Bromocriptine, originally marketed as Parlodel and subsequently under many brand names,[1] is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic malignant syndrome, and, as an adjunct, type 2 diabetes.
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| Trade names | Originally Parlodel, subsequently many[1] |
| Other names | 2-Bromoergocriptine; CB-154 |
| AHFS/Drugs.com | Monograph, International Drug Names |
| MedlinePlus | a682079 |
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| Routes of administration | By mouth, vaginal, intravenous |
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| Bioavailability | 28% of oral dose absorbed |
| Metabolism | Extensively liver-mediated |
| Elimination half-life | 12–14 hours |
| Excretion | 85% bile (feces), 2.5–5.5% urine |
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| ECHA InfoCard | 100.042.829 |
| Chemical and physical data | |
| Formula | C32H40BrN5O5 |
| Molar mass | 654.606 g·mol−1 |
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It was patented in 1968 and approved for medical use in 1975.[2]
Medical uses
editBromocriptine is used to treat acromegaly and conditions associated with hyperprolactinemia like amenorrhea, infertility, hypogonadism, and prolactin-secreting adenomas. It is also used to prevent ovarian hyperstimulation syndrome[3][4][5] and to treat Parkinson's disease.[3]
Since the late 1980s it has been used, off-label, to reduce the symptoms of cocaine withdrawal but the evidence for this use is poor.[6] Bromocriptine has been successfully used in cases of galactorrhea precipitated by dopamine antagonists like risperidone.
A quick-release formulation of bromocriptine, Cycloset, is also used to treat type 2 diabetes.[7][8][9] When administered within 2 hours of awakening, it increases hypothalamic dopamine level. That results to a significant weight loss as well as decreases in blood glucose levels, hepatic glucose production, and insulin resistance.[10] It therefore acts as an adjunct to diet and exercise to improve glycemic control and cardiovascular risk.[10][11]
Side effects
editMost frequent side effects are nausea, orthostatic hypotension, headaches, and vomiting through stimulation of the brainstem vomiting centre.[12] Vasospasms with serious consequences such as myocardial infarction and stroke that have been reported in connection with the puerperium, appear to be extremely rare events.[13] Peripheral vasospasm (of the fingers or toes) can cause Raynaud's Phenomenon.
Bromocriptine use has been anecdotally associated with causing or worsening psychotic symptoms (its mechanism is in opposition of most antipsychotics, whose mechanisms generally block dopamine receptors).[14] It should be understood, however, that the greater affinity bromocriptine and many similar antiparkinson's drugs have for the D2S receptor form (considered to be mostly present at inhibitory D2 autoreceptor locatations)[15] relative to the D2L form, sufficiently low partial agonist activity (ie where a molecule binding to a receptor induces limited effects while preventing a stronger ligand like dopamine from binding), and, possibly, the functional selectivity of a particular drug may generate antidopaminergic effects that are more similar than oppositional in nature to antipsychotics.
