Robin J. Slaughter

The clinical toxicology of metamfetamine.

Introduction. Metamfetamine is a highly addictive amfetamine analog that acts primarily as a central nervous system (CNS) stimulant. The escalating abuse of this drug in recent years has lead to an increasing burden upon health care providers. An understanding of the drugs toxic effects and their medical treatment is therefore essential for the successful management of patients suffering this form of intoxication. Aim. The aim of this review is to summarize all main aspects of metamfetamine poisoning including epidemiology, mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management. Methods. A summary of the literature on metamfetamine was compiled by systematically searching OVID MEDLINE and ISI Web of Science. Further information was obtained from book chapters, relevant news reports, and web material. Epidemiology. Following its use in the Second World War, metamfetamine gained popularity as an illicit drug in Japan and later the United States. Its manufacture and use has now spread to include East and South-East Asia, North America, Mexico, and Australasia, and its world-wide usage, when combined with amfetamine, exceeds that of all other drugs of abuse except cannabis. Mechanisms of toxicity. Metamfetamine acts principally by stimulating the enhanced release of catecholamines from sympathetic nerve terminals, particularly of dopamine in the mesolimbic, mesocortical, and nigrostriatal pathways. The consequent elevation of intra-synaptic monoamines results in an increased activation of central and peripheral α±- and β-adrenergic postsynaptic receptors. This can cause detrimental neuropsychological, cardiovascular, and other systemic effects, and, following long-term abuse, neuronal apoptosis and nerve terminal degeneration. Toxicokinetics. Metamfetamine is rapidly absorbed and well distributed throughout the body, with extensive distribution across high lipid content tissues such as the blood-brain barrier. In humans the major metabolic pathways are aromatic hydroxylation producing 4-hydroxymetamfetamine and N-demethylation to form amfetamine. Metamfetamine is excreted predominantly in the urine and to a lesser extent by sweating and fecal excretion, with reported terminal half-lives ranging from ∼5 to 30 h. Clinical features. The clinical effects of metamfetamine poisoning can vary widely, depending on dose, route, duration, and frequency of use. They are predominantly characteristic of an acute sympathomimetic toxidrome. Common features reported include tachycardia, hypertension, chest pain, various cardiac dysrhythmias, vasculitis, headache, cerebral hemorrhage, hyperthermia, tachypnea, and violent and aggressive behaviour. Management. Emergency stabilization of vital functions and supportive care is essential. Benzodiazepines alone may adequately relieve agitation, hypertension, tachycardia, psychosis, and seizure, though other specific therapies can also be required for sympathomimetic effects and their associated complications. Conclusion. Metamfetamine may cause severe sympathomimetic effects in the intoxicated patient. However, with appropriate, symptom-directed supportive care, patients can be expected to make a full recovery.

The clinical toxicology of gamma-hydroxybutyrate, gamma-butyrolactone and 1,4-butanediol

