Electrophysiologic effects of flecainide relative to serum and tissue concentrations in rabbits after chronic drug administration.
The effects of chronic treatment with flecainide on the cellular electrophysiology and the relationship of the electrophysiologic effects to serum and myocardial flecainide concentrations were determined in rabbit ventricular myocardium. Two groups of rabbits were administered flecainide at doses of 7.5 mg/kg body weight (dose I) and 20 mg/kg body weight (dose II) intraperitoneally (i.p.) twice daily for 12-14 days; a third group received saline. Serum and myocardial flecainide concentrations with dose II (0.44 +/- 0.15 micrograms/ml and 3.0 +/- 1.4 micrograms/g, respectively) were significantly (p less than 0.01) higher than with dose I (0.19 +/- 0.11 micrograms/ml and 0.81 +/- 0.15 micrograms/g, respectively). At 1.0-Hz stimulation, only the high dose produced significant changes in transmembrane action potentials of right ventricular myocardial fibers, which showed a 17.6% (n = 6, p less than 0.05) decrease in maximal upstroke velocity (Vmax) of phase 0 and 19.5% (n = 6, p less than 0.05) prolongation of effective refractory period (ERP). Repetitive stimuli led to an exponential decline in Vmax with both dosage regimens. The magnitude of Vmax decrease was frequently dependent and was greater with the higher dose. The rate of decrease of Vmax per action potential (AP) during train of stimuli in rabbits treated with dose II was 0.037 +/- 0.012 (n = 5) at 2.0-Hz stimulation, and the recovery time constant from use-dependent block at 4.0-Hz stimulation increased significantly from 12.6 +/- 3.6% decrease in Vmax with the low dose to 35.6 +/- 7.1% decrease with the high dose. The data show that sodium channel inhibition by chronic flecainide administration is a function of dose, serum, and myocardial flecainide concentrations.
Kamiya
K
K
Cardiology Section, Wadsworth VA Hospital, Los Angeles, California 90073.
Kannan
R
R
Matin-Asgari
A
A
Singh
B N
BN
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D005260:Female; D005424:Flecainide / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008564:Membrane Potentials / Q000187:drug effects; D011817:Rabbits
D005424:Flecainide