Continuing Education Activity
Edrophonium is a medication used in the diagnosis of myasthenia gravis. It is in the acetylcholinesterase class of drugs. This activity reviews the indications, action, contraindications for edrophonium as a valuable agent in the management of myasthenia gravis. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the diagnosis of patients with myasthenia gravis and related conditions.
- Identify the mechanism of action of edrophonium.
- Describe the potential adverse effects of edrophonium.
- Recall, analyze, and select appropriate monitoring and toxicity of edrophonium.
- Discuss interprofessional team strategies for improving care coordination and communication to advance edrophonium and improve outcomes.
Edrophonium is a reversible acetylcholinesterase inhibitor with rapid onset and short duration of action resulting in an increase of acetylcholine in the neuromuscular junction (NMJ). Since the early 1930s, it has served as a diagnostic tool for myasthenia gravis (MG). MG is a neuromuscular disorder characterized by muscular weakness due to antibody production that inhibits or destroys post-synaptic nicotinic acetylcholine receptors in the NMJ. Muscle weakness in MG presents as ptosis, diplopia, dysarthria, dysphagia and can progress to fatal respiratory depression in critically ill patients. For many years, edrophonium, marketed as the Tensilon test, was FDA-approved to be utilized to diagnose MG. Edrophonium briefly ameliorated the symptoms of MG by increasing the amount of acetylcholine in the NMJ synapses. The increased levels of acetylcholine in the NMJ resulted in brief improvements in skeletal muscular strength in MG patients. Edrophonium's historical use was in MG patients with ptosis or extraocular muscle weaknesses with immediate improvement upon the administration of the drug. As of 2018, the FDA discontinued edrophonium, and it is no longer available in the United States due to its high rate of false-positive results and the development of serological antibody testing as the gold standard for the diagnosis of MG.
Edrophonium is FDA-approved for use in the reversal of non-depolarizing neuromuscular blocking agents (NMBA) after a surgical procedure. Nonetheless, neostigmine is preferably utilized instead of edrophonium in the reversal of non-depolarizing NMBA. Neostigmine has a longer duration of action, and it is 12 to 16 times more potent than edrophonium making it more effective in reversing long-acting non-depolarizing NMBA. In rare cases, when using edrophonium as a reversing agent, it is administered simultaneously with atropine to minimize the muscarinic side effects. If administering glycopyrronium with edrophonium, its administration must be a few minutes before edrophonium since it has a slower onset of action.
Mechanism of Action
Acetylcholine synthesis and storage occur in the presynaptic neurons of the NMJ. Upon its release from the presynaptic neurons, acetylcholine binds to postsynaptic nicotinic acetylcholine receptors. In the NMJ, acetylcholine is metabolized by acetylcholinesterases via hydrolysis resulting in attenuating its physiological effects. Edrophonium is a synthetic short-acting acetylcholinesterase competitive inhibitor that functions by forming non-covalent bonds at the serine-103 allosteric site of acetylcholinesterase enzymes. Thus, edrophonium increases the amount of acetylcholine in the NMJ synapses. The higher amounts of acetylcholine in the NMJ synapses overcome the antibodies on the nicotinic receptors in MG, resulting in a brief improvement of muscular strength. Edrophonium has a rapid onset of action occurring within 1 minute of administration, and it has a short duration of action lasting 10 minutes.
The edrophonium test for the diagnosis of MG is preferably performed in an incremental approach. Initially, the patient receives 2 mg intravenously (IV) of edrophonium. After each 60 second interval, the patient will receive another 2 mg IV dose until the symptoms improve. MG symptoms usually improve after 4 to 6 mg for the majority of patients. Therefore, this incremental approach of administering 2 mg doses every 60 seconds prevents unnecessary muscarinic side effects. 0.4 to 0.6 mg of atropine must be readily available when performing the Tensilon test. Atropine is reserved for situations where serious side effects of bradycardia or bronchospasm manifest in patients receiving edrophonium.
Edrophonium is rarely utilized for the reversal of non-depolarizing NMBA after a surgical procedure. Nonetheless, for the rare cases where it is used, an IV dose of 0.5 to 1.0 mg/kg of edrophonium is either simultaneously administered with atropine or a few minutes after glycopyrrolate to prevent bradycardia and other cholinergic adverse effects.
The adverse effects of edrophonium occur due to the increased levels of acetylcholine binding to muscarinic acetylcholine receptors. The more serious adverse effects are cardiac arrhythmias, especially bradycardia, atrioventricular block, and cardiac arrest. The muscarinic cholinergic adverse effects also include bronchoconstriction due to airway smooth muscle contraction secondary to increased stimulation of muscarinic receptors. Other adverse effects include bronchial secretions, diarrhea, salivation, lacrimation, increased urinary frequency and urgency, and miosis. The majority of the adverse effects can be attenuated with the simultaneous administration of atropine, which functions as a muscarinic receptor antagonist to prevent the development of these cholinergic adverse effects.
Absolute contraindications to edrophonium include hypersensitivity to edrophonium, patients with gastrointestinal and/or urinary obstruction. Edrophonium administration requires extreme vigilance and monitoring in patients with cardiac arrhythmias and asthma. Physicians are cautious with the use of edrophonium in asthmatic patients due to possible oxygen desaturation from bronchoconstriction and increased bronchial secretions. In the setting of non-depolarizing NMBA reversal, edrophonium administration is contraindicated and cannot be administered when the peripheral nerve stimulation does not elicit at least one twitch.
Heart rate, respiratory rate, and blood pressure require monitoring when administering edrophonium. In the use of edrophonium for MG diagnosis, a cumulative dose of 10 mg is the recommended maximum to prevent excessive cholinergic muscarinic side effects.
Overdose of edrophonium will result in muscarinic symptoms due to the cholinergic crisis manifested by excessive acetylcholine binding to muscarinic receptors. The cholinergic crisis includes diarrhea, increased urination, miosis, muscle weakness, bronchospasm, bradycardia, emesis, and lacrimation. The more serious outcomes of edrophonium overdose involve respiratory muscle weakness and cardiac arrhythmias that can progress to a fatal outcome. The treatment of an edrophonium overdose is atropine. Atropine is an ideal antidote for edrophonium since it has a similar onset of action as edrophonium. Atropine functions by competitively inhibiting the muscarinic receptors on structures innervated by postganglionic cholinergic nerves and inhibiting muscarinic receptors on smooth muscle.
Enhancing Healthcare Team Outcomes
Neurologists and other healthcare providers historically utilized edrophonium to aid in the diagnosis of MG. In rare situations, it can serve as a reversal agent for non-depolarizing NMBA after a surgical procedure. Edrophonium’s adverse effects manifest due to its cholinergic profile. The adverse effects of edrophonium can progress to fatal outcomes secondary to respiratory muscle weakness or cardiac arrhythmias. Therefore, it is imperative that healthcare workers utilizing edrophonium monitor vital signs closely and have atropine readily available; this requires working as an interprofessional healthcare team that includes clinicians, specialists, mid-level practitioners, nurses, and pharmacists.
The administration of edrophonium and the management of its adverse effects is enhanced when using an interprofessional healthcare team approach. Pharmacists should be consulted for information regarding dosing, drug-drug interactions, and contraindications for patients with extensive comorbidities. Nursing staff must be educated on the adverse effect profile of edrophonium and recognize when the patient is decompensating since, in many situations, they are the sole healthcare worker caring for the patient. Ultimately, an interprofessional approach for the utilization and monitoring of edrophonium will ensure appropriate administration, adequate management of adverse effects, and prevention of fatal outcomes. [Level 5]