Acetylcholinesterase agents

Weinstock M, et al. Pharmacological activity of novel acetylcholinesterase agents of potential use in the treatment of Alzheimer s disease. In Advances in Behavioral Bidogy. Lachman C (Ed.). Plenum Press, New York, 1986,... 

Individuals with hereditary low plasma cholinesterase levels (Kalow 1956 Lehman and Ryan 1956) and those with paroxysmal nocturnal hemoglobinuria, which is related to abnormally low levels of erythrocyte acetylcholinesterase (Auditore and Hartmann 1959), would have increased susceptibility to the effects of anticholinesterase agents such as methyl parathion. Repeated measurements of plasma cholinesterase activity (in the absence of organophosphate exposure) can be used to identify individuals with genetically determined low plasma cholinesterase. 

The memory deficits characteristic of Alzheimer s disease have not yet been successfully treated. There is reason to believe that potent acetylcholinesterase-resistant cholinomimetics might be effective in treating these deficits, but systemic administration of agents of this type, such as bethanechol, does not adequately deliver such... 

Administer anticholinergic agent 1-2 min before acetylcholinesterase inhibitor... 

The dual inhibition of acetylcholinesterase and butyrylcholinesterase may lead to broader efficacy. As acetylcholinesterase activity decreases with disease progression, the acetylcholinesterase-selective agents may lose their effect, while the dual inhibitors may still be effective due to the added inhibition of butyrylcholinesterase. However, this has not been demonstrated clinically. 

Both the G- and V-agents have the same physiological action on humans. They are potent inhibitors of the enzyme acetylcholinesterase (AChE), which is required for the function of many nerves and muscles in nearly every multicellular animal. Normally, AChE prevents the accumulation of acetylcholine after its release in the nervous system. Acetylcholine plays a vital role in stimulating voluntary muscles and nerve endings of the autonomic nervous system and many structures within the CNS. Thus, nerve agents that are cholinesterase inhibitors permit acetylcholine to accumulate at those sites, mimicking the effects of a massive release of acetylcholine. The major effects will be on skeletal muscles, parasympathetic end organs, and the CNS. 

Organophosphate Ester Hydraulic Fluids. The biomarkers of effects after exposure to organophosphate ester hydraulic fluids are well established in cases of delayed neuropathy (clinical signs of peripheral neuropathy). Further study would be helpful to determine whether certain effects (such as diarrhea after oral exposure) are due to direct action of the toxic agent on the target organ or to inhibition of acetylcholinesterase at the acetylcholine nerve receptor site on the organ. 

Although bicyclophosphates do not inhibit acetylcholinesterase, they exhibit a synergistic toxic effect with materials that do. Individuals who have had previous exposure to cholinesterase inhibitors such as nerve agents and commercial organophosphate or carbamate pesticides may be at a greater risk from exposure to bicyclophosphates. 

Presently available methods to diagnose and biomonitor exposure to anticholinesterases, e.g., nerve agents, rely mostly on measurement of residual enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in blood. More specific methods involve analysis of the intact poison or its degradation products in blood and/or urine. These approaches have serious drawbacks. Measurement of cholinesterase inhibition in blood does not identify the anticholinesterase and does not provide reliable evidence for exposure at inhibition levels less than 20 %. The intact poison and its degradation products can only be measured shortly after exposure. Moreover, the degradation products of pesticides may enter the body as such upon ingestion of food products containing these products. 

Exposure to nerve agents is not restricted to the battlefield. Possible terrorist use of these weapons and the destruction of the chemical weapon depots certainly will increase the risk of exposure. Since treatment for intoxication with at least some of these organophosphorus (OP) acetylcholinesterase (AChE) inhibitors is still far from ideal, research efforts are devoted towards finding an effective treatment. 

Field First Aid Nerve agents are the most toxic of the known chemical warfare agents. Chemically similar to organophosphate pesticides, their method of acting is to inhibit acetylcholinesterase enzymes. Individuals whose skin or clothing is contaminated with... 

Acetylcholinesterase An enzyme that hydrolyzes the neurotransmitter acetylcholine. The action of this enzyme is inhibited by nerve agents. 

Nerve Agent Substances that interfere with the central nervous system. Organic esters of phosphoric acid used as a chemical warfare agent because of their extreme toxicity (tabun-GA, sarin-GB, soman-GD, GF, and VX). All are potent inhibitors of the enzyme, acetylcholinesterase, which is responsible for the degradation of the neurotransmitter, acetylcholine in neuronal synapses or myoneural junctions. Nerve agents are readily absorbed by inhalation and/or through intact skin. 

Organophosphorous Compound Containing elements of phosphorous and carbon, the physiological effects of such a compound include inhibition of acetylcholinesterase. A number of pesticides including parathion and malathione, and virtually all nerve agents, are organophosphorous compounds. 

Pyridostigmine Bromide An antidote enhancer that blocks acetylcholinesterase, protecting it from nerve agents. When taken in advance of nerve agent exposure, pyridostigmine bromide increases survival provided that atropine and oxime and other measures are taken. 

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