1. Drugs affecting neuromuscular transmission Professor Ian Hughes, 9.83; i.e.hughes@leeds.ac.uk motor nerve - skeletal (striated) muscle ONLY single long cell from CNS; action potential (Na channels) invades terminal opening Ca channels; intracellular Ca rises; vesicles release ACh by exocytosis; diffusion to receptors (ligand operated ion channel [2xalpha,beta,gamma,delta]); Na flows out; depolarisation of endplate; if sufficient depolarisation then voltage operated Na channels open and a propogated action potential followed by contraction results in muscle.

2. action potential calcium entry Ca++ choline recapture ACh (10,000) in vesicle choline acetylase R acetylcholine esterase ACh Choline pre- synaptic receptors + - diffusion

3. Pre-synaptic actions block nerve action potential; lignocaine prevent choline uptake ; hemicholinium triethylcholine block choline acetylase affect release mechanism ; Ca++ entry excess Mg++ ; botulinus toxin; affect pre-synaptic receptors ; discharge vesicles; beta bungarotoxin ; black widow spider venom affect potassium channels; 4-aminopyridine; TEA

4. Post-synaptic actions competitive blockers; tubocurarine, pancuronium, gallamine, fazadinium, atracurium, vecuronium depolarising blockers; suxamethonium ( succinylcholine) odds and sods; decamethonium, dantroline

5. Competitors (Tc) and depolarisers (Sux) - mechanism of action [Tc] mV map epp...... Sux stim

6. Compare:--- -----------------------------competitors -- depolarisers fasciculationsno yes paralysis (man)flaccidflaccid paralysis (bird)flaccidspastic tetanic stimulationfadesmaintain anticholinesterasereversedeepen K channel blockerreversedeepen +depolariserreversedeepen +competitordeepenreverse multiply innervated---------contracts muscle

7. Uses of neuromuscular blockers entubation - fast and short action relaxation during surgery - long action, reversible, controlled soften electro-convulsive therapy - short and fast action (use with anaesthetic) special conditions - renal or hepatic failure; manipulations; exceptionally convulsions.

8. Drugs tubocurarine - quaternary; release histamine;some ganglion block hence BP falls; hepatic 70%, renal 30%; 30-40 min pancuronium - longer lasting; renal 75% vecuronium - short (20 min); hepatic 85%, renal 15% gallamine - renal 90%; 30-40 min fazadinium - short; hepatic 90% (diazo reduction) atracurium - short; pH dependent chemical destruction rocuronium, mivacurium

9. Drugs suxamethonium - (Scoline); depolariser; short (3-10min); scoline pains and muscle damage; K+ levels increased; dysrhythmias; hydrolysed by esterases (defect). decamethonium - initial depolarising, later competitive characteristics; longer lasting. dantroline - acts to inhibit Ca++ release in muscle; used in malignant hyperthermia and severe muscle spasm.