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Basic and Clinical Pharmacology 12th edition by Bertram Katzung

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Katzung and Trevor Pharmacology Examination and Board Review 11th
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 S C H E D U L E O F C O N T R O L L E D D R U G S1

SCHEDULE I Anabolic Steroids:

Fluoxymesterone (Androxy)
(All nonresearch use illegal under federal law.) Methyltestosterone (Android, Testred, Methitest)
Flunitrazepam (Rohypnol) Nandrolone decanoate (Deca-Durabolin) Non US
Narcotics:
Heroin and many nonmarketed synthetic narcotics Nandrolone phenpropionate (Durabolin) Non US
Hallucinogens: Oxandrolone (Oxandrin), Oxymetholone (Androl-50)
LSD Stanozolol (Winstrol),
MDA, STP, DMT, DET, mescaline, peyote, bufotenine, ibogaine, Testolactone (Teslac),
psilocybin, phencyclidine (PCP; veterinary drug only) Testosterone and its esters
Marijuana
Methaqualone
SCHEDULE IV
(Prescription must be rewritten after 6 months or five refills; differs from
SCHEDULE II Schedule III in penalties for illegal possession.)
(No telephone prescriptions, no refills.)2 Opioids:
Opioids: Butorphanol (Stadol)
Opium Difenoxin 1 mg + atropine 25 mcg (Motofen)
Opium alkaloids and derived phenanthrene alkaloids: codeine, Pentazocine (Talwin)
morphine, (Avinza, Kadian, MSContin, Roxanol), hydromorphone Stimulants:
(Dilaudid ), oxymorphone (, Exalgo), oxycodone (dihydroxycodei- Armodafinil (Nuvigil)
none, a component of Oxycontin, Percodan, Percocet, Roxicodone, Diethylpropion (Tenuate) not in US
Tylox)
Modafinil (Provigil)
Designated synthetic drugs: meperidine (Demerol), methadone,
levorphanol (Levo-Dromoran), fentanyl (Duragesic, Actiq, Phentermine (Ionamin, Adipex-P)
Fentora), alfentanil (Alfenta), sufentanil (Sufenta), remifentanil Depressants:
(Ultiva), tapentadol (Nycynta) Benzodiazepines
Stimulants: Alprazolam (Xanax)
Coca leaves and cocaine Chlordiazepoxide (Librium)
Amphetamine Clonazepam (Klonopin)
Amphetamine complex (Biphetamine) Clorazepate (Tranxene)
Amphetamine salts (Adderall) Diazepam (Valium)
Dextroamphetamine (Dexedrine, Procentra) Estazolam (ProSom)
Lisdexamfetamine (Vyvanse) Flurazepam (Dalmane)
Methamphetamine (Desoxyn) Halazepam (Paxipam)
Methylphenidate (Ritalin, Concerta, Methylin, Daytrana, Medadate) Lorazepam (Ativan)
Above in mixtures with other controlled or uncontrolled drugs Midazolam (Versed)
Cannabinoids: Oxazepam (Serax)
Nabilone (Cesamet) Prazepam (Centrax)
Depressants: Quazepam (Doral)
Amobarbital (Amytal) Temazepam (Restoril)
Pentobarbital (Nembutal) Triazolam (Halcion)
Secobarbital (Seconal) Chloral hydrate (Somnote)
Eszopiclone (Lunesta)
SCHEDULE III Meprobamate (Equanil, Miltown, etc)
(Prescription must be rewritten after 6 months or five refills.) Methobarbital (Mebaral)
Opioids: Methohexital (Brevital)
Buprenorphine (Buprenex, Subutex ) Paraldehyde
Mixture of above Buprenorphine and Naloxone (Suboxone) Phenobarbital
The following opioids in combination with one or more active non- Zaleplon (Sonata)
opioid ingredients, provided the amount does not exceed that shown: Zolpidem (Ambien)
Codeine and dihydrocodeine: not to exceed 1800 mg/dL or 90 mg/
tablet or other dosage unit
SCHEDULE V
Dihydrocodeinone (hydrocodone in Hycodan, Vicodin, and
Lortab): not to exceed 300 mg/dL or 15 mg/tablet (As any other nonopioid prescription drug)
Opium: 500 mg/dL or 25 mg/5 mL or other dosage unit (paregoric) Codeine: 200 mg/100 mL
Stimulants: Difenoxin preparations: 0.5 mg + 25 mcg atropine
Benzphetamine (Didrex) Dihydrocodeine preparations: 10 mg/100 mL
Phendimetrazine (Bontril) Diphenoxylate (not more than 2.5 mg and not less than 0.025 mg of
Depressants: atropine per dosage unit, as in Lomotil)
Schedule II barbiturates in mixtures with noncontrolled drugs or in Ethylmorphine preparations: 100 mg/100 mL
suppository dosage form Opium preparations: 100 mg/100 mL
Butabarbital (Butisol) Pregabalin (Lyrica)
Ketamine (Ketalar) Pyrovalerone (Centroton, Thymergix)
Cannabinoids:
Dronabinol (Marinol)
1
See http://www.usdoj.gov/dea/pubs/scheduling.html for additional details.
2
Emergency prescriptions may be telephoned if followed within 7 days by a valid written prescription annotated to indicate that it was previously placed by
telephone.
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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 SECTION I BASIC PRINCIPLES

1
C H A P T E R

Introduction
Bertram G. Katzung, MD, PhD

CASE STUDY

A 26-year-old man is brought by friends to the emergency him from walking out of the emergency department and
department of the city hospital because he has been behav- into traffic on the street. His blood pressure is 160/100 mm
ing strangely for several days. A known user of metham- Hg, heart rate 100, temperature 39°C, and respirations 30/
phetamine, he has not eaten or slept in 48 hours. He min. His arms show evidence of numerous intravenous
threatened to shoot one of his friends because he believes injections. The remainder of his physical examination is
this friend is plotting against him. On admission, the man is unremarkable. After evaluation, the man is given a sedative,
extremely agitated, appears to be underweight, and is unable fluids, a diuretic, and ammonium chloride parenterally.
to give a coherent history. He has to be restrained to prevent What is the purpose of the ammonium chloride?

Pharmacology can be defined as the study of substances that THE HISTORY OF PHARMACOLOGY
interact with living systems through chemical processes, especially
by binding to regulatory molecules and activating or inhibiting Prehistoric people undoubtedly recognized the beneficial or
normal body processes. These substances may be chemicals toxic effects of many plant and animal materials. Early written
administered to achieve a beneficial therapeutic effect on some records from China and Egypt and the traditions of India list
process within the patient or for their toxic effects on regulatory remedies of many types, including a few that are still recognized
processes in parasites infecting the patient. Such deliberate thera- as useful drugs today. Most, however, were worthless or actually
peutic applications may be considered the proper role of medical harmful. In the 1500 years or so preceding the present, there
pharmacology, which is often defined as the science of substances were sporadic attempts to introduce rational methods into
used to prevent, diagnose, and treat disease. Toxicology is the medicine, but none was successful owing to the dominance of
branch of pharmacology that deals with the undesirable effects of systems of thought that purported to explain all of biology and
chemicals on living systems, from individual cells to humans to disease without the need for experimentation and observation.
complex ecosystems (Figure 1–1). These schools promulgated bizarre notions such as the idea that

1
2 SECTION I Basic Principles

19th, and early 20th centuries laid the foundation needed for
Chemical
understanding how drugs work at the organ and tissue levels.
Paradoxically, real advances in basic pharmacology during this
time were accompanied by an outburst of unscientific claims by
Pharmacokinetics

Patient Environment manufacturers and marketers of worthless “patent medicines.”

Not until the concepts of rational therapeutics, especially that of
the controlled clinical trial, were reintroduced into medicine—
only about 60 years ago—did it become possible to accurately
Intended Unintended Other evaluate therapeutic claims.
target targets organisms Around the same time, a major expansion of research efforts in
tissues
all areas of biology began. As new concepts and new techniques
Pharmacodynamics

were introduced, information accumulated about drug action and

Food the biologic substrate of that action, the drug receptor. During
chain the last half-century, many fundamentally new drug groups and
Therapeutic
effects
new members of old groups were introduced. The last three
decades have seen an even more rapid growth of information and
understanding of the molecular basis for drug action. The molec-
Toxic More ular mechanisms of action of many drugs have now been identi-
effects organisms fied, and numerous receptors have been isolated, structurally
characterized, and cloned. In fact, the use of receptor identifica-
Medical pharmacology Environmental
and toxicology toxicology tion methods (described in Chapter 2) has led to the discovery of
many orphan receptors—receptors for which no ligand has been
FIGURE 1–1 Major areas of study in pharmacology. The actions discovered and whose function can only be surmised. Studies of
of chemicals can be divided into two large domains. The first (left the local molecular environment of receptors have shown that
side) is that of medical pharmacology and toxicology, which is aimed receptors and effectors do not function in isolation; they are
at understanding the actions of drugs as chemicals on individual strongly influenced by other receptors and by companion regula-
organisms, especially humans and domestic animals. Both beneficial tory proteins.
and toxic effects are included. Pharmacokinetics deals with the Pharmacogenomics—the relation of the individual’s genetic
absorption, distribution, and elimination of drugs. Pharmaco- makeup to his or her response to specific drugs—is close to
dynamics concerns the actions of the chemical on the organism. The becoming a practical area of therapy (see Box: Pharmacology &
second domain (right side) is that of environmental toxicology, which Genetics). Decoding of the genomes of many species—from
is concerned with the effects of chemicals on all organisms and their
bacteria to humans—has led to the recognition of unsuspected
survival in groups and as species.
relationships between receptor families and the ways that recep-
tor proteins have evolved. Discovery that small segments of RNA
can interfere with protein synthesis with extreme selectivity has
disease was caused by excesses of bile or blood in the body, that led to investigation of small interfering RNAs (siRNAs) and
wounds could be healed by applying a salve to the weapon that microRNAs (miRNAs) as therapeutic agents. Similarly, short
caused the wound, and so on. nucleotide chains called antisense oligonucleotides (ANOs)
Around the end of the 17th century, and following the example synthesized to be complementary to natural RNA or DNA can
of the physical sciences, reliance on observation and experimentation interfere with the readout of genes and the transcription of RNA.
began to replace theorizing in medicine. As the value of these These intracellular targets may provide the next major wave of
methods in the study of disease became clear, physicians in Great advances in therapeutics.
Britain and on the Continent began to apply them to the effects The extension of scientific principles into everyday therapeutics is
of traditional drugs used in their own practices. Thus, materia still going on, although the medication-consuming public is still
medica—the science of drug preparation and the medical use of exposed to vast amounts of inaccurate, incomplete, or unscientific
drugs—began to develop as the precursor to pharmacology. information regarding the pharmacologic effects of chemicals. This has
However, any real understanding of the mechanisms of action of resulted in the irrational use of innumerable expensive, ineffective,
drugs was prevented by the absence of methods for purifying and sometimes harmful remedies and the growth of a huge “alterna-
active agents from the crude materials that were available and— tive health care” industry. Unfortunately, manipulation of the legisla-
even more—by the lack of methods for testing hypotheses about tive process in the United States has allowed many substances
the nature of drug actions. promoted for health—but not promoted specifically as “drugs”—to
In the late 18th and early 19th centuries, François Magendie, avoid meeting the Food and Drug Administration (FDA) standards
and later his student Claude Bernard, began to develop the meth- described in Chapter 5. Conversely, lack of understanding of basic
ods of experimental physiology and pharmacology. Advances in scientific principles in biology and statistics and the absence of critical
chemistry and the further development of physiology in the 18th, thinking about public health issues have led to rejection of medical
 CHAPTER 1 Introduction 3

Pharmacology & Genetics

It has been known for centuries that certain diseases are inherited, absent or nonfunctional. Homozygous knockout mice usually
and we now understand that individuals with such diseases have have complete suppression of that function, whereas heterozy-
a heritable abnormality in their DNA. During the last 10 years, the gous animals usually have partial suppression. Observation of
genomes of humans, mice, and many other organisms have been the behavior, biochemistry, and physiology of the knockout mice
decoded in considerable detail. This has opened the door to a often defines the role of the missing gene product very clearly.
remarkable range of new approaches to research and treatment. It When the products of a particular gene are so essential that even
is now possible in the case of some inherited diseases to define heterozygotes do not survive to birth, it is sometimes possible to
exactly which DNA base pairs are anomalous and in which chro- breed “knockdown” versions with only limited suppression of
mosome they appear. In a small number of animal models of such function. Conversely, “knockin” mice, which overexpress certain
diseases, it has been possible to correct the abnormality by gene proteins of interest, have been bred.
therapy, ie, insertion of an appropriate “healthy” gene into somatic Some patients respond to certain drugs with greater than usual
cells. Human somatic cell gene therapy has been attempted, but sensitivity to standard doses. It is now clear that such increased
the technical difficulties are great. sensitivity is often due to a very small genetic modification that
Studies of a newly discovered receptor or endogenous ligand results in decreased activity of a particular enzyme responsible for
are often confounded by incomplete knowledge of the exact role eliminating that drug. (Such variations are discussed in Chapter 4.)
of that receptor or ligand. One of the most powerful of the new Pharmacogenomics (or pharmacogenetics) is the study of the
genetic techniques is the ability to breed animals (usually mice) in genetic variations that cause differences in drug response among
which the gene for the receptor or its endogenous ligand has individuals or populations. Future clinicians may screen every
been “knocked out,” ie, mutated so that the gene product is patient for a variety of such differences before prescribing a drug.

science by a segment of the public and to a common tendency to are uniquely skilled in exploiting discoveries from academic and
assume that all adverse drug effects are the result of malpractice. governmental laboratories and translating these basic findings into
Two general principles that the student should remember are (1) commercially successful therapeutic breakthroughs.
that all substances can under certain circumstances be toxic, and the Such breakthroughs come at a price, however, and the escalat-
chemicals in botanicals (herbs and plant extracts) are no different ing cost of drugs has become a significant contributor to the
from chemicals in manufactured drugs except for the proportion of inflationary increase in the cost of health care. Development of
impurities (greater in botanicals); and, (2) that all dietary supplements new drugs is enormously expensive, and to survive and prosper,
and all therapies promoted as health-enhancing should meet the same big pharma must pay the costs of drug development and market-
standards of efficacy and safety as conventional drugs and medical ing and return a profit to its shareholders. Today, considerable
therapies. That is, there should be no artificial separation between controversy surrounds drug pricing. Critics claim that the costs of
scientific medicine and “alternative” or “complementary” medicine. development and marketing are grossly inflated by marketing
activities, which may consume as much as 25% or more of a com-
pany’s budget in advertising and other promotional efforts.
PHARMACOLOGY & THE Furthermore, profit margins for big pharma have historically
PHARMACEUTICAL INDUSTRY exceeded all other industries by a significant factor. Finally, pricing
schedules for many drugs vary dramatically from country to coun-
A truly new drug (one that does not simply mimic the structure
try and even within countries, where large organizations can
and action of previously available drugs) requires the discovery of
negotiate favorable prices and small ones cannot. Some countries
a new drug target, ie, the pathophysiologic process or substrate of
have already addressed these inequities, and it seems likely that all
a disease. Such discoveries are usually made in public sector insti-
countries will have to do so during the next few decades.
tutions (universities and research institutes), and the molecules
that have beneficial effects on such targets are often discovered in
the same laboratories. However, the development of new drugs usu- GENERAL PRINCIPLES OF
ally takes place in industrial laboratories because optimization of a
class of new drugs requires painstaking and expensive chemical,
PHARMACOLOGY
pharmacologic, and toxicologic research. In fact, much of the THE NATURE OF DRUGS
recent progress in the application of drugs to disease problems can
be ascribed to the pharmaceutical industry including “big pharma,” In the most general sense, a drug may be defined as any substance
the multibillion-dollar corporations that specialize in drug discov- that brings about a change in biologic function through its
ery and development. As described in Chapter 5, these companies chemical actions. In most cases, the drug molecule interacts as an
4 SECTION I Basic Principles

agonist (activator) or antagonist (inhibitor) with a specific mol- body (eg, from the site of administration to the site of action).
ecule in the biologic system that plays a regulatory role. This target Drugs much larger than MW 1000 do not diffuse readily between
molecule is called a receptor. The nature of receptors is discussed compartments of the body (see Permeation, in following text).
more fully in Chapter 2. In a very small number of cases, drugs Therefore, very large drugs (usually proteins) must often be
known as chemical antagonists may interact directly with other administered directly into the compartment where they have their
drugs, whereas a few drugs (osmotic agents) interact almost exclu- effect. In the case of alteplase, a clot-dissolving enzyme, the drug
sively with water molecules. Drugs may be synthesized within the is administered directly into the vascular compartment by intrave-
body (eg, hormones) or may be chemicals not synthesized in the nous or intra-arterial infusion.
body (ie, xenobiotics, from the Greek xenos, meaning “stranger”).
Poisons are drugs that have almost exclusively harmful effects. Drug Reactivity and Drug-Receptor Bonds
However, Paracelsus (1493–1541) famously stated that “the dose Drugs interact with receptors by means of chemical forces or
makes the poison,” meaning that any substance can be harmful if bonds. These are of three major types: covalent, electrostatic, and
taken in the wrong dosage. Toxins are usually defined as poisons hydrophobic. Covalent bonds are very strong and in many cases
of biologic origin, ie, synthesized by plants or animals, in contrast not reversible under biologic conditions. Thus, the covalent bond
to inorganic poisons such as lead and arsenic. formed between the acetyl group of acetylsalicylic acid (aspirin)
To interact chemically with its receptor, a drug molecule must and cyclooxygenase, its enzyme target in platelets, is not readily
have the appropriate size, electrical charge, shape, and atomic broken. The platelet aggregation–blocking effect of aspirin lasts
composition. Furthermore, a drug is often administered at a loca- long after free acetylsalicylic acid has disappeared from the blood-
tion distant from its intended site of action, eg, a pill given orally stream (about 15 minutes) and is reversed only by the synthesis of
to relieve a headache. Therefore, a useful drug must have the nec- new enzyme in new platelets, a process that takes several days.
essary properties to be transported from its site of administration Other examples of highly reactive, covalent bond-forming drugs
to its site of action. Finally, a practical drug should be inactivated are the DNA-alkylating agents used in cancer chemotherapy to
or excreted from the body at a reasonable rate so that its actions disrupt cell division in the tumor.
will be of appropriate duration. Electrostatic bonding is much more common than covalent
bonding in drug-receptor interactions. Electrostatic bonds vary
The Physical Nature of Drugs from relatively strong linkages between permanently charged ionic
molecules to weaker hydrogen bonds and very weak induced
Drugs may be solid at room temperature (eg, aspirin, atropine),
dipole interactions such as van der Waals forces and similar phe-
liquid (eg, nicotine, ethanol), or gaseous (eg, nitrous oxide). These
nomena. Electrostatic bonds are weaker than covalent bonds.
factors often determine the best route of administration. The most
Hydrophobic bonds are usually quite weak and are probably
common routes of administration are described in Table 3–3. The
important in the interactions of highly lipid-soluble drugs with
various classes of organic compounds—carbohydrates, proteins,
the lipids of cell membranes and perhaps in the interaction of
lipids, and their constituents—are all represented in pharmacol-
drugs with the internal walls of receptor “pockets.”
ogy. As noted above, oligonucleotides, in the form of small seg-
The specific nature of a particular drug-receptor bond is of less
ments of RNA, have entered clinical trials and are on the threshold
practical importance than the fact that drugs that bind through
of introduction into therapeutics.
weak bonds to their receptors are generally more selective than
A number of useful or dangerous drugs are inorganic elements,
drugs that bind by means of very strong bonds. This is because weak
eg, lithium, iron, and heavy metals. Many organic drugs are weak
bonds require a very precise fit of the drug to its receptor if an inter-
acids or bases. This fact has important implications for the way
action is to occur. Only a few receptor types are likely to provide
they are handled by the body, because pH differences in the vari-
such a precise fit for a particular drug structure. Thus, if we wished
ous compartments of the body may alter the degree of ionization
to design a highly selective short-acting drug for a particular recep-
of such drugs (see text that follows).
tor, we would avoid highly reactive molecules that form covalent
bonds and instead choose a molecule that forms weaker bonds.
Drug Size A few substances that are almost completely inert in the
The molecular size of drugs varies from very small (lithium ion, chemical sense nevertheless have significant pharmacologic effects.
MW 7) to very large (eg, alteplase [t-PA], a protein of MW For example, xenon, an “inert” gas, has anesthetic effects at ele-
59,050). However, most drugs have molecular weights between vated pressures.
100 and 1000. The lower limit of this narrow range is probably set
by the requirements for specificity of action. To have a good “fit” Drug Shape
to only one type of receptor, a drug molecule must be sufficiently The shape of a drug molecule must be such as to permit binding to
unique in shape, charge, and other properties, to prevent its bind- its receptor site via the bonds just described. Optimally, the drug’s
ing to other receptors. To achieve such selective binding, it appears shape is complementary to that of the receptor site in the same way
that a molecule should in most cases be at least 100 MW units in that a key is complementary to a lock. Furthermore, the phenome-
size. The upper limit in molecular weight is determined primarily non of chirality (stereoisomerism) is so common in biology that
by the requirement that drugs must be able to move within the more than half of all useful drugs are chiral molecules; that is, they
 CHAPTER 1 Introduction 5

