Inhibition of AChE slows or prevents the degradation of ACh released at synapses, and this can greatly prolong the activation of cholinoreceptors produced by synapti-cally released ACh. In a functional sense, the indirect cholinomimetic effect of AChE inhibitors is more selective than the effect of directly acting cholinomimetics, because the inhibitors of AChE increase the activation of cholinoreceptors only at active cholinergic synapses. This permits strengthening of the phasic stimulation of synaptically activated cholinoreceptors rather than the persistent activation by directly acting cholinomimetics. At therapeutic concentrations, inhibitors of AChE do not activate cholinoreceptors at sites that do not receive cholinergic synaptic input, such as endothelial mus-carinic receptors, and therefore do not present the same risk of eliciting large vasodilator responses.
Acetylcholinesterase can be inhibited by two general mechanisms. In the first mechanism, positively charged quaternary ammonium compounds bind to the anionic site and prevent ACh from binding—a simple competitive inhibition. In the second mechanism, the agents act either as a false substrate for the cho-linesterase or directly attack the esteratic site; in both cases they covalently modify the esteratic site and non-competitively prevent further hydrolytic activity. Either mechanism can be effective in preventing the hydroly
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