| The symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and is converted to dopamine in the basal ganglia. This is thought to be the mechanism whereby levodopa relieves the symptoms of Parkinson's disease.
When levodopa is administered orally it is rapidly converted to dopamine by decarboxylation in peripheral tissues so that only a small portion of a given dose is transported unchanged to the CNS. For this reason, large doses of levodopa are required for adequate therapeutic effect and these may often be attended by nausea and other adverse reactions, some of which are attributable to dopamine formed in peripheral tissues.
Since levodopa competes with certain aminoacids, the absorption of levodopa may be impaired in some patients on a high protein diet.
Carbidopa inhibits decarboxylation of peripheral levodopa. It does not cross the blood-brain barrier and does not affect the metabolism of levodopa within the CNS. Since its decarboxylase inhibiting activity is limited to peripheral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain. Combined therapy with levodopa and carbidopa reduces the amount of levodopa required for optimum therapeutic benefit by about 75 to 80%, permits an earlier response to therapy, and also reduces the incidence of nausea, vomiting and cardiac arrhythmias. Combined therapy, however, does not decrease adverse reactions due to central effects of levodopa.
Following simultaneous administration of carbidopa and levodopa in man, both plasma levels and plasma half-life of levodopa are markedly increased over those found when the same dosage of levodopa is given alone, while plasma levels of dopamine and homovanillic acid are reduced or do not change. Nevertheless, the plasma levels vary greatly between patients.
Pyridoxine HCl (vitamin B6), in oral doses of 10 to 25 mg, may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine.
For the treatment of Parkinson's disease.
Sinemet is not recommended for the treatment of drug-induced extrapyramidal reactions.Although the administration of carbidopa permits control of Parkinson's disease with much lower doses of levodopa, there is no conclusive evidence at present that this is beneficial other than reducing nausea and vomiting, permitting more rapid titration, and providing a somewhat smoother response to levodopa. Carbidopa does not decrease adverse reactions due to central effects of levodopa. By permitting more levodopa to reach the brain, particularly when nausea and vomiting is not a dose-limiting factor, certain adverse CNS effects, e.g., dyskinesias, may occur at lower dosages and sooner during therapy with Sinemet than with levodopa |
