Poisoning with acetylcholinesterase insecticides

Obidoxime is an antidote used to treat poisoning with insecticides of the organophosphate type (p. 102). Phosphorylation of acetylcholinesterase causes an irreversible inhibition of ace-Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

C. Bronchoconstriction and secretion and muscular weaknesses occur from acetylcholine accumulation after inhibition of acetylcholinesterase. Parathion is an organophosphate insecticide that inhibits acetylcholinesterase, and it is readily available. Poisoning with compound 1080 (fluorocitrate) inhibits mitochondrial respiration and causes seizures and car-... 

The clinical manifestations of anticholinesterase insecticide poisoning include any or all of the following pinpoint pupils, excessive lacrimation, excessive salivation, bronchorrhea, bron-chospasm and expiratory wheezes, hyperperistalsis producing abdominal cramps and diarrhea, bradycardia, excessive sweating, fas-ciculations and weakness of skeletal muscles, paralysis of skeletal muscles (particularly those involved with respiration), convulsions, and coma. Symptoms of anticholinesterase poisoning and their response to antidotal therapy depend on the action of excessive acetylcholinesterase at different receptor types (Table 10-11). 

Mode of Action. All of the insecticidal carbamates are cholinergic, and poisoned insects and mammals exhibit violent convulsions and other neuromuscular disturbances. The insecticides are strong carbamylating inhibitors of acetylcholinesterase and may also have a direct action on the acetylcholine receptors because of their pronounced stmctural resemblance to acetylcholine. The overall mechanism for carbamate interaction with acetylcholinesterase is analogous to the normal three-step hydrolysis of acetylcholine however, is much slower than with the acetylated enzyme. 

Parathion and Paraoxon. Again, this represents a reaction (the sulfur oxidation of a thiophosphate pesticide) that is familiar to most in the pesticide area. Unlike heptachlor epoxide, paraoxon is not a stable compound and its actual presence in a poisoned animal was very difficult to demonstrate. The oxons of other organo-phosphorothioates are not so elusive. In any event, the paraoxon metabolite is an excellent example of where an understanding of metabolic processes and their potential toxicological significance alerted scientists to the likelihood that such a metabolite existed. Many years of work with similar compounds had established that the insecticidal thiophosphates required oxidation to the P=0 form in order to inhibit the neurotrasmitter acetylcholinesterase, the biochemical basis of their toxic action. Paraoxon was eventually isolated in vivo and now consideration of the oxon is a vital part of the overall risk assessment of this group of pesticides. 

Serious poisonings due to misuse of OP insecticides have been reported for more than four decade.s. OPs are some of the most widely used insecticides in the world, and the agents comprising these insecticides have a common mechanism of action. Although the structures are diverse in nature, the mechanisms by which the OP in.secticides elicit their toxicity are identical and are associated with the inhibition of the nervous ti.ssuc acetylcholinesterase (AChE) (Chambers and Levi, 1992). 

PAM CL Pralidoxime, chloride, Protopam , is an antidote to organophosphate poisoning such as might result from exposure to nerve agents or some insecticides. The drug, which helps restore an enzyme called acetylcholinesterase, must be used in conjunction with atropine to be effective. Restores normal control of skeletal muscle contraction (relieves twitching and paralysis). 

In insects poisoned by organic phosphorus compounds, assays for acetylcholinesterase show that this enzyme becomes increasingly inhibited dvuring the first hour and the levels of free acetylcholine rise sharply (Small-man and Fisher, 1958). This rise causes a great increase in spontaneous nerve activity (neuronal hyperexcitation), both autonomic and somatic. This state brings about liberation of tissue toxins, ion imbalance, with eventual paralysis, dehydration, and death this sequence is reminiscent of that caused by the chlorinated insecticides (see Section 7.6c for this comparison and for general information on biochemistry of the insect nervous system). 

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