Edrophonium side effects. Edrophonium: Uses, Mechanism of Action, and Side Effects

08.11.202123.07.2023 by alexxlab

What are the main uses of edrophonium. How does edrophonium work in the body. What are the potential side effects of edrophonium administration. Why is edrophonium no longer available in the United States. How is edrophonium administered for various purposes.

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Understanding Edrophonium: A Powerful Acetylcholinesterase Inhibitor

Edrophonium is a synthetic, short-acting acetylcholinesterase inhibitor that has played a significant role in medical diagnostics and treatment. Its rapid onset and brief duration of action make it unique among similar compounds. By increasing acetylcholine levels in the neuromuscular junction (NMJ), edrophonium has been utilized for various medical purposes, primarily in the diagnosis and management of neuromuscular disorders.

Key Characteristics of Edrophonium

Rapid onset of action (within 1 minute)
Short duration of effect (approximately 10 minutes)
Reversible inhibition of acetylcholinesterase
Increases acetylcholine levels in the NMJ

Historical Uses of Edrophonium in Medical Practice

Since the early 1930s, edrophonium has been an essential tool in the medical field, particularly in the diagnosis and management of neuromuscular disorders. Its primary applications have included:

Diagnosis of Myasthenia Gravis

For many years, edrophonium was the go-to diagnostic tool for myasthenia gravis (MG). The drug was marketed as the Tensilon test and received FDA approval for this purpose. How did the Tensilon test work? When administered to patients with suspected MG, edrophonium would briefly ameliorate symptoms by increasing acetylcholine levels in the NMJ, resulting in temporary improvements in skeletal and muscular strength.

Differentiation of Cholinergic Crisis from Myasthenic Crisis

Edrophonium played a crucial role in distinguishing between cholinergic crisis and myasthenic crisis in patients with MG. This differentiation was vital for determining the appropriate course of treatment in emergency situations.

Reversal of Non-depolarizing Neuromuscular Blocking Agents

While not the preferred option, edrophonium has been FDA-approved for reversing the effects of non-depolarizing neuromuscular blocking agents (NMBAs) after surgical procedures. However, neostigmine is generally favored due to its longer duration of action and higher potency.

Mechanism of Action: How Edrophonium Works in the Body

To understand how edrophonium functions, it’s essential to grasp the basic processes occurring at the neuromuscular junction. How does acetylcholine transmission normally work at the NMJ?

Acetylcholine is synthesized and stored in presynaptic neurons.
Upon release, acetylcholine binds to postsynaptic nicotinic acetylcholine receptors.
Acetylcholinesterase enzymes in the NMJ break down acetylcholine via hydrolysis, terminating its effects.

Edrophonium interferes with this process by inhibiting acetylcholinesterase enzymes. How does it achieve this inhibition? The drug forms non-covalent bonds at the serine-103 allosteric site of acetylcholinesterase enzymes, effectively blocking their action. This inhibition results in increased acetylcholine levels in the NMJ synapses.

In the context of myasthenia gravis, the elevated acetylcholine levels can temporarily overcome the antibodies blocking nicotinic receptors, leading to a brief improvement in muscular strength. This mechanism formed the basis of the Tensilon test for MG diagnosis.

Administration of Edrophonium: Dosage and Protocols

The administration of edrophonium varies depending on its intended use. What are the specific protocols for different applications of edrophonium?

Diagnosis of Myasthenia Gravis (Historical Protocol)

The Tensilon test for MG diagnosis followed an incremental approach:

Initial dose: 2 mg intravenously (IV)
Subsequent doses: 2 mg IV at 60-second intervals
Typical effective dose: 4 to 6 mg for most patients
Maximum dose: Up to 10 mg if needed

This gradual approach helped minimize unnecessary muscarinic side effects. Importantly, 0.4 to 0.6 mg of atropine was kept readily available to counteract potential serious side effects such as bradycardia or bronchospasm.

Differential Diagnosis of Myasthenia Gravis vs. Cholinergic Crisis

For distinguishing between MG and cholinergic crisis, the protocol involved:

Preparation of 1 mL (10 mg) edrophonium in a tuberculin syringe
Initial administration of 0.2 mL (2 mg) IV
Observation for cholinergic reactions (e.g., muscle fasciculations, increased weakness)
Immediate discontinuation and atropine administration if cholinergic reaction occurs

Reversal of Neuromuscular Block

While rarely used for this purpose, when edrophonium is employed to reverse non-depolarizing NMBAs after surgery, it is typically administered simultaneously with atropine to minimize muscarinic side effects. If glycopyrronium is used instead of atropine, it should be given a few minutes before edrophonium due to its slower onset of action.

