Neuromuscular blockers

Question 1

What type nAChRs are there

Answer 1

neuronal and muscular

Question 2

Where are neuronal nAChRs found

Answer 2

CNS and PNS

Question 3

Where are muscular nAChRs found

Answer 3

neuromuscular synapse

Question 4

What is the function of nAChRs (4)

Answer 4

Mediate fast excitatory transmission

Modulation of synaptic transmission

Cognitive processes e.g. learning and memory

Control of movement

Question 5

What is the role of nAChRs in disease/ What diseases do nAChRs play a part in (5)

Answer 5

Myasthenia gravis

Nicotine addiction

Parkinson’s

Alzheimer’s

Schizophrenia

Question 6

What is the structure of nAChRs

Answer 6

Pentameric (5 subunits)

Each subunit has 4 transmembrane domains: TM1, TM2, TM3, TM4

The 5 subunits join together to form a pore within the cell membrane. Each subunit can be a different SUBTYPE

The nAChR contains 20 TM domains

Has an amine group and a carboxylic acid group

Question 7

how does activation of the nAChR result in an end plate potential

Answer 7

Ach binds to alpha subunits (partial overlap with other subunits)

Binding of 1st Ach enhances binding of 2nd Ach

Channel opens within 20usec causing an influx of cations

The subunits are orientated such that the TM2 regions line the pore

TM2 is helical with a kink that forces a leucine residue into a tight ring which blocks the pore

Acetylcholine binding causes TM2 to rotate, relaxing the constriction and allowing ion flow

TM2 has negatively charged amino acids orientated towards the channel pore

TM2 domains provide selectivity of the pore for cations, preferably monovalent

The electrochemical gradient controls the direction in which the ions move (therefore only potassium and sodium flow through)

Question 8

How is the nAChR selective

Answer 8

Neuromuscular transmission allows the nervous system to communicate with skeletal muscle and cause a contraction

Motor nerves from the spinal chord synapse with skeletal muscle fibres. Each nerve fibre branches into as many as 200 non-myelinated branches

Each branch forms an end plate region on a single muscle fibre known as the MOTOR ENDPLATE

Neurotransmitter is always Ach and receptor is always nAChR

Question 9

Why does an end plate potential open voltage gated sodium channels

Answer 9

Influx of Na+ ions through the nAChR leads to a mini-end plate potential

The more Na+ ions that diffuse in down the electrochemical gradient cause an end plate potential

Endplate potential leads to a voltage change which causes the opening of VGNa+ channels

Question 10

Why does the opening of VGNa+ channels result in muscle contraction

Answer 10

Causes an action potential which therefore stimulates the release of calcium ions

Ca2+ leads to muscle contractions

Question 11

list the key uses of neuromuscular blockers in a clinical setting

Answer 11

Tracheal intubation

Skeletal muscle relaxation during surgery

Question 12

What is rapid sequence induction

Answer 12

technique used to quickly and safely intubate patients who are at risk of aspirating gastric contents into their lungs

Question 13

What are the steps to Rapid sequence induction

Answer 13

1. Induction (getting patient to sleep)
   
   • Patient pre-oxygenated
   • Given general anaesthetic
   • Given neuromuscular blocker to relax skeletal muscle
   • Patient intubated
     § Endotracheal tube (ETT) intubation
     § Laryngeal mask airway (LMA)
   • Given analgesic drugs e.g. opioids
2. Maintenance (keeping patient asleep)
   
   • Continued administration of oxygen and general anaesthetic
   • Top up doses of muscle relaxant guided by neuromuscular monitoring
   • Analgesia as required (e.g. opioids)
3. Emergence (waking the patent up)
   
   • Neuromuscular blockade reversed
   • Patient given 100% oxygen and general anaesthetic stopped
   • LMA/ETT removed when a patient begins spontaneously breathing and wakes up

Question 14

Why is tracheal intubation needed during surgery

Answer 14

To permit ventilation of lungs

Delivery of oxygen and removal of carbon dioxide

Question 15

Why is it sometimes beneficial to relax skeletal muscle during surgery e.g. abdominal surgery

Answer 15

To paralyse larynx to be able to intubate to ventilate the lungs

Improved surgical access - relaxed muscles make it easier to access deep structures like organs or blood vessels

Reduced risk of injury - when muscles are tense or contracting, it creates physical resistance, relaxed muscles make it easier to manipulate tissues

Prevention of involuntary movements - ensures that the surgical field remains stable

Question 16

How does duration of surgery and speed of onset impact the choice of neuromusclar blocker used

Answer 16

Duration of surgery
- short acting vs long acting NMBs
- Reduces the need for frequent redosing

Speed of onset
- Emergent or rapid airway management (extremely rapid onset of 30-60s)
Elective surgeries (speed is not as critical so can do 2-3min)

Question 17

What is the pharmacological action of non-depolarising NMB i.e. agonist or antagonist

Answer 17

Antagonist

Non-depolarizing NMBs bind to the nicotinic ACh receptors on the muscle endplate but do not activate them.

