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Bromocriptine (INN; trade names Parlodel, Cycloset), an ergoline derivative, is a dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease (PD), hyperprolactinaemia, neuroleptic malignant syndrome, and type 2 diabetes.

Indications[edit]

Amenorrhea, female infertility, galactorrhea, hypogonadism, and acromegaly may all be caused by pituitary problems, such as hyperprolactinaemia, and therefore, these problems may be treated with this drug. Bromocriptine has completely treated gestational macromastia eliminating the need for reduction surgery, in a recent case.^[1]Since the late 1980s it has been used, off-label, to reduce the symptoms of cocaine withdrawal.^[2]^[3] In 2009, bromocriptine mesylate was approved by the FDA for treatment of type 2 diabetes under the trade name Cycloset (VeroScience). It is currently unknown how this drug improves glycemic control, but it has been shown to reduce HbA1c by ~0.5 percentage points.^[4]

Pharmacology[edit]

Bromocriptine is a potent agonist at dopamine D2 receptors^[5] and various serotonin receptors. It also inhibits the release of glutamate, by reversing the glutamate GLT1 transporter.^[6]

Bromocriptine agonizes the following monoamine receptors:^[7]

Dopamine D₁ family
- D₁ (K_i=682 nM)
- D₅ (K_i=496 nM)
Dopamine D₂ family
- D₂ (K_i=2.96 nM)
- D₃ (K_i=5.42 nM)
- D₄ (K_i=328 nM)
Serotonin 5-HT
- 5-HT_1A (K_i=12.9 nM)
- 5-HT_1B (K_i=355 nM)
- 5-HT_1D (K_i=10.7 nM)
- 5-HT_2A (K_i=107 nM)
- 5-HT_2B (K_i=56.2 nM)
- 5-HT_2C (K_i=741 nM)
- 5-HT₆ (K_i=33 nM)
Adrenergic α family
- α_1A (K_i=4.17 nM)
- α_1B (K_i=1.38 nM)
- α_1D (K_i=1.12 nM)
- α_2A (K_i=11.0 nM)
- α_2B (K_i=34.7 nM)
- α_2C (K_i=28.2 nM)
Adrenergic β family
- β₁ (K_i=589 nM)
- β₂ (K_i=741 nM)

Other properties for serotonin are yet unknown.

Side effects[edit]

Most frequent side effects are nausea, orthostatic hypotension, headaches, and vomiting through stimulation of the brainstem vomiting centre.^[8] Bromocriptine can cause worsening of liver problems. 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.^[9] 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).^[10] Pulmonary fibrosis has been reported when bromocriptine was used in high doses for the treatment of Parkinson's disease.^[11]

Chemistry[edit]

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, 2-bromoergocriptine, is a semisynthetic derivative of a natural ergot alkaloid, ergocriptin (a derivative of lysergic acid), which is synthesized by bromination of ergocriptin using N-bromosuccinimide.

E. Fluckiger, A. Hofmann, U.S. Patent 3,752,814 (1973).
A. Hofmann, E. Flueckiger, DE 1926045 (1969).

References[edit]

