Myasthenia Gravis

Pharmacotherapeutics V
Angeles University Foundation
College of Allied Medical Professions
Department of Pharmacy
Myasthenia Gravis
• Neuromuscular disorder characterized by weakness and fatigability of
skeletal muscles.
• Decrease in the number of available acetylcholine receptors (AChRs)
at neuromuscular junctions due to an antibody-mediated
autoimmune attack
• It is an autoimmune disease that causes decrease in number of
acetylcholine receptors, that's why the acetylcholine cannot bind to
its receptor and produce its effects
Etiology & Epidemiology

•Genetics • Incidence: Estimated at 2.1 to

1. per million people per year
•Thymus Abnormality • Female: 30s
•Drug-Induced • Male: 60s (60 to 70 years old)

•Aminoglycosides • Female-to-male Ratio - 3:2

•Penicillamine • More prevalent in
•Fluoroquinolones female
•Hydroxychloroquine
NOTES FROM PREVIOUS SLIDE
● Usually for autoimmune disease the specific cause is “unknown”

● Genetics
○ Inherited
○ They give genetic predisposition to the patient already, patient already exposed
because of their genetic composition
● Human Leukocyte Antigen (HLA’s)
○ Plays a big role for our Histocompatibility Complex which makes our cells more
susceptible to immune attacks or response

● Thymus Abnormality
○ Thymus gland
■ This is where T-cells mature, some T cells are also produced here but mostly dito
sila nag mmature
○ They trigger and maintain the production of antibodies that blocks the acetylcholine
○ Adult patients w/ MG: Their thymus is abnormally large kasi physiologically thymus
gets smaller in time or nawawala and it is only evident in “childhood”
Continuation notes for “Drug Induce”
● Aminoglycosides
○ Protein synthesis inhibitors
○ Antibacterial - 30’s ribosomal subunit level
○ Aside from being antibacterial, they affect neuromuscular transmission by inhibiting the release of acetylcholine
○ Interferes with release of acetylcholine from the presynaptic cleft

● Penicillamine
○ Commonly used for the treatment of “Wilson's disease” yung copper toxicity
○ There are 3 mechanism on how it can exacerbate myasthenia gravis
■ Alteration of the choline receptors
■ Stimulation of b-cells lymphocytes
● Pag b cells production of antibodies, specifically auto antibodies
■ Inhibition of suppressor T-cells lymphocytes
● Suppressor T-cells: limits and maintains the production of T-cells and it limits its activity
○ When you discontinue the use of penicillamine the myasthenic state also subsides

● Fluoroquinolones
○ Commonly used: Ciprofloxacin, ofloxacin
○ Same with aminoglycosides they also interfere with neuromuscular transmission kaya nag kakaroon ng inhibition for the
acetylcholine action

● Hydroxychloroquine
○ Antimalarial DMARDS
○ One of the primary treatments for SLE
○ The problem with hydroxychloroquine kase, like others they have an effect on neuromuscular transmission kaya they can induce
or exacerbate Myasthenia gravis, so in practice we should watch out for this types of drug if the patient has a history or being
treated with myasthenia gravis
ADDITIONAL NOTES
Synthesis of Acetylcholine
➔ Acetylcholine is formed by the combination of choline and acetyl coenzyme A (COA) with the help of
the enzyme choline acetyltransferase
➔ This acetylcholine then will be transported to the vesicle inside the presynaptic terminal, so inside this
vesicle meron siyang mga kasamang proteins, mga ATP
➔ Once acetylcholine is already ready, it will be released from the vesicle and then it will be released into
the synapse going to the postsynaptic terminal
➔ Once nasa post synaptic terminal na siya, mag bbind na siya sa mga receptors niya, yung mga
acetylcholine receptors
➔ The binding of this acetylcholine to its receptor produces depolarization at the region of the muscle
fiber
➔ If the depolarization is sufficiently large, meaning na fulfill na yung “all or nothing principle” it will
initiate an action potential which will propagate along the muscle fiber triggering a muscle contraction
◆ Basically the MOA of acetylcholine: It depolarizes the muscle fiber and if it fulfills the “all or
nothing” principle, it will initiate an action-potential that will trigger muscle contraction
➔ After it triggers muscle contraction, the acetyl cholinesterase enzyme hydrolyzes then the
acetylcholine to choline. This choline will then be transported back to the presynaptic terminal for
reuptake na (uulit na cycle nun)
Pathophysiology
● The fundamental defect is a decrease in the number of available AChRs at the
postsynaptic muscle membrane.
○ Basically, if there are not much receptors there, magkakaroon ng failure of
transmission sa mga neuromuscular junctions, kaya nag kakaroon ng weakness of
muscle contraction or humihina yung muscle tone kasi hindi masydo nakakabind
acetylcholine, wala masytado muscle contraction = no action potential = no
depolarization
● The neuromuscular abnormalities in MG are brought about by an autoimmune response
mediated by specific anti-AChR antibodies
1. Accelerated turnover or increased degradation of AChRs by a mechanism involving
cross-linking and rapid endocytosis of the receptors;
2. Damage to the postsynaptic muscle membrane by the antibody in collaboration
with complement system; and
○ Complement system: can cause opsonization and rapid degradation specifically
for this type of receptor
3. Blockade of the active site of the AChR, i.e., the site that normally binds ACh.
○ Sometimes yung mga autoantibodies natin, di lang nila sinisira yung mga acetylcholine
receptor, they also do competitive antagonism, so nag bbind sila dun sa receptor para di
maka bind acetylcholine
CONTINUATION FROM THE PREVIOUS SLIDE

