Comparison of the Effects of Cocaine and Its Metabolites on Cardiovascular Function in Anesthetized Rats

Erzouki, Hashim K.; Baum, Ira; Goldberg, Sharon; Schindler, Charles W.

doi:10.1097/00005344-199310000-00008

Cited by 45 publications

(28 citation statements)

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“…In particular, unlike CC, BE and EM are slowly excreted by the body and increase blood pressure due to a possible sympathomimetic effect, creating serious cardiovascular complications. The fact that both these compounds increase blood pressure without having a concomitant local anaesthetic effect, may contribute to the toxicity often observed hours after CC administration [2,31].…”

Section: Kinetics Of Cocaine and The Cardiac Responsementioning

confidence: 99%

Markers of cardiac oxidative stress and altered morphology after intraperitoneal cocaine injection in a rat model

Fineschi¹,

Baroldi

Centini

et al. 2001

International Journal of Legal Medicine

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This study was designed to assess the parameters of myocardial oxidative stress and related cardiac morphological changes following intraperitoneal cocaine exposure in rats. The cardiac levels of reduced glutathione(GSH), oxidised glutathione(GSSG), ascorbic acid (AA), and the production of malondialdehyde (MDA) were measured, as well as the variations of activity in the enzyme systems involved in cell antioxidant defence, glutathione peroxidase (GSH-Px), glutathione reductase (GR) and superoxide dismutase (SOD). After chronic cocaine administration for 30 days GSH was significantly depleted in the heart from 30 min (P < 0.001) to 24 h (P < 0.001) after exposure, and GSSG was increased for a similar time (P < 0.05 at 30 min and P < 0.01 at 24 h). SOD increased during the first hour (P < 0.001), GR and GSH-Px both increased from 30 min to 24 h, and these increases were statistically significant (P < 0.01 and P < 0.001 at 30 min and P < 0.01 and P < 0.001 at 24 h, respectively). The AA levels increased after 1 h (P < 0.01), remaining significantly so for 24 h (P < 0.001) and MDA increased from 30 min to 24 h, all values being highly significant (P < 0.001). The body weight was significantly (P < 0.001) reduced in both cocaine groups (40 mg/kg x 30 days and 40 mg/kg x 10 days + 60 mg/kg x 20 days). The heart weight (P < 0.01) and its percentage of the body weight (P < 0.001) were significantly higher in these two groups than in the controls. Similarly, in the noradrenaline 4 mg/ kg x 30 days group, the body weight was significantly (P < 0.001) reduced and the heart weight (P < 0.01) and its percentage of body weight (P < 0.001) were significantly higher than in the controls. In comparing the cocaine and noradrenaline experiments, the frequency and extent of cardiac lesions obtained with 40 mg/kg x 10 days + 60 mg/kg x 20 days of cocaine were similar to those with 8 mg/kg of noradrenaline at 24 h. In this experimental model, cocaine administration compromised the antioxidant defence system of the heart associated with a significant increase of heart weight and the percentage of body weight.

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Section: Kinetics Of Cocaine and The Cardiac Responsementioning

confidence: 99%

Markers of cardiac oxidative stress and altered morphology after intraperitoneal cocaine injection in a rat model

Fineschi¹,

Baroldi

Centini

et al. 2001

International Journal of Legal Medicine

View full text Add to dashboard Cite

show abstract

“…9 The proposed mechanism for the cardiac arrhythmia and conduction disturbances associated with cocaine overdose is the blockage of cardiac sodium channels by cocaine. 10,11 The two major metabolites of cocaine, benzoylecgonine and ecgonine methyl ester, do not have any cocaine-like stimulant activity when administered to experimental animals. However continuous intravenous (iv) infusion of benzoylecgonine and ecgonine methyl ester in doses of 0.45 and 1.5 mg/kg/min, respectively, for 30 min to anesthetized rats have been shown to significantly increase the blood pressure without affecting either the heart rate or the QRS duration.…”

Section: Introductionmentioning

confidence: 99%

Cocaine and alcohol interactions in the rat: Contribution of cocaine metabolites to the pharmacological effects

Pan

Hedaya

1999

Journal of Pharmaceutical Sciences

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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.

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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).…”

mentioning

confidence: 99%

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

O’Leary

Digregorio²,

Chahine³

2003

Mol Pharmacol

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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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Comparison of the Effects of Cocaine and Its Metabolites on Cardiovascular Function in Anesthetized Rats

Cited by 45 publications

References 0 publications

Markers of cardiac oxidative stress and altered morphology after intraperitoneal cocaine injection in a rat model

Markers of cardiac oxidative stress and altered morphology after intraperitoneal cocaine injection in a rat model

Cocaine and alcohol interactions in the rat: Contribution of cocaine metabolites to the pharmacological effects

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

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