Clinical pharmacology of antiarrhythmic drugs: variability of metabolism and dose requirements

Abstract

The clinical use of the presently available antiarrhythmic agents is rendered difficult by narrow therapeutic ranges, highly variable drug elimination kinetics, and complex dose-concentration-effect relations. Because of their electrophysiological mechanisms of action, these drugs may produce proarrhythmic effects, conduction disturbances, and myocardial depression even at the assumed optimum therapeutic serum levels. Several antiarrhythmic drugs, such as procainamide, quinidine, propafenone, encainide, and amiodarone, are transformed to pharmacologically active metabolites, which may contribute to their antiarrhythmic and toxic effects. In addition to marked genetic differences in hepatic metabolism rates (polymorphic hydroxylation and acetylation), some drugs, e.g., quinidine, propafenone, and amiodarone, produce an inhibition of hepatic metabolizing enzymes and thus cause practically relevant drug interactions. A careful dosage adaptation in individual patients is therefore required to achieve maximum therapeutic benefit and to reduce the risk of unwanted side effects. Serum drug concentration measurements may contribute to an improved use of antiarrhythmic agents, but monitoring alone does not replace the electrophysiological assessment of therapeutic efficacy.