Indications

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).[1] Since the early 1930s, it has been 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, and 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 was classically used for differentiation of cholinergic crisis from the myasthenic crisis.[2] 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 and muscular strength in MG patients. Edrophonium's historical use was in MG patients with ptosis or extraocular muscle weaknesses with immediate improvement upon drug administration. As of 2018, the FDA discontinued edrophonium, which 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 diagnosing MG.[3]

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 to reverse non-depolarizing NMBA.[4] 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.[5][6]

Novel use of edrophonium challenge test for diagnosis of blepharospasm has been suggested. The clinical features of blepharospasm are augmented by edrophonium. However, further research is needed before instituting this test into clinical practice.[7]

Mechanism of Action

Acetylcholine synthesis and storage occur in the presynaptic neurons of the NMJ. Acetylcholine binds to postsynaptic nicotinic acetylcholine receptors upon its release from the presynaptic neurons. In the NMJ, acetylcholine is metabolized by acetylcholinesterases via hydrolysis, 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 a short duration of action lasting 10 minutes.[8][9]

Administration

Diagnosis of Myasthenia Gravis: The edrophonium test for MG diagnosis is 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 most 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.[1][10]

Differential Diagnosis of Myasthenia Gravis vs. Cholinergic Crisis: A tuberculin syringe containing 1 mL (10 mg) of edrophonium is prepared with an intravenous needle of 0.2 mL (2 mg) and is administered intravenously. The needle is left in situ. If there is a cholinergic reaction (skeletal muscle fasciculations and increased muscle weakness)  after administering the edrophonium, the drug is immediately discontinued, and atropine is administered intravenously.

Reversal of Neuromuscular Block: Edrophonium is rarely used to reverse 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.[11]

Use in the Specific Patient Population

Patients with Hepatic Impairment: No information has been provided in the manufacturer's product labeling regarding the use of edrophonium in patients with hepatic impairment.

Patients with Renal Impairment: No information has been provided in the manufacturer's product labeling regarding the use of edrophonium in patients with renal impairment.

Pregnancy Considerations: The safety of edrophonium use during pregnancy has not been established according to the manufacturer's product labeling.

Breastfeeding Considerations: Edrophonium has a short half-life and quaternary ammonium structure; hence it is unlikely to be excreted into breastmilk or orally absorbed by the infant. Administering the edrophonium just after breastfeeding and waiting 2 to 3 hours before breastfeeding should avoid any adverse drug reactions in the infant. There is no information regarding the use of edrophonium during breastfeeding. Therefore, using edrophonium in nursing mothers requires risk-benefit analysis considering possible hazards to mother and child.[12]

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. Clinicians can attenuate most of the adverse effects with the simultaneous administration of atropine, which functions as a muscarinic receptor antagonist to prevent developing these cholinergic adverse effects.[13]

Contraindications

Absolute contraindications to edrophonium include hypersensitivity to edrophonium patients with gastrointestinal and 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.

According to the manufacturer's product labeling information, the excipient contains sodium sulfite, which may cause allergic reactions, including anaphylaxis. The clinical presentation of sulfite allergy includes hives, rhinorrhea, bronchoconstriction, flushing, and cardiovascular collapse. Hence use with extreme caution in patients with sulfite allergy.[14]

Monitoring

Heart, respiratory, and blood pressure require monitoring when administering edrophonium. In using edrophonium for MG diagnosis, a cumulative dose of 10 mg is the recommended maximum to prevent excessive cholinergic muscarinic side effects.[15] According to the manufacturer's labeling, whenever edrophonium is used for testing, a syringe containing 1 mg of atropine sulfate should be immediately available to be given intravenously to counteract severe cholinergic reactions.

Toxicity

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. Hence, clinicians must ensure patent airway and circulation. 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. Atropine can be administered up to 1.2 mg intravenously initially and repeated every 20 minutes until secretions are controlled. If convulsions are present, clinicians should institute appropriate supportive measures. For convulsions, supportive treatment is required.[16]

Enhancing Healthcare Team Outcomes

Neurologists and other healthcare providers historically utilized edrophonium to aid in diagnosing MG. In rare situations, it can be 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, nurses, and pharmacists. Myasthenia gravis (MG) is a chronic medical condition requiring high coordination among professionals and disciplines. The care pathway model has been described. A study examined the comprehensive and multidisciplinary care for diagnosing and treating patients with myasthenia gravis. The study concluded that the interprofessional care pathway model for myasthenia gravis could help achieve better patient outcomes.[17]

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 to using and monitoring edrophonium will ensure appropriate administration, adequate management of adverse effects, and prevention of fatal outcomes. [Level 5]