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CHOLINERGIC AGONISTS-DIRECT

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) These agents directly stimulate postganglionic cholinergic receptors. They vary in selectivity for various muscarinic and nicotinic receptors.

Specific Substances

    A) GENERAL TERMS
    1) Cholinomimetics
    2) Cholinergic agents
    3) Direct cholinergic agonists
    ACETYLCHOLINE
    1) Acetylethanoltrimethylammonium Hydroxide
    BETHANECHOL
    1) Carbamylmethylcholine Chloride
    CEVIMELINE
    1) Cevimeline hydrochloride hemihydrate
    2) cis-2-Methylspiro(1,3-oxathiolane-5,3)
    3) quinuclidine hydrochloride hydrate(2:2:1)
    4) Spiro(1-azabicyclo(2.2.2)octane-3,5-(1,3)
    5) oxathiolane), 2-methyl-,hydrochloride,
    6) hydrate(2:1),cis-
    7) AF102B
    8) Exovac(R)
    9) FKS 508
    10) SND 5088
    11) SNI-2011
    12) SNK 508
    13) Molecular formula: C10-H17-N-O-S.Cl-H.1/2H2-O
    14) CAS 153504-70-2
    CHOLINE
    1) Bilineurine
    2) Choline esters
    3) 2-Hydroxyethyltrimethylammonium Hydroxide
    4) CAS 62-49-7
    CHOLINERGIC AGONISTS
    1) Muscarinics
    2) Parasympathomimetics
    METHACHOLINE
    1) Acetyl-B-Methylcholine Chloride
    2) CAS 55-92-5 (Methacholine)
    3) CAS 62-51-1 (Methacholine Chloride)
    PILOCARPINE
    1) CAS 54-71-7 (Pilocarpine Hydrochloride)
    2) CAS 148-72-1 (Pilocarpine Nitrate)

Available Forms Sources

    A) FORMS
    1) ACETYLCHOLINE is available as Miochol Intraocular solution, containing 20 mg acetylcholine and 56 mg mannitol in a vial and an ampule 2 mL of sodium acetate as the diluent, combined to form a 1:100 solution (Prod Info MIOCHOL(R) -E intraocular solution, 2006).
    2) BETHANECHOL is available as 5 mg, 10 mg, 25 mg, and 50 mg tablets (Prod Info bethanechol chloride oral tablets, 2005).
    3) CEVIMELINE hydrochloride is available as 30 mg hard gelatin capsules (Prod Info EVOXAC(R) oral capsules, 2006).
    4) METHACHOLINE CHLORIDE is available as 100 mg of methacholine chloride powder, in a 20 mL vial, for reconstitution (Prod Info PROVOCHOLINE(R) inhalation powder, 2004).
    5) PILOCARPINE is available as a 4% ophthalmic gel, as ophthalmic solutions of 1%, 2%, 4%, and 6%, and as a 5 mg film-coated tablet (Prod Info PILOPINE HS(R) ophthalmic gel, 2007; Prod Info pilocarpine hcl oral tablets, 2006; Prod Info pilocarpine hcl ophthalmic solution, 2004).
    B) USES
    1) ACETYLCHOLINE is used to produce miosis in patients who are undergoing ophthalmic surgery, and rapid miosis is needed (Prod Info MIOCHOL(R) -E intraocular solution, 2006).
    2) BETHANECHOL is used for the treatment of urinary retention (Prod Info bethanechol chloride oral tablets, 2005).
    3) CEVIMELINE is indicated for the treatment of dry mouth in Sjogren's Syndrome patients (Prod Info EVOXAC(R) oral capsules, 2006).
    4) METHACHOLINE is used for the diagnosis of asthma (Prod Info PROVOCHOLINE(R) inhalation powder, 2004).
    5) PILOCARPINE: Ophthalmically, it is used to control intraocular pressure. Orally, it is used to treat symptoms of dry mouth in head and neck cancer patients and in patients with Sjogren's Syndrome (Prod Info PILOPINE HS(R) ophthalmic gel, 2007; Prod Info pilocarpine hcl oral tablets, 2006; Prod Info pilocarpine hcl ophthalmic solution, 2004).

