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Katzung & Trevor’s
Pharmacology
Examination
& Board Review
Twelfth Edition
Bertram G. Katzung, MD, PhD

Professor Emeritus of Pharmacology
Department of Cellular & Molecular Pharmacology
University of California, San Francisco
Marieke Kruidering-Hall, PhD

Professor & Academy Chair of Pharmacology Education
Anthony J. Trevor, PhD

Professor Emeritus of Pharmacology and Toxicology
New York Chicago San Francisco Athens London Madrid Mexico City
Milan New Delhi Singapore Sydney Toronto
Trevor_FM_p0i-vi.indd 1 7/19/18 2:42 PM

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Contents
Preface v
part IV
part I DRUGS WITH IMPORTANT ACTIONS
BASIC PRINCIPLES 1 ON SMOOTH MUSCLE 145
1. Introduction 1 16. H
istamine, Serotonin, Drugs Used in
Obesity, & the Ergot Alkaloids 145
2. Pharmacodynamics 16
17. Vasoactive Peptides 155
3. Pharmacokinetics 26
18. Prostaglandins & Other Eicosanoids 161
4. Drug Metabolism 35
19. Nitric Oxide, Donors, & Inhibitors 168
5. Pharmacogenomics 41
20. D
rugs Used in Asthma & Chronic
part II Obstructive Pulmonary Disease 172
AUTONOMIC DRUGS 47
part V
6. Introduction to Autonomic Pharmacology 47 DRUGS THAT ACT IN THE CENTRAL
NERVOUS SYSTEM 181
7. Cholinoceptor-Activating
& Cholinesterase-Inhibiting Drugs 60
21. Introduction to CNS Pharmacology 181
8. Cholinoceptor Blockers & Cholinesterase
Regenerators 69 22. Sedative-Hypnotic Drugs 188
9. Sympathomimetics 76 23. Alcohols 196
10. Adrenoceptor Blockers 85 24. Antiseizure Drugs 203
25. General Anesthetics 212

part III
CARDIOVASCULAR DRUGS 93 26. Local Anesthetics 220
27. Skeletal Muscle Relaxants 225

11. Drugs Used in Hypertension 93
28. D
rugs Used in Parkinsonism &
12. D
rugs Used in the Treatment of Angina Other Movement Disorders 233
Pectoris 103
29. Antipsychotic Agents & Lithium 241
13. Drugs Used in Heart Failure 112
30. Antidepressants 249
14. Antiarrhythmic Drugs 122
31. Opioid Analgesics & Antagonists 257
15. D
iuretics & Other Drugs That Act on the
Kidney 134 32. Drugs of Abuse 266
iii
iii

iv CONTENTS
47. Antimycobacterial Drugs 397

part VI
48. Antifungal Agents 404
DRUGS WITH IMPORTANT ACTIONS
ON BLOOD, INFLAMMATION, 49. Antiviral Agents 411
& GOUT 275
50. M
iscellaneous Antimicrobial Agents &
Disinfectants, Antiseptics, & Sterilants 423
33. A
gents Used in Cytopenias; Hematopoietic
Growth Factors 275 51. Clinical Use of Antimicrobial Agents 429
34. Drugs Used in Coagulation Disorders 284 52. Antiprotozoal Drugs 435
35. Agents Used in Dyslipidemia 296 53. C
linical Pharmacology of the
Antihelminthic Drugs 444
36. N
SAIDs, Acetaminophen, & Drugs Used in
Rheumatoid Arthritis & Gout 304 54. Cancer Chemotherapy 450
55. Immunopharmacology 463

part VII
ENDOCRINE DRUGS 315 part IX
TOXICOLOGY 477
37. Hypothalamic & Pituitary Hormones 315
38. Thyroid & Antithyroid Drugs 324 56. Environmental & Occupational Toxicology 477
39. A
drenocorticosteroids & Adrenocortical 57. Heavy Metals 483
Antagonists 330 58. Management of the Poisoned Patient 489
40. Gonadal Hormones & Inhibitors 337
part X
41. P
ancreatic Hormones, Antidiabetic Drugs, SPECIAL TOPICS 497
& Glucagon 348
42. A
gents That Affect Bone Mineral 59. D
rugs Used in Gastrointestinal
Homeostasis 357 Disorders 497
60. D
ietary Supplements & Herbal
part VIII Medications 507
CHEMOTHERAPEUTIC DRUGS 367 61. I mportant Drug Interactions & Their
Mechanisms 512
43. B
eta-Lactam Antibiotics & Other Cell
Wall- & Membrane-Active Antibiotics 368 Appendix I. S
trategies for Improving Test
Performance 519
44. T
etracyclines, Macrolides, Clindamycin,
Chloramphenicol, Streptogramins, & Appendix II. Key Words for Key Drugs 522
Oxazolidinones 377
Appendix III. Examination 1 535
45. Aminoglycosides & Spectinomycin 385
Appendix IV. Examination 2 551
46. Sulfonamides, Trimethoprim,
& Fluoroquinolones 390 Index 567

Preface
This book is designed to help students review pharmacology are analyzing the answers, make sure that you understand why
and to prepare for both regular course examinations and board each choice is either correct or incorrect.
examinations. The twelfth edition has been revised to make Sixth, each chapter includes a Checklist of focused tasks
such preparation as active and efficient as possible. As with that you should be able to do once you have finished the
earlier editions, rigorous standards of accuracy and currency chapter.
have been maintained in keeping with the book’s status as the Seventh, most chapters end with a Summary Table that
companion to the Basic & Clinical Pharmacology textbook. This lists the most important drugs and includes key information
review book divides pharmacology into the topics used in most concerning their mechanisms of action, effects, clinical uses,
courses and textbooks. Major introductory chapters (eg, auto- pharmacokinetics, drug interactions, and toxicities.
nomic pharmacology and CNS pharmacology) are included Eighth, when preparing for a comprehensive examination,
for integration with relevant physiology and biochemistry. The you should review the strategies described in Appendix I if
chapter-based approach facilitates use of this book in conjunc- you have not already done so. Then review the list of drugs in
tion with course notes or a larger text. We recommend several Appendix II: Key Words for Key Drugs. Students are also
strategies to make reviewing more effective (Appendix I con- advised to check this appendix as they work through the chap-
tains a summary of learning and test-taking strategies that most ters so they can begin to identify drugs out of the context of a
students find useful). chapter that reviews a restricted set of drugs.
First, each chapter has a short discussion of the major con- Ninth, after you have worked your way through most or
cepts that underlie its basic principles or the specific drug group, all of the chapters and have a good grasp of the Key Drugs,
accompanied by explanatory figures and tables. The figures you should take the comprehensive examinations, each of 100
are in full color and some are new to this edition. Students questions, presented in Appendices III and IV. These exami-
are advised to read the text thoroughly before they attempt to nations are followed by a list of answers, each with a short
answer the study questions at the end of each chapter. If a con- explanation or rationale underlying the correct choice and
cept is found to be difficult or confusing, the student is advised the numbers of the chapters in which more information can
to consult a regular textbook such as Basic & Clinical Pharma- be found if needed. We recommend that you take an entire
cology, 14th edition. examination or a block of questions as if it were a real exami-
Second, each drug-oriented chapter opens with an Overview nation: commit to answers for the whole set before you check
that organizes the group of drugs visually in diagrammatic form. the answers. As you work through the answers, make sure that
We recommend that students practice reproducing the overview you understand why each answer is either correct or incorrect.
diagram from memory. If you need to, return to the relevant chapters(s) to review the
Third, a list of High-Yield Terms to Learn and their defini- text that covers key concepts and facts that form the basis for
tions is near the front of most chapters. Make sure that you are the question.
able to define those terms. We recommend that this book be used with a regular text.
Fourth, many chapters include a Skill Keeper question that Basic & Clinical Pharmacology, 14th edition (McGraw-Hill,
prompts the student to review previous material and to see links 2018), follows the chapter sequence used here. However, this
between related topics. We suggest that students try to answer review book is designed to complement any standard medical
Skill Keeper questions on their own before checking the answers pharmacology text. The student who completes and under-
that are provided at the end of the chapter. stands Pharmacology: Examination & Board Review will greatly
Fifth, each of the sixty-one chapters contains up to ten improve his or her performance and will have an excellent com-
sample questions followed by a set of answers with explana- mand of pharmacology.
tions. For most effective learning, you should take each set of Because it was developed in parallel with the textbook
sample questions as if it were a real examination. After you have Basic & Clinical Pharmacology, this review book represents the
answered every question, work through the answers. When you authors’ interpretations of chapters written by contributors to

vi PREFACE
that text. We are grateful to those contributors, to our other her excellent copyediting and proofreading contributions to
faculty colleagues, and to our students, who have taught us most this edition.
of what we know about teaching.
We very much appreciate the invaluable contributions to Bertram G. KKatzung, MD, PhD
this text afforded by the editorial team of Peter Boyle and Marieke Kruidering-Hall, PhD
Michael Weitz. The authors also thank Katharine Katzung for Anthony J. Trevor, PhD

PART I BASIC PRINCIPLES
1
C H A P T E R
Introduction
Pharmacology is the body of knowledge concerned with the drugs, eg, absorption, metabolism, excretion, etc. Pharmaco-
action of chemicals on biologic systems. Medical pharmacol- dynamics denotes the actions of the drug on the body, such as
ogy is the area of pharmacology concerned with the use of mechanism of action and therapeutic and toxic effects. The first
chemicals in the prevention, diagnosis, and treatment of disease, part of this chapter reviews the basic principles of pharmacoki-
especially in humans. Toxicology is the area of pharmacology netics and pharmacodynamics that will be applied in subsequent
concerned with the undesirable effects of chemicals on biologic chapters. The second part of the chapter reviews the discovery
systems. Pharmacokinetics describes the effects of the body on and development of new drugs and the regulation of drugs.
Nature of drugs
Pharmacodynamics Pharmacokinetics
Receptor, Inert Movement

receptor binding of drugs in Absorption Distribution Metabolism Elimination
sites sites body
Drug development & regulation
Safety & Animal Clinical Patents &

efficacy testing trials generic drugs
Trevor_Ch01_p001-p015.indd 1 7/13/18 6:00 PM

