disease. Dementia is a nonspecific term applied to any chronic, progressive, non-reversible
neurodegenerative process that results in diminished intellectual function; AD is merely
one type of dementia. Dementia can also occur secondary to multiple strokes affecting
the brain, producing so-called multi-infarct dementiaorvascular dementia. It is also
important to differentiate dementia from delirium. Delirium (also sometimes called
encephalopathy) is a reversible reduction in intellectual functioning, typically mani-
festing as confusion or agitation. In the elderly, delirium not infrequently arises from
overmedication or excessive medication. Acetylcholinesterase inhibitors are of no value
in the treatment of delirium, and in fact may make it worse. Interestingly, for reasons
that remain unclear, acetylcholinesterase inhibitors, such as donepezil, do demonstrate
weak activity in vascular dementia.
8.2.2.5 Acetylcholinesterase Inhibitors: Clinical Use in Glaucoma
Another use for acetylcholinesterase inhibitors is in glaucoma, in which high intraocu-
lar pressure can lead to permanent damage to the optic disk, resulting in blindness. The
local instillation of physostigmine(8.14)or echothiophate (8.19) solution in the eye
results in a long-lasting decrease in the intraocular pressure as well as myosis (contraction
of the pupil).
8.2.2.6 Acetylcholinesterase Inhibitors: Industrial Use as Insecticides
Uncharged carbamates, such as carbaryl (8.20, sevin), can penetrate the CNS of insects
(which do not use AChE in their neuromuscular junction) and they act quite selectively
as insecticides with a low toxicity to mammals (median lethal dose [LD 50 ] in the rat =
540 mg/kg, p.o.). Many useful insecticides can thus be found in this group. Malathion
(8.21) is a pro-drug, since the thiophosphate must be bioactivated to the phosphate
form—a transformation carried out by insects but not mammals. Additionally, the ester
groups of malathion are rapidly hydrolyzed in higher organisms to water-soluble and
490 MEDICINAL CHEMISTRY