Academic Department of Accident and Emergency Medicine, Imperial College School of Medicine, St Marys Hospital, London W2 1NY, UK
Keywords: metabolism; drug misuse
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Introduction |
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Metabolic consequences of drug misuse are uncommon, but are increasing as illicit drug use becomes more widespread. Although the range of medical problems produced is very wide, metabolic problems most commonly occur with heroin, cocaine and the ecstasy group of drugs, which are therefore the main theme of this review.
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Diamorphine (heroin) |
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Other opioids, such as codeine and methadone, are implicated less commonly.18 35 In general, rhabdomyolysis is a result of the heavy sedation produced as the patient lies comatose and motionless for a number of hours after an overdose of diamorphine. In most cases, lack of muscle tone and immobility appear to be sufficient to lead to rhabdomyolysis as a result of direct compression of skeletal muscle tissue. This mechanism is aggravated by hypoxaemia, acidosis, hypovolaemia and hypothermia, which often coexist in the deeply unconscious patient. However, it is also possible that a direct toxic effect is responsible, as rhabdomyolysis associated with heroin abuse has been linked to myocardial cell damage.41 Cardiac damage and non-Q-wave myocardial infarction may also be caused by myocardial hypoperfusion.29
Rhabdomyolysis has also been reported in patients who have not experienced periods of unconsciousness.14 In some cases, the damage may be severe enough to lead to renal failure requiring haemodialysis. Rarely, heroin-induced rhabdomyolysis can be complicated by other consequences of coma and pressure, leading to prolonged and incomplete recovery, as case reports have shown: myelitis, neuropathies and compartment syndromes can complicate the picture.7 26 Compartment syndromes are not uncommon. Intracompartmental pressures should be measured when necessary, and fasciotomy may need to be performed.24
Once suspected, the diagnosis of heroin-induced rhabdomyolyosis is usually straightforward. Occasionally there may be no symptoms in the conscious patient and, in a significant number of cases, there are no signs over the muscles indicating that damage has occurred.14 Ultrasound may be helpful in confirming the diagnosis and location of the lesion by revealing hyperechoic areas within the muscles.43 More commonly, muscle swelling and tenderness occur. If there is any significant degree of rhabdomyolysis, plasma aspartate transferase, alanine transferase, creatine kinase and lactate dehydrogenase concentrations increase markedly. The most serious biochemical complications are hyperkalaemia and hypocalcaemia.45 Even at an early stage, large amounts of haem and myoglobin may be found in urine. Increasing plasma urea and creatinine concentrations indicate the onset of renal failure. Management consists of fluid replacement and early establishment of adequate urine flow. Hyperkalaemia needs to be managed attentively, but excessive amounts of calcium should not be given during the hypocalcaemic phase in order to prevent later exacerbation of hypercalcaemia. If acute renal failure occurs, it should be managed conventionally.
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Opioid withdrawal syndrome |
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Heroin leucoencephalopathy |
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MDMA (ecstasy) |
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Two case reports of fatal hyperthermia following MDMA ingestion appeared in the British literature5 6 and, in 1992, a series of seven fatal cases was reported.16 A subsequent collation of literature reports31 drew attention to the importance of a high body temperature as a predictor of a fatal outcome. The mean recorded temperature in fatalities was 41.6°C, compared with 40.5°C in the hyperthermic survivors. It seems apparent that cases of severe hyperthermia and deaths from heat stroke were mainly the result of prolonged dancing without rest and without taking enough liquid to enable normal temperature control by sweating15 (Table 1). Collapse occurred, sometimes with convulsions. When examined in hospital, these patients tended to have a very high heart rate and a low arterial pressure, and had body temperatures as high as 43°C. Deaths have resulted, usually because the body cannot sustain the massive stress of high body temperature. As well as its amphetamine-like properties, the role of the serotonergic effect of the drug may be important in some cases, and may explain some fatalities where physical exercise was only minimal.
