Ropinirole: Difference between revisions - Wikipedia


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{{Short description|Dopamine agonist medication}}

▲{{Use dmy dates|date=OctoberFebruary 20222024}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Drugbox

| Watchedfields = changed

| verifiedrevid = 459456110

| IUPAC_name = 4-[2-(Dipropylamino)ethyl]-1,3-dihydro-2''H''-indol-2-one▼

| imageL = Ropinirole Structural Formulae.svg

| widthL = 160

| altL =

| imageR = Ropinirole ball-and-stick model.png

| widthR = 160

| altR =

<!--Clinical data-->

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| Drugs.com = {{drugs.com|monograph|ropinirole-hydrochloride}}

| MedlinePlus = a698013

| DailyMedID = Ropinirole

| routes_of_administration = [[By mouth]]▼

| ATC_prefix = N04▼

| ATC_suffix = BC04▼

| ATC_supplemental = <br />{{ATCvet|V03|AB96}}▼

| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->

| legal_BR = C1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023-08-03 |access-date=2023-08-16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023-04-04}}</ref>

| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_NZ = <!-- Class A, B, C -->

| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->

| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->

| legal_EU =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_status = Rx-only

▲| routes_of_administration = [[By mouth]]

<!--Pharmacokinetic data-->

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<!--Identifiers-->

| IUPHAR_ligand = 7295▼

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 91374-21-9

▲| ATC_prefix = N04

▲| ATC_suffix = BC04

▲| ATC_supplemental = <br />{{ATCvet|V03|AB96}}

| PubChem = 5095

▲| IUPHAR_ligand = 7295

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00268

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<!--Chemical data-->

▲| IUPAC_name = 4-[2-(Dipropylamino)ethyl]-1,3-dihydro-2''H''-indol-2-one

| C=16 | H=24 | N=2 | O=1

| smiles = O=C2Nc1cccc(c1C2)CCN(CCC)CCC

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}}

<!-- Definition and medical uses -->

'''Ropinirole''', sold under the brand name '''Requip''' among others, is a [[medication]] used to treat [[Parkinson's disease]] (PD) and [[restless legs syndrome]] (RLS).<ref name=BNF76>{{cite book|title=British National Formulary |date=2018 |publisher=Pharmaceutical Press |isbn=978-0-85711-338-2 |pages=419–420 |edition=76th}}</ref> In PD the dose needs to be adjusted to the effect and treatment should not be suddenly stopped.<ref name=BNF76/> It is taken [[by mouth]].<ref name=AHFS2019/>

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It was approved for medical use in the United States in 1997.<ref name=AHFS2019/> It is available as a [[generic medication]].<ref name=BNF76/> In 20202021, it was the 156th142nd most commonly prescribed medication in the United States, with more than 34{{nbsp}}million prescriptions.<ref>{{cite web | title = The Top 300 of 20202021 | url = https://clincalc.com/DrugStats/Top300Drugs.aspx | website = ClinCalc | access-date=14 January 2024 | archive-date=15 7January October2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live 2022}}</ref><ref>{{cite web | title = Ropinirole - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Ropinirole | access-date = 714 OctoberJanuary 20222024}}</ref>

==Medical uses==

Ropinirole is prescribed for mainly [[Parkinson's disease]], RLSrestless 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 [[SSRI]]s<ref>{{ClinicalTrialsGov|NCT00334048}} - "Treating Sexual Dysfunction From SSRI Medication: a Study Comparing Requip CR to Placebo"</ref> or antipsychotics.

A 2008 [[meta-analysis]] found that ropinirole was less effective than [[pramipexole]] in the treatment of restless legs syndrome.<ref name="pmid18226947">{{cite journal | vauthors = Quilici S, Abrams KR, Nicolas A, Martin M, Petit C, Lleu PL, Finnern HW | title = Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome | journal = Sleep Med | volume = 9 | issue = 7 | pages = 715–26 | date = October 2008 | pmid = 18226947 | doi = 10.1016/j.sleep.2007.11.020 | url = }}</ref>

=== Dosage ===

Ropinirole is available in various preparations, ranging from a 0.25&nbsp;mg tablet to a 5&nbsp;mg tablet. The primary reason is [[dose titration]]. [[Modified-release dosage|Prolonged-release]] tablets are available in 2–8&nbsp;mg doses.

