| Drug Alert Legend | |||
| Should only be used in a setting where ventilatory support in a hospital is available. |
Likely to worsen MG. |
May worsen MG but are usually tolerated. Use with caution. Have caused problems in rare cases but are not a problem for the majority of people with MG. |
Have been shown to cause a temporary form of MG (autoimmune) |
This article is a practical guide to those drugs which may affect Myasthenia Gravis, with advice as to how to minimise the impact when a decision is made to use one of these drugs. It is intended for use by the treating doctor or dentist, and whilst it will hopefully inform those who have MG, it is not intended to replace professional advice. Each case is different, and only the treating professional can advise in individual situations.
The information is set out under the headings of diseases or conditions that the various drugs are used for so that the patient with Myasthenia Gravis can take it to their GP, Specialist, Hospital Doctor or Dentist and they can easily see which drugs can be used.
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Drugs may worsen MG by
There are a few clear cut examples of drugs that can actually cause a temporary form of autoimmune MG which usually settles once the drug is ceased. It is less clear whether these drugs will worsen pre-existing MG.
Many reports of drugs affecting MG have caused problems in only one person, or a perhaps a few. Some drugs can theoretically cause problems but have not actually done so in the clinical setting. This means that the majority of MG patients can take the drugs without problems, and the benefits of the treatment should not be denied to them. The important point is for patients and doctors alike to be alert to the early signs of an exacerbation of the MG when a new drug is started, even if it is not on the list.
It is also important to remember that many acute illnesses themselves can worsen MG, and in many of these case reports it has been impossible to tell if it was the drug or the illness that was the problem e.g. was the pneumonia caused by an unrecognised flare up of MG, with aspiration into the lung, or was the worsening MG due to the pneumonia or the antibiotic used to treat it?
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This guide is intended for use by the treating doctor or dentist. For ease of use the drugs have been categorised into those that should be avoided and those that can be used with caution. In deciding which drugs to use, there are other factors to take into account: e.g. a drug may be essential, so will be used despite the likelihood of worsening the MG. On the other hand, a drug may be less likely to cause worsening of MG, but there will be other drugs which will do the job just as well, so it will be avoided.
LEGEND:
Drugs marked:
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are those which will almost certainly worsen MG and should only be used in a setting where ventilatory support in a hospital is available. |
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are those which may worsen MG but are usually tolerated. |
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are those which have caused problems in 1 or a few cases, and are not a problem for the majority of people with MG. |
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have been known to trigger autoimmune MG. They do not necessarily worsen pre-existing MG. |
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Drugs with no symbol can be used, but there are clinical factors that need to be taken into account. |
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How to minimize the impact of new Medications
Most drugs marked
or ![]()
can be used safely in MG even if they cause a mild deterioration in symptoms.
If it is considered necessary to use them, the following measures can be helpful:
It’s important that patients and health professionals be alert to the early signs of an exacerbation of MG when a new drug is commenced, even if it is not on this list.
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Drugs Used in the treatment of Myasthenia Gravis
Pyridostigmine (Mestinon ™) and Neostigmine are used to treat MG. They may aggravate the weakness or even cause a cholinergic crisis (which can mimic a myasthenic crisis) if used in too high a dose. There is a maximum response level, above which further increases in dose do not increase strength. It needs to be accepted that normal strength may not be attainable, even with treatment.
Other symptoms of overdose are: abdominal cramps, diarrhea, increased salivation and contracted pupils.
Note: use of bulk laxatives (such as methylcellulose) can decrease absorption of pyridostigmine and require an increase in dose.
Corticosteroids (e.g. Prednisone, Prednisolone)
Transient worsening of MG with high dose steroids (50mg/day or greater) occurs
in about 50% of patients, but these doses may be needed to obtain quicker control
of the disease. This doesn’t preclude its use as benefits outweigh disadvantages
e.g. improvement in MG leads to overall improvement in strength. Exacerbations
can be severe, requiring mechanical ventilation, but less likely if started
at a lower dose and gradually increased. Concomitant use of plasmapheresis or
immunoglobulin infusion may prevent worsening weakness.
The corticosteroids interfere with neuromuscular junction transmission, but can also cause weakness via a steroid induced myopathy of the proximal muscles if used in very high doses e.g. it is the muscles themselves that can be weakened.
