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Pramipexole

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Pramipexole
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
Pharmacokineticdata
Bioavailability>90%
Protein binding15%
Eliminationhalf-life8–12 hours
ExcretionUrine(90%),feces(2%)
Identifiers
  • (S)-N 6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.124.761Edit this at Wikidata
Chemical and physical data
FormulaC10H17N3S
Molar mass211.33g·mol−1
3D model (JSmol)
  • n1c2c(sc1N)C[C@@H](NCCC)CC2
  • InChI=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/s1checkY
  • Key:FASDKYOPVNHBLU-ZETCQYMHSA-NcheckY
(verify)

Pramipexole,sold under the brandMirapexamong others, is a medication used to treatParkinson's disease(PD) andrestless legs syndrome(RLS).[8]In Parkinson's disease it may be used alone or together withlevodopa.[8]It is takenby mouth.[8]Pramipexole is adopamine agonistof the non-ergolineclass.[8]

Pramipexole was approved for medical use in the United States in 1997.[8]It is available as ageneric medication.[9]In 2021, it was the 209th most commonly prescribed medication in the United States, with more than 2million prescriptions.[10][11]

Medical uses

[edit]

Pramipexole is used in the treatment ofParkinson's disease(PD) andrestless legs syndrome(RLS).[8]Use inpregnancyandbreastfeedingis of unclear safety.[1]

A 2008meta-analysisfound that Pramipexole was more effective thanRopinirolein the treatment of RLS.[12]

It is occasionally prescribedoff-labelfordepression.Its effectiveness as an antidepressant may be a product of its strong partial agonistic activity on and preferential occupation of dopamine D3receptors at low doses (see table below); as well, the drug has been shown to desensitize the inhibitory D2autoreceptors but not the postsynaptic D2receptors, leading to an increase in dopamine and serotonin levels in theprefrontal cortex.[13]Chronic administration of Pramipexole may also result in desensitization of D3autoreceptors, leading to reduced dopamine transporter function.[14]Trials have shown mixed results for depression.[15]

Pramipexole has also been used as a treatment forREM 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 behavior disorder symptoms, but randomized controlled trials have not been performed, so the evidence for its role in this disorder is weak.[16]

Side effects

[edit]

Commonside effectsof Pramipexole may include:[17][4][5]

  • Headache
  • Peripheral edema[18]
  • Hyperalgesia(body aches and pains)
  • Nauseaandvomiting
  • Sedationandsomnolence
  • Decreasedappetiteand subsequentweight loss
  • Orthostatic hypotension(resulting indizziness,lightheadedness,and possiblyfainting,especially when standing up)
  • Insomnia
  • Hallucinations(seeing, hearing, smelling, tasting or feeling things that are not there),amnesiaand confusion
  • Twitching, twisting, or otherunusual body movements
  • Unusual tiredness or weakness
  • Pramipexole (and related D3-preferring dopamine agonist medications such asropinirole) can induce "impulsive-compulsive spectrum disorders"[19]such ascompulsive gambling,punding,hypersexuality,andovereating,even in people without any prior history of these behaviors.[20][21][22]There have also been reported detrimental side effects related to impulse-control disorders resulting fromoff-labeluse of Pramipexole or other dopamine agonists in treating clinical depression.[23]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.[23]
  • Augmentation:[a]Especially when used to treatrestless legs syndrome,long-term Pramipexole treatment may exhibit drug augmentation, which is "an iatrogenic worsening of RLS symptoms following treatment with dopaminergic agents"[24]and may include an earlier onset of symptoms during the day or a generalized increase in symptoms.[25][26][27]

Pharmacology

[edit]

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
D2S 3.3 130 Super 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 the5-HT1A,5-HT1B,5-HT1D,andα2-adrenergic receptors.[28][33]It has negligible affinity (>10,000 nM) for theD1,D5,5-HT2,α1-adrenergic,β-adrenergic,H1,andmACh receptors.[28][33]All sites were assayed using human materials.[28][29]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 D3receptor function in rodent models and tasks for neuropsychiatric disorders.[34]Of note, it appears that Pramipexole, in addition to having effects on dopamine D3receptors, 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 theR-stereoisomerof Pramipexole (which has much lower affinity to the dopamine receptors when compared to theS-isomer) side by side with the effects of theS-isomer.[35]

Parkinson's disease is aneurodegenerative diseaseaffecting thesubstantia nigra,a component of thebasal ganglia.The substantia nigra has a high quantity ofdopaminergicneurons,which arenervecellsthatreleasetheneurotransmitterknown asdopamine.When dopamine is released, it may activatedopamine receptorsin thestriatum,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 D4dopamine receptors, Pramipexole may directly stimulate the underfunctioning dopamine receptors in thestriatum,thereby restoring the dopamine signals needed for proper functioning of the basal ganglia.

Pramipexole can increasegrowth hormoneindirectly through its inhibition ofsomatostatin.[36]

Society and culture

[edit]

Brand names

[edit]

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

Research

[edit]

Pramipexole has been evaluated for the treatment ofsexual dysfunctionexperienced by some users ofselective serotonin reuptake inhibitor(SSRI)antidepressants.[37]Pramipexole has shown effects on pilot studies in a placebo-controlledproof of conceptstudy inbipolar disorder.[38][39][40]It is also being investigated for the treatment ofclinical depressionandfibromyalgia.[41][42][43]

Derivatives

[edit]

Derivativesof Pramipexole include CJ-998, CJ-1037, CJ-1638, CJ-1639,[44]D-264, D-440,[45]and D-512.[45]

Explanatory notes

[edit]
  1. ^The term "augmentation" has different meanings depending on the context. In the context of thepharmacological 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

[edit]
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