Neuromuscular blocking drugs Flashcards
How does excitation differ in post synaptic membrane in muscle vs ganglionic
Differenct nAChR for muscle vs ganglionic nAChR…..
these are muscle type nicotinic receptors, different to ganglionic neurone nicotinic recepor (so some selectivity can be developed)
What nervous system do NM blocking drugs affect
Somatic NS –> alpha motor neurons coming from the spinal cord….
A single axon innervating skeletal muscle fibres
Cholinergic
How is acetylcholine made
Acetyl CoA + choline
by cholineacetyl transferase (CAT)
Where else is cholineacetyl transferase found in the body other than cholinergic neurons
Nowhere else
What type of receptor is present on muscle fibre
Nicotinic Acetylcoline receptor…..
It is a cation channel (most sodium influx but also escape of K+ and small amount of Ca2+ comes in too)
What is the name of the depolarisation in the post synaptic membrane
The end plate potential
Differentiate end plate potential to action potential
End plate potential is graded (dependent on concentration of nicotinic receptor and amount of ACh),
AP is all or nothing
Where is the highest concentration of nicotinic receptors in skeletal muscle
Centre of the muscle
How is acetylcholine broken down
by acetylcholineesterase…. into acetic acid and choline…..
Choline taken back up by transporter in presynaptic membrane
State the 2 types of NM blocking drugs
Competitive antagonist (non depolarising)
Depolarising blockers (AGONISTS of nAChR)
How many subunits in the type 1 receptors
5
Where does acetylcholine bind to the receptors
Onto the TWO alpha subunits of the nicotinc receptor
Differentiate the composition of muscle type and ganglion type nicotinc receptors
Muscle type: 2a b d e
Ganglion: 2a, 3b
Note that each subunit is comprised of 4 TM segments
Also note that there are 5 potential subunits: a, b, d, e and g
Example of drugs that work on central processes to reduce outflow from CNS to affect muscle
SPASMOLYTICS (diazepam and baclofen) they reduce outflw from CNS to allow relaxation in spasticity e.g. due to MS
Example of drug affecting conduction of nerve AP in motor neurone to affect muscle
Local anaesthetic (meant to block action potential in sensory fibres, but can also affect motor)
Which drugs can affect ACh release from the presynaptic neuron to affect muscle
Ca2+ entry blockers (required to release NT)
Neurotoxins (e.g. venom) can cause paralysis e.g. botulinum toxin which prevents release ACh release from presynaptic cell
Hemicholinim (stops reuptake of choline to reduce ACh synthesis and thus release form the presynaptic membrane)
What drugs affect DEPOLARISATION OF MOTOR END-PLATE causing AP INITIATION to affect muscle
TUBOCURARINE
SUXAMETHONIUM
What drugs affect PROPAGATION OF AP ALONG MUSCLE FIBRE + MUSCLE CONTRACTION to affect muscle
Spasmolytic dantrolene (reduces release of Ca2+ from the SR reducing propogation)
Where is the action of NM blockin drugs
POST synaptic….. end place receptors
Give an example of each type of NM blocking drug
Competitive antagonist (non depolarising) –> tubocuarine and atracurium
Depolarising blockers (AGONISTS of nAChR) –> suxamethonium (=succinylcholine)
What is done when NM blocking drugs are used
Assist respiration
Differentiate chemical structure of competitve antagonists vs depolarising blockers
Ach has quarternary ntirogen
The suxamethonium basically 2 molecules of ACh stuck together. It has 2 quartnery nitrogens, so it can stimulate both of the a subunits at the same time this increases efficacy. There is efficacy and affinity for ACh receptor (agonist)
competitve antagonists have more rigid structures than depolarising blockers with less rotation about the double bond. Tubocuranine still has quarternary nitrogen but only has affinity and no efficiacy for the receptor
What is the strucutre of the succinylcholine (=suxamethonium)
Basically 2 acetylcholines stuck together (so they have efficacy and affinity)
MOA of depolarising blocker
Overstimulation of the nicotinic receptor suxamethonium stays in the synaptic cleft for a long period of time, rather than rapid removal like ACh
EXTENDED E.P. DEPOLARISATION –> ‘DEPOLARISATION BLOCK’ (PHASE 1)
FASCICULATIONS –> FLACCID PARALYSIS (loss of tone , compared with spastic paralysis) (as it stimulates individual fibres as it diffuses through)
State the suxamethonium pharmacokinetics
IV (highly charged due to two quarternary nitrogens)
Duration of paralysis is 5 minutes (SHORT)
METABOLISED BY PSEUDO-CHOLINESTERASE IN LIVER & PLASMA
Uses of suxamethonium
Both Es and both brutal
Endotracheal intubation –> to relax muscle to intubate for investigation
Muscle relaxant for ECT –> electoconvulsive therapy involves stimuation across temporal lobes…. it prevents muscle contraction during this treatment of sever depression
Unwanted effects of suxamethonium
