Module 3.3.1 (Pharmacological Treatment of Myasthenia Gravis) Flashcards
What is the general MOA of immunosuppressants for the treatment of MG?
Improves muscle strength by suppressing abnormal antibodies
- Suppresses IgGI and IgG3
- Binding of AChR antibodies to AChR which result in impairment of neuromuscular transmission –> doesn’t occur anymore
What is the MOA and site of action for the following immunosuppressants;
A) Glucocorticoid
B) Azathioprine
C) Mycophenolate mofetil
D) Cyclosporine
E) Tacrolimus
A)
- Glucocorticoid response elements in DNA
- Regulate gene transcription
B)
- DNA
- False nucleotide incorporation
C)
- Inosine monophosphate dehydrogenase –> inhibits IMPDH
D)
- Calcineurin inhibitor –> inhibits phosphatase activity
E)
- Calcineurin inhibitor –> inhibits phosphatase activity
Whats an example of Plasmapheresis Immunoglobulin? How does it help treat MG?
IV Ig
- Removes destructive antibodies by binding to circulating autoantibodies
- Inhibition of destruction of junctional folds of the postsynaptic membrane
- Increases the number of AChRs at the NMJ
For reversible inhibitors of anticholinesterases;
A) What is an example of a short-acting one?
B) What is an example of a medium-acting (injection) one?
C) what is an example of a medium-acting (oral) one?
A)
- Edrophonium –> used for diagnosis of MG
B)
- Neostigmine –> to reverse competitive neuromuscular block
C)
- Neostigmine
- Pyridostigmine
Both used orally in the treatment of myasthenia gravis
What is the general MOA of neostigmine and pyridostigmine (anticholinesterase)? Does it cross the BBB?
Indicated for the symptomatic management of MG
- Inhibit acetylcholinesterase (AChE)
- Prevent break down of ACh –> increased binding to the limited number of receptors due to increased concentration of endogenous ACh in the synapse
- Improve neuromuscular transmission and increasing muscular contraction
does not cross BBB
Where is there enhancement of cholinergic transmission when neostigmine and pyridostigmine (anticholinesterase) is used?
- Autonomic cholinergic synapses
- Skeletal neuromuscular junction
- CNS synapses
increase amount of ACH
What are some of the muscarinic effects on autonomic cholinergic synapses (anticholinesterases)?
Muscarinic effects (parasympathetic nervous system) of anticholinesterases are identical to those of direct-acting muscarinic agonists –> due to increased amount of acetylcholine at the synapse
- Increased glandular secretion
- Increase tone and motility of GI smooth muscle
- Braydcardia
- Bronchial constriction
- Miosis (pupil constriction)
- Decreased intraocular pressure
- Urinary urgency
What are some of the effects on the neuromuscular junction (NMJ)(anticholinesterases)? What is it dependent on?
Effects of anticholinesterases at NMJ are dose dependent
- Acting on nicotinic receptors
- At therapeutic doses - increase in force of contraction
Toxic Doses
- At toxic doses – reduction in force of contraction
- Reduced contraction due to excessive amount of ACh at NMJ
- Keep end-plate in a constant state of depolarisation
- Cause depolarising neuromuscular blockade
- Twitching
What are some of the effects on the CNS (anticholinesterases)? What is it dependent on?
Effects of anticholinesterases on the CNS is dose dependent
- Therapeutic doses – produce mild stimulation, result in convulsion
- Toxic doses – depress the CNS, respiratory depression
- For CNS effects – needs to cross blood-brain barrier (BBB)
- Tertiary compounds (physostigmine) and non-polar organophosphates cross BBB
> Neostigmine and pyridostigmine DO NOT cross BBB
What are the active sites of acetylcholine?
- Catalytic site
- Anionic site
For edrophonium (short-acting anticholinesterase), where does it bind to? What is it used for and what are the effects of it?
- Quaternary ammonium compound
- Binds to anionic site of enzyme only
- Ionic bond easily reversible
- Very short acting
- MAINLY use for differential diagnosis of myasthenia gravis
- Briefly relieves weakness in myasthenia gravis involving the eye muscles
For neostigmine and pyridostigmine (medium-acting anticholinesterase), where does it bind to? Why is it long-lasting?
- Binds at both anionic and catalytic sites –> reversible
- Acts as a substrate for AChE, like Ach –> increases Ach levels
- Hydrolysis of the carbamylated enzyme is slow (minutes) compared to Ach (milliseconds)
- Long-lasting effect
Summarise the 3 different forms of reversible anticholinesterases
See attached image
How does myasthenia gravis damage/destroy acetylcholine receptors?
By complement fixation or by inducing the muscle cell to eliminate the receptors through endocytosis
What is a cholinergic crisis? Examples (DUMBBELLS)
Pyridostigmine and neostigmine when used within therapeutic dose –> less likely to cause a cholinergic crisis
Excessive muscarinic stimulation –> respiratory depression (results from neuromuscular blockade and CNS depression)
- D - Diarrhoea
- U - Urination
- M - Miosis (constriction of the pupil of the eye)
- B - Bradycardia (slow heart beat)
- B - Bronchospasm (difficulty breathing)
- E - Emesis and Excitation of skeletal muscle
- L - Lacrimation (excessive tear production)
- L - Lethargy (fatigue)
- S - Salivation (excessive drooling)
