L-DOPA/Levodopa

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. 

L-DOPA/Levodopa Dopa Decarboxylase Dopamine System Dopamine- 3-hydroxylase Dopaminergic Neurotoxicity Dose... 

Dopamine synthesis in dopaminergic terminals (Fig. 46-3) requires tyrosine hydroxylase (TH) which, in the presence of iron and tetrahydropteridine, oxidizes tyrosine to 3,4-dihydroxyphenylalanine (levodopa.l-DOPA). Levodopa is decarboxylated to dopamine by aromatic amino acid decarboxylase (AADC), an enzyme which requires pyri-doxyl phosphate as a coenzyme (see also in Ch. 12). 

Since Parkinson s disease arises from a deficiency of DA in the brain, the logical treatment is to replace the DA. Unfortunately, dopamine replacement therapy cannot be done with DA because it does not cross the blood-brain barrier. However, high doses (3-8 g/day, orally) of L(-)-DOPA (levodopa), a prodrug of DA, have a remarkable effect on the akinesia and rigidity. The side effects of such enormous doses are numerous and unpleasant, consisting initially of nausea and vomiting and later of uncontrolled movements (limb dyskinesias). The simultaneous administration of carbidopa (4.75) or benserazide (4.76)—peripheral DOPA decarboxylase inhibitors—allows the administration of smaller doses, and also prevents the metabolic formation of peripheral DA, which can act as an emetic at the vomiting center in the brainstem where the blood-brain barrier is not very effective and can be penetrated by peripheral DA. 

Pharmacologic strategies for dopaminergic therapy of Parkinson s disease. Drugs and their effects are highlighted (see text). MAO, monoamine oxidase COMT, catechol-O-methyltransferase DOPAC, dihydroxyphenylacetic acid L-DOPA, levodopa 3-OMD, 3-0-methyldopa. 

Dopamine, abbreviated DA, is a biosynthetic compound and neurotransmitter produced in the body from the amino acid tyrosine by several pathways. It is synthesized in the adrenal gland where it is a precursor to other hormones (see Epinephrine) and in several portions of the brain, principally the substantia nigra and hypothalamus. Dopamine is stored in vesicles in the brain s presynaptic nerve terminals. It is closely associated with its immediate precursor, L-Dopa (levodopa). Casmir Funk (1884—1967) first synthesized Dopa in racemic form... 

Many symptoms of manganese toxicity disappear after the victim is removed from the source of exposure. L-Dopa (levodopa) can reverse some symptoms, but complete recovery is not expected. Calcium-EDTA (the calcium disodium salt of ethylenediaminetetraacetic acid) will help improve an acute manganese-induced psychosis. 

Another example is to be found in the drug therapy of Parkinson s disease. The use of L-dopa (levodopa) as a prodrug for dopamine has already been described. However, to be effective, large doses of L-dopa (3-8 g per day) are required, and over a period of time these dose levels lead to side-effects such as nausea and vomiting. L-Dopa is susceptible to the enzyme dopa decarboxylase and as a result, much of the L-dopa administered is decarboxylated to L-dopamine before it reaches the central nervous system (Fig. 8.21). 

Logic would dictate that increasing brain levels of DA should ameliorate symptoms permanently (a cure ), or at least temporarily. Direct parenteral DA administration is useless since the compound does not penetrate the blood-brain barrier (BBB) (however, see Chapter 10 for cardiovascular applications). It was shown that oral dosing with L-DOPA (levodopa, Dopar) could successfully act as a pro-drug to the extent it entered the brain (on a specific carrier) and was then decarboxylated to DA there. The clinical results in terms of decreased tremors and rigidity were dramatic. However, there were complications... 

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