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ANTIMYASTHENICS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Antimyasthenics are reversible anticholinesterase agents used in the diagnosis or treatment of myasthenia gravis. They are also used postoperatively for reversal of neuromuscular blockade. Guanidine is used to reduce symptoms of muscle weakness and easy fatigability associated with the myasthenic syndrome of Eaton-Lambert. Guanidine is not indicated for the treatment of myasthenia gravis.
    B) NOTE: Physostigmine, another anticholinesterase agent, is described in its own management, as are the organophosphate and carbamate insecticides.

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) AMBENONIUM
    2) EDROPHONIUM
    3) EPTASTIGMINE
    4) GUANIDINE
    5) GUANIDINE HYDROCHLORIDE
    6) NEOSTIGMINE
    7) PYRIDOSTIGMINE

Available Forms Sources

    A) FORMS
    1) AMBENONIUM: Available as 10 mg tablets (Prod Info MYTELASE(R) oral tablets, 2011).
    2) EDROPHONIUM: Was available as 10 mg/mL injection
    a) NOTE: As of 2/18/2008, edrophonium chloride is no longer available in the United States (Baxter Healthcare Corporation, 2008).
    3) GUANIDINE HYDROCHLORIDE: Available as 125 mg tablets (Prod Info guanidine HCl oral tablets, 2003).
    4) NEOSTIGMINE: Neostigmine bromide is available as 15 mg tablets. Neostigmine methylsulfate is available as 0.5 mg/mL and 1 mg/mL solution for injection (Prod Info neostigmine methylsulfate IV, IM, subcutaneous injection solution, 2009; Prod Info PROSTIGMIN(R) oral tablets, 2006).
    5) PYRIDOSTIGMINE: Available as 60 mg tablets, 180 mg sustained release tablets, 60 mg/5mL syrup, and 5 mg/mL injection (Prod Info pyridostigmine bromide oral tablets, 2010; Prod Info REGONOL(R) IV injection, 2009; Prod Info MESTINON(R) oral syrup, oral tablets, oral Timespan(R) tablets, 2008).
    B) USES
    1) Antimyasthenics are reversible anticholinesterase agents used in the diagnosis or treatment of myasthenia gravis. They are also used postoperatively for reversal of neuromuscular blockade (Prod Info MYTELASE(R) oral tablets, 2011; Prod Info Guanidine hydrochloride tablets, 2003; Prod Info neostigmine methylsulfate IV, IM, subcutaneous injection solution, 2009; Prod Info PROSTIGMIN(R) oral tablets, 2006; Prod Info pyridostigmine bromide oral tablets, 2010; Prod Info REGONOL(R) IV injection, 2009; Prod Info MESTINON(R) oral syrup, oral tablets, oral Timespan(R) tablets, 2008).
    2) Guanidine is used to reduce symptoms of muscle weakness and easy fatigability associated with the myasthenic syndrome of Eaton-Lambert. Guanidine is not indicated for the treatment of myasthenia gravis (Prod Info guanidine HCl oral tablets, 2003).

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: Antimyasthenics (ambenonium, neostigmine, pyridostigmine) are reversible anticholinesterase agents used in the diagnosis and treatment of myasthenia gravis. They may also be used postoperatively for reversal of neuromuscular blockade. Guanidine is used to reduce symptoms of muscle weakness and easy fatigability associated with the myasthenic syndrome of Eaton-Lambert. Guanidine is not indicated for the treatment of myasthenia gravis. Specific antimyasthenics include the following: ambenonium, edrophonium, guanidine hydrochloride, neostigmine, and pyridostigmine. Note: Physostigmine, the cholinesterase inhibitors used to treat Alzheimer's disease (rivastigmine, donepezil, galantamine), and organophosphate and carbamate insecticides are covered in separate managements.
    B) PHARMACOLOGY: The antimyasthenics are cholinesterase inhibitors which act on CNS, muscarinic, and nicotinic receptors. Because they enhance impulse transmission at neuromuscular junctions, these agents improve the skeletal muscle weakness in myasthenia gravis. Specifically, guanidine increases the release of acetylcholine following nerve impulse. In addition, it slows the rate of depolarization and repolarization in muscle cell membranes.
    C) TOXICOLOGY: When there is too much inhibition of the enzyme cholinesterase, cholinergic crisis occurs. There is an excess of acetylcholine, because of enzyme which metabolizes it is inhibited by these agents.
    D) EPIDEMIOLOGY: Exposures are relatively uncommon.
    E) WITH THERAPEUTIC USE
    1) Nausea, vomiting, diarrhea, abdominal cramps, increased peristalsis, increased salivation, increased bronchial secretions, miosis, diaphoresis, muscle cramps, fasciculation, weakness, hypotension, syncope, rash, flushing, urticaria, allergic reactions, including anaphylaxis have been reported with antimyasthenics. Bromide toxicity from high-dose pyridostigmine bromide has occurred which manifests as various neurologic, psychiatric, gastrointestinal, and dermatologic effects. GUANIDINE: The following adverse effects have been reported with guanidine use: Gastric irritation, anorexia, nausea, diarrhea, abdominal pain, dry mouth, diaphoresis, bone marrow suppression (anemia, leukopenia, and thrombocytopenia), palpitations, tachycardia, atrial fibrillation, hypotension, elevation of blood creatinine, uremia, chronic interstitial nephritis, acute interstitial nephritis, renal tubular necrosis, elevated liver enzymes, rash, flushing or pink complexion, folliculitis, petechiae, purpura, ecchymoses, dryness and scaling of the skin, paresthesia of lips, face, hands, feet, cold sensations in hands and feet, nervousness, lightheadedness, jitteriness, increased irritability, tremor, trembling sensation, ataxia, emotional lability, psychotic state, confusion, mood changes, and hallucinations.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Malaise, fatigue, nausea, rhinorrhea, and frequent urination may occur.
    2) SEVERE TOXICITY: Signs and symptoms of significant exposure to the antimyasthenics are generally those of cholinergic crisis, and involve the central nervous system, the respiratory system, the parasympathetic nervous system, and the neuromuscular junction. In addition to muscle weakness or fasciculations, some or all symptoms of the SLUDGE syndrome may develop (salivation, lacrimation, urination, defecation, gastrointestinal cramping, and emesis). Seizure, bradydysrhythmias, acute lung injury, bronchorrhea, bronchospasm, hypotension, and hypertension may also occur. Nervous hyperirritability, fibrillary tremors and myoclonus, salivation, vomiting, diarrhea, hypoglycemia, and circulatory disturbances have been reported following severe guanidine intoxication.
    0.2.3) VITAL SIGNS
    A) Hypotension may occur from peripheral actions. However, hypertension may also be seen secondary to the anxiety resulting from the effects on other organ systems.
    B) Likewise, bradydysrhythmias are common from the antimyasthenics, but tachycardia may occur due to increased epinephrine release from the adrenal glands as well as secondary to the anxiety resulting from the effects on other organ systems.
    C) Respiratory rate may be increased in patients with airway compromise.
    0.2.4) HEENT
    A) Miosis, blurred vision, and excessive secretions in the nose and throat may be present.
    0.2.5) CARDIOVASCULAR
    A) Bradydysrhythmias and varying degrees of AV block, atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular asystole have been reported. Secondary to slowed heart rate and conduction, cardiac output falls, and hypotension may occur.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Parkinsonian-like symptoms have been reported during therapeutic use of pyridostigmine.
    2) Paresthesia of lips, face, hands, feet, cold sensations in hands and feet, nervousness, lightheadedness, jitteriness, increased irritability, tremor, trembling sensation, ataxia, emotional lability, psychotic state, confusion, mood changes, and hallucinations have been reported following the use of guanidine.
    B) WITH POISONING/EXPOSURE
    1) Seizures and coma have been described; profound weakness and muscle fasciculations may also occur. In less severe cases, headache, dizziness, and dysarthria may occur.
    2) Nervous hyperirritability, fibrillary tremors and convulsive contractions of muscle have been reported following severe guanidine intoxication.
    0.2.15) MUSCULOSKELETAL
    A) Profound skeletal muscle weakness and fasciculations may occur.
    0.2.20) REPRODUCTIVE
    A) Neostigmine and pyridostigmine have been classified as FDA pregnancy category C. An infant with birth defects was born to a woman who took 4 to 8 times the usual dose of pyridostigmine throughout pregnancy, but it is not clear that these anomalies were related to pyridostigmine. Pyridostigmine given near term and/or during labor has resulted in neonatal myasthenia. Anticholinesterase drugs given IV near term may cause uterine irritability and induce premature labor. Guanidine is excreted in breast milk and breastfeeding should be discontinued. The concentration of pyridostigmine in breast milk was 36% to 113% of maternal plasma.
    0.2.22) OTHER
    A) BROMIDE INTOXICATION secondary to high-dose pyridostigmine bromide therapy has occurred.

