Cholinesterase Inhibitors

A large number of autonomic neurons are cholinergic in nature. Cholinergic terminals contain a large number of small acetylcholine (ACh)-containing, membrane-bound vesicles concentrated near the synaptic end. Following their release from the pre-synaptic end, ACh molecules activate cholinoreceptors on the post-synaptic membrane. Acetylcholinesterase (AChE) is a tetrameric protein that catalyzes the hydrolysis of acetylcholine. The active site of AChE includes a serine hydroxyl group that is rendered more nucleophilic through the proton-acceptor action of a nearby histidine residue. The serine residue exerts a nucleophilic attack on the carbonyl carbon of acetylcholine. AChE inhibitors may act by either competitively blocking hydrolysis without reacting with the enzyme, or may acylate the serine hydroxyl group, forming a carbamyl ester, which is more stable than acetate and is less likely to abandon the active site of the enzyme. AChE inhibitors, which increase the availability of acetylcholine in central synapses, as well as muscarinic agonists, have become the main approach to symptomatic treatment of patients with Alzheimer's disease (AD). These agents do not reverse the progression of the disease, but they do contribute to modest improvements in memory, thinking and reasoning skills in AD patients.