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Management of the hyperthermic patient |
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Hepatic damage |
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Hyponatraemia |
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Hyponatraemia is an uncommon complication of MDMA ingestion. Only a few cases have been reported.19 22 27 28 The death of Leah Betts achieved wide publicity in the popular press, and it became clear that fatal water intoxication can be precipitated by excessive water drinking in ecstasy users. Fifteen cases were identified between August 1994 and December 1995 by the National Poisons Information Service (London), with serum Na+ concentrations of <130 mmol litre1. The clinical pattern was remarkably uniform, with initial vomiting and disturbed behaviour, followed by drowsiness and agitation and, in seven cases, epileptiform convulsions. Drowsiness, a mute state and disorientation were observed for up to 3 days (Hartung TK, Schofield E, Short AI, Parr MJA, Henry JA, unpublished).
The neurological dysfunction is caused by haemodilution, with a rapid decrease in serum Na+ concentration, leading to intracellular movement of water and, subsequently, to cerebral oedema. The patients developed severe illness within 12 h of ingesting ecstasy, suggesting that there is an acute drop in serum Na+ concentration secondary to unrestricted fluid ingestion. The hyponatraemia appears to involve inappropriate secretion of antidiuretic hormone. One case of MDMA-induced hyponatraemia has been documented in which antidiuretic hormone concentrations were measured, and it was confirmed that concentrations of antidiuretic hormone were in fact inappropriately increased, the plasma arginine vasopressin concentration being 4.5 pmol litre1.19 It has been shown more recently that secretion of antidiuretic hormone is markedly increased following administration of 40 mg MDMA in healthy volunteers.15 It thus appears that this phenomenon is not an idiosyncratic effect of the drug, but is a predictable pharmacological effect. Thus, anyone taking MDMA who drinks large amounts of water without exercising and sweating is risking hyponatraemia with its attendant complications. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a well recognized phenomenon which may occur postoperatively2 or after the administration of psychoactive drugs.42 However, in most drug- or illness-induced cases, it arises gradually as a result of normal intake of fluid with restriction of output by antidiuretic hormone, whereas in ecstasy-associated cases, there has been an excessive intake of fluid within a short space of time. This results in an acute onset of symptoms, and it can occur with Na+ concentrations which might not otherwise appear to be dangerously low. Most patients seem to make a steady recovery without neurological sequelae once they reach medical care. Fluid restriction is usually sufficient and any administration of fluids should be avoided if there is any suspicion of hyponatraemia, but the use of intravenous mannitol, loop diuretics or hypertonic saline may be considered.
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Cocaine |
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In most cases, the effects of cocaine are relatively short-lived because its elimination half-life is 3060 min, and the patient is usually asymptomatic within 2 h. However, heavy cocaine use may be associated with more prolonged symptoms and may lead to rhabdomyolysis or hyperthermia. Its unwanted metabolic effects derive from central nervous system stimulation resulting from blockade of dopamine re-uptake, so that the patient may be agitated, violent, hallucinating or convulsing. The exertion involved can generate heat, leading to hyperthermia and contributing to rhabdomyolysis. In addition, blockade of norepinephrine re-uptake leads to marked sympathomimetic effects as a result of alpha-1 and beta-1 stimulation. These include tachycardia and hypertension, but may also be responsible for the development of hyperthermia and rhabdomyolysis. The mode of use may be relevant: intravenous use is a risk factor for complications, as is the use of free base crack cocaine, which is smoked and rapidly enters the circulation through the pulmonary vasculature. Crack cocaine may also be swallowed, with serious consequences.30
Seizures, hyperactivity, hypokalaemia, severe muscle contraction and hyperthermia may be important causes of rhabdomyolysis in cocaine intoxication. These may interact with ischaemia secondary to hypotension or vasoconstriction. The incidence of cocaine-associated rhabdomyolysis has not yet been defined, but there have been numerous case reports, and more cases are being seen with growing use of the drug.47 One study found that 24% of patients attending an emergency department with cocaine toxicity had evidence of rhabdomyolysis, but most had no associated symptoms. A survey in Miami of 39 patients presenting with rhabdomyolysis after cocaine use, found a mean creatine kinase concentration of 12 187 u litre1. Thirteen had renal failure, seven of whom developed disseminated intravascular coagulation; six patients died.38 The development of renal failure is not uncommon as a consequence of cocaine-induced rhabdomyolysis.34 In occasional cases, renal failure may occur in the absence of rhabdomyolysis. Cocaine may also hasten progression to uraemia in patients with underlying renal insufficiency.
