Echothiophate

1. Mechanism of action: Echothiophate [ek-oe-THI-oh-fate] is an organophosphate that covalently binds via its phosphate group to the serine-OH group at the active site of acetylcholinesterase

Figure  Covalent modification of acetylcholinesterase by echothiophate; also shown is the reactivation of the enzyme with pralidoxime. R = (CH3)3N+-CH2-CH2-

Once this occurs, the enzyme is permanently inactivated, and restoration of acetylcholinesterase activity requires the synthesis of new enzyme molecules. Following covalent modification of acetylcholinesterase, the phosphorylated enzyme slowly releases one of its ethyl groups. The loss of an alkyl group, which is called aging, makes it impossible for chemical reactivators, such as pralidoxime (see below), to break the bond between the remaining drug and the enzyme.


2. Actions: Actions include generalized cholinergic stimulation, paralysis of motor function (causing breathing difficulties), and convulsions. Echothiophate produces intense miosis and, thus, has found therapeutic use. Atropine in high dosage can reverse many of the muscarinic and some of the central effects of echothiophate. 

3. Therapeutic uses: An ophthalmic solution of the drug is used directly in the eye for the chronic treatment of open-angle glaucoma. The effects may last for up to one week after a single administration. Echothiophate is not a first-line agent in the treatment of glaucoma. In addition to its other side effects, the potential risk for causing cataracts limits the use of echothiophate. 

4. Reactivation of acetylcholinesterase: Pralidoxime can reactivate inhibited acetylcholinesterase. However, it is unable to penetrate into the CNS. The presence of a charged group allows it to approach an anionic site on the enzyme, where it essentially displaces the phosphate group of the organophosphate and regenerates the enzyme. If given before aging of the alkylated enzyme occurs, it can reverse the effects of echothiophate, except for those in the CNS. With the newer nerve agents, which produce aging of the enzyme complex within seconds, pralidoxime is less effective. Pralidoxime is a weak acetylcholinesterase inhibitor and, at higher doses, may cause side effects similar to other acetylcholinsterase inhibitors.


back to cholinergic agonist