Lecture 30: Neuromuscular Blockers

Question 1

Write some notes on the nicotinic Ach receptor found at the neuromuscular junction:

Answer 1

• Transmembrane
• Five subunits, two Alphas bind ACh
• Both must be bound simultaneously allowing Na to cross

Question 2

Write some notes on the chemistry of non-depolarising muscle relaxants:

Answer 2

• All quaternary ammonium compounds
• Mimic the quaternary nitrogen atom of ACh which binds to the alpha subunit of nicotinic receptors
• Exerts competitive antagonsim
• Concentration at NMJ can decline as drug eliminated, then ACh can outcompete it and diminish its effects

Question 3

Why do these drugs bind in the same way as ACh yet cause antagonism?

Answer 3

Probably related to bulky rigid nature of drug molecules

-> Binds but does not allow usual conformational change and bulk may actually block the ionophore

Question 4

What are the non-depolarising agents to be aware of and their timeframes:

Answer 4

Short: 10-15mins: MIVACURIUM
Intermed: 25-45min: Atracurium, vecuronium, Rocuronium
Long:45-90mins: Pancuronium

Question 5

What are the other defining features of Mivacurium?

Answer 5

Rapid metabolism by plasma esterase’s responsible for relatively fast offset

Question 6

What are the other defining features of Atracurium:

Answer 6

Spontaneous degredation independent of liver and kidney: good in hepatic or renal failure

Question 7

What are the other defining features of Vecuronium?

Answer 7

Probably least potential for histamine release

Question 8

What are the other defining features of Rocuronium?

Answer 8

Fastest onset of the non-depolarisers. LOCAL reputation for analphylaxis

Question 9

What are the other defining features of Pancuronium?

Answer 9

Longest acting. Some vagolytic effect (Tachycardia)

Question 10

Describe the train of four concept:

Answer 10

Four stimuli are given and four responses are measured. once drug administered, no responses are measured. As it wears off a response might be measured after the first stimulus and as recovery continues you will see fade with each stimulus. I.e each response to a stim is decreasing. Once TOF ratio is 80% it is considered acceptable for recovery

Question 11

What is fade seen on the TOF a manifestation of?

Answer 11

Manifestation of block at pre-junctional receptor

NDNMBs block prejunctional receptors as well as those on post synaptic membranes

• (these pre, once activated are resp. for ACh vesicle mobilisation)
• Blockade = Reduced mobilisation thus less ACh is released for successive stimuli and twitch height becomes less (Fade)

Has proven an adequate surrogate for blockade at the post synaptic membrane

Question 12

Describe the antagonism of non-depolarising blockade: i.e what you want to do reverse it

Answer 12

NDNMB can be reversed providing not too profound
- Reverse after 1-2 twitches on train of four (TOF)

Reversal by: Anticholinesterase i.e neostigmine BUT cholineesterase present outside CNS ie muscunaric so coadministered with Atropine

Question 13

What is sugammadex?

Answer 13

The first selective muscle relaxant binding agent

Question 14

Write some notes on sugammadex:

Answer 14

• Binds to rocuronium and vecuronium and makes them unavailable to bind to nicotinic receptors
• Avoids cholinergic side effects of neostigmine
• Can be used at any level of relaxation i.e large doses if relaxation is profound
• Expensive
• Can cause anaphylaxis

Question 15

What is the common depolarising neuromuscular blockade?

Answer 15

Suxamethonium (Succinylcholine)

Question 16

Write some notes on suxamethonium

Answer 16

• Structurally 2ACh molecules bound
• Thus one molecule can bind the two alpha subunits
• Agonise the receptor - Produces twitch
• BUT Sux breakdown by cholineesterase is much much slower than Ach. Thus ionophore remains open and membrane cant repolarise.
• Thus: we see initial uncoordinated twitches (Fasciculations) then paralysis

Question 17

Describe the timeline of Suxamethonium:

Answer 17

Onset is rapid (60sec)
Offset is rapid (3-5mins)

• Offset is combined effect of Sux metabolism by cholinesterase at the NMJ and Sux removal from plasma by plasma cholinesterase’s

Question 18

Why does suxamethonium need to be treated with respect?

Answer 18

• DNMB causes K to rise (prolonged leak)
  = Catastrophic rise in patients with upregulation of extrajunctional nicotinic receptors.
• Raises ICP
• May cause bradycardia
• Common cause of anaphylaxis
• Potent trigger for malignant hyperthermia
• Approx 1:3200 have genetic deficit in plasma cholinesterases = increased duration for hours (applies to mivacurium too)

Question 19

Why use suxmethonium at all?

Answer 19

• Rapid control of airway in pt with high risk aspiration

- Nothing produces good intubation conditions so quickly