More active isomer Less active isomer

* *

Flat, hydrophobic regions Polar region

FIGURE 1–2 Cartoon illustrating the nonsuperimposibility of the two stereoisomers of carvedilol on the β receptor. The “receptor surface”
has been grossly oversimplified. The chiral center carbon is denoted with an asterisk. One of the two isomers fits the three-dimensional configu-
ration of binding site of the β-adrenoceptor molecule very well (left), and three groups, including an important polar moiety (an hydroxyl group,
indicated by the central dashed line), bind to key areas of the surface. The less active isomer cannot orient all three binding areas to the recep-
tor surface (right). (Molecule generated by means of Jmol, an open-source Java viewer for chemical structures in 3D [http://jmol.sourceforge.
net/] with data from DrugBank [http://www.drugbank.ca].)

can exist as enantiomeric pairs. Drugs with two asymmetric centers drugs rather than with the separate enantiomers. At present, only a
have four diastereomers, eg, ephedrine, a sympathomimetic drug. In small percentage of the chiral drugs used clinically are marketed as
most cases, one of these enantiomers is much more potent than its the active isomer—the rest are available only as racemic mixtures.
mirror image enantiomer, reflecting a better fit to the receptor mol- As a result, many patients are receiving drug doses of which 50%
ecule. If one imagines the receptor site to be like a glove into which is less active, inactive, or actively toxic. Some drugs are currently
the drug molecule must fit to bring about its effect, it is clear why a available in both the racemic and the pure, active isomer forms.
“left-oriented” drug is more effective in binding to a left-hand Unfortunately, the hope that administration of the pure, active
receptor than its “right-oriented” enantiomer. enantiomer would decrease adverse effects relative to those pro-
The more active enantiomer at one type of receptor site may duced by racemic formulations has not been firmly established.
not be more active at another receptor type, eg, a type that may be However, there is increasing interest at both the scientific and the
responsible for some other effect. For example, carvedilol, a drug regulatory levels in making more chiral drugs available as their
that interacts with adrenoceptors, has a single chiral center and active enantiomers.
thus two enantiomers (Figure 1–2, Table 1–1). One of these
enantiomers, the (S)(−) isomer, is a potent β-receptor blocker. The
(R)(+) isomer is 100-fold weaker at the β receptor. However, the TABLE 1–1 Dissociation constants (Kd) of the
isomers are approximately equipotent as α-receptor blockers. enantiomers and racemate of carvedilol.
Ketamine is an intravenous anesthetic. The (+) enantiomer is a
α Receptors β Receptors
more potent anesthetic and is less toxic than the (−) enantiomer.
Form of Carvedilol (Kd, nmol/L1) (Kd, nmol/L)
Unfortunately, the drug is still used as the racemic mixture.
Finally, because enzymes are usually stereoselective, one drug R(+) enantiomer 14 45
enantiomer is often more susceptible than the other to drug- S(−) enantiomer 16 0.4
metabolizing enzymes. As a result, the duration of action of one R,S(±) enantiomers 11 0.9
enantiomer may be quite different from that of the other. 1
The Kd is the concentration for 50% saturation of the receptors and is inversely pro-
Similarly, drug transporters may be stereoselective. portionate to the affinity of the drug for the receptors.
Unfortunately, most studies of clinical efficacy and drug elimi- Data from Ruffolo RR et al: The pharmacology of carvedilol. Eur J Pharmacol
nation in humans have been carried out with racemic mixtures of 1990;38:S82.
6 SECTION I Basic Principles

Rational Drug Design • D + R → drug-receptor complex → effector molecule → effect

• D + R → D-R complex → activation of coupling molecule →
Rational design of drugs implies the ability to predict the appropri- effector molecule → effect
ate molecular structure of a drug on the basis of information about
• Inhibition of metabolism of endogenous activator → increased
its biologic receptor. Until recently, no receptor was known in suf- activator action on an effector molecule → increased effect
ficient detail to permit such drug design. Instead, drugs were devel-
oped through random testing of chemicals or modification of drugs Note that the final change in function is accomplished by an
already known to have some effect (see Chapter 5). However, the effector mechanism. The effector may be part of the receptor
characterization of many receptors during the past three decades has molecule or may be a separate molecule. A very large number of
changed this picture. A few drugs now in use were developed receptors communicate with their effectors through coupling mol-
through molecular design based on knowledge of the three-dimen- ecules, as described in Chapter 2.
sional structure of the receptor site. Computer programs are now
available that can iteratively optimize drug structures to fit known A. Types of Drug-Receptor Interactions
receptors. As more becomes known about receptor structure, ratio- Agonist drugs bind to and activate the receptor in some fashion,
nal drug design will become more common. which directly or indirectly brings about the effect (Figure
1–3A). Receptor activation involves a change in conformation in
the cases that have been studied at the molecular structure level.
Receptor Nomenclature Some receptors incorporate effector machinery in the same mol-
The spectacular success of newer, more efficient ways to identify ecule, so that drug binding brings about the effect directly, eg,
and characterize receptors (see Chapter 2) has resulted in a variety opening of an ion channel or activation of enzyme activity.
of differing, and sometimes confusing, systems for naming them. Other receptors are linked through one or more intervening
This in turn has led to a number of suggestions regarding more coupling molecules to a separate effector molecule. The five
rational methods of naming receptors. The interested reader is major types of drug-receptor-effector coupling systems are dis-
referred for details to the efforts of the International Union of cussed in Chapter 2. Pharmacologic antagonist drugs, by bind-
Pharmacology (IUPHAR) Committee on Receptor Nomenclature and ing to a receptor, compete with and prevent binding by other
Drug Classification (reported in various issues of Pharmacological molecules. For example, acetylcholine receptor blockers such as
Reviews) and to Alexander SPH, Mathie A, Peters JA: Guide to atropine are antagonists because they prevent access of acetylcho-
receptors and channels (GRAC), 4th edition. Br J Pharmacol line and similar agonist drugs to the acetylcholine receptor site
2009;158(Suppl 1):S1–S254. The chapters in this book mainly and they stabilize the receptor in its inactive state (or some state
use these sources for naming receptors. other than the acetylcholine-activated state). These agents reduce
the effects of acetylcholine and similar molecules in the body
(Figure 1–3B), but their action can be overcome by increasing the
DRUG-BODY INTERACTIONS dosage of agonist. Some antagonists bind very tightly to the recep-
tor site in an irreversible or pseudoirreversible fashion and cannot
The interactions between a drug and the body are conveniently
be displaced by increasing the agonist concentration. Drugs that
divided into two classes. The actions of the drug on the body are
bind to the same receptor molecule but do not prevent binding of
termed pharmacodynamic processes (Figure 1–1); the principles
the agonist are said to act allosterically and may enhance (Figure
of pharmacodynamics are presented in greater detail in Chapter 2.
1–3C) or inhibit (Figure 1–3D) the action of the agonist mole-
These properties determine the group in which the drug is classi-
cule. Allosteric inhibition is not overcome by increasing the dose
fied, and they play the major role in deciding whether that group
of agonist.
is appropriate therapy for a particular symptom or disease. The
actions of the body on the drug are called pharmacokinetic pro-
B. Agonists That Inhibit Their Binding Molecules
cesses and are described in Chapters 3 and 4. Pharmacokinetic
processes govern the absorption, distribution, and elimination of Some drugs mimic agonist drugs by inhibiting the molecules
drugs and are of great practical importance in the choice and responsible for terminating the action of an endogenous agonist.
administration of a particular drug for a particular patient, eg, a For example, acetylcholinesterase inhibitors, by slowing the
patient with impaired renal function. The following paragraphs destruction of endogenous acetylcholine, cause cholinomimetic
provide a brief introduction to pharmacodynamics and pharma- effects that closely resemble the actions of cholinoceptor agonist
cokinetics. molecules even though cholinesterase inhibitors do not bind or
only incidentally bind to cholinoceptors (see Chapter 7). Because
they amplify the effects of physiologically released agonist ligands,
Pharmacodynamic Principles their effects are sometimes more selective and less toxic than those
Most drugs must bind to a receptor to bring about an effect. of exogenous agonists.
However, at the cellular level, drug binding is only the first in
what is often a complex sequence of steps: C. Agonists, Partial Agonists, and Inverse Agonists
• Drug (D) + receptor-effector (R) → drug-receptor-effector Figure 1–4 describes a useful model of drug-receptor interaction.
complex → effect As indicated, the receptor is postulated to exist in the inactive,
 CHAPTER 1 Introduction 7

Drug Receptor Effects

Agonist +

A+C A alone

Response
–
A+B
B

A+D

Log Dose
Competitive
inhibitor

Allosteric
activator

Allosteric inhibitor

FIGURE 1–3 Drugs may interact with receptors in several ways. The effects resulting from these interactions are diagrammed in the dose-
response curves at the right. Drugs that alter the agonist (A) response may activate the agonist binding site, compete with the agonist (compet-
itive inhibitors, B), or act at separate (allosteric) sites, increasing (C) or decreasing (D) the response to the agonist. Allosteric activators (C) may
increase the efficacy of the agonist or its binding affinity. The curve shown reflects an increase in efficacy; an increase in affinity would result in
a leftward shift of the curve.

nonfunctional form (Ri) and in the activated form (Ra). in the same way but do not evoke as great a response, no matter
Thermodynamic considerations indicate that even in the absence how high the concentration. In the model in Figure 1–4, partial
of any agonist, some of the receptor pool must exist in the Ra form agonists do not stabilize the Ra configuration as fully as full ago-
some of the time and may produce the same physiologic effect as nists, so that a significant fraction of receptors exists in the Ri–D
agonist-induced activity. This effect, occurring in the absence of pool. Such drugs are said to have low intrinsic efficacy. Thus,
agonist, is termed constitutive activity. Agonists are those drugs pindolol, a β-adrenoceptor partial agonist, may act either as an
that have a much higher affinity for the Ra configuration and agonist (if no full agonist is present) or as an antagonist (if a full
stabilize it, so that a large percentage of the total pool resides in agonist such as epinephrine is present). (See Chapter 2.) Intrinsic
the Ra–D fraction and a large effect is produced. The recognition efficacy is independent of affinity (as usually measured) for the
of constitutive activity may depend on the receptor density, the receptor.
concentration of coupling molecules (if a coupled system), and the In the same model, conventional antagonist action can be
number of effectors in the system. explained as fixing the fractions of drug-bound Ri and Ra in the
Many agonist drugs, when administered at concentrations suf- same relative amounts as in the absence of any drug. In this situa-
ficient to saturate the receptor pool, can activate their receptor-ef- tion, no change will be observed, so the drug will appear to be
fector systems to the maximum extent of which the system is without effect. However, the presence of the antagonist at the
capable; that is, they cause a shift of almost all of the receptor pool receptor site will block access of agonists to the receptor and pre-
to the Ra–D pool. Such drugs are termed full agonists. Other drugs, vent the usual agonist effect. Such blocking action can be termed
called partial agonists, bind to the same receptors and activate them neutral antagonism.
8 SECTION I Basic Principles

agitation, the inverse of sedation (see Chapter 22). Similar inverse

Effect agonists have been found for β-adrenoceptors, histamine H1 and
Ri Ra H2 receptors, and several other receptor systems.

D D D. Duration of Drug Action

Termination of drug action is a result of one of several processes.
In some cases, the effect lasts only as long as the drug occupies the
Ri – D Ra – D receptor, and dissociation of drug from the receptor automatically
Effect
terminates the effect. In many cases, however, the action may
persist after the drug has dissociated because, for example, some
coupling molecule is still present in activated form. In the case of
Ra + Da drugs that bind covalently to the receptor site, the effect may per-
Full agonist sist until the drug-receptor complex is destroyed and new recep-
tors or enzymes are synthesized, as described previously for aspirin.
In addition, many receptor-effector systems incorporate desensiti-
Response

zation mechanisms for preventing excessive activation when ago-

Ra + Dpa
nist molecules continue to be present for long periods. (See
Partial agonist Chapter 2 for additional details.)
Ra + Ri
Ra + Dant + Ri + Dant
Constitutive Antagonist E. Receptors and Inert Binding Sites
activity Ri + Di To function as a receptor, an endogenous molecule must first be
Inverse agonist
selective in choosing ligands (drug molecules) to bind; and second,
Log Dose
it must change its function upon binding in such a way that the
function of the biologic system (cell, tissue, etc) is altered. The
FIGURE 1–4 A model of drug-receptor interaction. The receptor selectivity characteristic is required to avoid constant activation of
is able to assume two conformations. In the Ri conformation, it is the receptor by promiscuous binding of many different ligands. The
inactive and produces no effect, even when combined with a drug ability to change function is clearly necessary if the ligand is to cause
molecule. In the Ra conformation, the receptor can activate down- a pharmacologic effect. The body contains a vast array of molecules
stream mechanisms that produce a small observable effect, even in
that are capable of binding drugs, however, and not all of these
the absence of drug (constitutive activity). In the absence of drugs,
endogenous molecules are regulatory molecules. Binding of a drug
the two isoforms are in equilibrium, and the Ri form is favored.
Conventional full agonist drugs have a much higher affinity for the Ra
to a nonregulatory molecule such as plasma albumin will result in
conformation, and mass action thus favors the formation of the Ra–D no detectable change in the function of the biologic system, so this
complex with a much larger observed effect. Partial agonists have an endogenous molecule can be called an inert binding site. Such
intermediate affinity for both Ri and Ra forms. Conventional antago- binding is not completely without significance, however, because it
nists, according to this hypothesis, have equal affinity for both recep- affects the distribution of drug within the body and determines the
tor forms and maintain the same level of constitutive activity. Inverse amount of free drug in the circulation. Both of these factors are of
agonists, on the other hand, have a much higher affinity for the Ri pharmacokinetic importance (see also Chapter 3).
form, reduce constitutive activity, and may produce a contrasting
physiologic result.
Pharmacokinetic Principles
In practical therapeutics, a drug should be able to reach its
What will happen if a drug has a much stronger affinity for the intended site of action after administration by some convenient
Ri than for the Ra state and stabilizes a large fraction in the Ri–D route. In many cases, the active drug molecule is sufficiently lipid-
pool? In this scenario the drug would reduce any constitutive soluble and stable to be given as such. In some cases, however, an
activity, thus resulting in effects that are the opposite of the effects inactive precursor chemical that is readily absorbed and distrib-
produced by conventional agonists at that receptor. Such drugs uted must be administered and then converted to the active drug
have been termed inverse agonists (Figure 1–4). One of the best by biologic processes—inside the body. Such a precursor chemical
documented examples of such a system is the γ-aminobutyric acid is called a prodrug.
(GABAA) receptor-effector (a chloride channel) in the nervous In only a few situations is it possible to apply a drug directly to
system. This receptor is activated by the endogenous transmitter its target tissue, eg, by topical application of an anti-inflammatory
GABA and causes inhibition of postsynaptic cells. Conventional agent to inflamed skin or mucous membrane. Most often, a drug
exogenous agonists such as benzodiazepines also facilitate the is administered into one body compartment, eg, the gut, and must
receptor-effector system and cause GABA-like inhibition with move to its site of action in another compartment, eg, the brain in
sedation as the therapeutic result. This inhibition can be blocked the case of an antiseizure medication. This requires that the drug
by conventional neutral antagonists such as flumazenil. In addi- be absorbed into the blood from its site of administration and
tion, inverse agonists have been found that cause anxiety and distributed to its site of action, permeating through the various
 CHAPTER 1 Introduction 9

Lumen

Interstitium

A B C D

FIGURE 1–5 Mechanisms of drug permeation. Drugs may diffuse passively through aqueous channels in the intercellular junctions (eg,
tight junctions, A), or through lipid cell membranes (B). Drugs with the appropriate characteristics may be transported by carriers into or out of
cells (C). Very impermeant drugs may also bind to cell surface receptors (dark binding sites), be engulfed by the cell membrane (endocytosis),
and then released inside the cell or expelled via the membrane-limited vesicles out of the cell into the extracellular space (exocytosis, D).

barriers that separate these compartments. For a drug given orally lipid:aqueous partition coefficient of a drug determines how
to produce an effect in the central nervous system, these barriers readily the molecule moves between aqueous and lipid media. In
include the tissues that make up the wall of the intestine, the walls the case of weak acids and weak bases (which gain or lose electrical
of the capillaries that perfuse the gut, and the blood-brain barrier, charge-bearing protons, depending on the pH), the ability to
the walls of the capillaries that perfuse the brain. Finally, after move from aqueous to lipid or vice versa varies with the pH of the
bringing about its effect, a drug should be eliminated at a reason- medium, because charged molecules attract water molecules. The
able rate by metabolic inactivation, by excretion from the body, or ratio of lipid-soluble form to water-soluble form for a weak acid
by a combination of these processes. or weak base is expressed by the Henderson-Hasselbalch equation
(described in the following text). See Figure 1–5B.
A. Permeation
Drug permeation proceeds by several mechanisms. Passive diffu- 3. Special carriers—Special carrier molecules exist for many
sion in an aqueous or lipid medium is common, but active pro- substances that are important for cell function and too large or too
cesses play a role in the movement of many drugs, especially those insoluble in lipid to diffuse passively through membranes, eg,
whose molecules are too large to diffuse readily (Figure 1–5). peptides, amino acids, and glucose. These carriers bring about
movement by active transport or facilitated diffusion and, unlike
1. Aqueous diffusion—Aqueous diffusion occurs within the passive diffusion, are selective, saturable, and inhibitable. Because
larger aqueous compartments of the body (interstitial space, cyto- many drugs are or resemble such naturally occurring peptides,
sol, etc) and across epithelial membrane tight junctions and the amino acids, or sugars, they can use these carriers to cross mem-
endothelial lining of blood vessels through aqueous pores that—in branes. See Figure 1–5C.
some tissues—permit the passage of molecules as large as MW Many cells also contain less selective membrane carriers that are
20,000–30,000.* See Figure 1–5A. specialized for expelling foreign molecules. One large family of such
Aqueous diffusion of drug molecules is usually driven by the transporters binds adenosine triphosphate (ATP) and is called the
concentration gradient of the permeating drug, a downhill move- ABC (ATP-binding cassette) family. This family includes the
ment described by Fick’s law (see below). Drug molecules that are P-glycoprotein or multidrug resistance type 1 (MDR1) trans-
bound to large plasma proteins (eg, albumin) do not permeate porter found in the brain, testes, and other tissues, and in some
most vascular aqueous pores. If the drug is charged, its flux is also drug-resistant neoplastic cells, Table 1–2. Similar transport molecules
influenced by electrical fields (eg, the membrane potential from the ABC family, the multidrug resistance-associated pro-
and—in parts of the nephron—the transtubular potential). tein (MRP) transporters, play important roles in the excretion of
some drugs or their metabolites into urine and bile and in the
2. Lipid diffusion—Lipid diffusion is the most important limit- resistance of some tumors to chemotherapeutic drugs. Several other
ing factor for drug permeation because of the large number of transporter families have been identified that do not bind ATP but
lipid barriers that separate the compartments of the body. Because use ion gradients to drive transport. Some of these (the solute car-
these lipid barriers separate aqueous compartments, the rier [SLC] family) are particularly important in the uptake of
neurotransmitters across nerve-ending membranes. The latter car-
∗
riers are discussed in more detail in Chapter 6.
The capillaries of the brain, the testes, and some other tissues are char-
acterized by the absence of pores that permit aqueous diffusion. They 4. Endocytosis and exocytosis—A few substances are so large or
may also contain high concentrations of drug export pumps (MDR
pumps; see text). These tissues are therefore protected or “sanctuary” impermeant that they can enter cells only by endocytosis, the pro-
sites from many circulating drugs. cess by which the substance is bound at a cell-surface receptor,
10 SECTION I Basic Principles

TABLE 1–2 Some transport molecules important in pharmacology.

