Cardiogenic shock associated with calcium-channel and beta blockers: reversal with intravenous calcium chloride

Two cases in which oral ingestion of beta blocker and slow calcium-channel blocker was associated with profound hypotension and bradycardia are reported, including one case in which serum levels of both drugs were documented in the normal range at a time of severe clinical toxicity. Though unresponsive to usual therapeutic interventions, both patients showed an immediate and dramatic response to intravenous calcium chloride. It is recommended that intravenous calcium chloride be considered in any patient using routine doses of these two agents who presents with hypotension and/or bradycardia.     

Recurrent rhabdomyolysis in association with cocaine use

As the popularity of cocaine increases in our society, so does the frequency and variety of medical complications associated with its use. A growing number of cases have implicated cocaine use in the development of rhabdomyolysis and its complication, acute renal failure. We have reported the first case of recurrent rhabdomyolysis and acute renal failure directly associated with cocaine use. Although adulterants might cause muscle damage, we believe cocaine should be added to the list of drugs that are capable of producing rhabdomyolysis.     

Case series of individuals with analytically confirmed acute mephedrone toxicity

Context.?Previous reports of acute toxicity/harm associated with mephedrone use have been based on self-reported mephedrone use; toxicological screening has not been undertaken in these cases to determine whether mephedrone has been used. Objective.?To report the first case series of analytically confirmed mephedrone-related acute toxicity. Materials and methods.?Serum samples were collected from individuals presenting to an emergency department (ED) with acute toxicity related to self-reported mephedrone use. Toxicological analysis, by gas-chromatography coupled with mass-spectrometry and liquid chromatography with tandem mass-spectrometry was performed to qualitatively confirm mephedrone use. Symptoms/signs of acute mephedrone toxicity and basic physiological parameters were extracted from the routine ED records. Results.?Acute mephedrone-related toxicity was analytically confirmed in seven male patients; the mean?±?SD age was 24.6?±?6.5 years (range 16–36 years). Agitation (four patients) was the most common symptom/sign reported; other common symptoms/signs included: palpitations (two patients); chest pain (two patients); self-limiting pre-hospital seizures (one patient) and headaches (one patient). The mean heart rate was 109.1?±?21.8 (range 80–140) beats per minute; one patient had a “severe” tachycardia (heart rate of ≥140?bpm). The mean systolic blood pressure was 153.0?±?39.6 (range 110–210) mmHg; three patients had clinically significant hypertension (systolic blood pressure ≥160?mmHg). Discussion.?These analytically confirmed acute mephedrone toxicity presentations had clinical features of toxicity consistent with an acute sympathomimetic toxidrome (e.g. hypertension, tachycardia and agitation). These findings are similar to the pattern of toxicity seen with other sympathomimetic recreational drugs such as 3,4-Methylenedioxymethamphetamine (MDMA) and cocaine. Conclusion.?The process for determining whether a novel psychoactive substance should be controlled often relies on demonstrated/proven acute harm associated with its use. It is important that clinical toxicologists undertake appropriate biological sampling and toxicological analyses in suspected cases of “novel psychoactive drug” toxicity. This will ensure that both clinicians and legislative authorities are informed of the confirmed pattern of toxicity associated with these drugs.     

Sirenomelia accompanying exposure of the embryo to cocaine.

We have reported two cases of sirenomelia sequence associated with a history of cocaine exposure during a major part or the entire extent of the first trimester of pregnancy. The two infants were delivered during a 2 1/2-year interval in a newborn population in which prenatal cocaine exposure rose to an estimated 25%. The incidence of sirenomelia in this population was 18-fold higher than previously reported. The potential relationship between sirenomelia and cocaine exposure during the first month of pregnancy warrants further investigation.     

American mistletoe exposures

American mistletoe is generally considered to be extremely toxic. Although there are no data to support this contention, both the lay public and medical professionals often respond very aggressively after ingestion of any portion of this plant. To determine if American mistletoe is deserving of this reputation, the outcomes of 1,754 exposures to this plant were examined. All mistletoe data extracted from the American Association of Poison Control Centers national data collection system for the period of 1985 to 1992 were analyzed according to patient age, gastrointestinal decontamination therapy, patient outcome, and geographic region of the exposure. Pediatric exposures accounted for 92.1% of the cases, and 94.7% of the reported cases were accidental exposures. Of all cases, 99.2% had an outcome associated with no morbidity, and there were no fatalities. Apparently, patient outcome was not influenced by the use of gastrointestinal decontamination techniques—96.2% of treated patients remained asymptomatic versus 96.3% of patients who received no therapy. The accidental ingestion of American mistletoe is not associated with profound toxicity.     