Laboratory Monitoring

    A) Monitor vital signs; institute continuous pulse oximetry and cardiac monitoring.
    B) Monitor for clinical evidence of weakness, respiratory distress or SLUDGE symptoms, and fasciculations.
    C) Monitor serum electrolytes in patients with vomiting and diarrhea.
    D) Serum concentrations of the antimyasthenics is not generally available or clinically useful in guiding treatment. Cholinesterase testing may be preferable, as the antimyasthenics will depress cholinesterase activity; however, after an acute exposure, measurement of levels are usually only helpful if followed over a period of time. Although cholinesterase levels do not correlate well with toxicity, less than 80% activity is associated with severe symptomatology. Clinical findings are often more helpful in guiding treatment than laboratory evaluation in these patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Symptomatic and supportive care is the mainstay of treatment in patients who present with mild to moderate antimyasthenic toxicity.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Early intubation (note that patients may be sensitive to the effects of depolarizing and nondepolarizing neuromuscular blockers), with assisted ventilation should be performed if the patient presents with respiratory depression or respiratory distress that does not respond rapidly to atropine. Adequate circulatory support with IV fluids and vasopressors (if needed) should be assured if patient presents with circulatory collapse. Treat seizures with benzodiazepines. Treat with pralidoxime and atropine as outlined in the antidote section below.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal can be considered within the first hour after large ingestion, with appropriate level of consciousness, patent airway, and the patient able to drink the charcoal.
    2) HOSPITAL: Administer activated charcoal if the patient presents early after large ingestion with appropriate level of consciousness, patent airway, and can drink the charcoal.
    D) AIRWAY MANAGEMENT
    1) Perform endotracheal intubation and provide assisted ventilation as required (note that patients maybe sensitive to the effects of depolarizing and nondepolarizing neuromuscular blockers, lower doses may be utilized).
    E) ANTIDOTE
    1) ATROPINE: Will reverse many of the muscarinic manifestations (bronchorrhea, bradycardia, hypersalivation, gastrointestinal symptoms). ADULTS: 2 to 5 mg IV repeat every 10 to 30 minutes as needed. PEDIATRIC: 0.05 mg/kg. The endpoint is drying of secretions; large doses may be required.
    2) 2-PAM: May reverse muscle weakness and fasciculations. Treat moderate to severe poisoning (fasciculations. muscle weakness, respiratory depression, coma, seizures) with 2-PAM in addition to atropine. One regimen is an initial bolus of at least 30 mg/kg followed by an infusion of more than 8 mg/kg/hour of 2-PAM. An alternative simpler adult dose includes the following: 1 to 2 g 2-PAM in 100 mL of 0.9% saline infused over 15 to 30 min. Followed by infusion of 500 mg to 1 g/hr as a 2.5% solution. Alternatively, the initial dose may be repeated every 1 hr and then every 3 to 8 hours if muscle weakness or fasciculations persist.
    F) ENHANCED ELIMINATION
    1) There are no useful techniques to enhance elimination of antimyasthenic drugs.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic children or adults with small acute inadvertent ingestions may be monitored at home.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions, and those who are symptomatic should be referred in a healthcare facility.
    3) ADMISSION CRITERIA: Admit patients with persist symptoms. Admit all patients with severe symptoms (respiratory distress or depression, CNS depression or significant weakness, hemodynamic instability) to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity, or in whom the diagnosis is not clear.
    H) PITFALLS
    1) Failure to distinguish weakness from cholinergic excess from exacerbation of myasthenia gravis.
    I) PHARMACOKINETICS
    1) AMBENONIUM: Poor bioavailability, Tmax:: 1 to 2 hours. NEOSTIGMINE: Poor bioavailability, Tmax: 1 to 2 hours; protein binding: 15% to 25%; Vd: 0.2 L/kg. Hepatic metabolism. Elimination half-life: 15 to 90 min. PYRIDOSTIGMINE: 10% to 20% bioavailable; Tmax: 1 to 2 hours. Not protein-bound. Vd: 0.5 to 1.7 L/kg. Elimination half-life: 97 to 200 minutes.
    J) DIFFERENTIAL DIAGNOSIS
    1) Overdose of cholinesterase inhibitors used for Alzheimer's disease, organophosphate insecticides, carbamate insecticides, gastroenteritis, and muscarine-containing mushrooms like Clitocybe dealbata.

Range Of Toxicity

    A) TOXICITY: Toxic serum or blood concentrations of the antimyasthenics have not been established. Depression of cholinesterase activity to less than 80% of normal is frequently associated with severe symptoms.
    B) THERAPEUTIC DOSES: AMBENONIUM: Adults: 5 to 75 mg orally 3 to 4 times a day; MAX dose: 200 mg/day. EDROPHONIUM: Adults: For diagnostic test for myasthenia gravis: 2 mg IV over 15 to 30 seconds; if no cholinergic symptoms develop in 45 seconds, give additional 8 mg IV at 2 mg/min. GUANIDINE: Initially, 10 to 15 mg/kg/day in 3 or 4 divided doses; may be gradually increased to 35 mg/kg/day. NEOSTIGMINE: Varies by indication: 15 to 375 mg orally daily; titrate to response. Injection: 0.25 to 0.5 mg IM or SubQ with subsequent doses based on response. Reversal of neuromuscular blockade: 0.5 to 2 mg IV slowly (with atropine sulfate); repeat as needed; rarely should total dose exceed 5 mg. PYRIDOSTIGMINE: 180 to 1500 mg/day orally, titrated to response.

Clinical Effects

Summary Of Exposure

    A) USES: Antimyasthenics (ambenonium, neostigmine, pyridostigmine) are reversible anticholinesterase agents used in the diagnosis and treatment of myasthenia gravis. They may also be used postoperatively for reversal of neuromuscular blockade. Guanidine is used to reduce symptoms of muscle weakness and easy fatigability associated with the myasthenic syndrome of Eaton-Lambert. Guanidine is not indicated for the treatment of myasthenia gravis. Specific antimyasthenics include the following: ambenonium, edrophonium, guanidine hydrochloride, neostigmine, and pyridostigmine. Note: Physostigmine, the cholinesterase inhibitors used to treat Alzheimer's disease (rivastigmine, donepezil, galantamine), and organophosphate and carbamate insecticides are covered in separate managements.
    B) PHARMACOLOGY: The antimyasthenics are cholinesterase inhibitors which act on CNS, muscarinic, and nicotinic receptors. Because they enhance impulse transmission at neuromuscular junctions, these agents improve the skeletal muscle weakness in myasthenia gravis. Specifically, guanidine increases the release of acetylcholine following nerve impulse. In addition, it slows the rate of depolarization and repolarization in muscle cell membranes.
    C) TOXICOLOGY: When there is too much inhibition of the enzyme cholinesterase, cholinergic crisis occurs. There is an excess of acetylcholine, because of enzyme which metabolizes it is inhibited by these agents.
    D) EPIDEMIOLOGY: Exposures are relatively uncommon.
    E) WITH THERAPEUTIC USE
    1) Nausea, vomiting, diarrhea, abdominal cramps, increased peristalsis, increased salivation, increased bronchial secretions, miosis, diaphoresis, muscle cramps, fasciculation, weakness, hypotension, syncope, rash, flushing, urticaria, allergic reactions, including anaphylaxis have been reported with antimyasthenics. Bromide toxicity from high-dose pyridostigmine bromide has occurred which manifests as various neurologic, psychiatric, gastrointestinal, and dermatologic effects. GUANIDINE: The following adverse effects have been reported with guanidine use: Gastric irritation, anorexia, nausea, diarrhea, abdominal pain, dry mouth, diaphoresis, bone marrow suppression (anemia, leukopenia, and thrombocytopenia), palpitations, tachycardia, atrial fibrillation, hypotension, elevation of blood creatinine, uremia, chronic interstitial nephritis, acute interstitial nephritis, renal tubular necrosis, elevated liver enzymes, rash, flushing or pink complexion, folliculitis, petechiae, purpura, ecchymoses, dryness and scaling of the skin, paresthesia of lips, face, hands, feet, cold sensations in hands and feet, nervousness, lightheadedness, jitteriness, increased irritability, tremor, trembling sensation, ataxia, emotional lability, psychotic state, confusion, mood changes, and hallucinations.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Malaise, fatigue, nausea, rhinorrhea, and frequent urination may occur.
    2) SEVERE TOXICITY: Signs and symptoms of significant exposure to the antimyasthenics are generally those of cholinergic crisis, and involve the central nervous system, the respiratory system, the parasympathetic nervous system, and the neuromuscular junction. In addition to muscle weakness or fasciculations, some or all symptoms of the SLUDGE syndrome may develop (salivation, lacrimation, urination, defecation, gastrointestinal cramping, and emesis). Seizure, bradydysrhythmias, acute lung injury, bronchorrhea, bronchospasm, hypotension, and hypertension may also occur. Nervous hyperirritability, fibrillary tremors and myoclonus, salivation, vomiting, diarrhea, hypoglycemia, and circulatory disturbances have been reported following severe guanidine intoxication.

