Cocaethylene causes dose-dependent reductions in cardiac function in anesthetized dogs.
Twelve million Americans abuse both cocaine and ethanol each year because this drug combination produces a pronounced and prolonged euphoria. However, these substances in combination are substantially more toxic than either drug alone. This toxicity may be due to cocaethylene, which has been detected in the serum of patients who have used cocaine and ethanol and two require emergency treatment. Cocaethylene is a pharmacologically active cocaine metabolite formed in the liver only in the presence of ethanol. To investigate the cardiovascular effects of cocaethylene, we randomized 15 mongrel dogs to receive 11.25 mg/kg (n = 4), 7.5 mg/kg (n = 6), or 3.75 mg/kg (n = 5) of cocaethylene as an intravenous (i.v.) bolus. These doses were chosen to achieve serum concentrations of cocaethylene consistent with those observed in patients with cocaine and ethanol toxicity. The ECG and the femoral arterial, left ventricular (LV), and pulmonary artery pressure were measured continuously, and cardiac output (CO) and serum levels of cocaethylene were monitored at specific intervals before and after drug administration. The maximal rate of increase and decrease in LV pressure (LVP), i.e., (dP/dt)max and (dP/dt)min, were determined as our indexes of ventricular contractility and relaxation. Cocaethylene concentrations peaked 2-4 min after each bolus and then decreased in a curvilinear manner. Cocaethylene's half-life (t1/2) was 150 +/- 15.1 min (mean +/- SEM). The greatest hemodynamic changes occurred at the peak cocaethylene serum concentrations in each group. In comparison with control measurements, cocaethylene in concentrations of 11.25 and 7.5 mg/kg decreased (dP/dt)max by 81 and 43% and decreased (dP/dt)min by 80 and 36%, respectively. In these two groups, cocaethylene decreased stroke volume (SV) by 29 and 33% and reduced mean arterial pressure (MAP) by 65 and 30%, respectively. Cocaethylene increased pulmonary artery wedge pressure (PAWP) by 70 and 67% in the 11.25- and 7.5-mg/kg groups. These hemodynamic changes persisted for 60 min after the bolus administration. In each of the three groups, cocaethylene increased the QRS interval duration by 60, 32, and 44% and the QTc interval by 38, 21, and 17%. These ECG changes persisted for 120 min. These experiments suggest cocaethylene depresses the myocardium. Cocaethylene may be a major contributor to the delayed but substantial cardiotoxicity that occurs in individuals who use both cocaine and ethanol.
Wilson
L D
LD
Department of Emergency Medicine, Mt. Sinai Medical Center Cleveland, Ohio 44106, USA.
Henning
R J
RJ
Suttheimer
C
C
Lavins
E
E
Balraj
E
E
Earl
S
S
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D003042:Cocaine / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity; D003864:Depression, Chemical; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects
C066444:cocaethylene; D003042:Cocaine