Lecture 10 - Neuromuscular Blocking Drugs

Question 1

What is a neuromuscular junction?

Answer 1

Synapse of the axon terminal of a motor neuron with a motor end plate

Question 2

What is a motor end plate?

Answer 2

A highly excitable region of muscle fibre plasma membrane responsible for initiation of action potentials across the muscle’s surface leading to muscle contraction

Question 3

What happens at neuromuscular junctions (NMJs) and what is the neurotransmitter involved?

Answer 3

NMJ is the location where the neurone activates muscle to contract
- Acetylcholine

Question 4

What is a neuromuscular junction?

Answer 4

The junction between an motor neuron axon terminal and a motor end plate

Question 5

Describe the events in the process required to make the muscle contract starting from the arrival of an action potential at the axon terminal of a motor neurone.

Answer 5

1) An action potential propagates along the motor neurone of a muscle fibre to the axon terminal
2) The AP depolarises the neuronal membrane, this stimulates voltage gated Ca2+ channels to open
3) Ca2+ ions diffuse into the axon terminal. This triggers acetylcholine-containing vesicles to move to and fuse with the presynaptic membrane
4) ACh is released into synaptic cleft by exocytosis and diffuses from presynaptic terminal to motor end plate
5) (KEY PART) ACh binds to nicotinic receptors on motor end plate, this opens Na+ and K+ channels. More Na+ ions move into the muscle fibre than K+ ions out, this depolarises the membrane of the muscle fibre and generates an END PLATE POTENTIAL (EPP)
6) Local currents depolarise the plasma membrane of the muscle fibre adjacent to the motor end plate. This generates an action potential which spreads along the rest of the muscle membrane
7) Action of ACh is terminated by acetylcholinesterase. Choline produced by the breakdown of ACh is recycled by reuptake back into the presynaptic terminal for new synthesis of ACh

Question 6

What type of proteins are nicotinic receptors, what are the 5 subunits of these receptors, and what is the combination of subunits in muscular nicotinic receptors?

Answer 6

• Ligand gated ion channels
• alpha, beta, gamma, delta, epsilon
• 2a, 1b, 1d, 1e (2 alpha subunits are where ligand binds)

Question 7

What kind of potential is an End Plate Potential?

Answer 7

It is a GRADED POTENTIAL - dependent on how much acetylcholine is released and how many receptors are stimulated

Question 8

How does an End Plate Potential propagate an action potential?

Answer 8

The grading is dependent on the stimulation of the receptors on the end plate. If enough receptors are stimulated, the end plate potential reaches a threshold and propagates an action potential along the muscle fibre

Question 9

What are the 3 main neuromuscular blocking drugs?

Answer 9

Suxamethonium
Tubocurarine
Atracurium

Question 10

What are the two types of neuromuscular blocking drugs and which of tubocurarine and suxamethonium is which?

Answer 10

Non-depolarising (competitive antagonist) - Tubocurarine

Depolarising (agonist) - Suxamethonium

Question 11

How do both types of drug interact with consciousness, pain sensation and respiratory?

Answer 11

Both do NOT affect consciousness or pain sensation

Both ALWAYS assist respiratory until drug is inactive or antagonised

Question 12

Where is the location of action of neuromuscular blocking drugs and how does each type affect this?

Answer 12

Post-synaptic, act on the nicotinic receptors on the motor end plate

• Non-depolarising are competitive antagonistic molecules, they bind with no efficacy and prevent agonist molecules from binding
• Depolarising are agonist molecules, they bind and cause overstimulation resulting in depolarisation block of the NMJ (a.k.a phase 1 block)

Question 13

What type of neuromuscular blocking drug is suxamethonium and what is its mechanism of action?

Answer 13

Depolarising NM blocking drug, agonist molecule for nicotinic receptors

• Stimulates the nicotinic receptors on the end plate
• Isn’t metabolised as quickly as ACh so remains bound to the receptor and continually stimulates it
• Very quickly the receptors will switch off
• This is a depolarisation block caused by overstimulation (phase 1 block)

Question 14

What does suxamethonium cause as it diffuses into the muscle fibre and what kind of paralysis does it cause after it has acted?

Answer 14

Causes fasciculations - individual fibre twitches as the suxamethonium begins to stimulate the nicotinic receptors but haven’t switched them off yet

Flaccid paralysis, no muscle tone

Question 15

Regarding the pharmacokinetics of suxamethonium, by what route is it administered, what is the duration of paralysis and what enzymes metabolise it and where?

Answer 15

• Administered intravenously (highly charged)
• 5 minutes paralysis
• Metabolised by pseudocholinesterase in liver and plasma

Question 16

What are the uses of suxamethonium?

