Healthcare Professionals: Research

Medications and Myasthenia Gravis

(A Reference for Health Care Professionals)

Copyright © 2000 by Myasthenia Gravis Foundation of America.  All rights reserved.
Most recent revision August 10, 2004.

Robert M. Pascuzzi, MD
Professor and Vice-Chairman
Department of Neurology
Indiana University School of Medicine
Indianapolis, Indiana 46202 USA

Prepared by the Professional and Public Information Committee

Myasthenia Gravis Foundation of America
October, 2000

Patients with myasthenia gravis (MG) or Lambert-Eaton syndrome (LES) may have worsening of symptoms upon exposure to a variety of medications. The relationship between MG and medication effects is complex. Some medications (such as penicillamine and alpha interferon) appear to cause MG in occasional patients, while other drugs (such as aminoglycoside antibiotics and quinine) may lead to MG symptoms by simply unmasking a pre-existing mild case. In patients with known MG there is a long list of drugs which are reported to be associated with increased weakness. The following summary is intended to provide the health care professional with a concise literature-based review of adverse drug effects in patients with neuromuscular junction disease. The references allow the interested reader to access the original articles for further information. There are several major issues regarding interpretation and use of this information.

1. The majority of the medical literature reporting adverse drug effects is anecdotal, often involving isolated cases of patients experiencing increased weakness in the setting of use of a particular drug. In these cases it is difficult to know with certainty the cause and effect relationship between the drug and increasing MG weakness. For example, an MG patient with pneumonia who receives an antibiotic may become weaker as a result of the antibiotic, or from the effects of the pneumonia, fever, other medication changes. In some patients the pneumonia may have occurred as a result of increasing MG (leading to aspiration), and further weakness may simply be from the patient’s flare-up of myasthenia.
2. There is little in the way of prospective or controlled study of adverse drug effects. For most drugs the actual incidence of adverse effects is unknown. The literature emphasizes those patients who had increased weakness with use of a drug. In general we do not know how may MG patients have used the same drug without side effects.
3. A drug may be hazardous in some but not all MG patients. If the percentage of adversely affected patients is low, and the drug is highly likely to benefit the majority of patients, it would be appropriate to use the drug if clinically indicated.
4. While In-vitro studies and animal studies may suggests an adverse drug effect, the observations may not correlate with clinically significant side effects.

For several decades many lists have been compiled suggesting which drugs should be avoided or used only with caution in MG. The summary of drug effects below is incomplete and new observations regarding drug use in MG become available every year. As new drugs are released, they will be prescribed for patients with MG, and new reports of potential adverse effects will certainly become available. Clearly, it behooves the clinician and patient to be alert to the potential for increasing MG weakness whenever a new medication is started. As the Professional and Public Information Committee of the MGFA remains vigilant in monitoring reports of adverse effects, the information on this web-site will require periodic updating.

Several superb literature reviews of adverse drug effects are available in the medical literature (see references 1-6).

The prototype neuromuscular junction disease is myasthenia gravis. Familiarity with this disorder assists the clinician in recognizing other involving defective neuromuscular transmission. Furthermore, since MG is the most common of the junctional diseases, it represents the most common clinical setting in which use of specific drugs may lead to clinical worsening. Myasthenia gravis is an autoimmune disorder of neuromuscular transmission involving the production of autoantibodies directed against the nicotinic AChR. Receptor antibodies are detectable in the sera of 80-90% of patients with MG. The prevalence of MG is about 1 in 10-20,000. Women are affected about twice as often as men. Symptoms may begin at virtually any age with a peak in women in the second and third decades, while the peak in men occurs in the fifth and sixth decades. Associated autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosis, and pernicious anemia are present in about 5% of patients. Thyroid disease occurs in about 10%, often in association with antithyroid antibodies. About 10-15% of MG patients have thymoma which is usually a benign tumor, and lymphoid hyperplasia with proliferation of germinal centers is present in 50-70% of patients.

There are three iatrogenic causes of autoimmune MG (D-penicillamine, interferon alpha, and bone marrow transplantation).

D-Penicillamine is used to treat Wilson’s disease, rheumatoid arthritis, other chronic autoimmune diseases, and cystinuria. Use of D-penicillamine has been associated with a variety of immune-mediated complications including polymyositis, systemic lupus erythematosis, nephritis due to immune complex deposition, scleroderma, and pemphigus. Since the initial reports of penicillamine-related autoimmune MG by Bucknall et al. and Czlonkowska in 1975 over 100 such cases have been documented in the literature.^7,8 The symptoms in penicillamine-induced MG are usually mild and may be limited to extraocular muscles, including isolated ptosis.⁹ Patients develop AChR antibodies, classic electromyographical abnormalities, and the typical improvement with use of cholinesterase inhibitors. Nerve-muscle preparation studies from intercostal muscle biopsies have shown reduced MEPP amplitude typical for acquired MG. Other than taking penicillamine, the patients are indistinguishable from those with idiopathic autoimmune MG.^10-16 The diagnosis can be easily missed, especially in patients presenting with respiratory failure.¹⁷ Myasthenia is reported to occur in from 1% to 7% of all patients on penicillamine.^18,19 One group found MG in 5 out of 71 consecutive patients with penicillamine-treated rheumatoid arthritis within a two year period.¹⁹ The frequency of MG from penicillamine therapy may be less for patients with Wilson’s disease than those receiving the drug for treatment of rheumatoid arthritis, suggesting an underlying susceptibility to an immune-mediated process. Onset of MG symptoms typically occurs from two to twelve months following the initiation of penicillamine.²⁰ In general MG is less severe than idiopathic MG although some patients require mechanical ventilation. Discontinuation of penicillamine leads to complete resolution of MG symptoms in 2-6 months in the majority of patients. By one year MG symptoms have completely resolved in about 70% of patients, the titer of AChR antibodies improves, and the electrophysiological abnormalities improve or resolve.^20,21 The fact that some patients remain symptomatic long after stopping penicillamine suggests that in some cases, especially those with rheumatoid arthritis or other underlying autoimmune disease, MG may have been present subclinically prior to treatment with penicillamine and simply exacerbated by exposure to the drug. The management of MG involves discontinuation of penicillamine, and the use of conventional treatments available for the treatment of autoimmune MG.