2 PART I Basic Principles
■■ I. THE NATURE OF DRUGS (eg, between a cation and an anion), and much weaker interac-
tions (eg, hydrogen, van der Waals, and hydrophobic bonds).
Drugs in common use include inorganic ions, nonpeptide organic
molecules, small peptides and proteins, nucleic acids, lipids, and carbo-
hydrates. Some are found in plants or animals, and others are partially PHARMACODYNAMIC PRINCIPLES
or completely synthetic. Many drugs found in nature are alkaloids,
A. Receptors
which are molecules that have a basic (alkaline) pH in solution, usually
as a result of amine groups in their structure. Many biologically impor- Drug actions are mediated through the effects of drug ligand
tant endogenous molecules and exogenous drugs are optically active; molecules on drug receptors in the body. Most receptors are large
that is, they contain one or more asymmetric centers and can exist as regulatory molecules that influence important biochemical pro-
enantiomers. The enantiomers of optically active drugs usually differ, cesses (eg, enzymes involved in glucose metabolism) or physiologic
sometimes more than 1000-fold, in their affinity for biologic receptor processes (eg, ion channel receptors, neurotransmitter reuptake
sites. Furthermore, such enantiomers may be metabolized at different transporters, and ion transporters).
rates in the body, with important clinical consequences. If drug-receptor binding results in activation of the receptor
molecule, the drug is termed an agonist; if inhibition results,
A. Size and Molecular Weight the drug is considered an antagonist. Some drugs mimic agonist
Drugs vary in size from molecular weight (MW) 7 (lithium) molecules by inhibiting metabolic enzymes, eg, acetylcholinesterase
to over MW 50,000 (thrombolytic enzymes, antibodies, other inhibitors. As suggested in Figure 1–1, a receptor molecule may
proteins). Most drugs, however, have MWs between 100 and have several binding sites. Quantitation of the effects of drug-
1000. Drugs smaller than MW 100 are rarely sufficiently selective receptor interaction as a function of dose (or concentration) yields
in their actions, whereas drugs much larger than MW 1000 are dose-response curves that provide information about the nature of
often poorly absorbed and poorly distributed in the body. Most the drug-receptor interaction. Dose-response phenomena are dis-
protein drugs (“biologicals”) are commercially produced in cell, cussed in more detail in Chapter 2. A few drugs are enzymes them-
bacteria, or yeast cultures using recombinant DNA technology. selves (eg, thrombolytic enzymes, pancreatic enzymes). These drugs
do not act on endogenous receptors but on substrate molecules.
B. Drug-Receptor Bonds
Drugs bind to receptors with a variety of chemical bonds. These B. Receptor and Inert Binding Sites
include very strong covalent bonds (which usually result in irre- Because most ligand molecules are much smaller than their recep-
versible action), somewhat weaker reversible electrostatic bonds tor molecules (discussed in the text that follows), specific regions
High-Yield Terms to Learn (continued)

Drugs Substances that act on biologic systems at the chemical (molecular) level and alter their functions
Drug receptors The molecular components of the body with which drugs interact to bring about their effects
Distribution phase The phase of drug movement from the site of administration into the tissues
Elimination phase The phase of drug inactivation or removal from the body by metabolism or excretion
Endocytosis, exocytosis Endocytosis: Absorption of material across a cell membrane by enclosing it in cell membrane mate-
rial and pulling it into the cell, where it can be processed or released. Exocytosis: Expulsion of mate-
rial from vesicles in the cell into the extracellular space
Permeation Movement of a molecule (eg, drug) through the biologic medium
Pharmacodynamics The actions of a drug on the body, including receptor interactions, dose-response phenomena, and
mechanisms of therapeutic and toxic actions
Pharmacokinetics The actions of the body on the drug, including absorption, distribution, metabolism, and elimina-
tion. Elimination of a drug may be achieved by metabolism or by excretion. Biodisposition is a term
sometimes used to describe the processes of metabolism and excretion
Transporter A specialized molecule, usually a protein, that carries a drug, transmitter, or other molecule across a
membrane in which it is not permeable, eg, Na+/K+ ATPase, serotonin reuptake transporter, etc
Mutagenic An effect on the inheritable characteristics of a cell or organism—a mutation in the DNA; usually
tested in microorganisms with the Ames test
Carcinogenic An effect of inducing malignant characteristics
Teratogenic An effect on the in utero development of an organism resulting in abnormal structure or function;
not generally heritable

CHAPTER 1 Introduction 3
High-Yield Terms to Learn (continued)

Placebo An inactive “dummy” medication made up to resemble the active investigational formulation as
much as possible but lacking therapeutic effect
Single-blind study A clinical trial in which the investigators—but not the subjects—know which subjects are receiving
active drug and which are receiving placebos
Double-blind study A clinical trial in which neither the subjects nor the investigators know which subjects are receiving
placebos; the code is held by a third party
IND Investigational New Drug Exemption; an application for FDA approval to carry out new drug trials in
humans; requires animal data
NDA New Drug Application; seeks FDA approval to market a new drug for ordinary clinical use; requires
data from clinical trials as well as preclinical (animal) data
Phases 1, 2, and 3 of Three parts of a clinical trial that are usually carried out before submitting an NDA to the FDA;
clinical trials adaptive trials, combined two or more phases
Positive control A known standard therapy, to be used in addition to placebo, to evaluate the superiority or inferior-
ity of a new drug in relation to the other drugs available
Orphan drugs Drugs developed for diseases in which the expected number of patients is small. Some countries
bestow certain commercial advantages on companies that develop drugs for uncommon diseases
Drug Receptor Effects
Agonist +
A+C A alone
Response
–
A+B
B
A+D
Log Dose
Competitive
inhibitor
Allosteric
activator
Allosteric inhibitor
FIGURE 1–1 Potential mechanisms of drug interaction with a receptor. Possible effects resulting from these interactions are diagrammed
in the dose-response curves at the right. The traditional agonist (drug A)-receptor binding process results in the dose-response curve denoted
“A alone.” B is a pharmacologic antagonist drug that competes with the agonist for binding to the receptor site. The dose-response curve pro-
duced by increasing doses of A in the presence of a fixed concentration of B is indicated by the curve “A + B.” Drugs C and D act at different
sites on the receptor molecule; they are allosteric activators or inhibitors. Note that allosteric inhibitors do not compete with the agonist drug
for binding to the receptor, and they may bind reversibly or irreversibly. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical
Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 1–3.)

of receptor molecules provide the local areas responsible for drug into nerve endings by selective transport molecules. Selective
binding. Such areas are termed receptor sites or recognition sites. inhibitors for these transporters often have clinical value; for
In addition, drugs bind to some nonregulatory molecules in the example, several antidepressants act by inhibiting the transport of
body without producing a discernible effect. Such binding sites amine neurotransmitters back into the nerve endings from which
are termed inert binding sites. In some compartments of the they have been released or into nearby cells.
body (eg, the plasma), inert binding sites play an important role
in buffering the concentration of a drug because bound drug does 4. Endocytosis—Endocytosis occurs through binding of the
not contribute directly to the concentration gradient that drives molecule to specialized components (receptors) on cell mem-
diffusion. Albumin and orosomucoid (α1-acid glycoprotein) are 2 branes, with subsequent internalization by infolding of that area of
important plasma proteins with significant drug-binding capacity. the membrane. The contents of the resulting intracellular vesicle
are subsequently released into the cytoplasm of the cell. Endocy-
tosis permits very large or very lipid-insoluble chemicals to enter
PHARMACOKINETIC PRINCIPLES cells. For example, large molecules such as proteins may cross
cell membranes by endocytosis. Smaller, polar substances such
To produce useful therapeutic effects, most drugs must be as vitamin B12 and iron combine with special proteins (B12 with
absorbed, distributed, and eliminated. Pharmacokinetic principles intrinsic factor and iron with transferrin), and the complexes enter
make rational dosing possible by quantifying these processes. cells by this mechanism. Because the substance to be transported
must combine with a membrane receptor, endocytotic transport
The Movement of Drugs in the Body can be quite selective. Exocytosis is the reverse process, that is, the
expulsion of material that is membrane-encapsulated inside the cell
To reach its receptors and bring about a biologic effect, a drug
out of the cell. Most neurotransmitters are released by exocytosis.
molecule (eg, a benzodiazepine sedative) must travel from the site
of administration (eg, the gastrointestinal tract) to the site of action
(eg, the brain). B. Fick’s Law of Diffusion
Fick’s law predicts the rate of movement of molecules across a
A. Permeation barrier. The concentration gradient (C1 – C2) and permeability
Permeation is the movement of drug molecules into and within coefficient for the drug and the area and thickness of the barrier
the biologic environment. It involves several processes, the most membrane are used to compute the rate as follows:
important of which include the following:
Permeability coefficient
Rate = C1 − C2 × × Area (1)
1. Aqueous diffusion—Aqueous diffusion is the movement of Thickness
molecules through the watery extracellular and intracellular spaces.
The membranes of most capillaries have small water-filled pores Thus, drug absorption into the blood is faster within organs
that permit the aqueous diffusion of molecules up to the size of with large surface areas, such as the small intestine, than from
small proteins between the blood and the extravascular space. This organs with smaller absorbing areas (the stomach). Furthermore,
is a passive process governed by Fick’s law (see later discussion). drug absorption is faster from organs with thin membrane barriers
The capillaries in the brain, testes, and some other organs lack (eg, the lung) than from those with thick barriers (eg, the skin).
aqueous pores, and these tissues are less exposed to some drugs.
C. Water and Lipid Solubility of Drugs
2. Lipid diffusion—Lipid diffusion is the passive movement of
1. Solubility—The aqueous solubility of a drug is often a func-
molecules through lipid bilayer cell membranes and other lipid bar-
tion of the electrostatic charge (degree of ionization, polarity) of
riers. Like aqueous diffusion, this process is governed by Fick’s law.
the molecule, because water molecules behave as dipoles and are
attracted to charged drug molecules, forming an aqueous shell
3. Transport by special carriers—Drugs that do not readily
around them. Conversely, the lipid solubility of a molecule is
diffuse through membranes may be transported across barriers
inversely proportional to its charge.
by mechanisms that carry similar endogenous substances. A very
Many drugs are weak bases or weak acids. For such molecules,
large number of such transporter molecules have been identified,
the pH of the medium determines the fraction of molecules
and many of these are important in the movement of drugs or as
charged (ionized) versus uncharged (nonionized). If the pKa of
targets of drug action. Unlike aqueous and lipid diffusion, car-
the drug and the pH of the medium are known, the fraction of
rier transport is not governed by Fick’s law and has a maximum
molecules in the ionized state can be predicted by means of the
capacity, ie, is saturable. Important examples are transporters for
Henderson-Hasselbalch equation:
ions (eg, Na+/K+ ATPase), for neurotransmitters (eg, transport-
ers for serotonin, norepinephrine), for metabolites (eg, glucose,  Protonated form 
log  = pK a − pH (2)
amino acids), and for foreign molecules (xenobiotics) such as  Unprotonated form
anticancer drugs.
After release, amine neurotransmitters (dopamine, norepi- “Protonated” means associated with a proton (a hydrogen ion);
nephrine, and serotonin) and some other transmitters are recycled this form of the equation applies to both acids and bases.

