Billman G E
Department of Physiology, Ohio State University, Columbus, USA.
Crit Rev Toxicol. 1995;25(2):113-32. doi: 10.3109/10408449509021610.
It has become increasingly apparent that cocaine abuse can provoke lethal cardiac events, including myocardial infarction and ventricular fibrillation. The mechanisms responsible for these cardiotoxic actions of cocaine largely remain to be determined. Cocaine has two primary pharmacological properties that can adversely affect the heart and vasculature. Cocaine acts both as a local anesthetic (sodium and potassium channel blockade) and as a powerful cardiac stimulant that accentuates the actions of the sympathetic nervous system (inhibition of central and peripheral neuronal catecholamine uptake). The local anesthetic properties could impair impulse conduction, as well as elicit inhomogeneities in repolarization (refractory period), which creates an ideal substrate for reentrant arrhythmias. In addition, high doses of cocaine can depress contractile function due to inhibition of sodium/calcium exchange that results from decreased sodium influx (local anesthetic action). These actions are particularly obvious when sympathomimetic effects of cocaine are blunted. In a similar manner, the cocaine-induced accumulation of catecholamines potentiates the activation of alpha- and beta-adrenergic receptors, which can provoke coronary vasospasm (myocardial ischemia and infarction), increased contractile force (increased metabolic demand), and cardiac arrhythmias. The activation of adrenergic receptors will elicit a cascade of second messengers, ultimately provoking an increase in cytosolic calcium. These elevations in cytosolic calcium can provoke oscillations in membrane potential, triggering sustained action potential generation and extrasystoles. In particular, activation of the alpha IA-adrenergic receptor subtype and corresponding increase in calcium influx via voltage sensitive (L type) channels may play a critical role in the genesis of malignant arrhythmias. Thus, the adrenergic and local anesthetic properties of cocaine could act synergistically to elicit toxic actions on the heart.
越来越明显的是，可卡因滥用会引发致命的心脏事件，包括心肌梗死和心室颤动。可卡因这些心脏毒性作用的机制很大程度上仍有待确定。可卡因有两种主要的药理特性，可对心脏和血管系统产生不利影响。可卡因既作为局部麻醉剂（钠和钾通道阻滞），又作为强大的心脏兴奋剂，增强交感神经系统的作用（抑制中枢和外周神经元儿茶酚胺摄取）。局部麻醉特性可能会损害冲动传导，并导致复极化（不应期）不均匀，这为折返性心律失常创造了理想的基质。此外，高剂量的可卡因可因钠内流减少（局部麻醉作用）导致钠/钙交换受抑制，从而降低收缩功能。当可卡因的拟交感神经效应减弱时，这些作用尤为明显。同样，可卡因诱导的儿茶酚胺蓄积会增强α和β肾上腺素能受体的激活，这可引发冠状动脉痉挛（心肌缺血和梗死）、增加收缩力（增加代谢需求）以及导致心律失常。肾上腺素能受体的激活会引发一系列第二信使，最终导致细胞内钙增加。细胞内钙的这些升高可引发膜电位振荡，触发持续动作电位的产生和早搏。特别是，αIA - 肾上腺素能受体亚型的激活以及通过电压敏感（L型）通道相应增加的钙内流可能在恶性心律失常的发生中起关键作用。因此，可卡因的肾上腺素能和局部麻醉特性可能协同作用，对心脏产生毒性作用。
