Introduction to Pharmacology
© 1997, 2003 Taylor & Francis
In the ocean depths off Madagascar, obsolete fish keep their laggard appointments.
In the depths of the human mind, obsolete assumptions go their daily rounds. And
there is little difference between the two, except that the fish do no harm.
Robert Ardrey
African Genesis, 1967
That which in the beginning may be just like poison, but at the end is like nectar,
and which awakens one to self-realization, is said to be happiness in the mode of
goodness.
Bhagavad Gita
Nothing in life is to be feared, it is only to be understood.
Marie Curie
© 1997, 2003 Taylor & Francis
Introduction to Pharmacology
Second Edition
Mannfred A. Hollinger, Ph.D.
Professor Emeritus,
Department of Medical
Pharmacology and Toxicology
University of California, Davis
© 1997, 2003 Taylor & Francis
First published 1997 by Taylor & Francis
Second edition published 2003 by Taylor & Francis
11 New Fetter Lane, London EC4P 4EE
Simultaneously published in the USA and Canada
by Taylor & Francis Inc,
29 West 35th Street, New York, NY 10001
Taylor & Francis is an imprint of the Taylor & Francis Group
© 1997, 2003 Taylor & Francis
Typeset in 10/12 pt Sabon by Graphicraft Limited, Hong Kong

Preface to the second edition x
PART 1
Fundamentals of pharmacokinetics 1
1 Introduction 3
2 Absorption and distribution 23
3 Metabolism and elimination 44
4 Drug interactions 61
PART 2
Fundamentals of pharmacodynamics and
toxicodynamics 73
5 Drug receptors 75
6 Dose–response relationship 90
7 Drug toxicity 101
8 Treating drug overdose 137
PART 3
Drugs that replace, cure, or treat symptoms 147
9 Hormones 149
10 Chemotherapeutic agents 164
11 Drug treatment of symptoms: neuropharmacology and
substance abuse 181
12 Cardiovascular drugs 241
© 1997, 2003 Taylor & Francis
PART 4
Drug development 265
13 Drug discovery by the pharmaceutical industry 267
14 Pharmaceutical development of drugs and the FDA 299
15 Animals in research 316
16 Alternative medicine 341
Appendix: The History of drug abuse laws in the United States 351
Glossary 376

an interest in learning about the diverse aspects of pharmacology in society—not
simply about the curative aspects of drugs. It is hoped that not only students in the
biological sciences but also those in the social sciences will find some, if not all, of the
book’s contents informative and useful.
This book has been organized to provide a logical continuum of information relat-
ing to drugs, beginning with the inevitable historical discovery of drugs in food. With
this background, important pharmacological principles will be considered relating to
drug absorption, distribution, metabolism, and elimination. This material forms the
corpus of the chapters that constitute Part 1. In essence, the emphasis is placed upon
pharmacokinetic aspects of drug action. Having gained access to the body, how
do drugs produce an effect and how can the effect be quantified for comparative
purposes? In Part 2, the student is exposed to the concepts of drug–receptor inter-
action and the transduction of drug binding into pharmacodynamic or toxicodynamic
responses. Factors influencing drug toxicity, as well as underlying principles of man-
aging drug overdose, also will be presented as the inevitable “other side of the coin.”
Part 3 reiterates, in more detail, the concept introduced in Part 1 that drugs can be
classified into four broad categories: (1) drugs that replace physiological inadequa-
cies, (2) drugs that cure, (3) drugs that treat symptoms, and (4) drugs that alter mood
or behavior. In this regard, hormones, antibiotics, and neuroactive agents provide
© 1997, 2003 Taylor & Francis
examples, respectively, in their own chapters. In addition, the pharmacology of sub-
stance abuse as well as the evolution of drug abuse laws and the use of drugs in
sports are also discussed. In Part 4, the final three chapters deal with the development
of drugs by the pharmaceutical industry and the challenges they face in new drug
discovery as well as dealing with the FDA. The section concludes with a discussion of
the controversial use of experimental animals in research, an area often neglected in
the study of pharmacology.
Mannfred A. Hollinger
Davis, California
Preface to the first edition ix

