Levodopa Amino acids

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

The production of dopamine and norepinephrine in your brain begins with the amino acid tyrosine, which is obtained from your diet. Tyrosine is converted to the amino acid levodopa, or L-DOPA, by the en2yme tyrosine hydroxylase. One very important cofactor is iron. Without iron, tyrosine hydroxylase fails to function normally. People with anemia have reduced body levels of iron and, as consequently, may have reduced tyrosine hydroxylase activity and thus reduced production of norepinephrine and dopamine. The decreased brain levels of these important neurotransmitters may lead to a slight depression, although most likely only in people with severe anemia. Generally, in a normal healthy person, the production of these two neurotransmitters is not easily affected by the contents of the diet. 

Intropin ) is a catecholamine that occurs in the mammalian CNS, in several higher plants and alga. It is a major central neurotransmitter, a dopamine receptor agonist and a SYMPATHOMIMETIC, with predominantly (Pi-subtype) p-ADRENOCEPTOR AGONIST actions. It Can be used as a cardiac STIMULANT and ANTIHYPOTENSIVE in cardiogenic hypotension. Its precursor amino acid, levodopa, is used as an ANTIPARKINSONIAN AGENT. 

The seminal report by Cotzias et al. (59) in 1967, describing dramatic symptomatic improvement of parkinsonian patients given high oral doses of racemic dopa, was followed by more clinical trials that confirmed the efficacy and safety of the levo isomer. The effectiveness of levodopa requires penetration of the drug into the CNS and its subsequent enzymatic decarboxylation to dopamine. Dopamine does not cross the blood-brain barrier, because it exists primarily in its protonated form under physiologic conditions (pKa = 10.6 [NH2]) (60). The precursor amino acid levodopa, however, is less basic (pKa = 8.72 [NH2]) and, thus, can penetrate the CNS. 

Parkinson s disease is characterized by a deficiency of dopamine (3.43a) in the brain. Although administration of this neurotransmitter is useless, because it does not penetrate the blood—brain barrier, a very successful clinical procedure is to give oral doses of the corresponding amino acid, levodopa (3.43b) (Cotzias, Van Woert and Schiffer, 1967). The acid enters the brain on a specific carrier and is decarboxylated there. 

Dopamine replacanent - This most effective treatment for Parkinson s disease is supplied by the naturally-occurring amino acid levodopa (I, L-3, -dihydroxyphenylalanine " ). In the usual oral doses of 2.5 to 6 g daily it enters the brain and is deceurboxylated to form dopamine (II)... 

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. 

While a number of drugs, e.g. a-methyl dopa, inhibit the enzyme they have little effect on the levels of brain DA and NA, compared with inhibition of tyrosine hydroxylase and they also affect the decarboxylation of other amino acids. Some compounds, e.g. a-methyl dopa hydrazine (carbidopa) and benserazide, which do not easily enter the CNS have a useful role when given in conjunction with levodopa in the treatment of Parkinsonism (see Chapter 15) since the dopa is then preserved peripherally and so more enters the brain. 

FIGURE 29-2. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma and brain compartments by an active transport mechanism. Levodopa is metabolized by dopa decarboxylase, monoamine oxidase, and catechol-O-methyltransferase. Carbidopa does not cross the blood-brain barrier. Large, neutral amino acids in food compete with levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport across the brain (plasma compartment to brain compartment). Food and anticholinergics delay gastric emptying resulting in levodopa degradation in the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes before or 60 minutes after meals. 

Levodopa, a dopamine precursor, is the most effective agent for PD. Patients experience a 40% to 50% improvement in motor function. It is absorbed in the small intestine and peaks in the plasma in 30 to 120 minutes. A stomach with excess acid, food, or anticholinergic medications will delay gastric emptying time and decrease the amount of levodopa absorbed. Antacids decrease stomach acidity and improve levodopa absorption. Levodopa requires active transport by a large, neutral amino acid transporter protein from the small intestine into the plasma and from the plasma across the blood-brain barrier into the brain (Fig. 29-2). Levodopa competes with other amino acids, such as those contained in food, for this transport mechanism. Thus, in advanced disease, adjusting the timing of protein-rich meals in relationship to levodopa doses may be helpful. Levodopa also binds to iron supplements and administration of these should be spaced by at least 2 hours from the levodopa dose.1,8,16,25... 

