see also:

• acetylcholinesterase inhibitor poisoning - organophosphate insecticides, etc
• pharmacology main index
• parasympathetics

• 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;

• 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)

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

• 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.
• see acetylcholinesterase inhibitor poisoning - organophosphate insecticides, etc