Transporter Physiologic Function Pharmacologic Significance

NET Norepinephrine reuptake from synapse Target of cocaine and some tricyclic antidepressants
SERT Serotonin reuptake from synapse Target of selective serotonin reuptake inhibitors and some tricyclic
antidepressants
VMAT Transport of dopamine and norepinephrine into Target of reserpine and tetrabenazine
adrenergic vesicles in nerve endings
MDR1 Transport of many xenobiotics out of cells Increased expression confers resistance to certain anticancer drugs;
inhibition increases blood levels of digoxin
MRP1 Leukotriene secretion Confers resistance to certain anticancer and antifungal drugs

MDR1, multidrug resistance protein-1; MRP1, multidrug resistance-associated protein-1; NET, norepinephrine transporter; SERT, serotonin reuptake transporter; VMAT, vesicular
monoamine transporter.

engulfed by the cell membrane, and carried into the cell by pinching lipid solubility, ionization of drugs may markedly reduce their abil-
off of the newly formed vesicle inside the membrane. The substance ity to permeate membranes. A very large percentage of the drugs in
can then be released inside the cytosol by breakdown of the vesicle use are weak acids or weak bases (Table 1–3). For drugs, a weak
membrane, Figure 1–5D. This process is responsible for the trans- acid is best defined as a neutral molecule that can reversibly dis-
port of vitamin B12, complexed with a binding protein (intrinsic sociate into an anion (a negatively charged molecule) and a proton
factor) across the wall of the gut into the blood. Similarly, iron is (a hydrogen ion). For example, aspirin dissociates as follows:
transported into hemoglobin-synthesizing red blood cell precursors
in association with the protein transferrin. Specific receptors for the
transport proteins must be present for this process to work.
The reverse process (exocytosis) is responsible for the secretion
of many substances from cells. For example, many neurotransmit-
ter substances are stored in membrane-bound vesicles in nerve
endings to protect them from metabolic destruction in the cyto- A drug that is a weak base can be defined as a neutral molecule
plasm. Appropriate activation of the nerve ending causes fusion of that can form a cation (a positively charged molecule) by combin-
the storage vesicle with the cell membrane and expulsion of its ing with a proton. For example, pyrimethamine, an antimalarial
contents into the extracellular space (see Chapter 6). drug, undergoes the following association-dissociation process:

B. Fick’s Law of Diffusion

The passive flux of molecules down a concentration gradient is
given by Fick’s law:

Note that the protonated form of a weak acid is the neutral,

more lipid-soluble form, whereas the unprotonated form of a
weak base is the neutral form. The law of mass action requires that
these reactions move to the left in an acid environment (low pH,
where C1 is the higher concentration, C2 is the lower concentra- excess protons available) and to the right in an alkaline environ-
tion, area is the cross-sectional area of the diffusion path, perme- ment. The Henderson-Hasselbalch equation relates the ratio of
ability coefficient is a measure of the mobility of the drug protonated to unprotonated weak acid or weak base to the mole-
molecules in the medium of the diffusion path, and thickness is cule’s pKa and the pH of the medium as follows:
the thickness (length) of the diffusion path. In the case of lipid
diffusion, the lipid:aqueous partition coefficient is a major deter-
minant of mobility of the drug, because it determines how readily
the drug enters the lipid membrane from the aqueous medium.
This equation applies to both acidic and basic drugs. Inspection
C. Ionization of Weak Acids and Weak Bases; the confirms that the lower the pH relative to the pKa, the greater will
Henderson-Hasselbalch Equation be the fraction of drug in the protonated form. Because the
The electrostatic charge of an ionized molecule attracts water uncharged form is the more lipid-soluble, more of a weak acid will
dipoles and results in a polar, relatively water-soluble and lipid-in- be in the lipid-soluble form at acid pH, whereas more of a basic
soluble complex. Because lipid diffusion depends on relatively high drug will be in the lipid-soluble form at alkaline pH.
 CHAPTER 1 Introduction 11

TABLE 1–3 Ionization constants of some common drugs.

Drug pKa1 Drug pKa1 Drug pKa1

Weak acids Weak bases Weak bases (cont’d)

Acetaminophen 9.5 Albuterol (salbutamol) 9.3 Isoproterenol 8.6
2
Acetazolamide 7.2 Allopurinol 9.4, 12.3 Lidocaine 7.9
Ampicillin 2.5 Alprenolol 9.6 Metaraminol 8.6
Aspirin 3.5 Amiloride 8.7 Methadone 8.4
2
Chlorothiazide 6.8, 9.4 Amiodarone 6.6 Methamphetamine 10.0
Chlorpropamide 5.0 Amphetamine 9.8 Methyldopa 10.6
2
Ciprofloxacin 6.1, 8.7 Atropine 9.7 Metoprolol 9.8
Cromolyn 2.0 Bupivacaine 8.1 Morphine 7.9
Ethacrynic acid 2.5 Chlordiazepoxide 4.6 Nicotine 7.9, 3.12
Furosemide 3.9 Chloroquine 10.8, 8.4 Norepinephrine 8.6
2
Ibuprofen 4.4, 5.2 Chlorpheniramine 9.2 Pentazocine 7.9
Levodopa 2.3 Chlorpromazine 9.3 Phenylephrine 9.8
2
Methotrexate 4.8 Clonidine 8.3 Physostigmine 7.9, 1.8
2
Methyldopa 2.2, 9.2 Cocaine 8.5 Pilocarpine 6.9, 1.42
Penicillamine 1.8 Codeine 8.2 Pindolol 8.6
Pentobarbital 8.1 Cyclizine 8.2 Procainamide 9.2
Phenobarbital 7.4 Desipramine 10.2 Procaine 9.0
Phenytoin 8.3 Diazepam 3.0 Promethazine 9.1
Propylthiouracil 8.3 Diphenhydramine 8.8 Propranolol 9.4
Salicylic acid 3.0 Diphenoxylate 7.1 Pseudoephedrine 9.8
3
Sulfadiazine 6.5 Ephedrine 9.6 Pyrimethamine 7.0–7.3
2
Sulfapyridine 8.4 Epinephrine 8.7 Quinidine 8.5, 4.4
Theophylline 8.8 Ergotamine 6.3 Scopolamine 8.1
2 2
Tolbutamide 5.3 Fluphenazine 8.0, 3.9 Strychnine 8.0, 2.3
Warfarin 5.0 Hydralazine 7.1 Terbutaline 10.1
Imipramine 9.5 Thioridazine 9.5
1
The pKa is that pH at which the concentrations of the ionized and nonionized forms are equal.
2
More than one ionizable group.
3
Isoelectric point.

Application of this principle is made in the manipulation of breast milk; aqueous humor; and vaginal and prostatic secretions
drug excretion by the kidney. Almost all drugs are filtered at the (Table 1–4).
glomerulus. If a drug is in a lipid-soluble form during its passage As suggested by Table 1–3, a large number of drugs are weak
down the renal tubule, a significant fraction will be reabsorbed by bases. Most of these bases are amine-containing molecules. The
simple passive diffusion. If the goal is to accelerate excretion of nitrogen of a neutral amine has three atoms associated with it plus
the drug (eg, in a case of drug overdose), it is important to pre- a pair of unshared electrons (see the display that follows). The
vent its reabsorption from the tubule. This can often be accom- three atoms may consist of one carbon (designated “R”) and two
plished by adjusting urine pH to make certain that most of the hydrogens (a primary amine), two carbons and one hydrogen (a
drug is in the ionized state, as shown in Figure 1–6. As a result of secondary amine), or three carbon atoms (a tertiary amine).
this partitioning effect, the drug is “trapped” in the urine. Thus, Each of these three forms may reversibly bind a proton with the
weak acids are usually excreted faster in alkaline urine; weak bases unshared electrons. Some drugs have a fourth carbon-nitrogen
are usually excreted faster in acidic urine. Other body fluids in bond; these are quaternary amines. However, the quaternary
which pH differences from blood pH may cause trapping or amine is permanently charged and has no unshared electrons with
reabsorption are the contents of the stomach and small intestine; which to reversibly bind a proton. Therefore, primary, secondary,
12 SECTION I Basic Principles

Cells of the
Interstitium nephron Urine
pH 7.4 pH 6.0

Lipid H
H diffusion
R N H
0.001 mg R N H 0.001 mg

H+ H+

H H
+ +
0.398 mg R N H R N H 10 mg

H H

0.399 mg 10 mg
total total

FIGURE 1–6 Trapping of a weak base (methamphetamine) in the urine when the urine is more acidic than the blood. In the hypothetical
case illustrated, the diffusible uncharged form of the drug has equilibrated across the membrane, but the total concentration (charged plus
uncharged) in the urine (more than 10 mg) is 25 times higher than in the blood (0.4 mg).

and tertiary amines may undergo reversible protonation and vary DRUG GROUPS
their lipid solubility with pH, but quaternary amines are always in
the poorly lipid-soluble charged form. To learn each pertinent fact about each of the many hundreds of
drugs mentioned in this book would be an impractical goal and,
fortunately, is unnecessary. Almost all the several thousand drugs
currently available can be arranged into about 70 groups. Many of
the drugs within each group are very similar in pharmacodynamic
actions and in their pharmacokinetic properties as well. For most
groups, one or more prototype drugs can be identified that typify

TABLE 1–4 Body fluids with potential for drug “trapping” through the pH-partitioning phenomenon.
Total Fluid: Blood Total Fluid: Blood
Concentration Ratios Concentration Ratios
for Sulfadiazine for Pyrimethamine
1 1
Body Fluid Range of pH (acid, pKa 6.5) (base, pKa 7.0)

Urine 5.0–8.0 0.12–4.65 72.24–0.79

2
Breast milk 6.4–7.6 0.2–1.77 3.56–0.89
Jejunum, ileum contents 7.5–8.03 1.23–3.54 0.94–0.79
2 4
Stomach contents 1.92–2.59 0.11 85,993–18,386
2
Prostatic secretions 6.45–7.4 0.21 3.25–1.0
3 4
Vaginal secretions 3.4–4.2 0.11 2848–452
1
Body fluid protonated-to-unprotonated drug ratios were calculated using each of the pH extremes cited; a blood pH of 7.4 was used for blood:drug ratio. For example, the
steady-state urine:blood ratio for sulfadiazine is 0.12 at a urine pH of 5.0; this ratio is 4.65 at a urine pH of 8.0. Thus, sulfadiazine is much more effectively trapped and excreted
in alkaline urine.
2
Lentner C (editor): Geigy Scientific Tables, vol 1, 8th ed. Ciba Geigy, 1981.
3
Bowman WC, Rand MJ: Textbook of Pharmacology, 2nd ed. Blackwell, 1980.
4
Insignificant change in ratios over the physiologic pH range.
 CHAPTER 1 Introduction 13

the most important characteristics of the group. This permits clas- prescription sales package; Physicians’ Desk Reference (PDR) is a
sification of other important drugs in the group as variants of the compendium of package inserts published annually with supple-
prototype, so that only the prototype must be learned in detail and, ments twice a year. It is sold in bookstores and distributed free to
for the remaining drugs, only the differences from the prototype. licensed physicians. The package insert consists of a brief descrip-
tion of the pharmacology of the product. This brochure contains
much practical information, and it is also used as a means of shift-
SOURCES OF INFORMATION ing liability for untoward drug reactions from the manufacturer
Students who wish to review the field of pharmacology in prepara- onto the practitioner. Therefore, the manufacturer typically lists
tion for an examination are referred to Pharmacology: Examination every toxic effect ever reported, no matter how rare. Micromedex is
and Board Review, by Trevor, Katzung, and Masters (McGraw- an extensive subscription website maintained by the Thomson
Hill, 2010). This book provides over 1000 questions and explana- Corporation (http://clinical.thomsonhealthcare.com/products/phy-
tions in USMLE format. A short study guide is USMLE Road sicians/). It provides downloads for personal digital assistant
Map: Pharmacology, by Katzung and Trevor (McGraw-Hill, 2006). devices, online drug dosage and interaction information, and
Road Map contains numerous tables, figures, mnemonics, and toxicologic information. A useful and objective quarterly hand-
USMLE-type clinical vignettes. book that presents information on drug toxicity and interactions
The references at the end of each chapter in this book were is Drug Interactions: Analysis and Management. Finally, the FDA
selected to provide reviews or classic publications of information maintains an Internet website that carries news regarding recent
specific to those chapters. More detailed questions relating to basic drug approvals, withdrawals, warnings, etc. It can be accessed at
or clinical research are best answered by referring to the journals http://www.fda.gov. The MedWatch drug safety program is a free
covering general pharmacology and clinical specialties. For the e-mail notification service that provides news of FDA drug warn-
student and the physician, three periodicals can be recommended ings and withdrawals. Subscriptions may be obtained at https://
as especially useful sources of current information about drugs: service.govdelivery.com/service/user.html?code=USFDA.
The New England Journal of Medicine, which publishes much
original drug-related clinical research as well as frequent reviews of
topics in pharmacology; The Medical Letter on Drugs and REFERENCES
Therapeutics, which publishes brief critical reviews of new and old Drug Interactions: Analysis and Management (quarterly). Wolters Kluwer
Publications.
therapies, mostly pharmacologic; and Drugs, which publishes
Pharmacology: Examination & Board Review, 9th ed. McGraw-Hill Companies, Inc.
extensive reviews of drugs and drug groups.
Symposium: Allosterism and collateral efficacy. Trends Pharmacol Sci
Other sources of information pertinent to the United States 2007;28(8):entire issue.
should be mentioned as well. The “package insert” is a summary USMLE Road Map: Pharmacology; McGraw-Hill Companies, Inc.
of information that the manufacturer is required to place in the The Medical Letter on Drugs and Therapeutics. The Medical Letter, Inc.

CASE STUDY ANSWER

In the case study, the patient intravenously self-administered the drug to the protonated, charged form, which is poorly
an overdose of methamphetamine, a weak base. This drug is reabsorbed and thus more rapidly eliminated. Note that not
freely filtered at the glomerulus, but can be rapidly reab- all experts recommend forced diuresis and urinary pH
sorbed in the renal tubule. Administration of ammonium manipulation after methamphetamine overdose because of
chloride acidifies the urine, converting a larger fraction of the risk of renal damage (see Figure 1–6).
This page intentionally left blank
 2
C H A P T E R

Drug Receptors &

Pharmacodynamics
Mark von Zastrow, MD, PhD∗

CASE STUDY

A 51-year-old man presents to his medical clinic due to dif- the medical history is remarkable only for mild hyperten-
ficulty breathing. The patient is afebrile and normotensive, sion that was recently treated with propranolol. The physi-
but tachypneic. Auscultation of the chest reveals diffuse cian instructs the patient to discontinue use of propranolol,
wheezes. The physician provisionally makes the diagnosis of and changes the patient’s antihypertensive medication to
bronchial asthma and administers epinephrine by intramus- verapamil. Why is the physician correct to discontinue
cular injection, improving the patient’s breathing over several propranolol? Why is verapamil a better choice for managing
minutes. A normal chest X-ray is subsequently obtained, and hypertension in this patient?

Therapeutic and toxic effects of drugs result from their interac- 1. Receptors largely determine the quantitative relations
tions with molecules in the patient. Most drugs act by associating between dose or concentration of drug and pharmacologic
with specific macromolecules in ways that alter the macromole- effects. The receptor’s affinity for binding a drug determines the
cules’ biochemical or biophysical activities. This idea, more than a concentration of drug required to form a significant number of
drug-receptor complexes, and the total number of receptors
century old, is embodied in the term receptor: the component of may limit the maximal effect a drug may produce.
a cell or organism that interacts with a drug and initiates the chain 2. Receptors are responsible for selectivity of drug action. The
of events leading to the drug’s observed effects. molecular size, shape, and electrical charge of a drug determine
Receptors have become the central focus of investigation of whether—and with what affinity—it will bind to a particular
drug effects and their mechanisms of action (pharmacodynamics). receptor among the vast array of chemically different binding
The receptor concept, extended to endocrinology, immunology, sites available in a cell, tissue, or patient. Accordingly, changes
and molecular biology, has proved essential for explaining many in the chemical structure of a drug can dramatically increase or
aspects of biologic regulation. Many drug receptors have been decrease a new drug’s affinities for different classes of receptors,
with resulting alterations in therapeutic and toxic effects.
isolated and characterized in detail, thus opening the way to pre-
cise understanding of the molecular basis of drug action. 3. Receptors mediate the actions of pharmacologic agonists
and antagonists. Some drugs and many natural ligands, such
The receptor concept has important practical consequences for as hormones and neurotransmitters, regulate the function of
the development of drugs and for arriving at therapeutic decisions receptor macromolecules as agonists; this means that they
in clinical practice. These consequences form the basis for under- activate the receptor to signal as a direct result of binding to it.
standing the actions and clinical uses of drugs described in almost Some agonists activate a single kind of receptor to produce all
every chapter of this book. They may be briefly summarized as their biologic functions, whereas others selectively promote
follows: one receptor function more than another.
Other drugs act as pharmacologic antagonists; that is, they
bind to receptors but do not activate generation of a signal; con-
sequently, they interfere with the ability of an agonist to activate
the receptor. The effect of a so-called “pure” antagonist on a cell
∗ or in a patient depends entirely on its preventing the binding of
The author thanks Henry R. Bourne, MD, for major contributions to
this chapter. agonist molecules and blocking their biologic actions. Other

15
16 SECTION I Basic Principles

antagonists, in addition to preventing agonist binding, sup- precision. This idealized relation underlies the more complex rela-
press the basal signaling (“constitutive”) activity of receptors. tions between dose and effect that occur when drugs are given to
Some of the most useful drugs in clinical medicine are phar- patients.
macologic antagonists.
Concentration-Effect Curves & Receptor
Binding of Agonists
MACROMOLECULAR NATURE
Even in intact animals or patients, responses to low doses of a drug
OF DRUG RECEPTORS usually increase in direct proportion to dose. As doses increase,
Most receptors are proteins, presumably because the structures of however, the response increment diminishes; finally, doses may be
polypeptides provide both the necessary diversity and the neces- reached at which no further increase in response can be achieved.
sary specificity of shape and electrical charge. Receptors vary In idealized or in vitro systems, the relation between drug concen-
greatly in structure and can be identified in many ways. tration and effect is described by a hyperbolic curve (Figure 2–1A)
Traditionally, drug binding was used to identify or purify recep- according to the following equation:
tors from tissue extracts; consequently, receptors were discovered
after the drugs that bind to them. However, advances in molecular
biology and genome sequencing have effectively reversed this
order. Now receptors are being discovered by predicted structure
or sequence homology to other (known) receptors, and drugs that where E is the effect observed at concentration C, Emax is the
bind to them are developed later using chemical screening meth- maximal response that can be produced by the drug, and EC50 is
ods. This effort has revealed, for many known drugs, a larger the concentration of drug that produces 50% of maximal effect.
diversity of receptors than previously anticipated. It has also iden- This hyperbolic relation resembles the mass action law, which
tified a number of “orphan” receptors, so-called because their describes association between two molecules of a given affinity. This
ligands are presently unknown, which may prove to be useful resemblance suggests that drug agonists act by binding to (“occupy-
targets for the development of new drugs. ing”) a distinct class of biologic molecules with a characteristic affin-
The best-characterized drug receptors are regulatory proteins, ity for the drug receptor. Radioactive receptor ligands have been used
which mediate the actions of endogenous chemical signals such as to confirm this occupancy assumption in many drug-receptor sys-
neurotransmitters, autacoids, and hormones. This class of recep- tems. In these systems, drug bound to receptors (B) relates to the
tors mediates the effects of many of the most useful therapeutic concentration of free (unbound) drug (C) as depicted in Figure 2–1B
agents. The molecular structures and biochemical mechanisms of and as described by an analogous equation:
these regulatory receptors are described in a later section entitled
Signaling Mechanisms & Drug Action.
Other classes of proteins that have been clearly identified as
drug receptors include enzymes, which may be inhibited (or, less
commonly, activated) by binding a drug (eg, dihydrofolate in which Bmax indicates the total concentration of receptor sites
reductase, the receptor for the antineoplastic drug methotrexate); (ie, sites bound to the drug at infinitely high concentrations of free
+ + drug) and Kd (the equilibrium dissociation constant) represents
transport proteins (eg, Na /K -ATPase, the membrane receptor
for cardioactive digitalis glycosides); and structural proteins (eg, the concentration of free drug at which half-maximal binding is
tubulin, the receptor for colchicine, an anti-inflammatory agent). observed. This constant characterizes the receptor’s affinity for
This chapter deals with three aspects of drug receptor function, binding the drug in a reciprocal fashion: If the Kd is low, binding
presented in increasing order of complexity: (1) receptors as deter- affinity is high, and vice versa. The EC50 and Kd may be identical,
minants of the quantitative relation between the concentration of but need not be, as discussed below. Dose-response data are often
a drug and the pharmacologic response, (2) receptors as regulatory presented as a plot of the drug effect (ordinate) against the loga-
proteins and components of chemical signaling mechanisms that rithm of the dose or concentration (abscissa). This mathematical
provide targets for important drugs, and (3) receptors as key deter- maneuver transforms the hyperbolic curve of Figure 2–1 into a
minants of the therapeutic and toxic effects of drugs in patients. sigmoid curve with a linear midportion (eg, Figure 2–2). This
expands the scale of the concentration axis at low concentrations
(where the effect is changing rapidly) and compresses it at high
concentrations (where the effect is changing slowly), but has no
RELATION BETWEEN DRUG special biologic or pharmacologic significance.
CONCENTRATION & RESPONSE
Receptor-Effector Coupling &
The relation between dose of a drug and the clinically observed
response may be complex. In carefully controlled in vitro systems, Spare Receptors
however, the relation between concentration of a drug and its When a receptor is occupied by an agonist, the resulting conforma-
effect is often simple and can be described with mathematical tional change is only the first of many steps usually required to
 CHAPTER 2 Drug Receptors & Pharmacodynamics 17

