Poisoning by specific drugs - clinical features and management - Ethanol to Opiates - technical
Ethanol is commonly ingested in beverages before, or concomitantly with, the deliberate ingestion of other substances in overdose. It is also used as a solvent and is found in many cosmetic and antiseptic preparations. It is rapidly absorbed through the gastric and intestinal mucosae. Gastric alcohol dehydrogenase isoenzyme has a role in metabolizing ethanol before absorption, thereby preventing ethanol entering the systemic circulation, particularly following ingestion of moderate amounts of alcohol. Absorbed ethanol is initially and principally converted to acetaldehyde by an NAD-dependent hepatic alcohol dehydrogenase. A small proportion is oxidized by the microsomal ethanol oxidizing system (MEOS) and the catalase pathway. Acetaldehyde is removed by oxidation via the NAD-dependent enzyme aldehyde dehydrogenase, to yield acetate and, subsequently, CO2 and water. About 95% of ingested ethanol is oxidized to acetaldehyde and acetate; the remainder is excreted unchanged in the urine, and, to a lesser extent, in the breath and through the skin.
Mechanisms of toxicity
Ethanol is a central nervous system depressant that interferes with cortical processes in small doses and may depress medullary function in large doses. The effects of ethanol on the central nervous system are generally proportional to the blood ethanol concentration. Ethanol is also a peripheral vasodilator. In the severely intoxicated, it may cause hypothermia and hypotension. Ethanol metabolism results in accumulation of free NADH, with resulting increase in the NADH:NAD ratio and inhibition of hepatic gluconeogenesis, which may cause hypoglycaemia, particularly in children or when poisoning follows fasting, exercise, or chronic malnutrition. An increase in the lactate:pyruvate ratio may also ensue, with development of hyperlactataemia.
Ethanol is a central nervous depressant that exacerbates the effects of other central nervous system depressants, in particular, hypnotic agents. The fatal dose of ethanol alone is between 300 and 500 ml absolute alcohol, if this is ingested in less than 1 h. The features of ethanol poisoning are summarized in Bullet list 1.
Severe hypoglycaemia typically occurs within 6 to 36 h of ingestion of a moderate to large amount of alcohol by either a previously malnourished individual or one who has fasted for the previous 24 h; it is common in children 5 years of age or less. The patient is often comatose, hypothermic, and convulsing, with conjugate deviation of the eyes, trismus, and extensor plantar reflexes; the usual features of hypoglycaemia (e.g. flushing, sweating, tachycardia) are often absent. Convulsions are the most common presenting sign in children with hypoglycaemia. Lactic acidosis (usually only mild) is an uncommon but potentially serious complication of acute ethanol intoxication, and occurs particularly in patients with severe liver disease, pancreatitis, or sepsis. Hypovolaemia, which may accompany severe intoxication, predisposes to lactic acidosis.
Supportive measures are all that are required for most patients with acute ethanol poisoning, even if the blood ethanol concentration is very high. Particular care should be taken to protect the airway. In more severe cases, acid–base status should be determined. Lactic acidosis requires correction of hypoglycaemia, hypovolaemia, and circulatory insufficiency, if present. An infusion of sodium bicarbonate will be necessary in those patients in whom a lactic acidosis persists.
Bullet list 1 Clinical features of ethanol poisoning
Mild intoxication (500–1500 mg/litre)
- Emotional lability, and slight impairment of visual acuity, muscular coordination, and reaction time
Moderate intoxication (1500–3000 mg/litre)
- Visual impairment, sensory loss, muscular incoordination, slowed reaction time, slurred speech
Severe intoxication (3000–5000 mg/litre)
- Marked muscular incoordination, blurred or double vision, sometimes stupor and hypothermia, occasionally hypoglycaemia and convulsions
Coma (>5000 mg/litre)
- Depressed reflexes, respiratory depression, hypotension, and hypothermia. Death may occur from respiratory or circulatory failure or as the result of aspiration of stomach contents in the absence of a gag reflex
Blood sugar should be determined hourly in severe cases and the rate of intravenous glucose adjusted accordingly. If blood sugar concentrations decrease despite an infusion of 5 to 10% dextrose, a 50% glucose solution, 50 ml intravenously, should be given because hypoglycaemia is usually unresponsive to glucagon.
Haemodialysis may be considered if the blood ethanol concentration exceeds 7500 mg/litre and if a severe metabolic acidosis is present, which has not been corrected by the measures outlined earlier. Fructose is of negligible clinical benefit in accelerating ethanol oxidation and may cause acidosis; it should not be used.
