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Section I. Basic Principles
Chapter 1. Introduction
Pharmacology can be defined as the study of substances that interact with living systems through
chemical processes, especially by binding to regulatory molecules and activating or inhibiting
normal body processes. These substances may be chemicals administered to achieve a beneficial
therapeutic effect on some process within the patient or for their toxic effects on regulatory
processes in parasites infecting the patient. Such deliberate therapeutic applications may be
considered the proper role of medical pharmacology, which is often defined as the science of
substances used to prevent, diagnose, and treat disease. Toxicology is that branch of pharmacology
which deals with the undesirable effects of chemicals on living systems, from individual cells to
complex ecosystems.
History of Pharmacology
Prehistoric people undoubtedly recognized the beneficial or toxic effects of many plant and animal
materials. The earliest written records from China and from Egypt list remedies of many types,
including a few still recognized today as useful drugs. Most, however, were worthless or actually
harmful. In the 2500 years or so preceding the modern era there were sporadic attempts to introduce
rational methods into medicine, but none were successful owing to the dominance of systems of
thought that purported to explain all of biology and disease without the need for experimentation
and observation. These schools promulgated bizarre notions such as the idea that disease was
caused by excesses of bile or blood in the body, that wounds could be healed by applying a salve to
the weapon that caused the wound, and so on.
Around the end of the 17th century, reliance on observation and experimentation began to replace
theorizing in medicine, following the example of the physical sciences. As the value of these
methods in the study of disease became clear, physicians in Great Britain and on the Continent
began to apply them to the effects of traditional drugs used in their own practices. Thus, materia
medica—the science of drug preparation and the medical use of drugs—began to develop as the
precursor to pharmacology. However, any understanding of the mechanisms of action of drugs was
prevented by the absence of methods for purifying active agents from the crude materials that were
available and—even more—by the lack of methods for testing hypotheses about the nature of drug
In the late 18th and early 19th centuries, François Magendie and later his student Claude Bernard
began to develop the methods of experimental animal physiology and pharmacology. Advances in
chemistry and the further development of physiology in the 18th, 19th, and early 20th centuries laid
the foundation needed for understanding how drugs work at the organ and tissue levels.
Paradoxically, real advances in basic pharmacology during this time were accompanied by an
outburst of unscientific promotion by manufacturers and marketers of worthless "patent medicines."
It was not until the concepts of rational therapeutics, especially that of the controlled clinical trial,
were reintroduced into medicine—about 50 years ago—that it became possible to accurately
evaluate therapeutic claims.
About 50 years ago, there also began a major expansion of research efforts in all areas of biology.
As new concepts and new techniques were introduced, information accumulated about drug action
and the biologic substrate of that action, the receptor. During the last half-century, many
fundamentally new drug groups and new members of old groups were introduced. The last 3
decades have seen an even more rapid growth of information and understanding of the molecular
basis for drug action. The molecular mechanisms of action of many drugs have now been identified,
and numerous receptors have been isolated, structurally characterized, and cloned. In fact, the use of
receptor identification methods (described in Chapter 2: Drug Receptors & Pharmacodynamics) has
led to the discovery of many orphan receptors—receptors for which no ligand has been discovered
and whose function can only be surmised. Studies of the local molecular environment of receptors
have shown that receptors and effectors do not function in isolation—they are strongly influenced
by companion regulatory proteins. Decoding of the genomes of many species—from bacteria to
humans—has led to the recognition of unsuspected relationships between receptor families.
Pharmacogenomics—the relation of the individual's genetic makeup to his or her response to
specific drugs—is close to becoming a practical area of therapy (see Pharmacology & Genetics).
Much of that progress is summarized in this resource.
The extension of scientific principles into everyday therapeutics is still going on, though the
medication-consuming public, unfortunately, is still exposed to vast amounts of inaccurate,
incomplete, or unscientific information regarding the pharmacologic effects of chemicals. This has
resulted in the faddish use of innumerable expensive, ineffective, and sometimes harmful remedies
and the growth of a huge "alternative health care" industry. Conversely, lack of understanding of
basic scientific principles in biology and statistics and the absence of critical thinking about public
health issues has led to rejection of medical science by a segment of the public and a common
tendency to assume that all adverse drug effects are the result of malpractice. Two general
principles that the student should always remember are, first, that all substances can under certain
circumstances be toxic; and second, that all therapies promoted as health-enhancing should meet the
same standards of evidence of efficacy and safety, ie, there should be no artificial separation
between scientific medicine and "alternative" or "complementary" medicine.
