Drugs Affecting the Neuromuscular Junction Flashcards
why is the NMJ special?
It is specialised so that it should always work. If there is a pre-synaptic event, then there will be contraction.
What makes up the nicotinic ACh receptor?
5 subunits:
2x alpha 4
3x Beta 2
There are 2 binding sites for ACh.
enables sodium influx and potassium efflux
What type of feedback is used upon ACh release?
nAChR uses a positive feedback on release on the presynaptic terminal to allow the re-uptake of ACh.
Are there any drugs that interfere with CAT (Cholinacetyltransferase)?
no known drugs so far
What drug blocks carrier transports ACh into vesicles?
Vesamicol
What drug blocks the choline transporters?
Hemicholinium
What blocks exocytosis of vesicle?
Toxins
What is the Botulinum toxin?
Clostridium botulinum is an anaerobic bacteria.
10^-12g toxin - lethal to a mouse.
Block of cholinergic synapses (muscle paralysis - death)
How does the botulinum toxin work?
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.
What can treat botulinum poisoning?
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,
What immunological treatment is there fore the botulinum toxin?
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
what are neuromuscular blockers?
Adjunct (add on) to anaesthesia.
Pharmacological agents that act at the nicotinic ACh receptor.
What are the two categories of neuromuscular blockers?
Non depolarising blocker - Antagonists
Depolarising blocker - Agonist
What was the first non-depolarising blocker?
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.
What are some modern non-depolarising blockers?
Pancuronium
Vecuronium
How do non-depolarising blockers work?
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.
What is the depolarising blocker and how does it work?
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.
How do depolarising blockers lead to paralysis?
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.
When is Suxamethonium used?
Used in brief procedures (intubation)
Broken down by Plasma cholinesterase leading to rapid recovery compared to non-depolarising blockers
What are some unwanted effects
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)
What are cholinesterase inhibitors?
Post-synaptic modulators
Interact with AChE and plasma Cholinesterases.
Prevents breakdown of Ach enhancing synaptic function
Give examples of AChE inhibitors?
Edrophonium - ionic interaction (minutes)
Neostigmine - covalent bonds (hours)
Organophosphates - phosphorylation (irreversible)
How do cholinesterases reverse effects?
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)
When would Cholinesterase inhibitors be used?
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
