WordNet

an ACE inhibitor (trade name Vasotec) that blocks the formation of angiotensin in the kidney and so results in vasodilation; administered after heart attacks (同)Vasotec

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/03/20 23:19:24」(JST)

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Not to be confused with Allopurinol.

Enalapril 3D structure

Enalapril (marketed as Vasotec in the USA, Enaladex in some other countries, and Enacard for veterinary use^[1]) is an angiotensin converting enzyme (ACE) inhibitor used in the treatment of hypertension and some types of chronic heart failure. ACE converts the peptide hormone angiotensin I to angiotensin II. One of the actions of angiotensin II is the vasoconstriction of blood vessels resulting in an increase in blood pressure. ACE inhibitors such as enalapril prevent this effect. Enalapril has been shown to lower the death rate in systolic heart failure.^[2] Enalapril was the first member of the group known as the dicarboxylate-containing ACE inhibitors.

Development

Enalapril as a treatment for high blood pressure works by modulating the renin-angiotensin-aldosterone system (RAAS).

Squibb developed the first inhibitor, captopril, but it had adverse effects such as a metallic taste (which, as it turned out, was due to the sulfhydryl group). Merck & Co. developed enalapril as a competing prodrug.

Enalaprilat

Enalaprilat, the first dicarboxylate-containing ACE inhibitor, was developed partly to overcome these limitations of captopril. The sulfhydryl moiety was replaced by a carboxylate moiety, but additional modifications were required in its structure-based design to achieve a similar potency to captopril.

Enalaprilat, however, had a problem of its own. The consequence of the structural modifications was it proved to have unfavourable ionisation characteristics to allow sufficient potency for oral administration (in tablets). Thus, it was only suitable for intravenous administration. This was overcome by the researchers at Merck by the esterification of enalaprilat with ethanol to produce enalapril.

As a prodrug, enalapril is metabolised in vivo to the active form enalaprilat by various esterases. Peak plasma enalaprilat concentrations occur two to four hours after oral administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life two to six hours) and a subsequent prolonged phase (elimination half-life 36 hours), the latter representing equilibration of drug from tissue distribution sites.

The prolonged phase does not contribute to drug accumulation on repeated administration, but is thought to be of pharmacological significance in mediating drug effects. Renal impairment [particularly creatinine clearance < 20 ml/min (< 1.2 l/h)] results in significant accumulation of enalaprilat and necessitates dosage reduction. Accumulation is probably the cause of reduced elimination in healthy elderly individuals and in patients with concomitant diabetes, hypertension and heart failure.

A prototype for others

Most importantly, perhaps, the QSAR-based modifications in structure serendipitously led to an improved understanding of the structure of ACE, which aided in the development of subsequent carboxylate-containing ACE inhibitors.

Enalapril, a prodrug, is converted by de-esterification to converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies.

Side effects

Most common side effects include hypotension, dizziness when standing up, and dry cough.^[3]

Synthesis

^[4]

References

^ Enacard listed at http://www.drugs.com.
^ McMurray JJV, Systolic heart failure, N Engl J Med, 362:228, Jan. 21, 2010).
^ Listed at http://www.drugs.com.
^ Patchett, A. A.; in Chronicles of Drug Discovery, Vol. 3; Lednicer, D., ed., ACS Books, Washington, DC, 1993, 125.

External links

Wikimedia Commons has media related to: Enalapril

Prescribing Information for VASOTEC^{[dead link]}

UpToDate Contents

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2. 高血圧緊急症の薬物治療 drug treatment of hypertensive emergencies
3. 乳児および小児における心不全のマネージメント management of heart failure in infants and children
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5. 天疱瘡の病因、臨床症状、および診断 pathogenesis clinical manifestations and diagnosis of pemphigus

English Journal

Preventing progression of cardiac hypertrophy and development of heart failure by paricalcitol therapy in rats.

Bae S, Yalamarti B, Ke Q, Choudhury S, Yu H, Karumanchi SA, Kroeger P, Thadhani R, Kang PM.SourceCardiovascular Division, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, CLS 910, Boston, MA 02215, USA.
Cardiovascular research.Cardiovasc Res.2011 Sep 1;91(4):632-9. Epub 2011 May 11.
AIMS: Vitamin D deficiency is associated with cardiac hypertrophy and heart failure, and vitamin D therapy prevents the progression of cardiac hypertrophy in animal models. Here, we examine whether vitamin D therapy prevents progression of pre-existing cardiac hypertrophy and development of heart fa
PMID 21565836

Effects of ACE inhibition on circulating endothelial progenitor cells, vascular damage, and oxidative stress in hypertensive patients.

