Description of Physostigmine
Physostigmine is a parenteral and ophthalmic cholinesterase inhibitor. Physostigmine is similar to neostigmine except that it is a tertiary amine while neostigmine is a quaternary amine. This difference may explain the increased activity of physostigmine in the CNS. Physostigmine most commonly is used as an ophthalmic agent in the treatment of open-angle glaucoma. It has also been used to counteract toxic anticholinergic effects (both central and peripheral) of other drugs which cause anticholinergic toxicity, particularly in overdose situations. Until recently, physostigmine was used to treat tricyclic antidepressant (TCA) overdose, but it is no longer recommended for this purpose due to its own potentially harmful effects including seizures and life-threatening bradyarrhythmias progressing to asystole. Physostigmine has been used to treat Alzheimer’s disease and hereditary ataxias. While some improvements were noted in some studies, the drug has not been well established in these diseases. Extracted physostigmine was first used ophthalmically, for glaucoma, in 1875. It was first synthesized in 1935, and is accepted by the FDA as a pre-1938 drug. A sustained-release form of physostigmine salicylate (Synapton®) has completed phase III investigation for Alzheimer’s disease as of August 1996.
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Mechanism of Action of Physostigmine
Physostigmine competes with acetylcholine for its binding site on acetylcholinesterase. By interfering with the enzymatic destruction of acetylcholine, physostigmine potentiates the action of acetylcholine on both the skeletal muscle (nicotinic receptor) and the GI tract (muscarinic receptor).
Physostigmine acts primarily at muscarinic cholinergic synapses and within the CNS, having less effect at the myoneural junction at low doses. At higher doses, physostigmine exerts some effects not related to acetylcholinesterase inhibition. Physostigmine may act at the myoneural junction to cause a depolarizing block. It also can exert a direct blocking action within autonomic ganglia and directly potentiate CNS depression.
Specific responses to cholinesterase inhibitors parallel cholinergic stimulation: increased skeletal muscle tone (nicotinic); increased gastric motility and GI tone (muscarinic); bradycardia (muscarinic); ureteral constriction (muscarinic); stimulation of the sweat and salivary glands (muscarinic); and constriction of the bronchi (muscarinic). Some evidence suggests there is also a direct action on skeletal muscle.
Physostigmine causes miosis by stimulating cholinergic responses in the eye. The drug decreases intraocular pressure, presumably by inducing ciliary muscle contraction, which widens the trabecular meshwork, allowing for increased outflow of aqueous humor.
In the past, physostigmine was used to manage TCA overdose. Although some patients regained consciousness after physostigmine administration, physostigmine did not correct the cardiac arrhythmias. Arrhythmias secondary to TCA overdose were determined to be secondary to the quinidine-like effects of the TCA and not to anticholinergic toxicity. Because of this and the fact that physostigmine can induce seizures, the drug is no longer recommended for treatment of TCA overdose.
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Pharmacokinetics
Physostigmine is administered via intravenous or intramuscular injection or applied topically to the eye. It is distributed widely throughout the body and crosses the blood-brain barrier. The mode of excretion is unknown; a small amount is excreted in the urine.
•Route-Specific Pharmacokinetics
Intravenous Route
Peak effects are seen in approximately 5 minutes when given IV. Cholinesterase hydrolyzes physostigmine, making its duration of action approximately 1 to 2 hours when given IV.
Intramuscular Route
Peak effects of physostigmine are seen in approximately 5 minutes when given IM.
Other Route(s)
Ophthalmic route
Peak effects are seen in within 10 to 30 minutes when applied topically to the eye. Cholinesterase hydrolyzes physostigmine, making its duration of action approximately 12 to 36 hours after ophthalmic use.
