The Actions of Ibutilide and Class Ic Drugs on the Slow Sodium Channel: New Insights Regarding Individual Pharmacologic Effects Elucidated Through Combination Therapies

Abstract

Background: Ibutilide (I) has been reported to block I_k and to delay inactivation of the slow Na⁺ current (S-Na). There is debate about the clinical importance of the latter. Class Ic drugs block the fast Na⁺ channel, but their effect on S-Na is uncertain. If Ic treatment before infusion lessened the QT increase with I, this result would suggest both an Ic effect on S-Na and significant S-Na actions of I.

Methods: We infused I, 2 mg over 30 minutes, to 6 patients pretreated with propafenone (n = 5) or flecainide (n = 1) (group 1) and compared their increase with the QT increase seen with I alone in a combined group of 85 patients from our lab and the multicenter I database (group 2).

Results: The QTc increased in group 2, 65 ms, from 413 to 478 ms. This effect was attenuated by 47% in group 1 patients to 34 ms (P < .01). There appeared to be a dose-response relationship between Ic dose and its effects on QTc prolongation. The lowest dose of propafe none had minimal effect on the increase in QTc with I (72 ms), while higher doses of propafenone and high doses of flecainide attenuated the increase to 13 to 39 ms. Nonetheless, ibutilide efficacy was not changed, possibly suggesting differing importance of K⁺ channel and slow sodium-channel effects in atrial versus ventricular tissues, and having implications for means to reduce some antiarrhythmic drug proarrhythmia without reducing efficacy.

Conclusions: (1) Pretreatment with Ic agents can reduce the increase in QTc seen with I; (2) I's effect in humans appears to be at least partly mediated through the delay of S-Na inactivation; and (3) Ic agents probably inhibit S-Na.