© 1995 American Heart Association, Inc.
Articles |
Cardiac Electrophysiological Actions of the Histamine H1-Receptor Antagonists Astemizole and Terfenadine Compared With Chlorpheniramine and Pyrilamine
From the Department of Pharmacology, Merck Research Laboratories, West Point, Pa.
Correspondence to Joseph J. Salata, Department of Pharmacology, Merck Research Laboratories, Sumneytown Pike, PO Box 4, WP26-265, West Point, PA 19486.
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.
Key Words: early afterdepolarization • delayed rectifier potassium current • torsade de pointes
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