Bromocriptine

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.

Bromocriptine

Clinical data
Trade names	Originally Parlodel, subsequently many[1]
Other names	2-Bromoergocriptine; CB-154
AHFS/Drugs.com	Monograph, International Drug Names
MedlinePlus	a682079
Pregnancy category	AU: A
Routes of administration	By mouth, vaginal, intravenous
ATC code	G02CB01 (WHO) N04BC01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
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
Identifiers
IUPAC name (5′α)-2-Bromo-12′-hydroxy-5′-(2-methylpropyl)-3′,6′,18-trioxo-2′-(propan-2-yl)ergotaman
CAS Number	25614-03-3 Y
PubChem CID	31101
IUPHAR/BPS	35
DrugBank	DB01200 Y
ChemSpider	28858 Y
UNII	3A64E3G5ZO
KEGG	D03165 Y
ChEBI	CHEBI:3181 Y
ChEMBL	ChEMBL493 Y
CompTox Dashboard (EPA)	DTXSID1022687
ECHA InfoCard	100.042.829
Chemical and physical data
Formula	C32H40BrN5O5
Molar mass	654.606 g·mol−1
3D model (JSmol)	Interactive image
SMILES BrC1=C(C[C@H]2N(C)C3)C4=C(C=CC=C4C2=C[C@H]3C(N[C@]5(C(C)C)O[C@@]6(N([C@@H](CC(C)C)C(N7CCC[C@H]76)=O)C5=O)O)=O)N1
InChI InChI=1S/C32H40BrN5O5/c1-16(2)12-24-29(40)37-11-7-10-25(37)32(42)38(24)30(41)31(43-32,17(3)4)35-28(39)18-13-20-19-8-6-9-22-26(19)21(27(33)34-22)14-23(20)36(5)15-18/h6,8-9,13,16-18,23-25,34,42H,7,10-12,14-15H2,1-5H3,(H,35,39)/t18-,23-,24+,25+,31-,32+/m1/s1 Y Key:OZVBMTJYIDMWIL-AYFBDAFISA-N Y
(verify)

It was patented in 1968 and approved for medical use in 1975.^[2]

Medical uses

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^[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

Most 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 henomenon.

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 D_2S receptor form (considered to be mostly present at inhibitory D₂ autoreceptor locatations)^[15] 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.^[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

Pharmacodynamics

Bromocriptine in a dopamine receptor bound conformation.

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-HT_2A receptor agonist, bromocriptine is described as non-hallucinogenic.^[26]

As an silent antagonist of the serotonin 5-HT_2B receptor,^[24] bromocriptine has been said not to pose a risk of cardiac valvulopathy.^[27] 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.^[27] 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.^{[28][29][30][31]} In any case, bromocriptine seems to have lower risk than certain other drugs.^[28]

Activities of bromocriptine at various sites^{[21][22][24][32]}

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	?	Partial agonist
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][32]

Chemistry

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.^[33][34]

History

Bromocriptine was discovered by scientists at Sandoz in 1965 and was first published in 1968; it was first marketed under the brand name Parlodel.^[35][36]

A quick-release formulation of bromocriptine was approved by the FDA in 2009.^[37]

Society and culture

Brand names

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.^[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

