COMT inhibitors, actions

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... 

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... 

Destruction or removal of transmitter from site of action Tolcapone (COMT inhibitor) Phenelzine (MAO inhibitor) Tricyclic antidepressants (inhibit neuronal transport) Physostigmine (cholinesterase inhibitor)... 

Codrugs are also named mutual prodrugs. Their design consists of the linking, in a unique molecule, of at least two different synergistic drugs that are released in vivo at the desired site of action. An example is found in the association of L-dopa to the catechol 0-methyltransferase (COMT) inhibitor entacapone (Figure 36.24). ... 

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). 

After five years of treatment about half of patients will experience the drug becoming less effective and a gradual recurrence of symptoms, especially hypokinesia, occurs. Another type of deterioration is the shortening of action of each dose with time ( end of dose deterioration ) and unpredictable fluctuations ( on-off effect ) in response to treatment, which can happen quite abmptly. It is not known why these effects occur, but they may be due to advance of the disease process. End of dose deterioration can be alleviated to a certain extent by the use of modified release preparations of levodopa or by the concurrent use of catechol-o-methyl transferase (COMT) inhibitors, for example enta-capone. COMT inhibitors prevent the peripheral breakdown of levodopa by an enzyme, COMT. 

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... 

Inhibitors of MAO (e.g., pargyline and nialamidej can cause an increase in the concentration ofNE, DA, and 5-HT in the brain and other tissues accompanied by a variety of pharmacological effects. No striking pharmacological action in the periphery can be attributed to the inhibition of COMT. However, the COMT inhibitors entacapone and tocapone are efficacious in the therapy of Parkinson s disease (see Chapter 20). 

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). 

COMT inhibitor enhances levodopa access to CNS neurons adjunctive use in Parkinson s disease. Tox exacerbates levodopa effects. Tolcapone is similar in action and use but may be hepatotoxic. 

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). 

FIGURE 11.11. Mechanisms of actions of levodopa, dopamine receptor agonists, COMT inhibitors, and MAO-B inhibitors. 

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. 

COMT is, for many of the same reasons as with chorismate mutase, well suited for the study with computational techniques. The reaction mechanism it catalyzes is the same mechanism that operates in the absence of the enzyme, specifically, the S 2 mechanism, facilitating comparison of the bare solution-phase reaction with the catalyzed reaction. The subsfiate and cofactor do not covalendy bind to the enzyme, so that defining the QM region and the MM region should be relatively uncomplicated. Lasdy, the X-ray crystal structure of COMT bound with the inhibitor 3,5-dinitrocatechol has been determined with a resolution of 2 kP An interesting twist to this enzyme is that the active site includes a metal cation, Mg " ". This crystal structure allows for a natural starting point for computational exploration of the means of the catalytic action of COMT. The rate acceleration provided by COMT is substantial the reaction is 10 times faster within the enzyme than in solution. " ... 

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... 

TERMINATION OF THE ACTIONS OF CATECHOLAMINES The actions of NE and Epi are terminated by (1) reuptake into nerve terminals by NET (2) dilution by diffusion out of the junctional cleft and uptake at end organs and extraneuronal sites by ENT, OCTl, and OCT2. Subsequent to uptake, the catecholamines are subject to metabolic transformation by MAO and catechol-0-methyltransferase (COMT). In addition, catecholamines are metabolized by sulfotransferases (see Chapter 3). Termination of action by a powerful degradative enzymatic pathway, such as that provided by AChE in cholinergic transmission, is absent from the adrenergic system. Inhibitors of neuronal reuptake of catecholamines (e.g., cocaine, imipramine) potentiate the effects of the... 

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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