Page 1076 - Basic _ Clinical Pharmacology ( PDFDrive )

1062 SECTION X Special Topics

reduced antimuscarinic effects should be selected, eg, nortriptyline (Figure 60–2). There is a progressive loss of neurons, especially
or desipramine (see Table 30–2). cholinergic neurons, and thinning of the cortex. An inflamma-
tory process involving the NLRP3 inflammasome appears to
Drugs Used in Alzheimer’s Disease contribute to this pathology, and anti-inflammatory nonsteroidal
anti-inflammatory drugs (NSAIDs), eg, mefenamic acid, reverse
Alzheimer’s disease (AD) is characterized by progressive memory some of the markers of Alzheimer’s disease in animal models.
impairment, dementia, and cognitive dysfunction, and may lead The loss of cholinergic neurons results in a marked decrease in
to a completely vegetative state, resulting in early death. Preva- choline acetyltransferase and other markers of cholinergic activity.
lence increases with age and may be as high as 20% in individuals Patients with Alzheimer’s disease are often exquisitely sensitive to
over 85, although long-term epidemiologic studies suggest that the central nervous system toxicities of drugs with antimuscarinic
the overall prevalence of dementia has decreased in the USA and effects. Some evidence implicates excess excitation by glutamate
Europe over the last 15–30 years (see Langa 2017). The annual cost as a contributor to neuronal death. In addition, abnormalities of
of dementia in the United States is estimated at $150–$215 billion mitochondrial function may contribute to neuronal death.
annually. Both familial and sporadic forms have been identified. Many methods of treatment of Alzheimer’s disease have been
Early onset of Alzheimer’s disease is associated with several gene explored (Table 60–3). Much attention has been focused on the
defects, including trisomy 21 (chromosome 21), a mutation of the cholinomimetic drugs because of the evidence of loss of cholin-
gene for presenilin-1 on chromosome 14, and an abnormal allele, ergic neurons noted earlier. Monoamine oxidase (MAO) type
ε4, for the lipid-associated protein, ApoE, on chromosome 19. B inhibition with selegiline (l-deprenyl) has been suggested to
Unlike the common forms (ApoE ε2 and ε3), the ε4 form strongly have some beneficial effects. One drug that inhibits N-methyl-
correlates with the formation of amyloid β deposits (see below). d-aspartate (NMDA) glutamate receptors is available (see below),
Pathologic changes include increased deposits of amyloid and “ampakines,” substances that facilitate synaptic activity at
beta (Aa) peptide in the cerebral cortex, which eventually forms glutamate AMPA receptors, are under intense study. Some evi-
extracellular plaques and cerebral vascular lesions, and intra- and dence suggests that lipid-lowering statins are beneficial. So-called
interneuronal fibrillary tangles consisting of the tau protein cerebral vasodilators are ineffective.

Microglia

Neuron

Aβ
ApoE4 Nucleus
Mitochondrion Oligomers
Truncated E4 Signaling
molecules
Impaired
synapse
Neurite

Tau

Amyloid
plaque

Neurofibrillary
tangles

FIGURE 60–2 Some processes involved in Alzheimer’s disease. From the left: Mitochondrial dysfunction, possibly involving glucose utiliza-
tion; synthesis of protein tau and aggregation in filamentous tangles; synthesis of amyloid beta (Aβ) and secretion into the extracellular space,
where it may interfere with synaptic signaling and accumulates in plaques. (Reproduced, with permission, from Roberson ED, Mucke L: 100 years and count-
ing: Prospects for defeating Alzheimer’s disease. Science 2006;314:781. Reprinted with permission from AAAS.)