Ethanol alters hemodynamic responses to cocaine in rats

Alcohol, 1999

Cocaine-induced cardiovascular responses in rats during acute ethanol withdrawal. ALCOHOL 19 (2) [131][132][133][134][135][136][137] 1999.-The effects of cocaine administration during acute ethanol withdrawal on both the cardiovascular system and cocaine pharmacokinetics are unclear. This study demonstrated differences in the cardiovascular effects of i.v.-administered cocaine during acute ethanol withdrawal in awake, freely moving rats. The altered responses to cocaine while in acute ethanol withdrawal compared to control animals included: enhanced increases in mean arterial pressure and systemic vascular resistance, attenuated heart rate decreases, and enhanced cardiac index and stroke volume decreases. These results may suggest that acute ethanol withdrawal disrupts myocardial contractility when the myocardium is subjected to a large increase in blood pressure. Serial arterial blood sampling in additional groups of rats were done to assess plasma cocaine concentrations and to confirm the absence of ethanol in the blood. Plasma cocaine concentrations were not effected by acute ethanol withdrawal. These results indicate that the altered cardiovascular responses to cocaine during acute ethanol withdrawal were not a result of differences in cocaine plasma concentrations.

Pharmacology Biochemistry and Behavior, 1988

PHARMACOL BIOCHEM BEHAV 31(4) 877-883, 1988.-Intranasal cocaine (COC) and oral ethanol (ETOH) were administered to nine research volunteers during dally experimental sessions. Following the determination of baseline cardiovascular indexes, an ETOH cocktail (0, 19.4, 38.7, or 58.1 g of ETOH in lemonade) was consumed over a ten-minute period. Cocaine hydrochloride (4, 48, 96 mg) was inhaled 25 minutes after the start of ETOH drinking. Breath samples were collected 50 minutes after the start of ETOH drinking to estimate blood alcohol level (BAL). The effect of these doses, alone and in combination, on heart rate (HR) and blood pressure (BP), while resting and while performing a serial acquisition task, were determined. COC and ETOH alone significantly increased HR up to 6 bpm without affecting BP. Combining the two highest doses of COC with the highest BAL increased HR by 20 bpm. During task performance, in the absence of drug, HR was increased up to 5 bpm, and BP was unchanged. Combining the highest COC dose and BAL with task performance increased HR by 40 bpm. Small increases in BP were also observed under these conditions. These results indicate that combinations of ETOH, COC and task performance produce greater increases in HR than BP, and, in addition, this increase in HR is greater than that observed following COC, ETOH, or task performance alone. Ethanol Cocaine Heart rate Blood pressure Drug interaction Humans

Academic Emergency Medicine, 2009

Objectives: In combination, cocaine and ethanol are more cardiotoxic than is either substance alone. These substances together constitute a drug abuse combination that commonly results in fatality. Previously the authors have demonstrated that cardiotoxicity of cocaine and ethanol is in part due to synergistic myocardial-depressant effects. However, it remains unclear whether this myocardial depression is associated with concomitant adverse effects on coronary blood flow in relation to these substances. The aim of this study was to investigate combined effects of cocaine and ethanol on myocardial blood flow, in relation to indices of myocardial function. Methods: Anesthetized dogs were instrumented for hemodynamic monitoring with Doppler flow probes placed on the circumflex and left anterior descending (LAD) coronary arteries. Dogs were randomized to three groups (each n = 6): ethanol (E, 1.5 g ⁄ kg followed by placebo), cocaine (C, placebo followed by cocaine, 7.5 mg ⁄ kg IV), or cocaine plus ethanol (C + E). All measurements were made at control, after placebo or ethanol, and then at fixed time intervals after cocaine or placebo bolus over 3 hours. Results: In both the C + E and the C groups, circumflex blood flow (CBF) decreased by 71% (95% confidence interval [CI] = 56% to 85%) and 57% (95% CI = 43% to 72%, both p < 0.04 vs. baseline) immediately after cocaine bolus. This was associated with transient depression of cardiac output, myocardial contractile function, and rate-pressure product (RPP), all indices of myocardial oxygen demand. A subsequent rebound increase of coronary sinus blood flow (CSBF) of 56% (95% CI = 26% to 137%, p < 0.03) compared to baseline occurred only in the C group and was associated with increases of myocardial contractile function and RPP. In the C + E group, 2 hours after drug administration, there was a decrease in CSBF of 49% (95% CI = 32% to 67%; p < 0.01) compared to baseline, which was associated with concomitant numerical decreases of the indices of myocardial oxygen demand and accumulation of cocaethylene. Conclusions: Acute decreases in myocardial flow secondary to cocaine, and cocaine and ethanol in combination, were similar and temporally associated with cocaine's direct myocardial-depressant effects. Rebound increases in myocardial function and blood flow due to cocaine were attenuated by ethanol. Delayed myocardial depression and decreases in myocardial blood flow were observed only with coadministration of cocaine and ethanol.