Introduction. Gamma-hydroxybutyrate (GHB) and its precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), are drugs of abuse which act primarily as central nervous system (CNS) depressants. In recent years, the rising recreational use of these drugs has led to an increasing burden upon health care providers. Understanding their toxicity is therefore essential for the successful management of intoxicated patients. We review the epidemiology, mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management of poisoning due to GHB and its analogs and discuss the features and management of GHB withdrawal. Methods. OVID MEDLINE and ISI Web of Science databases were searched using the terms “GHB,” “gamma-hydroxybutyrate,” “gamma-hydroxybutyric acid,” “4-hydroxybutanoic acid,” “sodium oxybate,” “gamma-butyrolactone,” “GBL,” “1,4-butanediol,” and “1,4-BD” alone and in combination with the keywords “pharmacokinetics,” “kinetics,” “poisoning,” “poison,” “toxicity,” “ingestion,” “adverse effects,” “overdose,” and “intoxication.” In addition, bibliographies of identified articles were screened for additional relevant studies including nonindexed reports. Non-peer-reviewed sources were also included: books, relevant newspaper reports, and applicable Internet resources. These searches produced 2059 nonduplicate citations of which 219 were considered relevant. Epidemiology. There is limited information regarding statistical trends on world-wide use of GHB and its analogs. European data suggests that the use of GHB is generally low; however, there is some evidence of higher use among some sub-populations, settings, and geographical areas. In the United States of America, poison control center data have shown that enquiries regarding GHB have decreased between 2002 and 2010 suggesting a decline in use over this timeframe. Mechanisms of action. GHB is an endogenous neurotransmitter synthesized from glutamate with a high affinity for GHB-receptors, present on both on pre- and postsynaptic neurons, thereby inhibiting GABA release. In overdose, GHB acts both directly as a partial GABAb receptor agonist and indirectly through its metabolism to form GABA. Toxicokinetics. GHB is rapidly absorbed by the oral route with peak blood concentrations typically occurring within 1 hour. It has a relatively small volume of distribution and is rapidly distributed across the blood–brain barrier. GHB is metabolized primarily in the liver and is eliminated rapidly with a reported 20–60 minute half-life. The majority of a dose is eliminated completely within 4–8 hours. The related chemicals, 1,4-butanediol and gamma butyrolactone, are metabolized endogenously to GHB. Clinical features of poisoning. GHB produces CNS and respiratory depression of relatively short duration. Other commonly reported features include gastrointestinal upset, bradycardia, myoclonus, and hypothermia. Fatalities have been reported. Management of poisoning. Supportive care is the mainstay of management with primary emphasis on respiratory and cardiovascular support. Airway protection, intubation, and/or assisted ventilation may be indicated for severe respiratory depression. Gastrointestinal decontamination is unlikely to be beneficial. Pharmacological intervention is rarely required for bradycardia; however, atropine administration may occasionally be warranted. Withdrawal syndrome. Abstinence after chronic use may result in a withdrawal syndrome, which may persist for days in severe cases. Features include auditory and visual hallucinations, tremors, tachycardia, hypertension, sweating, anxiety, agitation, paranoia, insomnia, disorientation, confusion, and aggression/combativeness. Benzodiazepine administration appears to be the treatment of choice, with barbiturates, baclofen, or propofol as second line management options. Conclusions. GHB poisoning can cause potentially life-threatening CNS and respiratory depression, requiring appropriate, symptom-directed supportive care to ensure complete recovery. Withdrawal from GHB may continue for up to 21 days and can be life-threatening, though treatment with benzodiazepines is usually effective.

Diethylene glycol poisoning.

Introduction. Diethylene glycol (DEG) is a clear, colorless, practically odorless, viscous, hygroscopic liquid with a sweetish taste. In addition to its use in a wide range of industrial products, it has also been involved in a number of prominent mass poisonings spanning back to 1937. Despite DEGs toxicity and associated epidemics of fatal poisonings, a comprehensive review has not been published. Methods. A summary of the literature on DEG was compiled by systematically searching OVID MEDLINE and ISI Web of Science. Further information was obtained from book chapters, relevant news reports, and web material. Aim. The aim of this review is to summarize all main aspects of DEG poisoning including epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, toxicity of DEG, diagnosis, and management. Epidemiology. Most of the documented cases of DEG poisoning have been epidemics (numbering over a dozen) where DEG was substituted in pharmaceutical preparations. More often, these epidemics have occurred in developing and impoverished nations where there is limited access to intensive medical care and quality control procedures are substandard. Toxicokinetics. Following ingestion, DEG is rapidly absorbed and distributed within the body, predominantly to regions that are well perfused. Metabolism occurs principally in the liver and both the parent and the metabolite, 2-hydroxyethoxyacetic acid (HEAA), are renally eliminated rapidly. Mechanisms of toxicity. Although the mechanism of toxicity is not clearly elucidated, research suggests that the DEG metabolite, HEAA, is the major contributor to renal and neurological toxicities. Clinical features. The clinical effects of DEG poisoning can be divided into three stages: The first phase consists of gastrointestinal symptoms with evidence of inebriation and developing metabolic acidosis. If poisoning is pronounced, patients can progress to a second phase with more severe metabolic acidosis and evidence of emerging renal injury, which, in the absence of appropriate supportive care, can lead to death. If patients are stabilized, they may then enter the final phase with various delayed neuropathies and other neurological effects, sometimes fatal. Toxicity of DEG. Doses of DEG necessary to cause human morbidity and mortality are not well established. They are based predominantly on reports following some epidemics of mass poisonings, which may underestimate toxicity. The mean estimated fatal dose in an adult has been defined as ∼1 mL/kg of pure DEG. Management. Initial treatment consists of appropriate airway management and attention to acid–base abnormalities. Prompt use of fomepizole or ethanol is important in preventing the formation of the toxic metabolite HEAA; hemodialysis can also be critical, and assisted ventilation may be required. Conclusions. DEG ingestion can lead to serious complications that may prove fatal. Prognosis may be improved, however, with prompt supportive care and timely use of fomepizole or ethanol.

