paracetamol poisoning

POISONING BY SPECIFIC PHARMACEUTICAL AGENTS
*** Analgesics
Paracetamol
Paracetamol (acetaminophen) is the drug most commonly used in overdose in the UK. Toxicity results from formation of an intermediate reactive metabolite which binds covalently to cellular proteins, causing cell death. This results in hepatic and occasionally renal failure. In therapeutic doses, the toxic intermediate metabolite is detoxified in reactions requiring glutathione, but in overdose, glutathione reserves become exhausted.
Management
Activated charcoal may be used in patients presenting within 1 hour. Antidotes for paracetamol act by replenishing hepatic glutathione. Acetylcysteine given intravenously (or orally in some countries) is highly efficacious if administered within 8 hours of the overdose. However, since efficacy declines thereafter, administration should not be delayed in patients presenting after 8 hours to await a paracetamol blood concentration result. The antidote can be stopped if the paracetamol concentration is shown to be below the appropriate treatment line. The most important adverse effect of acetylcysteine is related to dose-related histamine release, the anaphylactoid reaction, which causes itching and urticaria, and in severe cases, bronchospasm and hypotension. Most cases can be managed by temporary discontinuation of acetylcysteine and administration of an antihistamine. An alternative antidote in paracetamol poisoning is methionine 2.5 g orally 4-hourly to a total of four doses, but it is less effective, especially after delayed presentation. If a patient presents more than 15 hours after ingestion, liver function tests, prothrombin time (or international normalised ratio-INR), renal function tests and a venous bicarbonate should be measured, the antidote started, and a poisons information centre or local liver unit contacted for advice if results are abnormal. An arterial blood gas sample should be taken in patients with severe liver function abnormalities; metabolic acidosis indicates severe poisoning. Liver transplantation should be considered in individuals who develop life-threatening liver failure due to paracetamol poisoning.
If multiple ingestions of paracetamol have taken place over several hours or days (i.e. a staggered overdose), acetylcysteine should be given when the paracetamol dose exceeds 150 mg/kg body weight in any one 24-hour period or 75 mg/kg body weight in high-risk groups( enzyme induction e.g. those on anticonvulsant or chronic alcohol excess and glutathione depletion e.g. malnutrition, eating disorders ).
Salicylates (aspirin)
Clinical features
Salicylate overdose commonly causes nausea, vomiting, sweating, tinnitus and deafness. Direct stimulation of the respiratory centre produces hyperventilation and respiratory alkalosis. Peripheral vasodilatation with bounding pulses and profuse sweating occurs in moderately severe poisoning. Serious salicylate poisoning is associated with metabolic acidosis, hypoprothrombinaemia, hyperglycaemia, hyperpyrexia, renal failure, pulmonary oedema, shock and cerebral oedema. Agitation, confusion, coma and fits may occur, especially in children. Toxicity is enhanced by acidosis, which increases salicylate transfer across the blood-brain barrier.
Management
Activated charcoal should be administered if the patient presents early. Multiple doses of activated charcoal may enhance salicylate elimination but currently are not routinely recommended.
The plasma salicylate concentration should be measured at least 2 (in symptomatic patients) or 4 hours (asymptomatic patients) after overdose and repeated in patients with suspected serious poisoning, since concentrations may continue to rise some hours after overdose. In adults, concentrations above 500 mg/L and 700 mg/L suggest serious and life-threatening poisoning respectively, although clinical status is more important than the salicylate concentration in assessing severity.
Dehydration should be corrected carefully, as there is a risk of pulmonary oedema, and metabolic acidosis should be identified and treated with intravenous sodium bicarbonate (8.4%), once plasma potassium has been corrected. Urinary alkalinisation is indicated for adult patients with salicylate concentrations above 500 mg/L.
Haemodialysis is very effective at removing salicylate and correcting acid-base and fluid balance abnormalities, and should be considered when serum concentrations are above 700 mg/L in adult patients with severe toxic features, or when there is renal failure, pulmonary oedema, coma, convulsions or refractory acidosis.
