LECARDOP 25/250

Indications

• Parkinson's disease
• Parkinsonian syndromes

Dosage

Children: The use of carbidopa in children is not well established; therefore, paediatric dosing should be determined by a specialist and tailored to the individual child's needs, closely

Adults: The recommended dosage of carbidopa is typically 75 mg to 200 mg per day, administered in divided doses based on the combination with levodopa. The specific dosage should be guided by individual patient response and tolerability.

Mechanism of action

Carbidopa inhibits the enzyme aromatic L-amino acid decarboxylase (DDC), which is essential for the metabolism of levodopa in the periphery. By inhibiting DDC, carbidopa prevents the conversion of levodopa to dopamine outside the brain, allowing more levodopa to cross the blood-brain barrier where it can be converted to dopamine. This mechanism enhances the effectiveness of levodopa therapy in treating Parkinson's disease.

Pharmacodynamics

Carbidopa increases the bioavailability of levodopa by inhibiting its metabolism in the gastrointestinal tract and the periphery. This results in higher plasma levels of levodopa, which can enhance dopaminergic activity in the brain. The combination of carbidopa and levodopa has shown to increase the half-life of levodopa significantly, leading to improved clinical outcomes in patients with Parkinson's disease.

Pharmacokinetics

Carbidopa is not significantly absorbed from the gastrointestinal tract when taken alone and does not cross the blood-brain barrier. When administered with levodopa, it enhances levodopa's absorption and bioavailability, allowing more levodopa to enter the central nervous system. The half-life of carbidopa is approximately 1.5 hours, and it is primarily excreted unchanged in the urine.

Adverse effects

• Nausea
• Vomiting
• Dizziness
• Headache
• Dry mouth
• Constipation
• Orthostatic hypotension
• Dyskinesia
• Confusion
• Hallucinations

Interactions

• Iron salts may reduce the absorption of carbidopa/levodopa
• Antipsychotics may counteract the effects of levodopa
• MAO inhibitors can increase the risk of hypertensive crisis when combined with levodopa

Precautions

• Use with caution in patients with a history of psychotic disorders
• Monitor for the development of dyskinesias
• Caution in patients with severe cardiovascular disease
• Risk of melanoma has been reported; monitor skin changes

Pregnancy

Carbidopa is classified as category C, meaning risk cannot be ruled out. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether carbidopa is excreted in human milk. Caution should be exercised when administered to a nursing woman.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets
• Extended-release tablets

Indications

• Parkinson's disease
• Dopamine-responsive dystonia

Dosage

Children: Refer to the BNF for Children for recommended doses in paediatric patients.

Adults: Refer to the BNF for specific dosing guidelines based on the individual patient's condition and response.

Mechanism of action

Levodopa crosses the blood-brain barrier and is decarboxylated to form dopamine. This supplemental dopamine compensates for the decreased levels of endogenous dopamine due to neurodegeneration. The activation of dopaminergic receptors in the brain, particularly in the caudate nucleus and substantia nigra, leads to improved motor function. The current understanding suggests that the therapeutic effects of levodopa result from its conversion to dopamine by serotonergic terminals and some intrastriatal cells.

Pharmacodynamics

Levodopa is able to penetrate the blood-brain barrier, unlike dopamine. When combined with a peripheral dopa decarboxylase inhibitor, the conversion of levodopa to dopamine outside the brain is minimized, allowing for a higher concentration of levodopa to reach the central nervous system. Once in the brain, levodopa is converted to dopamine by aromatic L-amino-acid decarboxylase, enhancing dopaminergic neurotransmission.

Pharmacokinetics

Levodopa is absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring within 1 to 2 hours post-administration. Its bioavailability can be influenced by factors such as the presence of food and the use of dopa decarboxylase inhibitors. Levodopa is distributed widely in body tissues and is metabolized primarily in the liver and kidneys. The elimination half-life of levodopa ranges from 1.5 to 2 hours, and it is excreted predominantly as metabolites in the urine.