Vital Signs

    3.3.1) SUMMARY
    A) Hypotension may occur from peripheral actions. However, hypertension may also be seen secondary to the anxiety resulting from the effects on other organ systems.
    B) Likewise, bradydysrhythmias are common from the antimyasthenics, but tachycardia may occur due to increased epinephrine release from the adrenal glands as well as secondary to the anxiety resulting from the effects on other organ systems.
    C) Respiratory rate may be increased in patients with airway compromise.
    3.3.2) RESPIRATIONS
    A) Respiratory rate may be rapid if there is airway compromise.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) GUANIDINE: Fever has been reported following therapeutic use (Prod Info guanidine HCl oral tablets, 2003).
    3.3.4) BLOOD PRESSURE
    A) Hypotension may occur, but patients may also be hypertensive as a reflection of their distress.
    3.3.5) PULSE
    A) Heart rate may be slow from the pharmacologic effects of the drugs, or rapid if the patient is in distress.

Heent

    3.4.1) SUMMARY
    A) Miosis, blurred vision, and excessive secretions in the nose and throat may be present.
    3.4.3) EYES
    A) Pupils may be miotic.
    B) A test dose of 10 mg of edrophonium given to normal controls resulted in fasciculations of the eyelids and facial muscles. Distortion of vision and lacrimation were also present (Osserman & Kaplan, 1952).
    C) Adverse effects associated with anticholinesterase agents, including ambenonium chloride, are generally the result of overdosage and may include miosis and increased lacrimal secretions (Prod Info MYTELASE(R) oral tablets, 2011).
    D) NEOSTIGMINE: Visual changes and miosis has been reported with the use of neostigmine bromide (Prod Info PROSTIGMIN(R) oral tablets, 2006).
    E) PYRIDOSTIGMINE: Miosis has been reported with the use of pyridostigmine bromide (Prod Info pyridostigmine bromide oral tablets, 2010).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) Increased secretions in the pharynx may be noted.
    2) GUANIDINE: Sore throat has been reported following the use of guanidine (Prod Info guanidine HCl oral tablets, 2003).

Cardiovascular

    3.5.1) SUMMARY
    A) Bradydysrhythmias and varying degrees of AV block, atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular asystole have been reported. Secondary to slowed heart rate and conduction, cardiac output falls, and hypotension may occur.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) Bradydysrhythmias and varying degrees of AV block, atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular asystole have been reported.
    2) MECHANISM: The primary effect of the antimyasthenics on the heart is slowing of the cardiac rate and conduction, with consequent fall in cardiac output and hypotension.
    a) On the cellular level this may be due to decrease of the slope of diastolic depolarization and an increase in the maximum diastolic potential of the pacemaker cells, resulting in abolition of phase four diastolic depolarization and progressive shift of the pacemaker to a more distal site (Arsura et al, 1987).
    3) RISK FACTORS: Dysrhythmias are more likely to occur in patients being treated with digitalis, calcium channel blockers, beta blockers, and patients with acute myocardial infarction or ischemia, hypersensitive carotid sinus syndrome, sick sinus syndrome, or in those with preexisting inflammatory, infiltrative, or degenerative disease of the conducting system (Okun et al, 2001; Arsura et al, 1987).
    4) DOSE-RESPONSE: Many of these cardiovascular effects occur in patients with normal therapeutic doses of the antimyasthenics.
    5) CASE REPORT: Ventricular asystole was reported in a patient after receiving a 10 mg intravenous dose of edrophonium to treat paroxysmal atrial tachycardia (Rossen et al, 1976). This patient was not on digitalis.
    6) ONSET: The onset of cardiovascular effects after an oral dose of 45 mg neostigmine was 30 minutes after ingestion, and effects became maximum at 90 minutes.
    a) This occurred after salivation was noted, but before the gastrointestinal effects of the drug were seen (Goodman & Bruckner, 1937).
    7) Cardiac arrhythmias (including bradycardia, tachycardia, atrioventricular (AV) block, and nodal rhythm) and non-specific ECG changes have been reported with the use of neostigmine bromide (Prod Info PROSTIGMIN(R) oral tablets, 2006).
    B) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) GUANIDINE: Palpitation, tachycardia, atrial fibrillation, and hypotension have been reported following the use of guanidine (Prod Info guanidine HCl oral tablets, 2003).
    b) NEOSTIGMINE: Hypotension and syncope have been reported with the use of neostigmine bromide (Prod Info PROSTIGMIN(R) oral tablets, 2006).
    c) EDROPHONIUM: Edrophonium decreases peripheral vascular resistance, but has little effect on cardiac index, mean pressure, or left ventricular systolic ejection time. Edrophonium may prolong conduction time through the AV node (Youngberg, 1979).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) Studies done in dogs have not shown an exaggerated heart rate slowing or other adverse cardiac effects following the administration of antimyasthenics in the presence of beta adrenergic blockade (Wagner et al, 1982).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) Increased oral, tracheal, and bronchial secretions may cause dyspnea and airway obstruction. Bronchospasm and pulmonary edema may occur in severe cases.
    2) NEOSTIGMINE: Dyspnea has been reported with the use of neostigmine bromide (Prod Info PROSTIGMIN(R) oral tablets, 2006).
    B) APNEA
    1) Myasthenic patients already on antimyasthenic medications may develop respiratory failure during the Tensilon(R) (edrophonium) test (McLellan, 1973).
    C) BRONCHORRHEA
    1) WITH POISONING/EXPOSURE
    a) Adverse effects associated with anticholinesterase agents are generally the result of overdosage and may include increased pharyngeal and bronchial secretions (Prod Info MYTELASE(R) oral tablets, 2011; Prod Info pyridostigmine bromide oral tablets, 2010; Prod Info PROSTIGMIN(R) oral tablets, 2006).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Parkinsonian-like symptoms have been reported during therapeutic use of pyridostigmine.
    2) Paresthesia of lips, face, hands, feet, cold sensations in hands and feet, nervousness, lightheadedness, jitteriness, increased irritability, tremor, trembling sensation, ataxia, emotional lability, psychotic state, confusion, mood changes, and hallucinations have been reported following the use of guanidine.
    B) WITH POISONING/EXPOSURE
    1) Seizures and coma have been described; profound weakness and muscle fasciculations may also occur. In less severe cases, headache, dizziness, and dysarthria may occur.
    2) Nervous hyperirritability, fibrillary tremors and convulsive contractions of muscle have been reported following severe guanidine intoxication.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) Coma and seizures may occur in severe cases. Headache, dizziness, dysarthria, and visual changes may occur in less severe cases.
    B) EXTRAPYRAMIDAL DISEASE
    1) CASE REPORT: Parkinsonism developed in a patient receiving pyridostigmine 360 mg/day for myasthenia gravis. Withdrawal of pyridostigmine resulted in resolution of parkinsonian symptoms. Rechallenge was not attempted (Iwasaki et al, 1988).
    C) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) GUANIDINE: Paresthesia of lips, face, hands, feet, cold sensations in hands and feet, nervousness, lightheadedness, jitteriness, increased irritability, tremor, trembling sensation, ataxia, emotional lability, psychotic state, confusion, mood changes, and hallucinations have been reported following the use of guanidine (Prod Info guanidine HCl oral tablets, 2003).
    b) NEOSTIGMINE: Dizziness, loss of consciousness, drowsiness, headache, weakness, and dysarthria have been reported with the use of neostigmine bromide (Prod Info PROSTIGMIN(R) oral tablets, 2006).
    2) WITH POISONING/EXPOSURE
    a) GUANIDINE: Nervous hyperirritability, fibrillary tremors and convulsive contractions of muscle have been reported following severe guanidine intoxication (Prod Info guanidine HCl oral tablets, 2003).
    b) Adverse effects associated with anticholinesterase agents, including ambenonium chloride, are generally the result of overdosage and may include generalized malaise with anxiety and vertigo (Prod Info MYTELASE(R) oral tablets, 2011).
    D) PARALYSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 28-year-old man developed muscular paralysis (lasting about 35 minutes) after receiving 5 mg of neostigmine instead of the desired dose of 2.5 mg, used to reverse the neuromuscular blockade at the end of an epigastric hernia repair surgery. Following supportive care, he recovered completely (Sharma, 2008).
    E) SEIZURE
    1) WITH THERAPEUTIC USE
    a) NEOSTIGMINE: Seizures have been reported with the use of neostigmine bromide (Prod Info PROSTIGMIN(R) oral tablets, 2006).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEUROPATHY
    a) In RATS, 20 to 80 mg/kg of pyridostigmine given by gavage resulted in acute local necrosis, leukocyte infiltration, and marked changes in the motor endplates at the neuromuscular junction (Gebbers et al, 1986).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) GUANIDINE: Gastric irritation, anorexia, nausea, vomiting, abdominal pain, diarrhea, and dry mouth have been reported following the use of guanidine (Prod Info guanidine HCl oral tablets, 2003).
    2) WITH POISONING/EXPOSURE
    a) GUANIDINE: Salivation, vomiting, and diarrhea have been reported following severe guanidine intoxication (Prod Info guanidine HCl oral tablets, 2003).
    b) Adverse effects associated with anticholinesterase agents are generally the result of overdosage and may include nausea, vomiting, diarrhea, abdominal pain, increased peristalsis, and excessive salivation (Prod Info MYTELASE(R) oral tablets, 2011; Prod Info pyridostigmine bromide oral tablets, 2010; Prod Info PROSTIGMIN(R) oral tablets, 2006).
    B) FLATULENCE/WIND
    1) Bowel sounds may be extremely loud, and have been compared to "a storm at sea" (Goodman & Bruckner, 1937).
    2) NEOSTIGMINE: Flatulence has been reported with the use of neostigmine bromide (Prod Info PROSTIGMIN(R) oral tablets, 2006).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) GUANIDINE: abdominal cramping has been reported following the use of guanidine (Prod Info guanidine HCl oral tablets, 2003).
    2) WITH POISONING/EXPOSURE
    a) PYRIDOSTIGMINE: Acute overdose (390 to 900 mg) in young adults resulted in signs of abdominal cramps, diarrhea, emesis, nausea, and hypersalivation (Almog et al, 1991).
    b) Adverse effects associated with anticholinesterase agents, including ambenonium chloride, are generally the result of overdosage and may include abdominal pain (Prod Info MYTELASE(R) oral tablets, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) GUANIDINE: Abnormal liver function tests have been reported following the use of guanidine (Prod Info guanidine HCl oral tablets, 2003).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) Urinary incontinence or frequency may occur.
    2) GUANIDINE: Elevation of blood creatinine, uremia, chronic interstitial nephritis, acute interstitial nephritis, and renal tubular necrosis have been reported following the use of guanidine (Prod Info guanidine HCl oral tablets, 2003).
    B) MICTURITION
    1) WITH POISONING/EXPOSURE
    a) Adverse effects associated with anticholinesterase agents, including ambenonium chloride, are generally the result of overdosage and may include urinary urgency (Prod Info MYTELASE(R) oral tablets, 2011).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) GUANIDINE: Bone marrow suppression, including anemia, leukopenia, and thrombocytopenia have been reported following the use of guanidine (Prod Info guanidine HCl oral tablets, 2003).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) Dermatitis or urticaria may occur.
    B) ALOPECIA
    1) PYRIDOSTIGMINE: Reversible alopecia areata has been reported during therapeutic use of pyridostigmine bromide (Field, 1980).
    C) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) GUANIDINE: Rash, flushing or pink complexion, folliculitis, petechiae, purpura, ecchymoses, sweating, dryness and scaling of the skin have been reported following the use of guanidine (Prod Info guanidine HCl oral tablets, 2003).
    b) NEOSTIGMINE: Rash, flushing, and urticaria have been reported with the use of neostigmine bromide (Prod Info PROSTIGMIN(R) oral tablets, 2006).
    c) PYRIDOSTIGMINE: Diaphoresis has been reported with the use of pyridostigmine bromide (Prod Info pyridostigmine bromide oral tablets, 2010).
    D) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Adverse effects associated with anticholinesterase agents, including ambenonium chloride, are generally the result of overdosage and may include sweating (Prod Info MYTELASE(R) oral tablets, 2011).
    b) NEOSTIGMINE: Diaphoresis has been reported with the use of neostigmine bromide (Prod Info PROSTIGMIN(R) oral tablets, 2006).

