Ropinirole
Dopamine agonist medication
From Wikipedia, the free encyclopedia
Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS).[3] It is taken by mouth.[4]
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| Trade names | Requip, Repreve, Ronirol, others |
| Other names | SK&F-101468; SK&F101468; SKF-101468; SKF101468 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a698013 |
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| Routes of administration | By mouth |
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| Bioavailability | 50%[2] |
| Metabolism | Liver (CYP1A2)[2] |
| Elimination half-life | 5-6 hours[2] |
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| ECHA InfoCard | 100.110.353 |
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| Formula | C16H24N2O |
| Molar mass | 260.381 g·mol−1 |
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Common side effects include sleepiness, vomiting, and dizziness.[4] Serious side effects may include pathological gambling, hypersexuality, low blood pressure with standing and hallucinations.[3][4] Use in pregnancy and breastfeeding is of unclear safety.[5] It is a dopamine agonist and works by triggering dopamine D2 receptors.[4]
It was approved for medical use in the United States in 1997.[4] It is available as a generic medication.[3] In 2023, it was the 212th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[6][7]
Medical uses
Ropinirole is prescribed for mainly Parkinson's disease, restless legs syndrome, and extrapyramidal symptoms. It can also reduce the side effects caused by selective serotonin reuptake inhibitors, including Parkinsonism syndrome as well as sexual dysfunction and erectile dysfunction caused by either SSRIs[8] or antipsychotics.
A 2008 meta-analysis found that ropinirole was less effective than pramipexole in the treatment of restless legs syndrome.[9]
Side effects
Ropinirole can cause nausea, dizziness, hallucinations, orthostatic hypotension, and sudden sleep attacks during the daytime. Unusual side effects specific to D3 agonists such as ropinirole and pramipexole can include hypersexuality, punding and compulsive gambling, even in patients without a history of these behaviours.[10]
Ropinirole is also known to cause an effect known as "augmentation" when used to treat restless legs syndrome, where over time treatment with dopamine agonists will cause restless legs syndrome symptoms to become more severe. This usually leads to constant dosage increases in an attempt to offset the symptom progression. Symptoms will return to the level of severity they were experienced at before treatment was initiated if the drug is stopped; however, both ropinirole and pramipexole are known to cause painful withdrawal effects when treatment is stopped and the process of taking a patient who has been using the medication long-term off these drugs is often very difficult and should be supervised by a medical professional.[11]
Pharmacology
Pharmacodynamics
| Target | Ki (nM) | IA% | Action |
|---|---|---|---|
| D1 | >10,000 | ? | Agonist |
| D2 | 3.7 | 100% | Full Agonist |
| D3 | 2.9 | 97% | Full Agonist |
| D4 | 7.8 | 81% | Partial Agonist |
| D5 | >10,000 | ? | Agonist |
Ropinirole acts as a D2, D3, and D4 dopamine receptor agonist with highest affinity for D3, which are mostly found in the limbic areas.[13] It is weakly active at the 5-HT2, and α2 receptors and is said to have virtually no affinity for the 5-HT1, GABA, mAChRs, α1-, and β-adrenoreceptors.[14] It is a potent agonist of the 5-HT2B receptor, but shows biased agonism at this receptor and does not appear to pose a risk of cardiac valvulopathy.[15][16] The comprehensive receptor interactions of ropinirole have been described.[17][18][19][20][21][22]
Ropinirole produces marked hypolocomotion at lower doses (1–50 mg/kg i.p.) and causes hyperlocomotion at higher doses (100 mg/kg i.p.) in rodents.[23] The former effect is thought to be mediated by activation of inhibitory presynaptic dopamine autoreceptors and reduced dopamine release, while the latter action is thought to be due to stimulation of postsynaptic dopamine receptors.[23] Activation of postsynaptic dopamine D2 receptors is thought to be involved in the antiparkinsonian effects of dopamine D2 receptor agonists like ropinrole.[23]
Pharmacokinetics
Ropinirole is metabolized primarily by cytochrome P450 CYP1A2 to form two metabolites; SK&F-104557 and SK&F-89124, both of which are renally excreted,[24] and at doses higher than clinical, is also metabolized by CYP3A4. At doses greater than 24 mg, CYP2D6 may be inhibited, although this has been tested only in vitro.[2]
7-Hydroxyropinirole (SK&F-89124), a major metabolite of ropinirole in rats but minor metabolite in humans (<5% of dose), is a highly potent dopamine receptor agonist with antiparkinsonian activity similarly to ropinirole.[25][26][27][28][29] It has been reported to be 30-fold more potent than ropinirole as a dopamine D2 receptor agonist in vitro.[30][31] However, ropinirole and 7-hydroxyropinirole were equipotent in terms of antiparkinsonian activity in rodents in vivo.[29] 7-Hydroxyropinirole is said to be the only metabolite of ropinirole known to possess significant dopaminergic activity in vivo, although other ropinirole metabolites have also been found to have dopaminergic activity.[32][27][29]
Chemistry
Ropinirole is a partial ergoline. The chemical structure of the LSD metabolite 2-oxo-LSD is slightly related,[33] and a notable analogue is DPAI (2-desoxo-2-ene-ropinirole).[34][35][36]
History
Society and culture
It is manufactured by GlaxoSmithKline (GSK), Mylan Pharmaceuticals, Cipla, Dr. Reddy's Laboratories and Sun Pharmaceutical. The discovery of the drug's utility in restless legs syndrome has been used as an example of successful drug repurposing.[41]
Lawsuit
In November 2012, GlaxoSmithKline was ordered by a Rennes appeals court to pay Frenchman Didier Jambart 197,000 euros ($255,824); Jambart had taken ropinirole from 2003 to 2010 and exhibited risky hypersexual behavior and gambled excessively until stopping the medication.[42] This behavior displayed is characteristic of Dopamine Dysregulation Syndrome.[43]