American Heart Journal, 1992

Although significant morbidity and mortality have been associated with the combined use of cocaine and ethanol, the cardiovascular effects of this combination are unknown. In this study, the effect of ethanol on cocaine-induced cardiovascular alterations was examined in two groups (n = 8 each) of dogs, which were randomized to receive either ethanol (1.68 gm/kg intravenously) or saline solution and cocaine (2 mg/kg intravenously). Ethanol had no effect on heart rate, mean arterial pressure, or rate-pressure product; but it increased ventricular end-diastolic pressure (p &amp;lt; 0.05), reduced coronary diameter (p &amp;lt; 0.02), and decreased ejection fraction by 16% +/- 4% (p &amp;lt; 0.005) from baseline. Cocaine produced increases in mean arterial pressure, rate-pressure product, and left ventricular end-diastolic pressure that were similar in both groups. After administration of cocaine, left ventricular ejection fraction decreased 16% +/- 2% (p &amp;lt; 0.001) from the baseline value in controls and 32% +/- 5% (p &amp;lt; 0.0002 vs baseline; p &amp;lt; 0.01 vs controls) in the ethanol group. Coronary diameter decreased (p &amp;lt; 0.05) in both groups after administration of cocaine; however, there was no difference between groups in the response of coronary circulation to cocaine. Cocaine and ethanol depress myocardial function, and their effects are additive. Failure of ethanol to enhance cocaine-induced coronary vasoconstriction suggests that the additive myocardial depressant effect of this combination is not related to ischemia but rather to a direct toxic effect of these drugs. Individuals who combine ethanol and cocaine may be at increased risk of hemodynamic compromise.

Life Sciences, 1993

This study examined the effects of cocaine on cardiac output in conscious freelymoving rats. Although pressor responses were similar at all doses, 14 of 32 rats had consistent declines in cardiac output (> 15%) and greater increases in systemic vascular resistance after administration of cocaine (5 mg/Kg, i.v.). Procaine (10 mg/Kg i.v.) did not mimic this effect in either subgroup. We propose that a subpopulation of rats exists with an enhanced susceptibility to cocaine-induced cardiac and systemic vascular alterations at higher doses.

Pharmacology Biochemistry and Behavior, 1999

KNUEPFER, M. M. AND P. J. MUELLER. Review of evidence for a novel model of cocaine-induced cardiovascular toxicity. PHARMACOL BIOCHEM BEHAV 63 (3) 489-500, 1999.-Cocaine is known to produce life-threatening cardiovascular complications in some but not all individuals. This review considers the premise that an appropriate animal model for cocaine-induced cardiotoxicity should be characterized by varying sensitivity in the population to the deleterious effects of cocaine. We have studied such a model in which physiological, biochemical, and pathological sensitivity to cocaine varies in rats. Our studies have identified a subset of rats that respond to cocaine with a decrease in cardiac output and a substantial increase in systemic vascular resistance (named vascular responders). In contrast, another group, designated mixed responders, is characterized by a smaller increase in systemic vascular resistance and a small increase in cardiac output. We reported that vascular responders are more likely to develop hypertension and cardiomyopathies with repeated cocaine administration. Under chloralose anesthesia, vascular responders have more profound pressor responses to cocaine and an initial brief spike in renal sympathetic nerve activity not usually noted in mixed responders. Vascular responders have higher resting and cocaine-induced dopamine turnover in the striatum. In addition, vascular responders have higher alpha-adrenergic vasoconstrictor tone, whereas mixed responders have higher adrenergic cardiac tone. The difference in cardiac output and systemic vascular resistance responses to cocaine in these two subsets of the population can be prevented by L-type calcium channel, muscarinic, or alpha-adrenergic blockade. Similar hemodynamic response variability is noted with other psychoactive agents and with acute stress, suggesting that the response patterns are not unique to cocaine. We propose that individual hemodynamic response variability is dependent on differences in CNS responsiveness and correlated with the incidence of cardiovascular disease.

