Physostigmine (Monograph)

Brand name: Antilirium
Drug class: Parasympathomimetic (Cholinergic) Agents
- Anticholinesterase Agents
VA class: AU300
CAS number: 57-64-7

Medically reviewed by Drugs.com on Aug 15, 2023. Written by ASHP.

Introduction

Reversible anticholinesterase agent.

Uses for Physostigmine

Reversal of Anticholinergic Effects

Carefully weigh risks and potential benefits of physostigmine therapy when making individual decisions about its use since serious adverse effects (including seizures and asystole) may occur with physostigmine therapy.

The manufacturers state that physostigmine is used to reverse CNS effects resulting from clinical or toxic dosages of drugs (e.g., some antihistamines, antimuscarinics, antiparkinsonian agents, phenothiazines) capable of producing anticholinergic syndrome and from intoxication with certain plants (e.g., Atropa belladonna [deadly nightshade], Brugmansia species [angels’ trumpet], Datura stramonium [jimsonweed, thorn apple, locoweed], Lantana camara). However, routine use not recommended because of potentially serious adverse effects (e.g., seizures, bronchospasm, bradycardia, asystole); many clinicians advise to reserve use for treatment of severe or life-threatening symptoms (e.g., extensive delirium or agitation, hallucinations, hyperthermia, severe sinus or supraventricular tachycardia, seizures) in patients who fail to respond to alternative therapy.

Has also been used successfully in the treatment of tricyclic antidepressant-induced anticholinergic toxicity, but currently is rarely used because of potentially serious adverse effects (seizures, bronchospasm, bradycardia, asystole). Precise role controversial; most clinicians advise against the routine use of physostigmine in tricyclic intoxication, and some clinicians recommend to reserve use only for life-threatening anticholinergic symptoms refractory to other treatment.

Treatment to reverse anticholinergic effects (e.g., delirium, prolonged somnolence) produced by atropine and/or scopolamine preanesthetic medications.

Alzheimer’s Disease

Has been used with variable results in the treatment of dementia of the Alzheimer’s type^{† [off-label]} (Alzheimer’s disease), alone or combined with lecithin.

HereditaryAtaxias

Has been used for the treatment of Friedreich’s ataxia and other hereditary ataxias^{† [off-label]} (spinocerebellar degenerations) (designated an orphan drug by FDA for these uses).

Physostigmine Dosage and Administration

General

• Atropine sulfate injection should always be readily available. (See Cautions.)

Administration

Administer by slow IV injection or by IM injection; has also been administered by sub-Q injection and orally^{† [off-label]}.

Oral Administration

Oral dosage form not currently commercially available.

IV Administration

Rate of Administration

Administer at a slow, controlled rate: ≤1 mg/minute in adults and ≤0.5 mg/minute in children. (See Reversal of Anticholinergic Effects under Uses and also see Rapid IV Administration under Cautions.)

Dosage

Available as physostigmine salicylate; dosage expressed in terms of the salt.

Pediatric Patients

Reversal of Anticholinergic Effects

IV

Initially, 0.02 mg/kg; if no response, repeat dose at 5- to 10-minute intervals until response occurs, adverse cholinergic effects develop, or a total dose of 2 mg has been administered. Alternatively, 0.03 mg/kg or 0.9 mg/m², as necessary.

IM

Initially, 0.02 mg/kg; if no response, repeat dose at 5- to 10-minute intervals until response occurs, adverse cholinergic effects develop, or a total dose of 2 mg has been administered. Alternatively, 0.03 mg/kg or 0.9 mg/m², as necessary.

Adults

Reversal of Anticholinergic Effects

IV

Initially, 0.5–2 mg; may repeat dose every 20 minutes until response occurs or adverse cholinergic effects occur. If initial doses are effective, administer 1–4 mg, as necessary, at intervals (usually 30–60 minutes) as life-threatening signs (e.g., arrhythmias, seizures, deep coma) recur.

To reverse anticholinergic effects of atropine or scopolamine preanesthetic medications, administer a dose twice that of the anticholinergic drug, on a weight basis.