^ Ezem, Osuagwu, Opara (February 2011). "Gestational gigantomastia with complete resolution in a Nigerian woman". BMJ. doi:10.1136/bcr.01.2010.2632. Cite uses deprecated parameters (help)
^ AJ Giannini, P Baumgartel, LR DiMarzio. Bromocriptine therapy in cocaine withdrawal. J. Clinical Pharmacology. 27: 267-270,1987.
^ FS Tenant, AA Sagherian. Double-blind comparison of amantadine hydrochloride and bromocriptine mesylate for ambulatory withdrawal from cocaine dependence. Archives of General Medicine. 147: 109-112,1987.
^ Pijl H, Ohashi S, Matsuda M, et al. (August 2000). "Bromocriptine: a novel approach to the treatment of type 2 diabetes". Diabetes Care 23 (8): 1154–61. doi:10.2337/diacare.23.8.1154. PMID 10937514. Cite uses deprecated parameters (help)
^ De Leeuw Van Weenen, J. E.; Parlevliet, E. T.; Maechler, P.; Havekes, L. M.; Romijn, J. A.; Ouwens, D. M.; Pijl, H.; Guigas, B. (2010). "The dopamine receptor D2 agonist bromocriptine inhibits glucose-stimulated insulin secretion by direct activation of the α2-adrenergic receptors in beta cells". Biochemical Pharmacology 79 (12): 1827. doi:10.1016/j.bcp.2010.01.029. PMID 20138024. edit
^ "ScienceDirect - European Journal of Pharmacology : Bromocriptine, an ergot alkaloid, inhibits excitatory amino acid release mediated by glutamate transporter reversal". Retrieved 2010-08-31.
^ National Institute ofMental Health. PDSD Ki Database (Internet) [cited 2013 Jul 24]. ChapelHill (NC): University of North Carolina. 1998-2013. Available from: http://pdsp.med.unc.edu/pdsp.php
^ 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. edit
^ 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. edit
^ Boyd, A. (1995). "Bromocriptine and psychosis: a literature review". The Psychiatric quarterly 66 (1): 87–95. doi:10.1007/BF02238717. PMID 7701022. edit
^ Todman, D.; Oliver, W.; Edwards, R. (1990). "Pleuropulmonary fibrosis due to bromocriptine treatment for Parkinson's disease". Clinical and experimental neurology 27: 79–82. PMID 2129961. edit

External links[edit]

www.AcromegalyCommunity.com: Emotional and communal support for those touched by Acromegaly- page discussing drug, side effects, and prescription programs
MedlinePlus DrugInfo medmaster-a682079
http://www.drugs.com/pro/bromocriptine.html

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 周産期心筋症：治療および予後 peripartum cardiomyopathy treatment and prognosis
2. 2型糖尿病における持続性高血糖のマネージメント management of persistent hyperglycemia in type 2 diabetes mellitus
3. 高プロラクチン血症のマネージメント management of hyperprolactinemia
4. パーキンソン病に対する神経保護療法 neuroprotective therapy for parkinson disease
5. 悪性症候群 neuroleptic malignant syndrome

English Journal

Not only dopamine D(2) receptors involved in Peony-Glycyrrhiza Decoction, an herbal preparation against antipsychotic-associated hyperprolactinemia.

Wang D, Wong HK, Zhang L, McAlonan GM, Wang XM, Sze SC, Feng YB, Zhang ZJ.SourceSchool of Chinese Medicine, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong, China.
Progress in neuro-psychopharmacology & biological psychiatry.Prog Neuropsychopharmacol Biol Psychiatry.2012 Dec 3;39(2):332-8. doi: 10.1016/j.pnpbp.2012.07.005. Epub 2012 Jul 11.
Clinical studies have demonstrated the effectiveness of an herbal preparation called Peony-Glycyrrhiza Decoction (PGD) in alleviating antipsychotic-induced hyperprolactinemia (hyperPRL). In the present study, we further examined the pharmacological action of PGD on prolactin (PRL) secretion using in
PMID 22796279

Diminished adrenal sensitivity and ACTH efficacy in obese premenopausal women.

Roelfsema F, Pijl H, Keenan DM, Veldhuis JD.SourceDepartment of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
European journal of endocrinology / European Federation of Endocrine Societies.Eur J Endocrinol.2012 Nov;167(5):633-42. doi: 10.1530/EJE-12-0592. Epub 2012 Aug 21.
BACKGROUND: The ACTH-cortisol axis in women is activated and associated with decreased ACTH potency, estimated by relating ACTH and cortisol pulse masses. Recently, a new accurate method for constructing the endogenous dose-response relationship was introduced, which is based on the relation between
PMID 22909443

Japanese Journal

ブロモクリプチン (新臨床糖尿病学(上)糖尿病学の最新動向) -- (糖尿病の予防・管理・治療)

松田昌文
日本臨床 70(-) (1020(増刊3)), 734-739, 2012-05
NAID 40019325446

最新の薬物治療 (特集高プロラクチン血症とプロラクチン産生下垂体腫瘍) -- (プロラクチン産生下垂体腫瘍の治療)

