Ropinirole

Ropinirole

Clinical data
Trade names	Requip, Repreve, Ronirol, others
AHFS/Drugs.com	Monograph
MedlinePlus	a698013
License data	US DailyMed: Ropinirole
Routes of administration	By mouth
ATC code	N04BC04 (WHO) QV03AB96 (WHO)
Legal status
Legal status	BR: Class C1 (Other controlled substances)[1] US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	50%[2]
Metabolism	Liver (CYP1A2)[2]
Elimination half-life	5-6 hours[2]
Identifiers
IUPAC name 4-[2-(Dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one
CAS Number	91374-21-9^Y
PubChem CID	5095
IUPHAR/BPS	7295
DrugBank	DB00268^Y
ChemSpider	4916^Y
UNII	030PYR8953
KEGG	D08489^Y
ChEBI	CHEBI:8888^Y
ChEMBL	ChEMBL589^Y
CompTox Dashboard (EPA)	DTXSID8045195
ECHA InfoCard	100.110.353
Chemical and physical data
Formula	C16H24N2O
Molar mass	260.381 g·mol^−1
3D model (JSmol)	Interactive image
SMILES O=C2Nc1cccc(c1C2)CCN(CCC)CCC
InChI InChI=1S/C16H24N2O/c1-3-9-18(10-4-2)11-8-13-6-5-7-15-14(13)12-16(19)17-15/h5-7H,3-4,8-12H2,1-2H3,(H,17,19)^Y Key:UHSKFQJFRQCDBE-UHFFFAOYSA-N^Y
(verify)

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]

Common side effects include sleepiness, vomiting, and dizziness.[4] Serious side effects may include pathological gambling, 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 2022, it was the 163rd most commonly prescribed medication in the United States, with more than 3 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 of these drugs is often very difficult and generally should be supervised by a medical professional.[11]

Pharmacology

Binding Table[12]

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-HT_2B receptor, but shows biased agonism at this receptor and does not appear to pose a risk of cardiac valvulopathy.[15][16]

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,[17] 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]

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.[18]

Lawsuits

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.[19]

References

1. Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
2. Tompson DJ, Vearer D (December 2007). "Steady-state pharmacokinetic properties of a 24-hour prolonged-release formulation of ropinirole: results of two randomized studies in patients with Parkinson's disease". Clinical Therapeutics. 29 (12): 2654–2666. doi:10.1016/j.clinthera.2007.12.010. PMID 18201581.
3. British National Formulary (76th ed.). Pharmaceutical Press. 2018. pp. 419–420. ISBN 978-0-85711-338-2.
4. "Ropinirole Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
5. "Ropinirole Pregnancy and Breastfeeding Warnings". Drugs.com. Retrieved 3 March 2019.
6. "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
7. "Ropinirole Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
8. Clinical trial number NCT00334048 at ClinicalTrials.gov - "Treating Sexual Dysfunction From SSRI Medication: a Study Comparing Requip CR to Placebo"
9. Quilici S, Abrams KR, Nicolas A, Martin M, Petit C, Lleu PL, et al. (October 2008). "Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome". Sleep Med. 9 (7): 715–26. doi:10.1016/j.sleep.2007.11.020. PMID 18226947.
10. Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE (April 2009). "Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease". Mayo Clinic Proceedings. 84 (4): 310–316. doi:10.4065/84.4.310. PMC 2665974. PMID 19339647.
11. "What is Augmentation?" (PDF). Austin, Texas: Restless Legs Syndrome (RLS) Foundation. Archived from the original (PDF) on 9 May 2018. Retrieved 8 May 2018.
12. Coldwell MC, Boyfield I, Brown T, Hagan JJ, Middlemiss DN (1999). "Comparison of the functional potencies of ropinirole and other dopamine receptor agonists at human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells". British Journal of Pharmacology. 127 (7): 1696–1702. doi:10.1038/sj.bjp.0702673. PMC 1566138. PMID 10455328.
13. Shill HA, Stacy M (2009). "Update on ropinirole in the treatment of Parkinson's disease". Neuropsychiatric Disease and Treatment. 5: 33–36. PMC 2695212. PMID 19557097.
14. Eden RJ, Costall B, Domeney AM, Gerrard PA, Harvey CA, Kelly ME, et al. (January 1991). "Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist". Pharmacology, Biochemistry, and Behavior. 38 (1): 147–154. doi:10.1016/0091-3057(91)90603-Y. PMID 1673248. S2CID 26842270.
15. Bender AM, Parr LC, Livingston WB, Lindsley CW, Merryman WD (August 2023). "2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery". J Med Chem. 66 (16): 11027–11039. doi:10.1021/acs.jmedchem.3c01178. PMC 11073569. PMID 37584406. S2CID 260924858. Functionally Biased Agonists. Conversely, a compound presenting as an agonist in 5-HT2B functional assays does not necessarily pose a risk for valvulopathy. In 5-HT2B calcium flux assays, certain known VHD-associated compounds displayed an agonist profile comparable to that of ropinirole, an approved treatment for Parkinson's disease (PD) and restless leg syndrome.122 Because ropinirole is not known to be associated with VHD or similar cardiopathies, it is thought that calcium flux may not be the optimal assay for screening 5-HT2B agonists for potential VHD-related risks. In additional readouts of 5-HT2B receptor activation (calcium-sensitive NFAT-mediated transcription of a β-lactamase reporter gene, accumulation of InsPs in LiCl-treated cells, recruitment of β-arrestin to agonist-occupied receptors, and phosphorylation of the extracellular signal-regulated kinase ERK2), ropinirole was found to be "distinct from the seven known valvulopathic 5- HT2B receptor agonists [studied] in that it is much less potent, albeit not less efficacious, than the VHD-associated drugs in all but one of the 5-HT2B receptor functional assays employed." 66
16. Huang XP, Setola V, Yadav PN, Allen JA, Rogan SC, Hanson BJ, et al. (October 2009). "Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment". Mol Pharmacol. 76 (4): 710–22. doi:10.1124/mol.109.058057. PMC 2769050. PMID 19570945.
17. Tompson D, Hewens D, Earl N, Oliveira D, Taubel J, Swan S, et al. (7–11 June 2009). An open-label, parallel-group, repeat-dose study to investigate the effects of end-stage renal disease and haemodialysis on the pharmacokinetics of ropinirole] (PDF). 13th International Congress of Parkinson’s Disease and Movement Disorders. Paris, France. Archived from the original (PDF) on 17 March 2012.
18. Lipp E (1 August 2008). "Novel Approaches to Lead Optimization". Genetic Engineering & Biotechnology News. Vol. 28, no. 14. p. 20. Retrieved 28 September 2008.
19. Wong C (29 November 2012). "Court Rules Parkinson's Drug Turned Straight Patient Into A Gay Sex Addict". Huffington Post.