Cocaethylene Causes Dose-Dependent Reductions in Cardiac Function in Anesthetized Dogs

Wilson, Lance D.; Henning, Robert J.; Suttheimer, Craig; Lavins, Eric S.; Balraj, Elizabeth; Earl, Sandra

doi:10.1097/00005344-199512000-00017

Cited by 38 publications

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“…Cocaethylene is a metabolite of cocaine and ethanol that is synthesized when the two drugs are coingested (Dean et al, 1991;Brzezinski et al, 1994). Cocaethylene slows cardiac conduction and delays repolarization, conditions that are known to promote arrhythmias (Erzouki et al, 1993;Wilson et al, 1995;Henning and Wilson, 1996). Cocaethylene is a potent inhibitor of the native cardiac Na ϩ current (Xu et al, 1994).…”

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confidence: 99%

“…In addition, cocaethylene inhibits human ethera-go-go potassium channels that produce the rapidly activating component of the cardiac delayed rectifier current (Ferreira et al, 2001;O'Leary, 2002). Cocaethylene inhibition of cardiac sodium and potassium channels may contribute to the increased incidence of sudden death associated with the combined use of cocaine and alcohol (Wilson et al, 1995;Henning and Wilson, 1996).…”

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confidence: 99%

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Closing and Inactivation Potentiate the Cocaethylene Inhibition of Cardiac Sodium Channels by Distinct Mechanisms

O’Leary

Digregorio²,

Chahine³

2003

Molecular Pharmacology

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Cocaethylene, a metabolite of cocaine and alcohol, is a potent inhibitor of the cardiac (Na v 1.5) sodium channel heterologously expressed in Xenopus laevis oocytes. Cocaethylene produces minimal tonic block under resting conditions but causes a potent use-dependent inhibition during repetitive depolarization and a hyperpolarizing shift in the steady-state inactivation. The data are consistent with a state-dependent binding mechanism, which has high affinity for inactivated channels (K I ϭ 17 M) and low affinity for resting channels (K R ϭ 185 M). Mutations of the interdomain D3-D4 linker eliminated rapid inactivation and weakened the cocaethylene inhibition, consistent with an important role for fast inactivation in cocaethylene binding. A rapid component of cocaethylene inhibition was observed in a noninactivating mutant of Nav1.5 that was tightly linked to channel opening and displayed properties consistent with a pore blocking mechanism. Hyperpolarization caused the noninactivating mutant channel to close, trapping cocaethylene and slowing the recovery. Mutation of a conserved isoleucine (I1756C) located near the extracellular end of the D4S6 segment accelerated the recovery of the noninactivating channel, suggesting that this mutation facilitates cocaethylene untrapping, which seems to be the rate-limiting step in the recovery when the channel is closed. This contrasts with the rapidly inactivating channel, where the I1756C mutation did not alter the recovery from cocaethylene inhibition. The data suggest that additional mechanisms, such as more stable cocaethylene binding, may be a more important determinant of recovery kinetics when the channels are inactivated. The data indicate that deactivation and inactivation slow the recovery and potentiate the cocaethylene inhibition of the Nav1.5 channel by distinct mechanisms.

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confidence: 99%

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confidence: 99%

Closing and Inactivation Potentiate the Cocaethylene Inhibition of Cardiac Sodium Channels by Distinct Mechanisms

O’Leary

Digregorio²,

Chahine³

2003

Molecular Pharmacology

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“…Other studies have reported cardiac toxicity related to CE, but typically at greater serum concentrations of CE. 45 Serum cocaine levels remained significantly greater than the serum cocaine concentrations later in the study; however, the delayed decreases in myocardial function were not observed in the cocaine only group. Other cocaine or ethanol metabolites were not measured and potentially could have played a role in the cardiotoxicity observed.…”