Non-steroidal anti-inflammatory drugs (NSAIDs)
Clinical features
Overdose of most NSAIDs (e.g. ibuprofen, diclofenac, naproxen, indometacin) usually causes little more than minor abdominal discomfort, vomiting and/or diarrhoea, but convulsions occur occasionally, especially with mefenamic acid. Coma, prolonged seizures, apnoea, liver dysfunction and renal failure can occur after substantial overdose but are rare. Features of toxicity are unlikely to develop more than 6 hours after overdose.
Management
Electrolytes, liver function tests and a full blood count should be checked in all but the most trivial cases. Activated charcoal may be given if the patient presents sufficiently early. Symptomatic treatment for nausea and gastrointestinal irritation may be necessary.

Antidepressants
Tricyclic antidepressants (TCAs)
TCAs continue to be used frequently in overdose and carry a high morbidity and mortality relating to their sodium channel-blocking, anticholinergic and ?-adrenoceptor-blocking effects.
Clinical features
Anticholinergic effects are common. Life-threatening complications are frequent, including convulsions, coma, arrhythmias (ventricular tachycardia, ventricular fibrillation and, less commonly, heart block) and hypotension, which results from inappropriate vasodilatation or impaired myocardial contractility. Serious complications appear to occur more commonly with dosulepin and amitriptyline.
Management
Activated charcoal should be administered if the patient presents sufficiently early. All patients with possible tricyclic overdose should have a 12-lead ECG and ongoing cardiac monitoring for at least 6 hours. Prolongation of the QRS interval (especially if > 0.16 s) indicates severe sodium channel blockade and is associated with an increased risk of arrhythmia (Fig. 9.3). Arterial blood gases should be measured in patients with suspected severe poisoning.
In patients with arrhythmias, severe ECG effects or acidosis, intravenous sodium bicarbonate (50 mL of 8.4% solution) should be administered and repeated to correct pH. The correction of the acidosis and the sodium loading that result is often associated with rapid improvement in ECG features and arrhythmias. Hypoxia and electrolyte abnormalities should also be corrected. Anti-arrhythmic drugs should only be given on specialist advice. Prolonged convulsions should be treated with intravenous benzodiazepines.
Selective serotonin re-uptake inhibitors (SSRIs)
The SSRIs, including fluoxetine, paroxetine, fluvoxamine, sertraline and citalopram, are commonly used to treat depression, in part because they are less toxic than TCAs.
Clinical features and management
Overdose may produce nausea and vomiting, tremor, insomnia and sinus tachycardia. Agitation, drowsiness and convulsions occur infrequently and may be delayed for several hours after ingestion. Occasionally, features of serotonin syndrome may develop, especially if SSRIs are taken in combination or with other serotonergic agents. Cardiac arrhythmias, e.g. junctional bradycardias, occur infrequently. Most patients require supportive care only.
Lithium
Severe lithium toxicity is uncommon after intentional overdose and is more often encountered in patients taking therapeutic doses as a result of drug interactions (e.g. with diuretics or NSAIDs), deteriorating renal function or dehydration, or because an excessive dose has been prescribed.
Clinical features
Nausea, diarrhoea, polyuria, dizziness and tremor may progress to muscular weakness, drowsiness, confusion, myoclonus, fasciculations, choreoathetosis and renal failure. Coma, convulsions, ataxia, cardiac dysrhythmias (e.g. heart block), blood pressure disturbances and renal failure may occur in severe poisoning.
Management
Activated charcoal is ineffective. Gastric lavage is of theoretical benefit if used early after overdose, but lithium tablets are likely to remain intact in the stomach and may be too large for aspiration via a lavage tube. Some advocate whole bowel irrigation after substantial overdose but efficacy is unknown.
Lithium concentrations should be measured immediately in symptomatic patients or after at least 6 hours in asymptomatic patients following acute overdose. Adequate hydration should be maintained with intravenous fluids. Convulsions should be treated.
In patients with features suggesting severe toxicity associated with high lithium concentrations (e.g. > 4.0 mmol/L after chronic poisoning or > 7.5 mmol/L after acute poisoning), haemodialysis should be considered. Lithium concentrations are lowered substantially during dialysis but rebound increases occur after discontinuation, and multiple sessions may be required.