Tolcapone Dopamine

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. 

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. 

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. 

A final pharmacological strategy for treatment of Parkinson s disease comes from enzyme inhibition. This was initally done with an MAO inhibitor, L-deprenyl (selegiline, Eldepryl), but more recent drugs have become available that are COMT inhibitors. L-Deprenyl is an inhibitor of MAOB, which is the form of MAO selective to dopamine. Thus, it may increase the amount of available dopamine for release. Second, it may protect dopamine neurons by reducing the oxidative stress concomitant with dopamine metabolism (Olanow 1997). Third, L-deprenyl is metabolized into amphetamine and methamphetamine, which may contribute to their antiparkinsonian effects. Unlike other treatments for Parkinson s disease, L-deprenyl seems to slow the progression of the disease. Tolcapone (Tasmar) is a COMT inhibitor, which prevents extracellular breakdown of dopamine. 

Another approach to the therapy of Parkinson s disease involves the use of enzyme inhibitors. For example, inhibition of the enzyme monoamine oxidase B (MAO-B) by selegiline (4.105) improves the duration of L-DOPA therapy because it inhibits the breakdown of dopamine but not of NE. Likewise, inhibitors of catechol-O-methyl-transferase (COMT) can also be exploited as agents for the treatment of Parkinson s disease. L-DOPA and dopamine become inactivated by methylation the COMT enzyme responsible for this metabolic transformation can be clocked by agents such as entacapone (4.106) or tolcapone (4.107), allowing higher levels of L-DOPA and dopamine to be achieved in the corpus striamm of the brain. 

Preclinical and clinical results indicate that both entacapone and tolcapone are orally active, nontoxic and well-tolerated drugs. The adjuvant L- dopa therapy with DDC inhibitor + COMT-inhibitor (+ possible MAO inhibitor) may substitute for the present double therapy in the treatment of Parkinson s disease [27-40]. Together with the development of dopamine agonists and MAO inhibitors, the inhibition of COMT will constitute major progress in the treatment of Parkinson s disease in the near future. 

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. 

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 (Fig. 1.3) was designed as an inhibitor of the enzyme catechol O-methyl-transferase, and is useful in the L-DOPA treatment of Parkinson s disease [10]. In avoiding the methylation of L-DOPA as well as that of dopamine, it prolongs the beneficial activities of these molecules. 

Catechol-O-methyltransferase inhibitors (entacapone, tolcapone) reduce the peripheral breakdown of dopamine. 

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... 

DOPAMINERGICS - ENTACAPONE, TOLCAPONE DOPAMINERGICS -SELEGIUNE Possible risk of severe hypertensive reactions Theoretical risk due to additive inhibitory effect on dopamine metabolism Manufacturers recommend limiting the dose of selegiline to a maximum of 10 mg... 

Tolcapone is an inhibitor of catchol-O-methyltransferase, which catalyses a relatively minor pathway of dopamine metabolism. It therefore enhances the action of dopamine. 

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. 

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. 

Tolcapone and entacopone are reversible inhibitors of catechol-O-methyltransferase (COMT), which normally transfers a methyl group from the metabolic intermediate S-adenosyl-L-methionine to the 3-phenolic moiety of dopamine, resulting in inactivation of the neurotransmitter (Fig. 25.2). Therefore, because tolcapone and entacopone block the activity of COMT, they prolong the activity of dopamine. Because COMT also inactivates levodopa, COMT Inhibitors prolong the action of levodopa. (Fig. 25.2). 

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. 

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