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Drugs that may aggravate Myasthenia Gravis

Antimicrobials

Many antibiotics have been shown to cause problems in myasthenics. With the exception of Telithromycin (see below), they can be divided into

  • those that are likely to cause problems and should be avoided if possible, and
  • those that have only caused problems in a handful of myasthenics and can be used with caution. 

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

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.
 
2. The other antibiotic most likely to cause problems are only available as intramuscular and intravenous preparations (with the exception of Clindamhycin).

Aminoglycosides. Avoid use if possible.
This class of antibiotic is likely to cause problems if used systemically, as they can cause neuromuscular blockade (e.g. blocking transmission between nerve and muscle) even in people without MG

Gentamicin, Tobramycin, Amikacin

These are only used intramuscularly, almost always in a hospital setting for serious infections. They should be avoided if at all possible, but there will be times when an infection is life-threatening and their use in Myasthenics may need to be considered. Tobramycin probably has the weakest neuromuscular blocking effect of the aminoglycosides.

Streptomycin

Only used in rare cases, special permission needs to be obtained to prescribe it for anyone.

Neomycin

This is the aminoglycoside most likely to cause blockade, but it is almost always used in topical preparations (e.g. ointments), where it is unlikely to cause problems. It has, however, been used orally for bowel sterilization before surgery.

Bacitracin and Polymixin. Avoid use in systemic form.
These antibiotics were noted to cause problems when used systemically in the 1960s. They are now only available in topical form, usually mixed with other ingredients, and are safe to use in that form.

Colistin. Avoid use.
Only used intravenously. It can be very toxic, which limits its use to very serious infections not responding to other antibiotics. Even in patients without MG it can produce complete neuromuscular blockade with respiratory arrest. This can be after one dose, or after many days of treatment.

Lincomycin (only for IM/IV use), Clindamycin (IV/IM/oral form)
Can cause neuromuscular transmission blockade / directly block muscle fibre contraction in the laboratory, so theoretically could cause problems.
Note: Clindamycin is available as a vaginal gel and skin lotion. There is some systemic absorption, and although small, sufficient to be implicated in cases of pseudomembranous colitis with both preparations. Caution should therefore be exercised.

 3. Use the following oral antibiotics with caution:

Quinolone antibiotics.
There have been a number of cases of acute exacerbation with Ciprofloxacin and Norfloxacin. Caution should also be exercised with others in the family (e.g. Moxifloxacin) as it is thought that quinolones directly affect neuromuscular transmission.

Macrolide antibiotics – Erythromycin / Azithromycin
There is one case report of a serious exacerbation with azithromycin requiring mechanical ventilation for 6 days. This patient also had an exacerbation from erythromycin.

Tetracyclines (e.g. oral forms doxycycline, minocycline; IV form tigecycline)

Sulfonamides (e.g. Septrin™ Bactrim™)

Ampicillin
There is little evidence of problems with other penicillins.

Primaxin™ (Imipenem / cilastatin)
Only available for intravenous treatment of serious infections in hospitalised patients.


4. Malaria Treatment
& Chloroquine (Chlorquin™), Hydroxychloroquine (Plaquenil™),
Quinidine. Avoid use if possible
These drugs from the quinine family are also commonly used to treat SLE. They have been shown to induce MG (with or without anti-acetylcholine receptor antibodies) but can also exacerbate pre-existing MG by interfering with neuromuscular transmission. The effect can be seen with short term treatment (e.g. malaria) or longer term treatment (SLE).

  
5. Antihelminthic (worming) Treatments

Pyrantel. Available without prescription (Combantrin™, Anthel™, Early Bird™)


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Cardiovascular Drugs

1. Class 1 Anti-arrhythmics: Avoid use if possible

Procainamide and Quinidine.
These drugs block neurotransmission and are likely to cause severe exacerbations in known myasthenics. They may also cause new symptoms in those without MG (unmasking previously undiagnosed disease?) Procainamide can cause an auto-immune SLE-like syndrome, and possibly an MG syndrome. They should only be used in a hospital setting for life threatening arrhythmias when there are no alternatives. Quinidine is rarely used now.