Nicotinic plant poisoning

Introduction. A wide range of plants contain nicotinic and nicotinic-like alkaloids. Of this diverse group, those that have been reported to cause human poisoning appear to have similar mechanisms of toxicity and presenting patients therefore have comparable toxidromes. This review describes the taxonomy and principal alkaloids of plants that contain nicotinic and nicotinic-like alkaloids, with particular focus on those that are toxic to humans. The toxicokinetics and mechanisms of toxicity of these alkaloids are reviewed and the clinical features and management of poisoning due to these plants are described. Methods. This review was compiled by systematically searching OVID MEDLINE and ISI Web of Science. This identified 9,456 papers, excluding duplicates, all of which were screened. Reviewed plants and their principal alkaloids. Plants containing nicotine and nicotine-like alkaloids that have been reported to be poisonous to humans include Conium maculatum, Nicotiana glauca and Nicotiana tabacum, Laburnum anagyroides, and Caulophyllum thalictroides. They contain the toxic alkaloids nicotine, anabasine, cytisine, n-methylcytisine, coniine, n-methylconiine, and γ-coniceine. Mechanisms of toxicity. These alkaloids act agonistically at nicotinic-type acetylcholine (cholinergic) receptors (nAChRs). The nicotinic-type acetylcholine receptor can vary both in its subunit composition and in its distribution within the body (the central and autonomic nervous systems, the neuromuscular junctions, and the adrenal medulla). Agonistic interaction at these variable sites may explain why the alkaloids have diverse effects depending on the administered dose and duration of exposure. Toxicokinetics. Nicotine and nicotine-like alkaloids are absorbed readily across all routes of exposure and are rapidly and widely distributed, readily traversing the blood–brain barrier and the placenta, and are freely distributed in breast milk. Metabolism occurs predominantly in the liver followed by rapid renal elimination. Clinical features. Following acute exposure, symptoms typically follow a biphasic pattern. The early phase consists of nicotinic cholinergic stimulation resulting in symptoms such as abdominal pain, hypertension, tachycardia, and tremors. The second inhibitory phase is delayed and often heralded by hypotension, bradycardia, and dyspnea, finally leading to coma and respiratory failure. Management. Supportive care is the mainstay of management with primary emphasis on cardiovascular and respiratory support to ensure recovery. Conclusions. Exposure to plants containing nicotine and nicotine-like alkaloids can lead to severe poisoning but, with prompt supportive care, patients should make a full recovery.

The clinical toxicology of the designer “party pills” benzylpiperazine and trifluoromethylphenylpiperazine

