10 - Neuromuscular Blocking Drugs

Question 1

What are alpha motor neurones?
Where are they located?
What do they innervate?

Answer 1

Large, multipolar lower motor neurones of the brainstem and spinal cord.
Their cell body is in the ventral horn of the spinal chord.
They innervate extrafusal muscle fibres of skeletal muscle and are directly responsible for initiating their contraction

Question 2

In terms of motor neurones, how does the somatic system differ from the autonomic?

Answer 2

in the somatic nervous system, only a single axonal cell is involved in the innervation of the skeletal muscle (one 1 neurone - no ganglion)

Question 3

What type of transmission occurs in the neuromuscular junctions of the somatic system?

Answer 3

cholinergic

Question 4

What type of receptor is found at the neuromuscular junction?

Answer 4

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

Question 5

Where are these (nACh) receptors found on the muscle fibre?

Answer 5

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

Question 6

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

Answer 6

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 7

Where is acetylcholinesterase found?

Answer 7

It is bound to the basement membrane in the synaptic cleft

Question 8

State the three main neuromuscule blockers.

Answer 8

Tubocurarine
Atracurium
Suxamethonium

Question 9

State the two main types of nicotinic acetylcholine receptor.

Answer 9

Ganglionic
Muscle

NOTE: they are slightly different in structure, so more selective drugs can be developed against

Question 10

Describe the structure of nicotinic acetylcholine receptors.

Answer 10

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 11

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

Answer 11

2

Question 12

Name two drugs that are used as spasmolytics

What site do they act upon and describe their action.

Answer 12

Diazepam
Baclofen (GABA receptor agonist)

Act on the CNS
They both facilitate GABA transmission

Question 13

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

Answer 13

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

Question 14

What do local anaesthetics have their effect on?

Answer 14

Conduction of action potentials in sensory neurones - decreases stimulation to the sensory cortex

Question 15

What can be the result of injecting local anaesthetic into a motor neurone?

Answer 15

may see some muscle weakness

Question 16

Describe the action of neurotoxins.

Answer 16

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

Question 17

What are the two types of neuromuscular blocker?

Answer 17

Depolarising

Non-depolarising (competitive)

Question 18

What type of drug is dantrolene and what is its mechanism of action?

Answer 18

a spasmolytic

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

Question 19

(NM blocking drugs act nicotinic receptors on the motor end plate)
Describe the difference in mechanism of action between depolarising and non-depolarising NM blockers.
Name NM blockers fall into each category?

Answer 19

Depolarising = suxamethonium = nicotinic acetylcholine receptor AGONIST

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

Question 20

How do NM blockers affect consciousness and pain sensation?

Answer 20

They do NOT

NOT GENERAL ANAESTHETICS OR ANALGESICS

Question 21

What must you always do when giving NM blockers?

Answer 21

Assist respiration because of their effect on respiratory muscle action

Question 22

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

Answer 22

Non-depolarising = big, bulky molecules with limited movement around their bonds
have affinity and no efficacy (are antagonists)

(depolarising) Suxamethonium = made up of two acetylcholine molecules - more flexible and allows rotation. As it is made up of two acetylcholine molecules it can binds to the two alpha subunits and activate the receptor.
possesses affinity and efficacy - very effective agonist

Question 23

Describe the mechanism of action suxamethonium.

Answer 23

Suxamethonium is a nicotinic receptor agonist.
It causes an extended end plate depolarisation leading to a depolarising block of the NMJ (caused by overstimulation)
This is a phase 1 block

Question 24

What are the impacts of suxamethonium?

Answer 24

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

This leads to flaccid paralysis

Question 25

What is the duration of paralysis of suxamethonium?

Answer 25

5 mins

Question 26

How is suxamethonium metabolised?

Answer 26

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

Question 27

What are the 2 main uses of suxamethonium?

Answer 27

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

Question 28

State and explain four unwanted effects of suxamethonium.

Answer 28

Post-operative muscle pains
• Due to initial fasciculations

Hyperkalaemia
• if there is soft tissue injury (e.g. burns), there is loss of some neurones innervating the tissues
• (deinnervation supersensitivity) - upregulation of receptors in the skeletal muscle
• suxamethonium administration - exaggerated response with a bigger influx of sodium and bigger efflux of potassium
• This can lead to ventricular arrhythmias/cardiac arrest

Bradycardia
• due to the direct muscarinic action on the heart
• usually prevented because suxamethonium is usually given after GA and hence following administration of atropine (muscarinic antagonist)

Raised intraocular pressure
• AVOID for eye injuries and glaucoma

Question 29

Describe the mechanism of action of tubocurarine.

Answer 29

a competitive nicotinic acetylcholine receptor antagonist.

Blocking this proportion means the end-plate potential generated will NOT reach the threshold. Only 70-80% block is required to achieve full relaxation of the muscles

Question 30

What are the effects of tubocurarine?

Answer 30

(same as suxamethonium)
Initially fasciculations
causes flaccid paralysis

Question 31

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

Answer 31

Order:
• Extrinsic eye muscles (first to relax, last to go back to normal)
• Small muscles of the face, limbs and pharynx
• Respiratory muscles

Question 32

State two uses of tubocurarine.

Answer 32

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

Question 33

How can the actions of non-depolarising NM blockers be reversed?

Answer 33

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

Question 34

What else must you give with physostigmine (anti-cholinesterase) when trying to reverse the actions of (non-depolarising) NM blockers?

Answer 34

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 35

How are all NM blockers administered?

Answer 35

Intravenously

Question 36

What is the duration of paralysis of tubocurarine?

Answer 36

40 mins

Question 37

Describe the metabolism and excretion of tubocurarine?

Answer 37

It is NOT metabolised at all

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

Question 38

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

Answer 38

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 39

State some unwanted effects of tubocurarine.

Answer 39

MAIN EFFECTS: ganglion block + histamine release from mast cells cause most of the unwanted effects
• HYPOTENSION
• TACHYCARDIA – reflex tachycardia in response to hypotension
• BRONCHOSPASM
• EXCESSIVE SECRETIONS
• APNOEA