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Acetylcholinesterase inhibitors


  • AChE is one of most efficient enzymes, can hydrolyse 3,105 ACh /min per molecule of AChE → turnover time of 150 microseconds:
    • AChE has binding site for quaternary gp of choline & esteratic subsite, thus after cleavage of ACh, the choline-AChE conjugate releases choline & the acetyl enzyme is rapidly hydrolised forming the active enzyme again;


Reversible carbamyl esters:

  • These serve as alternative substrates but are slowly hydrolysed by AChE & the carbamoylated enzyme conjugate is much more stable ⇒ inactivating enzyme for 15-30min instead of the 150 microseconds & in vivo duration of action is usually about 3-4hrs ;
  • Physostigmine:
    • alkaloid from ordeal bean (Physostigma venenosum) in W.Africa;
    • historic timeline: UK 1840; studied 1855; isolated 1864; Rx use 1877 -glaucoma;
    • a tertiary amine, can also block nicotinic receptors;
  • Neostigmine:
    • introduced 1931 as GIT stimulant, later helped myas.gravis;
    • a quaternary ammonium → also has direct cholinergic activity;
    • Post-op to reverse curariforms: 1-5mg IV (with atropine);
  • Edrophonium:
    • used to diagnose myasth.gravis (Ab's to ACh receptors)

"Relatively reversible" carbamates:

  • Carbaryl: household insectic. with low dermal toxicity (even used Rx headlice!)
  • Baygon: household insecticide;

Irreversible organophosphates:

  • 1st synthesised 1854, but main studies started 1932, esp. WWII;
    • → “nerve gases” (sarun, soman, tabun);
    • → insecticides (parathion, malathion);
  • These serve as true hemisubstrates since the resulting phosphorylated or phosphonylated enzyme is extremely stable necessitating new AChE to be made unless a cholinesterase reactivator is given early:
    • eg. pralidoxime which exerts a nucleophilic attack on the phosphorus, splitting off oxime-phosphonate & leaving regenerated AChE;
    • NB. pralidoxime of no benefit in antagonising the reversible anticholinesterases as these rapidly hydrolyse anyway & pralidoxime has weak anticholinesterase activity itself!
  • It must be emphasised that P-AChE tend to “age” rapidly so that within minutes or hours they become completely resistant to activators as there is loss of alkyl/alkoxy gps making it more stable.
acheis.txt · Last modified: 2008/09/15 12:27 (external edit)