Drugs Affecting the Neuromuscular Junction

Question 1

why is the NMJ special?

Answer 1

It is specialised so that it should always work. If there is a pre-synaptic event, then there will be contraction.

Question 2

What makes up the nicotinic ACh receptor?

Answer 2

5 subunits:
2x alpha 4
3x Beta 2

There are 2 binding sites for ACh.

enables sodium influx and potassium efflux

Question 3

What type of feedback is used upon ACh release?

Answer 3

nAChR uses a positive feedback on release on the presynaptic terminal to allow the re-uptake of ACh.

Question 4

Are there any drugs that interfere with CAT (Cholinacetyltransferase)?

Answer 4

no known drugs so far

Question 5

What drug blocks carrier transports ACh into vesicles?

Answer 5

Vesamicol

Question 6

What drug blocks the choline transporters?

Answer 6

Hemicholinium

Question 7

What blocks exocytosis of vesicle?

Answer 7

Toxins

Question 8

What is the Botulinum toxin?

Answer 8

Clostridium botulinum is an anaerobic bacteria.
10^-12g toxin - lethal to a mouse.
Block of cholinergic synapses (muscle paralysis - death)

Question 9

How does the botulinum toxin work?

Answer 9

Has 2 subunits:
1st - binds to presynaptic membrane
2nd - (peptidases) cleave proteins involved in exocytosis and thus blocking it.

Therefore blocks cholinergic synapses causing paralysis and eventually death.

Question 10

What can treat botulinum poisoning?

Answer 10

4-aminopyridine.
Blocker of voltage gates K channels and therefore reduces K efflux during the repolarisation phase of an action potential. This leads to prolonged depolarisation and leads to increased Ca influx,

Question 11

What immunological treatment is there fore the botulinum toxin?

Answer 11

If early enough, and the toxin is not yet inside the cell then can use antitoxins:
Antibody against toxin
Binding prevents entry into the nerve terminal

Question 12

what are neuromuscular blockers?

Answer 12

Adjunct (add on) to anaesthesia.

Pharmacological agents that act at the nicotinic ACh receptor.

Question 13

What are the two categories of neuromuscular blockers?

Answer 13

Non depolarising blocker - Antagonists

Depolarising blocker - Agonist

Question 14

What was the first non-depolarising blocker?

Answer 14

Curare (D-tubocurarine)
Blow-dart poison used by Amazonian tribes
2 similar moieties to ACh and therefore enables this drug to bind to nAChR and block them.

Question 15

What are some modern non-depolarising blockers?

Answer 15

Pancuronium

Vecuronium

Question 16

How do non-depolarising blockers work?

Answer 16

Competetive antagonists at nAChRs
Leads to a decreased end plate potential.
Leads to muscle relaxation (paralysis) when given clinically (15min - 2hrs)

Given along side lower doses of anaesthesia as this is safer than a high anaesthesia dose.

Question 17

What is the depolarising blocker and how does it work?

Answer 17

Suxamethonium (2 ACh molecules linked by acetyl groups)

Agonist at nAChRs

Causes endplate depolarisation to increase.
Leads to action potentials (contractions)
These are uncoordinated, fine contractions.
Drug is not broken down by AChE leading to prolonged depolarisation and thus paralysis.

Question 18

How do depolarising blockers lead to paralysis?

Answer 18

Due to constant APs being produced, once the voltage gated Na channels are inactivated after AP, there are too many inactivated to then cause a phase 1 block.

Question 19

When is Suxamethonium used?

Answer 19

Used in brief procedures (intubation)

Broken down by Plasma cholinesterase leading to rapid recovery compared to non-depolarising blockers

Question 20

What are some unwanted effects

Answer 20

Bradycardia - activation of mAChRs in the heart
K release
Important in burns (if muscles are denervated)
Leads to cardiac arrest.

Cause damage to the eye by increasing pressure intraocularly.

Prolonged paralysis (phase 2 block - inactivation of nAChRs)

Question 21

What are cholinesterase inhibitors?

Answer 21

Post-synaptic modulators

Interact with AChE and plasma Cholinesterases.

Prevents breakdown of Ach enhancing synaptic function

Question 22

Give examples of AChE inhibitors?

Answer 22

Edrophonium - ionic interaction (minutes)

Neostigmine - covalent bonds (hours)

Organophosphates - phosphorylation (irreversible)

Question 23

How do cholinesterases reverse effects?

Answer 23

Reverse effects of non-depolarising blocking drugs.
Given at the end of operations
Increase Ach levels to compete with the antagonist

(would make effects of depolarising blockers worse)

Question 24

When would Cholinesterase inhibitors be used?

Answer 24

In myasthenia Gravis

• Muscle weakness – failure of NMJ transmission
• Autoimmune: Antibody against nicotinic AChRs
• Progressive: Death
• Drugs – Initial benefit:  ACh levels to try to overcome  in nAChRs

• Management:  Edrophonium
– short duration; Diagnostic test of drug efficacy  Neostigmine
– medium duration; muscarinic side effects  Pyridostigmine
– Better oral absorption; long duration; less powerful