Pharmacodynamics and side effects of flecainide acetate

Abstract

We compared side effects with flecainide trough levels and ECG intervals among 43 patients who received flecainide for up to 34 months. Flecainide plasma levels were higher when associated with cardiovascular side effects (mean 1063 ng/ml; range 296 to 2050 ng/ml) than when no side effects occurred (mean 609 ng/ml; range 89 to 1508 ng/ml; P less than 0.001). The PR interval (P less than 0.001), QRS interval (P less than 0.001), and the rate-corrected QT interval (P less than 0.001) were greater at the time of cardiovascular side effects, but the rate-corrected JT interval was not. The therapeutic-toxic window for flecainide plasma level was 381 ng/ml (at least 50% probability of efficacy) to 710 ng/ml (less than 10% probability of cardiovascular side effects). The risk of cardiovascular side effects increases at higher plasma levels of flecainide and is associated with greater increases in the PR and QRS intervals from baseline than are routinely observed during flecainide dosing.

Cardiac Ultrarapid Delayed Rectifiers

“…The voltage dependence of block indicates a favored interaction with the open state, along with additional voltage dependence pointing to a site of action exposed to about 23% of the membrane voltage field from the inside. Flecainide does not affect I Kur at concentrations up to 10 ÌM (upper limit of therapeutic range is 2 ÌM) [50], and propafenone is similarly a weak I Kur blocker at substantially supratherapeutic concentrations [51]. Quinidine's effect on human I Kur is age-independent, in contrast to its effects on I to which show developmental alterations [52].…”

A high performance liquid chromatographic method for the quantitation of flecainide in plasma

“…Flecainide acetate [2,5-di(2,2,2-trifluoroethoxy)-N-(2-piperidylmethy1)benzamide acetate] has been shown to markedly suppress ventricular and supraventricular rhythm disorders (Duff et al, 1981;Conard et al, 1982; Crozier et at., 1987;Salerno et al, 1986;Zeigler et al, 1988). Because of the wide range of concentrations of flecainide acetate seen in the serum of patients exhibiting >90% suppression of ventricular ectopic beats (200-1000 pg/L) (Duff et al, 1981;Anderson el al., 1981;Hodges et al, 1982) and the apparent increased risk of proarrhythmic effects at serum concentrations >lo00 pg/L (Morganroth and Horowitz, 1984), monitoring of drug concentrations will be likely to play a role in the management of patients treated with this drug.…”

Stereoselective disposition of flecainide in relation to the sparteine/debrisoquine metaboliser phenotype.

“…Were this subject to develop renal failure during flecainide administration, both routes of elimination would be impaired. Consequently at standard doses of flecainide, very high plasma concentrations may be attained, which could in turn have proarrhythmic effects (Salerno et al, 1986 (Gaedigk & Eichelbaum, 1989 …”

“…It has been established recently that Woosley, 1986). In up to 20% of patients, pro-the metabolism of flecainide cosegregates with arrhythmic effects occur which in some cases are that of sparteine/debrisoquine (Beckmann et al, associated with very high flecainide plasma con-1988; Mikus et al, 1989), and it may be concentrations (Salerno et al, 1986). Flecainide cluded that flecainide is metabolised by cytoelimination is impaired in patients with renal chrome P4501ID6.…”