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

04.11.202123.07.2023 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.

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The History and Applications of Edrophonium

Edrophonium, a reversible acetylcholinesterase inhibitor, has played a significant role in medical diagnostics and treatment since the 1930s. Its rapid onset and short duration of action have made it a valuable tool in various clinical scenarios.

Historical Use in Myasthenia Gravis Diagnosis

For decades, edrophonium was the go-to diagnostic tool for myasthenia gravis (MG), a neuromuscular disorder characterized by muscle weakness. The drug’s ability to temporarily increase acetylcholine levels in the neuromuscular junction (NMJ) provided a quick and noticeable improvement in MG symptoms, particularly in patients with ptosis or extraocular muscle weakness.

Current Status and Discontinued Use

As of 2018, the FDA discontinued edrophonium in the United States. Why was this decision made? The high rate of false-positive results and the development of more accurate serological antibody testing for MG diagnosis led to its discontinuation. This shift in diagnostic approach highlights the evolving nature of medical practices and the importance of embracing more precise diagnostic methods.

Mechanism of Action: How Edrophonium Works

Understanding the mechanism of action of edrophonium is crucial for appreciating its clinical effects and potential applications.

Inhibition of Acetylcholinesterase

Edrophonium functions as a competitive inhibitor of acetylcholinesterase enzymes. How does this inhibition occur? The drug forms non-covalent bonds at the serine-103 allosteric site of acetylcholinesterase enzymes, effectively preventing them from breaking down acetylcholine in the NMJ.

Increased Acetylcholine Levels

By inhibiting acetylcholinesterase, edrophonium leads to an increase in acetylcholine levels in the NMJ synapses. This surge in acetylcholine can temporarily overcome the effects of antibodies on nicotinic receptors in MG patients, resulting in a brief improvement of muscular strength.

Clinical Applications of Edrophonium

While its use has become limited in recent years, edrophonium still has some clinical applications worth noting.

Reversal of Neuromuscular Blocking Agents

Edrophonium is FDA-approved for reversing the effects of non-depolarizing neuromuscular blocking agents (NMBA) 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.

Potential Use in Blepharospasm Diagnosis

Recent research has suggested a novel use for edrophonium in diagnosing blepharospasm, a condition characterized by involuntary eyelid contractions. How does edrophonium affect blepharospasm symptoms? The drug appears to augment the clinical features of blepharospasm, potentially making it a useful diagnostic tool. However, further research is needed before this application can be widely adopted in clinical practice.

Administration and Dosage Guidelines

The administration of edrophonium requires careful consideration and monitoring due to its rapid onset and potential side effects.

Historical Myasthenia Gravis Diagnosis Protocol

When used for MG diagnosis, edrophonium was typically administered in an incremental approach:

Initial dose: 2 mg intravenously (IV)
Subsequent doses: 2 mg IV every 60 seconds until symptom improvement
Total dose: Usually 4 to 6 mg for most patients

This gradual approach helped minimize unnecessary muscarinic side effects.

Neuromuscular Block Reversal

In the rare cases where edrophonium is used to reverse non-depolarizing NMBA:

Typical dose: 0.5 to 1 mg/kg IV
Often administered with atropine (7 to 10 mcg/kg) to counteract muscarinic side effects

Side Effects and Precautions

Like all medications, edrophonium can cause side effects, some of which can be serious.

Common Side Effects

The most frequent side effects of edrophonium administration include:

Nausea and vomiting
Increased salivation
Diarrhea
Abdominal cramps
Muscle fasciculations

Serious Side Effects

More severe reactions that require immediate attention include:

Bradycardia (slow heart rate)
Bronchospasm
Syncope (fainting)
Seizures (in rare cases)

To mitigate these risks, atropine (0.4 to 0.6 mg) should always be readily available when administering edrophonium.

Contraindications and Drug Interactions

Understanding the contraindications and potential drug interactions of edrophonium is crucial for safe administration.

Contraindications

Edrophonium should be avoided in patients with:

Known hypersensitivity to the drug
Mechanical intestinal or urinary obstruction
Peritonitis
Severe bradycardia or heart block

Drug Interactions

Edrophonium may interact with several medications, including:

Other cholinesterase inhibitors (potential additive effects)
Succinylcholine (prolonged neuromuscular blockade)
Beta-blockers (increased risk of bradycardia)
Certain antibiotics (potential neuromuscular blocking effects)

Healthcare providers should carefully review a patient’s medication history before administering edrophonium.

Future Perspectives and Research Directions

While edrophonium’s use has declined in recent years, ongoing research continues to explore its potential applications and alternatives.

Improving Diagnostic Accuracy

The discontinuation of edrophonium for MG diagnosis has sparked research into more accurate and reliable diagnostic methods. How can we improve the diagnosis of neuromuscular disorders? Researchers are focusing on developing more sensitive and specific serological tests and exploring novel imaging techniques to visualize neuromuscular junction dysfunction.

Alternative Acetylcholinesterase Inhibitors

The limitations of edrophonium have led to increased interest in alternative acetylcholinesterase inhibitors. What other drugs are being investigated? Compounds with longer duration of action and fewer side effects are being studied, potentially offering improved options for neuromuscular block reversal and management of conditions like myasthenia gravis.

In conclusion, while edrophonium’s role in clinical practice has diminished, its historical significance and mechanism of action continue to inform our understanding of neuromuscular disorders and pharmacology. As medical science advances, the lessons learned from edrophonium’s use will undoubtedly contribute to the development of more effective and safer diagnostic and therapeutic options for patients with neuromuscular conditions.

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]