Danielsson B R, Skold A C, Azarbayjani F
Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Uppsala, S-751 24, Sweden.
Curr Pharm Des. 2001 Jun;7(9):787-802. doi: 10.2174/1381612013397744.
Class III antiarrhythmic drugs, like almokalant, dofetilide and ibutilide, cause a spectrum of malformations in experimental teratology studies. The pattern of developmental toxic effects is very similar to those reported for phenytoin, which is an established human and animal teratogen. The toxic effects are characterised by embryonic death, decreased fetal weights, and stage specific malformations, such as distal digital reductions, orofacial clefts and cardiovascular defects. Class III antiarrhythmics decrease the excitability of cardiac cells by selectively blocking the rapid component of the delayed rectified potassium channel (IKr), resulting in prolongation of the repolarisation phase of the action potential. Phenytoin, which decrease the excitability of neurones, has recently also been shown to block IKr, in addition to its known blockade of sodium channels. Animal studies indicate that IKr is expressed in the embryo and that the embryonic heart is extremely susceptible to IKr-blockers during a restricted period in early development. At concentrations not affecting the maternal heart, the embryonic heart reacts with bradycardia, arrhythmia and cardiac arrest when exposed to such drugs. Available studies strongly support the idea that birth defects after in utero exposure to both selective and non-selective IKr-blockers (like phenytoin) are initiated by concentration dependent embryonic bradycardia/arrhythmia resulting in 1) hypoxia; explaining embryonic death and growth retardation, 2) episodes of severe hypoxia, followed by generation of reactive oxygen species within the embryo during reoxygenation, causing orofacial clefts and distal digital reductions, and 3) alterations in embryonic blood flow and blood pressure, inducing cardiovascular defects.
Ⅲ类抗心律失常药物，如阿吗卡兰、多非利特和伊布利特，在实验性致畸学研究中会导致一系列畸形。发育毒性效应模式与苯妥英钠所报告的非常相似，苯妥英钠是一种已确定的人类和动物致畸剂。毒性效应的特征为胚胎死亡、胎儿体重减轻以及特定阶段的畸形，如远端指骨发育不全、口面部裂隙和心血管缺陷。Ⅲ类抗心律失常药物通过选择性阻断延迟整流钾通道（IKr）的快速成分来降低心肌细胞的兴奋性，导致动作电位复极化阶段延长。苯妥英钠可降低神经元的兴奋性，最近还显示除了已知的阻断钠通道外，它也能阻断IKr。动物研究表明，IKr在胚胎中表达，并且胚胎心脏在早期发育的受限时期对IKr阻滞剂极其敏感。在不影响母体心脏的浓度下，胚胎心脏在接触此类药物时会出现心动过缓、心律失常和心脏骤停。现有研究有力地支持了这样一种观点，即子宫内接触选择性和非选择性IKr阻滞剂（如苯妥英钠）后出现的出生缺陷是由浓度依赖性胚胎心动过缓/心律失常引发的，导致：1）缺氧，解释了胚胎死亡和生长迟缓；2）严重缺氧发作，随后在再氧合过程中胚胎内产生活性氧，导致口面部裂隙和远端指骨发育不全；3）胚胎血流和血压改变，诱发心血管缺陷。
