title: Cardiotoxicity of new antihistamines and cisapride.
abstract: Although the new second-generation nonsedative antihistamines terfenadine and astemizole were launched as highly selective and specific H(1)-receptor antagonists, they were later found to cause prolongation of the QT-interval and severe cardiac arrhythmias. The prolongation of the QT-interval is caused by the blockade of one or more of the cardiac potassium channels, among which the delayed rectifier I(Kr), encoded by the HERG-gene, appears to be the most significant. The potency of the prokinetic drug cisapride to block I(Kr) appears to be similar to that of terfenadine (IC(50) about 50 nmol/l). These drugs cause problems when overdosed, used in combination with inhibitors of their CYP3A4-mediated metabolism, or when given to individuals with altered drug kinetics (the aged) or patients with existing cardiac disease (congenitally long QT). Moreover, interactions with other QT-interval prolonging drugs require special attention. Active hydrophilic metabolites of the second-generation antihistaminic compounds (ebastine-carebastine, loratadine-desloratadine, terfenadine-fexofenadine, astemizole-norastemizole) are new compounds with probably reduced risk for drug interactions and cardiac toxicity.
authors.affiliation: Institute of Biomedicine/Pharmacology, Biomedicum Helsinki, University of Helsinki, P.O. Box 63, FIN-00014, Finland. ilari.paakkari@helsinki.fi
authors.forename: Ilari
authors.initials: I
authors.lastname: Paakkari
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D016589:Astemizole / Q000009:adverse effects; D001562:Benzimidazoles / Q000009:adverse effects; D002090:Butyrophenones / Q000009:adverse effects; D017332:Cetirizine / Q000009:adverse effects; D020117:Cisapride / Q000009:adverse effects*; D006331:Heart Diseases / Q000139:chemically induced* / Q000503:physiopathology; D006634:Histamine H1 Antagonists / Q000009:adverse effects*; D006801:Humans; D017336:Loratadine / Q000009:adverse effects; D010880:Piperidines / Q000009:adverse effects; D017366:Serotonin Receptor Agonists / Q000009:adverse effects*; D016593:Terfenadine / Q000009:adverse effects; D014311:Triprolidine / Q000009:adverse effects / Q000031:analogs & derivatives*
chemical_list: D001562:Benzimidazoles; D002090:Butyrophenones; D006634:Histamine H1 Antagonists; D010880:Piperidines; D017366:Serotonin Receptor Agonists; D014311:Triprolidine; C058251:carebastine; D017336:Loratadine; D016593:Terfenadine; D016589:Astemizole; C043648:acrivastine; C058249:ebastine; D020117:Cisapride; C106448:tecastemizole; D017332:Cetirizine