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a LANGE medical book

Basic & Clinical

Pharmacology
Fourteenth Edition

Edited by
Bertram G. Katzung, MD, PhD
Professor Emeritus
Department of Cellular & Molecular Pharmacology
University of California, San Francisco

New York Chicago San Francisco Athens London Madrid Mexico City
Milan New Delhi Singapore Sydney Toronto
Basic & Clinical Pharmacology, Fourteenth Edition

Copyright © 2018 by McGraw-Hill Education. All rights reserved. Printed in the United States of America. Except as permitted under the United
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1987 by Appleton & Lange; copyright © 1984, 1982 by Lange Medical Publications.

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ISBN 978-1-259-64115-2
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ISSN 0891-2033

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Contents
Preface vii
Authors ix

S E C T I O N I 10. Adrenoceptor Antagonist Drugs

David Robertson, MD, & Italo Biaggioni, MD 156
BASIC PRINCIPLES   1 S E C T I O N III
Introduction: The Nature of Drugs &
1. 
CARDIOVASCULAR-RENAL
Drug Development & Regulation
Bertram G. Katzung, MD, PhD 1 DRUGS  173

2. Drug Receptors & Pharmacodynamics 11. Antihypertensive Agents

Mark von Zastrow, MD, PhD 20 Neal L. Benowitz, MD 173

Pharmacokinetics & Pharmacodynamics:

3.  Vasodilators & the Treatment of
12. 
Rational Dosing & the Time Course Angina Pectoris
of Drug Action Bertram G. Katzung, MD, PhD 194
Nicholas H. G. Holford, MB, ChB, FRACP 41
13. Drugs Used in Heart Failure
4. Drug Biotransformation Bertram G. Katzung, MD, PhD 212
Maria Almira Correia, PhD 56
14. Agents Used in Cardiac Arrhythmias
5. Pharmacogenomics Robert D. Harvey, PhD,
& Augustus O. Grant, MD, PhD 228
Jennifer E. Hibma, PharmD,
& Kathleen M. Giacomini, PhD 74
15. Diuretic Agents
Ramin Sam, MD, Harlan E. Ives, MD, PhD,
S E C T I O N II & David Pearce, MD 254

AUTONOMIC DRUGS   89 S E C T I O N IV
6. Introduction to Autonomic Pharmacology
Bertram G. Katzung, MD, PhD 89
DRUGS WITH IMPORTANT ACTIONS
ON SMOOTH MUSCLE   277
Cholinoceptor-Activating &
7. 
Cholinesterase-Inhibiting Drugs 16. Histamine, Serotonin, & the Ergot Alkaloids
Achilles J. Pappano, PhD 107 Bertram G. Katzung, MD, PhD 277

8. Cholinoceptor-Blocking Drugs 17. Vasoactive Peptides

Achilles J. Pappano, PhD 124 Ian A. Reid, PhD 300

Adrenoceptor Agonists &

9.  The Eicosanoids: Prostaglandins,
18. 
Sympathomimetic Drugs Thromboxanes, Leukotrienes, & Related
Italo Biaggioni, MD, & David Robertson, MD 137 Compounds
John Hwa, MD, PhD, &
Kathleen Martin, PhD 321

iii
iv    CONTENTS
19. Nitric Oxide
Samie R. Jaffrey, MD, PhD 339
20. Drugs Used in Asthma
Joshua M. Galanter, MD, &
Homer A. Boushey, MD 346
S E C T I O N V & GOUT   591
DRUGS THAT ACT IN THE CENTRAL
NERVOUS SYSTEM   367
Introduction to the Pharmacology of
21. 
CNS Drugs
John A. Gray, MD, PhD 367
22. Sedative-Hypnotic Drugs
Anthony J. Trevor, PhD 381
23. The Alcohols
Anthony J. Trevor, PhD 396
24. Antiseizure Drugs
Roger J. Porter, MD, &
Michael A. Rogawski, MD, PhD 409
25. General Anesthetics
Helge Eilers, MD, & Spencer Yost, MD 440
26. Local Anesthetics
Kenneth Drasner, MD 459
27. Skeletal Muscle Relaxants
Marieke Kruidering-Hall, PhD, &
Lundy Campbell, MD 474
Pharmacologic Management of
28. 
Parkinsonism & Other
Movement Disorders
Michael J. Aminoff, MD, DSc, FRCP 492
29. Antipsychotic Agents & Lithium
Charles DeBattista, MD 511
30. Antidepressant Agents
Charles DeBattista, MD 532
31. Opioid Agonists & Antagonists
Mark A. Schumacher, PhD, MD,
Allan I. Basbaum, PhD, &
Ramana K. Naidu, MD 553
32. Drugs of Abuse
Christian Lüscher, MD 575
S E C T I O N VI
DRUGS USED TO TREAT DISEASES
OF THE BLOOD, INFLAMMATION,
Agents Used in Cytopenias; Hematopoietic
33. 
Growth Factors
James L. Zehnder, MD 591
34. Drugs Used in Disorders of Coagulation
James L. Zehnder, MD 608
35. Agents Used in Dyslipidemia
Mary J. Malloy, MD, &
John P. Kane, MD, PhD 626
Nonsteroidal Anti-Inflammatory Drugs,
36. 
Disease-Modifying Antirheumatic Drugs,
Nonopioid Analgesics, &
Drugs Used in Gout
Ahmed A. Negm, MD, &
Daniel E. Furst, MD 642
S E C T I O N VII
ENDOCRINE DRUGS   667
37. Hypothalamic & Pituitary Hormones
Roger K. Long, MD, &
Hakan Cakmak, MD 667
38. Thyroid & Antithyroid Drugs
Betty J. Dong, PharmD, FASHP, FCCP, FAPHA 687
Adrenocorticosteroids & Adrenocortical
39. 
Antagonists
George P. Chrousos, MD 703
40. The Gonadal Hormones & Inhibitors
George P. Chrousos, MD 720
Pancreatic Hormones & Antidiabetic
41. 
Drugs
Martha S. Nolte Kennedy, MD, &
Umesh Masharani, MBBS, MRCP (UK) 747

Agents That Affect Bone Mineral
42. 
Homeostasis
Daniel D. Bikle, MD, PhD 772
S E C T I O N VIII
CHEMOTHERAPEUTIC DRUGS   793
Beta-Lactam & Other Cell Wall- &
43. 
Membrane-Active Antibiotics
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD 795
Tetracyclines, Macrolides, Clindamycin,
44. 
Chloramphenicol, Streptogramins, &
Oxazolidinones
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD 815
45. Aminoglycosides & Spectinomycin
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD 826
Sulfonamides, Trimethoprim,
46. 
& Quinolones
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD 834
47. Antimycobacterial Drugs
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD 842
48. Antifungal Agents
Harry W. Lampiris, MD, &
Daniel S. Maddix, PharmD 853
49. Antiviral Agents
Sharon Safrin, MD 863
Miscellaneous Antimicrobial Agents;
50. 
Disinfectants, Antiseptics, & Sterilants
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD 895
51. Clinical Use of Antimicrobial Agents
Harry W. Lampiris, MD, &
Daniel S. Maddix, PharmD 904
52. Antiprotozoal Drugs
Philip J. Rosenthal, MD 917
CONTENTS    v
Clinical Pharmacology of the
53. 
Antihelminthic Drugs
Philip J. Rosenthal, MD 938
54. Cancer Chemotherapy
Edward Chu, MD 948
55. Immunopharmacology
Douglas F. Lake, PhD, &
Adrienne D. Briggs, MD 977
S E C T I O N IX
TOXICOLOGY  1003
Introduction to Toxicology: Occupational &
56. 
Environmental
Daniel T. Teitelbaum, MD 1003
57. Heavy Metal Intoxication & Chelators
Michael J. Kosnett, MD, MPH 1020
58. Management of the Poisoned Patient
Kent R. Olson, MD 1035
S E C T I O N X
SPECIAL TOPICS   1047
Special Aspects of
59. 
Perinatal & Pediatric Pharmacology
Gideon Koren, MD, FRCPC, FACMT 1047
60. Special Aspects of Geriatric Pharmacology
Bertram G. Katzung, MD, PhD 1058
61. Dermatologic Pharmacology
Dirk B. Robertson, MD, &
Howard I. Maibach, MD 1068
Drugs Used in the Treatment of
62. 
Gastrointestinal Diseases
Kenneth R. McQuaid, MD 1087
Therapeutic & Toxic Potential of
63. 
Over-the-Counter Agents
Valerie B. Clinard, PharmD, &
Robin L. Corelli, PharmD 1120
vi    CONTENTS

Dietary Supplements & Herbal

64.  Appendix: Vaccines, Immune Globulins, &
Medications Other Complex Biologic Products
Cathi E. Dennehy, PharmD, & Harry W. Lampiris, MD, &
Candy Tsourounis, PharmD 1131 Daniel S. Maddix, PharmD 1175

