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CARBACHOL CHLORIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Carbachol chloride is a direct-acting cholinergic compound.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C6-H15-N2-O2.Cl

Available Forms Sources

    A) FORMS
    1) Carbachol chloride occurs as hygroscopic, hard, white or faintly yellow prismatic crystals or as a crystalline powder. It is odorless or has a slight amine-like odor. It is very soluble in water, is slightly soluble in methanol or ethanol, and is practically insoluble in acetone, chloroform, and ether (HSDB, 1993).
    B) USES
    1) Carbachol chloride is a direct-acting cholinergic compound (Budavari, 1989; Reynolds, 1993). As such, it is used as a miotic agent in human medicine and as a parasympathomimetic agent in large animal veterinary medicine (ie, for colic in horses) (Budavari, 1989; EPA, 1985).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) CHOLINERGIC SYNDROME -
    1) Carbachol chloride is a direct-acting cholinergic compound.
    2) Carbachol chloride is used as a miotic in human medicine and a parasympathomimetic in large animal veterinary medicine (ie, for colic in horses). It is used as a miotic agent in intraocular surgery, where it has been shown to be less toxic to the endothelium than acetylcholine. It had no substantial toxic effects on the corneal endothelium when injected intracamerally in cats.
    3) Carbachol chloride is used as eye drops to lower intraocular pressure in glaucoma, by instillation into the anterior chamber of the eye to produce miosis in cataract surgery, in the treatment of intestinal atony and urinary retention, and to halt paroxysmal supraventricular tachycardia.
    a) Carbachol chloride can be used to lower intraocular pressure in glaucomatous dogs. It has been used experimentally to increase blood pressure and produce cardiovascular stimulant effects in experimental animals when infused directly into the cerebral ventricles. It causes seizures and brain damage when injected directly into the amygdala or hippocampus of rats.
    b) Carbachol chloride can be absorbed following ingestion or dermal contact. At the time of this review, no data were found on whether or not it can be systemically absorbed by inhalation, although it did increase airway resistance in sheep and human volunteers following inhalation exposure by direct stimulation of airway smooth muscle. In normal and asthmatic human subjects, bronchoconstriction induced by inhaled carbachol chloride could be prevented by prior inhalation of cromolyn sodium.
    c) Carbachol directly stimulates muscarinic sites, but also stimulates acetylcholine release and has pronounced nicotinic effects on the neuromuscular skeletal muscle junction, postganglionic autonomic nervous system, and adrenal medulla.
    B) Typical CHOLINERGIC symptoms include MUSCARINIC EFFECTS (miosis, flushing, bradycardia, bronchospasm, increased bronchial secretions, involuntary urination and/or defecation, nausea, vomiting, sweating, lacrimation, salivation, hypotension, hypothermia, and seizures). CARBACHOL also produces NICOTINIC EFFECTS (muscle cramps, fasciculations, weakness, paralysis, tachycardia, and hypertension).
    C) Carbachol chloride releases toxic and irritating fumes of chloride, ammonia, and oxides of nitrogen when heated to decomposition. Inhalation exposure to such fumes would be predicted to result in respiratory tract irritation with bronchospasm, chemical pneumonitis, or noncardiogenic pulmonary edema.
    0.2.3) VITAL SIGNS
    A) Hypothermia may occur. Hypotension and bradycardia are muscarinic effects. Hypertension and tachycardia are nicotinic effects.
    0.2.4) HEENT
    A) Miosis is a common finding. Topical ocular effects include miosis, myopia, difficulty in visual accommodation, ciliary spasm, ocular pain, and eyelid twitching. Lacrimation commonly occurs.
    B) Bullous keratopathy and iritis have occurred following cataract surgery in some patients administered carbachol chloride during the procedure. Carbachol chloride can lower intraocular pressure in glaucoma.
    C) Salivation commonly occurs with systemic poisoning.
    0.2.5) CARDIOVASCULAR
    A) Vasodilation (accompanied by reflex tachycardia) and hypotension may be seen at moderate doses. Bradycardia ensues with large doses. Decreased myocardial contractility, syncope, circulatory collapse, and cardiac arrest may be noted.
    B) Various dysrhythmias and heart block may occur. Tachycardia and hypertension may be nicotinic effects of carbachol chloride.
    0.2.6) RESPIRATORY
    A) Dyspnea and bronchoconstriction may be noted, and are more pronounced in asthmatic patients. Life-threatening bronchospasm or pulmonary edema may occur. Increased bronchial secretions may be seen.