1. "Bromocriptine international brand names". Drugs.com. Archived from the original on 6 August 2017. Retrieved 13 July 2017.
2. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 533. ISBN 9783527607495.
3. "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
4. 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.
5. 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.
6. 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.
7. "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
8. 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.
9. 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.
10. 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.
11. 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.
12. Weil C (1986). "The safety of bromocriptine in long-term use: a review of the literature". Current Medical Research and Opinion. 10 (1): 25–51. doi:10.1185/03007998609111089. PMID 3516579.
13. Iffy L, McArdle JJ, Ganesh V, Hopp L (1996). "Bromocriptine related atypical vascular accidents postpartum identified through medicolegal reviews". Medicine and Law. 15 (1): 127–34. PMID 8691994.
14. Boyd A (1995). "Bromocriptine and psychosis: a literature review". The Psychiatric Quarterly. 66 (1): 87–95. doi:10.1007/BF02238717. PMID 7701022. S2CID 29539691.
15. 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.
16. 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.
17. "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.
18. "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
19. Montanari F, Pinto M, Khunweeraphong N, Wlcek K, Sohail MI, Noeske T, et al. (January 2016). "Flagging Drugs That Inhibit the Bile Salt Export Pump" (PDF). Molecular Pharmaceutics. 13 (1): 163–71. doi:10.1021/acs.molpharmaceut.5b00594. PMID 26642869. S2CID 46496531.
20. Nirenberg MJ (August 2013). "Dopamine agonist withdrawal syndrome: implications for patient care". Drugs & Aging. 30 (8): 587–92. doi:10.1007/s40266-013-0090-z. PMID 23686524. S2CID 207489653.
21. Millan 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". J Pharmacol Exp Ther. 303 (2): 791–804. doi:10.1124/jpet.102.039867. PMID 12388666. S2CID 6200455.
22. Newman-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". J Pharmacol Exp Ther. 303 (2): 805–14. doi:10.1124/jpet.102.039875. PMID 12388667. S2CID 35238120.
23. de Leeuw van Weenen JE, Parlevliet ET, Maechler P, Havekes LM, Romijn JA, Ouwens DM, et al. (June 2010). "The dopamine receptor D2 agonist bromocriptine inhibits glucose-stimulated insulin secretion by direct activation of the alpha2-adrenergic receptors in beta cells". Biochemical Pharmacology. 79 (12): 1827–36. doi:10.1016/j.bcp.2010.01.029. PMID 20138024.
24. Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verrièle L, Carpentier N, et al. (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes". J Pharmacol Exp Ther. 303 (2): 815–22. doi:10.1124/jpet.102.039883. PMID 12388668. S2CID 19260572.
25. Shirasaki Y, Sugimura M, Sato T (September 2010). "Bromocriptine, an ergot alkaloid, inhibits excitatory amino acid release mediated by glutamate transporter reversal". European Journal of Pharmacology. 643 (1): 48–57. doi:10.1016/j.ejphar.2010.06.007. PMID 20599932.
26. Gumpper RH, Roth BL (January 2024). "Psychedelics: preclinical insights provide directions for future research". Neuropsychopharmacology. 49 (1): 119–127. doi:10.1038/s41386-023-01567-7. PMID 36932180.
27. Cavero I, Guillon JM (2014). "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy". J Pharmacol Toxicol Methods. 69 (2): 150–61. doi:10.1016/j.vascn.2013.12.004. PMID 24361689.
28. Samson SL, Ezzat S (June 2014). "AACE/ACE Disease State Clinical Review: Dopamine Agonists for Hyperprolactinemia and the Risk of Cardiac Valve Disease". Endocr Pract. 20 (6): 608–616. doi:10.4158/EP14148.RA. PMID 24969114. 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.
29. Elenkova A, Shabani R, Kalinov K, Zacharieva S (July 2012). "Increased prevalence of subclinical cardiac valve fibrosis in patients with prolactinomas on long-term bromocriptine and cabergoline treatment". Eur J Endocrinol. 167 (1): 17–25. doi:10.1530/EJE-12-0121. PMID 22511808.
30. Boguszewski CL, dos Santos CM, Sakamoto KS, Marini LC, de Souza AM, Azevedo M (March 2012). "A comparison of cabergoline and bromocriptine on the risk of valvular heart disease in patients with prolactinomas". Pituitary. 15 (1): 44–49. doi:10.1007/s11102-011-0339-7. PMID 21847572.
31. Tan LC, Ng KK, Au WL, Lee RK, Chan YH, Tan NC (February 2009). "Bromocriptine use and the risk of valvular heart disease". Mov Disord. 24 (3): 344–349. doi:10.1002/mds.22228. PMID 18989898.
32. National Institute of Mental Health. PDSP Ki Database (Internet). ChapelHill (NC): University of North Carolina. Available from: "PDSP Database - UNC". Archived from the original on 2021-04-13. Retrieved 2021-04-12.
33. US 3752814, Fluckiger E, Hofmann A, "2-Bromo-alpha-ergocryptine", issued 14 August 1973, assigned to Sandoz AG
34. DE 1926045A1, Hofmann A, Flueckiger E, Troxler F, "Verfahren zur Herstellung einer neuen heterocyclischen Verbindung [Process for the preparation of a new heterocyclic compound]", issued 21 September, assigned to Sandoz AG
35. Sneader W, Corey EJ (2005). Drug Discovery: A History. John Wiley & Sons. p. 352. ISBN 9780471899792.
36. Beekman AM, Barrow RA (2014). "Fungal Metabolites as Pharmaceuticals". Australian Journal of Chemistry. 67 (6): 827. doi:10.1071/CH13639.
37. Holt RI, Barnett AH, Bailey CJ (December 2010). "Bromocriptine: old drug, new formulation and new indication". Diabetes, Obesity & Metabolism. 12 (12): 1048–57. doi:10.1111/j.1463-1326.2010.01304.x. PMID 20977575. S2CID 22908831.

External links

• MedlinePlus DrugInfo medmaster-a682079