2. Ionization of weak acids and bases—Weak bases are Membranes of

ionized—and therefore more polar and more water-soluble—when the nephron
Blood Urine
they are protonated. Weak acids are not ionized—and so are less pH 7.4 pH 6.0
water-soluble—when they are protonated.
1.0 µM Lipid 1.0 µM
The following equations summarize these points: diffusion
H H
RNH3+ RNH2 + H+ R N H R N H
protonated weak Unprotonated weak proton
base (charged, base (uncharged, (3) H+ H+
more water-soluble) more lipid-soluble)
RCOOH RCOO – + H+
protonated weak Unprotonated weak proton H H
acid (uncharged, acid (charged, (4)
R N+ H R N+ H
more lipid-soluble) more water-soluble)
H H
0.4 µM 10.0 µM
The Henderson-Hasselbalch relationship is clinically impor-
tant when it is necessary to estimate or alter the partition of drugs 1.4 µM total 11.0 µM total
between compartments of differing pH. For example, most drugs
are freely filtered at the glomerulus, but lipid-soluble drugs can
be rapidly reabsorbed from the tubular urine. If a patient takes an FIGURE 1–2 The Henderson-Hasselbalch principle applied to
overdose of a weak acid drug, for example, aspirin, the excretion drug excretion in the urine. Because the nonionized, uncharged form
diffuses readily across the lipid barriers of the nephron, this form may
of this drug is faster in alkaline urine. This is because a drug that is
reach equal concentrations in the blood and urine; in contrast, the
a weak acid dissociates to its charged, polar form in alkaline solu-
ionized form does not diffuse as readily. Protonation occurs within
tion, and this form cannot readily diffuse from the renal tubule the blood and the urine according to the Henderson-Hasselbalch
back into the blood; that is, the drug is trapped in the tubule. equation. Pyrimethamine, a weak base of pKa 7.0, is used in this
Conversely, excretion of a weak base (eg, pyrimethamine, amphet- example. At blood pH, only 0.4 μmol of the protonated species will
amine) is faster in acidic urine (Figure 1–2). be present for each 1.0 μmol of the unprotonated form. The total
concentration in the blood will thus be 1.4 μmol/L if the concentra-
tion of the unprotonated form is 1.0 μmol/L. In the urine at pH 6.0,
Absorption of Drugs 10 μmol of the nondiffusible ionized form will be present for each
A. Routes of Administration 1.0 μmol of the unprotonated, diffusible form. Therefore, the total
Drugs usually enter the body at sites remote from the target tis- urine concentration (11 μmol/L) may be almost 8 times higher than
sue or organ and thus require transport by the circulation to the the blood concentration.
intended site of action. To enter the bloodstream, a drug must
be absorbed from its site of administration (unless the drug has concentration gradient is a major determinant of the rate of absorp-
been injected directly into the vascular compartment). The rate tion. Drug concentration in the vehicle is particularly important in
and efficiency of absorption differ depending on a drug’s route of the absorption of drugs applied topically.
administration as well as the drug’s physicochemical properties.
In fact, for some drugs, the amount absorbed may be only a small Distribution of Drugs
fraction of the dose administered when given by certain routes. A. Determinants of Distribution
The amount absorbed into the systemic circulation divided by the
1. Size of the organ—The size of the organ determines the con-
amount of drug administered constitutes its bioavailability by
centration gradient between blood and the organ. For example,
that route. Common routes of administration and some of their
skeletal muscle can take up a large amount of drug because the
features are listed in Table 1–1.
concentration in the muscle tissue remains low (and the blood-
tissue gradient high) even after relatively large amounts of drug
B. Blood Flow
have been transferred; this occurs because skeletal muscle is a very
Blood flow influences absorption from intramuscular and subcu- large organ. In contrast, because the brain is smaller, distribution
taneous sites and, in shock, from the gastrointestinal tract as well. of a smaller amount of drug into it will raise the tissue concentra-
High blood flow maintains a high concentration gradient between tion and reduce to zero the blood-tissue concentration gradient,
the drug depot and the blood and thus facilitates absorption. preventing further uptake of drug unless it is actively transported.
C. Concentration 2. Blood flow—Blood flow to the tissue is an important deter-
The concentration of drug at the site of administration is important minant of the rate of uptake of drug, although blood flow may not
in determining the concentration gradient relative to the blood affect the amount of drug in the tissue at equilibrium. As a result,
as noted previously. As indicated by Fick’s law (Equation 1), the well-perfused tissues (eg, brain, heart, kidneys, and splanchnic

TABLE 1–1 Common routes of drug administration. TABLE 1–2 Average values for some physical volumes
within the adult human body.
Oral (swallowed) Offers maximal convenience; absorption
is often slower. Subject to the first-pass Compartment Volume (L/kg body weight)
effect, in which a significant amount of the
agent is metabolized in the gut wall, portal Plasma 0.04
circulation, and liver before it reaches the
systemic circulation. Bioavailability may be Blood 0.08
limited by the first pass effect.
Extracellular water 0.2
Buccal and sublingual Direct absorption into the systemic venous
(not swallowed) circulation, bypassing the hepatic portal Total body water 0.6
circuit and first-pass metabolism.
Fat 0.2–0.35
Intravenous Instantaneous and complete absorption (by
definition, bioavailability is 100%). Poten-
tially more dangerous.
to extravascular tissue proteins, which results in a marked reduc-
tion in the plasma concentration of chloroquine.
Intramuscular Often faster and more complete (higher bio-
availability) than with oral administration.
Large volumes may be given if the drug is B. Apparent Volume of Distribution and Physical Volumes
not too irritating. First-pass metabolism is The apparent volume of distribution (Vd) is an important phar-
avoided.
macokinetic parameter that reflects the above determinants of the
Subcutaneous Slower absorption than the intramuscular distribution of a drug in the body. Vd relates the amount of drug
route. First-pass metabolism is avoided. in the body to the concentration in the plasma (Chapter 3). In
Rectal (suppository) The rectal route offers partial avoidance of
contrast, the physical volumes of various body compartments are
the first-pass effect. Larger amounts of drug less important in pharmacokinetics (Table 1–2). However, obe-
and drugs with unpleasant taste are better sity alters the ratios of total body water to body weight and fat to
administered rectally than by the buccal or total body weight, and this may be important when using highly
sublingual routes.
lipid-soluble drugs. A simple approximate rule for the aqueous
Inhalation Route offers delivery closest to respiratory compartments of the normal body is as follows: 40% of total body
tissues (eg, for asthma). Usually very rapid weight is intracellular water and 20% is extracellular water; thus,
absorption (eg, for anesthetic gases).
water constitutes approximately 60% of body weight.
Topical The topical route includes application to
the skin or to the mucous membrane of the
eye, ear, nose, throat, airway, or vagina for
Metabolism of Drugs
local effect. Drug disposition is a term sometimes used to refer to metabo-
lism and elimination of drugs. Some authorities use disposition
Transdermal The transdermal route utilizes application to
the skin for systemic effect. Absorption usu- to denote distribution as well as metabolism and elimination.
ally occurs very slowly (because of the thick- Metabolism of a drug sometimes terminates its action, but other
ness of the skin), but the first-pass effect is effects of drug metabolism are also important. Some drugs when
avoided.
given orally are metabolized before they enter the systemic circula-
tion. This first-pass metabolism was referred to in Table 1–1 as
organs) usually achieve high tissue concentrations sooner than one cause of low bioavailability. Drug metabolism occurs primar-
poorly perfused tissues (eg, fat, bone). ily in the liver and is discussed in greater detail in Chapter 4.
3. Solubility—The solubility of a drug in tissue influences the A. Drug Metabolism as a Mechanism of Activation or
concentration of the drug in the extracellular fluid surrounding Termination of Drug Action
the blood vessels. If the drug is very soluble in the cells, the con- The action of many drugs (eg, sympathomimetics, phenothi-
centration in the perivascular extracellular space will be lower and azines) is terminated before they are excreted because they are
diffusion from the vessel into the extravascular tissue space will be metabolized to biologically inactive derivatives. Conversion to an
facilitated. For example, some organs (such as the brain) have a inactive metabolite is a form of elimination.
high lipid content and thus dissolve a high concentration of lipid- In contrast, prodrugs (eg, levodopa, minoxidil) are inactive
soluble agents rapidly. as administered and must be metabolized in the body to become
active. Many drugs are active as administered and have active
4. Binding—Binding of a drug to macromolecules in the blood metabolites as well (eg, morphine, some benzodiazepines).
or a tissue compartment tends to increase the drug’s concentration
in that compartment. For example, warfarin is strongly bound to B. Drug Elimination Without Metabolism
plasma albumin, which restricts warfarin’s diffusion out of the Some drugs (eg, lithium, many others) are not modified by the
vascular compartment. Conversely, chloroquine is strongly bound body; they continue to act until they are excreted.

First-order elimination Zero-order elimination
5 units/h 2.5 units/h

elimination elimination rate
Plasma concentration
rate
2.5 units/h 2.5 units/h
2.5 units/h
1.25
units/h
Time (h) Time (h)
FIGURE 1–3 Comparison of first-order and zero-order elimination. For drugs with first-order kinetics (left), rate of elimination (units
per hour) is proportional to concentration; this is the more common process. In the case of zero-order elimination (right), the rate is constant
and independent of concentration.
Elimination of Drugs This occurs with drugs that saturate their elimination mechanisms
at concentrations of clinical interest. As a result, the concentra-
Along with the dosage, the rate of elimination following the last
tions of these drugs in plasma decrease in a linear fashion over
dose (disappearance of the active molecules from the site of action,
time. Such drugs do not have a constant half-life. This is typical
the bloodstream, and the body) determines the duration of action
of ethanol (over most of its plasma concentration range) and of
for many drugs. Therefore, knowledge of the time course of con-
phenytoin and aspirin at high therapeutic or toxic concentrations.
centration in plasma is one factor used in predicting the intensity
and duration of effect for most drugs. Note: Drug elimination
is not the same as drug excretion: A drug may be eliminated by Pharmacokinetic Models
metabolism long before the modified molecules are excreted A. Multicompartment Distribution
from the body. For most drugs and their metabolites, excretion After absorption into the circulation, many drugs undergo an
is primarily by way of the kidney. Volatile anesthetic gases, a early distribution phase followed by a slower elimination phase.
major exception, are excreted primarily by the lungs. For drugs Mathematically, this behavior can be simulated by means of a
with active metabolites (eg, diazepam), elimination of the parent “two-compartment model” as shown in Figure 1–4. The two
molecule by metabolism is not synonymous with termination of compartments consist of the blood and the extravascular tissues.
action. For drugs that are not metabolized, excretion is the mode (Note that each phase is associated with a characteristic half-life:
of elimination. A small number of drugs combine irreversibly with t1/2α for the first phase, t1/2β for the second phase. Note also that
their receptors, so that disappearance from the bloodstream is not when concentration is plotted on a logarithmic axis, the elimina-
equivalent to cessation of drug action: These drugs may have a very tion phase for a first-order drug is a straight line.)
prolonged action. For example, phenoxybenzamine, an irreversible
inhibitor of α adrenoceptors, is eliminated from the bloodstream B. Other Distribution Models
in less than 1 h after administration. The drug’s action, however,
A few drugs behave as if they were distributed to only 1 compart-
lasts for 48 h, the time required for turnover of the receptors.
ment (eg, if they are restricted to the vascular compartment).
A. First-Order Elimination Others have more complex distributions that require more than 2
compartments for construction of accurate mathematical models.
The term first-order elimination indicates that the rate of elimina-
tion is proportional to the concentration (ie, the higher the concen-
tration, the greater the amount of drug eliminated per unit time).
The result is that the drug’s concentration in plasma decreases ■■ II. DRUG DEVELOPMENT
exponentially with time (Figure 1–3, left). Drugs with first-order & REGULATION
elimination have a characteristic half-life of elimination that is
constant regardless of the amount of drug in the body. The concen- The sale and use of drugs are regulated in most countries by
tration of such a drug in the blood will decrease by 50% for every governmental agencies. In the United States, regulation is by the
half-life. Most drugs in clinical use demonstrate first-order kinetics. Food and Drug Administration (FDA). New drugs are devel-
oped in industrial or academic laboratories. Before a new drug
B. Zero-Order Elimination can be approved for regular therapeutic use in humans, a series
The term zero-order elimination implies that the rate of elimina- of animal and experimental human studies (clinical trials) must
tion is constant regardless of concentration (Figure 1–3, right). be carried out.

