Neuromuscular Junction Blocking Drugs

Question 1

Describe how impulses are transmitted across synapses.

Answer 1

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

Question 2

What type of receptor is found at the neuromuscular junction?

Answer 2

Nicotinic acetylcholine receptors

Question 3

Where are these receptors found on the muscle fibre?

Answer 3

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

Question 4

What does depolarisation of this membrane cause? Describe the character of this depolarisation.

Answer 4

This causes a change in end plate potential 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

It is bound to the basement membrane in the synaptic cleft

Question 6

State the three main neuromuscule blockers.

Answer 6

Tubocurarine - quaternary ammonium compound
Atracurium
Suxamethonium

Question 7

State the two main types of nicotinic acetylcholine receptor.

Answer 7

Ganglionic

Muscle

Question 8

Describe the structure of nicotinic acetylcholine receptors.

Answer 8

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 9

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

Answer 9

2

Question 10

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

Answer 10

Diazepam
Baclofen (GABA receptor agonist)

They both facilitate GABA transmission

Question 11

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

Answer 11

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

Question 12

What do local anaesthetics have their effect on?

Answer 12

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

Question 13

Describe the action of neurotoxins.

Answer 13

Neurotoxins inhibit the release of acetylcholine and hence block the contraction of respiratory skeletal muscle causing death

Question 14

What are the two types of neuromuscular blocker?

Answer 14

Depolarising

Non-depolarising

Question 15

Name another spasmolytic that has a different action to create the same effect.

Answer 15

Dantrolene – it works in the muscle fibres themselves by inhibiting calcium release in the muscle fibre

Question 16

Describe the difference in mechanism of action between depolarising and non-depolarising NM blockers. Which NM blockers fall into each category?

Answer 16

Depolarising = suxamethonium - nicotinic acetylcholine receptor AGONIST

Non-depolarising = tubocurarine + atracurium - nicotinic acetylcholine receptor antagonist

Question 17

How do NM blockers affect consciousness and pain sensation?

Answer 17

They do NOT

Question 18

What must you always do when giving NM blockers?

Answer 18

Assist respiration because of their effect on respiratory muscle action

Question 19

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

Answer 19

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

Suxamethonium = made up of two acetylcholine molecules that are linked together. This is more flexible and allows rotation. As it is madeup of two acetylcholine molecules it can binds to the two alpha subunits and activate the receptor.

Question 20

Describe the mechanism of action suxamethonium.

Suxamethonium is a nicotinic receptor agonist.

Answer 20

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 21

What does suxamethonium normally cause before causing the flaccid paralysis?

Answer 21

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

Question 22

What is the duration of paralysis of suxamethonium?

Answer 22

5 mins

Question 23

How is suxamethonium metabolised?

Answer 23

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

Question 24

What are some uses of suxamethonium?

Answer 24

Endotracheal intubation – relaxes the muscles of the airways Muscle relaxant for electroconvulsive therapy – treatment for severe clinical depression

Question 25

State and explain four unwanted effects of suxamethonium.

Answer 25

Post-operative muscle pains - Due to initial fasciculations

Hyperkalaemia - If there is soft tissue injury or burns you will lose some neurones innervating the tissuea, Then you will get upregulation 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 effects 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 26

Describe the mechanism of action of tubocurarine.

Answer 26

Tubocurarine is a competitive nicotinic acetylcholine receptor antagonist. 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 27

Describe the order of relaxation of skeletal muscles and the order in which they return back to normal when given tubocurarine.

Answer 27

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 28

State two uses of tubocurarine.

Answer 28

Relaxation of muscles during surgical operations (this means that less general anaesthetic is needed) Permit artificial ventilation

Question 29

How can the actions of NM blockers be reversed?

Answer 29

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

Question 30

What else must you give with this drug when trying to reverse theactions of NM blockers?

Answer 30

Atropine 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

Question 31

How are all NM blockers administered?

Answer 31

Intravenously

Question 32

What is the duration of paralysis of tubocurarine?

Answer 32

40 mins

Question 33

Describe the metabolism and excretion of tubocurarine?

Answer 33

It is NOT metabolised at all

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

Question 34

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

Answer 34

Impairment of hepatic or renal function increases the duration of action of tubocurarine Under these conditions you would use ATRACURIUM (15 min duration) and is NOT affected by liver or kidney function

Question 35

State some unwanted effects of tubocurarine.

Answer 35

MAIN EFFECTS: ganglion block + histamine release from mast cells cause most of the unwanted effects

HYPOTENSION – 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