Pramipexole Explained

Watchedfields:changed
Verifiedrevid:464213026
Tradename:Mirapex, Mirapexin, Sifrol, others
Dailymedid:Pramipexole
Pregnancy Au:B3
Routes Of Administration:By mouth
Atc Prefix:N04
Atc Suffix:BC05
Legal Br:C1
Legal Br Comment:[1]
Legal Ca:Rx-only
Legal Ca Comment:[2]
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[3] [4]
Legal Status:Rx-only
Bioavailability:>90%
Protein Bound:15%
Elimination Half-Life:8–12 hours
Excretion:Urine (90%), feces (2%)
Index2 Label:as salt
Cas Number:104632-26-0
Pubchem:119570
Iuphar Ligand:953
Drugbank:DB00413
Chemspiderid:106770
Unii:83619PEU5T
Kegg:D05575
Kegg2:D00559
Chebi:8356
Chembl:301265
Iupac Name:(S)-N6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine
C:10
H:17
N:3
S:1
Smiles:n1c2c(sc1N)C[C@@H](NCCC)CC2
Stdinchi:1S/C10H17N3S/c1-2-5-12-7-3-4-8-9(6-7)14-10(11)13-8/h7,12H,2-6H2,1H3,(H2,11,13)/t7-/m0/s1
Stdinchikey:FASDKYOPVNHBLU-ZETCQYMHSA-N

Pramipexole, sold under the brand Mirapex among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS).[5] In Parkinson's disease it may be used alone or together with levodopa.[5] It is taken by mouth.[5] Pramipexole is a dopamine agonist of the non-ergoline class.[5]

Pramipexole (and related D3-preferring dopamine agonist medications such as ropinirole) can induce "impulsive-compulsive spectrum disorders"[6] such as compulsive gambling, punding, hypersexuality, and overeating, even in people without any prior history of these behaviours.[7] [8] [9] 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.[10] The incidence and severity of impulse-control disorders for those taking the drug for depression are 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.[10]

Pramipexole was approved for medical use in the United States in 1997.[5] Use in pregnancy and breastfeeding is of unclear safety.[11] It is available as a generic medication.[12] In 2021, it was the 209th most commonly prescribed medication in the United States, with more than 2million prescriptions.[13] [14]

Medical uses

Pramipexole is used in the treatment of Parkinson's disease (PD) and restless legs syndrome (RLS).[5] Use in pregnancy and breastfeeding is of unclear safety.[11]

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, so the evidence for its role in this disorder is weak.[19]

Side effects

Common side effects of pramipexole may include:[20] [21] [22]

Pharmacology

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

Activities of pramipexole at various sites[28] [29] [30] [31] [32] ! Site! Affinity (Ki, nM)! Efficacy (Emax, %)! Action
D2S3.3130Super agonist
D2L3.970Partial agonist
D30.570Partial agonist
D43.942Partial agonist
Notes: Pramipexole also possesses lower affinity (500–10,000 nM) for the 5-HT1A, 5-HT1B, 5-HT1D, and α2-adrenergic receptors.[33] It has negligible affinity (>10,000 nM) for the D1, D5, 5-HT2, α1-adrenergic, β-adrenergic, H1, and mACh receptors. All sites were assayed using human materials. Pramipexole is a super agonist at the presynaptic D2S receptor, S referring to a shorter amino acid sequence which desensitize overtime unlike postsynaptic D2L receptors.

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.[34] 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.[35]

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.[36]

Society and culture

Brand names

Brand names include Mirapex, Mirapex ER, Mirapexin, Sifrol, Glepark, and Oprymea.

Research

Pramipexole has been evaluated for the treatment of sexual dysfunction experienced by some users of selective serotonin reuptake inhibitor (SSRI) antidepressants.[37] Pramipexole has shown effects on pilot studies in a placebo-controlled proof of concept study in bipolar disorder.[38] [39] [40] It is also being investigated for the treatment of clinical depression and fibromyalgia.[41] [42] [43]

Derivatives

Derivatives of pramipexole include CJ-998, CJ-1037, CJ-1638, CJ-1639,[44] D-264, D-440,[45] and D-512.[45]

Notes and References

  1. Web site: Anvisa . Brazilian Health Regulatory Agency . 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. live . 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 . 3 August 2023 . 16 August 2023 . . pt-BR . 4 April 2023.
  2. Web site: Product monograph brand safety updates . Health Canada . February 2024 . 24 March 2024.
  3. Web site: Sifrol EPAR . European Medicines Agency . 17 September 2018 . 17 October 2020 . 18 October 2020 . https://web.archive.org/web/20201018084830/https://www.ema.europa.eu/en/medicines/human/EPAR/sifrol . live .
  4. Web site: Mirapexin EPAR . European Medicines Agency . 17 September 2018 . 17 October 2020 . 18 October 2020 . https://web.archive.org/web/20201018112127/https://www.ema.europa.eu/en/medicines/human/EPAR/mirapexin . live .
  5. Web site: Pramipexole Dihydrochloride Monograph for Professionals . Drugs.com . American Society of Health-System Pharmacists . 22 March 2019 . 3 April 2019 . https://web.archive.org/web/20190403034528/https://www.drugs.com/monograph/pramipexole-dihydrochloride.html . live .
  6. Napier TC, Kirby A, Persons AL . The role of dopamine pharmacotherapy and addiction-like behaviors in Parkinson's disease . Progress in Neuro-Psychopharmacology & Biological Psychiatry . 102 . 109942 . August 2020 . 32272129 . 10.1016/j.pnpbp.2020.109942 . ... 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. . 215237629 .
  7. Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE . 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 . 19339647 . 2665974 . 10.4065/84.4.310 .
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  12. Book: British national formulary : BNF 76. 2018. Pharmaceutical Press. 9780857113382. 417–418. 76.
  13. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
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  21. Web site: Mirapex- pramipexole dihydrochloride tablet . DailyMed . 1 March 2020 . 17 October 2020 . 18 October 2020 . https://web.archive.org/web/20201018092447/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=688fa4d7-de12-4930-8bc5-0169297c1da6 . live .
  22. Web site: Mirapex ER- pramipexole dihydrochloride tablet, extended release . DailyMed . 5 February 2020 . 17 October 2020 . 21 October 2020 . https://web.archive.org/web/20201021152917/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e2902ed1-cfeb-4815-adc3-129c577917a1 . live .
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