Pharmacodynamic evaluation of the cardiovascular effects after the coadministration of cocaine and ethanol.
One of the most common drug dependencies occurring with alcoholism is cocaine dependence. This combination is particularly worrisome because of the increased risk of cardiovascular events associated with their coabuse. Although it is well known that ethanol increases the cardiovascular effects of cocaine by inhibiting cocaine clearance and the formation of cocaethylene, it has also been postulated that ethanol enhances the cardiovascular effects of cocaine independent of the two latter mechanisms. In this study, we investigated the cardiovascular pharmacodynamics of the cocaine-ethanol interaction to determine whether ethanol directly enhanced the cardiovascular effects of cocaine. Dogs (n = 6) were administered cocaine alone (3 mg/kg i.v.) and in combination with ethanol (1 g/kg i.v.) on separate study days. Blood pressure, heart rate, and the electrocardiogram were monitored continuously, and blood samples were collected periodically after drug administration. Concentration-time data were fitted to a two-compartment model, and concentration-effect data were fitted to a simple E(max) model using WinNonlin software. Pharmacokinetic and pharmacodynamic parameters were compared between the two treatment phases by a paired t test. The administration of ethanol before cocaine resulted in a decrease in cocaine clearance, but there were no differences in any of the other pharmacokinetic or pharmacodynamic parameter values between the cocaine alone and cocaine plus ethanol phases. As has been demonstrated in previous animal and human studies, the clearance of cocaine was decreased by prior administration of ethanol. However, ethanol did not change the concentration-effect relationship of the cardiovascular response to cocaine administration. It is concluded from this study that ethanol does not directly enhance the cardiovascular effects of cocaine.
Laizure
S Casey
SC
Department of Clinical Pharmacy, University of Tennessee, Suite 308, 910 Madison Ave., Memphis, TN 38163, USA. claizure@utmem.edu
Parker
Robert B
RB
D000437:Alcoholism / Q000209:etiology; D000818:Animals; D000889:Anti-Arrhythmia Agents; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D003042:Cocaine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000209:etiology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004562:Electrocardiography; D000431:Ethanol / Q000737:chemistry / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D023421:Models, Animal; D009200:Myocardial Contraction
D000889:Anti-Arrhythmia Agents; D004338:Drug Combinations; D000431:Ethanol; C066444:cocaethylene; D003042:Cocaine