Irreversible cholinesterase inhibitors HC、 CH-0、 C- >CH-0 soflurophate Dashed line:bond that is hydrolyzed in binding to the enzyme. HC2-0 Echothiophate 4sC2一0、‖ %9-0>P-0 〉一《 Parathion c-0、 Shaded esters:points of P-S-CH-C-0-C2Ms detoxification of the HC-0 molecule(metabolized)in mammals and birds but not in insects. Malathion Malaoxon Cholinesterase inhibitors-mechanisms of action Drugs in this class Drugs in this class are carbamyl esters have no cationic instead of acetyl group.They only esters that bind to interact with the the anionic site esteratic site (Glu),same as with (His/Ser).These acetvlcholine.The drugs contain a carbamyl aroup is labile group or an transferred to Ser. organic group that However the can be released to carbamylated phosphorylate Ser. enzyme is much The phosphorylated slower to hvdrolvze enzvme is thereby reducing inactivated and is the recovery of very stable.No enzyme activity. appreciable hydrolysis occurs. ld-NO HP.Rang et al.Pharmacology,5 Ed 1111 Irreversible cholinesterase inhibitors Dashed line: bond that is hydrolyzed in binding to the enzyme. Shaded esters: points of detoxification of the molecule (metabolized) in mammals and birds but not in insects. Cholinesterase inhibitors – mechanisms of action His447 Ser203 Glu334 H.P. Rang et al. Pharmacology, 5th Ed. Drugs in this class are carbamyl esters instead of acetyl esters that bind to the anionic site (Glu), same as with acetylcholine. The carbamyl group is transferred to Ser. However the carbamylated enzyme is much slower to hydrolyze, thereby reducing the recovery of enzyme activity. Drugs in this class have no cationic group. They only interact with the esteratic site (His/Ser). These drugs contain a labile group or an organic group that can be released to phosphorylate Ser. The phosphorylated enzyme is inactivated and is very stable. No appreciable hydrolysis occurs