Tolcapone Levodopa

Drugs used to increase DA fundion are levodopa, tolcapone, entacapone, bromocriptine, pramipexole, ropinirole, and selegiline. Drugs that decrease ACh fundion are benztropine, trihexyphenidyl, and amantadine. The properties of each are described. 

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. 

Entacapone and tolcapon are selective and reversible catechol-O-methyltransferase (COMT) inhibitors which also inhibit the break down of levodopa to 3-methoxy-4-hydroxy-L-phenylalanine. 

Combined with levodopa and a decarboxylase inhibitor more stable levodopa levels can be obtained. Tolcapon has been withdrawn in many countries because of serious liverfunction disturbances, rhab-domyolysis and neuroleptic malignant syndrome. 

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. 

Geriatric Considerations - Summary Entacapone inhibits peripheral COMT and increases levodopa s effects. Itsprimary role is as adjunctive therapy to prolong the beneficial effects of levodopa and to decrease end-of-dose fluctuations in response to treatment. Concurrent use of levodopa is necessary for entacapone to be effective and unlike tolcapone, hepatic monitoring is not required. 

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... 

The pharmacologic effects of tolcapone and entacapone are similar, and both are rapidly absorbed, bound to plasma proteins, and metabolized before excretion. However, tolcapone has both central and peripheral effects, whereas the effect of entacapone is peripheral. The half-life of both drugs is approximately 2 hours, but tolcapone is slightly more potent and has a longer duration of action. Tolcapone is taken in a standard dosage of 100 mg three times daily some patients require a daily dose of twice that amount. By contrast, entacapone (200 mg) needs to be taken with each dose of levodopa, up to five times daily. 

Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesias, nausea, and confusion. It is often necessary to lower the daily dose of levodopa by about 30% in the first 48 hours to avoid or reverse such complications. Other adverse effects include diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, and an orange discoloration of the urine. Tolcapone may cause an increase in liver enzyme levels and has been associated... 

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. 

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. 

Entacapone and tolcapone are peripheral inhibitors of catechol-O-methyl-transferase (COMT). COMT metabolises levodopa to an inactive product so their use enables greater amounts of levodopa to reach the brain. They are licensed for use as an adjunct to co-beneldopa and co-careldopa for patients who experience end-of-dose deterioration and cannot be stabilised on the combined preparations alone. 

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... 

Tolcapone Study Group (1999) Efficacy and tolerability of tolcapone compared widi bromocripdne in levodopa treated parkinsonian padents. Mov Disord 14 38 44. 

In 40 patients (mean age 64 years, 22 men) who took tolcapone for 3-7 months and were given entacapone in dosages titrated to 800-2000 mg/day after a transition period of 3-6 months with co-beneldopa, the improvements in on and off times were less impressive than they had been with tolcapone and there were more adverse effects (3). One patient had diarrhea and orthostatic hypertension with both drugs, but another six patients had increased dyskinesias and hallucinations and one developed myoclonus. There was no evidence of liver toxicity with either drug. The authors pointed out that entacapone, unlike tolcapone, not only increases the half-life of levodopa but also its peak concentration, causing significantly enhanced levodopa-related adverse effects. There is therefore a paradox entacapone appears to be safer but overall causes more adverse effects. 

The introduction of tolcapone had a major impact on the management of Parkinson s disease, and within months tens of thousands of patients throughout the world were treated with it. Tolcapone was considered to be useful in prolonging the half-life of levodopa, thereby allowing dosage reduction and possibly smoother therapeutic responses. 

Sabate M, Bosch A, Pedros C, Figueras A. Vitiligo associated with tolcapone and levodopa in a patient with Parkinson s disease. Ann Pharmacother 1999 33(ll) 1228-9. 

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

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... 

FIGURE 20-7 Pharmacological preservation of L-DOPA and striatal dopamine. The principal site of action of inhibitors of catechol-O-methyltransferase (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. AAD, aromatic L-amino acid decarboxylase DA, dopamine DOPAC, 3,4-dihydroxyphenylacetic acid MAO, monoamine oxidase 3MT, 3-methoxyl-tyramine 3-O-MD, 3-O-methyl DOPA. 

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