γ-Hydroxybutyric acid (GHB) is a liquid that is abused as a body-building agent (it stimulates growth hormone release) and as an intoxicant in clubs and ‘raves’. It is a precursor of γ-aminobutyric acid (GABA) and acts as an agonist at GABAB receptors as well as at a GHB-specific receptor in the brain.
Low doses cause mild agitation, excitement, nausea, and vomiting with euphoria and hallucinations at higher doses. Coma, bradycardia, and respiratory depression occur in the most severely poisoned. The most unique aspect of GHB poisoning is its very brief duration. Patients may progress from deep coma, requiring intubation, to self-extubation and full alertness over only a few hours.
A GHB withdrawal syndrome can occur in chronic abusers with clinical features occurring within 6 to 12 h of the last dose. Features include insomnia, tremor, and confusion, which may progress to delirium not dissimilar to the alcohol withdrawal syndrome.
There is no role for gastrointestinal decontamination due to the rapid rate of absorption. Supportive measures to maintain adequate ventilation and circulation should be employed, and this is often all that is required. GHB withdrawal should be managed as for acute alcohol withdrawal.
Intentional overdose with insulin and oral hypoglycaemic agents is uncommon. However, deaths from insulin and sulphonylurea poisoning have been reported. Chlorpropamide, because of its long half-life, may induce prolonged hypoglycaemia. In all cases of poisoning with insulin and sulphonylurea, prompt diagnosis and treatment is essential if death or cerebral damage from neuroglycopenia are to be prevented. Metformin rarely causes hypoglycaemia since its mode of action is to increase glucose utilization. Lactic acidosis is a potentially serious complication of metformin overdose.
Features of overdosage include drowsiness, coma, twitching, convulsions, depressed limb reflexes, extensor plantar responses, tachypnoea, pulmonary oedema, tachycardia, and circulatory failure. Hypoglycaemia is to be expected and hypokalaemia, cerebral oedema, and metabolic acidosis might occur. Neurogenic diabetes insipidus and persistent vegetative states are possible long-term complications. Cholestatic jaundice has been described as a late complication of chlorpropamide poisoning.
The blood or plasma glucose concentration should be measured urgently and intravenous glucose given. Glucagon may be ineffective.
Recurring hypoglycaemia is highly likely. A continuous infusion of glucose, together with carbohydrate-rich meals, is required in cases of severe insulin overdosage, though there may be difficulty in maintaining normoglycaemia. In the case of sulphonylurea overdosage, however, further glucose (although its administration may be unavoidable) only serves to increase the already high-circulating insulin concentrations. Diazoxide 1.25 mg/kg body weight intravenously over 1 h, repeated at 6-hourly intervals if necessary, has therefore been recommended since it increases blood glucose concentrations and raises circulating catecholamine concentrations while blocking insulin release.
Most medicinal preparations of iron are as the ferrous salt. Ferrous iron is oxidized to the ferric state before being absorbed. It is important to differentiate vitamin preparations that contain iron from medicinal preparations, since the former generally do not cause significant clinical problems unless very large amounts are taken. Since iron toxicity is quite closely related to dose per kilogram ingested, serious poisoning is more likely to occur in young children than in adults. The anticipated toxicity of iron is normally estimated by calculating the dose of elemental iron present in the preparation, which varies from salt to salt. Ingestions above 150 mg/kg of elemental iron are generally extremely severe and may be fatal.
Mechanisms of toxicity
Iron salts are both locally corrosive within the gastrointestinal tract and in the cell act as cellular toxins, probably by altering the function of mitochondria. In severe poisoning, patients are unconscious and suffer from circulatory collapse. In this situation hepatic injury is also seen.
Depending on the severity of poisoning features may vary, and in severe cases, features would be expected within the first 6 h and include nausea, vomiting, and abdominal pain. Iron will stain the vomit and diarrhoea and may also cause intestinal ulceration and result in haemorrhage. Large amounts of iron may be visible on a straight abdominal radiograph, but this should not be done routinely to confirm iron ingestion in children. Other reported features include leucocytosis. Following absorption of iron there is often a period of relative calm during which iron is taken into cells before its toxic effects manifest. In severe poisoning, patients may pass into unconsciousness during this phase and develop profound hypotension, metabolic acidosis, and features of hepatic necrosis and renal failure. Such patients require intensive supportive care and mortality rates are high. In patients who recover from significant poisoning, gut strictures following scarring from ulceration may be problematic. The commonest site is around the pylorus, particularly in young children.