structive input and am willing to try to answer any questions. My email is

Mannfred A. Hollinger
Oro Valley, Arizona
© 1997, 2003 Taylor & Francis
Introduction 1Part 1
Fundamentals of
pharmacokinetics
© 1997, 2003 Taylor & Francis
Introduction 3
Chapter 1
Introduction
HISTORY
Pharmacology is one of the pillars of the drug discovery process. While the medicinal/
organic chemist may create the candidate compound (sometimes referred to as a new
chemical entity, NCE), it is the pharmacologist who is responsible for testing it for
pharmacological activity. An NCE is eventually investigated by several other groups
of scientists (toxicologists, microbiologists, and clinicians) if it has demonstrated a
potential therapeutic effect.
Pharmacology studies the effects of drugs and how they exert their effects. For
example, penicillin cures certain bacterial infections and acetylsalicylic acid (ASA)
can reduce inflammation. How do they accomplish these respective effects? Through
research we now know that penicillin can disrupt the synthesis of cell walls in suscep-
tible bacterial strains by inhibiting a key enzyme, while ASA can inhibit the action of
a human cell membrane enzyme known as cyclooxygenase, which is responsible for
the synthesis of a number of inflammatory mediators.
Modern pharmacology owes part of its development to Friedrich Worler, who
inaugurated the field of synthetic organic chemistry in 1828 with the synthesis of
urea. This achievement catalyzed the formation of an entire industry (the German
dye industry), which ultimately led to the synthesis of NCEs, many of which were

antimicrobial agent
Horace Wells and William T. G. Morton, introduced volatile anesthetics in the 1840s
Henri Bequerel (1896), Pierre and Marie Curie (1898), discovery and awareness of radioactive
principles
Alexander Fleming, discoverer of penicillin
Rosalyn Yalow (1921– ), development of the radioimmunoassay, Nobel prize winner in 1977
Stanley Cohen and Herbert Boyer, genetic engineering in the 1980s
in the United States at the University of Michigan. Abel was an excellent scientist and
is credited with the isolation of both epinephrine and histamine and with the pre-
paration of crystalline insulin. Additional important individuals in the history of
pharmacology are shown in Table 1.1.
Clinical pharmacology owes much of its foundation to the work of William With-
ering. Born in 1741 in Shropshire, England, Withering was interested in various
aspects of science, and graduated with an MD from the University of Edinburgh.
Withering became interested in the disorder known as “dropsy” and learned about a
herbal treatment for this disorder from an old woman herbalist in Shropshire. How-
ever, her herbal recipe contained more than 20 plants. Fortunately, because of his
interest and knowledge of botany, he identified the active ingredient as coming from
the plant Digitalis purpurea. With the publication of his book An Account of the
Foxglove in 1785, Withering introduced Digitalis for the therapy of congestive heart
failure, or dropsy, as he knew the condition.
Withering was unaware that dropsy was caused by cardiac insufficiency. In com-
mon with his time, he believed that the kidney was responsible for dropsy (peripheral
fluid accumulation) and was therefore the site of action of Digitalis in the condition.
Nevertheless, his clinical observations were precise: “Let the medicine therefore be
given in doses, and at the intervals mentioned above; let it be continued until it either
acts on the kidneys, the stomach, the pulse or the bowels; let it be stopped upon the
first appearance of any one of these effects, and I will maintain that the patient will
not suffer from its exhibition, nor the practitioner be disappointed in any reasonable
expectation.”