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). 

L-Dopa. Dopamine itself cannot penetrate the blood-brain barrier however, its natural precursor, L-dihydroxy-phenylalanine (levodopa), is effective in replenishing striatal dopamine levels, because it is transported across the blood-brain barrier via an amino acid carrier and is subsequently decarboxy-lated by DOPA-decarboxylase, present in striatal tissue. Decarboxylation also takes place in peripheral organs where dopamine is not needed, likely causing undesirable effects (tachycardia, arrhythmias resulting from activation of Pi-adrenoceptors [p. 114], hypotension, and vomiting). Extracerebral production of dopamine can be prevented by inhibitors of DOPA-decarboxylase (car-bidopa, benserazide) that do not penetrate the blood-brain barrier, leaving intracerebral decarboxylation unaffected. Excessive elevation of brain dopamine levels may lead to undesirable reactions, such as involuntary movements (dyskinesias) and mental disturbances. 

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. 

If levodopa is administered alone, it is extensively metabolized by L-aromatic amino acid decarboxylase in the liver, kidney, and gastrointestinal tract. To prevent this peripheral metabolism, levodopa is coadministered with carbidopa (Sinemet), a peripheral decarboxylase inhibitor. The combination of levodopa with carbidopa lowers the necessary dose of levodopa and reduces peripheral side effects associated with its administration. 

Dopamine does not cross the blood-brain barrier and if given into the peripheral circulation has no therapeutic effect in parkinsonism. However, (-)-3-(3,4-dihydroxyphenyl)-L-alanine (levodopa), the immediate metabolic precursor of dopamine, does enter the brain (via an L-amino acid transporter, LAT), where it is decarboxylated to dopamine (see Figure 6-5). Several noncatecholamine dopamine receptor agonists have also been developed and may lead to clinical benefit, as discussed in the text that follows. 

Dopa is the amino acid precursor of dopamine and norepinephrine (discussed in Chapter 6). Its structure is shown in Figure 28-3. Levodopa is the levorotatory stereoisomer of dopa. 

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... 

Cimbura and Kofoed (50),mentioned earlier, used GLC to separate amphetamine and methamphetamine after acetylation with acetic anhydride in methanol. Derivatives were extracted using diethyl ether and chromatographed op columns of either 3% OV-17, OV-1, or SE-30. Column temperature was 160°C. They also reported the chromatographic determination of acetylated morphine on 3% SE-30, OV-1, or OV-17 at temperatures of 220°C. Cruickshank et al.(21) separated 21 amino acids as their trifluoroacetylated methyl esters. The column was 5% neopentyl glycol succinate on Gas Chrom P. Column temperatures were both isothermal and programmed 65°C for 20 min at 1.5°C/min then 2°C/min until 42.5 min then 4°C/min until 60 min then isothermal until about 75 min (see Figure 12.2). Chang et al. (19), used BSA/pyridine to form the TMS derivatives of levodopa, methyldopa, tyrosine. 

Amantadine Unclear may inhibit the effects of excitatory amino acids in the basal ganglia. May be used alone during early/mild stages or added to drug regimen when levodopa loses effectiveness. 

Tyrosine is converted to dopa by the rate-limiting enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin, and is inhibited by a-methyltyrosine. Dopa is decarboxylated to dopamine by L-aromatic amino acid decarboxylase, which requires pyridoxal phosphate (vitamin B6) as a coenzyme. Carbidopa, which is used with levodopa in the treatment of parkinsonism, inhibits this enzyme. Dopamine is converted to norepinephrine by dopamine P-hydroxylase, which requires ascorbic acid (vitamin C), and is inhibited by diethyldithiocarbamate. Norepinephrine is converted to epinephrine by phenylethanolamine A -methyltransferase (PNMT), requiring S-adeno-sylmethionine. The activity of PNMT is stimulated by corticosteroids. 

