Cholinergic agents such as nicotine, muscarine, and pilocarpine act by mimicking acetylcholine at nicotinic and muscarinic sites. Acetylcholinesterase inhibitors such as neostigmine, pyridostigmine, and organophosphates promote the accumulation of acetylcholine by irreversibly or reversibly inhibiting the enzyme. These agents are used therapeutically for conditions like glaucoma but produce toxic effects in high doses by overstimulating cholinergic receptors. Pralidoxime can reactivate phosphorylated acetylcholinesterase and reverse some effects of organophosphate poisoning.
36. The Extremely Slow Hydrolysis of Phosphorylated-AChE New enzyme synthesis is required for recovery of enzyme function
37. Various “States” of Acetylcholinesterase Clockwise: free AChE, acetylated AChE, carbamylated AChE, phosphorylated AChE
38. 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
39. 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
40. 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