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P R IN C IP LE S o f P H A R M A C O LO G Y
T H E P AT H O P H YS I O LO G I C B A S I S O F D R U G T H E R A P Y

Fo u rt h Ed it io n
P R IN C IP LE S o f P H A R M A C O LO G Y
T H E P AT H O P H YS I O LO G I C B A S I S O F D R U G T H E R A P Y

Fo u rt h Ed it io n

David E. Go lan, MD, PhD

Editor-in-Chief

Ehrin J. Arm s tro ng , MD, MS c

April W. Arm s tro ng , MD, MPH
Associate Editors
Acquisitions Editor: Matthew Hauber
Product Development Editor: John Larkin
Marketing Manager: Mike McMahon
Production Project Manager: Bridgett Dougherty
Design Coordinator: Holly McLaughlin
Manufacturing Coordinator: Margie Orzech
Prepress Vendor: Absolute Service, Inc.

Fourth edition

Copyright © 2017 Wolters Kluwer.

Copyright © 2006, 2011 Wolters Kluwer Health/Lippincott Williams & Wilkins.

All rights reserved. This book is protected by copyright. No part o this book may be reproduced or transmitted in any
orm or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any in ormation
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Library of Congress Cataloging-in-Publication Data

Names: Golan, David E., editor. | Armstrong, Ehrin J., editor. | Armstrong,
April W., editor.
Title: Principles o pharmacology : the pathophysiologic basis o drug
therapy / David E. Golan, editor in chie ; Ehrin J. Armstrong, April W.
Armstrong, associate editors.
Other titles: Principles o pharmacology (Golan)
Description: Fourth edition. | Philadelphia : Wolters Kluwer Health, [2017] |
Includes bibliographical re erences and index.
Identif ers: LCCN 2015048962 | ISBN 9781451191004
Subjects: | MESH: Pharmacological Phenomena | Drug Therapy
Classif cation: LCC RM301 | NLM QV 38 | DDC 615/.1—dc23 LC record available at http://lccn.loc.gov/2015048962

This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any
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To our students and the patients they will serve
 Contents
Preface ........................................................................................... ix S e c t io n IIB
Preface to the First Edition............................................................. xi Principles of Autonomic and Peripheral
Nervous System Pharmacology 126
Acknowledgments........................................................................ xiii
Contributors....................................................................................xv 10 Cholinergic Pharmacology............................................. 127
Alireza Atri, Michael S. Chang, and Gary R. Strichartz
S E C T IO N I 11 Adrenergic Pharmacology ............................................. 150
Fundamental Principles of Pharmacology 1 Nidhi Gera, Ehrin J. Armstrong, and David E. Golan
12 Local Anesthetic Pharmacology ................................... 167
1 Drug–Receptor Interactions .............................................. 2 Quentin J. Baca, Joshua M. Schulman, and
Francis J. Alenghat and David E. Golan Gary R. Strichartz
2 Pharmacodynamics ........................................................... 17
Quentin J. Baca and David E. Golan S e c t io n IIC
3 Pharmacokinetics .............................................................. 27 Principles of Central Nervous System Pharmacology 183
Quentin J. Baca and David E. Golan
13 Pharmacology of GABAergic and
4 Drug Metabolism ............................................................... 43 Glutamatergic Neurotransmission................................ 184
F. Peter Guengerich
Stuart A. Forman, Hua-Jun Feng, Janet Chou, Jianren Mao,
5 Drug Transporters .............................................................. 56 and Eng H. Lo
Baran A. Ersoy and Keith A. Ho master
14 Pharmacology of Dopaminergic
6 Drug Toxicity ....................................................................... 70 Neurotransmission .......................................................... 206
Michael W. Conner, Catherine Dorian-Conner, David G. Standaert and Victor W. Sung
Vishal S. Vaidya, Laura C. Green, and David E. Golan
15 Pharmacology of Serotonergic and
7 Pharmacogenomics .......................................................... 87 Central Adrenergic Neurotransmission ....................... 227
Amber Dahlin and Kelan Tantisira Stephen J. Haggarty and Roy H. Perlis
16 Pharmacology of Abnormal Electrical
S E C T IO N II Neurotransmission in the Central Nervous System..... 249
Principles of Neuropharmacology 96 Susannah B. Cornes, Edmund A. Gri f n, Jr., and
Daniel H. Lowenstein
S e c t io n IIA 17 General Anesthetic Pharmacology............................... 265
Fundamental Principles of Neuropharmacology 97 Jacob Wouden and Keith W. Miller
18 Pharmacology of Analgesia ........................................... 288
8 Principles of Cellular Excitability and Robert S. Gri f n and Cli ord J. Wool
Electrochemical Transmission......................................... 98
19 Pharmacology of Drugs of Abuse ................................. 308
Elizabeth Mayne, Lauren K. Buhl, and Gary R. Strichartz
Peter R. Martin and Sachin Patel
9 Principles of Nervous System
Physiology and Pharmacology ...................................... 110 S E C T IO N III
Joshua M. Galanter, Susannah B. Cornes, and
Principles of Cardiovascular Pharmacology 335
Daniel H. Lowenstein
20 Pharmacology of Cholesterol and
Lipoprotein Metabolism.................................................. 336
Tibor I. Krisko, Ehrin J. Armstrong, and David E. Cohen

vii
viii Contents
21 Pharmacology o Volume Regulation ........................... 358
Hakan R. Toka and Seth L. Alper
22 Pharmacology o Vascular Tone ................................... 385
William M. Oldham and Joseph Loscalzo
23 Pharmacology o Hemostasis and Thrombosis .......... 403
Ehrin J. Armstrong and David E. Golan
24 Pharmacology o Cardiac Rhythm ................................ 433
Ehrin J. Armstrong and David E. Clapham
25 Pharmacology o Cardiac Contractility ........................ 454
Ehrin J. Armstrong
26 Integrative Cardiovascular Pharmacology:
Hypertension, Ischemic Heart Disease,
and Heart Failure ............................................................. 469
James M. McCabe and Ehrin J. Armstrong
S E C T IO N IV
Principles o Endocrine Pharmacology
27 Pharmacology o the Hypothalamus
and Pituitary Gland .......................................................... 498
Anand Vaidya and Ursula B. Kaiser
28 Pharmacology o the Thyroid Gland ............................. 514
Anthony Hollenberg and William W. Chin
29 Pharmacology o the Adrenal Cortex ........................... 524
Rajesh Garg and Gail K. Adler
30 Pharmacology o Reproduction..................................... 541
Ehrin J. Armstrong and Robert L. Barbieri
31 Pharmacology o the Endocrine Pancreas
and Glucose Homeostasis .............................................. 561
Giulio R. Romeo and Steven E. Shoelson
32 Pharmacology o Bone Mineral Homeostasis ............ 580
David M. Slovik and Ehrin J. Armstrong
S E C T IO N V
Principles o Chemotherapy
33 Principles o Antimicrobial and
Antineoplastic Pharmacology ....................................... 603
Donald M. Coen, Vidyasagar Koduri, and David E. Golan
34 Pharmacology o Bacterial In ections: DNA
Replication, Transcription, and Translation ................. 622
Alexander J. McAdam and Donald M. Coen
35 Pharmacology o Bacterial and Mycobacterial
In ections: Cell Wall Synthesis ...................................... 641
David W. Kubiak, Ramy A. Arnaout, and Sarah P. Hammond
36 Pharmacology o Fungal In ections .............................. 661
Chelsea Ma and April W. Armstrong
37 Pharmacology o Parasitic In ections .......................... 674
Louise C. Ivers and Edward T. Ryan
38 Pharmacology o Viral In ections .................................. 694
Jonathan Z. Li and Donald M. Coen
39 Pharmacology o Cancer: Genome Synthesis,
Stability, and Maintenance ............................................ 723
David A. Barbie and David A. Frank
40 Pharmacology o Cancer: Signal Transduction .......... 750
David A. Barbie and David A. Frank
41 Principles o Combination Chemotherapy ................... 770
Quentin J. Baca, Donald M. Coen, and David E. Golan
S E C T IO N V I
Principles o Inf ammation and Immune Pharmacology 782
42 Principles o Inf ammation and
the Immune System......................................................... 783
Eryn L. Royer and April W. Armstrong
43 Pharmacology o Eicosanoids ....................................... 794
David M. Dudzinski and Charles N. Serhan
44 Histamine Pharmacology ............................................... 819
Elizabeth A. Brezinski and April W. Armstrong
45 Pharmacology o Hematopoiesis
and Immunomodulation .................................................. 830
497
Andrew J. Wagner, Ramy A. Arnaout, and George D. Demetri
46 Pharmacology o Immunosuppression ........................ 844
Elizabeth A. Brezinski, Lloyd B. Klickstein, and
April W. Armstrong
47 Integrative Inf ammation Pharmacology:
Peptic Ulcer Disease ....................................................... 864
Dalia S. Nagel and Helen M. Shields
48 Integrative Inf ammation Pharmacology: Asthma ...... 877
Joshua M. Galanter and Stephen Lazarus
49 Integrative Inf ammation Pharmacology: Gout ........... 895
Ehrin J. Armstrong and Lloyd B. Klickstein
S E C T IO N V II
Environmental Toxicology 904
50 Environmental Toxicology............................................... 905
Laura C. Green, Sarah R. Armstrong, and
Joshua M. Galanter
602
S E C T IO N V III
Fundamentals o Drug Development and Regulation 918
51 Drug Discovery and Preclinical Development ............ 919
John L. Vahle, David L. Hutto, and Maarten Postema
52 Clinical Drug Evaluation and
Regulatory Approval........................................................ 933
Mark A. Goldberg and Alexander E. Kuta
53 Systematic Detection o Adverse Drug Events ........... 946
Jerry Avorn
S E C T IO N IX
Frontiers in Pharmacology 954
54 Protein Therapeutics ....................................................... 955
Quentin J. Baca, Benjamin Leader, and David E. Golan
55 Drug Delivery Modalities ................................................ 979
Joshua D. Moss and Robert Langer
Credit List .................................................................................... 987
Index............................................................................................ 991

The editors are grate ul or many help ul suggestions rom
readers o the f rst, second, and third editions o Principles
o Pharmacology: The Pathophysiologic Basis o Drug
Therapy. The ourth edition eatures many changes to re ect
the rapidly evolving nature o pharmacology and drug de-
velopment. We believe that these updates will continue to
contribute to the learning and teaching o pharmacology both
nationally and internationally:
■ Comprehensive updates o ull-color f gures throughout
the textbook—about 450 in all. Every f gure has been
updated and colorized, and over 50 f gures are new or
substantially modif ed to highlight advances in our un-
derstanding o physiologic, pathophysiologic, and phar-
macologic mechanisms. As in the f rst three editions, our
collaboration with a single illustrator creates a uni orm
“look and eel” among the f gures that acilitates under-
standing and helps the reader make connections across
broad areas o pharmacology.
■ Comprehensive updates and additions in the undamen-
tals o pharmacology. Along with extensive updates in
the chapters on drug–receptor interactions, pharmaco-
dynamics, pharmacokinetics, drug metabolism, drug
toxicity, and pharmacogenomics, a new chapter on drug
transporters has been added. The f rst section o the text-
book now provides a comprehensive ramework or the
undamental principles o pharmacology that serve as the
oundation or material in all subsequent chapters.
■ Comprehensive updates o all 37 drug summary tables.
These tables, which have been particularly popular with
readers, group drugs and drug classes according to mech-
anism o action and list clinical applications, serious and
common adverse e ects, contraindications, and therapeu-
tic considerations or each drug discussed in the chapter.
■ Comprehensive updates o all chapters, including new
drugs approved through 2014–2015. We have ocused
especially on newly discovered and revised mecha-
nisms that sharpen our understanding o the physiology,
Preface
pathophysiology, and pharmacology o the relevant sys-
tem. Sections throughout the book contain substantial
amounts o new and updated material, especially the chap-
ters on drug–receptor interactions; drug toxicity; pharma-
cogenomics; adrenergic pharmacology; local anesthetic
pharmacology; the pharmacology o serotonergic and
central adrenergic neurotransmission; the pharmacology
o analgesia; the pharmacology o cholesterol and lipopro-
tein metabolism; the pharmacology o volume regulation;
the pharmacology o vascular tone; the pharmacology
o hemostasis and thrombosis; the pharmacology o the
thyroid gland; the pharmacology o the endocrine pan-
creas and glucose homeostasis; the pharmacology o bone
mineral homeostasis; the pharmacology o bacterial DNA
replication, transcription, and translation; the pharmacol-
ogy o bacterial and mycobacterial cell wall synthesis;
the pharmacology o viral in ections; the pharmacology
o cancer; the pharmacology o eicosanoids; the pharma-
cology o immunosuppression; the undamentals o drug
development and regulation; and protein therapeutics.
As with the third edition, we have recruited a panel o
new, expert chapter authors who have added tremendous
strength and depth to the existing panel o authors, and the
editorial team has reviewed each chapter in detail to achieve
uni ormity o style, presentation, and currency across the
entire text.
Finally, we would like to acknowledge the immeasur-
able contributions o the late Armen H. Tashjian, Jr., MD,
to the conception, design, and implementation o this text.
Armen was our riend, mentor, and close colleague, and his
indomitable spirit lives on in this ourth edition o Principles
o Pharmacology: The Pathophysiologic Basis o Drug
Therapy.
David E. Golan, MD, PhD
Ehrin J . Armstrong, MD, MSc
April W. Armstrong, MD, MPH
ix