The amount of cocaine used does not predict the likelihood of a fatal outcome. Fatal blood concentrations in cocaine users who die from other causes, such as road traffic accidents, are similar to those who have died of cocaine toxicity.21 Another factor whose relevance is not widely appreciated is the formation of cocaethylene, an ethyl homologue of cocaine which is formed in the liver only in the presence of ethanol. Cocaethylene has pharmacodynamically similar properties to cocaine; although it is metabolized along the same pathways as cocaine, its plasma elimination half-life is three to five times that of cocaine, so that the potential for accumulation to toxic levels is greater. This is probably why the risk of immediate death is 18- to 25-fold greater for ingestion of alcohol during use of cocaine than for use of cocaine alone.1 4 Many binge users of cocaine drink relatively heavily during sessions because they are aware that this interaction prolongs the effects of cocaine use. Another factor which may influence the severity of symptoms in patients presenting with cocaine toxicity is the concentration of plasma cholinesterase (pseudocholinesterase). This enzyme is responsible for the detoxification of cocaine in the body, and it has been shown that patients with life-threatening cocaine toxicity had lower plasma cholinesterase activity than those who had non-life-threatening toxicity.17 The low cholinesterase concentrations may be related to poorer nutritional status of regular cocaine users.
Early intervention with high-dose diazepam is probably the most effective first-line measure to prevent the progression of symptoms and ultimately to prevent rhabdomyolysis. Haloperidol or droperidol are not indicated as first-line drugs as they may increase the risk of seizures. Nitrates are appropriate for hypertension and, although beta-blockers may carry the risk of inducing alpha-adrenergic vasoconstriction, a short-acting beta-antagonist such as esmolol can be used. However, by the time the patient has presented, rhabdomyolysis may be established and conventional treatments will then be required to prevent the development of renal impairment or to manage established renal failure. Hyperpyrexia may be severe and the immediate management should include high-dose diazepam, urgent restoration of fluid balance and the administration of dantrolene.
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Cocaine excited delirium |
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There are currently no medical management guidelines for excited delirium. Physical restraint is clearly counterproductive, and may contribute to a fatal outcome in a hyperthermic, agitated patient, but is usually necessary in the interest of public safety. Once the patient reaches medical care, diazepam is the agent most likely to be of use, reducing neuronal excitability and acting as a pharmacological restraint. Urgent fluid replacement is probably of considerable importance, though there is, as yet, no evidence to support this.
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Other drugs |
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Phencyclidine is an important cause of rhabdomyolysis, but is very rarely used outside the USA. In one series of 1000 cases, 22 had rhabdomyolysis.38 Cannabis is very widely used and has powerful pharmacological effects. However, metabolic complications are unusual. There is a single case report of hyperthermia following cannabis use, in which an individual developed hyperthermia after jogging.46 Volatile substance abuse (solvent misuse) is a common means of intoxication in young people. Heavy exposure can lead to neuropathic damage, but chronic toluene exposure can also produce metabolic consequences. Toluene-induced renal tubular acidosis can cause hypokalaemia, increasing the risk of cardiac dysrhythmias and leading to hypokalaemic paralysis, rhabdomyolysis and renal calculi.25
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Conclusion |
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References |
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