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

confusion. Other side effects are constipation, urinary
retention, and blurred vision through cycloplegia. All
anticholinergic drugs must be used with caution in
patients with narrow-angle glaucoma (Chapter 65).
Amantadine. Amantadine (SYMMETREL), an antiviral
agent used for the prophylaxis and treatment of
influenza A (Chapter 58), has antiparkinsonian activity.
Amantadine appears to alter DA release in the striatum,
has anticholinergic properties, and blocks NMDA
glutamate receptors. However, it is not well understood
which of amantadine’s pharmacological effects are
responsible for its antiparkinsonian actions. In any case,
the effects of amantadine in PD are modest. It is used as
initial therapy of mild PD. It also may be helpful as an
adjunct in patients on levodopa with dose-related fluctuations
and dyskinesias. The antidyskinetic properties
of amantadine have been attributed to actions at NMDA
receptors (Hallett and Standaert, 2004), although the
closely related NMDA receptor antagonist memantine
(discussed later) does not seem to have this effect.
Amantadine is usually administered at a dose of 100 mg
twice a day and is well tolerated. Dizziness, lethargy, anticholinergic
effects, and sleep disturbance, as well as nausea and vomiting,
have been observed occasionally, but even when present, these
effects are mild and reversible.
Neuroprotective Treatments for Parkinson Disease. It would be
desirable to identify a treatment that modifies the progressive degeneration
that underlies PD rather than simply controlling the symptoms.
Current research strategies are based on the disease
mechanisms described earlier (e.g., energy metabolism, oxidative
stress, environmental triggers, and excitotoxicity) and on discoveries
related to the genetics of PD (Yacoubian and Standaert, 2008).
Several studies have examined the potential neuroprotective effects
of existing medications. In a randomized controlled trial, levodopa
did not worsen the disease state. Some benefits persisted for several
weeks after treatment was stopped, but whether this was truly a “neuroprotective”
effect remains uncertain (Fahn et al., 2004).
Two trials have attempted to examine the effect of pramipexole
or ropinirole on neurodegeneration in PD (Parkinson Study
Group, 2002; Whone et al., 2003). Both trials observed that in
patients treated with either one of these agonists, there was a reduced
rate of loss of markers of dopaminergic neurotransmission measured
by brain imaging compared with a similar group of patients treated
with levodopa. These intriguing data should be viewed cautiously,
particularly because there is considerable uncertainty about the relationship
of the imaging results techniques used and the true rate of
neurodegeneration (Albin and Frey, 2003).
Inhibition of MAO-B in the brain reduces the overall catabolism
of DA, which may decrease the formation of potentially toxic
free radicals and consequently the rate of neurodegeneration in PD.
The protective role of selegiline in idiopathic PD was evaluated in
several multicenter randomized trials. Unfortunately, distinguishing
long-term neuroprotective effects from short-term symptomatic
effects was difficult in the earlier studies (Parkinson Study
Group, 1993; Yacoubian and Standaert, 2008). A different study
design showed more convincingly a neuroprotective effect of
rasagiline (2008).
Another strategy under study is the use of compounds that
augment cellular energy metabolism such coenzyme Q10, a cofactor
required for the mitochondrial electron-transport chain. A small study
has demonstrated that this drug is well tolerated in PD and has suggested
that coenzyme Q10 may slow the course of the disease (Shults
et al., 2002). A much larger study is in progress. Therapies directly
targeting the molecules which are implicated in the pathogenesis of
PD are still in a nascent stage, and may require unconventional delivery
strategies such as gene therapy (Lewis and Standaert, 2008).
Clinical Summary. Pharmacological treatment of PD
should be tailored to the individual patient. Drug therapy
is not obligatory in early PD; many patients can
be managed for a time with exercise and lifestyle interventions.
For patients with mild symptoms, MAO-B
inhibitors, amantadine, or (in younger patients) anticholinergics
are reasonable choices. In most patients,
treatment with a dopaminergic drug, either levodopa
or a DA agonist, is eventually required. Large controlled
clinical trials provide convincing evidence for a
reduced rate of motor fluctuation in patients in which
DA agonists are used as initial treatment. This benefit
was, however, accompanied by an increased rate of
adverse effects, especially somnolence and hallucinations
(Parkinson Study Group, 2000; Rascol
et al., 2000). Practitioners prefer DA agonist as initial
therapy in younger patients in order to reduce the
occurrence of motor complications. In older patients
or those with substantial comorbidity, levodopa/
carbidopa is generally better tolerated.
ALZHEIMER’S DISEASE (AD)
Clinical Overview. The brain region most vulnerable to
neuronal dysfunction and cell loss in AD is the medial
temporal lobe, including entorhinal cortex and hippocampus.
Typical early AD symptoms are due to dysfunction
of these structures resulting in anterograde
episodic memory loss: repeated questions, misplaced
items, missed appointments, and forgotten details of
daily life. A typical patient presents with memory dysfunction
that is noticeable by the patient and/or family
members, but not severe enough to impair daily function.
Because current diagnostic criteria for AD require the
presence of dementia (i.e., cognitive impairments sufficient
to reduce function), these patients are generally
given a diagnosis of mild cognitive impairment (MCI).
Patients with MCI progress at a rate of about 10% per
619
CHAPTER 22
TREATMENT OF CENTRAL NERVOUS SYSTEM DEGENERATIVE DISORDERS