Introduction. Benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) are synthetic phenylpiperazine analogues. BZP was investigated as a potential antidepressant in the early 1970s but was found unsuitable for this purpose. More recently, BZP and TFMPP have been used as substitutes for amfetamine-derived designer drugs. They were legally available in a number of countries, particularly in New Zealand, and were marketed as party pills, but are now more heavily regulated. This article will review the mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management of poisoning due to BZP and TFMPP. Methods. OVID MEDLINE and ISI Web of Science were searched systematically for studies on BZP and TFMPP and the bibliographies of identified articles were screened for additional relevant studies including nonindexed reports. Nonpeer-reviewed sources were also accessed. In all, 179 papers excluding duplicates were identified and 74 were considered relevant. Mechanisms of action. BZP and TFMPP have stimulant and amfetamine-like properties. They enhance the release of catecholamines, particularly of dopamine, from sympathetic nerve terminals, increasing intra-synaptic concentrations. The resulting elevated intra-synaptic monoamine concentrations cause increased activation of both central and peripheral α- and 𝛃-adrenergic postsynaptic receptors. BZP has primarily dopaminergic and noradrenergic action while TFMPP has a more direct serotonin agonist activity. Toxicokinetics. There is limited information on the kinetics of these drugs. Following ingestion, peak plasma concentrations are reached after 60 to 90 min. Both drugs would be expected to cross the blood brain barrier and they are metabolized mainly by hydroxylation and N-dealkylation catalyzed by cytochrome P450 and catechol-o-methyl transferase enzymes. In humans, only small amounts of both BZP and TFMPP are excreted in the urine, suggesting a low bioavailability. The serum half-lives of BZP and TFMPP are relatively short with elimination being essentially complete in 44 h for BZP and 24 h for TFMPP. Clinical features. These compounds can cause harmful effects when taken recreationally. Commonly reported features include palpitations, agitation, anxiety, confusion, dizziness, headache, tremor, mydriasis, insomnia, urine retention, and vomiting. Seizures are induced in some patients even at low doses. Severe multiorgan toxicity has been reported, though fatalities have not been recorded conclusively. Management. Supportive care including the termination of seizures is paramount, with relief of symptoms usually being provided by benzodiazepines alone. Conclusions. BZP and TFMP can cause sympathomimetic effects in the intoxicated patient. Appropriate, symptom-directed supportive care should ensure a good recovery.

Poisoning due to water hemlock

Introduction. Water hemlock, which encompasses a range of species divided across two genera (Cicuta and Oenanthe), are regarded as being among the most poisonous plants both in North America and in the United Kingdom. Despite their toxicity, the literature consists almost entirely of case reports. Aim. The aim of this review is to summarize this literature by covering all aspects of taxonomy and botanical characterization, principal toxins, basic pharmacology including mechanisms of toxicity, and the clinical features, diagnosis, and management of poisoning. Mechanisms of toxicity. The principal toxins, cicutoxin and oenanthotoxin, belong to a group of C17 conjugated polyacetylenes. They act as (noncompetitive) gamma-aminobutyric acid antagonists in the central nervous system (CNS), resulting in unabated neuronal depolarization that can lead to seizures. Ingestion of even a small amount of plant matter may result in severe intoxication. Features. After ingestion, the patient is most likely to experience CNS stimulatory effects including seizures that, in the absence of aggressive supportive care, can result in death. Other features include nausea, vomiting, diarrhea, tachycardia, mydriasis, rhabdomyolysis, renal failure, coma, respiratory impairment, and cardiac dysrhythmias. Management. Treatment consists mainly of prompt airway management and seizure control, plus decontamination if achieved early and after stabilization. In the event of renal failure, the use of hemodialysis has been employed successfully. Conclusions. The ingestion of water hemlock can lead to serious complications that may be fatal. Prognosis is good, however, if prompt supportive care is provided.

Delayed seizure-like activity following analytically confirmed use of previously unreported synthetic cannabinoid analogues

Synthetic cannabinoid use has become widespread, leading to increased burdens on health care providers. Symptoms range from agitation and psychosis to seizures and acute kidney injury. We report a case where a patient was assessed and treated twice within 12 h for seizures following synthetic cannabinoid intoxication. Blood sample determinations showed low concentrations of analogues not previously reported, some of which are legal. Clinicians should be aware that synthetic cannabinoids may cause an array of severe health consequences. Given the ever evolving structure of available analogues, clinicians must also be prepared for other unexpected adverse effects.

