Levodopa

Levodopa is the metabolic precursor of dopamine. Unlike dopamine itself, it crosses the blood–brain barrier.

It is combined with a peripheral dopa-decarboxylase inhibitor to lessen systemic effects: Madopar = levodopa + benserazide; Sinemet = carbidopa + levodopa.

It is the main and often the only treatment for PD in the elderly, and the most effective drug available.

It is effective for tremor, bradykinesia and rigidity.

Several formulations exist, distinguished by their rates of absorption. Standard levodopa is given three or four times daily, preferably 30 minutes before meals.

Most patients are controlled in the first years of PD on 300–600 mg per day. It should be started at low doses and increased very gradually until the appropriate effect is obtained.

The dispersible form (dispersible Madopar) achieves peak plasma concentration faster and is used for early-morning akinesia, allowing the first standard dose to be taken at the same time.

As disease progresses the dose must be increased progressively, and adverse effects become frequent.

Peripheral side effects: nausea, vomiting, anorexia and hypotension.

Neuropsychiatric side effects: sedation, nightmares, vivid dreams, hallucinations, delusions and delirium — all dose-related and especially common in older patients.

Long-term complications after several years: motor fluctuations with the on–off phenomenon, delayed effect of levodopa and wearing-off between doses; and involuntary movements — chorea, athetosis and dystonia. These complications require revision of the timing of levodopa administration.

Gastric emptying is delayed in at least 70% of PD patients, even without levodopa, and levodopa slows it further. Levodopa retained in the stomach is metabolised to dopamine and becomes unavailable for systemic absorption.

In patients with the on–off phenomenon, gastric emptying may normalise in the "on" phase; conversely, variable emptying causes erratic levodopa absorption and itself contributes to the on–off phenomenon.

Direct duodenal infusion of levodopa has been advocated to solve this problem; increasing the ratio of decarboxylase inhibitor to levodopa has also been suggested to improve dopamine availability.

A critical examination point: levodopa is not considered to improve non-motor symptoms or signs, or posture and gait.

Role in diagnosis: in the Queen Square Brain Bank criteria, supportive features include excellent (70–100%) response to levodopa, severe levodopa-induced chorea and levodopa response sustained for five years or more; a negative response to large doses of levodopa (with malabsorption excluded) is an exclusion criterion.

Levodopa challenge test (Box 53.1): give a fasting patient 150–250 mg levodopa with a decarboxylase inhibitor and assess tremor, rigidity and akinesia of the limbs every 30 minutes for two to three hours. This is an indicator of dopaminergic response, not a formal diagnostic test for PD.

Poor levodopa response points to a Parkinson-plus syndrome, vascular parkinsonism or normal pressure hydrocephalus.

Adjuncts that extend or modify levodopa action: COMT inhibitors (entacapone, tolcapone) prolong its effect; Stalevo is the fixed triple combination; amantadine 200–400 mg/day reduces peak-dose dyskinesia.

Drug interactions/cautions: metoclopramide is contraindicated; domperidone is used for levodopa-induced nausea; dietary protein competes with levodopa for absorption, hence pre-meal dosing.