Pneumomediastinum from nasal insufflation of cocaine

Chest pain is a common presenting symptom of cocaine users to the emergency department that requires a thorough work up. Pneumomediastinum is an uncommon complication of cocaine abuse that occurs more commonly when cocaine is smoked, but can also occur when cocaine is nasally insufflated. Our case report presents a patient with pneumomediastinum secondary to cocaine insufflation and reviews the necessary diagnostic tests that must be performed to rule out secondary pneumomediastinum, a severe life-threatening condition. Our case is unique, as it is one of a few reported cases of pneumomediastinum occurring after the use of intranasal cocaine.     

Ecstasy induced retropharyngeal emphysema.

This is the first reported case of isolated retropharyngeal emphysema caused by ingestion of the amphetamine derivatives "Ecstasy" and "Speed". The same complication has been reported with marihuana, cocaine, and heroin abuse. The condition resolved spontaneously and this seems to be the experience of others who have reported cases of cervical emphysema and pneumomediastinum associated with substance abuse. Because of the self limiting nature of this condition, extensive investigations may not be necessary but hospital admission and close observation are still mandatory.     

Developmental shift from local to central control of norepinephrine release in the cardiac-sympathetic axis: effects of cocaine and related drugs.

Developmental exposure to cocaine is associated with cardiovascular abnormalities as well as neurobehavioral disturbances. Because of the profound influence of cocaine on noradrenergic neurotransmission, we examined its acute effects on norepinephrine release from cardiac nerve terminals in the neonatal rat, as assessed by turnover measurements. Cocaine reduced norepinephrine turnover at all ages studied, but with an apparent transition in the mechanism of action related to the development of central control of sympathetic tone. At 1 day of age, before the establishment of functional connections between the central nervous system and sympathetic neurons, cocaine acted primarily through blockade of norepinephrine reuptake and consequent activation of alpha-2 adrenergic autoreceptors that inhibit transmitter release. Accordingly, its effects were shared by the uptake inhibitor, desmethylimipramine and the alpha-2 agonist, clonidine, but not by drugs whose actions depend upon sympathetic activity or high tonic release of transmitter (yohimbine, pargyline or chlorisondamine). By 21 days, when neuronal activity is under dynamic control by the central nervous system, cocaine was still effective in shutting off norepinephrine release, but the effect was no longer dependent upon blockade of reuptake; desmethylimipramine did not reduce turnover at this age, but clonidine, pargyline and chlorisondamine did. Yohimbine evoked a profound increase in turnover by 21 days.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular disorders associated with cocaine use: myths and truths

Cocaine produces a pattern of cardiovascular responses that are associated with apparent myocardial ischemia, arrhythmias, and other life-threatening complications in some individuals. Despite recent efforts to better understand the causes of cocaine-induced cardiovascular dysfunction, there remain a number of unanswered questions regarding the specific mechanisms by which cocaine elicits hemodynamic responses. This review will describe the actions of cocaine on the cardiovascular system and the evidence for the mechanisms by which cocaine elicits hemodynamic and pathologic responses in humans and animals. The emphasis will be on experimental data that provide the basis for our understanding of the mechanisms of cardiovascular toxicity associated with cocaine. More importantly, this review will identify several controversies regarding the causes of cocaine-induced cardiovascular toxicity that as yet are still debated. The evidence supporting these findings will be described. Finally, this review will outline the obvious deficits in our current concepts regarding the cardiovascular actions of cocaine in hope of encouraging additional studies on this grave problem in our society.     

Potentiation of cocaine and d-amphetamine toxicity with caffeine.