Musculoskeletal

    3.15.1) SUMMARY
    A) Profound skeletal muscle weakness and fasciculations may occur.
    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) Extreme weakness from cholinergic crisis may occur, but this may also be a symptom of myasthenia gravis. The treatments of these 2 conditions are exactly opposite, so a correct diagnosis based on careful history and physical exam is crucial. Muscle fasciculations may also occur.
    2) Acute overdose (390 to 900 mg) in young healthy adults resulted in signs of muscle weakness and fasciculations (Almog et al, 1991).
    B) MUSCLE FASCICULATION
    1) WITH POISONING/EXPOSURE
    a) Adverse effects associated with anticholinesterase agents are generally the result of overdosage and may include muscle fasciculation, muscle cramps, weakness, and spasms (Prod Info MYTELASE(R) oral tablets, 2011; Prod Info pyridostigmine bromide oral tablets, 2010; Prod Info PROSTIGMIN(R) oral tablets, 2006).
    C) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) NEOSTIGMINE: Arthralgia has been reported with the use of neostigmine bromide (Prod Info PROSTIGMIN(R) oral tablets, 2006).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) GUANIDINE: Hypoglycemia and circulatory disturbances have been reported following severe guanidine intoxication (Prod Info guanidine HCl oral tablets, 2003).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) NEOSTIGMINE: Allergic reactions, including anaphylaxis have been reported with the use of neostigmine bromide (Prod Info PROSTIGMIN(R) oral tablets, 2006).

