Tolcapone Carbidopa

Levodopa adjunct DOPA decarboxylase inhibitor COMT inhibitors Carbidopa Tolcapone Entacapone... 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

The COMT inhibitors are used as adjuncts to levodopa7 carbidopa in Fhrkinson s disease Tolcapone is a potent COMT inhibitor that easily crosses the blood-brain barrier. However, the drug is associated with liver damage... 

Tolcapone (Tasmar) and entacapone (Comtan) are used only in conjunction with carbidopa/L-dopa to prevent the peripheral conversion of L-dopa to dopamine (increasing the area under the curve of L-dopa by approximately 35%). Thus, on time is increased by about 1 hour. These agents significantly decrease off time and decrease L-dopa requirements. Concomitant use of nonselective MAO inhibitors should be avoided to prevent inhibition of the pathways for normal catecholamine metabolism. 

The starting and recommended dose of tolcapone is 100 mg three times daily as an adjunct to carbidopa/L-dopa. Its use is limited by the potential for fatal liver toxicity. Strict monitoring of liver function is required, and tolcapone should be discontinued if liver function tests are above the upper limit of normal or any signs or symptoms suggestive of hepatic failure exist. It should be reserved for patients with fluctuations that have not responded to other therapies. 

Because entacapone has a shorter half-life, 200 mg is given with each dose of carbidopa/L-dopa up to eight times a day. Dopaminergic adverse effects may occur and are managed easily by reducing the carbidopa/L-dopa dose. Brownish-orange urine discoloration may occur (as with tolcapone), but there is no evidence of hepatotoxicity from entacapone. 

The two COMT inhibitors in clinical use are tol-capone (Tasmar) and entacapone fComtan). They are used in combination with levodopa-carbidopa. In patients with motor fluctuations, they increase the on time. Adverse effects are similar to those observed with levodopa-carbidopa alone. Tolcapone therapy can cause fatal hepatotoxicity and so should be used only in patients who do not respond to other therapies. Patients taking tolcapone require close monitoring of liver enzymes for signs of hepatic changes. 

Adjunctive treatment of Parkinson s disease PO Initially, 100-200 mg 3 times a day concomitantly with each dose of carbidopa and levodopa. Maximum 600 mg/day Dosage in hepatic impairment Patients with moderate to severe cirrhosis should not receive more than 200 mg tolcapone 3 times a day... 

COMT inhibitors Entacapone Tolcapone Help prevent breakdown of dopamine in peripheral tissues allows more levodopa to reach the brain. Useful as an adjunct to levodopa/carbidopa administration may improve and prolong effects of levodopa. 

The following are new, non-ergot dopamine agonists that have been approved for the treatment of Parkinson s disease. Pramipexole and ropinirole are effective as first-line and adjunctive therapy, whereas tolcapone should only be used as an adjunct in patients on levodopa/carbidopa. 

Tolcapone [TOLE ka pone] is a nitrocatechol derivative that represents a new class of anti-Parkinson s drugs. It selectively and reversibly inhibits both peripheral and central catechol-O-methyl-transferase (COMT) (Figure 8.11). Normally, the methylation of levo-dopa by COMT to 3-O-methyldopa is a minor pathway for levodopa metabolism. However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS. Inhibition of COMT by tolcapone leads to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater concentrations of brain dopamine. Tolcapone has been demonstrated to reduce the frequency of the on-off phenomenon. 

Adverse effects Diarrhea is the most common side effect of tolcapone. As expected, /evocfopa-related adverse effects increase when tolcapone is added. These include postural hypotension, nausea, sleep disorders, anorexia, dyskinesias, and hallucinations. Most seriously, fulminating hepatic necrosis is associated with tolcapone use. Baseline and frequent, regular determinations of hepatic serum enzymes are suggested by the manufacturer. Any elevations above normal are cause for discontinuation. Because of the hepatotoxicity, tolcapone should only be used as an adjunct in patients on levodopa/carbidopa who are experiencing symptom fluctuations. 

LEVODOPA, SELEGILINE, POSSIBLY RASAGILINE, ENTACAPONE, TOLCAPONE MAOIs Risk of adrenergic syndrome -hypertension, hyperthermia, arrhythmias - and dopaminergic effects with selegiline Levodopa and related drugs are precursors of dopamine. Levodopa is predominantly metabolized to dopamine, and a smaller proportion is converted to epinephrine and norepinephrine. Effects are due to inhibition of MAOI, which breaks down dopamine and sympathomimetics Avoid concurrent use. Onset may be 6-24 hours after ingestion. Carbidopa and benserazide, which inhibit dopa decarboxylase that converts L-dopa to dopamine, is considered to minimize this interaction. However, MAOIs should not be used in patients with Parkinson s disease on treatment with levodopa. Imipramine and amitriptyline are considered safer by some clinicians... 

May combine tolcapone with both the immediate and sustained-release form of levodopa/carbidopa Obtain vital signs assess for hypotension. 

Finally, MAO-B inhibitors such as selegiline and the COMT inhibitors tolcapone (Tasmar, Roche) and entacapone (Comtan, Novartis) extend the action of L-dopa. Entacapone is now available in fixed-dose combinations with carbidopa/L-dopa as well (Stalevo, Novartis). 

