Carbidopa in Parkinson’s disease

Adjunct to levodopa/carbidopa in Parkinson s disease longer acting than bromocriptine... 

As adjund to Ievodopa/carbidopa in Parkinson s disease As adjund to Ievodopa/carbidopa in Parkinson s disease... 

Pergolide (Permax) D1 and D2 agonist. More potent than bromocriptine. Adjunct to levodopa/carbidopa in Parkinson s Disease patients. Dyskinesia, nausea, rhinitis, constipation, dizziness, hallucinations, somnolence... 

Carbidopa (4.75), a hydrazine analog of a-methyldopa, is an important DOPA decarboxylase inhibitor. It is used to protect the DOPA that is administered in large doses in Parkinson s disease (section 4.4.4) from peripheral decarboxylation. DOPA concentrations in the CNS will therefore increase without requiring the administration of extremely high, toxic doses of DOPA. The exclusive peripheral mode of action of carbidopa is due to its ionic character and inability to cross the blood-brain barrier. Because of this effect, carbidopa is co-administered with DOPA in a single tablet formulation as a first-line therapy for Parkinson s disease. Benserazide (4.76) has similar activity. 

The etiology of progressive death of dopaminergic neurons in substantia nigra of Parkinson s disease brains remains unclear. Dopamine deficiency in Parkinson s disease is commonly treated with L-dopa and carbidopa, a periphera dopa decarboxylase inhibitor (Sinemet). Since its introduction, L-dopa has been shown to be effective in treating Parkinson s disease. However, high concentrations of L-dopa produce side effects such as psychosis, on-off effects, abnormal involuntary movements, and akinetic crisis. 

Block G, Liss C, Reines S, Irr J, Nibbelink D. Comparison of immediate-release and controlled release carbidopa/levodopa in Parkinson s disease a multicenter 5-year study. The CR First Study Group. Eur Neurol 1997 37 23-27. 

Q5 Present the rationale for prescribing carbidopa in combination with L-dopa in Parkinson s disease. 

Parkinson s disease is caused by the oxidative stress-induced loss of dopaminergic neurons and can be effectively treated with levo-dopa in combination with dopa decarboxylase inhibitors such as carbidopa or catechoi-0-methyltransferase inhibitors such as tolca-pone. Levodopa is well known to increase the life spans of patients with Parkinson s disease. It may do this by enhancing brain dopamine levels and inhibiting tyrosine hydroxylase, which produces oxygen radicals. Several dopamine receptor agonists are available for use in Parkinson s disease and are extensively used in patients suffering from the adverse effects of levodopa. Anticholinergics such as trihexyphenidyl are also used in Parkinson s disease. 

Nelson MV, Berchou RC, LeWitt PA, et al. Pharmacodynamic modeling of concentration-effect relationships after controlled release carbidopa/ levodopa (Sinemet CR4) in Parkinson s disease. Neurology 1990 40 70-74. 

Carbidopa (Lodosyn) Diminishes decarboxylation of l-dopa in periphery tissues. Improve effect of l-dopa, decrease required dose of l-dopa by about 75%, i nausea and vomiting. Adjunct in Parkinson s disease. Does not alleviate most side effects caused by levodopa. Has no known toxicities when administered alone. 

Lcibcrman, A., Goodgold, A.. Jonas, S. and Leibowitz, M. (1975) Comparison of dopa decarboxylase inhibitor (carbidopa) combined with levodopa and levodopa alone in Parkinson s disease. Neurology, 25, 911. 

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. 

The main clinical use of COMT inhibitors is as adjunct (or additional adjunct) in the therapy of Parkinson s disease. The standard therapy of Parkinson s disease is oral L-dopa (as a drug levodopa) given with a dopa decarboxylase (DDC) inhibitor (e.g. carbidopa and benserazide), which does not reach the brain. When the peripheral DDC is inhibited, the concentration of 3-O-methyldopa (3-OMD), a product of COMT, in plasma is many times that of L-dopa. Since the half-life of 3-OMD is about 15 h, compared to about 1 h for L-dopa, the concentration of 3-OMD remains particularly high during chronic therapy, especially if new slow release L-dopa preparations are used. A triple therapy (L-dopa plus DDC inhibitor plus COMT-inhibitor) will... 

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). 

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. 

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. 

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. 

Parkinson s disease As an adjunct to levodopa/carbidopa to treat patients with idiopathic Parkinson s disease who experience the signs and symptoms of end-of-dose wearing-off. The effectiveness of entacapone has not been systematically evaluated in patients with idiopathic Parkinson s disease who do not experience end-of-dose wearing-off. ... 

Parkinson s disease Adjunct in the management of parkinsonian patients being treated with levodopa/carbidopa who exhibit deterioration in the quality of their response to this therapy. 

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. 

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. 

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... 

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