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PHYSOSTIGMINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Physostigmine is a reversible inhibitor of cholinesterase activity. It effectively increases the concentration of acetylcholine at the sites of cholinergic transmission. Physostigmine poisoning causes acetylcholine excess at muscarinic, nicotinic, and CNS sites.

Specific Substances

    1) Eserine
    2) Eserolein, methylcarbamate (ester)
    3) Fisostigmina
    4) Physostigmine salicylate
    5) Physostol
    6) CAS 57-47-6
    1.2.1) MOLECULAR FORMULA
    1) C15-H21-N3-O2

Available Forms Sources

    A) FORMS
    1) Physostigmine salicylate is available in parenteral form as physostigmine salicylate 1 mg/mL in 2 mL ampules (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    2) Ophthalmic preparations were available as either the 0.25% and 0.5% solutions, or as an ointment (Prod Info Eserine Sulfate(R), 1994).
    B) SOURCES
    1) Physostigmine is an alkaloid which was originally derived from Calabar beans, which are the seeds of the vine Physostigma venenosum (Budavari, 1996).
    C) USES
    1) Physostigmine salicylate has been used intravenously to reverse anticholinergic toxicity (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    2) Physostigmine ophthalmic solution has been used to treat glaucoma (Prod Info Eserine Sulfate(R), 1994).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Physostigmine is used intravenously to reverse anticholinergic toxicity and as an ocular preparation for glaucoma.
    B) PHARMACOLOGY: Physostigmine is a carbamate with reversible inhibition of cholinesterase activity. It effectively increases the concentration of acetylcholine at the sites of cholinergic transmission and crosses the blood-brain barrier. Physostigmine poisoning causes acetylcholine excess at muscarinic, nicotinic, and CNS sites.
    C) TOXICOLOGY: Excessive doses cause cholinergic excess, which includes bradycardia/asystole, nausea/vomiting, sweating, hypersalivation, bronchospasm, seizures, or pulmonary edema. Death may occur due to respiratory failure.
    D) EPIDEMIOLOGY: Poisoning is uncommon and rarely severe.
    E) WITH THERAPEUTIC USE
    1) Diaphoresis, excessive salivation, nausea, vomiting, abdominal pain, depression, anxiety, fatigue, dysphoria, urinary incontinence have been reported. Bradycardia or seizures may occur if IV administration of physostigmine salicylate is too rapid.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, bradycardia, sweating, hypersalivation, and bronchospasm.
    2) SEVERE TOXICITY: Severe bradycardia/asystole, seizures, and pulmonary edema.
    0.2.20) REPRODUCTIVE
    A) Teratogenic effects have been observed in mice studies.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Physostigmine plasma concentrations are not clinically useful or readily available.
    C) No specific lab work is needed in most patients.
    D) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (seizures, bradycardia/asystole, nausea/vomiting, sweating, hypersalivation, bronchospasm, or pulmonary edema).
    E) Monitor oral secretions, lung sounds, and pulse oxygenation for signs of pulmonary edema.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) The vast majority of physostigmine overdoses require only supportive care. Treat diaphoresis and excessive salivation with supportive care. Nausea and vomiting can be treated with antiemetics.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Patients with bradycardia or asystole should be treated with atropine (1 to 2 mg IV). There is a theoretical risk of respiratory depression that would require intubation. Bronchospasm and pulmonary edema should be treated with atropine (1 to 2 mg). The doses of atropine should be proportional to the symptoms of the patient and should be titrated to reverse bradycardia causing hypotension, bronchospasm, or pulmonary edema. Treat seizures with IV benzodiazepines.
    C) DECONTAMINATION
    1) PREHOSPITAL: There is no method of decontamination that is useful.
    2) HOSPITAL: There is no method of decontamination that is useful.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with severe intoxication (respiratory depression, severe bronchospasm or bronchorrhea not responding to atropine).
    E) ANTIDOTE
    1) Atropine is the antidote for physostigmine. It is used to treat bradycardia with associated hypotension, bronchorrhea, bronchospasm, or pulmonary edema. Initial dose of atropine is 1 to 2 mg IV and should be titrated to reverse these clinical effects. There is no maximum dose of atropine. Atropine infusions are generally not indicated due to the short duration of physostigmine.
    F) DYSRHYTHMIAS
    1) Bradycardia and asystole may develop. Treat with atropine and per Advanced Cardiovascular Life Support (ACLS) guidelines.
    G) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are not of value due to the large volume of distribution and short duration of action of physostigmine and wide availability of an antidote.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with inadvertent ingestions, including children who have ingested small amounts of the ophthalmic solution, can be managed at home.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions or children with significant ingestions should be referred to a healthcare facility for observation for 4 hours. All Symptomatic patients should be sent to a healthcare facility for observation for 4 hours.
    3) ADMISSION CRITERIA: Patients with persistent nausea and/or vomiting, sweating, and hypersalivation should be admitted. Patients with seizures, bradycardia/asystole, bronchospasm, or pulmonary edema should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (dysrhythmias), or in whom the diagnosis is not clear.
    I) PITFALLS
    1) Not identifying a possible septic patient or other agents. Not administering sufficient atropine to prevent pulmonary edema or bradycardia/asystole.
    J) PHARMACOKINETICS
    1) Oral bioavailability: 7% to 12%. Metabolism: rapid metabolism through hydrolysis; extensively metabolized and conjugated in the liver. Protein binding: 45% to 55% protein bound. Excretion: Approximately 80% is excreted in the feces, 13% in the urine, both mainly as metabolites. Elimination half-life: 4 hours.
    K) TOXICOKINETICS
    1) Onset of symptoms generally occurs within 5 to 30 minutes. Toxicity may persist for greater than 4 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Toxicity from other cholinergic agents such as organophosphate or carbamate insecticides; direct acting cholinergic drugs such as pilocarpine, bethanechol, cevimeline, antimyasthenics such as neostigmine or pyridostigmine; or cholinergic drugs for Alzheimer including donepezil.

