- As classical competitive enzyme inhibitors, they have a high affinity for the active
site but are not substrates. The enzyme is occupied by the inhibitor for relatively
long periods, and therefore cannot handle ACh efficiently, as a result of the satura-
tion phenomenon. - The inhibitor acylates the serine hydroxyl of AChE, forming an ester more stable
than acetate, such as a carbamate or phosphate. The hydrolysis of these esters takes
a long time even if they are not irreversible, as was formerly thought. Acetycholine
cannot then be hydrolyzed, since the active site is covalently occupied.
A representative of the first group of inhibitors is edrophonium (8.12), a short-acting
drug that binds to the anionic site of the enzyme and also forms a hydrogen bond with
the imidazole nitrogen of the active site. Ambenonium (8.13) also does not react cova-
lently with the enzyme but has a much longer duration of action than edrophonium.
The second group of AChE inhibitors is represented by the alkaloid physostigmine
(8.14, eserine) isolated from the seeds of Physostigma venenosum, the Calabar bean,
which has been used in West Africa in witch ordeals. Synthesic analogs such as neostig-
mine (8.15) and its congeners are also active. They have a very high affinity for the
enzyme and will carbamoylate the serine hydroxyl of the active site. Because the half-
life of the dimethyl-carbamoyl ester is 20–30 minutes, as compared to only micro-
seconds for the acetylated enzyme, AChE is inhibited for several hours after a single
dose of such drugs.
8.2.2.3 Acetylcholinesterase Inhibitors: Use in Myasthenia Gravis
Both groups of AChE inhibitors are used therapeutically. One use of anticholinesterase
drugs is in myasthenia gravis. This is an autoimmune disease caused by the develop-
ment of antibodies against the patient’s own ACh receptors, accompanied by disturbed
neuromuscular transmission. The disturbance is caused by a reduction in the number of
nerve terminals and an increase in the width of the synaptic cleft. Normally, nicotinic
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