This book represents a new approach to the teaching o a
f rst or second year medical school pharmacology course.
The book, titled Principles of Pharmacology: The Patho-
physiologic Basis of Drug Therapy, departs rom standard
pharmacology textbooks in several ways. Principles of
Pharmacology provides an understanding o drug action
in the ramework o human physiology, biochemistry, and
pathophysiology. Each section o the book presents the
pharmacology o a particular physiologic or biochemical
system, such as the cardiovascular system or the in am-
mation cascade. Chapters within each section present the
pharmacology o a particular aspect o that system, such as
vascular tone or eicosanoids. Each chapter presents a clini-
cal vignette, illustrating the relevance o the system under
consideration; then discusses the biochemistry, physiology,
and pathophysiology o the system; and, f nally, presents the
drugs and drug classes that activate or inhibit the system by
interacting with specif c molecular and cellular targets. In
this scheme, the therapeutic and adverse actions o drugs are
understood in the ramework o the drug’s mechanism o ac-
tion. The physiology, biochemistry, and pathophysiology are
illustrated using clear and concise f gures, and the pharma-
cology is depicted by displaying the targets in the system
on which various drugs and drug classes act. Material rom
the clinical vignette is re erenced at appropriate points in the
discussion o the system. Contemporary directions in mo-
lecular and human pharmacology are introduced in chapters
on modern methods o drug discovery and drug delivery and
in a chapter on pharmacogenomics.
Preface
t o t h e Firs t Ed it io n
This approach has several advantages. We anticipate that
students will use the text not only to learn pharmacology but
also to review essential aspects o physiology, biochemistry,
and pathophysiology. Students will learn pharmacology in a
conceptual ramework that osters mechanism-based learning
rather than rote memorization, and that allows or ready incor-
poration o new drugs and drug classes into the student’s und
o knowledge. Finally, students will learn pharmacology in a
ormat that integrates the actions o drugs rom the level o an
individual molecular target to the level o the human patient.
The writing and editing o this textbook have employed a
close collaboration among Harvard Medical School students and
aculty in all aspects o book production, rom student– aculty
co-authorship o individual chapters to student– aculty editing o
the f nal manuscript. In all, 43 HMS students and 39 HMS ac-
ulty have collaborated on the writing o the book’s 52 chapters.
This development plan has blended the enthusiasm and per-
spective o student authors with the experience and expertise
o aculty authors to provide a comprehensive and consistent
presentation o modern, mechanism-based pharmacology.
David E. Golan, MD, PhD
Armen H. Tashjian, J r., MD
Ehrin J . Armstrong, MD, MSc
Joshua M. Galanter, MD
April W. Armstrong, MD, MPH
Ramy A. Arnaout, MD, DPhil
Harris S. Rose, MD
FOUNDING EDITORS
xi

The editors are grate ul or the support o students and aculty
rom around the world who have provided encouragement
and help ul suggestions.
Stuart Ferguson continued his exemplary work as an execu-
tive assistant by managing all aspects o project coordination,
including submission o chapter manuscripts, multiple layers
o editorial revisions, coordination o f gure generation and
revision, and delivery o the f nal manuscript. We are extraor-
dinarily grate ul or his unwavering dedication to this project.
Rob Duckwall did a superb job to update the ull-color
f gures. Rob’s standardization and coloration o the f gures in
this textbook re ect his creativity and expertise as a leading
medical illustrator. His artwork is a major asset and highlight
o this textbook.
Quentin Baca electronically rendered the striking image
on the cover o this textbook. We are most grate ul or his
creativity and expertise.
The editors would like to thank the publication, editorial,
and production sta at Wolters Kluwer or their expert man-
agement and production o this handsome volume.
David Golan would like to thank the many aculty, stu-
dent, and administrative colleagues whose support and un-
derstanding were critical or the success ul completion o
this project. Members o the Golan laboratory and aculty
and sta in the Department o Biological Chemistry and
Acknowledgments
Molecular Pharmacology at Harvard Medical School and in
the Hematology Division at Brigham and Women’s Hospital
and the Dana-Farber Cancer Institute were gracious and sup-
portive throughout. Deans Je rey Flier and John Czajkowski
were especially supportive and encouraging. Laura, Liza,
and Sarah provided valuable insights at many critical stages
o this project and were constant sources o support and love.
Ehrin Armstrong would like to thank colleagues at the
University o Colorado and the Denver Veterans Adminis-
tration Medical Center or providing academic support and
guidance. Greg Schwartz and Jim Beck were especially en-
couraging. Ki any, Larry, and Ginger were a constant source
o support and love throughout.
April Armstrong would like to thank Drs. David Golan
and Laura Green or their constant support over the years.
She thanks her dedicated coauthors Eryn Royer, Elizabeth
Brezinski, and Chelsea Ma or their hard work. She also
thanks Drs. David Norris, David West, and Fu-Tong Liu
or ostering her career. She is grate ul or the love o her
amily—Amy, Yanni, and Susan.
Credit lines identi ying the original source o a f gure or
table borrowed or adopted rom copyrighted material, and
acknowledging the use o noncopyrighted material, are gath-
ered together in a list at the end o the book. We thank all o
these sources or permission to use this material.
xiii

Gail K. Adler, MD, PhD
Associate Pro essor o Medicine
Harvard Medical School
Associate Physician
Division o Endocrinology, Diabetes
and Hypertension
Department o Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Francis J . Alenghat, MD, PhD
Assistant Pro essor
Department o Medicine, Section o
Cardiology
University o Chicago
Chicago, Illinois
Seth L. Alper, MD, PhD
Pro essor o Medicine
Harvard Medical School
Renal Division and Molecular and
Vascular Medicine Division
Department o Medicine
Beth Israel Deaconess Medical Center
Boston, Massachusetts
April W. Armstrong, MD, MPH
Associate Dean or Clinical Research
Director o Clinical Research, Southern
Cali ornia Clinical and Translational
Science Institute (SC CTSI)
Vice Chair, Department o Dermatology
Associate Pro essor o Dermatology
University o Southern Cali ornia
Los Angeles, Cali ornia
Ehrin J . Armstrong, MD, MSc
Associate Pro essor o Medicine
Division o Cardiology
University o Colorado School
o Medicine
Denver, Colorado
Sarah R. Armstrong, MS, DABT
Consultant in Toxicology
Amherst, Massachusetts
Ramy A. Arnaout, MD, DPhil
Assistant Pro essor o Pathology
Harvard Medical School
Associate Director, Clinical
Microbiology
Department o Pathology
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Alireza Atri, MD, PhD
Ray Dolby Endowed Chair in Brain
Health Research
Ray Dolby Brain Health Center
Cali ornia Pacif c Medical Center
San Francisco, Cali ornia
Visiting Scientist in Neurology
Harvard Medical School
Boston, Massachusetts
J erry Avorn, MD
Pro essor o Medicine
Harvard Medical School
Chie , Division o
Pharmacoepidemiology
Brigham and Women’s Hospital
Boston, Massachusetts
Quentin J . Baca, MD, PhD
Chie Resident in Anesthesia
Department o Anesthesiology,
Perioperative and Pain Medicine
Stan ord University School o
Medicine
Palo Alto, Cali ornia
David A. Barbie, MD
Assistant Pro essor o Medicine
Harvard Medical School
Associate Physician
Department o Medical Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
Contributors
Robert L. Barbieri, MD
Kate Macy Ladd Pro essor o
Obstetrics, Gynecology and
Reproductive Biology
Department o Obstetrics, Gynecology
and Reproductive Biology
Harvard Medical School
Chairman, Department o Obstetrics
and Gynecology
Brigham and Women’s Hospital
Boston, Massachusetts
Elizabeth A. Brezinski, MD
Resident in Dermatology
Harvard Combined Dermatology
Residency Training Program
Boston, Massachusetts
Lauren K. Buhl, MD, PhD
Clinical Fellow in Anaesthesia
Harvard Medical School
Resident in Anaesthesia
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Michael S. Chang, MD
Assistant Pro essor o Orthopedic
Surgery
University o Arizona College o
Medicine
Complex Spine Surgeon
Sonoran Spine Center
Phoenix, Arizona
William W. Chin, MD
Bertarelli Pro essor o Translational
Medical Science, Emeritus
Harvard Medical School
Boston, Massachusetts
Chie Medical O f cer and Executive
Vice President
Pharmaceutical Research and
Manu acturers o America
Washington, DC
xv
xvi Contributors
J anet Chou, MD
Instructor, Department of Pediatrics
Harvard Medical School
Assistant in Medicine
Department of Immunology
Children’s Hospital Boston
Boston, Massachusetts
David E. Clapham, MD, PhD
Aldo R. Castañeda Professor of
Cardiovascular Research
Professor of Neurobiology
Harvard Medical School
Chief, Basic Cardiovascular Research
Department of Cardiology
Children’s Hospital Boston
Boston, Massachusetts
Donald M. Coen, PhD
Professor of Biological Chemistry and
Molecular Pharmacology
Harvard Medical School
Boston, Massachusetts
David E. Cohen, MD, PhD
Robert H. Ebert Professor of Medicine
and Health Sciences and
Technology
Director, Harvard-Massachusetts
Institute of Technology Division of
Health Sciences and Technology
Harvard Medical School
Director of Hepatology
Division of Gastroenterology,
Hepatology and Endoscopy
Department of Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Michael W. Conner, DVM
Vice President
Theravance Biopharma, U.S., Inc.
South San Francisco, California
Susannah B. Cornes, MD
Assistant Professor, Department
of Neurology
University of California, San Francisco
Department of Neurology
UCSF Medical Center
San Francisco, California
Amber Dahlin, PhD, MMSc
Instructor in Medicine
Harvard Medical School
Associate Epidemiologist
Channing Division of Network
Medicine, Department of Medicine,
Brigham and Women’s Hospital
Boston, Massachusetts
George D. Demetri, MD
Professor of Medicine
Department of Medical Oncology
Co-Director, Ludwig Center
Harvard Medical School
Department of Medical Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
Catherine Dorian-Conner, PharmD, PhD
Consultant in Toxicology
Half Moon Bay, California
David M. Dudzinski, MD, J D
Clinical Fellow in Medicine
Harvard Medical School
Fellow, Department of Cardiology
Massachusetts General Hospital
Boston, Massachusetts
Baran A. Ersoy, PhD
Instructor in Medicine
Harvard Medical School
Investigator
Brigham and Women’s Hospital
Boston, Massachusetts
Hua-J un Feng, MD, PhD
Instructor in Anaesthesia
Harvard Medical School
Assistant in Pharmacology
Massachusetts General Hospital
Boston, Massachusetts
Stuart A. Forman, MD, PhD
Associate Professor of Anesthesia
Harvard Medical School
Boston, Massachusetts
David A. Frank, MD, PhD
Associate Professor of Medicine
Harvard Medical School
Departments of Medicine and
Medical Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
J oshua M. Galanter, MD
Assistant Professor, Department of
Medicine
University of California, San Francisco
San Francisco, California
Rajesh Garg, MD
Assistant Professor of Medicine
Harvard Medical School
Associate Physician
Division of Endocrinology, Diabetes
and Hypertension
Department of Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Nidhi Gera, PhD
Research Fellow
Department of Biological Chemistry
and Molecular Pharmacology
Harvard Medical School
Boston, Massachusetts
David E. Golan, MD, PhD
Professor of Biological Chemistry and
Molecular Pharmacology
George R. Minot Professor of Medicine
Dean for Basic Science and
Graduate Education
Special Advisor for Global Programs
Harvard Medical School
Senior Physician, Hematology
Division, Brigham and
Women’s Hospital and
Dana-Farber Cancer Institute
Department of Biological Chemistry
and Molecular Pharmacology,
Department of Medicine
Harvard Medical School
Boston, Massachusetts
Mark A. Goldberg, MD
Associate Professor of Medicine,
Part-time
Harvard Medical School
Boston, Massachusetts
Advisor
Medical and Regulatory Strategy
Synageva BioPharma Corp.
Lexington, Massachusetts
Laura C. Green, PhD, DABT
President and Senior Toxicologist
Green Toxicology, LLC
Brookline, Massachusetts
Edmund A. Gri f n, J r., MD, PhD
Assistant Professor of Clinical
Psychiatry
Department of Psychiatry
Columbia University
Attending Psychiatrist
New York-Presbyterian Hospital
New York, New York
Robert S. Gri f n, MD, PhD
Clinical Assistant Professor of
Anesthesiology
Weill Cornell Medical College
Assistant Attending Anesthesiologist
Hospital for Special Surgery
New York, New York
F. Peter Guengerich, PhD
Professor, Department of Biochemistry
Vanderbilt University School of
Medicine
Nashville, Tennessee

