VPT 321: Veterinary Neuropharmacology (2+1) copy 1

Mechanism of action of organophosphorus compounds

MECHANISM OF ACTION

• The four stages of anticholinesterase action produced by these compounds are:
• Inhibition (phosphorylation), reactivation, aging and regeneration/recovery
  • Phosphorylation: Organophosphorus compounds react only at the esteratic site of cholinesterase to form a phosphorylated enzyme.
  • Reactivation: Following alkylphosphorylation, spontaneous reactivation can occur. But the rate is dependent on the nature of the alkyl group.
  • Aging
    • Aging is the loss of one alkyl group, which generally occurs more rapidly than spontaneous hydrolysis.
    • Aging makes the product more resistant to regeneration by oximes.
    • Pralidoxime is a compound that is used to reactivate the enzyme cholinesterase from organophosphorus compounds. This agent combines with the cation binding site which orients the oxime group of this agent to react with the elecrophillic phosphorus atom.
    • The oxime-phosphonate is split off, leaving the regenerated enzyme.
  • Regeneration: If the enzyme is not reactivated, new acetylcholinesterase must be synthesized. This takes weeks or months. However, recovery can occur more rapidly since only a small fraction of acetylcholinesterase is needed to be resynthesized.