Rational Prescribing &

65. 
Index 1183
Prescription Writing
Paul W. Lofholm, PharmD, &
Bertram G. Katzung, MD, PhD 1146

Important Drug Interactions &

66. 
Their Mechanisms
John R. Horn, PharmD, FCCP 1156
Preface

The fourteenth edition of Basic & Clinical Pharmacology continues Significant revisions in this edition include:
the extensive use of full-color illustrations and expanded coverage
of transporters, pharmacogenomics, and new drugs of all types • Major revisions of the chapters on immunopharmacology,
emphasized in prior editions. In addition, it reflects the major antiseizure, antipsychotic, antidepressant, antidiabetic, anti-
expansion of large-molecule drugs in the pharmacopeia, with inflammatory, and antiviral drugs, prostaglandins, and central
nervous system neurotransmitters.
numerous new monoclonal antibodies and other biologic agents.
• Continued expansion of the coverage of general concepts relat-
Case studies accompany most chapters, and answers to ques- ing to newly discovered receptors, receptor mechanisms, and
tions posed in the case studies appear at the end of each chapter. drug transporters.
The book is designed to provide a comprehensive, authoritative, • Descriptions of important new drugs released through May 2017.
and readable pharmacology textbook for students in the health • Many revised illustrations in full color that provide significantly
sciences. Frequent revision is necessary to keep pace with the rapid more information about drug mechanisms and effects and help
changes in pharmacology and therapeutics; the 2–3 year revision to clarify important concepts.
cycle of this text is among the shortest in the field, and the avail-
An important related educational resource is Katzung &
ability of an online version provides even greater currency. The
Trevor’s Pharmacology: Examination & Board Review, (Trevor AJ,
book also offers special features that make it a useful reference for
Katzung BG, & Kruidering-Hall, M: McGraw-Hill). This book
house officers and practicing clinicians.
provides a succinct review of pharmacology with approximately
This edition continues the sequence used in many pharmacol-
one thousand sample examination questions and answers. It is
ogy courses and in integrated curricula: basic principles of drug
especially helpful to students preparing for board-type examina-
discovery, pharmacodynamics, pharmacokinetics, and pharma-
tions. A more highly condensed source of information suitable for
cogenomics; autonomic drugs; cardiovascular-renal drugs; drugs
review purposes is USMLE Road Map: Pharmacology, second edi-
with important actions on smooth muscle; central nervous system
tion (Katzung BG, Trevor AJ: McGraw-Hill, 2006). An extremely
drugs; drugs used to treat inflammation, gout, and diseases of
useful manual of toxicity due to drugs and other products
the blood; endocrine drugs; chemotherapeutic drugs; toxicology;
is Poisoning & Drug Overdose, by Olson KR, ed; 7th edition,
and special topics. This sequence builds new information on a
McGraw-Hill, 2017.
foundation of information already assimilated. For example, early
This edition marks the 35th year of publication of Basic &
presentation of autonomic nervous system pharmacology allows
Clinical Pharmacology. The widespread adoption of the first
students to integrate the physiology and neuroscience they have
thirteen editions indicates that this book fills an important need.
learned elsewhere with the pharmacology they are learning and
We believe that the fourteenth edition will satisfy this need even
prepares them to understand the autonomic effects of other drugs.
more successfully. Chinese, Croatian, Czech, French, Georgian,
This is especially important for the cardiovascular and central ner-
Indonesian, Italian, Japanese, Korean, Lithuanian, Portuguese,
vous system drug groups. However, chapters can be used equally
Spanish, Turkish, and Ukrainian translations of various editions
well in courses and curricula that present these topics in a different
are available. The publisher may be contacted for further
sequence.
information.
Within each chapter, emphasis is placed on discussion of drug
I wish to acknowledge the prior and continuing efforts of
groups and prototypes rather than offering repetitive detail about
my contributing authors and the major contributions of the
individual drugs. Selection of the subject matter and the order
staff at Lange Medical Publications, Appleton & Lange, and
of its presentation are based on the accumulated experience of
McGraw-Hill, and of our editors for this edition, Caroline
teaching this material to thousands of medical, pharmacy, dental,
Define and Greg Feldman. I also wish to thank Alice Camp and
podiatry, nursing, and other health science students.
Katharine Katzung for their expert proofreading contributions.
Major features that make this book particularly useful in
Suggestions and comments about Basic & Clinical Pharmacology
integrated curricula include sections that specifically address the
are always welcome. They may be sent to me in care of the
clinical choice and use of drugs in patients and the monitoring of
publisher.
their effects—in other words, clinical pharmacology is an integral
part of this text. Lists of the trade and generic names of commer-
Bertram G. Katzung, MD, PhD
cial preparations available are provided at the end of each chapter
San Francisco
for easy reference by the house officer or practitioner evaluating a
June 2017
patient’s drug list or writing a prescription.

vii
Authors

Michael J. Aminoff, MD, DSc, FRCP Edward Chu, MD

Professor, Department of Neurology, University of Professor of Medicine and Pharmacology & Chemical
California, San Francisco Biology; Chief, Division of Hematology-Oncology,
Director, University of Pittsburgh Cancer Institute,
Allan I. Basbaum, PhD
University of Pittsburgh School of Medicine, Pittsburgh
Professor and Chair, Department of Anatomy and W.M.
Keck Foundation Center for Integrative Neuroscience, Valerie B. Clinard, PharmD
University of California, San Francisco Associate Professor, Department of Clinical Pharmacy,
School of Pharmacy, University of California,
Camille E. Beauduy, PharmD
San Francisco
Assistant Clinical Professor, School of Pharmacy,
University of California, San Francisco Robin L. Corelli, PharmD
Clinical Professor, Department of Clinical Pharmacy,
Neal L. Benowitz, MD
School of Pharmacy, University of California,
Professor of Medicine and Bioengineering &
San Francisco
Therapeutic Science, University of California,
San Francisco Maria Almira Correia, PhD
Professor of Pharmacology, Pharmaceutical Chemistry
Italo Biaggioni, MD
and Biopharmaceutical Sciences, Department of Cellular
Professor of Pharmacology, Vanderbilt University School
& Molecular Pharmacology, University of California,
of Medicine, Nashville
San Francisco
Daniel D. Bikle, MD, PhD
Charles DeBattista, MD
Professor of Medicine, Department of Medicine, and
Professor of Psychiatry and Behavioral Sciences, Stanford
Co-Director, Special Diagnostic and Treatment Unit,
University School of Medicine, Stanford
University of California, San Francisco, and Veterans
Affairs Medical Center, San Francisco Cathi E. Dennehy, PharmD
Professor, Department of Clinical Pharmacy, University
Homer A. Boushey, MD
of California, San Francisco School of Pharmacy,
Chief, Asthma Clinical Research Center and Division
San Francisco
of Allergy & Immunology; Professor of Medicine,
Department of Medicine, University of California, Betty J. Dong, PharmD, FASHP, FCCP, FAPHA
San Francisco Professor of Clinical Pharmacy and Clinical Professor
of Family and Community Medicine, Department of
Adrienne D. Briggs, MD
Clinical Pharmacy and Department of Family and
Clinical Director, Bone Marrow Transplant Program,
Community Medicine, Schools of Pharmacy and
Banner Good Samaritan Hospital, Phoenix
Medicine, University of California, San Francisco
Hakan Cakmak, MD
Kenneth Drasner, MD
Department of Medicine, University of California,
Professor of Anesthesia and Perioperative Care,
San Francisco
University of California, San Francisco
Lundy Campbell, MD
Helge Eilers, MD
Professor, Department of Anesthesiology and
Professor of Anesthesia and Perioperative Care,
Perioperative Medicine, University of California
University of California, San Francisco
San Francisco, School of Medicine, San Francisco
Daniel E. Furst, MD
George P. Chrousos, MD
Carl M. Pearson Professor of Rheumatology, Director,
Professor & Chair, First Department of Pediatrics,
Rheumatology Clinical Research Center, Department of
Athens University Medical School, Athens, Greece
Rheumatology, University of California, Los Angeles

ix
x    AUTHORS
Joshua M. Galanter, MD
Department of Medicine, University of California,
San Francisco
Kathleen M. Giacomini, PhD
Professor of Bioengineering and Therapeutic Sciences,
Schools of Pharmacy and Medicine, University of
California, San Francisco
Augustus O. Grant, MD, PhD
Professor of Medicine, Cardiovascular Division, Duke
University Medical Center, Durham
John A. Gray, MD, PhD
Associate Professor, Department of Neurology, Center for
Neuroscience, University of California, Davis
Robert D. Harvey, PhD
Professor of Pharmacology and Physiology, University of
Nevada School of Medicine, Reno
Jennifer E. Hibma, PharmD
Department of Bioengineering and Therapeutic Sciences,
Schools of Pharmacy and Medicine, University of
California, San Francisco
Nicholas H. G. Holford, MB, ChB, FRACP
Professor, Department of Pharmacology and Clinical
Pharmacology, University of Auckland Medical School,
Auckland
John R. Horn, PharmD, FCCP
Professor of Pharmacy, School of Pharmacy, University
of Washington; Associate Director of Pharmacy Services,
Department of Medicine, University of Washington
Medicine, Seattle
John Hwa, MD, PhD
Professor of Medicine and Pharmacology, Yale University
School of Medicine, New Haven
Harlan E. Ives, MD, PhD
Professor Emeritus of Medicine, Department of
Medicine, University of California, San Francisco
Samie R. Jaffrey, MD, PhD
Greenberg-Starr Professor of Pharmacology,
Department of Pharmacology, Cornell University Weill
Medical College, New York City
John P. Kane, MD, PhD
Professor of Medicine, Department of Medicine;
Professor of Biochemistry and Biophysics; Associate
Director, Cardiovascular Research Institute, University of
California, San Francisco
Bertram G. Katzung, MD, PhD
Professor Emeritus, Department of Cellular & Molecular
Pharmacology, University of California, San Francisco
Gideon Koren, MD, FRCPC, FACMT
Consultant, Kiryat Ono, Israel
Michael J. Kosnett, MD, MPH
Associate Clinical Professor of Medicine, Division of
Clinical Pharmacology and Toxicology, University of
Colorado Health Sciences Center, Denver
Marieke Kruidering-Hall, PhD
Academy Chair in Pharmacology Education; Professor,
Department of Cellular and Molecular Pharmacology,
University of California, San Francisco
Douglas F. Lake, PhD
Associate Professor, The Biodesign Institute, Arizona
State University, Tempe
Harry W. Lampiris, MD
Professor of Clinical Medicine, UCSF, Interim Chief,
ID Section, Medical Service, San Francisco VA Medical
Center, San Francisco
Paul W. Lofholm, PharmD
Clinical Professor of Pharmacy, School of Pharmacy,
University of California, San Francisco
Roger K. Long, MD
Professor of Pediatrics, Department of Pediatrics,
University of California, San Francisco
Christian Lüscher, MD
Departments of Basic and Clinical Neurosciences,
Medical Faculty, University Hospital of Geneva, Geneva,
Switzerland
Daniel S. Maddix, PharmD
Associate Clinical Professor of Pharmacy, University of
California, San Francisco
Howard I. Maibach, MD
Professor of Dermatology, Department of Dermatology,
University of California, San Francisco
Mary J. Malloy, MD
Clinical Professor of Pediatrics and Medicine,
Departments of Pediatrics and Medicine, Cardiovascular
Research Institute, University of California,
San Francisco
Kathleen Martin, PhD
Associate Professor, Yale Cardiovascular Center, Yale
University, New Haven
Umesh Masharani, MBBS, MRCP (UK)
Professor of Medicine, Department of Medicine,
University of California, San Francisco
Kenneth R. McQuaid, MD
Professor of Clinical Medicine, University of California,
San Francisco; Chief of Gastroenterology, San Francisco
Veterans Affairs Medical Center, San Francisco
Ramana K. Naidu, MD
Department of Anesthesia and Perioperative Care,
University of California, San Francisco