Stephen J . Haggarty, PhD
Associate Pro essor o Neurology
Harvard Medical School
Director, Chemical Neurobiology
Laboratory
Center or Human Genetic Research
Massachusetts General Hospital
Boston, Massachusetts
Sarah P. Hammond, MD
Assistant Pro essor o Medicine
Harvard Medical School
Associate Physician
Brigham and Women’s Hospital
Boston, Massachusetts
Keith A. Hoffmaster, PhD
Director, Global Program
Management
Translational Clinical Oncology
Novartis Institutes or Biomedical
Research
Cambridge, Massachusetts
Anthony Hollenberg, MD
Pro essor o Medicine
Harvard Medical School
Chie , Division o Endocrinology,
Diabetes and Metabolism
Beth Israel Deaconess Medical Center
Boston, Massachusetts
David L. Hutto, DVM, PhD, DACVP
Corporate Senior Vice President and
Chie Scientif c O f cer—Sa ety
Assessment
Charles River Laboratories, Inc.
Wilmington, Massachusetts
Louise C. Ivers, MD, MPH, DTM&H
Associate Pro essor o Medicine
Harvard Medical School
Associate Physician
Department o Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Ursula B. Kaiser, MD
Pro essor o Medicine
Harvard Medical School
Chie , Division o Endocrinology,
Diabetes and Hypertension
Brigham and Women’s Hospital
Boston, Massachusetts
Lloyd B. Klickstein, MD, PhD
Head o Translational Medicine
New Indications Discovery Unit
Novartis Institutes or
Biomedical Research
Cambridge, Massachusetts
Vidyasagar Koduri, MD, PhD
Clinical Fellow in Hematology/
Oncology
Dana Farber Cancer Institute/Harvard
Cancer Center
Boston, Massachusetts
Tibor I. Krisko, MD
Instructor
Department o Medicine
Harvard Medical School
Boston, Massachusetts
Sta Gastroenterologist
Department o Gastroenterology/
Medicine
Boston VA Medical Center
Jamaica Plain, Massachusetts
David W. Kubiak, PharmD
Adjunct Clinical Assistant Pro essor
o Pharmacy Practice
Massachusetts College o Pharmacy
and Health Sciences
Adjunct Assistant Pro essor o
Pharmacology
Massachusetts General Hospital
Institute o Health Pro essions
Adjunct Clinical Assistant Pro essor
o Pharmacy Practice
Northeastern University Bouvé
College o Heath Sciences
Co-Director o Antimicrobial
Stewardship and Advanced Practice
In ectious Diseases Pharmacy
Specialist
Brigham and Women’s Hospital
Boston, Massachusetts
Alexander E. Kuta, PhD
Vice President and Head o US
Regulatory A airs
EMD Serono, Inc.
Rockland, Massachusetts
Robert Langer, ScD
David H. Koch Institute Pro essor
Departments o Chemical Engineering
and Bioengineering
Massachusetts Institute o Technology
Cambridge, Massachusetts
Senior Lecturer on Surgery
Children’s Hospital Boston
Boston, Massachusetts
Stephen Lazarus, MD
Pro essor o Medicine
Division o Pulmonary and Critical
Care Medicine
Director, Training Program in Pulmonary
and Critical Care Medicine
University o Cali ornia, San Francisco
San Francisco, Cali ornia
xvii Contributors
Benjamin Leader, MD, PhD
Chie Executive O f cer
ReproSource
Woburn, Massachusetts
J onathan Z. Li, MD, MMSc
Assistant Pro essor o Medicine
Harvard Medical School
Brigham and Women’s Hospital
Boston, Massachusetts
Eng H. Lo, PhD
Pro essor o Radiology
Harvard Medical School
Director, Neuroprotection
Research Laboratory
Departments o Radiology
and Neurology
Massachusetts General Hospital
Boston, Massachusetts
J oseph Loscalzo, MD, PhD
Hersey Pro essor o the Theory and
Practice o Medicine
Harvard Medical School
Chairman, Department o Medicine
and Physician-in-Chie
Brigham and Women’s Hospital
Boston, Massachusetts
Daniel H. Lowenstein, MD
Pro essor, Department o Neurology
University o Cali ornia, San Francisco
Director, UCSF Epilepsy Center
UCSF Medical Center
San Francisco, Cali ornia
Chelsea Ma, MD
Resident Physician
Internal Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
Boston, Massachusetts
J ianren Mao, MD, PhD
Richard J. Kitz Pro essor o
Anaesthesia Research
Harvard Medical School
Chie , Division o Pain Medicine
Massachusetts General Hospital
Boston, Massachusetts
Peter R. Martin, MD
Pro essor, Departments o Psychiatry
and Pharmacology
Vanderbilt University
Director, Division o Addiction
Psychiatry and Vanderbilt
Addiction Center
Vanderbilt University Medical Center
Nashville, Tennessee
xviii Contributors
Elizabeth Mayne, MD, PhD
Resident in Pediatrics and Child
Neurology
Department of Pediatrics
Stanford University School of
Medicine
Palo Alto, California
Alexander J . McAdam, MD, PhD
Associate Professor of Pathology
Harvard Medical School
Medical Director
Infectious Diseases Diagnostic
Laboratory
Boston Children’s Hospital
Boston, Massachusetts
J ames M. McCabe, MD
Assistant Professor of Medicine
University of Washington
Director, Cardiac Catheterization
Laboratory
University of Washington Medical
Center
Seattle, Washington
Keith W. Miller, MA, DPhil
Edward Mallinckrodt Professor
of Pharmacology
Department of Anaesthesia
Harvard Medical School
Pharmacologist, Department of
Anesthesia, Critical Care and
Pain Medicine
Massachusetts General Hospital
Boston, Massachusetts
J oshua D. Moss, MD
Assistant Professor of Medicine
Heart Rhythm Center
University of Chicago Medical Center
Chicago, Illinois
Dalia S. Nagel, MD
Clinical Instructor, Department
of Ophthalmology
Mount Sinai School of Medicine
Attending Physician
Department of Ophthalmology
Mount Sinai Hospital
New York, New York
William M. Oldham, MD, PhD
Instructor in Medicine
Harvard Medical School
Associate Physician
Pulmonary and Critical Care Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Sachin Patel, MD, PhD
Assistant Professor, Departments
of Psychiatry and Molecular
Physiology and Biophysics
Vanderbilt University Medical Center
Nashville, Tennessee
Roy H. Perlis, MD, MSc
Director, Center for Experimental
Drugs and Diagnostics
Center for Human Genetic Research
and Department of Psychiatry
Massachusetts General Hospital
Associate Professor of Psychiatry
Harvard Medical School
Boston, Massachusetts
Maarten Postema, PhD
Director of Chemistry
EISAI Inc.
Andover, Massachusetts
Giulio R. Romeo, MD
Instructor in Medicine
Harvard Medical School
Staff Physician, Adult Diabetes
Section
Joslin Diabetes Center
Staff Physician, Division of
Endocrinology BIDMC
Boston, Massachusetts
Eryn L. Royer, BA
Medical Student
University of Colorado School of
Medicine
Aurora, Colorado
Edward T. Ryan, MD
Professor of Medicine
Harvard Medical School
Professor of Immunology and
Infectious Diseases
Harvard T.H. Chan School of
Public Health
Director, Tropical Medicine
Massachusetts General Hospital
Boston, Massachusetts
J oshua M. Schulman, MD
Assistant Professor of Dermatology
University of California, Davis
Director of Dermatopathology
Sacramento VA Medical Center
Sacramento, California
Charles N. Serhan, PhD
Simon Gelman Professor of
Anaesthesia (Biological Chemistry
and Molecular Pharmacology)
Department of Anesthesiology,
Perioperative and Pain Medicine
Harvard Medical School
Director, Center for Experimental
Therapeutics and Reperfusion Injury
Brigham and Women’s Hospital
Boston, Massachusetts
Helen M. Shields, MD
Professor of Medicine
Harvard Medical School
Physician, Department of Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Steven E. Shoelson, MD, PhD
Professor of Medicine
Harvard Medical School
Associate Director of Research,
Section Head, Cellular and
Molecular Physiology
Joslin Diabetes Center
Boston, Massachusetts
David M. Slovik, MD
Associate Professor of Medicine
Harvard Medical School
Endocrine Unit
Massachusetts General Hospital
Boston, Massachusetts
Chief, Division of Endocrinology
Newton-Wellesley Hospital
Newton, Massachusetts
David G. Standaert, MD, PhD
John N. Whitaker Professor and Chair,
Department of Neurology
University of Alabama at Birmingham
Director, Division of
Movement Disorders
University Hospital
Birmingham, Alabama
Gary R. Strichartz, PhD
Professor of Anaesthesia
(Pharmacology),
Harvard Medical School
Director, Pain Research Center,
Department of Anesthesiology,
Perioperative and Pain Medicine
Brigham and Women’s Hospital
Boston, Massachusetts

Victor W. Sung, MD
Associate Professor, Department of
Neurology, Division of Movement
Disorders
The University of Alabama at
Birmingham
Birmingham, Alabama
Kelan Tantisira, MD, MPH
Associate Professor of Medicine
Harvard Medical School
Associate Physician
Channing Division of Network
Medicine and Division of
Pulmonary and Critical Care
Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Hakan R. Toka, MD, PhD
Assistant Professor of Medicine
Division of Nephrology and
Hypertension
Eastern Virginia Medical School
Norfolk, Virginia
J ohn L. Vahle, DVM, PhD, DACVP
Senior Research Pathologist, Department
of Toxicology and Pathology
Lilly Research Laboratories
Indianapolis, Indiana
Anand Vaidya, MD
Assistant Professor of Medicine
(Endocrinology)
Harvard Medical School
Division of Endocrinology, Diabetes,
and Hypertension
Brigham and Women’s Hospital
Boston, Massachusetts
Vishal S. Vaidya, PhD
Associate Professor of Medicine
Head, Systems Toxicology
Program, Laboratory of Systems
Pharmacology
Harvard Medical School
Brigham and Women’s Hospital
Associate Professor of Environmental
Health
Harvard T.H. Chan School of
Public Health
Boston, Massachusetts
xix Contributors
Andrew J . Wagner, MD, PhD
Assistant Professor, Department of
Medicine
Harvard Medical School
Medical Director, Ambulatory Oncology
Center for Sarcoma and Bone Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
Clifford J . Woolf, MB, BCh, PhD
Professor of Neurology
and Neurobiology
Harvard Medical School
Director, F.M. Kirby
Neurobiology Center
Children’s Hospital Boston
Boston, Massachusetts
J acob Wouden, MD
Radiologist, Washington Hospital
Medical Staff
Washington Hospital Healthcare Group
Fremont, California
 I
Fundamental Principles of
Pharmacology
 B C

1
Drug–Receptor Interactions
Fra n c is J . Ale n g h a t a n d David E. Go la n
α β
γ
INTRODUCTION & CASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2–33
INTR Int GD
G DP
n racee llular Recep
nt e tors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
CONFORMATION AND D CH
CHE EMISTRY Y OF IInt
ntrra ce
cellllular Enzymes and Signal
DRUGS AND D RE
RECE
CEPT
PTOR
ORS S ..................................2 Traa ns
nsduduct
c ion Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
IImp
mpaa ctt of Drug Binding on the Receptor . . . . . . . . . . . . . . . . . . . 5 Transcription Factorss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Membrane Effects on Drug–Receptor Inter erac
acti tion
ons . . . . . . . . . . 6 Structural Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
MOLECULAR AND CEL LLU
LULA LAR R DETERMINANTS OF Nucleic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DR
RUG SEL ELECECTI
TIVITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Extracellular Targetss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Cell Surface
Surfrfac
acc e Ad
Adhheesion
sion
sion R
Receptors
eceptors . . . . . . . . . . . . . . . . . . . . . . . . 14
MAJ OR TYPES OF DRUG RECEPTORS . . . . . . . . . . . . . . . . . . . . . . . 6
Tra
Trans
nsme
memb mbra
rane
ne Ion Cha hannels . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 PROCESSING OF SIGNALS RESULTING FROM
Transmembrane G Protein-Coupl pled
ed Recepec epto tors . . . . . . . . . . . . . 9 DRUG–RECEPTOR INTERACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . 14
Tra
rans
nsme
memb mbra
rane
ne Receptors with Linked Enzymatic Domains . . . 11 CELLULAR REGULATION OF DRUG–RECEPTOR
Receptor Tyrosine Kinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 INTERACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Receptor Tyrosine Phosphatases . . . . . . . . . . . . . . . . . . . . . . 12 DRUGS THAT DO NOT FIT THE DRUG–RECEPTOR MODEL. . . . . 16
Tyrosine
y Kinase-Associated Receptors p . . . . . . . . . . . . . . . . . 12 CONCLUSION
CONCL
ON CLUSUSIO IONNA AND
ND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . 16
Receptor Serine/Threonine Kinasess . . . . . . . . . . . . . . . . . . . 12 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Receptor Guanylyl Cyclasess . . . . . . . . . . . . . . . . . . . . . . . . . . 12

