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Reference material for UK healthcare professionals. Doses and licensing change — verify against the current SmPC and local policy before use.

Drug monographs / Physostigmine

Physostigmine

The antidote whose danger and whose usefulness are the same property: it crosses into the brain.

AntidoteAnticholinergicAntimuscarinicDeliriumPoisoningToxicology

At a glance

ClassReversible carbamate acetylcholinesterase inhibitor; a tertiary amine, so it crosses the blood–brain barrier
Antidote forAntimuscarinic (anticholinergic) delirium — antihistamines, antimuscarinic plants (Datura, deadly nightshade), atropine/hyoscine, some antipsychotics
Why it is uniqueThe only anticholinesterase that enters the CNS — quaternary agents (neostigmine, glycopyrronium) do not
Adult doseLess than 2 mg total, in 0.5 mg increments, slow IV over at least 5 minutes — titrated to effect, on NPIS advice
Onset / durationMinutes / short — often 30–60 min, so resedation is common and re-dosing may be needed
Do not give inTricyclic or sodium-channel-blocker poisoning, or a wide QRS — the setting of the asystole reports
If you overshootCholinergic excess (bradycardia, bronchorrhoea, seizures) — reverse with atropine, roughly half the physostigmine dose
UK productNone licensed — no physostigmine product on the emc; departments hold an unlicensed import or none at all

Why this drug is interesting

The antimuscarinic toxidrome — hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter — is common and, in its agitated delirious form, genuinely difficult to manage. The usual reflex is to sedate: benzodiazepines, sometimes an antipsychotic, occasionally intubation. Physostigmine does something different. It raises acetylcholine at the receptors the poison has blocked, and so it treats the cause rather than blanketing the effect.

It can do this in the brain because of one structural fact: physostigmine is a tertiary amine and crosses the blood–brain barrier, where the quaternary anticholinesterases — neostigmine, pyridostigmine, glycopyrronium — cannot. That single property is why physostigmine is the antidote for central antimuscarinic delirium and the others are not. It is also, in a different setting, why it is dangerous. The drug that reaches the brain to wake a delirious patient is the same drug that reaches the heart and the seizure threshold when the poisoning it is given for is the wrong one.

Pharmacology

Mechanism

Physostigmine is a carbamate that carbamylates acetylcholinesterase, reversibly inhibiting the enzyme that breaks down acetylcholine at the synapse. Acetylcholine accumulates and competes the antimuscarinic poison off its receptors. The effect is felt at both muscarinic and nicotinic synapses, and — uniquely among the anticholinesterases used clinically — centrally as well as peripherally, because the molecule crosses the blood–brain barrier.

Kinetics — the short clock

The clinically important kinetic fact is that physostigmine's action is short. Its plasma half-life is of the order of 15–20 minutes and its clinical effect commonly lasts 30–60 minutes — frequently shorter than the antimuscarinic poison it is given to treat, most of which (antihistamines, antimuscarinic plant alkaloids, tricyclics) outlast it comfortably. Resedation and recurrence of delirium are therefore common, and are not a treatment failure but an expected consequence of the mismatch in duration. The patient needs continued observation, and a repeat dose is often required.

Using it in the antimuscarinic toxidrome

Physostigmine is both diagnostic and therapeutic: a delirious, agitated patient with dry skin, dilated pupils, a tachycardia and absent bowel sounds who wakes and settles after a small slow dose has both confirmed the toxidrome and been treated for it. The candidates are the pure or predominant antimuscarinics — first-generation antihistamines, antimuscarinic plants (Datura/jimsonweed, deadly nightshade), atropine and hyoscine themselves, benztropine, and some antipsychotics — not the mixed-action poisons discussed below.

The evidence — better than its reputation

For the pure antimuscarinic toxidrome the modern evidence is consistent and favourable, even though it is all observational.

  • Burns 2000 — a retrospective comparison of 52 patients: physostigmine controlled agitation and reversed delirium in 96% and 87% of patients, respectively, where benzodiazepines controlled agitation in only 24% and were ineffective in reversing delirium. Complications were lower with physostigmine first (7% versus 46%, P<.002) and recovery faster.2
  • Boley 2019 — a prospective study of 154 patients: delirium control in 79% of those given physostigmine versus 36% of those not, an odds ratio of about 6.6, with adverse events rare and no different between groups.3
  • Watkins 2015 — 815 anticholinergic toxidromes in the ToxIC registry: patients given physostigmine alone had a lower intubation rate (1.9% vs 8.4%, OR 0.21, 95% CI 0.05–0.87), yet physostigmine was used less often than benzodiazepines — the reputation outrunning the data.4
  • Arens 2018 — a 10-year retrospective review of 191 cases: 95.3% had no documented adverse effect; seizures and QTc prolongation each occurred in 1.0%, emesis in 2.1%; average initial doses were 1.0–1.75 mg and the antidote often improved or resolved anticholinergic delirium when administered in doses less than 2 mg. The series did record one death 6 hours after administration — a single event, not clearly attributable to the drug, but the honest counterweight to the safety figures.5

Dosing

When NOT to give it

The wider point is that physostigmine is safe in the poisoning it is for and dangerous in the poisonings it is not for. Its reputation was built on the second category and then applied, wrongly, to the first — which is why Watkins found it underused even where it helps.4 The discipline is diagnostic: give it for a pure antimuscarinic delirium, and withhold it wherever a mixed-action or membrane-active poison is possible.