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: Muscarinic direct-acting cholinergic agents include acetylcholine, bethanechol, carbachol, cevimeline, choline, methacholine, and pilocarpine. These agents are used to treat glaucoma (pilocarpine), neurogenic atonic bladder (bethanechol) or Alzheimer disease (cevimeline) or to diagnose bronchial airway hyperactivity (methacholine). Muscarinic mushrooms are discussed in a separate management (Mushrooms-Muscarine/Histamine). Nicotinic agents (eg, carbachol, nicotinic plant alkaloids) are also discussed in separate managements.
    B) PHARMACOLOGY: These agents directly stimulate postganglionic cholinergic receptors and vary in selectivity for muscarinic receptors and nicotinic sites. Acetylcholine, methacholine, bethanechol, and pilocarpine have predominantly muscarinic effects, stimulating gastrointestinal, urinary, uterine, bronchial, cardiac, vascular, exocrine, CNS cortex, and brain stem receptors. Cevimeline is a muscarinic agonist (derivative of acetylcholine) which has demonstrated at least partial direct muscarinic M1-receptor agonist activity in the CNS.
    C) TOXICOLOGY: Toxicity occurs when acetylcholinesterase (AChE) does not adequately metabolize acetylcholine (ACh) in the synapse, leaving an excessive amount of ACh to interact with receptors. ACh functions as a neurotransmitter in the CNS where it may cause agitation and excitability followed by lethargy and seizures. In the peripheral nervous system, it affects neuromuscular junctions and the autonomic nervous system (ANS). The ANS manifests both parasympathetic findings (muscarinic: bradycardia, hypersecretion, gastrointestinal smooth muscle contraction, bronchoconstriction, and miosis) and sympathetic findings (mostly nicotinic/stimulatory: tachycardia, hypertension, bronchodilation, mydriasis, and diaphoresis).
    D) EPIDEMIOLOGY: Direct-acting cholinergic agent toxicity is an uncommon occurrence, and severe manifestations are rare except for carbachol. Pilocarpine and carbachol eye drops are used to treat glaucoma, are absorbed systemically, and cause infrequent problems.
    E) WITH THERAPEUTIC USE
    1) Adverse effects depend upon the individual agents but may include peripheral muscarinic effects (eg, salivation, lacrimation, frequent urination, diarrhea, vomiting, and miosis) and central muscarinic effects (eg, visual hallucinations and dystonias). Methacholine stimulates muscarinic contraction of airway smooth muscle and increases tracheobronchial secretions.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Peripheral muscarinic effects may include salivation, lacrimation, frequent urination, diarrhea, vomiting, and miosis. Central muscarinic effects may include visual hallucinations and dystonias.
    2) SEVERE POISONING: Peripheral muscarinic effects include bradycardia, bronchorrhea, and bronchospasm. Central muscarinic effects may include sedation, muscular rigidity, seizures, or coma. Nicotinic receptor activation may stimulate postganglionic sympathetic and parasympathetic neurons, neuromuscular junctions, and CNS neurons. Clinical effects may include excitation early (eg, hypertension, tachycardia, vomiting, diarrhea, fasciculations, and seizures) and inhibition later (eg, hypotension, bradydysrhythmias, paralysis, and coma).
    0.2.20) REPRODUCTIVE
    A) Acetylcholine, bethanechol, carbachol chloride, cevimeline, and pilocarpine are in pregnancy category C.

