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

drug in plasma usually peak between 0.5 and 2 hours
after an oral dose. The t 1/2
in plasma is short (1-3 hours).
The rate and extent of absorption of levodopa depends
on the rate of gastric emptying, the pH of gastric juice,
and the length of time the drug is exposed to the
degradative enzymes of the gastric and intestinal
mucosa. Competition for absorption sites in the small
bowel from dietary amino acids also may have a marked
effect on the absorption of levodopa; administration of
levodopa with high-protein meals delays absorption and
reduces peak plasma concentrations. Entry of the drug
into the CNS across the blood-brain barrier also is mediated
by a membrane transporter for aromatic amino
acids, and competition between dietary protein and levodopa
may occur at this level. In the brain, levodopa is
converted to DA by decarboxylation primarily within
the presynaptic terminals of dopaminergic neurons in
the stratium. The DA produced is responsible for the
therapeutic effectiveness of the drug in PD; after release,
it is either transported back into dopaminergic terminals
by the presynaptic uptake mechanism or metabolized by
the actions of MAO and catechol-O-methyltransferase
(COMT) (Figure 22–4).
In clinical practice, levodopa is almost always
administered in combination with a peripherally acting
inhibitor of aromatic L-amino acid decarboxylase, such
HO
HO
HO
Levododa
3,4-Dihydroxyphenylacetic
Acid (DOPAC)
HO
HO
OH
COOH
3-O-Methyldopa
NH 2
NH 2 COMT
H 3 CO
NH 2
COOH
HO
COOH
AADC
Dopamine
3-Methoxytyramine
MAO
ALDH
COMT
DβH
Norepinephrine
COMT
H 3 CO
HO
3-Methoxy-4-hydroxyphenylacetic
Acid (HVA)
H 3 CO
HO
MAO
ALDH
NH 2
COOH
Figure 22–4. Metabolism of levodopa (L-DOPA). ALDH, aldehyde
dehydrogenase; COMT, catechol-O-methyltransferase;
DβH, dopamine β-hydroxylase; AADC, aromatic L-amino acid
decarboxylase; MAO, monoamine oxidase.
as carbidopa or benserazide (available outside the U.S.),
drugs that do not penetrate well into the CNS. If
levodopa is administered alone, the drug is largely decarboxylated
by enzymes in the intestinal mucosa and other
peripheral sites so that relatively little unchanged drug
reaches the cerebral circulation and probably <1% penetrates
the CNS. In addition, DA release into the circulation
by peripheral conversion of levodopa produces
undesirable effects, particularly nausea. Inhibition of
peripheral decarboxylase markedly increases the fraction
of administered levodopa that remains unmetabolized
and available to cross the blood-brain barrier
(Figure 22–5) and reduces the incidence of GI side
effects.
In most individuals, a daily dose of 75 mg carbidopa is sufficient
to prevent the development of nausea. For this reason, the most
commonly prescribed form of carbidopa/levodopa (SINEMET, ATAMET,
others) is the 25/100 form, containing 25 mg carbidopa and 100 mg
levodopa. With this formulation, dosage schedules of three or more
tablets daily provide acceptable inhibition of decarboxylase in most
individuals. Occasionally, individuals will require larger doses of carbidopa
to minimize gastrointestinal side effects, and administration of
supplemental carbidopa (LODOSYN) may be beneficial. Carbidopa/
levodopa is also available in an orally disintegrating tablet (PARCOPA).
This may be useful in patients with swallowing difficulty, although it
is important to note that levodopa is not absorbed through the oral
mucosa, and must still be delivered to the small intestine for absorption.
Thus, the time to onset of action of PARCOPA is not appreciably
different from that of standard oral formulations.
entacapone
tolcapone
carbidopa
Periphery
3-O-MD
COMT
L-DOPA
AADC
DA
CNS (Striatum)
DOPAC
selegiline
(low dose)
MAO-B
rasagiline
AADC
L-DOPA DA
tolcapone
3MT
COMT
Figure 22–5. Pharmacological preservation of L-DOPA and striatal
dopamine. The principal site of action of inhibitors of catechol-Omethyltransferase
(COMT) (such as tolcapone and entacapone) is
in the peripheral circulation. They block the O-methylation of
levodopa (L-DOPA) and increase the fraction of the drug available
for delivery to the brain. Tolcapone also has effects in the CNS.
Inhibitors of MAO-B, such as low-dose selegiline and rasagiline,
will act within the CNS to reduce oxidative deamination of DA,
thereby enhancing vesicular stores. AADC, aromatic L-amino acid
decarboxylase; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic
acid; MAO, monoamine oxidase; 3MT, 3-methoxyltyramine; 3-O-
MD, 3-O-methyl DOPA
615
CHAPTER 22
TREATMENT OF CENTRAL NERVOUS SYSTEM DEGENERATIVE DISORDERS