64.0
Dose
Serum concentration (C) (µg/mL) (logarithmic scale) Distribution

Distribution
32.0 Blood Tissues
phase t1/2α
Elimination
t1/2β
16.0
8.0
Elimination phase
4.0
t1/2β
2.0
1.0
0 2 4 6 12 18 24
Time (h) (linear scale)
FIGURE 1–4 Serum concentration-time curve after administration of a drug as an intravenous bolus. This drug follows first-order kinetics
and appears to occupy 2 compartments. The initial curvilinear portion of the data represents the distribution phase, with drug equilibrating
between the blood compartment and the tissue compartment. The linear portion of the curve represents drug elimination. The elimination
half-life (t1/2β) can be extracted graphically as shown by measuring the time between any 2 plasma concentration points on the elimination
phase that differ by twofold. (See Chapter 3 for additional details.)
New drugs may emerge from a variety of sources. Some are greater than $500 million although the true cost is often hidden
the result of identification of a new target for a disease. Rational by the manufacturer.
molecular design or screening is then used to find a molecule that
selectively alters the function of the target. New drugs may result
from the screening of hundreds of compounds against model dis- ANIMAL TESTING
eases in animals. In contrast, many so-called “me-too” drugs are
the result of simple chemical alteration of the pharmacokinetic The animal testing of a specific drug that is required before human
properties of an original prototype agent. studies can begin is a function of its proposed use and the urgency
of the application. Thus, a drug proposed for occasional topical use
requires less extensive testing than one destined for chronic systemic
SAFETY & EFFICACY administration.
Because of the urgent need, anticancer drugs and some anti-
Because society expects prescription drugs to be safe and effec- viral drugs require less evidence of safety than do drugs used in
tive, governments regulate the development and marketing of treatment of less threatening diseases. Urgently needed drugs are
new drugs. Current regulations in the USA require evidence of often investigated and approved on an accelerated schedule.
relative safety (derived from acute and subacute toxicity testing
in animals) and probable therapeutic action (from the pharmaco- A. Acute Toxicity
logic profile in animals) before human testing is permitted. Some Acute toxicity studies are required for all new drugs. These studies
information about the pharmacokinetics of a compound is also involve administration of incrementing doses of the agent up to
required before clinical evaluation is begun. Chronic toxicity test the lethal level in at least 2 species (eg, 1 rodent and 1 nonrodent).
results are generally not required, but testing must be underway
before human studies are started. The development of a new B. Subacute and Chronic Toxicity
drug and its pathway through various levels of testing and regula- Subacute and chronic toxicity testing is required for most agents,
tion are illustrated in Figure 1–5. The cost of development of a especially those intended for chronic use. Doses are selected
new drug, including false starts and discarded molecules, may be based on the results of acute tests. Tests are usually conducted

In vitro Animal Clinical testing Marketing

studies testing
(Is it safe
Phase 1 pharmacokinetics?) Generics
Biologic become
products 20–100
subjects (Does it available
Phase 2 work in
patients?)
100–200
Efficacy, patients
Lead compound selectivity, Phase 3
mechanism (Does it work,
double blind?) Phase 4
1000–6000
patients (Postmarketing
Chemical surveillance)
synthesis
Drug metabolism, safety assessment
0 2 4 8–9 20
Years (average) IND NDA (Patent expires
(Investigational (New Drug 20 years after filing
New Drug) Application) of application)
FIGURE 1–5 The development and testing process required to bring a new drug to market in the United States. Some requirements may
be different for drugs used in life-threatening diseases. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology,
12th ed. McGraw-Hill, 2012: Fig. 5–1.)
for 2–4 weeks (subacute) and 6–24 months (chronic), in at least TABLE 1–3 FDA ratings of drug safety in pregnancy.*
2 species.
Category Description
A Controlled studies in women fail to demonstrate a

TYPES OF ANIMAL TESTS risk to the fetus in the first trimester (and there is no
evidence of a risk in later trimesters), and the pos-
A. Pharmacologic Profile sibility of fetal harm appears remote
The pharmacologic profile is a description of all the pharmacologic B Either animal reproduction studies have not demon-
effects of a drug (eg, effects on cardiovascular function, gastroin- strated a fetal risk but there are no controlled studies
testinal activity, respiration, hepatic and renal function, endocrine in pregnant women, or animal reproduction studies
have shown an adverse effect (other than a decrease
function, CNS). Both graded and quantal dose-response data are
in fertility) that was not confirmed in controlled
gathered. studies in women in the first trimester (and there is
no evidence of a risk in later trimesters)
B. Reproductive Toxicity
C Either studies in animals have revealed adverse effects
Reproductive toxicity testing involves the study of the fertility on the fetus (teratogenic or embryocidal or other) and
effects of the candidate drug and its teratogenic and mutagenic there are no controlled studies in women, or studies
toxicity. Until 2015, the FDA had used a 5-level (A, B, C, D, X) in women and animals are not available. Drugs should
be given only when the potential benefit justifies the
minimally descriptive scale to summarize information regarding the potential risk to the fetus
safety of drugs in pregnancy (Table 1–3). For drugs submitted after
June 2015, the letter scale has been abolished in favor of a narra- D There is positive evidence of human fetal risk, but
the benefits from use in pregnant women may be
tive description of the safety or hazards of each drug, and separate acceptable despite the risk (eg, if the drug is needed
categories are established for pregnancy, lactation, and for males in a life-threatening situation or for a serious dis-
and females of reproductive potential. The new system is designated ease for which safer drugs cannot be used or are
the Pregnancy and Lactation Labeling Rule (PLLR) and is set ineffective)
forth at https://www.fda.gov/Drugs/DevelopmentApprovalProcess/ X Studies in animals or human beings have demon-
DevelopmentResources/Labeling/ucm093307.htm. New labeling strated fetal abnormalities or there is evidence of fetal
for drugs approved after 2001 will be phased in. Teratogenesis can risk based on human experience or both, and the
risk of the use of the drug in pregnant women clearly
be defined as the induction of developmental defects in the somatic
outweighs any possible benefit. The drug is contrain-
tissues of the fetus (eg, by exposure of the fetus to a chemical, infec- dicated in women who are or may become pregnant
tion, or radiation). Teratogenesis is studied by treating pregnant *
Because of lack of definitive evidence for many drugs, many experts consider the
female animals of at least 2 species at selected times during early A through X ranking system to be too simplistic and inaccurate; they prefer more
pregnancy when organogenesis is known to take place and by later detailed narrative descriptions of evidence available for each drug in question. See
examining the fetuses or neonates for abnormalities. Examples Pregnancy and Lactation Labeling Rule, text.

of drugs known to have teratogenic effects include thalidomide, other highly toxic drugs; these are carried out by administering
isotretinoin, valproic acid, ethanol, glucocorticoids, warfarin, lith- the agents to volunteer patients with the target disease. In phase
ium, and androgens. Mutagenesis denotes induction of changes in 1 studies, the acute effects of the agent are studied over a broad
the genetic material of animals of any age and therefore induction range of dosages, starting with one that produces no detectable
of heritable abnormalities. The Ames test, the standard in vitro test effect and progressing to one that produces either a significant
for mutagenicity, uses a special strain of salmonella bacteria whose physiologic response or a very minor toxic effect.
growth depends on specific nutrients in the culture medium. Loss
of this dependence as a result of exposure to the test drug signals B. Phase 2
a mutation. Many carcinogens (eg, aflatoxin, cancer chemothera- A phase 2 trial involves evaluation of a drug in a moderate number
peutic drugs, and other agents that bind to DNA) have mutagenic of sick patients (eg, 100–200) with the target disease. A placebo or
effects and test positive in the Ames test. The dominant lethal test positive control drug is included in a single-blind or double-blind
is an in vivo mutagenicity test carried out in mice. Male animals are design. The study is carried out under very carefully controlled
exposed to the test substance before mating. Abnormalities in the conditions, and patients are closely monitored, often in a hospital
results of subsequent mating (eg, loss of embryos, deformed fetuses) research ward. The goal is to determine whether the agent has
signal a mutation in the male’s germ cells. the desired efficacy (ie, produces adequate therapeutic response)
at doses that are tolerated by sick patients. Detailed data are col-
C. Carcinogenesis lected regarding the pharmacokinetics and pharmacodynamics of
Carcinogenesis is the induction of malignant characteristics in the drug in this patient population.
cells. Carcinogenicity is difficult and expensive to study, and
the Ames test is often used to screen chemicals because there is C. Phase 3
a moderately high degree of correlation between mutagenicity in A phase 3 trial usually involves many patients (eg, 1000–6000
the Ames test and carcinogenicity in some animal tests, as previ- or more, in many centers) and many clinicians who are using
ously noted. Agents with known carcinogenic effects include the drug in the manner proposed for its ultimate general use (eg,
coal tar, aflatoxin, dimethylnitrosamine and other nitrosamines, in outpatients). Such studies usually include placebo and posi-
urethane, vinyl chloride, and the polycyclic aromatic hydrocar- tive controls in a double-blind crossover design. The goals are to
bons in tobacco smoke (eg, benzo[a]pyrene) and other tobacco explore further, under the conditions of the proposed clinical use,
products. the spectrum of beneficial actions of the new drug, to compare it
with placebo (negative control) and older therapy (positive con-
trol), and to discover toxicities, if any, that occur so infrequently
CLINICAL TRIALS as to be undetectable in phase 2 studies. Very large amounts of
data are collected and these studies are usually very expensive.
Human testing of new drugs in the United States requires Unfortunately, relatively few phase 3 trials include the current
approval by institutional committees that monitor the ethical standard of care as a positive control.
(informed consent, patient safety) and scientific aspects (study If the drug successfully completes phase 3, an NDA is submit-
design, statistical power) of the proposed tests. Such testing also ted to the FDA. If the NDA is approved, the drug can be mar-
requires the prior approval by the FDA of an Investigational keted and phase 4 begins.
New Drug (IND) Exemption application, which is submitted
by the developer to the FDA (Figure 1–5). The IND includes D. Phase 4
all the preclinical data collected up to the time of submission Phase 4 represents the postmarketing surveillance phase of
and the detailed proposal for clinical trials. The major clinical evaluation, in which it is hoped that toxicities that occur very
testing process is usually divided into 3 phases that are car- infrequently will be detected and reported early enough to pre-
ried out to provide information for a New Drug Application vent major therapeutic disasters. Manufacturers are required to
(NDA). The NDA includes all the results of preclinical and inform the FDA at regular intervals of all reported untoward drug
clinical testing and constitutes the request for FDA approval reactions. Unlike the first 3 phases, phase 4 has not been rigidly
of general marketing of the new agent for prescription use. A regulated by the FDA in the past. Because so many drugs have
fourth phase of study (the surveillance phase) follows NDA been found to be unacceptably toxic only after they have been
approval. In particularly lethal conditions, the FDA may permit marketed, there is considerable current interest in making phase 4
carefully monitored treatment of patients before phases 2 and surveillance more consistent, effective, and informative.
3 are completed.
E. Adaptive Clinical Trials
A. Phase 1 Because the traditional 3-phase clinical trials are often prolonged
A phase 1 trial consists of careful evaluation of the dose-response and expensive, a newer type of clinical trial is currently under
relationship and the pharmacokinetics of the new drug in a small development. Adaptive trials are aimed at combining 2 or more of
number of normal human volunteers (eg, 20–100). An excep- the traditional phases and altering conditions, dosage, and targets
tion is the phase 1 trials of cancer chemotherapeutic agents and as the trial progresses, based on data being collected.

