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 administered, guided by careful monitoring of effect (measurements of blood coagulation or serum glucose) and aided by ancillary measures (avoiding tissue trauma that may lead to hemorrhage; regulation 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 produce optimal benefit. In such situations, it may be necessary to add another drug to the treatment regimen. In treating hypertension, for example, administration of a second drug often allows the prescriber to reduce the dose and toxicity of the first drug (see Chapter 11).
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 glucocorticoid 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, adjunctive 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 immunosuppressive 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 administration 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 in this chapter and are described in detail in later chapters. Many receptors, such as catecholamines, histamine, acetylcholine, and corticosteroids, and their associated therapeutic uses were discovered by analyzing effects of the physiologic chemical signals. This approach continues to be fruitful. For example, mis-expression of microRNAs (miRNAs), small RNAs that regulate protein expression by binding to protein-coding (messenger) RNAs, was linked recently to Duchenne muscular dystrophy. Current preclinical investigations include the utility of RNA-based therapy for this and other diseases.
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 phenothiazine anti-psychotics. Often such agents turn out to interact with receptors for endogenous substances (eg, opioids and phenothiazines for endogenous opioid and dopamine receptors, respectively). This approach is evolving toward understanding the structural details of how chemically similar agents differ in binding to receptors. For example, X-ray crystallography of β1 and β2 adrenoceptors shows that their orthosteric binding sites are identical; drugs discriminate between subtypes based on differences in traversing a divergent “vestibule” to access the orthosteric site. Many GPCRs have such passages, revealing a new basis for improving the selectivity of GPCR-targeted drugs.