DEFINING THE ACCESS PATH FOR LOCAL ANESTHETIC DRUGS

电压门控Na+通道在许多严重心律失常中起着重要作用，是许多抗心律失常药物的靶点。虽然这些药物可以控制心律失常，但它们往往是心律失常，并可能导致心源性猝死。它们的临床疗效和促心律失常电位可归因于它们与Na+通道的动力学相互作用。控制它们的药代动力学的主要因素与Na+通道对门控状态的不同亲和力和到达它们的结合位点的不同途径有关，这些通道由激活和失活门保护。这些因素也是开放通道阻断药物（如氟卡因胺和奎尼丁）和灭活通道阻断药物（如利多卡因和美西林）临床行为差异的基础。目前的提案从三个方面解决了药物获取途径的问题；1)确定利多卡因是否通过外部亲水通路影响其药代动力学；2)研究确定在药代动力学中重要的亲水通路和疏水通路的方法；3)研究开放通道和失活通道阻断药物使用的通路可能存在的差异。该研究还可以进一步了解在药物通道相互作用中重要的Na+通道的结构特征，并为更安全的使用和抗心律失常药物的新设计提供更好的见解。

The voltage-gated Na+ channel plays an important role in many serious arrhythmias and is the target of many antiarrhythmic drugs. While these drugs may control arrhythmia, they are often proarrhythmic and may contribute to sudden cardiac death. Their clinical efficacy and proarrhythmic potential can be attributed to their kinetic interaction with the Na+ channel. Major factors controlling their pharmacokinetics relate to the differential affinities toward gating states of the Na+ channel and differential uses of access paths to their binding site, guarded by activation and inactivation gates. These factors also underlie the differences in clinical behavior of open-channel blocking drugs such as flecainide and quinidine and inactivated-channel blocking drugs such as lidocaine and mexilitine. The current proposal addresses issues of drug- access paths in three parts; 1) to determine whether lidocaine uses an external hydrophilic path to affect its pharmacokinetics, 2) to develop methods to define hydrophilic and hydrophobic access paths important in the pharmacokinetics, and 3) to investigate possible differences in the access paths used by open-channel and inactivated-channel blocking drugs. The study may also result in further information on structural features of the Na+ channel important in drug-channel interaction and offer better insights for safer use and new design of antiarrhythmic drugs.