The pharmacodynamic and pharmacokinetic interaction between single doses of flecainide acetate and verapamil: Effects on cardiac function and drug clearance

Abstract

Flecainide and verapamil are antiarrhythmic agents that may be used in combination. We have examined their pharmacodynamic interaction by M-mode echocardiography and electrocardiography in eight normal male volunteers (24 +/- 1.8 years of age). Flecainide decreased the left ventricular ejection fraction (LVEF) (-4.4 +/- 1.2%, p less than 0.008), but verapamil did not. Neither drug affected cardiac output or vascular resistance. Both drugs increased the PR interval (12 +/- 4 msec, p less than 0.01 for flecainide; 12 +/- 5, p less than 0.04 for verapamil). Flecainide, but not verapamil, increased the QTc interval (23 +/- 8 msec, p less than 0.02). Both drugs also increased the systolic time interval ratio (PEPc/LVETc) (0.074 +/- 0.012, p less than 0.0004 for flecainide; 0.029 +/- 0.008, p less than 0.007 for verapamil). The combination of flecainide and verapamil had additive effects on myocardial contractility and on atrioventricular conduction. Verapamil slightly decreased the plasma clearance of flecainide (7.78 +/- 0.60 ml/kg/min for flecainide alone, 7.34 +/- 0.48 ml/kg/min for flecainide and verapamil together, p less than 0.05). On the other hand, flecainide had no effect on the plasma clearance of verapamil, which suggests that there was little interaction between the two drugs on their pharmacokinetic parameters.

Antihypertensive therapy: special focus on drug interactions

“…Similar cardiodepressive effects may be seen with the concurrent use of antiarrhythmics [134] (including amiodarone [132]). A further rare, but dangerous, interaction resulting in atrioventricular-block and hypotension has been reported between clonidine and verapamil [133].…”

“…Class I antiarrhythmics Fleccainide [134] Negative inotropism Impairment of AV-conduction AV-block Heart failure Diltiazem Verapamil Nilvadipine…”

Effects of CYP2D6*10, CYP3A5*3, CYP1A2*1F, and ABCB1 C3435T polymorphisms on the pharmacokinetics of flecainide in healthy Chinese subjects

“…In this retrospective analysis using a Bayesian method, it was estimated that the CL/F in IMs was lower than in homozygous EMs (0.25 ± 0.05 vs. 0.37 ± 0.08 L/h/kg, p < 0.05) among male patients under 70 years old. However, this population analysis involved a range of doses (1.4 -5.0 mg/kg/day) with various dosing frequencies (6) , and some drugs known to affect the pharmacokinetics of fl ecainide, such as digoxin (22) and verapamil (14) might be co-administered; therefore, this comparison may not be accurate. In the present study, we did not fi nd a signifi cant association between CYP2D6*10 and the pharmacokinetics of fl ecainide in this small group of healthy subjects after a single 100-mg dose.…”

“…Although fl ecainide has been considered to be a substrate for CYP2D6, it shows pharmacokinetic interactions with verapamil, suggesting CYP3A or ABCB1 might be involved in the metabolism or disposition of fl ecainide (14) . In the present study, the CYP3A5*3/*3 subjects who had no active CYP3A5 enzyme had a 26 % higher systemic exposure (AUC 0-∞ ) and 17 % lower CL/F of fl ecainide than the combined group of CYP3A5*1/*1 and CYP3A5*1/*3 subjects.…”

“…Amiodarone, a nonspecifi c inhibitor of several CYP enzymes including CYP1A2, CYP2C9, CYP2D6, and CYP3A4, interacts with fl ecainide, resulting in a decreased clearance of fl ecainide by about 30 % , and this interaction was independent of CYP2D6 phenotypes (9) . It has been reported that verapamil, a potent inhibitor of CYP3A and P-glycoprotein (P-gp, gene ABCB1), induced a small but signifi cant decrease in the clearance of fl ecainide (7.78 ± 0.60 vs. 7.34 ± 0.48 mL/kg/min, p < 0.05), suggesting a possible role of CYP3A and/or ABCB1 in the disposition of fl ecainide (14) .…”