Levodopa COMT inhibitors

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). 

The main clinical use of COMT inhibitors is as adjunct (or additional adjunct) in the therapy of Parkinson s disease. The standard therapy of Parkinson s disease is oral L-dopa (as a drug levodopa) given with a dopa decarboxylase (DDC) inhibitor (e.g. carbidopa and benserazide), which does not reach the brain. When the peripheral DDC is inhibited, the concentration of 3-O-methyldopa (3-OMD), a product of COMT, in plasma is many times that of L-dopa. Since the half-life of 3-OMD is about 15 h, compared to about 1 h for L-dopa, the concentration of 3-OMD remains particularly high during chronic therapy, especially if new slow release L-dopa preparations are used. A triple therapy (L-dopa plus DDC inhibitor plus COMT-inhibitor) will... 

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. 

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... 

Levodopa is a better substrate for COMT than MAO and when given with an ExCDDI most of it is o-methylated to OMD (Fig. 15.4). Recently COMT inhibitors have been developed which act either just peripherally (entacopone) or centrally as well... 

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. 

WARNING Cases of fulminant liver failure resulting in death have occurred Uses Adjunct to carbidopa/levodopa in Parkinson Dz Action COMT inhibitor slows levodopa metabolism Dose 100 mg PO tid w/ 1st daily levodopa/carbidopa dose, then dose 6 12 h later -1- w/ renal impair Caution [C, ] Contra Hqjatic impair, w/ nonselective MAOI Disp Tabs SE Constipation, XCTOstomia, vivid dreams, hallucinations, anorexia, N/D, orthostasis, liver failure, Rhabdomyolysis Interactions T Effects OF CNS dqjressants, SSRIs, TCAs, warfarin, EtOH t risk of hypotensive crisis W/ nonselective MAOIs (phenelzine, tranylc5 promine) EMS Has been associated w/ liver failure and death may experience hallucinations concurrent EtOH use can T CNS dqjression T effects of warfarin severe D is common sevoal wks afto starting OD May cause NA and dizziness... 

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. 

A recently introduced class of drugs for the treatment of parkinsonism is the catechol-O-methyl transferase (COMT) inhibitors. COMT metabolizes catechol compounds, including dopamine and levodopa (see Chapter... 

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. 

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. 

Presented in Fig. 9.3 is an example of a model used to extrapolate the 6-month trial results of a COMT inhibitor (entacapone) used in combination with levodopa versus levodopa alone in the treatment of Parkinson s disease. This particular model is an example of a Markov model... 

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... 

In patients with severe parkinsonism and long-term complications of levodopa therapy such as the on-off phenomenon, a trial of treatment with a COMT inhibitor or rasagiline may be helpful. Regulation of dietary protein intake may also improve response fluctuations. Deep brain stimulation is often helpful in patients who fail to respond adequately to these measures. Treating patients who are young or have mild parkinsonism with rasagiline may delay disease progression and merits consideration. 

Lamberti P, Zoccolella S, Iliceto G, Armenise E, Fraddosio A, de Mari M, Livrea P. Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson s disease patients. Mov Disord 2005 20 69-72. 

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 primary problem associated with COMT inhibitors is an initial increase in dyskinesias.10 This problem may be due to the fact that the COMT inhibitor is allowing more levodopa to reach the brain, and that the levodopa dosage needs to be lowered accordingly. Other side effects include nausea, diarrhea, dizziness, and muscle pain/cramps. 

Olanow CW Stocchi F. COMT inhibitors in Parkinson s disease can they prevent and/or reverse levodopa-induced motor complications Neurology. 2004 62(suppl 1) S72-S81. 

Sometimes one may have a new opportunity to ameliorate disease with adjunct—or supplementary or additional—therapy. An example would be the use of a drug called carbidopa in Parkinson disease (PD). PD patients have reduced levels of dopamine in the brain, and treatment with levodopa (l-DOPA) increases the concentration of dopamine in the brain. Unfortunately, before it reaches the brain, some of the levodopa is converted into dopamine by the enzyme called COMT in the periphery. Carbidopa is a COMT inhibitor that stops this breakdown of levodopa in the periphery so that more of the levodopa crosses the blood-brain barrier and enters the brain where it can be effective once converted by enzymes in the brain into dopamine. 

Various strategies have been devised to overcome these problems. Controlled release preparations of levodopa tend to be associated with an inadequate initial response and disabling dyskinesia at the end of the dose. A more effective approach appears to be the use of a COMT inhibitor, e.g. entacapone, which can sometimes aUay early end-of-dose deterioration without causing dyskinesia. This is now the main indication for its use. In any event, many patients with Parkinson s disease take at least two and sometimes more drugs at frequent intervals each day, an outcome that tends to rule their lives. 

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