Neuromuscular blocking drugs

Question 1

Describe neuromuscular impulse transmission

Answer 1

Action potential propagates along the presynaptic neurone => depolarisation of presynaptic membrane => opening of voltage gated calcium channels => calcium influx => ACh vesicle exocytosis

Question 2

What type of receptor is found at the NMJ?*

Answer 2

Nicotinic acetylcholine receptors

*Note: nAChR at the NMJ slightly differ in structure to the nAChR of the ANS

Question 3

Where are these receptors found on the muscle fibre?

Answer 3

Motor end plate (usually in high concentration in the middle of the muscle fibres)

Question 4

Describe the character of the depolarisation of the end plate region

Answer 4

This is a graded potential meaning that it is dependent on the amount of acetylcholine released and the number of receptors stimulated
Once the end plate potential reaches a threshold, it generates an action potential that propagates in both directions along the muscle fibre

Question 5

Where is acetylcholinesterase found?

Answer 5

Bound to the post-synaptic membrane of the muscle end plate

Question 6

Describe the structure of nicotinic acetylcholine receptors.

Answer 6

They consist of 5 subunits (subunits can be alpha, beta, gamma, delta, epsilon)
There are always 2 alpha subunits, which bind to acetylcholine and activate the receptor

Question 7

How many molecules of acetylcholine are required to activate one nicotinic acetylcholine receptor?

Answer 7

2

Question 8

Name two drugs that are used as spasmolytics in the CNS and describe their action.

Answer 8

Diazepam
Baclofen (GABA receptor agonist)
- They both facilitate GABA transmission

Question 9

Give some examples of conditions in which CNS spasmolytics may be used.

Answer 9

They are both useful in some forms of cerebral palsy and spasticity following strokes

Question 10

What do local anaesthetics have their effect on?

Answer 10

Conduction of action potentials in motor neurones (so if you inject local anaesthetic too close to a motor neurone then you may see some muscle weakness)

Question 11

What drugs inhibit ACh release by exocytosis?

Answer 11

• Hemicholinium
• Ca2+ entry blockers
• Neurotoxins (e.g. botulinum toxin prevents the contraction of respiratory skeletal muscle causing respiratory arrest and death)

Question 12

What are the two types of neuromuscular blockers?

Answer 12

Depolarising

Non-depolarising

Question 13

Name another spasmolytic with a different site of action to create the same effect

Answer 13

Dantrolene
- It works in the muscle fibres themselves by inhibiting calcium release from the sarcoplasmic reticulum in the muscle fibre

Question 14

Name and describe depolarising and non-depolarising neuromuscular blocking drugs

Answer 14

DEPOLARISING:
e.g. Suxamethonium
= nicotinic acetylcholine receptor agonist

NON-DEPOLARISING
e.g. tubocurarine, atracurium
= nicotinic acetylcholine receptor competitive antagonist

Question 15

Do NM blockers affect consciousness and pain sensation?

Answer 15

No

Question 16

What must you always do when giving NM blockers?

Answer 16

Assist respiration (until drug is inactive or antagonised) because of their effect on respiratory muscle action

Question 17

Describe the difference in structure between non-depolarising and depolarising NM blockers?

Answer 17

Non-depolarising = tend to be big, bulky molecules with limited movement around their bonds

Suxamethonium (depolarising) = made up of two acetylcholine molecules linked together (more flexible and allows rotation).
As it is made up of two acetylcholine molecules, one suxamethonium can bind to the two alpha subunits and activate the receptor.

Question 18

Describe the mechanism of action suxamethonium (and state the route of administration)

Answer 18

ROA = i.v. (highly charged)
It causes an extended end plate depolarisation leading to a depolarising block of the NMJ
= This is a phase 1 block

NOTE: it is not metabolised as rapidly as acetylcholine so it will remain bound to the nicotinic receptors making them switch off due to overstimulation
It eventually results in FLACCID PARALYSIS

Question 19

What does suxamethonium normally cause before causing the flaccid paralysis?

Answer 19

Fasciculations – individual fibre twitches as the suxamethonium begins to stimulate the nicotinic receptor (remember it is an agonist)

Question 20

What is the duration of paralysis of suxamethonium?

Answer 20

~5 mins (short)

Question 21

How is suxamethonium metabolised?

Answer 21

It is metabolised by pseudocholinesterase (butyrylcholinesterase) in the liver and plasma

Question 22

What are some uses of suxamethonium?

Answer 22

Endotracheal intubation – relaxes the muscles of the airways

Muscle relaxant for electroconvulsive therapy (treatment for severe clinical depression)

Question 23

State and explain four unwanted effects of suxamethonium.

Answer 23

Post-operative muscle pains
- Due to initial fasciculations

Hyperkalaemia

• If there is soft tissue injury or burns you will lose some neurones innervating the tissue
• Then you will get up-regulation of receptors in the skeletal muscle (deinnervation supersensitivity)
• So if you give suxamethonium you get an exaggerated response with a bigger influx of sodium and bigger efflux of potassium

Bradycardia

• This is due to the direct muscarinic action on the heart
• This effect tends to be prevented because suxamethonium is usually given after GA and hence following administration of atropine (muscarinic antagonist) in the pre-med

Raised intraocular pressure
- AVOID for eye injuries and glaucoma

Question 24

Describe the mechanism of action of tubocurarine.

Answer 24

Tubocurarine is a competitive nicotinic acetylcholine receptor antagonist; naturally occurring alkaloid found in South American plant (but a range of synthetic drugs now available)

You only need 70-80% block to achieve full relaxation of the muscles
If you block this proportion of the receptors then the end-plate potential generated will NOT reach the threshold

Question 25

State the effect of tubocurarine and the order of relaxation of skeletal muscle (and reverse)

Answer 25

This also causes flaccid paralysis.
Order:
- Extrinsic eye muscles (first to relax, last to go back to normal)
- Small muscles of the face, limbs and pharynx
- Respiratory muscles

Question 26

State two uses of tubocurarine.

Answer 26

1. Relaxation of muscles during surgical operations (so less general anaesthetic is needed)
2. Permit artificial ventilation

Question 27

How can the actions of non-depolarising NM blockers be reversed? What drug combination might be used, and why?

Answer 27

Give an anti-cholinesterase (e.g. physostigmine)

Giving physostigmine will raise the synaptic concentration of acetylcholine at ALL cholinergic synapses (not just the neuromuscular junctions) so you need some atropine to block these unwanted effects
=> anti-cholinesterase + atropine

Question 28

How is tubocurarine administers? What is the duration of paralysis?

Answer 28

Intra-venously (highly charged)

1-2hrs (long)

Question 29

Describe the metabolism and excretion of tubocurarine?

Answer 29

It is NOT metabolised at all

It is excreted in the urine (70%) and bile (30%)

Question 30

Does tubocurarine cross the BBB or placenta?

Answer 30

No

Question 31

Under which conditions would you get an increased duration of action of tubocurarine? What would you change under these conditions?

Answer 31

Impairment of hepatic or renal function increases the duration of action of tubocurarine

Under these conditions you would use ATRACURIUM instead (15 min duration) and is NOT affected by liver or kidney function

Question 32

State some unwanted effects of tubocurarine.

Answer 32

Ganglion block + histamine release from mast cells cause most of the unwanted effects:

HYPOTENSION

• ganglion blockade = reduced TPR
• histamine can act on H1 receptors and cause vasodilation

TACHYCARDIA
- reflex tachycardia in response to hypotension

BRONCHOSPASM
- caused by histamine release

EXCESSIVE SECRETIONS (bronchial and salivary)
- histamine release 

APNOEA – which is why you assist respiration