II. Indications

  1. Late-stage Parkinson's Disease to minimize "off" periods
  2. Extends Levodopa Half-Life to reduce off-time (not indicated as monotherapy)

III. Mechanism

  1. Catechol O-methyltransferase (COMT) catalyzes the transfer of a methyl group to the phenol group on Catecholamines
    1. Starts the intracellular metabolism of Catecholamines (Dopa, Dopamine, Epinephrine, Norepinephrine)
  2. COMT Inhibitors decrease the metabolism of Levodopa, increasing its Bioavailability and Half-Life
    1. Agents listed here (e.g. Entacapone, Tolcapone) are selective, reversible COMT Inhibitors
    2. COMT Inhibitors have no anti-Parkinsonism effect on their own (their only effect is when combined with Levodopa)

IV. Precautions

  1. May need to reduce Levodopa dose after start of COMT Inhibitor
    1. Indicated if increased Dyskinesia, Nausea, Hallucinations
  2. Avoid Tolcapone due to hepatotoxicity
  3. Avoid stopping COMT Inhibitors abruptly
    1. Risk of Neuroleptic Malignant Syndrome

V. Dosing: Entacapone (Comtan)

  1. Peripherally acting with reduction of "off" time by 1 hour/day
  2. Entacapone (Comtan)
    1. Start 200 mg with each dose of Carbidopa/Levodopa
    2. Maximum: Up to 8 doses (1600 mg/day)
  3. Entacapone with Carbidopa/Levodopa (Stalevo)
    1. Patient takes Stalevo, just as they would take Carbidopa/Levodopa (Sinemet) alone
    2. Consider lowering the Carbidopa/Levodopa when adding Entacapone
    3. Maximum: 8 tabs/day (6 tabs if 200 mg/dose Entacapone)

VI. Dosing: Opicapone (Ongentys)

  1. Peripherally acting with reduction of "off" time by 1 hour/day
  2. Start: 50 mg once nightly
  3. Decrease dose to 25 mg daily if moderate hepatic dysfunction

VII. Dosing: Tolcapone (Tasmar)

  1. Listed for historical reasons
  2. Acts both peripherally and centrally
  3. AVOID due to rare lethal hepatotoxicity
    1. If used, obtain written consent and obtain Liver Function Tests every 2-4 weeks for 6 months
  4. Start: 100 mg orally three times daily
  5. May increase to 200 mg orally three times daily
  6. Maximum: 600 mg/day

VIII. Adverse Effects

  1. Safety: Class
    1. Pregnancy Category C
    2. Unknown Safety in Pregnancy
  2. Orthostatic Hypotension
  3. Dyskinesias associated with Carbidopa/Levodopa may worsen
  4. Urine Discoloration (dark orange-brown)
  5. Diarrhea (esp. Tolcapone)
  6. Hepatotoxicity (Tolcapone)

IX. Drug Interactions

  1. Avoid with non-selective MAO Inhibitors
    1. Risk of Catecholamine toxicity
  2. Sedatives or CNS Depressants
    1. COMT Inhibitors may exaggerate CNS Depressant effects
  3. Caution with Catecholamines (risk of increased adrenergic effects)
    1. Isoproterenol
    2. Epinephrine
    3. Norepinephrine
    4. Dopamine
    5. Dobutamine

XI. References

  1. (2021) Med Lett Drugs Ther 63(1618): 25-32
  2. Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 46-7
  3. Hamilton (2020) Tarascon Pocket Pharmacopoeia

Images: Related links to external sites (from Bing)

Related Studies

Cost: Medications

entacapone (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
ENTACAPONE 200 MG TABLET Generic $0.43 each
ongentys (on 10/20/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
ONGENTYS 50 MG CAPSULE $21.63 each

Ontology: entacapone (C0165921)

Definition (NCI) A nitrocatechol compound with anti-parkinsonian property. Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), which catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure including dihydroxyphenylalanine (DOPA), catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. When administered in conjunction with dopaminergic agents such as L-DOPA, entacapone prevents the metabolism and inactivation of adjunct drugs, thereby increasing the bioavailability of these compounds by facilitating their passage across the blood-brain barrier.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C071192
SnomedCT 116116003, 387018000
English 2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)propenamide, entacapone, (E)-2-cyano-3-(3,4-dihydroxy-5-nitro-phenyl)-N,N-diethyl-prop-2-enamide, entacapone (medication), ENTACAPONE, entacapone [Chemical/Ingredient], Entacapone, Entacapone (product), Entacapone (substance)
Spanish entacapona (producto), entacapona (sustancia), entacapona

Ontology: tolcapone (C0246330)

Definition (NCI) A benzophenone derivative and a catechol-O-methyltransferase (COMT) inhibitor. Tolcapone selectively and reversibly inhibits COMT, an enzyme that catalyzes the metabolism of biologically active catechols and their hydroxylated metabolites by transferring the methyl group of S-adenosyl-L-methionine to the phenolic group of catechol-containing substrates. When given in conjunction with a peripheral dopa decarboxylase inhibitor and levodopa, tolcapone may prevent the metabolism of levodopa to 3-methoxy-4-hydroxy- L-phenylalanine (3-OMD) in the brain and peripheral tissues leading to increased bioavailability and enhancement of delivery to the central nervous system (CNS) of levodopa.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C066340
SnomedCT 108464002, 386851002
English 3,4-dihydroxy-5'-methyl-5-nitrobenzophenone, tolcapone, 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone, Methanone,(3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)-, tolcapone (medication), tolcapone [Chemical/Ingredient], Tolcapone, Tolcapone (product), Tolcapone (substance), TOLCAPONE
Spanish tolcapona (producto), tolcapona (sustancia), tolcapona

Ontology: Catechol-O-methyltransferase inhibitor (C0595267)

Definition (MSH) Compounds and drugs that inhibit or block the activity of CATECHOL O-METHYLTRANSFERASE enzymes. Drugs in this class are used in management of central nervous system disorders such as PARKINSON DISEASE.
Concepts Pharmacologic Substance (T121)
MSH D065098
SnomedCT 356845001, 372646000
English Catech-O-methyltransferas inhb, Catechol-O-methyltransferase inhibitor, Catechol O Methyltransferase Inhibitors, Catechol O-Methyltransferase Inhibitors, O-Methyltransferase Inhibitors, Catechol, Catechol-O-methyltransferase inhibitor (product), Catechol-O-methyltransferase inhibitor (substance), Catechol O-methyltransferase (COMT) Inhibitors
Spanish inhibidor de catecol-O-metiltransferasa (sustancia), inhibidor de catecol-O-metiltransferasa, inhibidor de la catecol-O-metiltransferasa (producto), inhibidor de la catecol-O-metiltransferasa (sustancia), inhibidor de la catecol-O-metiltransferasa

Ontology: Tasmar (C0595276)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C066340
English Tasmar, tolcapone (Tasmar), tasmar, Roche brand of tolcapone

Ontology: Comtan (C0876730)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C071192
English Comtan, comtan, Novartis brand of entacapone

Ontology: opicapone (C2933912)

Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C549349
English opicapone, 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide