Physostigmine Salicylate

Class: Parasympathomimetic (Cholinergic) Agents
VA Class: AU300
CAS Number: 57-64-7
Brands: Antilirium

Introduction

Reversible anticholinesterase agent.a

Uses for Physostigmine Salicylate

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.109 148 149 150 151 152 153 156 157 158 159 a

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 syndrome148 149 a b and from intoxication with certain plants (e.g., Atropa belladonna [deadly nightshade], Brugmansia species [angels’ trumpet], Datura stramonium [jimsonweed, thorn apple, locoweed], Lantana camara).139 148 149 a b 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.139 140 141 142 143 144 147 148 149 150 151 152 a

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Has also been used successfully in the treatment of tricyclic antidepressant-induced anticholinergic toxicity,109 147 151 152 153 154 155 156 157 159 160 but currently is rarely used because of potentially serious adverse effects (seizures, bronchospasm, bradycardia, asystole).109 147 150 151 152 153 156 157 158 159 Precise role controversial; most clinicians advise against the routine use of physostigmine in tricyclic intoxication,109 147 151 152 153 154 155 156 157 158 159 161 and some clinicians recommend to reserve use only for life-threatening anticholinergic symptoms refractory to other treatment.109 153 157

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

Alzheimer’s Disease

Has been used with variable results in the treatment of dementia of the Alzheimer’s type (Alzheimer’s disease), alone or combined with lecithin.117 118 119 120 121 122 123 124 125 126 127 128 129 130 131

HereditaryAtaxias

Has been used for the treatment of Friedreich’s ataxia and other hereditary ataxias (spinocerebellar degenerations)135 136 137 138 (designated an orphan drug by FDA for these uses).135

Physostigmine Salicylate Dosage and Administration

General

  • Atropine sulfate injection should always be readily available.149 (See Cautions.)

Administration

Administer by slow IV injection or by IM injection;149 has also been administered by sub-Q injection and orally.b

Oral Administration

Oral dosage form not currently commercially available.b

IV Administration

Rate of Administration

Administer at a slow, controlled rate: ≤1 mg/minute in adults and ≤0.5 mg/minute in children.149 (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.149 b

Pediatric Patients

Reversal of Anticholinergic Effects
IV

Initially, 0.02 mg/kg;149 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.149 Alternatively, 0.03 mg/kg or 0.9 mg/m2, as necessary.b

IM

Initially, 0.02 mg/kg;149 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.149 Alternatively, 0.03 mg/kg or 0.9 mg/m2, as necessary.b

Adults

Reversal of Anticholinergic Effects
IV

Initially, 0.5–2 mg;b may repeat dose every 20 minutes until response occurs or adverse cholinergic effects occur.b 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.b

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

IM

Initially, 0.5–2 mg;b may repeat dose every 20 minutes until response occurs or adverse cholinergic effects occur.b 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.b

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

Alzheimer’s Disease
Oral

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.119 120 121 130

Dosage of 2–2.5 mg every 2 hours 6 or 7 times daily also has been used.118 119 120 121 130

Prescribing Limits

Pediatric Patients

Reversal of Anticholinergic Effects
IV

Maximum total dose of 2 mg.149

IM

Maximum total dose of 2 mg.149

Adults

Alzheimer’s Disease
Oral

Maximum 16 mg daily.121

Cautions for Physostigmine Salicylate

Contraindications

  • Asthma.149 b

  • Gangrene.149 b

  • Diabetes.149 b

  • Cardiovascular disease.149 b

  • Mechanical obstruction of the intestinal or urogenital tract.149 b

  • Any vagotonic state.149 b

  • Concomitant use of choline esters (e.g., methacholine, bethanechol) or depolarizing neuromuscular blocking agents (e.g., succinylcholine).149 b

  • 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).149 b If overdosage occurs, mechanical ventilation with repeated bronchial aspiration and IV atropine are recommended.149 b

Rapid IV Administration

Possible bradycardia, hypersalivation leading to respiratory problems, and/or seizures associated with rapid IV administration; asystole also has been reported.148 149 150 151 a Administer at a slow controlled rate.149 (See IV Administration under Dosage and Administration.)

Parasympathetic Stimulation

Discontinue therapy if excessive salivation, vomiting, urination, or defecation occurs.149 b Reduce dosage if excessive sweating or nausea occurs.149 b Atropine sulfate injection should always be readily available.149 Observe patient for evidence of bronchial constriction; perform cardiac monitoring.141 142 144

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.149

General Precautions

Concomitant Diseases

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

Specific Populations

Pregnancy

Category C.c

Lactation

Safety not established in nursing women.149

Pediatric Use

Reserve use for life-threatening situations only.b

Common Adverse Effects

Nausea,149 vomiting,149 epigastric pain,b miosis,b salivation,149 sweating,b lacrimation,b dyspnea,b bronchospasm.b

Physostigmine Salicylate Pharmacokinetics

Absorption

Bioavailability

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

Following oral administration (oral dosage form not currently commercially available), physostigmine may undergo saturable metabolism prior to reaching the systemic circulation.100 101 102 103

Onset

Following parenteral administration, 3–8 minutes.b

Duration

Following parenteral administration, 30 minutes to 5 hours.b

Distribution

Extent

Widely distributed throughout the body;b readily penetrates the blood-brain barrier.149 b

Elimination

Metabolism

Metabolized via hydrolysis by cholinesterases.b

Elimination Route

Not fully elucidated; very small amounts excreted in urine.b

Half-life

15–40 minutes.100 101

Stability

Storage

Parenteral

Injection

15–30°C.149 b

Actions

  • Inhibits acetylcholinesterase and prolongs and exaggerates the central and peripheral effects of acetylcholine.149 b

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

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

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

Advice to Patients

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.149

  • 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.149

  • Importance of informing patients of other important precautionary information.149 (See Cautions.)

Preparations

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

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

Physostigmine Salicylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Bulk

Powder*

Parenteral

Injection

1 mg/mL*

Physostigmine Salicylate Injection

Akorn

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions April 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

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b. AHFS Drug Information 2008. McEvoy GK, ed. Physostigmine salicylate. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 1284-6.

c. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1998:866-7.

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