Range Of Toxicity

    A) TOXICITY: There is no specific toxic dose to physostigmine. In some cases, the recommended IV dose of 1 to 2 mg in adults has caused seizures and cardiac dysrhythmias, likely secondary to the underlying condition being treated. Physostigmine may be particularly dangerous when used in the setting of a tricyclic antidepressant overdose; 2 mg of physostigmine has led to asystole and death in these patients. Adults have survived IV doses of 12 mg over 45 minutes, and ingestion of 1 gram.
    B) THERAPEUTIC DOSES: ADULTS: IV: 2 mg IV over 2 to 3 minutes is the usual dose for anticholinergic toxicity, no faster than 1 mg/min, may be repeated if necessary. OPHTHALMIC: One drop of 0.25% solution or one centimeter of 0.25% ointment to the eye 3 times daily for glaucoma. CHILDREN: 0.02 mg/kg IV over 2 to 3 minutes, at a rate no more than 0.5 mg/minute. MAX: 2 mg total dosage.

Clinical Effects

Summary Of Exposure

    A) USES: Physostigmine is used intravenously to reverse anticholinergic toxicity and as an ocular preparation for glaucoma.
    B) PHARMACOLOGY: Physostigmine is a carbamate with reversible inhibition of cholinesterase activity. It effectively increases the concentration of acetylcholine at the sites of cholinergic transmission and crosses the blood-brain barrier. Physostigmine poisoning causes acetylcholine excess at muscarinic, nicotinic, and CNS sites.
    C) TOXICOLOGY: Excessive doses cause cholinergic excess, which includes bradycardia/asystole, nausea/vomiting, sweating, hypersalivation, bronchospasm, seizures, or pulmonary edema. Death may occur due to respiratory failure.
    D) EPIDEMIOLOGY: Poisoning is uncommon and rarely severe.
    E) WITH THERAPEUTIC USE
    1) Diaphoresis, excessive salivation, nausea, vomiting, abdominal pain, depression, anxiety, fatigue, dysphoria, urinary incontinence have been reported. Bradycardia or seizures may occur if IV administration of physostigmine salicylate is too rapid.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, bradycardia, sweating, hypersalivation, and bronchospasm.
    2) SEVERE TOXICITY: Severe bradycardia/asystole, seizures, and pulmonary edema.