INTRODUCTION Drug receptors are macromolecules that, upon binding to a

Why is it that one drug a ects cardiac unction and another
alters the transport o specif c ions in the kidney? Why do
antibiotics e ectively kill bacteria but rarely harm patients?
These questions can be answered by f rst examining the in-
teraction between a drug and its specif c molecular target and
then considering the role o that action in a broader physi-
ologic context. This chapter ocuses on the molecular details
o drug–receptor interactions, emphasizing the variety o
receptors and their molecular mechanisms. This discussion
provides a conceptual basis or the action o the many drugs
and drug classes discussed in this book. It also serves as a
background or Chapter 2, Pharmacodynamics, which dis-
cusses the quantitative relationships between drug–receptor
interactions and pharmacologic e ect.
Although drugs can theoretically bind to almost any
three-dimensional target, most drugs achieve their desired
(therapeutic ) e ects by interacting selectively with target
molecules that play important physiologic or pathophysi-
ologic roles. In many cases, selectivity o drug binding to
receptors also determines the undesired (adverse ) e ects
o a drug. In general, drugs are molecules that interact with
specif c molecular components o an organism to cause bio-
chemical and physiologic changes within that organism.
drug, mediate those biochemical and physiologic changes.
CONFORMATION AND CHEMISTRY OF
DRUGS AND RECEPTORS
An understanding o why a drug binds to a particular receptor
can be ound in the structure and chemical properties o the
two molecules. This section discusses the basic determinants
o receptor structure and the chemistry o drug–receptor
binding. The discussion here ocuses primarily on the inter-
actions o drugs that are small molecules with target recep-
tors that are mainly macromolecules (especially proteins),
but many o these principles also apply to the interactions
o antibody- or other protein-based therapeutics with their
molecular targets (see Chapter 54, Protein Therapeutics).
Because many human and microbial drug receptors are
proteins, it is use ul to review the our major levels o protein
structure (Fig. 1-1). At the most basic level, proteins consist
o long chains o amino acids, the sequences o which are
determined by the sequences o the DNA that code or the
proteins. A protein’s amino acid sequence is re erred to as
its primary structure . Once a long chain o amino acids has
been synthesized on a ribosome, many o the amino acids

2

In te n t o n e n jo yin g h is n e w ly o u n d
re tire m e n t, Mr. B h a s m a d e a p o in t o
p la yin g te n n is a s o te n a s p o s s ib le d u r-
in g th e p a s t ye a r. Fo r th e p a s t 3 m o n th s ,
h o w e ve r, h e h a s n o te d in cre a s in g a -
tig u e . Mo re o ve r, h e is n o w u n a b le to
f n is h a m e a l, d e s p ite h is typ ica lly vo ra cio u s a p -
p e tite . Wo rrie d a n d w o n d e rin g w h a t th e s e s ym p -
to m s m e a n , Mr. B s ch e d u le s a n a p p o in tm e n t w ith
h is d o cto r. On p hys ica l e xa m in a tio n , th e p hys icia n
n o te s th a t Mr. B h a s a n e n la rg e d s p le e n , e xte n d in g
a p p ro xim a te ly 10 cm b e lo w th e le t co s ta l m a rg in ;
th e p hys ica l e xa m is o th e rw is e w ith in n o rm a l lim -
its . Blo o d te s ts s h o w a n in cre a s e d to ta l w h ite b lo o d
ce ll co u n t (70,0 0 0 ce lls /m m 3 ) w ith a n a b s o lu te in -
cre a s e in n e u tro p h ils , b a n d o rm s , m e ta m ye lo cyte s ,
a n d m ye lo cyte s , b u t n o b la s t ce lls (u n d i e re n tia te d
p re cu rs o r ce lls ). Cyto g e n e tic a n a lys is o m e ta p h a s e
ce lls d e m o n s tra te s th a t 90% o Mr. B’s m ye lo id ce lls
p o s s e s s th e Ph ila d e lp h ia ch ro m o s o m e (in d ica tin g a
tra n s lo ca tio n b e tw e e n ch ro m o s o m e s 9 a n d 22), co n -
f rm in g th e d ia g n o s is o ch ro n ic m ye lo id le u ke m ia .
Th e p hys icia n in itia te s th e ra p y w ith imatinib, a h ig h ly
s e le ctive in h ib ito r o th e BCR-Ab l tyro s in e kin a s e
u s io n p ro te in th a t is e n co d e d b y th e Ph ila d e lp h ia
ch ro m o s o m e . Ove r th e n e xt m o n th , th e ce lls
begin to interact with nearby amino acids in the polypeptide
chain. These interactions, which are typically mediated by
hydrogen bonding, give rise to the secondary structure o a
protein by orming well-def ned con ormations such as the
helix, pleated sheet, and barrel. As a result o their
highly organized shape, these structures o ten pack tightly
with one another, urther def ning the overall shape o the
protein. Tertiary structure results rom the interaction o
amino acids more distant rom one another along a single
amino acid chain. These interactions include hydrogen bond
and ionic bond ormation as well as the covalent linkage
o sul ur atoms to orm intramolecular disulf de bridges.
Finally, polypeptides may oligomerize to orm more com-
plex structures. The con ormation that results rom the
interaction o separate polypeptides is re erred to as the qua-
ternary structure .
Di erent portions o a protein’s structure generally have
di erent a f nities or water, and this eature has an additional
e ect on the protein’s shape. Because both the extracellular
and intracellular environments are composed primarily o
water, hydrophobic protein segments are o ten drawn to the
inside o the protein or shielded rom water by insertion into
lipid bilayer membranes. Conversely, hydrophilic protein
segments are o ten located on a protein’s exterior sur ace.
A ter all o this twisting and turning is completed, each pro-
tein has a unique shape that determines its unction, location
in the body, relationship to cellular membranes, and binding
interactions with drugs and other macromolecules.
The site on the receptor at which the drug binds is
called its binding site . Each binding site has unique chemi-
cal characteristics that are determined by the specif c
properties o the amino acids that make up the site. The
C h a p t e r 1 Drug–Receptor Interactions 3
co n ta in in g th e Ph ila d e lp h ia ch ro m o s o m e d is a p p e a r
co m p le te ly ro m Mr. B’s b lo o d , a n d h e b e g in s to e e l
w e ll e n o u g h to co m p e te in a s e n io rs te n n is to u rn a -
m e n t. Mr. B co n tin u e s to ta ke im a tin ib e ve ry d a y,
a n d h e h a s a co m p le te ly n o rm a l b lo o d co u n t a n d n o
a tig u e . He is n o t s u re w h a t th e u tu re w ill b rin g , b u t
h e is g la d to h a ve b e e n g ive n th e ch a n ce to e n jo y a
h e a lthy re tire m e n t.
Questions
1 . How does imatinib interrupt the activity o the BCR-Abl
tyrosine kinase usion protein?
2 . Unlike imatinib, most o the older therapies or chronic
myeloid leukemia (such as inter eron- ) had signif cant
“ u-like” adverse e ects. Why did these therapies
cause signif cant adverse e ects in most patients,
whereas (as in this case) imatinib causes adverse
e ects in very ew patients?
3 . Why is imatinib a selective therapy or chronic myeloid
leukemia? Is this selectivity related to the lack o ad-
verse e ects associated with imatinib therapy?
4 . How does the BCR-Abl protein a ect intracellular
signaling pathways?
three-dimensional structure, shape, and reactivity o the
site, and the inherent structure, shape, and reactivity o the
drug, determine the orientation o the drug with respect to
the receptor and govern how tightly these molecules bind to
one another. Drug–receptor binding is the result o multiple
chemical interactions between the two molecules, some
o which are airly weak (such as van der Waals orces)
and some o which are extremely strong (such as covalent
bonding). The sum total o these interactions provides the
specif city o the overall drug–receptor interaction. The a-
vorability o a drug–receptor interaction is re erred to as the
a f nity o the drug or its binding site on the receptor. This
concept is discussed in more detail in Chapter 2. The chem-
istry o the local environment in which these interactions
occur—such as the hydrophobicity, hydrophilicity, and pKa
o amino acids near the binding site—may also a ect the
a f nity o the drug–receptor interaction. The primary orces
that contribute to drug–receptor a f nity are described below
and in Table 1-1.
van der Waals orces , resulting rom the polarity induced
in a molecule by the shi ting o its electron density in re-
sponse to the close proximity o another molecule, provide
a weak attractive orce or drugs and their receptors. This
induced polarity is a ubiquitous component o all molecular
interactions. Hydrogen bonds have substantial strength and
are o ten important or drug–receptor association. This type
o bond is mediated by the interaction between positively
polarized hydrogen atoms (which are covalently attached
to more electronegative atoms such as nitrogen or oxygen)
and negatively polarized atoms (such as oxygen, nitrogen,
or sul ur that are covalently attached to less electronega-
tive atoms such as carbon or hydrogen). Ionic interactions ,
4 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Primary
Amino a cids
Secondary
Be ta ple a te d Alpha he lix
s he e t
Tertiary
Be ta ple a te d s he e t
Alpha he lix
Quaternary
FIGURE 1-1. Levels of protein structure. Protein structure can be divided
into our levels o complexity, re erred to as primary, secondary, tertiary,
and quaternary structure. Primary structure is determined by the sequence
o amino acids that make up the polypeptide chain. Secondary structure is
determined by the interaction o positively polarized hydrogen atoms with
negatively polarized atoms (such as oxygen) on the same polypeptide chain.
These interactions result in a number o characteristic secondary patterns
o protein con ormation, including the helix and pleated sheet. Tertiary
structure is determined by the interactions o amino acids that are relatively
ar apart on the protein backbone. These interactions, which include ionic
bonds and covalent disulf de linkages (among others), give proteins their
characteristic three-dimensional structure. Quaternary structure is deter-
mined by the binding interactions among two or more independent protein
subunits.
which occur between atoms with opposite charges, are
stronger than hydrogen bonds but less strong than covalent
bonds. Covalent bonding results rom the sharing o a pair o
electrons between two atoms on di erent molecules. Cova-
lent interactions are so strong that, in most cases, they are
essentially irreversible. Table 1-1 indicates the mechanism
o interaction and relative strength o each o these types o
bonds. As noted above, the environment in which drugs and
receptors interact also a ects the avorability o binding.
The hydrophobic effect re ers to the mechanism by which the
unique properties o the ubiquitous solvent water cause the
interaction o a hydrophobic molecule with a hydrophobic
binding site to be enhanced.
Rarely is drug–receptor binding caused by a single type
of interaction; rather, it is a combination of these binding
interactions that provides drugs and receptors with the
forces necessary to form a stable drug–receptor complex.
In general, multiple weak orces comprise the majority o
drug–receptor interactions. For example, imatinib orms
many van der Waals interactions and hydrogen bonds with
the ATP-binding site o the BCR-Abl tyrosine kinase. The
sum total o these relatively weak orces creates a strong
(high a f nity) interaction between this drug and its recep-
tor (Fig. 1-2). Ionic and hydrophobic interactions exert
orce at a greater distance than van der Waals interactions
and hydrogen bonds; or this reason, the ormer interac-
tions are o ten critical to initiate the association o a drug
and receptor.
Although relatively rare, covalent interactions between
a drug and its receptor are a special case. The ormation
o a covalent bond is o ten essentially irreversible, and in
such cases, the drug and receptor orm an inactive complex.
To regain activity, the cell must synthesize a new receptor
molecule to replace the inactivated protein; and the drug
molecule, which is also part o the inactive complex, is
generally not available to inhibit other receptor molecules.
Drugs that modi y their target receptors (o ten enzymes)
through this mechanism are sometimes called suicide sub-
strates . Aspirin is an example o such a drug; it irrevers-
ibly acetylates cyclooxygenases to reduce the production
o prostaglandins (anti-in ammatory e ect) and thrombox-
anes (antiplatelet e ect) (see Chapter 43, Pharmacology o
Eicosanoids).
The molecular structure o a drug dictates the physical
and chemical properties that contribute to its specif c bind-
ing to the receptor. Important actors include hydrophobicity,
ionization state (pKa), con ormation, and stereochemistry o
the drug molecule. All o these actors combine to determine
the complementarity o the drug to the binding site. Recep-
tor binding pockets are highly specif c, and small changes
in the drug can have a large e ect on the a f nity o the
drug–receptor interaction. For example, the stereochemistry
o the drug has a great impact on the strength o the bind-
ing interaction. Warfarin is synthesized and administered as
a racemic mixture (a mixture containing 50% o the right-
handed molecule and 50% o the le t-handed molecule);
however, the S enantiomer is our times more potent than
the R because o a stronger interaction o the S orm with its
binding site on vitamin K epoxide reductase. Stereochem-
istry can also a ect toxicity in cases where one enantiomer
o a drug causes the desired therapeutic e ect and the other
enantiomer causes an undesired toxic e ect, perhaps due to
an interaction with a second receptor or to metabolism to a
toxic species. Although it is sometimes di f cult or pharma-
ceutical companies to synthesize and puri y individual en-
antiomers on a large scale, a number o currently marketed
drugs are produced as individual enantiomers in cases where
one enantiomer has higher e f cacy and/or lower toxicity
than its mirror image.
 C h a p t e r 1 Drug–Receptor Interactions 5

TABLE 1-1 Relative Strength o Bonds between Receptors and Drugs

BOND TYPE MECHANISM BOND STRENGTH
van der Waals Shi ting electron density in areas o a molecule, or in a molecule as a whole, results in the generation o
transient positive or negative charges. These areas interact with transient areas o opposite charge
on another molecule.

Hydrogen Hydrogen atoms bound to nitrogen or oxygen become more positively polarized, allowing them to bond
to more negatively polarized atoms such as oxygen, nitrogen, or sul ur.

Ionic Atoms with an excess o electrons (imparting an overall negative charge on the atom) are attracted to
atoms with a def ciency o electrons (imparting an overall positive charge on the atom).

Covalent Two bonding atoms share electrons.

