Organophosphates cholinesterase inhibitors’ compound

Chronic exposure to certain organophosphate compounds, including some organophosphate cholinesterase inhibitors, causes neuropathy associated with demyelination of axons. 

Exposure to some organophosphate cholinesterase inhibitors results in a delayed neuropathy characterized by degeneration of axons and myelin. This effect is not associated with the inhibition of acetylcholinesterase, but rather with the inhibition of an enzyme described as neuropathy target esterase (NTE) however, the exact mechanism of toxicity is not yet fully understood (Munro et al., 1994). For some organophosphate compounds, delayed neuropathy can be induced in experimental animals at relatively low exposure levels, whereas for others the effect is only seen following exposure to supralethal doses when the animal is protected from the acute toxic effects caused by cholinesterase inhibition. 

The Committee examined five organophosphate pesticides (acephate, chlorpyrifos, dimethoate, disulfoton, and ethion), which are all cholinesterase inhibitors and may be present as residues in fruits and vegetables. Chlorpyrifos was used as the index compound. The TEF was defined as the ratio of the NOAEL or LOAEL for each pesticide to the NOAEL or LOAEL for chlorpyrifos. TEFs based on LOAELs were used when a NOAEL could mot be established for two of the compounds. 

The UK Pesticide Safety Directorate (PSD) has decided to use the TEF approach for assessment of combined risk from exposure to mixtures of acetyl cholinesterase inhibitors (organophosphate (OP) compounds and carbamates) (PSD 1999). Despite clear differences in the action of carbamates and OP compounds, the index compounds selected for all acetyl cholinesterase inhibitors were either aldicarb (carbamate) or chlorpyrifos (OP). The POD for determining relative potency was predetermined as the dose level that produced 20% inhibition of red blood cell cholinesterase in a 90-day dietary study in rats. 

Organophosphates The second class of cholinesterase inhibitors is made up of organophosphorous compounds with the general formula ... 

Excessive muscular blockade may be caused by compounds such as the cholinesterase inhibitors. Such inhibitors, exemplified by the organophosphate insecticides such as malathion (chap. 5, Fig. 12) (see also chap. 7) and nerve gases (e.g., isopropylmethylphosphonofluor-idate), cause death by blockade of respiratory muscles as a result of excess acetylcholine accumulation. This is due to inhibition of the enzymes normally responsible for the inactivation of the acetylcholine (see chap. 7). Respiratory failure may also result from the inhibition of cellular respiration by cyanide, for example, or central effects caused by drugs such as dextropropoxyphene. 

Watson, A., Bakshi, K., Opresko, D., Young, R., Hauschild, V., King, J. (2006). Cholinesterase inhibitors as chemical warfare agents community preparedness guidelines. In Toxicology of Organophosphate and Carbamate Compounds (R.C. Gupta, ed.), pp. 47-68. Elsevier Academic Press, New York. 

Chemical/Pharmacetical/Other Class Soman is a human-made nonpersistent anticholinesterase compound or organophosphate (OP) nerve agent, irreversible cholinesterase inhibitor, and chemical warfare agent. It is a light liquid with a camphorlike odor. 

When activities are measured in whole blood that contains both AChE and BuChE, the following selective inhibitors are must often applied to differentiate between the two cholinesterases ethopropazine, quinidinc, and iso-OMPA inhibit BuChE, and Huperzine A and BW2845c51 inhibit AChE. iso-OMPA is an organophosphate, and the other compounds arc reversible cholinesterase inhibitors. 

As the A-alkylpyridine compounds are quaternary ammonium derivatives, it is likely that they exert their action mainly at peripheral nicotinic and muscarinic sites. Thus, organophosphate inhibition of the rat diaphragm may be reversed by these compounds in vitro [222], and Wolthuis and Meeter [223] showed neuromuscular blockade and inhibition of cholinesterase by DFP in vivo to be reversed by obidoxime and by PAM at the voluntary neuromuscular junction, but only very weakly in the brain. PAM and MINA also restore tetanus to the rat diaphragm in vitro after organophosphate exposure [224]. PAM is superior to both TMB-4 and obidoxime against soman poisoning whereas obidoxime is superior to PAM against tabun. Thus the effectiveness of the oxime varies with the cholinesterase inhibitor. 

The pharmacology of the organophosphorus cholinesterase inhibitors has many facets. Much has been discovered concerning their mode of action and the therapeutic measures to be adopted in the event of intoxication by these compounds. Accepting the specificity of the antidotes used in these therapies, laboratory studies with them may indicate the principal locus of the toxic effects of the organophosphates. Because of the multiplicity of the biological effects of the organophosphorus pesticides, whether these effects... 

Potency of Nerve Agents as Cholinesterase Inhibitors. The potency of the anticholinesterase activity of nerve agents and other organophosphates is measured by either the bimolecular rate constant (kj) for the reaction of the phosphate compound with the enzyme or by the molar concentration causing 50% inhibition of the enzyme (I50) in vitro. The relationship between I50 and kj as a function of time (r) is expressed by the following equation (Eto 1974) ... 

Organophosphates and their family of conqmunds are potent neurotoxins that share structural similarities to chemical warfare agents such as sarin, soman and VX. Organophosphates are cholinesterase inhibitors and exposure to OP compounds leads to increased neurotransmitter accumulation. Classical synq)toms of OP exposure include salivation, lacrimination, urination and defecation. E q)osure to OP con )ounds can cause Ettigue, dizziness, vomiting, paralysis and even death (2). 

Fonnum, F, Sterri, S.H., 2006. Tolerance development to toxicity of cholinesterase inhibitors. In Gupta, R.C. (Ed.), Toxicology of Organophosphate and Carbamate Compounds, Elsevier/Academic Press, San Diego, CA, pp. 257-267. 

P. J. Bushnell and V. C. Moser, Behavioral toxicity of cholinesterase inhibitors in Toxicology of Organophosphate and Carbamate Compounds, ed. R. Gupta, Academic Press, San Diego, 2006, pp. 347-360. 

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