By occupying these receptors, they prevent acetylcholine from binding and triggering muscle contraction.

Since these drugs block the action of acetylcholine without causing receptor activation, they effectively prevent depolarization of the muscle membrane, leading to muscle relaxation.

Question 18

What is the pharmacological action of depolarising NMB i.e. agonist or antagonist

Answer 18

Agonist

Depolarizing NMBs (e.g., succinylcholine) bind to the nicotinic ACh receptors and mimic the action of acetylcholine by activating these receptors, causing an initial depolarization of the muscle membrane.

This leads to brief muscle contractions or fasciculations.

However, unlike acetylcholine, depolarizing NMBs are not rapidly broken down by acetylcholinesterase.

As a result, they continue to occupy the receptor and keep it in a depolarized state.

Since the receptor remains depolarized, it becomes desensitized and unresponsive to further stimulation, preventing any new action potentials and leading to flaccid paralysis of the muscles.

Question 19

How does antagonist at the nAChR inhibit the generation of an end plate potential and therefore muscle contraction

Answer 19

Since ACh cannot bind to the receptor, the nAChR ion channels do not open, and there is no influx of sodium ions into the muscle cell.

Without the influx of Na⁺, depolarization of the motor end plate does not occur, and the end plate potential (EPP) is not generated.

Question 20

What are some examples of Non-depolarising blocking agents

Answer 20

Rocuronium

Pancuronium

Vecuronium

Atracurium

mivacurium

Question 21

How are the majority of non-depolarising NMBs metabolised

Answer 21

Metabolised in the liver (ester hydrolysis) followed by excretion into urine and bile

Question 22

What is Hoffman elimination and which NMB is metabolised this way

Answer 22

Hoffman elimination = spontaneous degradation that occurs at body temperature and pH

Question 23

How is mivacurium metabolised

Answer 23

Hydrolysis by plasma cholinesterases

Question 24

What are the most common side effects of non-depolarising NMBs

Answer 24

Tubocurarine causes histamine release causing:
- Blonchospasms
- Dilation of peripheral blood vessels
§ Decrease blood pressure
- Excessive secretions

Some older agents also have an effect at muscarinic and nicotinic receptors not found at the neuromuscular junction causing
- Hypertension
- Tachycardia

Newer aginets have been developed with the aim of avoiding these side effects
- E.g. vecuronium

Question 25

What is rapid sequence induction and why are non depolarising blockers not suitable for use in this type of anaesthesia?

Answer 25

Rapid sequence induction = method of achieving rapid control of the airway whilst minimising the risk of regurgitation and aspiration of gastric contents Sequential administration of hypnotic agent and muscle relaxant followed by tracheal intubation within 1 min of giving the muscle relaxant NMBs are not suitable as they have a longer time of onset and are not rapid enough (take longer than 1 min)

Question 26

Why does suxamethonium have a longer duration of action than acetyl choline?

Answer 26

Suxamethonium is metabolised by an enzyme in the blood called plasma cholinesterase Acetylcholine is broken down in the synaptic cleft by acetylcholinesterase Metabolism of suxamethonium takes 5-10 minutes whereas metabolism of acetylcholine is much quicker Suxamethonium therefore stays in the synaptic cleft for longer and therefore has a much longer duration of action

Question 27

Why does suxamethonium cause muscle fasciculations

Answer 27

Suxamethonium activates the nicotinic acetylcholine receptor (nAChR) This leads to the development of EPP (end plate potential) This activates voltage gated Na+ ion channels Which leads to muscle contraction (fasciculation)

Question 28

Why does a longer duration of action result in muscle relaxation

Answer 28

Prolonged activation can lead to a depolarisation block Prolonged activation of nAChR leads to generation of end plate potential This leads to the inactivation of VGNa+ channels - As they cannot return to their resting state - this means they are constantly in their inactivation state which makes it impossible for the cell to produce subsequent action potentials Therefore leads to muscle relaxation

Question 29

What is the difference between desensitisation and depolarisation block? (cause, mechanism, example, reversibility)

Answer 29

Depolarisation block still leads to the generation of an end plate potential whereas a desensitisation block does not Depolarisation Block * Cause: Persistent depolarization of the cell membrane. * Mechanism: Voltage-gated sodium channels remain inactivated, preventing action potentials. * Example: Succinylcholine-induced muscle paralysis, hyperkalaemia. * Reversibility: Requires repolarization. Desensitisation Block * Cause: Prolonged or repeated receptor activation. * Mechanism: Receptors (e.g., nicotinic) become unresponsive, even if the stimulus is present. * Reversibility: Requires removal of the stimulus or receptor recovery.

Question 30

Why does suxamethonium cause parasympathetic side effects and what are they?

Answer 30

Suxamethonium acts as an agonist at nicotinic acetylcholine receptors at the neuromuscular junction, but it can also stimulate muscarinic acetylcholine receptors in parasympathetic pathways * Bradycardia * Increased bronchial and salivary secretion * Increased gastric tone

Question 31

What is malignant hypepyrexia and why does suxamethonium sometimes trigger it? How is it treated?

