Electrophysiologic effects of amiodarone: Experimental and clinical observation relative to serum and tissue drug concentrations

Abstract

Oral amiodarone is a potent antiarrhythmic agent with a slow onset of action. Its electrophysiologic properties following chronic administration are well known, but its acute electrophysiologic actions are poorly defined. The objectives of the present study were to correlate the electrophysiologic actions of intravenous amiodarone in humans with the acute and chronic effects of the drug relative to plasma and tissue concentrations of the drug. In humans (n = 10), 5 mg/kg intravenous amiodarone (serum concentration 6.50 ± 3.34 μg/ml at 10 minutes; 2.13 ± 0.71 μg/ml at 20 minutes, n = 7) increased the AH interval by 16.4% (p < 0.005), the antegrade effective refractory period (ERP) of the atrioventricular (AV) node by 14.4% (p < 0.025), and the functional refractory period (FRP) of the AV node by 15.5% (p < 0.005). The ERP or FRP of the atrium of the right ventricle was not significantly changed; there was no effect on the HV interval or the QT and R-R intervals of the ECG. In rabbits (n = 11) given 10 mg/kg intravenous amiodarone (mean ± SD serum concentration 0.49 ± 0.17 μg/ml; mean myocardial concentration 7.0 ± 1.9 μg/gm, n = 3), there were no significant effects on the ECG intervals. In isolated rabbit sinoatrial (SA) node, atria, and AV node (three preparations) superfused with 5 × 10⁻⁶ M amiodarone (3.41 μg/ml), there was no effect on the action potential duration (APD) or other parameters of the transmembrane potential. Rabbits chronically pretreated with amiodarone (20 mg/kg intraperitoneally) for 3 weeks had serum drug concentrations of 0.98 ± 0.52 μg/ml (n = 4) and myocardial levels of 11.52 ± 7.2 μg/gm at 3 weeks and 0.50 ± 0.18 μg/ml and 14.8 ± 6.4 μg/gm, respectively, at 6 weeks. Compared to the values in control series, the spontaneous cycle length of the SA node was prolonged by 24% (p < 0.05) at 3 weeks and 35.5% (p < 0.01) at 6 weeks. The Vmax was affected in none of the tissues but APD was significantly lengthened in all. In atria the APD was increased by 27.6% (p < 0.01) at 3 weeks and 32.8% (p < 0.01) at 6 weeks; in ventricular muscle the corresponding values were 11.0% (p < 0.05) and 25.3% (p < 0.01). Our clinical and experimental data indicate major differences between the chronic and acute electrophysiologic effects of amiodarone, differences which are relevant to the interpretation of the antiarrhythmic actions of the drug following intravenous and oral adminitration.