Contra-indications

• Hypersensitivity to levodopa or any component of the formulation
• Concurrent use of non-selective monoamine oxidase inhibitors (MAOIs)

Adverse effects

• Nausea
• Vomiting
• Orthostatic hypotension
• Dizziness
• Dyskinesia
• Hallucinations
• Confusion
• Sleep disturbances
• Dry mouth

Interactions

• levodopa+linezolid: Severe (increases risk of elevated blood pressure)
• metoclopramide+levodopa: Severe (decreases effects)
• asenapine+levodopa: Moderate (decreases effects)
• risperidone+levodopa: Moderate (decreases effects)
• entacapone+levodopa: Moderate (increases exposure)
• mao-b inhibitors+levodopa: Moderate (increases effects)
• opicapone+levodopa: Moderate (increases exposure)
• tetrabenazine+levodopa: Moderate (decreases effects)
• tolcapone+levodopa: Moderate (increases exposure)
• amisulpride+levodopa: Unknown (decreases effects)

Precautions

• Use with caution in patients with cardiovascular disease
• Monitor for signs of dyskinesia
• May cause hallucinations or confusion, particularly in elderly patients
• Regular monitoring of blood pressure is recommended

Pregnancy

Levodopa should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus. Consultation with a healthcare provider is essential.

Breast-feeding

Levodopa is excreted in breast milk, and caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place, away from light. Keep out of reach of children.

Formulations

• Tablets
• Oral solution
• Sustained-release formulations

Mechanism of action

Carbidopa is an inhibitor of the DDC which in order, inhibits the peripheral metabolism of levodopa. DDC is very important in the biosynthesis of L-tryptophan to serotonin and the modification of L-DOPA to dopamine. DDC can be found in the body periphery and in the blood-brain barrier. The action of carbidopa is focused on peripheral DDC as this drug cannot cross the blood-brain barrier. Hence, it will prevent the metabolism of [levodopa] in the periphery but it will not have any activity on the generation of dopamine in the brain.

Pharmacodynamics

When mixed with [levodopa], carbidopa inhibits the peripheral conversion of [levodopa] to dopamine and the decarboxylation of [oxitriptan] to serotonin by aromatic L-amino acid decarboxylase. This results in an increased amount of [levodopa] and [oxitriptan] available for transport to the central nervous system. Carbidopa also inhibits the metabolism of [levodopa] in the GI tract, thus, increasing the bioavailability of [levodopa]. The presence of additional units of circulating [levodopa] can increase the effectiveness of the still functional dopaminergic neurons and it has been shown to alleviate symptoms for a time. The action of carbidopa is very important as [levodopa] is able to cross the blood-brain barrier while dopamine cannot. Hence the administration of carbidopa is essential to prevent the transformation of external [levodopa] to dopamine before reaching the main action site in the brain. The coadministration of carbidopa with [levodopa] has been shown to increase the half-life of [levodopa] more than 1.5 times while increasing the plasma level and decreasing clearance. The combination therapy has also shown an increase of the recovery of [levodopa] in urine instead of dopamine which proves a reduced metabolism. This effect has been highly observed by a significant reduction in [levodopa] requirements and a significant reduction in the presence of side effects such as nausea. It has been observed that the effect of carbidopa is not dose-dependent.

Mechanism of action

Levodopa by various routes crosses the blood brain barrier, is decarboxylated to form dopamine. This supplemental dopamine performs the role that endogenous dopamine cannot due to a decrease of natural concentrations and stimulates dopaminergic receptors. MOST WIDELY ACCEPTED THEORY IS THAT LEVODOPA INCR LEVEL OF DOPAMINE & THUS ACTIVATION OF DOPAMINE RECEPTORS IN EXTRA-PYRAMIDAL CENTERS IN THE BRAIN (PRIMARILY IN CAUDATE NUCLEUS & SUBSTANTIA NIGRA). The present data indicate that the major effects observed after administration of exogenous levodopa are not due to a direct action of levodopa on dopamine receptors, or to extrastriatal release of dopamine, but to conversion of levodopa to dopamine by serotonergic terminals and probably some intrastriatal cells. EFFECTS OF LEVODOPA ON HUMAN & MURINE MELANOMA CELLS EXAMINED. WHEN EXPONENTIALLY GROWING CELLS WERE EXPOSED TO L-DOPA, CHARACTERISTIC INHIBITION OF THYMIDINE INCORPORATION OBSERVED. IN RATS, DOPAMINERGIC AGONISTS ALL CAUSED DECR IN SERUM PROLACTIN LEVELS.

Pharmacodynamics

Levodopa is able to cross the blood-brain barrier while dopamine is not. The addition of a peripheral dopa decarboxylase inhibitor prevents the conversion of levodopa to dopamine in the periphery so that more levodopa can reach the blood-brain barrier. Once past the blood-brain barrier, levodopa is converted to dopamine by aromatic-L-amino-acid decarboxylase.