Physostigmine

Physostigmine is a tertiary amine carbamate cholinesterase inhibitor that crosses the blood brain barrier. Its main use is the diagnosis and treatment of antimuscarinic delirium where central toxicity is severe or the diagnosis is uncertain. Supply is irregular in many countries, including parts of East Africa.

Classification. Reversible acetylcholinesterase inhibitor; tertiary amine; central and peripheral action.

Mechanism. Carbamylates acetylcholinesterase in the brain and periphery, raising acetylcholine to overcome competitive muscarinic blockade.

Pharmacodynamics. Onset 3 to 8 minutes after IV injection; duration 30 to 90 minutes, which is often shorter than the toxin, so delirium can recur. Muscarinic excess causes bradycardia, bronchorrhoea and seizures.

Pharmacokinetics. Hydrolysed by cholinesterases; elimination half life 15 to 40 minutes; minimal renal excretion of unchanged drug.

Antimuscarinic delirium (pure anticholinergic toxidrome), adult.

• Pre-conditions: 12 lead ECG with QRS under 100 ms, no evidence of tricyclic antidepressant or other sodium channel blocker overdose, no bradycardia, continuous ECG, atropine and airway equipment ready.

• Physostigmine 0.5 to 1 mg IV, injected slowly over at least 5 minutes.

• Repeat 0.5 to 1 mg every 10 to 15 minutes if agitation persists and no cholinergic signs appear.

• Usual total 2 mg; rarely more than 4 mg in the first hour.

• Recurrence: repeat bolus, or rarely an infusion under toxicology advice.

Children. 0.02 mg/kg IV (maximum 0.5 mg each dose) over at least 5 minutes, repeated every 5 to 10 minutes to a total of 2 mg.

Other uses. Reversal of postoperative central anticholinergic syndrome after hyoscine or atropine, at the same doses.

Benzodiazepines. Remain first line for agitation in mixed or uncertain overdoses; physostigmine is reserved for clear antimuscarinic delirium.

Contraindications. Tricyclic antidepressant or other sodium channel blocker overdose, or QRS 100 ms or more (asystole reported); bradycardia or heart block; asthma; mechanical gut or bladder obstruction; gangrene; depolarising neuromuscular block; cholinesterase inhibitor poisoning.

Warnings. Rapid IV injection causes bradycardia, asystole, seizures and hypersalivation with airway compromise. Some products contain sodium metabisulphite, which can provoke reactions in sulphite sensitive patients.

Adverse effects. Nausea, vomiting, salivation, sweating, diarrhoea, bradycardia, bronchospasm, bronchorrhoea, seizures, fasciculation.

Interactions. Prolongs suxamethonium block. Additive with other cholinergic agents. Beta blockers increase bradycardia risk.

Special groups.

• Pregnancy: limited data; use if delirium is dangerous; avoid in labour.

• Breastfeeding: short half life; brief interruption of feeding for a few hours is enough.

• Older adults: same dose given more slowly; more prone to bradycardia.

• Kidney and liver impairment: no adjustment.

Reversal of cholinergic excess. Atropine IV at about half the physostigmine dose given (for example 0.5 to 1 mg in adults), repeated for bradycardia or bronchorrhoea.

Formulation. Injection 1 mg/mL (salicylate).

Administration. Undiluted or diluted in 10 mL 0.9% sodium chloride, IV over at least 5 minutes in adults. Do not give IM in a delirious patient where onset is unpredictable.

Baseline. 12 lead ECG with QRS and QTc; glucose; temperature; toxicology history.

Monitoring. Continuous ECG, pulse oximetry and blood pressure for at least 2 hours after the last dose; delirium score; secretions; recurrence of agitation.

Disposition. Observe until free of delirium for several hours after the last dose; admit if repeated doses were needed.

Referral and escalation. Discuss with a poisons centre or toxicologist before use when the toxin is unknown or mixed.