Laboratory Monitoring

    A) Monitor vital signs, including pulse oximetry.
    B) Monitor for evidence of respiratory distress, bronchospasm, or bronchorrhea. Obtain a chest x-ray in patients with respiratory distress to evaluate for pulmonary edema.
    C) Monitor serum electrolytes in patients with significant toxicity.
    D) Obtain an ECG and institute continuous cardiac monitoring in patients with significant toxicity.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Atropine, an antimuscarinic agent, is the mainstay of therapy for life-threatening muscarinic effects (bronchorrhea, bronchospasm, and bradycardia). Large doses of intravenous atropine may be required in the first 24 hours (up to 50 mg in one case). Nicotinic effects do not respond to atropine. Supportive care is the primary treatment for nicotinic poisoning with emphasis on respiratory and cardiovascular systems. These agents may be absorbed by oral, intravenous, ocular, and subcutaneous routes, but the systemic manifestations are treated the same.
    B) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) IV atropine and supportive care are usually sufficient treatment for mild to moderate toxicity. Administer inhaled beta2-adrenergic agonists (eg albuterol) for bronchospasm.
    C) MANAGEMENT OF SEVERE TOXICITY
    1) Large doses of IV atropine may be required for severe muscarinic findings to dry secretions. Epinephrine IV may assist in overcoming severe cardiovascular responses or bronchoconstriction. Administer inhaled beta2-adrenergic agonists (eg, albuterol) for bronchospasm, as well as inhaled ipratropium bromide and systemic corticosteroids as needed. Treat seizures with IV benzodiazepines. Otherwise, meticulous supportive care with attention directed to oxygenation, ventilation, and circulation generally are sufficient.
    D) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal is generally not necessary since direct-acting cholinergic agonists can induce spontaneous vomiting.
    2) HOSPITAL: If the patient 1) has taken a significant overdose or there is a serious co-ingestant that binds charcoal, 2) if the patient is alert and able to tolerate charcoal and not persistently vomiting, and 3) if the ingestion was recent, then charcoal may be administered. Gastric lavage and whole bowel irrigation are generally not indicated.
    E) AIRWAY MANAGEMENT
    1) Administer 100% oxygen as needed for respiratory support. Intubate and provide assisted ventilation as necessary. This is not likely unless a very large exposure has occurred.
    F) ANTIDOTE
    1) Atropine is the antidote for muscarinic symptoms. Administer IV atropine liberally until secretions slow/cease. There is no antidote for nicotinic symptoms.
    G) ENHANCED ELIMINATION
    1) Enhanced elimination is generally not necessary or effective.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Symptoms are generally mild unless large amounts have been ingested or taken. Patients may be observed at home for mild symptoms after inadvertent exposures, but should be evaluated for any concerning symptoms (eg, shortness of breath, wet cough, any distress).
    2) OBSERVATION CRITERIA: Any patient with a deliberate overdose or who manifests respiratory distress, cardiovascular compromise, dehydration, sedation, agitation, or severe CNS findings should be sent to a healthcare facility for observation. If symptoms resolve in the emergency department and the home social situation permits, the patient may be discharged.
    3) ADMISSION CRITERIA: If the above findings persist despite treatment in the emergency department, admit the patient to the appropriate level of care.
    4) CONSULT CRITERIA: Consult a medical toxicologist as needed for patients with significant toxicity, especially for patients admitted to the ICU, or in whom the diagnosis is uncertain.
    I) PITFALLS
    1) Underestimation of amount of atropine a toxic patient may require to dry the secretions.
    J) PHARMACOKINETICS
    1) Pharmacokinetics depends on the specific agent involved.
    2) ACETYLCHOLINE is rapidly metabolized by acetylcholinesterase upon absorption and, thus, has a very short duration of action (approximately 10 minutes).
    3) BETHANECHOL: Peak effects occur 60 to 90 minutes and last for about one hour after ingestion in therapeutic doses, but effects may persist for up to 6 hours with large doses (300 to 400 mg). It does not penetrate the blood-brain barrier.
    4) CEVIMELINE: Peak plasma levels occur within 2 hours following oral doses. Protein binding is mild (20%). It has an elimination half-life of approximately 5 hours.
    5) METHACHOLINE is a quaternary ammonium compound not readily inactivated by cholinesterase, and thus has more prolonged effects than acetylcholine.
    6) PILOCARPINE: Topical effects peak at 30 minutes. Duration is usually 4 to 8 hours and, rarely, up to 20 hours. It binds to serum and ocular tissues.
    K) TOXICOKINETICS
    1) There are little data on these agents in overdose except that pilocarpine may cause symptoms for a few days to weeks, depending on the amount consumed.
    L) PREDISPOSING CONDITIONS
    1) Myasthenia gravis, use of acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine, tacrine), chronic or excessive exposure to organophosphates.
    M) DIFFERENTIAL DIAGNOSIS
    1) Cholinergic overstimulation may occur from two main categories of agents: cholinomimetics and cholinolytics. The cholinomimetics include acetylcholine releasers (black widow spider venom), anticholinesterases (edrophonium, neostigmine, organic phosphorus insecticides), indirect nicotinic agonists (ethanol, local anesthetics), and direct-acting muscarinic and nicotinic agonists. Cholinolytics include direct nicotinic antagonists (nicotine), indirect nicotinic antagonists (physostigmine), direct muscarinic antagonists (antihistamines, phenothiazines), and agents that inhibit acetylcholine release (botulinum toxin, crotalid venom).
    0.4.4) EYE EXPOSURE
    A) Eye drops are absorbed rapidly, so eye irrigation likely will not decrease absorption.

