Treatment carbidopa

Table 15 gives a sampling of other pharmaceuticals derived from hydraziae. Cefazolin, a thiadiazole tetrazole derivative, is one of the most widely used antibacterial dmgs in U.S. hospitals (see Antibiotics, P-LACTAMs). Procarbazine, an antineoplastic, is a monomethyUiydrazine derivative (220). Fluconazole has shown some promise in the treatment of AIDS-related fungal infections. Carbidopa is employed in the treatment of Parkinson s disease. FurazoHdone is a veterinarian antibacterial. 

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. 

During early treatment witii levodopa and carbidopa, adverse reactions are usually not a problem. But as the disease progresses, die response to die drug may become less, and the period of time tiiat each dose is effective begins to decrease, leading to more frequent doses, and more adverse reactions. 

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. 

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. 

Carbidopa An inhibitor of aromatic L-amino acid decarboxylase used with L-dopa in the treatment of Parkinson s disease. 

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. 

Other causes of PKU secondary to defective tetrahydrobiopterin synthesis include GTP cyclohydrolase deficiency and 6-pyravoyltetrahydrobiopterin synthase deficiency. Patients with either defect have psychomotor retardation, truncal hypotonia with limb hypertonia, seizures and a tendency to hyperthermia. The intravenous administration of BH4 may lower blood phenylalanine levels but this cofactor may not readily cross the blood-brain barrier. Treatment with synthetic pterin analogs or supplementation with tryptophan and carbidopa may prove more efficacious, particularly if treatment is started early in life. 

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. 

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. 

Parkinsonian patients receiving levodopa/carbidopa therapy who demonstrate a deteriorating response to this treatment 10 mg per day administered as divided doses of 5 mg each taken at breakfast and lunch. There is no evidence that additional benefit will be obtained from the administration of higher doses. 

After 2 to 3 days of treatment, attempt to reduce the dose of levodopa/carbidopa. A reduction of 10% to 30% appears typical. Further reductions of levodopa/carbidopa may be possible during continued selegiline therapy. 

Parkinson cf/sease Adjunctive treatment to levodopa/carbidopa in the management of the signs and symptoms of Parkinson disease. 

Transferring patients not currently treated with entacapone tablets from carbidopa/levodopa to carbidopa, levodopa, and entacapone combination tablets In patients with Parkinson disease who experience the signs and symptoms of end-of-dose wearing-off on their current standard release carbidopa/levodopa treatment, clinical experience shows that patients with a history of moderate or severe dyskinesias or taking more than 600 mg/day of levodopa are likely to require a reduction in daily levodopa dose when entacapone is added to their treatment. Maintenance therapy Individualize therapy and adjust for each patient according to the desired therapeutic response. 

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. 

Geriatric Considerations - Summary Levodopa is a percursor to dopamine and is converted to dopamine in the CNS. Clinical effectiveness is increased by taking in combination with carbidopa, a dopa decarboxylase inhibitor. This combination is often the initial treatment for Parkinson s disease. 

Adjunctive treatment for parkinsonism PO Initially, 5 mg in the morning. May increase up to 10 mg/day in divided doses, such as 5 mg at breakfast and lunch, given concomitantly with each dose of carbidopa and levodopa. 

Adjunctive treatment of Parkinson s disease PO Initially, 100-200 mg 3 times a day concomitantly with each dose of carbidopa and levodopa. Maximum 600 mg/day Dosage in hepatic impairment Patients with moderate to severe cirrhosis should not receive more than 200 mg tolcapone 3 times a day... 

Oppenheim G Estrogen in the treatment of depression neuropharmacological mechanisms. Arch Gen Psychiatry 43 569-573, 1986 Oren DA, Moul DE, Schwartz PJ, et al A controlled trial of levodopa plus carbidopa in the treatment of winter seasonal affective disorders a test of the dopamine hypothesis. J Chn Psychopharmacol 14 196-200, 1994 Ormandy G, Jope RS Analysis of the convulsant-potentiating effects of lithium in rats. Exp Neurol 111 356-361, 1991... 

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. 

Levodopa and peripheral dopa-decarboxylase inhibitor, carbidopa or benserazide in the treatment of parkinsonism. 

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