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

09.11.202124.07.2023 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 used for myasthenia gravis diagnosis. How is edrophonium administered for different purposes.

Содержание

Understanding Edrophonium: A Powerful Acetylcholinesterase Inhibitor

Edrophonium is a synthetic, short-acting acetylcholinesterase inhibitor that has played a significant role in the diagnosis and management of various neuromuscular disorders. Its rapid onset and brief duration of action make it a unique tool in the medical field. However, recent developments have led to changes in its clinical applications.

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 neuromuscular junction

Why is edrophonium’s short duration of action significant? This characteristic allows for quick assessment of its effects while minimizing the risk of prolonged side effects, making it particularly useful in diagnostic settings.

Historical Uses of Edrophonium in Myasthenia Gravis Diagnosis

For decades, edrophonium played a crucial role in the diagnosis of myasthenia gravis (MG), a neuromuscular disorder characterized by muscle weakness and fatigue. The drug was marketed as the Tensilon test and was FDA-approved for MG diagnosis.

The Tensilon Test Procedure

Initial dose: 2 mg intravenously (IV)
Subsequent doses: 2 mg IV every 60 seconds
Typical effective dose: 4-6 mg
Maximum total dose: 10 mg

How did the Tensilon test work? In patients with MG, the increased acetylcholine levels resulting from edrophonium administration would temporarily overcome the antibody-mediated blockade of acetylcholine receptors, leading to a brief improvement in muscle strength.

Why is the Tensilon test no longer used for MG diagnosis? As of 2018, the FDA discontinued edrophonium in the United States due to its high rate of false-positive results and the development of more accurate serological antibody testing methods for diagnosing MG.

Mechanism of Action: How Edrophonium Works in the Body

To understand edrophonium’s effects, it’s essential to grasp its mechanism of action at the neuromuscular junction (NMJ).

The Neuromuscular Junction and Acetylcholine

Acetylcholine is synthesized and stored in presynaptic neurons
Upon release, it binds to postsynaptic nicotinic acetylcholine receptors
Acetylcholinesterase enzymes normally break down acetylcholine, limiting its effects

How does edrophonium interfere with this process? Edrophonium forms non-covalent bonds at the serine-103 allosteric site of acetylcholinesterase enzymes, competitively inhibiting their action. This inhibition results in increased acetylcholine levels in the NMJ synapses.

Current FDA-Approved Uses of Edrophonium

While its role in MG diagnosis has been discontinued, edrophonium retains FDA approval for specific medical applications.

Reversal of Non-depolarizing Neuromuscular Blocking Agents

Edrophonium is approved for use in reversing the effects of non-depolarizing neuromuscular blocking agents (NMBAs) after surgical procedures. However, it’s important to note that neostigmine is generally preferred for this purpose.

Why is neostigmine often chosen over edrophonium for NMBA reversal? Neostigmine has a longer duration of action and is 12 to 16 times more potent than edrophonium, making it more effective in reversing long-acting non-depolarizing NMBAs.

Potential Side Effects and Precautions

While edrophonium can be a valuable tool in certain medical situations, it’s crucial to be aware of its potential side effects and take necessary precautions.

Common Side Effects

Muscarinic effects: bradycardia, bronchospasm, increased salivation
Nicotinic effects: muscle fasciculations, increased muscle weakness

How are these side effects managed? When administering edrophonium, it’s essential to have atropine (0.4 to 0.6 mg) readily available to counteract severe muscarinic side effects such as bradycardia or bronchospasm.

Precautions in Administration

Use an incremental approach when administering edrophonium
Monitor patients closely for signs of cholinergic crisis
Have atropine available for immediate use if needed
Consider alternative agents (e.g., neostigmine) for NMBA reversal when possible

Why is an incremental approach recommended for edrophonium administration? This method helps minimize unnecessary muscarinic side effects by allowing for dose adjustment based on the patient’s response.

Emerging Research and Potential New Applications

While edrophonium’s use has decreased in recent years, researchers continue to explore its potential in other areas of medicine.

Edrophonium Challenge Test for Blepharospasm

Recent studies have suggested a novel use of the edrophonium challenge test for diagnosing blepharospasm, a condition characterized by involuntary eye muscle contractions.

How does edrophonium affect blepharospasm? Interestingly, the clinical features of blepharospasm are augmented by edrophonium administration, potentially providing a diagnostic tool for this condition.

Is this test ready for clinical use? While promising, further research is needed before the edrophonium challenge test for blepharospasm can be incorporated into routine clinical practice.

Comparison with Other Acetylcholinesterase Inhibitors

To fully appreciate edrophonium’s unique properties, it’s helpful to compare it with other acetylcholinesterase inhibitors used in clinical practice.

Edrophonium vs. Neostigmine

Onset of action: Edrophonium (1 minute) vs. Neostigmine (7-11 minutes)
Duration of action: Edrophonium (10 minutes) vs. Neostigmine (1-2 hours)
Potency: Neostigmine is 12-16 times more potent than edrophonium

Why is neostigmine preferred for NMBA reversal despite edrophonium’s faster onset? Neostigmine’s longer duration of action and higher potency make it more suitable for ensuring complete reversal of neuromuscular blockade, especially with long-acting NMBAs.