logy, and immunology. Pharmacology should be distinguished from the profession of
pharmacy, whose responsibilities include the identification, verification, standardiza-
tion, compounding, and dispensing of drugs and dosage forms of drugs. Additional
useful definitions relative to pharmacology are shown in Table 1.2.
Associating the word science with pharmacology implies a systematic investigation
of observable phenomena that can be quantified and controlled—a state that reflects
much of modern pharmacology. However, as we shall see, this has not always been
the case. As mentioned earlier, pharmacology involves the study of drugs. However,
what is a drug?
The word drug is believed to have been derived from the French word drogue,
which refers to a dry substance and probably reflects the use of herbs in early therapy.
Broadly defined, a drug is a chemical substance that can alter or influence the respons-
iveness of a biological system. The action of a drug is mediated by a naturally
occurring process of the body. A drug either mimics, facilitates, or antagonizes a
normally occurring phenomenon. Although people can, and do, argue about what a
drug is to them, perhaps it may be helpful at this point to present several “official”
views as to what a drug is. To begin with, let us examine how the governmental
© 1997, 2003 Taylor & Francis
6 Pharmacokinetics
agency most concerned with drugs defines a drug. According to the Food and Drug
Administration (FDA):
A. All drugs are chemicals, BUT, all chemicals are not drugs;
1. All drugs are poisons, BUT, all poisons are not drugs;
B. Definitions
1. chemical—a substance composed of a combination of elements (electrons,
protons, and neutrons);
2. drug—a chemical which is utilized for the diagnosis, prevention, cure or ameli-
oration of an unwanted health condition;
a. Federal Food, Drug, and Cosmetic (FDC) Act Sec. 201. [321] (g)(1)—
The term “drug” means (A) articles recognized in the official United

Introduction 7
HISTORY—ROLE OF PLANTS
Since time immemorial, plants have been used for treating diseases in humans and
animals, as well as being involved in the spiritual needs in humans. The role of plants
in early religion can be seen in friezes (carvings) from the eighth century bc in
Mesopotamia. These carvings clearly depict mandrake flowers and poppy heads.
Early belief in the curative powers of plants and certain substances rested exclusively
upon traditional knowledge, that is, empirical information not subjected to critical
examination (i.e., ethnopharmacology).
The question has been asked: “how over time, have we been ‘shaped’ by the
shifting alliances that we have formed and broken with various members of the
vegetable world as we have made our way through the maze of history?” The an-
swer, in part, is that plants have always played a significant role in mediating human
cultural experiences in the world at large, be that role dietary, medicinal, or to alter
consciousness. These are roles that they still play today, whether in the realm of
medicine, religion, or jurisprudence.
One of the most provocative theories relating to our relationship with plants is the
suggestion that their consumption may have contributed to the relatively rapid organ-
ization of the human brain’s information-processing capacity. This is a process that
occurred over a relatively short anthropological time frame. Specifically, this pro-
posal suggests that hallucinogenic compounds such as psilocybin, dimethyltryptamine,
and harmaline were present in the protohuman diet and that their psychopharmaco-
logical effects catalyzed the emergence of human self-reflection.
The theory boldly suggests that the tripling of human brain size from Homo hablis
was facilitated by mutagenic, psychoactive plants that functioned as a chemical “miss-
ing link.” While this proposal certainly does not represent a mainstream scientific
view, it illustrates, nevertheless, the impact that plants, particularly psychoactive
ones, continue to have in our attempts to define ourselves.
We can only speculate as to the actual sequence of events in the genesis of our
relationship with plants. However, the knowledge of plant effects undoubtedly began

