POISONING BY SPECIFIC PHARMACEUTICAL AGENTS

1. POISONING BY SPECIFIC PHARMACEUTICAL AGENTS

2. 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

3. Management is summarised in. 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

4. 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

5. 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'

6. 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 barrie

7. 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

8. 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.

9. 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

10. 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

11. 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 α-adrenoceptor-blocking effects

12. 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

13. 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. 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

14. 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.

15. 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

16. Cardiovascular medications β-blockers These have negative inotropic and chronotropic effects. Some have additional properties that may increase toxicity, such as blockade of sodium channels (e.g. propranolol) or potassium channels (e.g. sotalol). Clinical features The major features of toxicity are bradycardia and hypotension. Heart block, pulmonary oedema and cardiogenic shock occur in severe poisoning. Beta-blockers with sodium channel-blocking effects may cause seizures, confusion and coma, while sotalol may be associated with repolarisation abnormalities (including QTc prolongation) and torsades de pointes. Management Intravenous fluids may reverse hypotension but care is required to avoid pulmonary oedema. Bradycardia and hypotension may respond to high doses of atropine (up to 3 mg in an adult). The adrenoceptor agonist isoproterenol (isoprenaline) may also be effective but high doses are often needed. Glucagon (5-10 mg over 10 mins, then 1-5 mg/hr by infusion), which does not act via adrenoceptors, is now more commonly used

17. Calcium channel blockers Calcium channel blockers are highly toxic in overdose via blockade of L-type calcium channels. Dihydropyridines such as nifedipine or amlodipine affect vascular smooth muscle in particular, resulting in vasodilatation. 'Rate-limiting' calcium channel blockers such as diltiazem and verapamil have direct cardiac effects, resulting in bradycardia and reduced myocardial contractility. Clinical features Hypotension is associated with vasodilatation and myocardial depression. Bradycardias and heart block may also occur, especially with verapamil and diltiazem. Non-cardiac effects include gastrointestinal disturbances, confusion, metabolic acidosis, hyperglycaemia and hyperkalaemia. Management Hypotension should be corrected with intravenous fluids, taking care to avoid pulmonary oedema. Persistent hypotension may respond to intravenous calcium gluconate (10 mg i.v. over 5 mins, repeated as required). Isoproterenol and glucagon may also be useful. Successful use of intravenous insulin with glucose (10-20% dextrose with insulin at 0.5-1.0 U/kg/hr), so-called 'hyperinsulinaemia euglycaemic therapy', has been reported in patients unresponsive to other strategies. Cardiac pacing may be needed for severe unresponsive bradycardias or heart block

18. Cardiac glycosides (including oleander) Poisoning with digoxin is usually accidental, arising from prescription of an excessive dose, impairment of renal function or drug interactions. In South Asia, deliberate self-poisoning with yellow oleander (Thevetia peruviana), which contains cardiac glycosides, is common. • Clinical features Characteristic cardiac effects of toxicity are tachyarrhythmias (either atrial or ventricular) and bradycardias, with or without atrioventricular block. Ventricular bigeminy is common and atrial tachycardia with evidence of atrioventricular block is highly suggestive of the diagnosis. Severe poisoning is associated with hyperkalaemia. Non-cardiac features include confusion, headache, nausea, vomiting, diarrhoea and (rarely) altered colour vision. • Management Activated charcoal is commonly administered to patients presenting early after ingestion of an acute overdose, although evidence of benefit is lacking. Urea, electrolytes and creatinine should be measured, a 12-lead ECG performed and cardiac monitoring instituted. Hypoxia, hypokalaemia (sometimes associated with concurrent diuretic use), hypomagnesaemia and acidosis increase the risk of arrhythmias and should be corrected. Significant bradycardias may respond to atropine, although temporary pacing is sometimes needed. Ventricular arrhythmias may respond to intravenous magnesium If available, digoxin-specific antibody fragments should be administered when there are severe ventricular arrhythmias or unresponsive bradycardias. This antidote has been shown to be effective for both digitalis and yellow oleander poisoning.

19. Antimalarials Chloroquine Chloroquine is highly toxic; doses of 5 g or more of chloroquine base are likely to be fatal in an adult. Clinical features Features of toxicity occur within 1 hour of ingestion and include nausea, vomiting, agitation, drowsiness, hypokalaemia, acidosis, headaches and blurred vision. Coma, convulsions and hypotension may occur in severe poisoning. ECG changes indicating conduction and repolarisation delay (prolonged QRS and QTc intervals) occur and are associated with ventricular tachycardia (including torsades de pointes), ventricular fibrillation and sudden death. • Management Activated charcoal should be given to all patients presenting within 1 hour of ingestion of chloroquine in amounts greater than 15 mg/kg. The cardiac rhythm should be monitored and dysrhythmias managed. The arterial pH should be corrected, but hypokalaemia is thought to have a protective effect and should not be corrected in the first 8 hours after poisoning. High-dose diazepam (2 mg/kg body weight i.v. over 30 mins) has been suggested as having a protective effect, especially if given in the early stages of severe chloroquine poisoning, but evidence is limited as yet. Respiratory support may be required

20. Quinine Quinine salts are widely used for treating malaria and leg cramps. Deaths have been reported with as little as 1.5 g in an adult and 900 mg in a child. • Clinical features Features of toxicity include nausea, vomiting, tremor, tinnitus and deafness. Hypotension, haemolysis, renal failure, ataxia, convulsions and coma are features of serious poisoning. Conduction and repolarisation delay results in prolonged QRS and QTc intervals on the ECG, and ventricular tachycardia (including torsades de pointes), ventricular fibrillation and sudden death may occur. Quinine-induced retinal vasoconstriction and retinal photoreceptor cell toxicity may result in blurred vision and impaired colour perception. This usually develops a few hours after overdose and progresses to constriction of the visual field, scotoma and complete blindness associated with pupillary dilatation and unresponsiveness to light. Fundoscopy may show retinal artery spasm, disc pallor and retinal oedema. Although visual loss can be permanent, some degree of recovery often occurs over several weeks. • Management Multiple-dose activated charcoal should be commenced in patients who have taken quinine in amounts greater than 15 mg/kg. Gastric lavage may also be considered if patients have presented within 1 hour. All patients should have a 12-lead ECG and cardiac monitoring, and their urea, electrolytes and glucose checked. Dysrhythmias, hypotension, seizures and coma should be managed as. There are no effective treatments for the visual effects of quinine. Stellate ganglion block and retrobulbar or intravenous injections of vasodilators such as nitrates were previously used but are ineffective, as are haemodialysis and haemoperfusion