Impact o Drug Binding on the Receptor The principle o induced f t suggests that drug–receptor
binding can have pro ound e ects on the con ormation o
How does drug binding produce a biochemical and/or physi-
the receptor. By inducing con ormational changes in the re-
ologic change in the organism? In the case o receptors with
ceptor, many drugs not only improve the quality o the bind-
enzymatic activity, the binding site o the drug is o ten the
ing interaction but also alter the action o the receptor. The
active site at which an enzymatic trans ormation is cata-
change in shape induced by the drug is sometimes identi-
lyzed, and the catalytic activity o the enzyme is inhibited
cal to that caused by the binding o an endogenous ligand.
by drugs that prevent substrate binding to the site or that
For example, exogenously administered insulin analogues
covalently modi y the site. In cases where the binding site is
all stimulate the insulin receptor to the same extent, despite
not the active site o the enzyme, drugs can cause a change
their slightly di erent amino acid sequences. In other cases,
by preventing the binding o endogenous ligands to their
drug binding alters the shape o the receptor so as to make it
receptor binding pockets. In many drug–receptor interac-
more or less unctional than normal. For example, imatinib
tions, however, the binding o a drug to its receptor results
binding to the BCR-Abl tyrosine kinase causes the protein to
in a change in the con ormation o the receptor. Altering the
assume an enzymatically inactive con ormation, thus inhib-
shape o the receptor can a ect its unction, including en-
iting the kinase activity o the receptor.
hancing the a f nity o the drug or the receptor. Such an
Another way to describe the induced f t principle is to
interaction is o ten re erred to as induced f t, because the re-
consider that many receptors exist in multiple con orma-
ceptor’s con ormation changes so as to improve the quality
tional states—such as inactive (or closed), active (or open),
o the binding interaction.
and desensitized (or inactivated)—and that the binding o a

A B Glu 286
C
Me t 290 Imatinib

Ile 313

Imatinib P he 382
Ala 269
Gly 383
As p 381
As n 368 Activa tion loop
of kina s e
Thr 315

P he 382 Lys 271

As p 363

Le u 248 P he 317
As p 381 Arg 367 Tyr 393
Tyr 253 Va l 256

Me t 318
Gly 321

Le u 370

FIGURE 1-2. Structural basis o specif c enzyme inhibition: imatinib interaction with the BCR-Abl kinase. A. The kinase portion o the BCR-Abl tyrosine
kinase is shown in a ribbon ormat (gray). An analogue o imatinib, a specif c inhibitor o the BCR-Abl tyrosine kinase, is shown as a space-f lling model (blue ).
B. Detailed diagram o the intermolecular interactions between the drug (shaded in purple ) and amino acid residues in the BCR-Abl protein. Hydrogen bonds
are indicated by dashed lines, while van der Waals interactions (indicated by halos around the amino acid name and its position in the protein sequence)
are shown or nine amino acids with hydrophobic side chains. C. The interaction o the drug (blue ) with the BCR-Abl protein (gray) inhibits phosphorylation
o a critical activation loop (green-highlighted ribbon format), thus preventing catalytic activity.
6 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
drug to the receptor stabilizes one or more o these con or-
mations. Quantitative models that incorporate these concepts
o drug–receptor interactions are discussed in Chapter 2.
Membrane E ects on Drug–Receptor
Interactions
The structure o the receptor also determines where the pro-
tein is located in relationship to cellular boundaries such as
the plasma membrane. Proteins that have large hydrophobic
domains are able to reside in the plasma membrane because
o the membrane’s high lipid content. Many receptors that
span the plasma membrane have lipophilic domains that are
located in the membrane and hydrophilic domains that re-
side in the intracellular and extracellular spaces. Other drug
receptors, including a number o transcription regulators
(also called transcription actors ), have only hydrophilic do-
mains and reside in the cytoplasm, nucleus, or both.
Just as the structure o the receptor determines its loca-
tion in relationship to the plasma membrane, the structure o
a drug a ects its ability to gain access to the receptor. For
example, many drugs that are highly water-soluble are un-
able to pass through the plasma membrane and bind to target
molecules in the cytoplasm. Certain hydrophilic drugs are
able to pass through transmembrane channels (or use other
transport mechanisms) and gain ready access to cytoplasmic
receptors. Drugs that are highly lipophilic, such as many
steroid hormones, are o ten able to pass through the hydro-
phobic lipid environment o the plasma membrane without
special channels or transporters and thereby gain access to
intracellular targets.
Drug-induced alterations in receptor shape can allow
drugs bound to cell sur ace receptors to a ect unctions
inside cells. Many cell sur ace receptors have extracellular
domains that are linked to intracellular e ector molecules by
receptor domains that span the plasma membrane and extend
into the cytoplasm. In some cases, changing the shape o
the extracellular domain can alter the con ormation o the
membrane-spanning and/or intracellular domains o the
receptor, resulting in a change in receptor unction. In other
cases, drugs can cross-link the extracellular domains o two
receptor molecules, orming a dimeric receptor complex that
activates e ector molecules inside the cell.
All o these actors—drug and receptor structure, the
chemical orces in uencing drug–receptor interaction, drug
solubility in water and in the plasma membrane, and the
unction o the receptor in its cellular environment—con er
substantial specif city on the interactions between drugs
and their target receptors. This book discusses numerous
examples o drugs that can gain access and bind to receptors,
induce con ormational changes in the receptors, and thereby
produce biochemical and physiologic e ects. Specif city o
drug–receptor binding suggests that, armed with the knowl-
edge o the structure o a receptor, one could theoretically
design a drug that interrupts or enhances receptor activity.
This process, known as rational drug design, could poten-
tially increase the e f cacy and reduce the toxicity o drugs
by optimizing their structure so that they bind more selec-
tively to their targets. Rational drug design was f rst used to
develop highly selective agents such as the antiviral prote-
ase inhibitor ritonavir and the antineoplastic tyrosine kinase
inhibitor imatinib. Indeed, urther rounds o rational drug
design have led to the development o second-generation
protease inhibitors and antineoplastics with high a f nity or
the mutated drug targets that can evolve in patients who de-
velop resistance to f rst-generation drugs. The rational drug
design approach is discussed in greater detail in Chapter 51,
Drug Discovery and Preclinical Development.
MOLECULAR AND CELLULAR
DETERMINANTS OF DRUG SELECTIVITY
The ideal drug would interact only with a molecular target
that causes the desired therapeutic e ect but not with molec-
ular targets that cause unwanted adverse e ects. Although
no such drug has yet been discovered (i.e., all drugs cur-
rently in clinical use have the potential to cause adverse
e ects as well as therapeutic e ects; see Chapter 6, Drug
Toxicity), pharmacologists can take advantage o several de-
terminants o drug selectivity in an attempt to reach this goal.
Selectivity o drug action can be con erred by at least two
classes o mechanisms, including (1) the cell-type specif c-
ity o receptor subtypes and (2) the cell-type specif city o
receptor–e ector coupling.
Although many potential receptors or drugs are widely
distributed among diverse cell types, some receptors are
more limited in their distribution. Systemic administration o
drugs that interact with such localized receptors can result in
a highly selective therapeutic e ect. For example, drugs that
target ubiquitous processes such as DNA synthesis are likely
to cause signif cant toxic side e ects; this is the case with
many currently available chemotherapeutics or the treat-
ment o cancer. Other drugs that target cell-type restricted
processes such as acid generation in the stomach may have
ewer adverse e ects. Imatinib, or example, is an extremely
selective drug because the BCR-Abl protein is not expressed
in normal (noncancerous) cells. In general, the more re-
stricted the cell-type distribution o the receptor targeted by
a particular drug, the more selective the drug is likely to be.
Similarly, even though many di erent cell types may ex-
press the same molecular target or a drug, the e ect o that
drug may di er in the various cell types because o di er-
ential receptor–e ector coupling mechanisms or di erential
requirements or the drug target in the various cell types.
For example, although voltage-gated calcium channels are
ubiquitously expressed in the heart, cardiac pacemaker cells
are relatively more sensitive to the e ects o calcium chan-
nel blocking agents than are cardiac ventricular muscle cells.
This di erential e ect is attributable to the act that action po-
tential propagation depends mainly on the action o calcium
channels in cardiac pacemaker cells, whereas sodium chan-
nels are more important than calcium channels in the action
potentials o ventricular muscle cells. In general, the more
the receptor–e ector coupling mechanisms di er among the
various cell types that express a particular molecular target
or a drug, the more selective the drug is likely to be.
MAJ OR TYPES OF DRUG RECEPTORS
Given the great diversity o drug molecules, it might seem
likely that the interactions between drugs and their molecular
targets would be equally diverse. This is only partly true. In act,
most o the currently understood drug–receptor interactions
can be classif ed into six major groups. These groups com-
prise the interactions between drugs and (1) transmembrane
 C h a p t e r 1 Drug–Receptor Interactions 7

A B C D

α β
γ
GDP

FIGURE 1-3. Major types of interactions between drugs and receptors. Most drug–receptor interactions can be divided into six groups, our o which are
shown here. A. Drugs can bind to ion channels spanning the plasma membrane, causing an alteration in the channel’s conductance. B. Heptahelical recep-
tors spanning the plasma membrane are unctionally coupled to intracellular G proteins. Drugs can in uence the actions o these receptors by binding to
the extracellular sur ace or transmembrane region o the receptor. C. Drugs can bind to the extracellular domain o a transmembrane receptor and cause a
change in signaling within the cell by activating or inhibiting an enzymatic intracellular domain (rectangular box) o the same receptor molecule. D. Drugs can
di use through the plasma membrane and bind to cytoplasmic or nuclear receptors. This is o ten the pathway used by lipophilic drugs (e.g., drugs that bind
to steroid hormone receptors). Additionally, drugs can bind to enzymes and other targets in the extracellular space and to cell sur ace adhesion receptors
without the need to cross the plasma membrane (not shown).

ion channels; (2) transmembrane receptors coupled to intra-
cellular G proteins; (3) transmembrane receptors with linked
enzymatic domains; (4) intracellular receptors, including en-
zymes, signal transduction molecules, transcription actors,
structural proteins, and nucleic acids; (5) extracellular targets;
and (6) cell sur ace adhesion receptors (Fig. 1-3). Table 1-2
provides a summary o each major interaction type.
Knowing whether and to what extent a drug activates or
inhibits its target provides valuable in ormation about the in-
teraction. Although pharmacodynamics (the e ects o drugs
on the human body) is covered in detail in the next chapter, it
is use ul to state brief y the major pharmacodynamic relation-
ships between drugs and their targets be ore examining the mo-
lecular mechanisms o drug–receptor interactions. Agonists are
molecules that, upon binding to their targets, cause a change
in the activity of those targets. Full agonists bind to and acti-
vate their targets to the maximal extent possible. For example,
acetylcholine binds to the nicotinic acetylcholine receptor and
induces a con ormational change in the receptor-associated ion
channel rom a nonconducting to a ully conducting state. Par-
tial agonists produce a submaximal response upon binding to
their targets. Inverse agonists cause constitutively active targets
to become inactive. Antagonists inhibit the ability of their tar-
gets to be activated (or inactivated) by physiologic or pharma-
cologic agonists. Drugs that directly block the binding site o
a physiologic agonist are called competitive antagonists ; drugs
that bind to other sites on the target molecule, and thereby pre-
vent the con ormational change required or receptor activation
(or inactivation), may be either noncompetitive or uncompetitive
antagonists (see Chapter 2). As the mechanism o each drug–
receptor interaction is outlined in the next several sections, it
will be use ul to consider at a structural level how these di er-
ent pharmacodynamic e ects could be produced.
Transmembrane Ion Channels
Many cellular unctions require the passage o ions and
other hydrophilic molecules across the plasma membrane.

