Physostigmine (Systemic)


VA CLASSIFICATION
Primary: AU300

Commonly used brand name(s): Antilirium.

Another commonly used name is
eserine. Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Cholinergic (cholinesterase inhibitor)—

antidote (to anticholinergics)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Toxicity, anticholinergic agent (treatment)—Physostigmine is indicated to reverse toxic effects on the central nervous system (CNS) caused by drugs and plants capable of producing anticholinergic poisoning in clinical or toxic dosages {01} {07} {08} {09}. Physostigmine is not recommended for treatment of routine anticholinergic poisoning or those not responding to less toxic alternatives because of potential complications such as bradycardia, seizures, and asystole {05} {07}.

[Ataxias, hereditary (treatment)]1—FDA has granted physostigmine an orphan drug designation for use in Friedreich's and other inherited ataxias {03} {04}.

Unaccepted
Physostigmine has been reported to antagonize the CNS depressant effects of benzodiazepines; however, physostigmine should not be used in benzodiazepine overdosage because of its nonspecific action and potential toxicity {05} {07}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Mechanism of action/Effect:


Antidote (to anticholinergics):

Antagonizes action of anticholinergics, which block the postsynaptic receptor sites of acetylcholine, by reversibly inhibiting the destruction of acetylcholine by acetylcholinesterase, thereby increasing the concentration of acetylcholine at sites of cholinergic transmission {01} {12}.

Since physostigmine is a lipid-soluble tertiary amine, which (unlike the quaternary amines neostigmine and pyridostigmine) can cross the blood-brain barrier, it acts against both central and peripheral anticholinergic effects {01}.


Distribution:

Easily penetrates the blood-brain barrier {12}.

Biotransformation:

Rapidly hydrolyzed by cholinesterases {01}.

Time to peak effect

Intramuscular—20 to 30 minutes {11}.

Intravenous—Within 5 minutes {13}.

Duration of action:

Intramuscular and intravenous—30 to 60 minutes {11} {13}.

Elimination:
    Very small amounts eliminated in urine; largely destroyed in body by hydrolysis {10}.


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Studies in humans have not been done {01}. Physostigmine crosses the blood-brain barrier and would be expected to cross the placenta {15}.

Breast-feeding

It is not known whether physostigmine is excreted in breast milk.

Pediatrics

No information is available on the relationship of age to the effects of physostigmine in pediatric patients. However, physostigmine should be used in children only in life-threatening situations.

Physostigmine injection that contains benzyl alcohol as a preservative should not be used in newborn and immature infants. The use of benzyl alcohol in neonates has been associated with a fatal toxic syndrome consisting of metabolic acidosis and CNS, respiratory, circulatory, and renal function impairment.


Geriatrics


No information is available on the relationship of age to the effects of physostigmine in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Choline esters (acetylcholine, bethanechol, carbachol, methacholine){01}{06}    (effects of acetylcholine and methacholine are markedly enhanced by prior administration of physostigmine, since these medications are hydrolyzed by acetylcholinesterase; physostigmine produces only additive effects when used concurrently with carbachol or bethanechol)


» Succinylcholine{01}{14}    (concurrent use with physostigmine is not recommended since high doses of physostigmine may cause muscle fasciculation and ultimately, a depolarization block, which may be additive to that produced by the depolarizing neuromuscular blocking agents)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Asthma{01}{13}    (increase in bronchial secretions and other respiratory effects of physostigmine may aggravate condition {05})


» Cardiovascular disease{01}{13} or
» Gangrene or
» Intestinal or urogenital tract obstruction, mechanical, or any vagotonic state{01}    (these conditions may be exacerbated by physostigmine)


Parkinsonism    (akinesia, rigidity, and tremor may be increased {05})


» Organophosphate poisoning    (physostigmine may potentiate anticholinesterase activity {07})


Sensitivity to physostigmine

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure and{05}
Heart rate and rhythm{13}{16}    (monitoring is recommended because physostigmine has been reported to cause bradycardia and hypotension {07})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Irregular heartbeat{01}
    
muscle twitching{05}
    
shortness of breath, troubled breathing, wheezing, or tightness in chest{01}{12}
    
unusual tiredness or weakness

With too rapid intravenous administration {01}
    
Convulsions{07}{13}
    
difficulty in breathing{05}
    
slow heartbeat{07}{13}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Diarrhea{05}{12}
    
increased sweating{01}{12}
    
increased watering of mouth{01}{05}{12}
    
nausea or vomiting{01}{12}
    
stomach cramps or pain{12}

Incidence less frequent
    
Frequent urge to urinate{05}{12}
    
increase in bronchial secretions{05}{12}
    
nervousness or restlessness{01}{12}
    
unusually small pupils{06}{12}
    
unusual watering of eyes{06}





Overdose
For specific information on the agents used in the management of physostigmine overdose, see:    • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph.