Muscarinic receptor blockers may improve muscle rigidity and tremor in Parkinsons disease but result in very little improvement in bradykinesia thus, they are mainly considered as adjunctive to the use of drugs that improve dopaminergic function. Selegiline is the inhibitor of MAO type B, and pramipexole is a non-ergot DA receptor agonist. Carbidopa inhibits peripheral AAAD (dopa decarboxylase) tolcapone is an inhibitor of COMT. Levodopa causes a high incidence of dose-dependent dyskinesias that are not slow in onset, like tardive dyskinesia that results from chronic administration of DA receptor blockers. 

Tolcapone is an antiparkinson agent that inhibits catechol-O-methyl transferase (COMT), thus blocking the degradation of catechols including dopamine and levodopa. This may lead to more sustained levels of dopamine and consequently a more prolonged antiparkinson s effect. It is indicated as an adjunct to levodopa/carbidopa for the management of signs and symptoms of Parkinson s disease. 

Two COMT inhibitors presently are available for this use in the United States, tolcapone (Tasmar) and entaca-pone (Comtan). Both these agents have been shown in double-blind trials to reduce the clinical symptoms of wearing off in patients treated with levodopa/carbidopa. Although the magnitude of their clinical effects and mechanisms of action are similar, they differ with respect to... 

Two COMT inhibitors are available for this use, tolcapone (tasmar) and entacapone (comtan). Tolcapone has a relatively long duration of action, allowing for administration two to three times a day, and appears to act by both central and peripheral inhibition of COMT. The duration of action of entacapone is short, around 2 hours, so it usually is administered simultaneously with each dose 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 observed in patients treated with levodopa/carbidopa alone and include nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations. An adverse effect associated with tolcapone is hepatotoxicity tolcapone should be used only in patients who have not responded to other therapies and with appropriate monitoring of hepatic transaminases. Entacapone has not been associated with hepatotoxicity and requires no special monitoring. Entacapone also is available in fixed-dose combinations with levodopa/carbidopa (stalevo). 

DA agonists levodopa, bromocriptine, 1 pergolide, pramipexole 1 MAO-B inhibitor selegOine 1 AAAD inhibitor carbidopa I M blockers benztropine, trihexiphenidyl j COMT inhibitor tolcapone 1 Amantadine MAOIs phenelzine, tranylcypromine TCAs amitriptyline, imipramine, clomipramine SSRIs fluoxetine, paroxetine, sertraline Others bupropion, mirtazapine, trazodone, venlafaxine... 

Tolcapone may be of value in patients being treated with levodopa-carbidopa because it... 

Tolcapone is an inhibitor of catechol-O-methyltransferase used adjunctively in patients treated with levodopa-carbidopa The drug decreases the formation of 3-O-methyldopa (30MD) from levodopa. TTiis has the effect of improving patient response to levodopa, partly by increasing levodopa levels and also by decreasing competition between 30MD and levodopa for active transport by carrier mechanisms involved in transport across the blood-brain barrier. The answer is (B). 

In one study, healthy subjects were given desipramine 25 mg three times daily for 3 days then 50 mg three times daily for 10 days. For the last 5 days they were also given levodopa/carbidopa 100/25 mg three times daily and either a placebo or tolcapone 200 mg three times daily. The addition of tolcapone to combined treatment with levodopa/carbidopa and desipramine did not lead to any changes in haemodynamics or catecholamine levels, nor to any changes in desipramine pharmacokinetics. ... 

Entacapone and tolcapone increase the AUC of levodopa given with benserazide or carbidopa. This may require a reduction in the levodopa dose to avoid symptoms of dopamine excess when first starting the COMT inhibitor. Tolcapone increases the levels of benserazide, but neither entacapone nor tolcapone alters carbidopa pharmacokinetics. 

Entacapone and tolcapone have been shown to increase the AUC and prolong the elimination half-life of levodopa (as levodopa/benser-azide or levodopa/carbidopa) without altering the maximum levodopa level. COMT inhibitors can therefore improve the clinical condition of patients with Parkinson s disease, which is mainly seen as a decrease in off time. However, as levodopa levels are raised, there may be an accompanying increase in the adverse effects oflevodopa (e.g. dyskinesias, nausea, vomiting, orthostatic hypotension, hallucinations). " ... 

The effects of COMT inhibitors on the pharmacokinetics of dopa-decar-boxylase inhibitors has also been studied. Neither entacapone nor tolcapone altered the pharmacokinetics of carbidopa. However, tolcapone increased the serum levels of benserazide in patients with Parkinson s disease. The benserazide levels remained within the usual range in patients taking levodopa products containing benserazide 25 mg and tolcapone 200 mg three times daily. However, with a 50-mg dose of benserazide the AUC of benserazide was increased 4.8-fold with standard-release preparation and 2.3-fold with a controlled-release preparation. ... 

Sedek G, Jorga K, Schmitt Bums RS, Leese P. Effect of tolcapone on plaana levodopa concentrations after coadministration with levodopa/carbidopa to healthy volunteers. Clin... 

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