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Drugs that may aggravate Myasthenia Gravis
Many antibiotics have been shown to cause problems in myasthenics. With the exception of Telithromycin (see below), they can be divided into
In general, the antibiotics most likely to cause problems are only available as intramuscular and intravenous preparations, and therefore likely to be used only in the hospital setting or are only available as topical preparations (e.g. eye/ear drops, creams) and unlikely to cause problems as so little is absorbed into the body. In the general practice setting, Norfloxacin, Ciprofloxacin, Erythromycin, Azithromycin and the Tetracyclines are the antibiotics to use with caution. It is best to simply choose the appropriate oral antibiotic and remain watchful for increasing weakness, particularly difficulty swallowing or breathing. Remember that acute illness, dehydration and fever can also worsen the MG.
1. Contra-indicated Antibiotics |
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| Telithromycin (known as Ketek™ in the USA, UK and Europe) stands alone in being the one medication that has been rated contra-indicated in MG, and should not be used in any MG patient, even if their disease is well controlled. Another antibiotic should be used instead. This drug is not registered for use, nor available in Australia, but beware when traveling overseas, as this is an oral drug, and can therefore be given by a GP or as an outpatient treatment. |
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| Aminoglycosides. Avoid use if possible. |
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Bacitracin and Polymixin. Avoid use in systemic form. |
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Colistin. Avoid use. |
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Lincomycin (only for IM/IV use), Clindamycin (IV/IM/oral form) |
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| Quinolone antibiotics. |
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Macrolide antibiotics – Erythromycin / Azithromycin |
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Tetracyclines (e.g. oral forms doxycycline, minocycline; IV form tigecycline) |
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Sulfonamides (e.g. Septrin™ Bactrim™) |
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Ampicillin |
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Primaxin™ (Imipenem / cilastatin) |
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Chloroquine (Chlorquin™), Hydroxychloroquine
(Plaquenil™), |
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| Pyrantel. Available without prescription (Combantrin™, Anthel™, Early Bird™) |
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| Procainamide and Quinidine. |
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Lignocaine is used intravenously for life threatening arrhythmias. It also blocks neuromuscular transmission, and is likely to make MG worse, so should only be used if there is no alternative. NB Lignocaine is safe to use as a local anaesthetic for minor procedures. The other Class 1 anti-arrhythmics are Flecainide (Tambocur™), Mexiletine (Mexitil™) and Disopyramide (Rythmodan™) and are only used for life threatening arrythmias. Theoretically, they are also likely to make MG worse. |
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| There are many in this class, often identifiable by the “olol”
ending. |
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| Verapamil (Veracaps™, Isoptin™). There have been documented
cases of weakness, and in one case, respiratory failure in patients with
MG who have taken Verapamil. It seems to be especially problematic for
those with Lambert-Eaton Myasthenic Syndrome (LEMS). |
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| A number of the Statins have caused muscle weakness by exacerbating
MG. There have also been a number of cases where antibody positive MG
has developed after use of these drugs, and has then improved once the
drug was withdrawn. |
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| Alpha Methyldopa. (Aldomet™, Hydopa™) |
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| Diuretics can lead to low potassium levels, which in turn can exacerbate muscle |
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This is an important category, as there is an increased incidence of Systemic Lupus Erythematosus (an inflammatory arthritis) and Rheumatoid Arthritis in people with MG (and vice versa)
| Penicillamine |
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Chloroquine (Chlorquin™), Hydroxychloroquine
(Plaquenil™) - also used in treatment of Malaria. Avoid
use if possible. Quinine tablets used for leg cramps can worsen muscle weakness in MG. The quinine in tonic water also produces weakness in some myasthenics, but the effect is usually very mild as the amount of quinine is so small. |
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Monitor drug levels carefully
Thyroid disease occurs in 10% of people with MG. If MG worsens for no apparent
reason, check for hyperthyroidism. For those already diagnosed with hypothyroidism,
an excess of thyroid hormone can exacerbate MG, so the dose of Thyroxine needs
to be monitored closely.