Pulmonary fibrosis has been reported when bromocriptine was used in high doses for the treatment of Parkinson's disease.[16]
Use to suppress milk production after childbirth was reviewed in 2014 and it was concluded that in this context a causal association with serious cardiovascular, neurological or psychiatric events could not be excluded with an overall incidence estimated to range between 0.005% and 0.04%. Additional safety precautions and stricter prescribing rules were suggested based on the data.[17][18] It is a bile salt export pump inhibitor.[19]
After long-term use of dopamine agonists, a withdrawal syndrome may occur during dose reduction or discontinuation with the following possible side effects: anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. For some individuals, these withdrawal symptoms are short-lived and they make a full recovery, for others a protracted withdrawal syndrome may occur with withdrawal symptoms persisting for months or years.[20]
Pharmacology
editPharmacodynamics
edit
Bromocriptine is a partial agonist of the dopamine D2 receptor.[21][22][23] It also interacts with other dopamine receptors and with various serotonin and adrenergic receptors.[21][22][24] Bromocriptine has additionally been found to inhibit the release of glutamate by reversing the GLT1 glutamate transporter.[25]
Despite acting as a serotonin 5-HT2A receptor agonist, bromocriptine is described as non-hallucinogenic.[26]
As an antagonist of the serotonin 5-HT2B receptor,[24] bromocriptine has not been associated with cardiac valvulopathy.[27] This is in contrast to other ergolines acting instead as 5-HT2B receptor agonists such as cabergoline and pergolide but is similar to lisuride which likewise acts as a 5-HT2B receptor antagonist.[27]
| Site | Affinity (Ki [nM]) | Efficacy (Emax [%]) | Action |
|---|---|---|---|
| D1 | 692 | ? | ? |
| D2S | 5.0 | 41 | Partial agonist |
| D2L | 15 | 28 | Partial agonist |
| D3 | 6.8 | 68 | Partial agonist |
| D4 | 372 | 0 | Silent antagonist |
| D5 | 537 | ? | ? |
| 5-HT1A | 13 | 72 | Partial agonist |
| 5-HT1B | 355 | 66 | Partial agonist |
| 5-HT1D | 11 | 86 | Partial agonist |
| 5-HT2A | 107 | 69 | Partial agonist |
| 5-HT2B | 56 | 0 | Silent antagonist |
| 5-HT2C | 741 | 79 | Partial agonist |
| 5-HT6 | 33 | ? | ? |
| 5-HT7 | 11–126 | ? | ? |
| α1A | 4.2 | 0 | Silent antagonist |
| α1B | 1.4 | ? | ? |
| α1D | 1.1 | ? | ? |
| α2A | 11 | 0 | Silent antagonist |
| α2B | 35 | 0 | Silent antagonist |
| α2C | 28 | 0 | Silent antagonist |
| α2D | 68 | ? | ? |
| β1 | 589 | ? | ? |
| β2 | 741 | ? | ? |
| H1 | >10,000 | – | – |
| M1 | >10,000 | – | – |
| Notes: All receptors are human except α2D-adrenergic, which is rat (no human counterpart), and 5-HT7, which is rat/mouse.[21][28] | |||
Chemistry
editLike all ergopeptides, bromocriptine is a cyclol; two peptide groups of its tripeptide moiety are crosslinked, forming the >N-C(OH)< juncture between the two rings with the amide functionality.
Bromocriptine is a semisynthetic derivative of a natural ergot alkaloid, ergocryptine (a derivative of lysergic acid), which is synthesized by bromination of ergocryptine using N-bromosuccinimide.[29][30]
History
editBromocriptine was discovered by scientists at Sandoz in 1965 and was first published in 1968; it was first marketed under the brand name Parlodel.[31][32]
A quick-release formulation of bromocriptine was approved by the FDA in 2009.[33]
Society and culture
editBrand names
editAs of July 2017, bromocriptine was marketed under many brand names worldwide, including Abergin, Barlolin, Brameston, Brocriptin, Brom, Broma-Del, Bromergocryptine, Bromergon, Bromicon, Bromocorn, Bromocriptin, Bromocriptina, Bromocriptine, Bromocriptine mesilate, Bromocriptine mesylate, Bromocriptine methanesulfonate, Bromocriptini mesilas, Bromocriptinmesilat, Bromodel, Bromokriptin, Bromolac, Bromotine, Bromtine, Brotin, Butin, Corpadel, Cripsa, Criptine, Criten, Cycloset, Degala, Demil, Deparo, Deprolac, Diacriptin, Dopagon, Erenant, Grifocriptina, Gynodel, kirim, Kriptonal, Lactodel, Medocriptine, Melen, Padoparine, Palolactin, Parlodel, Pravidel, Proctinal, Ronalin, Semi-Brom, Serocriptin, Serocryptin, Suplac, Syntocriptine, Umprel, Unew, Updopa, Upnol B, and Volbro.[1]
As of July 2017 it was also marketed as a combination drug with metformin as Diacriptin-M, and as a veterinary drug under the brand Pseudogravin.[1]
References
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- ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 533. ISBN 9783527607495.
