Clinical Selectivity: Beneficial versus Toxic Effects of Drugs

Clinical Selectivity: Beneficial versus Toxic Effects of Drugs

Although 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.

It 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.

A. Beneficial and Toxic Effects Mediated by the Same Receptor-Effector Mechanism

Much 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.

In 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 drug .

B. Beneficial and Toxic Effects Mediated by Identical Receptors but in Different Tissues or by Different Effector Pathways

Many 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 glucocor-ticoid hormones.

Three 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 asthma.

C. Beneficial and Toxic Effects Mediated by Different Types of Receptors

Therapeutic 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.

Several 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.

Thus, 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.