Muscle Relaxants

Question 1

Triad / quartet of anaesthesia:

Answer 1

1. Sleep / unaware / hypnosis / loss of consciousness
2. Analgesia
3. Muscle relaxation
4. (Homeostasis)

Question 2

neuromuscular junction.

Answer 2

The NMJ is the place where the terminal end of the nerve meets the muscle fibre – and where electrical signal is converted to a muscle contraction.

Question 3

Process of an action potential

Answer 3

calcium enters the cell from the extracellular space and causes exocytosis of acetylcholine (ACh) which are stored in vesicles inside the nerve terminal.

Acetylcholine is released from the terminal of the nerve, into the synaptic cleft where it binds to the nicotinic receptor on the muscle membrane. This is a very rapid process and involves ligand-gated channels (the ACh is the ligand).

Once ACh binds to the nicotinic receptor, it causes depolarisation (called the motor end-plate) with resultant muscle contraction.

**Nicotinic receptors have five subunits and for this receptor to be activated, two acetylcholine molecules need to bind.

When two ACh bind, it causes the receptor to change shape (conformational change) to allow the central port to open so that Na can travel out (against the concentration gradient), and K can travel into the cell.

It’s the potassium that is responsible for the resting membrane potential (which is negative) inside the cell, so when K moves out, depolarisation occurs on the muscle side of the synapse.

This then causes an action potential along the muscle membrane which causes Ca to enter the cell and attach to troponin C, which inhibits the troponin I from inhibiting the troponin T and then allows the actin and myosin myofilaments to slide over one another – resulting in muscle contraction.

Question 4

General info on muscle relaxants

Answer 4

• only relaxes the skeletal muscle (striated), not the smooth muscle
• Only causes relaxation  no analgesic or hypnotic / sleep-inducing effect
• must ventilate patient!

Question 5

Classification of muscle relaxants

Answer 5

1. Depolarising: binds to the nACh receptor and causes depolarisation (suxamethonium is now the ligand, not ACh)
2. Non-depolarising = binds to the post-synaptic nACh receptor and prevents ACh from binding (competitive antagonists) - Onset of action & duration of action proportional to dose
   - Doesn’t cross placenta or BBB (H20-soluble)

Question 6

Name the different drugs in each group

Answer 6

1. Depolarising
   - Suxamethonium
2. Non-depolarising:
   - Curare
   - Pancuronium
   - Alcuronium
   - Atracurium
   - Cis-atracurium
   - Mivacurium
   - Rocuronium
   - Vecuronium

Question 7

The ideal muscle relaxant

Answer 7

• Non-depolarizing
• Short onset of action
• Dose-dependent duration of action
• No side effects
• Elimination independent of organ function
• No active or toxic metabolites

Question 8

Suxamethonium MOA and TOA

Answer 8

Scoline is another name for suxamethonium

ultra-short duration of action & structurally similar to acetylcholine
suxamethonium is used when the operation is short or there is risk of aspiration

MOA: Binds to post-synaptic nACh receptors, depolarizes (agonist) post-synaptic membrane, and then occupies receptor 1000x longer than Ach. Unlike ACh, Suxamethonium is not inactivated by the acetylcholinesterases. Therefore, the membrane can’t depolarize again and thus there is relaxation of the muscle (known as a phase 1 block)

Termination of action:
- Spontaneous  uncouples from receptor and is degraded by plasma-cholinesterases (pseudo / butyl)
- No antagonist / reversal necessary

Question 9

phase II block suxamethonium

Answer 9

If repeated doses are given, it causes ongoing movement of Na out and K in, and ongoing change in membrane potential. The membrane potential tries to restore itself, but it cannot restore itself by the time the next dose of suxamethonium is given thus, no normal depolarization can occur. It then starts to behave like a competitive antagonist because it is occupying the receptor and not allowing the membrane potential to restore itself  this is called a phase II block.

Question 10

Clinical use of suxamethonium

Answer 10

• Only muscle relaxant with short onset of action, short duration of action, and that is 100% reliable
• Dose  1 mg/kg (babies 2 mg/kg)
• Usually given IVI, but may be given IMI
• Intubate within 60 seconds
• Duration  ± 8 min (6 – 12 minutes depending on amount of plasma-cholinesterase present in blood)

Question 11

Indications fo Suxamethonium

Answer 11

• Intubation in patient with a high risk of aspiration (‘rapid sequence induction’)  full stomach (not NPO), incompetent LES, increased intra-abdominal pressure, reflux etc.
• Difficult airway
• Short surgery time (<10 min)
• Treatment of laryngospasm

Question 12

S/E of Suxa

Answer 12

• Cardiac dysrhythmias
  o Bradycardia  muscarinic stimulation prevented by atropine which blocks the parasympathetic effects
  o Tachycardia  stimulation of autonomic ganglia
• Respiratory  bronchial secretions and risk of bronchospasm
• Hyperkalaemia (C/I in burns due to hyperkalaemia) C/I in kidney failure
• Fasciculations: prevent by giving NDMR 3-5 min before suxa
• transient incr ICP and IOP
• Muscle pain

Question 13

Complications of suxamethonium use

Answer 13

• Masseter muscle rigidity > makes intubation very difficult
• May ‘trigger’ malignant hyperthermia!
• Anaphylactic reactions
• Scoline apnoea / prolonged block

Question 14

Malignant hyperthermia

Answer 14

masseter muscle rigidity, tachycardia, metabolic acidosis, hypercapnia, and hyperthermia

Question 15

Scoline (Suxa) apnoea / prolonged block

Answer 15

when patients have abnormal pseudo-cholinesterases (genetic)
when patient has too little pseudo-cholinesterases (preg, liver disease, burns)

Causes = atypical pseudo-cholinesterases, other non-depolarising drugs, opiates, inhalational agents, **hypothermia, phase II block

Dx = nerve stimulator no twitches in response to stimulation

Mx = sedated, ventilated

Question 16

Drug interactions with suxamethonium

Answer 16

• Prolong duration of effect = lithium, ecothiopate eye drops (glaucoma), cyclophosphamide
• Nodal and ventricular rhythms = digitalis, aminophylline, halothane

Question 17

THERE IS A TABLE OF NDMR - Go look at it and memorize !

