Neuromuscular Junction Flashcards
What is the somatic efferent motor system?
Component of PNS associated with VOLUNTARY control of skeletal muscles.
Also responsible for reflex arc - utilising interneurones.
Cell bodies of somatic motor efferent system are in the BRAIN STEM.
What is the motor unit?
1 motor neurone connects the CNS to the skeletal muscle fibre, cell bodies are in the brain stem.
BUT a single axon can innervate multiple fibres… just that each fibre is only innervated by a single motor neurone.
The motor unit = the skeletal muscle fibre and the single motor neurone that innervates it.
What is the NMJ?
Pre-synaptic terminal, with synaptic cleft and then the motor end plate.
high density of nicotinic ACh receptors.
How is ACh released at the NMJ?
AP causes Ca2+ influx, causing fusion of ACh storage vesicles with pre-synaptic terminal and release across synaptic cleft.
ACh metabolised by acetylcholinesterases…
Acts on nicotinic ACh receptors.
What ACh receptors are found on the motor end plate?
Ligand-gated ion channel allowing Na+ in, K+ out = to depolarise the end plate and generated end plate potential.
Contains 2 alpha subunits, 1 Beta, 1 Delta and 1 Gamma = pentameric = 5 subunits….
In autonomic ganglia = 2 alpha3, with 3beta..
in CNS, = a4, a7, B,D,Y…
How is NMJ signal spread?
ACh binds to nACh receptors in motor end plate, leads to Na+ influx, K+ efflux via its channel.
= Depolarisation is called the End Plate Potential.
This initiates the opening of proximal VG Na+ channels = amplifying the ion flux, to generate an AP in muscle cell.
but only once!
Signal is rapidly terminated by AChE…
How does NMJ lead to contraction?
Excitation-Contraction coupling.
AP propagates down T-tubules to penetrate into muscle fibre.
Depolarisation causes opening of L-Type Ca2+ channels
and stimulates Ca2+ induced, Ca2+ release from SR.
= by opening Ryanodine Ca2+ channels.
Why are NMJ blockers needed in surgery?
During anaesthesia induction, there are motor reflexes that can hinder intubation.
Need to immobilise areas under investigation…
Muscle spasm can occur with mechanical manipulation of limbs and nerves.
What are NMJ blocking drugs?
Non-depolarising agents = antagonists to nACh receptors.
Depolarising agents = weak nicotinic ACh receptor agonists!?
What is d-Tubocurarine?
Found in plant called Curare, but poor oral absorption…
Can cause paralysis by blocking NMJ transmission, but doesn’t hinder nerve conduction or muscle contractility.
Competitive antagonist to nACh receptor at NMJ…
But since an excess of ACh is released at NMJ, need to block most receptors to work…
= Tubocurarine reduces End Plate Potential so it cannot exceed threshold to initiate AP…
What are the synthetic derivatives of d-Tubocurarine?
Atracurium, Pancuronium and Gallamine.
With shorter durations of action, safer and paralysis fades rapidly after surgery…
= Non-depolarising NMJ blockers…
What is alpha-Bungarotoxin?
Irreversible binder to nACh receptors at NMJ.
Inhibits ACh from binding, stopping ACh-induced contraction…
But not used in clinic !!!
What are the side effects of non-depolarising blockers?
Hypotension = as also blockade of ganglion#
Cause histamine release in Mast Cells = which can cause bronchospasm..
Respiratory failure = so need to be assisted ventilation in surgery!!!
With Gallamine and Pancuronium = M2 blockade = tachycardia…
What are depolarising blocking agents?
Symmetrical bisquarternary ammonium compounds which are structurally similar to ACh…. but have +ve charged nitrogen atoms.
= Affinity to alpha subunits in post-synaptic nACh receptors…
Decamethonium, Suxamethonium..
What is the MoA of depolarising blocking agents?
Initially, they bind and activate nACh receptors…
to cause typical depolarisation of muscle…
But! Suxamethonium is slowly hydrolysed by plasma cholinesterases.
= so depolarisation is maintained at the end plate.
= LOSING electrical excitability..
What are the results of depolarising agents?
By being slowly hydrolysed by plasma cholinesterases, they maintain depolarisation at Endplate…
and muscle loses its electrical excitability…
Therefore, there is initial twitching of skeletal muscle… but then produces rapid block.
What is Phase 1 of depolarising agent block?
Depolarising phase.
As they are agonists to nACh receptors…
Slowly hydrolysed by plasma cholinesterases…
Muscle gets held in a depolarised state and proximal VG Na+ channels become refractory = so don’t respond to ACh binding at nicotinic receptor.
= Muscle becomes flaccid as Ca2+ is taken into stores…
Channel will remain inactive until the membrane repolarises….
This depolarised state keeps VG Na+ channels refractory
What is Phase 2 of depolarising agent block?
The desensitiation phase.
With persistent stimulation, leads to nACh receptor desensitisation.
The receptor will remain inactive until the ligand is removed…
Transmission is blocked despite partial repolarisation occuring due to Na+/K+ ATPase.
What is the train of Four?
An assessment to measure the depth of anaesthesia?
What are the advantages to suxamethonium/depolarising block?
Less likely to elicit Histamine release like non-depolarising blockers…
Can be used for surgery during pregnancy/ C sections.
As suxamethonium is poorly crossed to placenta as ionised = safer for babies.
Rapid onset with a short duration of action… used to intubate.