The antiarrhythmic efficacy of amiodarone and desethylamiodarone, alone and in combination, in dogs with acute myocardial infarction.

Abstract

Antiarrhythmic activity of amiodarone's desethyl metabolite, which accumulates during oral amiodarone therapy, has been postulated to explain the delayed onset of antiarrhythmic effects during long-term amiodarone therapy. To determine their relative antiarrhythmic efficacy, amiodarone and its desethyl metabolite, desethylamiodarone, were administered to mongrel dogs with ventricular tachycardia 24 hr after ligation of the left anterior descending coronary artery. Cumulative doses of amiodarone, desethylamiodarone, a combination of amiodarone and desethylamiodarone, or the vehicle for drug administration were given at 1 hr intervals. Both amiodarone and desethylamiodarone suppressed ventricular arrhythmias in a dose-dependent fashion. The metabolite, however, was more potent with a 50% elfective concentration for suppression of premature ventricular complexes of 1.4 mg/liter compared with 4.6 mg/liter for the parent compound. Plasma and myocardial drug concentrations were similar to those measured during long-term amiodarone therapy in man, with desethylamiodarone producing greater myocardial concentrations than amiodarone for a given plasma concentration. Coadministration of the metabolite along with the parent drug resulted in suppression of arrhythmias at lower doses of amiodarone than when the latter was administered alone, and concentration-response analysis indicated an additive antiarrhythmic effect. These experiments suggest that the accumulation of desethylamiodarone that occurs with long-term oral amiodarone therapy contributes importantly to the antiarrhythmic effects of the drug, and may account for the gradual increase in antiarrhythmic action during the course of amiodarone therapy. Circulation 77, No. 1, [200][201][202][203][204][205][206][207][208] 1988

Efficacy, Safety, and Determinants of Conversion of Atrial Fibrillation and Flutter With Oral Amiodarone

“…[21][22][23] The present study showed that for conversion of atrial fibrillation, plasma concentrations of desethylamiodarone were more important than those of the parent compound. This is in agreement with previous studies 24 and is possibly related to a high myocardium/plasma concentration ratio in the case of desethylamiodarone. 25 In contrast, reduction of the ventricular rate during ongoing atrial fibrillation was clearly correlated with plasma levels of amiodarone itself.…”

Hemodynamic and Electrocardiographic Effects of Graded Doses of Amiodarone in Healthy Dogs Anesthetized with Morphine/Alpha Chloralose

“…Eight additional studies have been conducted on the electrophysiologic effects of amiodarone in dogs; however, all dogs in those studies were anesthetized with sodium pentobarbital, making comparisons with our data inappropriate. 20,[23][24][25][26][27][28][29][30] Ware and colleagues 10 compared cardiovascular parameters after graded doses to a predose measurement. They found that dP/dt max , ejection fraction, and end-systolic elastance (E max ) decreased slightly after a dose 10 mg/kg, while LV end-diastolic pressure increased slightly.…”

Hepatotoxicity After Continuous Amiodarone Infusion in a Postoperative Cardiac Infant

“…Metabolite serum concentrations rival the parent compound in chronic therapy, and animal studies suggest 70% of the antiarrhythmic effect of amiodarone may be attributed to this active metabolite. 8 The volume of distribution is large, with adipose tissue as a major site of collection. 9 When therapy is begun, the drug redistributes into peripheral tissues 80 times faster than it is eliminated from the body, making continuous IV infusion the most efficient means of maintaining stable serum concentrations.…”