Figure 17.17 • Aging of phosphorylated enzyme.

these poisons. Several compounds can provide a nucleophilic attack on the phosphorylated enzyme and cause regeneration of the free enzyme. Substances such as choline, hydroxyl-amine, and hydroxamic acid have led to the development of more effective cholinesterase reactivators, such as nicotinic hydroxamic acid and pyridine-2-aldoxime methiodide (2-PAM). A proposed mode of action for the reactivation of cholinesterase that has been inactivated by isoflurophate by 2-PAM is shown in Figure 17.16.

Cholinesterases that have been exposed to phosphorylat-ing agents (e.g., sarin) become refractory to reactivation by cholinesterase reactivators. The process is called aging and occurs both in vivo and in vitro with AChE and BuChE. Aging occurs by partial hydrolysis of the phosphorylated moiety that is attached to the serine residue at the esteratic site of the enzyme (Fig. 17.17).

Phosphate esters used as insecticidal agents are toxic and must be handled with extreme caution. Symptoms of toxic-ity are nausea, vomiting, excessive sweating, salivation, miosis, bradycardia, low blood pressure, and respiratory difficulty, which is the usual cause of death.

The organophosphate insecticides of low toxicity, such as malathion, generally cause poisoning only by ingestion of relatively large doses. Parathion or methylparathion, however, cause poisoning by inhalation or dermal absorption. Because these compounds are so long acting, cumulative and serious toxic manifestations may result after several small exposures.


Isofluorphate, USP. Isofluorphate, diisopropylphos-phorofluoridate (Floropryl), is a colorless liquid soluble in water to the extent of 1.54% at 25°C, which decomposes to give a pH of 2.5. It is soluble in alcohol and to some extent in peanut oil. It is stable in peanut oil for a period of 1 year but decomposes in water in a few days. Solutions in peanut oil can be sterilized by autoclaving. The compound should be stored in hard glass containers. Continued contact with soft glass is said to hasten decomposition, as evidenced by discoloration.

Isofluorphate must be handled with extreme caution. Contact with eyes, nose, mouth, and even skin should be avoided because it can be absorbed readily through intact epidermis and more so through mucous tissues.

Because isofluorphate irreversibly62 inhibits cholinesterase, its activity lasts for days or even weeks. During this period, new cholinesterase may be synthesized in plasma, erythro-cytes, and other cells.

A combination of atropine sulfate and magnesium sulfate protects rabbits against the toxic effects of isofluorphate. Atropine sulfate counteracts the muscarinic effect, and magnesium sulfate counteracts the nicotinic effect of the drug.63 Isofluorphate has been used in the treatment of glaucoma.

Echothiophate Iodide, USP. Echothiophate iodide, (2-mercaptoethyl)trimethylammonium iodide, s-ester with o,o-diethylphosphorothioate (Phospholine Iodide), occurs as a white, crystalline, hygroscopic solid that has a slight mercaptan-like odor. It is soluble in water (1:1) and dehydrated alcohol (1:25); aqueous solutions have a pH of about 4 and are stable at room temperature for about 1 month.

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