What drugs should be avoided in myasthenia gravis?

Background

Myasthenia gravis is a rare autoimmune disease with a prevalence of approximately 14 to 20 cases per 100,000 people.1-3 Overall, the prevalence of myasthenia gravis is increasing in the United States with an annual growth rate of about 1.07%, partially due to increased occurrence in elderly patients as well as improved diagnostic strategies. Women are often affected at a younger age than men, and overall, they represent about 60% of patients with myasthenia gravis.4

Normally, muscle contraction depends on the binding of acetylcholine released from motor nerve terminals to postsynaptic receptors on the muscle end-plate region.5 Muscle depolarization is terminated by acetylcholinesterase in the postsynaptic muscle membrane, which hydrolyzes the acetylcholine. However, in individuals with myasthenia gravis, acetylcholine receptor (AChR) antibodies bind to the AChR, cause internalization and degradation of AChR, block the binding of acetylcholine to AChR, and ultimately prevent muscles from contracting. Patients with seronegative myasthenia gravis do not have detectable AChR antibodies and may have anti-muscle-specific tyrosine kinase (MuSK) antibodies. Seronegative myasthenia gravis typically presents with more severe disease.

Muscle fatigue and weakness are the key presenting symptoms of myasthenia gravis.5 Ptosis or diplopia due to extraocular muscle weakness are common during initial presentation. Patients may also present with chewing and swallowing problems, while others present with weakness of limbs. The symptoms typically become worse throughout the day. The disease may be limited to the external ocular muscles (a less severe form of the disease) or may be more generalized, involving muscles of the face, oropharyngeal areas, upper torso, and proximal extremities.6,7 Respiratory paralysis can also occur in very severe exacerbations. Although the disease is progressive, patients experience intermittent periods of very active disease and remission. Although the etiology of most exacerbations is unknown, medications, medical procedures, and infections have all been implicated in myasthenia gravis flares.8

Medications associated with myasthenia gravis exacerbation

Many medications are implicated in either inducing or worsening myasthenia gravis or affecting neuromuscular transmission.8 Mechanisms have been described to explain the interaction of these drugs and the disease: (1) neuronal transmission may be inhibited at the presynaptic terminal; (2) lack of acetylcholine release (possibly related to inhibition of calcium influx into the presynaptic terminal); (3) blockade of the postsynaptic AChRs, thereby preventing the binding of acetylcholine to the postsynaptic AChR; and (4) prevention of action potential transmission past the postsynaptic terminal due to changes in postsynaptic ion permeability.6,9 Another proposed mechanism is that the pyrimidine or pyridine moiety of certain drugs, such as voriconazole, interacts with AChR.10

Because evidence of exacerbations or first presentations of myasthenia gravis have mainly been published in case reports, it is difficult to determine a true incidence with each agent. In addition, questionable temporal relationships or other confounding factors sometimes make interpretation of the case reports difficult. Nonetheless, medications that have been implicated in myasthenia gravis are reported in the Table, and these agents should be used cautiously in this population. Additional details on some of these medications are provided under the Table.

Table. Medications that reportedly exacerbate myasthenia gravis.a,5,11-18
Medication categorySpecific medications or medication classNotes
AnestheticsBupivacaine, cocaine, desflurane, isoflurane, lidocaine, prilocaine, procaine, sevofluraneLocal anesthetics are unlikely to cause or exacerbate MG in small doses
Anti-infectivesAminoglycosides, fluoroquinolones, macrolides, telithromycinAntiretroviral agents, clindamycin, metronidazole, nitrofurantoin, tetracyclines, and vancomycin are less frequently linked to MG exacerbation
AntiarrhythmicsProcainamide, quinidine 
AnticonvulsantsCarbamazepine, ethosuximide, gabapentin, phenobarbital, phenytoin 
AntihypertensivesBeta blockersAlthough calcium channel blockers have been associated with MG exacerbations in a few case reports, current literature reviews do not include these agents
AntimalarialsChloroquine, hydroxychloroquine, mefloquine, quinine 
AntipsychoticsClozapine, haloperidol, lithium, olanzapine, phenothiazines, quetiapine 
AntirheumaticPenicillamine 
Contrast agentsDiatrizoate meglumine, iohexol, iothalamate,Older contrast agents have higher association
GlucocorticoidsDexamethasone, methylprednisolone, prednisoneAlso commonly used for MG treatment
Immune checkpoint inhibitorsIpilimumab, nivolumab, pembrolizumab, sintilimab 
Neuromuscular blockersAtracurium, cisatracurium, mivacurium, pancuronium, rocuronium, vecuroniumPatients with MG are resistant to depolarizing neuromuscular blockers (ie, succinylcholine) and sensitive to nondepolarizing neuromuscular blockers
Ophthalmologic agentsBetaxolol, echothiophate, proparacaine, timolol, tropicamide 
Respiratory depressantsBenzodiazepines
Opioids		Medications that lead to respiratory depression must be used cautiously in MG
StatinsAtorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatinStatins may be used in patients with MG at the lowest possible dose and with careful monitoring
Tyrosine kinase inhibitorsImatinib, lornatinib, nilotinibA few recent case reports suspect MG association, but an established association is unclear at this time
Miscellaneous agentsAdalimumab, botulinum toxin, cisplatin, fludarabine, magnesium, riluzole, glatiramer acetate, interferon alpha 
aNot an all-inclusive list.
Abbreviation: MG=myasthenia gravis.