1.0 1.0

Receptor-bound drug (B)

Emax Bmax

Drug effect (E)

0.5 0.5

EC50 Kd

Drug concentration (C) Drug concentration (C)

A B

FIGURE 2–1 Relations between drug concentration and drug effect (A) or receptor-bound drug (B). The drug concentrations at which
effect or receptor occupancy is half-maximal are denoted by EC50 and Kd, respectively.

produce a pharmacologic response. The transduction process that in the receptor; thus, the effects of full agonists can be considered
links drug occupancy of receptors and pharmacologic response is more efficiently coupled to receptor occupancy than can the effects
often termed coupling. The relative efficiency of occupancy-response of partial agonists (described in text that follows). Coupling effi-
coupling is partially determined by the initial conformational change ciency is also determined by the biochemical events that transduce
receptor occupancy into cellular response. Sometimes the biologic
effect of the drug is linearly related to the number of receptors
bound. This is often true for drug-regulated ion channels, eg, in
which the ion current produced by the drug is directly proportional
to the number of receptors (ion channels) bound. In other cases, the
biologic response is a more complex function of drug binding to
A B C
receptors. This is often true for receptors linked to enzymatic signal
transduction cascades, eg, in which the biologic response often
Agonist effect

D increases disproportionately to the number of receptors occupied by

0.5 drug.
Many factors can contribute to nonlinear occupancy-response
coupling, and often these factors are only partially understood.
The concept of “spare” receptors, regardless of the precise bio-
E
chemical mechanism involved, can help us to think about these
effects. Receptors are said to be “spare” for a given pharmacologic
response if it is possible to elicit a maximal biologic response at a
concentration of agonist that does not result in occupancy of the
EC50 (A) EC50 (B) EC50 (C) EC50 (D,E) Kd full complement of available receptors. Experimentally, spare
receptors may be demonstrated by using irreversible antagonists to
Agonist concentration (C) (log scale)
prevent binding of agonist to a proportion of available receptors
FIGURE 2–2 Logarithmic transformation of the dose axis and and showing that high concentrations of agonist can still produce
experimental demonstration of spare receptors, using different con- an undiminished maximal response (Figure 2–2). Thus, the same
centrations of an irreversible antagonist. Curve A shows agonist maximal inotropic response of heart muscle to catecholamines can
response in the absence of antagonist. After treatment with a low be elicited even under conditions in which 90% of the β adreno-
concentration of antagonist (curve B), the curve is shifted to the ceptors are occupied by a quasi-irreversible antagonist. Accordingly,
right. Maximal responsiveness is preserved, however, because the myocardial cells are said to contain a large proportion of spare β
remaining available receptors are still in excess of the number
adrenoceptors.
required. In curve C, produced after treatment with a larger concen-
How can we account for the phenomenon of spare receptors?
tration of antagonist, the available receptors are no longer “spare”;
instead, they are just sufficient to mediate an undiminished maximal
In the example of the β adrenoceptor, receptor activation pro-
response. Still higher concentrations of antagonist (curves D and E) motes binding of guanosine triphosphate (GTP) to an interme-
reduce the number of available receptors to the point that maximal diate signaling protein and activation of the signaling
response is diminished. The apparent EC50 of the agonist in curves D intermediate may greatly outlast the agonist-receptor interaction
and E may approximate the Kd that characterizes the binding affinity (see the following section on G Proteins & Second Messengers).
of the agonist for the receptor. In such a case, the “spareness” of receptors is temporal. Maximal
18 SECTION I Basic Principles

response can be elicited by activation of relatively few receptors producing a half-maximal response (ie, two receptors stimulate
because the response initiated by an individual ligand-receptor two effectors). Now imagine that the number of receptors
binding event persists longer than the binding event itself. increases 10-fold to 40 receptors but that the total number of
In other cases, in which the biochemical mechanism is not effectors remains constant. Most of the receptors are now spare in
understood, we imagine that the receptors might be spare in num- number. As a result, a much lower concentration of agonist suf-
ber. If the concentration or amount of cellular components other fices to occupy 2 of the 40 receptors (5% of the receptors), and
than the receptors limits the coupling of receptor occupancy to this same low concentration of agonist is able to elicit a half-
response, then a maximal response can occur without occupancy maximal response (two of four effectors activated). Thus, it is
of all receptors. Thus, the sensitivity of a cell or tissue to a particu- possible to change the sensitivity of tissues with spare receptors by
lar concentration of agonist depends not only on the affinity of the changing receptor number.
receptor for binding the agonist (characterized by the Kd) but also
on the degree of spareness—the total number of receptors present
compared with the number actually needed to elicit a maximal Competitive & Irreversible Antagonists
biologic response. Receptor antagonists bind to receptors but do not activate them.
The concept of spare receptors is very useful clinically because The primary action of antagonists is to prevent agonists (other
it allows one to think precisely about the effects of drug dosage drugs or endogenous regulatory molecules) from activating recep-
without needing to consider biochemical details of the signaling tors. Some antagonists (so-called “inverse agonists,” see Chapter
response. The Kd of the agonist-receptor interaction determines 1), also reduce receptor activity below basal levels observed in the
what fraction (B/Bmax) of total receptors will be occupied at a absence of bound ligand. Antagonists are divided into two classes
given free concentration (C) of agonist regardless of the receptor depending on whether or not they reversibly compete with agonists
concentration: for binding to receptors.
In the presence of a fixed concentration of agonist, increasing
concentrations of a reversible competitive antagonist progres-
sively inhibit the agonist response; high antagonist concentra-
tions prevent response completely. Conversely, sufficiently high
Imagine a responding cell with four receptors and four effec- concentrations of agonist can surmount the effect of a given con-
tors. Here the number of effectors does not limit the maximal centration of the antagonist; that is, the Emax for the agonist
response, and the receptors are not spare in number. Consequently, remains the same for any fixed concentration of antagonist
an agonist present at a concentration equal to the Kd will occupy (Figure 2–3A). Because the antagonism is competitive, the pres-
50% of the receptors, and half of the effectors will be activated, ence of antagonist increases the agonist concentration required

A B

Agonist
Agonist alone
alone
Agonist effect (E)

Agonist effect (E)

Agonist +
competitive antagonist

Agonist +
noncompetitive antagonist

C C' = C (1 + [ l ] / K) EC50

Agonist concentration Agonist concentration

FIGURE 2–3 Changes in agonist concentration-effect curves produced by a competitive antagonist (A) or by an irreversible antagonist (B).
In the presence of a competitive antagonist, higher concentrations of agonist are required to produce a given effect; thus the agonist concen-
tration (C’) required for a given effect in the presence of concentration [I] of an antagonist is shifted to the right, as shown. High agonist concen-
trations can overcome inhibition by a competitive antagonist. This is not the case with an irreversible (or noncompetitive) antagonist, which
reduces the maximal effect the agonist can achieve, although it may not change its EC50.
 CHAPTER 2 Drug Receptors & Pharmacodynamics 19

for a given degree of response, and so the agonist concentration- achievement of maximum response to agonist, although a higher
effect curve is shifted to the right. agonist concentration will be required (Figure 2–2B and C; see
The concentration (C′) of an agonist required to produce a Receptor-Effector Coupling & Spare Receptors).
given effect in the presence of a fixed concentration ([I]) of com- Therapeutically, irreversible antagonists present distinct advan-
petitive antagonist is greater than the agonist concentration (C) tages and disadvantages. Once the irreversible antagonist has
required to produce the same effect in the absence of the antago- occupied the receptor, it need not be present in unbound form to
nist. The ratio of these two agonist concentrations (dose ratio) is inhibit agonist responses. Consequently, the duration of action of
related to the dissociation constant (Ki) of the antagonist by the such an irreversible antagonist is relatively independent of its own
Schild equation: rate of elimination and more dependent on the rate of turnover of
receptor molecules.
C' [l] Phenoxybenzamine, an irreversible α-adrenoceptor antagonist,
=1+
C Ki is used to control the hypertension caused by catecholamines
released from pheochromocytoma, a tumor of the adrenal
medulla. If administration of phenoxybenzamine lowers blood
Pharmacologists often use this relation to determine the Ki of
pressure, blockade will be maintained even when the tumor epi-
a competitive antagonist. Even without knowledge of the relation
sodically releases very large amounts of catecholamine. In this
between agonist occupancy of the receptor and response, the Ki
case, the ability to prevent responses to varying and high concen-
can be determined simply and accurately. As shown in Figure 2–3,
trations of agonist is a therapeutic advantage. If overdose occurs,
concentration-response curves are obtained in the presence and
however, a real problem may arise. If the α-adrenoceptor blockade
in the absence of a fixed concentration of competitive antagonist;
cannot be overcome, excess effects of the drug must be antago-
comparison of the agonist concentrations required to produce
nized “physiologically,” ie, by using a pressor agent that does not
identical degrees of pharmacologic effect in the two situations
act via α receptors.
reveals the antagonist’s Ki. If C′ is twice C, for example, then
Antagonists can function noncompetitively in a different way;
[I] = Ki.
that is, by binding to a site on the receptor protein separate from
For the clinician, this mathematical relation has two important
the agonist binding site, and thereby modifying receptor activity
therapeutic implications:
without blocking agonist binding (see Figure 1–3C and D).
1. The degree of inhibition produced by a competitive antagonist Although these drugs act noncompetitively, their actions are
depends on the concentration of antagonist. The competitive reversible if they do not bind covalently. Such drugs are often
β-adrenoceptor antagonist propranolol provides a useful
example. Patients receiving a fixed dose of this drug exhibit a called allosteric modulators. For example, benzodiazepines bind
wide range of plasma concentrations, owing to differences noncompetitively to ion channels activated by the neurotransmit-
among individuals in clearance of propranolol. As a result, ter γ-aminobutyric acid (GABA), enhancing the net activating
inhibitory effects on physiologic responses to norepinephrine effect of GABA on channel conductance.
and epinephrine (endogenous adrenergic receptor agonists)
may vary widely, and the dose of propranolol must be adjusted
accordingly.
2. Clinical response to a competitive antagonist also depends on Partial Agonists
the concentration of agonist that is competing for binding to Based on the maximal pharmacologic response that occurs when all
receptors. Again, propranolol provides a useful example: When receptors are occupied, agonists can be divided into two classes:
this drug is administered at moderate doses sufficient to block
the effect of basal levels of the neurotransmitter norepinephrine, partial agonists produce a lower response, at full receptor occu-
resting heart rate is decreased. However, the increase in the pancy, than do full agonists. Partial agonists produce concentra-
release of norepinephrine and epinephrine that occurs with tion-effect curves that resemble those observed with full agonists in
exercise, postural changes, or emotional stress may suffice to the presence of an antagonist that irreversibly blocks some of the
overcome this competitive antagonism. Accordingly, the same receptor sites (compare Figures 2–2 [curve D] and 2–4B). It is
dose of propranolol may have little effect under these condi- important to emphasize that the failure of partial agonists to pro-
tions, thereby altering therapeutic response. duce a maximal response is not due to decreased affinity for binding
Some receptor antagonists bind to the receptor in an irrevers- to receptors. Indeed, a partial agonist’s inability to cause a maximal
ible or nearly irreversible fashion, either by forming a covalent pharmacologic response, even when present at high concentrations
bond with the receptor or by binding so tightly that, for practical that saturate binding to all receptors, is indicated by the fact that
purposes, the receptor is unavailable for binding of agonist. After partial agonists competitively inhibit the responses produced by full
occupancy of some proportion of receptors by such an antagonist, agonists (Figure 2–4C). Many drugs used clinically as antagonists are
the number of remaining unoccupied receptors may be too low for actually weak partial agonists. Partial agonism can be useful in some
the agonist (even at high concentrations) to elicit a response com- clinical circumstances. For example, buprenorphine, a partial agonist
parable to the previous maximal response (Figure 2–3B). If spare of μ-opioid receptors, is a generally safer analgesic drug than mor-
receptors are present, however, a lower dose of an irreversible phine because it produces less respiratory depression in overdose.
antagonist may leave enough receptors unoccupied to allow Buprenorphine is effectively antianalgesic when administered to
20 SECTION I Basic Principles

A B
100 1.0
Percentage of maximal binding
80 0.8 Partial agonist
Full agonist

Response
60 Partial agonist 0.6
Full agonist
40 0.4

20 0.2

0 0.0
–10 –8 –6 –10 –8 –6
log (Partial agonist) log (Full agonist or partial agonist)

C
Partial agonist
1.0
component
Full agonist
0.8
component
Response

Total response
0.6

0.4

0.2

0.0
–10 –8 –6
log (Partial agonist)

FIGURE 2–4 A: The percentage of receptor occupancy resulting from full agonist (present at a single concentration) binding to receptors
in the presence of increasing concentrations of a partial agonist. Because the full agonist (filled squares) and the partial agonist (open squares)
compete to bind to the same receptor sites, when occupancy by the partial agonist increases, binding of the full agonist decreases. B: When
each of the two drugs is used alone and response is measured, occupancy of all the receptors by the partial agonist produces a lower maximal
response than does similar occupancy by the full agonist. C: Simultaneous treatment with a single concentration of full agonist and increasing
concentrations of the partial agonist produces the response patterns shown in the bottom panel. The fractional response caused by a single
high concentration of the full agonist (filled squares) decreases as increasing concentrations of the partial agonist compete to bind to the
receptor with increasing success; at the same time the portion of the response caused by the partial agonist (open squares) increases, while the
total response—ie, the sum of responses to the two drugs (filled triangles)—gradually decreases, eventually reaching the value produced by
partial agonist alone (compare with B).

morphine-dependent individuals, however, and may precipitate a hormones lead to increased blood sugar, an effect that is physio-
drug withdrawal syndrome due to competitive inhibition of mor- logically opposed by insulin. Although glucocorticoids and insulin
phine’s agonist action. act on quite distinct receptor-effector systems, the clinician must
sometimes administer insulin to oppose the hyperglycemic effects
of a glucocorticoid hormone, whether the latter is elevated by
Other Mechanisms of Drug Antagonism endogenous synthesis (eg, a tumor of the adrenal cortex) or as a
Not all the mechanisms of antagonism involve interactions of result of glucocorticoid therapy.
drugs or endogenous ligands at a single type of receptor, and some In general, use of a drug as a physiologic antagonist produces
types of antagonism do not involve a receptor at all. For example, effects that are less specific and less easy to control than are the
protamine, a protein that is positively charged at physiologic pH, effects of a receptor-specific antagonist. Thus, for example, to treat
can be used clinically to counteract the effects of heparin, an anti- bradycardia caused by increased release of acetylcholine from
coagulant that is negatively charged. In this case, one drug acts as vagus nerve endings, the physician could use isoproterenol, a
a chemical antagonist of the other simply by ionic binding that β-adrenoceptor agonist that increases heart rate by mimicking
makes the other drug unavailable for interactions with proteins sympathetic stimulation of the heart. However, use of this physi-
involved in blood clotting. ologic antagonist would be less rational—and potentially more
Another type of antagonism is physiologic antagonism between dangerous—than would use of a receptor-specific antagonist such
endogenous regulatory pathways mediated by different receptors. as atropine (a competitive antagonist at the receptors at which
For example, several catabolic actions of the glucocorticoid acetylcholine slows heart rate).
 CHAPTER 2 Drug Receptors & Pharmacodynamics 21

SIGNALING MECHANISMS & DRUG circumvent the barrier posed by the lipid bilayer of the plasma
membrane. These strategies use (1) a lipid-soluble ligand that
ACTION crosses the membrane and acts on an intracellular receptor; (2) a
Until now we have considered receptor interactions and drug transmembrane receptor protein whose intracellular enzymatic
effects in terms of equations and concentration-effect curves. We activity is allosterically regulated by a ligand that binds to a site on
must also understand the molecular mechanisms by which a drug the protein’s extracellular domain; (3) a transmembrane receptor
acts. Such understanding allows us to ask basic questions with that binds and stimulates a protein tyrosine kinase; (4) a ligand-
important clinical implications: gated transmembrane ion channel that can be induced to open or
close by the binding of a ligand; or (5) a transmembrane receptor
• Why do some drugs produce effects that persist for minutes, protein that stimulates a GTP-binding signal transducer protein
hours, or even days after the drug is no longer present?
(G protein), which in turn modulates production of an intracellu-
• Why do responses to other drugs diminish rapidly with pro-
lar second messenger.
longed or repeated administration?
Although the five established mechanisms do not account
• How do cellular mechanisms for amplifying external chemical
signals explain the phenomenon of spare receptors? for all the chemical signals conveyed across cell membranes,
• Why do chemically similar drugs often exhibit extraordinary they do transduce many of the most important signals exploited
selectivity in their actions? in pharmacotherapy.
• Do these mechanisms provide targets for developing new drugs?
Most transmembrane signaling is accomplished by a small Intracellular Receptors for
number of different molecular mechanisms. Each type of mecha-
nism has been adapted, through the evolution of distinctive pro- Lipid-Soluble Agents
tein families, to transduce many different signals. These protein Several biologic ligands are sufficiently lipid-soluble to cross the
families include receptors on the cell surface and within the cell, plasma membrane and act on intracellular receptors. One class of
as well as enzymes and other components that generate, amplify, such ligands includes steroids (corticosteroids, mineralocorticoids,
coordinate, and terminate postreceptor signaling by chemical sec- sex steroids, vitamin D), and thyroid hormone, whose receptors
ond messengers in the cytoplasm. This section first discusses the stimulate the transcription of genes by binding to specific DNA
mechanisms for carrying chemical information across the plasma sequences near the gene whose expression is to be regulated. Many
membrane and then outlines key features of cytoplasmic second of the target DNA sequences (called response elements) have
messengers. been identified.
Five basic mechanisms of transmembrane signaling are well These “gene-active” receptors belong to a protein family that
understood (Figure 2–5). Each uses a different strategy to evolved from a common precursor. Dissection of the receptors by

1 2 3 4 5
Drug

Outside
cell
R
Membrane R R R E
G
Inside
cell
A B Y Y~P C D

FIGURE 2–5 Known transmembrane signaling mechanisms: 1: A lipid-soluble chemical signal crosses the plasma membrane and acts on
an intracellular receptor (which may be an enzyme or a regulator of gene transcription); 2: the signal binds to the extracellular domain of a
transmembrane protein, thereby activating an enzymatic activity of its cytoplasmic domain; 3: the signal binds to the extracellular domain of a
transmembrane receptor bound to a separate protein tyrosine kinase, which it activates; 4: the signal binds to and directly regulates the open-
ing of an ion channel; 5: the signal binds to a cell-surface receptor linked to an effector enzyme by a G protein. (A, C, substrates; B, D, products;
R, receptor; G, G protein; E, effector [enzyme or ion channel]; Y, tyrosine; P, phosphate.)
22 SECTION I Basic Principles

within minutes (eg, glucocorticoids will not immediately

relieve the symptoms of acute bronchial asthma).
2. The effects of these agents can persist for hours or days after the
agonist concentration has been reduced to zero. The persis-
tence of effect is primarily due to the relatively slow turnover
Ligand-binding of most enzymes and proteins, which can remain active in cells
domain
for hours or days after they have been synthesized. Consequently,
hsp90 it means that the beneficial (or toxic) effects of a gene-active
hormone usually decrease slowly when administration of the
Steroid
hormone is stopped.