Assessment of severity
Although dose is related to toxicity, patients may be sometimes inaccurate in their history, and since vomiting is a frequent early feature it may be difficult to assess exactly how much iron has been absorbed. Plasma concentration measurements on more than one occasion may assist this process. Early, relatively high concentrations (>90 mmol/litre or 5 mg/ml) are more likely to indicate severe poisoning. In this situation, iron will be circulating free in plasma and may result in toxicity.
Iron does not bind to charcoal, and in patients who present early and who have ingested large quantities of iron, consideration should therefore be given to gastric aspiration or lavage. However, in most patients who have ingested such large quantities, vomiting is an early feature, and hence gastric lavage is rarely performed in practice. In the case of ingestion of slow-release preparations of iron, whole-bowel irrigation has been advocated, though data on its efficacy is anecdotal. In patients with significant elevated iron levels and features suggestive of significant poisoning, the specific iron-chelating agent desferrioxamine should be administered. There are few human data to support the usual dose regimen of desferrioxamine (15 mg/kg per hour up to a maximum of 80 mg/kg).
It has been shown that giving 15 mg/kg per hour for more than 24 h can lead to pulmonary effects, including ARDS. The toxicity seen from desferrioxamine during its use in the management of chronic disorders, such as haemachromatosis and haemoglobinopathies, is not a normal feature of its use in the management of iron poisoning and should not therefore be used as a guide to limit dosing. Desferrioxamine may cause hypotension as an adverse effect. In addition, there are occasional reports of anaphylactoid reactions. In view of these potential adverse effects, desferrioxamine should not be used unless specifically indicated. Iron desferrioxamine complex colours urine red. Once desferrioxamine has been administered, interpretation of iron concentrations becomes impossible because the iron bound to desferrioxamine is detected in the laboratory assay.
Patients who have not developed features of poisoning within 6 h have probably not ingested very large quantities of iron, unless they have taken a slow release product. The majority of patients merely require treatment for their gastrointestinal disturbance. Since iron preparations are more commonly given to women who are pregnant than other groups of the population, iron overdose may be seen more frequently in pregnant women. There is currently no evidence to suggest these patients should be treated differently because of pregnancy, and desferrioxamine should certainly not be withheld in patients who are deemed to require it.
Poisoning with isoniazid is potentially very serious, but uncommon.
Mechanisms of toxicity
Isoniazid depresses brain concentrations of γ-aminobutyric acid (GABA), thus leading to seizures.
The ingestion of 80 to 150 mg isoniazid/kg body weight is likely to cause severe poisoning. Nausea, vomiting, slurred speech, dizziness, and visual hallucinations may develop. Stupor, coma, and convulsions follow rapidly and may be associated with hyperthermia, hyperreflexia, extensor plantar responses, and later, rhabdomyolysis. In addition, dilated pupils, sinus tachycardia, and urinary retention may be observed. In severe cases, hypotension, acute renal failure and respiratory failure may ensure. Marked metabolic (lactic) acidosis is common. Less commonly, hyperglycaemia, ketoacidosis, glycosuria, and ketonuria are found.
Supportive measures including the correction of metabolic acidosis should be instituted immediately if the patient is unconscious. Pyridoxine (1 g for 1 g of isoniazid ingested) should be given intravenously to control convulsions. When the ingested dose of isoniazid is unknown, an initial intravenous dose of 5 g pyridoxine should be given. Diazepam alone may be ineffective, but the use of diazepam and pyridoxine is synergistic and both should be used in those with convulsions. Pyridoxine 5 g may be repeated if convulsions persist (in one case, 52 g pyridoxine was given intravenously without ill effects).
Lithium carbonate remains the drug of choice for the treatment of recurrent bipolar illness. It has a low therapeutic index and toxicity is usually the result of therapeutic overdosage (chronic toxicity) rather than deliberate self-poisoning (acute toxicity). Chronic toxicity is usually explained by a reduction in lithium renal clearance without a reduction in dose. However, single large doses are occasionally ingested by individuals on long-term treatment with the drug (acute on therapeutic toxicity).
