Neuromuscular Blocking Drugs

Question 1

Outline how Ach is synthesised in NMJs

Answer 1

• Acetyl CoA (+choline acetyl transferase) → ACh
• CAT is found in cholinergic nerve terminals such as NMJs

Question 2

Outline how synaptic transmission across the NMJ and then evoking the AP across the motor end plate occurs starting from action potential at the presynaptic cholinergic nerve terminal and ending at breakdown of ACh

Answer 2

1. Action potential arrives at the presynaptic nerve terminal
2. Leading to depolarisation of the membrane
3. Causing opening of the voltage-sensitive calcium channels
4. Causing calcium influx
5. This leads to vesicle exocytosis
6. ACh propagates across the NMJ synapse
7. ACh binds nicotinic acetylcholine receptors on the end plate. These receptors are ion channel linked
8. This causes sodium ion influx
9. This causes depolarisation of the membarne called end plate potential
10. Once the end plate potential reaches a threshold, it generates an action potential
11. The AP propagates bi-directionally, causing stimulation of the muscle
12. Acetylcholinesterase is bound to the basement membrane in the synaptic cleft and breaks down acetylcholine to acetate and choline

Question 3

What are the 3 main neuromuscular blockers?

Answer 3

1. Suxamethonium
2. Atracurium
3. Tubocurarine

SAT

Question 4

What are the 2 main subtypes of nicotinic receptors?

Answer 4

1. Ganglionic
2. Muscle

Question 5

What does it mean to say that motor end plate potentials are graded potentials?

Answer 5

Depends on:

• How much ACh is released
• How many receptors are stimulated

Question 6

Describe the structure of the nicotinic acetylcholic receptor and the nature of the interaction between the receptors and acetylcholine in order to activate it

Answer 6

• 5 subunits
• 2 alpha subunits
• Both these subunits must bind acetylcholine in order for activation of the receptor, so you need 2 ACh molecules to activate one receptor

Question 7

List 3 spasmolytics

Answer 7

1. Diazepam
2. Baclofen
3. Dantrolene

Question 8

1) What type of drug is Diazepam and what is its mechanism of action?
2) What conditions is it particularly useful in the management of?

Answer 8

1)

• Spasmolytic
• Facilitates GABA transmission

2)

• Cerebral palsy
• Spasticity following stroke

Question 9

1) What type of drug is Baclofen and what is its mechanism of action?
2) What conditions is it particularly useful in the management of?

Answer 9

1)

• Spasmolytic
• It is a GABA receptor agonist

2)

• Cerebral palsy
• Spasticity following stroke

Question 10

1) What is the site / process that local anaesthetics target?
2) Thus what unwanted effect may you be prone to developing after administration of local anaesthetics?

Answer 10

1)

• Blocks the conduction of action potentials in motor neurones

2)

• Muscle weakness

Question 11

Give 3 ways that ACh release can be impaired using drugs, with drug names or type of drug

Answer 11

1. Hemicholinium - blocks choline reuptake into pre-synaptic nerve terminals thereby preventing ACh synthesis by choline acetylation - thus indirectly impairing ACh release
2. Botulinum toxin - blocks release of ACh from pre-synaptic nerve terminals
3. Ca²⁺ entry blockers - prevent the influx of Ca²⁺, thereby preventing the stimulation of ACh exocytosis

Question 12

How does the spasmolytic Dantrolene work?

Answer 12

• Inhibits Ca²⁺ release within the muscle fibres, thereby inhiting muscular contraction

Question 13

What must you always ensure you do when administering neuromuscular blocking drugs such as Suxamethonium, Atracurium, Tubocurarine?

Answer 13

• Always assist breathing because these will also impair respiratory muscles which is dangerous

Question 14

What is the mechanism of action of Suxamethonium?

Answer 14

• Nicotinic receptor agonist
• Metabolised much more slowly than ACh
• Causes phase 1 block - causes extended end plate depolarisation which results in a depolarisation block of the NMJ
• I.e. it overstimulates the receptor until it switches off and can’t be stimulated further by ACh
• It also causes fasciculations as individual fibres begin to twitch as Suxamethonium binds receptors and stimulates contraction
• These fasciculations can cause flaccid paralysis - a decrease in muscle tone

Question 15

What is the route of administration of Suxamethonium?

