W6: Pharmacology Of NMJ Flashcards
What enzyme synthesises ACh?
CAT = choline acetyltransferase
Presynaptic modulation by drugs
Synthesis of acetylcholine (by CAT) - no drugs
Carrier transports ACh into vesicle - blocked by Vesamicol
Choline transporter - blocked by Hemicholinium
Exocytosis of vesicle - blocked by toxins
What is Botulinum Toxin?
- from an anaerobic bacterium
- very lethal
- very selective to ACh nerve endings
How is botulinum toxin lethal?
- it has 2 subunits: 1st binds to presynaptic membrane, 2nd it cleaves proteins involved in exocytosis
- blocks cholinergic synapses so causes muscle paralysis causing death by suffocation. Muscle paralysis leads to death.
Clinical use of BT?
Botox = wrinkle - remover (local injection into skin)
Paralyses some muscles of the skin so they don’t wrinkle
How do you treat botulinum poisoning - pharmacological?
4-aminopyridine:
- blocker of voltage gated K+ channels
- pre-synaptic mechanism leads to increase in ACh release
- the decrease in K+ efflux during repolarisation phase of action potential leads to a prolonged depolarisation, so increased Ca2+ influx into presynaptic terminal, triggering exocytosis.
Immunological treatment for botulinum poisoning
Antitoxin - antibody against the toxin
Binding prevents entry into the nerve terminal
Only effective if not enough BT has entered the terminal yet
Drugs acting post-syntactically: neuromuscular blockers
Adjunct to general anaesthesia
Act at nicotinic AChR
Non-depolarising and depolarising blockers
Action of non-depolarising blockers
Block the nAChRs by binding to them. E.g. Pancuronium, Vecuronium
Competitive antagonists, compete with ACh. So less ACh binding, so less receptor activation, so less sodium entry, hence reducing end plate potential so threshold is not reached and no AP generated because VGNa+ do not open, and if decreased far enough, NMJ is blocked causing paralysis.
Use and recovery from non-depolarising blockers
Use adjunct to general anaesthesia. IV administration. Allows use of lower amount of anaesthetic so is safer. Lasts 15mins-2hrs
Recovery from liver metabolism or direct renal excretion.
Action of suxamethonium (depolarising blocker)
Agonist at nAChRs
- Causes end plate depolarisation, causing APs and uncoordinated, fine contractions (fasciulations/twitches)
- Not broken down by AChE in synaptic cleft, so causes prolonged depolarisation and thus paralysis due to the inactivation of voltage gated Na+ channels = phase 1 block
Uses and recovery of suxamethonium
Brief procedures: IV - short action, 10mins. Intubation. Produces flaccid paralysis which relaxes muscles (hence allowing tube down someone’s throat)
Broken down by plasma cholinesterase (rapid recovery compared to non-depolarising blockers)
Unwanted effects of suxamethonium
Bradycardia - (activation of muscarinic ACh receptors in the heart)
K+ release (efflux) (via nAChRs) - important in burns patients since they already have hyperkalaemia (esp if muscles are denervated, lots of nicotinic receptors expressed on the muscle in hopes of releasing more ACh) leading to cardiac arrest
Increased intraocular pressure (contraction of extraocular muscles)
Prolonged paralysis due to deficiency of plasma cholinesterase = phase 2 block (due to inactivation of nAChRs)
Actions of cholinesterase inhibitors
Interact with AChE and plasma cholinesterase
Prevents breakdown of ACh so enhances synaptic function and prolongs action potentials
Affects other synapses where ACh is the transmitter, e.g., postganglionic parasympathetic nerves and autonomic ganglia
Cholinesterase inhibitor drugs and how they affect duration of action
Edrophonium - ionic interaction (weak so lasts a few minutes)
Neostigmine - covalent bones (strong so lasts hours and body must make new enzymes)
Organophosphate - phosphorylation = irreversible. A chemical weapon; pesticides. Reactivated by Pralidoxime if given early.