Range Of Toxicity

    A) TOXICITY: CEVIMELINE: Nausea and vomiting, mild hypotension with tachycardia, and borderline QTc interval prolongation were reported in a woman after she ingested 20 30-mg cevimeline tablets. The patient recovered with supportive care. PILOCARPINE: The lethal dose in an adult has been estimated to be as low as 60 milligrams in an acute poisoning; however, an adult was reported to have developed cholinergic symptoms, but survived, after inadvertent subcutaneous administration of 80 mg pilocarpine.
    B) THERAPEUTIC DOSE: ACETYLCHOLINE: 0.5 to 2 mL of a 1:100 solution instilled intraocularly to produce miosis. BETHANECHOL: 10 to 50 mg orally 3 or 4 times/day. CEVIMELINE: 30 mg orally 3 times daily. PILOCARPINE (ophthalmic): 2 drops in the affected eye 3 or 4 times daily ; (oral): 5 mg 3 or 4 times daily; maximum 30 mg/day.

Clinical Effects

Summary Of Exposure

    A) USES: Muscarinic direct-acting cholinergic agents include acetylcholine, bethanechol, carbachol, cevimeline, choline, methacholine, and pilocarpine. These agents are used to treat glaucoma (pilocarpine), neurogenic atonic bladder (bethanechol) or Alzheimer disease (cevimeline) or to diagnose bronchial airway hyperactivity (methacholine). Muscarinic mushrooms are discussed in a separate management (Mushrooms-Muscarine/Histamine). Nicotinic agents (eg, carbachol, nicotinic plant alkaloids) are also discussed in separate managements.
    B) PHARMACOLOGY: These agents directly stimulate postganglionic cholinergic receptors and vary in selectivity for muscarinic receptors and nicotinic sites. Acetylcholine, methacholine, bethanechol, and pilocarpine have predominantly muscarinic effects, stimulating gastrointestinal, urinary, uterine, bronchial, cardiac, vascular, exocrine, CNS cortex, and brain stem receptors. Cevimeline is a muscarinic agonist (derivative of acetylcholine) which has demonstrated at least partial direct muscarinic M1-receptor agonist activity in the CNS.
    C) TOXICOLOGY: Toxicity occurs when acetylcholinesterase (AChE) does not adequately metabolize acetylcholine (ACh) in the synapse, leaving an excessive amount of ACh to interact with receptors. ACh functions as a neurotransmitter in the CNS where it may cause agitation and excitability followed by lethargy and seizures. In the peripheral nervous system, it affects neuromuscular junctions and the autonomic nervous system (ANS). The ANS manifests both parasympathetic findings (muscarinic: bradycardia, hypersecretion, gastrointestinal smooth muscle contraction, bronchoconstriction, and miosis) and sympathetic findings (mostly nicotinic/stimulatory: tachycardia, hypertension, bronchodilation, mydriasis, and diaphoresis).
    D) EPIDEMIOLOGY: Direct-acting cholinergic agent toxicity is an uncommon occurrence, and severe manifestations are rare except for carbachol. Pilocarpine and carbachol eye drops are used to treat glaucoma, are absorbed systemically, and cause infrequent problems.
    E) WITH THERAPEUTIC USE
    1) Adverse effects depend upon the individual agents but may include peripheral muscarinic effects (eg, salivation, lacrimation, frequent urination, diarrhea, vomiting, and miosis) and central muscarinic effects (eg, visual hallucinations and dystonias). Methacholine stimulates muscarinic contraction of airway smooth muscle and increases tracheobronchial secretions.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Peripheral muscarinic effects may include salivation, lacrimation, frequent urination, diarrhea, vomiting, and miosis. Central muscarinic effects may include visual hallucinations and dystonias.
    2) SEVERE POISONING: Peripheral muscarinic effects include bradycardia, bronchorrhea, and bronchospasm. Central muscarinic effects may include sedation, muscular rigidity, seizures, or coma. Nicotinic receptor activation may stimulate postganglionic sympathetic and parasympathetic neurons, neuromuscular junctions, and CNS neurons. Clinical effects may include excitation early (eg, hypertension, tachycardia, vomiting, diarrhea, fasciculations, and seizures) and inhibition later (eg, hypotension, bradydysrhythmias, paralysis, and coma).

