Chemistry:Pramipexole

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Short description: Dopamine agonist medication
Pramipexole
Pramipexole.svg
Pramipexole ball-and-stick model.png
Clinical data
Pronunciation/ˌpræmɪˈpɛksoʊl/
Trade namesMirapex, Mirapexin, Sifrol, others
AHFS/Drugs.comMonograph
MedlinePlusa697029
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability>90%
Protein binding15%
Elimination half-life8–12 hours
ExcretionUrine (90%), feces (2%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC10H17N3S
Molar mass211.33 g·mol−1
3D model (JSmol)
  (verify)

Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS).[6] In Parkinson's disease it may be used alone or together with levodopa.[6] It is taken by mouth.[6] Pramipexole is a dopamine agonist of the non-ergoline class.[6]

Pramipexole (and related D3-preferring dopamine agonist medications such as ropinirole) can induce "impulsive-compulsive spectrum disorders"[7] such as compulsive gambling, punding, hypersexuality, and overeating, even in people without any prior history of these behaviours.[8][9][10] There have also been reported detrimental side effects related to impulse-control disorders resulting from off-label use of pramipexole or other dopamine agonists in treating clinical depression.[11] The incidence and severity of impulse-control disorders for those taking the drug for depression is not fully understood because the drug has not been approved for the treatment of depression and the first major studies of its efficacy in treating anhedonic depression were conducted in 2022. There have been anecdotal reports of abrupt and severe personality changes related to impulsivity and loss of self-control in a minority of patients regardless of the condition being treated, although the incidence of these side effects is not yet fully known.[11]

Pramipexole was approved for medical use in the United States in 1997.[6] Use in pregnancy and breastfeeding is of unclear safety.[1] It is available as a generic medication.[12] In 2020, it was the 193rd most commonly prescribed medication in the United States, with more than two million prescriptions.[13][14]

Medical uses

Pramipexole is used in the treatment of Parkinson's disease (PD) and restless legs syndrome (RLS).[6] Use in pregnancy and breastfeeding is of unclear safety.[1]

A 2008 meta-analysis found that pramipexole was more effective than ropinirole in the treatment of RLS.[15]

It is occasionally prescribed off-label for depression. Its effectiveness as an antidepressant may be a product of its strong partial agonistic activity on and preferential occupation of dopamine D3 receptors at low doses (see table below); as well, the drug has been shown to desensitize the inhibitory D2 autoreceptors but not the postsynaptic D2 receptors, leading to an increase in dopamine and serotonin levels in the prefrontal cortex.[16] Chronic administration of pramipexole may also result in desensitization of D3 autoreceptors, leading to reduced dopamine transporter function.[17] Trials have shown mixed results for depression.[18]

Pramipexole has also been used as a treatment for REM sleep behaviour disorder, but it is not licensed for use in this disorder. Observational studies suggest it may reduce the frequency and intensity of REM sleep behaviour disorder symptoms, but randomised controlled trials have not been performed, and so the evidence for its role in this disorder is weak.[19]

Side effects

Common side effects of pramipexole may include:[20][2][3]

  • Headache
  • Peripheral edema[21]
  • Hyperalgesia (body aches and pains)
  • Nausea and vomiting
  • Sedation and somnolence
  • Decreased appetite and subsequent weight loss
  • Orthostatic hypotension (resulting in dizziness, lightheadedness, and possibly fainting, especially when standing up)
  • Insomnia
  • Hallucinations (seeing, hearing, smelling, tasting or feeling things that are not there), amnesia and confusion
  • Twitching, twisting, or other unusual body movements
  • Unusual tiredness or weakness
  • Impulsive-compulsive behaviors: pramipexole (and related D3-preferring dopamine agonist medications such as ropinirole) can induce "impulsive-compulsive spectrum disorders"[22] such as compulsive gambling, punding, hypersexuality, and overeating, even in people without any prior history of these behaviours.[23][24][10]
  • Augmentation:[lower-alpha 1] Especially when used to treat restless legs syndrome, long-term pramipexole treatment may exhibit drug augmentation, which is "an iatrogenic worsening of RLS symptoms following treatment with dopaminergic agents"[25] and may include an earlier onset of symptoms during the day or a generalized increase in symptoms.[26][27][28]

Pharmacology

The activity profile of pramipexole at various sites has been characterized as follows:

