Pharmacology of the Neuromuscular junction Flashcards

1
Q

Draw an overview of neurotransmission at the Neuromuscular junction?

A

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

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2
Q

What are the 3 ways to block neuromuscular transmission?

A

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

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3
Q

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

A

We can inhibit ACh release by; - 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)

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4
Q

What is ACh duration of action limited by?

A

Its rate of uptake or rate of degradation

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5
Q

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

A

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)

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6
Q

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

A

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

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7
Q

What happens after ACh binds to the Nicotinic acetylcholine receptor ?

A

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

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8
Q

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

A

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

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9
Q

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

A

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!

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10
Q

What are non-depolarising blockers?

A

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

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11
Q

What is the difficulty with non-depolarising blockers?

A

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

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12
Q

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

A

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

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13
Q

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

A

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

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14
Q

What are depolarising blockers?

A

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

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15
Q

What are non-depolarising blockers not metabolised by?

A

Acetylcholine esterase

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16
Q

How do depolarising blockers generally work?

A

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

17
Q

What are the steps of depolarising blockers?

A

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

18
Q

What are the 2 phases in Depolarising blockers?

A

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

19
Q

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

A

Table

20
Q

What is Postoperative myalgia?

A

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

21
Q

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

A

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

22
Q

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

A

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

23
Q

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

A

By hydrolysis

24
Q

Give 3 features of Acetylcholinesterase (ACh.E)?

A

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

25
Q

Give 3 features of Plasma cholinesterase ?

A

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

26
Q

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

A

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

27
Q

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

A

Table

28
Q

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

A

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

29
Q

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

A

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

30
Q

How does anticholinesterases affect the CNS?

A

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

31
Q

How does anticholinesterases affect the Autonomic nervous system?

A

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

32
Q

What are the 4 clinical uses of anticholinesterase’s?

A

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

33
Q

How do Anticholinesterases helps those with Myasthenia Gravis?

A

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

34
Q

What is Sugammadex and its function?

A

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