Features of intoxication include thirst, polyuria, diarrhoea, and vomiting, and, in more serious cases, tremor, impairment of consciousness, hypertonia, and convulsions; irreversible neurological damage may occur. Measurement of the serum lithium concentration confirms the diagnosis. Chronic toxicity is usually associated with concentrations above 1.5 mmol/litre. However, acute massive overdosage may produce much higher concentrations without causing toxic features, at least initially. This is explained by plasma lithium concentrations that are substantially higher than central nervous system lithium concentrations before distribution is complete.
Activated charcoal does not adsorb lithium. Treatment is supportive together with measures to enhance the rate of lithium elimination. Haemodialysis should be considered if neurological features are present, if renal function is impaired, and if chronic toxicity or acute on therapeutic toxicity are the modes of presentation. The efficacy of haemodialysis is limited by the relatively slow movement of lithium ions across cell membranes. It is easy to reduce serum lithium concentrations but they frequently rebound when treatment is stopped and clinical improvement is much slower. Repeated haemodialysis sessions are usually required. Continous haemodiafiltration can be used if conventional haemodialysis is not available, though clearance is less efficient.
Lysergic acid diethylamide (LSD)
Lysergic acid diethylamide acts as an antagonist at peripheral 5-HT receptor subtypes, but as a 5-HT2A receptor agonist in the central nervous system. LSD and MDMA (ecstasy) are sometimes combined (‘XL’; ‘candyflipping’) to increase the response to MDMA.
The ability of LSD to distort reality is well known. Visual hallucinations, distortion of images, agitation, excitement, dilated pupils, tachycardia, hypertension, hyperreflexia, tremor, and hyperthermia are common; auditory hallucinations are rare. Time seems to pass very slowly, and behaviour may become disturbed with paranoid delusions. Panic attacks are relatively common, but frank psychotic episodes (which may result in homicide) are not. The psychoactive effects can last for 48 h. Episodic visual disturbances (‘flashbacks’; hallucinogen persisting perception disorder) occur in which the effects of LSD are re-experienced without further exposure to the drug. The symptoms include false fleeting perceptions in the peripheral fields, flashes of colour, geometric pseudohallucinations, and positive afterimages. These disturbances may persist for several years but are often treatable with benzodiazepines and exacerbated by phenothiazines.
Most patients will require little more than reassurance and sedation. Supportive measures are all that can be offered to those who are seriously ill.
Metoclopramide is an antiemetic, which has dopamine receptor antagonist properties, and therefore may cause dystonic reactions at therapeutic doses and after overdose. Such adverse effects are more common in young adults and women.
As the clinical features are normally benign, all that is required is to treat a dystonic reaction with either an anticholinergic (e.g. benztropine 1–2 mg intravenously in an adult) or diazepam (10–20 mg intravenously). Dystonia is extremely distressing for patients and should be treated promptly.
Organic nitrates such as isosorbide mononitrate and isosorbide dinitrate are vasodilators that act by relaxing vascular smooth muscle. These drugs are essentially nitric oxide donors, which increase nitric oxide-induced activation of guanylate cyclase with subsequent elevation of cGMP concentrations. Their effects in overdose are directly related to their therapeutic actions. These drugs undergo extensive first pass metabolism in the liver. Exposure to inorganic nitrates is principally via drinking water.
The symptoms and signs caused by pharmaceutical nitrates in overdose are due primarily to excessive arteriolar and venous dilatation. Headache and vomiting are common, accompanied by flushing of the skin and dizziness. Sinus tachycardia, severe orthostatic hypotension, and syncope may develop. Convulsions and coma may be seen in severely poisoned patients. In contrast to poisoning by inorganic nitrates, methaemoglobinaemia is seen very rarely with organic nitrates. Moreover, methaemoglobinaemia caused by inorganic nitrates is in fact due to conversion of nitrate to nitrite by gastrointestinal bacteria, following ingestion. This is encountered primarily among infants bottle-fed with formula milk that has been made up with water with a high nitrate content.
Nonsteroidal anti-inflammatory drugs
These include a variety of different groups of drugs, all acting by inhibition of cycloxygenase enzymes. The newer, so-called selective, agents are thought to inhibit the inducible form of cycloxygenase more than the other forms of the enzyme. These drugs therefore all tend to inhibit prostaglandin synthesis, and the main toxicity seen in overdose is on the kidney. In very large doses, central nervous system effects may be seen but these are uncommon.
Non-steroidal anti-inflammatory drugs come in different chemical groupings: oxicams (meloxicam, piroxicam, tenoxicam) and phenylpropionic (arylpropionic) acid derivatives (e.g. fenbufen, ibuprofen, naproxen, tiaprofenic acid, mefenamic acid). The COX-2 selective agents are also potentially nephrotoxic in overdose due to inhibition of renal prostaglandin synthesis.
