Dopamine Entacapone

Antiparkinsonian agents Bromocriptine Dopamine Entacapone Levodopa Peroxide Pramipexole Rasagiline derivatives Lasdostigil m30... 

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. 

Inhibitors of catechoI-O-methyl-transferase (COMT). L-Dopa and dopamine become inactivated by methyla-tion. The responsible enzyme can be blocked by entacapone, allowing higher levels of L-dopa and dopamine to be achieved in corpus striatum. 

Drugs metabolized by COMT Administer drugs known to be metabolized by COMT (ie, isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, methyidopa, apomorphine, isoetherine, bitolterol) with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, arrhythmias, and excessive changes in blood pressure. 

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. 

This approach is also applied successfully in Parkinson s disease. Drugs such as entacapone inhibit the activity of the enzyme catechol-omethyltransferase (COMT), which is involved in degradation of the neurotransmitter dopamine, and thus increase and prolong the availability of dopamine in the synaptic cleft. Inhibition of COMT and substitution of L-Dopa are often combined in the therapy of Parkinson patients. 

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. 

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... 

Entacapone inhibits catechol-O-methyltransferase (COMT), one of the principal enzymes responsible for the metabolism of dopamine the action of levodopa is thus prolonged. It is most effective for patients with early end-of-dose deterioration, and allows them to take levodopa at 3- or 4-hourly intervals, giving a more predictable and useful response. Entacapone is preferred to long-acting preparations of levodopa whose main disadvantage is their slow onset of action. It can increase the dyskinesias seen in the late stages of Parkinson s disease. 

Entacapone is an inhibitor of catechol-O-methyltrans-ferase, which catalyses a relatively minor pathway of dopamine metaboUsm. It therefore enhances the action of dopamine. 

Clinically important, potentially hazardous interactions with amitriptyline, amoxapine, amphetamines, bupropion, citalopram, clomipramine, cyproheptadine, desipramine, dextroamphetamine, dextromethorphan, diethylpropion, dopamine, doxepin, entacapone, ephedra, ephedrine, epinephrine, fluoxetine, fluvoxamine, ginseng, imipramine, levodopa, mazindol, meperidine, methamphetamine, nefazodone, nortriptyline, paroxetine, phendimetrazine, phentermine, phenylephrine, pizotifen, propoxyphene, protriptyline, pseudoephedrine, rizatriptan, sertraline, sibutramine, sumatriptan, sympathomimetics, tramadol, tricyclic antidepressants, trimipramine, tryptophan, venlafaxine, zolmitriptan... 

The antiparkinsonian agents (except trihexyphenidyl) inhibited both Ap and aS oligomer formations, with dopamine, levodopa, prami-pexole, and entacapone displaying the strongest in vitro activity. 

Drugs that exert their effect indirectly and require a functional background The catechol O-methyltransferase inhibitor entacapone, the effect of which is due to the accumulation of nonmetabolized dopamine... 

Carbidopa inhibits peripheral decarboxylation of levodopa, making more levodopa available for transport to the brain. Levodopa is a precursor of dopamine, which is deficient in parkinsonism patients. Entacapone inhibits the enzyme that metabohzes levodopa (catechol-O-methyltransferase [COMT]), which increases and prolongs levodopa plasma levels. The combination is indicated in the treatment of idiopathic Parkinson disease (1) to substitute (with equivalent strength of each of the 3 immediate-release components) for the previously administered individual products, (2) to replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients experience signs and symptoms of end-of-dose wearing-off (only for patients taking a total daily dose of levodopa of 600 mg or less and not experiencing dyskinesias). 

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. 

---