Cocaethylene, a metabolite of cocaine and ethanol, is a potent blocker of cardiac sodium channels
Xu, Y.Q.; Crumb, W.J.; Clarkson, C.W.
Journal of Pharmacology and Experimental Therapeutics 271(1): 319-325
1994
ISSN/ISBN: 0022-3565 PMID: 7965731 Document Number: 429943
Cocaethylene is an active metabolite of cocaine believed to play a causative role in the increased incidence of sudden death in individuals who coadminister ethanol with cocaine. However, the direct effects of cocaethylene on the heart have not been well defined. In this study, we defined the effects of cocaethylene on the cardiac Na current (I-Na) in guinea pig ventricular myocytes at 16 degree C using the whole-cell patch-clamp method. Cocaethylene (10-50 mu-M) produced both a significant tonic block and a rate-dependent block of I-Na at cycle lengths between 2 and 0.2 sec. Cocaethylene produced a significantly greater tonic block than cocaine at a concentration of 50 mu-M and produced a significantly greater use-dependent block over a 5-fold range of drug concentrations (10-50 mu-M) and cycle lengths (0.2-1.0 sec). Analysis of channel-blocking characteristics revealed that cocaethylene had a significantly higher affinity for inactivated channels (K-di 5.1 +- 0.6 mu-M, n = 15) compared with cocaine (K-di = 7.9 +- 0.5 mu-M, n = 10) (P lt .01) and that cocaethylene produced a significantly greater hyperpolarizing shift of the steady-state I-Na inactivation curve (P lt .05). Cocaethylene also had a significantly longer time constant for recovery from channel block at -140 mV (12.24 +- 0.88 sec, n = 16) compared with cocaine (8.33 +- 0.56 sec, n = 14) (P lt .01). These results indicate that cocaethylene is a more potent blocker of cardiac I-Na than cocaine and suggest that the formation of cocaethylene in vivo could contribute to the development of cardiac conduction disturbances in individuals who self-administer high levels of both ethanol and cocaine.