The effect of caffeine when combined with cocaine or amphetamine was studied in rats. Animals were pretreated with intraperitoneal vehicle (normal saline [NS]) or caffeine 100 mg/kg, then challenged with intraperitoneal cocaine (0, 35, 50, 70, or 90 mg/kg) or intraperitoneal d-amphetamine (0, 15, 25, 35, or 42 mg/kg). Animal behavior, time to, and incidences of seizures and death were recorded. This dose of caffeine alone did not cause seizures or death. Caffeine pretreatment significantly increased the incidence of overt seizures induced by either cocaine or amphetamine. Caffeine increased the incidence of cocaine-induced death from 10% to 90% at the 70 mg/kg cocaine dose (P less than .01). Caffeine increased amphetamine-induced death from 0% to 80% at 15 mg/kg (P less than or equal to .01), 10% to 70% at 25 mg/kg (P less than or equal to .01), and 30% to 80% at 35 mg/kg (P less than or equal to .01). To investigate mechanisms, additional animals were pretreated with the adenosine agonist, 2-chloroadenosine (2.5 and 10 mg/kg), before being challenged with NS, 90 mg/kg cocaine, or 42 mg/kg amphetamine. Pretreatment with 2-chloroadenosine had no affect in reducing cocaine or amphetamine toxicity. Combination pretreatment with caffeine and 2-chloroadenosine potentiated cocaine toxicity. The phosphodiesterase inhibitor, pentoxifylline, did not potentiate cocaine toxicity. The authors conclude that caffeine potentiates the acute toxicity of both cocaine and amphetamine, and that the failure of 2-chloroadenosine to alter this suggests that the toxicity of the stimulants cocaine and amphetamine may be modulated by nonspecific rather than specific adenosine- or phosphodiesterase-induced mechanisms.     

Use and acute toxicity associated with the novel psychoactive substances diphenylprolinol (D2PM) and desoxypipradrol (2-DPMP)

Introduction. Over the last decade there has been greater use of novel psychoactive substances ('legal highs') across Europe and the United States, including increasing reports of use of diphenylprolinol (D2PM) and desoxypipradrol (2-DPMP). This review will discuss the pharmacology and mechanisms of action of these two compounds, available data on their sources and prevalence of use and reports of acute toxicity and fatalities associated with their use. Methods. PubMed was searched using the search terms 'D2PM', '2-DPMP', 'diphenyl-2-pyrrolidinyl-methanol', 'diphenylprolinol', '2-diphenylmethylpiperidine' and 'desoxypipradrol'. These searches identified 70 articles, only five of which were relevant. Pharmacology and mechanisms of action. D2PM is a pyrrolidine analogue and 2-DPMP is a desoxy analogue of pipradrol. Animal studies have shown that 2-DPMP increases the release of dopamine and decreases dopamine re-uptake comparable to the effects of cocaine. The binding and activity of D2PM at the dopamine re-uptake transporter, based on currently published data, is also similar to cocaine, although it appears that D2PM has less biological activity. Sources and prevalence of use. D2PM and 2-DPMP is available from internet-based suppliers and street level drug dealers; there is currently no systematic data to be able to determine the relative importance of these routes of supply. There is no population level, and limited subpopulation level, data on the prevalence of use of D2PM/2-DPMP. In one 2011 study, 1.6% of 315 individuals in 'gay friendly' nightclubs in South London reported that they had used a pipradrol: 1.0% had used within the last year and 0.6% had used or were planning to use a pipradrol on the night of the survey. Acute toxicity. Reports on internet discussion fora describe prolonged euphoria and stimulant effects including euphoria, sweating and bruxism with use of D2PM and 2-DPMP. The first report of analytically confirmed acute D2PM toxicity described chest pain and sympathomimetic features (hypertension and tachycardia). Five individuals with analytically confirmed acute D2PM toxicity developed agitation/anxiety and/or insomnia lasting 24-96 h in addition to sympathomimetic features (palpitations, anxiety and agitation). Reports of 49 enquiries relating to a 'legal high' product called 'Whack' (which on analysis was found to contain 2-DPMP and fluorotropacocaine) commonly described unwanted cardiovascular (hypertension in 10/49 and tachycardia in 12/49) and neuropsychiatric (agitation in 14/49 and psychosis in 13/49) effects; the neuropsychiatric effects were prolonged, and persisted for up to 5 days. No analysis of biological samples was undertaken so it is not possible to determine which of these agents if any was responsible for the clinical features. In a series of 26 cases related to the use of 'Ivory Wave' (analysis of a similar 'Ivory Wave' product showed that it contained 2-DPMP), 96% had neuropsychiatric features. Cases presented up to 1 week after use with tachycardia, dystonia, rhabdomyolysis, agitation, hallucinations and paranoia. Confirmatory biological sample analysis was either not available (85.3% of cases) or negative (2.9% of cases) for 2-DPMP; it was positive for 2-DPMP in four (11.8%) of the cases (80% of those where biological analysis was undertaken). D2PM and 2-DPMP related fatalities. Although 2-DPMP has been detected in three fatalities, its role in these deaths has not yet been established. There have been no reports of deaths directly attributed to either D2PM or 2-DPMP. Conclusions. There is emerging evidence of the use of D2PM and 2-DPMP in Europe. D2PM and 2-DPMP have sympathomimetic properties similar to cocaine and, in addition, prolonged and clinically significant neuropsychiatric symptoms have been reported.     

