Anticholinesterases irreversible

ACh is metabolised extraneuronally by the enzyme acetylcholinesterase, to reform precursor choline and acetate. Blocking its activity with various anticholinesterases has been widely investigated and some improvement in memory noted. Such studies have invariably used reversible inhibition because of the toxicity associated with long-term irreversible inhibition of the enzyme. Physostigmine was the pilot drug. It is known to improve memory in animals and some small effects have been seen in humans (reduces number of mistakes in word-recall tests rather than number of words recalled), but it really needs to be given intravenously and has a very short half-life (30 min). 

Irreversible anticholinesterases include the organophosphorus inhibitors and ambenonium, which irreversibly phosphorylate the esteratic site. Such drugs have few clinical uses but have been developed as insecticides and nerve gases. Besides blocking the muscarinic receptors with atropine sulphate in an attempt to reduce the toxic effects that result from an accumulation of acetylcholine, the only specific treatment for organopho-sphate poisoning would appear to be the administration of 2-pyridine aldoxime methiodide, which increases the rate of dissociation of the organophosphate from the esteratic site on the enzyme surface. 

As given in classification, these agents are of two type e.g. reversible and irreversible. The reversible anticholinesterases have a structural resemblance to acetylcholine, are capable of combining with anionic and esteratic sites of cholinesterase as well as with acetylcholine receptor. The complex formed with the esteratic site of cholinesterase is less readily hydrolyzed than the acetyl esteratic site complex formed with acetylcholine. Edrophonium forms reversible complex with the anionic site and has shorter duration of action. Also, neostigmine and edrophonium have a direct stimulating action at cholinergic sites. 

Anticholinesterases also react with Achase but the intermediate ester formed will not hydrolyze easily. As a result the enzyme is tied up irreversibly with the inhibitor and the Ach can go on working at its receptors with impunity. 

Tacrine is a non-competitive, irreversible inhibitor of both acetyl and butyryl cholinesterase, with a greater potency for the latter enzyme. Based on the outcome of placebo-controlled, double-blind studies, tacrine was the first anticholinesterase to be licensed for the symptomatic treatment of AD in the United States. The main disadvantage of tacrine lies in its hepatotoxicity (approximately 50% of patients were found to develop elevated liver transaminases which reversed on discontinuation of the drug). Because of such side effects and limited efficacy, tacrine is no longer widely prescribed. 

Other anticholinesterases recently licensed in Europe include metrifonate. This is an irreversible organophosphorus inhibitor of acetylcholinesterase and is a pro-drug for dichlorvos. The development of metrifonate was delayed because some patients developed muscle weakness and a delayed neurotoxicity has been described for compounds that are chemically related to the drug. 

Lemercier, G., Carpentier, P., Sentenac-Roumanou, H., Morelis, P. (1983). Histological and histochemical changes in the central nervous system of the rat poisoned by an irreversible anticholinesterase organophosphorus compound. Acta Neuro-pathol. 61 123-9. 

The clinically useful anticholinesterase agents diisopropyl fluorophosphate (DFP, Floropryl) and echothiophate iodide (Phospholine Iodide [PI]) demonstrate an indirect-acting mechanism resulting in increased levels of acetylcholine at the cholinergic receptor sites. The inhibition of acetylcholinesterase produces a relatively long-lasting and irreversible effect of maintaining active levels of acetylcholine at the parasympathetic synapses. 

Echothiophate iodide is a long-lasting cholinesterase inhibitor of the irreversible type, as is isofluorphate. Unlike the latter, however, it is a quaternary salt, and when applied locally, its distribution in tissues is limited, which can be very de.sirablc. It is used as a long-acting anticholinesterase agent in the treatment of glaucoma. 

Chemical/Pharmacetical/Other Class Soman is a human-made nonpersistent anticholinesterase compound or organophosphate (OP) nerve agent, irreversible cholinesterase inhibitor, and chemical warfare agent. It is a light liquid with a camphorlike odor. 

Both AChE and BChE are of the serine hydrolase class, which includes proteases such as trypsin (see PROTEASE inhibitors). Characteristically, such enzymes can be inhibited through covalent linkage of constituent parts of irreversible anticholinesterases such as dyflos (DFP, diisopropylfluorophosphonate). The active site of the enzyme contains a catalytic triad with a glutamate residue, a serine residue and a histidine imidazole ring. The mechanism of the catalysis of break down of AChE has been characterized, and the reaction progresses at a very fast rate. 

Ecostatin econazolenitrate, ecothiopate ecothiopate iodide, ecothiopate iodide [ban, inn] (echothiopate diethoxyphosphinylthiocholine Ml 217 Camsilon Phospholine Iodide ) is an irreversible (organophosphate group) ANTICHOLINESTERASE. It is a PARASYMPATHOMIMETIC used topically as a miotic in ANTIGLAUCOMA TREATMENT. 

Obviously, by the very nature of their being, anticholinesterase drugs must be antagonists that is, they stop the enzyme from hydrolysing acetylcholine. This antagonism can be either reversible or irreversible depending on how the drug reacts with the active site. 

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