Bromocriptine

Bromocriptine 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{{cite web|title=Bromocriptine mesylate tablets -- original uses|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017962s065s068lbl.pdf|publisher=FDA|date=January 2012|url-status=live|archive-url=https://web.archive.org/web/20170228152534/http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017962s065s068lbl.pdf|archive-date=2017-02-28}} For label updates see [https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017962 FDA index page for NDA 017962] {{webarchive|url=https://web.archive.org/web/20170629041043/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017962 |date=2017-06-29 }}{{cite journal | vauthors = Molitch ME | title = Diagnosis and Treatment of Pituitary Adenomas: A Review | journal = JAMA | volume = 317 | issue = 5 | pages = 516–524 | date = February 2017 | pmid = 28170483 | doi = 10.1001/jama.2016.19699 | s2cid = 205077946 }}{{cite journal|vauthors=Tang H, Mourad SM, Wang A, Zhai SD, Hart RJ|date=14 Apr 2021|title=Dopamine agonists for preventing ovarian hyperstimulation syndrome|journal=The Cochrane Database of Systematic Reviews|volume=2021 |issue=4 |pages=CD008605 |doi=10.1002/14651858.CD008605.pub4 | pmc=8092425 |pmid=33851429}} and to treat Parkinson's disease.

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.{{cite journal | vauthors = Minozzi S, Amato L, Pani PP, Solimini R, Vecchi S, De Crescenzo F, Zuccaro P, Davoli M | title = Dopamine agonists for the treatment of cocaine dependence | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD003352 | date = May 2015 | volume = 2015 | pmid = 26014366 | pmc = 6999795 | doi = 10.1002/14651858.CD003352.pub4 }} 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.{{cite web|title=Bromocriptine mesylate tablet label|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020866s006s007lbl.pdf|publisher=FDA|date=February 2017|url-status=live|archive-url=https://web.archive.org/web/20180513230418/https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020866s006s007lbl.pdf|archive-date=2018-05-13}}. For label updates see [https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020866 FDA index page for NDA 020866] {{webarchive|url=https://web.archive.org/web/20170628072832/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020866 |date=2017-06-28 }}{{cite journal | vauthors = Garber AJ, Blonde L, Bloomgarden ZT, Handelsman Y, Dagogo-Jack S | title = The role of bromocriptine-QR in the management of type 2 diabetes expert panel recommendations | journal = Endocrine Practice | volume = 19 | issue = 1 | pages = 100–6 | date = 2013 | pmid = 23337160 | doi = 10.4158/EP12325.OR }}{{cite journal | vauthors = Liang W, Gao L, Li N, Wang B, Wang L, Wang Y, Yang H, You L, Hou J, Chen S, Zhu H, Jiang Y, Pan H | title = Efficacy and Safety of Bromocriptine-QR in Type 2 Diabetes: A Systematic Review and Meta-Analysis | journal = Hormone and Metabolic Research | volume = 47 | issue = 11 | pages = 805–12 | date = October 2015 | pmid = 26332757 | doi = 10.1055/s-0035-1559684 | s2cid = 423132 }} 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.{{cite journal | vauthors = Birhan MT, Ayele TM, Abebe FW, Dgnew FN | title = Effect of bromocriptine on glycemic control, risk of cardiovascular diseases and weight in patients with type 2 diabetes: a systematic review | journal = Diabetology & Metabolic Syndrome | volume = 15 | issue = 1 | pages = 151 | date = July 2023 | pmid = 37415177 | pmc = 10324265 | doi = 10.1186/s13098-023-01073-2 | doi-access = free }} It therefore acts as an adjunct to diet and exercise to improve glycemic control and cardiovascular risk.{{cite journal | vauthors = Defronzo RA | title = Bromocriptine: a sympatholytic, d2-dopamine agonist for the treatment of type 2 diabetes | journal = Diabetes Care | volume = 34 | issue = 4 | pages = 789–94 | date = April 2011 | pmid = 21447659 | pmc = 3064029 | doi = 10.2337/dc11-0064 }}

Most frequent side effects are nausea, orthostatic hypotension, headaches, and vomiting through stimulation of the brainstem vomiting centre.{{cite journal | vauthors = Weil C | title = The safety of bromocriptine in long-term use: a review of the literature | journal = Current Medical Research and Opinion | volume = 10 | issue = 1 | pages = 25–51 | year = 1986 | pmid = 3516579 | doi = 10.1185/03007998609111089 }} 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.{{cite journal | vauthors = Iffy L, McArdle JJ, Ganesh V, Hopp L | title = Bromocriptine related atypical vascular accidents postpartum identified through medicolegal reviews | journal = Medicine and Law | volume = 15 | issue = 1 | pages = 127–34 | year = 1996 | pmid = 8691994 }} 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).{{cite journal | vauthors = Boyd A | title = Bromocriptine and psychosis: a literature review | journal = The Psychiatric Quarterly | volume = 66 | issue = 1 | pages = 87–95 | year = 1995 | pmid = 7701022 | doi = 10.1007/BF02238717 | s2cid = 29539691 }} It should be understood, however, that the greater affinity bromocriptine and many similar antiparkinson's drugs have for the D_2S receptor form (considered to be mostly present at inhibitory D₂ autoreceptor locatations){{cite journal | vauthors = Ford CP | title = The role of D2-autoreceptors in regulating dopamine neuron activity and transmission | journal = Neuroscience | volume = 282 | pages = 13–22 | date = December 2014 | pmid = 24463000 | pmc = 4108583 | doi = 10.1016/j.neuroscience.2014.01.025 }} relative to the D_2L 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.{{cite journal | vauthors = Todman DH, Oliver WA, Edwards RL | title = Pleuropulmonary fibrosis due to bromocriptine treatment for Parkinson's disease | journal = Clinical and Experimental Neurology | volume = 27 | pages = 79–82 | year = 1990 | pmid = 2129961 }}

