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

07.11.202123.07.2023 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 myasthenia gravis diagnosis. How is edrophonium administered for different purposes.

Содержание

Understanding Edrophonium: A Rapidly Acting Acetylcholinesterase Inhibitor

Edrophonium is a synthetic compound that acts as a reversible acetylcholinesterase inhibitor. Its rapid onset and short duration of action make it unique among drugs in its class. But what exactly does this mean for its use in medicine?

Acetylcholinesterase is an enzyme responsible for breaking down acetylcholine, a crucial neurotransmitter in the nervous system. By inhibiting this enzyme, edrophonium effectively increases the levels of acetylcholine in the neuromuscular junction (NMJ), the site where nerve impulses are transmitted to muscles.

Historical Context and Current Status

Edrophonium has been used in medical practice since the early 1930s. For many years, it was a key diagnostic tool for myasthenia gravis (MG), a neuromuscular disorder characterized by muscle weakness. However, as of 2018, the FDA discontinued edrophonium in the United States. Why was this decision made?

High rate of false-positive results in MG diagnosis
Development of more accurate serological antibody testing for MG
Availability of safer and more effective alternatives for other uses

Despite its discontinuation for MG diagnosis, edrophonium still has some approved uses and potential applications in modern medicine.

Mechanism of Action: How Edrophonium Works in the Body

To understand the effects of edrophonium, we need to delve into its mechanism of action at the molecular level. How does this drug interact with the body’s systems to produce its effects?

Edrophonium functions by forming non-covalent bonds at the serine-103 allosteric site of acetylcholinesterase enzymes. This binding inhibits the enzyme’s ability to break down acetylcholine, leading to increased acetylcholine levels in the NMJ synapses.

Key Characteristics of Edrophonium’s Action

Rapid onset: Effects are observed within 1 minute of administration
Short duration: Action typically lasts about 10 minutes
Competitive inhibition: Edrophonium competes with acetylcholine for binding sites on the enzyme

This rapid and short-lived action profile makes edrophonium unique among acetylcholinesterase inhibitors and influences its potential applications in medicine.

FDA-Approved Uses of Edrophonium

While edrophonium’s use has become more limited in recent years, it still retains FDA approval for specific medical purposes. What are these approved uses?

The primary FDA-approved use for edrophonium is the reversal of non-depolarizing neuromuscular blocking agents (NMBA) after surgical procedures. NMBAs are used during surgery to paralyze muscles, and their effects need to be reversed at the end of the procedure.

Comparison with Alternative Agents

Despite its approval, edrophonium is not the preferred agent for NMBA reversal. Why is this the case?

Neostigmine is often preferred due to its longer duration of action
Neostigmine is 12 to 16 times more potent than edrophonium
Neostigmine is more effective in reversing long-acting non-depolarizing NMBAs

When edrophonium is used for NMBA reversal, it’s typically administered simultaneously with atropine to minimize muscarinic side effects. In some cases, glycopyrronium may be used instead of atropine, but it needs to be administered a few minutes before edrophonium due to its slower onset of action.

Historical Use in Myasthenia Gravis Diagnosis

For many years, edrophonium played a crucial role in the diagnosis of myasthenia gravis. How was it used in this context, and why was it eventually discontinued?

The so-called “Tensilon test” involved administering edrophonium to patients suspected of having MG. In patients with MG, the increased acetylcholine levels resulting from edrophonium administration would briefly overcome the antibody-mediated blockade of nicotinic receptors, leading to a temporary improvement in muscle strength.

The Tensilon Test Procedure

Initial dose of 2 mg edrophonium administered intravenously
Additional 2 mg doses given at 60-second intervals
Observation for improvement in MG symptoms (e.g., ptosis, diplopia)
Total dose typically between 4-6 mg for most patients

Despite its widespread use, the Tensilon test had significant limitations. These included a high rate of false-positive results and the risk of serious side effects. With the development of more accurate serological antibody tests for MG, the use of edrophonium for diagnosis became obsolete.

