Pramipexole was approved for medical use in the United States in 1997.[8] It is available as a generic medication.[9] In 2022, it was the 193rd most commonly prescribed medication in the United States, with more than 2million prescriptions.[10][11]
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.[13] Chronic administration of Pramipexole may also result in desensitization of D3 autoreceptors, leading to reduced dopamine transporter function.[14] Trials have shown mixed results for depression.[15]
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 behavior disorder symptoms, but randomized controlled trials have not been performed, so the evidence for its role in this disorder is weak.[16]
Pramipexole (and related D3-preferring dopamine agonist medications such as ropinirole) can induce "impulsive-compulsive spectrum disorders"[19] such as compulsive gambling, punding, hypersexuality, and overeating, 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 from off-label use 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 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"[24] and may include an earlier onset of symptoms during the day or a generalized increase in symptoms.[25][26][27]
Pharmacology
The activity profile of Pramipexole at various sites has been characterized as follows:
Notes: Pramipexole also possesses lower affinity (500–10,000 nM) for the 5-HT1A, 5-HT1B, 5-HT1D, and α2-adrenergic receptors.[28][34] It has negligible affinity (>10,000 nM) for the D1, D5, 5-HT2, α1-adrenergic, β-adrenergic, H1, and mACh receptors.[28][34] 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 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 dopaminergicneurons, which are nervecells 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.
Plasma Concentration of 0.25mg PO after a single dose.
Immediate-Release Pramipexole displays a Tmax of approximately 2 hours and 3 hours if taken with a high-fat meal. Extended-Release Pramipexole displays a Tmax of ~6 hours and ~8 hours if taken with food. The AUC of Pramipexole remains unaltered regardless of food presence. Steady-State is achieved within 3 days and 5 days for the IR and ER formulation respectively. Pramipexole is eliminated via the renal organic cation transporter as an unchanged drug showing no signs of any hepatic-mediated metabolism. Pramipexole has been shown to inhibit CYP2D6 with a Ki of 30μM which is significantly higher than the maximum approved dosage of 4.5mg/day thus any enzyme-mediated drug interactions wouldn't be clinically relevant. [38][39]
Society and culture
Brand names
Brand names include Mirapex, Mirapex ER, Mirapexin, Sifrol, Glepark, and Oprymea.[citation needed]
Derivatives of Pramipexole include CJ-998, CJ-1037, CJ-1638, CJ-1639,[47] D-264, D-440,[48] and D-512.[48]
Explanatory notes
^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).
^Quilici S, Abrams KR, Nicolas A, Martin M, Petit C, Lleu PL, et al. (October 2008). "Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome". Sleep Med. 9 (7): 715–26. doi:10.1016/j.sleep.2007.11.020. PMID18226947.
^Napier TC, Kirby A, Persons AL (August 2020). "The role of dopamine pharmacotherapy and addiction-like behaviors in Parkinson's disease". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 102: 109942. doi:10.1016/j.pnpbp.2020.109942. PMID32272129. S2CID215237629. ... 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.
^Wolters EC, van der Werf YD, van den Heuvel OA (September 2008). "Parkinson's disease-related disorders in the impulsive-compulsive spectrum". Journal of Neurology. 255 (Suppl 5): 48–56. doi:10.1007/s00415-008-5010-5. PMID18787882. S2CID24531331.
^ abElliott C. "The Degradation Drug". The American Scholar. Archived from the original on 15 September 2022. Retrieved 15 September 2022.
^"Pramipexole Monograph for Professionals". Drugs.com. Archived from the original on 25 November 2021. Retrieved 11 December 2020. 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.
^ abcdKvernmo T, Härtter S, Burger E (August 2006). "A review of the receptor-binding and pharmacokinetic properties of dopamine agonists". Clinical Therapeutics. 28 (8): 1065–1078. doi:10.1016/j.clinthera.2006.08.004. PMID16982285.
^ abNewman-Tancredi A, Cussac D, Audinot V, Nicolas JP, De Ceuninck F, Boutin JA, et al. (November 2002). "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. doi:10.1124/jpet.102.039875. PMID12388667. S2CID35238120.
^Mierau J, Schneider FJ, Ensinger HA, Chio CL, Lajiness ME, Huff RM (June 1995). "Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors". European Journal of Pharmacology. 290 (1): 29–36. doi:10.1016/0922-4106(95)90013-6. PMID7664822.
^ abMillan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). "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. doi:10.1124/jpet.102.039867. PMID12388666. S2CID6200455.
^DeBattista C, Solvason HB, Breen JA, Schatzberg AF (April 2000). "Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression". Journal of Clinical Psychopharmacology. 20 (2): 274–275. doi:10.1097/00004714-200004000-00029. PMID10770475.
^Goldberg JF, Burdick KE, Endick CJ (March 2004). "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. doi:10.1176/appi.ajp.161.3.564. PMID14992985.
^Goodwin GM, Martinez-Aran A, Glahn DC, Vieta E (November 2008). "Cognitive impairment in bipolar disorder: neurodevelopment or neurodegeneration? An ECNP expert meeting report". European Neuropsychopharmacology. 18 (11): 787–793. doi:10.1016/j.euroneuro.2008.07.005. PMID18725178. S2CID18520604.