Ligand-Regulated Transmembrane
Enzymes Including Receptor
hsp90
Tyrosine Kinases
This class of receptor molecules mediates the first steps in signal-
ing by insulin, epidermal growth factor (EGF), platelet-derived
growth factor (PDGF), atrial natriuretic peptide (ANP), trans-
Transcription- forming growth factor-β (TGF-β), and many other trophic hor-
activating mones. These receptors are polypeptides consisting of an
domain extracellular hormone-binding domain and a cytoplasmic enzyme
DNA-binding
domain, which may be a protein tyrosine kinase, a serine kinase,
domain or a guanylyl cyclase (Figure 2–7). In all these receptors, the two
domains are connected by a hydrophobic segment of the polypep-
tide that crosses the lipid bilayer of the plasma membrane.
Altered transcription The receptor tyrosine kinase signaling pathway begins with
of specific genes binding of ligand, typically a polypeptide hormone or growth fac-
tor, to the receptor’s extracellular domain. The resulting change in
FIGURE 2–6 Mechanism of glucocorticoid action. The glucocor- receptor conformation causes two receptor molecules to bind to
ticoid receptor polypeptide is schematically depicted as a protein one another (dimerize), which in turn brings together the tyrosine
with three distinct domains. A heat-shock protein, hsp90, binds to kinase domains, which become enzymatically active, and phos-
the receptor in the absence of hormone and prevents folding into phorylate one another as well as additional downstream signaling
the active conformation of the receptor. Binding of a hormone ligand proteins. Activated receptors catalyze phosphorylation of tyrosine
(steroid) causes dissociation of the hsp90 stabilizer and permits con- residues on different target signaling proteins, thereby allowing a
version to the active configuration.
single type of activated receptor to modulate a number of bio-
chemical processes. (Some receptor tyrosine kinases form oligo-
meric complexes larger than dimers upon activation by ligand, but
recombinant DNA techniques has provided insights into their the pharmacologic significance of such higher-order complexes is
molecular mechanism. For example, binding of glucocorticoid presently unclear.)
hormone to its normal receptor protein relieves an inhibitory Insulin, for example, uses a single class of receptors to trigger
constraint on the transcription-stimulating activity of the protein. increased uptake of glucose and amino acids and to regulate
Figure 2–6 schematically depicts the molecular mechanism of metabolism of glycogen and triglycerides in the cell. Similarly,
glucocorticoid action: In the absence of hormone, the receptor is each of the growth factors initiates in its specific target cells a
bound to hsp90, a protein that appears to prevent normal folding complex program of cellular events ranging from altered mem-
of several structural domains of the receptor. Binding of hormone brane transport of ions and metabolites to changes in the expres-
to the ligand-binding domain triggers release of hsp90. This sion of many genes.
allows the DNA-binding and transcription-activating domains of Inhibitors of receptor tyrosine kinases are finding increased use
the receptor to fold into their functionally active conformations, in neoplastic disorders in which excessive growth factor signaling
so that the activated receptor can initiate transcription of target is often involved. Some of these inhibitors are monoclonal anti-
genes. bodies (eg, trastuzumab, cetuximab), which bind to the extracel-
The mechanism used by hormones that act by regulating gene lular domain of a particular receptor and interfere with binding of
expression has two therapeutically important consequences: growth factor. Other inhibitors are membrane-permeant “small
1. All of these hormones produce their effects after a characteristic molecule” chemicals (eg, gefitinib, erlotinib), which inhibit the
lag period of 30 minutes to several hours—the time required receptor’s kinase activity in the cytoplasm.
for the synthesis of new proteins. This means that the gene- The intensity and duration of action of EGF, PDGF, and other
active hormones cannot be expected to alter a pathologic state agents that act via receptor tyrosine kinases are limited by a process
 CHAPTER 2 Drug Receptors & Pharmacodynamics 23

EGF molecules

+EGF

–EGF
Outside

Inside
P P
Y Y
Y Y

S S~P

ATP ADP

FIGURE 2–7 Mechanism of activation of the epidermal growth factor (EGF) receptor, a representative receptor tyrosine kinase. The
receptor polypeptide has extracellular and cytoplasmic domains, depicted above and below the plasma membrane. Upon binding of EGF
(circle), the receptor converts from its inactive monomeric state (left) to an active dimeric state (right), in which two receptor polypeptides bind
noncovalently. The cytoplasmic domains become phosphorylated (P) on specific tyrosine residues (Y), and their enzymatic activities are
activated, catalyzing phosphorylation of substrate proteins (S).

called receptor down-regulation. Ligand binding often induces Cytokine Receptors

accelerated endocytosis of receptors from the cell surface, followed
Cytokine receptors respond to a heterogeneous group of peptide
by the degradation of those receptors (and their bound ligands).
ligands, which include growth hormone, erythropoietin, several
When this process occurs at a rate faster than de novo synthesis of
kinds of interferon, and other regulators of growth and differen-
receptors, the total number of cell-surface receptors is reduced
tiation. These receptors use a mechanism (Figure 2–8) closely
(down-regulated), and the cell’s responsiveness to ligand is corre-
resembling that of receptor tyrosine kinases, except that in this
spondingly diminished. A well-understood example is the EGF
case, the protein tyrosine kinase activity is not intrinsic to the
receptor tyrosine kinase, which undergoes rapid endocytosis fol-
receptor molecule. Instead, a separate protein tyrosine kinase,
lowed by proteolysis in lysosomes after EGF binding; genetic
from the Janus-kinase (JAK) family, binds noncovalently to the
mutations that interfere with this process cause excessive growth
receptor. As in the case of the EGF receptor, cytokine receptors
factor-induced cell proliferation and are associated with an
dimerize after they bind the activating ligand, allowing the bound
increased susceptibility to certain types of cancer. Endocytosis of
JAKs to become activated and to phosphorylate tyrosine residues
other receptor tyrosine kinases, most notably receptors for nerve
on the receptor. Phosphorylated tyrosine residues on the receptor’s
growth factor, serves a very different function. Internalized nerve
cytoplasmic surface then set in motion a complex signaling dance
growth factor receptors are not rapidly degraded and are translo-
by binding another set of proteins, called STATs (signal transduc-
cated in endocytic vesicles from the distal axon, where receptors
ers and activators of transcription). The bound STATs are them-
are activated by nerve growth factor released from the innervated
selves phosphorylated by the JAKs, two STAT molecules dimerize
tissue, to the cell body. In the cell body, the growth factor signal is
(attaching to one another’s tyrosine phosphates), and finally the
transduced to transcription factors regulating the expression of
STAT/STAT dimer dissociates from the receptor and travels to the
genes controlling cell survival. This process effectively transports a
nucleus, where it regulates transcription of specific genes.
critical survival signal from its site of release to its site of signaling
effect, and does so over a remarkably long distance—up to 1 meter
in certain sensory neurons. Ligand- and Voltage-Gated Channels
A number of regulators of growth and differentiation, including Many of the most useful drugs in clinical medicine act by mimick-
TGF-β, act on another class of transmembrane receptor enzymes ing or blocking the actions of endogenous ligands that regulate the
that phosphorylate serine and threonine residues. ANP, an impor- flow of ions through plasma membrane channels. The natural
tant regulator of blood volume and vascular tone, acts on a trans- ligands are acetylcholine, serotonin, GABA, and glutamate. All of
membrane receptor whose intracellular domain, a guanylyl cyclase, these agents are synaptic transmitters.
generates cGMP (see below). Receptors in both groups, like the Each of their receptors transmits its signal across the plasma
receptor tyrosine kinases, are active in their dimeric forms. membrane by increasing transmembrane conductance of the
24 SECTION I Basic Principles

Cytokine molecules

+ Cytokine

P~Y Y~P
R R R R

JAK JAK JAK JAK

Y~P
P~Y STAT STAT

Y~P
STAT STAT
P~Y

FIGURE 2–8 Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers. However,
after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of
signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate transcription.

relevant ion and thereby altering the electrical potential across the vascular smooth muscle, producing antiarrhythmic effects and
membrane. For example, acetylcholine causes the opening of the reducing blood pressure without mimicking or antagonizing any
ion channel in the nicotinic acetylcholine receptor (nAChR), known endogenous transmitter.
+
which allows Na to flow down its concentration gradient into
cells, producing a localized excitatory postsynaptic potential—a
Na+
depolarization. ACh ACh
The nAChR is one of the best characterized of all cell-surface δ
receptors for hormones or neurotransmitters (Figure 2–9). One γ
α α
form of this receptor is a pentamer made up of four different
polypeptide subunits (eg, two α chains plus one β, one γ, and one Outside
β
δ chain, all with molecular weights ranging from 43,000 to
50,000). These polypeptides, each of which crosses the lipid
bilayer four times, form a cylindrical structure that is 8 nm in
diameter. When acetylcholine binds to sites on the α subunits, a
conformational change occurs that results in the transient opening
of a central aqueous channel through which sodium ions penetrate
from the extracellular fluid into the cell.
The time elapsed between the binding of the agonist to a
ligand-gated channel and the cellular response can often be mea- Inside
sured in milliseconds. The rapidity of this signaling mechanism is
crucially important for moment-to-moment transfer of informa-
tion across synapses. Ligand-gated ion channels can be regulated Na+
by multiple mechanisms, including phosphorylation and endocy-
tosis. In the central nervous system, these mechanisms contribute
FIGURE 2–9 The nicotinic acetylcholine (ACh) receptor, a ligand-
gated ion channel. The receptor molecule is depicted as embedded
to synaptic plasticity involved in learning and memory. in a rectangular piece of plasma membrane, with extracellular fluid
Voltage-gated ion channels do not bind neurotransmitters above and cytoplasm below. Composed of five subunits (two α, one
directly but are controlled by membrane potential; such channels β, one γ, and one δ), the receptor opens a central transmembrane ion
are also important drug targets. For example, verapamil inhibits channel when ACh binds to sites on the extracellular domain of its α
voltage-gated calcium channels that are present in the heart and in subunits.
 CHAPTER 2 Drug Receptors & Pharmacodynamics 25

G Proteins & Second Messengers original signal. This mechanism also helps explain how signaling
by G proteins produces the phenomenon of spare receptors. The
Many extracellular ligands act by increasing the intracellular con-
family of G proteins contains several functionally diverse sub-
centrations of second messengers such as cyclic adenosine-3′,5′-
families (Table 2–1), each of which mediates effects of a particular
monophosphate (cAMP), calcium ion, or the phosphoinositides
set of receptors to a distinctive group of effectors. Note that an
(described below). In most cases, they use a transmembrane sig-
endogenous ligand (eg, norepinephrine, acetylcholine, serotonin,
naling system with three separate components. First, the extracel-
many others not listed in Table 2–1) may bind and stimulate
lular ligand is selectively detected by a cell-surface receptor. The
receptors that couple to different subsets of G proteins. The appar-
receptor in turn triggers the activation of a G protein located on
ent promiscuity of such a ligand allows it to elicit different G
the cytoplasmic face of the plasma membrane. The activated G
protein-dependent responses in different cells. For instance, the
protein then changes the activity of an effector element, usually an
body responds to danger by using catecholamines (norepinephrine
enzyme or ion channel. This element then changes the concentra-
and epinephrine) both to increase heart rate and to induce con-
tion of the intracellular second messenger. For cAMP, the effector
striction of blood vessels in the skin, by acting on Gs-coupled β
enzyme is adenylyl cyclase, a membrane protein that converts
adrenoceptors and Gq-coupled α1 adrenoceptors, respectively.
intracellular adenosine triphosphate (ATP) to cAMP. The corre-
Ligand promiscuity also offers opportunities in drug development
sponding G protein, Gs, stimulates adenylyl cyclase after being
(see Receptor Classes & Drug Development in the following
activated by hormones and neurotransmitters that act via specific
text).
Gs-coupled receptors. There are many examples of such receptors,
Receptors coupled to G proteins are often called “G protein-
including β adrenoceptors, glucagon receptors, thyrotropin recep-
coupled receptors” (GPCRs), “seven-transmembrane” (7-TM), or
tors, and certain subtypes of dopamine and serotonin receptors.
“serpentine” receptors. GPCRs make up the largest receptor fam-
Gs and other G proteins use a molecular mechanism that
ily and are so-named because the receptor polypeptide chain
involves binding and hydrolysis of GTP (Figure 2–10). This
“snakes” across the plasma membrane seven times (Figure 2–11).
mechanism allows the transduced signal to be amplified. For
Receptors for adrenergic amines, serotonin, acetylcholine (musca-
example, a neurotransmitter such as norepinephrine may encoun-
rinic but not nicotinic), many peptide hormones, odorants, and
ter its membrane receptor for only a few milliseconds. When the
even visual receptors (in retinal rod and cone cells) all belong to
encounter generates a GTP-bound Gs molecule, however, the
the GPCR family. All were derived from a common evolutionary
duration of activation of adenylyl cyclase depends on the longevity
precursor. A few GPCRs (eg, GABAB and metabotropic glutamate
of GTP binding to Gs rather than on the receptor’s affinity for
receptors) require stable assembly into either homodimers (com-
norepinephrine. Indeed, like other G proteins, GTP-bound Gs
plexes of two identical receptor polypeptides) or heterodimers
may remain active for tens of seconds, enormously amplifying the
(complexes of different isoforms) for functional activity. However,
in contrast to tyrosine kinase and cytokine receptors, most GPCRs
are thought to be able to function as monomers.
All GPCRs transduce signals across the plasma membrane in
Agonist essentially the same way. Often the agonist ligand—eg, a cate-
cholamine or acetylcholine—is bound in a pocket enclosed by
the transmembrane regions of the receptor (as in Figure 2–11).
R R* The resulting change in conformation of these regions is trans-
GTP
mitted to cytoplasmic loops of the receptor, which in turn acti-
E vate the appropriate G protein by promoting replacement of
GDP GDP by GTP, as described above. Amino acids in the third cyto-
G–GDP G–GTP plasmic loop of the GPCR polypeptide are generally thought to
play a key role in mediating receptor interaction with G proteins
(shown by arrows in Figure 2–11). The structural basis for ligand
E*
binding to β adrenoceptors was determined recently using X-ray
crystallography.
Pi

Receptor Regulation
FIGURE 2–10 The guanine nucleotide-dependent activation- G protein-mediated responses to drugs and hormonal agonists often
inactivation cycle of G proteins. The agonist activates the receptor
attenuate with time (Figure 2–12, top). After reaching an initial
(R→R*), which promotes release of GDP from the G protein (G),
allowing entry of GTP into the nucleotide binding site. In its GTP-
high level, the response (eg, cellular cAMP accumulation, Na+
bound state (GGTP), the G protein regulates activity of an effector influx, contractility, etc) diminishes over seconds or minutes, even
enzyme or ion channel (E→E*). The signal is terminated by hydrolysis in the continued presence of the agonist. This “desensitization” is
of GTP, followed by return of the system to the basal unstimulated often rapidly reversible; a second exposure to agonist, if provided a
state. Open arrows denote regulatory effects. (Pi, inorganic few minutes after termination of the first exposure, results in a
phosphate.) response similar to the initial response.
26 SECTION I Basic Principles

TABLE 2–1 G proteins and their receptors and effectors.

G Protein Receptors for Effector/Signaling Pathway

Gs β-Adrenergic amines, glucagon, histamine, serotonin, and many ↑ Adenylyl cyclase →↑ cAMP
other hormones
Gi1, Gi2, Gi3 α2-Adrenergic amines, acetylcholine (muscarinic), opioids, sero- Several, including:
tonin, and many others ↓ Adenylyl cyclase →↓ cAMP
+
Open cardiac K channels →↓ heart rate
Golf Odorants (olfactory epithelium) ↑ Adenylyl cyclase →↑ cAMP
Go Neurotransmitters in brain (not yet specifically identified) Not yet clear
Gq Acetylcholine (muscarinic), bombesin, serotonin (5-HT2), and ↑ Phospholipase C →↑ IP3, diacylglycerol, cytoplasmic Ca2+
many others
Gt1, Gt2 Photons (rhodopsin and color opsins in retinal rod and cone cells) ↑ cGMP phosphodiesterase →↓ cGMP (phototransduction)
cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate.

Many GPCRs are regulated by phosphorylation, as illustrated terminal tail (Figure 2-12, panel B). The presence of phosphoser-
by rapid desensitization of the β adrenoceptor. The agonist-induced ines increases the receptor’s affinity for binding a third protein,
change in conformation of the receptor causes it to bind, activate, β-arrestin. Binding of β-arrestin to cytoplasmic loops of the recep-
and serve as a substrate for a family of specific receptor kinases, tor diminishes the receptor’s ability to interact with Gs, thereby
called G protein-coupled receptor kinases (GRKs). The activated reducing the agonist response (ie, stimulation of adenylyl cyclase).
GRK then phosphorylates serine residues in the receptor’s carboxyl Upon removal of agonist, GRK activation is terminated, and the
desensitization process can be reversed by cellular phosphatases.
For β adrenoceptors, and many other GPCRs, β-arrestin bind-
ing also accelerates endocytosis of receptors from the plasma
Agonist membrane. Endocytosis of receptors promotes their dephosphory-
lation by a receptor phosphatase that is present at high concentra-
tion on endosome membranes, and receptors then return to the
Outside plasma membrane. This helps explain the ability of cells to recover
N
receptor-mediated signaling responsiveness very efficiently after
II
agonist-induced desensitization. Several GPCRs—including
I
III β adrenoceptors if persistently activated—instead traffic to lyso-
VII
Ag IV
somes after endocytosis and are degraded. This process effectively
VI V attenuates (rather than restores) cellular responsiveness, similar to
the process of down-regulation described above for the epidermal
Inside growth factor receptor. Thus, depending on the particular receptor
HO C and duration of activation, endocytosis can contribute to either
G
OH protein
rapid recovery or prolonged attenuation of cellular responsiveness
OH OH (Figure 2–12).

FIGURE 2–11 Transmembrane topology of a typical “serpen- Well-Established Second Messengers

tine” GPCR. The receptor’s amino (N) terminal is extracellular (above
the plane of the membrane), and its carboxyl (C) terminal intracellu- A. Cyclic Adenosine Monophosphate (cAMP)
lar. The terminals are connected by a polypeptide chain that tra- Acting as an intracellular second messenger, cAMP mediates such
verses the plane of the membrane seven times. The hydrophobic hormonal responses as the mobilization of stored energy (the
transmembrane segments (light color) are designated by Roman breakdown of carbohydrates in liver or triglycerides in fat cells
numerals (I–VII). The agonist (Ag) approaches the receptor from the
stimulated by β-adrenomimetic catecholamines), conservation of
extracellular fluid and binds to a site surrounded by the transmem- 2+
water by the kidney (mediated by vasopressin), Ca homeostasis
brane regions of the receptor protein. G proteins interact with cyto-
plasmic regions of the receptor, especially with portions of the third
(regulated by parathyroid hormone), and increased rate and con-
cytoplasmic loop between transmembrane regions V and VI. The tractile force of heart muscle (β-adrenomimetic catecholamines).
receptor’s cytoplasmic terminal tail contains numerous serine and It also regulates the production of adrenal and sex steroids (in
threonine residues whose hydroxyl (-OH) groups can be phosphory- response to corticotropin or follicle-stimulating hormone), relax-
lated. This phosphorylation may be associated with diminished ation of smooth muscle, and many other endocrine and neural
receptor-G protein interaction. processes.
 CHAPTER 2 Drug Receptors & Pharmacodynamics 27

A Agonist

Response
(cAMP)

1 2 3 4 5 1 2

Time

B Agonist in extracellular space

1 2
-OH -OH
GRK
-OH -OH
ATP
-OH -OH Coated pit
P P
P
GS
5 β−Arr
3

4
6 Lysosome
P'ase

-OH P
-OH
Endosomes P
-OH

FIGURE 2–12 Rapid desensitization, resensitization, and down-regulation of β adrenoceptors. A: Response to a β-adrenoceptor agonist
(ordinate) versus time (abscissa). (Numbers refer to the phases of receptor function in B.) Exposure of cells to agonist (indicated by the
light-colored bar) produces a cyclic AMP response. A reduced cAMP response is observed in the continued presence of agonist; this “desensiti-
zation” typically occurs within a few minutes. If agonist is removed after a short time (typically several to tens of minutes, indicated by broken
line on abscissa), cells recover full responsiveness to a subsequent addition of agonist (second light-colored bar). This “resensitization” fails to
occur, or occurs incompletely, if cells are exposed to agonist repeatedly or over a more prolonged time period. B: Agonist binding to receptors
initiates signaling by promoting receptor interaction with G proteins (Gs) located in the cytoplasm (step 1 in the diagram). Agonist-activated
receptors are phosphorylated by a G protein-coupled receptor kinase (GRK), preventing receptor interaction with Gs and promoting binding of
a different protein, β-arrestin (β-Arr), to the receptor (step 2). The receptor-arrestin complex binds to coated pits, promoting receptor internal-
ization (step 3). Dissociation of agonist from internalized receptors reduces β-Arr binding affinity, allowing dephosphorylation of receptors by a
phosphatase (P’ase, step 4) and return of receptors to the plasma membrane (step 5); together, these events result in the efficient resensitiza-
tion of cellular responsiveness. Repeated or prolonged exposure of cells to agonist favors the delivery of internalized receptors to lysosomes
(step 6), promoting receptor down-regulation rather than resensitization.
28 SECTION I Basic Principles