Question 18

Further classification of NDMR

Answer 18

Aminosteroids
- Vecuronium
- Rocuronium
- Pancuronium

Benzyl Isoquinolones
- Atracurium
- Cisatracurium
- Mivacurium

Question 19

Reversal of NDMR

Answer 19

• decr [NDMR] in synaptic cleft due to redistribution of NDMR and metabolism in organs (spontaneous reversal)
• incr [ACh] at nicotinic receptor anti-cholinesterases (reversal)

Question 20

Anticholinesterases:
Mechanism of action

Answer 20

• Transient inhibition / blocking of acetylcholinesterase enzyme in the synaptic cleft
• incr [ACh] at the nicotinic receptor
• Displaces NDMR and reverses the muscle blockade

Question 21

Examples of anticholinesterases

Answer 21

• Neostigmine (intermediate) = covalent binding (reversible)
• Pyridostigmine (intermediate) = covalent binding (reversible)
• Edrophonium (short-acting) = H-bonds (irreversible)

Question 22

C/I of anticholinesterases

Answer 22

when it increases at the muscarinic receptors, it can cause bradycardia, bronchospasm, airway secretions, and a painful increase in gut peristalsis

Question 23

How to decrease these parasympathetic sx of anticholinesterases

Answer 23

Combine with antimuscarinic agent

1. Atropine  0.02 mg/kg
   - Crosses the BBB  confusion in elderly
   - Prominent tachycardia
   - Delayed bradycardia
2. Glycopyrrolate  0.01 mg/kg
   - Doesn’t cross the BBB
   - Better antimuscarinic effect
   - Longer duration of action (2 hours)

Question 24

Sugamadex

Answer 24

Another drug for reversal of NDMR
encapsulates the NDMR and thus removes the antagonist from the cleft
- Only reverses rocuronium and vecuronium
- If necessary, could give immediately after administration of rocuronium

Question 25

When to give reversal:

Answer 25

- At end of surgery whenever NDMR was used  can only give when patient is reversible (when the increase in [ACh] will predictably overcome the antagonism)

Question 26

Monitoring of neuromuscular blockade

Answer 26

- Ulnar nerve  adductor pollicis muscle - Facial nerve  orbicularis oculi - Posterior tibial nerve  flexor hallucis brevis - The electrical stimulus is a single pulse of 1- 0.1Hz and is delivered 1 – 10 seconds apart - “Twitches” (muscle contraction) are assessed - One can look at the strength of the twitch or contraction - The twitch is displayed as a line on the monitor, with strength of the twitch being reflected by height of the line - The shorter the line, or the weaker the twitch / contraction, the greater the degree of the block

Question 27

Fade with neuromuscular monitoring

Answer 27

The fourth twitch is weaker than the first twitch and this phenomenon is called “fade”. As the block becomes more established, and more of the receptors are becoming occupied 75% - lose 4th twitch 80% - lose 3rd twitch 90% - lose 2nd twitch 95-100% - lose 1st twitch all of them

Question 28

Post-tetanic count:

Answer 28

If you have no twitches on train of four stimulation, then you have quite a deep block if you want to evaluate just how deep the block is, you can do a post-tetanic count. A tetanic stimulation is a continuous stimulation down the nerve. With a neuromuscular blocker, you will still have a very strong tetanic contraction (despite the blockade).

Question 29

Train of four (TOF) ratio:

Answer 29

The ratio of the height / strength of the fourth twitch, compared to the height / strength of the first twitch If no neuromuscular blockage  the fourth twitch will be equally as strong as the first twitch ( 𝑇4/𝑇1=100%). In partial blockade  the fourth twitch will be lower than the first twitch ( 𝑇4/𝑇1=50%). 40% = Unable to lift hand or head 60% = able to open eyes 70% = able to lift head 5 sec 80% = normal vital capacity and inspiratory force

Question 30

Phases of NDMR: **NB!

Answer 30

- During intense (profound) block = no response to either TOF or PTC stimulation - During deep block = response to PTC but not to TOF stimulation - Intense (profound) block & deep block together constitute the “period of no response to TOF stimulation” - Reappearance of the responses to TOF stimulation indicates the start of moderate block - Finally, when all four responses to TOF stimulation are present and a TOF ratio can be measured, the recovery period has started

Question 31

When to give reversal of NDMR:

Answer 31

- Can give when two or more twitches are present  patient is “reversible”

Question 32

Inability to reverse neuromuscular blockade:

Answer 32

- Intensity of block - Severe hypothermia - Acid-base derangements - Organ dysfunction - Drug interactions o Antibiotics o Lithium o Magnesium sulphate o Benzodiazepines - Neurological conditions o Myasthenia gravis - Electrolyte derangements (rare) o Serum potassium o Serum calcium o Serum magnesium

Question 33

Diagnosis of residual paralysis:

Answer 33

- Under anaesthetic  apnoea - If awake  inability to: o Elevate head for 5 seconds o Maintain hand grip for 5 seconds o Stick out tongue for 5 seconds o Bite down on tongue depressor for 5 seconds o Negative inspiratory pressure -40cm water

Question 34

TOF and Post tetanic facillitation with suxamethonium?

Answer 34

Depolarizing muscle relaxants (suxamethonium) does NOT demonstrate fade and there is NO post-tetanic facilitation!