Properties of reversible cholinesterase inhibitors Short-acting cholinesterase inhibitors Edrophonium-a quaternary ammonium compound that binds to the anionic site of the enzyme only.The ionic bond is reversible and drug action is brief.Clinical use: diagnosis of myesthenia gravis. Medium-duration cholinesterase inhibitors Neostigmine,pyridostigmine-carbamyl esters that interact with the anionic site. The carbamylated enzyme is much slower to hydrolyze,thus reducing the recovery of the enzyme.Both drugs target mainly NMJ and can be used orally for treating myesthernia gravis.Pyridostigmine lasts longer than neostigmine,the latter is used i.v.to competitively reverse neuromuscular block. Physostigmine-also in this class and is naturally occurring in the Calabar bean.It targets postganglionic parasympathetic junctions and is used as eye drops for treating glaucoma. Properties of irreversible cholinesterase inhibitors Dyflos(isofluorophate)-contains a labile group(fluoride)but not cationic group. The phosphorylated enzyme is inactivated and no hydrolysis is detectable.Used for treating glaucoma. Ecothiopate,parathion-contain an organic group that is released to phosphorylate the enzyme at serine residue.Ecothiopate is used as eye drops for treatment of glaucoma and targets mainly the postganglionic parasympathetic junction.Parathion is used as insecticide but can cause poisoning in humans. Malathion is more readily detoxified in mammals than parathion,and is more available as an insecticide for public use. Sarin-a warfare agent,its mechanism of action resembles that of some commonly used insecticides.Like other nerve agents,sarin attacks the nervous system by forming a covalent bond with the serine residue at the active site.Fluoride is the leaving group,and the resulting phosphoester is robust but biologically inactive. 1212 Properties of reversible cholinesterase inhibitors • Short-acting cholinesterase inhibitors Edrophonium – a quaternary ammonium compound that binds to the anionic site of the enzyme only. The ionic bond is reversible and drug action is brief. Clinical use: diagnosis of myesthenia gravis. • Medium-duration cholinesterase inhibitors Neostigmine, pyridostigmine – carbamyl esters that interact with the anionic site. The carbamylated enzyme is much slower to hydrolyze, thus reducing the recovery of the enzyme. Both drugs target mainly NMJ and can be used orally for treating myesthernia gravis. Pyridostigmine lasts longer than neostigmine, the latter is used i.v. to competitively reverse neuromuscular block. Physostigmine – also in this class and is naturally occurring in the Calabar bean. It targets postganglionic parasympathetic junctions and is used as eye drops for treating glaucoma. Properties of irreversible cholinesterase inhibitors Dyflos (isofluorophate) – contains a labile group (fluoride) but not cationic group. The phosphorylated enzyme is inactivated and no hydrolysis is detectable. Used for treating glaucoma. Ecothiopate, parathion – contain an organic group that is released to phosphorylate the enzyme at serine residue. Ecothiopate is used as eye drops for treatment of glaucoma and targets mainly the postganglionic parasympathetic junction. Parathion is used as insecticide but can cause poisoning in humans. Malathion is more readily detoxified in mammals than parathion, and is more available as an insecticide for public use. Sarin – a warfare agent, its mechanism of action resembles that of some commonly used insecticides. Like other nerve agents, sarin attacks the nervous system by forming a covalent bond with the serine residue at the active site. Fluoride is the leaving group, and the resulting phosphoester is robust but biologically inactive