Vital Signs

    3.3.3) TEMPERATURE
    A) HYPOTHERMIA: Profuse sweating and hypothermia may occur (Guerra & Ives, 1983).

Heent

    3.4.3) EYES
    A) Miosis is a common finding with systemic poisoning.
    1) Topical ocular effects include miosis (lasting 10 to 20 minutes with acetylcholine and 4 to 8 hours with pilocarpine) (Rizzuti, 1967), myopia and difficulty in visual accommodation, ciliary spasm, and ocular pain (Prod Info PILOPINE HS(R) ophthalmic gel, 2007).
    a) Miosis and profound decreased vision was reported in a 13-year-old boy who swam in a freshwater lake for 3 hours while wearing a pilocarpine Ocusert in his right eye. Miosis resolved following removal of the Ocusert (Kushnick et al, 1996).
    B) Lacrimation commonly occurs with systemic poisonings (Hendrickson et al, 2004).
    C) BRICK RED TEARS: Choline poisoning stimulates the flow of brick red tears due to a protoporphyrin pigment (Tashiro & Stix, 1935).
    D) CYTOTOXIC EFFECTS: Histological evidence of anterior corneal damage associated with the prolonged use of pilocarpine in normal rabbit eyes has been reported.
    1) A gel formulation, applied less frequently than the drop formulation, was associated with a milder toxic effect than the drop formulation in this animal model (Liu et al, 1989).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) Salivation commonly occurs with systemic poisonings (Hendrickson et al, 2004).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Vasodilation (accompanied by reflex tachycardia) may occur at moderate doses (Prod Info bethanechol chloride oral tablets, 2005).
    B) BRADYCARDIA
    1) Bradycardia occurs with large doses. Decreased myocardial contractility, syncope, circulatory collapse, and cardiac arrest may also occur (Prod Info pilocarpine hcl oral tablets, 2006; Prod Info PROVOCHOLINE(R) inhalation powder, 2004).
    C) HEART BLOCK
    1) Various dysrhythmias, primarily heart block, may occur. Atrial fibrillation (120 beats/min) with left bundle branch block was observed on an ECG in a patient poisoned with pilocarpine (Cordner et al, 1986).
    2) CASE REPORT: Third-degree AV block with a slow idioventricular escape rate (20 beats/min) was described in an 89-year-old man following administration of 2% pilocarpine eye drops every hour for 7 hours (Littmann et al, 1987).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) Dyspnea and bronchoconstriction may be noted and are more pronounced in asthmatic patients. Bronchospasm or pulmonary edema may be life-threatening.
    B) SPUTUM ABNORMAL - AMOUNT
    1) Bronchial secretions are increased and bouts of coughing may occur (Cordner et al, 1986).
    C) HYPERVENTILATION
    1) Tachypnea was initially reported in 2 patients poisoned with pilocarpine (Cordner et al, 1986).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CHOLINERGIC CRISIS
    1) Muscle cramps, fasciculations, weakness, and paralysis may occur, especially in those agents with greater nicotinic effects (eg, carbachol, methacholine, arecholine).
    B) SEIZURE
    1) Seizures, vertigo, and tremors may occur.
    C) HEADACHE
    1) Frontal headaches have been described with pilocarpine (Kushnick et al, 1996).
    D) IMPAIRED COGNITION
    1) CASE SERIES: Three elderly patients with Alzheimer dementia experienced exacerbations of cognitive symptoms (eg, memory loss, hallucinations, labile affect, confusion, agitation) within hours of administration of pilocarpine eye drops (2 patients also received epinephrine eye drops) (Reyes et al, 1987).
    2) CASE SERIES: Confusion was also reported in 2 patients poisoned with pilocarpine (Cordner et al, 1986).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Gastrointestinal motility is increased, resulting in nausea, vomiting, and abdominal pain (Hendrickson et al, 2004).
    b) CEVIMELINE/CASE REPORT: A 47-year-old woman experienced nausea and several episodes of vomiting after intentionally ingesting 20 30-mg cevimeline tablets (10 mg/kg). The patient also experienced somnolence and diaphoresis. With supportive care, she recovered uneventfully and was transferred to a psychiatric facility (Voskoboynik et al, 2011).
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea or involuntary defecation may occur (Hendrickson et al, 2004).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLECYSTITIS
    1) WITH THERAPEUTIC USE
    a) Cholecystitis has been reported as a postmarketing adverse event with therapeutic use of cevimeline (Prod Info EVOXAC(R) oral capsules, 2006).
    B) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Elevated hepatic enzymes and abnormal hepatic function have been reported after therapeutic use of cevimeline (Prod Info EVOXAC(R) oral capsules, 2006).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Excessive sweating is expected following overdoses of these drugs due to muscarinic agonist effects in sweat glands (Voskoboynik et al, 2011; Hendrickson et al, 2004).
    2) CASE REPORT: Excessive perspiration resulted in miliaria crystallina (tiny superficial vesicular lesions) in a man receiving parenteral bethanechol (Rochmis & Koplon, 1967).