    B) Carbachol chloride releases toxic and irritating fumes of chloride, ammonia, and oxides of nitrogen when heated to decomposition. Inhalation exposure to such fumes would be predicted to result in respiratory tract irritation with bronchospasm, chemical pneumonitis, or noncardiogenic pulmonary edema.
    0.2.7) NEUROLOGIC
    A) Muscle cramps, fasciculations, weakness, and paralysis may be noted. Seizures, coma, headache, vertigo, and tremors may develop.
    0.2.8) GASTROINTESTINAL
    A) GI motility is increased, resulting in nausea, vomiting, diarrhea, involuntary defecation, belching, and abdominal pain. Esophageal rupture has occurred.
    0.2.10) GENITOURINARY
    A) Stimulation of ureters, urinary bladder, gallbladder and biliary ducts occurs. Involuntary urination may be noted.
    0.2.14) DERMATOLOGIC
    A) Skin flushing and sweating may occur.
    0.2.15) MUSCULOSKELETAL
    A) Muscle cramps, fasciculations, weakness, and paralysis may develop.
    0.2.20) REPRODUCTIVE
    A) Carbachol is classified as FDA pregnancy category C. It is not known whether carbachol affects reproductive function or causes fetal harm when administered during pregnancy. In animal studies, carbachol was teratogenic and fetotoxic to developing embryos. Carbachol should be used during pregnancy only if necessary.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Carbachol blood levels are not clinically useful.
    B) BLOOD GASES
    1) Monitor arterial blood gases and/or pulse oximetry in patients with significant exposure.
    C) Cardiac monitoring may be necessary in symptomatic patients.
    D) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.
    E) Monitor arterial blood gases and/or pulse oximetry, pulmonary function tests, and chest x-ray in patients with significant exposure.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL
    1) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) ATROPINE
    1) ATROPINE - sulfate is the drug of choice for muscarinic effects.
    2) DOSE - ADULTS - initial dose of 2 to 4 mg IV repeated every 3 to 60 min as needed to control muscarinic symptoms, then as needed for 24 to 48 hrs. As much as 50 mg of atropine sulfate may be required in the first 24 hrs.
    3) CHILD - initial dose 0.04 to 0.08 mg/kg up to 4 mg (usual dose 1 mg IV), repeated every 5 min as necessary.
    4) Drying of pulmonary secretions is the best therapeutic end-point for atropine administration.
    C) Epinephrine may assist in overcoming severe cardiovascular or bronchoconstrictor responses (DOSE - 0.1 to 1.0 mg SQ).
    1) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    D) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    F) Monitor ECG if cardiac arrhythmias are present. Monitor arterial blood gases, pulmonary function tests, and chest x-ray if severe bronchospasm or pulmonary edema are present.
    G) Cholinesterase regenerators such as pralidoxime (2-PAM chloride) and obidoxime are ineffective.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    B) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    C) Respiratory tract irritation, if severe, can progress to pulmonary edema which may be delayed in onset up to 24 to 72 hours after exposure in some cases.
    D) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    E) SYSTEMIC TOXICITY
    1) No data were found on whether or not carbachol chloride can be systemically absorbed by inhalation. If systemic cholinergic effects are present following inhalation exposure -
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    B) If keratitis or iritis are suspected, obtaining ophthalmologic consultation is advisable.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) Carbachol chloride is absorbed through intact skin.
    3) ATROPINE
    a) ATROPINE - sulfate is the drug of choice for muscarinic effects.
    b) DOSE - ADULTS - initial dose of 2 to 4 mg IV repeated every 3 to 60 min as needed to control muscarinic symptoms, then as needed for 24 to 48 hrs. As much as 50 mg of atropine sulfate may be required in the first 24 hrs.
    c) CHILD - initial dose 0.04 to 0.08 mg/kg up to 4 mg (usual dose 1 mg IV), repeated every 5 min as necessary.
    d) Drying of pulmonary secretions is the best therapeutic end-point for atropine administration.
    4) Epinephrine may assist in overcoming severe cardiovascular or bronchoconstrictor responses (DOSE - 0.1 to 1.0 mg SQ).
    a) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    5) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    a) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    b) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    6) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    7) Monitor ECG if cardiac arrhythmias are present. Monitor arterial blood gases, pulmonary function tests, and chest x-ray if severe bronchospasm or pulmonary edema are present.
    8) Cholinesterase regenerators such as pralidoxime (2-PAM chloride) and obidoxime are ineffective.

