, PhD Professor of Medicine, Department of Medicine, University of California, San Francisco Samie R. Jaffrey, MD, PhD Associate Professor of Pharmacology, Department of Pharmacology, Cornell University Weill Medical College, New York City John P. Kane, MD, PhD Professor of Medicine, Department of Medicine; Professor of Biochemistry and Biophysics; Associate Director, Cardiovascular Research Institute, University of California, San Francisco Bertram G. Katzung, MD, PhD Professor Emeritus, Department of Cellular & Molecular Pharmacology, University of California, San Francisco Gideon Koren, MD Professor and Chairman, Ivey Chair in Molecular Toxicology, University of Western Ontario; Director, The Motherisk Program, Professor of Pediatrics, Pharmacology, Pharmacy, Medicine, and Medical Genetics, The University of Toronto; Senior Scientist, The Research Institute, The Hospital for Sick Children, Toronto Michael J. Kosnett, MD, MPH Associate Clinical Professor of Medicine, Division of Clinical Pharmacology and Toxicology, University of Colorado Health Sciences Center, Denver Douglas F. Lake, PhD Associate Professor, The Biodesign Institute, Arizona State University, Tempe Harry W. Lampiris, MD Associate Professor of Medicine, School of Medicine, University of California, San Francisco Paul W. Lofholm, PharmD Clinical Professor of Pharmacy, School of Pharmacy, University of California, San Francisco Christian L�scher, MD Departements des Neurosciences Fondamentales et Cliniques, University of Geneva Daniel S. Maddix, PharmD Associate Clinical Professor of Pharmacy, University of California, San Francisco Howard I. Maibach, MD Professor of Dermatology, Department of Dermatology, University of California, San Francisco Mary J. Malloy, MD Clinical Professor of Pediatrics and Medicine, Departments of Pediatrics and Medicine, Cardiovascular Research Institute, University of California, San Francisco Susan B. Masters, PhD Professor of Pharmacology & Academy Chair of Pharmacology Education, Department of Cellular & Molecular Pharmacology, University of California, San Francisco Kenneth R. McQuaid, MD Professor of Clinical Medicine, Department of Medicine, University of California, San Francisco; Director of Gastrointestinal Endoscopy, San Francisco Veterans Affairs Medical Center, San Francisco Brian S. Meldrum, MB, PhD Professor Emeritus, GKT School of Medicine, Guy's Campus, London Herbert Meltzer, MD, PhD Professor of Psychiatry and Pharmacology, Vanderbilt University, Nashville Roger A. Nicoll, MD Professor of Pharmacology and Physiology, Departments of Cellular & Molecular Pharmacology and Physiology, University of California, San Francisco Martha S. Nolte, MD Clinical Professor, Department of Medicine, University of California, San Francisco Kent R. Olson, MD Clinical Professor, Departments of Medicine, and Pharmacy, University of California, San Francisco; Medical Director, San Francisco Division, California Poison Control System Achilles J. Pappano, PhD Professor, Department of Pharmacology, University of Connecticut Health Center, Farmington William W. Parmley, MD Emeritus Professor of Medicine, University of California, San Francisco Roger J. Porter, MD Adjunct Professor of Neurology, University of Pennsylvania, Philadelphia; Adjunct Professor of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda Ian A. Reid, PhD Professor Emeritus, Department of Physiology, University of California, San Francisco David Robertson, MD Director, Center for Space Physiology and Medicine, Vanderbilt University, Nashville Dirk B. Robertson, MD Professor of Clinical Dermatology, Department of Dermatology, Emory University School of Medicine, Atlanta Philip J. Rosenthal, MD Professor of Medicine, University of California, San Francisco, San Francisco General Hospital Sharon Safrin, MD Associate Clinical Professor, Department of Medicine, University of California, San Francisco Alan C. Sartorelli, PhD Alfred Gilman Professor of Pharmacology, Department of Pharmacology, Yale University School of Medicine, New Haven Mark A. Schumacher, PhD, MD Associate Professor, Department of Anesthesia and Perioperative Care, University of California, San Francisco Don Sheppard, MD Assistant Professor, Departments of Medicine, Microbiology and Immunology, McGill University, Montreal Emer M. Smyth, PhD Assistant Professor, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia Daniel T. Teitelbaum, MD Professor, University of Colorado School of Medicine, Aurora and Colorado School of Mines, Golden Anthony J. Trevor, PhD Professor Emeritus, Department of Cellular & Molecular Pharmacology, University of California, San Francisco Candy Tsourounis, PharmD Associate Professor of Clinical Pharmacy, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco Robert W. Ulrich, PharmD Associate Professor, University of Southern California School of Pharmacy, Los Angeles C. Varkey-Altamirano, BS Los Angeles Mark von Zastrow, MD, PhD Associate Professor, Departments of Psychiatry and Cellular & Molecular Pharmacology, University of California, San Francisco Walter L. Way, MD Professor Emeritus, Departments of Anesthesia and Cellular & Molecular Pharmacology, University of California, San Francisco Paul F. White, PhD, MD Professor and Holder of the Margaret Milam McDermott Distinguished Chair of Anesthesiology, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas Southwestern Medical School, Dallas James L. Zehnder, MD Professor of Pathology and Medicine, Pathology Department, Stanford University School of Medicine, Stanford Print Close Window Note: Large images and tables on this page may necessitate printing in landscape mode. Copyright © The McGraw-Hill Companies. All rights reserved. Basic and Clinical Pharmacology > Chapter 1. Introduction > CASE STUDY A 26-year-old man is brought by friends to the emergency department of the city hospital because he has been behaving strangely for several days. A known user of methamphetamine, he has not eaten or slept in 48 hours. He threatened to shoot one of his friends because he believes his friend is plotting against him. On admission, the man is extremely agitated, appears to be underweight, and is unable to give a coherent history. He has to be restrained to prevent him from walking out of the emergency department and into traffic on the street. His blood pressure is 160/100 mm Hg, heart rate 100, temperature 39°C, and respirations 30/min. His arms show evidence of numerous intravenous injections. The remainder of his physical examination is unremarkable. After evaluation, the man is given a sedative, fluids, a diuretic, and ammonium chloride parenterally. What is the purpose of the ammonium chloride? INTRODUCTION TO PHARMACOLOGY: INTRODUCTION Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. These substances may be chemicals administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulatory processes in parasites infecting the patient. Such deliberate therapeutic applications may be considered the proper role of medical pharmacology, which is often defined as the science of substances used to prevent, diagnose, and treat disease. Toxicology is the branch of pharmacology that deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystems (Figure 1�1). Figure 1�1 Schematic diagram of the areas of study in pharmacology. The actions of chemicals can be divided into two large domains. The first (left side) is that of medical pharmacology and toxicology, which is aimed at understanding the actions of drugs as chemicals on individual organisms, especially humans and domestic animals. Both beneficial and toxic effects are included. Pharmacokinetics deals with the absorption, distribution, and elimination of drugs. Pharmacodynamics concerns the actions of the chemical on the organism. The second domain (right side) is that of environmental toxicology, which is concerned with the effects of chemicals on all organisms and their survival in groups and even species. THE HISTORY OF PHARMACOLOGY Prehistoric people undoubtedly recognized the beneficial or toxic effects of many plant and animal materials. Early written records from China and Egypt and the traditions of India list remedies of many types, including a few that are still recognized as useful drugs today. Most, however, were worthless or actually harmful. In the 1500 years or so preceding the present, there were sporadic attempts to introduce rational methods into