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Anti Epileptic Drugs (Anti-Convulsants)
The overall risk of using anti-epileptics in MG is thought to be small. The benefits will usually outweigh the risks with most of the drugs in this class. As always, care needs to be taken to watch for increased weakness when starting new medications.
| Phenytoin (Dilantin™). Avoid use if
possible |
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Trimethadione. Avoid. |
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Barbiturates. Use with caution. |
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Ethosuximide (Zarontin™) and Carbamazepine (Tegretol™) |
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Gabapentin (Neurontin™) |
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Lithium. Use with caution. |
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Chlorpromazine (Largactil™) Avoid use. |
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Benzodiazepines e.g. diazepam (Valium™,
oxazepam (Serepax™), temazepam
(Normison™, Temaze™). Use with caution. |
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(e.g. Propantheline, Oxybutinin, Atropine, Buscopan). Use with
caution. These are anti-cholinergics, and have the opposite effect to Pyridostigmine (Mestinon™). For this reason they may be marked as contra-indicated in the drug company literature. However, they work on different receptors (mainly the autonomic nervous system rather than skeletal muscle) and in practice do not seem to cause problems for most myasthenics at normal dosages. Nevertheless, there are some who will experience significant worsening of their symptoms. They can be used to minimise the side effects of Mestinon (such as abdominal cramps or diarrhoea), and are likely to be beneficial. However, higher doses of powerful anti-cholinergics such as atropine can mask the signs of a Mestinon overdosage (excessive sweating, contracted pupils, excessive salivation) with the danger of an impending cholinergic crisis not being recognised. |
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Ocular Drugs - Use with caution.
Even though these drugs are used in drop form, they are absorbed into the circulation and occasionally cause an increase in weakness.
Acetazolamide |
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Proparacaine/tropicamide |
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Beta Blocker eye drops |
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Ecothiophate (glaucoma) |
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General Anaesthetic Agents (for use only by anaesthetists)
General anaesthetic agents are an extremely important group of drugs where MG is concerned. They are only used by specialist anaesthetists, or general practitioners trained in anaesthesia. For the specialist anaesthetists, their training covers MG in detail, and they are well versed in what to do. Therefore the most important thing for the patient to do is to let the anaesthetist know that MG is present, and if possible see them for a consultation before the anaesthetic. Particularly for severe MG, it is very important that the anaesthetic takes place in a hospital that has an ICU with the ability to provide mechanical ventilation, should the need arise.
For elective surgery, it is wise to plan ahead and allow sufficient time to make sure that control of the myasthenia gravis is optimal. The risk of complications from significant general surgery is higher if the MG is poorly controlled e.g. difficulty swallowing may increase the risk of post-operative pneumonia. Seeing the MG treating doctor about three weeks before the procedure allows time to make any necessary changes to treatment. At times, pre-operative treatment with IV immunoglobulin or plasmapheresis may be necessary.
Most drugs used in the anaesthetic process, including the narcotics used for pain relief during and after surgery, can mildly worsen MG due to their non-specific side effects. Some drugs, however, have a specific effect, in particular the neuromuscular blocking agents. Some types of operations do not require their use, whilst others do, even in someone with MG.
Neuromuscular Blocking Drugs Most importantly, relatively small doses of Non-depolarising blockers(such as Vecuronium) can cause profound and prolonged paralysis in someone with MG. It is for this reason that anaesthetic / ICU facilities that enable mechanical respiration must be available. In some cases, paralysis has lasted for days or weeks. At times, it is necessary to use these drugs, and they can be used as long as it is remembered that myasthenics can be about ten times more sensitive to the effects. Conversely, if a patient is already on pyridostigmine (Mestinon™), larger doses may be needed to obtain paralysis. This is because pyridostigmine is closely related to the neostigmine which is used to reverse the effect of these drugs. The depolarising blockers (such as suxamethenium) work in a different way, and are likely to be less problematic for myasthenics. Neostigmine does not reverse the effects of this group of neuromuscular blockers, and can in fact make paralysis more prolonged. Therefore, the anaesthetist must be cautious when the patient is on pyridostigmine. The concomitant use of antibiotics known to affect the neuromuscular junction (see antibiotic section) can increase the chance of problems occurring. Intravenous magnesium has been shown to increase the effect of vecuronium. |
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Inhalation Anaesthetics |
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Local Anaesthetics - Can be used safely
Given by local injection by doctors and dentists to do minor procedures whilst the patient is awake. e.g. lignocaine (Xylocaine™), bupivacaine (Marcaine™), articaine (Septonest™) and prilocaine (Citanest™). In this form they are safe to use. They are also found in gels (e.g. for mouth ulcers/teething), and can be used safely. Mepivocaine (Scandones™) has a shorter duration of action and may be preferable.