Range Of Toxicity

    A) The minimum lethal human dose to this agent has not been delineated.
    B) A dose of 0.5 mg/kg orally produced cholinergic attacks, but was not fatal to a 10-year-old child.
    C) An elderly man developed severe toxicity after ingesting 400 to 500 mg.

Clinical Effects

Summary Of Exposure

    A) CHOLINERGIC SYNDROME -
    1) Carbachol chloride is a direct-acting cholinergic compound.
    2) Carbachol chloride is used as a miotic in human medicine and a parasympathomimetic in large animal veterinary medicine (ie, for colic in horses). It is used as a miotic agent in intraocular surgery, where it has been shown to be less toxic to the endothelium than acetylcholine. It had no substantial toxic effects on the corneal endothelium when injected intracamerally in cats.
    3) Carbachol chloride is used as eye drops to lower intraocular pressure in glaucoma, by instillation into the anterior chamber of the eye to produce miosis in cataract surgery, in the treatment of intestinal atony and urinary retention, and to halt paroxysmal supraventricular tachycardia.
    a) Carbachol chloride can be used to lower intraocular pressure in glaucomatous dogs. It has been used experimentally to increase blood pressure and produce cardiovascular stimulant effects in experimental animals when infused directly into the cerebral ventricles. It causes seizures and brain damage when injected directly into the amygdala or hippocampus of rats.
    b) Carbachol chloride can be absorbed following ingestion or dermal contact. At the time of this review, no data were found on whether or not it can be systemically absorbed by inhalation, although it did increase airway resistance in sheep and human volunteers following inhalation exposure by direct stimulation of airway smooth muscle. In normal and asthmatic human subjects, bronchoconstriction induced by inhaled carbachol chloride could be prevented by prior inhalation of cromolyn sodium.
    c) Carbachol directly stimulates muscarinic sites, but also stimulates acetylcholine release and has pronounced nicotinic effects on the neuromuscular skeletal muscle junction, postganglionic autonomic nervous system, and adrenal medulla.
    B) Typical CHOLINERGIC symptoms include MUSCARINIC EFFECTS (miosis, flushing, bradycardia, bronchospasm, increased bronchial secretions, involuntary urination and/or defecation, nausea, vomiting, sweating, lacrimation, salivation, hypotension, hypothermia, and seizures). CARBACHOL also produces NICOTINIC EFFECTS (muscle cramps, fasciculations, weakness, paralysis, tachycardia, and hypertension).
    C) Carbachol chloride releases toxic and irritating fumes of chloride, ammonia, and oxides of nitrogen when heated to decomposition. Inhalation exposure to such fumes would be predicted to result in respiratory tract irritation with bronchospasm, chemical pneumonitis, or noncardiogenic pulmonary edema.

Vital Signs

    3.3.1) SUMMARY
    A) Hypothermia may occur. Hypotension and bradycardia are muscarinic effects. Hypertension and tachycardia are nicotinic effects.
    3.3.3) TEMPERATURE
    A) Hypothermia may occur in acute poisoning (Sangster et al, 1979; (HSDB, 1996)).
    3.3.4) BLOOD PRESSURE
    A) Hypotension and bradycardia are muscarinic effects of carbachol chloride (Schulz et al, 2006)(Lewis, 1996; ((HSDB, 1996)).
    B) Hypertension and tachycardia are nicotinic effects of carbachol chloride (JEF Reynolds , 1991) .
    3.3.5) PULSE
    A) Bradycardia and hypotension are muscarinic effects of carbachol chloride (Schulz et al, 2006; Sax & Lewis, 1989) .
    B) Tachycardia and hypertension are nicotinic effects of carbachol chloride (JEF Reynolds , 1991) .