The mechanism for penicillamine induced MG is unclear.²² Studies of penicillamine reaction with purified AChR from Torpedo California show covalent attachment to two receptor subunits, alpha and gamma, presumed to result from reduction and formation of mixed disulfides.¹² Penicillamine modifies the equilibrium of ACh binding properties of both purified receptor and receptor rich membrane fragments.¹² Penicillamine given to normal rats in doses equivalent to human therapy results in no acute neuromuscular abnormalities.²³ Prolonged administration to guinea pigs in high doses results in a mild degree of neuromuscular block.²⁴ Therefore, there is little evidence to suggest that the drug has a direct effect on neuromuscular transmission. The latency to onset of symptoms and the presence of AChR antibodies indicate that the drug induces the autoimmune attack. Reduced sulphoxidation capacity observed in 8 of 9 patients with penicillamine-induced MG suggests that poor sulphoxidation may predispose the patient to developing MG.²⁵ Other drugs with similarities to penicillamine also used in the treatment of rheumatoid arthritis include tiopronin and pyrithioxin. An occasional association with MG has been reported with both drugs.^26,27

Patients treated with interferon alpha develop a variety of autoantibodies and autoimmune diseases. The initial reports of interferon induced MG occurred in 1995 when a 66 year old man was reported having developed sero-positive generalized MG about 6 months after starting interferon alpha therapy for leukemia.²⁸ Subsequently, MG has developed in other patients during interferon alpha-2b treatment for malignancy.^29,30 Patients treated for chronic active hepatitis C with interferon alpha have also developed autoimmune MG with onset from 6-9 months after starting treatment. In one case MG symptoms persisted for at least 7 months after stopping the drug.^31,32 Fulminant myasthenic crisis may occur after interferon alpha therapy.³³

Regarding the mechanism of interferon-induced MG; the expression of interferon gamma at motor endplates of transgenic mice results in generalized weakness, abnormal NMJ function, and improvement with cholinesterase inhibitors. Immunoprecipitation analysis indicates that a previously unidentified 87-kD target antigen is recognized by sera from those transgenic mice and also from human MG patients. Such studies suggest that the expression of interferon gamma at motor endplates in these transgenic mice provokes an autoimmune humoral response, similar to that which occurs in human MG.³⁴ While the number of anecdotal case reports has increased to suggest a cause and effect relationship between interferon alpha and MG,^34a,34b,34c recent reports have also suggested that MG may occur independently in association with hepatitis C.^34d,34e

The third iatrogenic cause for autoimmune MG is bone marrow transplantation (BMT), first reported in 1983 in association with thymoma and antiskeletal muscle antibodies.^35,36 Myasthenia occurs as one manifestation of the graft versus host disease (GVHD).^37,38 Acute GVHD immediately after BMT is generally not associated with neurological manifestations. In contrast, chronic GVHD is associated with several neurologic problems including polymyositis and MG.³⁹ Some patients develop both of these neuromuscular disorders rendering the diagnosis difficult. MG seems more likely to occur in patients treated with BMT for aplastic anemia, some of whom have shown AChR antibodies prior to transplantation. In BMT-associated MG the clinical features are classic for autoimmune MG; AChR antibodies are present, symptoms respond to CEI, and improve with immunosuppressive therapy.^40,41 The onset of MG tends to be delayed from several months to as long as 10 years after BMT.^42,43,39 Myasthenia is a relatively uncommon neurological complication of BMT. In one series of 6 children having neuromuscular complications of allogenic BMT only one had MG while four had myositis, and one had chronic inflammatory demyelinating polyneuropathy.⁴⁴ Patients respond to CEI and immunosuppressive therapy typical for autoimmune MG.

Hypermagnesemia is an uncommon clinical situation associated with the use of magnesium-containing drugs.⁴⁵ Magnesium (Mg++)is contained in some antacids and laxatives. Magnesium sulfate (MgSO4) is used in the treatment of preeclampsia/eclampsia, for hemodynamic control during anesthesia and the early postoperative period⁴⁶, and in patients depleted of Mg++ (such as chronic alcoholism). Normal serum magnesium runs 1.5 to 2.5 mEq/l (2 to 3 mg/dl) which is stabilized through exchange with tissue stores in bone, liver, muscle, and brain; also, serum Mg++ concentration is maintained via renal excretion. Patients having renal failure are predisposed to developing hypermagnesemia, and should avoid magnesium-containing antacids and laxatives for this reason.^47,48 Elevated serum magnesium levels due to oral use of magnesium-containing compounds is very uncommon, so long as the patient has normal renal function.^49,50 Hypermagnesemia is occasionally seen with use of enemas, but usually in patients with an underlying GI tract disorder.^49,51 In the treatment of preeclampsia hypermagnesemia occurs commonly due to administration of high doses of parenteral MgSO4, at times resulting in serious side effects in the mother or the newborn.^52-54 The clinical features of hypermagnesemia correlate fairly well with the serum magnesium levels.^49,55,56 In treating preeclampsia, the neuromuscular transmission effects are monitored and used as a limiting factor in dosage. With serum levels above 5 mEq/l, the muscle stretch reflexes become reduced, while levels of 9 to 10 mEq/l are associated with absent reflexes and clinically significant weakness. In treating preeclampsia, muscle stretch reflexes are tested serially, and magnesium administration is stopped if the reflexes disappear.⁵³ Serum levels between 3.5 and 7 mEq/l are usually associated with no significant adverse effects in preeclamptic women, but clinical weakness is common with levels greater than 10 mEq/l and death from respiratory failure can occur.^52,53 Serum levels above 14 mEq/l can induce acute cardiac arrhythmia including heart block and arrest. Additional symptoms from autonomic nervous system involvement include dry mouth, dilated pupils, urinary retention, hypotension, and flushing skin thought to be from presynaptic blockade at autonomic ganglia.⁵⁷ Although patients can develop severe weakness, mental status is usually not directly affected.⁵⁶ Extraocular muscles tend to be spared. Reduced level of consciousness may occur indirectly as a result of hypoxia, hypercarbia or hypotension.

