[The effect of second generation histamine antagonists on the heart].
The review summarizes recent progress in the study of the cardiac actions of second--generation antihistamines. Terfenadine and astemizole, two antihistamines of the second generation, are in vitro potent blockers of potassium channels (K+). It has been considered to be responsible for QT prolongation of the electrocardiogram and life--treating ventricular tachycardias called torsades de pointes. Loratadine and descarboethoxyloratadine, the major metabolite of loratadine were studied on a human cardiac K+ channel (hKv 1.5) cloned from human ventricle. Parent compound and its metabolite in high concentration blocked hKv1.5 channels. However, loratadine (10 mumol/L) failed to inhibit HERG potassium channel and HERG K+. Ebastine also inhibit potassium channels, cloned human Kv 1.5. Cetirizine was completely devoid of any inhibitory action on HERG K+ channels in concentration up to 30 mumd/L. On the other hand terfenadine and astemizole effectively blocked HERG K+ channels with nanomolar affinities (330 and 480 nmol/L, respectively), whereas loratadine was about 300-fold less potent. Fexofenadine--the major metabolite of terfenadine, does not block either HERG or Kv1.5. The quinea pig model (in vitro) revealed that only terfenadine, astemizole and ebastine produced significant QT interval prolongation and arrhythmogenic effects. The other nonsedating antihistamines including cetirizine, loratadine and the major metabolite of ebastine (carabastine), terfenadine (feksofenadine) and astemizole (norastemizole) were devoid of QT interval prolongation and other adverse ECG effects.
Grzelewska-Rzymowska
I
I
Kliniki Gruźlicy i Chorób Płuc IMW Akademii Medycznej w Łodzi.
Pietrzkowicz
M
M
Górska
M
M
D000818:Animals; D019540:Area Under Curve; D016589:Astemizole / Q000494:pharmacology; D002090:Butyrophenones / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D017336:Loratadine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D013610:Tachycardia / Q000188:drug therapy; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016171:Torsades de Pointes / Q000188:drug therapy
D002090:Butyrophenones; D006634:Histamine H1 Antagonists; D010880:Piperidines; D017336:Loratadine; D016593:Terfenadine; D016589:Astemizole; C093230:fexofenadine; C058249:ebastine