Ahmed A. Negm, MD
Department of Medicine, University of California,
Los Angeles
Martha S. Nolte Kennedy, MD
Clinical Professor, Department of Medicine, University
of California, San Francisco
Kent R. Olson, MD
Clinical Professor, Department of Medicine, Schools of
Medicine and Pharmacy, University of California, San
Francisco; Medical Director, San Francisco Division,
California Poison Control System, San Francisco
Achilles J. Pappano, PhD
Professor Emeritus, Department of Cell Biology and
Calhoun Cardiology Center, University of Connecticut
Health Center, Farmington
David Pearce, MD
Professor of Medicine, University of California,
San Francisco
Roger J. Porter, MD
Adjunct Professor of Neurology, University of
Pennsylvania, Philadelphia; Adjunct Professor of
Pharmacology, Uniformed Services University of the
Health Sciences, Bethesda
Ian A. Reid, PhD
Professor Emeritus, Department of Physiology,
University of California, San Francisco
David Robertson, MD
Elton Yates Professor of Medicine, Pharmacology and
Neurology, Vanderbilt University; Director, Clinical &
Translational Research Center, Vanderbilt Institute for
Clinical and Translational Research, Nashville
Dirk B. Robertson, MD
Professor of Clinical Dermatology, Department of
Dermatology, Emory University School of Medicine,
Atlanta
Michael A. Rogawski, MD, PhD
Professor of Neurology, Department of Neurology,
University of California, Davis
Philip J. Rosenthal, MD
Professor of Medicine, San Francisco General Hospital,
University of California, San Francisco
AUTHORS    xi
Sharon Safrin, MD
Associate Clinical Professor, Department of Medicine,
University of California, San Francisco; President, Safrin
Clinical Research, Hillsborough
Ramin Sam, MD
Associate Professor, Department of Medicine, University
of California, San Francisco
Mark A. Schumacher, PhD, MD
Professor, Department of Anesthesia and Perioperative
Care, University of California, San Francisco
Daniel T. Teitelbaum, MD
Adjunct Professor of Occupational and Environmental
Health, Colorado School of Public Health, Denver;
and Adjunct Professor, Civil and Environmental
Engineering, Colorado School of Mines, Golden
Anthony J. Trevor, PhD
Professor Emeritus, Department of Cellular & Molecular
Pharmacology, University of California, San Francisco
Candy Tsourounis, PharmD
Professor of Clinical Pharmacy, Medication Outcomes
Center, University of California, San Francisco School of
Pharmacy, San Francisco
Mark von Zastrow, MD, PhD
Professor, Departments of Psychiatry and Cellular &
Molecular Pharmacology, University of California,
San Francisco
Lisa G. Winston, MD
Clinical Professor, Department of Medicine, Division
of Infectious Diseases, University of California,
San Francisco; Hospital Epidemiologist, San Francisco
General Hospital, San Francisco
Spencer Yost, MD
Professor, Department of Anesthesia and Perioperative
Care, University of California, San Francisco; Medical
Director, UCSF-Mt. Zion ICU, Chief of Anesthesia,
UCSF-Mt. Zion Hospital, San Francisco
James L. Zehnder, MD
Professor of Pathology and Medicine, Pathology
Department, Stanford University School of Medicine,
Stanford
 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 Depressants:
Schedule II barbiturates in mixtures with noncontrolled drugs or in
(All nonresearch use illegal under federal law.) suppository dosage form
Flunitrazepam (Rohypnol) Barbiturates (butabarbital [Butisol], butalbital [Fiorinal])
Narcotics: Ketamine (Ketalar)
Heroin and many nonmarketed synthetic narcotics
Cannabinoids:
Hallucinogens: Dronabinol (Marinol)
LSD
Anabolic Steroids:
MDA, STP, DMT, DET, mescaline, peyote, bufotenine, ibogaine, Fluoxymesterone (Androxy), Methyltestosterone (Android, Testred),
psilocybin, phencyclidine (PCP; veterinary drug only) Oxandrolone (Oxandrin), Oxymetholone (Androl-50),
Marijuana Testosterone and its esters (Androgel)
Methaqualone

SCHEDULE II SCHEDULE IV
(Prescription must be rewritten after 6 months or five refills; differs from
(No telephone prescriptions, no refills.)2 Schedule III in penalties for illegal possession.)
Opioids: Opioids:
Opium: Opium alkaloids and derived phenanthrene alkaloids: Butorphanol (Stadol)
codeine, morphine (Avinza, Kadian, MSContin, Roxanol),
hydrocodone and hydrocodone combinations (Zohydro ER, Difenoxin 1 mg + atropine 25 mcg (Motofen)
Hycodan, Vicodin, Lortab), hydromorphone (Dilaudid), Pentazocine (Talwin)
oxymorphone (Exalgo), oxycodone (dihydroxycodeinone, a Stimulants:
component of Oxycontin, Percodan, Percocet, Roxicodone, Tylox) Armodafinil (Nuvigil)
Designated synthetic drugs: meperidine (Demerol), methadone, Diethylpropion (Tenuate) not in USA
levorphanol (Levo-Dromoran), fentanyl (Duragesic, Actiq, Modafinil (Provigil)
Fentora), alfentanil (Alfenta), sufentanil (Sufenta), remifentanil Phentermine (Adipex-P)
(Ultiva), tapentadol (Nycynta) Depressants:
Stimulants: Benzodiazepines: Alprazolam (Xanax), Chlordiazepoxide (Librium),
Coca leaves and cocaine Clobazam (Onfi), Clonazepam (Klonopin), Clorazepate (Tranxene),
Amphetamines: Amphetamine complex (Biphetamine), Diazepam (Valium), Estazolam, Flurazepam (Dalmane), Lorazepam
Amphetamine salts (Adderall), Dextroamphetamine (Dexedrine, (Ativan), Midazolam (Versed), Oxazepam, Quazepam (Doral),
Procentra), Lisdexamfetamine (Vyvanse), Methamphetamine Temazepam (Restoril), Triazolam (Halcion)
(Desoxyn), Methylphenidate (Ritalin, Concerta, Methylin, Carisoprodol (Soma)
Daytrana, Medadate), Above in mixtures with other controlled or Chloral hydrate
uncontrolled drugs
Eszopiclone (Lunesta)
Cannabinoids:
Nabilone (Cesamet) Lacosamide (Vimpat)
Depressants: Meprobamate
Amobarbital (Amytal) Methohexital (Brevital)
Pentobarbital (Nembutal) Paraldehyde not in USA
Secobarbital (Seconal) Phenobarbital
Tramadol (Ultram)
Zaleplon (Sonata)
SCHEDULE III Zolpidem (Ambien)
(Prescription must be rewritten after 6 months or five refills.)
Opioids:
Buprenorphine (Buprenex, Subutex) SCHEDULE V
Mixture of above Buprenorphine and Naloxone (Suboxone) (As any other nonopioid prescription drug)
The following opioids in combination with one or more active Codeine: 200 mg/100 mL
nonopioid ingredients, provided the amount does not exceed that Difenoxin preparations: 0.5 mg + 25 mcg atropine
shown: Dihydrocodeine preparations: 10 mg/100 mL
Codeine and dihydrocodeine: not to exceed 1800 mg/dL or 90 mg/ Diphenoxylate (not more than 2.5 mg and not less than 0.025 mg of
tablet or other dosage unit atropine per dosage unit, as in Lomotil)
Opium: 500 mg/dL or 25 mg/5 mL or other dosage unit (paregoric) Opium preparations: 100 mg/100 mL
Stimulants: Pregabalin (Lyrica)
Benzphetamine (Regimex)
Phendimetrazine

1
See https://www.deadiversion.usdoj.gov/schedules.
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. CMEA (Combat Methamphetamine Epidemic Act of 2005) establishes regulations for ephedrine, pseudoephedrine, and phenylpropanolamine
over-the-counter sales and purchases.
 SECTION I BASIC PRINCIPLES
Introduction: The Nature of
Drugs & Drug Development
& Regulation
Bertram G. Katzung, MD, PhD*
C ASE STUDY
A 78-year-old woman is brought to the hospital because of
suspected aspirin overdose. She has taken aspirin for joint pain
for many years without incident, but during the past year, she
has exhibited many signs of cognitive decline. Her caregiver
finds her confused, hyperventilating, and vomiting. The care-
giver finds an empty bottle of aspirin tablets and calls 9-1-1.
Pharmacology can be defined as the study of substances that
interact with living systems through chemical processes. These
interactions usually occur by binding of the substance to regula-
tory molecules and activating or inhibiting normal body processes.
These substances may be chemicals administered to achieve a
beneficial therapeutic effect on some process within the patient or
for their toxic effects on regulatory processes in parasites infecting
*
The author thanks Barry Berkowitz, PhD, for contributions to the
second part of this chapter.
1
C H A P T E R
In the emergency department, samples of venous and arterial
blood are obtained while the airway, breathing, and circulation
are evaluated. An intravenous (IV) drip is started, and gastro-
intestinal decontamination is begun. After blood gas results are
reported, sodium bicarbonate is administered via the IV. What
is the purpose of the sodium bicarbonate?
the patient. Such deliberate therapeutic applications may be con-
sidered the proper role of medical pharmacology, which is often
defined as the science of substances used to prevent, diagnose, and
treat disease. Toxicology is the branch of pharmacology that deals
with the undesirable effects of chemicals on living systems, from
individual cells to humans to complex ecosystems (Figure 1–1).
The nature of drugs—their physical properties and their inter-
actions with biological systems—is discussed in part I of this
chapter. The development of new drugs and their regulation by
government agencies are discussed in part II.
1
2    SECTION I Basic Principles

drug preparation and the medical uses of drugs—began to develop

Chemical
as the precursor to pharmacology. However, any real understand-
ing of the mechanisms of action of drugs was prevented by the
absence of methods for purifying active agents from the crude
Pharmacokinetics

Patient Environment materials that were available and—even more—by the lack of
methods for testing hypotheses about the nature of drug actions.
In the late 18th and early 19th centuries, François Magendie
and his student Claude Bernard began to develop the methods
Intended Unintended Other of experimental physiology and pharmacology. Advances in
target targets organisms chemistry and the further development of physiology in the
tissues
18th, 19th, and early 20th centuries laid the foundation needed
Pharmacodynamics