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.

2. Beta Blockers. Use with caution.

There are many in this class, often identifiable by the “olol” ending.
Atenolol (Noten™, Tenormin™), (seems to have the least effect on MG)
Metoprolol (Betaloc™, Minax™)
Propanolol (Inderal™, Deralin™) (seems to have the greatest effect on MG)
Carvedilol (Dilatrend™)
Sotalol (Sotacor™, Sotahexol™) (has a very weak B-blocking effect) etc.
Eye drops for glaucoma also use B blockers and enough can be absorbed to cause symptoms (see section on eye drops).
Beta blockers have been shown to affect neuromuscular transmission in the laboratory, but its clinical effect is less sure, although there are reports of both exacerbation of MG and new symptoms. Weakness can be difficult to assess, as B blockers commonly cause the side effect of fatigue, which can be profound and mistaken for worsening MG. It is a very useful class of drug (for angina, blood pressure, migraine, heart failure, heart arrhythmias and glaucoma) and has been demonstrated to reduce the risk of further heart attacks after an acute myocardial infarct, so it is worth a trial of treatment if they are the best alternative for the particular diagnosis.

3. Calcium Channel Blockers. Use with caution

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).
Calcium channel blockers are thought to decrease neuromuscular transmission in a number of ways, so all in this class should be used with caution.


4. Cholesterol lowering drugs: the Statins. Use with Caution.

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.
Statins can also cause a myositis (muscle inflammation) producing weakness of the muscles themselves.
All of the above are probably class effects e.g. are likely to occur with all statins. Treatment needs to be individualised according to the risk of heart disease. The benefit in reducing the risk of heart attacks in those with ischaemic heart disease is so powerful that it is appropriate to use it with careful monitoring in those who have both MG and IHD.

 5. Alpha Blockers

Alpha Methyldopa. (Aldomet™, Hydopa™)

6. Diuretics. Beware low potassium.

Diuretics can lead to low potassium levels, which in turn can exacerbate muscle


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Rheumatic Disease

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
Penicillamine has been shown to induce an autoimmune process that produces a form of MG that is exactly like idiopathic MG. It occurs in 1-7% of those who are commenced on the drug (usually for rheumatoid arthritis). 90% of those who developed MG whilst on Penicillamine had anti-acetylcholine Ab, but 70% resolved within 12 months of ceasing the drug (compared to a baseline resolution of 8% in a year with idiopathic MG). Most people did not require ongoing treatment.
Penicillamine has not been shown to exacerbate pre-existing MG, but as there is concern that it is unmasking idiopathic MG in those who develop it, it may be advisable to avoid its use. Some MG experts would go as far as to say it should never be used in someone with MG.

&

Chloroquine (Chlorquin™), Hydroxychloroquine (Plaquenil™) - also used in treatment of Malaria. Avoid use if possible.
These drugs from the quinine family are also commonly used to treat SLE. They have been shown to induce MG (with or without anti-acetylcholine receptor antibodies), but can also exacerbate pre-existing MG by interfering with neuromuscular transmission. The effect can be seen with short term treatment (e.g. malaria) or longer term treatment (SLE).

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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Thyroid Disease

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
Reduces sensitivity of acetylcholine receptors and has caused new symptoms of MG in previously well people. The weakness responds to neostigmine.

Trimethadione. Avoid.
Rarely used now. Has caused both SLE-like (ANF positive) and MG-like syndromes.

Barbiturates. Use with caution.
May increase weakness.

Ethosuximide (Zarontin™) and Carbamazepine (Tegretol™)
In the laboratory have been shown to decrease neuromuscular transmission, but clinical effect unlikely. The onset of SLE (Lupus) has been reported in some patients after use of ethosuximide.

Gabapentin (Neurontin™)
There has been one report of sero-positive MG developing in a person taking this drug. Symptoms improved after ceasing the drug, but antibodies remained positive. However, this drug has been used in many with MG without problems, and the significance of this one case is doubtful. This useful drug should not be denied to people with MG.


