Enzyme inhibition by these agents can be reversed by cholinesterase reactivators such as pralidoxime if administered before “aging” of AChE has occurred. Inhibition by agents that undergo rapid “aging” is not reversed. Except for echothiophate, these agents are extremely lipid soluble, and some are very volatile. Organophosphate Inhibitors of AChE (4)

Diisopropylflurophosphate (DFP) is a Substrate for AChE

The Extremely Slow Hydrolysis of Phosphorylated-AChE New enzyme synthesis is required for recovery of enzyme function

Various “ States ” of Acetylcholinesterase Clockwise: free AChE, acetylated AChE, carbamylated AChE, phosphorylated AChE

Acetylated-AChE Is Very Rapdily Hydrolyzed AChE + Acetylcholine  AChE-acetylated + choline AChE-acetylated + H 2 O  AChE + acetate Hydrolysis of AChE-acetylated is rapid, in the order of microseconds P

Carbamylated-AChE Is Hydrolyzed Slowly AChE + Carbamyl inhibitor  AChE-carbamylated + noncarbamylated metabolite AChE-carbamylated + H 2 O  AChE + carbamic acid derivative Hydrolysis of the AChE-carbamylated is slow, in the order of hours. The carbamylated enzyme is reversibly inhibited, and recovery of function is in the order of hours Enzyme after phosphorylation by neostigmine

Phosphorlylated-AChE Is Hydrolyzed Extremely Slowly AChE + organophosphate inhibitor  AChE-phosphorylated + nonphosphorylated metabolite AChE-phosphorylated + H 2 O  AChE + phosphorylated derivative Hydrolysis of the AChE-phosphorylated is extremely slow, in the order of days. The phosphorylated enzyme is considered to be irreversibly inhibited, and recovery of function is in the order of days. Pralidoxime, a reactivating agent, may be adminstered to a subject before the enzyme has “aged.” Enzyme after phosphorylation by DFP

AGING OF ACETYLCHOLINESTERASE

Loss of An Alkyl Group From Phosphorylated AChE “ Ages ” the Enzyme AChE, phosphorylated and inhibited by DFP “Aged” AChE

“ Aging ” of Phosphorylated- AChE

Cholinesterase Reactivation