Food
chain
Therapeutic
effects
Toxic More
effects organisms
Medical pharmacology Environmental
and toxicology toxicology
FIGURE 1–1 Major areas of study in pharmacology. The actions
of chemicals can be divided into two large domains. The first (left
side) is that of medical pharmacology and toxicology, which is aimed
at understanding the actions of drugs as chemicals on individual
organisms, especially humans and domestic animals. Both beneficial
and toxic effects are included. Pharmacokinetics deals with the
absorption, distribution, and elimination of drugs. Pharmacodynamics
concerns the actions of the chemical on the organism. The second
domain (right side) is that of environmental toxicology, which is
concerned with the effects of chemicals on all organisms and their
survival in groups and as species.
THE HISTORY OF PHARMACOLOGY
Prehistoric people undoubtedly recognized the beneficial or toxic
effects of many plant and animal materials. Early written records
list remedies of many types, including a few that are still recog-
nized as useful drugs today. Most, however, were worthless or
actually harmful. In the last 1500 years, sporadic attempts were
made to introduce rational methods into medicine, but none
was successful owing to the dominance of systems of thought
(“schools”) that purported to explain all of biology and disease
without the need for experimentation and observation. These
schools promulgated bizarre notions such as the idea that disease
was caused by excesses of bile or blood in the body, that wounds
could be healed by applying a salve to the weapon that caused the
wound, and so on.
Around the end of the 17th century, reliance on observation
and experimentation began to replace theorizing in physiology
and clinical medicine. As the value of these methods in the study
of disease became clear, physicians in Great Britain and on the
Continent began to apply them to the effects of traditional drugs
used in their own practices. Thus, materia medica—the science of
for 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
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 adequately evaluate
therapeutic claims.
Around the 1940s and 1950s, a major expansion of research
efforts in all areas of biology began. As new concepts and new
techniques were introduced, information accumulated about drug
action and the biologic substrate of that action, the drug receptor.
During the last 60 years, many fundamentally new drug groups
and new members of old groups were introduced. The last four
decades have seen an even more rapid growth of information
and understanding of the molecular basis for drug action. The
molecular mechanisms of action of many drugs have now been
identified, and numerous receptors have been isolated, structurally
characterized, and cloned. In fact, the use of receptor identifica-
tion methods (described in Chapter 2) has led to the discovery
of many orphan receptors—receptors for which no ligand has
been discovered and whose function can only be guessed. Stud-
ies of the local molecular environment of receptors have shown
that receptors and effectors do not function in isolation; they are
strongly influenced by other receptors and by companion regula-
tory proteins.
Pharmacogenomics—the relation of the individual’s genetic
makeup to his or her response to specific drugs—is becoming an
important part of therapeutics (see Chapter 5). Decoding of the
genomes of many species—from bacteria to humans—has led
to the recognition of unsuspected relationships between recep-
tor families and the ways that receptor proteins have evolved.
Discovery that small segments of RNA can interfere with protein
synthesis with extreme selectivity has led to investigation of small
interfering RNAs (siRNAs) and micro-RNAs (miRNAs) as ther-
apeutic agents. Similarly, short nucleotide chains called antisense
oligonucleotides (ANOs), synthesized to be complementary to
natural RNA or DNA, can interfere with the readout of genes and
the transcription of RNA. These intracellular targets may provide
the next major wave of advances in therapeutics.
Unfortunately, the medication-consuming public is still
exposed to vast amounts of inaccurate or unscientific information
regarding the pharmacologic effects of chemicals. This has resulted
in the irrational use of innumerable expensive, ineffective, and
 CHAPTER 1 Introduction: The Nature of Drugs & Drug Development & Regulation     3
sometimes harmful remedies and the growth of a huge “alternative
health care” industry. Furthermore, manipulation of the legislative
process in the United States has allowed many substances pro-
moted for health—but not promoted specifically as “drugs”—to
avoid meeting the Food and Drug Administration (FDA) stan-
dards described in the second part of this chapter. Conversely,
lack of understanding of basic scientific principles in biology and
statistics and the absence of critical thinking about public health
issues have led to rejection of medical science by a segment of the
public and to a common tendency to assume that all adverse drug
effects are the result of malpractice.
General principles that the student should remember are
(1) that all substances can under certain circumstances be toxic;
(2) that the chemicals in botanicals (herbs and plant extracts,
“nutraceuticals”) are no different from chemicals in manufactured
drugs except for the much greater proportion of impurities in
botanicals; and (3) that all dietary supplements and all therapies
promoted as health-enhancing should meet the same standards of
efficacy and safety as conventional drugs and medical therapies.
That is, there should be no artificial separation between scientific
medicine and “alternative” or “complementary” medicine. Ideally,
all nutritional and botanical substances should be tested by the
same types of randomized controlled trials (RCTs) as synthetic
compounds.
■■ I GENERAL PRINCIPLES OF
PHARMACOLOGY
THE NATURE OF DRUGS
In the most general sense, a drug may be defined as any sub-
stance that brings about a change in biologic function through
its chemical actions. In most cases, the drug molecule interacts
as an agonist (activator) or antagonist (inhibitor) with a specific
target molecule that plays a regulatory role in the biologic system.
This target molecule is called a receptor. The nature of recep-
tors is discussed more fully in Chapter 2. In a very small number
of cases, drugs known as chemical antagonists may interact
directly with other drugs, whereas a few drugs (osmotic agents)
interact almost exclusively with water molecules. Drugs may be
synthesized within the body (eg, hormones) or may be chemicals
not synthesized in the body (ie, xenobiotics). Poisons are drugs
that have almost exclusively harmful effects. However, Paracelsus
(1493–1541) famously stated that “the dose makes the poison,”
meaning that any substance can be harmful if taken in the wrong
dosage. Toxins are usually defined as poisons of biologic origin, ie,
synthesized by plants or animals, in contrast to inorganic poisons
such as lead and arsenic.
The Physical Nature of Drugs
To interact chemically with its receptor, a drug molecule must
have the appropriate size, electrical charge, shape, and atomic
composition. Furthermore, a drug is often administered at a
location distant from its intended site of action, eg, a pill given
orally to relieve a headache. Therefore, a useful drug must have
the necessary properties to be transported from its site of admin-
istration to its site of action. Finally, a practical drug should be
inactivated or excreted from the body at a reasonable rate so that
its actions will be of appropriate duration.
Drugs may be solid at room temperature (eg, aspirin, atro-
pine), liquid (eg, nicotine, ethanol), or gaseous (eg, nitrous oxide).
These factors often determine the best route of administration.
The most common routes of administration are described in
Chapter 3, Table 3–3. The various classes of organic compounds—
carbohydrates, proteins, lipids, and smaller molecules—are all rep-
resented in pharmacology. As noted above, oligonucleotides, in the
form of small segments of RNA, have entered clinical trials and are
on the threshold of introduction into therapeutics.
A number of useful or dangerous drugs are inorganic elements,
eg, lithium, iron, and heavy metals. Many organic drugs are weak
acids or bases. This fact has important implications for the way
they are handled by the body, because pH differences in the vari-
ous compartments of the body may alter the degree of ionization
of weak acids and bases (see text that follows).
Drug Size
The molecular size of drugs varies from very small (lithium ion,
molecular weight [MW] 7) to very large (eg, alteplase [t-PA], a
protein of MW 59,050). However, most drugs have molecular
weights between 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” to only one type of receptor, a drug molecule
must be sufficiently unique in shape, charge, and other properties
to prevent its binding to other receptors. To achieve such selective
binding, it appears that a molecule should in most cases be at least
100 MW units in size. The upper limit in molecular weight is
determined primarily by the requirement that drugs must be able
to move within the body (eg, from the site of administration to
the site of action). Drugs much larger than MW 1000 do not dif-
fuse readily between compartments of the body (see Permeation,
in following text). Therefore, very large drugs (usually proteins)
must often be administered directly into the compartment where
they have their effect. In the case of alteplase, a clot-dissolving
enzyme, the drug is administered directly into the vascular
compartment by intravenous or intra-arterial infusion.
Drug Reactivity & Drug-Receptor Bonds
Drugs interact with receptors by means of chemical forces or
bonds. These are of three major types: covalent, electrostatic, and
hydrophobic. Covalent bonds are very strong and in many cases
not reversible under biologic conditions. Thus, the covalent bond
formed between the acetyl group of acetylsalicylic acid (aspirin)
and cyclooxygenase, its enzyme target in platelets, is not readily
broken. The platelet aggregation–blocking effect of aspirin lasts
long after free acetylsalicylic acid has disappeared from the blood-
stream (about 15 minutes) and is reversed only by the synthesis
of new enzyme in new platelets, a process that takes several days.
4    SECTION I Basic Principles
Other examples of highly reactive, covalent bond-forming drugs
include the DNA-alkylating agents used in cancer chemotherapy
to disrupt cell division in the tumor.
Electrostatic bonding is much more common than covalent
bonding in drug-receptor interactions. Electrostatic bonds vary
from relatively strong linkages between permanently charged
ionic molecules to weaker hydrogen bonds and very weak induced
dipole interactions such as van der Waals forces and similar
phenomena. Electrostatic bonds are weaker than covalent bonds.
Hydrophobic bonds are usually quite weak and are probably
important in the interactions of highly lipid-soluble drugs with
the lipids of cell membranes and perhaps in the interaction of
drugs with the internal walls of receptor “pockets.”
The specific nature of a particular drug-receptor bond is of less
practical importance than the fact that drugs that bind through
