Neuromuscular blocking drugs Flashcards
Describe neuromuscular impulse transmission
Action potential propagates along the presynaptic neurone => depolarisation of presynaptic membrane => opening of voltage gated calcium channels => calcium influx => ACh vesicle exocytosis
What type of receptor is found at the NMJ?*
Nicotinic acetylcholine receptors
*Note: nAChR at the NMJ slightly differ in structure to the nAChR of the ANS
Where are these receptors found on the muscle fibre?
Motor end plate (usually in high concentration in the middle of the muscle fibres)
Describe the character of the depolarisation of the end plate region
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?
Bound to the post-synaptic membrane of the muscle end plate
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 in the CNS and describe their action.
Diazepam
Baclofen (GABA receptor agonist)
- They both facilitate GABA transmission
Give some examples of conditions in which CNS 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 too close to a motor neurone then you may see some muscle weakness)
What drugs inhibit ACh release by exocytosis?
- Hemicholinium
- Ca2+ entry blockers
- Neurotoxins (e.g. botulinum toxin prevents the contraction of respiratory skeletal muscle causing respiratory arrest and death)
What are the two types of neuromuscular blockers?
Depolarising
Non-depolarising
Name another spasmolytic with a different site of action to create the same effect
Dantrolene
- It works in the muscle fibres themselves by inhibiting calcium release from the sarcoplasmic reticulum in the muscle fibre
Name and describe depolarising and non-depolarising neuromuscular blocking drugs
DEPOLARISING:
e.g. Suxamethonium
= nicotinic acetylcholine receptor agonist
NON-DEPOLARISING
e.g. tubocurarine, atracurium
= nicotinic acetylcholine receptor competitive antagonist
Do NM blockers affect consciousness and pain sensation?
No
What must you always do when giving NM blockers?
Assist respiration (until drug is inactive or antagonised) because of their effect on respiratory muscle action
Describe the difference in structure between non-depolarising and depolarising NM blockers?
Non-depolarising = tend to be big, bulky molecules with limited movement around their bonds
Suxamethonium (depolarising) = made up of two acetylcholine molecules linked together (more flexible and allows rotation).
As it is made up of two acetylcholine molecules, one suxamethonium can bind to the two alpha subunits and activate the receptor.
Describe the mechanism of action suxamethonium (and state the route of administration)
ROA = i.v. (highly charged)
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 (short)
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 tissue
- Then you will get up-regulation 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 effect 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; naturally occurring alkaloid found in South American plant (but a range of synthetic drugs now available)
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
State the effect of tubocurarine and the order of relaxation of skeletal muscle (and reverse)
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 (so less general anaesthetic is needed)
- Permit artificial ventilation
How can the actions of non-depolarising NM blockers be reversed? What drug combination might be used, and why?
Give an anti-cholinesterase (e.g. physostigmine)
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
=> anti-cholinesterase + atropine
How is tubocurarine administers? What is the duration of paralysis?
Intra-venously (highly charged)
1-2hrs (long)
Describe the metabolism and excretion of tubocurarine?
It is NOT metabolised at all
It is excreted in the urine (70%) and bile (30%)
Does tubocurarine cross the BBB or placenta?
No
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 instead (15 min duration) and is NOT affected by liver or kidney function
State some unwanted effects of tubocurarine.
Ganglion block + histamine release from mast cells cause most of the unwanted effects:
HYPOTENSION
- ganglion blockade = reduced TPR
- 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