Magnesium interferes with neuromuscular transmission by inhibiting release of ACh.⁵⁸ Magnesium competitively blocks calcium entry at the motor nerve terminal. There may also be a more mild postsynaptic affect. Clinically, hypermagnesemia resembles Lambert-Eaton syndrome more so than autoimmune MG.⁵⁹ In addition, magnesium can potentiate the action of neuromuscular blocking agents, which has been emphasized in women who had cesarean section after treatment with Mg++ for preeclampsia.^60,61 Patients with underlying junctional disorders are more sensitive to Mg++-induced weakness. Patients with MG^62,-64 and Lambert-Eaton syndrome^65,66 have been reported to exacerbate in the setting of Mg++ use in spite of normal or only mildly elevated serum levels. Typically, increased MG symptoms occur with parenteral magnesium administration, but on occasion is seen with oral use.⁶⁶ Therefore, parenteral Mg++ administration should be avoided and oral Mg++ preparations used with caution in patients with known junctional disease (myasthenia gravis, Lambert Eaton syndrome, botulism, etc.).

The effect of standard parenteral doses of MgS04 on neuromuscular transmission of preeclampsia or preterm labor patients are significant, though largely subclinical. Train-of-four (TOF) recordings obtained from the thenar muscles before and 30 minutes after MgSO4 infusion shows an increase in tension of the contractile response in the control or baseline recordings, but the post infusion TOF shows no increase, but rather "fade’ of the response.⁶⁷ These data suggest that in this patient population clinically relevant infusions of MgSO4 produced significant changes in neuromuscular transmission as manifested by loss of the treppe phenomenon and diminished TOF response.⁶⁷

MgSO4 60mg/kg effects on residual neuromuscular block after administration of vecuronium is also significant.⁴⁶ Patients given Mg++ immediately upon recovery from vecuronium block or one hour later demonstrate rapid and profound recurarization as measured by electromyography and TOF studies.

Treatment of the hypermagnesemic patient depends on the severity of clinical symptoms. Discontinuation of magnesium is the first step; if the patient is significantly weak, administration of intravenous calcium gluconate 1 gram over three minutes can produce rapid, although temporary improvement (so long as the patient has normal renal function typical for a patient being treated for preeclampsia). If hypermagnesemia is more severe or if there are life threatening side effects such as cardiac arrhythmia or renal failure, hemodialysis is indicated.⁶⁸ If patients have MG or Lambert Eaton syndrome, they will respond poorly to calcium. Such patients may respond better to CEI.⁶³

Weakness from hypokalemia is believed to result from decreased excitability of muscle cell membranes.⁶⁹ Hypokalemia is implicated as a potential factor in worsening MG symptoms, especially in the setting of corticosteroid therapy, but the relationship has received only limited study.⁷⁰ Diuretics may aggravate MG weakness, possibly by depleting potassium.⁷¹ In spite of the crucial role of intracellular calcium concentration in ACh release little data exist on the effects of hypocalcemia on neuromuscular transmission. While hypocalcemia is well known to result in peripheral nerve hyperexcitability, tetany and convulsive seizures, there is no clear establishment of a clinically significant effect on neuromuscular transmission.⁴⁵ Clinical decompensation of MG patients during plasma exchange, ostensibly from citrate used in the intravenous replacement fluids, is suggested to be mediated by citrate induced hypocalcemia.⁷²

As botulinum toxin A has become increasingly utilized to treat focal dystonia and spasticity, it has become apparent that there is potential for symptomatic complications from excess toxin. Botulinum toxin blocks ACh release at the presynaptic motor nerve terminal (and causes dysautonomia by blocking muscarinic autonomic cholinergic function as well). The intracellular target of botulinum toxin appears to be a protein of the ACh vesicle membrane. The toxin is a zinc-dependent protease which cleaves protein components of the neuroexocytosis apparatus.^73-75 Not only is its’ effect local at the site of injection into muscle, but there is some degree of distant effect as well.⁷⁶ Dysphagia is a frequent side effect of botulinum injection for spasmodic dysphonia, typically lasting for about two weeks.⁷⁷ On occasion the dysphagia is severe, especially when patients report some degree of pretreatment dysphagia.⁷⁷ Prospective study of complications of botulinum toxin injections for cervical dystonia showed that prior to treatment 11% of patients had symptoms of dysphagia while 22% had radiologic evidence for abnormal peristalsis.⁷⁸ After injections of botulinum toxin new symptoms of dysphagia developed in an additional 33% of patients (those with pretreatment dysphagia were unchanged) and 50% developed new peristaltic abnormalities by radiographic study.⁷⁸ Single fiber EMG of the forearm muscle following treatment of cervical dystonia and hemifacial spasm show abnormal increase in mean jitter (suggesting impaired neuromuscular transmission) and six weeks after treatment there is increased fiber density indicating reinnervation.⁷⁹ In addition, mils abnormalities of cardiovascular reflexes suggest distant effects on autonomic function.⁷⁹ Previously undetected Lambert-Eaton syndrome has been unmasked in a patient following local botulinum toxin injection.⁸⁰ Myasthenic crisis has been reported following injections of botulism toxin.^80a Clearly, botulinum toxin is relatively contraindicated in patients with a known defect of neuromuscular transmission. In addition, the clinician should be alert to the development of excessive weakness in the region of local injection, or even remote sites, particularly with higher doses of botulinum toxin. Several excellent recent reviews of botulism are included in the reference list.^{80b, 80c}