Reproductive

    3.20.1) SUMMARY
    A) Neostigmine and pyridostigmine have been classified as FDA pregnancy category C. An infant with birth defects was born to a woman who took 4 to 8 times the usual dose of pyridostigmine throughout pregnancy, but it is not clear that these anomalies were related to pyridostigmine. Pyridostigmine given near term and/or during labor has resulted in neonatal myasthenia. Anticholinesterase drugs given IV near term may cause uterine irritability and induce premature labor. Guanidine is excreted in breast milk and breastfeeding should be discontinued. The concentration of pyridostigmine in breast milk was 36% to 113% of maternal plasma.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) AMBENONIUM CHLORIDE: Safety of use during pregnancy has not been established (Prod Info MYTELASE(R) oral tablets, 2011).
    2) EDROPHONIUM: Safety of use during pregnancy has not been established (Prod Info ENLON(R) intravenous injection, intramuscular injection, 2009).
    B) CONGENITAL ANOMALY
    1) An infant with microcephaly, a broad nasal bridge, a prominent nose, down slanting palpebral fissures, a high arched palate, a short neck, a broad chest, campylodactyly, hammer toes, and bilateral cryptorchism but a normal karyotype was born to a woman who took 4 to 8 times the usual dose of pyridostigmine throughout pregnancy (1500 to 3000 mg/day) (Niesen & Shah, 2000). It is not clear that these anomalies were related to pyridostigmine (Polizzi et al, 2001).
    C) LACK OF EFFECT
    1) NEOSTIGMINE
    a) Neostigmine has been used in pregnancy without producing fetal anomalies (Heinonen et al, 1977; Chambers et al, 1967; McNall & Jafarnia, 1965; Mellin, 1964; Foldes & McNall, 1962). The Collaborative Perinatal Project found no association between the use of neostigmine and congenital defects in 22 exposures during the first trimester of pregnancy (Heinonen et al, 1977).
    D) ANIMAL STUDIES
    1) NEOSTIGMINE
    a) During animal embryofetal development studies, there was no evidence of teratogenicity with administration of neostigmine methylsulfate during the period of organogenesis at doses up to approximately 0.16 times the maximum recommended human dose (MRHD) (Prod Info BLOXIVERZ(TM) intravenous injection, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) AMBENONIUM CHLORIDE: Safety of use during pregnancy has not been established (Prod Info MYTELASE(R) oral tablets, 2011).
    2) EDROPHONIUM: Safety of use during pregnancy has not been established (Prod Info ENLON(R) intravenous injection, intramuscular injection, 2009).
    3) GUANIDINE HYDROCHLORIDE: Safety of use during pregnancy has not been established (Prod Info guanidine HCl oral tablets, 2003).
    B) RISK SUMMARY
    1) NEOSTIGMINE
    a) There are no adequate or well-controlled studies of neostigmine in pregnant women. Use during pregnancy only if clearly needed (Prod Info BLOXIVERZ(TM) intravenous injection, 2015).
    C) PREGNANCY CATEGORY
    1) The manufacturer has classified pyridostigmine as FDA pregnancy category C (Prod Info REGONOL(R) IV injection, 2009).
    D) NEONATAL MYASTHENIA
    1) Administration of pyridostigmine near term and/or during labor has been reported to result in neonatal myasthenia. Infants born to mothers having received the drug have been reported to exhibit symptoms of general hypotonia, weak sucking and grasping reflexes, apnea, cyanotic attacks, and low plasma cholinesterases. Electromyographic studies confirmed the presence of myasthenia. Treatment with neostigmine usually results in rapid clinical response and resolution (Buckley et al, 1968; Blackhall et al, 1969). However, reports of no postpartum problems have occurred at term with births of normal infants (Perry et al, 1975).
    E) PREMATURE LABOR
    1) When given IV to pregnant women near term, anticholinesterase drugs may induce premature labor (Prod Info BLOXIVERZ(TM) intravenous injection, 2015; Prod Info PROSTIGMIN(R) oral tablets, 2008).
    F) ANIMAL STUDIES
    1) NEOSTIGMINE
    a) During animal embryofetal development studies, there were no reports of adverse effects on physical development, behavior, learning ability, or fertility in offspring exposed to neostigmine doses approximately 0.097 times the MRHD from gestation day 6 through lactation day 20 (Prod Info BLOXIVERZ(TM) intravenous injection, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) NEOSTIGMINE
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info BLOXIVERZ(TM) intravenous injection, 2015; Prod Info PROSTIGMIN(R) oral tablets, 2008).
    B) BREAST MILK
    1) GUANIDINE HYDROCHLORIDE
    a) Guanidine is excreted in human breast milk. The manufacturer recommends discontinuation of breastfeeding while the lactating female is receiving therapy with guanidine (Prod Info guanidine HCl oral tablets, 2003).
    2) NEOSTIGMINE
    a) Exercise caution when administering neostigmine to a lactating woman (Prod Info BLOXIVERZ(TM) intravenous injection, 2015).
    3) PYRIDOSTIGMINE
    a) The concentration of pyridostigmine in breast milk was 36% to 113% of maternal plasma, which implied a very low dose to the nursing infant (about 0.1% of the maternal dose) (Hardell et al, 1982).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) NEOSTIGMINE
    a) During animal fertility studies, IV administration of neostigmine showed no adverse effects on fertility in male or female animals at doses up to 8.1 mcg/kg/day (Prod Info BLOXIVERZ(TM) intravenous injection, 2015).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) NEOSTIGMINE: The carcinogenic potential of neostigmine has not been evaluated in long-term animal studies (Prod Info BLOXIVERZ(TM) intravenous injection, 2014).

Genotoxicity

    A) NEOSTIGMINE: There was no evidence of genotoxicity or mutagenicity in the following tests: the in vitro bacterial reverse mutation assay (Ames test), an in vitro Chinese hamster ovary cell chromosomal aberration assay, or an in vivo mouse bone marrow micronucleus assay (Prod Info BLOXIVERZ(TM) intravenous injection, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs; institute continuous pulse oximetry and cardiac monitoring.
    B) Monitor for clinical evidence of weakness, respiratory distress or SLUDGE symptoms, and fasciculations.
    C) Monitor serum electrolytes in patients with vomiting and diarrhea.
    D) Serum concentrations of the antimyasthenics is not generally available or clinically useful in guiding treatment. Cholinesterase testing may be preferable, as the antimyasthenics will depress cholinesterase activity; however, after an acute exposure, measurement of levels are usually only helpful if followed over a period of time. Although cholinesterase levels do not correlate well with toxicity, less than 80% activity is associated with severe symptomatology. Clinical findings are often more helpful in guiding treatment than laboratory evaluation in these patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum concentrations of the antimyasthenics is not generally available or clinically useful in guiding treatment. Cholinesterase testing may be preferable, as the antimyasthenics will depress cholinesterase activity; however, after an acute exposure, measurement of levels are usually only helpful if followed over a period of time. Although cholinesterase levels do not correlate well with toxicity, less than 80% activity is associated with severe symptomatology. Clinical findings are often more helpful in guiding treatment than laboratory evaluation in these patients.
    2) Although cholinesterase levels do not correlate well with clinical toxicity, acute depression of cholinesterase activity by 80% usually correlates with severe toxicity.
    3) It was found that patients who acutely overdosed on pyridostigmine (390 to 900 mg) experienced serum cholinesterase activity depletions of 25 to 79% which correlated with clinical signs (Almog et al, 1991).
    4) Clinical recovery was found to be faster than spontaneous recovery of the enzyme.

Methods

    A) OTHER
    1) Experimental techniques for the measuring of antimyasthenics in blood are not generally available to clinicians.
    2) PYRIDOSTIGMINE - Measurement of serum cholinesterase inhibition was found to be a reliable and sensitive diagnostic tool (Almog et al, 1991).
    a) In unpublished data, that dilution of the blood sample 1:50 with saline followed by incubation at 37 degrees C for 24 hours caused a complete decarbamylation of the enzyme. This was used to determine the baseline value of blood cholinesterase for each patient (Almog et al, 1991).

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) Admit patients with persist symptoms. Admit all patients with severe symptoms (respiratory distress or depression, CNS depression or significant weakness, hemodynamic instability) to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic children or adults with small acute inadvertent ingestions may be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity, or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate ingestions, and those who are symptomatic should be referred in a healthcare facility.

