Neuromuscular blocking drugs Flashcards
What is ACh synthesised from and which enzyme does this?
acetyl CoA and choline
choline acetyltransferase (CAT)
Where is CAT found?
only in cholinergic nerve terminals
What happens to ACh after it has acted on the receptors?
its broken down by acteylcholinesterase into choline and acetic acid and then reuptaken into the presynaptic nerve terminal
Where does the ACh bind at neuromuscular junctions?
Nicotonic acetylcholine receptors on the end plate (usually in the middle of the fibres)
Describe how nicotinic receptors work
they are ion linked channels - when the receptor is stimulated sodium ions influx
What is end plate potential?
Voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the NMJ
Where is the acetylcholinesterase bound?
to the basement membrane in the synaptic cleft
What are the three main neuromuscular blockers?
tubocurarine
atracurium
suxamethonium
What are the two main types of nicotinic receptors?
ganglionic (neuronal)
muscle (skeletal)
Describe the structure of the nicotinic receptor
membrane spanning
- 5 subunits
- 2 alpha subunits
- these alpha subunits found on the top of the receptor either side must be activated for receptor activation
How many molecules of ACh are needed to activate the nicotinic receptor?
2
What is diazepam and how does it work?
a spasmolytic
- it facilitates GABA transmission
- useful in cerebral palsy and spasticity after strokes etc.
Where do local anaesthetics work?
affect the conduction of AP down neurones
- unwanted SE caused when a motor neurone is affected and muscle weakness can occur
What does botulinum toxin do?
It inhibits the release of ACh so blocks the contraction of respiratory skeletal muscle therefore can be lethal (neurotoxins)
What are the two types of neuromuscular blocking drugs and where do they act?
Depolarising - Suxamethonium
Non-Depolarising - Tubocurarine
Are neuromuscular drugs post or pre-synaptic acting?
post - they act on the nicotinic receptors on the motor end plate
What are non-depolarising drugs and how do they work?
Competitive nicotinic receptor antagonist
What are depolarising drugs and how do they work?
Nicotinic receptor agonists
Do neuromuscular blocking drugs affect conciousness, pain? What should be done when they are given and why?
- NO
- NO
- Assist respiration as it affect respiratory muscles
Describe the structures of non depolarising drugs
big, bulky with relatively restricted motion around the bonds
Describe the structure of suxamethonium
made of two ACh molecules
- flexible and allows rotation
- one can stimulate the receptor alone
How does suxamethonium work?
It causes an extended end plate depolarisation -> leads to a depolarisation block of the NMJ
This is called a phase 1 block
- If you give a patient suxamethonium, it will slowly seep into the muscle fibres
- It will stimulate the nicotinic receptors
- It isn’t metabolised as rapidly as acetylcholine
- So it will remain bound to the nicotinic receptors and very quickly these receptors will switch off
- This is a depolarisation block caused by overstimulation
What can suxamethonium lead to?
Fasciculations: individual fibre twitches as the suxamethonium begins to stimulate nicotinic receptors
Describe the pharmacokinetics of suxamethonium
Route: Intravenous (highly charged)
Duration of paralysis: 5 minutes (short-lived)
Metabolised by pseudocholinesterase in the liver and plasma
What are the uses of suxamethonium?
Endotracheal Intubation: It relaxes the skeletal muscle of the airways
Muscle Relaxant for Electroconvulsive Therapy: This is a treatment for severe clinical depression
What are some unwanted effects of suxamethonium?
Post-operative muscle pains – This is due to the initial fasciculations
Bradycardia – This is due to the direct muscarinic action on the heart. But this effects tends to be prevented by the fact that suxamethonium is generally given after general anaesthetic when patients would have had atropine (competitive muscarinic antagonist) in their pre-med
Hyperkalaemia
Raised Intraocular Pressure – avoid for eye injuries and glaucoma
Flaccid paralysis
Fasciculations
Why does suxamethonium cause hyperkalaemia?
Soft tissue injury or burns can lead to ventricular arrhythmias/cardiac arrest. If there is a burn/soft tissue injury, you lose some of the neurones innervating the muscle and so you get upregulation of the receptors in the skeletal muscle = deinnervation supersensitivity. So if you give suxamethonium you will get an exaggerated response. You get bigger influx of sodium and bigger efflux of potassium
What is tubocurarine?
Non-depolarising neuromuscular blocker
Naturally occurring ammonium compound (alkaloid) found in South American plant
How does tubocurarine work?
Competitive nicotinic acetylcholine receptor antagonist
- You need about 70-80% block to achieve full relaxation of the muscles
- If you block this proportion of receptors, the end-plate potential generated won’t reach the threshold
What are the effects of tubocurarine?
- The effects are the same as suxamethonium
- This also produces flaccid paralysis
How does recovery of muscles occur following tubocurarine?
The skeletal muscles relax in a certain sequence and they get back to normal in the opposite order:
- Extrinsic eye muscles (relaxes first, gets back to normal last)
- Small muscles of the face, limbs, pharynx
- Respiratory muscles (relaxes last, gets back to normal first)
What is the effect of tubocurarine on the NM transmission?
You get a little shoulder in the action potential which is the end-plate potential
If tubocurarine has been given, you get the beginning of the depolarisation but the depolarisation is too small to trigger an action potential
What are the uses of tubocurarine?
Relaxation of skeletal muscles during surgical operations (less anaesthetic needed). This is because the NM blocker has taken the role of making the muscles relax so the dose of the GA can be lower
Permit Artificial Ventilation
How can the effects of non-depolarising neuromuscular drugs be reversed?
anti cholinesterases e.g. neostigmine
(Giving neostigmine increases ACh conc in all other cholinergic synpases so give atroping with it to block muscarinic over stimulation)
Describe the pharmacokinetics of tubocurarine
- All the neuromuscular blockers are given intravenously (highly charged)
- Does not cross the BBB or placenta
- Long duration of paralysis: 40-60 mins
- Not metabolised at all
- It is excreted in the urine (70%) and the bile (30%)
- If there is impairment in hepatic or renal function, the duration of action of tubocurarine is increas
Which drug should be given in place of tubocurarine if the patients has liver or kidney impairment?
atracurium as not affected by liver or kidney function
It is chemically unstable molecule and
due to the pH of the plasma it gets hydrolysed into two inactive fragments
What are the unwanted effects of tubocurarine?
- Ganglion block – it could block some of the nicotinic receptors in the ganglia
- Histamine release from mast cells
- Hypotension (due to ganglion blockade and histamine acting on the H1 receptors causing vasodilation)
- Tachycardia (May lead to arrhythmias, this is a reflex in response to the hypotension or could also be due to the blockade of vagal ganglia)
- Bronchospasm (caused by the histamine release)
- Excessive secretions (bronchial and salivary, caused by the histamine release)
Apnoea
Which two mechanisms cause the majority of unwanted effects of tubocurarine?
ganglion blockade and histamine release from mast cells