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH THERAPEUTIC USE
    1) Respirations may be increased secondary to increased bronchial secretions leading to hypoxia.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Physostigmine may reverse the hyperpyrexia seen from anticholinergic poisoning.
    B) WITH POISONING/EXPOSURE
    1) Following an overdose, lowering of body temperature may occur (HSDB , 2002).
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Physostigmine may also reverse the hypertension which may accompany anticholinergic crisis. Hypertension may develop.
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Heart rate is usually decreased secondary to cholinesterase inhibition leading to increased vagal tone on the heart. Tachycardia may also occur.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) IRRITATION
    a) Ocular instillation of physostigmine solution may cause stinging, burning, lacrimation with muscle twitching, conjunctival redness, headache and induced myopia with visual blurring (Grant & Schuman, 1993).
    b) The rare occurrence of iris cyst, retinal detachment, vitreous hemorrhage, and lens opacities have been reported (Prod Info Antilirium(R), physostigmine, 2000).
    2) MYDRIASIS
    a) CASE SERIES: In one series, all anticholinergic patients (n=9) who received physostigmine developed an increased pupil size (Nattel et al, 1979).
    b) Physostigmine did not affect pupil size in non-anticholinergic poisonings (Nattel et al, 1979).
    B) WITH POISONING/EXPOSURE
    1) MYDRIASIS
    a) Following a massive overdose (such as a suicidal overdose), the pupils are generally dilated and sluggishly reactive to light, rather than being constricted (Grant & Schuman, 1993).
    b) CASE REPORT: A 22-year-old man who deliberately ingested 1 g of powdered physostigmine salicylate was documented to have enlarged pupils (Cumming et al, 1968).
    2) MIOSIS
    a) Miosis may result following systemic poisoning from drinking small amounts of physostigmine eye drops or following inhalational exposure to vapors (HSDB , 2002; Grant & Schuman, 1993). Following instillation of solution into the eyes, miosis occurs within 10 to 30 minutes and may persist for 12 to 48 hours (HSDB , 2002).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Smaller doses given to anticholinergic patients resulted in significant increases in cardiac output, mean arterial pressure, and pulmonary capillary wedge pressures (Nilsson et al, 1983).
    b) Physostigmine given to patients with anticholinergic overdose significantly decreased the mean arterial pressure from 105.4 to 96.1 mmHg and the heart rate from 104 to 91.3 beats/min (Nattel et al, 1979). No effects were seen in non-anticholinergic overdoses.
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia may occur if IV administration of physostigmine salicylate is too rapid, exceeding the recommended rate of no more than 1 mg/min in adults or 0.5 mg/min in children (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    b) CASE SERIES: In a study of physostigmine for Alzheimer disease, 3 of 29 (10%) patients developed sinus bradycardia during the physostigmine treatment phase (Sano et al, 1993).
    C) VENTRICULAR TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Atrial fibrillation and ventricular tachycardia have been described in a patient who received 2 mg of physostigmine by IV push for Jimson weed overdose (Levy, 1977).
    D) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) In the setting of severe tricyclic antidepressant poisoning, physostigmine has resulted in asystole (Pentel & Peterson, 1980; Howland, 1998).
    E) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: One patient who overdosed on methyprylon and diazepam had an emergent increase in blood pressure from 180/90 to 240/140 after administration of physostigmine, requiring the use of diazoxide (Nattel et al, 1979).
    b) Administration of up to 2 mg of physostigmine given to volunteers significantly increased systolic blood pressure (117.3 +/- 2.9 to 127.5 +/- 2.5) and pulse (101.1 +/- 3.9 to 119.7 +/- 4.9) (Janowsky et al, 1986).
    F) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Premature ventricular contractions (PVCs) and ventricular bigeminy have been reported after a 1 mg dose of physostigmine in an 85-year-old man (Dysken & Janowsky, 1985). Administration of 0.5 mg did not result in the same toxicity.
    G) LACK OF EFFECT
    1) WITH THERAPEUTIC USE
    a) Twelve mg of physostigmine given intravenously to patients who had overdosed on non-anticholinergic drugs did not produce significant hemodynamic changes (Nilsson et al, 1983).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) EXCESSIVE SALIVATION
    1) WITH THERAPEUTIC USE
    a) Increased tracheobronchial secretions may develop (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008; Nattel et al, 1979; Walker et al, 1976).
    B) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Physostigmine may precipitate bronchospasm; asthma is considered a contraindication to the use of physostigmine (Howland, 1998).
