COCAINE - A REVIEW OF ITS TOXIC ACTIONS ON CARDIAC-FUNCTION

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(1A)-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.