MAOI Toxicity

Monoamine oxidase inhibitor toxicity arises from overdose, from interactions with tyramine rich food or with serotonergic and sympathomimetic drugs. It causes sympathetic overactivity, hypertensive crisis, hyperthermia and serotonin toxicity, often delayed by 6 to 24 hours.

MAOIs are now rarely prescribed, but toxicity still occurs with phenelzine, tranylcypromine, isocarboxazid and moclobemide, and with linezolid and methylene blue (which inhibit monoamine oxidase). Overdoses of more than 2 mg/kg are dangerous with irreversible agents.

Types. Irreversible non-selective inhibitors (phenelzine, tranylcypromine) are the most toxic; moclobemide is reversible and relatively safe alone.

Course. Symptoms may be delayed up to 24 hours, and last for days because enzyme inhibition persists for 2 to 3 weeks with irreversible inhibitors.

Pathophysiology.

Inhibition of monoamine oxidase raises stores of noradrenaline, serotonin and dopamine, so that indirect acting amines such as tyramine and serotonergic drugs cause massive transmitter release.

The effect is hypertension, hyperthermia and neuromuscular hyperactivity.

• Agitation, tremor, headache, sweating, tachycardia and hypertension.
• Hypertensive crisis with severe headache, chest pain, intracranial haemorrhage or pulmonary oedema.
• Hyperthermia, muscle rigidity, clonus, rhabdomyolysis and seizures.
• Later hypotension, coma and cardiovascular collapse.

Red flags.

• Temperature over 38.5 degrees Celsius, rigidity or rhabdomyolysis.
• Severe hypertension with neurological signs.
• Symptoms delayed up to 24 hours after a large ingestion.

• History of drug, dose, formulation, food and interacting drugs (SSRIs, tramadol, pethidine, dextromethorphan, amphetamines, linezolid).
• Blood pressure, temperature, ECG, creatine kinase, electrolytes, renal function, glucose, venous gas with lactate and coagulation.
• Serotonin toxicity features (clonus, hyperreflexia); head CT if neurological signs after hypertension.

Differential diagnosis. Serotonin toxicity from other drugs, sympathomimetic toxicity, neuroleptic malignant syndrome, malignant hyperthermia, phaeochromocytoma and anticholinergic toxicity.

• Activated charcoal 50 g orally once (1 g/kg, maximum 50 g, in children) within 1 hour if the airway is protected. Monitor the airway for aspiration. Avoid with reduced consciousness, ileus or gastrointestinal obstruction; no renal or hepatic adjustment; acceptable in pregnancy.
• Observe for at least 24 hours for irreversible agents, with continuous cardiac and temperature monitoring.
• Sedation: diazepam 5 to 10 mg intravenously, repeated every 5 to 10 minutes as needed. Maximum 30 mg in the first hour without specialist review. Monitor breathing, oxygen saturation and blood pressure. Use lower doses in older adults, respiratory disease and hepatic impairment; use only when needed in pregnancy.
• Hypertensive crisis: phentolamine 5 mg intravenously over 1 to 2 minutes, repeated every 5 to 10 minutes as needed. Maximum 15 mg in total in an hour. Monitor blood pressure continuously, heart rate and ECG. Avoid in coronary artery disease; use caution in hypotension; avoid beta blockers alone because of unopposed alpha effects.
• Alternative: glyceryl trinitrate infusion 10 micrograms/minute intravenously, increased every 5 minutes to a maximum of 200 micrograms/minute. Monitor blood pressure and headache; avoid with phosphodiesterase inhibitors and hypovolaemia.
• Hyperthermia and serotonin toxicity: external cooling, cyproheptadine 12 mg orally or via nasogastric tube once, then 2 mg every 2 hours until settled, then 8 mg every 6 hours (maximum 32 mg daily; monitor sedation; avoid in glaucoma and urinary retention), and rocuronium 1 mg/kg intravenously once with intubation for temperature over 41.1 degrees Celsius. Avoid suxamethonium and antipyretics.
• Hypotension late: fluids and low dose noradrenaline 0.05 micrograms/kg/minute titrated to a mean arterial pressure of 65 mmHg or higher (maximum 1 microgram/kg/minute; central line; monitor blood pressure and extravasation). Avoid indirect acting agents such as ephedrine and dopamine.
• Seizures: lorazepam 0.1 mg/kg intravenously (maximum 4 mg for each dose) over 2 minutes, repeated once after 5 to 10 minutes if seizures continue. Maximum 8 mg in total. Monitor breathing, oxygen saturation, blood pressure and sedation. Use lower doses in older adults, respiratory disease and hepatic impairment; use only when needed in pregnancy.
• Rhabdomyolysis: intravenous fluids to keep urine output over 1 mL/kg/hour.
• Avoid interacting drugs for 2 weeks after stopping an irreversible MAOI (5 weeks for fluoxetine).

Monitoring. Blood pressure, temperature, creatine kinase, renal function and ECG for at least 24 hours.

Referral and escalation. Poisons information centre for all; intensive care for hyperthermia, hypertensive crisis or rigidity.

Special groups. Pregnancy: the same treatment applies. Patients on MAOIs: written dietary and drug advice.