What Type of Drug is Physostigmine? Classification, Action, and Uses

October 10, 2025 •

4 min read

Physostigmine is a natural alkaloid originally extracted from the Calabar bean, used historically as an ordeal poison and later for its medicinal properties. Today, its primary classification is a reversible acetylcholinesterase inhibitor, which explains its role as an antidote for overdoses involving anticholinergic substances.

Quick Summary

Physostigmine is a reversible acetylcholinesterase inhibitor derived from the Calabar bean, known for its ability to cross the blood-brain barrier. It primarily serves as an antidote for central and peripheral anticholinergic toxicity.

Key Points

Drug Classification: Physostigmine is a reversible acetylcholinesterase inhibitor from the carbamate class.
Mechanism of Action: It works by inhibiting the enzyme that breaks down acetylcholine, causing an increase in acetylcholine levels at nerve synapses.
CNS Penetration: Unlike some other cholinesterase inhibitors, its tertiary amine structure allows it to cross the blood-brain barrier, affecting the central nervous system.
Primary Use: The main clinical use is as an antidote for severe anticholinergic toxicity, reversing both central (delirium) and peripheral effects.
Replaced Indications: Historically used for glaucoma and myasthenia gravis, its use has been largely replaced by newer, longer-acting drugs with fewer side effects.
Important Risks: Caution is required due to potential side effects like nausea, bradycardia, and seizures, especially in cases of tricyclic antidepressant overdose.
Antidote Superiority: For severe anticholinergic delirium, physostigmine is considered more effective than benzodiazepines at reversing the core cause.

The Primary Classification of Physostigmine

Physostigmine is a parasympathomimetic drug, specifically classified as a reversible acetylcholinesterase inhibitor. This means it mimics or enhances the effects of the parasympathetic nervous system. It belongs to the carbamate class of inhibitors and is characterized by its tertiary amine structure. This chemical characteristic is crucial as it allows the drug to effectively cross the blood-brain barrier, enabling it to exert its effects on the central nervous system (CNS), unlike some other related medications.

How Physostigmine Works: Mechanism of Action

The central mechanism of action for physostigmine is its inhibition of acetylcholinesterase (AChE), the enzyme responsible for breaking down the neurotransmitter acetylcholine (ACh) in the synaptic cleft. By binding reversibly to AChE, physostigmine prevents the rapid hydrolysis of acetylcholine. This interference leads to a temporary accumulation of acetylcholine at cholinergic synapses, thereby boosting cholinergic transmission in both the CNS and the peripheral nervous system.

This increase in acetylcholine concentration allows it to outcompete and displace anticholinergic agents from their receptors, reversing the effects of anticholinergic toxicity. The reversible nature of its inhibition is key to its use as an antidote, as its effect wears off as the carbamylated enzyme is reactivated.

Therapeutic Uses and Clinical Application

Physostigmine's unique properties make it invaluable in certain acute medical situations, although its broader historical use has been replaced by safer alternatives.

Critical Role as an Antidote

Physostigmine is primarily used as an antidote for severe anticholinergic toxicity. Anticholinergic toxicity can result from an overdose of various drugs, including:

Antihistamines (e.g., diphenhydramine)
Tricyclic antidepressants (TCAs)
Atropine and scopolamine
Some antipsychotics (e.g., clozapine, quetiapine)

Symptoms of anticholinergic toxicity include agitated delirium, hallucinations, blurred vision, tachycardia, and urinary retention. Physostigmine's central nervous system activity allows it to effectively reverse the delirium and agitation, often within minutes, and resolve peripheral symptoms.

Historical and Obsolete Indications

Historically, physostigmine was used for other conditions, but its short half-life and significant side-effect profile led to its replacement:

Glaucoma: Early use involved topical application to constrict pupils and increase aqueous humor outflow, but newer agents with fewer systemic side effects are now preferred.
Myasthenia Gravis: It was an early treatment for this autoimmune neuromuscular disease, but longer-acting cholinesterase inhibitors like neostigmine and pyridostigmine, which do not penetrate the CNS, became the preferred agents.
Alzheimer's Disease: Its potential role in improving cognitive function was explored due to the cholinergic deficit in Alzheimer's. However, its poor tolerability and short duration of action led to its discontinuation in favor of modern, longer-acting drugs like donepezil and rivastigmine.

