Mechanism of Action
Parkinson's disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous system affecting the mobility and control of the skeletal muscular system. Its characteristic features include resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility.
Current evidence indicates that 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 apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease.
When levodopa is administered orally it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. For this reason, large doses of levodopa are required for adequate therapeutic effect and these may often be accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed in extracerebral tissues.
Since levodopa competes with certain amino acids for transport across the gut wall, 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 central nervous system.
Since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain.
Patients treated with levodopa therapy for Parkinson's disease may develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia, and akinesia. The advanced form of motor fluctuations (‘on-off’ phenomenon) is characterized by unpredictable swings from mobility to immobility. Although the causes of the motor fluctuations are not completely understood, in some patients they may be attenuated by treatment regimens that produce steady plasma levels of levodopa.
SINEMET CR contains either 50 mg of carbidopa and 200 mg of levodopa, or 25 mg of carbidopa and 100 mg of levodopa in a sustained-release dosage form designed to release these ingredients over a 4- to 6-hour period. With SINEMET CR there is less variation in plasma levodopa levels than with SINEMET* (Carbidopa-Levodopa), the conventional formulation. However, SINEMET CR (Carbidopa-Levodopa) Sustained-Release is less systemically bioavailable than SINEMET (Carbidopa-Levodopa) and may require increased daily doses to achieve the same level of symptomatic relief as provided by SINEMET (Carbidopa-Levodopa).
In clinical trials, patients with moderate to severe motor fluctuations who received SINEMET CR did not experience quantitatively significant reductions in ‘off’ time when compared to SINEMET (Carbidopa-Levodopa). However, global ratings of improvement as assessed by both patient and physician were better during therapy with SINEMET CR than with SINEMET (Carbidopa-Levodopa). In patients without motor fluctuations, SINEMET CR, under controlled conditions, provided the same therapeutic benefit with less frequent dosing when compared to SINEMET (Carbidopa-Levodopa).
Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid.
Elimination half-life of levodopa in the presence of carbidopa is about 1.5 hours. Following SINEMET CR, the apparent half-life of levodopa may be prolonged because of continuous absorption.
In healthy elderly subjects (56-67 years old) the mean time-to-peak concentration of levodopa after a single dose of SINEMET CR 50-200 was about 2 hours as compared to 0.5 hours after standard SINEMET (Carbidopa-Levodopa). The maximum concentration of levodopa after a single dose of SINEMET CR was about 35% of the standard SINEMET (Carbidopa-Levodopa) (1151 vs. 3256 ng/mL). The extent of availability of levodopa from SINEMET CR was about 70-75% relative to intravenous levodopa or standard SINEMET (Carbidopa-Levodopa) in the elderly. The absolute bioavailability of levodopa from SINEMET CR (relative to I.V.) in young subjects was shown to be only about 44%. The extent of availability and the peak concentrations of levodopa were comparable in the elderly after a single dose and at steady state after t.i.d. administration of SINEMET CR 50-200. In elderly subjects, the average trough levels of levodopa at steady state after the CR tablet were about 2 fold higher than after the standard SINEMET (Carbidopa-Levodopa) (163 vs. 74 ng/mL).
In these studies, using similar total daily doses of levodopa, plasma levodopa concentrations with SINEMET CR fluctuated in a narrower range than with SINEMET (Carbidopa-Levodopa). Because the bioavailability of levodopa from SINEMET CR relative to SINEMET (Carbidopa-Levodopa) is approximately 70-75%, the daily dosage of levodopa necessary to produce a given clinical response with the sustained-release formulation will usually be higher.
The extent of availability and peak concentrations of levodopa after a single dose of SINEMET CR 50-200 increased by about 50% and 25%, respectively, when administered with food.
At steady state, the bioavailability of carbidopa from SINEMET Tablets is approximately 99% relative to the concomitant administration of carbidopa and levodopa. At steady state, carbidopa bioavailability from SINEMET CR 50-200 is approximately 58% relative to that from SINEMET.
Pyridoxine hydrochloride (vitamin B6), in oral doses of 10 mg to 25 mg, may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine.