• Anticholinesterases
    • Acetylcholine receptors
      • Nicotinic
        • Ligand gated ion channels
          Link:Receptors
      • Muscarinic
        • G protein linked
          Link:Receptors
      • Acetylcholine (ACh) binds to these receptors
        • At the NMJ around 200 vesicles are released per action potential each containing around 10,000 molecules of ACh per vesicle
          Link:Muscle physiology
        • It is made from acetylCoA and choline (found in diet and the liver), the formation of which is catalysed by choline acetyltransferase
        • ACh is broken down by acetylcholinesterase (AChE), or 'cholinesterase'
    • AChE/cholinesterase
      • Has anionic and esteratic blinding sites
      • Anionic
        • Binds the quaternary nitrogen of ACh
          • ACh
      • Esteratic
        • Binds to the acetate end of ACh
      • ACh and AChE
    • Specific Anticholinesterases
      • Neostigmine
        • A quaternary amine which binds to AChE
        • Cationic part binds to the anionic site
        • Terminal carbon binds the esteratic site
        • A phenol group in the middle breaks away leaving both sites of AChE occupied thereby slowing ACh hydrolysis
      • Organophosphates
        • Phosphorylate the esteratic site of AChE
        • Cause salivation, lacrimation, urination
        • Treatment is with atropine and pralidoxime
      • Edrophonium
        • Used in the diagnosis of myasthenia gravis
        • Pre-treatment with atropine is sometimes used to avoid bradycardia
        • Usually a test dose of 1-2mg is given followed by a further 5-6mg
        • Produces a rapid improvement but transient improvement in muscle strength for around 5 mins
        • Ongoing medical management of myasthenia can be achieved with oral pyridostigmine
        • Test can be positive with Lambert-Eaton syndrome as well so is not diagnostic
    • Mechanisms of action
      • Easily reversible inhibition (eg edrophonium)
      • Carbamylated complexes (eg neostigmine, pyridostigmine)
      • Irreversible inhibition (eg organophosphates)
    • AChE inhibitors (Anticholinesterases)
      • Increase ACh concentration by preventing its breakdown
      • As ACh is the main neurotransmitter of post-ganglionic parasympathetic nerve fibres, PSNS effects can occur with treatment with anticholinesterases.
      • Used to reverse NDMRs and in the treatment of myasthenia gravis