Neuromuscular blocking drugs

Question 1

How does excitation differ in post synaptic membrane in muscle vs ganglionic

Answer 1

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)

Question 2

What nervous system do NM blocking drugs affect

Answer 2

Somatic NS –> alpha motor neurons coming from the spinal cord….

A single axon innervating skeletal muscle fibres

Cholinergic

Question 3

How is acetylcholine made

Answer 3

Acetyl CoA + choline

by cholineacetyl transferase (CAT)

Question 4

Where else is cholineacetyl transferase found in the body other than cholinergic neurons

Answer 4

Nowhere else

Question 5

What type of receptor is present on muscle fibre

Answer 5

Nicotinic Acetylcoline receptor…..

It is a cation channel (most sodium influx but also escape of K+ and small amount of Ca2+ comes in too)

Question 6

What is the name of the depolarisation in the post synaptic membrane

Answer 6

The end plate potential

Question 7

Differentiate end plate potential to action potential

Answer 7

End plate potential is graded (dependent on concentration of nicotinic receptor and amount of ACh),

AP is all or nothing

Question 8

Where is the highest concentration of nicotinic receptors in skeletal muscle

Answer 8

Centre of the muscle

Question 9

How is acetylcholine broken down

Answer 9

by acetylcholineesterase…. into acetic acid and choline…..
Choline taken back up by transporter in presynaptic membrane

Question 10

State the 2 types of NM blocking drugs

Answer 10

Competitive antagonist (non depolarising)

Depolarising blockers (AGONISTS of nAChR)

Question 11

How many subunits in the type 1 receptors

Answer 11

5

Question 12

Where does acetylcholine bind to the receptors

Answer 12

Onto the TWO alpha subunits of the nicotinc receptor

Question 13

Differentiate the composition of muscle type and ganglion type nicotinc receptors

Answer 13

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

Question 14

Example of drugs that work on central processes to reduce outflow from CNS to affect muscle

Answer 14

SPASMOLYTICS (diazepam and baclofen) they reduce outflw from CNS to allow relaxation in spasticity e.g. due to MS

Question 15

Example of drug affecting conduction of nerve AP in motor neurone to affect muscle

Answer 15

Local anaesthetic (meant to block action potential in sensory fibres, but can also affect motor)

Question 16

Which drugs can affect ACh release from the presynaptic neuron to affect muscle

Answer 16

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)

Question 17

What drugs affect DEPOLARISATION OF MOTOR END-PLATE causing AP INITIATION to affect muscle

Answer 17

TUBOCURARINE

SUXAMETHONIUM

Question 18

What drugs affect PROPAGATION OF AP ALONG MUSCLE FIBRE + MUSCLE CONTRACTION to affect muscle

Answer 18

Spasmolytic dantrolene (reduces release of Ca2+ from the SR reducing propogation)

Question 19

Where is the action of NM blockin drugs

Answer 19

POST synaptic….. end place receptors

Question 20

Give an example of each type of NM blocking drug

Answer 20

Competitive antagonist (non depolarising) –> tubocuarine and atracurium

Depolarising blockers (AGONISTS of nAChR) –> suxamethonium (=succinylcholine)

Question 21

What is done when NM blocking drugs are used

Answer 21

Assist respiration

Question 22

Differentiate chemical structure of competitve antagonists vs depolarising blockers

Answer 22

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

Question 23

What is the strucutre of the succinylcholine (=suxamethonium)

Answer 23

Basically 2 acetylcholines stuck together (so they have efficacy and affinity)

Question 24

MOA of depolarising blocker

Answer 24

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)

Question 25

State the suxamethonium pharmacokinetics

Answer 25

IV (highly charged due to two quarternary nitrogens) Duration of paralysis is 5 minutes (SHORT) METABOLISED BY PSEUDO-CHOLINESTERASE IN LIVER & PLASMA

Question 26

Uses of suxamethonium

Answer 26

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

Question 27

Unwanted effects of suxamethonium

Answer 27

POST-OPERATIVE MUSCLE PAINS BRADYCARDIA HYPERKALAEMIA... INCREASE INTRA-OCULAR PRESSURE I Hurt P Bum

Question 28

How do non-depolarsing NM blocker work

Answer 28

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

Question 29

What block is achieved in non-depolarising NM blockers

Answer 29

70 - 80% BLOCK NECESSARY... in this case you don't get a suffieicnet end plate potential to reach an action potential

Question 30

Effets of non depolarising NM blockers, and which muscles are blocked at low to high dosage

Answer 30

Flaccid paralysis ``` Extrinsic eye muscle (double vision) THEN Small muscle of face limbs and pharynx THEN respiratory muscles ``` (RECOVER IN OPPOSITE DIRECTION)

Question 31

Eplain why in number 3 on the tubocurarine is there an action potential but nothing further down the muscle fibre

Answer 31

The endplate potneital is not sufficient to cause action potential (which is all or nothing) so there is no depolarisation

Question 32

Use of non-depolarising NM blocker

Answer 32

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

Question 33

How can the action of non-repolarising blockers be reversed

Answer 33

ACTIONS OF NON-DEPOLARISING BLOCKERS CAN BE REVERSED BY ANTICHOLINESTERASES e.g. neostigmine AND atropine (to block the increased effect at the muscarinic receptors)

Question 34

Pharmacokinetics of tubocurarine

Answer 34

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

Question 35

When might we not use tubacuranine? What is used instead

Answer 35

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.

Question 36

What are the unwanted effects of tubocurarine

Answer 36

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

Question 37

Why does suxamethonium cause muscle pain post operatively

Answer 37

Due to the fasciculations (make sure you know why fasciaulations occur)

Question 38

Why does suxamethonium cause bradycardia. What is the solution

Answer 38

suxamethonium also stimulates M2 receptors on the heart.... but atropine include in pre-medication. Atropine BLOCKS the muscarinic receptor

Question 39

Why does suxamethonium cuase hyperkalaemia. When would you not use suxamethonium and why

Answer 39

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.

Question 40

When else would you not use suxamethonium

Answer 40

Burns or glaucoma/eye injury

Question 41

Why does suxamethonium cause raised intraocular pressure

Answer 41

due to contraction of skeletal muscle around the eye.... avoid for glaucoma and eye injuries

Question 42

Outline 2 drug groups which cause depolarisation block

Answer 42

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

Question 43

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

Answer 43

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

Question 44

Which NM blocker is long acting and which is short

Answer 44

Long: tubacurarine Short: suxamethonium

Question 45

T/f tubocurarine can be used during obstetric surgery

Answer 45

T.... it cannot cross the placenta or the BBB as it is very highly charged

Question 46

Why does tubocurarine cause histamine release

Answer 46

Because it is a base, it can cause histamine release from mast cells (not a receptor mediated effect)