L Dopa in Parkinsons

Synonym: L-Dopa

See Parkinson's Disease Management for further details on drug choice and drug combinations.

• Early Parkinson's Disease - NICE recommend levodopa as one option for the treatment of early Parkinson's Disease, but does not recommend it as a universal first-line option.⁴ Other evidence-based options include dopamine agonists and MAO-8 inhibitors. Selection will depend on clinical preference, patient preference and the patient's lifestyle. The results of a large trial (the PD MED trial) are currently awaited.⁵
• A randomised controlled trial supported the use of levodopa in early Parkinson's Disease.⁶
• Long-term levodopa treatment is associated with adverse motor effects that limit its use. These are motor fluctuations (on-off phenomena, wearing off, dose failures, and freezing) and dyskinesias (peak-dose dyskinesias, diphasic dyskinesia, and dystonia).
• These adverse effects become more of a problem as the disease progresses and can be very disabling. They occur in 50-90% of people who have received levodopa for 5-10 years. They occur in virtually all younger patients and so careful consideration needs to be given to the ideal time for starting levodopa in this group. They are less likely to occur in those whose symptoms begin after the age of 70 years.
• The optimum use of levodopa is therefore in older patients with a limited life expectancy in whom it should be started immediately. For younger patients, a dopamine agonist rather than L-dopa is often more appropriate.

• Parkinson's Disease is caused by degeneration of the nigrostriatial pathway, resulting in a drop in the levels of the neurotransmitter dopamine. Levodopa works by increasing these levels.
• Levodopa is a precursor of dopamine, and is metabolised centrally and peripherally by dopa-decarboxylase and catechol-O-methyltransferase (COMT). Giving it in combination with an extra-cerebral dopa-decarboxylase inhibitor reduces adverse effects and enables the drug to be given at the lowest possible level that achieves effective brain-dopamine concentrations . The inhibitors used are benserazide (in co-beneldopa) and carbidopa (in co-careldopa).

• Narrow-angle glaucoma - can cause increased pressure, but rare
• Pregnancy/women of childbearing age without adequate contraception - evidence from animal studies, visceral and skeletal malformations in rabbits
• Breast feeding - may suppress lactation, may pass into breast milk, manufacturers recommend avoid
• Known L-dopa hypersensitivity

• Severe psychosis - levodopa known to cause anxiety, acute brain syndrome, toxic psychosis, hallucinations
• Severe endocrine disorders - can cause adrenal suppression, increase in growth hormone levels, decrease in prolactin levels
• Severe hepatic disease - levodopa can increase bilirubin and alkaline phosphatase levels
• Severe renal disease - polyuria, incontinence
• Severe cardiac disease - higher incidence of clinically-significant hypotension
• Under 25 - can affect growth hormone levels and skeletal maturation
• Pulmonary disease - has a variable effect on peak flow and FEV
• Peptic ulceration - some reports of gastrointestinal disturbance, but questionable whether due to levodopa (recent research suggests levodopa may be useful in promoting ulcer healing)
• Driving or operating machinery - warn patients re somnolence or sudden sleep onset, consider reducing dose or stopping treatment

• Drugs which interfere with central amine mechanisms - commonest in practice are metoclopramide, phenothiazines, reserpine, MAOIs, tricyclics, diazepam, ferrous sulphate
• Other anti-Parkinsonian agents - anticholinergics, amantadine, COMT inhibitors, dopamine agonists
• Enhances the effect of most major classes of antihypertensives
• Increased risk of arrhythmia with volatile inhaled anaesthetics

• Start at low dose, to reduce risk of side-effects. Always prescribe in combination with a dopa-decarboxylase inhibitor (as co-beneldopa or co-careldopa).
• Consider increasing dose of dopa-decarboxylase inhibitor, or co-prescribe domperidone if nausea and vomiting are a problem.
• Titrate over weeks or months to lowest dose that provides maximum mobility improvement without causing intolerable side-effects (in early disease, usually 300-400mg).
• Take with food initially to minimise side-effects. Once tolerated, take on an empty stomach to improve efficacy.
• Advise patients to keep a diary when initiating so symptoms can be related to drug or food intake.

Solutions are discussed in detail in Parkinson's Disease Management article.

• Gastrointestinal - symptoms include nausea, vomiting, anorexia, and diarrhoea.
• Psychiatric - symptoms include euphoria, anxiety, insomnia, somnolence.
• Neurological - involuntary movements can occur, e.g. facial tics, grimacing (usually after 2-3 months of treatment).
• Cardiovascular - hypotension can occur.
• On-off episodes - in some patients periods of relatively normal mobility (the "on" period) alternate with periods of weakness and restricted mobility (the "off" period).
• End of dose deterioration - the duration of benefit after each dose becomes shorter and shorter. This can be combated by reducing duration between each dose but maintaining same overall dose. There is no evidence that modified-release preparations reduce response fluctuations or end of dose deterioration, but trials have shown significant benefits in activities of daily living.

• Monitor dose and watch for response fluctuations on-off effects and dystonias.
• Appropriate monitoring of hepatic, renal and cardiovascular function should be instituted in patients with co-morbidity, but no other monitoring is required in otherwise fit patients.