Phosphate anticholinesterase

Mechanism of Action Reactivates cholinesterase activity by 2 formyl l methylpyri dinium ion. Therapeutic Effect Restores cholinesterase activity following organo-phosphate anticholinesterase poisoning. 

Grob, D. (1956). The manifestations and treatment of poisoning due to nerve gas and other organic phosphate anticholinesterases compounds. Arch. Intern. Med. 98 221-39. 

Grob D and Johns RJ (1956). Effects of V-agent organic phosphate anticholinesterase compound EA 1508 in man following accidental exposure. CWLR 2004. 

Azinphos-methyl (Guthion [CAS 86-50-0] Low-potency organo-phosphate anticholinesterase insecticide (see p 291). Requires metabolic activation. 0.2 mg/m S, SEN lOmg/m Brown waxy solid with a negligible vapor pressure. Not combustible. Breakdown products include sulfur dioxide, oxides of nitrogen, and phosphoric acid. 

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. 

Dialkylphosphorochloridates, (R0)2P(=0)C1, react with trialkyl phosphate esters to give organic pyrophosphates. Organopyrophosphates are anticholinesterase agents and should be handled with great caution (16). Atropine sulfate is a specific antidote. 

Barr, A.M. Poisoning by anticholinesterase organic phosphates Its significance In anaesthesia. Med. J. Aust. 1 792-796, 1964. 

Pralidoxime is administered by intravenous infusion, 1-2 g given over 15-30 minutes. In spite of the likelihood of aging of the phosphate-enzyme complex, recent reports suggest that administration of multiple doses of pralidoxime over several days may be useful in severe poisoning. In excessive doses, pralidoxime can induce neuromuscular weakness and other adverse effects. Pralidoxime is not recommended for the reversal of inhibition of acetylcholinesterase by carbamate inhibitors. Further details of treatment of anticholinesterase toxicity are given in Chapter 58. 

There is a vast chemistry of organophosphorus compounds, and even for arsenic, antimony, and bismuth, the literature is voluminous. Consequently only a few topics can be discussed here. It must also be noted that we discuss only the compounds that have P—C bonds. Many compounds sometimes referred to as organophosphorus compounds that are widely used as insecticides, nerve poisons, and so on, as a result of their anticholinesterase activity, do not, in general, contain P—C bonds. They are usually organic esters of phosphates or thiophosphates examples are the well-known malathion and parathion, (EtO)2Pv(S)(0C6H4NO2). Compounds with P—C bonds are almost entirely synthetic, though a few rare examples occur in Nature. 

The potency of the anticholinesterase activity of nerve agents and other organophosphates is expressed by the bimolecnlar rate constant (k ) for the reaction of the phosphate compound with the enzyme and by the molar concentration causing 50% inhibition of the enzyme when tested in vitro (I50). I50 data for several organophosphate nerve agents have been tabnlated by Dacre (1984). The relationship between I50 and kj as a function of time (t) is expressed by the following equation (Eto, 1974) ... 

Chemical/Pharmaceutical/Other Class Nonper-sistent anticholinesterase compound or organo-phosphate (OP) nerve agent, colorless to black liquid with no odor... 

H32. Hobbiger, F., Anticholinesterases. A comparison between the in vitro activity and the in vivo action of certain organic phosphates. Chetn. Ind. 1574-1576 (1954). 

Barckow D, Neuhaus G and Erdmann WD (1969). Zur Behandlung der schweren Parathion - (E 605) - Vergiftung mit dem Cholinesterase-Reaktivator Obidoxim (Toxogonin). Arch Toxicol, 24,133-146. Barr MA (1964). Poisoning by anticholinesterase organic phosphates it significance in anaesthesia. MedJAust, 00, 792-796. 

Figure 5.5 shows the relationship between hydrolyzability and anticholinesterase activity for seven substituted diethyl phenyl phosphates. The hydrolysis constants were determined in a buffer of pH 7.6 at 37°C and have the unit min-1. 

If rats, during a brief hexobarbitone anaesthesia, are intravenously injected with barely sublethal doses of organo-phosphorus cholinesterase inhibitors which are able to pass the blood-brain barrier, the animals produce a hypothermia of 4-6° in 2-3 h, followed by spontaneous recovery in 12-20 h. This phenomenon has also been demonstrated in mice but not in guinea pig or rabbit. A few clinical reports of human cases of organo-phosphate poisoning mention a severe drop in the body temperature of the victims. The anticholinesterase hypothermia in the rat can partly be prevented by systemic atropine, but not by atropine methyl nitrate (for details and references, see Meeter, 1971a). 

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