Page 18 - Basic _ Clinical Pharmacology ( PDFDrive )

4 SECTION I Basic Principles

Other examples of highly reactive, covalent bond-forming drugs TABLE 1–1 Dissociation constants (K ) of the
d
include the DNA-alkylating agents used in cancer chemotherapy enantiomers and racemate of carvedilol.
to disrupt cell division in the tumor.
Electrostatic bonding is much more common than covalent ` Receptors a Receptors
1
bonding in drug-receptor interactions. Electrostatic bonds vary Form of Carvedilol (K d , nmol/L ) (K d , nmol/L)
from relatively strong linkages between permanently charged R(+) enantiomer 14 45
ionic molecules to weaker hydrogen bonds and very weak induced S(−) enantiomer 16 0.4
dipole interactions such as van der Waals forces and similar R,S(±) enantiomers 11 0.9
phenomena. Electrostatic bonds are weaker than covalent bonds. 1
The K d is the concentration for 50% saturation of the receptors and is inversely
Hydrophobic bonds are usually quite weak and are probably proportionate to the affinity of the drug for the receptors.
important in the interactions of highly lipid-soluble drugs with Data from Ruffolo RR et al: The pharmacology of carvedilol. Eur J Clin Pharmacol
the lipids of cell membranes and perhaps in the interaction of 1990;38:S82.
drugs with the internal walls of receptor “pockets.”
The specific nature of a particular drug-receptor bond is of less Finally, because enzymes are usually stereoselective, one drug
practical importance than the fact that drugs that bind through enantiomer is often more susceptible than the other to drug-
weak bonds to their receptors are generally more selective than metabolizing enzymes. As a result, the duration of action of one
drugs that bind by means of very strong bonds. This is because enantiomer may be quite different from that of the other. Simi-
weak bonds require a very precise fit of the drug to its receptor larly, drug transporters may be stereoselective.
if an interaction is to occur. Only a few receptor types are likely Unfortunately, most studies of clinical efficacy and drug elimina-
to provide such a precise fit for a particular drug structure. Thus, tion in humans have been carried out with racemic mixtures of drugs
if we wished to design a highly selective short-acting drug for a rather than with the separate enantiomers. At present, only a small
particular receptor, we would avoid highly reactive molecules that percentage of the chiral drugs used clinically are marketed as the
form covalent bonds and instead choose a molecule that forms active isomer—the rest are available only as racemic mixtures. As a
weaker bonds. result, most patients receive drug doses of which 50% is less active or
A few substances that are almost completely inert in the inactive. Some drugs are currently available in both the racemic and
chemical sense nevertheless have significant pharmacologic the pure, active isomer forms. However, proof that administration of
effects. For example, xenon, an “inert” gas, has anesthetic effects the pure, active enantiomer decreases adverse effects relative to those
at elevated pressures. produced by racemic formulations has not been established.

Drug Shape Rational Drug Design
The shape of a drug molecule must be such as to permit binding to Rational design of drugs implies the ability to predict the appro-
its receptor site via the bonds just described. Optimally, the drug’s priate molecular structure of a drug on the basis of information
shape is complementary to that of the receptor site in the same way about its biologic receptor. Until recently, no receptor was known
that a key is complementary to a lock. Furthermore, the phenom- in sufficient detail to permit such drug design. Instead, drugs
enon of chirality (stereoisomerism) is so common in biology that were developed through random testing of chemicals or modifica-
more than half of all useful drugs are chiral molecules; that is, they tion of drugs already known to have some effect. However, the
can exist as enantiomeric pairs. Drugs with two asymmetric centers characterization of many receptors during the past three decades
have four diastereomers, eg, ephedrine, a sympathomimetic drug. has changed this picture. A few drugs now in use were developed
In most cases, one of these enantiomers is much more potent than through molecular design based on knowledge of the three-
its mirror image enantiomer, reflecting a better fit to the receptor dimensional structure of the receptor site. Computer programs
molecule. If one imagines the receptor site to be like a glove into are now available that can iteratively optimize drug structures
which the drug molecule must fit to bring about its effect, it is to fit known receptors. As more becomes known about receptor
clear why a “left-oriented” drug is more effective in binding to a structure, rational drug design will become more common.
left-hand receptor than its “right-oriented” enantiomer.
The more active enantiomer at one type of receptor site may Receptor Nomenclature
not be more active at another receptor type, eg, a type that may be The spectacular success of newer, more efficient ways to identify
responsible for some other effect. For example, carvedilol, a drug and characterize receptors (see Chapter 2) has resulted in a variety
that interacts with adrenoceptors, has a single chiral center and of differing, and sometimes confusing, systems for naming them.
thus two enantiomers (Table 1–1). One of these enantiomers, the This in turn has led to a number of suggestions regarding more
(S)(–) isomer, is a potent β-receptor blocker. The (R)(+) isomer rational methods of naming receptors. The interested reader is
is 100-fold weaker at the β receptor. However, the isomers are referred for details to the efforts of the International Union of
approximately equipotent as α-receptor blockers. Ketamine is an Pharmacology (IUPHAR) Committee on Receptor Nomenclature
intravenous anesthetic. The (+) enantiomer is a more potent anes- and Drug Classification (reported in various issues of Pharma-
thetic and is less toxic than the (–) enantiomer. Unfortunately, the cological Reviews and elsewhere) and to Alexander SP et al: The
drug is still used as the racemic mixture. Concise Guide to PHARMACOLOGY 2015/16: Overview.