    C) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Following an injectable overdose, spasm of the glottis with transient dyspnea, slowing of respirations, and paralysis of the diaphragm may occur. Death may occur as a result of respiratory paralysis (HSDB , 2002).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures may occur if IV administration of physostigmine salicylate is too rapid, exceeding the recommended rate of up to 1 mg/min in adults or 0.5 mg/min in children (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    b) Seizures have been reported in the treatment of anticholinergic overdose (Howland, 1998).
    c) CASE SERIES: Seizures were reported in 3/26 (12%) of patients receiving physostigmine after an anticholinergic overdose (Walker et al, 1976).
    d) CASE SERIES: In another series 2/21 (10%) of patients had seizures (Newton, 1975).
    e) CASE SERIES: In patients receiving physostigmine for the treatment of maprotiline overdose, 6 out of 7 (86%) developed seizures (Knudson & Heath, 1984).
    2) WITH POISONING/EXPOSURE
    a) Following an injectable overdose, seizures may occur within 5 to 25 minutes (HSDB , 2002).
    B) NONCONVULSIVE STATUS EPILEPTICUS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 66-year-old woman with no history of epilepsy developed right occipital non-convulsive status epilepticus (NCSE) with upbeat nystagmus after treatment with 2 doses of 1 mg IV physostigmine for anticholinergic syndrome. She presented in a comatose state with a Glasgow Coma Score of 8 and symptoms of anticholinergic syndrome. She was admitted to the ICU with suspected drug intoxication and treated with IV physostigmine. After the physostigmine infusion, she remained unconscious while EEG showed occipital spiking at regular intervals of 100 ms with fast phase upbeat nystagmus. She was then treated with 2 mg lorazepam, after which the nystagmus ceased, NCSE resolved, and she regained consciousness (Neugebauer et al, 2012).
    C) FEELING NERVOUS
    1) WITH THERAPEUTIC USE
    a) Restlessness has been described after physostigmine (Nilsson et al, 1983).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are common effects at therapeutic doses (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008; Sano et al, 1993; D'Mello & Sidell, 1991; Norris et al, 1993).
    2) WITH POISONING/EXPOSURE
    a) Following an injectable overdose, vomiting and diarrhea may occur within 5 to 25 minutes (HSDB , 2002).
    B) EXCESSIVE SALIVATION
    1) WITH POISONING/EXPOSURE
    a) Following an injectable overdose, increased salivation and sweating may occur within 5 to 25 minutes (HSDB , 2002).
    C) INCONTINENCE OF FECES
    1) WITH THERAPEUTIC USE
    a) Hyperperistalsis and defecation have been described (Nilsson et al, 1983; Howland, 1998).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY INCONTINENCE
    1) WITH THERAPEUTIC USE
    a) Acute urinary incontinence may occur after the use of physostigmine (Howland, 1998).
    B) POLYURIA
    1) WITH THERAPEUTIC USE
    a) Administration of physostigmine salicylate may result in excessive urination, emesis, salivation, and defecation (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Excessive sweating may occur with administration of physostigmine salicylate (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008; Nilsson et al, 1983; Howland, 1998; Sano et al, 1993).
    2) WITH POISONING/EXPOSURE
    a) Following an injectable overdose, increased salivation and sweating may occur within 5 to 25 minutes (HSDB , 2002).
    B) HYPERESTHESIA
    1) WITH POISONING/EXPOSURE
    a) Within 5 to 25 minutes following an injectable overdose, a marked cutaneous hyperesthesia generally occurs (HSDB , 2002).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) Muscle weakness and fasciculations may occur (Johnson, 1976) Walker et al, 1983; (Rumack, 1973; Mazza et al, 1994; Howland, 1998).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) DISORDER OF ENDOCRINE SYSTEM
    1) WITH THERAPEUTIC USE
    a) Up to 2 mg of physostigmine given to human volunteers caused a significant increase in serum prolactin, beta-endorphin, ACTH, cortisol, and epinephrine levels. It did not have a significant effect on growth hormone or norepinephrine levels (Janowsky et al, 1986).
    b) In volunteers, physostigmine (12.5 mcg/kg) increased growth hormone levels and enhanced the response to growth hormone releasing hormone (Mazza et al, 1994).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reaction may occur with physostigmine salicylate administration (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    b) Some product formulations contain sodium bisulfite, a sulfite which may cause an allergic-type reaction, including anaphylaxis, asthmatic episodes, and life-threatening reactions in sensitive patients, especially in patients with pre-existing asthma (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).