Reproductive

    3.20.1) SUMMARY
    A) Acetylcholine, bethanechol, carbachol chloride, cevimeline, and pilocarpine are in pregnancy category C.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    DRUGPREGNANCY CATEGORY
    ACETYLCHOLINEC
    BETHANECHOLC
    CARBACHOL CHLORIDEC
    CEVIMELINEC
    PILOCARPINEC
    References: Briggs et al, 1998; Prod Info Evoxac(TM), 2000; Prod Info Urecholine(R), 2000; Prod Info Ocusert(R), 1998

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, including pulse oximetry.
    B) Monitor for evidence of respiratory distress, bronchospasm, or bronchorrhea. Obtain a chest x-ray in patients with respiratory distress to evaluate for pulmonary edema.
    C) Monitor serum electrolytes in patients with significant toxicity.
    D) Obtain an ECG and institute continuous cardiac monitoring in patients with significant toxicity.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes in patients with significant toxicity.
    2) Blood levels of specific agents are not clinically useful.
    3) Monitor arterial blood gases or pulse oximetry for patients with significant exposure or respiratory symptoms.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Obtain an ECG and institute continuous cardiac monitoring in patients with significant toxicity.
    b) Pulmonary function testing and chest x-ray may be indicated in patients with dyspnea or bronchospasm.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Any patient who manifests respiratory distress, cardiovascular compromise, dehydration, sedation, agitation, or severe CNS findings that persist despite treatment in the emergency department, admit the patient to the appropriate level of care.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Symptoms are generally mild unless large amounts have been ingested or taken. Patients may be observed at home for mild symptoms after inadvertent exposures, but should be evaluated for any concerning symptoms (eg, shortness of breath, wet cough, any distress).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist as needed for patients with significant toxicity, especially for patients admitted to the ICU, or in whom the diagnosis is uncertain.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient with a deliberate overdose or who manifests respiratory distress, cardiovascular compromise, dehydration, sedation, agitation, or severe CNS findings should be sent to a healthcare facility for observation. If symptoms resolve in the emergency department and the home social situation permits, the patient may be discharged.