Activities of pramipexole at various sites[29][30][31][32][33]
Site Affinity (Ki, nM) Efficacy (Emax, %) Action
D2S 3.3 130 Full agonist
D2L 3.9 70 Partial agonist
D3 0.5 70 Partial agonist
D4 3.9 42 Partial agonist
Notes: Pramipexole also possesses lower affinity (500–10,000 nM) for the 5-HT1A, 5-HT1B, 5-HT1D, and α2-adrenergic receptors.[29][34] It has negligible affinity (>10,000 nM) for the D1, D5, 5-HT2, α1-adrenergic, β-adrenergic, H1, and mACh receptors.[29][34] All sites were assayed using human materials.[29][30]

While pramipexole is used clinically (see below), its D3-preferring receptor binding profile has made it a popular tool compound for preclinical research. For example, pramipexole has been used (in combination with D2- and or D3-preferring antagonists) to discover the role of D3 receptor function in rodent models and tasks for neuropsychiatric disorders.[35] Of note, it appears that pramipexole, in addition to having effects on dopamine D3 receptors, may also affect mitochondrial function via a mechanism that remains less understood. A pharmacological approach to separate dopaminergic from non-dopaminergic (e.g. mitochondrial) effects of pramipexole has been to study the effects of the R-stereoisomer of pramipexole (which has much lower affinity to the dopamine receptors when compared to the S-isomer) side by side with the effects of the S-isomer.[36]

Parkinson's disease is a neurodegenerative disease affecting the substantia nigra, a component of the basal ganglia. The substantia nigra has a high quantity of dopaminergic neurons, which are nerve cells that release the neurotransmitter known as dopamine. When dopamine is released, it may activate dopamine receptors in the striatum, which is another component of the basal ganglia. When neurons of the substantia nigra deteriorate in Parkinson's disease, the striatum no longer properly receives dopamine signals. As a result, the basal ganglia can no longer regulate body movement effectively and motor function becomes impaired. By acting as an agonist for the D2, D3, and D4 dopamine receptors, pramipexole may directly stimulate the underfunctioning dopamine receptors in the striatum, thereby restoring the dopamine signals needed for proper functioning of the basal ganglia.

Pramipexole can increase growth hormone indirectly through its inhibition of somatostatin. [37]

Society and culture

Brand names

Brand names include Mirapex, Mirapex ER, Mirapexin, Sifrol, Glepark, and Oprymea.[citation needed]

Research

Pramipexole has been evaluated for the treatment of sexual dysfunction experienced by some users of selective serotonin reuptake inhibitor (SSRI) antidepressants.[38] Pramipexole has shown effects on pilot studies in a placebo-controlled proof of concept study in bipolar disorder.[39][40][41] It is also being investigated for the treatment of clinical depression and fibromyalgia.[42][43][44]

Derivatives

Derivatives of pramipexole include CJ-998, CJ-1037, CJ-1638, CJ-1639,[45] D-264, D-440,[46] and D-512.[46]

Explanatory notes

  1. ↑ The term "augmentation" has different meanings depending on the context. In the context of the pharmacological management of psychiatric disorders, for example, it means enhancing treatment effects by adding a second drug (or other treatment intervention). In the present context, augmentation has the meaning given above (in the body of the article).

