Pharmacology of the NMJ Flashcards
what are the three ways to block neuromuscular transmission
presynaptically, by inhibiting ACh synthesis
-rate-limiting step is choline uptake
presynpatically, by inhibiting ACh release
Postsynaptically
- by interfering with the actions of ACh on the receptor
What are the ways of blocking ACh release
Local anaesthetics
General inhalation anaesthetics
Inhibitors/competitors of calcium
- magnesium ions (compete with calcium)
- some antibiotics (bind to ca2+)(ahminoglycosides (gentamicin) and tetracycline)
Neurotoxins
- botulinum toxin (clostridium botulinum)
- beta bungarotoxin (botox, stops the triggering of ACh)
Name some clinical uses of neuromuscular blocking drugs
endotracheal intubation
During surgical procedures
- to allow surgical access to abdominal cavity
- to ensure immobility
- allow relaxation to reduce displaced fracture or dislocation
- decrease in concentration of general anaesthetic needed
Infrequently used in intensive care
- mechanical ventilation at extremes of hypoxia
During electroconvulsive therapy
what is the structure of the nicotinic acetylcholine receptor
found in the NMJ but also in the brain and autonomic nervous system.
has a central pore of 0.7nm in diameter
two alpha helices forming the gate
two ACh receptors
nicotinic acetylcholine receptor agonist
this causes ACh to bind and causes a conformational change but then eventually leads to loss of control
nicotinic acetylcholine receptor antagonist
This channel is simply closed
what is the action of non-depolarising blockers = competitive antagonists of Nicotinic ACh receptors at the NMJ
TUBOCURARINE
prevents ACh binding to receptor by occupying site
Decreases the motor end plate potential (EPP)
decreases depolarisation of the motor end plate region
No activation of the muscle potential
What is the action of depolarising blockers = agonists of nicotinic acetylcholine receptor at the NMJJ = NOT METABALISED BY ACETYLCHOLINE ESTERASE
SUXAMETHONIUM
This initially causes a twitch due to a small AP which immediately goes away so does cause an initial conformational change.
Persistent depolarisation of the motor endplate
prolonged EPP
Prolonged depolarisation of the muscle membrane
Membrane potential above the threshold for the resting of the voltage-gated sodium channels
sodium channels remain refractory
no more muscle action potentials generated
Phase 1, in a depolarising block
Phase 1:
muscle fasciculations observed, then blocked
depolarisation inhibited (K+ leaks from the cells as sodium enters (hyperkalemia)
voltage gated na+ channels kept inactivated
Phase 2, in a depolarising block
prolonged/increased exposure to drug
‘desensitisation blockade’ - tissue desensitisation due to prolonged exposure -depolarisation cannot occur, even in the absence of the drug
the side effects of non-depolarising blockers
normally result in tachycardia responses and hypotension (AM) which leads to bronchospasm due to histamine release
the side effects of depolarising blockers include
brachycardia cardiac dysrhythmias raised intraocular pressure postoperative myalgia - feeling of flu or space malignant hyperthermia
What blocker can be used for ester hydrolysis and Hofmann elimination
atracurium
what blockers can be used for plasma cholinesterases
these provide a prolonged block
- mivacurium
- suxamethonium
what blockers can be used for hepatic metabolism
pancuronium
vecuronium
what blocker is unchanged in bile and urine
recuronium
what is the action of ACh regulated by
hydrolysis
acetylcholinesterase (synaptic cleft NMJ and is readily available)
true cholinesterase, specific for hydrolysis of ACh
present in conducting tissue and red blood cells
bound to basement membrane in the synaptic cleft
plasma cholinesterase
pseudocholinesterase, broad spectrum of substrates
widespread distribution
soluble in plasma
(prevents breakdown of ACh)
tell me more about anticholinesterases
they are all inhibitors of cholinesterases which result in:
- increase in availability of ACh at NMJ
- increases duration of activity of ACh at NMJ
- More ACh to compete with non-depolarising blockers
pancuronium
medium onset and long duration, non depolarising so tachycardia
vecuronium
medium onset and medium duration non depolarising with few side effects
rocuronium
fast onset and medium duration non-depolarising with tachycardia side effects
atracurium
medium onset with medium duration, non-depolarising with hypotension/bronchospasm side effects
mivacurium
fast onset with short duration, non-depolarising with hypotension/bronchospasm side effects
neostigmine and pyridostigmine
medium duration, anticholinesterase, formation of carbamylated enzyme complex
dyflos and marathon
long onset and act by irreversible inhibition
what slows the rate of hydrolysis
carbamylation
phosphorylation by dyflos/parathion irreversibly changes the enzyme unless
coaxed out by pralidoxime so there can be synthesis of a new enzyme
Effects of anticholinesterases on the CNS
Initial excitation with convulsions
unconsciousness and respiratory failure
Effects of anticholinesterases on the ANS
SLUDGE SALIVATION LACRIMATION URINATION DEFACATION GASTROINTESTINAL UPSET EMESIS (vomit)
what are the clinical uses of anticholinesterases
In anaesthesia
– Reverse non-depolarising muscle blockade
– Given with atropine or glycopyrrolate to counteract
parasympathetic effects
Myasthenia Gravis
– Increase neuromuscular transmission
Glaucoma
– Decrease intraocular pressure
Alzheimer’s disease
– Enhance the cholinergic transmission in the CNS
Myasthenia gravis
autoantibodies may be produced against the acetylcholine receptor blocking the interaction of the acetylcholine receptor with its ligand (acetylcholine) and leading to increased muscle weakness and death.
Sugammadex
Selective relaxant binding agent (SRBA)
• Reverses effects of rocuronium and vecuronium
