Pharmacology of the Neuromuscular junction

Question 1

Draw an overview of neurotransmission at the Neuromuscular junction?

Answer 1

1). Acetyl CoA and Choline are catabolised to create ACh and CoA 2). ACh is then packed into an empty vesicle 3). The release of ACh is facilitated by the presynaptic nicotinic ACh receptor and exocytosis occurs 4). ACh also has the ability to naturally leak out of the presynaptic cleft via the choline carrier 5). ACh crosses the membrane and binds to the post-synaptic nicotinic ACh receptor 6). ACh is broken down by AChE into Choline and Acetate 7). The choline transporter brings the Choline back to the pre-synapse

Question 2

What are the 3 ways to block neuromuscular transmission?

Answer 2

1). Presynaptically, by inhibiting ACh synthesis - rate limiting step is choline uptake 2). Presynaptically, by inhibiting ACh release 3). Postsynaptically -By interfering with the actions of Ate on. the receptor

Question 3

What are the 4 ways that we can presynaptically inhibit ACh release?

Answer 3

1. Local Anaesthetics
   * Stop propagation of action potentials
   
   2. General Inhalation Anaesthetics
   3. Inhibitors/Competitors of Calcium
      * Magnesium ions: Compete with calcium and prevent neurotransmitter release
      * Certain antibiotics:
      * Aminoglycosides (e.g., Gentamicin)
      * Tetracycline
   4. Neurotoxins
      * Botulinum toxin (e.g., Clostridium botulinum, Botox): Alters synaptobrevin and SNARE proteins
      * B-Bungarotoxin (e.g., Taiwanese banded krait): Alters synaptobrevin and SNARE proteins

Question 4

What is ACh duration of action limited by?

Answer 4

Its rate of uptake or rate of degradation

Question 5

What are the 4 reasons why we need Postsynaptic blocking drugs/neuromuscular blocking drugs?

Answer 5

**Endotracheal intubation
**During surgical procedures
**– To allow surgical access to abdominal cavity
– To ensure immobility
* (e.g.prevent cough during head and neck surgery)
– Allow relaxation to reduce displaced fracture or dislocation – ↓concentrion of general anaesthetic needed
**Infrequently in intensive care
**– Mechanical ventilation at extremes of hypoxia
During electroconvulsive therapy

Question 6

What does the structure of the nicotinic acetylcholine receptor look like?

Answer 6

It has 5 parts to the channel, 2 alpha protein parts which form the gate and allows ACh to bind and cause a conformational change Has a 0.7nm pore in middle

Question 7

What happens after ACh binds to the Nicotinic acetylcholine receptor ?

Answer 7

Sodium and potassium can pass in and out of the cell The more sodium that comes in, the greater the chance you have for end plate innervation

Question 8

What is the function of ACh receptor Agonists and name 2 of them?

Answer 8

Agonists bind and make the change we are interested, acting like the usual drug E.g - Nicotine and Suxamethonium Keep channel open like ACh does

Question 9

What is the function of ACh receptor Antagonists and name 2 of them?

Answer 9

Antagonists will inhibit the response that you would get from the substrate E.g - Tubocurarine and Atracurium Keep channel closed even if ACh is present Leads to loss of muscle control!

Question 10

What are non-depolarising blockers?

Answer 10

Competitive antagonists of Nicotinic ACh receptors at the Neuromuscular junction E.g - Tubocurarine and Atracurium

Question 11

What is the difficulty with non-depolarising blockers?

Answer 11

They are difficult to get into the blood supply, but once in they quickly give the adverse effects These drugs stop the control of muscles but don’t block pain! At high levels you begin tools the ability to breath and control respiratory muscles

Question 12

What are the 4 steps of how non-depolarising blockers work?

Answer 12

1). Prevents ACh binding to receptor by occupying site 2). Decreases the motor end plate potential (EPP) 3). Decreases depolarisation of the motor end plate region 4). No activation of the muscle action potential

Question 13

What happens to a graph of an impulse with a non-depolarising blocker?

Answer 13

The threshold for action potential will never be reached so three will be no contractile events

Question 14

What are depolarising blockers?

Answer 14

Agonists of Nicotinic ACh receptors at the Neuromuscular junction E.g - Suxamethonium

Question 15

What are non-depolarising blockers not metabolised by?

Answer 15

Acetylcholine esterase

Question 16

How do depolarising blockers generally work?

Answer 16

Binds to Nicotinic Acetylcholine receptors and acts as an agonist, causing a conformational change in receptor and allowing the influx of sodium Inititally muscle will twitch as Suxamethonium starts to open the receptors and cause action potentials but eventually they will stop and the patients muscle control will drop off Suxamethonium looks like 2 ACh molecules so it can bind to the receptors however enzymes cannot degrade it, meaning there will be a longer neurotransmission at the junction

Question 17

What are the steps of depolarising blockers?

