Mechanism of the delayed onset of action after intravenous amiodarone for treatment of ventricular arrhythmias

Abstract

AbstractThe onset of action of intravenous amiodarone (AM) for treatment of ventricular arrhythmias often occurs after at least several hours' delay. To investigate the mechanism of this delayed action, we gave i.v. AM at an initial loading dose of 2.5 mg/kg or 5.0 mg/kg over 10 min, followed immediately by infusion of 7.5 μg/kg.min or 10 μg/kg.min for 20 h in eight dogs. The concentration of AM and its major metabolite, N‐desethylamiodarone (DA), in plasma and myocardial tissue were determined immediately after the loading dose and at 20 h after infusion, respectively, while electrophysiologic parameters were measured at the same times. The concentration of AM and DA in plasma were also determined serially. The results showed that the concentration of AM or DA in plasma or myocardial tissue rose to the peak level within 5–15 min after the loading dose, the sinus cycle length and AV conduction Wenckebach point measured at this time increased significantly relative to baseline (P<0.05), while the ventricular effective refractory period (VERP) and ventricular exciting time (VET) at this time did not increase significantly (P>0.05). The concentration of AM or DA in plasma declined rapidly during the continuous infusion period and remained at a stable low level until infusion stopped. The concentration of AM or DA in the myocardial tissue at 20 h after continuous infusion was lower than immediately after the loading dose. The sinus cycle length and AV conduction Wenckebach point were shortened close to the baseline level, while the VERP and VET were unchanged 20 h after infusion. The delayed onset of action for treatment of ventricular arrhythmias after i.v. administration of AM cannot be explained by higher concentration of AM or its metabolite in myocardial tissue. The specific mechanism(s) of action of i.v. AM in its control of arrhythmias remain to be determined. Drug Dev. Res. 58:145–148, 2003. © 2003 Wiley‐Liss, Inc.