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.{{cite web|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/08/news_detail_002157.jsp&mid=WC0b01ac058004d5c1|title=European Medicines Agency - News and Events - CMDh endorses restricted use of bromocriptine for stopping breast milk production|date=2018-09-17|website=www.ema.europa.eu|url-status=live|archive-url=https://web.archive.org/web/20140828112730/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fnews_and_events%2Fnews%2F2014%2F08%2Fnews_detail_002157.jsp&mid=WC0b01ac058004d5c1|archive-date=2014-08-28}}{{cite web |url=http://m.aerzteblatt.de/news/59857.htm |title=EMA rät vom Abstillmittel Bromocriptin ab |access-date=2014-08-26 |url-status=live |archive-url=https://web.archive.org/web/20150609025916/http://m.aerzteblatt.de/news/59857.htm |archive-date=2015-06-09 |date=2014-08-25 }} "EMA rät vom Abstillmittel Bromocriptin ab", article in Ärzteblatt It is a bile salt export pump inhibitor.{{cite journal | vauthors = Montanari F, Pinto M, Khunweeraphong N, Wlcek K, Sohail MI, Noeske T, Boyer S, Chiba P, Stieger B, Kuchler K, Ecker GF | title = Flagging Drugs That Inhibit the Bile Salt Export Pump | journal = Molecular Pharmaceutics | volume = 13 | issue = 1 | pages = 163–71 | date = January 2016 | pmid = 26642869 | doi = 10.1021/acs.molpharmaceut.5b00594 | s2cid = 46496531 | url = http://www.zora.uzh.ch/id/eprint/118806/1/acs.molpharmaceut.pdf }}

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.{{cite journal | vauthors = Nirenberg MJ | title = Dopamine agonist withdrawal syndrome: implications for patient care | journal = Drugs & Aging | volume = 30 | issue = 8 | pages = 587–92 | date = August 2013 | pmid = 23686524 | doi = 10.1007/s40266-013-0090-z | s2cid = 207489653 }}

File:Bromocriptin.png

Bromocriptine is a partial agonist of the dopamine D₂ receptor.{{cite journal | vauthors = de Leeuw van Weenen JE, Parlevliet ET, Maechler P, Havekes LM, Romijn JA, Ouwens DM, Pijl H, Guigas B | title = The dopamine receptor D2 agonist bromocriptine inhibits glucose-stimulated insulin secretion by direct activation of the alpha2-adrenergic receptors in beta cells | journal = Biochemical Pharmacology | volume = 79 | issue = 12 | pages = 1827–36 | date = June 2010 | pmid = 20138024 | doi = 10.1016/j.bcp.2010.01.029 }} It also interacts with other dopamine receptors and with various serotonin and adrenergic receptors. Bromocriptine has additionally been found to inhibit the release of glutamate by reversing the GLT1 glutamate transporter.{{cite journal | vauthors = Shirasaki Y, Sugimura M, Sato T | title = Bromocriptine, an ergot alkaloid, inhibits excitatory amino acid release mediated by glutamate transporter reversal | journal = European Journal of Pharmacology | volume = 643 | issue = 1 | pages = 48–57 | date = September 2010 | pmid = 20599932 | doi = 10.1016/j.ejphar.2010.06.007 }}

Despite acting as a serotonin 5-HT_2A receptor agonist, bromocriptine is described as non-hallucinogenic.{{cite journal | vauthors = Gumpper RH, Roth BL | title = Psychedelics: preclinical insights provide directions for future research | journal = Neuropsychopharmacology | volume = 49 | issue = 1 | pages = 119–127 | date = January 2024 | pmid = 36932180 | doi = 10.1038/s41386-023-01567-7 | url = | pmc = 10700551 }}

