Myasthenia Gravis: Induction and Exacerbation Associated with Drugs
Myasthenia Gravis: lnduction and Exacerbation Associated with Drugs
Eric T. Wittbrodt, Pharm.D, Philadelphia College of Pharmacy and Science
Myasthenia gravis, an autoimmune disease in which acetylcholine receptor (AChR) antibodies hinder neuromuscular transmission, may be caused or worsened by some medications1. Four possible mechanisms have been proposed for the pharmacologic alteration of the neuromuscular impulse: presynaptic blockade may occur from local anesthetic agents; presynaptic acetylcholine release may be prevented by cationic drugs such as lithium and magnesium; post-synaptic binding of ACh to its receptor may be competitively prevented by nondepolarizing muscle blocking agents and aminoglycosides; and impulse transmission may be halted at the motor end plate.
A thorough review, of the literature revealed a long history of case reports which described drugrelated induction or worsening of myasthenia gravis. The probability of association of myasthenia gravis with individual agents or classes of agents, described as definite, probable, or possible, was based upon the frequency and quality of published experiences. Quality of reports for disease induction by drugs was based upon the presence of a positive edrophonium test, presence of ACh receptor antibodies, confirmation with electromyelographic tests, requirement for anticholinesterase therapy and recurrence upon rechallenge. These same criteria were used for evaluating the quality of reports of drug-related myasthenia gravis exacerbation, with the addition of whether or not the patients disease returned to baseline status after drug discontinuation.
A drug definitely linked to induction of myasthenia gravis is the antirheumatic agent penicillamine2-26. Penicillamine may be directly antigenic after binding to ACh receptors; anti-receptor antibodies are produced in response to this drug-receptor complex. No published reports have associated penicillamine with clinical worsening of existing myasthenia gravis; the mechanism of injury is believed to arise from immunologic effects rather than events at the neuromuscular synapse.
Corticosteroids, a cornerstone of pharmacologic management of myasthenia gravis, have been associated with clinical worsening of the disease 27-29. This may be due to a drug-induced myopathy superimposed upon chronic muscle weakness. The incidence of such myopathies are related to the dose and duration of corticosteroid therapy. Despite these instances of myasthenia gravis exacerbation and myopathy, corticosteroids remain first-line agents for the control of acute myasthenic flares.
The anticonvulsants phenytoin 30-32 and trimethadione 33,34 have been reported to induce myasthenia gravis. Phenytoin appears to affect ACh receptor responsiveness; there may be an immunologic component to the mechanism of trimethadione-induced disease.
Several anti-infectives, most notably the aminoglycosides, may induce or worsen myasthenia gravis35. The mechanism is unclear, but may involve impairment of ACh binding at the postsynaptic receptor. Ciprofloxacin, a fluoroquinolone anti-infective, has been linked to both worsening and induction of myasthenia gravis36,37.
Beta-adrenergic receptor blocking drugs, particular when used as oral antihypertensives or ocular antiglaucoma agents, have been reported to induce myasthenic symptoms in patients without a history of myasthenia gravis38-42.
Lithium carbonate, an antimanic psychotropic agent, has been reported to produce new onset myasthenic symptoms in 3 patients43-45; the mechanism may be a drug-induced reduction in the number of ACh receptors46.
Procainamide, a Type IA antiarrhythmic agent, may worsen or induce MG in some patients; acute pulmonary failure has resulted from its use in myasthenia gravis47-50. This agent has been shown to inhibit the neuron-to-muscle signaling at the synaptic junction in vitro51.
Drugs less strongly associated with induction or worsening of myasthenia gravis include oral anticholinergic agents52, systemic antibiotics53-57, oral antiarrhythmics58,59, chloroquine60,61, neuromuscular blocking drugs62-65, ocular anesthetics66, dextro-carnitine67,68, interferon-alpha69,70 radiocontrast media71-75, transdermal nicotine76, and levonorgestrel implant77.
Many different classes of drugs have been implicated in the induction or exacerbation of myasthenia gravis. The use of these agents should be approached with caution, especially those which have a definite or probable association with disease worsening. In the setting of an everexpanding pharmacologic armamentarium, it is crucial that the clinician be vigilant for signs of disease deterioration when adding drugs to the regimen of a patient myasthenia gravis. Symptoms of new onset muscle weakness, ptosis, diplopia, or dysphagia should be investigated thoroughly as possible myasthenia gravis. As part of the diagnostic work-up, intense scrutiny of the medication regimen is necessary to rule out drug-related causes.
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Eric T. Wittbrodt, Pharm D. Assistant Professor of Clinical Pharmacy Philadelphia College of Pharmacy and Science 600 S 43rd St Philadelphia , PA 19104 USA