Acetylcholinesterase inhibitors poisoning

Soman is an irreversible inhibitor of acetylcholinesterase. Unlike the case with some acetylcholinesterase inhibitors, recovery from sublethal poisoning by Soman requires enzyme resynthesis, rather than reversible binding to the enzyme. 

The pesticides most frequently responsible for equine poisonings are the organophosphate, carbamate, and chlorinated hydrocarbon insecticides. Both the organo-phosphates and the carbamates are acetylcholinesterase inhibitors and present clinical pictures similar to those seen in food-producing animals. Affected horses salivate and sweat profusely and have muscle incoordination and ataxia. The chlorinated hydrocarbons are strong CNS stimulants affected horses become hyperalert, then excited, and, in severe cases, develop convulsions. In almost all instances, the mode of horses being exposed to pesticides is topical. 

The onset of intoxication symptoms is dependent on the pathway of absorption within a few minutes of inhalation, from 15 min to 1 h after swallowing, and 2-3 h after cutaneous resorption, a toxic concentration will be reached in the blood. With indirect acetylcholinesterase inhibitors, e.g. parathion, symptoms of poisoning occur later. No exact data exist about the extent of bioavaUability in the human body. 

Answer D. The symptoms of cholinergic excess seen in this child are indicative of exposure to insecticides such as the organophosphate parathion, which cause irreversible inhibition of acetylcholinesterase. Other symptoms may include CNS excitation and stimulation of the skeletal NMJ, ultimately leading to paralysis of respiratory musdes— DUMB-BELSS. In addition to symptomatic support, management of AChE inhibitor poisoning involves the use of atropine and 2-PAM. 

Acetylcholine levels in the neuromuscular junction are rapidly reduced by the enzyme acetylcholinesterase. A number of nerve gas poisons act to inhibit acetylcholinesterase (such as sarin and VX), such that muscles are continuously stimulated to contract. This leads to blurred vision, bronchoconstriction, seizures, respiratory arrest, and death. The poisons are covalent modifiers of acetylcholinesterase therefore, recovery from exposure to such poisons requires the synthesis of new enzyme. A new generation of acetylcholinesterase inhibitors, which act reversibly (i.e., they do not form covalent bonds with the enzyme), are now being used to treat dementia, in particular dementia as brought about by Alzheimer s disease. 

Dimethyl fluorophosphate is a strong acetylcholinesterase inhibitor. It is not used as a military poison. Its toxic actions are similar to those of DFP the poisoning effects may be slightly greater than those of DFP. 

Marginally easier to break are some covalent bonds that link atoms other than carbon, although a swamping excess of the reagent is usually required. Two examples the restoration by mercaptan antidotes of cells poisoned by arsenicals (exchange of one As—S bond for another), and rescue of a victim poisoned by an acetylcholinesterase inhibitor, using an oxime antidote (exchange of one P—O bond for another), as described in Sections 12.0 and 12.3 respectively. 

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. 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

A potent irreversible inhibitor (abbreviated DFP) of many serine proteinases and serine esterases (especially acetylcholinesterase). This substance is EXTREMELY POISONOUS, but the vapor state can be minimized by using dry, water-miscible solvents such as 2-propanoL. Aqueous solutions become inactivated by hydrolysis, but solutions made with dry 2-propanol are stable at -20°C for many months. 

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. 

A third approach to protection against excessive acetylcholinesterase inhibition is pretreatment with reversible enzyme inhibitors to prevent binding of the irreversible organophosphate inhibitor. This prophylaxis can be achieved with pyridostigmine but is reserved for situations in which possibly lethal poisoning is anticipated, eg, chemical warfare (see Chapter 7). Simultaneous use of atropine is required to control muscarinic excess. 

Esterase activity is important in both the detoxication of organophosphates and the toxicity caused by them. Thus brain acetylcholinesterase is inhibited by organophosphates such as paraoxon and malaoxon, their oxidized metabolites (see above). This leads to toxic effects. Malathion, a widely used insecticide, is metabolized mostly by carboxylesterase in mammals, and this is a route of detoxication. However, an isomer, isomalathion, formed from malathion when solutions are inappropriately stored, is a potent inhibitor of the carboxylesterase. The consequence is that such contaminated malathion becomes highly toxic to humans because detoxication is inhibited and oxidation becomes important. This led to the poisoning of 2800 workers in Pakistan and the death of 5 (see chap. 5 for metabolism and chap. 7 for more details). 

Exposure to a toxic dose of OP results in inhibition of acetylcholinesterase and butyrylcholinesterase activities. The most common method to measure OP exposure is to assay acetylcholinesterase and butyrylcholinesterase activities in blood using a spectrophotometric method (EUman et al, 1961 Wilson et al, 2005 Worek et al, 1999). The drawbacks of activity assays are that they do not identily the OP. They show that the poison is a cholinesterase inhibitor but do not distinguish between nerve agents, OP pesticides, carbamate pesticides, and tightly bound, noncovalent inhibitors like tacrine and other anti-Alzheimer drugs. In addition, low-dose exposure, which inhibits less than 20% of the cholinesterase, carmot be determined by measuring acetylcholinesterase and butyrylcholinesterase activity because individual variability in activity levels is higher than the percent inhibition. 

These compounds inhibit the hydrolysis of the neurotransmitter acetylcholine by the enzyme acetylcholinesterase within the mammalian nervous system (Zwiener and Ginsburg, 1988). This inhibition causes acetylcholine levels to rise, thus causing cholinergic hyperstimulation at muscarinic and nicotinic receptors. There are important differences in the way carbamates and OPs bind to acetylcholinesterase as well as their abililty to affect the CNS. Carbamates are reversible inhibitors of cholinesterase enzymes. Carbamates create a reversible bond to the cholinesterase enzyme through carbamylation which can spontaneously hydrolyze, reversing toxicity. Carbamate poisoning produces toxicity similar to that of OPs however, the toxicity is usually of a shorter duration and less severe in nature (Lifshitz et al, 1994). In contrast, OPs inhibit cholinesterase via an irreversible bond of phosphate radicals... 

Prevention of organophosphate toxicity is aimed at protecting the acetylcholine receptor and/or acetylcholinesterase itself. Atropine can be used to prevent as well as to treat organophosphate poisonings. In addition, use of reversible inhibitors of acetylcholinesterase has been used to prevent organophosphate... 

---