Early afterdepolarizations and triggered activity induced by cocaine. A possible mechanism of cocaine arrhythmogenesis.

Kimura, Shin-ichi; Bassett, Arthur L.; Xi, Hongying; Myerburg, Robert J.

doi:10.1161/01.cir.85.6.2227

Cited by 81 publications

(39 citation statements)

References 41 publications

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“…If an afterdepolarization of significant magnitude occurs at a time when a critical number of cells can conduct an impulse an ectopic beat occurs, which can trigger a re-entrant rhythm. Afterdepolarizations are present in experimental models of cocaine administration and are proposed as one possible mechanism responsible for either monomorphic ventricular tachycardia or torsades des pointes [37].…”

Section: Potassium Channel Blockadementioning

confidence: 99%

Treatment of patients with cocaine‐induced arrhythmias: bringing the bench to the bedside

Hoffman

2010

Brit J Clinical Pharma

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Widespread use of cocaine and its attendant toxicity has produced a wealth of benchwork studies and small animal investigations that evaluated the effects of cocaine on the cardiovascular system. Despite this wealth of knowledge, very little is known about the frequency or types of arrhythmias in patients with significant cocaine toxicity. The likely aetiologies; catecholamine excess, sodium channel blockade, potassium channel blockade, calcium channel effects, or ischaemia may act alone or in concert to produce a vast array of clinical findings that are modulated by hyperthermia, acidosis, hypoxia and electrolyte abnormalities. The initial paper in the series by Wood & Dargan providing the epidemiological framework of cocaine use and abuse is followed by a detailed review of the electrophysiological effects of cocaine by O'Leary & Hancox. This review is designed to complement the previous papers and focuses on the diagnosis and treatment of patients with cocaine‐associated arrhythmias.

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Section: Potassium Channel Blockadementioning

confidence: 99%

Treatment of patients with cocaine‐induced arrhythmias: bringing the bench to the bedside

Hoffman

2010

Brit J Clinical Pharma

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“…The effects are similar to those seen with class Ia and Ic antidysrhythmics [9]. Other in vitro studies indicate that cocaine blocks delayed rectifier potassium channels [15] and, in high concentrations, decreases inotropy presumably by decreasing calcium influx [10]. Cocaine intoxication increases central sympathetic drive and circulating catecholamines [16].…”

Section: Introductionmentioning

confidence: 59%

“…Another potential dysrhythmogenic property of cocaine is its ability to block potassium channels [15,39]. Cocaine appears to interfere with the delayed rectifier potassium current by blocking the HERG channel [42,43].…”

Section: Cocainementioning

confidence: 99%

“…Increased intra-cellular calcium causes the cell to become relatively more depolarized, moving the membrane potential closer to the depolarization threshold leading to spontaneous myocardial depolarization and dysrhythmias [44]. Although in vitro models suggest that high concentrations of cocaine can decrease L-type calcium currents [15] and intra-cellular calcium levels (possibly via sodium 14 JOURNAL OF MEDICAL TOXICOLOGY I VOLUME 1, NUMBER 1 I DECEMBER 2005…”

Section: Cocainementioning

confidence: 99%

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The effect of amiodarone pretreatment on survival of mice with cocaine toxicity

et al. 2005

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Introduction: Cocaine is a common drug of abuse and use has been associated with ventricular dysrhythmias. Published guidelines suggest that amiodarone is the first line antidysrhythmic for ventricular tachycardia and fibrillation. However, the effects amiodarone in the setting of cocaine toxicity are unknown and unstudied. The purpose of this study was to evaluate the safety and efficacy of amiodarone pretreatment in a murine model of acute cocaine toxicity.Methods: This was a randomized, blinded, placebo controlled investigation using male CF-1 mice weighing 29-37 g. First, the safety of an intraperitoneal dose of amiodarone (40 mg/kg) was confirmed in 5 mice. Second, based on preliminary investigations, an approximate intraperitoneal LD 50 dose of cocaine (110 mg/kg) was identified and used as the cocaine dose in this study. Animals were then randomized to 2 groups. The control group received 0.5 mL of intraperitoneal 0.9% saline 30 minutes before cocaine. The study group received 40 mg/kg of intraperitoneal amiodarone (40 mg/kg) 30 minutes before cocaine. A blinded observer monitored mice for 2 hours after cocaine administration.Results: No mice in the amiodarone-only group developed any signs of toxicity or died. In the saline ϩ cocaine group 31/32 (96.9%; 95% CI 83.8 to 99.9) mice seized with a median time to seizure of 2.5 minutes, and 23/32 (71.9%; 95% CI 52.3 to 86.3) died with a median time to death of 5.5 minutes. In the amiodarone ϩ cocaine group 31/33 (93.9%; 95% CI 79.0 to 99.3) mice seized with a median time to seizure of 2.0 minutes, and 24/33 (72.7%; 95% CI 54.5 to 86.7) died with a median time to death of 6.0 minutes. All animals that died did so within 9 minutes. The difference in the proportion of animals dying in the amiodarone ϩ cocaine group compared to the saline ϩ cocaine group was 0.008 (Ϫ21 to 22%).Conclusions: In this study, pretreatment with amiodarone in cocaine poisoned mice resulted in no change in seizure incidence or mortality. However, definite conclusions about the reason for these findings cannot be drawn from this model.

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“…Cocaine can also result in cardioembolism due to its cardiotoxic effects, including myocardial infarction and cardiomyopathy [10]. Cocaine blocks potassium channels, resulting in prolongation of action potential duration (APD) and QT interval [11,12]. Cocaine toxicity has been associated with different cardiac arrhythmias, including torsades, but the combination of cocaine and ethanol is considered to be more arrhythmogenic than either substance alone [13,14].…”

mentioning

confidence: 99%

Neurotoxic and cardiotoxic effects of cocaine and ethanol

2009

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Introduction: 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.Case Report: 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.Conclusion: The combination of ethanol and cocaine has been associated with a significant increase in the incidence of neurological and cardiac emergencies including cerebral infarction, intracranial hemorrhage, myocardial infarction, cardiomyopathy, and cardiac arrhythmias. The alteration of cocaine pharmacokinetics and the formation of cocaethylene have been implicated, at least partially, in the increased toxicity of this drug combination.

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Early afterdepolarizations and triggered activity induced by cocaine. A possible mechanism of cocaine arrhythmogenesis.

Cited by 81 publications

References 41 publications

Treatment of patients with cocaine‐induced arrhythmias: bringing the bench to the bedside

Treatment of patients with cocaine‐induced arrhythmias: bringing the bench to the bedside

The effect of amiodarone pretreatment on survival of mice with cocaine toxicity

Neurotoxic and cardiotoxic effects of cocaine and ethanol

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