Overdose of mefenamic acid produces nausea, vomiting and, occasionally, bloody diarrhoea. Drowsiness, dizziness, and headaches are common, and hyperreflexia, muscle twitching, convulsions, cardiorespiratory arrest, hypoprothrombinaemia, and acute renal failure have been reported. In a study of 29 cases of mefenamic acid poisoning, convulsions were noted in 38% of patients, although only rarely were they persistent.
Treatment of poisoning with nonsteroidals is generally supportive. It is important to check renal function in patients who have ingested large doses at an interval after ingestion. Changes in serum potassium and elevations in serum creatinine are to be expected in patients ingesting toxic doses. Treatment of renal impairment is conventional. Dialysis may be required in very severe cases. Activated charcoal should only be considered in patients who have ingested very large doses of non-steroidals (generally >20 tablets). Convulsions with mefanamic acid are unlikely to be persistent, but if they are, should be managed by diazepam (10–20 mg intravenously) or lorazepam (3–4 mg intravenously). Other treatments should be symptomatic and supportive.
Opiates and opioids
Opioids are a large group of drugs, which act on opioid receptors and are usually used as analgesics. Widespread abuse of opiates, particularly heroin, causes many patients to present with unintentional overdose, which is normally from intravenous injection (needle marks visible) but may occur from inhalation. Oral ingestion in addicts is less common. Many addicts abuse other drugs in addition to opioids, and the combination of benzodiazepines and opioids are particularly hazardous. Some opioids have other effects not mediated through opioid receptors. Dextropropoxyphene is a sodium channel blocker and causes cardiac arrhythmias; methadone has been shown to inhibit potassium channels at high doses and is also associated with sudden death in susceptible patients due to QT prolongation.
Cardinal signs of opiate overdose are pinpoint pupils, reduced respiratory rate, and coma. Vomiting may also occur, particularly after intravenous injection in naive users, and complicates the clinical pattern due to aspiration pneumonia. Methadone acts slowly (peak effects usually 4–6 h after ingestion) though its onset may be more rapid when given intravenously. Noncardiogenic pulmonary oedema is seen in a proportion of severe opioid overdoses, and is treated by positive pressure ventilation. Hypothermia may occur in patients lying outside. Rhabdomyolysis has also been associated with opioid ingestion.
Buprenorphine, a partial agonist opioid, is now used as an alternative to methadone in replacement programmes. It too is potentially seriously toxic if given intravenously, and in some countries has been combined with naloxone to reduce the acute hazard. Use of dextropropoxyphene has been curtailed in the United Kingdom because of risk of sudden death early after overdose when used in the combination product co-proxamol (paracetamol and dextropropoxyphene). Patients who have ingested dextropropoxyphene should have a 12-lead ECG, particularly if they are unconscious, and any acid–base disturbance corrected to reduce the risk of arrhythmia.
Naloxone is a pure opioid antagonist. It will reverse the effects of all opioids if given in sufficient dose. In the event of veins not being accessible, intramuscular use is an alternative, but the onset will be slower. Use of naloxone by nebulizer has also been used in methadone poisoning. Failure of a suspected opioid poisoning to respond to an adequate dose of naloxone (at least 2.4 mg in an adult) should prompt reassessment of diagnosis. It may indicate co-ingestion of other central nervous system depressants, or ingestion of γ-hydroxybutyrate, which also causes small pupils and loss of consciousness.
Naloxone has a half-life of approximately 45 to 90 min so its duration of action is therefore much shorter than that of the opioids being treated. Naloxone may therefore be given by infusion; the normal advised dose is approximately two-thirds of that required to wake a patient, every hour. This dose can be reassessed at regular intervals depending on the expected half-life of the ingested product. Morphine has active metabolites (morphine 6-glucoronide), which may become relevant in large overdoses. This metabolite is renally excreted and more potent than the parent compound, thus poisoning may be prolonged in older people or in patients with renal impairment or renal damage following rhabdomyolysis.
Other supportive care should be administered as necessary including respiratory support. Significant hypotension due to pure opioid effects will usually respond to naloxone; patients who are managed just by ventilation may therefore be treated unnecessarily aggressively with fluid replacement. In some patients, high concentrations of opioids, such as codeine, cause histamine release and wealing and itching of the skin. These histamine effects should be treated conventionally with antihistamines.