Answer 17

Persistent depolarisation of the motor end plate Prolonged end plate potential Prolonged depolarisation of the muscle membrane Membrane potential above the threshold for the resetting of the voltage-gated sodium channels Sodium channels remain refractory No more muscle action potentials are generated

Question 18

What are the 2 phases in Depolarising blockers?

Answer 18

Phase 1 — Muscle fasciculations observed, then blocked — Repolarisation inhibited • K + leaks from cells (risk of hyperkalemia) — Voltage-gated Na+ channels kept inactivated due to change in endplate Phase 2 — Prolonged / increased exposure to drug — “Desensitisation blockade” • Depolarisation cannot occur, even in absence of drug

Question 19

Name the 6 different types of blockers, their onset, duration and side effects

Answer 19

Table

Question 20

What is Postoperative myalgia?

Answer 20

Muscle ache feeling like you’ve had the flu or been at the gym

Question 21

What are the 4 ways to metabolise and eliminate blockers and give examples of these?

Answer 21

Ester hydrolysis and Hofmann elimination — Atracurium Plasma cholinesterases — Mivacurium — Suxamethonium Hepatic metabolism — Pancuronium — Vecuronium - Effect of liver function Unchanged in bile/urine — Rocuronium - Effect of liver and kidney function

Question 22

What is an issue with using Plasma Cholinesterases to degrade blockers?

Answer 22

Some people have a mutation in the enzyme that breaks this down causing a Prolonged block (apnoea) ; -4% population takes 10 mins longer to break down drug -0.04% population hours more to break down drug than should Usually patents remain paralysed and unable to breath after surgery and cannot regain muscle function quick enough - Genetic testing should be done to prevent this

Question 23

How is the duration of action of Cholinesterase’s regulated?

Answer 23

By hydrolysis

Question 24

Give 3 features of Acetylcholinesterase (ACh.E)?

Answer 24

Acetylcholinesterase (ACh.E) — True cholinesterase, specific for hydrolysis of ACh — Present in conducting tissue and red blood cells — Bound to basement membrane in the synaptic cleft

Question 25

Give 3 features of Plasma cholinesterase ?

Answer 25

Plasma cholinesterase — Pseudocholinesterase, broad spectrum of substrates — Widespread distribution — Soluble in plasma

Question 26

What drugs are used to inhibit cholinesterase enzymes and what does this cause?

Answer 26

Anticholinesterase drugs; - Increase the availability at Neuromuscular function by decreasing degradation - Increase duration of activity of ACh at Neuromuscular junctions - More ACh to compete with non-depolarising blockers

Question 27

Give 4 examples of anticholinesterase drugs, their duration and mechanism of action?

Answer 27

Table

Question 28

What types of anticholinesterase drugs aren’t used in clinical practice and why?

Answer 28

Organophosphates as they are irreversible and ruin enzymes unless treated very quickly

Question 29

What does recovery from Dyflos/Parathion depend on and what drug can be used to try and coax off the drug?

Answer 29

Recovery depends on the synthesis of the new enzyme Can be coaxed off by pralidoxime

Question 30

How does anticholinesterases affect the CNS?

Answer 30

Central nervous system — Initial excitation with convulsions — Unconsciousness and respiratory failure

Question 31

How does anticholinesterases affect the Autonomic nervous system?

Answer 31

Autonomic nervous system — Salivation — Lacrimation — Urination — Defecation — Gastrointestinal upset — Emesis — Bradycardia — Hypotension — Bronchoconstriction — Pupillary constriction (miosis) Use acronym SLUDGE

Question 32

What are the 4 clinical uses of anticholinesterase’s?

Answer 32

In anaesthesia — Reverse non-depolarising muscle blockade — Given with atropine or glycopyrrolate to counteract parasympathetic effects Myasthenia Gravis — Increase neuromuscular transmission (Autoimmune response where body generates antibodies to the Ach receptor) Glaucoma — Decrease intraocular (eye) pressure Alzheimer’s disease — Enhance the cholinergic transmission in the CNS

Question 33

How do Anticholinesterases helps those with Myasthenia Gravis?

Answer 33

Myasthenia gravis; Autoantibodies may be produced against the acetylcholine receptor blocking the interaction of the acetylcholine receptor with its ligand (acetylcholine) and leading to increased muscle weakness and death. Patients have widespread muscle weakness - if given further increase of ACh for longer allows for bigger chance of muscle impulses Can restore muscle tone by giving more ACh

Question 34

What is Sugammadex and its function?

Answer 34

Sugammadex is a selective binding agent (SRBA) Used to reverse effects of rocuronium and vecuronium (non-depolarising drugs)