Dopamine carbidopa

MAO converts dopamine to DOPAC (3,4-dihydrox-yphenylacetic acid), which can be further metabolized by COMT to form homovanillic acid (HVA). HVA is the main product of dopamine metabolism and the principal dopamine metabolite in urine. Increased neuronal dopaminergic activity is associated with increases in plasma concentrations of DOPAC and HVA. COMT preferentially methylates dopamine at the 3 -hydroxyl position and utilizes S-adenosyl-L-methio-nine as a methyl group donor. COMT is expressed widely in the periphery and in glial cells. In PD, COMT has been targeted since it can convert l-DOPA to inactive 3-OMD (3-O-methyl-dopa). In the presence of an AADC inhibitor such as carbidopa, 3-OMD is the major metabolite of l-DOPA treatment. 

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. 

Dopaminergic drug are drug that affect the dopamine content of the brain. These drag include levodopa (Larodopa), carbidopa(Ladosyn), amantadine (Symmetrel),... 

Levodopa is a chemical formulation found in plants and animals that is converted into dopamine by nerve cells in the brain. Levodopa does cross die blood-brain barrier, and a small amount is dien converted to dopamine. This allows the drug to have a pharmacologic effect in patients witii Parkinson s disease (Pig. 29-1). Combining levodopa witii another drug (carbidopa) causes more levodopa to reach die brain. When more levodopa is available, the dosage of levodopa may be reduced. Carbidopa has no effect when given alone. Sinemet is a combination of carbidopa and levodopa and is available in several combinations (eg, Sinemet 10/100 has 10 mg of carbidopa and 100 mg of levodopa Sinemet CR is a time-released version of die combined drugs). 

Ach, acetylcholine CNS, central nervous system CD, carbidopa COMT, catechol-O-methyltransferase D1, a class of dopamine receptors which includes D, and D5 subtypes D2, a class of dopamine receptors which includes D2, D3, and D4 subtypes DA, dopamine LD, levodopa MAO, monoamine oxidase MD, maintenance dose NMDA, N-methyl-D-aspartate. 

Carbidopa, a dopa-decarboxylase inhibitor, is added to the levodopa in order to decrease the peripheral conversion of levodopa to dopamine. It does not cross the blood-brain barrier and does not interfere with levodopa conversion in the brain. Concomitant administration of carbidopa and levodopa allows for lower levodopa doses and minimizes levodopa peripheral side effects such as nausea, vomiting, anorexia, and hypotension. For most patients, at least 75 to 100 mg daily of carbidopa is required to adequately block dopamine decarboxylase in the peripheral metabolism of levodopa in most patients. Taking extra carbidopa may reduce nausea related to initiating levodopa.8,16... 

L-dopa is effective in the treatment of Parkinson s disease, a disorder characterised by low levels of dopamine, since L-dopa is metabolised into dopamine. However, this biosynthesis normally occurs in both the peripheral nervous system (PNS) and the central nervous system CNS. The related drug carbidopa inhibits aromatic L-amino acid decarboxylase only in the periphery, since it does not cross the blood-brain barrier. So, when carbidopa is given with L-dopa, it reduces the biosynthesis of L-dopa to dopamine in the periphery and, thus, increases the bioavailability of L-dopa for the dopaminergic neurons in the brain. Hence, carbidopa increases the clinical efficacy of L-dopa for Parkinsonian patients. 

The answer is c. (idardman, p 510.) Carbidopa is an inhibitor of aromatic L-amino acid decarboxylase. It cannot readily penetrate the central nervous system (CNS) and, thus, decreases the decarboxylation of L-clopa in the peripheral tissues. This promotes an increased concentration of L-clopa in the nigrostriatum, where it is converted to dopamine. In addition, the effective dose of L-dopa can be reduced... 

The answer is d. (Katz ng, pp 464-4670 Adding carbidopa decreases the amount of dopamine that is formed peripherally from dopa by dopa decarboxylase Depression, psychosis, and other psychiatric adverse effects of L-dopa are mediated by CN5 dopamine, so adding carbidopa does not make them less likely The combination of L-dopa and carbidopa reduces the extracerebral metabolism of L-dopa, resulting in decreased peripheral adverse effects. 

Patients sustain convulsions and neurological deterioration. The urine contains low levels of the metabolites of serotonin, norepinephrine and dopamine. The reductase also plays a role in the maintenance of tetrahydrofolate levels in brain, and some patients have had low folate levels in the serum and CNS. Treatment has been attempted with tryptophan and carbidopa to improve serotonin homeostasis and with folinic acid to replete diminished stores of reduced folic acid. This therapy is sometimes effective. Diagnosis involves assay of DHPR in skin fibroblasts or amniotic cells. Phenylalanine hydroxylase activity is normal. 

