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

05.11.202123.07.2023 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 used for diagnosing myasthenia gravis. How is edrophonium administered for different purposes.

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Understanding Edrophonium: A Rapid-Acting Acetylcholinesterase Inhibitor

Edrophonium is a synthetic, short-acting acetylcholinesterase inhibitor that has played a significant role in neuromuscular medicine. Its rapid onset and brief duration of action make it unique among similar drugs. But what exactly does edrophonium do, and why has its use changed over time?

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

These properties have made edrophonium valuable for specific medical applications, particularly in the diagnosis and management of neuromuscular disorders.

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. How did this diagnostic test work?

The edrophonium test, also known as the Tensilon test, involved administering the drug intravenously and observing for rapid improvement in muscle strength. In patients with MG, the increased acetylcholine levels would temporarily overcome the antibody-mediated blockade of acetylcholine receptors, leading to a brief improvement in symptoms.

Why is edrophonium no longer used for MG diagnosis?

Despite its historical importance, edrophonium is no longer available in the United States for MG diagnosis. Why has this change occurred?

High rate of false-positive results
Development of more accurate serological antibody tests
FDA discontinuation in 2018

The shift away from edrophonium highlights the importance of evolving diagnostic techniques in medicine, prioritizing accuracy and reliability.

Mechanism of Action: How Edrophonium Works in the Body

To understand edrophonium’s effects, it’s crucial to examine its mechanism of action at the molecular level. How does this drug influence neuromuscular transmission?

Edrophonium functions as a competitive inhibitor of acetylcholinesterase, the enzyme responsible for breaking down acetylcholine in the neuromuscular junction. By forming non-covalent bonds at the serine-103 allosteric site of acetylcholinesterase enzymes, edrophonium prevents the hydrolysis of acetylcholine.

The Consequences of Acetylcholinesterase Inhibition

Increased acetylcholine concentration in the synaptic cleft
Enhanced stimulation of postsynaptic nicotinic acetylcholine receptors
Temporary improvement in neuromuscular transmission
Brief enhancement of muscle strength in conditions like myasthenia gravis

This mechanism explains edrophonium’s rapid but short-lived effects, making it useful for diagnostic purposes and specific therapeutic applications.

Current Indications and Uses of Edrophonium

While edrophonium’s role in MG diagnosis has diminished, it retains FDA approval for certain medical applications. What are the current uses of this drug?

The primary FDA-approved indication for edrophonium is the reversal of non-depolarizing neuromuscular blocking agents (NMBAs) after surgical procedures. However, it’s important to note that neostigmine is generally preferred for this purpose due to its longer duration of action and higher potency.

Comparing Edrophonium and Neostigmine for NMBA Reversal

Neostigmine is 12 to 16 times more potent than edrophonium
Neostigmine has a longer duration of action
Neostigmine is more effective for reversing long-acting NMBAs

Despite these limitations, edrophonium may still be used in specific situations where a rapid, short-acting reversal agent is preferred.

Administration Techniques and Dosing Considerations

The administration of edrophonium varies depending on its intended use. How is this drug typically given, and what precautions should be taken?

Reversal of Neuromuscular Blockade

When used to reverse non-depolarizing NMBAs, edrophonium is typically administered intravenously. To minimize muscarinic side effects, it is often given simultaneously with atropine. If glycopyrronium is used instead of atropine, it should be administered a few minutes before edrophonium due to its slower onset of action.

Historical Administration for MG Diagnosis

Although no longer used for this purpose in the United States, the historical edrophonium test for MG diagnosis involved an incremental approach:

Initial dose of 2 mg IV
Additional 2 mg doses at 60-second intervals
Observation for symptom improvement
Total dose typically 4-6 mg for most patients

This careful titration helped minimize unnecessary side effects while still achieving diagnostic utility.

Potential Side Effects and Precautions

Like all medications, edrophonium can cause side effects. What are the most common adverse reactions, and how can they be managed?

The side effects of edrophonium primarily stem from its cholinergic activity and can be categorized into muscarinic and nicotinic effects.

Muscarinic Side Effects

Bradycardia
Bronchospasm
Increased salivation
Nausea and vomiting
Abdominal cramps
Diarrhea

Nicotinic Side Effects

Muscle fasciculations
Muscle weakness (in cases of overdose)

To mitigate these effects, atropine (0.4 to 0.6 mg) should be readily available during edrophonium administration. In cases of severe bradycardia or bronchospasm, prompt administration of atropine can counteract these muscarinic effects.

Emerging Research and Potential Future Applications

While edrophonium’s use has declined in some areas, researchers continue to explore its potential in other fields. What new applications are being investigated?

