The actions of ibutilide and class Ic drugs on the slow sodium channel: new insights regarding individual pharmacologic effects elucidated through combination therapies.
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 propafenone 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.
Reiffel
J A
JA
Electrophysiology Service, Cardiology Division, Department of Medicine, Columbia University College of Physicians & Surgeons, and The New York Presbyterian Hospital, New York, New York, USA.
Blitzer
M
M
D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005424:Flecainide / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D011405:Propafenone / Q000494:pharmacology / Q000627:therapeutic use; D011446:Prospective Studies; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; D015222:Sodium Channels; D013449:Sulfonamides; C067192:ibutilide; D011405:Propafenone; D005424:Flecainide