Riot control agents: the tear gases CN, CS and OC—a medical review

Introduction 2-Chloroacetophenone (CN), o-chlorobenzylidene malonitrile (CS) and oleoresin capsicum (OC) are common riot control agents. While serious systemic effects are uncommon, exposure to high concentrations may lead to severe complications and even death. The aim of this narrative review is to summarise all main aspects of the riot control agents CN, CS and OC toxicology, including mechanisms of toxicity, clinical features and management. Methods OVID MEDLINE and ISI Web of Science were searched for terms associated with CN, CS and OC toxicity in humans and those describing the mechanism of action, clinical features and treatment protocols. Results CN, CS and OC are effective lacrimating agents; evidence for toxicity, as measured by the threshold for irritation, is greatest for CN, followed by CS and OC. Typically, ocular and respiratory tract irritation occurs within 20–60 s of exposure. Ocular effects involve blepharospasm, photophobia, conjunctivitis and periorbital oedema. Following inhalation, effects may include a stinging or burning sensation in the nose, tight chest, sore throat, coughing, dyspnoea and difficulty breathing. Dermal outcomes are variable, more severe for CN and include dermal irritation, bulla formation and subcutaneous oedema. Removal from the contaminated area and fresh air is a priority. There is no antidote; treatment consists of thorough decontamination and symptom-directed supportive care. Ocular exposure requires thorough eye decontamination, an eye exam and appropriate pain management. Monitoring and support of respiratory function is important in patients with significant respiratory symptoms. Standard treatment protocols may be required with patients with pre-existing respiratory conditions. Dermal exposures may require systemic steroids for patients who develop delayed contact dermatitis. Conclusions CN, CS and OC are effective riot control agents. In the majority of exposures, significant clinical effects are not anticipated. The irritant effects can be minimised both by rapid evacuation from sites of exposure, decontamination and appropriate supportive care.

A seaman with blindness and confusion.

A male member of a fishing boat crew presented at a rural hospital 36 hours after having consumed a large amount of “bootleg” (home made) vodka. He had loss of vision and seemed to be confused. He was immediately evacuated by helicopter to a large urban hospital emergency department. On arrival, the patient developed seizures followed by circulatory shock. ### Short answers ### Long answers #### 1 Diagnosis This patient’s history of drinking illicit alcohol and the onset of visual impairment, confusion, seizures, and circulatory …

Was the death of Alexander the Great due to poisoning? Was it Veratrum album?

Objective. To investigate the death of Alexander the Great to determine if he died from natural causes or was poisoned and, if the latter, what was the most likely poison. Methods. OVID MEDLINE (January 1950–May 2013) and ISI Web of Science (1900–May 2013) databases were searched and bibliographies of identified articles were screened for additional relevant studies. These searches identified 53 relevant citations. Classical literature associated with Alexanders death. There are two divergent accounts of Alexanders death. The first has its origins in the Royal Diary, allegedly kept in Alexanders court. The second account survives in various versions of the Alexander Romance. Nature of the terminal illness. The Royal Diary describes a gradual onset of fever, with a progressive inability to walk, leading to Alexanders death, without offering a cause of his demise. In contrast, the Romance implies that members of Alexanders inner circle conspired to poison him. The various medical hypotheses include cumulative debilitation from his previous wounds, the complications of alcohol imbibing (resulting in alcohol hepatitis, acute pancreatitis, or perforated peptic ulcer), grief, a congenital abnormality, and an unhealthy environment in Babylon possibly exacerbated by malaria, typhoid fever, or some other parasitic or viral illness. Was it poisoning? Of all the chemical and botanical poisons reviewed, we believe the alkaloids present in the various Veratrum species, notably Veratrum album, were capable of killing Alexander with comparable symptoms to those Alexander reportedly experienced over the 12 days of his illness. Veratrum poisoning is heralded by the sudden onset of epigastric and substernal pain, which may also be accompanied by nausea and vomiting, followed by bradycardia and hypotension with severe muscular weakness. Alexander suffered similar features for the duration of his illness. Conclusion. If Alexander the Great was poisoned, Veratrum album offers a more plausible cause than arsenic, strychnine, and other botanical poisons.