VPT 421: Veterinary Toxicology (2+0)

MECHANISM OF ACTION

• Acetylcholine (ACh) is the mediator at junctions including those between:

  • Preganglionic and postganglionic neurons in both parasympathetic and sympathetic nervous system.
  • Postganglionic parasympathetic fibers and smooth muscles or glands.
  • Motor nerves and skeletal muscles.
  • Some neuron to neuron junctions in the CNS.
• ACh has a cationic site and an esteric site.

• ACh is immediately metabolised by the enzyme acetylcholinesterase (AChE) which has a anionic site and an esteratic site.
• The binding of acetylcholinesterase by different organophosphous inhibitors varies somewhat in affinity and reversibility.
• After binding, the enzyme is ‘phosphorylated’, and thus inhibited. Generally speaking, much of the binding of AChE by an OP is regarded as ‘irreversible’.

• There are four stages of anticholinesterase action produced by these compounds. They 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 pralidoxime. The rate is dependent on the R group of the organophosphorus compound. Pralidoxime was a compound that was generated to reactivate the enzyme cholinesterase. 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.
• Irreversible inhibition of acetylcholinesterase causes accumulation of acetylcholine in the neuromuscular junction, parasympathetic postganglionic terminals in smooth muscles, cardiac muscle and glands and in all autonomic ganglia and in cholinergic synapses in the CNS.