L9 - Drugs affecting neuromuscular junction

Question 1

Ways that drug can modify transmission:

Pre-synaptically, Post-synaptically

Answer 1

1. Pre-synaptically, to interfere with the synthesis, storage, or release of NT.
2. Post-synaptically, to interfere with the receptors, or removal mechanism of NT.

Question 2

Key steps in neuromuscular junction:

Answer 2

1. AP
2. Depolarisation
3. Open Ca channels
4. Ca influx
5. Release ACh by exocytosis
6. Activate nicotinic AChR on muscle membrane

Question 3

How ACh is made:

Answer 3

Ach made from choline and acetylcoenzyme A (AcCoA). Uses enzyme choline acetyl transferase (CAT). ACh stored in vesicles waiting for release by exocytosis.

Question 4

Botulinium toxin:

Answer 4

Hemicholiniums prevents uptake of precursor choline. So ACh doesn’t form. Releases botulinium toxin, B-bungarotoxin, Mg2+ ions.

Toxin is lethal and is very potent. It is found in uncooked foods and can cause botulism (food poisoning).
It can be used treat blepharospasm - prevents wrinkling.
It destroys major proteins that undergo exocytosis.
It can paralyse respiratory muscles and leads to death.

Question 5

Nicotinic ACh receptors (NAChR):

Answer 5

ACh diffuses across synapse and activates theses receptors on muscle membrane. AChE breaks the NT down.
Activated by nicotine so is an agonist. Receptor formed from five protein subunits α, α, β, γ, δ. Form around non-selective cation channel. Permeable to N and K. Channel opens when two molecules of ACh bind to the α subunits. Depolarisation occurs at end-plate region of muscle membrane - end plate potential.

Question 6

Drugs that inhibit transmission:

Clinical Use:

Answer 6

Reversible competitive antagonists bind at NAChR. Have affinity but not efficacy so block channel. ACh can’t bind. E.g. tubocurarine, vecuronium, atracurium and pancuronium.

Clinical Use:
Muscle Relaxants. Lower doses of anaesthetics can be administered. Effects 15-40 mins. Patient must be artificially ventilated. Neostigmine used to reverse effects.

Question 7

Depolarising muscle relaxants:

Answer 7

Suxamethonium (AKA succinylcholine).
Acts as agonist at NAChR. Has affinity and efficacy. Cause depolarisation. Not broken down by AChE so prolonged depolarisation. Na channels are in inactivated state (need to be returned to resting potential) so can’t support another AP.

Question 8

Suxamethonium:

Answer 8

Produce short-duration muscle relaxation.
Broken down by related enzyme in plasma - pseudo-cholinesterase. People who lack this drug have effects lasting hours.
Applied as intravenous injection.

Question 9

Anticholinesterase drugs:

Answer 9

AChE can be inhibited by neostigmine and edrophonium. Prevent breakdown of ACh and increase conc of NT. Neostigmine used to reverse effects of reversible competitive antagonists e.g. tubocurarine.
Does not reverse effects of Suxamethonium.

Question 10

Treatment for Myasthenia gravis:

Answer 10

Auto-immune disease due to weakness in neuromuscular. Neostigmine used to treat this. Increases conc of ACh so enhances neuromuscular transmission.
Edrophonium has a very short duration of action so used as a diagnosiss. Too much neostigmine causes non-depolarising block - paralyse skeletal muscles.