to store information outside of the physical brain for retrieval and transmission across
space and time. The capacity to relate past experiences to future possibilities and deal
in symbols, particularly language, is an inheritance from our Pliocene past that has
evolved from warning cries in the Oldavi gorge to Senate filibusters and “rap” music.
In this way, knowledge of the effect of plants on bodily functions probably became
part of our collective memory. Before the advent of writing, this collective memory
had to be communicated verbally and became the responsibility of certain members
of the group—a practice that continued into the Middle Ages in the form of lyrical
song or verse in order to make the information easier to remember.
There are many examples of plants that played significant roles in the lives of
ancient man. Perhaps one of the more interesting deals with a parasitic shrub that
is still used in traditional Christmas celebrations. Mistletoe (Viscum album) was
celebrated for its mysterious powers by the ancient Celts (fourth century bc). Celtic
priests (the Druids) were fascinated by the haphazard growing and blooming of the
shrub and considered it the most sacred plant of all. Interestingly, the presence of
mistletoe pollen in the peat moss “grave” of the 1500-year-old “Lindow Man,”
unearthed in 1984 near Manchester, England, contributed to the theory that this
individual had in fact been a Druid prince.
Druids harvested the mistletoe berry yearly and used it in their winter celebrations,
known as samain and imbolc, which were centered on the winter solstice. For this
celebration, the Druids concocted a strong potion of the berries, which researchers have
subsequently discovered contains a female-like steroid that may have stimulated the
libido (presumably structurally related to either estrogen or progesterone). Mistletoe has,
of course, become a contemporary symbol to Yuletide merrymakers as a license to kiss.
The Celts, and others, also used mistletoe for medical purposes. The Roman histo-
rian Pliny the Younger wrote that mistletoe was “deemed a cure for epilepsy; carried
about by women it assisted them to conceive, and it healed ulcers most effectually, if
only the sufferer chewed a piece of the plant and laid another piece on the sore.”
Modern herbalists continue to recommend mistletoe for the treatment of epilepsy,
hypertension, and hormone imbalances. However, it should be appreciated that

remedies, while rejecting the irrational concoctions and mixtures of medieval medicine.
He discounted the humoral theory of Galen, whose rediscovered works became the
foundation of medicine at the time. Galen postulated that there were four humors in
the body (blood, phlegm, yellow bile, and black bile); when these were in balance,
one enjoyed health, and when there was imbalance, sickness ensued. Paracelsus was
a freethinker and an iconoclast. His disenchantment with the teaching of medicine at
the University of Basle reached its climax on July 24, 1527, when he publicly burned
the standard medical textbooks of the day (e.g., Galen). All of this behavior was
deemed heresy, and not acceptable to the medical community of his time.
Paracelsus prescribed chemically defined substances with such success that enemies
within the profession had him prosecuted as a poisoner. This was primarily based
upon his use of inorganic substances in medicine, because his critics claimed that they
were too toxic to be used as therapeutic agents. He defended himself with the thesis
that has become axiomatic in pharmacology/toxicology: “If you want to explain any
poison properly, what then isn’t a poison? All things are poisons, nothing is without
poison; the dose alone causes a thing not to be poison.”
Plants, and natural products, continue to play a vital role in modern society both
as the source of conventional therapeutic agents and as herbal preparations in “health
food” stores. In 1994, half of the top 25 drugs on the market in terms of sales were
either natural products or based on natural products, now made synthetically or
semisynthetically. Examples of active plant compounds with therapeutic uses are
shown in Table 1.3.
It is estimated that 80 percent of people in developing countries are almost totally
dependent upon traditional healers for their health care, and that plants are the
major source of drugs for their traditional medical practitioners. In theory, in as
© 1997, 2003 Taylor & Francis
10 Pharmacokinetics
much as 80 percent of the world’s population live in developing countries, approxim-
ately 64 percent of the world’s population depends, therefore, almost entirely on
plants for medication.

Cocaine Local anesthetic
Colchicine Antigout
Digoxin Cardiotonic
Ephedrine Bronchodilator
Morphine Analgesic
Oubain Cardiotonic
Physostigmine Cholinergic
Quinine Antimalarial
Scopolamine Anticholinergic
Theophylline Bronchodilator
D-Tubocurarine Skeletal muscle relaxant
Vincristine Antineoplastic
© 1997, 2003 Taylor & Francis
Introduction 11
Taxol is a potent inhibitor of eukaryotic cell replication, blocking cells in the late
G2, or mitotic, phase of the cell cycle. Interaction of Taxol with cells results in the
formation of discrete bundles of stable microtubules as a consequence of reorganization
of the microtubule cytoskeleton. Microtubules are not normally static organelles but
are in a state of dynamic equilibrium with their components (i.e., soluble tubulin
dimers). Taxol alters this normal equilibrium, shifting it in favor of the stable,
nonfunctional microtubule polymer.
In addition to being an essential component of the mitotic spindle, and being
required for the maintenance of cell shape, microtubules are involved in a wide
variety of cellular activities, such as cell motility and communication between organelles
within the cell. Any disruption of the equilibrium within the microtubule system
would be expected to disrupt cell division and normal cellular activities in which
microtubules are involved.
As indicated earlier, plant products can be useful as starting materials for the
semisynthetic preparation of other drugs. An important example in this regard is the
Mexican yam, which produces a steroid precursor (diosgenin) vital to the synthesis of