Patients with underlying junctional disease such as MG are well known for the propensity towards prolonged weakness following anesthesia for surgical procedures. The cause for such potential difficulty is likely to be multifactorial. General anesthetics may potentiate neuromuscular blocking drugs in myasthenic patients. In addition, the inhalation anesthetics may have a direct effect on neuromuscular transmission. The routine administration of the inhalant anesthetic methoxyflurane is reported to unmask mild MG.⁸² With repeated exposure the patient developed fatigue, weakness and ptosis for several hours, which improved after CEI. In experimental studies some inhalation anesthetics appear to alter post-junctional sensitivity to ACh, affect ionic conductance, and induce shortening of ACh-activated channel open time.⁸³

In a normal person local anesthetic use is unlikely to cause significant neuromuscular weakness. Intravenous lidocaine, procaine, and other local anesthetic agents can potentiate the effect of neuromuscular blocking drugs. There appear to be both presynaptic and postsynaptic effects. Interference with propagation of the nerve action potential at the nerve terminal and reduced ACh release may account for the presynaptic effects. ⁸⁴ Local anesthetics also lead to reduced sensitivity of the postjunctional membrane to acetylcholine.⁸⁵ Harvey observed procaine to induce acute myasthenic crisis in 1939, but subsequent studies provide evidence to the contrary.^86,87

Depolarizing and nondepolarizing neuromuscular blockers affect the muscle membrane potential. Neuromuscular blocking drugs may be modified by the degree of neuromuscular block, the associated disease state, acid base status of the patient, and associated electrolyte imbalance. In patients with MG and Lambert Eaton syndrome relatively small amounts of nondepolarizing agents can produce profound and prolonged NMJ blockade. Prolonged paralysis from neuromuscular blockers may occur on occasion in patients without NMJ disease. Factors which may influence the duration of neuromuscular blockade include dosage and duration of therapy, concurrent drug use (including muscle relaxants, magnesium, and cimetidine), severity of underlying disease, electrolyte abnormalities, and renal insufficiency (which may lead to high drug concentrations).⁸⁸ Use of muscle relaxants for one week in a child resulted in a six week course of recovery.⁸⁹ Similarly, long-term weakness from vecuronium use is reported to occur in adults.^90,91 Paralysis lasted eight weeks after use of the neuromuscular blocker atracurium besilate.⁹² Patients with metabolic acidosis, high serum magnesium levels, renal failure, and high blood levels of 3-desacetyl-vecuronium appear more likely to experience prolonged paralysis.⁹³ Prolonged neuromuscular blockade can be severe enough to produce neurogenic muscle atrophy.⁹⁴ Corticosteroids may even potentiate the effects of muscle relaxants.⁹⁵ Prolonged weakness in intensive care patients can result from a multitude of causes, some leading to peripheral neuropathy and myopathy as well as junctional disturbance as above. In many patients there are multiple concomitant factors leading to the paralytic picture.^96,97

Depolarizing agents, including succinylcholine, should be used with caution in patients with known NMJ disease. The inhibition of hydrolysis by cholinesterase inhibitors will result in prolonged duration of action. Patients with MG are less sensitive to this drug than the nondepolarizing agents. Occasionally, patients with MG have their disease unmasked by the use of these drugs. Pharmacological effects of neuromuscular blockers are influenced by antibiotics, general anesthetics, local anesthetics, and antiarrhythmics which may complicate clinical weakness. Newer neuromuscular blocking agents having shorter duration of action may still aggravate MG and Lambert-Eaton syndrome weakness. Occasional reports of reduced plasma cholinesterase levels by plasma exchange or by genetic abnormalities have been associated with reports of prolonged apnea and muscle weakness in patients receiving depolarizing neuromuscular blocking drugs.

In 1941 Robinson and Molitor showed that tyrothricin (gramicidin) could produce respiratory failure in animals.⁹⁸ In 1956 Pridgen reported respiratory arrest as a result of intraperitoneal neomycin in humans.⁹⁹ He noted four patients without prior neuromuscular symptoms who developed apnea from intraperitoneal neomycin sulfate, two of whom died. Subsequently, numerous case reports of neuromuscular weakness from antibiotic administration thought to be a result of impaired neuromuscular transmission have been reported in normal patients, those concurrently receiving neuromuscular blocking drugs, those with MG, those with other disorders that might alter pharmacokinetics, and patients with exposure to other drugs having an adverse effect on neuromuscular transmission.^100-105

The aminoglycoside antibiotics are well established to impair neuromuscular transmission and produce clinically significant weakness, regardless of the method of administration.¹⁰³ Weakness appears to be dose-dependent and reflected by serum levels. Cholinesterase inhibitors, infusion of calcium, and aminopyridines can partially reverse the weakness produced by aminoglycosides.^106-108 Microelectrode studies on nerve muscle preparations suggest that the effect is presynaptic, postsynaptic or both, and may depend on the specific aminoglycoside. Tobramycin appears to have predominantly presynaptic effects similar to hypermagnesemia with impairment of ACh release.^109-111 In contrast, netilmicin acts postsynaptically by blocking the binding of ACh to receptors, as is caused by curare.^109-111 Of the studies of amikacin,¹¹² gentamicin,¹¹³ kanamycin,¹¹⁴ neomycin,¹¹⁵ netilmicin, streptomycin¹¹⁶ and tobramycin,¹¹⁷ neomycin appears to be the most potent in interfering with neuromuscular transmission, while tobramycin would appear to be the least toxic in this regard.¹⁰⁹

Gentamicin, neomycin, streptomycin, tobramycin and kanamycin have been reported to produce clinically significant muscle weakness on occasion in non-MG patients.⁴ Patients with infantile botulism and MG can also have increased weakness upon exposure to these antibiotics.^118-120