Other contraindications and cautions

Reactive airways / asthma
A cholinergic drug provokes bronchospasm and bronchorrhoea — avoid, or use with great caution
Mechanical bowel or bladder obstruction
Increased smooth-muscle activity is harmful with a fixed obstruction
Bradyarrhythmia or high-grade AV block
Enhancing vagal tone can worsen conduction — the same physiology as the asystole reports
Peripheral-only toxidrome
If there is no delirium, there is little to gain centrally and the risks remain — treat supportively

Adverse effects

In the antimuscarinic toxidrome, at the doses and rate above, adverse effects are uncommon — Arens documented none in 95% of 191 patients, with seizures and QTc prolongation each at 1%.5 When they occur they are the predictable consequence of too much cholinergic tone, too fast: bradycardia, hypersalivation, bronchorrhoea, lacrimation, vomiting, and — most feared — seizures and bradyasystole.

Practical use in the ED

  1. Confirm it is a pure antimuscarinic delirium. Dry, flushed, dilated pupils, tachycardic, urinary retention, absent bowel sounds, and agitated delirium — with no reason to suspect a tricyclic or other sodium-channel-blocking co-ingestant.
  2. Get an ECG and check the QRS. A wide QRS is a stop sign — treat with sodium bicarbonate, not physostigmine.
  3. Ring NPIS (0344 892 0111) and check TOXBASE. The drug is unlicensed and the indication off-label; confirm your department actually stocks it.
  4. Draw up atropine first, at about half the physostigmine dose, and keep it to hand.
  5. Give 0.5 mg by slow IV push over at least 5 minutes, and titrate in further 0.5 mg increments to a total of under 2 mg, stopping when the delirium clears.
  6. Keep the patient monitored and expect resedation. The effect is short; recurrence of delirium after 30–60 minutes is common and is treated with a repeat dose, not abandoned as failure.
  7. Do not intubate solely to sedate a patient who can instead be woken — the intubation the antidote spares is the outcome Watkins measured.4

Critical appraisal

Physostigmine's evidence base is entirely observational — retrospective series, a poison-centre registry and one prospective observational study — and there is no randomised trial. But the observational evidence points consistently in one direction: for the pure antimuscarinic toxidrome physostigmine is more effective than benzodiazepines and reasonably safe, and its historical reputation for danger derives from a distinct setting, tricyclic poisoning, in which it should not be used at all.23456

The structural observation is the familiar one for this site: a cheap, mechanism-obvious, apparently effective antidote with no licensed UK product — the same regulatory gap seen on the pyridoxine, pralidoxime and desferrioxamine pages. UK practice runs on TOXBASE, NPIS and regional stockholding, not on a label, and the practical failure mode is supply rather than dosing.

References

  1. 1
    Physostigmine — UK licensing status. An emc search on 14 September 2026 for both physostigmine and eserine returned "No search results" — there is no licensed UK product of any formulation. electronic Medicines Compendium. UK use is of an unlicensed imported physostigmine salicylate injection, off-label, on NPIS/TOXBASE advice.
  2. 2
    Burns MJ, Linden CH, Graudins A, Brown RM, Fletcher KE. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Annals of Emergency Medicine 2000;35(4):374–381. PubMed 10736125. Retrospective, 52 consecutive patients. Source of the 96%/87% agitation/delirium reversal figures and the 7% vs 46% complication comparison; concludes physostigmine is "more effective and safer than benzodiazepines" but that "a prospective controlled study is necessary".
  3. 3
    Boley SP, Olives TD, Bangh SA, Fahrner S, Cole JB. Physostigmine is superior to non-antidote therapy in the management of antimuscarinic delirium: a prospective study from a regional poison center. Clinical Toxicology 2019;57(1):50–55. PubMed 29956570. Prospective observational, 154 patients. Delirium control 79% vs 36%, OR ≈ 6.6; adverse events rare and not significantly different between groups.
  4. 4
    Watkins JW, Schwarz ES, Arroyo-Plasencia AM, Mullins ME; Toxicology Investigators Consortium investigators. The Use of Physostigmine by Toxicologists in Anticholinergic Toxicity. Journal of Medical Toxicology 2015;11(2):179–184. PubMed 25510306. 815 consecutive anticholinergic toxidromes in the ToxIC registry. Physostigmine alone associated with lower intubation (1.9% vs 8.4%, OR 0.21, 95% CI 0.05–0.87), yet used less often than benzodiazepines.
  5. 5
    Arens AM, Shah K, Al-Abri S, Olson KR, Kearney T. Safety and effectiveness of physostigmine: a 10-year retrospective review. Clinical Toxicology 2018;56(2):101–107. PubMed 28703024. Retrospective cohort, 191 cases. 95.3% had no documented adverse effect; seizures and QTc prolongation each 1.0%; average initial doses 1.0–1.75 mg; "often improved or resolved anticholinergic delirium when administered in doses less than 2 mg". Source of the dosing and safety figures used here.
  6. 6
    Pentel P, Peterson CD. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Annals of Emergency Medicine 1980;9(11):588–590. PubMed 7001962. Two patients given physostigmine to treat seizures in TCA toxicity who developed asystole — the origin of the contraindication in tricyclic and sodium-channel-blocker poisoning.
  7. 7
    National Poisons Information Service. TOXBASE · NPIS 0344 892 0111. Required: physostigmine in the antimuscarinic toxidrome is off-label use of an unlicensed preparation in the UK; confirm local stock and dosing with NPIS.

Last reviewed 2026-09-14 · Author: Dr Nirmalya Hore