Neuromuscular Blocking Drugs Flashcards
Which nervous system controls muscle innervation
Somatic nervous system
Where generally is the cell body of the alpha motor neurone
Spinal cord
How many neurons are between the cell body and muscle
1 single axon
Which horn of the spinal cord do you find the cell body of alpha motor neurone
Ventral horn
Specifically where do you find the cell body of the alpha motor neurone
Ventral horn of the spinal cord
What does CAT stand for
Choline acetyl transferase
What type of neurone do you find CAT in (X-ic receptor)
Cholinergic
What reaction does CAT catalyse
Acetyl CoA + choline ACh + CoA-SH
What is CoA-SH also known as
Co-enzyme A
What is the end plate
The post-synaptic membrane
What family of receptors does the receptor on the end plate belong to?
Nicotinic
With the first step being depolarisation of the presynaptic membrane, and ninth being an action potential propagating bidirectionally along the sarcolemma, describe the 9 steps and all the steps inbetween
1) Depolarisation of the presynaptic membrane
2) VGCC open
3) Ca2+ influx
4) ACh efflux
5) ACh binds to nicotinic ACh receptors on the end plate
6) Linked ion channel opens
7) Na+ influx
8) End plate potential reaches threshold
8) Action potential propagates bidirectionally
What type of receptor is the ACh receptor found on the end plate?
Nicotinic type-1 ion channel linked receptor
Which 3 molecules travel through the end plate ion channel when it opens after ACh stimulation? Which directions? What is similar of all 3 molecules that allows them to travel through together?
Na+ - influx
K+ - efflux
Ca2+ - influx
They are all cations
Is the potential that arises on the end plate of a muscle fibre graded or all or nothing?
Graded
Is the bidirectional action potential graded or all or nothing
All or nothing
What 2 factors does the size of the end plate potential depend upon
Amount of ACh released and how many receptors are stimulated
How long is a type-1 ion channel open for generally
Milliseconds
Whereabouts on a muscle fibre are the nicotinic ACh receptors usually found
Middle
Are nicotinic type-1 ion channel linked ACh receptors anion or cation channels
Cation
Under what circumstances is an action potential generated from an end plate potential
Normal
What enzyme breaks down ACh
Acetylcholinesterase
Where is acetylcholinesterase bound to
The basement membrane
What reaction does acetylcholinesterase catalyse
ACh –> acetic acid + choline
What is the fate of choline once it is made through the breakdown of ACh via acetylcholinesterase? What pump facilitates this
Can be pumped back into the presynaptic terminal through the choline pump to be reused to make more ACh
What are the three main neuromuscular blocking drugs
Tubocurarine, atracurium and suxamethonium
What are the two subtypes of nicotinic receptors
Ganglionic/(neuronal) type and muscle type
How many and what are the subunits on a nicotinic receptor
2 alpha, 1 beta delta and gamma.
Which subunit of the nicotinic acetylcholine receptor does ACh bind to
Alpha
How do drugs differentiate between ganglionic/neuronal cholinergic receptors and muscle type receptors
There is a slight difference in structure of the ganglionic/neuronal type and muscle type receptors that allows selectivity
Local anaesthetics: what site do they target/process do they affect
Conduction of action potential up/down neurones
What is the mechanism of a local anaesthetic
They block VGSC
Can/how do anaesthetics affect muscle intervention and why? Do they have selectivity
Local anaesthetics can cause muscle weakness because they block VGSC which is used to propagate AP to stimulate muscle contraction. Local anaesthetics do have a degree of selectivity to the relevant sensory neurone
Baclofen is a [X] receptor [agonist/antagonist]
GABA receptor agonist
Diazepam (Valium) is a [X] receptor [agonist/antagonist]
GABA receptor agonist
Name 2 GABA receptor agonists
Diazepam/Valium and baclofen
How do neurotoxins facilitate death (name neurotransmitter affected and the specific system which subsequently causes death when the function is impaired). Give an example of a neurotoxin
Inhibit the release of ACh which causes death through impairment of respiratory muscles
Where do neuromuscular blocking drugs act
Nicotinic receptors on the end plate/post synaptic membrane
What type of NMB drug is suxamethonium
Depolarising
What type of NMB drug is tubocurarine
Non-depolarising
Give an example of a depolarising NMB drug
Suxamethonium
Give two examples of non-depolarising NMB drugs
Tubocurarine and atracurium
Depolarising NMB drugs are [agonists/antagonists]
Agonists
Non-depolarising NMB drugs are [agonists/antagonists]
Antagonists
NMB [directly/indirectly] influence AP propagation
Indirectly
NMB drugs [are/are not] analgesic
Are not
NMB drugs [do/do not] affect consciousness, which class of drugs affect consciousness
Do not, general anaesthetics
What MUST you do when administering NMB drugs to ensure patient safety
Assist respiration
Describe the structure of suxamethonium, and properties of the drug (size/flexibility/rotation/efficacy/affinity/aromatics)
Two ACh molecules stuck together so relatively small; flexible and has rotational ability. Has both efficacy and affinity. No benzene rings.
Describe the structure of tubocurarine/non-depolarising drugs, and properties of the drug (size/flexibility/rotation/efficacy/affinity/aromatics)
Big, bulky, inflexible with relatively restricted rotation. No efficacy but strong affinity (competitive antagonist). Can have benzene rings.
Describe the MOA of suxamethonium. Mention metabolism. What is this type of depolarisation block called?
One suxamethonium molecule can bind to two alpha subunits and stimulate both. This overstimulates the nicotinic receptors. Suxamethonium isn’t metabolised as quick as ACh and so remains bound for so long causing so much overstimulation that the receptors switch off.