Heent

    3.4.1) SUMMARY
    A) Miosis is a common finding. Topical ocular effects include miosis, myopia, difficulty in visual accommodation, ciliary spasm, ocular pain, and eyelid twitching. Lacrimation commonly occurs.
    B) Bullous keratopathy and iritis have occurred following cataract surgery in some patients administered carbachol chloride during the procedure. Carbachol chloride can lower intraocular pressure in glaucoma.
    C) Salivation commonly occurs with systemic poisoning.
    3.4.3) EYES
    A) Miosis is a common finding with systemic poisoning (Schulz et al, 2006; Sax & Lewis, 1989). Topical ocular effects include miosis, myopia, difficulty in visual accommodation, ciliary spasm, ocular pain, and eyelid twitching ((HSDB, 1996); Grant, 1993).
    B) Lacrimation commonly occurs in systemic poisonings (Lewis, 1996; RTECS, 1996).
    C) Iritis - Bullous keratopathy and iritis have occurred following cataract surgery in some patients administered carbachol chloride during the procedure (Gelman & Rumack, 1991).
    D) Carbachol chloride can lower intraocular pressure in patients with glaucoma (JEF Reynolds , 1991).
    E) Chronic exposure - Decreased vision, conjunctival hyperemia, accommodation spasm, a burning sensation, and difficulty with night vision and reading have been seen with chronic therapeutic use.
    3.4.6) THROAT
    A) EXCESSIVE SALIVATION commonly occurs in systemic poisonings (Schulz et al, 2006).

Cardiovascular

    3.5.1) SUMMARY
    A) Vasodilation (accompanied by reflex tachycardia) and hypotension may be seen at moderate doses. Bradycardia ensues with large doses. Decreased myocardial contractility, syncope, circulatory collapse, and cardiac arrest may be noted.
    B) Various dysrhythmias and heart block may occur. Tachycardia and hypertension may be nicotinic effects of carbachol chloride.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Vasodilation (accompanied by reflex tachycardia) may be seen at moderate doses (Lewis, 1996).
    2) CASE REPORT - An 84-year-old man developed bradycardia, nausea, diaphoresis, hypotension and collapse after ingesting 400 to 500 mg carbachol. He became asystolic, but was resuscitated with epinephrine, atropine and mechanical ventilation. After resuscitation ECG revealed AV dissociation and hypotension persisted (Schulz et al, 2006).
    B) BRADYCARDIA
    1) Ensues with large doses (Schulz et al, 2006; JEF Reynolds , 1991; Sax & Lewis, 1989). Decreased myocardial contractility, syncope, circulatory collapse, and cardiac arrest may be noted.
    a) Carbachol is less likely to produce bradycardia than other direct-acting cholinergic agents, due to pronounced nicotinic effects (JEF Reynolds , 1991).
    C) CONDUCTION DISORDER OF THE HEART
    1) Cardiac dysrhythmias and heart block may occur (Sax & Lewis, 1989).
    a) Carbachol chloride has been used experimentally to increase blood pressure and produce cardiovascular stimulant effects in experimental animals when infused directly into the cerebral ventricles (Wu & Wei, 1982; Day & Roach, 1977).
    2) CASE REPORT - An 84-year-old man developed bradycardia, nausea, diaphoresis, hypotension and collapse after ingesting 400 to 500 mg carbachol. He became asystolic, but was resuscitated with epinephrine, atropine and mechanical ventilation. After resuscitation ECG revealed AV dissociation (Schulz et al, 2006).
    D) TACHYARRHYTHMIA
    1) Tachycardia and hypertension are nicotinic effects of carbachol chloride (JEF Reynolds , 1991) .

