Physostigmine

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Related FACEM curriculum (2022) learning objectives:

• ME 3.8.1.6(e) Principles of management of toxicological presentations including: Indications for antidotes
• ME 3.8.2.4 Identify the appropriate antidote or antivenom.

Toxicological Indications

• Central antimuscarinic (anticholinergic) delirium unresponsive to benzodiazepine sedation.
• Poisoning by isolated anticholinergic agents (e.g., atropine, benztropine).

Contraindications

• Bradydysrhythmias.
• Intraventricular block (QRS >100 ms).
• AV block.
• Bronchospasm.

Mechanism of Action

• Physostigmine is a tertiary amine carbamate that reversibly inhibits acetylcholinesterase.
• Increases acetylcholine concentration, overcoming postsynaptic muscarinic receptor blockade caused by anticholinergic agents.

Pharmacokinetics

• Poor oral absorption.
• Crosses the blood-brain barrier.
• Rapid metabolism by cholinesterase.
• Elimination half-life: ~20 minutes.

Administration

• Monitor patient in an area equipped for full resuscitation.
• Ensure absence of conduction defects on 12-lead ECG.
• Administer 0.5–1 mg IV slowly over 5 minutes.
  • Repeat every 10 minutes as needed, up to a total dose of 4 mg.
• Delirium may reoccur within 1–4 hours after initial response.
  • Repeat doses carefully titrated to clinical effect.

Therapeutic Endpoints

• Resolution of delirium.

Adverse Drug Reactions

• Overdose causes cholinergic stimulation:
  • Seizures (especially with rapid administration).
  • Bradycardia and varying degrees of heart block.
  • Bronchospasm, bronchorrhoea, nausea, vomiting, diarrhoea.
• Manage cholinergic overdose with supportive care and titrated atropine to resolve bradycardia and respiratory secretions.
• May prolong suxamethonium effects or inhibit non-depolarising neuromuscular blockers.

Specific Considerations

• Pregnancy: Safety not established; consider alternatives.
• Paediatrics: Initial dose: 0.02 mg/kg IV (max 0.5 mg).

Handy Tips

• Duration of action is short (~2 hours); repeat doses may not always be necessary after initial reversal.
• Avoid excessive benzodiazepine doses in delirious patients by using physostigmine, reducing risk of sedation and aspiration.
• May assist in persistent anticholinergic delirium during recovery from tricyclic antidepressant overdose.
• Avoid IV infusion due to risk of cholinergic crisis.
• Neostigmine is not a suitable substitute.

Pitfalls

• Inadequate or excessive dosing; avoid through careful titration to clinical effect.

Controversies

• Historical concerns about bradydysrhythmias/asystole may have been overstated.
• Debate on relative efficacy of benzodiazepines versus physostigmine in managing anticholinergic delirium.
• Advocacy for use in gamma-hydroxybutyrate (GHB) overdose lacks proven clinical benefit over supportive care.