- Physostigmine Salicylate
- Antilirium
- Isopto Eserine
- Antiglaucoma
- Central Nervous System Agent
- Cholinesterase Inhibitor
- Dermatologic: Diaphoresis
- Gastrointestinal: Abnormal defecation, Excessive salivation, Nausea and vomiting
- Cardiovascular: Bradyarrhythmia
- Immunologic: Hypersensitivity reaction
- Neurologic: Seizure
- May administer by IV or IM routes
- Intravenous: (Adults) Administer at a slow controlled rate not exceeding 1 mg/min ; however slower rates of administration have been recommended, at a rate of 0.5 mg/min (50 kg or greater)
- Intravenous: (Pediatric) Administer at a slow controlled rate not exceeding 0.5 mg/min ; however slower rates of administration have been recommended, at a rate of 0.5 mg/min (50 kg or less)
- Injection Solution: 1 MG/1 ML
- General Dosage Information: Physostigmine salicylate has not been found by the US FDA to be safe and effective, and the drug product labeling has not been approved by the FDA.
- Anticholinergic agent toxicity: 2 mg IV at a slow controlled rate of no more than 1 mg/min or IM; dose may be repeated if there are life-threatening signs such as arrhythmia, convulsions, or coma ; however slower rates of administration have been recommended
- Anticholinergic agent toxicity: Premedication, lorazepam 1 to 2 mg IV for seizure prophylaxis or sodium channel blockade revealed by ECG
- Anticholinergic agent toxicity: (50 kg or greater) 0.02 mg/kg IV at a rate of 0.5 mg/min or 2 mg IV over 4 minutes; reassess mental status in 15 minutes; if improvement without intolerable side effects, repeat dose every 1 to 2 hours as needed for delirium; discontinue if there are cholinergic signs (profuse diaphoresis, nausea, emesis, incontinence of urine or feces) or lack of neurobehavioral improvement
- Anticholinergic agent toxicity: (50 kg or less) 0.02 mg/kg IV at a rate of 0.5 mg/min or 1 mg IV over 2 minutes; reassess mental status in 15 minutes; if improvement without intolerable side effects, repeat dose every 1 to 2 hours as needed for delirium; discontinue if there are cholinergic signs (profuse diaphoresis, nausea, emesis, incontinence of urine or feces) or lack of neurobehavioral improvement
- Glaucoma: 1 centimeter of the 0.25% ophthalmic ointment 1-3 times daily
- Glaucoma: 1 drop of the 0.25% or 0.5% ophthalmic solution up to 4 times daily
- General Dosage Information: Physostigmine salicylate has not been found by the US FDA to be safe and effective, and the drug product labeling has not been approved by the FDA.
- Anticholinergic agent toxicity: 0.02 mg/kg IV at a slow controlled rate of no more than 0.5 mg/min or IM; dose may be repeated at 5 to 10 minute intervals if the toxic effects persist, and there is no sign of cholinergic effects, until a therapeutic effect is obtained up to a MAX dose of 2 mg
- Anticholinergic agent toxicity: (Adolescents, 50 kg or greater) 0.02 mg/kg IV at a rate of 0.5 mg/min or 2 mg IV over 4 minutes; reassess mental status in 15 minutes; if improvement without intolerable side effects, repeat doses every 1 to 2 hours as needed for delirium; discontinue if there are cholinergic signs (profuse diaphoresis, nausea, emesis, incontinence of urine or feces) or lack of neurobehavioral improvement
- Anticholinergic agent toxicity: (Adolescents and children, 50 kg or less) 0.02 mg/kg IV at a rate of 0.5 mg/min or 1 mg IV over 2 minutes; reassess mental status in 15 minutes; if improvement without intolerable side effects, repeat doses every 1 to 2 hours as needed for delirium; discontinue if there are cholinergic signs (profuse diaphoresis, nausea, emesis, incontinence of urine or feces) or lack of neurobehavioral improvement
- Anticholinergic agent toxicity: (Toddlers, less than 20 kg): 0.02 mg/kg IV at a rate of 0.5 mg/min or 0.5 mg IV over 1 minute; reassess mental status in 15 minutes; if improvement without intolerable side effects, repeat doses every 1 to 2 hours as needed for delirium; discontinue if there are cholinergic signs (profuse diaphoresis, nausea, emesis, incontinence of urine or feces) or lack of neurobehavioral improvement
