Lecture 11: Neuromuscular agents

Question 1

What are NMBA’s?

Answer 1

They are a class of drugs that paralyse patients by acting at the neuromuscular junction. They present significant risk however.

Question 2

Explain the sedative, analgesic and amnesic effects of NMBAs?

Answer 2

They have none

Question 3

Clinical use of NMBAs?

Answer 3

For intubation of the trachea avoiding damage to the vocal cords

Prevents deleterious movements during delicate procedures

Helps to improve conditions for ventiltion by removing the work of breathing and this can allow lowered ICP

Question 4

NMJ entities?

Answer 4

1. Presynaptic - ACh is made, stored and released
2. Synaptic cleft - 15nm and contins basil lamina
3. Post synaptic - Has ACh receptor

*Go and review NMJ*

Question 5

Structure of the Nicotinic Acetyl Choline Receptor (AChR)

Answer 5

- Pentameric ligand-gated ion channel

• Synthesised in muscle cells
• anchored to the endplate

Question 6

Classifications if NMBAs

Answer 6

Mechanism of action

• depolarising vs non-depolarising

Chemical Structure

• Benzylisoquinolones vs aminosteroids

Duration of action

• Ultra-short, short, intermediate, long

Question 7

Give and explain the action of a depolarising NMBA?

Answer 7

Succinylcholine (SCh)

Mimics the effects of ACh

one molecule binds simultaneously to the 2a subunits

Is really an agonist but blocks the NMJ after the inital stimulation as it doesnt allow for repolarisation

Is not susceptible to ACesterase but rather remains in receptor till plasma conc drops due to plasma cholinesterase or elimination by the kidneys

Question 8

AE of succylcholine?

Succinylcholine (SUX) Apnoea?

Answer 8

1. Can’t be reversed
2. anaphylaxis
3. Fasciculations - muscle pain in 1:5000
4. Masseter spasms
5. Cardiac dysrythmias - brady and tachycardia due to chatecholamine release
6. increase ICP, IgastricP, IocularP
7. may trigger malignant hyperpyrexia

This is what occurs in 1/3200 people that are homozygous for the deficiency.

Question 9

How do Non-depolarising NMBAs work?

Effect conc relationship?

Answer 9

• They are + charged quaternary ammonium compounds attracted to AChR that bind to one or both a subunits preventing ACh binding.
• Compeditive interaction between ACh an d NMBA occurs
• But if only one molecule is required to block then there is an obvious bias towards the NMBA
• Effect depends on conc of the NMBA and ACh but begins when >70% occupation and is considered complete at >90%

Question 10

Atracurium onset time and pathway of degradation?

AE?

Answer 10

Onset is 3-5 min so not that fast

Hofmann elimination at body pH and Temp that is independent of the liver or kidney

AE: CVS effects caused by histamine release, transient rash, hypotenstion or tachycardia

Question 11

Mivacurium onset, potency, AE?

Answer 11

3x more potent than Atracurium nut slow onset of 3-4min

Has a short duration of 20-25min

Hydrolysed by plasma (pseudo)cholinesterase (like SCh) but is a non-dep. NMBA

AE: less histamine that atracurium but, conditions causing abnormal pseudocholinesterase will delay recovery

Question 12

Rocuronium potency, use, duration, AE?

Answer 12

Intermediate duration of action around 40min

Low potency so high dose required

Rapid onset of action so useful for rapid intubation instead of SCh

Less anaphylaxis than SCh and minimal cardiac effects and low histamin release

Hepatic elimation mainly (90%) with the rest being renal

Question 13

Vecuronium duration, onset, AE

Answer 13

Intermediate duration

slower onset but similar duration to rocuronium

Active metabolite excreted in urine - prolonged duration in renal failure patients

minimal cardiac effects with least potential for anaphylaxis

Question 14

Pancuronium onset, potency, effects, removal

Answer 14

High potency and slow onset

longest acting (1.5-2h)

Has vagolytic effects causing increased blood pressure, HR and CO

Good for long cardiac surgical procedures

Minimal histamine release

Excreted by the Liver and Kidneys

Question 15

Reversal of NMBAs?

Answer 15

Accelerate reversal

• increase ACh concentration at the NMJ by stoping its breakdown via acetylcholinestersae = Neostigmine and Pyridostigmine
• Decrease plasma concentration of the NMBA

Question 16

AE of acetylcholineesterase blockers and how we overcome them?

Answer 16

Act at all cholinergic synaoese in the peripheral nervous system

Vagal effects such as bradycardia and bradyarrhythmias

Have potent parasympathetic activity that must be reversed by giving atropine or glycopyrrolate whicha are antimuscarinic drugs

Question 17

Example of how can we reversen a NMBA?

Answer 17

Sugammadex (works in 20sec-2min)

The perfect antidote for Rocuroniium and Vecuronium (to a lesser extent)

Restores normal neuromuscular function by selectively binding to Rocuronium

Binds to drug in the plasma and thus favours movement from NMJ out to the plasma.

Question 18

How do we monitor neuromuscular blockage?

Answer 18

We use TOF (train of 4) count of 4 and look for fade between them

If they have a 4th we measure the ratio of T4/T1

We are testing muscles with similar susseptability to NMBAs as the upper airway and laryngeal muscles as muscles like the diaphragm are less susseptable so start working first before the effects are actually worn off in the rest of the body.

Question 19

TOF response from non-dep vs dep NMBA?

Answer 19

Question 20

The danger of residual block and when can we begin to reverse the block?

Answer 20

Ventilatory response to hypoxia is imparied and does not return until the TOFR > 0.9

Reversal of the drug can only be given once a 4th twitch is visible, that is once spontaneous recovery has begun.