Respiratory

    3.6.1) SUMMARY
    A) Dyspnea and bronchoconstriction may be noted, and are more pronounced in asthmatic patients. Life-threatening bronchospasm or pulmonary edema may occur. Increased bronchial secretions may be seen.
    B) Carbachol chloride releases toxic and irritating fumes of chloride, ammonia, and oxides of nitrogen when heated to decomposition. Inhalation exposure to such fumes would be predicted to result in respiratory tract irritation with bronchospasm, chemical pneumonitis, or noncardiogenic pulmonary edema.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) Dyspnea and bronchoconstriction are more pronounced in asthmatic patients (Dubois & Dautrebande, 1958; Fabbri et al, 1983). Life-threatening bronchospasm or pulmonary edema may occur.
    B) BRONCHOSPASM
    1) Typical cholinergic symptoms include MUSCARINIC EFFECTS such as bronchospasm and increased bronchial secretions (Schulz et al, 2006; Sax & Lewis, 1989; JEF Reynolds , 1991).
    2) Carbachol chloride increased airway resistance in sheep and human volunteers following inhalation exposure by direct stimulation of airway smooth muscle (Abraham et al, 1984; (Dubois & Dautrebande, 1958; Fabbri et al, 1983).
    3) In normal and asthmatic human subjects, the bronchoconstriction induced by inhaled carbachol chloride could be prevented by prior inhalation of cromolyn sodium (Fabbri et al, 1983).
    C) RESPIRATORY CONDITION DUE TO CHEMICAL FUMES AND/OR VAPORS
    1) Carbachol chloride releases toxic and irritating fumes of chloride, ammonia, and oxides of nitrogen when heated to decomposition (Sax & Lewis, 1989; EPA, 1985); inhalation exposure would be predicted to result in respiratory tract irritation with bronchospasm, chemical pneumonitis, or noncardiogenic pulmonary edema.

Neurologic

    3.7.1) SUMMARY
    A) Muscle cramps, fasciculations, weakness, and paralysis may be noted. Seizures, coma, headache, vertigo, and tremors may develop.
    3.7.2) CLINICAL EFFECTS
    A) PARALYSIS
    1) Muscle cramps, fasciculations, weakness, and paralysis may be noted, especially with cholinergic agents with greater nicotinic effects, such as carbachol (JEF Reynolds , 1991).
    B) SEIZURE
    1) Seizures as well as vertigo and tremors may be noted (Sax & Lewis, 1989).
    C) COMA
    1) Coma may be noted (Sax & Lewis, 1989).
    a) Carbachol chloride causes seizures and brain damage when injected directly into the amygdala or hippocampus of rats (Turski et al, 1983).
    D) HEADACHE
    1) Headache may be noted (Gelman & Rumack, 1991)

Gastrointestinal

    3.8.1) SUMMARY
    A) GI motility is increased, resulting in nausea, vomiting, diarrhea, involuntary defecation, belching, and abdominal pain. Esophageal rupture has occurred.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) GI motility is increased, resulting in nausea, vomiting, and abdominal pain (JEF Reynolds , 1991; (HSDB, 1996)) Lewis, 1996).
    B) DIARRHEA
    1) Diarrhea, involuntary defecation, and belching may be seen (JEF Reynolds , 1991).
    C) RUPTURE OF ESOPHAGUS
    1) Esophageal rupture presenting with symptoms of vomiting, chest pain, and dyspnea was described in a 58-year-old man receiving carbachol parenterally (Cochrane, 1973).

Genitourinary

    3.10.1) SUMMARY
    A) Stimulation of ureters, urinary bladder, gallbladder and biliary ducts occurs. Involuntary urination may be noted.
    3.10.2) CLINICAL EFFECTS
    A) URINARY INCONTINENCE
    1) Stimulation of ureters, urinary bladder, gallbladder, and biliary ducts occurs (JEF Reynolds , 1991) . Involuntary urination may be noted (Sax & Lewis, 1989).

Dermatologic

    3.14.1) SUMMARY
    A) Skin flushing and sweating may occur.
    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) Flushing and sweating may occur (Schulz et al, 2006; Sax & Lewis, 1989; JEF Reynolds , 1991) .

Musculoskeletal

    3.15.1) SUMMARY
    A) Muscle cramps, fasciculations, weakness, and paralysis may develop.
    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) Muscle cramps, fasciculations, weakness, and paralysis might develop (Sax & Lewis, 1989; JEF Reynolds , 1991) .

