Bromocriptine

Template:Short description Template:Cs1 config Template:Main other {{#invoke:Infobox|infobox}}Template:Template other{{#invoke:TemplatePar |check |template=Template:Infobox_drug |all= |opt= pronounce= pronounce_ref= pronounce_comment= ATC_prefix= ATC_suffix= ATC_supplemental= ATCvet= biosimilars= CAS_number_Ref= CAS_number= CAS_supplemental= ChEBI= ChEBI_Ref= ChEMBL_Ref= ChEMBL= ChemSpiderID= ChemSpiderID_Ref= chirality= class= container_only= DailyMedID= data_page= DrugBank_Ref= DrugBank= Drugs.com= duration_of_action= INN= INN_EMA= IUPAC_name= IUPHAR_ligand= KEGG_Ref= KEGG= MedlinePlus= NIAID_ChemDB= PDB_ligand= PubChemSubstance= PubChem= StdInChIKey_Ref= StdInChIKey= StdInChI_Ref= StdInChI_comment= StdInChI= UNII_Ref= UNII= DTXSID= Verifiedfields= Watchedfields= addiction_liability= alt2= altL= altR= alt= bioavailability= boiling_high= boiling_notes= boiling_point= captionLR= caption= caption2= charge= chemical_formula= chemical_formula_ref= chemical_formula_comment= class1= class2= class3= class4= class5= class6= component1= component2= component3= component4= component5= component6= density= density_notes= dependency_liability= drug_name= elimination_half-life= engvar= excretion= image2= imageL= imageR= image= image_class= image_class2= image_classL= image_classR= Jmol= legal_AU= legal_BR= legal_CA= legal_DE= legal_EU= legal_NZ= legal_UK= legal_UN= legal_US= legal_AU_comment= legal_BR_comment= legal_CA_comment= legal_DE_comment= legal_UK_comment= legal_NZ_comment= legal_US_comment= legal_UN_comment= legal_EU_comment= legal_status= licence_CA= licence_EU= licence_US= license_CA= license_EU= license_US= mab_type= melting_high= melting_notes= melting_point= metabolism= metabolites= molecular_weight= molecular_weight_round= molecular_weight_unit= molecular_weight_ref= molecular_weight_comment= onset= pregnancy_AU= pregnancy_AU_comment= pregnancy_category= protein_bound= routes_of_administration= SMILES= smiles= solubility= sol_units= source= specific_rotation= synonyms= target= tradename= type= vaccine_type= verifiedrevid= width2= widthL= widthR= width= AAN= BAN= JAN= USAN= source_tissues= target_tissues= receptors= agonists= antagonists= precursor= biosynthesis= gt_target_gene= gt_vector= gt_nucleic_acid_type= gt_editing_method= gt_delivery_method= sec_combustion= Ac=Ag=Al=Am=Ar=As=At=Au=B=Ba=Be=Bh=Bi=Bk=Br=C=Ca=Cd=Ce=Cf=Cl=Cm=Cn=Co=Cr=Cs=Cu= D=Db=Ds=Dy=Er=Es=Eu=F=Fe=Fl=Fm=Fr=Ga=Gd=Ge=H=He=Hf=Hg=Ho=Hs=I=In=Ir=K=Kr=La=Li=Lr=Lu=Lv= Mc=Md=Mg=Mn=Mo=Mt=N=Na=Nb=Nd=Ne=Nh=Ni=No=Np=O=Og=Os=P=Pa=Pb=Pd=Pm=Po=Pr=Pt=Pu=Ra=Rb=Re=Rf=Rg=Rh=Rn=Ru=S=Sb=Sc=Se=Sg=Si=Sm=Sn=Sr=Ta=Tb=Tc=Te=Th=Ti=Tl=Tm=Ts=U=V=W=Xe=Y=Yb=Zn=Zr= index_label= index2_label= index_comment= index2_comment= CAS_number2= CAS_supplemental2= ATC_prefix2= ATC_suffix2= ATC_supplemental2= PubChem2= PubChemSubstance2= IUPHAR_ligand2= DrugBank2= ChemSpiderID2= UNII2= KEGG2= ChEBI2= ChEMBL2= PDB_ligand2= NIAID_ChemDB2= SMILES2= smiles2= StdInChI2= StdInChIKey2= CAS_number2_Ref= ChEBI2_Ref= ChEMBL2_Ref= ChemSpiderID2_Ref= DrugBank2_Ref= KEGG2_Ref= StdInChI2_Ref= StdInChIKey2_Ref= UNII2_Ref= DTXSID2= QID= QID2=PLLR= pregnancy_US= pregnancy_US_comment= |cat=Pages using infobox drug with unknown parameters |format=0|errNS=0

