Amiodarone: historical development and pharmacologic profile.

Although synthesized as a coronary dilator for use as an antianginal agent over 20 years ago, amiodarone hydrochloride has recently drawn much attention as a potent antiarrhythmic compound for the control of a variety of cardiac dysrhythmias. The rapidly expanding clinical and experimental data continue to emphasize the unusual electrophysiologic, pharmacologic, and especially pharmacokinetic properties of this benzofuran derivative. The compound is a potent coronary dilator and has minimal negative inotropic propensity of a direct nature while exhibiting a mild degree of noncompetitive sympathetic antagonism. Pharmacokinetically, it has a long elimination half-life with a correspondingly long and variable latency of onset of therapeutic effect. Electrophysiologically, the drug has the propensity to lengthen the action potential duration and hence the voltage-dependent effective refractory period in all cardiac tissues after long-term, rather than short-term, administration. It has little effect on depolarization, conduction velocity, or the slow response. The precise ionic mechanisms mediating its effects on repolarization are not known. Clinically, the electrophysiologic effects of the drug differ significantly when it is given by mouth over a longer period and when it is given intravenously, a difference that remains to be explained in terms of mechanism. These differences, however, account for the varying spectrum of the drug's action after single intravenous doses (when its antiarrhythmic effects are essentially explained by the drug's action on the atrioventricular node and possibly its antiadrenergic actions) in comparison to long-term oral administration, which predictably suppresses ectopic activity and lengthens the effective refractory period in all cardiac tissues. These features may account for the drug's remarkable efficacy in the control of supraventricular and ventricular tachyarrhythmias. The safe and rational therapeutic uses of amiodarone as an antiarrhythmic agent presuppose detailed understanding of its manifold pharmacodynamic and pharmacokinetic properties.