TABLE 1-2 Six Major Types of Drug–Receptor Interactions

RECEPTOR TYPE SITE OF DRUG–RECEPTOR INTERACTION SITE OF RESULTANT ACTION EXAMPLES
Transmembrane ion Extracellular, intrachannel, or intracellular Cytoplasm Amlodipine, diazepam,
channel lidocaine, omeprazole

Transmembrane linked to Extracellular or intramembrane Cytoplasm Albuterol, loratadine,

intracellular G protein losartan, metoprolol

Transmembrane with Extracellular or intracellular Cytoplasm Erlotinib, insulin, nesiritide,

linked enzymatic sunitinib
domain

Intracellular Cytoplasm or nucleus Cytoplasm or nucleus Atorvastatin, doxycycline,

levothyroxine, paclitaxel

Extracellular target Extracellular Extracellular Dabigatran, donepezil,

etanercept, lisinopril

Adhesion Extracellular Extracellular Eptif batide, natalizumab

8 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Specialized transmembrane channels regulate these pro-
cesses. The unctions o ion channels are diverse, including
undamental roles in neurotransmission, cardiac conduction,
muscle contraction, and secretion. Because o this, drugs tar-
geting ion channels can have a substantial impact on major
body unctions.
Three major mechanisms are used to regulate the activ-
ity o transmembrane ion channels. In some channels, the
conductance is controlled by ligand binding to the channel.
In other channels, the conductance is regulated by changes in
voltage across the plasma membrane. In still other channels,
the conductance is controlled by ligand binding to plasma
membrane receptors that are linked to the channel in some
way. The f rst group o channels is re erred to as ligand-
gated, the second as voltage-gated, and the third as second
messenger-regulated. Table 1-3 summarizes the mechanism
o activation and unction o each channel type.
Channels are generally highly selective or the ions they
conduct. For example, action potential propagation in neu-
rons o the central and peripheral nervous systems occurs as
a result o the synchronous stimulation o voltage-gated ion
channels that permit the selective passage o Na ions into
the cell. When the membrane potential in such a neuron be-
comes su f ciently positive, the voltage-gated Na channels
open, allowing a large in ux o extracellular sodium ions
that urther depolarizes the cell. The role o ion-selective
channels in action potential generation and propagation is
discussed in Chapter 8, Principles o Cellular Excitability
and Electrochemical Transmission.
Most ion channels share some structural similarity, re-
gardless o their ion selectivity, the magnitude o their
conductance, or their mechanism o activation (gating) or
inactivation. Ion channels are pore- orming macromolecules
consisting o one or more protein subunits that pass through
the plasma membrane. The ligand-binding domain can be ex-
tracellular, within the channel, or intracellular, whereas the
domain that interacts with other receptors or modulators is
most o ten intracellular. The structures o several ion chan-
nels have been determined to atomic resolution; the nico-
tinic acetylcholine (ACh) receptor provides an example o
the structure o an important ligand-gated ion channel. This
receptor consists o f ve subunits, each o which crosses the
TABLE 1-3 Three Major Types of Transmembrane Ion
Channels
MECHANISM OF
CHANNEL TYPE ACTIVATION FUNCTION
Ligand-gated Binding o ligand to Altered ion
channel conductance
Voltage-gated Change in Altered ion
transmembrane conductance
voltage gradient
Second messenger- Binding o ligand to Second
regulated transmembrane messenger
receptor with regulates ion
G protein-coupled conductance
cytosolic domain, o channel
leading to second
messenger generation
plasma membrane (Fig. 1-4). Two o the subunits have been
designated ; each contains a single extracellular binding
site or ACh. In the ree (nonliganded) state o the recep-
tor, the channel is occluded by amino acid side chains and
does not allow the passage o ions. Binding o two molecules
o acetylcholine to the receptor induces a con ormational
change that opens the channel and allows ion conductance.
Although the nicotinic ACh receptor appears to assume
only two states, open or closed, many ion channels assume
other states as well. For example, some ion channels are able
to become refractory or inactivated. In this state, the chan-
nel’s permeability cannot be altered or a certain period o
time, known as the channel’s re ractory period. The volt-
age-gated sodium channel undergoes a cycle o activation,
channel opening, channel closing, and channel inactiva-
tion. During the inactivation (re ractory) period, the channel
A
α α
γ
Liga nd binding s ite s
B
α α
O
Re ce ptor ga te clos e d
+
N
O
Ace tylcholine
Na +
α α
Na +
Re ce ptor ga te ope n
FIGURE 1-4. Ligand-gated nicotinic acetylcholine receptor. A. The plasma
membrane acetylcholine (ACh) receptor is composed o f ve subunits—two
subunits, a subunit, a subunit, and a subunit. B. The subunit has
been removed to show an internal schematic view o the receptor, demon-
strating that it orms a transmembrane channel. In the absence o ACh, the
receptor gate is closed, and cations (most importantly, sodium ions [Na ])
are unable to traverse the channel. C. When ACh is bound to both subunits,
the channel opens, and sodium can pass down its concentration gradient
into the cell.
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 VII.
OUTBREAK AT MPANZA.
Whilst McKenzie was demonstrating in the south-west, and
Leuchars was similarly occupied at Mapumulo, a state of affairs was
rapidly developing in the Mpanza valley,[127] not more than sixteen
miles from Greytown, destined soon to alter the whole character of
the situation.
Owing to the fact that neither McKenzie nor Leuchars had met with
any opposition whatever when dealing, as has been seen, promptly
and effectively with all cases of disaffection that came to their notice,
it was, by the end of March, generally supposed that all further
trouble was at an end, at any rate, for the time being. This conviction
was strengthened by the execution of the murderers of Hunt and
Armstrong. This execution, however, proved to be not the end, but
only the end of the first phase of the Insurrection.
How far the Trewirgie affair can be associated with what was taking
place in Mpanza valley is for the reader to judge, after consideration
of the facts that will be laid before him. To understand it, it is
necessary to examine the character and antecedents of the man
who, on the 4th of April, became the initiator of the second and far
more vigorous phase of the Rebellion. This is all the more necessary,
not only because the Natives generally refer to it as his Rebellion,[128]
but because he was the Chief of a comparatively small, low-class
tribe and almost unknown, either by Europeans or Natives, beyond
the division in which he lived. The rôle he took on was one which a
far more imposing man like Mehlokazulu (of Zulu War fame), or even
Zibebu (had he been living),[129] might have been proud to assume,
had opportunity favourable for so hazardous an enterprise presented
itself. Indeed, the general belief of the Natives of Natal and Zululand
in regard to the poll tax was that, if there was to be any overt action at
all, Dinuzulu himself would take it as head of the Zulu House. But for
his imprisonment and banishment to St. Helena, it is quite possible he
would have taken it. As he failed, or at any rate preferred to remain in
the background, it fell, of all Chiefs in this portion of South Africa, on
one Bambata to step forward as protagonist on this unique and
dramatic occasion.
As a section of the Native public appeared desirous of a change in
the way in which they were being governed, it devolved, of course, on
some one to take the lead. Who should this be? A Chief? Of course,
for, in a matter such as this, it would be altogether foreign to Native
sentiment for a mere commoner to do so. Look how Makanda and
Mjongo had failed. What Chief, then, so far forgetful of his own
interests, as well as of those of his tribe, would dare to translate into
action the spirit of resistance innate in the people? Who, in short,
would have the temerity to start an insurrection against a Government
which, however much it might be regarded as oppressive, had yet, as
Bambata well knew, delivered his ancestors, and those of a million
other Natives, from the wrongs, cruelties and inhumanity of Tshaka
and Dingana, and enabled every man, woman and child to sleep
peacefully in their homes for upwards of two generations, undisturbed
by death-dealing, predatory raids?
The question, therefore, arises as to how it came about that one so
petty and obscure as Bambata should stand forth, practically alone,
as the redresser of the nation's alleged wrongs. Who and what was
he?
Bambata was born about the year 1865 in the neighbourhood of
Mpanza valley. His father was Mancinza, alias Sobuza, member of
the Zondi tribe,[130] and his mother the daughter of Pakade, a well-
known Chief of the Cunu tribe, now for the most part living in Weenen
division. This woman was Mancinza's principal wife. In regard to the
principal wife, a tribe is, by custom, called on to contribute towards
her lobolo; an attempt was made to do this in the present instance.
The tribe, however, objected to the Chief taking a girl of the Cunu
tribe, and refused to assist in lobola-ing her.[131] Determined to marry
the girl, Mancinza delivered the necessary forty or more cattle out of
his own herd. A few months after the wedding, the bride became so
averse to living with her husband's three other wives that, after
accusing them of wishing to kill her, she deserted and took up her
abode at the kraal of another man of the same tribe. It was at this
establishment that Bambata was born. His mother then insisted on a
kraal being specially erected for her. This was done, the result of the
unusual action being that the former place was well-nigh wrecked, for
the other wives complained of their husband devoting too much
attention to Bambata's mother.
As a boy, Bambata was headstrong and fond of fighting. He
frequently neglected the cattle he had to herd. When chastised, he
took the beating well, never crying out or shouting as boys sometimes
do. He became expert in the use of the assegai, and was an
exceptionally fine runner. Owing to the latter qualification, he earned
the sobriquet of "Magadu" (short for Magaduzela, o wa bonel
'empunzini),[132] which stuck to him all his life. His father had a
double-barrelled, muzzle-loading shot gun. This the youth soon
accustomed himself to, and became a good shot. When he was
about 25 years of age, his father died. His uncle, Magwababa, to
whom there will be further reference later, was appointed to act as
Chief. After a few years, he was formally superseded by Bambata
himself. A year or two after becoming Chief, Bambata committed a
daring theft of three head of cattle belonging to a Boer. He was tried
and severely punished, though not imprisoned. On the amount of the
fine being raised by members of the tribe, he was released.
As Chief, he was harsh, extravagant and reckless, selfish and
domineering. On one occasion he fined a man, but, as the latter
would not pay, he attacked him with an armed body of men and
forced him to comply. He rapidly squandered the property his father
had left and, like his father, ran counter to the wishes of the tribe in
selecting his principal wife. The elders were in favour of his promoting
a particular woman, and opposed to his own choice, on the ground
that the woman was a twin. He ignored their wishes and, after one of
his wives (there were four in all), had committed adultery and been
expelled, whilst another had deserted, he erected a solitary hut for
the principal one—calling it Emkontweni (the place of the assegai)—
thereby following once more the irregular example set by his father.
In the meantime, the relations he stood in towards his European
neighbours were even less satisfactory. The total strength of his tribe
at the end of 1905 was 910 huts in Umvoti, 120 in New Hanover, 21
in Umgeni, and 91 in Lion's River, divisions, or 1,142 in all;
representing a total approximate population of 5,000 men, women,
and children, or about 500 capable of bearing arms. The system of
recruiting regiments was followed in this as in some other tribes of
Natal and Zululand. Owing, however, to limited numbers, there were
incorporated into each regiment men of widely differing ages. During
the twenty-four years Bambata was nominally Chief, he recruited only
two regiments.
Most of the kraals of the tribe, as well as his own, especially in the
Umvoti division, were distributed over a number of private farms. The
landlord of the farm on which he personally lived, viz. Aangelegen,
[133] demanded a rental of £3 per hut, this, of course being apart from
Government taxation. Such rent was undoubtedly high, although on
other farms in the same district a similar, and even heavier, charge
was not uncommon. Notwithstanding these obligations, he continued
in his career of extravagance. He illicitly purchased European liquor
and drank freely thereof, as well as of Native beer, though not so as
to become a confirmed drunkard. In order to make good what he had
squandered in drink and in other ways, he borrowed from lawyers
who, not being less importunate or exacting than other people,
usually got back their own with interest through the local Magistrate's
court. Bambata was constantly being sued, either on account of loans
or for outstanding rent, and to such indebtedness there seemed to be
no end. Instead of bracing himself up and endeavouring to meet his
obligations, he persisted in his reckless conduct, until he became a
nuisance to Europeans, on the one hand, and the members of his
tribe, on the other. A more perturbed spirit than he was at the close of
1905 it is scarcely possible to conceive. He, hereditary Chief of a
tribe, which, though of humble origin as compared with many of the
adjoining ones in Zululand and Natal, was of no mean size, seemed
to be daily losing his grip over the people and coming within
measurable distance of utter ruin. This prospect he was smart
enough to realize, and it was because he knew such end to be
sooner or later inevitable that his despondency grew to despair.
In common with all other Chiefs throughout the Colony, including
Zululand, he was required, in April, 1904, on coming with his people
to pay the hut and dog taxes, to give information in connection with
the census. He was the man who, as has been stated, protested to
the Magistrate against furnishing a few matter-of-fact details,
concluding with the remark: "If there be anything behind all this, we
shall be angry." The threat was uttered at Marshall's hotel, exactly two
years and a day before his starting the Insurrection not a mile from
the same hotel. Mr. J.W. Cross, the Magistrate, by way of pacifying
and convincing him that the Government had no sinister motive, said:
"You may as well expect the sun to fall from the heavens as imagine
that harm will come to you." "That was just what we wanted to hear,"
he exclaimed in reply.
In August, 1905, a faction fight occurred in the ward. Owing to having
taken part in it himself, Bambata was charged before the Magistrate,
but the case was not disposed of till early in 1906, as one of those
assaulted was too unwell to appear. He was convicted and sentenced
to pay a fine of £20, with an alternative of three months'
imprisonment. The Government was advised to depose him, as being
unfit for the position of Chief, and because he was always being
sued. About this time he visited his lawyer in Pietermaritzburg, from
whom, it seems, he learned that his deposition was in contemplation.
When, in September, 1905, the Poll Tax Act was proclaimed in
Umvoti division, no opposition was raised by the Zondi or other local
tribes; the headmen, however, complained that the law would result in
complete loss of the small control kraal-owners still retained over their
sons. Bambata took the opportunity of reminding the Magistrate of
the statement the latter had made when the census was being taken,
asking that official to reconcile the assurance then given with the
demand for the poll tax that was being made. The Magistrate was
unable to do this to Bambata's satisfaction.
As a matter of fact, there was considerable and general objection to
the tax, though not given expression to in the presence of officials as
at other magistracies. Among those who objected in the Zondi tribe
was the headman, Nhlonhlo. He assumed a determined and defiant
attitude. But for the part he took, Bambata might not have broken into
rebellion. Nhlonhlo called together the people about him, proceeded
with them to Bambata and declared they would not pay. Bambata
apparently did what he could to persuade, but without success. The
only reason why Nhlonhlo made the stand he did was because he
had five taxable sons, and did not see why all of these should be
liable. Like Bambata, he had got into difficulties with his own landlord,
and when, some years previously, the latter had sought to eject him,
he borrowed money of Bambata, more than half of which is said to be
still owing.