Answer 15

I.V.

Question 16

Give 2 uses of Suxamethonium

Answer 16

1. Relaxes skeletal muscle of the airways for endotracheal intubation
2. Muscle relaxant for electroconvulsive therapy

Question 17

How is Suxamethonium metabolised?

Answer 17

• Metabolised by pseudocholinesterase in the liver and the plasma

Question 18

Give 4 unwanted effects of Suxamethonium

Answer 18

1. Post-operative muscle pains - due to fasciculations
2. Bradycardia - due to direct muscarinic actions on the heart
3. Hyperkalaemia - following deinnervation supersensitivity from soft tissue injury / burns so when you give Suxamethonium, you get an aggravated response. So you get bigger sodium influx and bigger potassium efflux
4. Raised intraocular pressure - avoid for eye injury / glaucoma

Question 19

Describe the mechanism of action of Tubocurarine

Answer 19

• Competitive nicotinic acetylcholinic receptor antagonist
• Non-depolarising neuromuscular blocker
• You need 70-80% block to cause full relaxation of the muscle - if you do this, the end-plate potential generated won’t reach the threshold
• It also causes flaccid paralysis

Question 20

What is the order of muscles that relax and then recovery?

Answer 20

Relaxation:

1. Extrinsic eye muscles
2. Small muscles of the face, limbs and pharynx
3. Respiratory muscles

Recovery:

• Opposite way around

Question 21

What does this diagram tell you about how Tubocurarine affects NM transmission?

Answer 21

You won’t reach an end-plate potential large enough to pass the threshold so as to trigger contraction in the end-plate

However you will see a small shoulder in the action potential which is the end-plate potential

Question 22

Give 2 uses of Tubocurarine

Answer 22

1. Relaxation of skeletal muscles during surgical operations so as to necessitate lower amounts of general anaesthetic
2. Permit artificial ventilation by relaxing respiratory muscles

Question 23

What is the route of administration for all neuromuscular blockers?

Answer 23

Intravenous

Question 24

1) How is Tubocurarine metabolised?
2) How is it excreted?
3) Thus what happens if there are renal or liver disease?

Answer 24

1)

• Not metabolised at all

2)

• Excreted in urine and bile

3)

• Impaired excretion and because it’s not metabolised, it will just linger and have a greater duration of action

Question 25

When do you give atracurium over tubocurarine?

Answer 25

• When there is impaired renal or hepatic function which would result in unwanted increased duration of action tubocurarine as it is not metabolised and excretion will be impaired in this way
• So you give atracurium which is metabolised so won’t have prolonged action

Question 26

How is atracurium metabolised?

Answer 26

• pH of the plasma breaks down atracurium into 2 inactive fragments

Question 27

What are the 7 unwanted effects of tubocurarine administration and why do they happen?

Answer 27

1. Ganglion block – it could block some of the nicotinic receptors in the ganglia

2. Histamine release from mast cells

3. Hypotension

• Blood pressure can drop due to ganglion blockade
• Histamine can act on the H1 receptors on the vasculature and cause vasodilation

4. Tachycardia

• A reflex in response to the hypotension
• Could also be due to the blockade of vagal ganglia

5. Bronchospasm

• Caused by the histamine release

6. Excessive secretions (bronchial and salivary)

• Caused by the histamine release

7. Apnoea

NOTE the 2 main ones are GANGLION BLOCK AND HISTAMINE RELEASE, the others are derivatives of these

Question 28

1) How can you can reverse the effects of non-depolarising neuromuscular blockers - note you can’t use this for depolarising blockers
2) You must coadminister something else with one of these - what and with which, and why?

Answer 28

1)

• Increase [ACh] using anticholinesterases such as neostigmine - these don’t work with depolarising nm blockers

2)

• Must coadminister atropine with neostigmine (the anticholinesterase) to prevent muscarinic overstimulation where unwanted