The reversible inhibitors of acetylcholinesterase as pretreatment options against nerve agents’ intoxications

Nerve agents rapidly inactivate acetylcholinesterase (AChE), leading to the accumulation of acetylcholine in the synaptic cleft, ultimately causing death by respiratory failure. Due to the inefficiency of the standard antidotal therapy consisting of atropine, oxime, and diazepam, the pretreatment option is introduced, given to healthy individuals when a chemical attack is expected. The pyridostigmine bromide is currently the only approved drug for the pretreatment against nerve agent exposure, but in the past few decades, several other AChE inhibitors have been proposed including carbamates (physostigmine and rivastigmine) and the reversible inhibitors AChE used for the treatment of Alzheimer's disease (huperzine A, donepezil, and galanthamine). In this chapter, we present a comprehensive review of the newest in vitro and in vivo studies of these drugs as pretreatment options, along with the recently designed AChE reversible inhibitors, also tested in vitro for protection of the enzyme against irreversible inhibition by nerve agents. Special attention is paid to the results of the in vitro studies and kinetic behavior of AChE inhibitors and their relation to the protective effects exerted in the in vivo animal models.