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A case of Myasthenia Gravis

Case Scenario

Mrs. Jameel, 45 years of age, is a housewife. Since last month she was feeling fatigue of shoulder muscles while combing her hair. She had to perform some unusual physical work when her family was to move into a new residence and all the luggage and house-hold was to be packed for shifting. She felt extremely weak during the activity and was compelled to take rest at short intervals.

Learning Objectives:

  • What is Myasthenia gravis?
  • Etiology and patho-physiology of the disease.
  • Appraoches to pharmacotherapy of MG.
  • Classification of anticholinesterases.
  • Mechanism of action of anticholinesterases and their control.
  • How to distinguish between cholinergic crisis and myasthenic crisis.
  • Other uses of anticholinesterases.
  • Drugs that may precipitate MG.

Myasthenia Gravis:

It is a disease of neuro-muscular junction caused by immune mediated loss of acetylcholine receptor. It occurs in 30 out of 100,000 persons. Before age of 40 it is more common in women.

65% have thymic hyperplasia , 15% thymona in almost all cases autoimmune bodies against AChR.

In this disease, antibodies are produced against the main immunogenic region found on α1 subunits of nicotinic receptor-channel complex.

Nicotinic receptors are reduced by following processes:

  1. Antibody causes cross-linkages of receptors leading to internalization and degradation.
  2. Antibody also cause direct postsynaptic membrane damage.
  3. Antibody bind to the receptor and preventing agonists from binding.

Nicotinic Receptors:

  • Pentamer of four glycoproteins (one subunit is repeated)
  • Each subunit has four transmembrane segments.
  • Two binding sites are found for agonists, the interface between 2α and 2 adjacent subunits (β,γ,ε).
  • Agonist binding causes conformational change that makes it more permeable to cations mainly Na+, K+ and small amount of Ca++.
  • Single agonist binding cause negligible conformational change whereas binding of two agonists molecules cause major conformational change.
  • Prolonged occupation of the receptor diminishes receptor response.
  • Continued presence leads to depolarization blockade.
  • Later leads to restoration of resting membrane potential and receptors are desensitized. This state is refractory to the reversal by agonist.


  1. 2 mg Edrophonium I/V after baseline muscle strength has been recorded.
  2. If no reaction in 45 seconds, additional dose of 8mg may be injected.
  3. In case of MG, improvement in muscle strength lasting upto 5 mins is seen.


Again edrophonium is used. (1-2 mg I/V)

If muscarinic overactivity, no improvement or worsening of weakness is seen with dose. (Cholinergic crisis).

If inadequate, improvement with small dose of edrophonium is seen. (Myasthenic crisis)


Ocular MG: Only anticholinesterases are used.


  • Anticholinesterases with immunosuppressants are used (steroids, cyclosporine and azathioprine)
  • Removal of thymus
  • Administration of immunoglobulins
  • Plasmaphoresis

Anticholinesterases: Pyridostigmine is drug of choice. Neostigmine and ambemonium are the alternatives. Doses are titrated till effects are controlled and monitored by edrophonium.

Steroids: Cause initial exacerbation of symptoms followed by relief of symptoms.

Steroids act as immunosuppressants in following way:

  • Inhibit function of macrophages and antigen presenting cells.
  • Production of TNF-α, IL-1, metalloproteinases and plasminogen activators is reduced.
  • IL-12 and INF-γ are reduced, which are inducers of TH1 and cellular immunity.
  • Reduces leukotrienes, prostaglandins and PAF synthesis.
  • Reduces induction of COX-2 enzyme.


  • Cyclosporine binds to cyclophilin in T-cells which belong to intracellular proteins called immunophilins.
  • Cyclosporine and cyclophilin complex inhibits the cytoplasmic phophatase, calcineurin which is necessary for the activation of T-cell specific transcription factor.
  • This transcription factor, NF-AT, is involved in the synthesis of interleukins by activated T-cells.
  • IL-2, IL-3, INF-γ are not produced.
  • No effect on interaction of T-cells with these factors and with antigen.

Toxicity: Nephrotoxicity, hypertension, hyperglycemia, liver dysfunction, hyperkalemia, altered mental status, seizures and hirsutism.

Azathioprine: It is a prodrug of mercaptopurine. Both appear to produce immunosuppression by interfering with purine nucleic acid metabolism at steps that are required for the wave of lymphoid cell proliferation that follows antigenic stimulation. 2.5 mg/Kg daily.

Plamapheresis: It is reserved for myasthenic crisis and pre-operative control of MG.

IVig: It is the infusion of Immunoglobins collected from 20,000 donors. Possible MOA in autoimmune diseases are1:

  • Reversible blockade of Fc receptors on cells of the reticuloendothelial system by Fc fragments of injected immunoglobulins.
  • Fc-dependent feedback inhibition of autoantibody synthesis by B cells and modulation of suppressor or helper T cell functions.
  • Interference of IVIg with complement-mediated damage.
  • Modulation by IVIg of cytokine secretion.
  • V-region dependent modulation by IVIg of the expression of the autoimmune repertoire*.

