Regulation of potassium channels by nonsedating antihistamines

Terfenadine and astemizole are widely prescribed nonsedating antihistamines that have been associated with QT-interval prolongation and ventricular arrhythmias. Since potassium channels are intrinsically involved in repolarization, this study was designed to evaluate the effect of the nonsedating antihistamines on potassium channel modulation.

The whole-cell patch-clamp technique was used to study K+ currents in enzymatically isolated rat and guinea pig ventricular myocytes. Three distinct K+ channels were examined: the inward rectifier (IK1), the delayed rectifier (IK), and the transient outward (I(to)) currents. The dialyzing pipette solution was buffered with EGTA, and ionic channels other than potassium were pharmacologically inhibited or electrically inactivated. Both astemizole and terfenadine suppressed the IK1 channel by 17% to 50% in a voltage-dependent manner in rat and guinea pig myocytes. Ito was evaluated in rat ventricular myocytes. Both drugs also inhibited the maintained component of I(to) to a lesser extent, by 23%, in a dose-dependent, reversible manner. IK was examined mainly in guinea pig myocytes. Terfenadine but not astemizole slightly inhibited IK, by 9%, and only at higher drug concentrations. The medications had dose-dependent inhibitory actions, with specific K+ channel suppression evident only beginning at concentrations > 0.1 mumol/L.

These findings suggest that the mechanism of action of the rare proarrhythmic effects of the nonsedating antihistamines appears to be secondary to potassium channel blockade. A significant voltage-dependent blockade of the IK1 channel was demonstrated, as well as additional inhibitory effects on I(to) and IK channels. These actions lead to delayed repolarization, QT interval prolongation, and enhanced susceptibility to the development of premature ventricular depolarizations. Caution is advised in the prescription of nonsedating antihistamines, particularly in patients at risk of elevated serum levels of the antihistamine or patients with existing repolarization abnormalities.