Other antibiotics including tetracyclines, sulfonamides, penicillins, amino acid antibiotics, and fluoroquinolones have either been associated with anecdotal reports of increased weakness in myasthenic patients or implicated from in vitro studies to adversely affect neuromuscular transmission. Acute worsening of MG has been reported following administration of ciprofloxacin, a fluroroquinolone.^121,121a Exacerbation of MG has been reported with use of perfloxacin and also norfloxacin.^122,123

Clindamycin and lincomycin are monobasic amino acid antibiotics which differ from aminoglycosides.^124,125 The neuromuscular blockade produced by these drugs is not readily reversed with CEI. These drugs have pre- and postsynaptic affects by microelectrode studies with reduced MEPP frequency, reduced evoked transmitter release, and reduced sensitivity of the postjunctional AChR.^126,127 Junctional effects of lincomycin can be reversed with increased calcium concentration or with use of aminopyridines.¹²⁸ However, CEI may aggravate the effect. Clindamycin may also directly block muscle contractility.¹²⁷ Vancomycin may potentiate the neuromuscular blockade of succinylcholine.¹²⁹

Colistin, colistinmethate, and polymyxin B are reported to produce weakness, especially in patients with renal insufficiency and when used in combination with other neuromuscular blocking drugs or antibiotics.^130-135 Their mechanism of action includes reduced ACh release and, to some degree, postsynaptic blockade of the receptor.^136-138 Acute respiratory failure in MG may occur following a single intramuscular injection of colistimethate.¹³⁹ Colistin has been reported to cause acute weakness in patients with underlying MG.¹⁴⁰

While tetracycline has not been associated with weakness or abnormal in vitro abnormalities, several analogs of tetracycline, including rolitetracycline and oxytetracycline, are reported to exacerbate MG weakness. The mechanism for this effect is not known. Some studies show no deleterious effect of tetracycline.^141,109

Ampicillin is rarely reported to increase weakness of MG patients and increase the percent of decremental response on repetitive stimulation in rabbits with experimental MG.¹⁴² Ampicillin also can lead to single fiber EMG abnormalities.¹⁴³ In vitro studies on nerve-muscle preparations have not shown clear cut abnormalities to indicate if the effect is presynaptic or postsynaptic.¹⁴²

Myasthenic patients occasionally report increased weakness with erythromycin and physiological studies in normal humans suggest it has a presynaptic effect.^3,144 Severe exacerbation of MG has been reported beginning one hour after taking 500mg azithromycin (Zithromax), an azalid-antibiotic of the macrolid group. The patient required mechanical ventilation for six days. The same patient had previously had a similar exacerbation after taking another macrolid, erythromycin. Similar reports of acute myasthenic exacerbation have been reported with telitromycin, a new antibiotic of the ketolide class (Howard, JF, personal communication). Therefore, these antibiotics should also be used with caution in patients with MG.¹⁴⁵

Clearly the issue of antibiotic effects on neuromuscular transmission is complex and poses a vexing dilemma for the clinician. Nearly every antibiotic ever studied has demonstrated some deleterious effect or has been the subject of a clinical report suggesting exacerbation of MG. If a patient requires antibiotic treatment for an infection then the appropriate drugs should be utilized. When managing patients with junctional disease it simply behooves the clinician to remain alert to the potential for clinically significant adverse effects, especially if the patient becomes weaker in the setting of antibiotic use.

Quinidine and Quinine

Quinidine and its stereoisomer quinine can aggravate weakness in MG.¹⁴⁶ A number of reports suggest that the quinidine can unmask previously undiagnosed or asymptomatic MG.^147-149 The drug acts presynaptically to impair the formation or release of ACh. In large doses it may also have a postsynaptic effect with a curare-like action. A number of references in the literature suggest that quinine can also aggravate myasthenic weakness. Quinidine has been observed to potentiate weakness induced by nondepolarizing and depolarizing neuromuscular blocking drugs.^150,151 Quinine has been used as a diagnostic test for MG in the past. Harvey and Whitehill in 1937 reported the differential affects of quinine and prostigmine in the diagnostic evaluation of MG.¹⁵² Similarly, Eaton in 1943 pointed out the diagnostic usefulness of trials of prostigmine and alternatively, quinine.¹⁵³

Sieb et al. studied the effects of quinolone derivatives quinine, quinidine, and chloroquine on neuromuscular transmission using conventional microelectrode and patch-clamp techniques.¹⁵⁴ All three derivatives reduce quantal content of the endplate potential by 37-45% , and decrease the amplitude and decay time constant of the MEPP and miniature end-plate current. At progressively larger concentrations the MEPP becomes undetectable. The effect on MEPP is not reversed by neostigmine. Single-channel patch-clamp analysis of quinine effects reveal a long-lived open-channel and a closed-channel block of AChR. Tests for competitive inhibition or desensitization of the AChR by quinine in these concentrations are negative. Quinolone drugs adversely affect both presynaptic and postsynaptic aspects of neuromuscular transmission at concentrations close to those employed in clinical practice. Therefore they should not be used, or used only with extreme caution, in disorders having a reduced safety margin of neuromuscular transmission.¹⁵⁴ I have cared for patients whose MG decompensated in the setting of quinine 325mg qhs for treatment of leg cramps. In both cases the patients developed markedly increased weakness within hours to days of starting the medication. Anecdotal reports suggest that consumption of tonic water containing small amounts of quinine can result in exacerbation of myasthenic symptoms.