References

  1. ↑ 1.0 1.1 1.2 "Pramipexole Pregnancy and Breastfeeding Warnings". https://www.drugs.com/pregnancy/pramipexole.html. 
  2. ↑ 2.0 2.1 "Mirapex- pramipexole dihydrochloride tablet". 1 March 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=688fa4d7-de12-4930-8bc5-0169297c1da6. 
  3. ↑ 3.0 3.1 "Mirapex ER- pramipexole dihydrochloride tablet, extended release". 5 February 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e2902ed1-cfeb-4815-adc3-129c577917a1. 
  4. ↑ "Sifrol EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/sifrol. 
  5. ↑ "Mirapexin EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/mirapexin. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Pramipexole Dihydrochloride Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/pramipexole-dihydrochloride.html. 
  7. ↑ "The role of dopamine pharmacotherapy and addiction-like behaviors in Parkinson's disease". Progress in Neuro-Psychopharmacology & Biological Psychiatry 102: 109942. August 2020. doi:10.1016/j.pnpbp.2020.109942. PMID 32272129. "... features of ICSDs [impulsive-compulsive spectrum disorders] during D2/D3R treatment are consistent with the pharmacological profile of the drugs, the known role of D2/D3R in these behaviors, and the neuroanatomical substrates of D2/D3R-expressing brain systems of ICSDs as shown by modern human imaging studies. While we pose that D2/D3R agonist treatment is sufficient to mediate ICSDs, there likely are many factors that overlay this profile, e.g., genetic vulnerabilities, brain disease state, and maladaptations to the chronic therapy.". 
  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. ↑ "Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs". JAMA Internal Medicine 174 (12): 1930–1933. December 2014. doi:10.1001/jamainternmed.2014.5262. PMID 25329919. 
  10. ↑ 10.0 10.1 "Parkinson's disease-related disorders in the impulsive-compulsive spectrum". Journal of Neurology 255 (Suppl 5): 48–56. September 2008. doi:10.1007/s00415-008-5010-5. PMID 18787882. 
  11. ↑ 11.0 11.1 "The Degradation Drug". https://theamericanscholar.org/the-degradation-drug/. 
  12. ↑ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 417–418. ISBN 9780857113382. 
  13. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  14. ↑ "Pramipexole - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Pramipexole. 
  15. ↑ "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. 
  16. ↑ "Long-term administration of the dopamine D3/2 receptor agonist pramipexole increases dopamine and serotonin neurotransmission in the male rat forebrain". Journal of Psychiatry & Neuroscience 37 (2): 113–121. February 2012. doi:10.1503/jpn.110038. PMID 22023785. 
  17. ↑ "Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake". Neurobiology of Disease 74: 325–335. February 2015. doi:10.1016/j.nbd.2014.12.007. PMID 25511804. 
  18. ↑ "Clinical Experience With High-Dosage Pramipexole in Patients With Treatment-Resistant Depressive Episodes in Unipolar and Bipolar Depression". The American Journal of Psychiatry 173 (2): 107–111. February 2016. doi:10.1176/appi.ajp.2015.15060788. PMID 26844792. 
  19. ↑ "Pramipexole in the treatment of REM sleep behaviour disorder: A critical review". Psychiatry Res 243: 365–372. 30 September 2016. doi:10.1016/j.psychres.2016.06.055. PMID 27449005. 
  20. ↑ "MedlinePlus Drug Information: Pramipexole (Systemic)". United States National Library of Medicine. https://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203739.html. 
  21. ↑ "Clinical characteristics of pramipexole-induced peripheral edema". Archives of Neurology 57 (5): 729–732. May 2000. doi:10.1001/archneur.57.5.729. PMID 10815140. 
  22. ↑ "The role of dopamine pharmacotherapy and addiction-like behaviors in Parkinson's disease". Progress in Neuro-Psychopharmacology & Biological Psychiatry 102: 109942. August 2020. doi:10.1016/j.pnpbp.2020.109942. PMID 32272129. "... features of ICSDs [impulsive-compulsive spectrum disorders] during D2/D3R treatment are consistent with the pharmacological profile of the drugs, the known role of D2/D3R in these behaviors, and the neuroanatomical substrates of D2/D3R-expressing brain systems of ICSDs as shown by modern human imaging studies. While we pose that D2/D3R agonist treatment is sufficient to mediate ICSDs, there likely are many factors that overlay this profile, e.g., genetic vulnerabilities, brain disease state, and maladaptations to the chronic therapy.". 
  23. ↑ "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. 
  24. ↑ "Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs". JAMA Internal Medicine 174 (12): 1930–1933. December 2014. doi:10.1001/jamainternmed.2014.5262. PMID 25329919. 