weak bonds to their receptors are generally more selective than
drugs that bind by means of very strong bonds. This is because
weak bonds require a very precise fit of the drug to its receptor
if an interaction is to occur. Only a few receptor types are likely
to provide such a precise fit for a particular drug structure. Thus,
if we wished to design a highly selective short-acting drug for a
particular receptor, we would avoid highly reactive molecules that
form covalent bonds and instead choose a molecule that forms
weaker bonds.
A few substances that are almost completely inert in the
chemical sense nevertheless have significant pharmacologic
effects. For example, xenon, an “inert” gas, has anesthetic effects
at elevated pressures.
Drug Shape
The shape of a drug molecule must be such as to permit binding to
its receptor site via the bonds just described. Optimally, the drug’s
shape is complementary to that of the receptor site in the same way
that a key is complementary to a lock. Furthermore, the phenom-
enon of chirality (stereoisomerism) is so common in biology that
more than half of all useful drugs are chiral molecules; that is, they
can exist as enantiomeric pairs. Drugs with two asymmetric centers
have four diastereomers, eg, ephedrine, a sympathomimetic drug.
In most cases, one of these enantiomers is much more potent than
its mirror image enantiomer, reflecting a better fit to the receptor
molecule. If one imagines the receptor site to be like a glove into
which the drug molecule must fit to bring about its effect, it is
clear why a “left-oriented” drug is more effective in binding to a
left-hand receptor than its “right-oriented” enantiomer.
The more active enantiomer at one type of receptor site may
not be more active at another receptor type, eg, a type that may be
responsible for some other effect. For example, carvedilol, a drug
that interacts with adrenoceptors, has a single chiral center and
thus two enantiomers (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 isomers are
approximately equipotent as α-receptor blockers. Ketamine is an
intravenous anesthetic. The (+) enantiomer is a more potent anes-
thetic and is less toxic than the (–) enantiomer. Unfortunately, the
drug is still used as the racemic mixture.
TABLE 1–1 Dissociation constants (Kd) of the
enantiomers and racemate of carvedilol.
` Receptors a Receptors
Form of Carvedilol (Kd, nmol/L1) (Kd, nmol/L)
R(+) enantiomer 14 45
S(−) enantiomer 16 0.4
R,S(±) enantiomers 11 0.9
1
The Kd is the concentration for 50% saturation of the receptors and is inversely
proportionate to the affinity of the drug for the receptors.
Data from Ruffolo RR et al: The pharmacology of carvedilol. Eur J Clin Pharmacol
1990;38:S82.
Finally, because enzymes are usually stereoselective, one drug
enantiomer is often more susceptible than the other to drug-
metabolizing enzymes. As a result, the duration of action of one
enantiomer may be quite different from that of the other. Simi-
larly, drug transporters may be stereoselective.
Unfortunately, most studies of clinical efficacy and drug elimina-
tion in humans have been carried out with racemic mixtures of drugs
rather than with the separate enantiomers. At present, only a small
percentage of the chiral drugs used clinically are marketed as the
active isomer—the rest are available only as racemic mixtures. As a
result, most patients receive drug doses of which 50% is less active or
inactive. Some drugs are currently available in both the racemic and
the pure, active isomer forms. However, proof that administration of
the pure, active enantiomer decreases adverse effects relative to those
produced by racemic formulations has not been established.
Rational Drug Design
Rational design of drugs implies the ability to predict the appro-
priate molecular structure of a drug on the basis of information
about its biologic receptor. Until recently, no receptor was known
in sufficient detail to permit such drug design. Instead, drugs
were developed through random testing of chemicals or modifica-
tion of drugs already known to have some effect. However, the
characterization of many receptors during the past three decades
has changed this picture. A few drugs now in use were developed
through molecular design based on knowledge of the three-
dimensional structure of the receptor site. Computer programs
are now available that can iteratively optimize drug structures
to fit known receptors. As more becomes known about receptor
structure, rational drug design will become more common.
Receptor Nomenclature
The spectacular success of newer, more efficient ways to identify
and characterize receptors (see Chapter 2) has resulted in a variety
of differing, and sometimes confusing, systems for naming them.
This in turn has led to a number of suggestions regarding more
rational methods of naming receptors. The interested reader is
referred for details to the efforts of the International Union of
Pharmacology (IUPHAR) Committee on Receptor Nomenclature
and Drug Classification (reported in various issues of Pharma-
cological Reviews and elsewhere) and to Alexander SP et al: The
Concise Guide to PHARMACOLOGY 2015/16: Overview.
 CHAPTER 1 Introduction: The Nature of Drugs & Drug Development & Regulation     5
Br J Pharmacol 2015;172:5729. The chapters in this book mainly
use these sources for naming receptors.
DRUG-BODY INTERACTIONS
The interactions between a drug and the body are conveniently
divided into two classes. The actions of the drug on the body are
termed pharmacodynamic processes (Figure 1–1); the principles
of pharmacodynamics are presented in greater detail in Chapter 2.
These properties determine the group in which the drug is classi-
fied, and they play the major role in deciding whether that group is
appropriate therapy for a particular symptom or disease. The actions
of the body on the drug are called pharmacokinetic processes and
are described in Chapters 3 and 4. Pharmacokinetic processes gov-
ern the absorption, distribution, and elimination of drugs and are
of great practical importance in the choice and administration of a
particular drug for a particular patient, eg, a patient with impaired
renal function. The following paragraphs provide a brief introduc-
tion to pharmacodynamics and pharmacokinetics.
Pharmacodynamic Principles
Most drugs must bind to a receptor to bring about an effect.
However, at the cellular level, drug binding is only the first in a
sequence of steps:
• Drug (D) + receptor-effector (R) → drug-receptor-effector
complex → effect
• D + R → drug-receptor complex → effector molecule → effect
• D + R → D-R complex → activation of coupling molecule →
effector molecule → effect
• Inhibition of metabolism of endogenous activator → increased
activator action on an effector molecule → increased effect
Note that the final change in function is accomplished by an
effector mechanism. The effector may be part of the receptor
molecule or may be a separate molecule. A very large number
of receptors communicate with their effectors through coupling
molecules, as described in Chapter 2.
A. Types of Drug-Receptor Interactions
Agonist drugs bind to and activate the receptor in some fashion,
which directly or indirectly brings about the effect (Figure 1–2A).
Receptor activation involves a change in conformation in the
cases that have been studied at the molecular structure level. Some
receptors incorporate effector machinery in the same molecule, so
that drug binding brings about the effect directly, eg, opening of
an ion channel or activation of enzyme activity. Other receptors
are linked through one or more intervening coupling molecules
to a separate effector molecule. The major types of drug-receptor-
effector coupling systems are discussed in Chapter 2. Pharmaco-
logic antagonist drugs, by binding to a receptor, compete with
and prevent binding by other molecules. For example, acetylcho-
line receptor blockers such as atropine are antagonists because
they prevent access of acetylcholine and similar agonist drugs to
the acetylcholine receptor site and they stabilize the receptor in its
inactive state (or some state other than the acetylcholine-activated
state). These agents reduce the effects of acetylcholine and similar
molecules in the body (Figure 1–2B), but their action can be over-
come by increasing the dosage of agonist. Some antagonists bind
very tightly to the receptor site in an irreversible or pseudoirre-
versible fashion and cannot be displaced by increasing the agonist
concentration. Drugs that bind to the same receptor molecule but
do not prevent binding of the agonist are said to act allosterically
and may enhance (Figure 1–2C) or inhibit (Figure 1–2D) the
action of the agonist molecule. Allosteric inhibition is not usually
overcome by increasing the dose of agonist.
B. Agonists That Inhibit Their Binding Molecules
Some drugs mimic agonist drugs by inhibiting the molecules
responsible for terminating the action of an endogenous ago-
nist. For example, acetylcholinesterase inhibitors, by slowing the
destruction of endogenous acetylcholine, cause cholinomimetic
effects that closely resemble the actions of cholinoceptor agonist
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,
their effects are sometimes more selective and less toxic than those
of exogenous agonists.
C. Agonists, Partial Agonists, and Inverse Agonists
Figure 1–3 describes a useful model of drug-receptor interaction.
As indicated, the receptor is postulated to exist in the inactive,
nonfunctional form (Ri) and in the activated form (Ra). Ther-
modynamic considerations indicate that even in the absence of
any agonist, some of the receptor pool must exist in the Ra form
some of the time and may produce the same physiologic effect
as agonist-induced activity. This effect, occurring in the absence
of agonist, is termed constitutive activity. Agonists have a much
higher affinity for the Ra configuration and stabilize it, so that a
large percentage of the total pool resides in the Ra–D fraction and
a large effect is produced. The recognition of constitutive activity
may depend on the receptor density, the concentration of cou-
pling molecules (if a coupled system), and the number of effectors
in the system.
Many agonist drugs, when administered at concentrations
sufficient to saturate the receptor pool, can activate their receptor-
effector systems to the maximum extent of which the system is
capable; that is, they cause a shift of almost all of the receptor pool
to the Ra–D pool. Such drugs are termed full agonists. Other
drugs, called partial agonists, bind to the same receptors and acti-
vate them in the same way but do not evoke as great a response, no
matter how high the concentration. In the model in Figure 1–3,
partial agonists do not stabilize the Ra configuration as fully as
full agonists, so that a significant fraction of receptors exists in
the Ri–D pool. Such drugs are said to have low intrinsic efficacy.
Because they occupy the receptor, partial agonists can also prevent
access by full agonists. Thus, pindolol, a β-adrenoceptor partial
agonist, may act either as an agonist (if no full agonist is present)
or as an antagonist (if a full agonist such as epinephrine is pres-
ent). (See Chapter 2.) Intrinsic efficacy is independent of affinity
(as usually measured) for the receptor.
6    SECTION I Basic Principles