Section: Limitations and Future Questionsmentioning

confidence: 73%

Untitled

2001

Academic Emergency Medicine

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Abstract. Objectives: Simultaneous abuse of cocaine and ethanol affects 12 million Americans annually. In combination, these substances are substantially more toxic than either drug alone. Their combined cardiac toxicity may be due to independent effects of each drug; however, they may also be due to cocaethylene (CE), a cocaine metabolite formed only in the presence of ethanol. The purpose of this study was to delineate the role of CE in the combined cardiotoxicity of cocaine and ethanol in a model simulating their abuse. Methods: Twenty-three dogs were randomized to receive either 1) three intravenous (IV) boluses of cocaine 7.5 mg/kg with ethanol (1 g/kg) as an IV infusion (CϩE, n = 8), 2) three cocaine boluses only (C, n = 6), 3) ethanol infusion only (E, n = 5), or 4) placebo boluses and infusion (n = 4). Hemodynamic measurements, electrocardiograms, and serum drug concentrations were obtained at baseline, and then at fixed time intervals after each drug was administered. Results: Two of eight dogs in the CϩE group experienced cardiovascular collapse.The most dramatic hemodynamic changes occurred after each cocaine bolus in the CϩE and C only groups; however, persistent hemodynamic changes occurred in the CϩE group. Peak CE levels were associated with a 45% (SD Ϯ 22%, 95% CI = 22% to 69%) decrease in cardiac output (p < 0.05), a 56% (SD Ϯ 23%, 95% CI = 32% to 80%) decrease in dP/dt max (p < .006), and a 23% (SD Ϯ 15%, 95% CI = 7% to 49%) decrease in SVO 2 (p < 0.025). Ventricular arrhythmias were primarily observed in the CϩE group, in which four of eight dogs experienced ventricular tachycardia. Conclusions: Cocaine and ethanol in combination were more toxic than either substance alone. Co-administration resulted in prolonged cardiac toxicity and was dysrhythmogenic. Peak serum cocaethylene concentrations were associated with prolonged myocardial depression.

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“…32 In anaesthetized dogs, cocaethylene causes significant myocardial depression and slight heart rate increase. 33 The reduction in myocardial contractility may lead to a remarkable decrease in hepatic blood flow and, consequently, reduce metabolism of both cocaine, cocaethylene, and norcocaine in the liver. Therefore, changes in the pharmacodynamics with cocaine+alcohol coadministration may in return affect the pharmacokinetics and metabolism of cocaine.…”

Section: Discussionmentioning

confidence: 99%

Cocaine and alcohol interactions in the rat: Effect of cocaine and alcohol pretreatments on cocaine pharmacokinetics and pharmacodynamics

Pan¹,

Hedaya²

1999

Journal of Pharmaceutical Sciences

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This experiment was designed to investigate the effect of pretreatment with cocaine and alcohol on cocaine pharmacokinetics and pharmacodynamics. Four groups of rats (n = 8 per group) received one of the following pretreatments for two weeks: none, alcohol (10% v/v in drinking water), cocaine (15 mg/kg/day ip), and alcohol+cocaine (10% v/v in drinking water + 15 mg/kg/day ip). On the day of the experiment, cocaine was administered (30 mg/kg, ip) to each rat, either alone or in combination with alcohol (5 g/kg, po), in a balanced crossover experimental design. Plasma and brain ECF concentrations of cocaine and its three metabolites: benzoylecgonine, norcocaine, and cocaethylene were assayed by HPLC-UV. The percent change in brain dopamine concentration, mean arterial blood pressure, and heart rate were determined simultaneously. A sigmoid-E(max) model was used to describe the brain cocaine concentration-neurochemical effect (dopamine) relationship, and an indirect pharmacodynamic response model was used to describe the plasma cocaine concentration-cardiovascular effect relationships. Alcohol pretreatment led to significant increase in cocaine AUC(p), alpha(t1/2), and beta(t1/2). Cocaine pretreatment significantly increased cocaine bioavailability, absorption rate constant, TBC, and the formation clearance of cocaethylene. Acute alcohol coadministration with cocaine increased cocaine AUC(p) and bioavailability, reduced the fraction of cocaine dose converted to benzoylecgonine, and increased the formation of norcocaine. These results indicate that the pharmacokinetics of cocaine, either administered alone or in combination with alcohol, is significantly altered due to prior cocaine and/or alcohol use. Both cocaine and alcohol pretreatments increased the E(max) for dopamine, with no effect on the EC(50). Acute alcohol coadministration with cocaine significantly increased the E(max) for dopamine and reduced the EC(50). Cocaine pretreatment significantly decreased the I(max) for blood pressure, IC(50), and R(max). For the heart rate response, both alcohol and cocaine pretreatments significantly increased the IC(50), with no effect on I(max). These results indicate that both cocaine and alcohol pretreatments as well as acute alcohol coadministration lead to significant alterations in cocaine pharmacodynamics that are due, at least in part, to the changes in cocaine pharmacokinetics. If similar effects occur in humans, chronic cocaine and alcohol abusers may respond differently to cocaine administration compared to naïve users and may be at higher risks of cocaine central nervous system toxicity.

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Cocaethylene Causes Dose-Dependent Reductions in Cardiac Function in Anesthetized Dogs

Cited by 38 publications

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Closing and Inactivation Potentiate the Cocaethylene Inhibition of Cardiac Sodium Channels by Distinct Mechanisms

Closing and Inactivation Potentiate the Cocaethylene Inhibition of Cardiac Sodium Channels by Distinct Mechanisms

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Cocaine and alcohol interactions in the rat: Effect of cocaine and alcohol pretreatments on cocaine pharmacokinetics and pharmacodynamics

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