  25. ↑ "Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017)§". Movement Disorders 33 (7): 1077–1091. July 2018. doi:10.1002/mds.27260. PMID 29756335. https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=54361. Retrieved 13 November 2022. "… the specific goals of the current review were to … separately identify the RLS-specific side effect, which is augmentation.". 
  26. ↑ "Pramipexole Monograph for Professionals" (in en). https://www.drugs.com/monograph/pramipexole.html. "Augmentation of symptoms of restless legs syndrome (e.g., earlier onset of symptoms in the evening or afternoon, increase in symptoms, spread of symptoms to involve other extremities) reported; incidence increased with increasing duration of pramipexole treatment." 
  27. ↑ "Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology". Neurology 87 (24): 2585–2593. December 2016. doi:10.1212/WNL.0000000000003388. PMID 27856776. 
  28. ↑ "Restless Legs Syndrome and Other Movement Disorders of Sleep-Treatment Update". Current Treatment Options in Neurology 20 (12): 55. November 2018. doi:10.1007/s11940-018-0540-3. PMID 30411165. https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=54761. Retrieved 12 July 2022. "… augmentation of the RLS symptoms is a major limitation of oral dopaminergic therapy.". 
  29. ↑ 29.0 29.1 29.2 29.3 "A review of the receptor-binding and pharmacokinetic properties of dopamine agonists". Clinical Therapeutics 28 (8): 1065–1078. August 2006. doi:10.1016/j.clinthera.2006.08.004. PMID 16982285. 
  30. ↑ 30.0 30.1 "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 805–814. November 2002. doi:10.1124/jpet.102.039875. PMID 12388667. 
  31. ↑ "Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors". European Journal of Pharmacology 290 (1): 29–36. June 1995. doi:10.1016/0922-4106(95)90013-6. PMID 7664822. 
  32. ↑ "PDSP Ki Database Pramipexole Query". UNC. https://pdsp.unc.edu/databases/pdsp.php?recDDRadio=recDDRadio&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=Pramipexole&refDDRadio=refDDRadio&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query. 
  33. ↑ "Pramipexole dihydrochloride characteristics". https://www.bio-techne.com/p/small-molecules-peptides/pramipexole-dihydrochloride_4174#biological-activity. 
  34. ↑ 34.0 34.1 "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 791–804. November 2002. doi:10.1124/jpet.102.039867. PMID 12388666. 
  35. ↑ "Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation". Behavioural Pharmacology 19 (8): 786–795. December 2008. doi:10.1097/FBP.0b013e32831c3b2b. PMID 19020413. 
  36. ↑ "Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats". Brain Research 1437: 69–76. February 2012. doi:10.1016/j.brainres.2011.12.007. PMID 22227455. 
  37. ↑ "Comparison of pramipexole with and without domperidone co-administration on alertness, autonomic, and endocrine functions in healthy volunteers". British Journal of Clinical Pharmacology 64 (5): 591–602. November 2007. doi:10.1111/j.1365-2125.2007.02938.x. PMID 17578485. 
  38. ↑ "Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression". Journal of Clinical Psychopharmacology 20 (2): 274–275. April 2000. doi:10.1097/00004714-200004000-00029. PMID 10770475. 
  39. ↑ "Pramipexole for bipolar II depression: a placebo-controlled proof of concept study". Biological Psychiatry 56 (1): 54–60. July 2004. doi:10.1016/j.biopsych.2004.03.013. PMID 15219473. https://zenodo.org/record/1258802. Retrieved 3 August 2019. 
  40. ↑ "Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression". The American Journal of Psychiatry 161 (3): 564–566. March 2004. doi:10.1176/appi.ajp.161.3.564. PMID 14992985. 
  41. ↑ "Cognitive impairment in bipolar disorder: neurodevelopment or neurodegeneration? An ECNP expert meeting report". European Neuropsychopharmacology 18 (11): 787–793. November 2008. doi:10.1016/j.euroneuro.2008.07.005. PMID 18725178. 
  42. ↑ "Pramipexole in treatment-resistant depression: a 16-week naturalistic study". Bipolar Disorders 4 (5): 307–314. October 2002. doi:10.1034/j.1399-5618.2002.01171.x. PMID 12479663. 
  43. ↑ "Pramipexole in treatment-resistant depression: an extended follow-up". Depression and Anxiety 20 (3): 131–138. 2004. doi:10.1002/da.20038. PMID 15549689. 
  44. ↑ "A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications". Arthritis and Rheumatism 52 (8): 2495–2505. August 2005. doi:10.1002/art.21191. PMID 16052595. 
  45. ↑ "CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist". ACS Medicinal Chemistry Letters 2 (8): 620–625. August 2011. doi:10.1021/ml200100t. PMID 22125662. 
  46. ↑ 46.0 46.1 "D-512 and D-440 as novel multifunctional dopamine agonists: characterization of neuroprotection properties and evaluation of in vivo efficacy in a Parkinson's disease animal model". ACS Chemical Neuroscience 4 (10): 1382–1392. October 2013. doi:10.1021/cn400106n. PMID 23906010. 

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