What drugs should be avoided in myasthenia gravis?
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 category||Specific medications or medication class||Notes|
|Anesthetics||Bupivacaine, cocaine, desflurane, isoflurane, lidocaine, prilocaine, procaine, sevoflurane||Local anesthetics are unlikely to cause or exacerbate MG in small doses|
|Anti-infectives||Aminoglycosides, fluoroquinolones, macrolides, telithromycin||Antiretroviral agents, clindamycin, metronidazole, nitrofurantoin, tetracyclines, and vancomycin are less frequently linked to MG exacerbation|
|Anticonvulsants||Carbamazepine, ethosuximide, gabapentin, phenobarbital, phenytoin|
|Antihypertensives||Beta blockers||Although calcium channel blockers have been associated with MG exacerbations in a few case reports, current literature reviews do not include these agents|
|Antimalarials||Chloroquine, hydroxychloroquine, mefloquine, quinine|
|Antipsychotics||Clozapine, haloperidol, lithium, olanzapine, phenothiazines, quetiapine|
|Contrast agents||Diatrizoate meglumine, iohexol, iothalamate,||Older contrast agents have higher association|
|Glucocorticoids||Dexamethasone, methylprednisolone, prednisone||Also commonly used for MG treatment|
|Immune checkpoint inhibitors||Ipilimumab, nivolumab, pembrolizumab, sintilimab|
|Neuromuscular blockers||Atracurium, cisatracurium, mivacurium, pancuronium, rocuronium, vecuronium||Patients with MG are resistant to depolarizing neuromuscular blockers (ie, succinylcholine) and sensitive to nondepolarizing neuromuscular blockers|
|Ophthalmologic agents||Betaxolol, echothiophate, proparacaine, timolol, tropicamide|
|Medications that lead to respiratory depression must be used cautiously in MG|
|Statins||Atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin||Statins may be used in patients with MG at the lowest possible dose and with careful monitoring|
|Tyrosine kinase inhibitors||Imatinib, lornatinib, nilotinib||A few recent case reports suspect MG association, but an established association is unclear at this time|
|Miscellaneous agents||Adalimumab, botulinum toxin, cisplatin, fludarabine, magnesium, riluzole, glatiramer acetate, interferon alpha|
|aNot an all-inclusive list.
Abbreviation: MG=myasthenia gravis.
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
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.
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, 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
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.
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.
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.
- MG Facts. Myasthenia Gravis Foundation of America. Accessed June 8, 2020. myasthenia.org/What-is-MG/MG-Facts
- Casetta I, Groppo E, De Gennaro R, et al. Myasthenia gravis: a changing pattern of incidence. J Neurol. 2010;257(12):2015‐2019. doi:10.1007/s00415-010-5651-z
- Myasthenia gravis: epidemiology forecast to 2028. P&T Community. November 4, 2019. Accessed June 8, 2020. https://www.ptcommunity.com/wire/myasthenia-gravis-epidemiology-forecast-2028
- Men’s and women’s issues and myasthenia gravis. Conquer MG. February 1, 2018. Accessed June 5, 2020. https://www.myastheniagravis.org/mens-womens-issues-myasthenia-gravis/#:~:text=MG Incidence in Men and,in the 20s and 30s.
- Amato AA. Myasthenia gravis and other diseases of the neuromuscular junction. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th McGraw-Hill; 2018. Accessed June 09, 2020. http://accesspharmacy.mhmedical.com.proxy.cc.uic.edu/content.aspx?bookid=2129§ionid=192533554.
- Barrons RW. Drug-induced neuromuscular blockade and myasthenia gravis. Pharmacotherapy. 1997;17(6):1220-1232.
- Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis.Lancet. 2001;357(9274):2122‐2128. doi:10.1016/S0140-6736(00)05186-2
- Gummi RR, Kukulka NA, Deroche CB, Govindarajan R. Factors associated with acute exacerbations of myasthenia gravis. Muscle Nerve. 2019;60(6):693‐699. doi:10.1002/mus.26689
- Wittbrodt ET. Drugs and myasthenia gravis – An update. Arch Intern Med. 1997;157(4):399-408.
