title: Second-generation antihistamines: the risk of ventricular arrhythmias.
abstract: Some second-generation antihistamines, notably terfenadine and astemizole, have been associated with prolongation of the QT interval and the development of torsades de pointes, a potentially fatal ventricular arrhythmia. This rare adverse event has been associated with greatly elevated blood levels of these agents, resulting from drug overdose, hepatic insufficiency (dysfunction), or interactions with other drugs that inhibit their metabolism. This paper reviews the data concerning the effects of selected second-generation antihistamines on cardiac conduction, particularly the QT interval, to evaluate whether ventricular arrhythmias are a class effect of these agents. Electrocardiographic studies indicate that terfenadine and astemizole, but not loratadine or cetirizine, prolong the QT interval in laboratory animals. In vitro studies demonstrate that terfenadine and astemizole block the cardiac K+ channels, leading to delayed ventricular repolarization and QT-interval prolongation; in contrast, neither loratadine nor its metabolite, desloratadine, significantly inhibits cardiac K+ channels at clinically achievable blood levels. Studies in human volunteers confirm the absence of electrocardiographic effects of azelastine, cetirizine, fexofenadine, and loratadine administered at several times the recommended dose or concomitantly with agents that inhibit their metabolism and elimination. In conclusion, the data indicate that the potential to cause ventricular arrhythmias is not a class effect of second-generation antihistamines and that loratadine, cetirizine, azelastine, and fexofenadine are not associated with torsades de pointes or other ventricular arrhythmias.
authors.affiliation: Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: DuBuske
mesh_terms: D000818:Animals; D016589:Astemizole / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System; D004347:Drug Interactions; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects*; D006634:Histamine H1 Antagonists / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D009206:Myocardium / Q000378:metabolism; D015221:Potassium Channels; D012306:Risk; D017180:Tachycardia, Ventricular / Q000139:chemically induced*; D016593:Terfenadine / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D016171:Torsades de Pointes / Q000139:chemically induced
chemical_list: D006634:Histamine H1 Antagonists; D015221:Potassium Channels; D016593:Terfenadine; D016589:Astemizole; D003577:Cytochrome P-450 Enzyme System