Acetylcholinesterase inhibition tolerance

The toxicity of dichlorvos is due to inhibition of acetylcholinesterase and the signs of toxicity are generally similar to those caused by other organo-phosphorus insecticides. Dichlorvos is a direct inhibitor of cholinesterases thus, toxicity rapidly follows exposure and recovery is also rapid. With inhalation exposures, airway acetylcholinesterase inhibition is possible in the absence of significant blood enzyme inhibition. The fly head acetylcholinesterase appears more sensitive to inhibition by dichlorvos relative to mammalian brain acetylcholinesterase. At high doses, dichlorvos may cause hyperglycemia and abnormal glucose tolerance. 

In the body, metrifonate converts to the active metaboUte dichlorvos, (2,2-dichlorovinyl dimethyl phosphate), which is responsible for the inhibition of the enzyme acetylcholinesterase in the susceptible worm. This effect alone is unlikely to explain the antischistosomal properties of metrifonate (19). Clinically, metrifonate is effective only against infection caused by S. haematobium. Metrifonate is administered in three doses at 2-wk intervals (17). The dmg is well tolerated. Side effects such as mild vertigo, nausea, and cramps are dose-related. This product is not available in the United States. The only manufacturer of metrifonate is Bayer A.G. of Leverkusen, Germany. 

Zifrosilone (18) is a novel tight-binding inhibitor of acetylcholinesterase, which is in development as a potential therapeutic compound in the symptomatic treatment of Alzheimer s disease [72]. Pharmacokinetics and pharmacodynamics of the compound were studied in the dogs and rats after single intravenous and subcutaneous administrations. When evaluated in human healthy volunteers, the orally administered drug was well tolerated but displayed a strong dose-related inhibition of red blood cell acetylcholinesterase [73] and its development was consequently halted. 

Other types of inhibitors may not be so tolerable. Organophosphorus compounds, used in nerve gases and weed killers (e.g., parathion), form a covalent irreversible bond with the active serine and permanently inactivate acetylcholinesterase. This is a type of suicide inhibition because the inhibitor reacts with the enzyme much like a substrate, but becomes blocked in the intermediate state where the enzyme-phosphoryl bond is stable, in contrast to the hydrolyzable enzyme-acetyl bond. These compounds are life-threatening. 

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