Reproductive

    3.20.1) SUMMARY
    A) Teratogenic effects have been observed in mice studies.
    3.20.2) TERATOGENICITY
    A) METABOLIC DISORDER
    1) Biochemical, metabolic and behavioral toxic effects were observed in the offspring of mice administered physostigmine (RTECS , 2002).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    PHYSOSTIGMINEC
    Reference: Briggs et al, 1998

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS57-47-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Physostigmine plasma concentrations are not clinically useful or readily available.
    C) No specific lab work is needed in most patients.
    D) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (seizures, bradycardia/asystole, nausea/vomiting, sweating, hypersalivation, bronchospasm, or pulmonary edema).
    E) Monitor oral secretions, lung sounds, and pulse oxygenation for signs of pulmonary edema.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) CHOLINESTERASE ACTIVITY: In one case of massive oral overdose of physostigmine, the plasma and whole blood cholinesterase activity was shown to be depressed (Cumming et al, 1968).

Methods

    A) CHROMATOGRAPHY
    1) Physostigmine can be measured in biologic fluids by high performance liquid chromatography (HPLC) (Whelpton & Hurst, 1985), but most toxicology laboratories will not have this capability.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with persistent nausea and/or vomiting, sweating, and hypersalivation should be admitted. Patients with seizures, bradycardia/asystole, bronchospasm, or pulmonary edema should be admitted to an intensive care setting.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) Asymptomatic patients with inadvertent ingestions, including children who have ingested small amounts of the ophthalmic solution, can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (dysrhythmias), or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with deliberate ingestions or children with significant ingestions should be referred to a healthcare facility for observation for 4 hours. All Symptomatic patients should be sent to a healthcare facility for observation for 4 hours.

Monitoring

    A) Monitor vital signs and mental status.
    B) Physostigmine plasma concentrations are not clinically useful or readily available.
    C) No specific lab work is needed in most patients.
    D) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (seizures, bradycardia/asystole, nausea/vomiting, sweating, hypersalivation, bronchospasm, or pulmonary edema).
    E) Monitor oral secretions, lung sounds, and pulse oxygenation for signs of pulmonary edema.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) There is no method of decontamination that is useful.
    6.5.2) PREVENTION OF ABSORPTION
    A) There is no method of decontamination that is useful.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) The vast majority of physostigmine overdoses require only supportive care. Treat diaphoresis and excessive salivation with supportive care. Nausea and vomiting can be treated with antiemetics.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Patients with bradycardia or asystole should be treated with atropine (1 to 2 mg IV). There is a theoretical risk of respiratory depression that would require intubation. Bronchospasm and pulmonary edema should be treated with atropine (1 to 2 mg). The doses of atropine should be proportional to the symptoms of the patient and should be titrated to reverse bradycardia causing hypotension, bronchospasm, or pulmonary edema. Treat seizures with IV benzodiazepines.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis and hemoperfusion are not of value due to the large volume of distribution and short duration of action of physostigmine and wide availability of an antidote.

Range Of Toxicity

Summary

    A) TOXICITY: There is no specific toxic dose to physostigmine. In some cases, the recommended IV dose of 1 to 2 mg in adults has caused seizures and cardiac dysrhythmias, likely secondary to the underlying condition being treated. Physostigmine may be particularly dangerous when used in the setting of a tricyclic antidepressant overdose; 2 mg of physostigmine has led to asystole and death in these patients. Adults have survived IV doses of 12 mg over 45 minutes, and ingestion of 1 gram.
    B) THERAPEUTIC DOSES: ADULTS: IV: 2 mg IV over 2 to 3 minutes is the usual dose for anticholinergic toxicity, no faster than 1 mg/min, may be repeated if necessary. OPHTHALMIC: One drop of 0.25% solution or one centimeter of 0.25% ointment to the eye 3 times daily for glaucoma. CHILDREN: 0.02 mg/kg IV over 2 to 3 minutes, at a rate no more than 0.5 mg/minute. MAX: 2 mg total dosage.

