dogs: evidence for clinically relevant activity of the metabolite

It has been suggested that some of the effects of long-term amiodarone therapy may be due to accumulation of a metabolite, desethylamiodarone. To evaluate the pharmacologic actions of the metabolite, we gave single intravenous doses (10 or 25 mg/kg) of amiodarone or desethylamiodarone to anesthetized dogs. The resulting plasma and myocardial concentrations of both agents were similar to levels achieved with long-term oral amiodarone therapy in man. Amiodarone and desethylamiodarone produced frequency-dependent slowing in ventricular and atrioventricular nodal conduction and increased atrial and ventricular refractory periods. The relative effects of these agents on fastand slowchannel tissues differed, with amiodarone producing significantly greater prolongation of Wenckebach cycle length and desethylamiodarone producing larger increases in QRS duration, atrial refractory period, and ventricular refractory period. We conclude that desethylamiodarone has substantial electrophysiologic effects at clinically relevant concentrations and has relatively greater effect on fast-channel tissue in vivo than does amiodarone. The accumulation of desethylamiodarone probably accounts for some of the delayed electrophysiologic effects amiodarone. Circulation 75, No. 1, 265-271, 1987. AMIODARONE is very effective in the treatment of a wide variety of ventricular and supraventricular arrhythmias. 1-8 Enthusiasm for its use is increasing, but its mechanism of action remains unclear. Long-term therapy with amiodarone results in atrioventricular and intraventricular conduction slowing as well as prolongation of atrial, atrioventricular, and ventricular refractoriness.8 16 In contrast, single-dose administration of amiodarone depresses atrioventricular (AV) nodal properties but has little or no effect on atrial and ventricular refractoriness despite the achievement of equivalent plasma and myocardial amiodarone concentrations.9 10, 17, 18 The different effects of single-dose administration From the Departments of Pharnacology and Therapeutics and Medicine, McGill University, and the Divisions of Cardiology and Clinical Pharmacology, Montreal General Hospital, Montreal. Supported by operating grants from the Medical Research Council of Canada and the Quebec Heart Foundation. Dr. Talajic is a Canadian Heart Foundation Research Fellow, and Dr. Nattel is an MRC Research Scholar. Address for correspondence: Stanley Nattel, M.D., Department of Pharmacology and Therapeutics, McIntyre Medical Sciences Bldg., 3655 Drummond, Montrdal, Quebec H3G 1Y6, Canada. Received July 14, 1986; revision accepted Sept. 4, 1986. Vol. 75, No. 1, January 1987 in patients receiving long-term treatment with of amiodarone compared with long-term therapy may be due to time-dependent changes in thyroid status, 19 20 delayed biochemical effects,21 or the accumulation of an active metabolite. Desethylamiodarone, a major metabolite of amiodarone, accumulates significantly in the plasma and myocardium of patients on long-term amiodarone therapy.2224To date, little is known about desethylamiodarone's electrophysiologic actions, although it has been found to be more potent than amiodarone in prolonging QRS, QT, and QTc intervals in rats after both shortand long-term administration.25 Preliminary results have been presented showing that intravenous desethylamiodarone suppresses inducible ventricular arrhythmias after experimental myocardial infarction in dogs.26 However, no information concerning the effects of desethylamiodarone on myocardial refractoriness and conduction is available. Since changes in myocardial conduction and refractoriness are typically delayed after oral loading doses of amiodarone, accumulation of the N-desethyl metabolite may be partly responsible for these delayed changes. The purpose of this study was to evaluate the initial electrophysiologic effects of desethylami265 by gest on A ril 8, 2017 http://ciajournals.org/ D ow nladed from