Monitoring

    A) Monitor vital signs; institute continuous pulse oximetry and cardiac monitoring.
    B) Monitor for clinical evidence of weakness, respiratory distress or SLUDGE symptoms, and fasciculations.
    C) Monitor serum electrolytes in patients with vomiting and diarrhea.
    D) Serum concentrations of the antimyasthenics is not generally available or clinically useful in guiding treatment. Cholinesterase testing may be preferable, as the antimyasthenics will depress cholinesterase activity; however, after an acute exposure, measurement of levels are usually only helpful if followed over a period of time. Although cholinesterase levels do not correlate well with toxicity, less than 80% activity is associated with severe symptomatology. Clinical findings are often more helpful in guiding treatment than laboratory evaluation in these patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) 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) MONITORING OF PATIENT
    1) Monitor vital signs; institute continuous pulse oximetry and cardiac monitoring.
    2) Monitor for clinical evidence of weakness, respiratory distress or SLUDGE symptoms, and fasciculations.
    3) Monitor serum electrolytes in patients with vomiting and diarrhea.
    4) Serum concentrations of the antimyasthenics is not generally available or clinically useful in guiding treatment. Cholinesterase testing may be preferable, as the antimyasthenics will depress cholinesterase activity; however, after an acute exposure, measurement of levels are usually only helpful if followed over a period of time. Although cholinesterase levels do not correlate well with toxicity, less than 80% activity is associated with severe symptomatology. Clinical findings are often more helpful in guiding treatment than laboratory evaluation in these patients.
    B) ATROPINE
    1) The antimyasthenics primarily affect nicotinic sites; atropine will not reverse these effects (Grob & Johns, 1958).
    2) If muscarinic signs (bradycardia, increased tracheobronchial secretions, pulmonary edema, hypersalivation, gastrointestinal symptoms) are present, atropine therapy is indicated.
    3) DOSE
    a) Severely poisoned patients may require large doses of atropine to achieve adequate atropinization (ie, drying up the secretions). Early, prompt, and adequate atropinization is of paramount importance.
    b) Inject atropine sulfate intravenously slowly (ADULT: 2 to 5 milligrams; CHILD: 0.05 milligram/kilogram).
    c) Repeat dosage every 10 to 30 minutes or as needed to achieve and maintain full atropinization, as indicated by complete clearing of bronchial and pulmonary rales and a normal pulse.
    d) NOTE: Many parenteral atropine preparations are preserved with benzyl alcohol or chlorobutanol. High-dose atropine therapy may result in benzyl alcohol or chlorobutanol toxicity if these formulations are used.
    1) Preservative-free atropine injection is available.
    C) PRALIDOXIME
    1) EFFICACY
    a) 500 to 2000 milligrams 2-PAM given to normal volunteers who were made weak by an injection of various antimyasthenics led to improvement within 30 seconds which became maximal in 5 to 10 minutes.
    b) After about 20 minutes there was some return of weakness, which again responded to therapy with the oximes (Grob & Johns, 1958).
    c) The doses of oximes required to reverse weakness in myasthenic patients who had also received antimyasthenic drugs in too large a quantity were similar.
    d) In both groups, intravenous administration of 100 to 1000 milligrams 2-PAM or DAM usually produced slight to moderate reversal of plasma and red cell cholinesterase inhibition.
    1) It had no effect on the gastrointestinal symptoms, sweating, salivation, bradycardia, or central nervous symptoms produced by the anticholinesterase compounds (Grob & Johns, 1958).
    e) Intravenous injection of 2000 milligrams 2-PAM or DAM did not result in weakness if the antimyasthenic drugs were not given first in this experiment (Grob & Johns, 1958).
    2) INDICATIONS
    a) Severe antimyasthenic poisoning with nicotinic manifestations (muscle and diaphragmatic weakness, fasciculations, muscle cramps).
    3) DOSE
    a) PRALIDOXIME DOSE
    1) ADULT: A loading dose of 30 mg/kg (maximum: 2 grams) over 30 minutes followed by a maintenance infusion of 8 to 10 mg/kg/hr (up to 650 mg/hr) (Howland, 2011). In vitro studies have recommended a target plasma concentration of close to 17 mcg/mL necessary for pralidoxime to be effective, which is higher than the previously suggested concentration of at least 4 mcg/mL (Howland, 2011; Eddleston et al, 2002). ALTERNATE ADULT: An alternate initial dose for adults is 1 to 2 grams diluted in 100 mL of 0.9% sodium chloride infused over 15 to 30 minutes. Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). In patients with serious cholinergic intoxication, a continuous infusion of 500 mg/hr should be considered. In patients with acute lung injury, a 5% solution may be administered by a slow IV injection over at least 5 minutes (Howland, 2006). Intravenous dosing is preferred; however, intramuscular administration may be considered using a 1-g vial of pralidoxime reconstituted with 3 mL of sterile water for injection or 0.9% sodium chloride for injection, producing a solution containing 300 mg/mL (Howland, 2011). An initial intramuscular pralidoxime dose of 1 gram or up to 2 grams in cases of very severe poisoning has also been recommended (Haddad, 1990; S Sweetman , 2002).
    2) CHILD: A loading dose of 20 to 40 mg/kg (maximum: 2 grams/dose) infused over 30 to 60 minutes in 0.9% sodium chloride (Howland, 2006; Schexnayder et al, 1998). Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). ALTERNATE CHILD: An alternate loading dose of 25 to 50 mg/kg (up to a maximum dose of 2 g), followed via continuous infusion of 10 to 20 mg/kg/hr. In patients with serious cholinergic intoxication, a continuous infusion of 10 to 20 mg/kg/hr up to 500 mg/hr should be considered (Howland, 2006).
    3) Presently, the ideal dose has NOT been established and dosing is likely based on several factors: type of OP agent (ie, diethyl OPs appear to respond more favorably to oximes, while dimethyl OPs seem to respond poorly) which may relate to a variation in the speed of ageing, time since exposure, body load, and pharmacogenetics (Eddleston et al, 2008)
    4) CONTINUOUS INFUSION
    a) A continuous infusion of pralidoxime is generally preferred to intermittent bolus dosing to maintain a target concentration with less variation (Howland, 2011; Eddleston et al, 2008; Roberts & Aaron, 2007; Gallagher et al, 1989; Thompson, 1987). In an open label, randomized study of moderately severe organophosphate poisoned patients treated with high dose continuous infusions required less atropine, were less likely to be intubated and had shorter duration of ventilatory support than patients treated with intermittent bolus doses. HIGH DOSE CONTINUOUS INFUSION: In this study, an initial 2 g bolus (pralidoxime chloride or iodide) was given, followed by 1 g over an hour every hour for 48 hours. Followed by 1 g every 4 hours until the patient could be weaned from mechanical ventilation. The response to therapy was beneficial in patients exposed to either a dimethyl or diethyl organophosphate pesticide (Pawar et al, 2006).
    b) Infusion over a period of several days may be necessary and is generally well tolerated (Namba et al, 1971).
    5) MAXIMUM DOSE
    a) The maximum recommended dose for pralidoxime is 12 grams in 24 hours for adults (S Sweetman , 2002); based on WHO, this dose may be exceeded in severely poisoned adults (Tang et al, 2013).
    6) DURATION OF INTRAVENOUS DOSING
    a) Dosing should be continued for at least 24 hours after cholinergic manifestations have resolved (Howland, 2006). Prolonged administration may be necessary in severe cases, especially in the case of poisoning by lipophilic organophosphates (Wadia & Amin, 1988). Observe patients carefully for recurrent cholinergic manifestations after pralidoxime is discontinued.
    4) ADVERSE EFFECTS
    a) SUMMARY
    1) Minimal toxicity when administered as directed; adverse effects may include: pain at injection site; transient elevations of CPK, SGOT, SGPT; dizziness, blurred vision, diplopia, drowsiness, nausea, tachycardia, hyperventilation, and muscular weakness (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). Rapid injection may produce laryngospasm, muscle rigidity and tachycardia (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    b) MINIMAL TOXICITY
    1) When administered as directed, pralidoxime has minimal toxicity (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). Up to 40.5 grams have been administered over seven days (26 grams in the first 54 hours) without ill effects (Namba et al, 1971).
    2) One child developed delirium, visual hallucinations, tachycardia, mydriasis, and dry mucous membranes (Farrar et al, 1990). The authors were uncertain if these effects were related to 2-PAM or organophosphate poisoning per se.
    c) NEUROMUSCULAR BLOCKADE
    1) High doses have been reported to cause neuromuscular blockade, but this would not be expected to occur with recommended doses (Grob & Johns, 1958a).
    d) VISUAL DISTURBANCES
    1) Oximes have produced visual disturbances (eg, blurred vision, diplopia) (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    2) Transient increases in intraocular pressure may occur (Ballantyne B, 1987).
    e) ASYSTOLE
    1) Pralidoxime administered intravenously at an infusion rate of 2 grams over 10 minutes was associated with asystole in a single reported case, which occurred about 2 minutes after initiation of the infusion (Scott, 1986). A cause and effect relationship was not established.
    f) WEAKNESS
    1) Mild weakness, blurred vision, dizziness, headache, nausea, and tachycardia may occur if the rate of pralidoxime infusion exceeds 500 milligrams/minute (Jager & Stagg, 1958).
    g) ATROPINE SIDE EFFECTS
    1) Concomitant administration of pralidoxime may enhance the side effects of atropine administration (Hiraki et al, 1958). The signs of atropinization may occur earlier than anticipated when the agents are used together (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    h) CARDIOVASCULAR
    1) Transient dose-dependent increases in blood pressure have occurred in adults receiving 15 to 30 milligrams/kilogram of 2-PAM (Calesnick et al, 1967). Increases in systolic and diastolic blood pressure have been observed in healthy volunteers given parenteral doses of pralidoxime (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    2) Electrocardiographic changes and marked hypertension were observed at doses of 45 milligrams/kilogram (Calesnick et al, 1967).
    5) PHARMACOKINETICS
    a) HALF-LIFE: Pralidoxime is relatively short-acting with an estimated half-life of 75 minutes (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). One report found that the effective half-life of pralidoxime chloride was longer in poisoned individuals than in healthy volunteers. This was attributed to a reduced renal blood flow in the poisoned patients (Jovanovic, 1989).
    6) AVAILABLE FORMS
    a) VIALS
    1) Each 20-mL vial contains 1 gram of pralidoxime chloride (Prod Info PROTOPAM(R) Chloride injection, 2010)
    b) SELF-INJECTOR
    1) Each auto-injector contains 600-mg of pralidoxime chloride in 2 mL of a sterile solution containing 20 mg/mL benzyl alcohol, 11.26 mg/mL glycine in water for injection (Prod Info PRALIDOXIME CHLORIDE intramuscular injection, 2003).
    c) CONVERSION FROM AUTOINJECTOR TO IV SOLUTION
    1) In one study, the conversion of intramuscular pralidoxime (from a MARK I Injector) to an IV solution resulted in a stable and sterile solution for up to 28 days. It is suggested that this conversion may be used in a mass casualty situation when additional IV doses of pralidoxime are needed. The following method may be used to transfer the syringe content: (Corvino et al, 2006).
    a) Avoid a shattered glass incident by using a biological safety cabinet.
    b) Double-glove and use a 30 mL empty sterile glass vial.
    c) Sterilize the vial diaphragm with alcohol.
    d) To vent the vial, insert a 1 1/2 inch 21 gauge IV needle bent to 90 degrees.
    e) Obtain the pralidoxime syringe from the kit and place it over the top of the vial diaphragm.
    f) Keep the syringe perpendicular to the vial and grasp the barrel of the syringe and press down firmly until the needle is deployed, and allow the syringe contents to enter into the vial.
    g) Use 5 pralidoxime injectors for one vial, which will be 10 mL in each vial.
    h) A 19 gauge 1.5 inch 5 micro filter needle is used with the 5 or 10 mL syringe to withdraw the pralidoxime solution from the 30 mL vial.
    i) Each vial (10 mL) is used to prepare either 250 mL, 0.9% sodium chloride injection IV bag at 8 mg/mL OR 100 mL, 0.9% sodium chloride injection IV bag to yield a final pralidoxime concentration of 10 mg/mL; 3.33 mL should be added into a 100 mL bag and 6.66 mL should be added into a 250 mL bag.
    d) OTHER SALTS
    1) Pralidoxime mesylate (P2S) in the United Kingdom (UK License holder, Department of Health).
    2) Pralidoxime methisulfate (Contrathion(R)) available in Greece (from IFET), Turkey (from Keymen), Brazil (from Sanofi-Aventis), Italy (from Sanofi-Aventis) and France (from SERB).