For more specific information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Specific treatment—

Use of the antagonist atropine sulfate injection {01} {07}. See the package insert or Atropine in Anticholinergic/Antispasmodics (Systemic) for specific dosing guidelines for use of this product.

Use of intravenous administration of pralidoxime chloride {06} to counteract ganglionic and skeletal muscle effects. See the package insert for specific dosing guidelines for use of this product.

Treatment of convulsions or shock as appropriate.

Monitoring— May include monitoring of cardiac function.

Supportive care—Maintenance of open airway (possible suction of bronchial secretions); use of assisted respiration {06}.


General Dosing Information
The dosage of physostigmine should be reduced if excessive sweating or nausea occurs {01}.

Physostigmine should be discontinued if excessive symptoms of salivation, vomiting, urination, or diarrhea occur {01}.

Rapid intravenous administration may cause bradycardia, hypersalivation resulting in breathing difficulties, and possibly convulsions {01} {07} {13}.


Parenteral Dosage Forms

PHYSOSTIGMINE SALICYLATE INJECTION USP

Usual adult and adolescent dose
Antidote
Intramuscular or intravenous, 500 mcg (0.5 mg) {01} to 2 mg, {07} administered at a rate of not more than 1 mg per minute; {01} doses of 1 to 4 mg may be repeated, if necessary, at intervals of 20 to 30 minutes {07} as life-threatening signs recur.


Usual pediatric dose
Antidote
Intravenous, initially no more than 20 mcg (0.02 mg) per kilogram of body weight {17} administered over a period of at least one minute; {07} if toxic effects persist and there is no sign of cholinergic effects, dose may be repeated at five- to ten-minute intervals, if necessary, up to a maximum dose of 2 mg. {01}


Note: Use should be reserved for life-threatening situations only.
Physostigmine injection that contains benzyl alcohol as a preservative should not be used in newborn and immature infants. The use of benzyl alcohol in neonates has been associated with a fatal toxic syndrome consisting of metabolic acidosis and CNS, respiratory, circulatory, and renal function impairment.


Strength(s) usually available
U.S.—


1 mg per mL (Rx) [Antilirium (benzyl alcohol 2%)][Generic]

Canada—


1 mg per mL (Rx) [Antilirium (benzyl alcohol 2%)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.



Revised: 08/21/1992



References
  1. Antilirium product information, rec 5/89, U.S.
  1. Antilirium product information, CPS 1988, Canada.
  1. Kork R, Blass J, Spence M. Physostigmine in familial ataxias. Neurol 1977; 27[1]: 70-2.
  1. Rodriguez-Budelli M, Kork R, Blass J, et al. Action of physostigmine on inherited ataxias. Advanced Neurol, 1978, 21: 195-202.
  1. USP DI Orphan Drug and Biological Listing. 1991.
  1. American Hospital Formulary Service, 1991.
  1. Ellenhorn M, Barceloux D. Medical toxicology, New York: Elsevier Press 1988.
  1. Danze L, Langdorf M. Reversal of orphenadrine-induced ventricular tachycardia with physostigmine. J Emerg Med 1991; 9: 453-7.
  1. Aquilonius S, Hedstrand U. The use of physostigmine as an antidote in tricyclic anti-depressant intoxication. Acta Anaesth Scand 1978; 22: 40-5.
  1. Aquilonius S, Hartvig P. Clinical pharmacokinetics of cholinesterase inhibitors. Clin Pharmacokin 1986; 11: 236-49.
  1. Hartvig P, Wiklund L, Lindstrom B. Pharmacokinetics of physostigmine after intravenous, intramuscular and subcutaneous administration in surgical patients. Acta Anaesth Scand 1986: 30: 177-82.
  1. Somani S, Dube S. Physostigmine-an overview as pretreatment drug for organophosphate intoxication. Int J of Clin Pharm Ther Tox 1989; 27[8]: 367-87.
  1. Knoben J, Anderson P. Handbook of clinical drug data (6th ed.). Hamilton IL: Drug Intelligence Publications, 1988.
  1. Tatro D. Drug information facts, St. Louis, MO: J.B. Lippincott Co., 1990.
  1. Briggs G, Freeman R, Yaffe S. Drugs in pregnancy and lactation. Baltimore: Williams and Wilkins, 1990.
  1. Panelist comment, 1992 revision.
  1. Panel consensus, 1992 revision cycle.
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