Agonist Agonist

R G PLC PIP2 Membrane

Gs AC Membrane DAG

Rec IP3
PK-C *
ATP cAMP 5'-AMP
ATP ADP
Ca2+
PDE CaM S S~P
R2 cAMP4
R2C2 Pi

2C * E CaM-E *
ATP ADP

S S~P Response

Pi
2+
P'ase
FIGURE 2–14 The Ca -phosphoinositide signaling pathway.
Key proteins include hormone receptors (R), a G protein (G), a
phosphoinositide-specific phospholipase C (PLC), protein kinase C
Response substrates of the kinase (S), calmodulin (CaM), and calmodulin-
binding enzymes (E), including kinases, phosphodiesterases, etc.
(PIP2, phosphatidylinositol-4,5-bisphosphate; DAG, diacylglycerol; IP3,
FIGURE 2–13 The cAMP second messenger pathway. Key
inositol trisphosphate. Asterisk denotes activated state. Open arrows
proteins include hormone receptors (Rec), a stimulatory G protein
denote regulatory effects.)
(Gs), catalytic adenylyl cyclase (AC), phosphodiesterases (PDE) that
hydrolyze cAMP, cAMP-dependent kinases, with regulatory (R) and
catalytic (C) subunits, protein substrates (S) of the kinases, and
phosphatases (P’ase), which remove phosphates from substrate
proteins. Open arrows denote regulatory effects.
B. Phosphoinositides and Calcium
Another well-studied second messenger system involves hormonal
stimulation of phosphoinositide hydrolysis (Figure 2–14). Some
of the hormones, neurotransmitters, and growth factors that trig-
cAMP exerts most of its effects by stimulating cAMP-dependent ger this pathway bind to receptors linked to G proteins, whereas
protein kinases (Figure 2–13). These kinases are composed of a others bind to receptor tyrosine kinases. In all cases, the crucial
cAMP-binding regulatory (R) dimer and two catalytic (C) chains. step is stimulation of a membrane enzyme, phospholipase C (PLC),
When cAMP binds to the R dimer, active C chains are released to which splits a minor phospholipid component of the plasma
diffuse through the cytoplasm and nucleus, where they transfer membrane, phosphatidylinositol-4,5-bisphosphate (PIP2), into
phosphate from ATP to appropriate substrate proteins, often two second messengers, diacylglycerol (DAG) and inositol-
enzymes. The specificity of the regulatory effects of cAMP resides 1,4,5-trisphosphate (IP3 or InsP3). Diacylglycerol is confined to
in the distinct protein substrates of the kinases that are expressed the membrane, where it activates a phospholipid- and calcium-
in different cells. For example, liver is rich in phosphorylase kinase sensitive protein kinase called protein kinase C. IP3 is water-solu-
and glycogen synthase, enzymes whose reciprocal regulation by ble and diffuses through the cytoplasm to trigger release of Ca2+
cAMP-dependent phosphorylation governs carbohydrate storage by binding to ligand-gated calcium channels in the limiting mem-
2+
and release. branes of internal storage vesicles. Elevated cytoplasmic Ca
When the hormonal stimulus stops, the intracellular actions of concentration resulting from IP3-promoted opening of these
2+
cAMP are terminated by an elaborate series of enzymes. cAMP- channels promotes the binding of Ca to the calcium-binding
stimulated phosphorylation of enzyme substrates is rapidly protein calmodulin, which regulates activities of other enzymes,
reversed by a diverse group of specific and nonspecific phos- including calcium-dependent protein kinases.
phatases. cAMP itself is degraded to 5′-AMP by several cyclic With its multiple second messengers and protein kinases, the
nucleotide phosphodiesterases (PDE; Figure 2–13). Milrinone, a phosphoinositide signaling pathway is much more complex than
selective inhibitor of type 3 phosphodiesterases that are expressed the cAMP pathway. For example, different cell types may con-
in cardiac muscle cells, has been used as an adjunctive agent in tain one or more specialized calcium- and calmodulin-dependent
treating acute heart failure. Competitive inhibition of cAMP deg- kinases with limited substrate specificity (eg, myosin light-chain
radation is one way that caffeine, theophylline, and other meth- kinase) in addition to a general calcium- and calmodulin-
ylxanthines produce their effects (see Chapter 20). dependent kinase that can phosphorylate a wide variety of protein
 CHAPTER 2 Drug Receptors & Pharmacodynamics 29

substrates. Furthermore, at least nine structurally distinct types of Phosphorylation: A Common Theme
protein kinase C have been identified.
Almost all second messenger signaling involves reversible phos-
As in the cAMP system, multiple mechanisms damp or termi-
phorylation, which performs two principal functions in signaling:
nate signaling by this pathway. IP3 is inactivated by dephosphory-
amplification and flexible regulation. In amplification, rather like
lation; diacylglycerol is either phosphorylated to yield phosphatidic
GTP bound to a G protein, the attachment of a phosphoryl group
acid, which is then converted back into phospholipids, or it is
to a serine, threonine, or tyrosine residue powerfully amplifies the
deacylated to yield arachidonic acid; Ca2+ is actively removed from
2+ initial regulatory signal by recording a molecular memory that the
the cytoplasm by Ca pumps.
pathway has been activated; dephosphorylation erases the mem-
These and other nonreceptor elements of the calcium-phos-
ory, taking a longer time to do so than is required for dissociation
phoinositide signaling pathway are of considerable importance in
of an allosteric ligand. In flexible regulation, differing substrate
pharmacotherapy. For example, lithium ion, used in treatment of
specificities of the multiple protein kinases regulated by second
bipolar (manic-depressive) disorder, affects the cellular metabo-
messengers provide branch points in signaling pathways that may
lism of phosphoinositides (see Chapter 29). 2+
be independently regulated. In this way, cAMP, Ca , or other
second messengers can use the presence or absence of particular
C. Cyclic Guanosine Monophosphate (cGMP)
kinases or kinase substrates to produce quite different effects in
Unlike cAMP, the ubiquitous and versatile carrier of diverse mes- different cell types. Inhibitors of protein kinases have great poten-
sages, cGMP has established signaling roles in only a few cell tial as therapeutic agents, particularly in neoplastic diseases.
types. In intestinal mucosa and vascular smooth muscle, the Trastuzumab, an antibody that antagonizes growth factor receptor
cGMP-based signal transduction mechanism closely parallels the signaling (discussed earlier), is a useful therapeutic agent for breast
cAMP-mediated signaling mechanism. Ligands detected by cell- cancer. Another example of this general approach is imatinib, a
surface receptors stimulate membrane-bound guanylyl cyclase to small molecule inhibitor of the cytoplasmic tyrosine kinase Abl,
produce cGMP, and cGMP acts by stimulating a cGMP-dependent which is activated by growth factor signaling pathways. Imatinib
protein kinase. The actions of cGMP in these cells are terminated is effective for treating chronic myelogenous leukemia, which is
by enzymatic degradation of the cyclic nucleotide and by dephos- caused by a chromosomal translocation event that produces an
phorylation of kinase substrates. active Bcr/Abl fusion protein in hematopoietic cells.
Increased cGMP concentration causes relaxation of vascular
smooth muscle by a kinase-mediated mechanism that results in
dephosphorylation of myosin light chains (see Figure 12–2). In
these smooth muscle cells, cGMP synthesis can be elevated by two RECEPTOR CLASSES &
transmembrane signaling mechanisms utilizing two different gua- DRUG DEVELOPMENT
nylyl cyclases. Atrial natriuretic peptide, a blood-borne peptide
hormone, stimulates a transmembrane receptor by binding to its The existence of a specific drug receptor is usually inferred from
extracellular domain, thereby activating the guanylyl cyclase activ- studying the structure-activity relationship of a group of struc-
ity that resides in the receptor’s intracellular domain. The other turally similar congeners of the drug that mimic or antagonize its
mechanism mediates responses to nitric oxide (NO; see Chapter effects. Thus, if a series of related agonists exhibits identical rela-
19), which is generated in vascular endothelial cells in response to tive potencies in producing two distinct effects, it is likely that the
natural vasodilator agents such as acetylcholine and histamine. two effects are mediated by similar or identical receptor molecules.
After entering the target cell, nitric oxide binds to and activates a In addition, if identical receptors mediate both effects, a competi-
cytoplasmic guanylyl cyclase (see Figure 19–2). A number of use- tive antagonist will inhibit both responses with the same Ki; a
ful vasodilating drugs, such as nitroglycerin and sodium nitroprus- second competitive antagonist will inhibit both responses with its
side used in treating cardiac ischemia and acute hypertension, act own characteristic Ki. Thus, studies of the relation between struc-
by generating or mimicking nitric oxide. Other drugs produce ture and activity of a series of agonists and antagonists can identify
vasodilation by inhibiting specific phosphodiesterases, thereby a species of receptor that mediates a set of pharmacologic
interfering with the metabolic breakdown of cGMP. One such responses.
drug is sildenafil, used in treating erectile dysfunction and pulmo- Exactly the same experimental procedure can show that
nary hypertension (see Chapter 12). observed effects of a drug are mediated by different receptors. In
this case, effects mediated by different receptors may exhibit dif-
ferent orders of potency among agonists and different Ki values for
Interplay among Signaling Mechanisms each competitive antagonist.
The calcium-phosphoinositide and cAMP signaling pathways Wherever we look, evolution has created many different recep-
oppose one another in some cells and are complementary in oth- tors that function to mediate responses to any individual chemical
ers. For example, vasopressor agents that contract smooth muscle signal. In some cases, the same chemical acts on completely differ-
act by IP3-mediated mobilization of Ca2+, whereas agents that ent structural receptor classes. For example, acetylcholine uses
relax smooth muscle often act by elevation of cAMP. In contrast, ligand-gated ion channels (nicotinic AChRs) to initiate a fast (in
cAMP and phosphoinositide second messengers act together to milliseconds) excitatory postsynaptic potential (EPSP) in postgan-
stimulate glucose release from the liver. glionic neurons. Acetylcholine also activates a separate class of G
30 SECTION I Basic Principles

protein-coupled receptors (muscarinic AChRs), which mediate

slower (seconds to minutes) modulatory effects on the same neurons.
In addition, each structural class usually includes multiple subtypes of A
receptor, often with significantly different signaling or regulatory C
properties. For example, many biogenic amines (eg, norepinephrine, D
acetylcholine, and serotonin) activate more than one receptor, each of
which may activate a different G protein, as previously described (see

Response
also Table 2–1). The existence of many receptor classes and subtypes
for the same endogenous ligand has created important opportunities B
for drug development. For example, propranolol, a selective antago-
nist of β adrenoceptors, can reduce an accelerated heart rate without
preventing the sympathetic nervous system from causing vasocon-
striction, an effect mediated by α1 receptors.
The principle of drug selectivity may even apply to structurally
identical receptors expressed in different cells, eg, receptors for
steroids such as estrogen (Figure 2–6). Different cell types express Log drug dose
different accessory proteins, which interact with steroid receptors
and change the functional effects of drug-receptor interaction. For FIGURE 2–15 Graded dose-response curves for four drugs, illus-
example, tamoxifen acts as an antagonist on estrogen receptors trating different pharmacologic potencies and different maximal effi-
expressed in mammary tissue but as an agonist on estrogen recep- cacies. (See text.)
tors in bone. Consequently, tamoxifen may be useful not only in
the treatment and prophylaxis of breast cancer but also in the
prevention of osteoporosis by increasing bone density (see
Chapters 40 and 42). Tamoxifen may also create complications in potency and maximal efficacy of the drugs in relation to the
postmenopausal women, however, by exerting an agonist action in desired therapeutic effect. These two important terms, often con-
the uterus, stimulating endometrial cell proliferation. fusing to students and clinicians, can be explained by referring to
New drug development is not confined to agents that act on Figure 2–15, which depicts graded dose-response curves that relate
receptors for extracellular chemical signals. Increasingly, pharma- the dose of four different drugs to the magnitude of a particular
ceutical chemists are determining whether elements of signaling therapeutic effect.
pathways distal to the receptors may also serve as targets of selec-
tive and useful drugs. We have already discussed drugs that act on 1. Potency—Drugs A and B are said to be more potent than
phosphodiesterase and some intracellular kinases. There are several drugs C and D because of the relative positions of their dose-re-
additional kinase inhibitors presently in clinical trials, as well as sponse curves along the dose axis of Figure 2–15. Potency refers
preclinical efforts directed at developing inhibitors of G proteins. to the concentration (EC50) or dose (ED50) of a drug required to
produce 50% of that drug’s maximal effect. Thus, the pharmaco-
logic potency of drug A in Figure 2–15 is less than that of drug B,
RELATION BETWEEN DRUG DOSE & a partial agonist because the EC50 of A is greater than the EC50 of
B. Potency of a drug depends in part on the affinity (Kd) of recep-
CLINICAL RESPONSE tors for binding the drug and in part on the efficiency with which
We have dealt with receptors as molecules and shown how receptors drug-receptor interaction is coupled to response. Note that some
can quantitatively account for the relation between dose or concen- doses of drug A can produce larger effects than any dose of drug
tration of a drug and pharmacologic responses, at least in an ideal- B, despite the fact that we describe drug B as pharmacologically
ized system. When faced with a patient who needs treatment, the more potent. The reason for this is that drug A has a larger maxi-
prescriber must make a choice among a variety of possible drugs and mal efficacy (as described below).
devise a dosage regimen that is likely to produce maximal benefit For clinical use, it is important to distinguish between a drug’s
and minimal toxicity. To make rational therapeutic decisions, the potency and its efficacy. The clinical effectiveness of a drug
prescriber must understand how drug-receptor interactions underlie depends not on its potency (EC50), but on its maximal efficacy
the relations between dose and response in patients, the nature and (see below) and its ability to reach the relevant receptors. This
causes of variation in pharmacologic responsiveness, and the clinical ability can depend on its route of administration, absorption,
implications of selectivity of drug action. distribution through the body, and clearance from the blood or
site of action. In deciding which of two drugs to administer to a
patient, the prescriber must usually consider their relative effec-
Dose & Response in Patients tiveness rather than their relative potency. Pharmacologic potency
A. Graded Dose-Response Relations can largely determine the administered dose of the chosen drug.
To choose among drugs and to determine appropriate doses of a For therapeutic purposes, the potency of a drug should be
drug, the prescriber must know the relative pharmacologic stated in dosage units, usually in terms of a particular therapeutic
 CHAPTER 2 Drug Receptors & Pharmacodynamics 31

end point (eg, 50 mg for mild sedation, 1 mcg/kg/min for an

increase in heart rate of 25 bpm). Relative potency, the ratio of Cumulative percent Cumulative percent
equi-effective doses (0.2, 10, etc), may be used in comparing one 100 exhibiting dead at each dose
therapeutic effect
drug with another.

Percent individuals responding

2. Maximal efficacy—This parameter reflects the limit of the
dose-response relation on the response axis. Drugs A, C, and D
in Figure 2–15 have equal maximal efficacy, and all have greater
maximal efficacy than drug B. The maximal efficacy (sometimes 50
referred to simply as efficacy) of a drug is obviously crucial for
Percent
making clinical decisions when a large response is needed. It may Percent requiring requiring
be determined by the drug’s mode of interactions with receptors dose to achieve dose for a
∗ desired effect lethal effect
(as with partial agonists or by characteristics of the receptor-effec-
tor system involved.
Thus, diuretics that act on one portion of the nephron may
produce much greater excretion of fluid and electrolytes than
1.25 2.5 5 10 20 40 80 160 320 640
diuretics that act elsewhere. In addition, the practical efficacy of a Dose (mg)
drug for achieving a therapeutic end point (eg, increased cardiac ED50 LD50
contractility) may be limited by the drug’s propensity to cause a
toxic effect (eg, fatal cardiac arrhythmia) even if the drug could FIGURE 2–16 Quantal dose-effect plots. Shaded boxes (and the
otherwise produce a greater therapeutic effect. accompanying bell-shaped curves) indicate the frequency distribu-
tion of doses of drug required to produce a specified effect; that is,
B. Shape of Dose-Response Curves the percentage of animals that required a particular dose to exhibit
the effect. The open boxes (and the corresponding colored curves)
Although the responses depicted in curves A, B, and C of Figure
indicate the cumulative frequency distribution of responses, which
2–15 approximate the shape of a simple Michaelis-Menten rela- are lognormally distributed.
tion (transformed to a logarithmic plot), some clinical responses
do not. Extremely steep dose-response curves (eg, curve D) may
have important clinical consequences if the upper portion of the
curve represents an undesirable extent of response (eg, coma Some of these difficulties may be avoided by determining the
caused by a sedative-hypnotic). Steep dose-response curves in dose of drug required to produce a specified magnitude of effect
patients can result from cooperative interactions of several differ- in a large number of individual patients or experimental animals
ent actions of a drug (eg, effects on brain, heart, and peripheral and plotting the cumulative frequency distribution of responders
vessels, all contributing to lowering of blood pressure). versus the log dose (Figure 2–16). The specified quantal effect may
be chosen on the basis of clinical relevance (eg, relief of headache)
C. Quantal Dose-Effect Curves or for preservation of safety of experimental subjects (eg, using low
Graded dose-response curves of the sort described above have doses of a cardiac stimulant and specifying an increase in heart rate
certain limitations in their application to clinical decision making. of 20 bpm as the quantal effect), or it may be an inherently quan-
For example, such curves may be impossible to construct if the tal event (eg, death of an experimental animal). For most drugs,
pharmacologic response is an either-or (quantal) event, such as the doses required to produce a specified quantal effect in indi-
prevention of convulsions, arrhythmia, or death. Furthermore, the viduals are lognormally distributed; that is, a frequency distribu-
tion of such responses plotted against the log of the dose produces
clinical relevance of a quantitative dose-response relation in a
single patient, no matter how precisely defined, may be limited in a gaussian normal curve of variation (colored areas, Figure 2–16).
application to other patients, owing to the great potential vari- When these responses are summated, the resulting cumulative
frequency distribution constitutes a quantal dose-effect curve (or
ability among patients in severity of disease and responsiveness to
drugs. dose-percent curve) of the proportion or percentage of individuals
who exhibit the effect plotted as a function of log dose.
The quantal dose-effect curve is often characterized by stating
the median effective dose (ED50), which is the dose at which
∗
Note that “maximal efficacy,” used in a therapeutic context, does not 50% of individuals exhibit the specified quantal effect. (Note that
have exactly the same meaning that the term denotes in the more spe- the abbreviation ED50 has a different meaning in this context from
cialized context of drug-receptor interactions described earlier in this its meaning in relation to graded dose-effect curves, described in
chapter. In an idealized in vitro system, efficacy denotes the relative
maximal efficacy of agonists and partial agonists that act via the same previous text). Similarly, the dose required to produce a particular
receptor. In therapeutics, efficacy denotes the extent or degree of an toxic effect in 50% of animals is called the median toxic dose
effect that can be achieved in the intact patient. Thus, therapeutic effi- (TD50). If the toxic effect is death of the animal, a median lethal
cacy may be affected by the characteristics of a particular drug-receptor
interaction, but it also depends on a host of other factors as noted in the dose (LD50) may be experimentally defined. Such values provide
text. a convenient way of comparing the potencies of drugs in
32 SECTION I Basic Principles

