What are other dopamine agonists?

Dopamine Agonists: Available Agents and Clinical Applications

Primary Dopamine Agonists

The main dopamine agonists used clinically include both ergot-derived and non-ergot compounds, with distinct receptor profiles and pharmacokinetic properties that guide their specific applications.

Ergot-Derived Dopamine Agonists

• Bromocriptine: An older ergot derivative that binds to D2-like receptors and has been used since the mid-1970s for Parkinson's disease and hyperprolactinemia 1
• Pergolide: Another ergot-derived agonist with D2 receptor affinity, though concerns about fibrotic complications have limited its use 1, 2
• Cabergoline: A long-acting ergot derivative with the longest half-life (60+ hours) of all dopamine agonists, allowing once-daily dosing and providing sustained dopaminergic stimulation 3, 4
  • Has high specificity and affinity for dopamine D2 receptors 5
  • Standard initial dose is 0.25 mg twice weekly for hyperprolactinemia, with gradual increases up to 2 mg/week for most patients 6
  • Superior to bromocriptine in normalizing prolactin (83% vs 59%) with better tolerability (52% vs 72% adverse events) 7, 8

Non-Ergot Dopamine Agonists

• Pramipexole: A selective non-ergot D2 and preferentially D3 agonist with an elimination half-life of 5-10 hours 4

  • FDA-approved for both Parkinson's disease and restless legs syndrome 7
  • For RLS, dosing starts at 0.125 mg orally 2-3 hours before bedtime, with dose doubling every 4-7 days to a maximum of 0.5 mg 7
  • May help reduce dream enactment in REM sleep behavior disorder, though its mechanism is uncertain 7

• Ropinirole: Another selective non-ergot D2 (and preferentially D3) agonist with similar pharmacokinetics to pramipexole 4

  • FDA-approved for Parkinson's disease and restless legs syndrome 7
  • For RLS, beginning dose is 0.25 mg orally 1-3 hours before bedtime, increasing to 0.5 mg after 2-3 days, then 1 mg after 7 days, with weekly 0.5 mg increments to a maximum of 4 mg at week 7 if needed 7
  • Metabolized primarily by cytochrome P450 1A2, requiring dose adjustment with CYP1A2 inhibitors like ciprofloxacin or inducers like cigarette smoking 9

• Apomorphine: A water-soluble dopamine agonist used for continuous parenteral infusion to overcome motor fluctuations in advanced Parkinson's disease 10

• Lisuride: Another water-soluble agonist available for parenteral infusion in advanced disease 10

Key Clinical Distinctions

Receptor Selectivity and Duration of Action

• Pramipexole and ropinirole are highly selective for D2-like receptors with shorter half-lives (5-10 hours), requiring multiple daily doses 4
• Cabergoline is less selective but has a much longer half-life (60+ hours), allowing once-daily or even less frequent dosing 4
• The longer half-life of cabergoline provides sustained rather than pulsatile dopaminergic stimulation, which may be advantageous in certain conditions 3

Safety Profile Differences

• Ergot-derived agonists (bromocriptine, pergolide, cabergoline) carry risk of fibrotic complications including retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, cardiac valvulopathy, particularly at higher doses 9, 2

  • For cabergoline doses >2 mg/week, annual echocardiography with cardiac auscultation is recommended 6, 5
  • For doses ≤2 mg/week, echocardiographic surveillance can be reduced to every 5 years 6, 5

• Non-ergot agonists (pramipexole, ropinirole) reduce the risk of drug-induced fibrotic reactions compared to ergot derivatives 2

  • However, cases of possible fibrotic complications have been reported even with ropinirole, though causality is not established 9

Common Adverse Effects Across All Dopamine Agonists

• Dopaminergic effects: Nausea, orthostatic hypotension, sleepiness, headache, hallucinations, confusion 7
• Impulse control disorders: Pathological gambling, hypersexuality, compulsive spending, and other intense urges that patients cannot control 11, 9
  • These are dose-independent and may be more common in children and adolescents 6
  • Generally reversible upon dose reduction or treatment discontinuation 11
• Augmentation: Particularly relevant in restless legs syndrome, characterized by worsening and earlier onset of symptoms despite initial control 7, 9
  • Less common with newer dopamine agonists (pramipexole, ropinirole) compared to levodopa-carbidopa 7

Clinical Applications by Indication

Restless Legs Syndrome

• First-line agents: Ropinirole and pramipexole are both FDA-approved and recommended as first-line treatment 7
• These newer dopamine receptor agonists are associated with less rebound and symptom augmentation than dopamine precursors like levodopa-carbidopa 7

Hyperprolactinemia and Prolactinomas

• First-line agent: Cabergoline is the dopamine agonist of choice due to superior effectiveness and lower adverse effect profile compared to bromocriptine 7, 8
• Normalizes prolactin levels in 60-70% of patients, reduces tumor size by 80-88%, and improves visual deficits 7, 8

Parkinson's Disease

• All four agents (bromocriptine, pergolide, pramipexole, ropinirole) are effective for both early and advanced disease 1, 2
• In moderately advanced levodopa-treated patients with motor fluctuations, all significantly reduce "off" time, improve motor function, and reduce levodopa requirements 4
• The newer agonists (pramipexole, ropinirole, cabergoline) show very similar clinical effects with only minor superiority, if any, versus bromocriptine 4

REM Sleep Behavior Disorder

• Pramipexole may reduce dream enactment, though its mechanism is uncertain and may work by treating underlying periodic limb movement disorder 7
• Dosing starts at 0.125 mg at bedtime and can be increased slowly to 2.0 mg nightly 7

Important Drug Interactions and Contraindications

• Dopamine antagonists (phenothiazines, butyrophenones, thioxanthenes, metoclopramide) should not be administered concurrently as they may reduce efficacy 11, 9
• CYP1A2 inhibitors (ciprofloxacin) increase ropinirole levels, requiring dose adjustment 9
• Estrogen therapy reduces ropinirole clearance, potentially requiring dose adjustment 9
• Cigarette smoking increases ropinirole clearance due to CYP1A2 induction 9

Critical Monitoring Considerations

• Monitor for withdrawal symptoms (insomnia, apathy, anxiety, depression, fatigue, sweating, pain) during taper or discontinuation, which generally do not respond to levodopa 9
• Screen for impulse control disorders at each visit, as these can develop at any dose and may require dose reduction or discontinuation 11, 9
• In patients with hepatic impairment, use caution with cabergoline as it is extensively metabolized by the liver 11
• Watch for withdrawal-emergent hyperpyrexia and confusion resembling neuroleptic malignant syndrome with rapid dose reduction of ropinirole 9