Answer 16

Endotracheal intubation - relaxes skeletal muscle of the airways

Muscle relaxant for electroconvulsive therapy - treatment for severe clinical depression

Question 17

What are the unwanted effects of suxamethonium?

Answer 17

Post-operative muscle pains
Bradycardia - direct muscarinic action on the heart
Hyperkalaemia - soft tissue injury or burns lead to ventricular arrhythmias/cardiac arrest
Raised intraocular pressure - avoid using in patients with eye injuries or glaucoma

Question 18

What type of NM blocking drug is Tubocurarine?

Answer 18

Competitive nicotinic acetylcholine receptor antagonist - non-depolarising NM blocker

Question 19

Do competitive nicotinic receptor antagonists cause complete or incomplete block?

Answer 19

Incomplete as competitive so cannot 100% outcompete endogenous agonist

Question 20

What % of block does tubocurarine require for full relaxation of the muscles and why is this?

Answer 20

Need 70-80% block for full relaxation
- If this proportion of receptors are blocked then even if the remaining proportion are stimulated, the end plate potential won’t reach the threshold required for initiation of action potentials in the muscle fibre

Question 21

What type of paralysis does it produce, which 3 sets of skeletal muscles are paralysed and which order do they relax and return to normal?

Answer 21

Flaccid paralysis (same as suxamethonium)

• Extrinsic eye muscles (relaxes first, returns to normal last)
• Small muscles of the face, limbs, pharynx
• Respiratory muscles (relax last, return to normal first)

Question 22

You must be able to recognise a log dose-response curve showing the response of skeletal muscle to increasing concentrations of ACh and additionally how this would be altered in the presence of tubocurarine. What is the effect of tubocurarine on neuromuscular transmission?

Answer 22

Reduces amplitude of the End Plate Potential so no action potential is generated in the muscle fibre

• In a normal log D-R curve there is a large EPP and a corresponding action potential
• In a tubocurarine-affected D-R curve there is a small EPP and no corresponding action potential

Question 23

What are the uses of tubocurarine and other drugs like it and why are they used in these ways?

Answer 23

• Relaxation of skeletal muscles during surgery - less anaesthesia required
• Permits artificial ventilation

Question 24

How are the effects of tubocurarine and other NM blockers like it reversed?

Answer 24

Administration of ANTOCHOLINESTERASES - neostigmine (+atropine)
- Increases concentration of ACh at all NMJs to outcompete tubocurarine, atropine acts as a muscarinic antagonist and prevent unwanted stimulation of parasympathetic NS by the new high levels of ACh

Question 25

Why is tubocurarine ineffective if administered orally, what is the preferred administration route, and why does it not act centrally (on CNS)?

Answer 25

• Highly charged molecule so not easily absorbed enterally (in the gut) so little reaches systemic circulation
• Doesn’t act centrally as unable to cross BBB (again, highly charged and not lipid soluble)

Question 26

Regarding tubocurarine, what is the route of administration, the onset of action, the duration of action and the path of elimination?

Answer 26

• Intravenous administration
• Onset 2-3minutes
• Duration of paralysis 40-60minutes (long effect and slow metabolism)
• Is not metabolised so excretion is 70% in urine and 30% in bile (so care using if renal/hepatic function impaired)

Question 27

What are the unwanted effects of tubocurarine?

Answer 27

These are mainly due to ganglion blockade and histamine release from mast cells

• Hypotension - BP drops due to ganglion blockade and vasodilation caused by histamine
• Tachycardia - Reflex in response to hypotension, may lead to arrhythmias
• Bronchospasm - caused by histamine release
• Excessive secretions - caused by histamine release
• Apnoea - This is why respiration is always assisted in someone taking tubocurarine

Question 28

What is atracurium and what are its effects?

Answer 28

Another nicotinic antagonist acting at the NMJ, non-depolarising blocker like tubocurarine
- Has the same effects as tubocurarine but these last for a shorter duration

Question 29

When is atracurium used and why is this?

Answer 29

Used in patients needing tubocurarine but that have renal or hepatic impairment preventing safe removal of tubocurarine from their body
- Atracurium is useful here as it is a highly unstable molecule - due to the pH of the plasma, it gets hydrolysed into two inactive fragments

Question 30

What is the structure of suxamethonium and why is this important for its function?

Answer 30

Two ACh molecules joined together basically
- Allows one molecule of suxamethonium to bind to both alpha subunits on the nicotinic receptor so allows one molecule of suxamethonium to stimulate the nicotinic receptor where it would have taken two ACh molecules, also allows easier outcompeting of ACh