Clinical Selectivity: Beneficial
versus Toxic Effects of Drugs
we classify drugs according to their principal actions, it is clear that no drug causes only a single, specific
effect. Why is this so? It is exceedingly unlikely that any kind of drug
molecule will bind to only a single type of receptor molecule, if only because
the number of potential receptors in every patient is astronomi-cally large.
Even if the chemical structure of a drug allowed it to bind to only one kind of
receptor, the biochemical processes controlled by such receptors would take
place in many cell types and would be coupled to many other biochemical
functions; as a result, the patient and the prescriber would probably perceive
more than one drug effect. Accordingly, drugs are only selective— rather than specific—in their actions, because they bind
to one or a few types of receptor more tightly than to others and because these
receptors control discrete processes that result in distinct effects.
is only because of their selectivity that drugs are useful in clinical
medicine. Selectivity can be measured by comparing bind-ing affinities of a
drug to different receptors or by comparing ED50s for different
effects of a drug in vivo. In drug development and in clinical medicine,
selectivity is usually considered by separating effects into two categories: beneficial or therapeutic effects ver-sus toxic
or adverse effects. Pharmaceutical
advertisements and prescribers occasionally use the term side effect, implying that the effect in question is insignificant
or occurs via a pathway that is to one side of the principal action of the
drug; such implications are frequently erroneous.
of the serious drug toxicity in clinical practice represents a direct
pharmacologic extension of the therapeutic actions of the drug. In some of
these cases (eg, bleeding caused by anticoagulant therapy; hypoglycemic coma
due to insulin), toxicity may be avoided by judicious management of the dose of
drug adminis-tered, guided by careful monitoring of effect (measurements of
blood coagulation or serum glucose) and aided by ancillary mea-sures (avoiding
tissue trauma that may lead to hemorrhage; regula-tion of carbohydrate intake).
In still other cases, the toxicity may be avoided by not administering the drug
at all, if the therapeutic indication is weak or if other therapy is available.
certain situations, a drug is clearly necessary and beneficial but produces
unacceptable toxicity when given in doses that pro-duce optimal benefit. In
such situations, it may be necessary to add another drug to the treatment
regimen. In treating hyperten-sion, for example, administration of a second
drug often allows the prescriber to reduce the dose and toxicity of the first
drugs produce both their desired effects and adverse effects by acting on a
single receptor type in different tissues. Examples discussed in this book
include: digitalis glycosides, which act by inhibiting Na+/K+-ATPase in cell
membranes; methotrexate, which inhibits the enzyme dihydrofolate reductase; and
therapeutic strategies are used to avoid or mitigate this sort of toxicity.
First, the drug should always be administered at the lowest dose that produces
acceptable benefit. Second, adjunc-tive drugs that act through different
receptor mechanisms and produce different toxicities may allow lowering the
dose of the first drug, thus limiting its toxicity (eg, use of other immunosup-pressive
agents added to glucocorticoids in treating inflammatory disorders). Third,
selectivity of the drug’s actions may be increased by manipulating the
concentrations of drug available to receptors in different parts of the body,
for example, by aerosol administra-tion of a glucocorticoid to the bronchi in
advantages resulting from new chemical entities with improved receptor
selectivity were mentioned earlier and
are described in detail in later. Such drugs include α-and β-selective adrenoceptor agonists and
antagonists, H1 and H2 antihistamines, nicotinic and
muscarinic blocking agents, and receptor-selective steroid hormones. All these
receptors are grouped in functional families, each responsive to a small class
of endog-enous agonists. The receptors and their associated therapeutic uses
were discovered by analyzing effects of the physiologic chemical
signals—catecholamines, histamine, acetylcholine, and corticosteroids.
other drugs were discovered by exploiting therapeutic or toxic effects of
chemically similar agents observed in a clinical context. Examples include
quinidine, the sulfonylureas, thiazide diuretics, tricyclic antidepressants,
opioid drugs, and phenothiaz-ine antipsychotics. Often the new agents turn out
to interact with receptors for endogenous substances (eg, opioids and
phenothiaz-ines for endogenous opioid and dopamine receptors, respectively). It
is likely that other new drugs will be found to do so in the future, perhaps
leading to the discovery of new classes of receptors and endogenous ligands for
future drug development.
the propensity of drugs to bind to different classes of receptor sites is not
only a potentially vexing problem in treat-ing patients, it also presents a
continuing challenge to pharma-cology and an opportunity for developing new and
more useful drugs.