COMT inhibitors Catechol-O-methyltransferase

A newer classification of antiparkinson drugs is the catechol-O-methyltransferase (COMT) inhibitors. Examples of the COMT inhibitors are entacapone (Comtan) and tolcapone (Tasmar). 

When additional relief is needed, the addition of levodopa (L-dopa) should be considered. With the development of motor fluctuations, addition of a catechol-O-methyltransferase (COMT) inhibitor should be considered to extend L-dopa duration of activity. 

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. 

Chemical Class Catechol-O-methyltransferase (COMT) inhibitor nitrocatechol Clinical Pharmacology ... 

Modeling is an analytical tool that can be used to extrapolate shorter term clinical results, such as days of improved symptoms in Parkinson s disease patients in a study over 6 months, to longer time periods. A model was developed to extrapolate the results of a 6-month trial in which patients received either levodopa alone or levodopa plus the catechol-o-methyltransferase (COMT) inhibitor entacapone. Comtan (entacapone) is designed to reduce the metabolism of levodopa in peripheral tissue and vessels so that more of the drug is available in the brain at a more constant rate than is seen with levodopa alone. The 6-month clinical trial produced clinical results that allow us to establish entacapone s effect on the OFF time associated with levodopa therapy. OFF time refers to a re-emergence of symptoms prior to the next scheduled levodopa dose. Entacapone reduces the OFF time and increases the ON time of levodopa therapy. 

The dopamine prodrug levodopa remains the treatment option for PD, however, long-term levodopa therapy leads to dyskinesia. Alternatives for early PD therapy include monoamine oxidase B inhibitors, dopamine agonists, catechol-O-methyltransferase (COMT) inhibitors, and amantadine (Hauser and Zesiewicz,... 

Administration of a catechol-O-methyltransferase (COMT) inhibitor in conjunction with a drug that increases catecholamine levels would dramatically increase levels of catecholamines, leading to a hypertensive crisis, cardiac insufficiency, and possibly death. 

Which statement is an advantage of administering the catechol-O-methyltransferase (COMT) inhibitor entacapone (Comtan) to a client diagnosed with Parkinson s disease ... 

The catechol-O-methyltransferase (COMT) inhibitors work by inhibiting the peripheral metabolism of levodopa by COMT. Note that this enzyme is the major metabolising enzyme for levodopa when a decarboxylase inhibitor (e.g. benserazide) is being used. 

These drugs are thought to prolong the effect of levodopa by blocking an enzyme, catechol-O-methyltransferase (COMT), which eliminates dopamine. When given with levodopa, the COMT inhibitors increase the plasma concentrations and duration of action of levodopa... 

Pharmacology Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), which alters 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. 

Entacapone is a reversible inhibitor of peripheral catechol-O-methyltransferase (COMT). It is given at the dose of 200 mg with each dose of levodopa. It prolongs the action of levodopa and reduces synthesis of 3-O-methyldopa which is presumed to antagonize dopa passage through the blood-brain barrier. 

Mannisto, P. T Kaakkola, S. Catechol-O-methyltransferase (COMT) Biochanistry, molecular biology, pharmacology, and clinical efhcacy of the new selective COMT inhibitors, Pharmacol. Rev. 1999, 57, 593-628. 

In a classic paper, Snapper synthesized an ilimaquinone-agarose-affinity resin (30), which was incubated with homogenized bovine liver and then washed extensively.93 Proteins retained by the resin were separated by gel electrophoresis, yielding six main protein bands. Amino acid sequencing of these bands revealed three proteins involved in the activated methyl cycle — SAHase, S-adenosylmethionine synthetase (SAM synthetase), and catechol-O-methyltransferase (COMT) — as well as three unrelated proteins. Subsequent enzymatic assays established that ilimaquinone is a competitive inhibitor of SAHase, but has little effect on the activity of SAM synthetase or COMT. The authors noted that a consequence of SAHase inhibition would be the intracellular accumulation of SAH, which is a potent feedback inhibitor of methyltransferases. These results support the assertion that methylation events play an important role in cellular secretory events and vesicle-mediated processes. The study also highlighted the problem of nonspecific interactions as only one of the six isolated proteins was shown to interact in any way with the natural product. 

Some MAO is also present outside the dopaminergic neurone (6). DA can be inactivated by the enzyme catechol-O-methyltransferase (COMT), which is believed to be localised outside the presynaptic neurone. Tropolone is an inhibitor of COMT (7). 

NA has its action terminated by uptake. The tricyclic drug desipramine is an example of a potent inhibitor of this uptake mechanism as well as the newer SNRIs (venlafaxine) and cocaine (5). NA or DA present in a free state within the presynaptic terminal can be degraded by the enzyme MAO, which appears to be located in the outer membrane of mitochondria. Pargyline is an effective inhibitor of MAO (6). NA can be inactivated by the membrane-bound enzyme catechol-O-methyltransferase (COMT). Tropolone is an inhibitor of COMT. The normetanephrine (NM) formed by the action of COMT on NE can be further metabolised by MAO 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. 

Mechanism of action Inhibitors of catechol-O-methyltransferase (COMT), the enzyme that converts levodopa to 3-O-methyldopa (30MD). Increased plasma levels of 30MD are associated with poor response to levodopa, partly because the compound competes with levodopa for active transport into the CNS. 

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). 

Another mechanism that could contribute to the rapid disappearance of DA is metabolism by catechol O-methyltransferase (COMT) or monoamine oxidase (MAO). If this were the case, then the addition of a metabolic inhibitor would cause a decrease in the disappearance rate. Neither the addition of an MAO inhibitor, pargyline, nor a COMT inhibitor had a significant effect on the disappearance rate of DA in vivo [49]. Taken together these data indicate that the disappearance of DA observed with FSCV and microelectrodes is due solely to uptake of DA by the DA transporter. The presynaptic mechanisms involved in DA uptake are depicted in Figure 5. 

Lave, T. Dupin, S. Schmitt, M. Kapps, M. Meyer, J. Morgenroth, B. Chou, R.C. Jaeck, D. Coas-solo, P. Interspecies scaling of tolcapone, a new inhibitor of catechol-O-methyltransferase (COMT). Use of in vitro data from hepatocytes to predict metabolic clearance in animals and humans, Xenobiotica, 1996, 26, 839-851. 

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