Tidomet/Tidomet CR Mechanism of Action

Antiparkinsonism.
Pharmacology: Pharmacodynamics: Tidomet: Levodopa, a naturally occurring amino acid, is the immediate precursor of the neurotransmitter dopamine. The actions of levodopa are mainly those of dopamine.
Unlike dopamine, levodopa readily enters the CNS and is used in the treatment of conditions, such as Parkinson's disease, that are associated with depletion of dopamine in the brain. Levodopa is rapidly decarboxylated by peripheral enzymes so that very little unchanged drug is available to cross the blood-brain barrier for central conversion into dopamine.
Consequently, levodopa is usually given with a peripheral dopa-decarboxylase inhibitor such as carbidopa to increase the proportion of levodopa that can enter the brain. This enables the dosage of levodopa to be reduced and may diminish peripheral adverse effects, such as nausea and vomiting and cardiac arrhythmias, by blocking the peripheral production of dopamine. It may also provide a more rapid response at the start of therapy.
Tidomet CR: The symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in such patients because dopamine does not cross the blood brain barrier. However, levodopa, the precursor of dopamine, does cross the blood brain barrier and is converted to dopamine in the brain.
When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only small portion of a given dose is transported unchanged in the central nervous system. 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. Decarboxylase inhibiting activity of Carbidopa is limited to extracerebral tissues; hence the administration of carbidopa with levodopa makes more levodopa available to transport to the brain.
Controlled release preparation is designed to release Carbidopa 50 mg and Levodopa 200 mg over 4 to 6 hours period, there is a less variation in plasma levodopa levels than with the conventional formulation.
Pharmacokinetics: Tidomet: Levodopa is rapidly absorbed from the gastrointestinal tract by an active transport system. Most absorption takes place in the small intestine; absorption is very limited from the stomach, and since decarboxylation may take place in the stomach wall, delays in gastric emptying may reduce the amount of levodopa available for absorption. Peak plasma concentrations are achieved within 2 hours of oral doses. Levodopa is about 10 to 30% bound to plasma proteins. Levodopa is rapidly decarboxylated by the enzyme aromatic L-amino acid decarboxylase, mostly in the gut, liver, and kidney, to dopamine, which is metabolized in turn, principally to dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Other routes of metabolism include O-methylation, transamination, and oxidation, producing a variety of minor metabolites including noradrenaline and 3-O-methyldopa; the latter may accumulate in the CNS due to its relatively long half-life. The elimination half-life of levodopa itself is reported to be about 30 to 60 minutes.
Unlike dopamine, levodopa is actively transported across the blood-brain barrier, but because of the extent of peripheral decarboxylation very little is available to enter the CNS unless it is given with a peripheral dopa-decarboxylase inhibitor. In the presence of a peripheral dopa-decarboxylase inhibitor the major route of metabolism of levodopa becomes the formation of 3-O-methyldopa by the enzyme catechol-O-methyltransferase.
About 80% of an oral dose of levodopa is excreted in the urine within 24 hours, mainly as dihydroxyphenylacetic and homovanillic acids. Only small amounts of levodopa are excreted unchanged in the faeces.
Levodopa crosses the placenta and is distributed into breast milk.
Tidomet CR: 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. Tidomet in controlled release preparation have an apparent half life of levodopa may be prolonged because of continuous absorption. The mean time to peak concentration of levodopa after a single dose of co-careldopa controlled release preparation is about 2 hours as compared to 0.5 hours after conventional administration. The maximum concentration and extent availability of levodopa after a single dose of co-careldopa controlled release is about 35% and 70-75% respectively compared to conventional formulation. At steady state, carbidopa bioavailability from co-careldopa controlled release is approximately 58% relative to that from conventional formulation.