BACKGROUND: Type I antiarrhythmic drugs block the cardiac sodium channel in a use-dependent fashion. This use-dependent behavior causes increased drug binding and consequently increased sodium channel blockade at faster stimulation rates. Importantly, the kinetics of drug association and dissociation from the sodium channel differ for each type I antiarrhythmic drug. METHODS AND RESULTS: Thirty-five patients receiving type I antiarrhythmic drugs for the treatment of sustained monomorphic ventricular tachycardia (VT) were studied before and after drug therapy. A total of 41 drug studies were performed (lidocaine, n = 10; procainamide, n = 16; flecainide, n = 15). Sustained monomorphic VT of an identical electrocardiographic morphology was induced during the control and follow-up drug studies. During the control study, there was no significant change in the VT cycle length over time. Compared with control, significant prolongation of the onset VT cycle length was observed after treatment with procainamide and flecainide (increase of 52 +/- 24 and 80 +/- 49 msec, respectively) but not after treatment with lidocaine (increase of 8 +/- 37 msec). Additional drug-induced prolongation of the VT cycle length occurred during a 40-second observation period. This secondary "use-dependent" cycle length prolongation contributed significantly to the steady-state VT cycle length during treatment with flecainide (increase of 82 +/- 34 msec; p < 0.0001). Although a use-dependent increase in VT cycle length was observed with procainamide and lidocaine, the increase was not statistically significant (increase of 12 +/- 15 and 8 +/- 8 msec, respectively). The estimated time constants for the onset of use-dependent VT cycle length prolongation were distinctly different for the three drugs. Flecainide's prolongation of the VT cycle length occurred slowly, with an estimated time constant of 12.5 +/- 5.0 seconds. In contrast, the time course of VT cycle length prolongation was rapid during treatment with lidocaine and intermediate during treatment with procainamide (time constants of 0.52 +/- 0.51 and 4.0 +/- 1.3 seconds, respectively). CONCLUSIONS: Use-dependent prolongation of VT cycle length during treatment with type I antiarrhythmic drugs was observed in humans. This effect was clinically significant during treatment with flecainide (i.e., the use-dependent slowing of the heart rate improved the hemodynamic tolerance of the arrhythmia). Finally, the estimated time constants for the use-dependent prolongation of VT cycle length by the three test drugs are similar to their reported in vitro time constants for use-dependent sodium channel blockade.
BACKGROUND: Type I antiarrhythmic drugs block the cardiac sodium channel in a use-dependent fashion. This use-dependent behavior causes increased drug binding and consequently increased sodium channel blockade at faster stimulation rates. Importantly, the kinetics of drug association and dissociation from the sodium channel differ for each type I antiarrhythmic drug. METHODS AND RESULTS: Thirty-five patients receiving type I antiarrhythmic drugs for the treatment of sustained monomorphic ventricular tachycardia (VT) were studied before and after drug therapy. A total of 41 drug studies were performed (lidocaine, n = 10; procainamide, n = 16; flecainide, n = 15). Sustained monomorphic VT of an identical electrocardiographic morphology was induced during the control and follow-up drug studies. During the control study, there was no significant change in the VT cycle length over time. Compared with control, significant prolongation of the onset VT cycle length was observed after treatment with procainamide and flecainide (increase of 52 +/- 24 and 80 +/- 49 msec, respectively) but not after treatment with lidocaine (increase of 8 +/- 37 msec). Additional drug-induced prolongation of the VT cycle length occurred during a 40-second observation period. This secondary "use-dependent" cycle length prolongation contributed significantly to the steady-state VT cycle length during treatment with flecainide (increase of 82 +/- 34 msec; p < 0.0001). Although a use-dependent increase in VT cycle length was observed with procainamide and lidocaine, the increase was not statistically significant (increase of 12 +/- 15 and 8 +/- 8 msec, respectively). The estimated time constants for the onset of use-dependent VT cycle length prolongation were distinctly different for the three drugs. Flecainide's prolongation of the VT cycle length occurred slowly, with an estimated time constant of 12.5 +/- 5.0 seconds. In contrast, the time course of VT cycle length prolongation was rapid during treatment with lidocaine and intermediate during treatment with procainamide (time constants of 0.52 +/- 0.51 and 4.0 +/- 1.3 seconds, respectively). CONCLUSIONS: Use-dependent prolongation of VT cycle length during treatment with type I antiarrhythmic drugs was observed in humans. This effect was clinically significant during treatment with flecainide (i.e., the use-dependent slowing of the heart rate improved the hemodynamic tolerance of the arrhythmia). Finally, the estimated time constants for the use-dependent prolongation of VT cycle length by the three test drugs are similar to their reported in vitro time constants for use-dependent sodium channel blockade.