Dopamine Agonists

Dopamine agonists directly stimulate D2 and D3 receptors, bypassing the loss of presynaptic dopamine in Parkinson disease. They are used in Parkinson disease, restless legs syndrome and hyperprolactinaemia.

Classification. Non-ergot agonists (pramipexole, ropinirole, rotigotine, apomorphine) and ergot agonists (cabergoline, bromocriptine).

Pharmacokinetics. Pramipexole is cleared unchanged by the kidney. Ropinirole is metabolised by CYP1A2. Rotigotine is given as a 24-hour patch. Apomorphine has a half life of about 40 minutes and acts within 10 minutes subcutaneously.

• Pramipexole 0.125 mg three times daily, increased every 5 to 7 days to 0.5 to 1 mg three times daily; maximum 4.5 mg daily. Prolonged release 0.375 mg once daily, up to 4.5 mg.
• Ropinirole 0.25 mg three times daily, increased weekly to 3 to 9 mg daily; maximum 24 mg daily. Prolonged release 2 mg once daily, up to 24 mg.
• Rotigotine patch 2 mg/24 h, increased weekly to 6 to 8 mg/24 h in early disease and up to 16 mg/24 h in advanced disease.
• Apomorphine subcutaneous injection 1 to 10 mg for off periods, or infusion 1 to 4 mg/h while awake, after a supervised test dose.
• Cabergoline 0.25 to 0.5 mg twice weekly for hyperprolactinaemia.
• Bromocriptine 1.25 mg at night, increased to 2.5 mg three times daily; up to 30 mg daily in Parkinson disease.

Differences. Ergot agonists carry a fibrosis risk and are rarely used in Parkinson disease. Apomorphine is the most potent and the only rescue drug for sudden off periods.

• Early Parkinson disease: an agonist may delay levodopa in younger patients with mild disease; levodopa works better and is better tolerated in older adults.
• Advanced disease: add an agonist to reduce off time, or use apomorphine rescue injections or infusion.
• Restless legs syndrome: an alpha2delta ligand (pregabalin 150 to 300 mg at night) is first-line; pramipexole 0.125 to 0.5 mg or ropinirole 0.25 to 4 mg 2 hours before bed is an alternative, with a risk of augmentation. Treat iron deficiency when ferritin is under 75 microgram/L.
• Hyperprolactinaemia: cabergoline first-line.
• Apomorphine start: give domperidone 20 mg three times daily for at least 2 days before the first dose.

Selection. Avoid in people with dementia, psychosis, impulse control disorders or marked sleepiness.

Contraindications. Ergot agonists in cardiac valve disease and in pulmonary, retroperitoneal or pericardial fibrosis. Apomorphine with ondansetron (profound hypotension), with respiratory depression, dementia, psychosis, and in liver impairment. Severe psychosis for all.

Adverse effects. Nausea, orthostatic hypotension, leg oedema, hallucinations, sudden sleep onset, and impulse control disorders (gambling, hypersexuality, compulsive shopping or eating) in 10 to 15 percent. Dopamine agonist withdrawal syndrome on stopping. Apomorphine: injection site nodules, haemolytic anaemia, QT prolongation. Ergot agonists: valvular and other fibrosis.

Interactions. Dopamine antagonists oppose all agonists. Ciprofloxacin, fluvoxamine and oestrogens raise ropinirole levels. Cimetidine raises pramipexole levels.

Special groups.

• Pregnancy: avoid, except cabergoline for prolactinoma under specialist care.
• Breastfeeding: inhibit lactation; avoid.
• Older adults: lower doses; confusion and falls.
• Kidney impairment (pramipexole): creatinine clearance 20 to 50 mL/min, start 0.125 mg twice daily, maximum 2.25 mg daily; under 20 mL/min, 0.125 mg once daily, maximum 1.5 mg daily.
• Liver impairment: reduce ropinirole; avoid apomorphine.

Monitoring. Ask patient and carer about impulse behaviour at each visit; lying and standing blood pressure; sleepiness and driving; oedema; full blood count and direct antiglobulin test with apomorphine; ECG with apomorphine; echocardiogram, creatinine, ESR and chest radiograph before and during ergot agonists.

Referral and escalation. New gambling or other compulsive behaviour (reduce or stop the agonist), psychosis, severe orthostatic hypotension, or need for apomorphine infusion.