Whitcomb D C, Gilliam F R, Starmer C F, Grant A O
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
J Clin Invest. 1989 Nov;84(5):1629-36. doi: 10.1172/JCI114340.
The opiate analgesic propoxyphene produces cardiac toxicity when taken in overdose. We recently observed a patient with propoxyphene overdose in whom marked QRS widening was reversed by lidocaine. The reversal is apparently paradoxical as both agents block the inward sodium current (INa). We examined possible mechanisms of the reversal by measuring INa in rabbit atrial myocytes during exposure to propoxyphene and the combination of propoxyphene and lidocaine (60 and 80 microM, respectively). Propoxyphene caused use-dependent block of INa during pulse train stimulation. Block recovered slowly with time constants of 20.8 +/- 3.9 s. Block during lidocaine exposure recovered with time constants of 2-3 s. During exposure to the mixture, block recovered as a double exponential. The half time for recovery during exposure to the mixture was 1.6 +/- .9 s compared with a half-time of 14.3 +/- 2.9 s during exposure to propoxyphene alone. During pulse train stimulation, less steady-state block was observed during exposure to the mixture than during exposure to propoxyphene alone when the interval between pulses was greater than 0.95 s. Both drugs compete for a common receptor during the polarizing phase. The more rapid dissociation of lidocaine during the recovery period leads to less block during the mixture than during exposure to propoxyphene alone. The experiments suggest a mechanism for reversal of the cardiac toxicity of drugs which have slow unbinding kinetics.
阿片类镇痛药丙氧芬过量服用时会产生心脏毒性。我们最近观察到一名丙氧芬过量的患者，其明显增宽的QRS波群被利多卡因逆转。这种逆转显然自相矛盾，因为两种药物都阻断内向钠电流（INa）。我们通过在暴露于丙氧芬以及丙氧芬与利多卡因（分别为60和80微摩尔）的组合期间测量兔心房肌细胞中的INa，研究了这种逆转的可能机制。丙氧芬在串刺激期间引起INa的使用依赖性阻滞。阻滞随时间缓慢恢复，时间常数为20.8±3.9秒。利多卡因暴露期间的阻滞以2 - 3秒的时间常数恢复。在暴露于混合物期间，阻滞以双指数形式恢复。暴露于混合物期间恢复的半衰期为1.6±0.9秒，而单独暴露于丙氧芬期间的半衰期为14.3±2.9秒。在串刺激期间，当脉冲间隔大于0.95秒时，与单独暴露于丙氧芬相比，暴露于混合物期间观察到的稳态阻滞较少。两种药物在极化期竞争共同受体。利多卡因在恢复期更快的解离导致与单独暴露于丙氧芬相比，混合物期间的阻滞较少。这些实验提示了具有缓慢解离动力学的药物心脏毒性逆转的一种机制。
