Glaaser I W, Clancy C E
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, NY 10032, USA.
Handb Exp Pharmacol. 2006(171):99-121. doi: 10.1007/3-540-29715-4_4.
There are many factors that influence drug block of voltage-gated Na+ channels (VGSC). Pharmacological agents vary in conformation, charge, and affinity. Different drugs have variable affinities to VGSC isoforms, and drug efficacy is affected by implicit tissue properties such as resting potential, action potential morphology, and action potential frequency. The presence of polymorphisms and mutations in the drug target can also influence drug outcomes. While VGSCs have been therapeutic targets in the management of cardiac arrhythmias, their potential has been largely overshadowed by toxic side effects. Nonetheless, many VGSC blockers exhibit inherent voltage- and use-dependent properties of channel block that have recently proven useful for the diagnosis and treatment of genetic arrhythmias that arise from defects in Na+ channels and can underlie idiopathic clinical syndromes. These defective channels suggest themselves as prime targets of disease and perhaps even mutation specific pharmacological interventions.
有许多因素会影响电压门控钠通道（VGSC）的药物阻断。药理剂在构象、电荷和亲和力方面各不相同。不同药物对VGSC亚型具有不同的亲和力，并且药物疗效会受到诸如静息电位、动作电位形态和动作电位频率等内在组织特性的影响。药物靶点中多态性和突变的存在也会影响药物疗效。虽然VGSC一直是治疗心律失常的靶点，但其潜力在很大程度上被毒副作用所掩盖。尽管如此，许多VGSC阻滞剂表现出通道阻断的固有电压依赖性和使用依赖性特性，最近已证明这些特性对于诊断和治疗由钠通道缺陷引起的遗传性心律失常有用，这些遗传性心律失常可能是特发性临床综合征的基础。这些有缺陷的通道表明它们是疾病的主要靶点，甚至可能是突变特异性药物干预的靶点。
