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31
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17 – Dr Whitehead
Tuesday 31st October 2017
The Pharmacology of the Neuromuscular Junction
Pharmacology of the NMJ:

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Nicotinic ACh present pre-synaptically; influences release
CAT = synthetic enzyme for ACh
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)
Vesicles with special protein on them which takes ACh and loads it into vesicles for
exocytosis
Choline carrier takes choline back up into pre-synaptic element
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o Choline taken back up; used to make more ACh and then loaded into vesicle
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o Receptors for the neurotransmitter released by its own neuron is detecting itself,
called an auto-receptor
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 Mediate negative feedback on release
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 Makes synapse more reliable
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10
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Cholinacetyltransferase (CAT) from acetyl CoA & choline (No Drugs target this)
o Carrier transports ACh into vesicle (loads acetylcholine into vesicles (blocked by
Vesamicol – drug with no clinical use)
o Choline transporter – blocked by Hemicholinium – drug used for research but not
clinically
o Exocytosis of vesicle (blocked by toxins) – these drugs are actually toxins, stops
release of neurotransmitter

Botulinum Toxin
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Clostridium botulinum (anaerobic bacteria)
o Thrives in anaerobic environments
Source of potentially lethal food poisoning
10-12g toxin – lethal for mouse
2 subunits:
o 1- binds to presynaptic membrane (binds selectively to nerve endings of neurones
which release ACh – something specific on membrane)
o 2- (peptidases) cleaves proteins involved in exocytosis (inside nerve ending)
Kills you by affecting release of ACh by blocking exocytosis/ ACh release
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S
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E
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glands- GIT, smooth muscle contraction, secretion of saliva
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10
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g
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Drugs Acting post-synaptically: Neuromuscular blockers:
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More commonly used clinically
Working on post-synaptic receptor; so, at level of nicotinic receptor
Used as Adjunct (add-on) to anaesthesia
o Used when GA used to allow clinician to use lower conc of GA
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tubocurarine
o Depolarising blockers
 Agonists
 Both produce paralysis
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Structure of D-Tubocurarine has sites which block both sites on
ACh
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no action
potential
Use: adjunct to GA  15mins to 2hrs of muscle relaxation
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o So… the time that patient is paralysed depends on patient’s metabolism speed
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Causes end plate depolarisation
 Action potentials
 Uncoordinated, fine contractions/Twitches/fasciculations – motor endplates
firing randomly
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Not broken down by acetylcholinesterase (AChE) in synaptic cleft
 Prolonged depolarisation
 Paralysis; due to inactivation of voltage-gated Na+ channels = Phase 1 block
 Need to go through period of deactivation (refractory period) to allow
another action potential to be generated
 Absolute refractory period= can not fire action potential bc too many Vgated Na+ channels inactivated  so many in this drug, that you have to
wait a very long time before an action potential can be generated (veryy
long refractory period causes paralysis)
Suxamethonium:
o Brief procedures e
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intubation; 10mins
o Given intra-venously (IV)
o Broken down by plasma cholinesterase (rapid recovery compared to nondepolarising blockers
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Large driving force for K+ to leave cell, prolonged time
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31
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17 – Dr Whitehead
Burn has caused damage to nerve supply to muscle, you get postsynaptic super sensitivity, so muscles & motor end plate has
expressed more receptors to make up for fact that less ACh released
by damaged nerves
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Increase intraocular pressure (contraction of extraocular muscles)
 Extra-ocular Muscles around eye contract, squeezing eyeballs, increasing
pressure in eye
Prolonged paralysis = Phase 2 block
 Due to inactivation of nACh receptor (ligand-gated channel becomes
inactivated)
 Bc Suxamethonium not broken down quickly as normal (individual may not
have correct enzyme or less enzymatic activity)
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o

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Post-synaptic modulators: Cholinesterase inhibitors:

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Actions:
o Interact with AChE & plasma cholinesterase (where acetyl groups bind)
o Prevent breakdown of ACh
 Enhance synaptic function
o Affect other synapses than the NMJ, where ACh is transmitter
 Autonomic ganglia & postganglionic parasympathetic nerves (postganglionic innervate the end fibres/tissues)
 ACh is the neurotransmitter at pre-ganglionic fibres so there must
be ACh receptors expressed on cells and post-ganglionic fibres
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o End of operation
o Increases ACh levels- compete with antagonist (allows ACh to last longer in synapse
so it can out-compete the drug)  increase EPP
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B
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Myasthenia gravis:
o Autoimmune: antibody against nicotinic AChR
o Muscle weakness  progressive… death
o Muscle weakness bc failure of NMJ transmission
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 Neostigmine
 Drug used clinically to control symptoms, Medium duration,
muscarinic side effects
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Better oral absorption, long duration,
less powerful

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