Beta adrenergic blocking drugs have been observed on occasion to be associated with increasing weakness in MG patients including propranolol, oxprenolol, timolol, and practolol.^155-159 While beta blockers are unlikely to produce frank muscle weakness in normal patients, they are notorious for inducing subjective fatigue. Furthermore, occasional patients describe transient diplopia in the setting of beta blocker usage to raise the question of a NMJ mechanism in such patients.¹⁶⁰ In vitro microelectrode studies of nerve-muscle preparations reveal that atenolol, labetelol, metoprolol, nadolol , propranolol, and timolol all produced dose-dependent reduction in neuromuscular transmission in rat skeletal muscle.^161,162 Both presynaptic and postsynaptic affects have been observed. Reduced MEPP amplitude can be caused by any of the beta blockers, suggesting a postsynaptic site of action. Presynaptic abnormalities include reduced MEPP frequency, and with metoprolol and propranolol there is reduced quantal content. Propranolol seems to have the most marked effect impairing neuromuscular transmission with atenolol having the least.^161,162 The specific mechanism for the beta blocker junctional effect is unclear.

In 10 patients with mild to moderate MG who received intravenous propranolol 0.1 mg/kg at 1 mg/minute there was no detectable effect on the decrement to repetitive nerve stimulation or on "clinical tests", leading the investigators to conclude "there is no rapid deterioration of neuromuscular transmission in patients with moderately severe MG after injections with therapeutic doses of propranolol....".¹⁶³ Such findings are consistent with my own observations in practice - the use of beta blockers in MG patients is unlikely to cause significant worsening of their symptoms.

A variety of observations indicate that calcium channel blockers may adversely affect neuromuscular transmission.^171a Presynaptic reduction in ACh release and also postsynaptic curare-like effects have been observed in experimental settings.^164-166 Calcium channel blockers can potentiate the effect of neuromuscular blocking drugs.^167,168 Verapamil has been associated with increased weakness and respiratory failure with intravenous use in a patient with Duchenne dystrophy.¹⁶⁹ A patient with Lambert-Eaton syndrome exacerbated after receiving verapamil.¹⁷⁰ Verapamil is implicated as the cause for respiratory failure in a patient with MG.³ Jonker’s group prospectively studied the effects of intravenous administration of verapamil on decrement to repetitive nerve stimulation and clinical function in 10 patients with mild to moderate myasthenia gravis. Verapamil doses of 0.1 mg/kg given at a rate of at 1 mg/minute showed no adverse effects on neuromuscular transmission.¹⁶³

Protti et al. studied the effect of calcium channel blockers on transmitter release at normal human neuromuscular junction, observing that P-type calcium channel blockers blocked nerve evoked muscle action potentials and inhibited evoked synaptic transmission.¹⁷¹ But transmitter release was not affected either by nitrendipine, an L-type channel blocker, or omega-Conotoxin-GVIA, an N-type channel blocker. Those observations suggest that P-type channels mediate transmitter release at the motor nerve terminals.

Procainamide can lead to acute worsening of MG. Although the drug can induce autoimmune phenomena, the immediate onset of weakness and neuromuscular blockade would suggest a direct effect on neuromuscular transmission, as opposed to an indirect autoimmune process.^172,173 Procainamide appears to act presynaptically in reducing formation of ACh or inhibiting its release, and there is some evidence to implicate postsynaptic factors as well. Bretylium may induce muscle weakness as well as potentiate the effect of neuromuscular blockers.¹⁷⁴ Trimethaphan is a ganglionic blocking agent used occasionally for treating extreme hypertensive emergency and other acute vascular emergencies. It has been associated with acute neuromuscular weakness, including respiratory failure, and there is speculation that it has a curare-like action at the neuromuscular junction. In addition, the drug can potentiate neuromuscular blockade in patients receiving nondepolarizing and depolarizing neuromuscular blocking drugs.^175-178

Phenytoin has demonstrated presynaptic and postsynaptic affects on neuromuscular transmission invitro.^179,180 Occasional patients with MG have presented following treatment with phenytoin,^180,181 mephenytoin , and trimethadione.^182,183 In some of these cases the weakness has resolved following discontinuation of the anticonvulsant. In vitro studies of nerve-muscle preparations have shown that phenytoin reduces quantal release of acetylcholine from the motor nerve terminal; also, it produces a simultaneous increase in spontaneous release of neurotransmitter (and therefore increases the MEPP frequency). One explanation for this effect is a reduction in the size of the nerve action potential at the motor nerve terminal, or perhaps a reduction in calcium influx into the motor nerve terminal. Postsynaptic effects have also been observed with phenytoin including reduction in the MEPP amplitude (thought to be related to desensitization of the endplate).¹⁸⁴ Osserman and Genkins observed that barbiturates can aggravate MG weakness.¹⁸⁵ In vitro studies suggest that barbiturates and ethosuxamide produce postsynaptic neuromuscular blockade, while carbamazepine has an effect on presynaptic junctional function.^186,187 Trimethadione can induce a variety of autoimmune complications including systemic lupus and nephrotic syndrome.¹⁸⁸ Weakness in the setting of trimethadione has been associated with autoantibodies against skeletal muscle, nuclear antigens and thymus, and has gradually resolved following removal of the drug.^182,183

Recent reports have included the observation of seropositive myasthenia gravis occurring after three months of gabapentin therapy for painful neuropathy.^188a Following withdrawal of the drug, the patient became asymptomatic, although serologic studies remained abnormal. The same authors followed up their clinical experience with an evaluation of gabapentin in rats with experimental autoimmune myasthenia gravis, noting an abnormal decremental response to 3 Hz repetitive stimulation, transiently, following the exposure to gabapentin, while no decrement was observed in normal rats. The authors rightfully conclude that the drug should be used with some caution in myasthenia gravis. The point is of particular importance in myasthenics who have muscle cramps. Such patients should avoid quinine, and it has been a common practice to prescribe gabapentin for control of muscle cramps.

Another recent report emphasized the presence of a defect of neuromuscular transmission as demonstrated by a decremental response at high frequency repetitive stimulation in children who had received an overdose of carbamezapine.^188b

Further study of antiepileptic drugs is needed before sweeping guidelines can be made regarding their use in patients with junctional disease. In my judgment the overall risk of using anticonvulsants in MG patients is small.