DRUG PATENTS & GENERIC DRUGS QUESTIONS
A patent application is usually submitted around the time that a 1. A 3-year-old is brought to the emergency department hav-
ing just ingested a large overdose of chlorpropamide, an oral
new drug enters animal testing (Figure 1–5). In the United States,
antidiabetic drug. Chlorpropamide is a weak acid with
approval of the patent and completion of the NDA approval a pKa of 5.0. It is capable of entering most tissues. On
process give the originator the right to market the drug without physical examination, the heart rate is 110/min, blood pres-
competition from other firms for a period of 10–14 years from the sure 90/50 mm Hg, and respiratory rate 30/min. Which of
NDA approval date. After expiration of the patent, any company the following statements about this case of chlorpropamide
may apply to the FDA for permission to market a generic version overdose is most correct?
of the same drug if they demonstrate that their generic drug mol- (A) Urinary excretion would be accelerated by administra-
tion of NH4Cl, an acidifying agent
ecule is bioequivalent (ie, meets certain requirements for content,
(B) Urinary excretion would be accelerated by giving
purity, and bioavailability) to the original product. NaHCO3, an alkalinizing agent
(C) Less of the drug would be ionized at blood pH than at
stomach pH
DRUG LEGISLATION (D) Absorption of the drug would be slower from the stom-
ach than from the small intestine
Many laws regulating drugs in the United States were passed dur-
ing the 20th century. Refer to Table 1–4 for a partial list of this 2. Botulinum toxin is a large protein molecule. Its action on
cholinergic transmission depends on an intracellular action
legislation.
within nerve endings. Which one of the following processes
is best suited for permeation of very large protein molecules
into cells?
ORPHAN DRUGS (A) Aqueous diffusion
(B) Endocytosis
An orphan drug is a drug for a rare disease (in the United States, (C) First-pass effect
defined as one affecting fewer than 200,000 people). The study of (D) Lipid diffusion
such agents has often been neglected because profits from the sales (E) Special carrier transport
of an effective agent for an uncommon ailment might not pay the
3. A 12-year-old child has bacterial pharyngitis and is to receive
costs of development. In the United States, current legislation an oral antibiotic. She complains of a sore throat and pain
provides for tax relief and other incentives designed to encourage on swallowing. The tympanic membranes are slightly red-
the development of orphan drugs. dened bilaterally, but she does not complain of earache. Blood
pressure is 105/70 mm Hg, heart rate 100/min, temperature
TABLE 1–4 Selected legislation pertaining to drugs 37.8°C (100.1°F). Ampicillin is a weak organic acid with a pKa
in the United States. of 2.5. What percentage of a given dose will be in the lipid-
soluble form in the duodenum at a pH of 4.5?
Law Purpose and Effect (A) About 1%
(B) About 10%
Pure Food and Drug Prohibited mislabeling and adulteration of (C) About 50%
Act of 1906 foods and drugs (but no requirement for (D) About 90%
efficacy or safety) (E) About 99%
Harrison Narcotics Act Established regulations for the use of 4. Ampicillin is eliminated by first-order kinetics. Which of the
of 1914 opium, opioids, and cocaine (marijuana following statements best describes the process by which the
added in 1937) plasma concentration of this drug declines?
Food, Drug, and Cos- Required that new drugs be tested for
(A) There is only 1 metabolic path for drug elimination
metics Act of 1938 safety as well as purity (B) The half-life is the same regardless of the plasma
concentration
Kefauver-Harris Required proof of efficacy as well as safety (C) The drug is largely metabolized in the liver after oral
Amendment (1962) for new drugs administration and has low bioavailability
(D) The rate of elimination is proportional to the rate of
Dietary Supplement Amended the Food, Drug, and Cosmetics administration at all times
and Health Education Act of 1938 to establish standards for dietary
Act (1994) supplements but prohibited the FDA from
(E) The drug is distributed to only 1 compartment outside the
applying drug efficacy and safety standards vascular system
to supplements

5. The pharmacokinetics of a new drug are under study in a

phase 1 clinical trial. Which statement about the distribution
of drugs to specific tissues is most correct?
(A) Distribution to an organ is independent of blood flow 32
(B) Distribution of a lipid-soluble drug will be to adipose
tissue initially 16
(C) Distribution into a tissue depends on the unbound drug
concentration gradient between blood and the tissue 8
(D) Distribution is increased for drugs that are strongly
bound to plasma proteins
(E) Distribution has no effect on the half-life of the drug 4
6. The pharmacokinetic process or property that distinguishes 2

the elimination of ethanol and high doses of phenytoin and
aspirin from the elimination of most other drugs is called 1
(A) Distribution 0 1 2 3 4 5 6 7
(B) Excretion
(C) First-pass effect Time (h)
(D) First-order elimination
(E) Zero-order elimination
7. Which of the following statements about animal testing of 10. A large pharmaceutical company has conducted extensive
potential new therapeutic agents is most correct? animal testing of a new drug for the treatment of advanced
(A) Requires at least 3 years to discover late toxicities prostate cancer. The chief of research and development rec-
(B) Requires at least 1 primate species (eg, rhesus monkey) ommends that the company now submit an IND application
(C) Requires the submission of histopathologic slides and in order to start clinical trials. Which of the following state-
specimens to the FDA for evaluation by government ments is most correct regarding clinical trials of new drugs?
scientists (A) Phase 1 involves the study of a small number of normal
(D) Has good predictability for drug allergy-type reactions volunteers by highly trained clinical pharmacologists
(E) May be abbreviated in the case of some very toxic agents (B) Phase 2 involves the use of the new drug in a large
used in cancer number of patients (1000–5000) who have the dis-
ease to be treated under conditions of proposed use
8. The “dominant lethal” test involves the treatment of a male
(eg, outpatients)
adult animal with a chemical before mating; the pregnant
(C) Chronic animal toxicity studies must be complete and
female is later examined for fetal death and abnormalities.
reported in the IND
The dominant lethal test therefore is a test of
(D) Phase 4 involves the detailed study of toxic effects that
(A) Teratogenicity
have been discovered in phase 3
(B) Mutagenicity
(E) Phase 2 requires the use of a positive control (a known
(C) Carcinogenicity
effective drug) and a placebo
(D) Sperm viability
11. Which of the following would probably not be included in an
9. In a phase 1 clinical trial, “Novexum,” a new drug, was admin-
optimal phase 3 clinical trial of a new analgesic drug for mild
istered intravenously to 25 volunteers, and blood samples
pain?
were taken for several hours. Several inactive metabolites
(A) A negative control (placebo)
were found as well as declining concentrations of Novexum.
(B) A positive control (current standard analgesic therapy)
A graph was prepared as shown below, with the Novexum
(C) Double-blind protocol (in which neither the patient nor
plasma levels plotted on a logarithmic ordinate and time on a
immediate observers of the patient know which agent is
linear abscissa. It was concluded that the drug has first-order
active)
kinetics. From this graph, what is the best estimate of the
(D) A group of 1000–5000 subjects with a clinical condition
elimination half-life of Novexum?
requiring analgesia
(A) 0.5 h
(E) Prior submission of an NDA (new drug application) to
(B) 1 h
the FDA
(C) 3 h
(D) 4 h 12. The Ames test is frequently carried out before clinical trials
(E) 7 h are begun. The Ames test is a method that detects
(A) Carcinogenesis in primates
(B) Carcinogenesis in rodents
(C) Mutagenesis in bacteria
(D) Teratogenesis in any mammalian species
(E) Teratogenesis in primates

13. Which of the following statements about new drug develop- of answers, see Appendix I. In this question, the emphasis is
ment is most correct? clearly on pharmacokinetic principles. Ampicillin is an acid,
(A) If the need is great, drugs that test positive for teratoge- so it is more ionized at alkaline pH and less ionized at acidic
nicity, mutagenicity, or carcinogenicity can be tested in pH. The Henderson-Hasselbalch equation predicts that the
humans but the IND must specify safety measures to be ratio changes from 50/50 at the pH equal to the pKa to 1/10
taken (protonated/unprotonated) at 1 pH unit more alkaline than
(B) Food supplements and herbal (botanical) remedies must the pKa and 1/100 at 2 pH units more alkaline. For acids, the
be shown to be effective for the target condition before protonated form is the nonionized, more lipid-soluble form.
marketing is approved by the FDA The answer is A.
(C) All new drugs must be studied in at least 1 primate spe- 4. “First-order” means that the elimination rate is proportional
cies before NDA submission to the concentration perfusing the organ of elimination. The
(D) Orphan drugs are drugs that are no longer produced by half-life is a constant. The rate of elimination is proportional
the original manufacturer to the rate of administration only at steady state. The order of
(E) Phase 4 (surveillance) is the most rigidly regulated phase elimination is independent of the number of compartments
of clinical drug trials into which a drug distributes. The answer is B.
14. Which statement about the development of new drugs is 5. This is a straightforward question of pharmacokinetic distri-
most correct? bution concepts. Choice B is incorrect because distribution
(A) Because they may cause anaphylaxis, proteins cannot be depends on blood flow as well as solubility in the tissue; thus
used as drugs most drugs will initially distribute to high blood flow tissues
(B) Most drugs fall between 100 and 1000 in molecular and only later to larger, low-flow tissues, even if they are
weight more soluble in them. From the list of determinants of drug
(C) Drugs for systemic action that are to be administered orally distribution given on pages 5–6, choice C is correct.
should be highly water soluble and insoluble in lipids
(D) Water solubility is minimal in highly polarized (charged) 6. The excretion of most drugs follows first-order kinetics.
drug molecules However, ethanol and, in higher doses, aspirin and phenytoin
follow zero-order kinetics; that is, their elimination rates are
constant regardless of blood concentration. The answer is E.
ANSWERS 7. Drugs proposed for short-term use may not require long-
term chronic testing. For some drugs, no primates are used;
1. Questions that deal with acid-base (Henderson-Hasselbalch) for other agents, only 1 species is used. The data from the
manipulations are common on examinations. Since absorp- tests, not the evidence itself, must be submitted to the FDA.
tion involves permeation across lipid membranes, we can in Prediction of human drug allergy from animal testing is use-
theory treat an overdose by decreasing absorption from the ful but not definitive (see answer 12). Testing may be abbrevi-
gut and reabsorption from the tubular urine by making the ated for drugs for which there is urgent need; the answer is E.
drug less lipid-soluble. Ionization attracts water molecules and 8. The description of the test indicates that a chromosomal
decreases lipid solubility. Chlorpropamide is a weak acid, change (passed from father to fetus) is the toxicity detected.
which means that it is less ionized when protonated, ie, at This is a mutation. The answer is B.
acid pH. Choice C suggests that the drug would be less ion-
ized at pH 7.4 than at pH 2.0, which is clearly wrong for 9. Drugs with first-order kinetics have constant half-lives, and
weak acids. Choice D says (in effect) that the more ionized when the log of the concentration in a body compartment
form is absorbed faster, which is incorrect. A and B are oppo- is plotted versus time, a straight line results. The half-life
sites because NH4Cl is an acidifying salt and sodium bicar- is defined as the time required for the concentration to
bonate an alkalinizing one. (From the point of view of test decrease by 50%. As shown in the graph, the concentration
strategy, opposites in a list of answers always deserve careful of Novexum decreased from 16 units at 1 h to 8 units at 4 h
attention.) Because an alkaline environment favors ioniza- and 4 units at 7 h; therefore, the half-life is 7 h minus 4 h or
tion of a weak acid, we should give bicarbonate. The answer 3 h. The answer is C.
is B. Note that clinical management of overdose involves 10. Except for known toxic drugs (eg, cytotoxic cancer che-
many other considerations in addition to trapping the drug motherapy drugs), phase 1 is carried out in 25–50 normal
in urine; manipulation of urine pH may be contraindicated volunteers. Phase 2 is carried out in several hundred closely
for other reasons. monitored patients with the disease. Results of chronic toxic-
2. Endocytosis is an important mechanism for transport of ity studies in animals are required in the NDA and are usually
very large molecules across membranes. Aqueous diffusion underway at the time of IND submission. However, they do
is not involved in transport across the lipid barrier of cell not have to be completed and reported in the IND. Phase 4
membranes. Lipid diffusion and special carrier transport is the general surveillance phase that follows marketing of the
are common for smaller molecules. The first-pass effect has new drug. It is not targeted at specific effects. Positive con-
nothing to do with the mechanisms of permeation; rather, it trols and placebos are not a rigid requirement of any phase
denotes drug metabolism or excretion before absorption into of clinical trials, although placebos are often used in phase 2
the systemic circulation. The answer is B. and phase 3 studies. The answer is A.
3. U.S. Medical Licensing Examination (USMLE)-type ques- 11. The first 4 items (A–D) are correct; they would be included.
tions often contain a lengthy clinical description in the An NDA cannot be acted upon until the first 3 phases of clin-
stem. One can often determine the relevance of the clinical ical trials have been completed. (The IND must be approved
data by scanning the last sentence in the stem and the list before clinical trials can be conducted.) The answer is E.

