Flecainide Toxicity: Reversal of Drug Effects by Isoproterenol Infusion

Partial Reversal of Flecainide Toxicity by Isoproterenol.Introduction: Toxic levels of flecainide can cause life-threatening electrophysiologic and hemodynamic changes. Isoproterenol is known to reverse therapeutic drug effects in patients with ventricular and supraventricular tachycardias. In a single cell preparation it appears that isoproterenol increases inward Na current and it is conceivable that isoproterenol may also be capable of decreasing the electrophysiologic effects of flecainide toxicity. This study was aimed at detailed characterization of the electrophysiologic changes induced by toxic levels of flecainide, the extent that isoproterenol may reverse these changes, and the effect of beta blockade on these changes. Methods and Results: In this experimental model, using the strength-interval stimulation method, conduction time, and epicardial activation times, we defined the changes in conduction, refractoriness, and excitability caused by toxic levels of flecainide (> 3 μg/mL), during infusions of flecainide and isoproterenol, and lastly, these infusions and propranolol. In nine dogs, using atrial and ventricular stimulation at pacing rates of 120 and 210 beats/min, atrioventricular conduction, right ventricular refractoriness, and conduction changes were evaluated at baseline and following isoproterenol infusion (0.09 μg/kg/min), flecainide infusion (4 mg/kg followed by 5 mg/kg/hr), flecainide combined with isoproterenol infusion, and lastly, flecainide, isoproterenol, and propranolol (0.2 mg/kg). Compared to baseline, toxic levels of flecainide (3.71-3.86 μg/mL) produced a 64% and 93% increase in the atrial-His interval at pacing rates of 120 and 210 beats/minute, respectively. Isoproterenol reversed 15% and 55% of this prolongation. The His-ventricular conduction was prolonged by 82% and 124% after flecainide at 120 and 210 beats/min, respectively. These changes were reversed by 29% and 53% with isoproterenol. With flecainide, the relative and effective refractory periods of the ventricular myocardium (during right ventricular pacing) were lengthened by 16% and 19%, respectively, and reversed to baseline values following isoproterenol. None of the ventricular electrophysiologic parameters altered by flecainide were significantly affected with increasing pacing rate. The QRS complex duration increased by 59% with flecainide, and isoproterenol reversed 30% of this increase. Left ventricular (LV) activation time during right ventricular (RV) pacing increased by 88% with flecainide, 59% of which was reversed by isoproterenol. Propranolol resulted in complete elimination of the isoproterenol-produced partial reversal of flecainide toxicity. RV diastolic pacing threshold was raised by 61% with flecainide, but this effect was not reversed with isoproterenol. Conclusion: It is concluded that at least 30% of the toxic effects of flecainide can be reversed by isoproterenol. Such reversal may be useful in treating flecainide toxicity. Pacing threshold, however, does not improve with isoproterenol, and all the isoproterenol effects are abolished by propranolol. The electrophysiologic effects of toxic levels of flecainide were further aggravated with the addition of propranolol.