Neural signalling to skeletal muscles & drugs acting at the neuromuscular junction

===Lecture Details===
Wayne Hodgson; Week 11 MED1011; Pharmacology
===Lecture Content===
There are about 300000 vesicles in each bouton, each containing up to 5000 ACh molecules. Vesicle contents are called quantum of ACh. Skeletal NMJ is to reliably translate AP in nerve to muscle. At rest mini end plate potentials are generated, not enough to reach threshold potential. AP occurs when sufficient ACh is released. Larger response created by recruiting more motor units. Calcium influx causes ACh vesicle release, binds to alpha subunits of N receptor. Na channel opens, local depolarisation, spread, Ca release from SR, contraction of muscle. Drugs interfering with this can act presynaptically (inhibit synthesis/release) or postsynaptically.
Non depolarising blockers are competitve antagonists at N receptors, action is overcome by increasing ACh. They have no initial stimulant action, and they are not absorbed as they are highly polar and are instead given IV. Do not pass BBB/placenta.
Tubocuarine is a non depolarising blocker, has a long duration of 60-120 minutes. Used in poison darts. Vecuronium 20-40 minutes, rocuronium 15-80m, are all synthetic derivatives with less side effects. 
Depolarising blockers stimulate N receptors, action potentiated by increasing ACh, produced by high doses of nicotinic agents. Prevents cycles of depolarisation and repolarisation. Inactivates Na channels and causes receptors to be unresponsive to ACh. Suxamethonium is one such drug, is hydrolysed rapidly by cholinesterase. Acts 3-7 minutes. Cannot be reversed.
NM blocking drugs produce paralysis, decrease breathing, patient is conscious and feels pain. Facilitates intubation and ventilation.
Botulinim toxin is from clostridium botulinim, inhibits ACh release, binds to motor nerve terminals and cleaves SNAP-25 so vesicle cannot dock or release. Botox is botulinim toxin type A.
There are anticholinesterases to potentiate ACh; physostigmine, neostigmine, edrophonium. Irreversible anticholinesterases are used as nerve gases, insecticides, and in glaucoma. It is reflected by enhancement of ACh activity- sweating, bradycardia, increased salivation, resp failure. Treatment is with atropine which blocks M actions of ACh. For pesticides, pralidoxime is used.
Myasthenia gravis is autoantibodies to N receptors, reduced population, contraction is not sustained. Increasing muscle weakness after activity with recovery after short rest period. Treated with anticholinesterase, atropine can be given to block unwanted M effects. Corticosteroids or immunosuppressants can be used for antibodies.
===Readings===
====Rang (6th) Ch 10 144-167====