Known as a phase 1 block.
What drug stimulates a phase 1 block
Suxamethonium
What is a fasciculation and what drug causes this
Twitching of individual muscle fibres
How are NMB drugs administered
Intravenously
How is suxamethonium administered
Intravenously
Suxamethonium is [hydrophilic/lipophilic] because of X
Hydrophilic because of the two quaternary ammonium groups
Why is suxamethonium administered intravenously
The two quaternary ammonium groups on it make it lipid insoluble meaning it can’t cross lipid membranes and therefore wont be absorbed effectively
How long does paralysis on suxamethonium last
5 minutes
What metabolises suxamethonium and what two places is this enzyme found
Pdeudocholinesterase in the liver and plasma
What are the two clinical uses of suxamethonium
To relax the skeletal muscle of the airways for endotracheal intubation, and as a muscle relaxant for electroconvulsive therapy
What are the four major side effects of suxamethonium, explain them
Post-operative muscle pains: due to initial muscle fasciculations
Bradycardia: due to the direct muscarinic receptor stimulation of the muscarinic receptors on the heart
Hyperkalaemia: burns cause the loss of neurones in the muscle, which leads to upregulation of receptors in the skeletal muscle (deinnervation hypersensitivity). Suxamethonium then causes an exaggerated influx of sodium and also efflux of potassium.
Raised intraocular pressure: suxamethonium can cause contraction of the extraocular muscles.
What type of NMB drugs do you give burns patients?
Non-depolarising
What type of NMB drugs do you give glaucama and eye injury patients?
Non-depolarising
What is deinnervation supersensitivity and give an example of what can cause this
Upregulation of receptors in skeletal muscle e.g. through burns
How is bradycardia prevented when administering suxamethonium
Suxamethonium is administered after general anaesthetic and atropine premed -> atropine is a muscarinic receptor antagonist
What is special of tubocurarine when it comes to non-depolarising NMB drugs
It is typical of all other NMB drugs, came first
What is the MOA of tubocurarine. Mention EPP, AP and affinity, efficacy
Competitive antagonist, competes with endogenous ACh for the nicotinic receptor on the end plate. This prevents sufficient end plate potential being generated to stimulate an action potential. Has affinity but no efficacy.
What % block through tubocurarine do you have to achieve to achieve full relaxation of muscles
70-80%
What is the order the skeletal muscles relax in under the influence of tubocurarine
Extrinsic eye muscles -> small muscles of the face, limbs, pharynx -> respiratory muscles
What is the order the skeletal muscles lose their flaccid paralysis caused by tubocurarine
Respiratory muscles -> small muscles of the face, limbs pharynx -> extrinsic eye muscles
What is the little shoulder in a graph recording AP’s
The EPP
What are the two major clinical uses of tubocurarine
Relaxation of skeletal muscles during surgical operations and to permit artificial ventilation
Why would you use tubocurarine to relax skeletal muscles before surgical operations and what two benefits does this have to the patient
The NMB drug has relaxed muscles therefore means less general anaesthetic is needed which is good as it is safer and means the patient can be brought round quicker
How does tubocurarine permit artificial ventilation
It relaxes skeletal muscles allowing a ventilator to take control of the patients respiration
How do you reverse the effects of a non-depolarising blocker
Via anticholineesterase
How do you reverse the effects of a depolarising blocker
You can’t
The effects of [depolarising/non-depolarising] NMB drugs can be reversed
Non-depolarising
Give an example of an anti-cholinesterase
Neostigmine
How do anti-cholinesterase reverse the actions of a depolarising NMB
They prevent cholinesterase from breaking down ACh meaning they can then outcompete the tubocurarine
What must you administer with neostigmine and why
Atropine as neostigmine will inhibit anticholinesterases at every cholinergic synapse and so the atropine prevents muscarinic receptor overstimulation
How is tubocurarine administered and why
IV as it is highly charged/polar/lipophobic due to quaternary ammonium groups and therefore would be unable to cross the lipid bilayer to be absorbed by cells
What does the polar nature of NMB drugs prevent them from entering
The BBB and placenta
What is the duration of tubocurarine and why
Long, 1-2 hours bc it’s not metabolised at all n is excreted unchanged
What are the proportions / places tubocurarine is excreted
70% urine 30% bile
What would you use if someone is hepatically or renally impaired, how is this different, what is it’s duration of action
Atracurium, it is chemically highly unstable and is readily hydrolysed therefore lasts around 15 mins
What effect does tubocurarine have on mast cells and why
Stimulates histamine release from mast cells as it is highly basic
What effect does tubocurarine have on blood pressure and why
Hypotensive effect due to ganglionic nicotinic receptor blockade. Causes fall in TPR. Histamine also stimulates H1 receptors on vasculature to cause vasodilation
What effect does tubocurarine have on heart rate and why (2 reasons why). What can this lead to
Tachycardia, reflex due to hypotension. May lead to arrhythmias. Also may be because of vagal ganglia blockade; Vagus puts a break on the heart
What effect can tubocurarine have on the lungs and why
Bronchospasm due to histamine release
What effect can tubocurarine have on breathing and why
Apnoea due to a block in skeletal muscle fibres, including respiratory muscles
What are the 2 primary causes of the unwanted effects of tubocurarine
Ganglion blockade and histamine release from mast cells
What are 5 unwanted effects of tubocurarine caused by ganglion blockade and histamine release
Hypotension Tachycardia Bronchospasm Excessive secretions (bronchial and salivary) Apnoea
What effect does tubocurarine have on secretions and why
Excessive secretions (bronchial and salivary) due to histamine release