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| _other_data=(5Template:Primeα)-2-Bromo-12Template:Prime-hydroxy-5Template:Prime-(2-methylpropyl)-3Template:Prime,6Template:Prime,18-trioxo-2Template:Prime-(propan-2-yl)ergotaman

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| _datapage = Bromocriptine (data page) | _vaccine_target={{#ifeq: | vaccine | | _type_not_vaccine }} | _legal_all=S4Rx-onlyPOMRx-only | _ATC_prefix_supplemental=G02Template:ATC | _has_EMA_link = | CAS_number=25614-03-3 | PubChem=31101 | ChemSpiderID=28858 | ChEBI=3181 | ChEMBL=493 | DrugBank=DB01200 | KEGG=D03165 | _hasInChI_or_Key={{#if: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/s1OZVBMTJYIDMWIL-AYFBDAFISA-N |yes}} | UNII=3A64E3G5ZO | _hasJmol02 = |_hasMultipleCASnumbers = |_hasMultiplePubChemCIDs = |_hasMultipleChEBIs =

| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields= |Watchedfields=changed |verifiedrevid=459983915}} Bromocriptine, originally marketed as Parlodel and subsequently under many brand names,<ref name=brands/> 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.

It was patented in 1968 and approved for medical use in 1975.<ref name=Fis2006>Template:Cite book</ref>

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<ref name=OlderLabel>{{#invoke:citation/CS1|citation |CitationClass=web }} For label updates see FDA index page for NDA 017962 Template:Webarchive</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and to treat Parkinson's disease.<ref name=OlderLabel/>

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.<ref>Template:Cite journal</ref> 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.<ref name=DiabetesLabel>{{#invoke:citation/CS1|citation |CitationClass=web }}. For label updates see FDA index page for NDA 020866 Template:Webarchive</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name=":0">Template:Cite journal</ref> It therefore acts as an adjunct to diet and exercise to improve glycemic control and cardiovascular risk.<ref name=":0" /><ref>Template:Cite journal</ref>

Side effects

Most frequent side effects are nausea, orthostatic hypotension, headaches, and vomiting through stimulation of the brainstem vomiting centre.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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).<ref>Template:Cite journal</ref> 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)<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }} "EMA rät vom Abstillmittel Bromocriptin ab", article in Ärzteblatt</ref> It is a bile salt export pump inhibitor.<ref>Template:Cite journal</ref>

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.<ref name="pmid23686524">Template:Cite journal</ref>

Pharmacology

Pharmacodynamics

File:Bromocriptin.png

Bromocriptine in a dopamine receptor bound conformation.

Bromocriptine is a partial agonist of the dopamine D₂ receptor.<ref name="pmid12388666" /><ref name="pmid12388667" /><ref name="pmid20138024">Template:Cite journal</ref> It also interacts with other dopamine receptors and with various serotonin and adrenergic receptors.<ref name="pmid12388666" /><ref name="pmid12388667" /><ref name="pmid12388668" /> Bromocriptine has additionally been found to inhibit the release of glutamate by reversing the GLT1 glutamate transporter.<ref>Template:Cite journal</ref>

Despite acting as a serotonin 5-HT_2A receptor agonist, bromocriptine is described as non-hallucinogenic.<ref name="GumpperRoth2024">Template:Cite journal</ref>

As a silent antagonist of the serotonin 5-HT_2B receptor,<ref name="pmid12388668" /> bromocriptine has been said not to pose a risk of cardiac valvulopathy.<ref name="pmid24361689">Template:Cite journal</ref> 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.<ref name="pmid24361689" /> 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.<ref name="SamsonEzzat2014">Template:Cite journal</ref><ref name="ElenkovaShabaniKalinov2012">Template:Cite journal</ref><ref name="BoguszewskidosSantosSakamoto2012">Template:Cite journal</ref><ref name="TanNgAu2009">Template:Cite journal</ref> In any case, bromocriptine seems to have lower risk than certain other drugs.<ref name="SamsonEzzat2014" />

Template:Nowrap

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.<ref name="pmid12388666" /><ref name="PDSPKiDatabase" />

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.<ref>Template:Cite patent</ref><ref>Template:Cite patent</ref>

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.<ref>Template:Cite book</ref><ref>Template:Cite journal</ref>

A quick-release formulation of bromocriptine was approved by the FDA in 2009.<ref>Template:Cite journal</ref>

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.<ref name=brands>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name=brands/>

External links

• Template:MedlinePlusDrugInfo