Pharmacology of the Neuromuscular junction Flashcards
Draw an overview of neurotransmission at the Neuromuscular junction?
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 (acetylcholinesterase) into Choline and Acetate
7). The choline transporter brings the Choline back to the pre-synapse
What are the 3 ways to block neuromuscular transmission?
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 ACh on. the receptor
What are the 4 ways that we can presynaptically inhibit ACh release?
Using local anaesthetics which stops propagation of axon potentials
General inhalation anaesthetics
Inhibitors/competitions of Calcium (E.g - Magnesium ions won’t. trigger the release of a neurotransmitter if beating Calcium, and some antibiotics like Aminoglycosides (e.g Gentamicin) and Tetracycline)
Neurotoxins alter synaptobrevin and snare proteins (e.g Botulinum toxin - Clostridium botulinum, and B-Bungarotoxin - Taiwanese banded krait (Botox)
What is ACh duration of action limited by?
Its rate of uptake or rate of degradation
What are the 4 reasons why we need Postsynaptic blocking drugs/neuromuscular blocking drugs?
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
— Decrease concentration of general anaesthetic needed
Infrequently in intensive care
— Mechanical ventilation at extremes of hypoxia
During electroconvulsive therapy (electrical charges to either side of the brain to try and treat seizures)
What does the structure of the nicotinic acetylcholine receptor look like?
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
What happens after ACh binds to the Nicotinic acetylcholine receptor ?
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
What is the function of ACh receptor Agonists and name 2 of them?
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
What is the function of ACh receptor Antagonists and name 2 of them?
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!
What are non-depolarising blockers?
Competitive antagonists of Nicotinic ACh receptors at the Neuromuscular junction E.g - Tubocurarine and Atracurium
What is the difficulty with non-depolarising blockers?
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
What are the 4 steps of how non-depolarising blockers work?
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
What happens to a graph of an impulse with a non-depolarising blocker?
The threshold for action potential will never be reached so three will be no contractile events
What are depolarising blockers?
Agonists of Nicotinic ACh receptors at the Neuromuscular junction E.g - Suxamethonium
What are non-depolarising blockers not metabolised by?
Acetylcholine esterase
How do depolarising blockers generally work?
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
What are the steps of depolarising blockers?
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
Name the 6 different types of blockers, their onset, duration and side effects
Table
What are the 4 ways to metabolise and eliminate blockers and give examples of these?
Ester hydrolysis and Hofmann elimination
— Atracurium
Plasma cholinesterases
— Mivacurium
— Suxamethonium
Hepatic metabolism (Effect of liver function)
— Pancuronium
— Vecuronium
Unchanged in bile/urine (Effect of liver and kidney) function
— Rocuronium
What drugs are used to inhibit cholinesterase enzymes and what does this cause?
Anticholinesterase drugs;
- Increase the availability of ACh at NMJ by decreasing degradation
- Increase duration of activity of ACh at NMJ
- More ACh to compete with non-depolarising blockers
Give 4 examples of anticholinesterase drugs, their duration and mechanism of action?
Table
