9. Neuromuscular blocking drugs

Question 1

Where is choline acetyltransferase found and what does it do?

Answer 1

• Only found in cholinergic nerve terminals (motor)

* Synthesises ACh from Acetyl CoA and Choline

Question 2

How does an action potential lead to vesicle exocytosis in motor neurones?

Answer 2

• Depolarisation of membrane
• Opening of voltage sensitive calcium channels
• Calcium influx
• Vesicle exocytosis

Question 3

What are the targets for the ACh at neuromuscular junctions?

Answer 3

Nicotinic acetylcholine receptors on the end plate

Question 4

Describe how ACh stimulates the receptors on at the neuromuscular junction

Answer 4

• Nictonic receptors are ion channel linked
• Stimulation => conformation change + influx of sodium ions
• Depolarisation of membrane
- graded potential: depends on how much ACh and how many receptors stimulated
• Once end plate potential reaches threshold => action potential
• AP propagates in both directions
• Acetylcholinesterase is bound to the basement membrane in the synaptic cleft - it breaks down ACh to acetate and choline

Question 5

Name 3 of the main neuromuscular blockers

Answer 5

• Tubocurarine
• Atracurium
• Suxamethonium

Question 6

What are the 2 main subtypes of nicotinic receptors?

Answer 6

• Ganglionic (neuronal)

* Muscle (on skeletal muscle)

Question 7

How many subunits make up the nicotinic ACh receptor?

Answer 7

• 5 subunits

* 2 α subunits - must bind to ACh for receptor to be activated (so 2 ACh needed)

Question 8

Name a spasmolytic that facilitates GABA transmission

Answer 8

Diazepam

Question 9

Name a GABA receptor agonist

Answer 9

Baclofen

Question 10

What is the site of action for local anaesthetics?

Answer 10

Conduction of action potentials down a motor neurone

Question 11

Where do neuromuscular blocking drugs act?

Answer 11

Motor end plate (post-synaptic)

Question 12

How does dantrolene work?

Answer 12

• Spasmolytic
• Works in muscle fibres themselves
• Inhibits Ca2+ release

Question 13

What is the difference between depolarising and non-depolarising neuromuscular blocking drugs?

Answer 13

• Depolarising - nicotinic receptor agonists e.g. suxamethonium
• Non-depolarising - competitive nicotinic receptor antagonists e.g. tubocurarine, atracurium

Question 14

Do neuromuscular blocking drugs affect the following:

• consciousness
• respiration
• pain sensation

Answer 14

Only can affect respiration, so assistance needed

Question 15

How does the structure of a depolarising drug differ from non-depolarising?

Answer 15

Depolarising
• more flexible and allows rotation
• made up of 2 ACh molecules linked together - therefore only one needed to stimulate receptor

Non-depolarising
• big, bulky molecules
• restricted movement around the bonds

Question 16

Outline the mechanism of action of suxamethonium

Answer 16

• Extended end plate depolarisation => depolarisation block of the NMJ
• Phase 1 block
• Slowly seeps into muscle fibres
• Stimulates nicotinic receptors (agonist)
- isn’t metabolised rapidly
- remains bound => receptors switch off by overstimulation

Question 17

Suxamethonium causes fasciculations, what is this?

Answer 17

• Individual fibre twitches as it begins to stimulate nicotinic receptors
• Leads to flaccid paralysis - no muscle tone

Question 18

How is suxamethonium administered, what is the duration of paralysis and how is it metabolised?

Answer 18

• IV (highly charged)
• Paralysis for 5 minutes
• Metabolised by pseudocholinesterase in the liver and plasma

Question 19

What is suxamethonium used for?

Answer 19

• Endotracheal intubation - relaxes skeletal muscle of airways
• Relaxant for electroconvulsive therapy

Question 20

What are the unwanted effects of suxamethonium?

Answer 20

• Post-operative muscle pains (due to initial fasciculations)
• Bradycardia (muscarinic action) - but tends to be prevented by atropine in general anaesthetic
• Hyperkalaemia if there is a soft tissue injury
- loss of neurones innervating the muscle
- upregulation of receptors, deinnervation supersensitivity
- exaggerated response to drug
- bigger efflux of potassium
• Raised intraocular pressure

Question 21

What is the mechanism of action of tubocurarine?

Answer 21

• Competitive nicotinic ACh receptor antagonist
• 70-80% block for full relaxation
• End plate potential can’t reach threshold

Question 22

What are the effects of tubocurarine?

Answer 22

• Same as suxamethonium
• Flaccid paralysis
• Muscles relax in the following order:
- extrinsic eye muscles
- small muscles of the face, limbs, pharynx
- respiratory muscles
• Recovery in the opposite order

Question 23

What is tubocurarine used for?

Answer 23

• Relaxation of skeletal muscles during surgical operations - therefore less general anaesthetic needed
• Permit artificial ventilation

Question 24

How can you reverse the effects of non-depolarising blockers?

Answer 24

• Neostigmine (reversible anticholinesterase)
• Increases [ACh] in all other cholinergic synapses
- so give some atropine to block muscarinic receptor over stimulation

Question 25

How is tubocurarine administered, what is the duration of paralysis and how is it metabolised?

Answer 25

• IV (highly charged)
• Paralysis for 40-60 minutes
(• doesn’t cross BBB or placenta)
• Not metabolised - excreted in urine (70%) and bile (30%)
- hepatic or renal function impairment increases duration of action

Question 26

What do you administer if someone with hepatic or renal impairment is given tubocurarine?

Answer 26

• Atracurium
• Duration of action - 15 mins
• Chemically unstable - plasma pH causes hydrolysis into 2 inactive fragments

Question 27

What are the unwanted affects of tubocurarine?

Answer 27

• Could block some nicotinic receptors in ganglia
• Histamine release from mast cells
• Hypotension - ganglion blockade and histamine causing vasodilation
• Tachycardia => arrhythmias - due to reflex to hypotension, vagal ganglia blockade
• Bronchospasm - from histamine release
• Apnoea