Side Effects and Precautions Associated with Edrophonium Use

As with any pharmacological agent, edrophonium can cause various side effects. What are the most common adverse reactions associated with edrophonium administration?

Muscarinic Side Effects

Bradycardia
Bronchospasm
Increased salivation
Nausea and vomiting
Diarrhea
Sweating

To mitigate these effects, atropine is often administered alongside edrophonium, particularly when used for diagnostic purposes or reversal of neuromuscular blockade.

Nicotinic Side Effects

Muscle fasciculations
Muscle cramps
Weakness (in cases of overdose)

These effects are particularly important to monitor when using edrophonium to differentiate between myasthenic and cholinergic crises.

Current Status and Limitations of Edrophonium Use

Despite its historical significance, edrophonium has fallen out of favor in modern medical practice, particularly in the United States. Why is edrophonium no longer available in the US?

High rate of false-positive results in MG diagnosis
Development of more accurate serological antibody testing for MG
FDA discontinuation of edrophonium in 2018

The limitations of edrophonium in MG diagnosis include its potential to produce false-positive results and the availability of more reliable diagnostic methods. Serological antibody testing has emerged as the gold standard for diagnosing MG, offering greater accuracy and specificity.

Potential Future Applications and Research Directions

While edrophonium’s use has declined in its traditional applications, researchers continue to explore potential new uses for this compound. What novel applications of edrophonium are being investigated?

Diagnosis of Blepharospasm

Recent studies have suggested a potential role for edrophonium in diagnosing blepharospasm, a condition characterized by involuntary eyelid spasms. How might edrophonium be used in this context? The edrophonium challenge test could potentially augment the clinical features of blepharospasm, aiding in its diagnosis. However, further research is needed to validate this approach and establish its clinical utility.

Other Potential Applications

While not currently in widespread use, researchers continue to investigate other potential applications for edrophonium, including:

Assessment of neuromuscular function in critical care settings
Evaluation of other neuromuscular disorders
Potential therapeutic uses in combination with other agents

These areas of research highlight the ongoing interest in edrophonium’s unique pharmacological properties, despite its declining use in traditional contexts.

Comparison of Edrophonium with Other Acetylcholinesterase Inhibitors

To fully appreciate edrophonium’s place in medical practice, it’s helpful to compare it with other acetylcholinesterase inhibitors. How does edrophonium stack up against similar compounds?

Edrophonium vs. Neostigmine

Neostigmine is often preferred over edrophonium for reversing non-depolarizing NMBAs. Why is this the case?

Longer duration of action (neostigmine)
Higher potency (neostigmine is 12 to 16 times more potent)
More effective in reversing long-acting non-depolarizing NMBAs

Edrophonium vs. Pyridostigmine

Pyridostigmine is commonly used in the long-term management of MG. How does it differ from edrophonium?

Longer duration of action (pyridostigmine)
Oral administration possible (pyridostigmine)
More suitable for ongoing symptom management in MG

These comparisons highlight the unique characteristics of edrophonium, particularly its rapid onset and short duration of action, which made it valuable for diagnostic purposes but less suitable for ongoing treatment.

The Legacy of Edrophonium in Medical History

Although edrophonium is no longer widely used, its impact on medical practice, particularly in the field of neurology, cannot be overstated. How has edrophonium contributed to our understanding of neuromuscular disorders?

Improved diagnosis and management of myasthenia gravis
Enhanced understanding of cholinergic neurotransmission
Contributed to the development of other diagnostic tools and treatments
Played a role in anesthesia reversal techniques

The history of edrophonium serves as a testament to the evolving nature of medical science, where once-indispensable tools may be supplanted by more advanced techniques. Nonetheless, the principles underlying edrophonium’s use continue to inform modern medical practice and research.

As we look to the future, the story of edrophonium reminds us of the importance of continual innovation in medical diagnostics and treatment. While its use may have declined, the knowledge gained from decades of edrophonium research continues to shape our approach to neuromuscular disorders and pharmacological interventions.

Edrophonium – StatPearls – NCBI Bookshelf

Abdullah Naji; Michael L. Owens.

Author Information and Affiliations

Last Update: September 3, 2022.

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]

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References

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: Disclosure: Abdullah Naji declares no relevant financial relationships with ineligible companies.
: Disclosure: Michael Owens declares no relevant financial relationships with ineligible companies.