myasthenia gravis.pdf

Myasthenia gravis is a chronic autoimmune, neuromuscular disease that causes weakness in the skeletal muscles (the muscles that connect to your bones and contract to allow body movement in the arms and legs, and allow for breathing).

1. MyastheniaGravis
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Vijay salvekar
Dept of Pharmacology
GRY Institute of Pharmacy

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Background
•The word Myasthenia Gravis is derived from
Latin andGreek
Myasthenia –weakness
Gravis –serious
•literally means "grave muscleweakness"

3. •Myasthenia gravis (MG) -autoimmune disorder -
antibodies against AchRs atNMJ
•these antibodies attack and destroy AchRs &
postsynapticmolecules
•leadstoimpairedsignaltransductionmuscle
weakness andfatigability
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Anatomy
Neuromuscular Junction(NMJ)
Components:
Presynapticmembrane
Postsynapticmembrane
Synapticcleft
Presynaptic membrane contains Àch invesicles
ACh attaches to AChR on postsynapticmembrane

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Pathophysiology
In MG, antibodies are directed toward the
acetylcholine receptor at the neuromuscular junction
of skeletal muscles

8. Antibodies
85% anti-
AchR
antibodies
65%
Hyperplasia
10%Thymomas
15%
seronegative
40%Anti-Musk
antibodies
Others-antititin,
RyR, KV1,4Ab
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9. How do these antibodiesact?
1.Blocks the binding of ACh to theAChR.
2.Increases the degradation rate ofAChR
3.A complement-mediateddestruction
Resultsin:
nicotinic acetylcholinereceptors
postsynaptic membranefolds
Widened synapticcleft
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Epidemiology
•Prevalence: 1-7 in10,000
•Age.anyage
•20-30 yrs (young women), 50-60 yrs (oldermen)
•< 10% occur in children <10yrs
•Overall F:M =3:2
•More common in pts with family history of one or the
other autoimmunediseases

12. ClinicalPresentation
d improves withrest
•Fluctuating painless weakness increased byexertion
•Worses with repetitive activitiesan
Ocular muscle weakness
(85%) Asymmetric
Ptosis
Diplopia is very common
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13. Weakness of face and throatmuscles
Myasthenicsnarls
normal
duringattack
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14. Limb muscleweakness
Neck extensors >flexors
Upper limbs > lowerlimbs
Dropped headsyndrome
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•Respiratoryweakness
Weakness of the intercostal muscles and the
diaghram
Collapse the upperairway
Neuromuscular emergency -mechanicalventilation

16. Progression ofdisease
Mild to more severe over weeks tomonths
Usuallyspreadsfromocularfacial
bulbartruncallimbmuscles
The disease remains ocular in 16% of
patients
Death rate reduced from 30% to <5% with
pharmacotherapy andsurgery
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MyasthenicCrisis
•Exacerbation of weakness -endangerlife
•Respiratory failure (diaphragmatic and inter costal
muscleweakness)
•Cause –intercurrentinfection
•Cholinergic crisis -excessive anticholinesterase
medication

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Treatment
There are four basictherapies:
Symptomatic treatment -acetylcholinesterase
inhibitors
Rapid short-term -plasmapheresis and intravenous
immunoglobulin
Chronic long term -immunomodulating treatment -
glucocorticoids & immunosuppressivedrugs
Surgicaltreatment

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AnticholinesteraseMedications
•Pyridostigmine is the most widelyused
•Onset -15–30 min and lasts for 3–4h
•Dose -30–60 mg three to four timesdaily
•Frequency of the dose should be tailored tothe
patient’s individual requirements throughout theday

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Neostigmine
•Short-acting AChEinhibitor
•half-life -45-60minutes
•Poorly absorbed from theGIT
•Should be used only if pyridostigmine isunavailable

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Immunosuppression
•Is required in nearly all ptswith
-late-onsetMG
-thymomaMG
-MuSK-MG
•Suppress autoantibody production & its detrimental
effects atNMJ

22. Glucocorticoids
•First & most commonly usedimmunosuppressant
•Used when symptoms of MG are not adequately
controlled by cholinesterase inhibitorsalone
•MOA -inhibits MHC expression & IL-1production
IL-2 & IFN γproduction
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Prednisone–
•most commonlyused
•Decreases the severity of MGexacerbations
•Transient worsening might occurinitially
•Clinical improvement -2-4weeks
•marked improvement in40%
•Remissions are noted in30%

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Mycophenolatemofetil
•Choice for long-termtreatment
•MOA -prodrug of mycophenolicacid
-Inhibits inosine monophosphatedehydrogenase
•Lymphocyte proliferation, antibody production and
CMI areinhibited

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•Does not kill or eliminate preexisting autoreactive
lymphocytes
•Clinical improvement may be delayed for 2-6months
•Vomiting, diarrhoea, leucopenia and predisposition
to CMV infection, g.i. bleeds are the prominent
adverseeffects.

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Azathioprine
•It is a purine analog, reduces nucleic acid synthesis,
thereby interfering with T-and B-cellproliferation
•Is effective in 70%–90% of patients withMG
•When used in combination with prednisone -more
effective & better tolerated than prednisonealone
•Beneficial effect takes at least 3–6 months tobegin

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Calcineurininhibitors
•Cyclosporin -Used mainly in patients who do not
tolerate or respond toazathioprine
•Blocks synthesis of IL-2cytokine
•Dose 4–5 mg/kg perday
•Cyclosporine can cause nephrotoxicity, neurotoxicity,
hepatotoxicity, hyperlipidemia, hyperuricemia,
hyperglycemia, hirsutism and gumhyperplasia

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Tacrolimus
•Is ~100 times more potent thancyclosporin
•It binds to FK 506 binding protein (FKBP) and causes
inhibition of helper Tcells
•Beneficial effect appears more rapidly than that of
azathioprine
•less nephrotoxicity, hirsutism, hyperlipidemia than
cyclosporine
•Dose -0.1 mg/kg perday

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31. Thymectomy
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Thymectomy
•CarriedoutinallpatientswithgeneralizedMG-
aged between puberty and 55years
•Thymoma -Surgical removal is a must -possibility of
local tumorspread
•up to 85% of patients experience improvement after
thymectomy
•of these, ~35% achieve drug-freeremission

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Thankyou