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

622 potentially vagotonic properties, they should be used
with caution in patients with bradycardia or syncope.
Memantine (NAMENDA) is used either as an adjunct
or an alternative to cholinesterase inhibitors in AD, and
is also commonly used to treat other neurodegenerative
dementias. Memantine is a noncompetitive antagonist
of the NMDA-type glutamate receptor. It interacts with
the Mg 2+ binding site of the channel to prevent excessive
activation while sparing normal function (Lipton, 2007).
Memantine significantly reduces the rate of clinical
deterioration in patients with moderate to severe AD
(Raina et al., 2008). Whether this is due to a true disease-modifying
effect, possibly reduced excitotoxicity,
or to a symptomatic effect of the drug is unclear.
Adverse effects of memantine include headache or
dizziness, but are usually mild and reversible. The drug
is excreted by the kidneys, and dosage should be
reduced in patients with severe renal impairment.
SECTION II
NEUROPHARMACOLOGY
Treatment of Behavioral Symptoms. In addition to cognitive
decline, behavioral and psychiatric symptoms in
dementia (BPSD) are common, particularly in middle
stages of the disease. These symptoms, including irritability
and agitation, paranoia and delusional thinking,
wandering, anxiety, and depression, are a major source
of caregiver distress and often precipitate nursing home
placement. Treatment can be difficult, and nonpharmacological
approaches should generally be firstline
(Beier, 2007; Sink et al., 2005).
A variety of pharmacological options are also
available. In addition to their effects on cognitive measures,
both cholinesterase inhibitors and memantine
reduce some BPSD (Maidment et al., 2008; Trinh et al.,
2003). However, their effects are modest, and they do
not treat some of the most troublesome symptoms, such
as agitation (Howard et al., 2007). Furthermore,
because most AD patients are already treated with these
drugs, other options are often needed when behavioral
symptoms emerge.
Atypical antipsychotics, such as risperidone,
olanzapine, and quetiapine (Chapter 16), are the most
efficacious therapy for agitation and psychosis in AD.
Risperdone and olanzapine are effective, but their use
is often limited by adverse effects, including parkinsonism,
sedation, and falls (Schneider et al., 2006). In
addition, the use of atypical antipsychotics in elderly
patients with dementia-related psychosis has been
associated with a higher risk of stroke and overall
mortality (Douglas and Smeeth, 2008; Schneider
et al., 2005), leading the FDA to order inclusion of a
boxed warning in the prescribing information for all
drugs in this class. Unfortunately, there are few effective
alternatives.
Mood stabilizers (Chapter 16) have been the focus of several
trials for BPSD. Carbamazepine has shown some benefit in small trials
but carries numerous risks in the elderly, especially the potential
for drug-drug interactions. There is little evidence of benefit from
valproic acid. Lithium is of considerable interest given its ability to
inhibit glycogen synthase kinase, which is implicated in AD pathogenesis,
but clinical trial results are limited and concerns persist about
the narrow therapeutic window in elderly patients. Benzodiazepines
(Chapter 17) can be used for occasional control of acute agitation,
but are not recommended for long-term management because of their
adverse effects on cognition and other risks in the elderly population.
The typical antipsychotic haloperidol (Chapter 16) may be useful for
aggression, but sedation and extrapyramidal symptoms limit its use
to control of acute episodes.
Antidepressants (Chapter 15) can be useful for BPSD, particularly
when depression or anxiety contribute. Because of the adverse
anticholinergic effects of tricyclic agents, serotonergic antidepressants
are favored. These agents are generally well tolerated.
Trazodone has modest benefits, but for the most part, selective serotonin
reuptake inhibitors (SSRIs) are the preferred class of drugs.
Clinical Summary. The typical AD patient presenting in
early stages of disease should probably be treated with a
cholinesterase inhibitor. Patients and families should be
counseled that a realistic goal of therapy is to induce a
temporary reprieve from progression, or at least a reduction
in the rate of decline, rather than long-term recovery
of cognition. As the disease progresses, memantine can
be added to the regimen. Behavioral symptoms are often
treated with a serotonergic antidepressant or, if they are
severe enough to warrant the risk of higher mortality, an
atypical antipsychotic. Eliminating drugs likely to aggravate
cognitive impairments, particularly anticholinergics,
benzodiazepines, and other sedative/hypnotics, from the
patient’s regimen is another important aspect of AD pharmacotherapy.
HUNTINGTON’S DISEASE (HD)
Clinical Features. HD is a dominantly inherited disorder
characterized by the gradual onset of motor incoordination
and cognitive decline in midlife. Symptoms
develop insidiously, either as a movement disorder manifest
by brief, jerk-like movements of the extremities,
trunk, face, and neck (chorea) or as personality changes
or both. Fine-motor incoordination and impairment of
rapid eye movements are early features. Occasionally,
especially when the onset of symptoms occurs before
age 20, choreic movements are less prominent; instead,
bradykinesia and dystonia predominate. As the disorder