10. Neuromuscular blocking drugs Flashcards
what are the targets for acetylcholine at neuromuscular junctions?
nicotinic acetylcholine receptors on the end plate
what happens when nicotinic receptors are stimulated?
- nicotinic receptors are ion channel linked
- conformational change and sodium ion influx
- depolarisation of the membrane (end plate potential)
- action potential generated when threshold is reached
- propagation of the AP in both directions
- acetylcholinesterase is bound to the basement membrane in the synaptic cleft and breaks down acetylcholine to acetate and choline
what are the 3 main neuromuscular blockers?
- tubocurarine
- atracurium
- suxamethonium
what are the 2 main subtypes of nicotinic receptors?
- ganglionic (or neuronal)
- muscle
describe the nicotinic acetylcholine receptor
- span the membrane
- 5 subunits
- 2 a-subunits
- a-subunits must bind to ACh for the receptor to be activated THEREFORE 2 ACh molecules needed to activate receptor
name 2 spasmolytic drugs and their actions
- diazepam - facilitates GABA transmission
- baclofen - GABA receptor agonist
(3. dantrolene - reduces release of Ca2+ from SR)
what are diazepam and baclofen useful in?
some forms of cerebral palsy and spasticity following stroke
what is an unwanted effect of local anaesthetic?
muscle weakness
what drugs and toxins can interfere with ACh release?
- neurotoxins - inhibit release of ACh
- botulinum toxin
where do neuromuscular blocking drugs work?
on the nicotinic receptors on the motor end plate (post-synaptically)
depolarising nicotinic receptor agonists - suxamethonium
non-depolarising competitive nicotinic receptor antagonists - tubocurarine, atracurium
what do neuromuscular blocking drugs NOT affect?
- consciousness
- pain sensation
what should be done when giving neuromuscular blocking drugs?
assist respiration due to effects on the respiratory muscles
what is the structure of non-depolarising neuromuscular blocking drugs?
big, bulky molecules with restricted movement around the bonds
what is the structure of suxamethonium?
2 acetylcholine molecules linked together
what is the mechanism of action of suxamethonium?
- causes an extended end plate depolarisation -> leads to a depolarisation block of the NMJ
- isn’t metabolised as rapidly as ACh so will remain bound to the nicotinic receptors and will cause the receptors to quickly switch off (depolarisation block caused by overstimulation)
what are fasciculations and what causes them?
individual fibre twitches as the suxamethonium begins to stimulate nicotinic receptors, leading to flaccid paralysis
what are the pharmacokinetics of suxamethonium?
- intravenous route
- 5min duration of paralysis
- metabolised by pseudocholinesterase in the liver and plasma
what are the uses of suxamethonium?
- endotracheal intubation (relaxes the skeletal muscle of the airways)
- muscle relaxant for electroconvulsive therapy (treatment for severe clinical depression)
what are the unwanted effects of suxamethonium?
- post-operative muscle pains due to fasciculations
- bradycardia due to the direct muscarinic action on the heart
- hyperkalaemia
- raised intraocular pressure
why does suxamethonium cause hyperkalaemia?
- soft tissue injury/burns can lead to ventricular arrhythmias/cardiac arrest
- during a burn/soft tissue injury you lose some of the neurones innervating the muscle and there is upregulation of the receptors in the skeletal muscle = denervation supersensitivity
- giving suxamethonium will result in an exaggerated response leading to a bigger influx of sodium and bigger efflux of potassium
describe tubocurarine
- non-depolarising neuromuscular blocker
- naturally occurring ammonium compound (alkaloid) found in South American plant
what is the mechanism of action of tubocurarine?
- competitive nicotinic acetylcholine receptor antagonist
- 70-80% block is necessary to achieve full relaxation of the muscle as this will ensure the end-plate potential generated will not reach the threshold
what are the effects of tubocurarine?
- same as suxamethonium
- flaccid paralysis
- skeletal muscles relax in a certain sequence and go back to normal in the opposite order:
1. extrinsic eye muscles
2. small muscles of the face, limbs, pharynx
3. respiratory muscles
what are the uses of tubocurarine?
- relaxation of skeletal muscles during surgical operations (less anaesthetic needed)
- permit artificial ventilation
