week 12 L3: Skeletal neuromuscular junction Flashcards
What 3 drugs interact with nAChR?
tubocurarine (curarae), alpha-bungarotoxin, suxamethonium
How can these drugs be analysed?
The organ bath = salt solution
How does Organ Bath analysis work?
dissect out nerve from muscle (e.g. phrenic nerve hemi-diaphragm preparation)
electrically stimulate nerve, contract, physical change to electrical change
… results on a chart recorder
What effect does Tubocurarine have on muscle?
muscle relaxant, skeletal muscle paralysis
How to test tubocurarine effects?
Put drug into bath
Blocks size of neurally evoked twitch
What type of drug is Tubocurarine?
competitive antagonist
competing with ACh
What can reverse Tubocurarine?
neotigmine is an anti-cholinesterase
How do anti-cholinesterase enzymes work?
Inhibit acetylcholinesterase enzyme (breaks down ACh to acetate and choline)–> increase ACh levels + time spent in NMJ–> more likely to bind to nAChR.
reverses block on neuromuscular transmission
Is Tubocurarine non or pro depolarising to enplate?
non-depolarising neuromuscular blocker
What is Tubocurarine’s effect on epp & mepp?
reduce epp & mepp to below threshold–> no contraction on skeletal muscle
Acts on postsynaptic site to block receptors
Where does alpha-bungarotoxin (BTX) come from?
venom in Taiwan banded krait
Does the anti-cholinesterase (neotigmine) work with BTX?
No, as it binds irreversibly to agonist recognition site on nAChR of skeletal neuromuscular junction
Effect of Bungarotoxin on epp & mepp?
decrease epp and mepp as no ACh can bind to post nAChR
What kind of drug is BTX?
irreversible antagonist
What kind of drug is Succinylcholine?
agonist but still causes skeletal muscle paralysis
What is Succinylcholine used for?
rapid tracheal intubation (paralysis)
What is Succinylcholine metablised by?
Plasma cholinesterase
Is Succinylcholine broken down by acetlycholinesteras?
NO
What happens in the PHASE 1 BLOCK (Succinylcholine)?
consistent activation of nAChR,
Prolonged depolarisation,
Inactivation of Na+ channels,
No AP in muscle fibre
What happens in the PHASE 2 BLOCK (Succinylcholine)?
Desensitisation of nACh,
Re-polarisation of endplate,
Receptor desensitised, maintain blockage
Name two types of Cholinesterase enzymes
- “True” acetylcholinesterase (AChE)
2. Pseudo-cholinesterase
Where would you find “True” acetylcholinesterase (AChE)?
cholinergenic synapses
bound to postsynaptic membrane
Name 2 types of Pseudo-cholinesterase?
butyrylcholinesterase & plasma cholinesterase
Where would you find Pseudo-cholinesterase?
plasma
important in activating and depolarising neurotransmitter blocker, Suxamethonium
Effect of neogmine on epp and mepp?
increase amplitude of epp & mepp
prolongs their duration
by breaking down AChE to prolong time on R
What’s a clinical use of anti-cholinesterases
used to reverse non-depolarising skeletal muscle relaxants e.g. tubocurarine
what’s a disease that is treated with anti-cholinesterase?
Myasthenia Gravis
auto immune disease
loss of nAChR NMJ
muscular weakness paralysis
How do you diagnose/treat Myasthenia Gravis?
endrophonium
anticholinesterase
What effect would endophonium have on Q.C?
No change to Q.C
Transmitters not broken down, increase ACh content in synapse
twitch is created and prolonged
What is a disease with a decreased expression of a presynaptic terminal?
Lambert-Eton Myasthenic Syndrome
produce antibodies that bind to voltage gated Ca+ channels
decrease Ca+ into cell, decrease vesicles released
Effect of Q.C with Lamber Eton Myasthenic Syndrome?
Decrease epp as fewer vesicles released
mepp not decreased as same number of ACh in vesicles
pre-synaptic deficit
How to treat LEMS?
Pyridostigmine (AChE inhibitor)
DAP
How does DAP work?
blocks K+ channels prolong action potential prolonged action of Ca+ channels opening increase Ca+ influx increase vesicle release
Is Myasthenia Gravis post of presynaptic?
post synaptic effects
How do you effect the amplitude of mepp?
Decrease number of ACh in vesicle or effect number of receptors