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Drugs used in Psychiatry

Lithium. Use with caution.
Laboratory studies show a decrease in ACh muscle receptors in vitro (e.g. in cells outside of the body). It is common for Lithium to cause weakness, at times marked, when first started, even in people without MG. It usually improves within 2-4 weeks. Exacerbations of MG have been noted.

Chlorpromazine (Largactil™) Avoid use.
Has been shown to affect neuromuscular transmission and cause weakness. It may also prolong the effect of succinylcholine (see anaesthetic agents). The newer anti-psychotic medications appear to be less likely to have an effect, but should still be used with caution.

Benzodiazepines e.g. diazepam (Valium™, oxazepam (Serepax™), temazepam (Normison™, Temaze™). Use with caution.
The benzodiazepines have a muscle relaxant effect, but this is a central effect (e.g. on the brain) rather than on the neuromuscular junction. In large doses it can reduce the drive to breathe, and in a myasthenic who is already ‘under-breathing’ due to their muscle weakness, it could cause problems. These drugs are often quoted as being contraindicated (i.e. should never be used) in myasthenics, but if the myasthenia is reasonably well controlled they can be used with caution. The reluctance to use the hypnotics probably dates from the pre-immunosuppression era, when ‘brittle’, poorly controlled myasthenics were particularly vulnerable to the respiratory depressant effects.


________________________________________________________

Anti Spasmodics

(e.g. Propantheline, Oxybutinin, Atropine, Buscopan). Use with caution.
Used for overactive bladder, colicky abdominal pain (eg irritable bowel), and side effects of Mestinon.

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
Also used in oral (tablet) form for glaucoma, where the larger dose could be expected to have more chance of side effects.

Proparacaine/tropicamide
Used to dilate pupils for examination by Doctor.

Beta Blocker eye drops
eg Betaxolol (Betoptic™, Betoquin™), Timolol (Tenopt™, Timoptol™’ Used in glaucoma.

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
(also known as “Muscle relaxants” and not to be confused with the muscle relaxant effect of Diazepam (Valium™) or various drugs used in over the counter stress and headache remedies.)
These drugs have a direct effect on the neuromuscular junction, and by blocking transmission, cause paralysis, including the muscles of respiration. This enables surgery to be carried out (e.g. in the case of abdominal surgery). The relationship between these drugs, MG and the cholinesterase inhibitor drugs used to treat it (e.g. pyridostigmine, or (Mestinon™) is complex.

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.

Inhalation Anaesthetics
May have a direct effect on the neuromuscular junction and can increase the effect of the neuromuscular blocking drugs used during the same operation. Methoxyflurane has been shown to unmask mild MG.

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.

 

________________________________________________________

Botulinum Toxin - Avoid use.

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.
As always, the consequences of not treating will need to be taken into account. Interestingly, there has been some evidence that MG may occur independently in association with Hepatitis C, raising the question as to whether it is the interferon causing the MG in these patients.


________________________________________________________

Narcotics - Use with caution

Morphine, Pethidine, Fentanyl etc
As narcotics can cause respiratory depression by a separate mechanism (e.g. central nervous system effect) particular caution needs to be used in those with myasthenia induced respiratory insufficiency.

Cholinesterase inhibitors such as pyridostigmine (Mestino™) can increase the effect of the narcotics.

________________________________________________________

 
Magnesium

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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Hormonal Treatments

Levonorgestrol implant (Implanon)
There has been one case of a woman developing MG symptoms with positive anti-cholinesterase antibodies after Implanon insertion. Her symptoms were persistent but greatly improved after it was removed. The MG was possibly coincidental, and so use of Implanon is likely to be safe.


________________________________________________________


Smoking Cessation Treatment

Transdermal nicotine patch - Use with caution.
One case has been documented of MG symptoms worsening with the use of the patch, improving after removal and then recurring when re-applied. The patient was a heavy smoker, and the fact that smoking did not seem to worsen his MG was put down to the patch producing a continuous level of nicotine in the blood.

Picture

Source: http://hickoryneurology.net/myasthenia-medications-to-avoid.html


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