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

618 of levodopa/carbidopa. The action of entacapone is attributable principally
to peripheral inhibition of COMT. The common adverse
effects of these agents are similar to those of levodopa/carbidopa
alone and include nausea, orthostatic hypotension, vivid dreams,
confusion, and hallucinations. An important adverse effect associated
with tolcapone is hepatotoxicity. Up to 2% of the patients
treated have increased serum alanine aminotransferase and aspartate
transaminase; and at least three fatal cases of fulminant hepatic failure
in patients taking tolcapone have been observed, leading to addition
of a black box warning to the label. At present, tolcapone should
be used only in patients who have not responded to other therapies
and with appropriate monitoring for hepatic injury. Entacapone has
not been associated with hepatotoxicity and requires no special monitoring.
Entacapone also is available in fixed-dose combinations with
levodopa/carbidopa (STALEVO).
SECTION II
NEUROPHARMACOLOGY
Selective MAO-B Inhibitors. Two isoenzymes of MAO
oxidize monoamines. While both isoenzymes (MAO-A
and MAO-B) are present in the periphery and inactivate
monoamines of intestinal origin, the isoenzyme MAO-B
is the predominant form in the striatum and is responsible
for most of the oxidative metabolism of DA in the
brain. Two selective MAO-B inhibitors are used for the
treatment of PD: selegiline (ELDEPRYL, EMSAM, ZELAPAR)
and rasagiline (AZILECT). When used at recommended
doses, these agents selectively inactivate MAO-B
through irreversible inhibition of the enzyme (Elmer and
Bertoni, 2008). Both agents exert modest beneficial
effects on the symptoms of PD. The basis of this efficacy
is presumed to be the inhibition of breakdown of
DA in the striatum. Unlike nonspecific inhibitors of
MAO (such as phenelzine, tranylcypromine, and isocarboxazid),
selective MAO-B inhibitors do not substantially
inhibit the peripheral metabolism of catecholamines
and can be taken safely with levodopa. These agents also
do not exhibit the “cheese effect,” the potentially lethal
potentiation of catecholamine action observed when
patients on nonspecific MAO inhibitors ingest indirectly
acting sympathomimetic amines such as the tyramine
found in certain cheeses and wine.
Selegiline has been used for many years as a symptomatic
treatment for PD and is generally well tolerated in younger patients
with early or mild PD. In patients with more advanced PD or underlying
cognitive impairment, selegiline may accentuate the adverse
motor and cognitive effects of levodopa therapy. Metabolites of
selegiline include amphetamine and methamphetamine, which may
cause anxiety, insomnia, and other adverse symptoms. Recently,
selegiline has become available in an orally disintegrating tablet
(ZELEPAR) as well as a transdermal patch (EMSAM). Both of these
delivery routes are intended to reduce hepatic first-pass metabolism
and limit the formation of the amphetamine metabolites.
Unlike selegiline, rasagiline does not give rise to undesirable
amphetamine metabolites. In randomized controlled clinical trials,
rasagiline monotherapy was effective in early PD. Adjunctive
therapy significantly reduced levodopa-related “wearing off” symptoms
in advanced PD.
A consequence of the inhibition of MAO-B in the brain is a
reduction in the overall catabolism of DA, which may reduce the formation
of potentially toxic free radicals. This observation has led to
studies which have examined the question of whether MAO-B inhibition
can alter the rate of neurodegeneration in PD. The potential protective
role of selegiline in idiopathic PD was evaluated in several
multicenter randomized trials; although there was some evidence supporting
a neuroprotective effect, the outcomes were obscured by the
difficulty of distinguishing long-term neuroprotective effects from
short-term symptomatic effects (Parkinson Study Group, 1993;
Yacoubian and Standaert, 2008). A more recent study, using a different
design, has produced more convincing data suggesting a neuroprotective
effect of rasagiline (Olanow, 2008).
Although selective MAO-B inhibitors are generally well tolerated,
drug interactions can be troublesome. Similar to the nonspecific
MAO inhibitors, selegiline can lead to the development of
stupor, rigidity, agitation, and hyperthermia when administered with
the analgesic meperidine. Although the mechanics, of this interaction
is uncertain, selegiline or rasagiline should not be given in combination
with meperidine. Adverse effects have been reported from coadministration
of MAO-B inhibitors with tricyclic antidepressants
or with serotonin-reuptake inhibitors. However, interactions with
antidepressants are uncommon, and many patients do take these
combinations of medications without apparent adverse interaction;
nonetheless, concomitant administration of selegiline or rasagiline
with serotonergic drugs should be done with caution, especially in
patients on high doses of serotonin-reuptake inhibitors.
Muscarinic Receptor Antagonists. Antagonists of muscarinic
acetylcholine receptors were used widely for the
treatment of PD before the discovery of levodopa. The
biological basis for the therapeutic actions of anticholinergics
is not completely understood. They may act within
the neostriatum through the receptors that normally
mediate the response to intrinsic cholinergic innervation
of this structure, which arises primarily from cholinergic
striatal interneurons. Several muscarinic cholinergic
receptors have been cloned (Chapters 9 and 14); like the
DA receptors, these are GPCRs. Five subtypes of muscarinic
receptors exist. All five subtypes are probably
present in the striatum, although each one has a distinct
distribution (Hersch et al., 1994). Anticholinergic drugs
currently used in the treatment of PD include trihexyphenidyl
(2-4 mg three times per day), benztropine
mesylate (1-4 mg two times per day), and diphenhydramine
hydrochloride (25-50 mg three or four times per
day). Diphenhydramine also is a histamine H 1
antagonist
(Chapter 32).
All of these drugs have relatively modest
antiparkinsonian activity and are only used in the treatment
of early PD or as an adjunct to dopamimetic therapy.
Adverse effects result from their anticholinergic
properties. Most troublesome are sedation and mental