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enforcements, who do not arrive. The disproportion of work actually
in hand, to the men and women who do that work, is most
distressing.
There are great questions of missionary policy to settle. A strong
force of missionaries, adequately superintended by men who are
acquainted with the work they superintend, is the least that can be
asked in our missions. A close and detailed oversight of all mission
interests, working out a far-sighted policy, which changes only by
light that comes by actual experience in mission work, is of the
greatest value. It is clear this superintendency can not be
accomplished by periodical visits of some official whose whole life
has been spent in the home field. A secretary or a Mission Board is
of little account in determining the internal management in any far-
distant field. An occasional visit by some such official may do
incidental good in acquainting the missionaries with the condition in
the home Church, and in bringing to the people at home fresh facts
from the field. But for administrative purposes on the field such visits
are of little or no value.
The Methodist Episcopal Missions in Southern Asia have been
most highly favored in thirteen years of the missionary episcopacy,
with Bishop Thoburn to fill the office of superintendent and leader.
His administration is sure to become more and more monumental as
time reveals its scope and character. It is now clear that no other
episcopal supervision hitherto provided by Methodism is equal to this
missionary episcopacy for the far-distant mission fields.
The success of this policy and of Bishop Thoburn in that office
determines the question of the future policy of the Church in the
administration of the mission field of Southern Asia. The General
Conference of 1900 by a decisive vote increased the missionary
episcopal force in this field, and by an equally decisive vote elected
Dr. E. W. Parker and Dr. F. W. Warne to the missionary episcopacy,
and in co-ordinate authority with Bishop Thoburn.
The election of Dr. Parker as bishop was a general recognition of
his long and pre-eminently successful missionary career. The
election of Dr. Warne to a like office was in response to a like choice
of India, for this younger, but very efficient missionary, whose
pastorate and presiding eldership in the city of Calcutta had been of
such a character as to make him well qualified for the larger office to
which he has been called. But one year has passed since their
election, and a great change has come. Bishop Warne has been
eminently acceptable in his new office, and he has traveled widely
throughout the great field where Methodism has its foothold in the
southlands of Asia. But Bishop Parker’s stalwart form has yielded,
after a prolonged battle with an obscure disease which laid its hand
upon him within a few months after his election. His death demands
a reverent pause, while we drink in renewed inspiration from
reflection on his noble Christian manhood and really pre-eminent
service as a missionary.
Bishop Parker had labored over forty-two years as a missionary
to India, and it is a safe statement that in this more than twoscore
years he did more work than any missionary in India of any Church,
or perhaps in any land, in the same time. The work which he did in
laying broad foundations, winning men to Christ, calling into being
valuable mission agencies, and as a masterful, statesman-like
administration in the Church, has classified him, from two separate
and distinct sources, as “the most successful missionary in India.”
Every element of his noble Christian manhood and eminent ability
measured up to the requirements of this exceptional estimate of the
missionary and his work.
He has now ascended to his heavenly reward, to be forever with
the Lord and to share in his glory. The cablegram that reached us in
America was brief, but laden with a great sorrow and a greater
triumph, “Parker translated!” We will no more have his counsels, his
inspiring presence, the grasp of his strong hand, or hear his manly
voice in Indian Conferences. For this loss we weep. He was
“translated.” In this glad triumph we are filled with joy. Death is
abolished to such a saintly follower of his Lord passing from mortal
vision.
Bishop Parker was ready for other worlds. His recent testimony
was triumphant, in keeping with the godly life he lived. It was fitting
that the good bishop should take his departure from amidst the
glorious Indian hills he had loved so long. His last days were spent in
Naini Tal, amid the most varied mountain scenery in India. Here lies
the lake of wonderful clearness, stretching for a mile in length, filling
the basin. Around the lake is the mall, or broad road. From this road
others branch off, some circular and others zigzagging up the
mountains, which rise a thousand and more feet above the lake,
their sides clad from base to top with, evergreen, pines, and oak.
Here residences, churches, and schools nestle among the trees
wherever space can be found. Here tired missionaries go in May and
June to rest from the fiery heat of the plains below, and to gird
themselves anew with strength as they look upon God’s mountains.
From the northern ridge they look upon the whole mountain
amphitheater with its glorious lake “shimmering” in the sunlight, high-
rimmed with its border of living green, while to the north, stretching
hundreds of miles to east and west, rise the perpetually snow-
covered Himalaya mountains. The picture, one of nature’s wonders,
has few equals for inspiring beauty and grandeur combined. As the
man looks through the rare, clear, mountain air, on peaks and range
resting in quiet strength and majesty, he almost feels as if he was in
sight of the eternal hills where God is.
Amid such scenes, with his brave wife by his side, companion of
his missionary labors about him, and a host of God-fearing
Christians all over India, among whom were a multitude of the dusky
natives, waiting in sorrow because they “should see his face no
more,” the bishop was “translated.” As his Lord on the Mount of
Olivet took one look upon his disciples, and then a cloud received
him and he ascended on high, so his servant was translated from the
hills of Naini Tal; was caught up amid the clouds to be forever with
his Lord.
So the workmen fall. Others labor on, but they are
overburdened. They must be re-enforced. The young native Church
must be shepherded. Thousands of others will join the flock.
Just here we missionaries have our greatest fear. We are the
Church’s representatives. God is with us, and the doors are all open.
We have done all that men and women can do. Will the Church at
home sustain us in the great and glorious task that is appointed to
us? This is our only fear. So loyal and true are many of the hearts at
home to the cause of missions, that it seems unkind to speak of any
lack. Yet, while we love every generous impulse of those who give
money and time to that which, as missionaries, we give our lives and
our loved ones, we love our cause so much the more that we must
be true to its urgent needs and its perils for the want of a little money.
That our advance is retarded over a vast area, that many of our
institutions are imperiled, that native preachers are being dropped for
the lack of the small salary they require, and that we are being
compelled to ask of our Board to give up a section of our India
Church because missionary appropriations are cut down, is but an
outline of our care at this time. To the home Church we look for relief.
This relief can come only in one way. Our people at home, in the
most wonderful prosperity America ever knew, are not increasing
their gifts to missions with their growth in wealth. Some are, but most
are not. The aggregate of all moneys given by the Methodist
Episcopal Church for preaching the gospel in heathen lands is only
about twenty-two cents per member. This is all that is given to
declare Christ to the Christless nations! Our people are giving about
forty times as much for their own religious instruction and for the
gospel in Christianized lands. This proportion is distressing to the
missionary who stands among millions of people who have been
waiting nineteen centuries, and have never yet heard that a Savior
had been born into the world.
The writer is convinced that the measurable failure to give to the
cause of missions as our people are able to give, is due to the failure
to get the information to them in an effective way. It is not the writer’s
intention to locate the responsibility or discuss a policy of raising
missionary funds, but clearly a virtual standstill in receipts under
present conditions is defeat for the missionary cause.
One fact is certain, our present methods of raising funds leaves
the majority of our people without feeling the immediate and
imperative need of this cause, or inspiring them with the certainty of
gaining a great result by the investment of money in missions. We
are in the second year of the “Thank-offering” movement, and more
than eleven million dollars have been pledged toward the “Thank-
offering,” and certainly not nearly one hundred thousand dollars of
this amount has gone to missions. Not one dollar in a hundred!
One chief reason why this disparity exists is because all other
causes have employed special agencies to reach every nook and
corner of the Church, and the cause of missions is being operated at
long range and on general principles, often as only one of the
“benevolences,” and must necessarily fail to advance to any
considerable extent under present conditions and absolute
restrictions.
But there are hopeful indications. Some officials and some
pastors begin to see the situation and to inquire what can be done to
relieve the straits. A number of loyal souls are tenderly giving their
most cherished treasures to the cause of missions. In a year’s
campaign at home I have come in heart-touch with so many such
that I would gladly believe there is a multitude who cherish the cause
of missions as supreme, as it really is.
The Mission Conference in Burma, little company that it is, is
being re-enforced by a promising band of six missionaries, long
overdue it is true, but now gladly and gratefully received. Nearly all of
these are being sent by the sacrifice of people who give largely of
that which is a sacrifice to give. One missionary family is being sent
out and sustained for a part of this year by more than fifteen hundred
dollars given by the preachers of the Kansas and the St. Louis
Conferences. This very large giving of men of very small resources
to a special object that touched their hearts has put new courage into
all our little Burma Mission. In this giving they have helped put true-
hearted missionaries in the field, and I believe permanently enlarged
their sympathy for missions, if indeed they have not also indicated an
improved policy of raising mission funds.
The Woman’s Foreign Missionary Society, through some of its
young lady Auxiliaries, is doing most generous things for the re-
enforcements to Burma.
Burma has waited long for even small re-enforcements, and
needs yet many other things before it is fairly launched as a mission.
But with the re-enforcements we have now in immediate prospect,
we are so encouraged we can return to our field and take up the
work with renewed courage and hope, knowing of the increased
number of friends of missions who support us with money and
prayerful sympathy.
A hope I often cherished in times of great weariness and
discouragement seems in part being realized. Many times in
Rangoon, when wearied to exhaustion with the work of two or three
men, I have gone up to the Sway Dagon Pagoda, and, looking upon
its gilded mass and the Burmans chanting their meaningless
laudations, I have longed for heralds enough to bring these people
the gospel instead of Buddhism, and to replace the pagodas of the
land with Christian Churches; longed for re-enforcements that came
not. Then I turned into the northeast corner of the pagoda area and
looked upon the graves of the British officers who fell in the war of
1852 while storming that pagoda. Then down the slope up which that
band of Anglo-Saxons charged, to the graves of soldiers who were
buried where they fell. My blood warmed with the thought that these
men gave their lives without a word of complaint for their queen
whom they loved, and the flag which they raised over this far-distant
land, to the immense benefit of the land of Burma. Then I
remembered that the world-wide empire of which this is a part had
been secured and maintained by men who, as these, had laid down
their lives for the flag they loved.
From this scene and its suggestions I turned away, encouraged
to hold my post till re-enforcements would come up for the preaching
of the gospel of the Son of God, who sent me to Burma. Here was a
very human kind of encouragement. Looking up the shining pagoda
shaft I saw a sprout of the peepul-tree, the sacred tree of Buddhism,
which grows anywhere on any surface where its spores can find
lodgment; which when neglected has torn to fragments hundreds of
pagodas, here springing from the great pagoda two hundred feet
from the ground. It had found an opening through the gold leaf, or
perhaps had been buried in the mortar with which its surface had
been plastered, and had sent its roots deep into the brick mass of
the pagoda; while its green branches grew in a thriving cluster over
the gilded sides. What did it matter that this tree was two hundred
feet from the ground, and had no moisture save what its roots could
extract from the dry bricks and its leaves draw out of the air! This
peepul-tree can thrive anywhere!
Beautiful symbolism! The gilded colossal pagoda represents the
lifeless system of hoary Buddhism. The growing young tree
represents the religion of Jesus Christ, filled with the life of the Son
of God. It will crumble Buddhism back to dust, as that tree, if
fostered, will destroy the pagoda, Buddhism’s most ornate symbol.
Looking on this scene, my heart took new courage, as under
Divinely-given cheer, to labor on for the salvation of the Buddhists
and other people of Burma.
When describing the pagoda and its surrounding, at Adams,
New York, I dwelt at some length on the graves of the English
soldiers there, and spoke of their courage and self-sacrifice. There
was a large congregation present, nearly all of whom were strangers
to me. At the close of the service I saw a little man start from the rear
of the church and make his way down the side aisle, then across the
church, and as he came he quickened his step; and grasping my
hand he exclaimed with trembling voice: “I tried to come to church
this morning, having heard a man from Burma was to speak; but I
could not get here. I live nine miles back in the Adirondacks, and I
drove in to-night to hear you. I am so glad those graves of the
English soldiers are cared for; I was in the regiment that stormed that
pagoda hill in 1852.” He wrung my hand and shed tears of gladness
because I came from Burma and brought him a voice from the land
of the stirring scenes of his soldier life of forty-eight years ago.
There will be a day when every pagoda will crumble down, every
mosque and Hindu temple fall into decay, and Christian churches
stand in their places, and Burma, as all other parts of this needy
world, will be fully redeemed. In a brighter world there will be a time
of rejoicing over the gospel triumphs, and all who in person or by
proxy aided in the gospel victories in all the world, shall strike glad
hands, like the old soldier, and say, “I was there and helped in the
glorious work.”
CHAPTER XVII
Benefits of British Rule in Southern Asia
T HE missionary is one of the most interested students of

