Neuromuscular Blocking Drugs Flashcards
Describe how impulses are transmitted across synapses.
Action potential propagates along the presynaptic neurone -> depolarisation of presynaptic membrane -> opening of voltage gated calcium channels -> calcium influx -> vesicle exocytosis
What type of receptor is found at the neuromuscular junction?
Nicotinic acetylcholine receptors
Where are these receptors found on the muscle fibre?
Motor end plate (usually in the middle of the muscle fibres)
What does depolarisation of this membrane cause? Describe the character of this depolarisation.
This causes a change in end plate potential
This is a graded potential meaning that it is dependent on the amount of acetylcholine released and the number of receptors stimulated
Once the end plate potential reaches a threshold, it generates an action potential that propagates in both directions along the muscle fibre
Where is acetylcholinesterase found?
It is bound to the basement membrane in the synaptic cleft
State the three main neuromuscule blockers.
Tubocurarine
Atracurium
Suxamethonium
State the two main types of nicotinic acetylcholine receptor.
Ganglionic
Muscle
Describe the structure of nicotinic acetylcholine receptors.
They consist of 5 subunits (subunits can be alpha, beta, gamma, delta, epsilon)
There are always 2 alpha subunits, which bind to acetylcholine and activate the receptor
How many molecules of acetylcholine are required to activate one nicotinic acetylcholine receptor?
2
Name two drugs that are used as spasmolytics and describe theiraction.
Diazepam
Baclofen (GABA receptor agonist)
They both facilitate GABA transmission
Give some examples of conditions in which spasmolytics may be used.
They are both useful in some forms of cerebral palsy and spasticity following strokes
What do local anaesthetics have their effect on?
Conduction of action potentials in motor neurones (so if you inject local anaesthetic to a motor neurone then you may see some muscle weakness)
Describe the action of neurotoxins.
Neurotoxins inhibit the release of acetylcholine and hence block the contraction of respiratory skeletal muscle causing death
What are the two types of neuromuscular blocker?
Depolarising
Non-depolarising
Name another spasmolytic that has a different action to create the same effect.
Dantrolene – it works in the muscle fibres themselves by inhibiting calcium release in the muscle fibre
Describe the difference in mechanism of action between depolarising and non-depolarising NM blockers. Which NM blockers fall into each category?
Depolarising = suxamethonium = nicotinic acetylcholine receptor AGONIST Non-depolarising = tubocurarine + atracurium = nicotinic acetylcholine receptor antagonist
How do NM blockers affect consciousness and pain sensation?
They do NOT
What must you always do when giving NM blockers?
Assist respiration because of their effect on respiratory muscle action
Describe the difference in structure between non-depolarising and depolarising NM blockers?
Non-depolarising = big, bulky molecules with limited movement around their bonds Suxamethonium = made up of two acetylcholine molecules that are linked together. This is more flexible and allows rotation. As it is madeup of two acetylcholine molecules it can binds to the two alpha subunits and activate the receptor.
Describe the mechanism of action suxamethonium.
Suxamethonium is a nicotinic receptor agonist.
It causes an extended end plate depolarisation leading to a depolarising block of the NMJ
This is a phase 1 block
NOTE: it is not metabolised as rapidly as acetylcholine so it will remain bound to the nicotinic receptors making them switch off due to overstimulation
It eventually results in FLACCID PARALYSIS
What does suxamethonium normally cause before causing the flaccid paralysis?
Fasciculations – individual fibre twitches as the suxamethonium begins to stimulate the nicotinic receptor (remember it is an agonist)
What is the duration of paralysis of suxamethonium?
5 mins
How is suxamethonium metabolised?
It is metabolised by pseudocholinesterase (butyrylcholinesterase) in the liver and plasma
What are some uses of suxamethonium?
Endotracheal intubation – relaxes the muscles of the airways
Muscle relaxant for electroconvulsive therapy – treatment for severe clinical depression
State and explain four unwanted effects of suxamethonium.
Post-operative muscle pains
Due to initial fasciculations
Hyperkalaemia
If there is soft tissue injury or burns you will lose some neurones innervating the tissuea
Then you will get upregulation of receptors in the skeletal muscle – deinnervation supersensitivity
So if you give suxamethonium you get an exaggerated response with a bigger influx of sodium and bigger efflux of potassium
Bradycardia
This is due to the direct muscarinic action on the heart
This effects tends to be prevented because suxamethonium is usually given after GA and hence following administration of atropine (muscarinic antagonist) in the pre-med
Raised intraocular pressure
AVOID for eye injuries and glaucoma
Describe the mechanism of action of tubocurarine.
Tubocurarine is a competitive nicotinic acetylcholine receptor antagonist.
You only need 70-80% block to achieve full relaxation of the muscles
If you block this proportion of the receptors then the end-plate potential generated will NOT reach the threshold
Describe the order of relaxation of skeletal muscles and the orderin which they return back to normal when given tubocurarine.
This also causes flaccid paralysis.
Order:
Extrinsic eye muscles (first to relax, last to go back to normal)
Small muscles of the face, limbs and pharynx
Respiratory muscles
State two uses of tubocurarine.
Relaxation of muscles during surgical operations (this means that less general anaesthetic is needed)
Permit artificial ventilation
How can the actions of NM blockers be reversed?
Give an anti-cholinesterase (e.g. physostigmine)
What else must you give with this drug when trying to reverse theactions of NM blockers?
Atropine
Giving physostigmine will raise the synaptic concentration of acetylcholine at ALL cholinergic synapses (not just the neuromuscular junctions) so you need some atropine to block these unwanted effects
How are all NM blockers administered?
Intravenously
What is the duration of paralysis of tubocurarine?
40 mins
Describe the metabolism and excretion of tubocurarine?
It is NOT metabolised at all
It is excreted in the urine (70%) and bile (30%)
Under which conditions would you get an increased duration of action of tubocurarine? What would you change under these conditions?
Impairment of hepatic or renal function increases the duration of action of tubocurarine
Under these conditions you would use ATRACURIUM (15 min duration) and is NOT affected by liver or kidney function
State some unwanted effects of tubocurarine.
MAIN EFFECTS: ganglion block + histamine release from mast cells cause most of the unwanted effects
HYPOTENSION – histamine can act on H1 receptors and cause vasodilation
TACHYCARDIA – reflex tachycardia in response to hypotension
BRONCHOSPASM – caused by histamine release
EXCESSIVE SECRETIONS (bronchial and salivary) – histamine release
APNOEA – which is why you assist respiration
