Twindopa Mechanism of Action

Pharmacotherapeutic group: Dopaminergic agents. Dopa and dopa derivatives. Levodopa and decarboxylase inhibitor. ATC code: N04BA02.
Pharmacology: Pharmacodynamics: 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.
Levodopa and Carbidopa tablets are useful in relieving many of the symptoms of parkinsonism, particularly rigidity and bradykinesia. It is frequently helpful in the management of tremor, dysphagia, sialorrhoea, and postural instability associated with Parkinson's disease and syndrome.
When response to levodopa alone is irregular, and signs and symptoms of Parkinson's disease are not controlled evenly throughout the day, substitution of Levodopa and Carbidopa tablets usually reduces fluctuations in response. By reducing some of the adverse reactions produced by levodopa alone, Levodopa and Carbidopa tablets permits more patients to obtain adequate relief from the symptoms of Parkinson's disease.
Pharmacokinetics: Following oral dosing levodopa, in the absence of decarboxylase inhibitor, is rapidly but variably absorbed from the gastro-intestinal 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 homo vanillic acid and dihydroxy phenylactic 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 neurons it is decarboxylated to dopamine, stored and released from presynaptic neurons. Because levodopa is so rapidly decarboxylated in the gastro-intestinal 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 3% 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.