ACh receptors are destroyed by endocytosis via coated pits and proteolysis in lysosomes.
In myasthenia gravis, the receptors are crosslinked by antireceptor antibodies, which
facilitate the rate-limiting endocytosis step; receptor destruction occurs in less than half
the normal time, resulting in net receptor loss. The chronic disease is characterized clin-
ically by such muscular weakness and abnormal fatigue that patients cannot even keep
their eyes open. Acetylcholinesterase inhibitors increase the ACh concentration and
excitation of the neuromuscular junction, resulting in increased strength and endurance.
As expected, AChE inhibitors are also potent curare antidotes because the increased
ACh levels displace the blocker more readily.
8.2.2.4 Acetylcholinesterase Inhibitors: Clinical Use in Alzheimer’s Disease
Most recently, acetylcholinesterase inhibitors have been used to afford symptomatic
relief in Alzheimer’s disease (AD). In AD, neurons are progressively killed by some
neurotoxic factor, presumably mediated by β-amyloid. As the neurons die, they
decrease their production of acetylcholine; as acetylcholine production decreases,
symptoms such as decreased memory and confusion become apparent. Administering
an acetylcholinesterase inhibitor prolongs the effective half-life of the acetylcholine
that is being biosynthesized, thereby producing a symptomatic improvement. Since the
acetylcholinesterase inhibitors are not dealing with the underlying neuropathological
process (i.e.,β-amyloid mediated toxicity) they are not curative. Once the disease has
progressed to the point where neurons are no longer producing effective concentrations
of acetylcholine, these agents are no longer of value. The acetylcholinesterase inhibitors
currently in clinical use for AD include donepezil (8.16), rivastigmine (8.17), and
galantamine (8.18).
It is important to emphasize that dementia and Alzheimer’s disease are not synony-
mous terms. All Alzheimer’s disease is dementia, but not all dementia is Alzheimer’s
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