Pharmacology & Genetics
During the last 5 years, the genomes of humans, mice, and many other organisms have been
decoded in considerable detail. This has opened the door to a remarkable range of new approaches
to research and treatment. It has been known for centuries that certain diseases are inherited, and we
now understand that individuals with such diseases have a heritable abnormality in their DNA. It is
now possible in the case of some inherited diseases to define exactly which DNA base pairs are
anomalous and in which chromosome they appear. In a small number of animal models of such
diseases, it has been possible to correct the abnormality by "gene therapy," ie, insertion of an
appropriate "healthy" gene into somatic cells. Human somatic cell gene therapy has been attempted,
but the technical difficulties are great.
Studies of a newly discovered receptor or endogenous ligand are often confounded by incomplete
knowledge of the exact role of that receptor or ligand. One of the most powerful of the new genetic
techniques is the ability to breed animals (usually mice) in which the gene for the receptor or its
endogenous ligand has been "knocked out," ie, mutated so that the gene product is absent or
nonfunctional. Homozygous "knockout" mice will usually have complete suppression of that
function, while heterozygous animals will usually have partial suppression. Observation of the
behavior, biochemistry, and physiology of the knockout mice will often define the role of the
missing gene product very clearly. When the products of a particular gene are so essential that even
heterozygotes do not survive to birth, it is sometimes possible to breed "knockdown" versions with
only limited suppression of function. Conversely, "knockin" mice have been bred that overexpress
certain receptors of interest.
Some patients respond to certain drugs with greater than usual sensitivity. (Such variations are
discussed in Chapter 4: Drug Biotransformation.) It is now clear that such increased sensitivity is
often due to a very small genetic modification that results in decreased activity of a particular
enzyme responsible for eliminating that drug. Pharmacogenomics (or pharmacogenetics) is the
study of the genetic variations that cause individual differences in drug response. Future clinicians
may screen every patient for a variety of such differences before prescribing a drug.
The Nature of Drugs
In the most general sense, a drug may be defined as any substance that brings about a change in
biologic function through its chemical actions. In the great majority of cases, the drug molecule
interacts with a specific molecule in the biologic system that plays a regulatory role. This molecule
is called a receptor. The nature of receptors is discussed more fully in Chapter 2: Drug Receptors &
Pharmacodynamics. In a very small number of cases, drugs known as chemical antagonists may
interact directly with other drugs, while a few other drugs (eg, osmotic agents) interact almost
exclusively with water molecules. Drugs may be synthesized within the body (eg, hormones ) or
may be chemicals not synthesized in the body, ie, xenobiotics (from Gr xenos "stranger"). Poisons
are drugs. Toxins are usually defined as poisons of biologic origin, ie, synthesized by plants or
animals, in contrast to inorganic poisons such as lead and arsenic.
In order to interact chemically with its receptor, a drug molecule must have the appropriate size,
electrical charge, shape, and atomic composition. Furthermore, a drug is often administered at a
location distant from its intended site of action, eg, a pill given orally to relieve a headache.
Therefore, a useful drug must have the necessary properties to be transported from its site of
administration to its site of action. Finally, a practical drug should be inactivated or excreted from
the body at a reasonable rate so that its actions will be of appropriate duration.
The Physical Nature of Drugs
Drugs may be solid at room temperature (eg, aspirin, atropine), liquid (eg, nicotine, ethanol), or
gaseous (eg, nitrous oxide). These factors often determine the best route of administration. For
example, some liquid drugs are easily vaporized and can be inhaled in that form, eg, halothane,
amyl nitrite. The most common routes of administration are listed in Table 3–3. The various classes
of organic compounds—carbohydrates, proteins, lipids, and their constituents—are all represented
in pharmacology. Many drugs are weak acids or bases. This fact has important implications for the
way they are handled by the body, because pH differences in the various compartments of the body
may alter the degree of ionization of such drugs (see below).
Drug Size
The molecular size of drugs varies from very small (lithium ion, MW 7) to very large (eg, alteplase
[t-PA], a protein of MW 59,050). However, the vast majority of drugs have molecular weights
between 100 and 1000. The lower limit of this narrow range is probably set by the requirements for
specificity of action. In order to have a good "fit" to only one type of receptor, a drug molecule
must be sufficiently unique in shape, charge, etc, to prevent its binding to other receptors. To
achieve such selective binding, it appears that a molecule should in most cases be at least 100 MW
units in size. The upper limit in molecular weight is determined primarily by the requirement that
drugs be able to move within the body (eg, from site of administration to site of action). Drugs
much larger than MW 1000 will not diffuse readily between compartments of the body (see
Permeation, below). Therefore, very large drugs (usually proteins) must be administered directly
into the compartment where they have their effect. In the case of alteplase, a clot-dissolving
enzyme, the drug is administered directly into the vascular compartment by intravenous infusion.