Edrophonium vs. Pyridostigmine

Administration: Edrophonium (injection) vs. Pyridostigmine (oral or injection)
Duration of action: Edrophonium (10 minutes) vs. Pyridostigmine (3-6 hours)
Primary use: Edrophonium (diagnostic/reversal) vs. Pyridostigmine (MG treatment)

How does the difference in duration affect their clinical applications? Pyridostigmine’s longer duration makes it suitable for ongoing MG symptom management, while edrophonium’s short action is more appropriate for diagnostic tests or rapid reversal of neuromuscular blockade.

Future Perspectives and Ongoing Research

Despite the discontinuation of edrophonium for MG diagnosis, its unique pharmacological properties continue to intrigue researchers and clinicians.

Potential Areas of Future Research

Refinement of edrophonium’s use in blepharospasm diagnosis
Exploration of other neuromuscular disorders where edrophonium might provide diagnostic value
Investigation of edrophonium’s potential in treating organophosphate poisoning
Development of new formulations or delivery methods to optimize edrophonium’s effects

What challenges do researchers face in exploring new applications for edrophonium? The drug’s short duration of action and potential side effects present both opportunities and obstacles in developing new clinical applications.

The Role of Acetylcholinesterase Inhibitors in Neurodegenerative Diseases

While edrophonium itself may not be suitable for long-term treatment, its mechanism of action has inspired research into other acetylcholinesterase inhibitors for conditions such as Alzheimer’s disease and Parkinson’s disease.

How might insights from edrophonium research contribute to the development of new treatments? Understanding the precise mechanisms and effects of short-acting acetylcholinesterase inhibitors like edrophonium could inform the design of more targeted and effective drugs for various neurological conditions.

Practical Considerations for Healthcare Providers

For healthcare providers who may encounter situations where edrophonium use is considered, it’s crucial to understand the practical aspects of its administration and monitoring.

Key Points for Safe Administration

Ensure proper patient selection and screening for contraindications
Use the incremental dosing approach to minimize side effects
Have atropine readily available for emergency use
Closely monitor vital signs and muscle strength during and after administration
Be prepared to manage potential cholinergic crises

What are the signs of a cholinergic crisis that healthcare providers should watch for? Symptoms may include increased muscle weakness, fasciculations, excessive salivation, bradycardia, and respiratory distress.

Alternative Diagnostic Approaches for Myasthenia Gravis

With the discontinuation of the Tensilon test, healthcare providers need to be familiar with current best practices for MG diagnosis.

Serological testing for acetylcholine receptor antibodies
Electromyography (EMG) and nerve conduction studies
Ice pack test for ocular MG
Genetic testing for congenital myasthenic syndromes

How has the shift away from the Tensilon test affected MG diagnosis? While losing a rapid diagnostic tool, the move towards serological and electrophysiological testing has improved diagnostic accuracy and reduced the risks associated with pharmacological challenge tests.

Edrophonium in the Context of Neuromuscular Pharmacology

To fully appreciate edrophonium’s place in medicine, it’s important to consider its role within the broader context of neuromuscular pharmacology.

The Cholinergic System and Drug Targets

Acetylcholine synthesis and release
Nicotinic and muscarinic receptor subtypes
Acetylcholinesterase function and inhibition
Neuromuscular junction physiology

How does understanding the cholinergic system help in developing new therapies? Insights into the complex interplay of cholinergic signaling components can guide the development of more targeted and effective treatments for various neuromuscular and neurological disorders.

Edrophonium’s Unique Properties in Pharmacological Research

Despite its limited current clinical use, edrophonium remains a valuable tool in pharmacological research due to its rapid onset and short duration of action.

Why is edrophonium useful in studying neuromuscular transmission? Its quick effects allow researchers to observe real-time changes in neuromuscular function, providing insights into synaptic physiology and pathology.

Ethical Considerations and Patient Communication

As with any medical intervention, the use of edrophonium raises ethical considerations that healthcare providers must navigate.

Informed Consent and Risk Communication

Clearly explain the purpose and potential risks of edrophonium administration
Discuss alternative diagnostic or treatment options when applicable
Ensure patients understand the temporary nature of edrophonium’s effects
Address concerns about potential side effects and management strategies

How can healthcare providers effectively communicate the risks and benefits of edrophonium use? Using clear, non-technical language and providing written information can help patients make informed decisions about their care.

Balancing Diagnostic Utility and Patient Safety

The shift away from the Tensilon test for MG diagnosis highlights the ongoing challenge of balancing diagnostic utility with patient safety in medical practice.

What lessons can be learned from the evolution of MG diagnostic approaches? This case demonstrates the importance of continually reassessing established practices in light of new evidence and technological advancements to ensure the best patient outcomes.

Conclusion: The Legacy and Future of Edrophonium in Medicine

Edrophonium’s journey from a widely used diagnostic tool to its current limited applications reflects the dynamic nature of medical knowledge and practice. While its role in MG diagnosis has diminished, edrophonium continues to offer valuable insights into neuromuscular physiology and pharmacology.

As research progresses, new applications for edrophonium may emerge, potentially revitalizing its clinical significance. Meanwhile, the principles underlying its mechanism of action continue to inform the development of new treatments for a range of neurological and neuromuscular disorders.

For healthcare providers, understanding edrophonium’s properties, applications, and limitations remains important, both for its current uses and as a foundation for comprehending broader concepts in neuropharmacology. As medicine continues to evolve, the story of edrophonium serves as a reminder of the importance of ongoing research, critical evaluation of established practices, and the pursuit of safer, more effective diagnostic and therapeutic approaches.

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.