CNS effects of antihistamines: is there a third generation of non‐sedative drugs?

Summary It is widely accepted that the antihistamines have found their greatest therapeutic potential in the treatment and management of various allergic disorders, including seasonal and perennial rhinitis, urticaria and dermatological conditions. However, the most problematic aspect of their use is sedation, which can severely compromise the safe performance of cognitive and psychomotor tasks of everyday living. The associated increase in accident risk is important when deciding which antihistamine should be prescribed to ambulant patients with allergies and dermatological disorders. Meta‐analyses of placebo and verum (positive) controlled studies published in peer‐reviewed journals show distinct differences between antihistamines in the extent to which they exert sedative activity on the CNS. Evidence has emerged for three distinct groups, or generations, of antihistamines, at least as regards their untoward effects on the CNS. The first generation of antihistamines (e.g. promethazine, diphenhydramine) penetrate the CNS readily at virtually all clinical doses, while the second generation (e.g. cetirizine, loratadine), although they enter the brain, possess little CNS activity at their prescribed clinical dose (10 mg), but at higher doses there is increasing evidence of sedation and other CNS impairment. Fexofenadine is a third generation drug, which does not cross the blood–brain barrier and for which there is no objective evidence of sedation even at doses 2–3 times those normally used for seasonal allergic rhinitis. Improved patient compliance is likely to be associated with antihistamines that are similarly free from sedative side‐effects, thereby improving the efficacy and utility of the drug.