Narcotic analgesics do not directly interfere with neuromuscular transmission in myasthenia.^189,190 There may be an indirect effect on the myasthenic patient, however. Slaughter in 1950 demonstrated that cholinesterase inhibitors (neostigmine) may potentiate the effects of morphine, codeine, hydromorphone, and opium alkaloids.¹⁹¹ Grob reported sudden death abruptly after administration of morphine sulfate.¹⁹² Due to the tendency of narcotic analgesics to produce respiratory depression, they should be used with caution in patients who have respiratory insufficiency from myasthenia gravis or other neuromuscular diseases.

About 50% of patients with MG receiving treatment with high-dose corticosteroids have an early exacerbation; in about 10% this exacerbation is severe, requiring mechanical ventilation or a feeding tube.¹⁹³ The mechanism for this exacerbation is unclear. Using a lower starting dose of corticosteroids, with a gradual increase over time, may reduce the risk of early exacerbation.¹⁹⁴ In experimental neuromuscular preparations there appears to be some direct affect on neuromuscular transmission including depolarization of nerve terminals, reduced ACh release, altered MEPPs, alteration of choline transport, and intracellular potassium depletion - some of which may be clinically significant mechanisms of action.^195-198

Alternatively, the effect may be immune-mediated. Abramsky et al. found increased lymphocyte transformation in vitro in patients with prednisone-induced aggravation of weakness.¹⁹⁹ Nonreactive lymphocytes may be destroyed by corticosteroids, leading to enhanced proliferation of sensitized lymphocytes.^199-201

Although poorly understood, it is commonly believed among neuromuscular clinicians that MG may fluctuate with the menstrual cycle and pregnancy, suggesting an influence of estrogen or progesterone on neuromuscular transmission, the immune system or some other aspect of MG. On occasion estrogen therapy has been associated with increasing weakness in MG, including parenteral use after 3 to 5 days.^202-203 An isolated case occurred in a woman taking birth control pills.²⁰⁴ Another patient experienced the onset of MG about four months following implant of levonorgestrel (Norplant).²⁰⁵ Symptoms progressed over the next nine months, and AChR antibodies were present. Within one week of removal of the implant her symptoms markedly improved.²⁰⁵

Hyperthyroidism and hypothyroidism can be associated with increasing myasthenic weakness.^206,207 The mechanism is unclear. Any patient with underlying MG who develops progressive weakness should be screened for abnormal thyroid function unless there is an obvious alternative explanation.

Timolol, the beta adrenergic blocking eye drop, has been reported to be associated with increased myasthenic weakness.^157,159 Similar observations have been made with betaxolol hydrochloride.²⁰⁸ Echothiophate is a long-acting cholinesterase inhibitor used in the treatment of open angle glaucoma, and has been reported to be associated with muscle weakness and fatigue; temporally related to the use of the medication, resolving when the medication is stopped.²⁰⁹ The mechanism of weakness is not clear but might relate to long-acting cholinesterase inhibitor-induced cholinergic weakness.

Chlorpromazine was reported to produce increased muscle weakness in a schizophrenic patient with MG by McQuillen in 1963.²¹⁰ In vitro studies have demonstrated a postsynaptic effect with reduced MEPP and EPP amplitudes without change in quantal content or MEPP frequency.²¹¹ Still other studies have implicated a presynaptic site. Chlorpromazine and promazine can antagonize applied ACh, and may prolong effects of succinylcholine. Occasional reports note that in patients receiving chlorpromazine or phenelzine, subsequent administration of depolarizing neuromuscular blocking drugs results in prolonged neuromuscular blockade.

Subjective weakness is a common side effect of lithium carbonate. Exacerbation or unmasking of MG is reported.²¹² Lithium can prolong the effect of neuromuscular blockers.^213-214 The mechanism for the lithium-induced junctional effect may result from its accumulation inside the presynaptic motor nerve terminal and becoming a competitive cation for calcium; thus, reducing ACh synthesis and voltage-gated quantal release of ACh.²¹⁵ Other studies suggest that there is a reduced number of ACh receptors in denervated muscle preparations, raising the question that lithium may selectively increase the rate of breakdown of receptors without changing the rate of synthesis. The onset of weakness in a patient with MG can occur within days of starting lithium.

Amitriptyline, amphetamines, droperidol, haloperidol, imipramine, paraldehyde, and trichloroethanol have been found to impair neuromuscular transmission in experimental settings.^2,3

Chloroquine is widely used for treatment of malaria, but on occasion is used in the treatment of autoimmune connective tissue disorders including rheumatoid arthritis, discoid lupus, and even porphyria cutanea tarda. It has a variety of potential neurologic complications, including peripheral neuropathy and myopathy, as well as an effect on neuromuscular transmission. The mechanism of the chloroquine effect on neuromuscular transmission is controversial and may be multifactorial. Chloroquine appears to have a direct effect at the presynaptic level with reduced MEPP amplitude as well as having a postsynaptic effect with competitive postjunctional blockade.¹⁵⁴ Clinical support for the direct effect stems from observation of weakness developing within the first week after beginning chloroquine therapy, with absent AChR antibodies, and rapidly resolving symptoms upon drug withdrawal.²¹⁶ Chloroquine has been reported to directly reduce muscle membrane excitability. In addition, there is some belief that the drug may induce an autoimmune disorder similar to that triggered by D-penicillamine.^217,218 Several patients with autoimmune diseases (rheumatoid arthritis and SLE) developed clinical, physiologic, and pharmacological evidence for MG after prolonged use of chloroquine. These patients had AChR antibodies which eventually disappeared, as did the other abnormalities following discontinuation of the drug. In a review of twelve patients in which chloroquine exacerbated or unmasked MG about half were associated with long-term high-dose therapy while the remainder occurred in the setting of brief low-dose treatment for prevention of malaria.²¹⁹

