Cardiac Electrophysiological Actions of the Histamine H1-Receptor Antagonists Astemizole and Terfenadine Compared With Chlorpheniramine and Pyrilamine

Abstract We compared the cardiac electrophysiological actions of two types of H1-receptor antagonists—the piperidines, astemizole and terfenadine, and the nonpiperidines, chlorpheniramine and pyrilamine—in vitro in guinea pig ventricular myocytes and in vivo in chloralose-anesthetized dogs. Astemizole and terfenadine significantly increased action potential duration of guinea pig myocytes. This concentration-dependent prolongation of action potential duration was reverse frequency dependent and led to development of early afterdepolarizations, which occurred more frequently at higher concentrations and slower pacing frequencies. Astemizole and terfenadine potently blocked the rapidly activating component of the delayed rectifier, IKr, with IC50 values of 1.5 and 50 nmol/L, respectively. At 10 μmol/L, terfenadine but not astemizole blocked the slowly activating component of the delayed rectifier, IKs (58.4±3.1%), and the inward rectifier, IK1 (20.5±3.4%). Chlorpheniramine and pyrilamine blocked IKr relatively weakly (IC50=1.6 and 1.1 μmol/L, respectively) and IKs and IK1 less than 20% at 10 μmol/L. Astemizole and terfenadine (1.0 to 3.0 mg/kg IV) significantly prolonged the QTc interval and ventricular effective refractory period in vivo. Chlorpheniramine and pyrilamine (≤3.0 mg/kg) did not significantly affect these parameters. Block of repolarizing K+ currents, particularly IKr, by astemizole and terfenadine produces reverse rate–dependent prolongation of action potential duration and development of early afterdepolarizations, delays ventricular repolarization, and may underlie the development of torsade de pointes ventricular arrhythmias observed with the use and abuse of these agents.