without using animals. This can be achieved by using isolated enzymes or receptors
to determine if the drug has any binding affinity at all (see Chapter 13).
However, not everyone agrees that this renewed drug company enthusiasm for
going out in the field to seek plant-based drugs will be particularly widespread or
particularly effective in the long term. Nonenthusiasts contend that labor-intensive
plant collection methods are being supplanted by newer, laboratory-based chemistry
techniques (see Chapter 13) that are more efficient in creating new drug leads. For
every proven anticancer drug like Taxol, there are hundreds of plant compounds that
demonstrate initial promise in the test-tube, only to prove a disappointment later.
In the final analysis, will rational drug design, chemical synthesis, or combinatorial
chemistry prove to be enough? Or will the abundant natural diversity of chemical
structures found in nature provide new scaffolds and new chemical space for even
greater advancement in NCEs?
In the Western hemisphere there are more than 40 species of plants that are used
for hallucinogenic purposes alone. Although the structures of hallucinogenic substances
vary significantly, most plants owe their hallucinogenic properties to alkaloids, which
are cyclic structures containing nitrogen. At least 5000 higher plants contain alkaloids.
Despite their wide distribution among plants, our knowledge of their pharmacology
is still largely incomplete.
One of the challenges facing early, as well as contemporary, chemists is how to
extract the pharmacologically active principle (such as an alkaloid) from a plant.
This is desirable because it allows identification, assessment of pharmacological effects,
constant dosage, and the opportunity to create liquid forms of the extract. For exam-
ple, soaking plants in alcohol (ethanol) creates a tincture, which was, undoubtedly,
one of the first organic extractions performed by man.
In the process of preparing a tincture, some pharmacologically active constituents
of the plant are extracted by the alcohol. Although not all substances are soluble in
alcohol, those that are include the alkaloids. In the case of a tincture of raw opium, the
soluble alkaloids include morphine, codeine, noscapine, and papavarine. Such tinctures
of opium were the infamous laudanum preparations of the late 1800s (see Appendix).

mation, and other conditions.
Marine species comprise approximately one-half of total global diversity (estimates
range from 3 million to 500 million different species). Therefore, the marine world would
appear to offer significant potential resources for novel pharmacological compounds.
Unfortunately, much of the literature on marine natural products is characterized by
compounds with demonstrable cytotoxicity rather than pharmacological efficacy.
However, toxicological properties can conceivably be utilized therapeutically. For
example, one current therapeutic candidate, based upon its cytotoxicity, is bryostatin
1. Bryostatin, from the bryozoan Bugula neritina, is now in phase II trials (see Chap-
ter 14 for discussion of clinical trials). Research is currently under way to develop
aquaculture techniques for the harvesting of the bryozoan source. Because of the
relatively large number of possible drug candidates from marine sources, pharmaceu-
tical companies are forced to utilize their high-throughput screening technologies
with extensive arrays of drug target-specific assays (see Part 4, Chapter 13 for more
details) to test marine extracts.
An example of a natural product from a marine organism that has been commerci-
alized is an extract from sea whips (Pseudopterogoogia elisabethae). This extract is used
in the manufacture of certain cosmetic products. The active ingredient is believed
to be a class of diterpine glycosides (pseudopterosins) that apparently has some anti-
inflammatory activity.
Another marine product undergoing development is docosahexaenoic acid (DHA),
developed via fermentation of a microalgae. DHA is a major component in human
gray matter and is important for normal healthy development in infants. Various
groups, such as the World Health Organization, have recommended DHA’s inclusion
in infant formulas at levels similar to those found in human milk. DHA is presently
used in Belgium and Holland and is expected to gain approval in the United States.
ANIMAL SOURCES
Today, animal products such as insulin (extracted from the pancreas of cows and
pigs) are still being used for the treatment of diabetes mellitus and other disorders.
© 1997, 2003 Taylor & Francis

