Phosphate group, organophosphates

Since organophosphate toxicosis results in respiratory failure, the treatment approach for must include the maintenance of a patent airway. Artificial respiration may also need to be employed. The first pharmacological approach is the administration of atropine. Atropine competes with acetylcholine for its receptor site, thus reducing the effects of the neurotransmitter. N-methylpyridinium 2-aldoxime (2-PAM) is used in with atropine therapy as an effective means to restore the covalently bound enzyme to a normal state. It reacts with the phosphorylated cholinesterase enzyme removing the phosphate group. As previously mentioned, carbamates interact with cholinesterase by weak, ionic bonding thus 2-PAM is of no use to combat toxicosis caused by these compounds. However, atropine is effective to prevent the effects on respiration. 

Organophosphate A compound with a specific phosphate group that inhibits acetylcholinesterase. Used in chemical warfare and as an insecticide. 

Johannsen and colleagues (1977) report dermal LD50 values for rabbits at levels of >3,700 mg/kg for a group of triaryl phosphates, >5,000 mg/kg for dibutyl phenyl phosphate, 5,000 mg/kg for both asymmetrical and symmetrical triaryls, and >3,100 mg/kg for tributyl phosphate. This study looked at structural activity relationships for the organophosphate esters. 

The application of fluorogenic labeling to the determination of some organophosphate insecticides has been attempted [178,179]. Fenthion (0,0-dimethyl 0-[(4-metiiylthio)-m-tolyl] phosphorothioate), Ruelene (0-2-chloro-4-ferf.-butylphenyl O-methyl methyl-phosphoramidate), GC 6506 [dimethyl p-(methylthio)phenyl phosphate] and several other compounds which yield phenols on hydrolysis have been examined. The limits of detection for some of these labeled derivatives have been reported to be in the low nanogram range. The organophosphate Proban [0,0-dimethyl 0-(p-sulphamoylphenyl) phosphorothioate] has been determined directly without hydrolysis by dansylation of the free amino group of the molecule [180]. The derivative exhibited blue fluorescence, as compared to yellow for phenol and alkylamine dansyl derivatives. 

In the case of organophosphate poisoning, the effectiveness of 2-PAM is dependent on its early administration. The phosphorylated AChE tends to convert to a form that cannot be reactivated by the oximes. This phenomenon is known as aging process. It involves the removal of an alkyl group from the dialkyl phosphorylated enzyme, producing an anionic phosphate moiety that is insensitive to oximes and other nucleophiles (Figure 7.17) (O Brien, 1976). 

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