Levodopa Carbidopa

Levodopa with carbidopa is the most effective drug treatment for Parkinson disease motor symptoms and the reference against which other drugs are judged. It is also a time-critical medicine in hospital, because missed doses can cause rapid deterioration and a parkinsonism-hyperpyrexia syndrome.

Mechanism. Levodopa crosses the blood-brain barrier and is converted to dopamine by aromatic amino acid decarboxylase. Carbidopa inhibits this enzyme outside the brain and does not cross the barrier, which lowers the levodopa dose needed and reduces nausea and hypotension.

Pharmacokinetics. Levodopa is absorbed in the small intestine and competes with dietary amino acids for transport, so high-protein meals and delayed gastric emptying reduce and delay effects. Half-life with carbidopa is 1.5 hours, so doses are frequent. Complete peripheral decarboxylase inhibition needs carbidopa of at least 70 to 100 mg daily.

First-line use. Parkinson disease and other parkinsonian syndromes (levodopa response is less in atypical parkinsonism).

• Immediate-release tablets, oral levodopa and carbidopa in a 4 to 1 ratio (for example 100/25 mg): start 100/25 mg three times daily. Increase by one tablet daily every 1 to 2 days, or weekly in older adults, until response. Usual total levodopa 300 to 1000 mg daily in 3 to 5 doses. Usual label maximum is 8 tablets of 100/25 mg daily (carbidopa 200 mg); specialist doses can reach 1500 to 2000 mg of levodopa daily.

• Controlled-release tablets (for example 200/50 mg): start twice daily with at least 4 to 6 hours between doses. Bioavailability is about 70 to 75% of immediate-release, so the total levodopa dose is usually raised by 10 to 30% on conversion.

• Nausea at initiation: take with a small snack, or add carbidopa 25 mg with doses up to 200 mg daily. Domperidone 10 mg before doses is used where available, with QT caution. Avoid metoclopramide and prochlorperazine.

• Motor fluctuations: shorten the dose interval, add a catechol-O-methyltransferase inhibitor or monoamine oxidase B inhibitor, or add a dopamine agonist. Disabling fluctuations need specialist review for device-aided therapy.

Emergency and hospital use. Give doses on time, within 30 minutes of the usual times, in people admitted with or without Parkinson disease. If the oral route is not possible, give dispersible tablets by nasogastric tube, or use a rotigotine patch as a bridge under specialist advice. Never stop abruptly.

Kidney, liver, weight and age.

• Kidney and liver: no formal adjustment; use caution and titrate slowly.

• Older adults: start low and titrate slowly, because of hallucinations, hypotension and delirium.

Contraindications. Narrow-angle glaucoma, non-selective monoamine oxidase inhibitors within 14 days, undiagnosed suspicious skin lesions or melanoma history (in some labels), severe psychosis and hypersensitivity.

Serious adverse effects. Severe dyskinesia, hallucinations and psychosis, impulse control disorders, sudden sleep onset, orthostatic hypotension and syncope, dopamine dysregulation syndrome, haemolytic anaemia, and parkinsonism-hyperpyrexia syndrome on abrupt withdrawal.

Common adverse effects. Nausea, vomiting, dyskinesia, orthostatic hypotension, somnolence, vivid dreams and confusion. Long-term use may cause peripheral neuropathy.

Interactions.

• Iron salts chelate levodopa, so separate by 2 hours.

• Antipsychotics (except quetiapine and clozapine), metoclopramide and prochlorperazine antagonise the effect.

• Antihypertensives add hypotension. Non-selective monoamine oxidase inhibitors risk hypertensive crisis.

Common prescribing errors. Missed or delayed doses in hospital. Giving antipsychotics or metoclopramide. Crushing controlled-release tablets. Using a single large dose rather than frequent smaller doses.

Special groups.

• Pregnancy: avoid unless essential.

• Breastfeeding: may suppress lactation; avoid.

• Regional: the combination tablet is often the main dopaminergic drug available; supply of controlled-release and dispersible forms varies.

Formulations. Immediate-release tablets with levodopa/carbidopa of 100/10, 100/25 and 250/25 mg. Controlled-release tablets 100/25 and 200/50 mg. Dispersible and enteral gel forms exist.

Preparation. Take 30 minutes before or 1 hour after meals where possible, avoiding large protein loads, and with a small snack if nausea occurs. Swallow controlled-release tablets whole or halved on the score only.

Monitoring.

• Motor diary of OFF time and dyskinesia, lying and standing blood pressure, mental state, impulse control, weight and skin examination.

• Blood count, kidney and liver function periodically in long-term use, and vitamin B12 if neuropathy develops.

Stopping. Do not stop abruptly. Taper gradually and only under supervision.

Referral and escalation. Refer for wearing-off, disabling dyskinesia, psychosis or falls. Refer urgently for suspected parkinsonism-hyperpyrexia syndrome (rigidity, fever, confusion after missed doses).