- ^ a b "Bromocriptine mesylate tablets -- original uses" (PDF). FDA. January 2012. Archived (PDF) from the original on 2017-02-28. For label updates see FDA index page for NDA 017962 Archived 2017-06-29 at the Wayback Machine
- ^ Molitch ME (February 2017). "Diagnosis and Treatment of Pituitary Adenomas: A Review". JAMA. 317 (5): 516–524. doi:10.1001/jama.2016.19699. PMID 28170483. S2CID 205077946.
- ^ Tang H, Mourad SM, Wang A, Zhai SD, Hart RJ (14 Apr 2021). "Dopamine agonists for preventing ovarian hyperstimulation syndrome". The Cochrane Database of Systematic Reviews. 2021 (4): CD008605. doi:10.1002/14651858.CD008605.pub4. PMC 8092425. PMID 33851429.
- ^ Minozzi S, Amato L, Pani PP, Solimini R, Vecchi S, De Crescenzo F, et al. (May 2015). "Dopamine agonists for the treatment of cocaine dependence". The Cochrane Database of Systematic Reviews. 2015 (5): CD003352. doi:10.1002/14651858.CD003352.pub4. PMC 6999795. PMID 26014366.
- ^ "Bromocriptine mesylate tablet label" (PDF). FDA. February 2017. Archived (PDF) from the original on 2018-05-13.. For label updates see FDA index page for NDA 020866 Archived 2017-06-28 at the Wayback Machine
- ^ Garber AJ, Blonde L, Bloomgarden ZT, Handelsman Y, Dagogo-Jack S (2013). "The role of bromocriptine-QR in the management of type 2 diabetes expert panel recommendations". Endocrine Practice. 19 (1): 100–6. doi:10.4158/EP12325.OR. PMID 23337160.
- ^ Liang W, Gao L, Li N, Wang B, Wang L, Wang Y, et al. (October 2015). "Efficacy and Safety of Bromocriptine-QR in Type 2 Diabetes: A Systematic Review and Meta-Analysis". Hormone and Metabolic Research. 47 (11): 805–12. doi:10.1055/s-0035-1559684. PMID 26332757. S2CID 423132.
- ^ a b Birhan MT, Ayele TM, Abebe FW, Dgnew FN (July 2023). "Effect of bromocriptine on glycemic control, risk of cardiovascular diseases and weight in patients with type 2 diabetes: a systematic review". Diabetology & Metabolic Syndrome. 15 (1): 151. doi:10.1186/s13098-023-01073-2. PMC 10324265. PMID 37415177.
- ^ Defronzo RA (April 2011). "Bromocriptine: a sympatholytic, d2-dopamine agonist for the treatment of type 2 diabetes". Diabetes Care. 34 (4): 789–94. doi:10.2337/dc11-0064. PMC 3064029. PMID 21447659.
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- ^ Boyd A (1995). "Bromocriptine and psychosis: a literature review". The Psychiatric Quarterly. 66 (1): 87–95. doi:10.1007/BF02238717. PMID 7701022. S2CID 29539691.
- ^ Ford CP (December 2014). "The role of D2-autoreceptors in regulating dopamine neuron activity and transmission". Neuroscience. 282: 13–22. doi:10.1016/j.neuroscience.2014.01.025. PMC 4108583. PMID 24463000.
- ^ Todman DH, Oliver WA, Edwards RL (1990). "Pleuropulmonary fibrosis due to bromocriptine treatment for Parkinson's disease". Clinical and Experimental Neurology. 27: 79–82. PMID 2129961.
- ^ "European Medicines Agency - News and Events - CMDh endorses restricted use of bromocriptine for stopping breast milk production". www.ema.europa.eu. 2018-09-17. Archived from the original on 2014-08-28.
- ^ "EMA rät vom Abstillmittel Bromocriptin ab". 2014-08-25. Archived from the original on 2015-06-09. Retrieved 2014-08-26. "EMA rät vom Abstillmittel Bromocriptin ab", article in Ärzteblatt
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