As a silent antagonist of the serotonin 5-HT_2B receptor, bromocriptine has been said not to pose a risk of cardiac valvulopathy.{{cite journal | vauthors = Cavero I, Guillon JM | title = Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy | journal = J Pharmacol Toxicol Methods | volume = 69 | issue = 2 | pages = 150–61 | date = 2014 | pmid = 24361689 | doi = 10.1016/j.vascn.2013.12.004 | url = }} This is in contrast to other ergolines acting instead as 5-HT_2B receptor agonists such as cabergoline and pergolide but is similar to lisuride which likewise acts as a 5-HT_2B receptor antagonist. However, in other research, bromocriptine has subsequently been found to be a partial agonist of the serotonin 5-HT_2B receptor and has been associated with cardiac valvulopathy and related complications.{{cite journal | vauthors = Samson SL, Ezzat S | title = AACE/ACE Disease State Clinical Review: Dopamine Agonists for Hyperprolactinemia and the Risk of Cardiac Valve Disease | journal = Endocr Pract | volume = 20 | issue = 6 | pages = 608–616 | date = June 2014 | pmid = 24969114 | doi = 10.4158/EP14148.RA | url = | quote = Bromocriptine was first described as a 5HT-2BR antagonist (22) but was subsequently found to have partial agonist properties (23,24). [...] Regarding bromocriptine, there was no increased incidence of valve regurgitation in PD patients on bromocriptine in the population-based study of Schade et al (33), despite the significant findings for cabergoline and pergolide. However, there is a case report implicating high doses of bromocriptine as the cause of triple valve disease in a PD patient (37), and 1 study reported a significant correlation between cumulative dose of bromocriptine and the risk of valve regurgitation in a PD cohort (38). Other publications have reported fibrotic events, including retroperitoneal, pericardial and pleural fibrosis, in PD patients on high-dose bromocriptine (39-43). [...] Although there seems to be a lower risk of valvulopathy with bromocriptine, as a partial 5HT-2BR agonist, there still appears to be some risk with high-dose bromocriptine in PD patients.}}{{cite journal | vauthors = Elenkova A, Shabani R, Kalinov K, Zacharieva S | title = Increased prevalence of subclinical cardiac valve fibrosis in patients with prolactinomas on long-term bromocriptine and cabergoline treatment | journal = Eur J Endocrinol | volume = 167 | issue = 1 | pages = 17–25 | date = July 2012 | pmid = 22511808 | doi = 10.1530/EJE-12-0121 | url = }}{{cite journal | vauthors = Boguszewski CL, dos Santos CM, Sakamoto KS, Marini LC, de Souza AM, Azevedo M | title = A comparison of cabergoline and bromocriptine on the risk of valvular heart disease in patients with prolactinomas | journal = Pituitary | volume = 15 | issue = 1 | pages = 44–49 | date = March 2012 | pmid = 21847572 | doi = 10.1007/s11102-011-0339-7 | url = }}{{cite journal | vauthors = Tan LC, Ng KK, Au WL, Lee RK, Chan YH, Tan NC | title = Bromocriptine use and the risk of valvular heart disease | journal = Mov Disord | volume = 24 | issue = 3 | pages = 344–349 | date = February 2009 | pmid = 18989898 | doi = 10.1002/mds.22228 | url = }} In any case, bromocriptine seems to have lower risk than certain other drugs.

Like 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.{{cite patent | country = US | number = 3752814 | title = 2-Bromo-alpha-ergocryptine | inventor = Fluckiger E, Hofmann A | url = https://patents.google.com/patent/US3752814A/en | assign = Sandoz AG | gdate = 14 August 1973 }}{{cite patent|country=DE|number=1926045A1|title=Verfahren zur Herstellung einer neuen heterocyclischen Verbindung [Process for the preparation of a new heterocyclic compound] |inventor = Hofmann A, Flueckiger E, Troxler F | assign = Sandoz AG |gdate = 21 September }}

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Bromocriptine was discovered by scientists at Sandoz in 1965 and was first published in 1968; it was first marketed under the brand name Parlodel.{{cite book| vauthors = Sneader W, Corey EJ |title=Drug Discovery: A History|date=2005|publisher=John Wiley & Sons|isbn=9780471899792|page=352|url=https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA352|language=en}}{{cite journal| vauthors = Beekman AM, Barrow RA |title=Fungal Metabolites as Pharmaceuticals|journal=Australian Journal of Chemistry|date=2014|volume=67|issue=6|pages=827|doi=10.1071/CH13639}}

A quick-release formulation of bromocriptine was approved by the FDA in 2009.{{cite journal | vauthors = Holt RI, Barnett AH, Bailey CJ | title = Bromocriptine: old drug, new formulation and new indication | journal = Diabetes, Obesity & Metabolism | volume = 12 | issue = 12 | pages = 1048–57 | date = December 2010 | pmid = 20977575 | doi = 10.1111/j.1463-1326.2010.01304.x | s2cid = 22908831 }}

As 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.{{cite web|title=Bromocriptine international brand names|url=https://www.drugs.com/international/bromocriptine.html|publisher=Drugs.com|access-date=13 July 2017|url-status=live|archive-url=https://web.archive.org/web/20170806023201/https://www.drugs.com/international/bromocriptine.html|archive-date=6 August 2017}}

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.

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