Drug Receptor Effects

Agonist +

A+C A alone

Response
–
A+B
B

A+D

Log Dose
Competitive
inhibitor

Allosteric
activator

Allosteric inhibitor

FIGURE 1–2 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
(competitive 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.

In the same model, conventional antagonist action can be
explained as fixing the fractions of drug-bound Ri and Ra in
the same relative amounts as in the absence of any drug. In this
situation, no change in activity will be observed, so the drug will
appear to be without effect. However, the presence of the antago-
nist at the receptor site will block access of agonists to the receptor
and prevent the usual agonist effect. Such blocking action can be
termed neutral antagonism.
What will happen if a drug has a much stronger affinity for the
Ri than for the Ra state and stabilizes a large fraction in the Ri–D
pool? In this scenario the drug will reduce any constitutive activity,
thus resulting in effects that are the opposite of the effects produced
by conventional agonists at that receptor. Such drugs are termed
inverse agonists (Figure 1–3). One of the best documented exam-
ples of such a system is the γ-aminobutyric acid (GABAA) receptor-
effector (a chloride channel) in the nervous system. This receptor is
activated by the endogenous transmitter GABA and causes inhibi-
tion of postsynaptic cells. Conventional exogenous agonists such
as benzodiazepines also facilitate the receptor-effector system and
cause GABA-like inhibition with sedation as the therapeutic result.
This sedation can be reversed by conventional neutral antagonists
such as flumazenil. Inverse agonists of this receptor system cause
anxiety and agitation, the inverse of sedation (see Chapter 22).
Similar inverse agonists have been found for β adrenoceptors,
histamine H1 and H2 receptors, and several other receptor systems.
D. Duration of Drug Action
Termination of drug action can result from several processes. In
some cases, the effect lasts only as long as the drug occupies the
receptor, and dissociation of drug from the receptor automatically
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 drugs that bind covalently to the receptor site, the effect may
persist until the drug-receptor complex is destroyed and new recep-
tors or enzymes are synthesized, as described previously for aspirin.
Another random document with
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 They returned to the well, and there, to French’s satisfaction,
found the missing duplicator parts laid out on the coping of the wall.
“Excellent, Sergeant. That’s all we want. I take it you will get the
pump away? You needn’t wait for me. I’m going out with Colonel
Domlio.”
While Coombe was bringing round the car the two men went to
the study for the letter. It was just as the colonel had described, and
French could see no clue to the sender.
They ran out then to the Upper Merton glen and Domlio pointed
out the spot at which the alleged incident had taken place. French
insisted on his describing the occurrence in the most minute manner.
He wished to form an opinion as to whether the man was relating
what he had seen or inventing the details as he went along.
After half an hour of close questioning on the lines of the
American third degree, French had to admit that the affair had either
happened as Domlio had said or that it had been rehearsed with
great care. On no point was he able to trip the colonel up, and
knowing the difficulty of inventing a story in which every detail is
foreseen and accounted for, he began to think the tale true. At all
events, with the mass of detail he now possessed, a similar
examination of Mrs. Berlyn should set the matter at rest.
French was in a thoughtful mood as they drove back to Torview.
He was up against the same old question which had troubled him so
many times in the past. Was his suspect guilty or was he the victim
of a plot?
The evidence against the man was certainly strong. Seven
separate facts pointed to his guilt. French ran over them in his mind:
1. Domlio had the necessary qualifications for partnership in the
crime. He knew the dramatis personæ and he was acquainted with
the works. He could have ordered the duplicator, and arranged for
Berlyn and Pyke to visit Tavistock on the night in question.
2. He was out in his car on that night at the time and for the
distance required.
3. He had denied this.
4. When cornered he had told a false story of a search for a lost
locket.
 5. The clothes of the dead man had been found in the very place
where French imagined Domlio would have hidden them.
6. There was a quite adequate motive if, as might well be, Domlio
was really attached to Mrs. Berlyn.
7. There was no other person whom French knew of who could
have been Berlyn’s confederate.
Many and many a man had been hanged on far less evidence
than there was here. With this mass of incriminating facts an arrest
was amply justifiable. Indeed, a conviction was almost assured.
On the other hand, every bit of this evidence was circumstantial
and could be explained on the assumption of Domlio’s innocence, by
supposing him to be the victim of a conspiracy on the part of the real
murderer.
French wondered if he could make the man reveal his own
outlook on the affair.
“Tell me, Colonel,” he said, “did it not strike you as a strange thing
that Mrs. Berlyn should stumble at just the point which ensured her
falling into your arms?”
Domlio slackened speed and looked around aggressively.
“Just what do you mean by that?”
“As a matter of fact,” French answered, sweetly, “what I mean is,
was the accident genuine or faked?”
The colonel squared his shoulders indignantly.
“I consider that a most unwarrantable remark,” he said, hotly,
“and I shall not answer it. I can only suppose your abominable calling
has warped your mind and made suspicion a disease with you.”
French glanced at him keenly. The man was genuinely angry.
And if so, it tended in his favour. Real indignation is difficult to
simulate and would not be called forth by an imaginary insult.
“If you think my remark unwarrantable, I shall withdraw it,” French
said, with his pleasant smile. “I simply wanted to know whether you
yourself believed in it. I think you do. Well, Colonel, I think that’s all
we can do to-night. I’m sorry to have given you all this annoyance,
but you can see I had no option.”
They had reached the gate of Torview. Domlio stopped the car.
“Then you are not going to arrest me?” he asked, with barely
concealed anxiety.
 “No. Why should I? You have accounted in a reasonable way for
the suspicious circumstances. So far as I can see, your explanation
is satisfactory. I can’t expect any more.”
The colonel gave a sigh of relief.
“To be quite candid,” he admitted, “I scarcely hoped that you
would accept it. After what has occurred, I can’t expect you to
believe me, but for what it’s worth I give you my word of honour that
what I have told you this time is the truth. I may tell you that I have
been afraid of this very development ever since the tragedy. How are
you getting to Ashburton? Shall I run you in?”
“It would be very good of you.”
It was with considerable uneasiness that French saw Colonel
Domlio drive off from the hotel in Ashburton. He had backed his
judgment that the man was innocent, but he recognised that he
might easily have made a mistake. At the same time Domlio could
scarcely escape otherwise than by suicide, and he felt sure that his
mind had been so much eased that he would not attempt anything
so drastic. As soon, however, as the car was out of sight he walked
to the police station and asked Daw to have a watch kept on the
man’s movements.
 Chapter Sixteen: Certainty at Last
That night as French was writing up his diary the question he had
asked Domlio recurred to him. “Tell me, Colonel,” he had said, “did it
not strike you as strange that Mrs. Berlyn should stumble at just the
point which ensured her falling into your arms?” He had asked it to
test the colonel’s belief in the incident. Now it occurred to him that on
its merits it required an answer.
Had the incident stood alone it might well have passed
unquestioned. But it was not alone. Two other matters must be
considered in conjunction with it.
First there was the coincidence that at the precise moment a
watcher armed with a camera should be present. What accident
should take a photographer to this secluded glen just when so
compromising a tableau should be staged? Was there here an
element of design?
Secondly, there was the consideration that if suspicion were to be
thrown on Domlio he must be made to take out his car secretly on
the fatal night. And how better could this be done than by the story of
the photograph? Once again, did this not suggest design?
If so, something both interesting and startling followed. Mrs.
Berlyn was privy to it. And if she were privy to it, was she not
necessarily implicated in the murder? Could she even be the
accomplice for whom he, French, had been searching?
There was, of course, her alibi. If she had been at the party at her
house at ten o’clock she could not have drugged Gurney’s tea. But
was she at her house?
Experience had made French sceptical about alibis. This one
certainly seemed watertight, and yet was it not just possible that Mrs.
Berlyn had managed to slip away from her guests for the fifteen or
twenty minutes required?
 It was evident that the matter must be tested forthwith, and
French decided that, having already questioned Mr. Fogden, he
would interview the Dr. and Mrs. Lancaster whom Lizzie Johnston
had mentioned as also being members of the party. They lived on
the Buckland road half a mile beyond the Berlyns’, and next morning
French called on them.
Dr. Lancaster, he had learned from Daw, was a newcomer to the
town, a young LL.D. who had been forced by a breakdown in health
to give up his career at the bar. He received French at once.
“I want to find out whether any member of the party could have
left the house about ten o’clock for fifteen or twenty minutes,” French
explained. “Do you think that you or Mrs. Lancaster could help me
out?”
“I can only speak for myself,” Dr. Lancaster smiled. “I was there
all the time, and I’m sure so was Mrs. Lancaster. But I’ll call her and
you can ask her.”
“A moment, please. Surely you can speak for more than
yourself? Were you not with the others?”
“With some of them. You see, what happened was this. When we
went in, Mrs. Berlyn said that she had been disappointed in that
three London friends, who were staying at Torquay and whom she
expected, had just telegraphed to say they couldn’t come. That
made our numbers wrong. She had intended to have three tables of
bridge, but now, as some of us played billiards, she suggested one
bridge table and snooker for the other five. She and I and—let me
see—Fogden and a Miss Pym, I think, and one other—I’m blessed if
I can remember who the other was—played snooker. So I wasn’t
with the other four between the time that we settled down to play and
supper.”
“What hour was supper?”
“About half past ten, I think. We broke up when it was over—
rather early, as a matter of fact. We reached home shortly after
eleven.”
“And you played snooker all the evening until supper?”
“No. After an hour or more we dropped it and played four-handed
billiards.”
“Then some player must have stood out?”
 “Yes. Mrs. Berlyn said she must go and see how the others were
getting along. She watched us play for some time, then went to the
drawing room. She came back after a few minutes to say that supper
was ready.”
“Now, Dr. Lancaster, just one other question. Can you tell me at
what time Mrs. Berlyn went into the drawing room?”
“I really don’t think I can. I wasn’t paying special attention to her
movements. I should say perhaps half an hour before supper, but I
couldn’t be sure.”
“That’s all right,” said French. “Now if I could see Mrs. Lancaster
for a moment I should be done.”
Mrs. Lancaster was a dark, vivacious little woman who seemed to
remember the evening in question much more clearly than did her
husband.
“Yes,” she said, “I was playing bridge with Miss Lucy Pym, Mr.
Cowls, and Mr. Leacock. I remember Mrs. Berlyn coming in about
ten. She laughed and said: ‘Oh, my children, don’t be frightened. I
couldn’t think of disturbing such a serious game. I’ll go back to our
snooker.’ She went away, and presently came back and called us to
the library to supper.”
“How long was she away, Mrs. Lancaster?”
“About twenty minutes, I should think.”
This seemed to French to be all that he wanted. However, he
thought it wise to get the key of the Berlyns’ house and have a look
at the layout. The drawing room was in front, with the library behind
it, but between the two there was a passage with a side door leading
into the garden. He felt satisfied as to the use to which that passage
had been put on the night in question. He could picture Mrs. Berlyn
fixing up the uneven number of guests, among whom would be some
who played billiards and some who did not. The proposals for
snooker and bridge would almost automatically follow, involving the
division of the party in two rooms. Mrs. Berlyn as hostess would
reasonably be the odd man out when the change was made from
snooker to billiards. The result of these arrangements would be that
when she slipped out to the works through the side door, each party
would naturally assume she was with the other, while if any question
as to this arose, her reëntry at supper-time would suggest to both
that she had gone out to overlook its preparation.
These discoveries justified French’s theory, but they did not prove
it, and he racked his brains for some test which would definitely
establish the point.
