Drugs for Parkinson Disease

Drugs for Parkinson disease restore dopaminergic tone or reduce cholinergic overactivity to improve motor symptoms. None halts the disease. Treatment aims to preserve function while avoiding motor complications and non-motor harm.

Classification. Levodopa with a decarboxylase inhibitor; dopamine agonists; monoamine oxidase B inhibitors; catechol-O-methyltransferase inhibitors; anticholinergic drugs; amantadine.

• Levodopa with carbidopa or benserazide: most effective, 300 to 800 mg of levodopa daily in 3 to 4 doses.
• Dopamine agonists: pramipexole, ropinirole, rotigotine patch, apomorphine.
• MAO-B inhibitors: rasagiline 1 mg daily, selegiline 5 to 10 mg daily, safinamide 50 to 100 mg daily.
• COMT inhibitors: entacapone 200 mg with each levodopa dose (maximum 2,000 mg daily), opicapone 50 mg at bedtime.
• Anticholinergic drugs: trihexyphenidyl 1 to 2 mg three times daily.
• Amantadine 100 mg twice daily.

Differences. Levodopa gives the largest benefit but produces motor complications over years. Agonists cause more sleepiness, hallucinations and impulse control disorders. Anticholinergic drugs help tremor but impair cognition.

• Early disease: start when symptoms affect function. Levodopa is first-line, particularly over age 70; in younger patients with mild disease an MAO-B inhibitor or dopamine agonist may delay levodopa.
• Motor complications (wearing-off, dyskinesia): shorten the dosing interval, add a COMT or MAO-B inhibitor or a dopamine agonist, add amantadine for dyskinesia, and refer for apomorphine infusion, levodopa intestinal gel or deep brain stimulation.
• Non-motor symptoms: constipation (macrogol); orthostatic hypotension (stop causes, fludrocortisone 100 microgram daily or midodrine 2.5 to 10 mg three times daily); psychosis (reduce anticholinergic and agonist drugs, quetiapine 12.5 to 25 mg at night or clozapine 6.25 to 25 mg); dementia (rivastigmine); drooling (glycopyrronium); REM sleep behaviour disorder (clonazepam 0.25 to 1 mg at night, melatonin).
• In hospital: give levodopa on time, at the usual times, within 30 minutes of the schedule. If the patient is nil by mouth, use a nasogastric tube or a rotigotine patch.
• Drugs to avoid: haloperidol, chlorpromazine, prochlorperazine and metoclopramide. Domperidone and ondansetron are suitable antiemetics.

Selection. Never stop drugs abruptly; parkinsonism-hyperpyrexia syndrome is life threatening.

Contraindications. Non-selective MAO inhibitors with levodopa. Narrow-angle glaucoma. Dopamine agonists in severe psychosis.

Adverse effects. Nausea, orthostatic hypotension, dyskinesia, hallucinations, impulse control disorders, sudden sleep onset, and neuroleptic malignant-like syndrome on withdrawal.

Interactions. MAO-B inhibitors with SSRIs, tramadol, pethidine and dextromethorphan (serotonin syndrome). Dopamine antagonists oppose all Parkinson drugs. Iron and high-protein meals reduce levodopa absorption.

Special groups.

• Pregnancy: limited data; use the lowest effective dose.
• Breastfeeding: levodopa and agonists may inhibit lactation.
• Older adults: start low; avoid anticholinergic drugs and amantadine in dementia.
• Kidney impairment: amantadine accumulates; reduce dose when creatinine clearance is under 60 mL/min.
• Liver impairment: reduce rasagiline and entacapone doses.

Monitoring. Motor diary, lying and standing blood pressure, mental state, impulse control behaviour, driving fitness, skin checks, vitamin B12.

Referral and escalation. Disabling motor fluctuations, psychosis, falls, dementia, poor response to levodopa (suggests atypical parkinsonism), or age under 50 at onset.