Ritchie R H, Sallustio B C, Hii J T, Horowitz J D
Department of Cardiology, The Queen Elizabeth Hospital, The University of Adelaide, Woodville, South Australia, Australia.
J Cardiovasc Pharmacol. 1998 Jun;31(6):876-84. doi: 10.1097/00005344-199806000-00011.
The myocardial concentration of many cardioactive drugs has been identified as an important determinant of their short-term effects in previous studies. Although sotalol is frequently administered via short-term intravenous injection, no previous studies had sought to correlate its uptake by the heart with its various effects. We determined the time course of short-term uptake of d,l-sotalol by human myocardium in vivo and investigated the relation between myocardial content of sotalol and the short-term hemodynamic, electrocardiographic, and electrophysiologic effects of the drug. Sixteen patients received a 20-mg intravenous bolus of sotalol at the time of diagnostic cardiac catheterization. Myocardial content of d- and l-sotalol (by using a paired transcoronary sampling technique) and the short-term hemodynamic and electrophysiologic effects of the drug were determined < or = 20 min after injection. Myocardial accumulation of sotalol was not enantioselective, proceeded very rapidly (maximal at 0.74 +/- 0.10 min, representing 2.05 +/- 0.45% of the total injected dose), and was not significantly influenced by left ventricular systolic function or the extent of coronary artery disease. Approximately one third of peak myocardial content was still present 17.5 min after sotalol administration. Maximal effects of the drug (reduction in spontaneous heart rate, p < 0.005; reduction in maximal rate of LV pressure increase (LV+dP/dtmax, p < 0.005); and prolongation of PR intervals, p < 0.02) were delayed by approximately 10 min relative to maximal myocardial sotalol content. The significant prolongation of AH intervals (p < 0.01) and atrioventricular nodal effective refractory periods (p < 0.0002) that was observed was also maximal 10 min after administration of sotalol. Thus a consistent delay between myocardial sotalol content and the short-term effects of the drug was observed. In conclusion, the accumulation of both d- and l-sotalol by the human myocardium is more rapid than that of any other agent studied to date, with considerable hysteresis between myocardial drug uptake and subsequent cardiac effects.
在先前的研究中，许多具有心脏活性药物的心肌浓度已被确定为其短期效应的重要决定因素。尽管索他洛尔经常通过短期静脉注射给药，但之前没有研究试图将心脏对它的摄取与其各种效应联系起来。我们测定了人体内d，l-索他洛尔在心肌中的短期摄取时间进程，并研究了索他洛尔的心肌含量与该药短期血流动力学、心电图和电生理效应之间的关系。16例患者在诊断性心导管插入术时接受了20mg索他洛尔静脉推注。注射后≤20分钟测定d-和l-索他洛尔的心肌含量（采用配对冠状动脉采样技术）以及该药的短期血流动力学和电生理效应。索他洛尔在心肌中的蓄积无对映体选择性，进行得非常迅速（在0.74±0.10分钟时达到最大值，占总注射剂量的2.05±0.45%），且不受左心室收缩功能或冠状动脉疾病程度的显著影响。索他洛尔给药后17.5分钟，仍有约三分之一的心肌含量峰值存在。该药的最大效应（自发性心率降低，p<0.005；左心室压力最大上升速率降低（LV + dP/dtmax，p<0.005）；PR间期延长，p<0.02）相对于最大心肌索他洛尔含量延迟约10分钟。观察到的AH间期显著延长（p<0.01）和房室结有效不应期显著延长（p<0.0002）在索他洛尔给药后10分钟时也达到最大值。因此，观察到心肌索他洛尔含量与该药短期效应之间存在一致的延迟。总之，人心脏对d-和l-索他洛尔的蓄积比迄今研究的任何其他药物都要快，心肌药物摄取与随后的心脏效应之间存在相当大的滞后现象。