government that can be found. Good or bad government affects
his work vitally. Not only does good government give him protection
from violence, but it gives settled peace to the people among whom
he preaches, and thus provides the best conditions for the success
of his calling. He can not wait for good government where it is not;
but where he has the benefits of a settled state of society that is
protected by wholesome laws promptly executed, he is one of the
first men to recognize the priceless benefits of such government.
Then he looks to the effect of government on the general conditions
of the people. His views of government are not narrow. He looks
ahead to the final effect on the mass of the people of the
Government under which he lives. From every standpoint the
missionaries whose fields lie under the British flag are best situated
of all men of like calling in foreign lands. It therefore comes to pass
that all missionaries, of whatever nationality, living in Southern Asia
are almost a unit in praise of the Government. This Government,
which has for more than forty years given protection to life, calling,
and property of its nearly three hundred million diverse peoples, and
that in unbroken peace, deserves the highest approval of all fair-
minded men.
Life is as well protected in Southern Asia as it is in almost any
land. The highest in the land and the meanest coolie are alike
protected before the law. Where any man thinks he can insult or
assault with even a little lordliness there is recourse to the law, and
that within reach of the lowliest and the poorest, and he can get
evenhanded justice for any injury, and that quickly. Perhaps in no
land is the man of high and the man of low degree dealt with with
more evenhanded and prompt justice than in Southern Asia. There
are many social distinctions made in Asia, most of all in Southern
Asia, peculiar to the land, and the Government adds its official
distinctions and social ranks. But when it comes to the law and its
administration in protection against all oppression and injustices,
these social conditions have no place. It appears to be true that in a
Briton’s mind there are two places where men of all stations have
equal rights—before a court, and at the sacramental altar in the
church. Every man is protected in the exercise of his religious faith,
and must not be molested by any. To revile another’s religion is to
bring down the swift penalty of the law.
It is possible for missionaries and other travelers to come and go
anywhere in the Indian Empire without a thought as to their personal
safety, as that is assured. Even unattended ladies make long
journeys, and with only native carriers, sometimes travel in
unfrequented regions and in the darkness; but so far as I can learn,
there has not for many years been an insult offered to one of them.
Some of our own workers live and travel in remote regions, even on
the extreme borders of the empire, and sometimes these are lone
women; but we do not hear of even serious inconveniences to them
on account of their isolation. This is due chiefly to the Government,
which protects life, persons, and calling.
It is, therefore, not surprising that the missionaries are among
the most devoted supporters of the British Government in Southern
Asia. It is likely they would support any Government under which
they would find themselves called to work. They would teach their
converts loyalty and obedience to law. But it is a great gain to be
able to say to all the peoples of the Indian Empire that the
Government under which they find themselves is one of the very
best the world has produced. And if it were necessary to say it, they
could truthfully add, better than any possible Government by native
rulers, better for themselves, and better for all people in the land. It is
a great pleasure to American missionaries to acknowledge the good
government of India, for in it they find many of the best principles in
which they believe. So far as I can learn, this just tribute from the
American missionaries is well nigh universal among them, and the
older they are and the longer they have lived in any part of this great
empire, the more confirmed they are in their views.
Of all the institutions of the Government that are most to be
commended, the courts are perhaps the most notable. There are
several features of these courts which are specially commendable.
They are prompt to a degree. Long, vexatious delays over
technicalities of law are most unusual. It is not infrequent that a
serious breach of law is brought to account very soon, and finally
settled. Certain it is that money and influence and the “tricks of
lawyers” can not long delay final decision on any case. Then there is
no crowding to the wall the poor man without influence or money to
aid him. The poorest can sue as a pauper, and have his case heard
in regular order with the rich man of high station. He can get as
certain justice, based on evidence. Cases are on record in recent
years to illustrate how the socially high and even the official class
have been rebuked and punished at the plaint of the lowliest in the
land. They would be well worth recording if their publication would
not be understood as too personal. It is this absolutely even-handed
justice that has called out the comment of the native of India, “The
English judge is not afraid of the face of man.” No partiality is shown
for race or condition.
The system of Government seems to be well worthy of study.
There is the viceroy, and associated with him, but not limiting his
powers, a Council representing the entire Empire. There are
lieutenant-governors over provinces. Then there are chief
commissioners over portions of the country that are not regarded of
sufficient importance to have lieutenant-governors. Under both these
officials the next officers in rank are commissioners over divisions,
and these in turn have deputy commissioners under them who
administer districts. Below the deputy commissioners there are
several lesser officers, usually over townships, but having a wide
range of duties. From viceroy down to deputy commissioners the
officers have certain executive, or executive and judicial powers
combined. The higher officers have also authority to some extent in
military affairs.
The army is made up of British troops and native soldiers, with a
great preponderance of the latter. There are also many belonging to
the military police. The same division is made in the civil police. The
police department is perhaps the most difficult branch of
Government to keep efficient and free from scandal, but there are
many worthy men in the police service.
In addition to the regular administrative officers mentioned there
are departmental officers, such as an engineering corps, which has
the care of all public works. There is the growing educational
department and a medical department including care of prisons,
hospitals, and a great forestry department, that conserves the
valuable forests of the empire. There is also a department of marine
with full official equipment.
There is a civil service system operating throughout all these
departments of government, including even the most subordinate
clerkships. The higher officials are usually brought out from some
part of Britain, and have been taken into Government employ after
the severest examinations. Their promotions are given by grade and
service, allowing also for special promotions for distinctive service.
Having been so placed that I have had to do with a wide range of
these officials, in most departments of the service, it becomes a
great pleasure to me to record the character of their official conduct
as I have found it in personal dealing. In the first place, they almost
without exception are men of courteous, gentlemanly manners. This
alone goes far to smooth the way in official transactions. Then I have
found them generally men who are very fair and even generous in
dealings where public interests, missionary matters, or property have
been dealt with. This is partly due to the system of aid given
especially to schools with which both the Government and the
missionary have to do, and partly due to fair dealing on general
principles, which I am led to believe from an experience all over the
province of Burma for a period of ten years, and from inquiries from
others of longer experience, is a British characteristic. This is
especially true of the better cultivated men. The snobbery of the
uneducated Briton is equal to that of the American of the same class.
In the whole range of my experience I have never met with other
than manly treatment from officials but twice, and then these were
not of the higher ranks, and one of them can not be said to be a
Briton. If an officer might be disposed to be unfair, he knows that
there is a superior above him that is ready to correct any abuse. But
the whole system of Indian service is well worth study, for it is not a
creation of a day, but the best fruit of England’s extensive colonial
experiences. In this matter it is well worth study, especially on the
part of America, which has now to enter upon the rule of large and
distant possessions. It is also to be noted that the wonder of
England’s Government is that she has been able to allow of a
diversity of Governments in her several possessions suited largely to
local conditions, so that no two of her colonies are entirely alike, and
yet she has been able to give protection, justice, and the largest
measure of liberty to each country that the people are able to utilize
for their own good. In these respects it is only fair to say her system
of Government over remote and diverse peoples is the best yet seen
on this globe.
Burmese Festival Cart

