Antihistamine activity, central nervous system and cardiovascular profiles of histamine H1 antagonists: comparative studies with loratadine, terfenadine and sedating antihistamines in guinea-pigs


Dr J. A. Hey Schering-Plough Research Institute. 2015 Galloping Hill Road Kenilworth. NJ 07033–0539. USA.


Background Sedation limits the clinical utility of classical H, antihistamines. while newer antihistamincs such as loratadine and terfenadine arc non-sedating. However, clinical use of terfenadine has been associated with rare but severe cardiac arrhythmias, in particular lorsades de pointes.

Objective To establish a quantitative experimental model for assessing the sedating and cardiotoxicity potential of non-sedating and sedating antihistamines.

Methods Drugs were administered intravenously and the integrated amplitude of the conical electroencephalogram (EEC) signal was recorded. The threshold dose that depressed EEG activity was compared with the dose required lo inhibit by 50% the peripheral bronchospasm elicited by 10 μg/ kg i.v., of histamine. In separate studies, the electrocardiogram (ECG) and cardiovascular effects of loratadine (30 and 100mg/kg, i.v.). terfeuadine (10mg/kg. i.v.). promethazine (5mg/kg. i.v.) and diphenhydramine (20 mg kg, i.v.) were evaluated.

Results The sedating antihistamines. diphenhydramine and promethazine. depressed the integrated EEG at doses between 0.6 and 2.0 limes their peripheral antihisiamine doses. Loratadine had no EEG depressant activity at 100 mg kg. i.v., a dose more than I 70 times its LD50 (0.58 mg kg, i.v.) against histamine bronchospasm. We were unable lo evaluate the EEG effects of terfenadine. because it produced cardiovascular collapse at 10 mg/kg. i.v. Loratadine and promethazinc did not produce adverse cardiovascular effects. nor did they alter normal ECG activity. Diphenhydramine produced brady-cardia followed by a transient hypertensive phase without affecting the QTc interval. In contrast, terfenadine elicited hypotension, bradycardia and significant arrhythmogenic activiy, causing a prolongation of the QTc interval and a torsades de pointes like ventricular arrhythmia. Pharmacokinetic studies after i.v. administration of loraladine (30 and 100 mg/kg) demonstrated plasma levels of loratadine and its major metabolite descarboethoxyloratadine to be several orders of magnitude greater than levels found in humans at the clinical dose of 10mg.

Conclusion The CNS depressant effects of H1 antihislamines arc promcthazine≅ diphenhdramine ≫ loratadine = placebo. Of the non-sedating antihistamines. loratadine was devoid of adverse cardiovascular effects whereas terfenadine caused a pronounced disruption of the normal ECG. characterized by a torsades de pointes-like effect.