Answer 31

Rare genetic condition Mutation in the calcium channel in the SR Intense spasm and dramatic rise in body temperature How suxamethonium triggers it * excessive calcium release in skeletal muscle caused by a mutation in the RYR1 gene or, less commonly, in the CACNA1S gene Treated - Dantrolene reduces calcium release from the sarcoplasmic reticulum - Cool core body temperature - ice/dialysis

Question 32

Why can suxamethonium cause prolonged paralysis

Answer 32

Genetic variations on plasma cholinesterase activity Anticholinesterase drugs Patients with liver damage

Question 33

Under what conditions can suxamethonium lead to hyperkalaemia

Answer 33

Normal conditions - plasma K+ levels not elevated to clinically significant levels Severe burns and certain neurological disorders much greater rises in K+ have been reported Leads to cardiac arrhythmias Denervation super sensitivity: in patients with denervated or severely damaged muscle, nAChR's are not localised to motor endplate but extend along surface of muscle - These receptors have a prolonged open time - This leads to increased K+ efflux causing cardiac arrhythmias

Question 34

How can the dose of rocuronium be altered to allow it to be used in rapid sequence induction?

Answer 34

At higher doses (from 0.6 to 1.2mg/kg) rocuronium's time of onset is around 75sec (60-120 seconds depending on dose)

Question 35

Compare and contrast the time of onset and duration of action of suxamethonium and rocuronium when used in rapid sequence induction

Answer 35

Suxamethonium time of onset is 60 sec and has a duration of action of 4-6 mins Rocuroniums time of onset is 60-120sec (dose dependent) and has a duration of action of >30 mins Time of onset between the two drugs are similar where as rocuronium has a much longer duration of action

Question 36

Why is a reversal agent needed to terminate rocuronium's paralytic action but not suxamethonium

Answer 36

Rocuronium requires reversal agents due to its longer action and lack of rapid enzymatic breakdown Whereas suxamethonium is rapidly metabolised by plasma cholinesterase

Question 37

Why is rocuronium a better choice of drug compared to suxamethonium when considering rapid sequence induction in a patient with a burn injury?

Answer 37

Rocuronium has a much more favourable side effect profile RSI in a burn injury patient - Must be re-intubated quickly - Burns = denervation super sensitivity - Suxamethonium could therefore cause hyperkalaemia and potentially fatal arrhythmias

Question 38

Why are reversal agents needed

Answer 38

Postoperative residual neuromuscular block is a serious threat which endangers patient safety * Patient must be kept anaesthetised until effects can be reversed Rocuronium needs reversal agents as it is not enzymatically metabolised

Question 39

What is the mechanism of action underlysing neostigmine's ability to reverse NMB induced paralysis?

Answer 39

Neostigmine is an acetylcholinesterase inhibitor This leads to increased levels of ACh at the neuromuscular junction. The higher ACh concentration outcompetes non-depolarizing neuromuscular blockers (e.g., rocuronium) at nicotinic receptors, restoring muscle contraction.

Question 40

What are the side effects associated with using neostigmine

Answer 40

Muscarinic Side Effects: * Cardiovascular: ○ Bradycardia (slow heart rate). ○ Hypotension. * Gastrointestinal: ○ Nausea, vomiting, abdominal cramps. ○ Diarrhea. ○ Increased salivation and gastric secretions. * Respiratory: ○ Bronchospasm. ○ Increased bronchial secretions. * Urinary: ○ Increased urination (due to bladder stimulation). Nicotinic Side Effects: * Skeletal Muscle: ○ Muscle cramps or twitching. ○ Weakness (at high doses, due to overactivation of neuromuscular junctions).

Question 41

What is the mechanism of action underlying glycopyrrolates ability to reduce neostogmines side effects

Answer 41

Elevated Ach and not limited to NMJ and occurs at muscarinic receptor sites in PNS Glycopyrrolate is a muscarinic acetylcholine receptor antagonist Neostigmine is combined with glycopyrrolate in order to neutralise the muscarininc side-effects It blocks muscarinic receptors, preventing the excessive cholinergic effects caused by neostigmine's increased acetylcholine. This reduces side effects such as bradycardia, bronchial secretions, salivation, and gastrointestinal upset.

Question 42

What effect will neostigmine have on suxamethonium's paralytic action and why?

Answer 42

The elevated Ach will not reverse the block and may enhance it as both suxamethonium and Ach are agonists at the nAChR

Question 43

What is the mechanism of action underlying the ability of sugammadex to reverse the paralytic action of aminosteroid neuromuscular blockers?

Answer 43

Reversal agent for aminosteroid NMBs * Rocuronium > vecuronium * RSI - reversal agent Modified gamma-cyclodextrin with a hydrophilic exterior and lipophilic centre Encapsulates all aminosteroid NMBs rendering them inactive * 1 sugammadex : 1 rocuronium Promotes dissociation of the aminosteroid from the neuromuscular junction (NMJ) Creates a concentration gradient from the NMJ to the plasma