Reproductive

    3.20.1) SUMMARY
    A) Carbachol is classified as FDA pregnancy category C. It is not known whether carbachol affects reproductive function or causes fetal harm when administered during pregnancy. In animal studies, carbachol was teratogenic and fetotoxic to developing embryos. Carbachol should be used during pregnancy only if necessary.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Carbachol chloride was not teratogenic in mice (Schardein, 1985).
    2) Carbachol chloride was teratogenic and fetotoxic to developing chicken embryos at a dose of 3 milligrams/egg (Landauer, 1975) and was lethal to chick embryos if applied between days 8 and 12, but not when applied earlier (Zamenhof, 1989). The significance of the latter finding for human reproduction is unclear.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Carbachol is classified as FDA pregnancy category C (Prod Info Isopto(R) Carbachol ophthalmic solution, 2007).
    2) It is not known whether carbachol affects reproductive function or causes fetal harm when administered during pregnancy. Carbachol should be used during pregnancy only if necessary (Prod Info Isopto(R) Carbachol ophthalmic solution, 2007).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether carbachol is excreted in human breast milk. Because many drugs are excreted into human milk, use caution when administering carbachol to a lactating woman (Prod Info Isopto(R) Carbachol ophthalmic solution, 2007).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS51-83-2 (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
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Carbachol blood levels are not clinically useful.
    B) BLOOD GASES
    1) Monitor arterial blood gases and/or pulse oximetry in patients with significant exposure.
    C) Cardiac monitoring may be necessary in symptomatic patients.
    D) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.
    E) Monitor arterial blood gases and/or pulse oximetry, pulmonary function tests, and chest x-ray in patients with significant exposure.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Carbachol blood levels are not clinically useful.
    B) ACID/BASE
    1) BLOOD GASES
    a) Monitor arterial blood gases and/or pulse oximetry in patients with significant exposure.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Cardiac monitoring may be necessary in symptomatic patients.
    b) Monitor arterial blood gases and/or pulse oximetry, pulmonary function tests, and chest x-ray in patients with significant exposure.
    2) PULMONARY FUNCTION TESTS
    a) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Carbachol blood levels are not clinically useful.
    B) BLOOD GASES
    1) Monitor arterial blood gases and/or pulse oximetry in patients with significant exposure.
    C) Cardiac monitoring may be necessary in symptomatic patients.
    D) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.
    E) Monitor arterial blood gases and/or pulse oximetry, pulmonary function tests, and chest x-ray in patients with significant exposure.

