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What drugs should be avoided in myasthenia gravis?

Myasthenia gravis is a rare autoimmune disease occurring in 0.25 to 2 people per 100,000
annually.1,2 Normally, for a synaptic transmission to occur at the neuromuscular junction, an
action potential must initiate depolarization of the presynaptic terminal. Once the presynaptic
terminal has been depolarized, there is an influx of calcium, which causes the release of
acetylcholine from vesicles. The acetylcholine then enters the synaptic cleft and binds to the
postsynaptic acetylcholine receptor (AChR). This interaction then causes a depolarization of
the postsynaptic terminal, which allows the signal to propagate and eventually ends in
stimulation of the muscle. In myasthenia gravis, formation of antibodies directed against the
AChR in the postsynaptic neuron form. The antibodies bind with the AChR, thus making
acetylcholine unable to complex with the AChR. This causes a decrease in the total number of
AChRs and muscle weakness due to diminished neurotransmission to the postsynaptic
membrane. 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. Respiratory paralysis can also occur in very severe
exacerbations. Although the disease is progressive, patients experience intermittent periods
of very active disease and remission.
Several medications are implicated in either inducing or worsening myasthenia gravis.1,3 Four
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, therefore preventing the binding of
acetylcholine to the postsynaptic AChR; and (4) prevention of action potential transmission
past the postsynaptic terminal secondary to changes in postsynaptic ion permeability.
More than 30 medications have been reported to have an effect on neuromuscular
transmission.1,3 The agents suspected in exacerbations or first presentations of myasthenia
gravis have mainly been published in case reports, therefore, it is difficult to describe a true
incidence with each agent. In addition, questionable temporal relationships or other
confounding factors sometimes make interpretation of the case reports difficult. Nonetheless,
it is prudent to use precaution when using the medications that have been implicated in
myasthenia gravis.
A simple way to remember the drugs that should be used with caution in myasthenia gravis is
the "14 As":4-7
ACTH and corticosteroids

prednisone

Analgesics

narcotics

Anesthetics, local

cocaine, procaine, lidocaine, bupivacaine,

prilocaine

Antacids or laxatives containing magnesium

Maalox, Mylanta

Antiarrhythmics

quinidine, lidocaine, procainamide

Antibiotics

aminoglycosides, quinolones, telithromycin,

azithromycin, erythromycin, clindamycin,
ampicillin, imipenem, vancomycin,
metronidazole

Anticonvulsants

phenytoin

Antihypertensives

beta-blockers, calcium channel blockers

Antimanics

lithium salts

Antipsychotics

chlorpromazine

Antirheumatic

chloroquine

Arthritis agents

penicillamine-induced myasthenia gravis

All neuromuscular blocking agents

Antimalarials

chloroquine, hydroxychloroquine

Approximately 1% to 7% of patients on penicillamine will develop myasthenia gravis.1,3

Penicillamine has been reported to induce the formation of anti-AChR antibodies in 90% 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 it causing an
exacerbation in a patient already diagnosed with myasthenia gravis. Patients who develop
myasthenia gravis while receiving penicillamine typically have a mild form of the disease,
often limited to the extraocular muscles. Initial presentation of the disease varies occurring
from 2 to 12 months after therapy has begun. Most patients have resolution of the disease
within 2 to 6 months following discontinuation.
Interferon alfa has also been implicated as the cause of myasthenia gravis in patients with
leukemia or hepatitis C.3 Rat data suggest the proposed mechanism may be an autoimmune

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response to the expression of interferon on motor endplates. The onset is from 6 to 9 months,
and it has been reported to last up to 7 months after discontinuation.
Corticosteroids, although a mainstay in the management of moderate to severe myasthenia
gravis, can also cause an exacerbation of muscle weakness.1-3 Patients 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 20% to 50% of patients initiated on high dose prednisone
will have an exacerbation of their disease in the first days to weeks of therapy, which is then
followed by a period of remission.
Overdoses of cholinesterase inhibitors may also exacerbate myasthenia gravis.3 Excessive
doses can result in acetylcholine accumulation, which causes increased bronchial secretions
leading to difficulty swallowing or breathing. It has been suggested that weakness 1 hour after
administration of pyridostigmine could indicate overdose, while weakness 3 or more hours
following a dose could indicate a suboptimal response to therapy.
Aminoglycosides are cited in numerous case reports involving their concomitant use with
neuromuscular blockers.1,3,4 Postoperative respiratory depression was reported in nearly all
cases. Limb or facial weakness has also been reported. Aminoglycosides have also been
documented to exacerbate preexisting myasthenia gravis, and have lead to worsening
symptoms within 1 hour of administration.
Summarized below are various medications that have been associated with exacerbations of
myasthenia gravis.
Table 1. Medications to be used with caution in myasthenia gravis.3-7
Drug

Onset (from initiation)

Resolution

Prednisone

1 to 2 weeks

1 to 20 days

Streptomycin

15 min to 1.5 hours

<24 hours

Iodinated contrast media

minutes

2 to 48 hours

Botulinum toxin

minutes

2 weeks

Procainamide

2 days to 2 weeks

12 hours to 10 days

Erythromycin

During infusion; 30 minutes after 2 to 3 days

dose

Ciprofloxacin

4 hours to 2 days

Several days

Ampicillin

12 hours to several days

48 hours

Quinidine

72 hours

48 hours

Lithium

10 days to 3 months

3 to 4 days

Timolol, acebutolol,
propranolol, oxprenolol,
practolol

24 hours to several days

24 hours to 8 weeks

Penicillamine

8 months

6 to 10 months

Chloroquine

1 week 3.5 years

5 days to 14 weeks

Phenytoin

4 to 6 years

2 to 3 months

Imipenem-cilastin

2 days

48 hours

Verapamil

4 days

2 weeks

Trimethaphan

2 to 17 hours

Procaine

7 minutes

Lidocaine

7 minutes

Aprotinin

during infusion

10 to 90 minutes

Levocarnitine

3 weeks

resolved after edrophonium

Several other drugs have been found to worsen myasthenia gravis including telithromycin,
magnesium, oxytocin, neuromuscular blockers, and anticholinergics.3-7 The Myasthenia
Gravis Foundation of America has a resource document for healthcare professionals that
discusses medications that may exacerbate myasthenia gravis (http://www.myasthenia.org
/hp_medicationsandmg.cfm). The document was last updated in January 2007.
In summary, many drugs have been implicated as a cause of myasthenia gravis or disease
exacerbation. Although the literature regarding implicated medications is limited, caution and
close monitoring when prescribing these agents is recommended, especially during an acute
exacerbation.
References
1. Barrons RW. Drug-induced neuromuscular blockade and myasthenia gravis.
Pharmacotherapy. 1997;17(6):1220-1232.
2. Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. Lancet. 2001;357:2122-2128.
3. Wittbrodt ET. Drugs and myasthenia gravis: an update. Arch Intern Med.
1997;157:399-408.
4. Karcic AA. Drugs that can worsen myasthenia gravis. Postgrad Med. 2000;108(2):25.
5. Pascuzzi R. Myasthenic crisis. Postgrad Med. 2000;107(4):211-222.
6. Yarom N, Barnea E, Nissan J, Gorsky M. Dental management of patients with
myasthenia gravis: A literature review. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod. 2005;100(2):158-163.
7. Kuczkowski KM. Labor analgesia for the parturient with neurological disease. Arch
Gynecol Obstet. 2006;247(3):41-46.

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