小野昌美,三木伸泰,市原淳弘
内分泌・糖尿病・代謝内科 34(2), 118-124, 2012-02
NAID 40019237015

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★リンクテーブル★

リンク元	「ドパミン」「下垂体前葉ホルモン」「ブロモクリプチン」「パーキンソン病治療薬」
拡張検索	「bromocriptine mesilate」「bromocriptine test」

「ドパミン」

Bromocriptine
Systematic (IUPAC) name
	(5′α)-2-bromo-12′-hydroxy-5′-(2-methylpropyl)-3′,6′,18-trioxo-2′-(propan-2-yl)ergotaman
Clinical data
Trade names	Parlodel
AHFS/Drugs.com	monograph
MedlinePlus	a682079
Pregnancy cat.	D (US)
Legal status	POM (UK) ℞-only (US)
Routes	oral, intravenous
Pharmacokinetic data
Bioavailability	28% of oral dose absorbed
Metabolism	?
Half-life	12-14 hours
Excretion	85% bile (faeces)
Identifiers
CAS number	25614-03-3
ATC code	G02CB01 N04BC01
PubChem	CID 31101
IUPHAR ligand	35
DrugBank	DB01200
ChemSpider	28858
UNII	3A64E3G5ZO
KEGG	D03165
ChEBI	CHEBI:3181
ChEMBL	CHEMBL493
Chemical data
Formula	C32H40BrN5O5
Mol. mass	654.595
	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 ; Key:OZVBMTJYIDMWIL-AYFBDAFISA-N ;
(what is this?) (verify)

　　[★]

英: dopamine DA DOA 3,4-dihydroxyphenethylamine
同: ドーパミン
化: 塩酸ドパミン, dopamine hydrochloride, ドパミン塩酸塩
商: イノバン、イブタント、カコージンD、カコージン、カタボン、ガバンス、クリトパン、ツルドパミ、ドパラルミン、ドミニン、トロンジン、プレドパ、マートバーン、ヤエリスタ
関: ドパミン受容体、カテコラミン。強心剤

概念

カテコラミンの一つ

生合成

チロシン→L-dopa→ドパミン→ノルアドレナリン→アドレナリン
脳、交感神経、交感神経節、副腎皮質のクロム親和性細胞で産生される

視床下部-下垂体系

視床下部弓状核や脳室周辺の隆起漏斗系ドパミンニューロンで産生される。
下垂体のD2受容体を介してホルモン分泌の調節を受けている。　→ e.g. プロラクチン放出抑制ホルモン(PIF)

ドパミン受容体

D₁受容体

低用量での血管拡張はこの受容体を介して起こる (GOO.249)

D₂受容体

中枢神経系に存在

神経伝達物質の薬理 (GOO.324)

神経伝達物質	トランスポーター阻害薬	受容体のサブタイプ	選択的作動薬	選択的阻害薬	受容体と共役する分子
ドパミン	cocaine mazindol nomifensine	D₁			G_s
		D₂	bromocriptine	sulpiride domperidone	G_i
		D₃	7-OH-DPAT
		D₄
		D₅			G_s

薬理学

低濃度

D₁受容体に作用して血管拡張→腎血流量↑→GFP↑→Na排出↑→利尿

やや高濃度

β₁受容体に作用→心拍出量↑・心収縮力↑(頻脈はない)・収縮期圧↑・拡張期圧不変

アドレナリン低用量投与と同じ？

高濃度

α₁受容体に作用→血管平滑筋収縮(→収縮期圧↑、拡張期圧↑？？？)

アドレナリン高用量投与と同じ？

ran]]

(PT.218)