experimental and clinical settings: Thus, if the ED50s of two drugs may change during the course of therapy; in these cases, responsive-
for producing a specified quantal effect are 5 and 500 mg, respec- ness usually decreases as a consequence of continued drug adminis-
tively, then the first drug can be said to be 100 times more potent tration, producing a state of relative tolerance to the drug’s effects.
than the second for that particular effect. Similarly, one can obtain When responsiveness diminishes rapidly after administration of a
a valuable index of the selectivity of a drug’s action by comparing drug, the response is said to be subject to tachyphylaxis.
its ED50s for two different quantal effects in a population (eg, Even before administering the first dose of a drug, the pre-
cough suppression versus sedation for opioid drugs). scriber should consider factors that may help in predicting the
Quantal dose-effect curves may also be used to generate informa- direction and extent of possible variations in responsiveness. These
tion regarding the margin of safety to be expected from a particular include the propensity of a particular drug to produce tolerance or
drug used to produce a specified effect. One measure, which relates tachyphylaxis as well as the effects of age, sex, body size, disease
the dose of a drug required to produce a desired effect to that which state, genetic factors, and simultaneous administration of other
produces an undesired effect, is the therapeutic index. In animal drugs.
studies, the therapeutic index is usually defined as the ratio of the Four general mechanisms may contribute to variation in drug
TD50 to the ED50 for some therapeutically relevant effect. The pre- responsiveness among patients or within an individual patient at
cision possible in animal experiments may make it useful to use such different times.
a therapeutic index to estimate the potential benefit of a drug in
humans. Of course, the therapeutic index of a drug in humans is A. Alteration in Concentration of Drug That Reaches
almost never known with real precision; instead, drug trials and the Receptor
accumulated clinical experience often reveal a range of usually effec- Patients may differ in the rate of absorption of a drug, in distribut-
tive doses and a different (but sometimes overlapping) range of ing it through body compartments, or in clearing the drug from
possibly toxic doses. The clinically acceptable risk of toxicity the blood (see Chapter 3). By altering the concentration of drug
depends critically on the severity of the disease being treated. For that reaches relevant receptors, such pharmacokinetic differences
example, the dose range that provides relief from an ordinary head- may alter the clinical response. Some differences can be predicted
ache in the majority of patients should be very much lower than the on the basis of age, weight, sex, disease state, and liver and kidney
dose range that produces serious toxicity, even if the toxicity occurs function, and by testing specifically for genetic differences that
in a small minority of patients. However, for treatment of a lethal may result from inheritance of a functionally distinctive comple-
disease such as Hodgkin’s lymphoma, the acceptable difference ment of drug-metabolizing enzymes (see Chapters 3 and 4).
between therapeutic and toxic doses may be smaller. Another important mechanism influencing drug availability is
Finally, note that the quantal dose-effect curve and the graded active transport of drug from the cytoplasm, mediated by a family
dose-response curve summarize somewhat different sets of infor- of membrane transporters encoded by the so-called multidrug
mation, although both appear sigmoid in shape on a semilogarith- resistance (MDR) genes. For example, up-regulation of MDR
mic plot (compare Figures 2–15 and 2–16). Critical information gene-encoded transporter expression is a major mechanism by
required for making rational therapeutic decisions can be obtained which tumor cells develop resistance to anticancer drugs.
from each type of curve. Both curves provide information regard-
ing the potency and selectivity of drugs; the graded dose-response B. Variation in Concentration of an Endogenous
curve indicates the maximal efficacy of a drug, and the quantal Receptor Ligand
dose-effect curve indicates the potential variability of responsive-
This mechanism contributes greatly to variability in responses to
ness among individuals.
pharmacologic antagonists. Thus, propranolol, a β-adrenoceptor
antagonist, markedly slows the heart rate of a patient whose
Variation in Drug Responsiveness endogenous catecholamines are elevated (as in pheochromocy-
Individuals may vary considerably in their response to a drug; toma) but does not affect the resting heart rate of a well-trained
indeed, a single individual may respond differently to the same marathon runner. A partial agonist may exhibit even more dra-
drug at different times during the course of treatment. Occasionally, matically different responses: Saralasin, a weak partial agonist at
individuals exhibit an unusual or idiosyncratic drug response, angiotensin II receptors, lowers blood pressure in patients with
one that is infrequently observed in most patients. The idiosyn- hypertension caused by increased angiotensin II production and
cratic responses are usually caused by genetic differences in raises blood pressure in patients who produce normal amounts of
metabolism of the drug or by immunologic mechanisms, includ- angiotensin.
ing allergic reactions.
Quantitative variations in drug response are in general more C. Alterations in Number or Function of Receptors
common and more clinically important. An individual patient is Experimental studies have documented changes in drug response
hyporeactive or hyperreactive to a drug in that the intensity of caused by increases or decreases in the number of receptor sites or
effect of a given dose of drug is diminished or increased compared by alterations in the efficiency of coupling of receptors to distal
with the effect seen in most individuals. (Note: The term hypersen- effector mechanisms. In some cases, the change in receptor num-
sitivity usually refers to allergic or other immunologic responses to ber is caused by other hormones; for example, thyroid hormones
drugs.) With some drugs, the intensity of response to a given dose increase both the number of β receptors in rat heart muscle and
 CHAPTER 2 Drug Receptors & Pharmacodynamics 33

cardiac sensitivity to catecholamines. Similar changes probably Before initiating therapy with a drug, the prescriber should be
contribute to the tachycardia of thyrotoxicosis in patients and may aware of patient characteristics that may limit the clinical response.
account for the usefulness of propranolol, a β-adrenoceptor These characteristics include the age and general health of the
antagonist, in ameliorating symptoms of this disease. patient and—most importantly—the severity and pathophysio-
In other cases, the agonist ligand itself induces a decrease in the logic mechanism of the disease. The most important potential
number (eg, down-regulation) or coupling efficiency (eg, desensiti- cause of failure to achieve a satisfactory response is that the diag-
zation) of its receptors. These mechanisms (discussed previously nosis is wrong or physiologically incomplete. Drug therapy is
under Signaling Mechanisms & Drug Actions) may contribute to always most successful when it is accurately directed at the
two clinically important phenomena: first, tachyphylaxis or toler- pathophysiologic mechanism responsible for the disease.
ance to the effects of some drugs (eg, biogenic amines and their When the diagnosis is correct and the drug is appropriate, an
congeners), and second, the “overshoot” phenomena that follow unsatisfactory therapeutic response can often be traced to com-
withdrawal of certain drugs. These phenomena can occur with pensatory mechanisms in the patient that respond to and oppose
either agonists or antagonists. An antagonist may increase the the beneficial effects of the drug. Compensatory increases in sym-
number of receptors in a critical cell or tissue by preventing down- pathetic nervous tone and fluid retention by the kidney, for
regulation caused by an endogenous agonist. When the antagonist example, can contribute to tolerance to antihypertensive effects of
is withdrawn, the elevated number of receptors can produce an a vasodilator drug. In such cases, additional drugs may be required
exaggerated response to physiologic concentrations of agonist. to achieve a useful therapeutic result.
Potentially disastrous withdrawal symptoms can result for the oppo-
site reason when administration of an agonist drug is discontinued. Clinical Selectivity: Beneficial versus Toxic
In this situation, the number of receptors, which has been decreased
by drug-induced down-regulation, is too low for endogenous ago-
Effects of Drugs
nist to produce effective stimulation. For example, the withdrawal Although we classify drugs according to their principal actions, it
of clonidine (a drug whose α2-adrenoceptor agonist activity reduces is clear that no drug causes only a single, specific effect. Why is this
blood pressure) can produce hypertensive crisis, probably because so? It is exceedingly unlikely that any kind of drug molecule will
the drug down-regulates α2 adrenoceptors (see Chapter 11). bind to only a single type of receptor molecule, if only because
Genetic factors also can play an important role in altering the the number of potential receptors in every patient is astronomi-
number or function of specific receptors. For example, a specific cally large. Even if the chemical structure of a drug allowed it to
genetic variant of the α2C adrenoceptor—when inherited together bind to only one kind of receptor, the biochemical processes
with a specific variant of the α1 adrenoceptor—confers increased controlled by such receptors would take place in many cell types
risk for developing heart failure, which may be reduced by early and would be coupled to many other biochemical functions; as a
intervention using antagonist drugs. The identification of such result, the patient and the prescriber would probably perceive
genetic factors, part of the rapidly developing field of pharmaco- more than one drug effect. Accordingly, drugs are only selective—
genetics, holds promise for clinical diagnosis and in the future rather than specific—in their actions, because they bind to one or
may help physicians design the most appropriate pharmacologic a few types of receptor more tightly than to others and because
therapy for individual patients. these receptors control discrete processes that result in distinct
Another interesting example of genetic determination of effects effects.
on drug response is seen in the treatment of cancers involving It is only because of their selectivity that drugs are useful in
excessive growth factor signaling. Somatic mutations affecting the clinical medicine. Selectivity can be measured by comparing bind-
tyrosine kinase domain of the epidermal growth factor receptor ing affinities of a drug to different receptors or by comparing ED50s
confer enhanced sensitivity to kinase inhibitors such as gefitinib in for different effects of a drug in vivo. In drug development and in
certain lung cancers. This effect enhances the antineoplastic effect clinical medicine, selectivity is usually considered by separating
of the drug and, because the somatic mutation is specific to the effects into two categories: beneficial or therapeutic effects ver-
tumor and not present in the host, the therapeutic index of these sus toxic or adverse effects. Pharmaceutical advertisements and
drugs can be significantly enhanced in patients whose tumors prescribers occasionally use the term side effect, implying that the
harbor such mutations. effect in question is insignificant or occurs via a pathway that is to
one side of the principal action of the drug; such implications are
frequently erroneous.
D. Changes in Components of Response Distal
to the Receptor A. Beneficial and Toxic Effects Mediated by the Same
Although a drug initiates its actions by binding to receptors, the Receptor-Effector Mechanism
response observed in a patient depends on the functional integrity Much of the serious drug toxicity in clinical practice represents a
of biochemical processes in the responding cell and physiologic direct pharmacologic extension of the therapeutic actions of the
regulation by interacting organ systems. Clinically, changes in drug. In some of these cases (eg, bleeding caused by anticoagulant
these postreceptor processes represent the largest and most impor- therapy; hypoglycemic coma due to insulin), toxicity may be
tant class of mechanisms that cause variation in responsiveness to avoided by judicious management of the dose of drug adminis-
drug therapy. tered, guided by careful monitoring of effect (measurements of
34 SECTION I Basic Principles