Journal of Pharmaceutical Sciences, 1999

0 The pharmacokinetics and pharmacodynamics of cocaine and its three metabolites, benzoylecgonine, norcocaine, and cocaethylene, were investigated in awake, freely moving rats. This work was performed to examine the effect of alcohol coadministration on the metabolic profile of cocaine and to determine the contribution of cocaine metabolites to the pharmacological responses observed after cocaine administration. The plasma and brain extracellular fluid concentration−time profiles were characterized after intravenous (iv) administration of cocaine and the three metabolites in a crossover experimental design. The neurochemical response, measured as the change in dopamine concentration in the nucleus accumbens, and the cardiovascular responses, measured as the change in the mean arterial blood pressure, heart rate, and QRS interval, were monitored simultaneously. Cocaethylene had the highest brain-to-plasma distribution ratio, followed by cocaine, norcocaine, and benzoylecgonine. The estimated total body clearances for cocaine, benzoylecgonine, norcocaine, and cocaethylene were 140 ± 19, 14.7 ± 1.2, 130 ± 19, and 111 ± 16 mL/min/kg, respectively. Alcohol coadministration increased the formation of norcocaine, decreased the formation of benzoylecgonine, and resulted in the formation of the pharmacologically active metabolite cocaethylene. When cocaine was administered with alcohol, 12.9 ± 3.1% to 15.3 ± 2.9% of the cocaine dose was converted to cocaethylene. Benzoylecgonine did not have any central nervous system or cardiovascular activities after iv administration. Compared with cocaine, norcocaine and cocaethylene had more potent and prolonged effects on the neurochemical, heart rate, and QRS interval responses, and were equipotent in increasing the mean arterial blood pressure. These results indicate that changes in the cocaine metabolic profile and the formation of the pharmacologically active metabolite cocaethylene are, at least partially, responsible for the more intense and longer lasting effects reported after using this drug in combination with alcohol.

Journal of Pharmaceutical Sciences, 1999

0 The effect of alcohol coadministration on cocaine pharmacokinetics and pharmacodynamics was investigated in awake, freely moving rats. Cocaine plasma and brain extracellular fluid (ECF) concentration−time profiles were characterized after intraperitoneal (ip) administration of 30 mg/kg cocaine to rats that were pretreated with either normal saline or alcohol at 5 g/kg in a balanced crossover experimental design. The neurochemical response to cocaine administration, measured as the change in dopamine concentration in the nucleus accumbens (N ACC) and the change in the mean arterial blood pressure were monitored simultaneously. Intragastric alcohol administration significantly increased cocaine systemic bioavailability after ip administration from 0.550 ± 0.044 to 0.754 ± 0.071. Also, the absorption rate constant increased from 0.199 ± 0.045 to 0.276 ± 0.059 min -1 due to alcohol coadministration; however, this increase was not significant. Alcohol inhibition of cocaine metabolism caused an increase in cocaine elimination half-life from 26.3 ± 3.6 to 40.0 ± 8.1 min. Also, cocaine tissue distribution was enhanced by alcohol, resulting in a significant increase in cocaine volume of distribution. Analysis of the brain cocaine concentration−neurochemical effect relationship by the sigmoid-E max pharmacodynamic model showed that E max increased from 850 ± 200 to 1550 ± 640% of baseline due to alcohol coadministration, whereas EC 50 decreased from 3400 ± 580 to 2000 ± 650 ng/mL, indicating higher cocaine potency in the presence of alcohol. The estimates of the indirect inhibitory pharmacodynamic model used to examine the plasma cocaine concentration− change in blood pressure relationship were not significantly different after the two treatments. These results indicate that alcohol significantly alters cocaine absorption, distribution, and elimination, resulting in higher and prolonged cocaine plasma concentration. Alcohol coadministration also potentiates the neurochemical response to cocaine administration.

Life Sciences, 1996

The effects of repeated cocaine administration on contractile responses were studied in adult rabbits. Repeated cocaine exposure caused a significant increase in the maximal response of the aorta to the agonists norepinephrine and serotonin as well as the receptor-independent stimulus KC1 when compared to the saline controls. Cocaine exposure caused a signiIicant increase in the wet weights of both the heart and aorta. When the contraction was normalized to the wet weight of the aorta there was no difIerence between rabbits administered cocaine and saline. Acute cocaine administration caused a time-dependent increase in immunoreactivity of the proto-oncogene c-Fos in the aorta. These results show that repeated cocaine administration leads to the development of cardiovascular hypertrophy.

Journal of medical toxicology : official journal of the American College of Medical Toxicology, 2009

Concurrent abuse of alcohol and cocaine results in the formation of cocaethylene, a powerful cocaine metabolite. Cocaethylene potentiates the direct cardiotoxic and indirect neurotoxic effects of cocaine or alcohol alone. A 44-year-old female with history of cocaine and alcohol abuse presented with massive stroke in the emergency department. CT scan revealed extensive left internal carotid artery dissection extending into the left middle and anterior cerebral arteries resulting in a massive left hemispheric infarct, requiring urgent decompressive craniectomy. The patient had a stormy hospital course with multiple episodes of torsades de pointes in the first 4 days requiring aggressive management. She survived all events and was discharged to a nursing home with residual right hemiplegia and aphasia. The combination of ethanol and cocaine has been associated with a significant increase in the incidence of neurological and cardiac emergencies including cerebral infarction, intracrania...