Potentiation of cocaine toxicity with calcium channel blockers

doi:10.1016/0735-6757(89)90246-5

The American Journal of Emergency Medicine

Volume 7, Issue 5, September 1989, Pages 464-468

https://doi.org/10.1016/0735-6757(89)90246-5 Get rights and content

Abstract

Three calcium channel blockers were studied for efficacy in preventing seizures and death from cocaine intoxication. Rats were first pretreated with a test drug then subjected to high dose intraperitoneal cocaine. In this model, control animals developed seizures within six minutes, followed by death within ten minutes. Animals that were pretreated with diltiazem, nifedipine, or verapamil developed seizures significantly faster than controls, and at specific doses the death rate was higher than in controls for all three drugs. The potentiation of seizures and death by 2 mg/kg nifedipine pretreatment was further shown by challenge with three different doses of cocaine. This study fails to demonstrate a protective effect and suggests augmentation of cocaine toxicity by pretreatment with the three currently available calcium channel blockers. Several mechanisms by which calcium channel blockers may augment cocaine-induced toxicity are discussed.

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Cited by (49)

Analysis of cocaine adulterants in human brain in cases of drug-related death
2018, Forensic Science International
Citation Excerpt :
It was suggested that the protective effects of calcium channel blockers against the cardiac toxicity might be the reason for adding them. Contrary to these assumptions, Derlet and Albertson [9] showed that diltiazem also potentiates COC toxicity. Local anesthetics induce the effect of oral numbness of COC and lead consumers to assume high quality when they taste the drug [3,4].
For different reasons, street cocaine is often diluted with pharmacologically active substances, the so-called adulterants such as levamisole or hydroxyzine. A controversial debate exists currently on the uptake of adulterants from cocaine preparations and drug-related death. Previous research convincingly argues that serious adverse side effects that affect the central nervous and cardiovascular systems can be a consequence of adulterated cocaine.
Having identified the presence of adulterants in lung tissue and blood, the concentrations of these substances in brain, an important target location, was of interest. This provides an opportunity to assess their role in cases of drug-related deaths.
We developed and validated a method for the analysis of cocaine, two cocaine metabolites and six adulterants, which can typically be found in cocaine preparations, and one adulterant metabolite in brain tissue by gas chromatography–mass spectrometry (GC–MS)¹. Ten brain samples which were tested positive for cocaine were analyzed. The homogenized brain tissue was embedded into drying paper for protein precipitation. During a subsequent solid-phase extraction (SPE), the eluate and one of the wash fractions were collected. After derivatization with N-Methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) in pyridine and isooctane, the extracts were analyzed by GC–MS.
The method was fully validated for cocaine (COC), benzoylecgonine (BZE), ecgonine methyl ester (EME), diltiazem (DIL), hydroxyzine (HYD), and levamisole (LEV) and partly validated for cetirizine (CET), lidocaine (LID), phenacetin (PHE), and procaine (PRO) in brain material. By analyzing post-mortem brain tissue of ten cocaine users, LEV, LID, and HYD as well as PHE were identified in contrast to DIL, PRO, and the HYD metabolite CET. HYD and LEV were found in moderate to high concentrations in some cases. Therefore, it cannot be excluded that they have caused adverse side effects.
Because adulterants can potentially affect the central nervous and cardiac systems, it is likely that they enhance COC toxicity.
Drug-related death: Adulterants from cocaine preparations in lung tissue and blood
2015, Forensic Science International
Citation Excerpt :
According to a study by Derlet and Albertson, exactly the opposite seems to be the true. They found out that the toxic effects of cocaine were potentiated at specific doses of diltiazem [12] and that no protective effect was observed [13]. In the present study, diltiazem was detected in three cases (Fig. 5).
The abuse of drugs such as street cocaine is known to cause a variety of toxic effects, some of which involve the lungs and often induce lethal complications. While the toxicity of cocaine itself is reviewed well, the influence of toxic effects of its adulterants on the human body is not thoroughly studied. Therefore, we examined heart blood, femoral vein blood and lung tissue from 11 cases for typically used adulterants in cocaine preparations and check whether if the concentrations in the lung tissue are higher than in the blood. The adulterants were isolated using solid-phase (SPE) and liquid–liquid extraction (LLE) and quantified via high-pressure-liquid-chromatography-time-of-flight–mass spectrometry (LC/TOF–MS). Five adulterants, i.e., phenacetin, lidocaine, diltiazem, levamisole and hydroxyzine, were detected. We found out that the concentration of these substances was often higher in the lung than in the analogous analysed body fluids. It should therefore be considered whether – for the determination in the cause of death – the lung should be examined in addition to heart blood, urine or brain tissue.