Towards the end of 1905, confidential information was received by

the Magistrate to the effect that Bambata was in league with the
Zulus, and that he had agreed to bell the cat by putting to death the
Magistrate and his staff on their visiting Mpanza to collect poll tax. As
a result of this, the collections were begun in another part of the
division instead of, as was usual, in Bambata's ward. So far, then,
from being the first, Bambata was the last Chief to be called on to
pay. More than this, he and his people were ordered to attend for the
purpose at the Magistrate's office in Greytown. The date fixed was
the 22nd February. After receiving the instructions, he requested the
Magistrate to come as usual to collect in Mpanza valley. Mr. Cross,
however, said he was unable to countermand the order.
On the day appointed, the people appeared at the Magistrate's office.
They arrived about 11 instead of 9 a.m. The Chief was not with them,
as he should have been. An induna appeared in his stead,
apologizing for the Chief's absence on the ground of ill-health. (He
was said to be suffering from a stomach-ache.) The Magistrate
naturally concluded Bambata was at his kraal some thirteen or
fourteen miles away, whereas, as was afterwards reported, he and a
number of young men had concealed themselves in a wattle-tree
plantation, overlooking, and about two and a half miles from,
Greytown. Those who came up to pay were chiefly elderly men. They
at first appeared very surly. In reply to a question as to where the
young men, i.e. those liable for the tax, were, the old men said they
had gone out courting.
About 8.30 p.m. the same day, information was received from Native
sources that Greytown was to be attacked during the night "after the
white people had gone to bed," for Bambata had gathered together
an impi and was with it in the trees overlooking Greytown, meaning
Mr. Layman's and Dr. Wright's plantations. It was explained that
payment of the tax that day was simply a ruse 'to hoodwink the
Europeans,' and that Bambata intended to recover the money paid in.
A similar rumour came from another quarter. Steps were thereupon
taken to warn and protect the inhabitants. There happened that night
to be a dance on in the town hall. The electric light was purposely
kept burning all night in the building as well as in the streets. The hall,
in the meantime, was quickly transformed into a lager. Arms were
issued and pickets posted in various directions.
This 'scare,' for such it was, was based on incorrect or insufficient
information. Careful inquiry of those actually with Bambata on the day
in question has resulted in the following explanation:—As directed,
the Chief called on his people to proceed to Greytown to pay the tax.
He instructed them all to assemble on the ridge just before coming
within sight of the town. Such procedure was not irregular, as Chiefs,
when calling on their people to pay hut tax, often direct them to
assemble at a given spot to afford an opportunity for preliminary
inspection. Quite contrary to Bambata's orders, it would seem, a
number of young men came up from Mpanza valley led by Nhlonhlo,
all being armed with shields and assegais. They proceeded to the
vicinity of a kraal beside the road, a couple of miles further away from
Greytown than where Bambata had directed them to assemble. On
learning this, Bambata, then some little way off, sent a messenger to
order the young men to put down their arms and go to Greytown with
the others and pay. They refused point-blank. "If," they said, "we are
to throw away our assegais and go empty-handed, we certainly shall
not comply." Bambata now borrowed a horse and moved to inspect
the other section of his people who were in front. As he went off,
Nhlonhlo's party were heard to shout to the lender of the horse, "If,
after your supplying him with a horse, Bambata should be arrested by
the white people, we shall stab you." When the Chief reached the
rendezvous, he found his uncle, Magwababa, had already been
driven into Greytown by Mr. Botha, whilst a number of others had
followed him. Of those present, some were not properly dressed[134]
and, moreover, had not the necessary money. He ordered them
home, telling them to sell their goats and so find the amount of the
tax. Others were sent into Greytown with a message to the man in
charge to say that Bambata was absent owing to a headache.
Already apprehensive as to what might happen, especially as he had,
contrary to custom, been summoned to Greytown without knowing
why such course had been adopted, and, again, finding that a few
hot-bloods, who had by then heard all about the Trewirgie affair, had
taken up arms for the purpose of protecting him, and, if need be,
resisting by force any attempt to arrest him, can anyone be surprised
that Bambata showed some hesitation about going forward? He was
in a dilemma. The course he took was, questionable as it seems, on
the side of law and order, at any rate for the time being. His people
were obviously inclined to get out of hand, and it required his
personal presence to check any rash or hostile demonstration. Had
he gone into Greytown and been apprehended, it is quite possible an
effort at rescue would have been made. As it was, nothing occurred.
Nor would anything have occurred, because his arrest was not
contemplated. It was, of course, bad enough that a body of young
men should have assembled where they did, armed with assegais, in
much the same way that those of Mveli's had done when Mr. Bennett
went to collect at Henley, but, at that time Bambata had apparently no
intention of attacking Greytown. Where he made a fatal mistake was
in not reporting the incident at once, as Mveli had done, thus placing
on the Government the onus of preserving peace. Rather than
sacrifice the lawlessly inclined he, by inaction at a critical moment,
caused himself to be identified with them in every respect. "If we fail
to denounce the crime, we become participators in it."[135] From the
moment he excused himself from appearing on the lying pretext that
he had a headache, it became more and more difficult for him to do
otherwise than rebel. At that moment he unfitted himself for the
position of Chief. This the Government, some days later, recognized,
whereupon Magwababa was appointed to act as Chief as from that
date.
On the day after the scare, a message was received from the
Secretary for Native Affairs summoning Bambata to attend at his
office in Pietermaritzburg. Two Native police were sent to say he was
to take an early train to Pietermaritzburg on the following morning
(Saturday). The messengers returned to say he had promised to
comply on the Monday. After the police had gone, Nhlonhlo
intervened and would not allow the Chief to keep the promise, for the
reason that, having by that time slept in the veld for three days with
men under arms, he would be looked on as already in revolt, and,
therefore, as a criminal to be put under arrest. Nhlonhlo and his impi
thereupon carried him off to another kraal. On Tuesday, a further
message was sent. After some trouble, the messengers found him
and delivered their message. He told them to inform the Magistrate
he was afraid of going to Pietermaritzburg, as he had heard the
European people had taken up arms against him.
At this stage, Mr. C. Tatham, an attorney of Greytown, who had one
of Bambata's relations working for him, Bambata himself, moreover,
being his client, sent to the Chief to say that, if afraid of obeying the
summons, he was to send a particular man to him, when Tatham
himself would go and see Bambata and, after explaining the position,
conduct him to the authorities. Bambata was besought by his wiser
followers to seize the opportunity, which he said he would do. The
man referred to arrived, but found Tatham unwell. The latter then sent
word to say Bambata was to come by himself, and, if afraid, he was
to proceed direct to Tatham's residence, when he would be
conducted to the Magistrate's office. On hearing this, Nhlonhlo
exclaimed: "He won't go." In reply to a remark about the probability of
Bambata being released on payment of a fine, Nhlonhlo remarked: "I
prefer he should die in our own hands, rather than be shot by
Europeans out of our sight." Others tried to persuade the Chief, but,
influenced by Nhlonhlo, Bambata remarked: "I won't go. Some of you
want me to be killed by myself. When they kill me, it will not be until
some of you have been laid out." References to the action of the
British Government in regard to Cetshwayo and Langalibalele were
unavailing, for Bambata replied: "When each of these was captured, it
was not until after some of their people had been killed, therefore I
too mean to resist." "If you are tired of him" (i.e. Bambata), said
Nhlonhlo to the peace-makers, "give him over to us." After the wiser
men had queried whether Nhlonhlo had a fortress where Bambata
could be hidden with any good prospect of success, the people
dispersed. Bambata was then conducted to the forest-clad hill above
the principal induna Mgombana's kraal, and there concealed.
On the 3rd March, a final message was dispatched to the effect that,
if Bambata continued any longer to disobey the Supreme Chief's
order, he would have to take the consequences, whatever they might
be. The bearers, however, failed to see him, as the people refused to
disclose his whereabouts. The message was delivered to the Chief's
brother Funizwe.
Major W.J. Clarke, with a force of 170 Natal Police and a troop,
U.M.R. (Helpmakaar), made a surprise visit to Mpanza on the 9th,
with the object of arresting Bambata, but failed, as the man hid
himself in the dense bush about those parts as soon as he saw the
force advancing. Clarke, thereupon, returned to Pietermaritzburg.[136]
In the meantime, Bambata, feeling that Natal could not afford him
protection, crossed into Zululand on Sunday, the 11th March,
boasting to his followers as he left, that when they next set eyes on
him he would be at the head of an army. Nothing more was heard of
him officially from the 11th until the morning of the 3rd April.
During his absence, Magwababa and Funizwe (Bambata's full
brother), together with the more important men of the tribe, including
the firebrand, Nhlonhlo, were summoned to Pietermaritzburg, the
object being to appoint a successor to Bambata, who had been
deposed as from the 23rd February. It was decided Funizwe should
succeed, but that, for a year, Magwababa was to act as Chief.
But where was Bambata at this time? Subsequent inquiries show
that, when he left for Zululand, travelling on foot, he was
accompanied by his chief wife, three children, and a mat-bearer, also
a young man, Ngqengqengqe by name. Among other places, he slept
at a relative's in Nkandhla district; he then proceeded on to Dinuzulu's
Usutu kraal by easy stages, leaving his wife and children at a place
some seven miles away from there. He reached Usutu on Sunday,
the 25th March.
Only long after the Insurrection was any account procurable of these
doings, particularly from the woman and children in question.
According to their evidence, this young man, Ngqengqengqe, had
been sent from Usutu kraal by Dinuzulu's minor induna to summon
Bambata, as Dinuzulu desired to see him. Bambata had several
interviews with Dinuzulu, being treated by the latter in a markedly
hospitable manner. Accommodation in a special establishment a few
yards from the kraal and Dinuzulu's own apartments, was provided.
His wife and children were brought the next day to Usutu and there
concealed. Dinuzulu, says Bambata's wife, through his principal
induna, Mankulumana, gave Bambata instructions to go back to
Natal, commit an act of rebellion and then flee to Nkandhla forests,
where Dinuzulu's men would join him. Bambata was, at the same
time, given a Mauser rifle and some ammunition. After spending four
days at Usutu, he started on his return journey, leaving his wife and
children at Dinuzulu's kraal. And there they continued to be
concealed for fourteen months.[137] Two young men were sent back
with Bambata to Natal, one being Cakijana (son of Gezindaka), who
soon began to play an important part. Bambata, accompanied by
these two, called at a kraal of Chief Matshana (son of Mondise) on
Friday, the 30th March, but was refused admission. He left the same
afternoon for Ngubevu drift (on the Tugela), having first assured
himself that it was not being watched by police.
About 7 a.m. on Tuesday, 3rd April, it was reported to the Magistrate
that Bambata was back in Mpanza valley (as a matter of fact he had
got back on the 31st March), and that he and an impi he had raised
had captured the acting Chief Magwababa on the preceding evening;
that they had surprised Magwababa in his hut, treated him with
violence, and, tying him with a reim,[138] had marched him off towards
that portion of the tribe that lies furthest from Greytown, and in the
vicinity of Marshall's hotel. The foregoing tale had been brought to a
farmer (Mr. Botha) at 3 a.m. by Magwababa's own wife who, from
what she saw, supposed her husband must by then be dead.
Afterwards it was discovered that the assailants had, on seizing
Magwababa, jeered at him in these terms: "Where are your white
friends now? We acknowledge, not a Natal king, but a black one."
In addition to arresting Magwababa, attempting to secure Funizwe
(who escaped through having slept in the field because afraid of his
brother), Bambata, assisted by his principal induna, Mgombana, and
other men, went about commandeering the young men, threatening
immediate death on failure to comply. The commandeering was
carried on throughout the whole of Monday night (2nd). That such
"club law" had to be adopted, shows that Bambata felt it difficult to get
members of the tribe to join, although some were only too eager to do
so. His tribe, for the most part, was against rebelling, and could be
forced into doing so only by the adoption of violent methods. But for
the presence of Cakijana, the reputed emissary from Dinuzulu, and
who in the name of Dinuzulu urged all to rise,[139] Bambata must
have failed to dragoon as many as he did.
The result of the report was that the Magistrate deemed it necessary
to proceed to Mpanza to investigate. He was accompanied by a clerk,
a civilian, Inspector J.E. Rose and two troopers of the Natal Police,
and a Native guide. They went along the main road as far as Mpanza
(Marshall's) hotel when, unaware that their movements were being
watched, they proceeded up Mpanza valley in the direction of Varty's
house in search of Magwababa's captors. Whilst looking for a drift to
cross the Mpanza, which passes the hotel about three-quarters of a
mile lower down, they were suddenly surprised by a body of men,
under the command of Bambata himself, fully armed with assegais
and some guns. Bambata's party immediately opened fire at short
range at the Inspector, who, with a couple of men, was leading. A few
shots were returned, when one of the enemy was wounded. The impi
had behaved in a deliberate and cold-blooded manner, well-knowing
the party was composed of Government officials. One would have
thought the smallness of the party was enough to have guaranteed its
safety. It would probably have made a considerable difference had it
been even smaller and unarmed. Evidently the temper of the people
had greatly changed. When the men were sent with Clarke to arrest
Bambata, he fled to Zululand. Now, when another, though smaller
party, appears on the scene, he, without warning, opens fire upon
them. Clearly something had occurred during the visit to Zululand to
embolden him to break out into open rebellion. The Magistrate's
party, on going into Mpanza valley, did so in no aggressive spirit, not
even to attempt arrest, but solely to find out what had become of the
acting Chief, as it was their duty to do. They could not, under the
circumstances, do otherwise than make their way back to the hotel
(on the main road) as best they could, through the thick thorn bush
that lay between. The three ladies in the hotel, Mesdames Hunter,
Marshall and Borham (and son), warned of their danger, proceeded
to effect an escape as speedily as they could. This was done with the
assistance of the police.
As a matter of fact, though unknown to the party at the time, the
rebels did not pursue, otherwise one or more must have been
overtaken. They made their way as rapidly as possible to the Police
Station, Keate's drift (on the Mooi River), reaching the post the same
afternoon.
Some time after the party had gone off, a number of the insurgents
proceeded to the hotel and, breaking into the canteen and cellar,
helped themselves freely to the large supply of liquor they found
there.
After representing the state of affairs to the Commandant, Colonel
Leuchars, whose Mapumulo command had, of course, by this time
demobilized, proceeded on his own responsibility, in the absence of
the Magistrate, to arrange for the defence of Greytown. The
necessary organization was effected the same evening with the
assistance of the Town Commandant (Major Menne). All available
men of the U.M.R. were mobilized; patrols were sent out in different
directions, and the local First Reserves put on to guard the
approaches to the town. The action taken was at once confirmed by
the Commandant.
Such Natal Police as were available, including the four officers, 100
non-commissioned officers and men who had the day previous been
to Richmond to carry out the executions referred to, were immediately
ordered to Greytown, not, however, receiving instructions until late in
the afternoon. On arrival at Greytown by train at about 8 a.m., the
force was joined by a detachment, raising the strength to six officers,
166 non-commissioned officers and men, under the command of
Lieut.-Col. G. Mansel, C.M.G., Chief Commissioner. The force
marched from Greytown about 10.30 a.m. and camped on Botha's
farm (adjoining Burrup's), six or seven miles from and above Mpanza
valley. The idea was there to await developments. Leuchars was, the
same day, appointed to command all troops in the district; this, of
course, brought Mansel's force under his orders.
Intelligence was received by Mansel the same afternoon by wire from
Keate's drift, to the effect that the European men and women, who
had taken refuge there, were unable to proceed through Mpanza
valley to Greytown, owing to insufficiency of escort. On account of the
hostile attitude assumed by Bambata, whose fastnesses were not
more than seven or eight miles from Keate's drift, the position of the
ladies was considered to be unsafe. Mansel accordingly decided,
without, however, submitting the matter for instructions, to bring in the
fugitives. Shortly before 3 p.m. a column, consisting of five officers
and 146 non-commissioned officers and men, left for the purpose. A
few men, together with some Nongqai (Zululand Native Police), were
left in charge of the camp.
The force, with Mansel in command, not having seen anything of the
enemy, although it had passed through Mpanza valley, arrived at the
drift at 4.30 p.m. It left again at 6.15, escorting the ladies and child.
The latter travelled in an open carriage drawn by two horses. The
police detachment at Keate's drift continued to hold the post under
Sub-Inspector Ottley. Mpanza hotel was reached just after sunset. A
short halt was made, when the column continued its march along the
road. There was an advanced guard of twenty-six men. The carriage
occupied a position in the centre of the main body. Every precaution
was taken. Connecting files were posted between the guard and main
body (about 150 yards apart), but, in Mpanza valley and for some
miles further on, the nature of the country was such that flankers
could not be thrown out, not even five yards on either side of the
road. The density of the bush about that part is remarkable. The
trees, though not more than twenty feet high, are so closely
intermingled, some of thorn, others of cactus variety, as to make it
difficult for a man to make his way through, even on foot. Add to this,
a three-strand wire fence running five yards from the road on either
side—the road itself not being more than thirty feet wide—and the
predicament the column would be in, in the event of attack at night,
can better be imagined than described. The worst is what actually did
happen. After the force had marched barely a mile from the hotel, and
just as the advanced guard, under Major O. Dimmick, 100 to 150
yards ahead of the main body, was passing through the worst section
of the forest along the route, and one of the nastiest spots to be found
either in Natal or Zululand—the time being about 8 p.m.—a sudden
and determined rush was made by the savages at the right rear of the
guard. As they rushed, they simultaneously shouted, at the top of
their voices, their newly-adopted war-cry "Usutu!"[140] Almost
instantly the rest of the right flank of the guard was attacked. Every
horse took fright, and, although each man was marching with his rifle
drawn, it was impossible to use it. The attack had come from the
higher side of the road, where the whole of the enemy, about 150 in
number, were in hiding, the spot being beside a huge solitary rock at
the foot of a steep, bush-covered hill, known by the Natives as
Hlenyane. The enemy's object was evidently to cut the advanced
guard off the main body.
Owing to the narrowness of the road, the way it was hemmed in by
the bush on either side, and the darkness—there being but half-
moon, with clouds about—the guard succeeded, only with great
difficulty and after considerable delay, in making their way back to the
main body. As it was, the leading section was completely cut off, and,
with three horses wounded, made its way on to the camp as best it
could.
The tactics of the enemy were evidently to deal first with the horse,
then with the man, after bringing the latter on to a level with himself.
Sergt. E.T.N. Brown, Lce.-Sergt. J.C.G.Harrison, and Tprs. A.H.
Aston and J.P. Greenwood were killed outright, whilst four were
wounded (one of them dangerously). Three horses were killed, and
nine wounded. All these had been stabbed, except two—shot through
the neck. When the attack started, the main body moved up,
dismounted, and volleyed into the bush on either side. Except for
those who came on to the road, it was quite impossible to see the
enemy, although at the outset they could not have been more than
five to ten yards off the road. They were in possession of several
firearms, but, owing to the heavy fire of the police, were obliged to
retire in different directions. It was afterwards ascertained they
withdrew by dragging themselves along their stomachs through the
undergrowth, done to avoid being hit.
During the action there were several acts of bravery. Among those
who behaved with conspicuous gallantry were Dimmick and Trooper
O. Folker. Trumpeter C. Milton, who was severely wounded, must
have been killed but for their carrying him out of danger, with much
difficulty and at great risk to themselves.