- Azzam R, Shaikh AG, Serra A, Katirji B. Exacerbation of myasthenia gravis with voriconazole.Muscle Nerve. 2013;47(6):928‐930. doi:10.1002/mus.23751
- Bird SJ. Overview of the treatment of myasthenia gravis. In: Goddeau RP, ed. UpToDate. UpToDate; 2020. Accessed June 10, 2020. https://www-uptodate-com.proxy.cc.uic.edu/contents/overview-of-the-treatment-of-myasthenia-gravis?search=myasthenia gravis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
- Cautionary drugs. Myasthenia Gravis Foundation of America. Accessed June 10, 2020. https://myasthenia.org/What-is-MG/MG-Management/Cautionary-Drugs
- Mukharesh L, Kaminski HJ. A neurologist’s perspective on understanding myasthenia gravis: clinical perspectives of etiologic factors, diagnosis, and preoperative treatment. Thorac Surg Clin. 2019;29(2):133‐141. doi:10.1016/j.thorsurg.2018.12.002
- Kopp CR, Jandial A, Mishra K, Sandal R, Malhotra P. Myasthenia gravis unmasked by imatinib. Br J Haematol. 2019;184(3):321. doi:10.1111/bjh.15557
- Desai A, Sriwastava S, Gadgeel SM, Lisak RP. New onset myasthenia gravis in a patient with non small cell lung cancer treated with lorlatinib a novel anti-cancer agent. J Neurol Sci. 2018;392:100‐101. doi:10.1016/j.jns.2018.06.024
- Pelechas E, Memi T, Markatseli TE, Voulgari PV, Drosos AA. Adalimumab-induced myasthenia gravis: case-based review [published online ahead of print, 2020 Apr 22]. Rheumatol Int. 2020;10.1007/s00296-020-04587-4. doi:10.1007/s00296-020-04587-4
- Bonanni L, Dalla Vestra M, Zancanaro A, Presotto F. Myasthenia gravis following low-osmolality iodinated contrast media. Case Rep Radiol. 2014;2014:963461. doi:10.1155/2014/963461
- She S, Yi W, Zhang B, Zheng Y. Worsening of myasthenia gravis after administration of antipsychotics for treatment of schizophrenia: a case report and review of literature. J Clin Psychopharmacol. 2017;37(5):620‐622. doi:10.1097/JCP.0000000000000741
- Van Berkel MA, Twilla JD, England BS. Emergency department management of a myasthenia gravis patient with community-acquired pneumonia: does initial antibiotic choice lead to cure or crisis? J Emerg Med. 2016;50(2):281‐285. doi:10.1016/j.jemermed.2015.04.019
- Karcic AA. Drugs that can worsen myasthenia gravis. Postgrad Med. 2000;108(2):25. doi:10.1080/00325481.2000.11445249
- Jones SC, Sorbello A, Boucher RM. Fluoroquinolone-associated myasthenia gravis exacerbation: evaluation of postmarketing reports from the US FDA adverse event reporting system and a literature review. Drug Saf. 2011;34(10):839‐847. doi:10.2165/11593110-000000000-00000
- Rath J, Mauritz M, Zulehner G, et al. Iodinated contrast agents in patients with myasthenia gravis: a retrospective cohort study. J Neurol. 2017;264(6):1209‐1217. doi:10.1007/s00415-017-8518-8
- Shanahan EM, Smith MD, Ahern MJ. Pulse methylprednisolone therapy for arthritis causing muscle weakness. Ann Rheum Dis. 1999;58(9):521‐522. doi:10.1136/ard.58.9.521
- Komiyama A, Arai H, Kijima M, Hirayama K. Extraocular muscle responses to high dose intravenous methylprednisolone in myasthenia gravis. J Neurol Neurosurg Psychiatry. 2000;68(2):214‐217. doi:10.1136/jnnp.68.2.214
- Bae JS, Go SM, Kim BJ. Clinical predictors of steroid-induced exacerbation in myasthenia gravis. J Clin Neurosci. 2006;13(10):1006‐1010. doi:10.1016/j.jocn.2005.12.041
- Veccia A, Kinspergher S, Grego E, et al. Myositis and myasthenia during nivolumab administration for advanced lung cancer: a case report and review of the literature. Anticancer Drugs. 2020;31(5):540‐544. doi:10.1097/CAD.0000000000000903
- Becquart O, Lacotte J, Malissart P, et al. Myasthenia gravis induced by immune checkpoint inhibitors. J Immunother. 2019;42(8):309‐312. doi:10.1097/CJI.0000000000000278
- Bird SJ. Differential diagnosis of myasthenia gravis. In: Goddeau RP, ed. UpToDate. UpToDate; 2020. Accessed June 10, 2020. https://www-uptodate-com.proxy.cc.uic.edu/contents/differential-diagnosis-of-myasthenia-gravis?search=myasthenia gravis&source=search_result&selectedTitle=5~150&usage_type=default&display_rank=5
- Gale J, Danesh-Meyer HV. Statins can induce myasthenia gravis. J Clin Neurosci. 2014;21(2):195‐197. doi:10.1016/j.jocn.2013.11.009
- Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016;87(4):419‐425. doi:10.1212/WNL.0000000000002790
Courtney Krueger, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
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.