Molecular pharmacology of second-generation antihistamines

Histamine was the first allergic mediator identified in the early part of this century. It has three defined receptors, but most effects of histamine in allergic reactions are through the H1 receptor. The first H1 antagonists were introduced into clinical use in the late 1940s, and drugs of this class are still the preferred initial choice for management of allergic rhinitis and urticaria. The first-generation drugs were characterized by nonspecific binding to many receptors and penetration of the blood-brain barrier, resulting in multiple side effects. Within the central nervous system (CNS), interference with normal histamine binding to the H1 receptor is associated with drowsiness and psychomotor impairment. The second-generation drugs have a much improved benefit/adverse effect profile, largely based on greater potency, receptor specificity, and lower CNS penetration. The potency of antihistamines for blocking H1 receptors can be compared by their inhibition of the cutaneous wheal and flare response to histamine. These drugs seem to have additional antiallergic properties related to blockade of mediator release and interference with cellular recruitment and activation. Clinical trials comparing the efficacy of antihistamines in rhinitis and asthma are reviewed. Recent studies have explored the potential of antihistamines to prevent the progression of allergy and their enhanced efficacy when combined with leukotriene antagonists.