The most important alternatives to levodopa therapy are direct-acting dopamine receptor agonists, such as ropinirole,pramipexole, or pergolide (Fig. 46-5). A number of studies have shown that use of these agents may help to delay the need for use of levodopa/carbidopa. This has... 

In the CNS and elsewhere, L-dopa is converted by L-amino acid decarboxylase (L-AAD) to dopamine. In the periphery, L-AAD can be blocked by administering carbidopa or benserazide, which does not cross the blood-... 

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. 

There is less risk of developing motor complications from monotherapy with dopamine agonists than from L-dopa. Because younger patients are more likely to develop motor fluctuations, dopamine agonists are preferred in this population. Older patients are more likely to experience psychosis from dopamine agonists therefore, carbidopa/L-dopa may be the best initial medication in elderly patients, particularly if cognitive problems or dementia is present. 

Six patients with Parkinson s disease were withdrawn from their antiparkinsonian medications (L-DOPA/carbidopa, bromocriptine, or lisuride) (Rabey et al. 1992, 1993). After 12 hours off medication, the subjects ate 250 g of cooked fava beans. Significant improvements in motor symptoms were noted, comparable to those seen with 125 mg of L-DOPA and 12.5 mg of carbidopa. In fact, three subjects developed severe dyskinesias after fava ingestion, akin to those seen after larger doses of pharmaceutical L-DOPA. Plasma levels of L-DOPA increased after fava ingestion in a manner comparable to that seen with administration of oral L-DOPA. These results suggest that the L-DOPA contained in fava beans was transported into the CNS and converted to dopamine. In five nonparkinsonian, healthy volunteers, a similar increase in plasma L-DOPA was observed after fava ingestion, although much lower. The difference in plasma L-DOPA between normal volunteers and parkinsonian patients is apparently due to a residual effect of carbidopa in the subjects with Parkinson s disease. Without carbidopa, the L-DOPA from fava is rapidly converted to dopamine in the blood stream and never crosses the blood-brain barrier. 

There is one further elaboration on this therapeutic scheme well worth knowing about. Dopa decarboxylase occurs in peripheral tissues and blood as well as in the brain. Close to 90% of administered L-dopa can be converted to dopamine by this enzyme before it gets into the brain. That is not good since a huge fraction of the L-dopa is lost. This problem was overcome in a very neat way. Carbidopa is an inhibitor of dopa decarboxylase that does not penetrate the blood-brain barrier ... 

Carbidopa therefore inhibits the conversion of L-dopa to dopamine in the peripheral tissues and the blood while leaving it unchanged in the brain. The combination of L-dopa and carbidopa is marketed as Sinemet and was the treatment of choice for parkinsonism for many years. Note the structural similarity between carbidopa and L-dopa. Carbidopa looks enough like L-dopa to occupy the L-dopa site on the decarboxylase. At the same time, the subtle structural differences render carbidopa indifferent to the enzyme. It is an inhibitor, not a substrate. 

Dopamine-Boosting Medications. Levodopa/carbidopa (Sinemet), bromocriptine (Parlodel), pramipexole (Mirapex), and ropinirole (Requip) increase dopamine nenrotransmission in the brain by one or another mechanism. These medications do not reliably induce sleep, and in some patients are activating. They are certainly not true sedative-hypnotics. They are most often used by neurologists to treat Parkinson s disease. 

Administration of levodopa plus carbidopa (or benserazide) remains the most effective treatment, but does not provide benefit beyond 3-5 y and is followed by gradual loss of symptom control, on-off fluctuations, and development of orobuccofacial and limb dyskinesias. These long-term drawbacks of levodopa therapy may be delayed by early monotherapy with dopamine receptor agonists. Treatment of advanced disease requires the combined administration of antiparkinsonian agents. 

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. 

Mecfianism of Action Levodopa is converted to dopamine in the basal ganglia thus increasing dopamine concentration in brain and inhibiting hyperactive cholinergic activity. Carbidopa prevents peripheral breakdown of levodopa, allowing more levo-dopa to be available for transport into the brain. Therapeutic Effect Reduces tremor and other symptoms of Parkinson s disease. 

Pharmacokinetics Carbidopa is rapidly and completely absorbed from the GI tract. Widely distributed. Excreted primarily in urine. Levodopa is converted to dopamine. Excreted primarily in urine. Half-life 1-2 hr (carbidopa) 1-3 hr (levodopa). 

Geriatric Considerations - Summary Levodopa is a precursor to dopamine and is converted to dopamine in the CNS. Carbidopa decreases peripheral conversion and increases CNS concentrations of levodopa. While sustained-release forms may be helpful in decreasing the wearing-off of levodopa effectiveness, there maybe little advantage over immediate-release preparations. This drug combination is often used as initial therapy for Parkinson s disease. 

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