Comparative Analysis of the Cardiotoxicity Proclivities of Second Generation Antihistamines in an Experimental Model Predictive of Adverse Clinical ECG Effects

Terfenadine and astemizole belong to the second generation histamine H1 antagonists and are widely prescribed for allergic and upper respiratory diseases. The popularity of the newer H1 antihistamines is due to their ability to provide relief from allergic symptoms without the undesirable side effect of sedation commonly associated with first generation H1 receptor antagonists such as diphenhydramine and promethazine. Recent clinical evidence that the second generation histamine H1 antagonists terfenadine and astemizole have the potential for inducing life threatening ventricular arrhythmias has raised questions as to whether other drugs in this class have similar cardiotoxic potential. The objective of this study was to evaluate and compare the arrhythmogenic potential of a series of second generation antihistamines in a quantitative experimental model predictive of adverse ECG effects in man. Antihistamines were given intravenously and electrocardiographic (ECG) and cardiovascular parameters (blood pressure and heart rate) were measured. The ECG wave form was analyzed to determine QTc interval, PR interval, QRS interval and heart rate. To determine the relative cardiotoxic potential of the antihistamines, the lowest dose producing significant prolongation of the QTc interval was compared with the dose required to inhibit by 50% the peripheral bronchospasm elicited by histamine at 10 micrograms/kg i.v. (antihistamine ED50). The second generation antihistamines studied were astemizole (CAS 68844-77-9), carebastine (CAS 90729-42-3), cetirizine hydrochloride (CAS 83881-52-1), ebastine (CAS 90729-43-4), norastemizole (CAS 75970-99-9), terfenadine (CAS 50679-08-8) and terfenadine carboxylate (CAS 83799-24-0). The second generation antihistamines astemizole, ebastine and terfenadine produced pronounced dose-dependent QTc interval prolongation effects. These arrhythmogenic effects occurred at doses that were between 1 and 4 times their respective peripheral antihistamine doses. These drugs produced significant disruption of the ECG wave form including large amplitude, morphologically aberrant T-waves and, in some cases, torsades de pointes-type arrhythmias. In contrast, terfenadine carboxylate (100 mg/kg i.v.), norastemizole (20 mg/kg, i.v.) and carebastine (50 mg/kg, i.v.), the major metabolites of terfenadine, astemizole and ebastine, were largely devoid of adverse ECG effects. Similarly, cetirizine (20 mg/kg, i.v.) was also found to not alter ECG or cardiovascular function. These findings demonstrate that terfenadine, astemizole and ebastine exhibit significant arrhythmogenic effects including QTc interval prolongation, bradycardia and distortion of the ECG morphology in the guinea pig. The relative cardiotoxicity of these antihistamines based on the separation of antihistamine activity and adverse ECG effects was similar for terfenadine and astemizole, but slightly less for ebastine. In this model carebastine, cetirizine, loratadine, norastemizole and terfenadine carboxylate are devoid of QTc prolongation effects. Given the structural similarity of terfenadine and ebastine it is not surprising that these drugs produce significant cardiotoxicity in this animal model. Taken together, these results indicate that the ability to cause QTc interval prolongation and the proclivity for producing arrhythmias is not a class effect and is seen only with some second generation nonsedating antihistamines.