Monitoring

    A) Monitor vital signs, including pulse oximetry.
    B) Monitor for evidence of respiratory distress, bronchospasm, or bronchorrhea. Obtain a chest x-ray in patients with respiratory distress to evaluate for pulmonary edema.
    C) Monitor serum electrolytes in patients with significant toxicity.
    D) Obtain an ECG and institute continuous cardiac monitoring in patients with significant toxicity.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Activated charcoal is generally not necessary since direct-acting cholinergic agonists can induce spontaneous vomiting. Eye drops are absorbed rapidly, so eye irrigation likely will not decrease absorption.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) If the patient 1) has taken a significant overdose or there is a serious co-ingestant that binds charcoal, 2) if the patient is alert and able to tolerate charcoal and not persistently vomiting, and 3) if the ingestion was recent, then charcoal may be administered.
    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) SUPPORT
    1) Monitor and support respiratory and cardiovascular function as needed.
    B) MONITORING OF PATIENT
    1) Monitor vital signs, including pulse oximetry.
    2) Monitor for evidence of respiratory distress, bronchospasm, or bronchorrhea. Obtain a chest x-ray in patients with respiratory distress to evaluate for pulmonary edema.
    3) Monitor serum electrolytes in patients with significant toxicity.
    4) Obtain an ECG and institute continuous cardiac monitoring in patients with significant toxicity.
    C) ATROPINE
    1) ATROPINE sulfate is the antidote of choice and will reverse the actions of the various cholinergic agonists at muscarinic and most nicotinic receptors.
    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.
    D) BRONCHOSPASM
    1) Epinephrine may assist in overcoming severe cardiovascular or bronchoconstrictor responses (DOSE: 0.1 to 1 milligram subcutaneously).
    2) BRONCHOSPASM SUMMARY
    a) Administer beta2 adrenergic agonists. Consider use of inhaled ipratropium and systemic corticosteroids. Monitor peak expiratory flow rate, monitor for hypoxia and respiratory failure, and administer oxygen as necessary.
    3) ALBUTEROL/ADULT DOSE
    a) 2.5 to 5 milligrams diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response, administer 2.5 to 10 milligrams every 1 to 4 hours as needed OR administer 10 to 15 milligrams every hour by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.5 milligram by nebulizer every 30 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).
    4) ALBUTEROL/PEDIATRIC DOSE
    a) 0.15 milligram/kilogram (minimum 2.5 milligrams) diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.25 to 0.5 milligram by nebulizer every 20 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).
    5) ALBUTEROL/CAUTIONS
    a) The incidence of adverse effects of beta2-agonists may be increased in older patients, particularly those with pre-existing ischemic heart disease (National Asthma Education and Prevention Program, 2007). Monitor for tachycardia, tremors.
    6) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm. PREDNISONE: ADULT: 40 to 80 milligrams/day in 1 or 2 divided doses. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 or 2 divided doses (National Heart,Lung,and Blood Institute, 2007).
    E) 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).
    F) PRALIDOXIME
    1) Cholinesterase regenerators such as pralidoxime (2-PAM) are ineffective as the cholinesterase enzyme is not blocked by the various cholinergic agonists.

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) Bronchodilators are indicated when dyspnea or bronchospasm occur.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) Eye drops are absorbed rapidly, so eye irrigation likely will not decrease absorption.

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).

Enhanced Elimination

    A) ENHANCED ELIMINATION
    1) Enhanced elimination is generally not necessary or effective.

Abstracts

Case Reports

    A) ROUTE OF EXPOSURE
    1) ORAL: A 46-year-old woman was started on oral pilocarpine for xerostomia and developed muscarinic symptoms (ie, sweating, abdominal cramping, excessive salivation, lacrimation, vomiting, anxiety, tremor, and profuse watery diarrhea) after inadvertently taking an initial 20 mg dose of pilocarpine (usual initial dose is much lower, but doses can be titrated to 20 to 30 mg daily in divided doses with chronic use). The patient had symptomatic relief following 0.5 mg of intravenous atropine and was restarted on therapy at 2.5 mg three times daily (Hendrickson et al, 2004).
    2) INJECTION: A 39-year-old woman was mistakenly given a subcutaneous injection of 2 mL of pilocarpine 4% ophthalmic drops (80 mg pilocarpine). Diaphoresis, salivation, and nausea were experienced soon after injection, followed by dry mouth, chills, and frequent urination and defecation for the next 6 hours. Tachypnea was still present by 12 hours. Symptoms slowly resolved over the next 4 days without medical intervention, as the medication error was discovered after her recovery (Kastl, 1987).

