Toxicity anticholinesterase effects

Rider JA, Moeller HC, Puletti EJ. 1966. Continuing studies on anticholinesterase effect of methyl parathion in humans and determination of level of incipient toxicity of OMPA [Abstract]. Fed Proc 25 687. 

In contrast to the beneficial effects of treatment with oximes in cases of OP intoxication, reports in the literatnre suggest that treatment of poisoning with certain anticholinesterase carbamates with some oximes should be avoided because they may actually potentiate carbamate action. Other oximes decrease carbamate toxicity. The effects observed are, in general, correlated with changes in the rates of carbamylation and decarbamylation in the presence of the various oximes . ... 

Berry I was unhappy about your phosphorylated oxime since it has been found that the toxic and anticholinesterase effects of ethyl-sarin were more reversible than those of sarin. However, your control experiments with liver show that the brain results cannot be attributed to rapid spontaneous reactivation. 

Based on their low LDjqS, most OPs and CM.s are classified a.s extremely toxic to birds and mammals after a single dose. However, by virtue of their short half-life, they are quickly metabolized by the body and excreted, allowing for a fast recovery from the toxicity. A different outcome is observed when exposure occurs by means of continuous smaller do,se,s. In this case, an accumulative anticholinesterase effect may be observed, even resulting in death after a few days. For aquatic animals, discrete studies have obtained no substantial information regarding (he molecular mechanism of action of OP.s. 

One non-anticholinesterase effect of OPs has been discussed in section 10.3.1.3, namely OPIDP. The degree to which non-acetylcholinesterase inhibition effects contribute to acute OP toxicity continues to be a matter of interest and has been reviewed. Thus, Chambers " noted a poor correlation between rat oral LD50 values of various phosphorothionate insecticides and inhibition potency of corresponding oxons for brain acetylcholinesterase. However, there are a number of possible explanations for this, other than differences in target molecule notably, differences in site and magnitude of desulfuration of the thionate to the active oxon may be important. Studies by Duysen and colleagues with acetylcholinesterase knockout mice suggested that non-acetylcholinesterase inhibitory effects must contribute to the acute toxicity of VX. Maxwell et... 

The alkyl and alkoxy substituents of phosphate or phosphonate esters also affect the phosphorylating abiUty of the compound through steric and inductive effects. A satisfactory correlation has been developed between the quantitative measure of these effects, Tafts s O, and anticholinesterase activity as well as toxicity (33). Thus long-chain and highly branched alkyl and alkoxy groups attached to phosphoms promote high stabiUty and low biological activity. 

Grob D, Garlick WL, Harvey AM. 1950. The toxic effects in man of the anticholinesterase insecticide parathion (p-nitrophenyl diethylthionophosphate). Johns Hopkins Med J 87 106-129. 

ACh is metabolised extraneuronally by the enzyme acetylcholinesterase, to reform precursor choline and acetate. Blocking its activity with various anticholinesterases has been widely investigated and some improvement in memory noted. Such studies have invariably used reversible inhibition because of the toxicity associated with long-term irreversible inhibition of the enzyme. Physostigmine was the pilot drug. It is known to improve memory in animals and some small effects have been seen in humans (reduces number of mistakes in word-recall tests rather than number of words recalled), but it really needs to be given intravenously and has a very short half-life (30 min). 

Famoxon is about 100 times more effective than famphur in controlling houseflies (Musca spp.), which confirms the generalization that the corresponding oxons are the most effective anticholinesterase agents and are, in fact, the actual toxicants (O Brien et al. 1965). 

The essence of ChR action consists in dephosphorylation of the enzyme inhibited, which becomes apparent as restoration of its activity, i.e. ability to perform enzymatic hydrolysis. Therapeutic efficacy of ChR is associated with their capability to eliminate toxic effects of anticholinesterases on nicotine receptors. 

EFFECTS OF OVEREXPOSURE GA is an anticholinesterase agent similar in action to GB. Although only about half as toxic as GB by inhalation, GA in low concentrations is more irritating to the eyes than GB. 

Irreversible anticholinesterases include the organophosphorus inhibitors and ambenonium, which irreversibly phosphorylate the esteratic site. Such drugs have few clinical uses but have been developed as insecticides and nerve gases. Besides blocking the muscarinic receptors with atropine sulphate in an attempt to reduce the toxic effects that result from an accumulation of acetylcholine, the only specific treatment for organopho-sphate poisoning would appear to be the administration of 2-pyridine aldoxime methiodide, which increases the rate of dissociation of the organophosphate from the esteratic site on the enzyme surface. 

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