Several studies have suggested that intravenous iodinated contrast can trigger or precipitate acute myasthenic worsening.^220-223 The initial reports of three patients in 1985 noted myasthenic crisis after administration of intravenous iodinated contrast.^{220, 221} These patients had abrupt apnea and several days of severe myasthenic weakness. The occurrence is controversial, and not uniformly observed.²²⁴ Frank reported a similar patient but found the overall risk of a severe reaction in MG patients to be only about 2 to 3% of all MG iodinated contrast exposures. One patient with Lambert Eaton syndrome developed acute transient respiratory insufficiency following intravenous contrast infusion, speculated to be on the basis of acute hypocalcemia from calcium binding of the contrast agent, and resulting presynaptic blockade with reduced ACh release.²²² While iodinated contrast may have a direct effect on neuromuscular transmission, an indirect mechanism is also possible, as part of a more nonspecific allergic-type contrast reaction. On the other hand, since patients with an acute intravenous contrast reaction typically receive medications such as diphenhydramine, which have significant anticholinergic side effects, perhaps some of the increased weakness could result from drugs used to treat the acute contrast reaction.²²⁵ In my own experience acute myasthenic deterioration has occurred in several patients receiving iodinated contrast during CT scanning of the chest (looking for thymoma). For that reason we routinely perform noncontrasted chest CT scan (or MR scan) when screening MG patients for thymoma.

D-L-carnitine (but not L-carnitine) has been to be associated with increased weakness in MG patients undergoing dialysis.²²⁶ The mechanism is not known but may relate to the affect caused by hemicholinium or a post-synaptic block by the accumulation of acylcarnitine esters.²²⁷ Emetine, used as an amoebocide and also the active ingredient of ipecac, has been observed to produce acute neuromuscular weakness as a side effect.^228,229

The following medications have also been the subject of reports suggesting a potential for aggravating MG weakness: intravenous sodium lactate,⁵ tetanus antitoxin,²³⁰and trihexyphenydyl (Artane).²³¹ Cocaine use may cause acute exacerbation of MG.²³²

Laboratory studies of the following drugs have demonstrated an abnormal effect on neuromuscular transmission. Amantadine reduces post-junctional sensitivity to ACh by interacting with the AChR ion channel of the AChR.²³³ Diphenhydramine can potentiate the neuromuscular block of barbiturates and neuromuscular blocking agents, and reduce the amount of neurotransmitter released from the motor nerve terminal.²²⁵ The H2 receptor blocker roxatidine impairs neuromuscular transmission in rat sciatic nerve-gastrocnemius muscle preparation.²³⁴

A patient with ALS treated with riluzole for three months developed new ptosis and diplopia.²³⁵ The patient had physiological and serological findings pointing to autoimmune myasthenia gravis. Riluzole was stopped and the patient’s clinical status improved, as well as improvement in the titer of AChR antibodies. While the patient may have had a coincidental chance association of ALS and autoimmune myasthenia gravis, the report is notable for several reasons. It is a perfect example of 50 years of literature which provides an anecdotal report observing an association between myasthenia gravis, worsening of symptoms, and a drug.

As with most of the literature on adverse drug effects in myasthenia gravis, the individual case reports and anecdotal observations must be considered in a thoughtful manner. One cannot be overly dogmatic about assuming that a reported association in an occasional patient is anything more than a chance coincidence. It would be inappropriate to ban the use of all drugs ever reported to be associated with a flare-up of myasthenia in such patients, as there would be very few drugs left that myasthenics could take. In addition, many of the conditions such as ALS that might be treated with quinine or gabapentin would be expected to have weakness and fatigue related to their primary disease (ALS) or a secondary effect of the disease such as hypoventilation, nutritional issues or the medications themselves. To detect drug-induced or drug-related myasthenia gravis in such patients can be very challenging. The best recommendation is to be alert to those drugs which have been reported in the literature to be associated with a development of or worsening of myasthenia gravis, and to be cautious in using such drugs in known myasthenics. One can safely say that many drugs can have an effect on neuromuscular transmission and, in occasional patients, appear to adversely effect their clinical status – particularly if they have a known underlying defect of neuromuscular transmission. It behooves the neurologist to consider the potential for increasing weakness in any patient receiving a new medication, even if it is not on a list of drugs reported to aggravate myasthenia gravis.

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Table 1. Drugs that impair neuromuscular transmission and may increase weakness in patients with underlying neuromuscular junction disorders

Antibiotics
Aminoglycosides
tobramycin
gentamicin
netilmicin
neomycin
streptomycin
kanamycin
fluoroquinolones
ciprofloxacin
norfloxacin
ofloxacin

Other antibiotics
tetracyclines
sulfonamides
penicillins
amino acid antibiotics
macrolides
azithromycin
clarithromycin
ritonavir

Other Quinolones
quinidine
quinine
chloroquine
fluoquinolone antibiotics
magnesium-containing preparations

Table 2. Drugs implicated as potentially harmful in myasthenia gravis patients based on either anecdotal case reports or in-vitro microelectrode studies (or both)

Beta blockers
propranolol
oxprenolol
timolol
practolol
atenolol
labetalol
metoprolol
nadolol

Calcium channel blockers
verapamil

Other cardiac drugs
procainamide
bretylium
trimethaphan

Anticonvulsant medication
phenytoin
barbiturates
ethosuximide
carbamazepine
gabapentin

Ophthalmologic medications
timolol
betaxolol hydrochloride echothiophate (a long-acting cholinesterase inhibitor used in the treatment of open angle glaucoma)

Psychiatric drugs
lithium carbonate
phenothiazines
amitriptyline
imipramine
amphetamines
haloperidol

Other drugs prescribed by neurologists
riluzole