Potential Novel Applications of Edrophonium

While its use has declined in recent years, researchers continue to explore potential new applications for edrophonium. What are some of these novel uses under investigation?

One area of interest is the potential use of edrophonium in diagnosing blepharospasm, a condition characterized by involuntary eye muscle contractions. How might edrophonium be useful in this context?

Edrophonium challenge test may augment clinical features of blepharospasm
Could potentially aid in differential diagnosis of eye movement disorders
Further research is needed to establish clinical validity and safety

It’s important to note that while this application shows promise, it is still in the research phase and has not been approved for clinical use. More studies are needed to determine the efficacy and safety of edrophonium in this context.

Administration and Dosing of Edrophonium

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

For Neuromuscular Block Reversal

When used to reverse non-depolarizing NMBAs after surgery, edrophonium is typically administered as follows:

Intravenous dose of 0.5 to 1 mg/kg
Often given simultaneously with atropine (7-10 mcg/kg) to counteract muscarinic side effects
Maximum recommended dose is 100 mg

Historical Use in MG Diagnosis (Tensilon Test)

Although no longer used for this purpose, the historical administration method for MG diagnosis was:

Initial 2 mg IV dose
Additional 2 mg doses every 60 seconds
Observation for symptom improvement
Total dose typically 4-6 mg

It’s crucial to note that edrophonium administration should always be performed under close medical supervision due to the risk of serious side effects.

Side Effects and Safety Considerations of Edrophonium

Like all medications, edrophonium can cause side effects. What are the most common and serious adverse effects associated with its use?

Common Side Effects

Nausea and vomiting
Increased salivation
Diarrhea
Abdominal cramps
Muscle fasciculations

Serious Side Effects

While less common, edrophonium can potentially cause more severe adverse effects, including:

Bradycardia (slow heart rate)
Bronchospasm
Hypotension (low blood pressure)
Seizures (in rare cases)

Due to these potential side effects, edrophonium should always be administered in a setting where immediate medical intervention is possible. Atropine (0.4 to 0.6 mg) should be readily available to counteract severe muscarinic side effects if they occur.

Precautions and Contraindications

Are there situations where edrophonium should not be used? Several contraindications and precautions exist:

Known hypersensitivity to edrophonium
Mechanical obstruction of the intestinal or urinary tract
Caution in patients with bradycardia, asthma, or seizure disorders
Careful monitoring required in patients with cardiovascular disease

Healthcare providers must carefully weigh the potential benefits against the risks when considering the use of edrophonium, particularly given the availability of alternative agents for most of its historical uses.

Future Perspectives: The Evolving Role of Edrophonium in Medicine

As medical knowledge and technology advance, the role of drugs like edrophonium continues to evolve. What does the future hold for this compound in medical practice?

While edrophonium’s use has significantly decreased in recent years, particularly with its discontinuation for MG diagnosis, it still retains some relevance in specific clinical scenarios. However, its future in medicine remains uncertain.

Potential Areas of Future Research

Further investigation into its use for diagnosing blepharospasm and other movement disorders
Exploration of potential applications in neurodegenerative disease research
Development of modified versions with improved safety profiles or longer duration of action

As our understanding of cholinergic systems in the body grows, it’s possible that new applications for edrophonium or similar compounds may be discovered. However, any new uses would need to demonstrate clear benefits over existing alternatives and have a favorable risk-benefit profile.

The Impact of New Technologies

Advances in medical technology may also influence the future of edrophonium. For example:

Development of more sensitive and specific diagnostic tests may further reduce the need for pharmacological challenge tests
Advances in neuromuscular monitoring during surgery may change approaches to NMBA reversal
Progress in targeted drug delivery systems could potentially allow for more localized administration, reducing systemic side effects

While the use of edrophonium has declined, its history and mechanism of action continue to inform our understanding of cholinergic systems and drug development. As such, even if its direct clinical use continues to decrease, the knowledge gained from studying edrophonium may contribute to future medical advancements.