cially bred, germ-free maggots is currently increasing within certain clinical specialties
(e.g., plastic surgery), particularly in Britain. Three-day-old maggots from the
greenbottle fly have been used in the treatment of open wounds such as ulcers.
Apparently, 100 maggots can eat 10 to 15 grams of dead tissue a day, leaving
wounds clean and healthy (today, the scientific standard of 10 larvae/cm
2
is used). In
one case an 83-year-old man with severe leg ulcers was saved the trauma of an
amputation due to successful treatment with maggots.
In a similar context, a recombinant version of a protein from a blood-feeding
hookworm is currently being investigated for its use in preventing blood clots. The
protein, designated NAP–5, is a member of a family of anticoagulant proteins. The
protein acts by inhibiting Factor Xa in the initial step of the blood-clotting cascade
leading to fibrin formation. If successful, this protein may replace an entire class of
40-year-old “blood-thinning” drugs, called heparins, which are widely used to pro-
tect against clot formation in heart-attack patients.
Another natural anticoagulant is hirudin, derived from the saliva of the leech
(hirudo is the Latin word for leech). Leeches, in fact, are still occasionally used
themselves therapeutically for certain topical applications. Another possible drug to
be used for the dissolution of blood clots is derived from bat saliva and acts as a
© 1997, 2003 Taylor & Francis
Introduction 15
plasminogen activator. It appears that saliva is a good place to look for possible
drugs affecting the blood-clotting system since sand fly saliva is also being examined
for this property.
Snake venoms have also been found to possess ingredients with important phar-
macological properties. Perhaps the best-known example is the drug captopril, which
is used in the management of hypertension. This drug is a dipeptide analog of
bradykinin-potentiating peptides (BPPs), originally identified in the venom of the
pit viper, Bothrops jararaca. The drug acts by inhibiting angiotensin-converting

Following the 1911 revolution, the Ministry of Health of the nationalist govern-
ment sought to curtail or eliminate traditional Chinese medicine. However, after the
communist revolution of 1949, the new government reversed the ban on traditional
medicine, establishing a number of traditional medical colleges and institutes whose
role is to train physicians and further investigate the uses of herbs. Even in Western
hospitals in China, apothecaries are available to dispense herbs upon request.
© 1997, 2003 Taylor & Francis
16 Pharmacokinetics
SOURCES OF DRUG INFORMATION
Today, in the United States, there are numerous sources of drug information, includ-
ing the Physicians’ Desk Reference (PDR), which is an industry-supported reference.
The PDR contains information identical to that contained in package inserts. No
comparative information on efficacy, safety, or cost is included. PDR versions cover-
ing both trade name protected and generic preparations are available.
The United States Pharmacopoeia (USP), founded in 1820, originally contained
“recipes” (formulas) for the preparation of drugs and drug products. The evolution
of the USP actually began in 1817 when a New York physician, Lyman Spalding,
recognized the need for drug standardization. At that time, medicine names and
formulations differed from one region to another.
Spalding organized a meeting with 10 other physicians in January 1820 in the U.S.
Capitol’s Senate Chamber. Following the week-long meeting, the groundwork was
laid for the compilation of the first Pharmacopoeia of the United States of America.
The book was designed to standardize 217 of the most fully recognized and best
understood medicines of that era.
USP standards first became legislatively mandated in 1848 when Congress enacted
the Drug Import Act. The USP gained further recognition in the 1906 Food and
Drugs Act and the 1938 Federal Food, Drug, and Cosmetic Act (see Appendix), in
which its standards of strength, quality, purity, packaging, and labeling are recog-
nized. These acts also recognized the standards of the USP’s sister publication, the
National Formulary (NF).