Chemistry:Ropinirole

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Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS).[1] It is taken by mouth.[2]

Common side effects include sleepiness, vomiting, and dizziness.[2] Serious side effects may include pathological gambling, hypersexuality, low blood pressure with standing and hallucinations.[1][2] Use in pregnancy and breastfeeding is of unclear safety.[3] It is a dopamine agonist and works by triggering dopamine D2 receptors.[2]

It was approved for medical use in the United States in 1997.[2] It is available as a generic medication.[1] In 2023, it was the 212th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[4][5]

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[6] or antipsychotics.

A 2008 meta-analysis found that ropinirole was less effective than pramipexole in the treatment of restless legs syndrome.[7]

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.[8]

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.[9]

Pharmacology

Binding Table[10]
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
Major Metabolites in vivo formed by CYP1A2-mediated metabolism of Ropinirole
https://doi.org/10.1093/nar/gkae300 https://pubs.acs.org/doi/10.1021/acs.jcim.3c00054 [PDB ID: 8IRS] [Rendered with SwissDrugDesign Software]

Ropinirole acts as a D2, D3, and D4 dopamine receptor agonist with highest affinity for D3, which are mostly found in the limbic areas.[11] 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.[12] 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.[13][14]

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,[15] 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.[16]

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.[17]

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.[18] This behavior displayed is characteristic of Dopamine Dysregulation Syndrome.[19]

References

  1. ↑ 1.0 1.1 1.2 British National Formulary (76th ed.). Pharmaceutical Press. 2018. pp. 419–420. ISBN 978-0-85711-338-2. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Ropinirole Hydrochloride Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/ropinirole-hydrochloride.html. 
  3. ↑ "Ropinirole Pregnancy and Breastfeeding Warnings" (in en). https://www.drugs.com/pregnancy/ropinirole.html. 
  4. ↑ "The Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  5. ↑ "Ropinirole Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Ropinirole. 
  6. ↑ Clinical trial number NCT00334048 at ClinicalTrials.gov - "Treating Sexual Dysfunction From SSRI Medication: a Study Comparing Requip CR to Placebo"
  7. ↑ "Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome". Sleep Med 9 (7): 715–26. October 2008. doi:10.1016/j.sleep.2007.11.020. PMID 18226947. 
  8. ↑ "Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease". Mayo Clinic Proceedings 84 (4): 310–316. April 2009. doi:10.4065/84.4.310. PMID 19339647. 
  9. ↑ "What is Augmentation?". Austin, Texas: Restless Legs Syndrome (RLS) Foundation. https://www.rls.org/file/what-is-augmentation.pdf. 
  10. ↑ "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. 1999. doi:10.1038/sj.bjp.0702673. PMID 10455328. 
  11. ↑ "Update on ropinirole in the treatment of Parkinson's disease". Neuropsychiatric Disease and Treatment 5: 33–36. 2009. PMID 19557097. 
  12. ↑ "Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist". Pharmacology, Biochemistry, and Behavior 38 (1): 147–154. January 1991. doi:10.1016/0091-3057(91)90603-Y. PMID 1673248. 
  13. ↑ "2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery". J Med Chem 66 (16): 11027–11039. August 2023. doi:10.1021/acs.jmedchem.3c01178. PMID 37584406. "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". 
  14. ↑ "Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment". Mol Pharmacol 76 (4): 710–22. October 2009. doi:10.1124/mol.109.058057. PMID 19570945. 
  15. ↑ "An open-label, parallel-group, repeat-dose study to investigate the effects of end-stage renal disease and haemodialysis on the pharmacokinetics of ropinirole"]. 13th International Congress of Parkinson’s Disease and Movement Disorders. Paris, France. 7–11 June 2009. http://www.richmondpharmacology.com/downloads/Publications/L3%20MDS%20ESRD%20poster.pdf. 
  16. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named TompsonD
  17. ↑ "Novel Approaches to Lead Optimization". Genetic Engineering & Biotechnology News 28 (14): 20. 1 August 2008. https://www.genengnews.com/insights/novel-approaches-to-lead-optimization/. Retrieved 28 September 2008. 
  18. ↑ "Court Rules Parkinson's Drug Turned Straight Patient Into A Gay Sex Addict". Huffington Post. 29 November 2012. http://www.huffingtonpost.com/2012/11/29/didier-jambart-parkinsons-drug-gay-sex-addict-glaxosmithkline_n_2212348.html. 
  19. ↑ "Dopamine Dysregulation Syndrome". Encyclopedia of Movement Disorders. 2010. pp. 323–326. doi:10.1016/B978-0-12-374105-9.00538-4. ISBN 978-0-12-374105-9. 

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