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

624 designated IT15. It encodes a protein of approximately 348,000 DA.
The trinucleotide repeat, which encodes the amino acid glutamine,
occurs at the 55’ end of IT15 and is followed directly by a second,
shorter repeat of (CCG) n
that encodes proline. The protein, named
huntingtin, does not resemble any other known protein, and the normal
function of the protein has not been identified. Mice with a
genetic knockout of huntingtin die early in embryonic life, so it must
have an essential cellular function. It is thought that the mutation
results in a gain of function—that is, the mutant protein acquires a
new function or property not found in the normal protein. The nature
of the function gained remains uncertain, although some evidence
points to effects on cellular energy metabolism and gene transcription
(Imarisio, 2008).
SECTION II
NEUROPHARMACOLOGY
Treatment of Huntington’s Disease
Symptomatic Treatment. Treatment for symptomatic HD
emphasizes the selective use of medications (Shoulson,
1992). None of the currently available medications slows
the progression of the disease. HD patients are frequently
very sensitive to side effects of medications. Treatment is
needed for patients who are depressed, irritable, paranoid,
excessively anxious, or psychotic. Depression can
be treated effectively with standard antidepressant drugs
with the caveat that drugs with substantial anticholinergic
profiles can exacerbate chorea. Fluoxetine (Chapter 15) is
effective treatment for both the depression and the irritability
manifest in symptomatic HD. Carbamazepine
(Chapter 21) also has been found to be effective for
depression. Paranoia, delusional states, and psychosis are
treated with antipsychotic drugs, but usually at lower
doses than those used in primary psychiatric disorders
(Chapter 16). These agents also reduce cognitive function
and impair mobility and thus should be used in the
lowest doses possible and should be discontinued when
the psychiatric symptoms resolve. In individuals with predominantly
rigid HD, clozapine, quetiapine (Chapter 16),
or carbamazepine may be more effective for treatment
of paranoia and psychosis.
The movement disorder of HD per se only rarely justifies
pharmacological therapy. For those with large-amplitude chorea
causing frequent falls and injury, tetrabenazine (XENAZINENITOMAN)
has recently become available in the U.S. for the treatment of chorea
associated with HD. Tetrabenazine, and the related drug reserpine,
are inhibitors of the vesicular monoamine transporter 2 (VMAT2),
and cause presynaptic depletion of catecholamines. Tetrabenazine
is a reversible inhibitor; inhibition by reserpine is irreversible and
may lead to long-lasting effects. Both drugs may cause hypotension
and depression with suicidality; the shorter duration of effect of tetrabenazine
greatly simplifies the clinical management. Antipsychotic
agents also can be used, but these often do not improve overall function
because they decrease fine motor coordination and increase
rigidity. Many HD patients exhibit worsening of involuntary movements
as a result of anxiety or stress. In these situations, judicious
use of sedative or anxiolytic benzodiazepines can be very helpful. In
juvenile-onset cases where rigidity rather than chorea predominates,
DA agonists have had variable success in the improvement of rigidity.
These individuals also occasionally develop myoclonus and
seizures that can be responsive to clonazepam, valproic acid, and
other anticonvulsants (Chapter 21).
Clinical Summary. HD is an autosomal dominant disorder
caused by mutations in the IT15 gene that encodes
huntingtin. The gene defect leads to progressive motor
and cognitive symptoms. At present there is no effective
treatment for the primary disorder, although antidepressant
and antipsychotic medications may be useful to
control specific symptoms and catecholamine depleting
agents may be useful to control the motor features
of the disease.
AMYOTROPHIC LATERAL
SCLEROSIS (ALS)
Clinical Features and Pathology. ALS (or Lou Gehrig’s
disease) is a disorder of the motor neurons of the ventral
horn of the spinal cord (lower motor neurons) and
the cortical neurons that provide their afferent input
(upper motor neurons). The disorder is characterized
by rapidly progressive weakness, muscle atrophy and
fasciculations, spasticity, dysarthria, dysphagia, and
respiratory compromise. Sensory, autonomic, and oculomotor
function is generally spared. While it was previously
thought that higher cortical function was also
unaffected, many ALS patients exhibit behavioral
changes and cognitive dysfunction, and there is clinical,
genetic, and neuropathological overlap between ALS
and frontotemporal dementia spectrum disorders
(Strong et al., 2009). ALS usually is progressive and
fatal. Most patients die of respiratory compromise and
pneumonia after 2-3 years, although some individuals
have a more indolent course and survive for many
years. The pathology of ALS corresponds closely to the
clinical features: There is prominent loss of the spinal
and brainstem motor neurons that project to striated
muscles (although the oculomotor neurons are spared),
as well as loss of the large pyramidal motor neurons in
layer V of motor cortex, which are the origin of the
descending corticospinal tracts.
Etiology. About 10% of ALS cases are familial (FALS), usually with
an autosomal dominant pattern of inheritance. Most of the mutations
responsible have not been identified, but an important subset of
FALS patients are families with a mutation in the gene for the
enzyme SOD1 (Rosen et al., 1993). Mutations in this protein
account for about 20% of cases of FALS. Most of the mutations are