Range Of Toxicity

Summary

    A) TOXICITY: CEVIMELINE: Nausea and vomiting, mild hypotension with tachycardia, and borderline QTc interval prolongation were reported in a woman after she ingested 20 30-mg cevimeline tablets. The patient recovered with supportive care. PILOCARPINE: The lethal dose in an adult has been estimated to be as low as 60 milligrams in an acute poisoning; however, an adult was reported to have developed cholinergic symptoms, but survived, after inadvertent subcutaneous administration of 80 mg pilocarpine.
    B) THERAPEUTIC DOSE: ACETYLCHOLINE: 0.5 to 2 mL of a 1:100 solution instilled intraocularly to produce miosis. BETHANECHOL: 10 to 50 mg orally 3 or 4 times/day. CEVIMELINE: 30 mg orally 3 times daily. PILOCARPINE (ophthalmic): 2 drops in the affected eye 3 or 4 times daily ; (oral): 5 mg 3 or 4 times daily; maximum 30 mg/day.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) ACETYLCHOLINE: 0.5 to 2 mL of a 1:100 solution instilled intraocularly to produce miosis (Prod Info MIOCHOL(R) -E intraocular solution, 2006).
    2) BETHANECHOL: 10 to 50 mg orally 3 or 4 times/day (Prod Info bethanechol chloride oral tablets, 2005).
    3) CEVIMELINE: 30 mg orally 3 times/day (Prod Info EVOXAC(R) oral capsules, 2006).
    4) METHACHOLINE: For diagnosis of asthma: nebulized, ascending serial concentrations of 0.025 to 25 mg/mL, 5 inhalations at each concentration (Prod Info PROVOCHOLINE(R) inhalation powder, 2004).
    5) PILOCARPINE
    a) OPHTHALMIC: 2 drops in the affected eye 3 or 4 times daily (Prod Info pilocarpine hcl ophthalmic solution, 2004).
    b) ORAL: For head and neck cancer patients, initially 5 mg 3 times/day, and may be adjusted up to 30 mg/day. For Sjogren's Syndrome patients, 5 mg 4 times daily (Prod Info pilocarpine hcl oral tablets, 2006).
    7.2.2) PEDIATRIC
    A) METHACHOLINE (5 years of age and older): For diagnosis of asthma: nebulized, ascending serial concentrations of 0.025 to 25 mg/mL, 5 inhalations at each concentration (Prod Info PROVOCHOLINE(R) inhalation powder, 2004).

Minimum Lethal Exposure

    A) SPECIFIC SUBSTANCE
    1) PILOCARPINE: The lethal dose in an adult has been estimated to be as low as 60 milligrams in an acute poisoning (Cordner et al, 1986).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) CEVIMELINE/CASE REPORT: A 47-year-old woman developed nausea and vomiting, mild hypotension with tachycardia (94 bpm), and borderline QTc interval prolongation (456 ms) after ingesting 20 30-mg cevimeline tablets (10 mg/kg). With supportive care, the patient recovered uneventfully (Voskoboynik et al, 2011).
    2) PILOCARPINE: Accidental subcutaneous injection into the deltoid area of 80 milligrams of pilocarpine resulted in cholinergic systems, but survival without treatment (Kastl, 1987).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ACETYLCHOLINE
    1) LD50- (SUBCUTANEOUS)RAT:
    a) 250 mg/kg (RTECS, 2002)
    B) METHACHOLINE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 44 mg/kg (RTECS, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) These agents directly stimulate postganglionic cholinergic receptors. They vary in selectivity for various muscarinic receptors and nicotinic sites.
    B) Acetylcholine, methacholine, bethanecol, and pilocarpine have predominantly muscarinic effects, stimulating GI, urinary, uterine, bronchial, cardiac, vascular, exocrine, CNS cortex, and brain stem receptors.
    C) Carbachol directly stimulates muscarinic sites but also stimulates release of acetylcholine and has more pronounced nicotinic effects on the neuromuscular skeletal muscle junction, postganglionic autonomic nervous system, and adrenal medulla.
    D) Cevimeline is a muscarinic agonist (quinuclidine derivative of acetylcholine) which has demonstrated at least partial direct muscarinic M1-receptor agonist activity in the CNS. Use as cholinergic therapy in Alzheimer's disease has been advocated. Cevimeline also exhibits high binding affinity for muscarinic M3 receptors on lacrimal and salivary gland epithelium.
    E) Bethanechol and pilocarpine have very little nicotinic effects, if any.

Physicochemical

Physical Characteristics

    A) CHOLINE is metabolized to trimethylamine in overdose (> 20 grams) and produces a fishy body odor (Growdon et al, 1977).
    B) BETHANECHOL chloride is a white, hygroscopic crystalline powder with a slight amine-like odor. It is freely soluble in water (Prod Info Urecholine(R), bethanechol chloride, 2000).

Molecular Weight

    A) ACETYLCHOLINE - 146.24 (RTECS , 2002)
    B) BETHANECHOL CHLORIDE - 196.71 (RTECS , 2002)
    C) CEVIMELINE HYDROCHLORIDE - 244.8 (S Sweetman , 2001)
    D) METHACHOLINE - 160.27 (RTECS , 2002)
    E) PILOCARPINE - 208.29 (RTECS , 2002)

References

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