Comparison with Other Cholinesterase Inhibitors


Feature	Physostigmine	Neostigmine	Donepezil	Rivastigmine
Drug Type	Reversible AChE Inhibitor, Carbamate	Reversible AChE Inhibitor, Carbamate	Reversible AChE Inhibitor, Non-competitive	Reversible AChE Inhibitor, Carbamate
CNS Penetration	Yes (Tertiary Amine)	No (Quaternary Amine)	Yes	Yes
Primary Clinical Use	Anticholinergic overdose antidote	Reversal of neuromuscular blockade, Myasthenia Gravis	Alzheimer's disease	Alzheimer's and Parkinson's dementia
Duration of Action	Short (~30-90 min)	Moderate (~1-2 hours)	Long (once daily dosing)	Long (twice daily oral, longer patch)
Route of Administration	IV/IM (Parenteral)	IV/IM/Oral	Oral	Oral/Transdermal Patch
Key Limiting Factors	Short half-life, significant side effects	Primarily peripheral effects	Side effects at high doses	Gastrointestinal side effects (oral)

Important Contraindications and Side Effects

While effective in specific situations, physostigmine's use requires careful consideration due to potential adverse effects. The risk of side effects increases with rapid administration or excessive doses.

Common side effects, which reflect cholinergic overstimulation, include:

Nausea and vomiting
Increased salivation and sweating
Diarrhea and abdominal cramps
Miosis (pupil constriction) and blurred vision

More severe, albeit less common, adverse effects can include seizures and cardiac complications such as bradycardia and asystole, particularly in cases of tricyclic antidepressant overdose with pre-existing cardiac conduction abnormalities.

Due to these risks, significant contraindications include:

Pre-existing cardiac conduction defects (e.g., prolonged QRS interval)
Hypersensitivity to the drug
Severe asthma or other bronchospastic diseases
Obstruction of the gastrointestinal or urinary tracts

Conclusion: The Modern Place of Physostigmine

Physostigmine's status in modern medicine has evolved from a broader therapeutic agent to a specialized, but highly valuable, antidote for severe anticholinergic toxicity. Its defining characteristic—its ability to inhibit acetylcholinesterase both centrally and peripherally—makes it uniquely effective for reversing the CNS effects of anticholinergic poisoning, such as delirium and hallucinations. While its short half-life and challenging side effect profile led to its replacement for treating chronic conditions like Alzheimer's disease, its rapid onset of action and titratable dosing make it a powerful tool in a specific emergency medicine context. Given the risk of serious side effects, its administration requires careful patient selection, continuous monitoring, and adherence to slow, controlled dosing regimens to maximize safety. Despite being underutilized in some contexts due to past safety concerns, modern toxicological practice recognizes physostigmine as a superior treatment for agitated delirium caused by anticholinergic overdose compared to sedatives like benzodiazepines. Read more about the benefits of physostigmine in treating anticholinergic delirium.

Frequently Asked Questions

The primary function of physostigmine is to act as an antidote for severe anticholinergic toxicity by inhibiting the enzyme acetylcholinesterase, which increases acetylcholine levels and reverses the toxic effects.

Physostigmine is effective in reversing CNS effects because its tertiary amine structure allows it to readily cross the blood-brain barrier. This enables it to increase acetylcholine levels in the brain and counteract central anticholinergic symptoms like delirium and agitation.

Common side effects include nausea, vomiting, increased salivation, sweating, diarrhea, abdominal cramps, and blurred vision.

Physostigmine is contraindicated in patients with significant cardiovascular disease (especially with QRS prolongation), asthma, or gastrointestinal/urinary obstructions. It is also generally avoided in suspected tricyclic antidepressant overdose due to cardiotoxicity risks.

A key difference is physostigmine's ability to cross the blood-brain barrier, which allows it to treat central nervous system effects. Many other inhibitors, like neostigmine, cannot readily do so.

Physostigmine is no longer used for Alzheimer's due to its short half-life and frequent, pronounced cholinergic side effects. Newer, longer-acting and better-tolerated drugs have been developed for this purpose.

Yes, physostigmine is a natural alkaloid extracted from the Calabar bean, which is indigenous to western Africa.