In conclusion, while edrophonium’s role in current medical practice is limited, its unique properties and historical significance make it an interesting subject of study. As research continues, we may yet discover new applications or derive new insights from this rapidly acting acetylcholinesterase inhibitor.

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]

Review Questions

Access free multiple choice questions on this topic.
Comment on this article.

References

1.: Pascuzzi RM. The edrophonium test. Semin Neurol. 2003 Mar;23(1):83-8. [PubMed: 12870109]
2.: Gilhus NE. Myasthenia Gravis. N Engl J Med. 2016 Dec 29;375(26):2570-2581. [PubMed: 28029925]
3.: Motomura M, Fukuda T. [Lambert-Eaton myasthenic syndrome]. Brain Nerve. 2011 Jul;63(7):745-54. [PubMed: 21747145]
4.: Pani N, Dongare PA, Mishra RK. Reversal agents in anaesthesia and critical care. Indian J Anaesth. 2015 Oct;59(10):664-9. [PMC free article: PMC4645356] [PubMed: 26644615]
5.: Zafirova Z, Dalton A. Neuromuscular blockers and reversal agents and their impact on anesthesia practice. Best Pract Res Clin Anaesthesiol. 2018 Jun;32(2):203-211. [PubMed: 30322460]
6.: Katz RL. Neuromuscular effects of d-tubocurarine, edrophonium and neostigmine in man. Anesthesiology. 1967 Mar-Apr;28(2):327-36. [PubMed: 6026052]
7.: Matsumoto S, Murakami N, Koizumi H, Takahashi M, Izumi Y, Kaji R. Edrophonium Challenge Test for Blepharospasm. Front Neurosci. 2016;10:226. [PMC free article: PMC4894005] [PubMed: 27375406]
8.: ROBERTS DV. THE ANATOMY AND PHYSIOLOGY OF THE NEUROMUSCULAR JUNCTION. Br J Anaesth. 1963 Sep;35:510-20. [PubMed: 14066100]
9.: Thapa S, Lv M, Xu H. Acetylcholinesterase: A Primary Target for Drugs and Insecticides. Mini Rev Med Chem. 2017;17(17):1665-1676. [PubMed: 28117022]
10.: Ing EB, Ing SY, Ing T, Ramocki JA. The complication rate of edrophonium testing for suspected myasthenia gravis. Can J Ophthalmol. 2000 Apr;35(3):141-4; discussion 145. [PubMed: 10812483]
11.: Engbaek J, Ording H, Ostergaard D, Viby-Mogensen J. Edrophonium and neostigmine for reversal of the neuromuscular blocking effect of vecuronium. Acta Anaesthesiol Scand. 1985 Jul;29(5):544-6. [PubMed: 2863917]
12.: Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Dec 3, 2018. Edrophonium. [PubMed: 29999829]
13.: Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H. Cholinergic Crisis Caused by Cholinesterase Inhibitors: a Retrospective Nationwide Database Study. J Med Toxicol. 2018 Sep;14(3):237-241. [PMC free article: PMC6097965] [PubMed: 29907949]
14.: Burbridge MA, Jaffe RA. Excipients in Anesthesia Medications. Anesth Analg. 2019 May;128(5):891-900. [PubMed: 29505449]
15.: Seybold ME. The office Tensilon test for ocular myasthenia gravis. Arch Neurol. 1986 Aug;43(8):842-3. [PubMed: 3729766]
16.: Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): May 17, 2021. Belladonna. [PubMed: 30000920]
17.: Payedimarri AB, Ratti M, Rescinito R, Vasile A, Seys D, Dumas H, Vanhaecht K, Panella M. Development of a Model Care Pathway for Myasthenia Gravis. Int J Environ Res Public Health. 2021 Nov 04;18(21) [PMC free article: PMC8582978] [PubMed: 34770107]

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