新Ⅲ类抗心律失常药及开发前景

THE PERSPECTIVE OF DEVELOPMENT OF NEW CLASS ⅢANTIARRHYTHMIC AGENTS

Ⅲ类抗心律失常药，与阻断钾通道有关，主要是抑制复极过程的离子流，如复极初期Ｉｔｏ（又分Ｉｔｏ１，Ｉｔｏ２），快速复极化的Ｉｋ（又分Ｉｋ．ｒ，Ｉｋ．ｓ，Ｉｋｕｒ，Ｉｋｐ）及复极化末期的Ｉｋ１。在病理条件下的尚有ＩＫ．ＡＴＰ，Ｉｋ．Ｎａ及ＩＫ．Ｃａ等。阻断钾通道可取消缺血心肌所致的ＡＰＤ及ＥＲＰ缩短效应。高度选择性阻断Ｉｋ．ｒ的Ⅲ类药物，如ｄ索他洛尔，ｄｏｆｅｔｉｌｉｄｅ等，有３个缺点：在缓慢心率时过度延长ＡＰＤ，在快速心率时延长ＡＰＤ的药效减弱或消失，及可能诱发Ｔｏｒｓａｄｅｄｅｐｏｉｎｔｓ（Ｔｄｐ）。如果Ⅲ类抗心律失常兼有阻断Ｉｋ．ｓ或ＩＮａ，ＩＣａ，或β－受体，则可改善抗心律失常活性及减少Ｔｄｐ的发生。本文中讨论了心肌钾通道，二项重要的抗心律失常大型临床试验ＣＡＳＴ及ＳＷＯＲＤ，对研究及开发新抗心律失常药的影响，以及形成心律失常的其他因子。最后，Ⅲ类抗心律失常药可以分成二种：单纯型及复合型（如胺碘酮）。

The class Ⅲ antiarrhythmic agents, its activity relating to the blockade of potassium channels, are mainly to suppress the ionic currents in the repolarization process, such as Ito at the early repolarization (subdivided into Ito1, Ito2), IK in the rapid repolarization (subdivided into IK· r, Ik· s, Ikur, Ikp), and IK1 at the last period of repolarization. There are the IK·ATP, IK·Na, and IK·Ca etc developed under pathological condictions. The shortened APD and ERP can be abolished by a blockade on potassium channels. The highly selective blockade on Ik·r, by the Ⅲ agents as dsotalol, and dofitilide, etc possess 3 main dfects, the overprolongation of APD at slow heart rate, a reduction or loss of efficacy at rapid heart rate and possibly inducing Torsade de points (Tdp). It is likely to improve the antiarrhythmic activity and diminish the probability of inducing Tdp by combining with the blockade on Ik·s, or INa, ICa, and betareceptors. In this review the potassium channels in myocardium, the impact on research and development of new antiarrhythmic agents by the clinical trials CAST and SWORD, and the factors involved in arrhythmias are discussed. Finally, the Class Ⅲ antiarrhythmic agents can be subgrouped as the simple and complex type which is likely more promising for the new drug development in the future.