Are one or two dangerous? Sulfonylurea exposure in toddlers

Sulfonylurea-based oral hypoglycemics are in widespread use in the adult population, increasing the potential for unintentional exposure in children. This article examines the risk of toxicity in children under 6 years of age who ingest one to two tablets of a sulfonylurea. We review the literature on sulfonylurea toxicity, including cases reported to the American Association of Poison Control Centers (AAPCC). The ingestion of one to two sulfonylurea tablets by a small child can lead to profound hypoglycemia with severe sequelae if untreated. As a result, all potential sulfonylurea ingestions by young children should be evaluated by a physician. A capillary glucose level must be rapidly determined at presentation and should then be repeated at regular intervals for up to 8 hours. A longer observation period is recommended for the extended release preparation of glipizide. Asymptomatic children who do not develop hypoglycemia within the recommended observation period may be safely discharged home. All children who exhibit clear symptoms of hypoglycemia or glucose levels < 60 mg/dL should be admitted for supplemental glucose (oral or intravenous), with careful observation of clinical condition and monitoring of serum glucose levels. In cases refractory to intravenous glucose, therapy with octreotide or diazoxide may be beneficial.     

Role of protein binding in cocaine-induced hepatic necrosis

The hepatotoxicity of cocaine in the mouse is associated with a significant amount (greater than 2 nmol/mg) of irreversible binding of a cocaine metabolite to hepatic protein. The drug-induced hepatic necrosis correlated with the degree of radiolabeled cocaine binding to hepatic protein and both were shown to be dependent on species high doses of the drug (30-65 mg/kg) and selective channeling of cocaine metabolism by either microsomal induction or esterase inhibition. Subcellular fractionation of hepatic tissue showed that greater than 66% of irreversible binding occurred in the microsomal fraction of the liver. Little (less than 0.2 nmol/mg of protein) binding was observed in other tissue protein of the mouse. Increased binding of radiolabeled material to hepatic protein in phenobarbital-pretreated mice was observed with 3H-benzoyl and 14C-methoxy but not with [3H3-C-N]cocaine. It is proposed that cocaine is metabolized by microsomal enzymes to a chemically reactive intermediate that binds to hepatic tissue protein to produce liver damage. The metabolic formation and subsequent hepatic toxicity of the reactive cocaine metabolite is species-dependent and is associated with binding of the intact norcocaine structure to tissue protein. Pretreatments which enhance hepatic microsomal metabolism or inhibit tissue esterase activity increase the amount of protein bound material and lead to production of cocaine hepatotoxicity.     