Analysis of cocaine and its adulterants in drugs for international trafficking seized by the Brazilian Federal Police
2015, Forensic Science International
Here, gas chromatography with nitrogen phosphorous detector (GC–NPD) method was developed and validated for the quantification of cocaine and adulterants (caffeine, 4-dimethylaminoantipyrine, levamisole, lidocaine and phenacetin) in illicit samples. The method was based on direct dilution of samples in methanol, sonication for 5 min and centrifugation. After appropriate dilution, an aliquot was injected into GC–MS in order to identify the active compounds and into GC–NPD for the analytes quantification. Bupivacaine was used as an internal standard. The method showed to be precise, accurate and linear over a range of 0.5–100% (weight/weight percentages) for all analytes, except phenacetin which showed a linear range between 2% and 100%. The method was successfully applied to 54 samples seized by the Brazilian Federal Police in the International Airport of Sao Paulo and mailing services during the year 2011. All the samples were associated with international trafficking and were apprehended while leaving the country. The purity of cocaine ranged from 16.5% to 91.4%. Cocaine was the only detected active compound in 29.6% of total samples. Among the identified cutting agents, levamisole was the most abundant (55.6% of the total samples) and relative concentrations (weight/weight percentages) ranged from 0.7% to 23%. Lidocaine, caffeine, phenacetin and 4-dimethylaminoantipyrine were also identified in these samples in minor concentrations. In contrast with what we initially hypothesized, drugs intended to international trafficking did not present high cocaine purity and most of the samples were laced with adulterants before leaving Brazil.
Rethinking cocaine-associated chest pain and acute coronary syndromes
2011, Mayo Clinic Proceedings
Every year more than 500,000 patients present to the emergency department with cocaine-associated complications, most commonly chest pain. Many of these patients undergo extensive work-up and treatment. Much of the evidence regarding cocaine's cardiovascular effects, as well as the current management of cocaine-associated chest pain and acute coronary syndromes, is anecdotally derived and based on studies written more than 2 decades ago that involved only a few patients. Newer studies have brought into question many of the commonly held theories and practices regarding the etiology, diagnosis, and treatment of this common clinical scenario. However, there continues to be a paucity of prospective, randomized trials addressing this topic as it relates to clinical outcomes. We searched PubMed for English-language articles from 1960 to 2011 using the keywords cocaine, chest pain, coronary arteries, myocardial infarction, emergency department, cardiac biomarkers, electrocardiogram, coronary computed tomography, observation unit, β-blockers, benzodiazepines, nitroglycerin, calcium channel blockers, phentolamine, and cardiomyopathy; including various combinations of these terms. We reviewed the abstracts to confirm relevance, and then full articles were extracted. References from extracted articles were also reviewed for relevant articles. In this review, we critically evaluate the limited historical evidence underlying the current teachings on cocaine's cardiovascular effects and management of cocaine-associated chest pain. We aim to update the reader on more recent, albeit small, studies on the emergency department evaluation and clinical and pharmacologic management of cocaine-associated chest pain. Finally, we summarize recent guidelines and review an algorithm based on the current best evidence.
Evaluation and management of the patient who has cocaine-associated chest pain
2006, Cardiology Clinics
Cocaine-associated chest pain
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Citation Excerpt :
In rats, nitrendipine has been shown to prevent cardiac toxicity caused by IV cocaine administration [118,119]. In another study in which rats were pretreated with diltiazem, nifedipine, or verapamil and then subjected to high doses of intraperitoneal cocaine, pretreatment with calcium channel blockers resulted in the development of seizures more quickly in pretreated animals than in controls, indicating that calcium channel blockers may actually potentiate cocaine-induced toxicity [120]. Although verapamil has been demonstrated to alleviate cocaine-induced coronary vasoconstriction in patients undergoing cardiac catheterization for the evaluation of chest pain [42], its role in cocaine-related ischemia and infarction remains unclear and requires further investigation.

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Original contributionPotentiation of cocaine toxicity with calcium channel blockers

Abstract

Ann Emerg Med

Ann Emerg Med

Neuropharmacology

Pharmacol Biochem Behav

Life Sci

Pharmacol Biochem Behav

Gen Pharmacol

Ann Emerg Med

Eur J Pharmacol

Ann Emerg Med

Brain Res

Gen Pharmacol

Medical risks of cocaine use

West J Med

Medical complications of cocaine abuse

N Engl J Med

Cocaine and other stimulants

N Engl J Med

Antidotes for cocaine poisoning

N Engl J Med

A calcium-channel blocker as antidote to the cardiac effects of cocaine intoxication

N Engl J Med

Original contribution
Potentiation of cocaine toxicity with calcium channel blockers