● *Anti-AchR autoantibodies, *anti-MuSK autoantibodies

○ These are the 2 main autoantibodies that are responsible for MG
○ In general mas madami mga anti-ChR autoantibodies than anti-MuSK
○ Anti-MuSK: are known as “Anti muscle specific tyrosine kinase antibodies”
■ These are proteins involved in the clustering of the acetylcholine receptor, so basically these muscle
specific tyrosine kinases are required for the formation and maintenance of of acetylcholine receptors
and pag wala ka ganto they are easily degraded and there is an inability and inefficiency with the
formation of these types of receptors pag wala kang muscle specific tyrosine kinase. As in relation with
MG meron kang auto antibodies na sumisira sa mga ganun so di na mmaintain yung mga acetylcholine
recpetors mo

● Anti-AChR autoantibodies:
○ Mas madami
○ The ones that destroy the receptors
○ The relation of thymus to MG, there is a strong association of the pathogenic Anti-AchR autoantibodies
and the thymus abnormalities.
○ Within the thymus (where T cells mature), there are muscle-like cells (myoid cells) that have
Acetylcholine receptors on their surface. They serve as some sort of autoantigen. Once the lymphocytes
that are specific to the Acetylcholine receptors are released from the thymus, they will target all of the
Acetylcholine receptors and hence why thymus abnormalities are a big concern for patients with MG
● This is just a diagram on how a normal count of Ach receptors looks like and what it looks like once an
individual has MG
● Take note of the appearance of the post and pre synaptic cleft, as well as the vesicle and
acetylcholinesterase.
Clinical Features
The cardinal features are weakness and fatigability of muscles (limbs), usually
asymmetric (one-sided)
• Diplopia and ptosis
○ Diplopia - double vision; ptosis - drooping of the eyelids
○ Caused by weakness of the extraocular muscles
• Facial weakness
○ Makes the ptx have difficulty smiling
• Difficulty in swallowing
○ Result of the weakness of the palate, tongue, and the pharynx. They
affect largely swallowing, specifically the soft palate and tongue
Diagnosis
• Physical Examination
○ The cardinal features of MG is weakness and fatigability of muscles.
○ Take note of the reflexes, muscle tone and strength, coordination and balance of muscles
○ Check muscle tone → weakness is observed BUT reflexes are okay, then it is still
diagnostic of MG.
○ MG → dapat walang impairment of neurological function at early stage
○ If weak muscle tone and strength, okay reflexes, impaired coordination and balance of
muscles are observed, then proceed to confirmatory test like the Anti-AChR
radioimmunoassay
• Anti-AChR radioimmunoassay (RIA)
○ This is a specific assay for the detection of Anti-AChR autoantibodies
○ If positive, then MG is confirmed
○ If negative, it does not exclude MG still for the diagnosis since there are other
autoantibodies that can cause MG like the anti-MuSK autoantibody
Diagnosis
• Single-fiber electromyography
○ Measures the electrical activity travelling between the brain and muscles
○ Fine wire electrodes are placed through the skin and to a muscle to test one specific
single muscle fiber
○ If weakness is detected, MG is confirmed
• Edrophonium chloride Test
○ Edrophonium chloride is injected, and if there is temporarily improvement of muscle
strength, then MG is confirmed
○ Edrophonium chloride is an organophosphate (anti-acetylcholinesterase)
• CT scan or MRI
○ These are just done to exclude extracranial lesions especially if there are ocular clinical
features that are associated with MG
● ONE EVIDENT DIFFERENTIAL DIAGNOSIS FOR MG IS
BOTULISM/BOTULINUM TOXICITY
● Botulism is caused by the bacteria Clostridium botulinum. This
interferes with Ach release from the presynaptic cleft.
● It somewhat mimic the clinical features of MG
Management
Goals of therapy: treat the symptoms and avoidance of drugs that may exacerbate
myasthenia

• Pyridostigmine - first line treatment

• Best initial symptomatic therapy for most patients with mild to moderate MG
■ 30–60 mg three to four times daily
■ Recommended max dose of 120mg q4-6h
• Pyridostigmine is an anti-acetylcholinesterase/acetylcholinesterase inhibitor and is given orally; IV
preparation may be given to ptx who cannot take oral drugs
• Alternative to Pyridostigmine is Neostigmine
• Atropine is given if ptx encountered Pyridostigmine overdose and manifests cholinergic symptoms
• Glucocorticoids - Initial dose of 15–25 mg/day
• Weak immunosuppressants but is still included in the first line treatment
• Only indicated for ptx who are still symptomatic or have slow improvement of
symptoms despite Pyridostigmine use
Management
• Thymectomy
(1) Surgical removal of thymoma/thymus
(2) Thymectomy as a treatment for MG
■ Thymectomy is done if:
● Thymoma is present
● Thymus gland is removed as part of the MG treatment
■ The management of thymoma is complete resection of the thymus and is sometimes
accompanied with chemotherapy and radiation even if the thymus is already removed.
■ If there is no thymoma/neoplasms, partial/complete thymectomy may be done
depending on the severity.
• Plasmapheresis or IVIg
■ Plasma of the blood is filtered
■ IVIg = Intravenous immunoglobulin that are manufactured outside of the body and can
decrease serum level of antibodies because it (IVIg) increases catabolism
■ Used if the patient needs immediate improvement as soon as possible
■ It removes AchR autoantibodies from the circulation.
Management
• Immunosuppressants
• Azathioprine, Cyclophosphamides
• Stronger immunosuppressants are used
• Cyclophosphamides are more commonly used in high doses because making use of such,
is like rebooting your immune system.
• High doses of Cyclophosphamides eliminates mature lymphocytes that are already
affected by MG