| Indication |
Used as an adjunct to levodopa / carbidopa in the symptomatic
treatment of patients with idiopathic Parkinson's Disease who experience
the signs and symptoms of end-of-dose "wearing-off". |
| Pharmacodynamics |
Entacapone is structurally and pharmacologically related to
tolcapone, but unlike tolcapone, is not associated with hepatotoxicity.
Entacapone is used in the treatment of Parkinson’s disease as an adjunct
to levodopa/carbidopa therapy. Entacapone is a selective and reversible
inhibitor of catechol-O-methyltransferase (COMT). In mammals, COMT is
distributed throughout various organs with the highest activities in the
liver and kidney. COMT also occurs in the heart, lung, smooth and
skeletal muscles, intestinal tract, reproductive organs, various glands,
adipose tissue, skin, blood cells and neuronal tissues, especially in
glial cells. COMT catalyzes the transfer of the methyl group of
S-adenosyl-L-methionine to the phenolic group of substrates that contain
a catechol structure. Physiological substrates of COMT include dopa,
catecholamines (dopamine, norepinephrine, and epinephrine) and their
hydroxylated metabolites. The function of COMT is the elimination of
biologically active catechols and some other hydroxylated metabolites.
COMT is responsible for the elimination of biologically active catechols
and some other hydroxylated metabolites. In the presence of a
decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for
levodopa, catalyzing the it to 3-methoxy-4-hydroxy-L-phenylalanine
(3-OMD) in the brain and periphery. |
| Mechanism of action |
The mechanism of action of entacapone is believed to be through
its ability to inhibit COMT in peripheral tissues, altering the plasma
pharmacokinetics of levodopa. When entacapone is given in conjunction
with levodopa and an aromatic amino acid decarboxylase inhibitor, such
as carbidopa, plasma levels of levodopa are greater and more sustained
than after administration of levodopa and an aromatic amino acid
decarboxylase inhibitor alone. It is believed that at a given frequency
of levodopa administration, these more sustained plasma levels of
levodopa result in more constant dopaminergic stimulation in the brain,
leading to a greater reduction in the manifestations of parkinsonian
syndrome. |
| Absorption |
Entacapone is rapidly absorbed (approximately 1 hour). The absolute bioavailability following oral administration is 35%. |
| Volume of distribution |
|
| Protein binding |
98% (bind to serum albumin) |
| Metabolism |
Metabolized via isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer. |
| Route of elimination |
Entacapone is almost completely metabolized prior to excretion,
with only a very small amount (0.2% of dose) found unchanged in urine.
As only about 10% of the entacapone dose is excreted in urine as parent
compound and conjugated glucuronide, biliary excretion appears to be the
major route of excretion of this drug. |
| Half life |
0.4-0.7 hour |
| Clearance |
|
| Toxicity |
Side effect include increase the occurrence of orthostatic
hypotension, severe rhabdomyolysis, dyskinesia, hallucinations,
hyperkinesia, hypokinesia, dizziness, fatigu,e gastrointestinal effects
including abdominal pain constipation diarrhea nausea |
