Neuromuscular 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 an end plate potential in the muscle fibre
This is a graded potential meaning that it is dependent on the amount of acetylcholine released and the number of receptors stimulated. more stimulation, more EPP.

Once the end plate potential reaches a threshold, it generates an action potential that propagates in both directions along the muscle fibre. (end plate is in the middle of the fibre so the potential goes on either directions)

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
Atracurium
Suxamethonium

Question 7

State the two main types of nicotinic acetylcholine receptor.

Answer 7

Ganglionic (part of ANS)

Muscle

Question 8

Describe the structure of nicotinic acetylcholine receptors.

Answer 8

They consist of 5 subunits (subunits can be either alpha, beta, gamma, delta or epsilon)
There are always 2 alpha subunits, which bind to acetylcholine and activate the receptor ie you need 2 ACh to bind to the two alpha subunits in order to open the channel for sodium influx

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 central spasmolytics and describe their action. (there are also spasmolytics that interfere with PROPAGATION OF AP ALONG MUSCLE FIBRE + MUSCLE CONTRACTION)

Answer 10

Diazepam
by facilitating GABA transmission

NB these are not neuromuscular blocking drugs

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 (look at tubocurarine on slide 7)

Depolarising= 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.

Answer 20

Suxamethonium is a nicotinic receptor agonist.
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 and so allows easier intubation
Muscle relaxant for electroconvulsive therapy – treatment for severe clinical depression

Question 25

State and explain four unwanted effects of suxamethonium.

Answer 25

1. Post-operative muscle pains
    Due to initial fasciculations
2. Hyperkalaemia
    If there is soft tissue injury or burns you will lose some neurones innervating the tissues
    Then you will get upregulation of receptors in the skeletal muscle – denervation hypersensitivity
    So if you give suxamethonium you get an exaggerated response with a bigger influx of sodium and bigger efflux of potassium (hyperkalaemia)

3.Bradycardia
 This is due to the direct muscarinic (PNS) action on the heart by suxamethonium
 This effects tends to be prevented by giving atropine

4.Raised intraocular pressure

Suxa is similar to Ach and causes contraction of extraocular muscles (S,I,L,M rectus, SO and IO and LPS)

 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 of nAChR 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 (flaccid paralysis) of skeletal muscles and the orderin which they return back to normal when given tubocurarine.

Answer 27

Tubocurarine also causes flaccid paralysis, to the following muscles in the descending order. (recovery is ascending order)
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

1. RELAXATION OF SKELETAL MUSCLES DURING SURGICAL OPERATIONS (= use LESS general ANAESTHETIC, high GA is used to block abdominal muscles in some operations, high dose so more dangerous. Using NM blocker is much safer which directly paralyses the abdominal muscles)
2. PERMIT ARTIFICIAL VENTILATION, if we don’t use NM blocker and use artificial ventilation then their natural drive to breathe will go against what the ventilator is trying to do ‘breathing against the ventilator’, so instead u paralyse the resp muscles and let ventilator do its job

Question 29

How can the actions of NM blockers be reversed?

Answer 29

Give an anti-cholinesterase (e.g. physostigmine). This increases ACh which out competes the NM blockers

Question 30

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

Answer 30

Atropine (muscarinic antagonist)
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 from muscarinic stimulation

Question 31

How are all NM blockers administered?

Answer 31

Intravenously

Question 32

What is the duration of paralysis of tubocurarine?

Answer 32

1-2hrs

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%) so need to be careful if patient has renal or hepatic diseases

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

Newer drug: ATRACURIUM (15 MIN; CHEM. UNSTABLE and so breaks down into inactive compounds in blood, without the need of being excreted or metabolised), beauty of this drug is that it does not rely on renal or hepatic excretion

Question 35

State some unwanted effects of tubocurarine.

Answer 35

MAIN EFFECTS: This drug causes ganglion block (autonomic ganglia have nicotinic AChR AND histamine release from mast cells.

This leads to the following side effects:
 HYPOTENSION – histamine can act on H1 receptors and cause vasodilation, ganglion block so reduced sympathetic tone (reduced TPR)

 TACHYCARDIA – reflex tachycardia in response to hypotension. Blockade of ganglia (esp. vagal ganglia) will reduce resting vagal tone on heart.

 BRONCHOSPASM – caused by histamine release
 EXCESSIVE SECRETIONS (bronchial and salivary) – caused by histamine

 APNOEA – caused by respiratory muscle blockade, which is why you assist respiration