For Parkinson's disease, the maximum recommended dose is 24&nbsp;mg per day, taken in three separate doses spread throughout the day for the immediate-release formulation. The maximum dose recommendations of ropinirole for subjects with [[Chronic kidney disease|end stage renal disease]] (ESRD) should be reduced by 25% compared with those recommended for subjects with normal renal function. A 25% dose reduction represents a more straightforward dosage regimen in terms of available tablet strength, compared with a 30% dose reduction.<ref name="RPL"/>

For RLS, the maximum recommended dose is 4&nbsp;mg per day, taken 1 to 3 hours before bedtime. A 52-week [[open label study]] had a mean dosage of 1.90&nbsp;mg, once daily 1 to 3 hours before bedtime.<ref name="52wkOpenLabel">{{cite journal | vauthors = Garcia-Borreguero D, Grunstein R, Sridhar G, Dreykluft T, Montagna P, Dom R, Lainey E, Moorat A, Roberts J | display-authors = 6 | title = A 52-week open-label study of the long-term safety of ropinirole in patients with restless legs syndrome | journal = Sleep Medicine | volume = 8 | issue = 7–8 | pages = 742–752 | date = November 2007 | pmid = 17512789 | doi = 10.1016/j.sleep.2006.09.009 }}</ref>

== Side effects ==

Ropinirole can cause nausea, dizziness, hallucinations, [[orthostatic hypotension]], and sudden sleep attacks during the daytime. Unusual side effects specific to D<sub>3</sub> agonists such as ropinirole and [[pramipexole]] can include [[hypersexuality]], [[punding]] and [[compulsive gambling]], even in patients without a history of these behaviours.<ref>{{cite journal | vauthors = Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE | title = Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease | journal = Mayo Clinic Proceedings | volume = 84 | issue = 4 | pages = 310–316 | date = April 2009 | pmid = 19339647 | pmc = 2665974 | doi = 10.4065/84.4.310 }}</ref>

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 RLSrestless 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.<ref>{{Cite web |url=https://www.rls.org/file/what-is-augmentation.pdf |title= What is Augmentation? | location = Austin, Texas | publisher = Restless Legs Syndrome (RLS) Foundation |access-date=8 May 2018 |archive-date=9 May 2018 |archive-url=https://web.archive.org/web/20180509080547/https://www.rls.org/file/what-is-augmentation.pdf |url-status=dead }}</ref>

== Pharmacology ==

Ropinirole acts as a [[Dopamine receptor D2|D<sub>2</sub>]], [[Dopamine receptor D3|D<sub>3</sub>]], and [[Dopamine receptor D4|D<sub>4</sub>]] [[dopamine]] [[receptor (biochemistry)|receptor]] [[agonist]] with highest [[Chemical affinity|affinity]] for D<sub>3</sub>, which are mostly found in the limbic areas.<ref>{{cite journal | vauthors = Shill HA, Stacy M | title = Update on ropinirole in the treatment of Parkinson's disease | journal = Neuropsychiatric Disease and Treatment | volume = 5 | pages = 33–36 | date = 2009 | pmid = 19557097 | pmc = 2695212 }}</ref> It is weakly active at the [[5-HT2 receptor|5-HT<sub>2</sub>]], and [[alpha-2 adrenergic receptor|α<sub>2</sub>]] receptors and is said to have virtually no affinity for the [[5-HT1 receptor|5-HT<sub>1</sub>]], [[GABA receptor|GABA]], [[muscarinic acetylcholine receptor|mAChRs]], [[alpha-1 adrenergic receptor|α<sub>1</sub>]]-, and [[Beta adrenergic receptor#.CE.B2 receptors|β-adrenoreceptors]].<ref name="RopPharmacology">{{cite journal | vauthors = Eden RJ, Costall B, Domeney AM, Gerrard PA, Harvey CA, Kelly ME, Naylor RJ, Owen DA, Wright A | display-authors = 6 | title = Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist | journal = Pharmacology, Biochemistry, and Behavior | volume = 38 | issue = 1 | pages = 147–154 | date = January 1991 | pmid = 1673248 | doi = 10.1016/0091-3057(91)90603-Y | s2cid = 26842270 }}</ref> It is a [[potency (pharmacology)|potent]] agonist of the [[5-HT2B receptor|5-HT<sub>2B</sub> receptor]], but shows [[biased agonist|biased agonism]] at this receptor and does not appear to pose a risk of [[cardiac valvulopathy]].<ref name="pmid37584406">{{cite journal | vauthors = Bender AM, Parr LC, Livingston WB, Lindsley CW, Merryman WD | title = 2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery | journal = J Med Chem | volume = 66 | issue = 16 | pages = 11027–11039 | date = August 2023 | pmid = 37584406 | doi = 10.1021/acs.jmedchem.3c01178 | s2cid = 260924858 | url = | quote = 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| pmc = 11073569 }}</ref><ref name="pmid19570945">{{cite journal | vauthors = Huang XP, Setola V, Yadav PN, Allen JA, Rogan SC, Hanson BJ, Revankar C, Robers M, Doucette C, Roth BL | title = Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment | journal = Mol Pharmacol | volume = 76 | issue = 4 | pages = 710–22 | date = October 2009 | pmid = 19570945 | pmc = 2769050 | doi = 10.1124/mol.109.058057 | url = }}</ref>

