Protection against Acetylcholinesterase Inhibitor Toxicity by Alpha-AdrenergicAgonists

摘要

In developing antidotes to poisoning by cholinesterase (ChE) inhibitors, severalpotential target sites at the cholinergic synapse have been studied, including the postsynaptic receptor and acetylcholinesterase (AchE) itself. Muscarinic receptor blocking agents such as atropine have been and continue to be the primary pharmacological intervention in cases of anticholinesterase poisoning. Oxime reactivators may prove useful when the enzyme is inhibited by an organophosphorus agent. One site which has received much less attention is the presynaptic site at the cholinergic nerve terminal. It is reasonable to expect that reducing acetylcholine release would decrease the toxicity of ChE inhibitors. In fact, inhibitory mechanisms are in place presynaptically to reduce cholinergic neuronal function in situations of postsynaptic overstimulation. These mechanisms include down-regulation or decreased postsynaptic receptor numbers, and decreased release of transmitter from the cholinergic nerve terminal. In cases where poisoning is slow enough, such adaptive changes allow for significant degrees of ChE inhibition without toxicity and even without overt symptoms. In cases of acute severe poisoning, such adaptive mechanisms are too slow to prevent the development of toxicity. Acceleration of presynaptic down-regulation by pharmacologic agents, therefore, may be of use under such circumstances. The examination of this approach to protection has been limited, perhaps due to a paucity of presynaptic cholinergic blocking agents, or from the fear that such agents might prove highly toxic.