Enhanced Elimination

    A) SUMMARY
    1) There are no useful techniques to enhance elimination of antimyasthenic drugs.

Range Of Toxicity

Summary

    A) TOXICITY: Toxic serum or blood concentrations of the antimyasthenics have not been established. Depression of cholinesterase activity to less than 80% of normal is frequently associated with severe symptoms.
    B) THERAPEUTIC DOSES: AMBENONIUM: Adults: 5 to 75 mg orally 3 to 4 times a day; MAX dose: 200 mg/day. EDROPHONIUM: Adults: For diagnostic test for myasthenia gravis: 2 mg IV over 15 to 30 seconds; if no cholinergic symptoms develop in 45 seconds, give additional 8 mg IV at 2 mg/min. GUANIDINE: Initially, 10 to 15 mg/kg/day in 3 or 4 divided doses; may be gradually increased to 35 mg/kg/day. NEOSTIGMINE: Varies by indication: 15 to 375 mg orally daily; titrate to response. Injection: 0.25 to 0.5 mg IM or SubQ with subsequent doses based on response. Reversal of neuromuscular blockade: 0.5 to 2 mg IV slowly (with atropine sulfate); repeat as needed; rarely should total dose exceed 5 mg. PYRIDOSTIGMINE: 180 to 1500 mg/day orally, titrated to response.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) AMBENONIUM
    a) MYASTHENIA GRAVIS TREATMENT: 5 mg to 75 mg orally 3 to 4 times a day; dose above 200 mg/day requires medical supervision (Prod Info MYTELASE(R) oral tablets, 2011).
    2) EDROPHONIUM
    a) MYASTHENIA GRAVIS DIAGNOSIS: 2 mg IV over 15 to 30 seconds; if no reaction in 45 seconds, give additional 8 mg IV. For patients with inaccessible veins, the diagnostic dose is 10 mg IM. The test may be repeated after 30 minutes with 2 mg IM to rule out false-negative reactions (Prod Info ENLON(R) intravenous injection, intramuscular injection, 2009).
    1) An alternative regimen is 1 mg IV as a test dose first to guard against significant adverse reactions followed by a 2 mg/min IV infusion for a total of 10 mg (Rossen et al, 1976).
    b) REVERSAL OF NEUROMUSCULAR BLOCKADE: 10 mg IV over 30 to 45 seconds; may be repeated as needed until a cholinergic response is detected; MAXIMUM DOSE: 40 mg IV (Prod Info ENLON(R) intravenous injection, intramuscular injection, 2009).
    3) GUANIDINE HYDROCHLORIDE
    a) EATON-LAMBERT SYNDROME: Initially, 10 to 15 mg/kg/day in 3 or 4 divided doses; may be gradually increased to 35 mg/kg/day or until development of side effects (Prod Info guanidine HCl oral tablets, 2003).
    4) NEOSTIGMINE
    a) MYASTHENIA GRAVIS TREATMENT: 15 to 375 mg/day orally, titrated to response and interval between doses variable (Prod Info PROSTIGMIN(R) oral tablets, 2008). Alternatively, 0.5 mg IM or subQ (unapproved use by these routes), with subsequent doses based on response (Prod Info neostigmine methylsulfate IV, IM, subcutaneous injection solution, 2009); transfer to oral (neostigmine bromide) as soon as patient tolerates (Prod Info neostigmine methylsulfate injection solution, 2005).
    b) POSTOPERATIVE DISTENTION/URINARY RETENTION PROPHYLAXIS (unapproved use): 0.25 mg SUBQ or IM; may repeat every 4 to 6 hours for 2 to 3 days as needed (Prod Info neostigmine methylsulfate IV, IM, subcutaneous injection solution, 2009).
    c) POSTOPERATIVE DISTENTION/URINARY RETENTION TREATMENT (unapproved use): 0.5 mg SUBQ or IM; after the bladder is emptied, continue injections every 3 hours for at least 5 times (Prod Info neostigmine methylsulfate IV, IM, subcutaneous injection solution, 2009).
    d) REVERSAL OF NEUROMUSCULAR BLOCKADE (for agents with shorter half-life): 0.03 mg/kg IV given over at least 1 minute, and concomitantly or just after an anticholinergic agent (eg, atropine sulfate or glycopyrrolate) up to a MAX total dose of 0.07 mg/kg or 5 mg, whichever is less (Prod Info BLOXIVERZ(TM) intravenous injection, 2013).
    e) REVERSAL OF NEUROMUSCULAR BLOCKADE (for agents with longer half-life): 0.07 mg/kg IV given over at least 1 minute and concomitantly or just after an anticholinergic agent (eg, atropine sulfate or glycopyrrolate) (Prod Info BLOXIVERZ(TM) intravenous injection, 2013)
    5) PYRIDOSTIGMINE
    a) MYASTHENIA GRAVIS TREATMENT: 180 to 1500 mg/day orally, titrated to response and interval between doses variable (Prod Info pyridostigmine bromide oral tablets, 2010; Prod Info MESTINON(R) oral syrup, oral tablets, oral Timespan(R) tablets, 2008).
    b) ORGANOPHOSPHATE POISONING PROPHYLAXIS: 30 mg orally 2 or 3 times a day (Sharabi et al, 1991; Keeler et al, 1991; Dunn & Sidell, 1989).
    1) Pyridostigmine 60 mg orally was safe in nonasthmatic patients and 50 mg was safe in asthmatic patients despite a decrease in FEV1 that was correlated to the degree of cholinesterase inhibition (Ram et al, 1991).
    c) REVERSAL OF NEUROMUSCULAR BLOCKADE: 0.1 to 0.25 mg/kg IV after spontaneous recovery of neuromuscular function has begun (with atropine or glycopyrrolate); additional doses not recommended (Prod Info REGONOL(R) IV injection, 2009).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) AMBENONIUM
    a) Safety and effectiveness have not been established in pediatric patients (Prod Info MYTELASE(R) oral tablets, 2011).
    2) EDROPHONIUM
    a) MYASTHENIA GRAVIS DIAGNOSIS
    1) INFANTS: 0.5 mg IV (Prod Info ENLON(R) intravenous injection, intramuscular injection, 2009).
    2) CHILDREN, WEIGHT 34 KG OR LESS: 1 mg IV; if no response after 45 seconds, titrate up to 5 mg in increments of 1 mg every 30 to 45 seconds. Alternatively, a total of 2 mg IM can be administered (Prod Info ENLON(R) intravenous injection, intramuscular injection, 2009).
    3) CHILDREN, WEIGHT MORE THAN 34 KG: 2 mg IV; if no response after 45 seconds, titrate up to 10 mg in increments of 1 mg every 30 to 45 seconds. Alternatively, a total of 5 mg IM can be administered (Prod Info ENLON(R) intravenous injection, intramuscular injection, 2009).
    3) GUANIDINE HYDROCHLORIDE
    a) Safety and efficacy have not been established in pediatric patients (Prod Info guanidine HCl oral tablets, 2003).
    4) NEOSTIGMINE
    a) MYASTHENIA GRAVIS TREATMENT
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info PROSTIGMIN(R) oral tablets, 2008).
    b) MYASTHENIA GRAVIS DIAGNOSIS
    1) IM: 0.04 mg/kg as a single dose (Saha et al, 2007; Raksadawan et al, 2002).
    c) REVERSAL OF NEUROMUSCULAR BLOCKADE
    1) .
    a) (for agents with shorter half-life): 0.03 mg/kg IV given over at least 1 minute, and concomitantly or just after an anticholinergic agent (eg, atropine sulfate or glycopyrrolate) up to a MAX total dose of 0.07 mg/kg or 5 mg, whichever is less (Prod Info BLOXIVERZ(TM) intravenous injection, 2013).
    b) (for agents with longer half-life): 0.07 mg/kg IV given over at least 1 minute and concomitantly or just after an anticholinergic agent (eg, atropine sulfate or glycopyrrolate) (Prod Info BLOXIVERZ(TM) intravenous injection, 2013)
    5) PYRIDOSTIGMINE BROMIDE
    a) MYASTHENIA GRAVIS TREATMENT
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info pyridostigmine bromide oral tablets, 2010; Prod Info MESTINON(R) oral syrup, oral tablets, oral Timespan(R) tablets, 2008).
    b) REVERSAL OF NEUROMUSCULAR BLOCKADE
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info REGONOL(R) IV injection, 2009).

