Clinical Pharmacology and Therapeutics

ALZHEIMER’S DISEASE 131
Cholinergic crisis
Treatment of myasthenia with anticholinesterases can be usefully
monitored clinically by observation of the pupil (a diameter
of 2 mm or less in normal lighting suggests overdose).
Overdosage produces a cholinergic crisis, and further drug
should be withheld.
ALZHEIMER’S DISEASE
Alzheimer’s disease (AD) is the most common cause of dementia.
Its incidence increases with age. It is estimated that approximately
500 000 people in the USA are affected. The symptoms
of Alzheimer’s disease are progressive memory impairment
associated with a decline in language, visuospatial function,
calculation and judgement. Ultimately, this leads to major
behavioural and functional disability. Acetylcholinesterase
inhibiting drugs, e.g. donepezil, can slow down the progression
of mild and moderate Alzheimer’s disease, but the benefit
is pitifully small and only temporary. Clinical trials of other
drug therapy, such as oestrogens, non-steroidal anti-inflammatory
drugs (NSAIDs), statins, metal chelation and vitamin E,
have failed to show conclusive benefit. Depression is commonly
associated with Alzheimer’s disease and can be treated
with a selective serotonin reuptake inhibitor (SSRI), e.g. sertraline.
Antipsychotic drugs and benzodiazepines are sometimes
indicated in demented patients for symptoms of psychosis
or agitation but their use is associated with an increased risk
of stroke.
PATHOPHYSIOLOGY
Specific pathological changes in the brains of patients with AD
can be demonstrated, for example by positron emission tomography
(PET) scanning (Figure 21.4). Forty per cent of AD
patients have a positive family history. Histopathology features
of AD are the presence of amyloid plaques, neurofibrillary tangles
and neuronal loss in the cerebrum. Degeneration of cholinergic
neurones has been implicated in the pathogenesis of
Alzheimer’s disease. Neurochemically, low levels of acetylcholine
are related to damage in the ascending cholinergic
tracts of the nucleus basalis of Meynert to the cerebal cortex.
Other neurotransmitter systems have also been implicated. The
brains of patients with Alzheimer’s disease show a reduction in
acetylcholinesterase, the enzyme in the brain that is primarily
responsible for the hydrolysis of acetylcholine. This loss is
mainly due to the depletion of cholinesterase-positive neurones
within the cerebral cortex and basal forebrain.
These findings led to pharmacological attempts to augment
the cholinergic system by means of cholinesterase inhibitors.
Donepezil, galantamine and rivastigmine are acetylcholinesterase
inhibitors that are licensed for the treatment of
mild to moderate AD. Memantine is an NMDA receptor
antagonist and inhibits glutamate transmission. It is licensed
for moderate to severe dementia in AD.
DONEPEZIL, GALANTAMINE AND RIVASTIGMINE
Use
Donepezil, galantamine and rivastigmine have been licensed for
the treatment of mild to moderate dementia in AD. Only specialists
in management of AD should initiate treatment. Regular
review through Mini-Mental State Examination with assessment
of global, functional and behavioural condition of the patient is
necessary to justify continued treatment (Table 21.2).
Mechanism of action
These drugs are centrally acting, reversible inhibitors of
acetylcholinesterase. Galantamine is also a nicotinic receptor
agonist.
60
50
FDG
11 C-PIB
40
30
20
10
0
3
2
1
0
Figure 21.4: PET images of the brain of a
67-year-old healthy control subject (left) and a
79-year-old Alzheimer’s disease patient (right).
The top images show 18 FDG uptake, and the
bottom images show Pittsburgh Compound-B
(PIB) retention. The left column shows lack of
PIB retention in the entire grey matter of the
healthy subject (bottom left) and normal 18 FDG
uptake (top left). Nonspecific PIB retention is
seen in the white matter (bottom left). The
right column shows high PIB retention most
marked in the frontal and temporoparietal
cortices of the Alzheimer patient (bottom right)
and generalized 18 FDG hypometabolism (top
right) (adapted from Klunk WE et al. Annals of
Neurology 2004; 55: 306–19).