Bromocriptine

Source: Wikipedia, the free encyclopedia.
Bromocriptine
Clinical data
Trade namesOriginally Parlodel, subsequently many[1]
Other names2-Bromoergocriptine; CB-154
AHFS/Drugs.comMonograph, International Drug Names
MedlinePlusa682079
Pregnancy
category
  • AU: A
intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability28% of oral dose absorbed
MetabolismExtensively liver-mediated
Elimination half-life12–14 hours
Excretion85% bile (feces), 2.5–5.5% urine
Identifiers
  • (5α)-2-Bromo-12-hydroxy-5-(2-methylpropyl)-3,6,18-trioxo-2-(propan-2-yl)ergotaman
JSmol)
  • 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=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 checkY
  • Key:OZVBMTJYIDMWIL-AYFBDAFISA-N checkY
  (verify)

Bromocriptine, originally marketed as Parlodel and subsequently under many brand names,

type 2 diabetes
.

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

Medical uses

Bromocriptine is used to treat

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, decreases blood glucose levels and hepatic glucose production and also 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,

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

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

As an

cardiac valvulopathy.[26] 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.[26]

Activities of bromocriptine at various sites[21][22][24][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][27]

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.[28][29]

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.[30][31]

A quick-release formulation of bromocriptine was approved by the FDA in 2009.[32]

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. ^ a b c d "Bromocriptine international brand names". Drugs.com. Archived from the original on 6 August 2017. Retrieved 13 July 2017.
  2. .
  3. ^ 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
  4. S2CID 205077946
    .
  5. .
  6. .
  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. PMID 23337160
    .
  9. .
  10. ^ .
  11. .
  12. .
  13. .
  14. .
  15. .
  16. .
  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. S2CID 46496531
    .
  20. .
  21. ^ .
  22. ^ .
  23. .
  24. ^ .
  25. .
  26. ^ .
  27. ^ a b 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.
  28. ^ E. Fluckiger, A. Hofmann, U.S. patent 3,752,814 (1973)
  29. Sandoz AG
     
  30. .
  31. .
  32. .

External links