Minimum Lethal Exposure

    A) ROUTE OF EXPOSURE
    1) INTRAMUSCULAR: Death has been reported following the intramuscular injection of 0.5 mg of neostigmine as a diagnostic test for myasthenia gravis (Merrill, 1948).
    2) INTRAVENOUS: A standard 10 mg dose of edrophonium given intravenously as a test for myasthenia gravis has resulted in cardiac arrest and death (Rossen et al, 1976).

Maximum Tolerated Exposure

    A) CASE REPORT: A 28-year-old man developed muscular paralysis (lasting about 35 minutes) after receiving 5 mg of neostigmine instead of the desired dose of 2.5 mg, used to reverse the neuromuscular blockade at the end of an epigastric hernia repair surgery. Following supportive care, he recovered completely (Sharma, 2008).
    B) Human volunteers receiving 30 mg of pyridostigmine every 8 hours over 3 days did not demonstrate any significant effects on the neuromuscular system (Borland et al, 1985).
    C) Neostigmine taken once as a 45 mg dose, however, led to severe toxicity in a volunteer (Goodman & Bruckner, 1937).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Toxic serum or blood concentrations of the antimyasthenics have not been established. Human volunteers given 0.5 microgram/kilogram intravenously of edrophonium developed a mean plasma concentration of 7.82 nanomoles/milliliter.
    b) In vitro experiments have demonstrated that a concentration of edrophonium in plasma of approximately 1 nanomole/milliliter will decrease cholinesterase activity by 80 percent.
    c) Toxic blood concentrations of the antimyasthenics have not been well established. After acute overdose, measurement of serum and red cell cholinesterase activity may be useful. Depression of cholinesterase activity to less 80 percent of normal is frequently associated with severe symptoms.
    d) PYRIDOSTIGMINE: One study found that patients who acutely overdosed on pyridostigmine (390 to 900 milligrams) experienced serum cholinesterase activity depletions of 25 to 79 percent synonymous with clinical signs. Clinical recovery was found to be faster than spontaneous recovery of the enzyme (Almog et al, 1991).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) NEOSTIGMINE
    1) LD50- (INTRAMUSCULAR)MOUSE:
    a) 0.395 mg/kg (Prod Info, 1989)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 0.54 mg/kg (Prod Info, 1989)
    3) LD50- (INTRAMUSCULAR)RAT:
    a) 0.423 mg/kg (Prod Info, 1989)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) 0.445 mg/kg (Prod Info, 1989)
    B) PYRIDOSTIGMINE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 2.7 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The antimyasthenics are cholinesterase inhibitors which act on CNS, muscarinic, and nicotinic receptors. Because of their enhancement of impulse transmission at neuromuscular junctions, these agents can improve the skeletal muscle weakness seen in myasthenia gravis.
    B) Ambenonium chloride inhibits cholinesterase thereby preventing the inactivation of acetylcholine. It has a longer duration of action in suppressing cholinesterase and possesses all the pharmacologic action of acetylcholine both muscarinic and nicotinic types (Prod Info MYTELASE(R) oral tablets, 2011).
    C) Edrophonium chloride is a short and rapid-acting cholinergic drug that inhibits acetylcholinesterase at cholinergic transmission sites (Prod Info TENSILON(R) intramuscular solution, intravenous solution, 2002).
    D) Guanidine increases the release of acetylcholine following a nerve impulse. In addition, it can slow the rates of depolarization and repolarization of muscle cell membranes (Prod Info guanidine HCl oral tablets, 2003).
    E) Neostigmine bromide is an anticholinesterase agent that competes with acetylcholine (ACh) for binding to acetylcholinesterase at cholinergic transmission sites. It facilitates impulse transmission across neuromuscular junctions thus, improving cholinergic action. It is also exerts direct cholinomimetic effects on skeletal muscle, autonomic ganglion cells and nerve cells of the central nervous system (Prod Info PROSTIGMIN(R) oral tablets, 2006).
    F) Pyridostigmine bromide is an analogue of neostigmine that inhibits acetylcholinesterase. It inhibits the breakdown of acetylcholine by cholinesterase, thus, facilitating free transmission of nerve impulses across the myoneuronal junction (Prod Info pyridostigmine bromide oral tablets, 2010; Prod Info REGONOL(R) IV injection, 2009; Prod Info MESTINON(R) oral syrup, oral tablets, oral Timespan(R) tablets, 2008).

Toxicologic Mechanism

    A) When there is too much inhibition of the enzyme cholinesterase, cholinergic crisis may result. This is the result of an imbalance of neurotransmitters whereby there is an excess of acetylcholine, as the enzyme which metabolizes it is inhibited by these drugs.

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) Overdose of pyridostigmine produced diarrhea, emesis, reddened feces, severe intestinal distress, tremors, and hypersalivation. Death was by intestinal intussusception (Kluwe et al, 1990).

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) DOG
    1) Pyridostigmine doses of 10 to 20 milligrams/kilogram were lethal in some beagles. Doses of 5 milligrams per kilogram produced significant toxicity (Kluwe et al, 1990).

References

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    67) Product Information: BLOXIVERZ(TM) intravenous injection, neostigmine methylsulfate intravenous injection. Eclat Pharmaceuticals (per FDA), Chesterfield, MO, 2013.
    68) Product Information: BLOXIVERZ(TM) intravenous injection, neostigmine methylsulfate intravenous injection. Eclat Pharmaceuticals (per FDA), Chesterfield, MO, 2014.
    69) Product Information: BLOXIVERZ(TM) intravenous injection, neostigmine methylsulfate intravenous injection. Eclat Pharmaceuticals (per FDA), Chesterfield, MO, 2015.
    70) Product Information: ENLON(R) intravenous injection, intramuscular injection, edrophonium chloride intravenous injection, intramuscular injection. Bioniche Pharma USA LLC (per manufacturer), Lake Forest, IL, 2009.
    71) Product Information: Guanidine hydrochloride tablets. Key Pharmaceuticals, Kenilworth, NJ, 2003.
    72) Product Information: MESTINON(R) oral syrup, oral tablets, oral Timespan(R) tablets, pyridostigmine bromide syrup oral syrup, oral tablets, oral Timespan(R) tablets. Valeant Pharmaceuticals North America, Aliso Viejo, CA, 2008.
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    75) Product Information: PROSTIGMIN(R) oral tablets, neostigmine bromide oral tablets. Valeant Pharmaceuticals, Aliso Viejo, CA, 2006.
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