Clinical pharmacology and beta-blocking efficacy of propafenone

Abstract

Propafenone, like encainide and flecainide, is an antiarrhythmic drug characterized by slow kinetics of interaction with cardiac sodium channels. In addition, it shares structural similarities with propranolol and has been shown to exert consistent beta-blocking action in vitro. On the other hand, the extent of beta-blockade noted after oral administration of propafenone in vivo has been reported to range from undetectable to clinically significant. Although the explanation for this discrepancy was initially unclear, recent work has convincingly demonstrated that the degree of beta-blockade during propafenone therapy reflects genetically determined variations in the metabolism of the parent drug, which has greater beta-blocking potency than do its metabolites. At lower dosages, beta-blockade is significantly greater and more likely to be clinically noticeable in the small percentage of patients who have poor metabolism and in whom deficient 5-hydroxylation is associated with higher plasma propafenone concentrations. Because this metabolic pathway is saturable, at the usual highest clinical dosage (900 mg/24 h) plasma propafenone concentration rises disproportionately in patients with normal 5-hydroxylation, and more comparable degrees of beta-blockade are noted in both metabolizer types. Beta-blockade during propafenone therapy, which can contribute both to the genesis of side effects and to the suppression of arrhythmias, is a potentially important drug effect that can largely be predicted by genetic variations in the metabolism of the drug.