*Inventory, stock, supply. 1Clin. exp. Immunol. (1991) 86, 192- 198REVIEWIntravenous immunoglobulins (IVIg) in the treatment of autoimmune diseasesS.-V. KAVERI, G. DIETRICH, V. HUREZ & M. D. KAZATCHKINE

Classification of Cholinergic drugs (Anticholinesterases)


i. Tertiary amines:


ii. Quarternary amines:





ii. Alcholols



i. Therapeutically useful


ii. War gases

  1. i.     Sarin
  2. ii.     Soman
  3. iii.     Tuban

iii. Insecticides

  1. Parathion
  2. ii.     Malathion
  3. iii.     Diisopropylflurophophate (DFP)
  4. iv.     Tetraethylpyrophosphate (TMPP)
  5. v.     Octamethylpyrophoramide (OMPA)


  1. Tacrine
  2. Donepezil
  3. Galantamine
  4. Rivastigmine

Mechanism of Action:

All cholinesterase inhibitors increase the concentration of endogenous acetylcholine at cholineceptors by inhibiting cholinesterases.

Quaternary Alcohols like Edrophonium bind electostatically and through H-bonding to the enzyme and prevent acetylcholine from binding it. Bond formed is weak so blockade is short lived.

Carbamate esters like neostigmine and physostigmine undergoes two-step hydrolysis sequence analogous to acetylcholine, however covalent bond formed is considerably resistant to hydrolysis, this step is considerably prolonged.

Organophophates forms a similar bond with the active site resulting in phophorylation of the enzyme. This phosphorylation is resistant to hydrolysis. If the process of aging occurs that is removal of one of the oxygen-phosphate bond results in even tighter bond between enzyme and phosphorus. Before aging occurs this bonding can be reversed by strong nucleophiles like oximes e.g Pralidoxime, which are called cholinesterase regenerator.

Adverse Effects:

Muscarinic: Miosis, salivation, sweating, bronchial constriction, vomiting and diarrhea.

CNS: Cognitive disturbances, convulsions and coma

Nicotinic: Depolarizing neuromuscular blockade.


  • Maintainance of vital signs: respiration is liable to be affected.
  • Decontamination to prevent further absorption.
  • Atropine parenterally large dose for muscarinic effects.
  • Treatment with pralidoxime.
  • Benzodiazepines for seizures.

Distinguishing between Cholinergic crisis and Myasthenic crisis:

Edrophonium, improvement means Myasthenic crisis otherwise cholinergic crisis.

Other uses of Anticholinesterases:

  • Glaucoma:
    • Contraction of ciliary muscles so as to facilitate outflow of aqueous humour.
    • Decreases its rate of secretion.

Not the first line of drugs (First line agents: β- blockers and prostaglandin derivatives)

  • Acute angle closure glaucoma:

Combination of direct muscarinic agonist and anticholinesterase before iridectomy.

  • Accomodative estropia (Strabismus caused by hypermetropic accommodative error) in young children.
  • Postoperative Ileus (atony or paralysis of the stomach or bowel following surgical manipulation)
  • Congenital megacolon (hirschsprung’s disease)
  • Urinary retention postoperatively or postpartrum secondary to spinal cord injury or disease (neurogenic bladder).
  • Reflux esophagitis: Increase tone of lower esophageal sphincter.THERE MUST NOT BE ANY MECHANICAL OBSTRUCTION OTHERWISE PERFORATIONS WILL OCCUR
  • Bethanecol: For GIT orally 10-25mg 3 to 4 times daily, for urinary symptoms S/C 5 mg repeated in 30 mins if necessary
  • Neostigmine: GIT 0.5-1 mg S/C, Oral 15mg
  • Myasthenia Gravis
  • Recovery from muscle relaxant
  • Paroxysmal supraventricular tachycardia: Edrophonium but replaced by adenosine and Calcium channel blockers verapamil and diltiazem.
  • Antimuscarinic drug intoxication: Atropine and Tricyclic antidepressants. Physostigmine is used but has adverse CNS effects.
  • Alzheimer’s Disease: Tacrine, donepezil, galantamine and rivastigmine are used.
Neostigmine Physostigmine
Synthetic Natural alkaloid obtained from Physostigma venenosum (calabar bean)
Quaternary amine Tertiary amine
Water soluble Lipid soluble
Can not cross blood brain barrier Can cross blood brain barrier
Poorly absorbed GIT Absorbed readily from GIT
No CNS effect at moderate dose CNS effect are present
Prostigmine Eserine
Has direct actions on nicotinic receptors No known dual action.


A simple way to remember the drugs that should be used with caution in myasthenia gravis is the “14 A’s”:1-4

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

Differentials (http://emedicine.medscape.com/article/1171206-differential)


  1. Karcic AA. Drugs that can worsen myasthenia gravis. Postgrad Med. 2000;108(2):25.
  2. Pascuzzi R. Myasthenic crisis. Postgrad Med. 2000;107(4):211-222.
  3. 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.
  4. Kuczkowski KM. Labor analgesia for the parturient with neurological disease. Arch Gynecol Obstet.   2006;247(3):41-46.





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  1. Great article about Myasthenia gravis. I just learn several complicated things about disease and found huge treatment objects. Thanks for letting us know about this topic!

  2. awes0me!helps a million tyms more if yo0 are an AMColian

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