POST-OPERATIVE MUSCLE PAINS
BRADYCARDIA
HYPERKALAEMIA…
INCREASE INTRA-OCULAR PRESSURE
I Hurt P Bum
How do non-depolarsing NM blocker work
NATURALLY OCCURING 4° AMMONIUM COMPOUND (ALKALOID) e.g. tubacuranine
Competitive nAChR anagonist
(all non deplarising NM blocking drugs use same mechanism)
(there is a quarternary nitrogen group like ACh so binding to the receptor can occur but there is no efficacy
What block is achieved in non-depolarising NM blockers
70 - 80% BLOCK NECESSARY… in this case you don’t get a suffieicnet end plate potential to reach an action potential
Effets of non depolarising NM blockers, and which muscles are blocked at low to high dosage
Flaccid paralysis
Extrinsic eye muscle (double vision) THEN Small muscle of face limbs and pharynx THEN respiratory muscles
(RECOVER IN OPPOSITE DIRECTION)
Eplain why in number 3 on the tubocurarine is there an action potential but nothing further down the muscle fibre
The endplate potneital is not sufficient to cause action potential (which is all or nothing) so there is no depolarisation
Use of non-depolarising NM blocker
RELAXATION OF SKELETAL MUSCLES DURING SURGICAL OPERATIONS (= LESS ANAESTHETIC) incl. abdominal muscle… use less general anaesthetic because although GA causes relaxation too, we can use less GA if we use muscle relaxant
PERMIT ARTIFICIAL VENTILATION
How can the action of non-repolarising blockers be reversed
ACTIONS OF NON-DEPOLARISING BLOCKERS CAN BE REVERSED BY ANTICHOLINESTERASES
e.g. neostigmine AND atropine (to block the increased effect at the muscarinic receptors)
Pharmacokinetics of tubocurarine
IV
Does not cross BBB or placenta (due to quarternary ammonium)
Paralysis is 1-2hrs (long)
Not metabolised
Excreted 70% in urine and 30% in the bile
When might we not use tubacuranine? What is used instead
If renal or hepatic function is impaired, because this will EXTEND the duration of action of this drug.
In this case, we give atracurium which is chemically unstable (and is hydrolysed in the plasma into 2 inactive components spontaneously, not dependent on renal or kidney function for its DOA)
Compare to tubacurarine which is excreted UNmetabolised.
What are the unwanted effects of tubocurarine
Due to 1. Ganglion block and 2. Histamine release:
BATH
Bronchospasm and excessive secretions due to HISTAMINE RELEASE
Apnoea- due to blockade of respiratory muscles (so assist respiration)
Tachycardia- block of vagal ganglia and reflex tachycardia due to vasodilation may lead to arrhythmias
Hypotension –> reduction in TPR because of block of ganglionic nAChR + histamine from mast cells
Why does suxamethonium cause muscle pain post operatively
Due to the fasciculations (make sure you know why fasciaulations occur)
Why does suxamethonium cause bradycardia. What is the solution
suxamethonium also stimulates M2 receptors on the heart…. but atropine include in pre-medication. Atropine BLOCKS the muscarinic receptor
Why does suxamethonium cuase hyperkalaemia. When would you not use suxamethonium and why
It increases NAChR stimulating (as it is an agonist), increasing sodium influx and potassium efflux (then it causes depolarisation block)
WOULD NOT USE in burns patients or other soft tissue injury, as here denervation happens, so receptors become more sensitive (denervation hypersensitivity), so more potassium is released. Can lead to ventricular arrhythmias and cardiac arrest.
When else would you not use suxamethonium
Burns or glaucoma/eye injury
Why does suxamethonium cause raised intraocular pressure
due to contraction of skeletal muscle around the eye…. avoid for glaucoma and eye injuries
Outline 2 drug groups which cause depolarisation block
Suxamethonium is an agonist and isn’t broken down by acetylcholinestease so remain so in the synapse causing the phase 1 block
Ecothiopate is an organophosphate and is a irreversible indirectly acting cholimomimitetic (ie irreversibly inhibits acetylcholinesterase) which causes build up of ACh in the synapse and also causes depolarising block
Tubocurarine is given in surgery as a muscle relaxant to permit easier surgery. Once the operation is complete, what could then be given to reverse the effect of this drug
It is a NM blocking drug, so it is working on the ACh receptors.
It is REVERSIBLE, so it can be surmounted. If you use a reversible anticholinesterase e.g Neostigmine.
However giving neostigmine could increase transmission at muscarinic receptors, so atropine is given to block any of these effects
Which NM blocker is long acting and which is short
Long: tubacurarine
Short: suxamethonium
T/f tubocurarine can be used during obstetric surgery
T…. it cannot cross the placenta or the BBB as it is very highly charged
Why does tubocurarine cause histamine release
Because it is a base, it can cause histamine release from mast cells (not a receptor mediated effect)
