Quinidine-enhanced β-blockade during treatment with propafenone in extensive metabolizer human subjects

Abstract

Propafenone, a sodium channel blocking antiarrhythmic drug with beta-blocking properties, is metabolized to non-beta-blocking metabolites in part by cytochrome P4502D6. Subtherapeutic doses of quinidine inhibit P4502D6 and increase plasma propafenone in extensive metabolizer subjects, in whom the active enzyme is present. In this study we tested the hypothesis that quinidine would enhance beta-blockade in extensive metabolizers receiving propafenone. Seven extensive and two poor metabolizers received propafenone (225 mg orally every 8 hours) plus quinidine sulfate (60 mg orally every 8 hours) or propafenone plus placebo for 7 days in a randomized, double-blind, crossover fashion. In extensive metabolizers, the coadministration of quinidine significantly increased the extent of propafenone-induced beta-blockade, assessed by a decrease in exercise heart rate and by sensitivity to isoproterenol. We conclude that low-dose quinidine enhances propafenone-induced beta-blockade in extensive metabolizers. Thus the polymorphic patterns of drug metabolism can result in clinically significant drug interactions on a genetic basis.

Electrophysiological properties of the propafenone-analogue GE 68 (1-[3-(phenylethyl)-2-benzofuryl]-2-(propylamino)-ethanol) in isolated preparations and ventricular myocytes of guinea-pig hearts

“…With GE 58 this type of proarrhythmic activity was not found in spontaneously beating Purkinje fibres of the guinea pig. Whether the lack of b-adrenoceptor blocking activity is advantageous remains to be discussed, since on the one hand in some patients a b-adrenoceptor blocking effect might cause severe side effects (Hill et al 1986;Harron and Brogden 1987;Stoschitzky et al 1990; Morike and Roden 1994;Viana et al 1994), but on the other hand it is assumed that b-blockade can reduce the proarrhythmic tendency of 1C drugs (Vaughan Williams 1991).…”

“…asthma, since racemic propafenone can provoke bronchospasm (Hill et al 1986). Due to the b-blocking activity of propafenone haemodynamic parameters might be influenced during anaesthesia with halothane or isoflurane (Viana et al 1994), and quinidine is able to enhance the b-blocking effect of propafenone in extensive metabolizer human subjects (Morike and Roden 1994). In human a major part of the depression of the rate pressure product by racemic propafenone appears to be the result of b-adrenoceptor antagonist activity (Stoschitzky et al 1990).…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…CYP2D6 status is generally thought to matter little for antiarrhythmic effect (Siddoway et al, 1987;Labbe et al, 2000), although some studies have suggested greater efficacy in those with reduced CYP2D6 activity (Jazwinska-Tamawska et al, 2001;Cai et al, 2002). PMs may be predisposed to more central nervous system adverse effects (76 versus 14% in EMs) (Siddoway et al, 1987) and greater ␤-blockade (Lee et al, 1990;Morike and Roden, 1994), although the latter result has been contradicted (Labbe et al, 2000). There is a case report of toxicity (dizziness and bradycardia) in a PM (Morike et al, 1995).…”

Fluoxetine impairs the CYP2D6-mediated metabolism of propafenone enantiomers in healthy Chinese volunteers

“…A previous study in white subjects found that low‐dose quinidine, a potent inhibitor of CYP2D6, increased total propafenone plasma concentration in patients with arrhythmia but caused no changes in QRS interval 13 . Another pharmacodynamic study showed that low‐dose quinidine significantly increased the extent of propafenone‐induced β‐blockade 14 . However, there has been no report concerning potential impairment of propafenone metabolism by fluoxetine either in white subjects or in Chinese subjects.…”