At last an idea occurred to him which he thought might at least
help.
In considering Mrs. Berlyn as her husband’s accomplice he had
been doubtful whether there would have been sufficient time for the
various actions. If after Berlyn’s arrival at the works with the body
Mrs. Berlyn had driven the car back to where it was found, changed
the magneto, and made the footprints, he did not believe she could
have walked home in time to wake the servants at the hour stated.
Nor did he believe that Berlyn, after disposing of the body in the
works, could have been able on foot to make Domlio’s in time to hide
the clothes in the well before the sergeant’s call.
He now wondered whether Mrs. Berlyn’s bicycle could have been
pressed into the service. Could the lady have brought the machine to
the works, lifted it into the tonneau of the car, carried it out on the
moor, and ridden back on it to the works? And could her husband
have used it to reach first Domlio’s and then Plymouth or some other
large town from which he had escaped?
To test the matter, French returned to Lizzie Johnston and asked
her if she knew what had become of the bicycle.
But the girl could not tell him. Nor could she recall when or where
she had seen it last. She supposed it had been sold at the auction,
but in the excitement of that time she had not noticed it.
“Where did Mrs. Berlyn get it, do you know?”
“From Makepeace’s. He has bicycles same as motors. He’ll tell
you about it.”
Half an hour later French was talking to Mr. Makepeace. He
remembered having some five years earlier sold the machine to Mrs.
Berlyn. He looked up his records, and after considerable trouble
found a note of the transaction. The bicycle was a Swift, and number
35,721. It had certain dimensions and peculiarities of which he gave
French details.
 French’s next call was on the auctioneer who had conducted the
sale of the Berlyn effects. Mr. Nankivell appeared au fait with the
whole case and was obviously thrilled to meet French. He made no
difficulty about giving the required information. A bicycle had not
been among the articles auctioned, nor had he seen one during his
visits to the house.
This was all very well as far as it went, but it was negative.
French wanted to find some one who could say definitely what had
happened to the machine. He consulted with Sergeant Daw and at
last came to the conclusion that if Peter Swann, the gardener-
chauffeur, could be found, he might be able to give the information.
Daw believed he had gone to Chagford, and he telephoned to the
sergeant there, asking him to make enquiries.
In the afternoon there was a reply to the effect that the man was
employed by a market gardener near Chagford, and French at once
took a car over to see him. Swann remembered the bicycle well, as
he had had to keep it clean. He had seen it in the woodshed on the
day before the tragedy, but next morning it was gone. He had looked
for it particularly, as he wished to use it to take a message to the
town and he had wondered where it could have got to. He had never
seen it again. He had not asked about it, as he had not considered
that his business.
Once again French experienced the keen delight of finding his
deductions justified by the event. In this whole case he had really
excelled himself. On several different points he had imagined what
might have occurred, and on a test being made, his idea had been
proved correct. Some work that! As he did not fail to remind himself,
it showed the highest type of ability.
The next thing was to find the bicycle. He returned for the night to
Ashburton, and next morning went down to see the superintendent
of police at Plymouth. That officer listened with interest to his story
and promised to have a search made without delay. When he had
rung up and asked for similar enquiries to be made in the other large
towns within a cycle ride of the moor, French found himself at a
loose end.
“You should have a look round the place,” the superintendent
advised. “There’s a lot to see in Plymouth.”
 French took the advice and went for a stroll round the city. He
was not impressed by the streets, though he admired St. Andrew’s
Church, the Guildhall, and some of the other buildings in the same
locality. But when, after wandering through some more or less
uninteresting residential streets, he unexpectedly came out on the
Hoe, he held his breath. The promenade along the top of the cliff
was imposing enough, though no better than he had seen many
times before. But the view of the Sound was unique. The sea, light
blue in the morning sun, stretched from the base of the cliff beneath
his feet out past Drake’s Island and the long line of the Breakwater to
a clear horizon. On the right was Mount Edgcumbe, tree clad to the
water’s edge, while far away out to the southwest was the faint white
pillar of the Eddystone lighthouse. French gazed and admired, then
going down to the Sutton Pool, he explored the older part of the town
for the best part of an hour.
When he presently reached the police station he was delighted to
find that news had just then come in. The bicycle had been found. It
had been pawned by a man, apparently a labourer, shortly after the
shop opened on the morning of Tuesday, the 16th August; the
morning, French reminded himself delightedly, after the crime. The
man had stated that the machine was his daughter’s and had been
given two pounds on it. He had not returned since, nor had the
machine been redeemed.
“We’re trying to trace the man, but after this lapse of time I don’t
suppose we shall be able,” the superintendent declared. “I expect
this Berlyn abandoned the machine when he reached Plymouth, and
our friend found it and thought he had better make hay while the sun
shone.”
“So likely that I don’t think it matters whether you find him or not,”
French returned.
“I agree, but we shall have a shot at it, all the same. By the way,
Mr. French, it’s a curious thing that you should call to-day. Only
yesterday I was talking to a friend of yours—an ass, if you don’t mind
my saying so, but married to one of the most delightful young women
I’ve ever come across. Lives at Dartmouth.”
“Dartmouth?” French laughed. “That gives me a clue. You mean
that cheery young optimist, Maxwell Cheyne? He is an ass right
enough, but he’s not a bad soul at bottom. And the girl’s a stunner.
How are they getting along?”
“Tip-top. He’s taken to writing tales. Doing quite well with them,
too, I believe. They’re very popular down there, both of them.”
“Glad to hear it. Well, Superintendent, I must be getting along.
Thanks for your help.”
French was full of an eager optimism as the result of these
discoveries. The disappearance of the bicycle, added to the
breakdown of the alibi, seemed definitely to prove his theory of Mrs.
Berlyn’s complicity.
But when he considered the identity of the person whom Mrs.
Berlyn had thus assisted, he had to admit himself staggered. That
Berlyn had murdered Pyke had seemed an obvious theory. Now
French was not so certain of it. The lady had undoubtedly been in
love with Pyke. Surely it was too much to suppose she would help
her husband to murder her lover?
Had it been the other way round, had Phyllis and Pyke conspired
to kill Berlyn, the thing would have been easier to understand. Wife
and lover against husband was a common enough combination. But
the evidence against this idea was strong. Not only was there the
identification of the clothes and birthmark, but there was the strong
presumption that the man who disposed of the crate in Wales was
Berlyn. At the same time this evidence of identification was not quite
conclusive, and French determined to keep the possibility in view
and test it rigorously as occasion offered.
And then another factor occurred to him, an extremely disturbing
factor, which bade fair to change his whole view of the case. He saw
that even if Pyke had murdered Berlyn it would not clear up the
situation. In fact, this new idea suggested that it was impossible
either that Pyke could have murdered Berlyn or that Berlyn could
have murdered Pyke.
What, he asked himself, must have been the motive for such a
crime? Certainly not merely to gratify a feeling of hate. The motive
undoubtedly was to enable the survivor to claim Phyllis as his wife
and to live with her in good social standing and without fear of his
rival. But the crime, French reminded himself, had a peculiar feature.
The staged accident on the moor involved the disappearance of both
actors, the murderer as well as the victim. If, then, the murderer
disappeared, he could not live with Phyllis. If either Berlyn or Pyke
were guilty, therefore, he had carried out the crime in a way which
robbed him of the very results for which he had committed it.
French saw that he was up against a puzzling dilemma. If Berlyn
had murdered Pyke, it was unlikely that Mrs. Berlyn would have
assisted. If, on the other hand, Pyke had murdered Berlyn, Mrs.
Berlyn’s action was clear, but not Pyke’s, for Pyke could get nothing
out of it.
French swore bitterly as he realised that in all probability his
former view of the case was incorrect and that he was once again
without any really satisfactory theory on which to work. Nor did some
hours’ thought point the way to a solution of his problem.
At least, however, he saw his next step. Mrs. Berlyn was the
accomplice of some one. That some one was doubtless alive and
biding his time until he thought it safe to join the lady. If so, she was
pretty sure to know his whereabouts. Could she be made to reveal
it?
French thought that if in some way he could give her a thorough
fright, she might try to get a warning through. It would then be up to
him to intercept her message, which would give him the information
he required.
This meant London. He slept the night in Plymouth, and next day,
which was Saturday, travelled up to Paddington.
 Chapter Seventeen: “Danger!”
Before leaving Plymouth French had wired to Mrs. Berlyn, asking
for an interview for the following Monday morning. On reaching the
Yard he found a reply. If he called round about half past ten the lady
would see him. He rang his bell for Sergeant Carter.
“I shall want you with me to-day, Carter,” he explained. “Have a
taxi ready at ten-fifteen.”
As they were driving toward Chelsea he explained the business.
“It’s to help me to shadow a woman, a Mrs. Phyllis Berlyn. Lives
at 70b Park Walk. There’s her photograph. When I go in, you keep
this taxi and be ready to pick me up when I want you.”
If he were to tap a possible S O S, he must begin by finding out if
his victim had a telephone. He therefore got out at the end of Park
Walk, and passing the house, turned into an entry leading to the lane
which ran along behind the row. The absence of wires front and rear
showed that the house was not connected up. Then he went to the
door and knocked. Mrs. Berlyn received him at once.
“I am very sorry, madame,” he began, gravely, “to have to come
on serious and unpleasant business. In my enquiries into the death
of Mr. Pyke certain facts have come out. These facts require an
explanation, and they point to you as being perhaps the only person
who can give it. I have, therefore, called to ask you some questions,
but I have to warn you that you are not bound to answer them, as in
certain eventualities anything you say might be used against you.”
Mrs. Berlyn looked startled.
“Whatever do you mean, Inspector?” she demanded. “You don’t
mean against me personally, I suppose, but against my husband? I
do not forget the terrible suggestion you made.”
“I mean against you personally, madam. As I say, I want an
explanation of certain facts. If you care to give it I shall hear it with
attention, but if you would prefer to consult a solicitor first, you can
do so.”
“Good gracious! Inspector, you are terrifying me! You are surely
not suggesting that you suspect me of complicity in this awful
crime?”
“I make no accusations. All I want is answers to my questions.”
Mrs. Berlyn grew slowly dead white. She moistened her dry lips.
“This is terrible,” she said in low tones. French had some twinges
of conscience, for, after all, he was only bluffing. He recognised,
however, that the greater the effect he produced, the more likely he
was to get what he wanted. He therefore continued his third degree.
“If you are innocent, madam, I can assure you that you have
nothing to fear,” he encouraged her, thereby naturally increasing her
perturbation. “Now would you like to answer my questions or not?”
She did not hesitate. “I have no option,” she exclaimed in
somewhat shaky tones. “If I do not do so your suspicions will be
confirmed. Ask what you like. I have nothing to hide and therefore
cannot give myself away.”
“I am glad to hear you say so,” French declared, grimly. “First I
want you to give me a more detailed account of your relations with
Colonel Domlio.”
“Why,” the lady explained, “I told you all about that on your last
visit. Colonel Domlio was very friendly, exceedingly friendly, I might
say. But we had no relations”—she stressed the word—“in the sense
which your question seems to indicate.”
“How did your friendship begin?”
“Through my husband. He and Colonel Domlio were old friends
and it was natural that we should see something of him. He visited at
our house and we at his.”
“That was when you first went to Ashburton, was it not?”
“Not only then. It was so all the time I lived there.”
“But I don’t mean that. I understand that about four months
before the tragedy your friendship became much more intense, if I
may use the word?”
“Intense is certainly not the word, but it is true that we met more
frequently after the time you mention. I thought I had explained that.
It was then that my husband became dissatisfied about my perfectly