Oral Exposure

    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) ATROPINE
    1) ATROPINE - sulfate is the drug of choice for muscarinic effects.
    2) DOSE - ADULTS - initial dose of 2 to 4 milligrams intravenously repeated every 3 to 60 minutes as needed to control muscarinic symptoms, then as needed for 24 to 48 hours. As much as 50 milligrams of atropine sulfate may be required in the first 24 hours.
    3) CHILD - initial dose 0.04 to 0.08 milligram/kilogram up to 4 milligrams (usual dose 1 milligram intravenously), repeated every 5 minutes as necessary.
    4) Drying of pulmonary secretions is the best therapeutic end-point for atropine administration.
    B) BRONCHOSPASM
    1) Epinephrine may assist in overcoming severe cardiovascular or bronchoconstrictor responses (DOSE - 0.1 to 1.0 milligram subcutaneously).
    2) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    E) MONITORING OF PATIENT
    1) Monitor ECG if cardiac arrhythmias are present. Monitor arterial blood gases, pulmonary function tests, and chest x-ray if severe bronchospasm or pulmonary edema are present.
    F) PRALIDOXIME
    1) INDICATIONS
    a) Cholinesterase regenerators such as pralidoxime (2-PAM chloride) and obidoxime are ineffective.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) BRONCHOSPASM
    1) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    B) IRRITATION SYMPTOM
    1) Respiratory tract irritation, if severe, can progress to noncardiogenic pulmonary edema which may be delayed in onset up to 24 to 72 hours after exposure in some cases.
    2) There are no controlled studies indicating that early administration of corticosteroids can prevent the development of noncardiogenic pulmonary edema in patients with inhalation exposure to respiratory irritant substances, and long-term use may cause adverse effects (Boysen & Modell, 1989).
    a) However, based on anecdotal experience, some clinicians do recommend early administration of corticosteroids (such as methylprednisolone 1 gram intravenously as a single dose) in an attempt to prevent the later development of pulmonary edema.
    1) Anecdotal experience with dimethyl sulfate inhalation showed possible benefit of methylprednisolone in the TREATMENT of noncardiogenic pulmonary edema (Ip et al, 1989).
    3) Anecdotal experience also indicated that systemic corticosteroids may have possible efficacy in the TREATMENT of drug-induced noncardiogenic pulmonary edema (Zitnik & Cooper, 1990; Stentoft, 1990; Chudnofsky & Otten, 1989) or noncardiogenic pulmonary edema developing after cardiopulmonary bypass (Maggart & Stewart, 1987).
    4) It is not clear from the published literature that administration of systemic corticosteroids early following inhalation exposure to respiratory irritant substances can PREVENT the development of noncardiogenic pulmonary edema. The decision to administer or withhold corticosteroids in this setting must currently be made on clinical grounds.
    C) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    D) CHOLINERGIC CRISIS
    1) SYSTEMIC TOXICITY - No data were found on whether or not carbachol chloride can be systemically absorbed following inhalation exposure. If systemic cholinergic effects are present following inhalation exposure:
    E) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    6.8.2) TREATMENT
    A) KERATITIS
    1) CONSULTATION - If keratitis or iritis are suspected, obtaining ophthalmologic consultation is advisable.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) SKIN ABSORPTION
    1) Carbachol chloride is absorbed through intact skin.
    B) ATROPINE
    1) ATROPINE - sulfate is the drug of choice for muscarinic effects.
    2) DOSE - ADULTS - initial dose of 2 to 4 milligrams intravenously repeated every 3 to 60 minutes as needed to control muscarinic symptoms, then as needed for 24 to 48 hours. As much as 50 milligrams of atropine sulfate may be required in the first 24 hours.
    3) CHILD - initial dose 0.04 to 0.08 milligram/kilogram up to 4 milligrams (usual dose 1 milligram intravenously), repeated every 5 minutes as necessary.
    4) Drying of pulmonary secretions is the best therapeutic end-point for atropine administration.
    C) BRONCHOSPASM
    1) Epinephrine may assist in overcoming severe cardiovascular or bronchoconstrictor responses (DOSE - 0.1 to 1.0 milligram subcutaneously).
    2) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    E) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    F) MONITORING OF PATIENT
    1) Monitor ECG if cardiac arrhythmias are present. Monitor arterial blood gases, pulmonary function tests, and chest x-ray if severe bronchospasm or pulmonary edema are present.
    G) PRALIDOXIME
    1) INDICATIONS
    a) Cholinesterase regenerators such as pralidoxime (2-PAM chloride) and obidoxime are ineffective.
    H) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) The minimum lethal human dose to this agent has not been delineated.
    B) A dose of 0.5 mg/kg orally produced cholinergic attacks, but was not fatal to a 10-year-old child.
    C) An elderly man developed severe toxicity after ingesting 400 to 500 mg.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) ADULT
    a) An 84-year-old man developed bradycardia, hypotension, AV dissociation, miosis, bronchorrhea, and diaphoresis after ingesting 400 to 500 mg carbachol. He then developed asystole, from which he was resuscitated and recovered, but died two weeks after exposure for unknown reason (Schulz et al, 2006).
    2) PEDIATRIC
    a) A dose of 0.5 milligram/kilogram orally produced cholinergic attacks, but was not fatal to a 10-year-old child (Sangster et al, 1979).

Workplace Standards

    A) ACGIH TLV Values for CAS51-83-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS51-83-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS51-83-2 :
    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 CAS51-83-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: (RTECS, 1996)
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 50 mcg/kg
    2) LD50- (ORAL)MOUSE:
    a) 15 mg/kg
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 3 mg/kg
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 2 mg/kg
    5) LD50- (ORAL)RAT:
    a) 40 mg/kg
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 4 mg/kg

Physicochemical

Physical Characteristics

    A) Carbachol chloride is a hard prismatic crystalline solid. It is hygroscopic and odorless. On standing in an open container, it develops a faint odor resembling an aliphatic amine (Budavari, 1996).

Molecular Weight

    A) 182.65 (Budavari, 1996)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
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