blockers).

Interactions Based on Distribution and Binding

Distribution of a drug can be altered by other drugs that compete for binding sites on plasma proteins. For example, antibacterial sulfonamides can displace methotrexate, phenytoin, sulfonylureas, and warfarin from binding sites on albumin. However, it is difficult to document many clinically significant interactions of this type, and they seem to be the exception rather than the rule. Changes in drug distribution can occur if one agent alters the size of the physical compartment in which another drug distributes. For example, diuretics, by reducing total body water, can increase plasma levels of aminoglycosides and lithium, possibly enhancing drug toxicities.

Interactions Based on Metabolic Clearance

Drug interactions of this type are well documented and have considerable clinical significance. The metabolism of many drugs can be increased by other agents that induce hepatic drug-metabolizing enzymes, especially cytochrome P450 isozymes. Induction of drug-metabolizing enzymes occurs predictably with the chronic administration of barbiturates, carbamazepine, ethanol, phenytoin, or rifampin. Conversely, the metabolism of some drugs may be decreased by other drugs that inhibit drug-metabolizing enzymes. Such inhibitors of drug-metabolizing enzymes include cimetidine, disulfiram, erythromycin, furanocoumarins (in grapefruit juice), ketoconazole, quinidine, ritonavir, and sulfonamides. The CYP3A4 isozyme of cytochrome P450, the dominant form in the human liver, is particularly sensitive to such inhibitory actions.

Drugs that reduce hepatic blood flow (eg, propranolol ) may reduce the clearance of other drugs metabolized in the liver, especially those subject to flow-limited hepatic clearance such as morphine and verapamil.

A modified form of an interaction based on metabolic clearance results from the ability of some drugs to increase the stores of endogenous substances by blocking their metabolism. These endogenous compounds may subsequently be released by other exogenous drugs, resulting in an unexpected action. The best-documented reaction of this type is the sensitization of patients taking MAO inhibitors to indirectly acting sympathomimetics (eg, amphetamine, phenylpropanolamine). Such patients may suffer a severe hypertensive reaction in response to ordinary doses of cold remedies, decongestants, and appetite suppressants.

D. Interactions Based on Renal Function

Excretion of drugs by the kidney can be changed by drugs that reduce renal blood flow (eg, blockers) or inhibit specific renal transport mechanisms (eg, the action of aspirin on uric acid secretion in the proximal tubule). Drugs that alter urinary pH can alter the ionization state of drugs that are weak acids or weak bases, leading to changes in renal tubular reabsorption.

Skill Keeper: Warfarin

(See Chapter 34)

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