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,<ref name="RPL">{{cite conference | vauthors = Tompson D, Hewens D, Earl N, Oliveira D, Taubel J, Swan S, Giorgi L | url = http://www.richmondpharmacology.com/downloads/Publications/L3%20MDS%20ESRD%20poster.pdf | title = An open-label, parallel-group, repeat-dose study to investigate the effects of end-stage renal disease and haemodialysis on the pharmacokinetics of ropinirole] | archive-url = https://web.archive.org/web/20120317130609/http://www.richmondpharmacology.com/downloads/Publications/L3%20MDS%20ESRD%20poster.pdf | archive-date=17 March 2012 | conference = 13th International Congress of Parkinson’s Disease and Movement Disorders | location = Paris, France | date = 7–11 June 2009 }}</ref> and at doses higher than clinical, is also metabolized by [[CYP3A4]]. At doses greater than 24&nbsp;mg, [[CYP2D6]] may be inhibited, although this has been tested only [[in vitro]].<ref name=TompsonD/>

==Society and culture==

It is manufactured by [[GlaxoSmithKline]] (GSK), [[Mylan|Mylan Pharmaceuticals]], [[Cipla]], [[Dr. Reddy's Laboratories]] and [[Sun Pharmaceutical]]. The discovery of the drug's utility in RLSrestless legs syndrome has been used as an example of successful [[drug repurposing]].<ref name=Lipp_GEN2008>{{Cite newsmagazine | vauthors = Lipp E | date =1 August 2008 | title =Novel Approaches to Lead Optimization | periodical =Genetic Engineering & Biotechnology News | series =Drug Discovery | publisher =Mary Ann Liebert | volume =28 | issue =14 | pages =20 | url =httphttps://www.genengnews.com/articlesinsights/chitem.aspx?aid=2550 | issn =1935novel-approaches-to-472Xlead-optimization/ | access-date =28 September 2008 }} ''Note: The opinion that ropinirole's use in RLS was a successful example of drug repurposes was reported as being that of Josef Scheiber, a post-doctoral fellow at the Novartis Institutes for BioMedical Research.''</ref>

===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.<ref>{{cite news| url=http://www.huffingtonpost.com/2012/11/29/didier-jambart-parkinsons-drug-gay-sex-addict-glaxosmithkline_n_2212348.html | work=Huffington Post | vauthors = Wong C | title=Court Rules Parkinson's Drug Turned Straight Patient Into A Gay Sex Addict | date=29 November 2012}}</ref>

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== References ==

{{Reflist|30em}}

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/ropinirole | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Ropinirole }}

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/ropinirole%20hcl | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Ropinirole hydrochloride }}

{{Antiparkinson}}

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{{Hallucinogens}}

{{Sexual dysfunction pharmacotherapies}}

{{Dopamine receptor modulators}}

{{Serotonin receptor modulators}}

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