DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Aggregation of Aβ is an important event in AD pathogenesis.
While plaques consist of highly ordered fibrils of Aβ, it appears that
soluble Aβ oligomers, perhaps as small as dimers, are more highly
pathogenic. Tau also aggregates to form the paired helical filaments
that make up neurofibrillary tangles. Post-translational modifications
of tau including phosphorylation, proteolysis, and other changes cause
loss of tau’s normal functions and increase its propensity to aggregate.
Mechanisms by which Aβ and tau induce neuronal dysfunction and
death may include direct impairment of synaptic transmission and
plasticity, excitotoxicity, oxidative stress, and neuroinflammation. The
factors underlying the selective vulnerability of particular cortical neurons
to the pathological effects of AD are not known.
Neurochemistry. The most striking neurochemical disturbance in AD
is a deficiency of acetylcholine. The anatomical basis of the cholinergic
deficit is atrophy and degeneration of subcortical cholinergic
neurons, particularly those in the basal forebrain (nucleus basalis of
Meynert) that provide cholinergic innervation to the cerebral cortex.
The selective deficiency of ACh in AD, as well as the observation
that central cholinergic antagonists such as atropine can induce a confusional
state that bears some resemblance to the dementia of AD,
has given rise to the “cholinergic hypothesis,” which proposes that a
deficiency of ACh is critical in the genesis of the AD symptoms
(Perry, 1986). Although viewing AD as a “cholinergic deficiency syndrome”
akin to the “dopaminergic deficiency syndrome” of PD provides
a useful framework, it is important to note that the deficit in
AD is far more complex. AD involves multiple neurotransmitter systems,
including glutamate, 5-HT, and neuropeptides, and there is
destruction of not only cholinergic neurons but also the cortical and
hippocampal targets that receive cholinergic input.
Treatment of Alzheimer’s Disease
At present, no disease-modifying therapy for AD is
available. While aggressive attempts to develop drugs
targeting Aβ, tau, apoE, and other molecules involved
in AD pathogenesis are underway (Roberson and
Mucke, 2006), current treatment is aimed at alleviating
symptoms.
Treatment of Cognitive Symptoms. Augmentation of the
cholinergic transmission is currently the mainstay of AD
treatment. Three drugs, donepezil, rivastigmine, and
galantamine, are widely used for this purpose; a fourth,
tacrine, was the first drug approved to treat AD but is
rarely used now because it has much more extensive side
effects compared to the newer agents (Table 22–2). All
four agents are reversible antagonists of cholinesterases,
enzymes that act to limit cholinergic neurotransmission
by catalyzing the cleavage of acetylcholine in the
synaptic cleft into choline and acetate (Chapter 10).
Cholinesterase inhibitors are the usual first-line therapy
for symptomatic treatment of cognitive impairments in
mild or moderate AD. These agents have a beneficial,
albeit quite modest, effect on cognition in clinical AD
studies (Birks, 2006). They are also widely used to treat
other neurodegenerative diseases with cholinergic
deficits, including dementia with Lewy bodies (Bhasin
et al., 2007) and vascular dementia (Kavirajan and
Schneider, 2007). In addition, they are sometimes used in
MCI, where they may also have symptomatic benefit but
do not slow the conversion to AD (Raschetti et al., 2007).
The drugs are usually well tolerated, with the most common
side effects being GI distress, muscle cramping, and
abnormal dreams. Because of their cholinergic and
Table 22–2
Cholinesterase Inhibitors Used for the Treatment of Alzheimer’s Disease
DONEPEZIL RIVASTIGMINE GALANTAMINE TACRINE a
Brand name ARICEPT EXELON, generic RAZADYNE, generic COGNEX
Enzymes inhibited b AChE AChE, BuChE AChE AChE, BuChE
Mechanism Noncompetitive Noncompetitive Competitive Noncompetitive
Typical maintenance dose c 10 mg once daily 9.5 mg/24h 8-12 mg twice daily 20 mg, four times
(transdermal) (immediate-release) daily
3-6 mg twice daily 16-24 mg/day
(oral) (extended-release )
FDA-approved indications Mild–severe AD Mild–moderate AD, Mild–moderate AD Mild–moderate AD
Mild–moderate PDD d
Metabolism e CYP2D6, CYP3A4 Esterases CYP2D6, CYP3A4 CYP1A2
a
Tacrine was the first cholinesterase inhibitor approved for the treatment of AD, but is now rarely used because of hepatotoxicity and adverse effects.
b
AChE (acetylcholinesterase) is the major cholinesterase in the brain; BuChE (butyrylcholinesterase) is a serum and hepatic cholinesterase that is
upregulated in AD brain. c Typical starting doses are one-half of the maintenance dose and are given for the first month of therapy. d PDD, Parkinson
disease dementia. e Drugs metabolized by CYP2D6 and CYP3A4 are subject to increased serum levels when co-administered with drugs known to
inhibit these enzymes, such as ketoconazole and paroxetine. Similarly, tacrine levels are increased by co-administration with the CYP1A2 inhibitors
theophylline, cimetidine, and fluvoxamine.