Cardiac Electrophysiological Actions of the Histamine H ₁ -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 mumol/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 mumol/L, respectively) and IKs and IK1 less than 20% at 10 mumol/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 (< or = 3.0 mg/kg) did not significantly affect these parameters. Block of repolarizing K+ currents, particularly IK1, 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.

Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease

“…The third drug, cisapride, a serotonin receptor agonist, also lengthens the action potential duration but was potent at a lower concentration than terfenadine (Figures 4d and e). These results are consistent with patch clamp measurements with the same compounds [25][26][27] .…”

Lack of Action Potential-Prolonging Effect of Terfenadine on Rabbit Myocardial Tissue Preparations

“…This contrasts with the observation that terfenadine prolongs APD in isolated myocardial cells. 2,25) Our preliminary observation that terfenadine administered through coronary perfusion did not prolong APD suggests that the lack of terfenadine effects on myocardial tissue is not due to limited drug access to the interior region of the preparations. There is a report that terfenadine increased APD by 10% in Langendorff-perfused guinea pig hearts.…”

“…2,28) Inhibition of the HERG channel itself by terfenadine was reported to be unaffected by stimulation frequency in the range of 0.1 to 3 Hz. 28) Thus the frequency dependence of APD prolongation by terfenadine could be ascribed to variation in the contribution of IKr in repolarization rather than to variations in inhibition of the channel by the drug.…”

“…2,7,8) Since then, the assessment of the risks incurred with noncardiovascular therapeutic agents for cardiac function has received great attention. Some researchers and organizations have postulated that analysis of APD in rabbit Purkinje fibers is the most adequate method for evaluation.…”

QT PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT Interval Prolongation by Human Pharmaceuticals

“…Although significant changes in HR including marked increases in it were occasionally observed, they were not considered to be related to the treatment since the changes were transient and no significant effect on HR was observed in anesthetized dogs (17,18). There was no significant change in QRS duration.…”