Myasthenia Gravis Flashcards
What is myasthenia Gravis?
An autoimmune disease characterised by the weakness of skeletal muscle
What causes the weakness of skeletal muscle?
Autoantibodies to the nicotinic acetylcholine receptor in skeletal muscle
Therefore transmission through neuromuscular junction is decreased
State some symptoms of Myasthenia Gravis
Ocular symptoms- droopy eyelids, double vision, restricted eye vision
May also have lack of facial expression, slurred speech, difficulty chewing, weakness in limbs, SOB - if severe myasthenic crisis
What tests can be done to detect MG
-Ice test- cooling muscles improves symptoms
-Blood test for autoantibodies
-Neurophysiology- electromyogram will detect decrease in muscle response
-Edrophonium- a short acting cholinesterase inhibitor. Causes increase in muscle strength (rarely used)
Treatment for MG
Acetylcholinesterase inhibitors: (anticholinesterases)
eg: pyridostigmine
Immunosuppressives: eg steroids or azathioprine
IV immunoglobin or plasma exchange:
for rapidly deteriorating MG or myasthenic crisis
Thymectomy
What usually happens in the NMJ to create muscle contraction? (Pathophysiology)
Action potential in,
causes voltage gated calcium channels to open,
influx of Ca2+,
Ca2+ goes into synaptic terminal,
causes exocytosis of acetylcholine, acetylcholine diffuses across synaptic cleft and interacts w/ receptors (nicotinic acetylcholine receptors),
Ligand gates ion channels open allowing SODIUM into cell,
End plate potential - stimulates action potential which then results in a muscle contraction
What is different to the pathophysiology of muscle contraction in MG?
Autoantibodies cause loss of nicotinic acetylcholine receptors therefore loss of transmission across synapse
Explain how acetylcholinesterase inhibitors help MG
Acetylcholinesterases located on post-synaptic membrane.
These break down acetylcholine to terminate contraction.
Want to BOOST transmission not lose it.
So inhibit acetylcholinesterases to stop break down of acetylcholine.
More acetylcholine which stays around in synapse, allowing increase of activity, causing increase contraction of muscle.
What is acetylcholine made from
Choline and cholineacetyl transferase
What is acetylcholine broken down into
Choline and acetate
What does acetylcholine esterase do
Uptakes choline into presynaptic terminal where it can be reused
What do cholinesterase inhibitors do
Block cholinesterase -> inc. acetylcholine and prolongs action therefore increase in contraction
What are the 2 types of cholinesterase
Acetylchoinesterase
butyrylcholinesterase
Where are nicotinic acetylcholine neurotransmitters found
In skeletal muscle in the somatic efferent system
In blood vessels in the sympathetic system
In salivary glands in the parasympathetic system
What nervous system do cholinesterase inhibitors mimic
parasympathomimetic
Mimic parasympathetic NS
(rest and digest, dec. HR, constrict bronchi, gland excretion, inc. GIT motility)
What is depolarization block?
Large doses cause depolarisation block of autonomic ganglia and the NMJ due to excessive ACh.
May also have central effects if cross BBB, may increase cognition, convulsions.
What medications interfere with NT transmission and cause deterioration of MG symptoms?
Phenytoin
clindamycin
macrolides
aminoglycosides
antimuscarinic agents
lidocaine
chlorpromazine
What medications increase muscle weakness and cause deterioration of MG symptoms?
Magnesium -> hypermagnesemia
benzodiazepines
beta blockers
diuretics
verapamil
statins
Treatment for MG with pyridostigmine
15mg QDS w/ food start
usual maintenance 60mg 4-6 x a day
assess cholinergic side effects
What is cholinergic crisis
Excessive acetylcholinesterase inhibitors
causes weakness
co-prescribe anti-cholinergic drugs w little nicotinic receptor effect (glycopyrrolate)
What is the shape of Acetylcholine esterase?
Like a squid ward head
has hydrophobic pocket, catalytic triad and serine proteases
What does a good reversible anticholinergic esterase drug need?
Good leaving group equal in efficiency of dissociation to acetyl group in acetylcholine
Leaving group should bind to serine and be less susceptible to hydrolysis
Contain positively charged motif to fit into active site
Carbamates!!!
Why are cabamates good reversible anticholinergic esterase drug?
Resonance stabilisation
carbonyl less electrophilic
Regeneration by nucleophile (water) more difficult.
what makes an irreversible anticholinergic esterase drug?
organophosphates
‘aging’ reactions forms covalent bond
What’s the antidote to an irreversible anticholinergic esterase drug?
Pralidoxime chloride (2-PAM)
has OH to act like water to regenerate enzyme
have positive N essential for strong binding to anionic site for acetylcholine