harmless friendship with Mr. Pyke. As I told you, Mr. Pyke and I
decided to see less of each other. I was therefore thrown more on
my own resources and frankly I was bored. I filled a little more of the
time with Colonel Domlio than formerly. That is all.”
“Who began this increased intimacy?”
“Our intimacy was not increased. We saw more of each other—a
very different thing. I began it; in this way. In London I heard some
lectures on insect life. I was interested in the subject and I asked
Colonel Domlio to let me see his collection. We began to talk about
it, and it ended in my going out with him occasionally to look for
specimens on the moor and also in my helping him to arrange them
afterwards. That was the beginning and end of what you are pleased
to call our ‘intimacy.’ ”
The look of fright had left Mrs. Berlyn’s eyes and she was
speaking now with more of her usual assurance.
“You sprained your ankle one day?”
“I twisted it slightly. It was painful for a few hours, but not really
much the worse.”
“You fell?”
“I did not fall. I should have done so, but Colonel Domlio sprang
forward and caught me and helped me down on to the grass. In a
few minutes I was better.”
“Now, Mrs. Berlyn,” and French’s voice was very grave, “what
you have to do is to convince me that that fall into Colonel Domlio’s
arms really was an accident.”
For a moment the lady looked at him uncomprehendingly; then
she flushed angrily.
“Oh,” she cried with a gesture of disgust, “how dare you? This is
insufferable! I shall not answer you. If you are coming here to insult
me I shall apply for protection to your superiors at Scotland Yard.”
“If I were you I should keep away from Scotland Yard as long as
you can,” French advised, drily. “In a case like this heroics will not
help you any. Tell me, did you know there was a photographer
watching the incident?”
“No,” she answered sullenly, while again her face showed fear.
“You knew there wasn’t?”
“I didn’t know anything about it.”
 “But you are not surprised to hear of the photographer?”
“I am. At least I should be if you assured me one was there.”
“Did you know that the handwriting of Colonel Domlio’s letter has
been identified?”
Once again the colour ebbed away from her face.
“What letter?” she cried, faintly. “I don’t know what letter you
mean or what you are talking about. You have made me quite
confused with your questions. I scarcely know what I am saying.”
French felt that he had got the effect he wanted. He therefore
reassured her by a few innocuous questions, then with a change of
manner he apologised for having given unnecessary annoyance and
took his leave.
The taxi was standing far down the street with the bonnet open
and the driver bending over the engine. French got in and he and
Carter sat watching the house.
For half an hour they waited; then Mrs. Berlyn appeared, and
walking to King’s Road, turned in the direction of Sloan Square.
Presently she hailed a taxi, causing French to congratulate himself
on his prevision.
Mrs. Berlyn drove to Victoria, and hurriedly paying off their own
man, the detectives followed her into the station. With a rapid look
round she made her way to the telephone boxes and disappeared
into one of them.
“I’ll drop out here, Carter,” French said. “You stick to the woman
and as far as possible keep in touch with the Yard.”
Approaching the boxes, French slipped into a convenient
doorway and watched until Mrs. Berlyn reappeared. As soon as she
was out of sight he entered the box she had left.
“Inspector from Scotland Yard speaking,” he told the operator.
“Keep the number of that last call. It’s wanted in connection with a
murder case. I’ll get you the authority to divulge. Now give me
Scotland Yard, please.”
He put through the request for the number, then returned to the
Yard to wait for the reply. After a short delay he received both
number and name: Thomas Ganope, news agent and tobacconist,
27 Oakley Street, off Russell Street.
 In half an hour he reached the place. Ganope’s was a small,
untidy shop, and Ganope a ruffianly-looking man with purple cheeks
and a cast in his left eye. He was the only occupant of the shop.
“Can I use your telephone?” French asked, laying a shilling on
the counter.
“Sure.”
French rang up his wife to say that he had mislaid Mr. Walker’s
address and could she let him have it again, a code message
designed for such occasions and to which no attention was paid, but
which enabled him to use a telephone without arousing suspicion, as
well as a writing pad, should such be available. For in this case his
quick eye had seen such a pad on the instrument and from many a
pad he had read the last message to be written from the impression
left on the paper. On chance, therefore, he made a pretense of
noting the mythical Mr. Walker’s address, and removing the top
sheet, put it in his pocketbook. Then he turned to Mr. Ganope.
“Say,” he said, confidentially, “what would you charge for taking in
telephone messages and sending them to an address? Private, you
know.”
Mr. Ganope looked him over keenly with one of his shrewd little
eyes.
“A bob a message, if it’s near by.”
“That’s a lot. Do you never do it for less?”
Mr. Ganope seemed disgusted.
“If you can get anyone to do it for less you’d better go to them,”
he advised, sourly.
“I might manage the money if I was sure the thing would be done
right,” French went on. “How do you send out the messages? I mean
is your arrangement reliable? Do you do it yourself or have you a
messenger?”
“Wot do you tyke me for, mister? Do you think the shop would run
itself while I was away? You don’t need to worry. You pay your bob
and you’ll get your message all right.”
“Not good enough for me. I want to know what kind of messenger
you’d send before I trust my business to you.”
“See ’ere,” the man declared, “I’ve been doing this business for
long enough to know all about ’ow it’s done. I’ve a good boy, if you
must know. You give ’im a penny or two a time if you’re nervous, and
you needn’t be afryde but you’ll get all there’s for you.”
French laid five shillings on the counter.
“Right,” he said. “There’s for the first five messages. Send to Mr.
James Hurley, care of Mr. William Wright, tobacconist, corner of
Bedford Place and Ivy Street.”
“I know it,” declared Ganope, pocketing the money.
Mr. William Wright was a distant connection of Mrs. French’s and
French knew that he would help him in the matter. He nodded to
Ganope and walked across to Ivy Street.
“Hullo, Joe! Some time since we’ve seen you here,” was Mr.
Wright’s greeting. “Come in behind and let’s hear the news.”
“I want you to do me a good turn, William,” French answered.
“There’s a boy I want to get hold of and I’ve fixed it that he’ll come
here asking for Mr. Hurley. Will you put him on to me when he turns
up? That’s all.”
“Surely, Joe,” and Mr. Wright turned the conversation to more
intimate matters.
“Just let me use your phone,” French asked, presently.
“Something I forgot.”
“Surely, Joe.”
Going into the little office at the back of the shop, French rang up
Ganope.
“Message for Hurley,” he explained in falsetto tones. “Mr. James
Hurley.”
“Right,” came from the other end.
“ ‘Cargo will be in at ten-fifteen to-morrow.’ That’s all. Repeat,
please.”
Mr. Ganope repeated slowly, evidently as he wrote, and French
settled down with his pipe to await the advent of the messenger.
In less than half an hour a sharp, foxy-looking boy turned up and
Mr. Wright sent him into the sitting-room to French.
“Hullo, sonny! You from Ganope’s?”
“Huh-huh,” said the boy. “Name of Hurley?”
“That’s right. You have a message for me?”
“Huh-huh.” He slowly produced an envelope, watching French
expectantly.
 French produced sixpence.
“There you are, sonny. Wait half a sec till I read this. There may
be an answer.”
He tore open the envelope and glanced at its contents.
“No, there’s nothing,” he went on. “You’re kept busy, I’m sure?”
“Huh-huh.”
“And maybe you don’t get too much money for it, either?”
The boy indicated that this was a true summary of his case.
“Well, how would half a crown for a little job for me suit you?”
The gleam in the boy’s eyes was sufficient answer.
“It’s just a little bit of information between you and me. No one
else would know anything about it. It wouldn’t take you two minutes
to give it to me. Are you on?”
“Ain’t I, gov’nor? You just try me.”
French took some money out of his pocket and slowly counted
out two single shillings and a sixpence. These he laid on the table in
a little pile.
“Tell me, sonny,” he said. “You had to take a message out this
morning shortly after eleven?”
“Huh-huh.”
“Where did you take it to?”
“You won’t tell the old man?”
“I’ll not, sonny. I give you my word.”
“Name o’ Pyke, seventeen Kepple Street.”
In spite of his training as an officer of the Yard, French started.
Pyke! He remained for a moment lost in thought. Pyke! Could this be
the solution at last? Could Mrs. Berlyn have transferred her
somewhat facile affections to Jefferson Pyke? Could these two be
guilty of the murder of both Stanley and Berlyn?
Here was a promising idea! In the first place, it was the solution
to the dilemma which had so greatly puzzled him. The crime had
been committed to enable the murderer to live with Phyllis in good
social standing. Therefore, the murderer could not have
disappeared. Therefore, it could not have been either Berlyn or
Pyke. There had been French’s problem.
But if Jefferson Pyke and Phyllis had been accomplices, all these
difficulties vanished. Berlyn and Pyke had disappeared because they
were dead. The murderer had survived to enjoy the fruits of his
crime. All the facts seemed to be met.
In itself, also, this new theory was likely enough. Jefferson and
Phyllis had been playmates and an old attachment might easily have
flamed up anew on their meeting at Ashburton. If so, there was the
motive for Berlyn’s murder. Stanley Pyke might also have been in the
way. Possibly Phyllis was so far entangled with him that to break
loose would have turned him into a dangerous enemy. Possibly the
accomplices feared that he might guess their crime. Under the
circumstances it was easy to see that their only safe scheme might
well have been to remove both men.
The details also worked in. Phyllis could have obtained the
information about the works necessary for the disposal of the body.
Jefferson was of the size and build of the man who had called for the
lorry and crate at Swansea, and though his colouring was different,
this could have been altered artificially. He could be biding his time
until he was sure the affair had blown over to take Phyllis out to his
estancia in the Argentine.
Another point occurred to French. Alfred Beer had stated, no
doubt in all good faith, that the conversation he had overheard in the
Berlyn’s shrubbery was between Mrs. Berlyn and Stanley Pyke, and
French had naturally assumed that the “ ’e” referred to was Berlyn.
But were he and Beer correct? Might the scene not equally well have
been between the lady and Jefferson and might “ ’e” not have been
Stanley? French decided to look up his notes of the matter at the
earliest opportunity.
He had little doubt that at long last he was on to the truth.
Jubilantly he handed over the half-crown to Ganope’s boy and
dismissed him with the assurance that he would never hear of the
matter again.
As to his next step there could be no question. He walked quickly
to Kepple Street and asked if Mr. Jefferson Pyke was at home.
Pyke was out, but was expected shortly. Hugging himself for his
luck, French said that if he might, he would like to wait for Mr. Pyke.
The landlady remembered his previous visit and made no difficulty
about showing him up to her lodger’s sitting room.
 Before the door closed behind her French saw that his lucky star
was still in the ascendant. There on the chimneypiece stood a note
addressed “Mr. Jefferson Pyke” in the same handwriting as that for
“Mr. James Hurley.”
French carried an old razor blade in his pocket and in less than a
minute the envelope was open. The note read:
“Danger. Meet me to-night at old time and place.”
French swore softly in high delight. He had them now! Here was
convincing proof of their guilt.
But it was insufficient to bring into court. He must get something
more definite. With skilful fingers he reclosed the envelope and put it
back where he had found it. Then he settled down to wait for Pyke.
In less than ten minutes the man appeared. French, smiling his
pleasant smile, greeted him apologetically.
“Sorry to trouble you again, Mr. Pyke, but I want to ask you for a
little further help in this Ashburton affair. I have made a discovery, but
first I must ask you to keep what I have to say to yourself.”
Pyke nodded.
“Of course, Mr. French. Sit down, won’t you, and tell me what I
can do for you.”
“All I want is a little information,” French declared, taking the
proffered chair. “I may tell you between ourselves that certain facts
suggest that Colonel Domlio may have been involved. Can you tell
me anything that might help me to a decision, anything that your
cousin told you or that Mr. Berlyn may have said in your presence?”
Pyke shook his head.
“Colonel Domlio?” he repeated. “Why, no! I never thought of such
a thing, and neither Stanley nor Berlyn ever said anything to suggest
it.”
French continued to question him long enough to convince him
that this was really the business on which he had called. Then he
tried to discount the effect which Mrs. Berlyn’s note would have when
at last the man had an opportunity to read it.
“I’ve been to see Mrs. Berlyn on this matter,” he explained. “I’m
afraid I was rather rude to her, but I just had to frighten her in order
to satisfy myself as to whether or not she suspected the colonel. But
at least I apologised afterward. I think she forgave me.”