Levodopa

Mechanism. Levodopa is the precursor of dopamine and, unlike dopamine, crosses the blood–brain barrier. It is combined with a peripheral dopa-decarboxylase inhibitor to lessen systemic effects — Madopar (levodopa + benserazide) and Sinemet (carbidopa + levodopa).

Indication. It is the main and often the only treatment for Parkinson's disease in the elderly, and is effective in tremor, bradykinesia and rigidity. Critically, it does not improve non-motor symptoms, posture or gait.

Dose and administration. Start at low doses and increase very gradually. Most patients are controlled in the first years on 300–600 mg/day, given three or four times daily, 30 minutes before meals. The dispersible form reaches peak plasma concentration faster and is used for early-morning akinesia.

Adverse effects. Peripheral — nausea, vomiting, anorexia and hypotension. Neuropsychiatric — sedation, nightmares, vivid dreams, hallucinations, delusions and delirium, all dose-related and common in older patients.

Long-term complications. After several years, motor fluctuations appear — delayed effect of levodopa, wearing-off between doses, and the on–off phenomenon — together with involuntary movements: chorea, athetosis and dystonia. These require revision of the timing of administration. Gastric emptying is delayed in at least 70% of patients, and levodopa retained in the stomach is metabolised to dopamine and lost, causing erratic absorption that itself contributes to the on–off phenomenon.

Diagnostic role. In the levodopa challenge, a fasting patient is given 150–250 mg with a decarboxylase inhibitor and tremor, rigidity and akinesia are assessed every 30 minutes for two to three hours. This indicates dopaminergic responsiveness and is not a formal diagnostic test. An excellent 70–100% response sustained for five years or more is a supportive criterion for PD; a negative response to large doses is an exclusion criterion.

New formulations and a new safety warning. Crexont (extended-release carbidopa/levodopa capsules) was FDA-approved in August 2024 for wearing-off, and Vyalev (foslevodopa/foscarbidopa) in October 2024 as the first 24-hour continuous subcutaneous infusion, which bypasses the gastrointestinal tract and solves the erratic gastric absorption problem without surgery. In March 2026 the FDA required a new label warning for all carbidopa/levodopa products regarding vitamin B6 deficiency and seizures.