Physostigmine: Action as a Central Cholinesterase Inhibitor

Physostigmine (brand name Anticholium) is a naturally occurring alkaloid from the calabar bean (Physostigma venenosum). Pharmacologically, physostigmine is a reversible cholinesterase inhibitor with the special property of crossing the blood-brain barrier effectively. This central action distinguishes physostigmine from peripherally acting cholinesterase inhibitors such as neostigmine and makes it the specific antidote for central anticholinergic syndrome. In Germany, physostigmine is established as an emergency antidote and belongs to the standard equipment of emergency medicine and toxicology.

Clinically, physostigmine is used primarily for poisoning with anticholinergic substances such as tricyclic antidepressants, first-generation antihistamines, tropane alkaloids (atropine, hyoscyamine, scopolamine), or certain plant constituents (angel's trumpet, datura, deadly nightshade). Additionally, physostigmine has historical significance in glaucoma therapy and can induce pupillary constriction as eye drops. In modern therapy, physostigmine plays a role in the eye only in specific situations.

Mechanism of Action

Physostigmine reversibly inhibits acetylcholinesterase and butyrylcholinesterase. Through inhibition, acetylcholine is no longer broken down in the synaptic cleft and its concentration increases. This elevated acetylcholine concentration leads to stronger activation of muscarinic and nicotinic receptors. In contrast to neostigmine, physostigmine is a tertiary amine and can cross the blood-brain barrier, so central cholinergic transmission is also enhanced.

This central action is the decisive therapeutic effect in central anticholinergic syndrome. In poisoning caused by anticholinergic substances, central acetylcholine receptors are blocked, leading to confusion, hallucinations, agitation, seizures, and sometimes coma. Physostigmine counteracts this effect directly by increasing central acetylcholine concentration and overcoming competitive inhibition.

Pharmacokinetically, physostigmine has a very rapid onset of action after intravenous administration (within 3 to 8 minutes). The duration of action is 30 to 60 minutes, so repeated doses or continuous infusion may be required for prolonged poisoning. Metabolism occurs through plasma cholinesterase and hepatically.

Therapeutic Indications

• Central anticholinergic syndrome: severe poisoning with atropine, scopolamine, tricyclic antidepressants (with caution), first-generation antihistamines, antiparkinsonian agents, certain plants such as angel's trumpet, deadly nightshade
• Postoperative anticholinergic symptoms: residual effects of anticholinergic substances used in anesthesia with confusion or agitation
• Diagnostic application: can be used to confirm anticholinergic syndrome when differential diagnosis is unclear
• Glaucoma: local application as eye drops, today largely replaced by other antiglaucoma agents
• Antagonism of sedation after certain anesthetics in specific situations, rather historical

Important: in poisoning with tricyclic antidepressants, physostigmine is indicated only in very selected cases because risks (seizures, asystole) exist. Standard is supportive therapy with sodium bicarbonate.

Dosage and Administration

Adults with central anticholinergic syndrome: 2 mg slowly intravenously over approximately 5 minutes, repeatable after 10 to 20 minutes. Maximum dose 4 mg per 30 minutes. For persistent symptoms, continuous infusion 1 to 4 mg per hour under intensive care monitoring.

Pediatric: 0.02 to 0.04 mg per kg, slowly intravenously, dose adjustment based on effect. Maximum dose 2 mg per 30 minutes. Use in children only in specialized pediatric settings.

Postoperatively for anticholinergic symptoms: 0.5 to 2 mg slowly intravenously, repeat if necessary.

Glaucoma eye drops: historical use 0.25 to 0.5 percent solution, rarely used in modern therapy.

Administration: exclusively under medical supervision in emergency or intensive care setting with capability for resuscitation. Before administration, have atropine as antidote ready for overreaction.

Renal insufficiency: generally no special adjustment needed. Hepatic insufficiency: caution, as plasma cholinesterase may be reduced.

Important: slow injection is critical because too rapid administration can cause severe bradycardia and bronchospasm.

Adverse Effects

Very common (cholinergic effect): increased salivation, tearing, sweating, nausea, vomiting, abdominal cramps, diarrhea, bradycardia, hypotension.

Common: bronchospasm with dyspnea, miosis (pupil constriction), accommodation spasm, muscle fasciculations, increased urinary frequency.

Occasional to rare: seizures (especially with too rapid administration or overdose), asystole, AV block, ventricular fibrillation (especially in tricyclic antidepressant poisoning), severe allergic reactions.

Cholinergic crisis: with overdose symptoms such as SLUDGE syndrome (salivation, lacrimation, urination, defecation, gastrointestinal distress, emesis), bradyarrhythmia, bronchospasm with respiratory failure, muscle weakness, seizures. Antidote: atropine.

Local at the eye (eye drops): eye pain, burning, accommodation spasm, temporary visual impairment, occasionally conjunctival irritation.

Drug Interactions

• Anticholinergics (atropine, tropicamide, tricyclic antidepressants, first-generation antihistamines): pharmacodynamic antagonists at the muscarinic receptor, this is the therapeutic purpose of use.
• Other cholinesterase inhibitors (neostigmine, pyridostigmine, donepezil): additive cholinergic effect.
• Beta blockers, calcium antagonists: additive bradycardia and hypotension, caution.
• Succinylcholine: through cholinesterase inhibition, prolonged effect of succinylcholine.
• Inhalation anesthetics, depolarizing muscle relaxants: caution with perioperative administration.
• Theophylline, beta-mimetics: pharmacodynamic antagonists at airways, can counteract bronchospasm from physostigmine.

Special Precautions

Pregnancy: in life-threatening central anticholinergic syndrome, physostigmine can be used despite lack of comprehensive data, because the benefit outweighs theoretical risk. Breast-feeding: with single emergency administration, generally no relevant concentrations in breast milk.

Contraindications: mechanical bowel obstruction, urinary tract obstruction, asthma bronchiale, severe COPD, severe cardiac preexisting conditions with bradyarrhythmia, concurrent treatment with depolarizing muscle relaxants (relative contraindication), poisoning with beta blockers or calcium antagonists (increased toxicity possible).

Precautions: in poisoning with tricyclic antidepressants, strict indication because additional cardiac toxicity threatens. With unclear poisoning etiology, test response first with low dose.

Before administration: cardiopulmonary history, ECG, ensure airway security, resuscitation readiness, atropine as antidote ready.

During therapy: continuous ECG, blood pressure, pulse oximetry, respiration, consciousness. At signs of cholinergic crisis, immediate antagonism with atropine.

Lifestyle: not relevant through acute use.

Fitness to drive: after acute use in context of poisoning, only after complete restoration of central function.

You Might Also Be Interested In

• Atropine, anticholinergic antidote in cholinergic crisis
• Neostigmine, peripheral cholinesterase inhibitor
• Pyridostigmine, cholinesterase inhibitor for myasthenia gravis
• Donepezil, cholinesterase inhibitor for Alzheimer's dementia
• Scopolamine, anticholinergic substance for motion sickness and palliative care

Frequently Asked Questions

Sources

• Gelbe Liste, Physostigmin active substance profile
• BfArM, Federal Institute for Drugs and Medical Devices
• German Society for Clinical Pharmacology and Therapy
• Poison Information Center North (GIZ Nord)
• AWMF, Guidelines for Poisonings and Antidote Use