AChE inhibitors antidote

ACh receptors are destroyed by endocytosis via coated pits and proteolysis in lysosomes. In myasthenia gravis, the receptors are crosslinked by antireceptor antibodies, which facilitate the rate-limiting endocytosis step receptor destmction occurs in less than half the normal time, resulting in net receptor loss. The chronic disease is characterized clinically by such muscular weakness and abnormal fatigue that patients cannot even keep their eyes open. Acetylcholinesterase inhibitors increase the ACh concentration and excitation of the neuromuscular junction, resulting in increased strength and endurance. As expected, AChE inhibitors are also potent curare antidotes because the increased ACh levels displace the blocker more readily. 

At present, professional toxicologists should determine more clearly a range of neurotoxicants, which can be used with maximal probability in terrorist acts, and concentrate their efforts on the development of combined antidotic means composed of ChR and cholinolytics (or agents possessing concurrently reactivating and cholinolytic activities), anticonvulsants and reversible AChE inhibitors. 

Other agents useful as cholinesterase reactivators include nicotinhydroxamic acid methoiodide and the bis-compound obidoxime (not available in the United States). Toxic overdoses of carbamate AChE inhibitors are not reversible with pralidoxime-type antidotes.13 In fact, because of some anti-AChE activity of their own, they would actually aggravate the toxicity of physostigmine and neostigmine overdoses. 

CBs, like OPs, act as inhibitors of ChE. They are treated as substrates by the enzyme and carbamylate the serine of the active site (Figure 10.8). Speaking generally, car-bamylated AChE reactivates more rapidly than phosphorylated AChE. After aging has occurred, phosphorylation of the enzyme is effectively irreversible (see Section 10.2.4). Carbamylated AChE reactivates when preparations are diluted with water, a process that is accelerated in the presence of acetylcholine, which competes as a substrate. Thus, the measurement of AChE inhibition is complicated by the fact that reactivation occurs during the course of the assay. Carbamylated AChE is not reactivated by PAM and related compounds that are used as antidotes to OP poisoning (see Box 10.1). 

Atropine Nonselective competitive antagonist at all muscarinic receptors in CNS and periphery Blocks muscarinic excess at exocrine glands, heart, smooth muscle Mandatory antidote for severe cholinesterase inhibitor poisoning Intravenous infusion until antimuscarinic signs appear continue as long as necessary Toxicity Insignificant as long as AChE inhibition continues... 

Pralidoxime Very high affinity for phosphorus atom but does not enter CNS Regenerates active AChE can relieve skeletal muscle end plate block Usual antidote for early-stage (48 h) cholinesterase inhibitor poisoning Intravenous every 4-6 h Toxicity Can cause muscle weakness in overdose... 

Oximes bind to AChE as reversible inhibitors and form complexes with AChE either at the acylation (catalytic) site, at the allosteric site, or at both sites of the enzyme and protect AChE from phosphorylation. When the reversible inhibitor binds to the catalytic site, the protection is due to direct competition between OP and reversible inhibitor. Binding of a reversible inhibitor to the allosteric site induces indirect protection of the active site. Differences in the mechanisms of enzyme reactivation and protection demonstrate how stereochemical arrangements of oximes can play a role in the potency of their therapeutic efficacy. Direct pharmacological effects, such as direct reaction with OPs (Van Helden et al., 1996), anticholinergic and sympathomimetic effects may also be relevant for the interpretation of antidotal potency of oximes. 

OP nerve agents, which are small lipophilic molecules, can easily penetrate the BBB by free diffusion and thereby inhibit AChE in the CNS (Mercey et al., 2012). Increased BBB permeability by OP nerve agents or other ChE inhibitors may lead to their enhanced entry into the brain, resulting in greater AChE inhibition and possibly resulting in subsequent maintenance of seizures and aggravation of their pathological consequences, such as edema and neuronal loss in certain brain structures. Evidently, increased BBB permeability may facilitate the entry of an antidote (oxime class) to the brain, which otherwise has limited access because of the BBB. 

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