The non-cardiac systemic side-effects of antihistamines: ebastine

Ebastine and its active metabolite carebastine show potent antagonism of histamine H1-mediated phenomena in a wide variety of in vitro and in vivo non-clinical experimental models. By contrast, activity is not seen against histamine H2- or H3-mediated, nor acetylcholine- or serotonin-mediated phenomena, and both compounds are virtually without effect in models measuring pharmacological effects on the central nervous system (CNS). Explanation of these observations is found in their high selectivity for the histamine H1 receptor and in their low in vivo potency in displacing [3H]-mepyramine from central histamine H1 receptors, indicating that they do not readily pass the blood-brain barrier. These findings have been mirrored in clinical experimental models where oral doses of ebastine (1-30 mg) showed clear dose-related inhibition of intradermal histamine-induced weal and flare responses, whereas doses of 90 mg were without anticholinergic effects on salivary flow, cardiovascular reflexes or pilocarpine-induced miosis. Furthermore, in an extensive series of controlled studies in specific clinical models for measuring objective effects on the CNS, ebastine in single doses of 10-90 mg and repeated doses of 10-30 mg once daily, had no clinically relevant effects on cognitive performance and visual co-ordination tests, nor on simulated car-tracking tests and real car-driving tests. Nor was their any interaction with ethanol or diazepam. On subjective test parameters (questionnaires and visual analogue scales) there were only a few isolated and random incidences of minor increases in some indices of sedation at the highest doses. Not surprisingly, therefore, the clear therapeutic benefit seen during the extensive and international use of ebastine (5-20 mg once daily) in the treatment of seasonal and perennial rhinitis and chronic idiopathic urticaria, has not been accompanied by signs of drug-induced anticholinergic effects (dry mouth, disturbances of visual accommodation) or sedation, making it an effective and well-tolerated first-line treatment alternative to other second-generation antihistamines.