Dopamine is synthesized in the terminals of dopaminergic fibers originating with the amino acid tyrosine and, subsequently, L-dihydroxyphenylalanine (L-dopa or levodopa), the rate-limiting metabolic precursor of dopamine. Fortunately, L-dopa is significantly less polar than dopamine and can gain entry into the brain via an active process mediated by a carrier of aromatic amino acids. Although L-dopa is itself basically pharmacologically inert, therapeutic effects can be produced by its decarboxylation to dopamine within the CNS. 

Absorption and metabolism The drug is absorbed rapidly from the small intestine (when empty of food). Levodopa has an extremely short half-life (1 to 2 hours), which causes fluctuations in plasma concentration. This may produce fluctuations in motor response ( on-off phenomenon), which may cause the patient to suddenly lose normal mobility and experience tremors, cramps, and immobility. Ingestion of meals, particularly if high in protein content, interferes with the transport of levodopa into the CNS. Large, neutral amino acids (for example, leucine and isoleucine) compete with levodopa for absorption from the gut and for transport across the blood-brain barrier. Thus levodopa should be taken on an empty stomach, typically 45 minutes before a meal. Withdrawal from the drug must be gradual. 

Correct choice = A. Parkinsonian patients show a deficiency of dopaminergic neurons, without a decrease in cholinergic actions. Elevated levels of dopamine can lead to behavorial disorders. Levodopa and large, neutral amino acids share a transport system that is needed to enter the brain thus high protein diets may lead to elevated levels of circulating amino acids, resulting in a decrease in levodopa uptake. Dyskinesia is usually seen with longer-term therapy and is dose-related and reversible. The mechanism of action of deprenyl is not understood. 

High-protein diets decrease the bioavailability of theophylline (high-carbohydrate diets increasing the bioavailability of theophylline) and reduce the effects of levodopa and methyldopa (from competition of amino acids for absorption),... 

Levodopa ( dopa stands for dihydroxyphenyl-alanine) is a natural amino acid precursor of dopamine. The latter carmot be used because it is rapidly metabolised in the gut, blood and liver by monoamine oxidase and catechol-O-methyltrans-... 

Another way round the problem of membrane permeability is to design a prodrug which can take advantage of a carrier protein in the cell membrane, such as the one responsible for carrying amino acids into a cell. The best known example of such a prodrug is levodopa (Fig. 8.13). 

Levodopa is even more polar and seems an unlikely prodrug. However, it is an amino acid and as such can make use of the special arrangements made in order to move amino acids across the blood-brain barrier. Amino acids are essential building blocks for all cells, but are incapable of crossing hydrophobic membranes by themselves. There is, however, a process by which amino acids can be shuttled through membranes such as the blood-brain barrier. This... 

BCAAs) is superior to standard protein solutions that are higher in aromatic amino acids (AAAs)J Metabolism of AAAs into false neurotransmitters that penetrate the blood-brain barrier (which itself may be perturbed in patients with HE) has been implicated as a cause of HE. A number of clinical trials have evaluated the use of BCAAs in the treatment of HE, with conflicting results. Reviews of these trials have also arrived at different conclusions. BCAAs may have a role in the malnourished patient with cirrhosis who is intolerant of protein supplementation, but the current data do not justify routine use of BCAAs for the treatment of HE. Impairment of dopaminergic transmission has also been proposed to cause HE, but trials with bromocriptine and levodopa failed to provide any benefit and are not recommended. ... 

Benserazide (BZ), 2-amino-3-hydroxy-A, -[(2,3,4-trihydroxyphenyl) methyl] propane hydrazide is an irreversible inhibitor of peripheral L-aromatic amino acid decarboxylase (AADC). The decarboxylase inhibitor drugs, e.g., carbidopa and benserazide, inhibit dopamine production outside the brain and permit direct deliveiy of dopamine (LD metabolite) to the brain. This synergistic therapy also minimizes the side effects such as nausea and vomiting induced by levodopa.1 2 Benserazide at the recommended therapeutic dose does not cross the blood-brain barrier to any significant degree. Synergistic effect of levodopa and benserazide reduces the required dose of levodopa for the optimal and earlier therapeutic response.3... 

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