One intriguing area of research involves the use of edrophonium in the diagnosis of blepharospasm, a condition characterized by involuntary eyelid spasms. Early studies suggest that edrophonium may augment the clinical features of blepharospasm, potentially serving as a diagnostic tool.

Challenges in Developing New Applications

Need for larger, controlled studies
Balancing diagnostic utility with potential side effects
Regulatory considerations given edrophonium’s current status

While promising, further research is necessary before edrophonium can be incorporated into clinical practice for these novel applications.

Edrophonium in the Context of Modern Neuromuscular Medicine

As medical knowledge and diagnostic techniques evolve, how does edrophonium fit into the current landscape of neuromuscular medicine?

The declining use of edrophonium for MG diagnosis reflects a broader trend towards more specific and sensitive diagnostic methods. Serological antibody testing has emerged as the gold standard for MG diagnosis, offering greater accuracy and reliability.

Factors Influencing the Shift Away from Edrophonium

Improved understanding of MG pathophysiology
Development of more specific autoantibody tests
Recognition of limitations in the edrophonium test’s sensitivity and specificity
Concerns about potential adverse reactions during testing

Despite these changes, edrophonium’s unique pharmacological properties ensure it retains a place in specific clinical scenarios, particularly in anesthesiology for NMBA reversal.

Comparing Edrophonium to Other Acetylcholinesterase Inhibitors

How does edrophonium stack up against other drugs in its class? Understanding these comparisons can shed light on its specific niche in medical practice.

Edrophonium belongs to a family of acetylcholinesterase inhibitors that includes neostigmine, pyridostigmine, and physostigmine. Each of these drugs has unique properties that influence their clinical applications.

Key Differences Among Acetylcholinesterase Inhibitors

Onset of action: Edrophonium is the fastest-acting
Duration of effect: Edrophonium has the shortest duration
Potency: Neostigmine is significantly more potent than edrophonium
Route of administration: Varies depending on the specific drug and indication
Selectivity for acetylcholinesterase: Differs among compounds, influencing side effect profiles

These differences explain why certain acetylcholinesterase inhibitors are preferred for specific clinical scenarios. For instance, pyridostigmine is often used for long-term MG management due to its longer duration of action and oral availability.

The Role of Edrophonium in Medical Education and Training

Despite its reduced clinical use, edrophonium continues to play a role in medical education. How does understanding this drug contribute to a broader comprehension of neuromuscular pharmacology?

Edrophonium serves as an excellent example for teaching several key concepts in pharmacology and neurology:

Mechanism of action of acetylcholinesterase inhibitors
Relationship between drug structure and function
Importance of onset and duration of action in clinical applications
Evolution of diagnostic techniques in medicine
Balancing efficacy and side effects in drug development

By studying edrophonium, medical students and residents gain insights into the complexities of neuromuscular junction physiology and the challenges of developing targeted therapies for neurological disorders.

Ethical and Practical Considerations in Edrophonium Use

The changing status of edrophonium raises important ethical and practical questions for healthcare providers. What factors should be considered when deciding whether to use this drug?

Ethical Considerations

Balancing potential benefits against risks of side effects
Ensuring informed consent, particularly for off-label uses
Addressing issues of drug availability and cost
Considering alternatives with potentially better safety profiles

Practical Considerations

Availability of the drug and necessary monitoring equipment
Staff training in proper administration and management of potential side effects
Integration with institutional protocols and guidelines
Documentation and reporting requirements, especially for less common uses

Healthcare providers must carefully weigh these factors when considering the use of edrophonium, ensuring that its application aligns with best practices and ethical standards of care.

Future Directions: The Legacy of Edrophonium in Drug Development

As the clinical use of edrophonium evolves, what lessons can be drawn from its history to inform future drug development efforts?

The story of edrophonium offers valuable insights for researchers and pharmaceutical companies working on new neuromuscular agents:

Importance of specificity in diagnostic tests
Value of rapid onset and short duration in certain clinical scenarios
Need for ongoing evaluation of established drugs as new technologies emerge
Potential for repurposing drugs for novel applications
Importance of understanding both intended and unintended pharmacological effects

These lessons may guide the development of new drugs targeting the neuromuscular junction, potentially leading to more effective and safer treatments for conditions like myasthenia gravis and other neuromuscular disorders.

Potential Areas for Future Research

Development of more selective acetylcholinesterase inhibitors
Exploration of novel diagnostic techniques for neuromuscular disorders
Investigation of edrophonium analogs with improved safety profiles
Further studies on the use of cholinergic agents in movement disorders

By building on the foundation laid by drugs like edrophonium, researchers may unlock new possibilities in neuromuscular medicine, ultimately improving patient care and outcomes.

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.