There is also a striking feature of the Government of
municipalities in India. Municipalities have not wholly self-
government, yet they are so ordered that the popular will has a
representation, even when it retards the actual progress of the city,
as it not infrequently does. The municipalities are governed by
commissioners, about half of whom are elected by the people, and
the other half are appointed by Government. The latter are not
Government officers, however. They may be as democratic in their
votes as any member of the municipal committee. But these
commissioners are representative of the different native races, as
well as the Europeans in the city. In a city like Rangoon there are
several great race divisions that are recognized on the municipal
committee, both elective and appointive. In the election of these
commissioners appears one of the most extreme examples of the
democratic principles that the writer knows of anywhere. Perhaps it
has no parallel. In the case of the ballot, it is allowed freely to all
Europeans and Americans on exactly the same conditions. They, as
aliens, never having become British subjects, and never intending to
do so, have the ballot the same as an Englishman. This broad
democracy has greatly surprised many Americans when I have told
them of it. The alien has a right to hold the office of city
commissioner, if elected, the peer of the native-born Briton. This is
the broadest democracy found anywhere within the defined limits of
franchise.
The Government has a vast system of railroads in India
amounting to sixteen thousand miles, with many other extensions
and new lines in prospect. These roads now reach nearly all the
districts which could sustain them. They are sometimes built for
military purposes, but they are mostly directed for the carrying of
traffic in times of peace. The province of Burma, one of the later
provinces to be thoroughly developed, is having railroads to all its
principal sections, and some of these roads are being projected to
the very borders. That to Kunlon is extended to the borders of China.
They also talk of a line from Rangoon through Western China, and
there is every likelihood of connections direct with Bengal. So the old
world moves under the impetus of Western enterprise. The
telegraphs attend the railway, and exist even far outside of railway
lines to all parts of the empire and to foreign lands. Let it be
remembered that probably none of these improvements would have
been thought of in the country had not it been taken in hand by an
enlightened and enterprising people from the West.
Great systems of canals have been constructed, and more than
thirty million acres of land are irrigated, and famine in this area is
forever forestalled. Larger plans are being suggested by the recent
famine. The famine relief works constructed many tanks on land too
high for irrigation from running streams.
Good pavements in cities and good roads have been made in
the land universally. These roads are nearly all metaled and kept in
good order.
Public buildings of the most substantial and imposing kind are
built in all capital cities. The Government wisely erects buildings in
keeping with its own governmental ideas, and with its declared
intention of remaining in the land to work out its plans. The public
parks and gardens are on an elaborate scale, and are enjoyed by
everybody. The memorials to great men of India and the great men
who have made India British territory are placed in all public
gardens. Great men and great deeds are set before the world as
they should be, that the world may emulate them. The latest design
is to build a memorial to Queen Victoria in the city of Calcutta, to
which many of the rajahs of India are subscribing. The building is to
cost perhaps more than five million dollars, and while it is a great
memorial to Queen Victoria, it is to be a museum of great men of
India as well. There will be other memorials established in other
cities of the Indian Empire also. The taxes of the Government are
reasonable. They are mostly placed directly on the earning power of
the individual, or tax upon land assessed in proportion to the amount
of grain it produces, There is also a tax on houses in villages outside
municipalities. The land tax is very just. If the land produces regular
good crops, it is taxed accordingly. If there is a failure of crops, the
tax is reduced or remitted. As land needs rest, it is allowed a tax at
fallow rates, which is very light indeed. The income tax is collected
chiefly in cities, but of all Government employees, beginning with the
viceroy. This tax is two per cent per month. This is to be paid out of
the monthly salary. But it is said this tax only reaches one out of
three hundred and fifty of the native-born inhabitants of India.
The Government claims to own the land, very much as the
American Government owns the public lands. But, of course, the
greater part of this land comes into the ownership of the people, and
is transferable as elsewhere in the world. In the comparatively rich
province of Burma, where there has been until recently much of the
very best land of the tropical world lying idle, grown into grass and
forests—land that never was cultivated, the land is given out freely to
would-be cultivators. They only have to show that they are prepared
to cultivate it. They have to pay nothing but for its survey. When it is
cultivated they get a title to it, and then they can sell it as the actual
owners. If it is grass land, the cultivators are allowed one year
exemption from tax. If forest land, ten years are allowed exemption.
A more liberal plan could not be devised than this. It is just here that
England’s policy in the country is shown. If a Burman asks for a
piece of land, and a European, any Englishman indeed, asks for the
same piece of land, the Burman will surely get it. One becomes more
and more convinced that the policy of Government in India is to
govern for the best interests of the Government. There is another
great plan of Government to aid agriculture. The people of all parts
of the Indian Empire are chiefly agricultural. They are like all Asiatics,
great borrowers of money. They generally mortgage the crop by the
time it springs out of the soil. The native money-lender demands as
much as three per cent a month; but here the Government comes
forward, and agrees to loan the agriculturalist money at six per cent
a year, and allow him to repay it in partial payments. This is
eminently fair, and any man can get it who can show that he can
repay it, and can give two personal securities. This seems a very
liberal proposition.
The Government has also devised a great school system to aid
in popular education. The schools of Southern Asia have been
almost entirely in the hands of the various religions of the land. The
Government has undertaken to work out a plan by which a very large
part of this education can be put under popular control, and yet be
allowed to remain under the direction of the various religious
communities that conduct schools. Of course, under the old order
there was but a small part of the community allowed to go to school,
and the teaching was of an inferior kind. Government would promote
education and give a fixed standard. To do this they had to put the
secular instruction of all schools under the Government, and allow
the religious instruction to be carried out according to the ideas of
every society concerned. So that we witness Mohammedan,
Christian, Hindu, and Buddhist schools, all drawing aid from
Government, and all passing the same Government examinations in
secular subjects, but each imparting its own religious instructions. To
aid in this educational scheme, the Government will give grants in
putting up buildings, in paying accredited teachers, and in giving
grants to current expenses on passes secured in Government
examinations. In addition, the Government has built up certain
schools entirely under its control, where no religion is taught.
In all this it will be seen that the Government, in keeping with its
declared purpose and position, is neutral in the matter of religion. It
ought to be clear to all who will see it, that the Christian Church
should avail itself of all this educational plan that is possible, so as to
mold the minds of all the young in Christian principles. Nearly all
mission schools are identified with this educational system, but there
is opportunity for much more of the same kind of work.
There is another great and merciful arm of Government to be
mentioned. In every municipality, and even in large villages, there is
hospital treatment for all who need medical or surgical aid. All this is
freely given to every applicant.
All cities and large towns have great hospitals where medicines
and food and shelter in bad cases are given freely to men of all
races and creeds. No disease is turned away, and no sick man
denied attention. This charitable effort of Government is far-reaching
in its beneficence. It is not so valuable as it might be, because it has
a prejudice of the populace to deal with. But the amount of suffering
that is relieved by Government in all the empire is enormous.
In cases of epidemics there is a Government order to fight the
disease in an organized way. If it is smallpox, which is very
prevalent, public vaccination is enforced. Cholera epidemics are
taken in hand vigorously, water purified, and quarantine established,
until the pestilence is put under control.
The last four years has called out all the agencies of a great
Government to battle with the Bubonic plague and the famine. It is
now more than four years since the plague began its ravages in
India, and a little over three years since the famine began its course
of devastation. Both of these dire visitations were grappled with from
the start, and the battle is still being waged.
A competent board of physicians and a large force of skilled
nurses were quickly organized, and they have been unremitting in
their efforts, and many of these have fallen victims to their difficult
and dangerous duty. A system of inspection was at once established
on all railroads and steamship lines throughout India and along its
coasts. Every traveler, irrespective of race or rank, has been
examined by medical experts. Yet in spite of this precaution the
deadly scourge has insidiously worked its way almost throughout the
empire. But still the Government grapples with the pestilence. One
can feel something of its terrors when it is noted that ninety-four per
cent of all who are seized by the plague die. Six hundred thousand
have died of the plague in five years. The greatest hostility has been
shown at times by the native population, in opposing the most
necessary plague regulations.
With plague almost all over the empire, the Government had at
the same time to undertake a most extensive plan for relieving a
famine that was ever undertaken by any Government in human
history. The famine had only one immediate cause—the lack of rain.
The greater rains over almost all India occur between June and
September. For years on overlapping territory the rains failed, or
were deficient. The world knows the story. One-fourth of the nearly
three hundred millions of this population of the empire were in the
terrors of famine, with its slow starvation of man and beast, with its
attendant cholera, plague, and other diseases. It is worthy of cordial
recognition and perpetual memory that this gigantic specter was met
by a Christian Government. It was not a Mohammedan or Hindu
people which fought back this monster calamity, but a Government
and a people whose sympathies were Christian. The Christians
hurried to the relief of those of non-Christian belief and alien people,
and hardly thought of their race or religion. They only knew they
were starving communities of fellow-beings, and they put forth
supreme efforts to relieve their hunger and other ills due to the
famine. Yes, this was done by a Christian Government, aided by
private Christian beneficence of distant lands, while their own co-
religionists, having money in many cases, owning nearly all the grain
in the empire, enough to have fed all the hungry at every stage of the
famine, gave practically nothing for famine relief! They held their
feasts, organized their tiger hunts, looked on the dance of the impure
nautch-girl, and reveled while their people starved and died, or owed
their life to a foreign race of the Christian faith.
The Government of India spent $92,650,000 on famine relief
during 1899 and 1900. The relief works were open nearly two years
before that, and help on a large scale continues still. This is the most
gigantic effort of all human history to meet a great national calamity.
Strange that these noble and statesman-like efforts should have
been belittled by any, much less by some who should have known
better.
The census of 1901 has been gathered, and these columns of
figures tell their sad story of suffering and death in the famine
districts. Of India’s two hundred and eighty-six millions of ten years
ago, sixty-six millions were residents in native-protected States. The
census of 1901 shows that British India increased its population by
ten millions, while the peoples of the native States decreased three
millions. British territory increased its population by four and one-half
per cent, and the-native States decreased by four and one-half per
cent.
A close inspection of the figures shows the decrease to be
largely due to the famine. What would have been the death-rate but
for the English Government’s immense relief?
The missionaries worked hand in hand with the British officers,
and I have never heard that either has ever spoken except in words
of praise of the other’s labors. This proves that good Governments
and faithful missionaries are invaluable to each other.
A crowning proof of the good government of Britain in India, is in
the fact that her population does not migrate to any adjacent State
where there is limited or unlimited native rule. But from all such
States there is a steady stream of immigration pouring into British
territory. None of India’s peoples migrate in any numbers to any
Oriental or Occidental country, but from every Oriental land there are
immigrants to sojourn or to settle in India under the justice,
protection, and peace of British rule.
The tropical world is fast coming under Western domination.
These lands must be lifted by new blood from the North and West,
and must serve the needs of our race. While this process is going
on, the world can afford to be happy over the fact that so large a part
of the tropical countries is under British rule.
Transcriber’s Notes
Punctuation, hyphenation, and spelling were made
consistent when a predominant preference was found in the
original book; otherwise they were not changed.
Simple typographical errors were corrected; unbalanced
quotation marks were remedied when the change was
obvious, and otherwise left unbalanced.
Illustrations in this eBook have been positioned between
paragraphs and outside quotations. In versions of this eBook
that support hyperlinks, the page references in the List of
Illustrations lead to the corresponding illustrations.
The first illustration is the cover. The illustration on the
Title Page is a photograph of a woman leaning against a
cocoanut tree (it is the leftmost part of the illustration on page
45 of this eBook). The four captionless illustrations are
identical decorative tailpieces.

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Katzung & Trevor’s Pharmacology

Examination and Board Review 12th

Basic & Clinical Pharmacology, 14th Edition Bertram G.

Basic & Clinical Pharmacology, 14th Edition Bertram G.

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Katzung & Trevor’s

Bertram G. Katzung, MD, PhD

Marieke Kruidering-Hall, PhD

Anthony J. Trevor, PhD

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eBook conversion by codeMantra

9. Sympathomimetics 76 23. Alcohols 196

10. Adrenoceptor Blockers 85 24. Antiseizure Drugs 203

25. General Anesthetics 212

27. Skeletal Muscle Relaxants 225

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47. Antimycobacterial Drugs 397

55. Immunopharmacology 463

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Receptor, Inert Movement

Drug development & regulation

Safety & Animal Clinical Patents &

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High-Yield Terms to Learn (continued)

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High-Yield Terms to Learn (continued)

Drug Receptor Effects

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2. Ionization of weak acids and bases—Weak bases are Membranes of

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First-order elimination Zero-order elimination

5 units/h 2.5 units/h

2.5 units/h 2.5 units/h

Time (h) Time (h)

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Serum concentration (C) (µg/mL) (logarithmic scale) Distribution

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In vitro Animal Clinical testing Marketing

A Controlled studies in women fail to demonstrate a

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DRUG PATENTS & GENERIC DRUGS QUESTIONS

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5. The pharmacokinetics of a new drug are under study in a

6. The pharmacokinetic process or property that distinguishes 2

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T HE missionary is one of the most interested students of

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Katzung & Trevor’s Pharmacology Examination and Board Review 12th Edition Bertram G. Katzung full chapter instant download

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47. Antimycobacterial Drugs 397

55. Immunopharmacology 463