Anti-infectives

Antimicrobial agents may interact with voltage-gated calcium channels presynaptically, with AChR postsynaptically, or a combination of these mechanisms.19 Generally, myasthenia gravis symptoms occur within 1 to 2 days after initiation.

Aminoglycosides are associated with myasthenia gravis in numerous case reports typically involving their concomitant use with neuromuscular blockers.6,9,20 Postoperative respiratory depression was reported in nearly all cases. Limb or facial weakness has also been reported. Aminoglycosides have also exacerbated preexisting myasthenia gravis and have led to worsening symptoms within 1 hour of administration.

Fluoroquinolones have consistently been associated with flares of myasthenia gravis. In 2011 the US Food and Drug Administration Adverse Event Reporting System was queried for reports of myasthenia gravis exacerbations occurring in patients taking fluoroquinolones.21 Out of 27 reports, and an additional 10 reports found in the literature, 2 patients died, and 11 patients required mechanical ventilation. Dyspnea has been reported as the most common myasthenia gravis symptom with fluoroquinolones.19

Macrolides have a possible association with myasthenia gravis that follows a similar timecourse to the fluoroquinolones.19

Antipsychotics

Numerous antipsychotics have been associated with myasthenia gravis exacerbation.18 Literature suggests that patients taking antipsychotics with an anticholinergic effect should be carefully monitored for myasthenia gravis. Delayed myasthenia gravis diagnosis is a known problem among patients with schizophrenia as the symptoms may overlap with other antipsychotic adverse effects. Myasthenia gravis should be suspected when ptosis, dysphagia, or muscle weakness are reported.

Contrast agents

A recent retrospective study evaluated the association of myasthenia gravis with low-osmolality contrast agents.22 Of the 73 patients with confirmed myasthenia gravis who were to undergo computed tomography with low-osmolality iodinated contrast agents, 9 developed delayed worsening of myasthenia gravis symptoms with 6 patients having severe symptoms. The median time to symptoms was 11 days. The authors concluded that other causes of the myasthenia gravis exacerbations were more likely than the contrast agents, but patients with myasthenia gravis receiving contrast should be monitored carefully.

Glucocorticoids

Glucocorticoids, although a mainstay in the management of moderate to severe myasthenia gravis, can also cause muscle weakness.6,7,9,23-25 Patients with myasthenia gravis are generally started on high doses of prednisone (60 to 100 mg/day) until the disease is in remission, then the dose is tapered to the lowest possible daily dose, and eventually switched to an every other day regimen. Approximately 25% to 75% of patients initiated on high-dose prednisone have an exacerbation of their disease in the first days to weeks of therapy, which is then followed by a period of remission. In one study, independent predictors of exacerbation caused by steroids included older age, bulbar symptoms, and severe neurologic presentation, especially in the initial phase of treatment. Proposed mechanisms include release of antibodies from degraded lymphocytes, increased cholinesterase activity in the neuromuscular junction, and increased immune-related reactions.

Immune checkpoint inhibitors

A number of reports are available associating immune checkpoint inhibitors such as avelumab, ipilimumab, pembrolizumab, tremelimumab, nivolumab, sintilimab, and atezolizumab with myasthenia gravis. The pathophysiology remains unknown, but generally signs and symptoms begin within 2 to 6 weeks of treatment with these agents.26 Patients should be screened for autoimmune disorders prior to initiating immune checkpoint inhibitors. In some patients, prior myasthenia has been exacerbated by immune checkpoint inhibitors, and in other patients myasthenia gravis occurs for the first time after initiation of an immune checkpoint inhibitor.27 Generally, therapy should be interrupted for patients who develop neurologic adverse events while receiving immune checkpoint inhibitors. Patients without severe symptoms may have a second trial of medication.26,27

Penicillamine

Approximately 1% of patients treated with penicillamine develop autoimmune myasthenia gravis.28 Penicillamine induces the formation of AChR antibodies in the majority of patients who develop myasthenia gravis while on this agent. While penicillamine is very well-documented to be a cause of myasthenia gravis, there are no reports of exacerbation in a patient already diagnosed with myasthenia gravis.

Statins

Although statins are known to cause myotoxicities, myasthenia gravis exacerbations have not been well-reported in the literature.11,29 In several case reports, patients taking statins developed myasthenia-like symptoms; in many of these cases, AChR antibodies were present. There was variability in the timing of the presentation and resolution of the symptoms relative to statin therapy. Some authors suggest these symptoms could be due to several potential mechanisms, including underlying myasthenia gravis aggravated by the muscle toxicity of statins or antibody-mediated myasthenia gravis induced by statins. Statins can be used in patients with myasthenia gravis with counseling on potential worsening of muscle weakness.

Myasthenia gravis management

It is possible for a number of medications to contribute to myasthenia gravis. When a medication is suspected, it is often withdrawn – at least temporarily.11 In some cases, rechallenge is possible. For most patients with myasthenia gravis, pyridostigmine is part of the initial treatment with corticosteroids or immunosuppression in patients who fail to respond.30 Patients with severe disease may require intravenous immunoglobulin (IVIG) or plasma exchange.

Summary

In summary, many drugs have been implicated as a cause of myasthenia gravis or disease exacerbation. Although the literature is limited, caution and close monitoring when prescribing these agents is recommended, especially during an acute exacerbation.

References

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Prepared by:
Courtney Krueger, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

July 2020

The information presented is current as of June 10, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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