Drug Reactivity and Drug-Receptor Bonds
Drugs interact with receptors by means of chemical forces or bonds. These are of three major types:
covalent, electrostatic, and hydrophobic. Covalent bonds are very strong and in many cases not
reversible under biologic conditions. Thus, the covalent bond formed between the activated form of
phenoxybenzamine and the receptor for norepinephrine (which results in blockade of the receptor)
is not readily broken. The blocking effect of phenoxybenzamine lasts long after the free drug has
disappeared from the bloodstream and is reversed only by the synthesis of new receptors, a
process that takes about 48 hours. Other examples of highly reactive, covalent bond-forming drugs
are the DNA-alkylating agents used in cancer chemotherapy to disrupt cell division in the neoplastic
Electrostatic bonding is much more common than covalent bonding in drug-receptor interactions.
Electrostatic bonds vary from relatively strong linkages between permanently charged ionic
molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der
Waals forces and similar phenomena. Electrostatic bonds are weaker than covalent bonds.
Hydrophobic bonds are usually quite weak and are probably important in the interactions of highly
lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with
the internal walls of receptor "pockets."
The specific nature of a particular drug-receptor bond is of less practical importance than the fact
that drugs which bind through weak bonds to their receptors are generally more selective than drugs
which bind through very strong bonds. This is because weak bonds require a very precise fit of the
drug to its receptor if an interaction is to occur. Only a few receptor types are likely to provide such
a precise fit for a particular drug structure. Thus, if we wished to design a highly selective short-
acting drug for a particular receptor, we would avoid highly reactive molecules that form covalent
bonds and instead choose molecules that form weaker bonds.
A few substances that are almost completely inert in the chemical sense nevertheless have
significant pharmacologic effects. For example, xenon, an "inert gas," has anesthetic effects at
elevated pressures.
Drug Shape
The shape of a drug molecule must be such as to permit binding to its receptor site. Optimally, the
drug's shape is complementary to that of the receptor site in the same way that a key is
complementary to a lock. Furthermore, the phenomenon of chirality (stereoisomerism) is so
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common in biology that more than half of all useful drugs are chiral molecules, ie, they exist as
enantiomeric pairs. Drugs with two asymmetric centers have four diastereomers, eg, ephedrine, a
sympathomimetic drug. In the great majority of cases, one of these enantiomers will be much more
potent than its mirror image enantiomer, reflecting a better fit to the receptor molecule. For
example, the (S)(+) enantiomer of methacholine, a parasympathomimetic drug, is over 250 times
more potent than the (R)(–) enantiomer. If one imagines the receptor site to be like a glove into
which the drug molecule must fit to bring about its effect, it is clear why a "left-oriented" drug will
be more effective in binding to a left-hand receptor than will its "right-oriented" enantiomer.
The more active enantiomer at one type of receptor site may not be more active at another type, eg,
a receptor type that may be responsible for some unwanted effect. For example, carvedilol, a drug
that interacts with adrenoceptors, has a single chiral center and thus two enantiomers (Table 1–1).
One of these enantiomers, the (S)(–) isomer, is a potent -receptor blocker. The (R)(+) isomer is
100-fold weaker at the receptor. However, the isomers are approximately equipotent as -receptor
blockers. Ketamine is an intravenous anesthetic. The (+) enantiomer is a more potent anesthetic and
is less toxic than the (–) enantiomer. Unfortunately, the drug is still used as the racemic mixture.
Table 1–1. Dissociation Constants (K d ) of the Enantiomers and Racemate of Carvedilol. 1
Form of
Inverse of Affinity for Receptors
(K d , nmol/L)
Inverse of Affinity for Receptors
(K d , nmol/L)
R (+) enantiomer 14
S (–) enantiomer 16
R,S (+/–)
Note: The K d is the concentration for 50% saturation of the receptors and is inversely proportionate
to the affinity of the drug for the receptors.
1 Data from Ruffolo RR et al: The pharmacology of carvedilol. Eur J Pharmacol 1990;38:S82.
Finally, because enzymes are usually stereoselective, one drug enantiomer is often more susceptible
than the other to drug-metabolizing enzymes. As a result, the duration of action of one enantiomer
may be quite different from that of the other.
Unfortunately, most studies of clinical efficacy and drug elimination in humans have been carried
out with racemic mixtures of drugs rather than with the separate enantiomers. At present, only about
45% of the chiral drugs used clinically are marketed as the active isomer—the rest are available
only as racemic mixtures. As a result, many patients are receiving drug doses of which 50% or more
is either inactive or actively toxic. However, there is increasing interest—at both the scientific and
the regulatory levels—in making more chiral drugs available as their active enantiomers.
Rational Drug Design
Rational design of drugs implies the ability to predict the appropriate molecular structure of a drug
on the basis of information about its biologic receptor. Until recently, no receptor was known in
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