title: Terfenadine alters action potentials in isolated canine Purkinje fibers more than acrivastine.
abstract: Acrivastine and terfenadine are second-generation antihistamines with similar pharmacologic profiles and comparable clinical efficacies for allergic rhinitis. However, terfenadine therapy has been associated with cardiovascular side effects that include prolonged QT interval, torsades de pointes, and ventricular fibrillation (VF). We examined the adverse effects induced by terfenadine on evoked action potentials (APs) in isolated canine cardiac Purkinje fibers and determined whether acrivastine causes similar disturbances in this preparation. Terfenadine produced a statistically significant decrease in the maximal rate of increase in the AP (dV/dt) at 10(-7) M, which corresponds to the highest plasma concentration observed clinically. The IC50 (mean +/- SEM) value for terfenadine-induced inhibition of dV/dt was 1.3 +/- 0.3 x 10(-6) M. The decrease in dV/dt caused by terfenadine became more pronounced with faster rates of stimulation. Acrivastine at a concentration of 10(-5) M, a value 10 times higher than plasma concentrations observed in clinical studies, caused no significant changes in AP duration (APD) or dV/dt. The IC50 (mean +/- SEM) value for the acrivastine-induced inhibition of dV/dt was estimated to be 8.0 +/- 3.7 x 10(-3) M. Terfenadine blocked the evoked AP at 3 x 10(-6) M, whereas no block was observed with acrivastine at 10(-3) M. The effective serum concentration of acrivastine is approximately 100 times higher than that of terfenadine. Because the IC50 value for inhibition of dV/dt for acrivastine is approximately 6,000 times greater than that for terfenadine, we estimate that acrivastine is approximately 60-fold less likely to cause disturbances in cardiac conduction than terfenadine.
authors.affiliation: Division of Pharmacology, Burroughs Wellcome, Research Triangle Park, North Carolina 27709.
authors.forename: D G
authors.initials: DG
authors.lastname: Lang
authors.forename: C M
authors.initials: CM
authors.lastname: Wang
authors.forename: T L
authors.initials: TL
authors.lastname: Wenger
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D016593:Terfenadine / Q000633:toxicity*; D014311:Triprolidine / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: D006634:Histamine H1 Antagonists; D014311:Triprolidine; D016593:Terfenadine; C043648:acrivastine