Treatment of cocaine cardiovascular toxicity: a systematic review

Introduction: Cocaine abuse is a major worldwide health problem. Patients with acute cocaine toxicity presenting to the emergency department may require urgent treatment for tachycardia, dysrhythmia, hypertension, and coronary vasospasm, leading to pathological sequelae such as acute coronary syndrome, stroke, and death. Objective: The objective of this study is to review the current evidence for pharmacological treatment of cardiovascular toxicity resulting from cocaine abuse. Methods: MEDLINE, PsycINFO, Database of Abstracts of Reviews of Effects (DARE), OpenGrey, Google Scholar, and the Cochrane Library were searched from inception to November 2015. Articles on pharmacological treatment involving human subjects and cocaine were selected and reviewed. Evidence was graded using Oxford Centre for Evidence-Based Medicine guidelines. Treatment recommendations were compared to current American College of Cardiology/American Heart Association guidelines. Special attention was given to adverse drug events or treatment failure. The search resulted in 2376 articles with 120 eligible involving 2358 human subjects. Benzodiazepines and other GABA-active agents: There were five high-quality (CEBM Level I/II) studies, three retrospective (Level III), and 25 case series/reports (Level IV/V) supporting the use of benzodiazepines and other GABA-active agents in 234 subjects with eight treatment failures. Benzodiazepines may not always effectively mitigate tachycardia, hypertension, and vasospasm from cocaine toxicity. Calcium channel blockers: There were seven Level I/II, one Level III, and seven Level IV/V studies involving 107 subjects and one treatment failure. Calcium channel blockers may decrease hypertension and coronary vasospasm, but not necessarily tachycardia. Nitric oxide-mediated vasodilators: There were six Level I/II, one Level III, and 25 Level IV/V studies conducted in 246 subjects with 11 treatment failures and two adverse drug events. Nitroglycerin may lead to severe hypotension and reflex tachycardia. Alpha-adrenoceptor blocking drugs: There were two Level I studies and three case reports. Alpha-1 blockers may improve hypertension and vasospasm, but not tachycardia, although evidence is limited. Alpha-2-adrenoceptor agonists: There were two high-quality studies and one case report detailing the successful use of dexmedetomidine. Beta-blockers and β/α-blockers: There were nine Level I/II, seven Level III, and 34 Level IV/V studies of β-blockers, with 1744 subjects, seven adverse drug events, and three treatment failures. No adverse events were reported for use of combined β/α-blockers such as labetalol and carvedilol, which were effective in attenuating both hypertension and tachycardia. Antipsychotics: Seven Level I/II studies, three Level III studies, and seven Level IV/V case series and reports involving 168 subjects have been published. Antipsychotics may improve agitation and psychosis, but with inconsistent reduction in tachycardia and hypertension and risk of extrapyramidal adverse effects. Other agents: There was only one high level study of morphine, which reversed cocaine-induced coronary vasoconstriction but increased heart rate. Other agents reviewed included lidocaine, sodium bicarbonate, amiodarone, procainamide, propofol, intravenous lipid emulsion, propofol, and ketamine. Conclusions: High-quality evidence for pharmacological treatment of cocaine cardiovascular toxicity is limited but can guide acute management of associated tachycardia, dysrhythmia, hypertension, and coronary vasospasm. Future randomized prospective trials are needed to evaluate new agents and further define optimal treatment of cocaine-toxic patients.     

Cocaine-associated dystonic reaction

Dystonic reactions are extrapyramidal motor dysfunctions that result from an insufficient activity of nigrostriatal dopamine and present clinically as spasms of the various muscle groups. Neuroleptic drugs are a known cause of dystonia and are the most frequently encountered trigger. Cocaine use has been associated with dystonias, though much less often. When reported in the setting of a dystonic reaction, cocaine has been described as a predisposing factor for the patient already using neuroleptic agents. Fewer reports of dystonia as a direct result of cocaine use, independent of neuroleptics, are found in the literature. The cases of two acute dystonic reactions secondary to cocaine use are presented, with a discussion of the pathophysiology and treatment alternatives.     

Cocaine-induced acute myocardial infarction

The use of cocaine as a recreational drug is rapidly escalating in this country. Because of this, an increase in cocaine-related morbidity and mortality is occurring. Cocaine toxicity has been recognized for several years and was thought to be related to high doses or repeated use. Now several researchers have reported that even recreational use of cocaine may cause serious injury and even death by precipitating an acute myocardial infarction (MI). This paper explores the relationship between cocaine abuse and acute MI as well as the care of the patient with a cocaine-induced MI.     