MPANZA
Sketch Plan

Showing attack on Magistrate's party (3rd) and ambuscade (4th April)

The following account by Dimmick will be read with interest:
"When the rebels started their attack, they volleyed into us; as they
did so, the majority, with assegais, sprang on to the road to stab, or
throw where that was impossible. The attack was directed more at
the rear of the guard than at its front and, for a moment or two, more
at the horse than the man. The practically simultaneous wounding of
many horses caused them, as well as the others, to plunge about.
During the resulting confusion, the guard, as the attack was being
delivered, was pressed forward. I suddenly heard Trumpeter Milton
on my left cry out. He had been struck in the back by, I believe, a
flung assegai. He bumped up against me and lay across his wallet. I
held on to him in the best way I could with my left hand, calling out to
the men to steady down. I went forward with him a distance of about
100 yards, shouting to my men as I did so, when, by the faint light of
the moon, I saw Hodge and Emanuel on foot in the road, the latter
having been knocked off his horse by a knobstick striking him on the
forehead. A few yards further on I saw Folker, Guest and others
coming back mounted. Folker made for me at once and took Milton
up on to the front of his saddle, whilst Guest considerably assisted
Emanuel. I told the men, about eight or ten of them, to bunch
together, when we began to work our way back. The enemy at this
time was in the bush on both sides of the road, being briskly fired at
by the main body."
After the rebels, who were commanded by Bambata in person,
assisted by his chief induna and Cakijana, had been beaten off, the
action having lasted five to ten minutes, the wounded were placed in
the carriage (promptly given up by the ladies), and the column moved
on.
An advanced guard was dispensed with. The men were all
dismounted and made to march in single file with fixed bayonets on
each side of the road, horses and vehicle inside. Three of the dead
were, at short intervals, picked up in the road and put into the
carriage.
For a mile or two there was occasional firing into the bush to keep off
the enemy, who, it was supposed, might be following. They shouted
obscene epithets at the police from a distance. The camp was not
reached till about midnight. As a matter of fact, the rebels, afraid of
being hit, did not follow, notwithstanding that one man was heard to
shout out from a hill "Bapakati!" (They are hemmed in!)
As far as could be seen, in addition to assegais, shields and
knobsticks, the enemy had about a dozen guns.
The ladies, after giving up the carriage, walked most of the way back
to camp, a distance of about six miles.
Reviewing the two foregoing incidents, it is, in the first place, difficult
to understand why the first expedition took place in the way it did. In
view of Bambata's attitude, firstly, on the 22nd February, in
connection with the poll tax; secondly, his refusal to attend at
headquarters when summoned, and quitting Natal for Zululand; and,
thirdly, his arresting Magwababa, who had just been formally
appointed as his acting successor, it seems as if the occasion was
one which required far stronger action than that which was taken. In
arresting Magwababa, Bambata did not do so out of personal spite,
although the relations between the two had for long been strained,
but because, supported by Dinuzulu, he was determined, if possible,
to bring about a general rebellion.
When the Chief Commissioner arrived on the scene, he knew
Bambata and his men were under arms; he knew that, after the
attack on the Magistrate's party, Bambata did not pursue, otherwise
one or more of the fugitives must have been killed. Moreover, there
was no good ground for suspecting an attack on the Keate's drift
station. As it was, the European residents referred to in the wire on
which Mansel acted were perfectly safe where they were, especially
as Bambata had, at the most, no more than 150 to 200 men, while
the station was protected by about twenty rifles.[141]
There thus being no immediate necessity for removing the "European
residents," it would seem the column should not have been marched
off merely to relieve an unthreatened post at the imminent risk of
being attacked on a road it was impossible to defend in the dark. The
situation certainly called for immediate action, not, it would seem, in
the direction of relieving Keate's drift, but of getting within striking
distance of the enemy and, after ascertaining his probable strength
and position, attacking him. It is, however, easy to be wise after the
event.
In going to Keate's drift, the mistakes were made of returning the
same day after an apparently unavoidably late start, and of returning
by the way that was used on the forward journey. It is a maxim in
Native warfare not to come back by the way one goes out. In this
case, just because it was impossible to do otherwise than return to
camp by the road (except by making a long detour), it would, no
doubt, have been wiser to have adopted the precaution of doing so in
the day-time. As there was an advanced guard when the column
proceeded to the drift, the enemy, of course, knew the kind of
formation to look out for.
The body of Sergeant Brown was not recovered until some days later,
[142] when it was seen lying on its back at right angles across, and in
the middle of, the road where the fight had been. It had been
purposely put there by the rebels, and had about it no fewer than
twenty-seven assegai wounds. The whole of the moustache and
upper lip had been cut off and carried away, as also the left forearm.
A deep incision, in the form of a cross, had also been made for some
purpose at the side of the left biceps. Deceased's helmet, too, had
been taken, as also his boots, tunic and breeches, whilst the way in
which the stomach and intestines had been ripped open, showed
those present that they were at war with savages indeed.
The horrible mutilation of this poor fellow's body was, however, not
done from sheer wantonness, but for a particular object, viz. to obtain
pieces of the flesh for medicinal purposes. This practice, so revolting
from a civilized person's point of view, is one usually followed by
Zulus and other South African races. Indeed, according to their
superstitions, to act thus is an indispensable accompaniment of
warfare.
On an inspection being made at the scene of the ambuscade, it was
noticed the bottom strands of the wire fence had been lifted to the top
one, and there tied. This had been done in several places, evidently
to enable the enemy to pass through quickly, whilst, at the same time,
sufficient to check horses.
An incident of the attack was that not only Aston but his dog was
killed, both almost on the same spot. Another feature was that not
one of the enemy was killed, though, as was afterwards ascertained,
ten or twelve were wounded. Such a result, as it happened, carried
with it mysterious significance in so far as the Natives were
concerned. To this attention must now be drawn.
Attached to Bambata's force, were three persons of importance, viz.:
Cakijana, Moses, and Malaza. The first was commonly understood to
be an emissary from Dinuzulu. He it was who had come specially to
foment the Rebellion;[143] the second had, for some years, carried on
Christian mission work within the tribe—during the Rebellion he acted
as a kind of "chaplain to the forces"; Malaza was the war-doctor, quite
indispensable, according to Native ideas, on such occasions.
By one or other of these, the belief was started that Bambata had
secured drugs from Dinuzulu, whose effect would be to prevent
European bullets from entering the body. This curious belief was
destined to play a remarkable part during the rising. It seems to have
originated from the Basutos.
The belief that the bodies of the "rightly disposed" would be
impervious to bullets, would appear to have existed, not only before
the attack on the police at Mpanza, but also before the one at the
kraal of Mjongo.
If there was anything that went to confirm the belief in "bullets not
entering," it must have been the comparative absence of casualties
among the rebels: (a) at Mjongo's kraal; (b) when the Magistrate's
party was attacked; and (c) when the police were ambuscaded at
Mpanza. It may, however, be mentioned that Malaza was wounded at
Mpanza, though not to such an extent as to oblige him to retire.
Immediately after their attack, the rebels cut the telegraph line
between Greytown and Keate's drift.

FOOTNOTES:
[127] This name, in full, is uMpanza, not iMpanza or Impanza, as
sometimes written.
[128] Cf. Wat Tyler's, Jack Cade's, and Monmouth's Rebellions in
England.
[129] Zibebu's loyalty was never doubted for a moment. His name
is mentioned here only because of his exceptionally fine qualities
as a military commander.