Therapeutic Dose

    7.2.1) ADULT
    A) POST-ANESTHESIA CARE
    1) 0.5 mg to 1 mg IM or IV at a slow, controlled rate, no more than 1 mg/min. Repeat doses may be administered at intervals of 10 to 30 minutes if desired patient response is not obtained (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    B) OVERDOSE OF ANTICHOLINERGIC MEDICATIONS
    1) 2 mg IM or IV at a slow, controlled rate, no more than 1 mg/min. Repeat doses may be administered if life threatening signs (eg, arrythmia, convulsions or coma) occur (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    7.2.2) PEDIATRIC
    A) OVERDOSE OF ANTICHOLINERGIC MEDICATIONS
    1) 0.02 mg/kg IM or IV at a slow rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAX: 2 mg total dosage (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).

Minimum Lethal Exposure

    A) ACUTE
    1) Time to death may occur from 5 minutes to 24 hours in severely poisoned patients, depending on factors such as dose and route (EPA, 1985).
    2) In the setting of severe tricyclic antidepressant poisoning, 2 mg of physostigmine has led to asystole and death (Pentel & Peterson, 1980).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) ANTICHOLINERGIC OVERDOSE PATIENTS
    a) Up to 22 mg administered over 48 hours to a tricyclic antidepressant overdose patient did not result in significant toxicity (Tobis & Das BN, 1976).
    1) However, the same patient returned to the hospital 6 days later in atrioventricular dissociation and 2 mg of physostigmine resulted in a generalized seizure.
    b) Twenty six one-milligram doses of physostigmine were administered to a 2 1/2-year-old child over 13 hours with no serious side effects (Burks et al, 1974).
    2) NON-ANTICHOLINERGIC OVERDOSE PATIENTS
    a) In comatose patients from non-anticholinergic drug overdoses, up to 12 mg given over 45 minutes did not result in significant toxicity (Nilsson et al, 1983).
    3) OTHER
    a) An adult patient survived deliberate ingestion of 1 gram of powered physostigmine salicylate (Cumming et al, 1968).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Neither therapeutic nor toxic serum concentrations have been established.

Workplace Standards

    A) ACGIH TLV Values for CAS57-47-6 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS57-47-6 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS57-47-6 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS57-47-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) Reference: RTECS, 2002; ITI, 1988
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 644 mcg/kg
    2) LD50- (ORAL)MOUSE:
    a) 3 mg/kg
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 740 mcg/kg
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 2 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Physostigmine is a reversible anticholinesterase. It inhibits the destructive action of acetylcholinesterase and thus prolongs and exaggerates the effect of acetylcholine (Prod Info Antilirium(R), physostigmine, 2000). Because this drug contains a tertiary amine, it can easily penetrate the blood brain barrier. Physostigmine reverses both central and peripheral anticholinergia. The duration of its effects is relatively short (45 to 60 minutes).

Physicochemical

Physical Characteristics

    A) PHYSOSTIGMINE
    1) Orthorhombic sphenoidal prisms or clusters of leaflets from ether or benzene (Budavari, 1996).
    2) Odorless, white microcrystalline powder (HSDB , 2002).
    3) Colorless or pinkish crystals (Lewis, 1996).
    B) PHYSOSTIGMINE SALICYLATE
    1) Acicular crystals
    C) PHYSOSTIGMINE SULFATE
    1) Deliquescent scales
    D) PHYSOSTIGMINE SULFITE
    1) White powder

Ph

    A) PHYSOSTIGMINE SALICYLATE
    1) 5.8 (0.5% solution)
    B) PHYSOSTIGMINE SULFATE
    1) 4.7 (0.05 M solution)

Molecular Weight

    A) 275.34 (Budavari, 1996)

Animal Toxicology

Clinical Effects

    11.1.10) PORCINE/SWINE
    A) Symptoms in one case of unanesthetized domestic pigs receiving 5 micrograms/kilogram/minute physostigmine salicylate by pulmonary arterial infusion for 2 hours (Stemler et al, 1990) include:
    1) CNS - Restlessness, sedation, muscle fasciculations
    2) GI - Defecation, salivation
    3) Cardiovascular - Increased heart rate, increased mean aortic pulmonary artery pressure
    4) Respiratory - Increased pulmonary artery wedge pressures, altered lung mechanics
    5) Hematologic - Increased hematocrit. Red blood cell acetylcholinesterase activity was at 74% inhibition by 45 minutes into the infusion.
    6) Temperature - Increased temperature

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