Singh B N
Department of Cardiology, Wadsworth VA Hospital, Los Angeles, California 90073.
Eur Heart J. 1993 Nov;14 Suppl H:14-23. doi: 10.1093/eurheartj/14.suppl_h.14.
Over the last decade, there has been an increasing confluence of experimental and clinical data on the gravity of proarrhythmic effects of class I agents. Over the same period, beta blockers have been shown to reduce mortality in a variety of subsets of patients. The properties of amiodarone and sotalol have also drawn attention to their potential as antifibrillatory compounds, perhaps acting principally by prolonging myocardial repolarization with little or no effect on conduction. However, amiodarone and sotalol are complex molecules and, therefore, attention is also focused on compounds that act simply by selective prolongation of cardiac repolarization. These agents have been termed 'pure' class III agents. The properties of sotalol, the prototype of class III agents, are of particular interest, as it is a racemic mixture of the levo- and dextro-isomers. The levo-isomer has 50 times the beta-blocking potency of the dextro-isomer, actions. Studies of the antiarrhythmic properties of beta blockers, d- and d,l-sotalol, and amiodarone may provide insights into the nature of class III actions. There is clinical evidence indicating that class III drugs exert a varying spectrum of antifibrillatory and proarrhythmic (characterized by torsade de pointes) actions for a given degree of prolongation of repolarization. These differences currently are not accountable in terms of specificity of their actions on ionic channels. There are differences between the so-called pure class III agents, such as sematilide, dofetilide and E-4031, and more complex compounds, such as sotalol and amiodarone, that also exert antiadrenergic actions. In the development of newer drugs an appropriate balance needs to be struck between proarrhythmic actions and the antifibrillatory properties. At present, it is unclear whether such antifibrillatory compounds should be relatively simple molecules with clearly-defined electrophysiologic profiles in terms of actions on ion channels, currents, receptors and pumps, or whether they need to be those with complex electropharmacologic profiles with multiplicity of actions.
在过去十年中，关于I类药物促心律失常作用的严重性，实验数据和临床数据越来越趋于一致。在同一时期，β受体阻滞剂已被证明可降低各类患者亚组的死亡率。胺碘酮和索他洛尔的特性也使其作为抗纤颤化合物的潜力受到关注，它们可能主要通过延长心肌复极化而对传导影响很小或没有影响来发挥作用。然而，胺碘酮和索他洛尔是复杂的分子，因此，注意力也集中在仅通过选择性延长心脏复极化起作用的化合物上。这些药物被称为“纯”III类药物。III类药物的原型索他洛尔的特性特别引人关注，因为它是左旋和右旋异构体的外消旋混合物。左旋异构体的β受体阻滞效力是右旋异构体的50倍。对β受体阻滞剂、d-和d,l-索他洛尔以及胺碘酮抗心律失常特性的研究可能有助于深入了解III类作用的本质。有临床证据表明，对于给定程度的复极化延长，III类药物会产生不同范围的抗纤颤和促心律失常（以尖端扭转型室速为特征）作用。目前，这些差异无法根据它们对离子通道作用的特异性来解释。所谓的纯III类药物，如司美利特、多非利特和E-4031，与更复杂的化合物，如索他洛尔和胺碘酮之间存在差异，后者还具有抗肾上腺素能作用。在开发新药时，需要在促心律失常作用和抗纤颤特性之间取得适当平衡。目前尚不清楚这种抗纤颤化合物应该是在离子通道、电流、受体和泵的作用方面具有明确电生理特征的相对简单的分子，还是需要是具有多种作用的复杂电药理特征的分子。
