Reactivation of Phosphorylated Acetylcholinesterase

1
Reactivation of Phosphorylated
Acetylcholinesterase

• Oximes are used to reactivate phosphorylated AChE
• The group (NOH) has a high affinity for the
  phosphorus atom
• Pralidoxime has a nucleophilic site that
  interacts with the phosphorylated site on
  phosphorylated-AChE

2
Pralidoxime Reacts Chemically with
Phosphorylated-AChE
The oxime group makes a nucleophilic attack upon
the phosphorus atom
3
Oxime Phosphonate and Regenerated AChE
4
Limitations of Pralidoxime

• Pralidoxime does not interact with
  carbamylated-AChE
• Pralidoxime in high doses can inhibit AChE
• Its quaternary ammonium group does not allow it
  to cross the blood brain barrier
• Aging of phosphorylated-AChE reduces the
  effectiveness of pralidoxime and other oxime
  reactivators

5
Other Cholinesterase Reactivators

• Diacetylmonoxime
• Crosses the blood brain barrier and in
  experimental animals, regenerates some of the CNS
  cholinesterase
• HI-6 is used in Europe
• Has two oxime centers in its structure
• More potent than pralidoxime

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Edrophonium
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Edrophonium is a Short Acting Inhibitor that
Binds to the Ionic Site but Not to the Esteratic
Site of AChE
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Acetylcholinesterase Inhibition
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Inhibition of Acetylcholinesterase Produces
Stimulation of All Cholinergic Sites
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Carbamyl Inhibitors of AChE

• Physostigmine
• Neostigmine (N)
• Pyridostigmine (N)
• Ambenonium (N)
• Demecarium (N)
• Carbaryl