Pharmacotherapeutic group: Dopa and dopa derivatives, levodopa and decarboxylase inhibitor
ATC Code: N04BA02
Levodopa is a precursor of dopamine, and is given as replacement therapy in Parkinson’s disease.
Carbidopa is a peripheral dopa decarboxylase inhibitor. It prevents metabolism of levodopa to dopamine in the peripheral circulation, ensuring that a higher proportion of the dose reaches the brain, where dopamine acts. A lower dose of levodopa can be used, reducing the incidence and severity of side effects.
Following oral dosing levodopa, in the absence of decarboxylase inhibitor, is rapidly but variably absorbed from the gastrointestinal tract. It has a plasma half-life of about 1 hour and is mainly converted by decarboxylation to dopamine, a proportion of which is converted to noradrenaline. Up to 30% is converted to 3-O-methyldopa which has a half-life of 9 to 22 hours. About 80% of levodopa is excreted in the urine within 24 hours mainly as homovanillic acid and dihydroxyphenylactic acid. Less than 1% is excreted unchanged.
Once in the circulation it competes with other neutral amino acids for transport across the blood brain barrier. Once it has entered the striatal neurones it is decarboxylated to dopamine, stored and released from presynaptic neurones. Because levodopa is so rapidly decarboxylated in the gastrointestinal tract and the liver, very little unchanged drug is available for transport into the brain. The peripheral decarboxylation reduces the therapeutic effectiveness of levodopa but is responsible for many of its side effects. For this reason levodopa is usually administered together with a peripheral decarboxylase inhibitor such as carbidopa, so that lower doses may be given to achieve the same therapeutic effect.
Carbidopa in the absence of levodopa, is rapidly but incompletely absorbed from the gastrointestinal tract following oral dosing. Following an oral dose approximately 50% is recorded in the urine, with about 30% of this as unchanged drug. It does not cross the blood brain barrier but crosses the placenta and is excreted in breast milk. Turnover of the drug is rapid and virtually all unchanged drug appears in the urine within 7 hours.
Carbidopa inhibits the peripheral decarboxylation of levodopa to dopamine but as it does not cross the blood brain barrier, effective brain levels of dopamine get produced with lower levels of levodopa therapy reducing the peripheral side effects, noticeably nausea and vomiting and cardiac arrhythmias.
Levomed is well established in medical use. Preclinical data is broadly consistent with clinical experience (For reproductive toxicity, see section 4.6).
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