Novel insights into the molecular mechanism of the cardiac actions of histamine H1 receptor antagonists

ABSTRACT: When compared to older first‐generation antihistamines, second‐generation antihistamines are characterized by improved selectivity for histamine receptors, absence of sedation, and, possibly, antiallergic properties distinct from their antihistaminic activity. Such a pharmacologic profile, arising from specific pharmacodynamic and pharmacokinetic properties, bears an obvious clinical advantage for the therapy of allergic diseases; thus second‐generation antihistamines have become the treatment of choice for chronic urticaria and allergic rhinitis. Despite such a therapeutic advantage, adverse cardiovascular effects associated with the use of some congeners belonging to the class of second‐generation antihistamines (particularly terfenadine and astemizole) have been reported, and a major concern about the therapeutic selection of antihistamines now is represented by their potentially severe arrhythmogenic properties. This article reviews the recent advances in the understanding of the pathogenesis and etiology of the cardiotoxic actions of some second‐generation antihistamines, underlining their molecular actions at the level of K⁺ channels controlling the cardiac action potential. In particular, emphasis is given to the interaction of second‐generation antihistamines with the K⁺ channels encoded by the human ether‐a‐gogo‐related gene (HERG), which is crucially involved in the repolarization process of the cardiac action potential. This review will also focus on the recent concerns over the potential cardiac adverse effects of first‐generation H₁ receptor blockers. The present exploration of the molecular basis of the adverse cardiac effects of antihistamines shows how important contributions in deciphering such complex phenomenon have emerged from disciplines and techniques not traditionally related to immunology, such as molecular genetics and cellular electrophysiology; it seems possible to anticipate that the exchange of results from such different disciplines in the future will provide patients and physicians with medications with improved therapeutic efficacy and safety for the clinical management of allergic diseases.