blood coagulation or serum glucose) and aided by ancillary mea- context. Examples include quinidine, the sulfonylureas, thiazide
sures (avoiding tissue trauma that may lead to hemorrhage; regula- diuretics, tricyclic antidepressants, opioid drugs, and phenothiaz-
tion of carbohydrate intake). In still other cases, the toxicity may ine antipsychotics. Often the new agents turn out to interact with
be avoided by not administering the drug at all, if the therapeutic receptors for endogenous substances (eg, opioids and phenothiaz-
indication is weak or if other therapy is available. ines for endogenous opioid and dopamine receptors, respectively).
In certain situations, a drug is clearly necessary and beneficial It is likely that other new drugs will be found to do so in the
but produces unacceptable toxicity when given in doses that pro- future, perhaps leading to the discovery of new classes of receptors
duce optimal benefit. In such situations, it may be necessary to and endogenous ligands for future drug development.
add another drug to the treatment regimen. In treating hyperten- Thus, the propensity of drugs to bind to different classes of
sion, for example, administration of a second drug often allows receptor sites is not only a potentially vexing problem in treat-
the prescriber to reduce the dose and toxicity of the first drug (see ing patients, it also presents a continuing challenge to pharma-
Chapter 11). cology and an opportunity for developing new and more useful
drugs.
B. Beneficial and Toxic Effects Mediated by Identical
Receptors but in Different Tissues or by Different
Effector Pathways REFERENCES
Many drugs produce both their desired effects and adverse effects Berridge MJ: Unlocking the secrets of cell signaling. Ann Rev Physiol 2005;67:1.
by acting on a single receptor type in different tissues. Examples Cabrera-Vera TM et al: Insights into G protein structure, function, and regulation.
Endocr Rev 2003;24:765.
discussed in this book include: digitalis glycosides, which act by Civelli O et al: Orphan GPCRs and their ligands. Pharmacol Ther
inhibiting Na+/K+-ATPase in cell membranes; methotrexate, 2006;110:525.
which inhibits the enzyme dihydrofolate reductase; and glucocor- Davies MA, Samuels Y: Analysis of the genome to personalize therapy for mela-
ticoid hormones. noma. Oncogene 2010;29:5545.
Three therapeutic strategies are used to avoid or mitigate this Feng XH, Derynck R: Specificity and versatility in TGF-beta signaling through
Smads. Annu Rev Cell Dev Biol 2005;21:659.
sort of toxicity. First, the drug should always be administered at Galandrin S, Oligny-Longpre G, Bouvier M: The evasive nature of drug efficacy:
the lowest dose that produces acceptable benefit. Second, adjunc- Implications for drug discovery. Trends Pharmacol Sci 2007;28:423.
tive drugs that act through different receptor mechanisms and Ginty DD, Segal RA: Retrograde neurotrophin signaling: Trk-ing along the axon.
produce different toxicities may allow lowering the dose of the Curr Opin Neurobiol 2002;12:268.
first drug, thus limiting its toxicity (eg, use of other immunosup- Gouaux E, MacKinnon R: Principles of selective ion transport in channels and
pumps. Science 2005;310:1461.
pressive agents added to glucocorticoids in treating inflammatory Hermiston ML et al: Reciprocal regulation of lymphocyte activation by tyrosine
disorders). Third, selectivity of the drug’s actions may be increased kinases and phosphatases. J Clin Invest 2002;109:9.
by manipulating the concentrations of drug available to receptors Kenakin T: Principles: Receptor theory in molecular pharmacology. Trends
in different parts of the body, for example, by aerosol administra- Pharmacol Sci 2004;25:186.
tion of a glucocorticoid to the bronchi in asthma. Mosesson Y, Yarden Y: Oncogenic growth factor receptors: Implications for signal
transduction therapy. Semin Cancer Biol 2004;14:262.
Pawson T: Dynamic control of signaling by modular adaptor proteins. Curr Opin
C. Beneficial and Toxic Effects Mediated by Different Cell Biol 2007;19:112.
Types of Receptors Rajagopal S, Rajagopal K, Lefkowitz RJ: Teaching old receptors new tricks- biasing
seven-transmembrane receptors. Nat Rev Drug Discov 2010;9:373.
Therapeutic advantages resulting from new chemical entities with
Roden DM, George AL Jr: The genetic basis of variability in drug responses. Nat
improved receptor selectivity were mentioned earlier in this chapter Rev Drug Discov 2002;1:37.
and are described in detail in later chapters. Such drugs include α- Rosenbaum DM, Rasmussen SG, Kobilka BK: The structure and function of
and β-selective adrenoceptor agonists and antagonists, H1 and H2 G-protein-coupled receptors. Nature 2009;459:356.
antihistamines, nicotinic and muscarinic blocking agents, and Rotella DP: Phosphodiesterase 5 inhibitors: Current status and potential applica-
tions. Nat Rev Drug Discov 2002;1:674.
receptor-selective steroid hormones. All these receptors are grouped
Small KM, McGraw DW, Liggett SB: Pharmacology and physiology of human
in functional families, each responsive to a small class of endog- adrenergic receptor polymorphisms. Ann Rev Pharmacol Toxicol
enous agonists. The receptors and their associated therapeutic 2003;43:381.
uses were discovered by analyzing effects of the physiologic Sorkin A, von Zastrow M: Endocytosis and signaling: Intertwining molecular
chemical signals—catecholamines, histamine, acetylcholine, and networks. Nat Rev Mol Cell Biol 2009;10:609.
Yu FH et al: Overview of molecular relationships in the voltage-gated ion channel
corticosteroids. superfamily. Pharmacol Rev 2005;57:387.
Several other drugs were discovered by exploiting therapeutic Yuan TL, Cantley LC: PI3K pathway alterations in cancer: Variations on a theme.
or toxic effects of chemically similar agents observed in a clinical Oncogene 2008;27:5497.
Another Random Scribd Document
with Unrelated Content
"Oh, I suppose one's own happiness is of chief importance," Eugenia
finally returned. "It isn't human to expect people to be utterly
wretched over others' sorrows. One can be sympathetic, of course,
and depressed now and then, but that is about all."
Then they walked on a few yards in silence before the older girl
added:
"Are you speaking of the same thing, Bab, that we discussed one
night in the moonlight a good many weeks ago? I believe it was the
first evening after Dick Thornton arrived in Brussels? Because if you
are, I still don't agree with you. Of course, I have been separated
from the rest of you most of the time lately, yet I don't think I am
mistaken. What makes you believe as you do, Barbara?"
The older girl put this question in as careless a tone as possible.
Then, although she and her companion were walking arm in arm,
she did not glance toward her. She did not even try to get an
impression of her expression in the moonlight.
Barbara shrugged her shoulders. "There are many signs, Eugenia,
and they cannot always be defined. But I don't think you would ever
see or understand them."
The slighting emphasis upon the pronoun was unmistakable;
nevertheless, Eugenia only smiled. Once Barbara's point of view
might have hurt her, but tonight she was not thinking of herself. She
had something else upon her mind, but was uncertain whether it
would be wise to discuss the subject, or leave it still in darkness.
"Well, perhaps you are right, Barbara," she admitted. "I had a note
from Nona yesterday, but she made no reference to Dick. She
wanted me to ask you a question for her, which perhaps neither of
us has the right to ask. I don't know, it has worried me a good deal
——"
She stopped because Barbara had turned in the path and was facing
her half belligerently and half affectionately.
"Don't be a goose, Eugenia, ask me anything you like. Certainly I
have bored you enough recently with my bad tempers and
complaints to have you say whatever you wish to me. It's funny,
Eugenia, but when we started for Europe I was sure I was going to
like you less than any one of the girls. Now you are the only one I
care very much about."
With this Barbara laughed, pretending that she was not altogether in
earnest. But there was no humor in her laughter.
Eugenia received her information gravely.
"That may be good of you, dear, but I don't believe you," she
returned. "Still I am glad you made the remark just at this minute. It
helps me with what I wish to say to you. Nona wanted me to find
out what it was that had changed your feeling for her. She says she
has done her best to discover for herself and has asked you to tell
her, but without success. She seems much distressed and is anxious
to make amends if she has injured you."
The older girl had to cease talking because Barbara had pulled away
and was walking on ahead without pretending to answer.
She was being rude and was aware of it. But it was better to be rude
than to have any human being discover how crimson her face had
become and how her lips were trembling. Eugenia's question had
taken her so by surprise. Several weeks before she had gone
through much the same kind of conversation with Nona and Mildred.
But the subject had never been mentioned again and she hoped was
happily over. It was too stupid to have Nona go on dwelling upon the
matter in this way and utterly pointless. She had told her that she
had nothing in the world against her. Surely one had the right to
one's likes and dislikes!
Quietly Eugenia continued after her guest. She made no effort to
stop her, although she realized that they were walking farther than
they had intended.
Finally Barbara must have appreciated the fact, because she stopped
and turned around.
"Let's go back home, I am dead tired," she murmured.
Of course Eugenia complied, and they continued in single file on the
return journey.
Walking alone, Barbara once or twice thought that she heard some
one tramping about in the underbrush not far away. But although
she glanced over in that direction she saw no one.
After five minutes more of silence Barbara caught up with Eugenia,
who was in the lead on the way home.
"Can we stop a minute somewhere, Gene, before we get back to the
house? I have something I want to tell you. I believe I'll feel relieved
once I have made a plain statement of a fact to myself as well as to
you. And it will be easier to say it out here in the moonlight than in
the light of day."
This time it was the older girl who hesitated.
"You said you were tired, Bab, and it is getting late. Besides, I am
not sure it is wise for us to be so far from the house alone." She
turned her head uneasily toward the left side of the woods. It was
on the same side that Barbara had believed she heard a noise. But
at present she was paying no attention.
"Please do as I ask you; a few minutes more cannot make any
difference."
Then, just as they had two months before, the girls found a fallen
tree and seated themselves on the trunk. But Barbara turned around
so that she could look directly at her companion. A shaft of light
shone straight across her face. Eugenia could see that the
characteristic little frown was there as well as the slight wrinkling of
the short, straight nose. Also that Barbara's eyes were serious,
although the expression of her mouth was partly humorous. She
looked very young and charming. Perhaps she was not so beautiful
as many other girls. Yet she had a kind of mocking grace, an
evanescent, will o' the wisp quality that was more fascinating than
ordinary beauty. Then beside this, she was so thoroughly human.
"Yes, I have a grievance against Nona, a perfectly dreadful one.
When I told her I didn't have, I just lied," she began directly. "Fact
of the matter is, I can't forgive Nona for being more attractive than I
am. I can't tell her this to her face though, can I, Eugenia? Nor can I
see exactly how I can let you tell her."
Barbara clasped her hands together. They felt very warm, although
the evening was cool. But then her cheeks were even hotter.
Nevertheless, a smile at herself, perhaps the best smile there is in
the world, flickered around the corners of Barbara's mouth.
"I know perfectly well what you are thinking, Eugenia. Nona has not
changed recently. If I cannot like her now because she is prettier
and more charming than I am, then why did I like her at the
beginning of our acquaintance? She was both those things then. But
the fact is, I didn't care then, because, because—Oh, why is it so
hard to get it out, Gene? I don't see why girls need always be
ashamed of caring for people who don't care for them? I didn't know
at first how much Dick Thornton was going to be interested in Nona
Davis, nor how much I cared for Dick. There, the worst is out and I
am glad of it!"
Then Barbara dropped her chin into her hands and sat staring at the
moon up over the top of the trees, waiting for her companion to
answer. Eugenia remained silent.
"Are you disgusted with me, Gene?" the younger girl asked the next
moment. "Goodness knows, I have been with myself, though I never
confessed the truth to any one, not even to Barbara Meade, until
this second. I haven't any right in the world to like Dick except as a
friend. He has always been only ordinarily nice and polite to me. I
really never thought of him seriously until after we left Paris. Then
when I found out he was writing to Nona and never to me, I was
terribly hurt. I had believed we were better friends than he and
Nona. At first I didn't see why I should mind so much, then by
degrees I suppose I began to find out. Anyhow, the only reason I
have for not liking Nona at present is jealousy. It is about the ugliest
fault there is, so I'm not very proud of myself. But as I intend to
make a clean breast of the subject tonight and then never mention it
again, you might as well hear the rest. I don't like Mildred so much
as I used to, because she evidently prefers to have Nona for Dick's
friend than to have me. And there are times when I'd like to pinch
her."
It was so absurd of Barbara to end her confession with this anti-
climax. Yet the older girl was not deceived. Because she endeavored
to make fun of herself and of the situation, she was no less in
earnest.
"Why don't you say something, Gene?" she pleaded the next instant.
"What shall I do? Am I ever going to be sensible again?"
Perhaps it was because Eugenia had been devoting herself to caring
for children for the past two months, or perhaps it was because she
had so strongly the mother feeling. For at this moment she wanted
to take Barbara in her arms. Really, there was not very much for her
to say under the circumstances. Should she insist that Dick was not
in love with Nona when she knew absolutely nothing about it? This
would, only make things harder for the other girl in the end. Barbara
was not a foolish, sentimental person; she was usually clear-sighted,
with sound common sense. Of course, she would stop caring for
Dick Thornton after a time if he felt no affection for her. But how
convince her of this at the present moment?
"I had been fearing something like this, Barbara," Eugenia said
finally. "I don't mean in connection with Nona. I never dreamed of
her entering into the situation. Dick is a splendid fellow, but after all
he has only one arm. Besides, I don't think Judge Thornton is really
wealthy. They spend a great deal of money. I know from all I have
heard that Judge Thornton makes a great deal, but that Mrs.
Thornton is very extravagant and very ambitious."
Barbara got up. "Let's go to bed, Gene dear. Of course, nothing you
can say will make any difference. But I promise to turn over a new
leaf. Away with all human weakness!"
Barbara started to wave her hand, but instead clutched at Eugenia's
arm frantically.
"Great heavens, who was that, Gene?" she whispered. "I am sure I
saw some one sliding along between the trees. He was crouched
over as if he feared we might see him."
Eugenia took the younger girl's arm. "It was no one, my dear. But
remember, this is a haunted house and a ghost is supposed to
wander all over the estate. Keep hold of my hand and we'll run to
the house. Perhaps we may get there before the ghost does."
 CHAPTER XIII
An Arrest
"I want you to know that I understand who the ghost was last night,
Eugenia," Barbara said unexpectedly next morning.
Eugenia was just about to leave her bedroom, Nicolete having gone
downstairs half an hour before.
At these words the older girl turned and stood straight and severe
with her shoulders braced against the wall as if for support.
"What do you mean?" she inquired slowly.
Barbara had not finished dressing. Indeed, she was in the
undignified attitude of sitting on one side of the bed putting on her
stockings. Nevertheless, she gazed at Eugenia squarely.
"I mean just what I said," she answered. "That is, of course, I don't
know the name or the age or the identity of the man I saw by
accident in the woods last night. But I realize that he must be the
same person you have been concealing ever since you took this
house. Naturally he must grow weary of the long confinement and
be obliged to go outdoors now and then at night."
Eugenia had not replied, so Barbara went on thinking aloud.
"Or else some one may have been coming to the house with a
message for the person in hiding. Of course, I don't know whether
your refugee is a man or woman. But whoever he or she may be,
goodness knows, I'll be grateful enough when the escape is over
and this house left behind!"
Eugenia's face whitened at the younger girl's words. Nevertheless,
she again turned as if she meant to leave the room without an
answer.
Barbara was too quick for her.
She took hold of both her shoulders and pulled her gently around.
"I would rather you would say something, Gene. I have been doing
all the talking ever since I arrived. One minute I can't decide
whether I ought to try and find out who this person is you have in
hiding, or what your reason is. Then I wonder if it is best I should
leave you alone? But please, please don't run any risks. You know
that if you are defying the German authorities and are found out,
what your punishment may be. What could I possibly do to help
you? I feel so powerless. I can't tell you how I have longed to
confide my suspicion to Dick Thornton or the girls and ask their
advice. But I have kept absolutely silent."
"Thank you," Eugenia said, and then waited another moment. "Sit
down, please, Barbara," she added. "I suppose it is only fair that I
offer you some explanation. You have been so good."
Barbara did as she was requested. But Eugenia continued to stand.
Her level, dark brows were drawn close together and her face was
pale. Otherwise she looked entirely self-possessed, sure of herself
and her position.
"I am not going to tell you that I have any one in hiding here,
Barbara. If questions are ever asked of you, you are to know
absolutely nothing. But I want you to understand that I appreciate
perfectly the danger of what I have undertaken and have done it
with my eyes open. If I am punished, well, at least I have always
faced the possibility. But after today, dear, if things go as we hope,
you need no longer worry over me. So far I feel pretty sure the
Germans in command of this part of the country have not suspected
our house in the woods of being anything more than a shelter for
defenseless Belgian children. And really that has been my chief
motive in all that I have done."
Barbara sighed. "God keep us through the day," she murmured,
quoting a childish prayer.
Then Eugenia went downstairs to her work and a short time later
the younger girl followed her.
Barbara was to remain until after lunch. But at her friend's request
she spent most of the time in the yard with the children and
Monsieur Bebé. Whatever went on inside the house neither she nor
any of the others were to be allowed to know.
As a special pleasure the children were to be permitted to eat their
luncheon under an old tree in the one-time garden. This garden now
held no flowers except two or three old rosebushes and overgrown
shrubs.
The heat of yesterday had returned and with it even more sultriness.
There were heavy clouds overhead, but no immediate sign of rain. It
was one of those days that are always peculiarly hard to endure.
The air was heavy and languid with a kind of brooding stillness that
comes before the storm.
The nerves of everybody seemed to be on edge. Monsieur Bebé had
lost his courage of yesterday and sat silent in his chair with his head
resting in his hand. Was he dreaming of Provence before France was
driven into war? Or was he hearing again the cracking of rifles, the
booming of cannon, all the noises of the past year of life in a trench?
Several times Barbara did her best to distract his attention, but the
French boy could do nothing more than try to be polite. It was
evident that he hardly heard what she said to him. Nicolete was too
engaged with her duties in the house to offer companionship.
Nevertheless, she came back and forth into the yard. Now and then
she would stop for a moment to speak to Monsieur Reney, who was
Monsieur Bebé only to Barbara, who had so named him.
Nicolete was busy in arranging the outdoor luncheon for the
children. For she it was who brought out the dishes and the chairs.
Only once did she have any assistance and then the maid from the
kitchen helped her with the luncheon table. Neither Eugenia nor the
woman whom they called "Louise" was seen all morning.
So to Barbara fell the entire task of looking after the children.
Perhaps it was the weather, perhaps they too were vaguely
conscious that something unusual was going on about them, for
they were extremely difficult.
Not once, but half a dozen times, each child insisted upon going into
the house to search for Eugenia. She could not be busy for so long a
time that she could not come out to them, they protested. This had
never happened before.
Jan and Bibo were particularly sulky, nevertheless Barbara continued
firm. Jan had been made her especial charge. Whatever happened
he must be kept away from all knowledge of what was transpiring in
the big house only a few yards off.
This world is ever a double mask with the face of tragedy painted
upon one side and of comedy upon the other.
So often Barbara thought of this during the long hours of the
morning.
Sometimes she was whirling about with the children in a ring,
singing at the top of her voice to keep their attention engaged. Yet
at the same moment her thoughts were all concentrated upon what
was going on in the house with Eugenia. Whom had she in hiding all
these weeks, risking her own liberty for his or her safety? And how
was it possible that any human being could escape from Belgium
whom the Germans wished to detain?
Yet not a carriage nor a human being approached the house from
the front. Of this Barbara was absolutely certain. Always when it was
possible she had kept a watchful lookout. Besides, there was Jan
who had appointed himself sentinel.
The boy could not consciously have been expecting disaster. Not a
human being had given him a hint of what was to take place. Yet he
simply refused to play when the other children invited him.
When Barbara explained that Eugenia insisted he remain out of the
house, he made no effort toward disobedience. He merely took up a
position as far away as possible, but one where he could still see the
house and at the same time keep a lookout ahead. For his quiet gray
eyes would study the landscape beyond him sometimes for five
minutes, then he would turn his head and gaze toward the house.
Satisfied that he could discover nothing wrong there, he would again
begin his former scrutiny.
He was an interesting figure; Barbara studied him whenever she had
a chance. Here was a child whom the war had not so far injured
physically. Although ill some weeks before he had since recovered.
Yet he would bear the scars that the war had made upon his spirit so
long as he should live. Bibo's lameness was as nothing to this boy's
hurt. There was a look of abnormal gravity in his eyes, of an
understanding of sorrows that a child of ten should know nothing of.
He was fearful and frightened and yet there was something
indomitable in the child's watching.
He recalled the gallant army of children crusaders who, led by
Stephen of France, went forth to wrest Jerusalem from the infidels.
So their little sentinels must have waited wide-eyed and courageous,
yet sick with dread, for the ravenous hosts to overpower them.
Another possibility worried Barbara and the children all morning.
There was a prospect that rain might come and so spoil their
luncheon party. Suppose they should be compelled to scamper for
shelter just at the critical moment in Eugenia's plans?
The rain did not come. It must have been just a little after twelve
o'clock when Eugenia finally walked down the front steps into the
yard. She did not look toward Barbara, but her appearance was
enough. Whatever she had wished to accomplish was now over.
Although at the moment she was engaged in learning a new Belgian
game, Barbara had to suggest that she be allowed to sit down for a
time. Eugenia might be able to look as calm as an inland lake, but
she felt uncomfortably agitated.
First Eugenia spoke to Monsieur Bebé. Then she walked down to
where Jan was standing. She said nothing to the boy, but put her
arm on his shoulder. Afterwards they walked back together toward
the other children. But Jan's expression had entirely changed. He
was smiling now and his cheeks were happily flushed, yet he kept
his hand tightly clutched in his friend's.
Soon after Nicolete came out of the house with a great tray of
sandwiches. There was real ham between some of them and peanut
butter between the others. Moreover, there was an enormous dish of
baked potatoes and another of beans. For some reason the children
did not understand, for it was neither Sunday nor a saint's day, they
were to have a feast.
The table, which had been easy enough to arrange, since it was only
a couple of boards laid upon carpenter's horses, was set in the
middle of the garden, partly shaded by an old elm tree. The garden
was just a few yards to the left of the house and in plain view of any
one approaching.
Naturally Eugenia took her place at the head of the table, with
Nicolete at the other end. Barbara was on Eugenia's right, with her
eyes on the scene ahead. She could see the edge of the woods with
the path that connected the house with the outside world. Jan was
next her with the same outlook upon the surroundings.
It was Jan who saw the two German officers approaching with a
guard of eight soldiers behind them a few moments later.
The boy had just lifted a sandwich to his lips when something in his
rigid attitude first attracted Barbara's attention. She then let her
knife drop onto the table.
The noise startled Eugenia, for she too looked up. Instantly Barbara
explained what was happening.
"Don't stir and please don't appear to be frightened before the
children," Eugenia ordered. "I must go and meet the officers, but I'll
wait until they are nearer."
So the German soldiers had a clear vision of Eugenia and the
children as they approached. The rough board table had no cover,
but in the center was a bunch of wild flowers that the children had
gathered in the neglected fields.
In order to keep them from seeing too soon what must inevitably
happen, Eugenia started the singing of a Belgian translation of the
Russian "Prayer for Peace."
It was perhaps the song that came most from her heart at the
moment, although she and her little companions had been trying to
learn it for several weeks past.
 "God the All Righteous One! Man hath defied Thee,
Yet to eternity sure standeth Thy word;
Falsehood and wrong shall not tarry beside Thee,
Give to us peace in our time, O Lord!"

Then when the German officers were within a few yards of her,
Eugenia got up and walked quietly forward. She did not go alone
though, because Jan held on to her skirts so tightly that there was
no possibility of tearing him loose.
"Will you wait a moment, please, until the children can be taken to
another part of the yard?" Eugenia asked quietly. "Some of them are
very young and will only be terrified and confused by our
conversation. I think most of them are afraid of soldiers."
There was no reproach in the girl's tone as she said this. But the
sting was inevitably there.
However, the older of the two officers bowed his head and Nicolete
led the reluctant children away.
By this time Barbara had placed herself at one side her friend next to
little Jan. And poor Monsieur Bebé, hearing the voices, had crept
blindly forward to within a few feet of the little company.
In the meantime the soldiers had divided: two of them stood before
the front door and two had retired to the rear of the house. The
other four guarded either side.
"You are under arrest, Fraulein," the German officer began. He was
stern, but rigidly polite.
"Very well," Eugenia answered. "In five minutes I can be ready to go
with you. But tell me, please, of what I am accused."
"You are accused of harboring a Belgian spy, a Colonel Carton, who
got back through the lines, disguised as a German soldier and into
his wife's home in Brussels. His effort was to obtain certain papers
and information and then return to King Albert and the British Allies.
We have reason to believe Colonel Carton is still in your house." The
officer at this instant drew a pair of handcuffs from his pocket.
Naturally Eugenia flinched, yet she held out her hands.
"Your intention is to search my house. You will, of course, do what
you wish. But remember that I am an American citizen and under
the protection of the United States flag."
Then one of the officers remained in the yard while the other led his
soldiers into the house.
Ten, fifteen minutes passed. Eugenia talked quietly to Barbara. She
begged her to ask permission of the hospital authorities to allow her
to stay with the children. She told her where she might obtain the
money for keeping up their expenses. Some time before she had
written a letter giving Barbara her power of attorney. Almost every
detail had been arranged.
Of course, Eugenia was frightened. She was not unlike other people,
only that she had a stronger will and sometimes a finer
determination.
Finally the German officer and his soldiers returned.
"We can find no trace of Colonel Carton or his wife," the younger
officer reported. "However, a servant from their household in
Brussels is here and I have reason to believe the two children of
Madame and Colonel Carton."
Still Jan, who had never let go his hold on Eugenia, did not flinch.
Not once did he even glance up toward one of the German soldiers,
nor give a sign that might betray him or his protector.
"I am sorry, but you must go with us until the circumstances can be
more thoroughly investigated," the older officer commanded.
A short time afterwards Eugenia went quietly away. One of the
soldiers carried her suitcase. Since she marched between them and
showed no intention of giving trouble, the officer had taken off the
handcuffs. Evidently he meant to be as courteous as possible under
the circumstances. Moreover, Eugenia's dignity was impressive.
All through the interview Barbara had felt her knees trembling so
beneath her that she felt unable to stand. Her hands were like ice
and her cheeks on fire; moreover, there was a lump in her throat
which made her totally unable to speak.
Nevertheless, she did speak whenever a question was asked of her,
nor did she shed a tear until Eugenia had gone.
It was curious, but no one broke down, not even Jan. He merely
kept his hold on Eugenia's skirt until she started to leave.
Then Eugenia herself unloosed his hands. He had been on his knees
before and he made no effort to get up afterwards.
Finally, when Barbara lifted the boy in her arms she found it was
because he was too weak to stand.
 CHAPTER XIV
A Month Later
Dick Thornton had taken lodgings in an old house in Brussels in a
once fashionable quarter of the city. He had a big reception room
and a small room adjoining. Recently Nona and Mildred had been
coming in to have tea with him on their afternoons of leisure. They
even dropped in occasionally in their daily walks. For in order to
keep their health and spirits each Red Cross nurse, following the
familiar rule, was given two hours off duty every afternoon.
But Barbara Meade had never seen the quarters where Dick lived.
Always she had pleaded some kind of an excuse in answer to his
invitations, until finally he had proffered them no more. Then for the
past month she had been taking Eugenia's place in her house in the
woods.
But this afternoon Barbara had made an appointment to meet Nona
and Mildred at Dick's at four o'clock.
Half an hour before the time, Dick came into the house with his
arms full of flowers which he had purchased from a little old woman
at the corner. She had become a great friend of his, for the flower
business was a poor one in a city where people had no money even
for food. So today Dick had purchased bunches of wall flowers and
others of columbine and larkspur. For the flowers grew in the old
woman's own garden within a sheltered suburb of Brussels. She
must have grown them and sold them in order that she might still
continue to sit in the same place. For so far as one could know she
had no other reason for her industry. She appeared to be entirely
alone and friendless.
Dick's sitting room was enormous, yet almost empty. The house had
been deserted by its owners early in the war. They had then
removed most of their belongings to London for safe keeping, soon
after hostilities broke out.
But Dick opened wide a pair of French windows until the atmosphere
of the room had grown cool and sweet. He then arranged his own
flowers and set out his own tea table in a somewhat clumsy fashion,
drawing four chairs conveniently near. They were the only four chairs
in the room and very different in character. Two of them were
enormous armchairs upholstered in Brussels tapestry, the other were
two small wooden ones which had probably served for the servant's
dining room.
But Dick was fairly well satisfied with the appearance of things, since
empty grandeur is much more satisfying than tawdry quantity.
Afterwards Dick disappeared to make an afternoon toilet.
It had been such ages since he had worn anything but the most
workaday clothes. Now and then when he came in tired at night and
discouraged with life from the sight of so much unnecessary sorrow,
he used to slip into a smoking jacket for an hour or so. Usually
several American fellows dropped in later, young doctors or other
men assisting with the Belgian relief work.
But today Dick felt the occasion to be a more important one.
Barbara was coming on an errand of grave importance. Yet one
might as well meet the situation as cheerfully as possible. Nothing
was ever to be gained by unnecessary gloom.
It still remained a task for Dick to dress himself with one of his arms
almost useless. At first it had been impossible and he had employed
a man to help him. But men were needed for more strenuous labors
these days than being another fellow's valet. So he had come to
taking care of himself in a somewhat awkward fashion. The collar
was his supreme difficulty, just as it frequently is with a man with
two perfectly good arms.
Today, of course, because Dick was in a hurry, his collar behaved in
a worse manner than usual. The collar button had to be searched for
under the bed for nearly five minutes, and then it did not seem to fit
the button-hole of the shirt.
Finally Dick sat down and began to smoke in an effort to soothe his
nerves. Mildred had promised to come along ahead of time to do
whatever was needed. As there was nothing more, except to adjust
his tiresome neckwear, he might as well wait in peace.
But in the meantime Dick read over the note from Barbara in which
she asked that the four of them might meet at his apartment. It was
the one place where it was possible that their conversation be
absolutely private. And what they had to discuss was a matter for
gravest secrecy.
Although Dick had previously arranged his hair with much care,
while reading the note he thrust his hand through it until his locks
rose in brown, Byronic confusion.
So when the first knock came at his sitting room door, convinced of
his sister's arrival, Dick strode to it, dangling his collar in his hand.
His appearance was not strictly conventional.
The girl at the door looked a little startled, then smiled and walked
into the room without invitation.
"I suppose I am first. I didn't mean to be," she explained. "But Dr.
Mason came out to see one of the children and brought me back to
town in the hospital motor car. So I got here sooner than I
expected."
"I am sorry. I thought you were Mildred. I mean, I hoped you were
Mildred." Dick laughed. "Sounds polite, doesn't it, what I am trying
to say? But the fact is, if you'll just take off your hat or your wrap, or
your gloves, why, I'll disappear for half a minute and come back with
a collar on."
Barbara nodded and her reluctant host disappeared.
She was glad of a few moments to look around. It was almost
homelike here in Dick's quarters, and not since leaving the little
"Farmhouse with the Blue Front Door" had she enjoyed the
sensation of home.
She certainly did not enjoy it at Eugenia's big house, although she
was now in full charge of the establishment. For there was always
the sense of Eugenia's loss and of the privations which she was
enduring.
Barbara did throw her hat to one side and her coat and gloves. The
freedom was pleasanter. Then, since small persons have a penchant
for large chairs and large persons for small ones, Barbara seated
herself in the most imposing chair in the room.
Not thinking of where she was, nor of what she was doing, she
slipped one small foot under her, leaned her head against the
upholstery and gazed critically around.
They were going to have tea and she was glad of it. Then she loved
the presence of so many simple outdoor flowers. Probably they had
been purchased for Nona's delectation, yet one could enjoy them
just the same.
Besides, Barbara was by this time convinced that she had entirely
recovered from any jealousy where Nona and Dick were concerned.
She had seen them very seldom in the past month. But this was not
because she had any more feeling in regard to the situation. It was
merely because she had more important matters to engage her
attention. Her talk with Eugenia seemed to have cleared the
emotional situation so far as she was concerned. Now her interest in
Dick and Nona was purely impersonal and friendly.
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