Lignocaine is used intravenously to treat cardiac arrhythmias (irregular heartbeat). It is likely to seriously worsen MG, but as it is usually used in life threatening situations the decision may be made to use it if there is no alternative. |
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Botulinum toxin directly affects the NM junction. It can have distant as well as local effects, and has been reported to worsen MG (in one case leading to a myasthenic crisis). In another case, Lambert-Eaton Syndrome was unmasked by the use of a local injection of botulinum toxin. |
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Interferon Alpha - Avoid use if possible.
Used in Chronic Hepatitis B and C, Leukaemia etc
Has been documented as causing a number of cases of seropositive generalised
MG, which can be severe. It has been known to cause a fulminant myasthenic
crisis. |
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Morphine, Pethidine, Fentanyl etc Cholinesterase inhibitors such as pyridostigmine (Mestino™) can increase the effect of the narcotics. |
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The normal use of medications containing magnesium (e.g. laxatives, antacids, magnesium supplements) is unlikely to cause a problem. However, in renal failure, the magnesium levels can rise and cause muscle weakness, and myasthenics are particularly prone.
Magnesium sulphate is used intravenously in high doses for severe toxaemia of pregnancy, and can cause serious weakness. The high magnesium levels can also increase the effect of neuromuscular blockers (e.g. Vecurionium) used in an aneasthetic (e.g. if a caesarian becomes necessary). This is an illness that would only be dealt with in a specialised hospital setting. |
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X-ray Examinations with Contrast
These agents are used to gain a better image in CT scans etc. The newer, non-ionic contrast agents are safe to use e.g. Iohexal (Omnipaque™).
Ionic contrast agents (Iothalamic acid, diatrizoate meglumine, diatrizoate methylsulfate) should be avoided. This is of historical interest only, as these older agents are no longer used. Radiology clinics now routinely use the safer non-ionic contrast agents. When they were in use, 2-3% of people with MG exposed to them develop exacerbations of weakness, at times very severe. There have been cases where ICU admission has been required for respiratory arrest (although some of these may have been due to an anaphylactic allergic reaction). |
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Levonorgestrol implant (Implanon) |
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Transdermal nicotine patch - Use with caution. |
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Vaccines come as “live attenuated” vaccines (e.g. the virus is live, but too weak to cause disease in people with normal immune responses) or they are “inactivated” (the virus is dead and usually only a part of the virus, or a copy of part of the virus is used).
The “live” vaccines should be used with great caution if a person’s immunity is low due to immunosuppressive treatment, particularly if it is a first dose (i.e. they will not have any pre-existing immunity, unlike when a ‘booster’ dose is given). Live vaccines do not have a direct effect on MG.
Inactivated vaccines are safe to use in MG, and may be particularly important in preventing the complications of infection (e.g. the Influenza Vaccine).
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With grateful thanks to the following people for their contributions in preparing this article:
Research: |
Dr Jean Foster MB BS (WA), General Practitioner. |
Advice: |
Dr Stephen Reddel MB BS FRACP PhD Dr Robert Edis MB BS (WA) FRACP |
Assistance: |
Ms Ruth Wilton, National Prescribing Service, for her help in obtaining background information for this article. |
References
1. Drugs and Myasthenia Gravis: An Update.
Eric Wittbrodt. PharmD.
Arch Intern Med, Vol 157 (4), Feb 24, 1997 (399-408)
2. Medications and Myasthenia Gravis (A reference for Health Care Professionals)
Robert M Pascuzzi, MD
Myasthenia Gravis Foundation of America, published 2000, updated 2007.
www.myasthenia.org
3. Drugs Which May Aggravate Myasthenia Gravis
Dr Stanley Freedman, published by the Myasthenia Gravis Association (UK)
www.mgauk.org
4. Dentistry and the Myasthenic
Dr Frederick S Cohn, published in MGA News (UK), originally published by MG
Foundation of Vancouver, Canada.
5. Statin-Associated Myasthenia Gravis.
Purvin, Kawasaki et al, Medicine, Vol 85, number 2, March 2006.
6. A Handbook for Myasthenics.
Myasthenia Gravis Friends and Support Group WA inc. Published June 2005.
7. MIMS Drug reference system, 2007.
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Health Professionals are invited to make comment
on this pamphlet or provide further information
felt to be appropriate e-mail contact@myastheniawa.info