Grzelewska-Rzymowska I, Pietrzkowicz M, Górska M
Kliniki Gruźlicy i Chorób Płuc IMW Akademii Medycznej w Łodzi.
Pneumonol Alergol Pol. 2001;69(3-4):217-26.
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.
本综述总结了第二代抗组胺药心脏作用研究的最新进展。特非那定和阿司咪唑这两种第二代抗组胺药，在体外是钾通道（K+）的强效阻滞剂。人们认为这与心电图QT间期延长以及致命性室性心动过速——尖端扭转型室速有关。对从人心室克隆出的人心脏K+通道（hKv 1.5）研究了氯雷他定及其主要代谢产物去乙氧羰基氯雷他定。母体化合物及其高浓度代谢产物可阻断hKv1.5通道。然而，氯雷他定（10 μmol/L）未能抑制HERG钾通道和HERG K+。依巴斯汀也能抑制克隆的人Kv 1.5钾通道。西替利嗪在浓度高达30 μmol/L时对HERG K+通道完全没有任何抑制作用。另一方面，特非那定和阿司咪唑以纳摩尔亲和力（分别为330和480 nmol/L）有效阻断HERG K+通道，而氯雷他定的效力约低300倍。特非那定的主要代谢产物非索非那定既不阻断HERG也不阻断Kv1.5。豚鼠模型（体外）显示，只有特非那定、阿司咪唑和依巴斯汀产生显著的QT间期延长和致心律失常作用。其他非镇静性抗组胺药，包括西替利嗪、氯雷他定以及依巴斯汀的主要代谢产物（卡瑞斯汀）、特非那定（非索非那定）和阿司咪唑（去甲阿司咪唑），均无QT间期延长及其他不良心电图效应。