IM

Initially, 0.5–2 mg; may repeat dose every 20 minutes until response occurs or adverse cholinergic effects occur. If initial doses are effective, administer 1–4 mg, as necessary, at intervals (usually 30–60 minutes) as life-threatening signs (e.g., arrhythmias, seizures, deep coma) recur.

To reverse anticholinergic effects of atropine or scopolamine preanesthetic medications, administer a dose twice that of the anticholinergic drug, on a weight basis.

Alzheimer’s Disease† [off-label]

Oral† [off-label]

Usually has been initiated at dosage of 0.5 mg given every 2 hours 6 or 7 times daily until beneficial effect is achieved, intolerable adverse effects occur, or a maximum total daily dose of 16 mg is achieved.

Dosage of 2–2.5 mg every 2 hours 6 or 7 times daily also has been used.

Prescribing Limits

Pediatric Patients

Reversal of Anticholinergic Effects

IV

Maximum total dose of 2 mg.

IM

Maximum total dose of 2 mg.

Adults

Alzheimer’s Disease†

Oral†

Maximum 16 mg daily.

Cautions for Physostigmine

Contraindications

• Asthma.

• Gangrene.

• Diabetes.

• Cardiovascular disease.

• Mechanical obstruction of the intestinal or urogenital tract.

• Any vagotonic state.

• Concomitant use of choline esters (e.g., methacholine, bethanechol) or depolarizing neuromuscular blocking agents (e.g., succinylcholine).

• Known hypersensitivity to physostigmine or any ingredient in the formulation.

Warnings/Precautions

Warnings

Cholinergic Crisis

Overdosage may result in cholinergic crisis (e.g., excessive salivation and sweating, miosis, nausea, vomiting, diarrhea, bradycardia or tachycardia, hypotension or hypertension, confusion, seizures, coma, severe muscle weakness, paralysis). If overdosage occurs, mechanical ventilation with repeated bronchial aspiration and IV atropine are recommended.

Rapid IV Administration

Possible bradycardia, hypersalivation leading to respiratory problems, and/or seizures associated with rapid IV administration; asystole also has been reported. Administer at a slow controlled rate. (See IV Administration under Dosage and Administration.)

Parasympathetic Stimulation

Discontinue therapy if excessive salivation, vomiting, urination, or defecation occurs. Reduce dosage if excessive sweating or nausea occurs. Atropine sulfate injection should always be readily available. Observe patient for evidence of bronchial constriction; perform cardiac monitoring.

Sensitivity Reactions

Sulfite Sensitivity

Injections may contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.

General Precautions

Concomitant Diseases

Use with caution in patients with epilepsy, parkinsonian syndrome, or bradycardia.

Specific Populations

Pregnancy

Category C.

Lactation

Safety not established in nursing women.

Pediatric Use

Reserve use for life-threatening situations only.

Common Adverse Effects

Nausea, vomiting, epigastric pain, miosis, salivation, sweating, lacrimation, dyspnea, bronchospasm.

Physostigmine Pharmacokinetics

Absorption

Bioavailability

Readily absorbed from the GI tract, mucous membranes, and subcutaneous tissue.

Following oral administration (oral dosage form not currently commercially available), physostigmine may undergo saturable metabolism prior to reaching the systemic circulation.

Onset

Following parenteral administration, 3–8 minutes.

Duration

Following parenteral administration, 30 minutes to 5 hours.

Distribution

Extent

Widely distributed throughout the body; readily penetrates the blood-brain barrier.

Elimination

Metabolism

Metabolized via hydrolysis by cholinesterases.

Elimination Route

Not fully elucidated; very small amounts excreted in urine.

Half-life

15–40 minutes.

Stability

Storage

Parenteral

Injection

15–30°C.

Actions

• Inhibits acetylcholinesterase and prolongs and exaggerates the central and peripheral effects of acetylcholine.

• Produces generalized cholinergic responses including miosis, increased tonus of intestinal musculature, constriction of bronchi, and stimulation of secretion by salivary and sweat glands.

• At sufficiently high dosage, directly blocks action at autonomic ganglia, causes muscle fasciculation and, ultimately, depolarization block.

• Some evidence that physostigmine may potentiate cholinergic mechanisms involved in memory storage and may improve short-term memory.

Advice to Patients

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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