- Cardiovascular: Hypotension (1% or greater )
- Gastrointestinal: Nausea (1% or greater ), Vomiting (1% or greater )
- Cardiovascular: Atrioventricular block, Bradyarrhythmia (1% or greater ), Cardiac dysrhythmia
- Neurologic: Loss of consciousness, Seizure
- 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. 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. 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. EPIDEMIOLOGY: Exposures are relatively uncommon. MILD TO MODERATE TOXICITY: Malaise, fatigue, nausea, rhinorrhea, and frequent urination may occur. 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. ADVERSE EFFECTS: 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.
Range of Toxicity:
- 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. 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.
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Symptomatic and supportive care is the mainstay of treatment in patients who present with mild to moderate antimyasthenic toxicity. MANAGEMENT OF SEVERE TOXICITY: 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.
- Decontamination: 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. HOSPITAL: Administer activated charcoal if the patient presents early after large ingestion with appropriate level of consciousness, patent airway, and can drink the charcoal.
- Airway management: 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).
- Antidote: 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-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.
- Monitoring of patient: Monitor vital signs; institute continuous pulse oximetry and cardiac monitoring. Monitor for clinical evidence of weakness, respiratory distress or SLUDGE symptoms, and fasciculations. Monitor serum electrolytes in patients with vomiting and diarrhea. 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.
- Enhanced elimination procedure: There are no useful techniques to enhance elimination of antimyasthenic drugs.
- Patient disposition: HOME CRITERIA: Asymptomatic children or adults with small acute inadvertent ingestions may be monitored at home. OBSERVATION CRITERIA: Patients with deliberate ingestions, and those who are symptomatic should be referred in a healthcare facility. 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. 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.