Concentration-dependent pharmacologic properties of sotalol.
Concentration-dependent pharmacologic properties of sotalol.
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索他洛尔的浓度依赖性药理学特性。
DOI：
10.1016/0002-9149(86)90692-2
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发表时间：
1986
期刊：
影响因子：
--
通讯作者：
Roden,DM
中科院分区：
文献类型：
--
作者：
Wang,T;Bergstrand,RH;Thompson,KA;Siddoway,LA;Duff,HJ;Woosley,RL;Roden,DM
索他洛尔是一种非选择性 β 受体拮抗剂，在体外浓度高于与心率减慢相关的浓度时，可延长动作电位持续时间和不应期。为了确定这种额外的作用是否可以在人类中表达，我们对 17 名患有慢性稳定室性早搏的患者进行了研究。每名患者均住院治疗，并在 48 小时无药物基线期间以及每三天增加索他洛尔剂量增量的治疗期间对心律失常频率进行量化。剂量为160、320、640和960mg/天，分1或2次给药。在每个剂量的第三天，在假定的稳态下使用连续 12 导联心电图测量动作电位持续时间指数，即速率校正 QT (QTc)，并通过最大运动诱发心率的降低来评估 β 受体阻断程度。在 17 名患者中，11 名患者在较宽的血浆浓度范围（340 至 3,440 ng/ml）下出现抗心律失常反应（VPC 减少 70% 至 100%）。对索他洛尔有反应的患者包括 8 名常规 β 受体拮抗剂治疗失败的患者。在整个组中，与 QTc 显着延长相关的浓度 (2,550 ng/ml) 大于与心率最大减慢 50% 降低相关的浓度 (804 ng/ml)。索他洛尔通常耐受性良好，但 1 例无反应者在首次 640 mg 剂量后 3 小时出现尖端扭转型室速，血浆索他洛尔浓度完全在其他患者测得的浓度范围内。索他洛尔的复极延长作用的浓度高于与心率减慢相关的浓度，可能有助于其临床效果。
Sotalol is a nonselective β-receptor antagonist that prolongs action potential duration and refractoriness in vitro at higher concentrations than those associated with heart rate slowing. To determine if this additional action can be expressed in humans, 17 patients with chronic stable ventricular premature complexes were studied. Each patient was hospitalized and arrhythmia frequency was quantified during a 48-hour drug-free baseline and during every third day of therapy with increasing incremental sotalol dosages. The dosages were 160, 320, 640 and 960 mg/day, administered in 1 or 2 doses. An index of action potential duration, the rate-corrected QT (QTc), was measured using serial 12-lead electrocardiograms on the third day of each dosage at presumed steady state and the degree of β-receptor blockade was assessed by the reduction of the maximal exercise-induced heart rate. Of the 17 patients, 11 had an antiarrhythmic response (70 to 100% reduction in VPCs), at a wide range of plasma concentrations (340 to 3,440 ng/ml). the responders to sotalol included 8 patients in whom therapy with conventional β-receptor antagonists had failed. In the group as a whole, the concentration associated with significant QTc prolongation (2,550 ng/ml) was greater than that associated with 50% reduction of the maximal slowing in heart rate (804 ng/ml). Sotalol was generally well tolerated, but in 1 nonresponder torsades de pointes developed 3 hours after the first 640-mg dose at a plasma sotalol concentration well within the concentration range measured in other patients. Sotalol's repolarization-prolonging actions are seen at higher concentrations than those associated with heart rate slowing and may contribute to its clinical effects.