中脳に細胞体を持つものが多く、黒質から線条体に至る黒質線条体系と黒質や腹側被蓋野から報酬系の神経核、辺縁系、前頭葉に至る中脳皮質系がある。視床下部やその周辺にもドーパミン作動性線維の細胞体とその終末があり、隆起漏斗系、隆起下垂体系、不確帯視床下部系、脳室周囲系を形成する。黒質線条体系の変性はパーキンソン病をもたらす。ドーパミン誘導体には幻覚剤となるものがある。ドーパミンの分泌増大や脳のD2受容体の増加は精神分裂病（統合失調症）の発病に関与している可能性がある。モルヒネはドーパミンの分泌を促進する。コカインは輸送体によるドーパミンの取り込みを阻害し作用の持続時間を延長する。一部の覚醒剤中毒はドーパミン輸送体の抑制による。

ホルモンの調節

プロラクチンは視床下部でドパミンの産生を促進　←　プロラクチン抑制因子として作用
ドパミンは視床下部でGnRHの分泌を抑制　→　卵巣機能の抑制
ドパミンは下垂体前葉？でD受容体に作用してプロラクチンを抑制　←　抗精神病薬(D2受容体をブロックする)を使うと高プロラクチン血症となる。

循環不全治療薬として

イノバン

下記のような急性循環不全(心原性ショック、出血性ショック)

(1) 無尿、乏尿や利尿剤で利尿が得られない状態　　←　　低濃度で用いれば、腎血流を増加させ尿量の増加が期待できる　→　ドパミン#薬理学
(2) 脈拍数の増加した状態　　←　　高濃度でなければ、頻脈を起こさず心拍出量を増やす。　→　ドパミン#薬理学
(3) 他の強心・昇圧剤により副作用が認められたり、好ましい反応が得られない状態

「下垂体前葉ホルモン」

　　[★]

英: anterior pituitary hormone
関: 下垂体前葉、下垂体、下垂体ホルモン、ホルモン

分泌されるホルモン

単純ペプチドホルモン

糖タンパク質ホルモン

GOO. chapter 55

名称		構造	分泌細胞	下垂体前葉細胞全細胞に対する産生細胞の割合	染色性		サブユニット	残基数 (aa.)	分子量 (kDa)	その他
成長ホルモン	GH	ペプチド	somatotroph	40-50%	好酸性		1	191	22
プロラクチン	PRL		mammotroph	10-25%	好酸性		1	199	23
副腎皮質刺激ホルモン	ACTH		corticotroph	0.1	好塩基性	嫌色素性	1	39	4.5	POMC由来
甲状腺刺激ホルモン	TSH	糖タンパク	thyrotroph	0.05	好塩基性		2	α: 92, β:118	28	αサブユニットは共通
卵胞刺激ホルモン	FSH		gonadotroph	10-15%	好塩基性		2	α: 92, β:111	32.6
黄体形成ホルモン	LH		gonadotroph	10-15%	好塩基性		2	α: 92, β:121	29.4

HIM.2196

Table 333-1 Anterior Pituitary Hormone Expression and Regulation
Cell	corticotrope	somatotrope	lactotrope	thyrotrope	gonadotrope
Tissue-specific transcription factor	T-Pit	Prop-1, Pit-1	Prop-1, Pit-1	Prop-1, Pit-1, TEF	SF-1, DAX-1
Fetal appearance	6 weeks	8 weeks	12 weeks	12 weeks	12 weeks
Hormone	POMC	GH	PRL	TSH	FSH LH
Chromosomal locus	2p	17q	6	－6q; －1p	－11p; －19q
Protein	ポリペプチド			糖タンパク
Amino acids	266 (ACTH 1–39)	191	199	211	210 204
Stimulators	CRH, AVP, gp-130 cytokines	GHRH, ghrelin, bromocriptine⁽¹⁾	estrogen, TRH, VIP	TRH	GnRH, activins, estrogen
Inhibitors	glucocorticoids	somatostatin, IGF-I	dopamine	T3, T4, dopamine, somatostatin, glucocorticoids	sex steroids, inhibin
Target gland	adrenal	liver, other tissues	breast, other tissues	thyroid	ovary, testis
Trophic effect	steroid production	IGF-I production, growth induction, insulin antagonism	milk production	T4 synthesis and secretion	sex steroid production, follicle growth, germ cell maturation