Fentanyl-contaminated cocaine outbreak with laboratory confirmation in New York City in 2019

BackgroundIllicitly manufactured fentanyl and fentanyl analogues (IMFs) are being increasingly suspected in overdose deaths. However, few prior outbreaks have been reported thus far of patients with laboratory-confirmed IMF toxicity after reporting intent to use only nonopioid substances. Herein we report a case series of nine patients without opioid use disorder who presented to two urban emergency departments (EDs) with opioid toxicity after insufflating a substance they believed to be cocaine.Case reportsOver a period of under three hours, nine patients from five discrete locations were brought to two affiliated urban academic EDs. All patients denied prior illicit opioid use. All patients endorsed insufflating cocaine shortly prior to ED presentation. Soon after exposure, all developed lightheadedness and/or respiratory depression. Seven patients received naloxone en route to the hospital; all had improvement in respiratory function by arrival to the ED. None of the patients required any additional naloxone administration in the ED. All nine patients were discharged home after observation.Blood +/− urine samples were obtained from eight patients. All patients who provided specimens tested positive for cocaine metabolites and had quantifiable IMF concentrations, as well as several detectable fentanyl derivatives, analogues, and synthetic opioid manufacturing intermediates.DiscussionIMF-contamination of illicit drugs remains a public health concern that does not appear to be restricted to heroin. This confirmed outbreak demonstrates that providers should elevate their level of suspicion for concomitant unintentional IMF exposure even in cases of non-opioid drug intoxication. Responsive public health apparatuses must prepare for future IMF-contamination outbreaks.     

Operational criteria for adverse drug reactions in evaluating suspected toxicity of a popular scabicide

A recently developed algorithm for the diagnosis of adverse drug reaction (ADR) was used to investigate the quality of evidence in reported cases of ADRs to 1% gamma benzene hexachloride (GBH), a popular scabicide and pediculicide currently under suspicion as a cause of central nervous system (CNS) toxicity, especially in children. Of the 53 reported cases of alleged toxicity, 37 were associated with lindane insecticide (greater than 1% GBH), which is not a pharmaceutical preparation. Of these 37 cases, 34 scored as definite or probable reactions on the algorithm. Of the 26 reports associated with the drug, 1% GBH, none scored as definite and only 6 as probable ADRs. Of these 6 probable cases, 5 represented inappropriate application or unintended ingestion. The use of rigorous operational criteria, such as those developed in this algorithm, permits a scientifically disciplined assessment of whether or not a drug has been fairly indicted, and also provides valuable clinical information about other aspects of suspected drug toxicity.     

Variation in Human Plasma Cholinesterase Activity During Low-Dose Cocaine Administration

Abstract

Background: Cocaine is metabolized by a number of enzymes, the activity of one of which, plasma cholinesterase has been associated with clinical manifestations of toxicity. Patients with life-threatening complications of cocaine intoxication have lower plasma cholinesterase activity than less toxic controls. In addition, relatively healthy cocaine users have lower plasma cholinesterase activity than noncocaine using controls. Thus, low plasma cholinesterase activity could be a contributing factor to cocaine toxicity, a consequence of cocaine use, or a confounding variable. The following study was designed to further assess the relationship between cocaine use and plasma cholinesterase activity. Methods: We studied fluctuations in plasma cholinesterase activity in nine subjects enrolled in an inpatient study of the behavioral pharmacology of smoked cocaine. Subjects used at least 2 g of cocaine weekly for at least 1 year prior to enrollment. The subjects were admitted to the research unit where they remained drug-free for 2 days. They then received smoked cocaine for 4 days (up to 405 mg over 5 hours daily) and were then drug-free again for 2 days. Plasma cholinesterase activity was measured at 9 AM and 4 PM each day. Results: Baseline plasma cholinesterase ranged from 265 to 930 U/L (normal > 450 TJ/L). The mean plasma cholinesterase increased 112 ± 100 U/L from day 1 to day 8 (p = 0.025). There was no daily change in plasma cholinesterase levels from 9 AM to 4 PM (15 ± 165 U/L, p > 0.6), and there was no difference in the daily change between high- and low-dose cocaine days (-3 ± 137 U/L vs 28 ± 165 U/L, p = 0.52). Conclusion: These preliminary data suggest that plasma cholinesterase levels do not change over a 7-hour period as a result of cocaine administration, but may increase during a period of inpatient study. Such an increase could potentially influence the pharmacokinetics or effects of cocaine studied in an inpatient setting and may give insight into the etiology of the observed low-plasma cholinesterase activity in cocaine users.