Cacciatore F, Bruzzese G, Vitale DF, Liguori A, de Nigris F, Fiorito C, Infante T, Donatelli F, Minucci PB, Ignarro LJ, Napoli C.SourceCardiovascular Rehabilitation, Salvatore Maugeri Foundation, IRCCS, Institute of Telese, 82037, Benevento, Italy, francesco.cacciatore@fsm.it.
European journal of clinical pharmacology.Eur J Clin Pharmacol.2011 Sep;67(9):877-83. Epub 2011 Mar 29.
PURPOSE: The pathogenic role of angiotensin-converting enzyme (ACE) inhibition in hypertensive patients regarding endothelial progenitor-cell (EPC) function is still poorly understood. The aim of the study was to evaluate EPC number, function, and relationship to carotid intima media thickness (IMT)
PMID 21445638

Japanese Journal

Study on the expression of renal ACE, ACE2 of surgery hypertensive rats(Basic medicine)

Zhang Zhao-qiang,Sun Xiao,Wang Bing-xiang,Zhang Yan-ling
Journal of brain science 36, 50-60, 2011-03-30
… One group served as control (n=7), others as hypertensive group (n=7), enalapril group [n=7,15mg/(kg・d)] and losartan group [n=7,15mg/(kg・d)]. … Enalapril and losartan were used as treatments of rats of enalapril group and losartan group after surgery. …
NAID 110008574015

アンギオテンシン転換酵素阻害薬(マレイン酸エナラプリル)が原因と考えられた血管性浮腫の1例

長島真由美,藤村奈緒,松山阿美子,伊藤彩,中村和子,廣門未知子,蒲原毅,池澤善郎
Journal of environmental dermatology and cutaneous allergology = / the Japanese Society for Dermatoallergology and Contact Dermatitis 4(4), 220-224, 2010-10-31
NAID 10027572266

Related Pictures

★リンクテーブル★

リンク元	「アンジオテンシン変換酵素阻害薬」「エナラプリル」
拡張検索	「enalapril maleate」「enalaprilat」

「アンジオテンシン変換酵素阻害薬」

Enalapril
Systematic (IUPAC) name
	(2S)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]pyrrolidine-2-carboxylic acid; ; (Diagrams above are enalapril and enalaprilat, respectively. Data below refers to enalapril unless indicated)
Clinical data
Trade names	Vasotec
AHFS/Drugs.com	monograph
MedlinePlus	a686022
Pregnancy cat.	C,D
Legal status	℞ Prescription only
Routes	I.V. and P.O.
Pharmacokinetic data
Bioavailability	60% (oral)
Metabolism	hepatic (to enalaprilat)
Half-life	11 hours (enalaprilat)
Excretion	renal
Identifiers
CAS number	75847-73-3
ATC code	C09AA02
PubChem	CID 5388962
DrugBank	DB00584
ChemSpider	4534998
UNII	69PN84IO1A
KEGG	D07892
ChEBI	CHEBI:4784
ChEMBL	CHEMBL578
Chemical data
Formula	C20H28N2O5
Mol. mass	376.447 g/mol
	SMILES O=C(O)[C@H]2N(C(=O)[C@@H](N[C@H](C(=O)OCC)CCc1ccccc1)C)CCC2;
	InChI InChI=1S/C20H28N2O5/c1-3-27-20(26)16(12-11-15-8-5-4-6-9-15)21-14(2)18(23)22-13-7-10-17(22)19(24)25/h4-6,8-9,14,16-17,21H,3,7,10-13H2,1-2H3,(H,24,25)/t14-,16-,17-/m0/s1 ; Key:GBXSMTUPTTWBMN-XIRDDKMYSA-N ;
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　　[★]

英: angiotensin-converting enzyme inhibitor angiotensin converting enzyme inhibitor , ACE inhibitor, ACEI
同: アンジオテンシン変換酵素阻害剤アンギオテンシン変換酵素阻害薬アンギオテンシン変換酵素阻害剤アンジオテンシン転換酵素阻害薬、ACE阻害薬 ACE阻害剤 ACE inhibitor、アンギオテンシン変換酵素拮抗薬, アンギオテンシン変換酵素拮抗薬, angiotensin-converting enzyme antagonist
関: アンジオテンシン, アンジオテンシン転換酵素 ACE, 1型アンジオテンシンII受容体拮抗薬アンジオテンシンII受容体拮抗薬 ARB

アンジオテンシン変換酵素阻害薬

カプトプリル captopril：
デラプリル delapril：アデカット：即効型
キナプリル quinapril：コナン：プロドラッグ
アラセプリル alacepril：
イミダプリル imidapril：タナトリル：空咳の頻度が少ない。糖尿病腎症に適応(腎保護)。プロドラッグ。T1/2 8hr
シラザプリル cilazapril：インヒベース：降圧効果がレニベースより強い。T1/2 53hr
テモカプリル temocapril：エースコール：プロドラッグ。排泄が尿中、糞中ほぼ同等であり、他のACE-Iのように腎排泄が主ではない。T1/2 22hr
ペリンドプリル perindopril：コバシル：有効域が広く、血管リモデリングの改善効果あり。
エナラプリル enalapril：レニベース：慢性心不全にも適応(心保護作用)
リシノプリル lisinopril：ロンゲス：肝代謝をほとんど受けず、未変化体のまま腎から排泄

薬剤名	成分名	高血圧	腎性高血圧	腎血管性高血圧	悪性高血圧	慢性心不全	1型糖尿病に伴う糖尿病性腎症
レニベース	エナラプリル	●	●	●	●	●
ロンゲス	リシノプリル	●				●
タナトリル	イミダプリル	●	●				●
エースコール	テモカプリル	●	●	●
コバシル	ペリンドプリル	●

=粉砕可能性

一般名	製品名	規格	剤形	用法				粉砕
アラセプリル	セタプリル	12.5,25,50	錠	1日	25-75mg	1日	1-2回分服
イミダプリル	タナトリル	2.5,5,10	錠	1日	2.5-10mg	1日	1回	○
エナラプリル	レニベース	2.5,5,10	錠	1日	2.5-10mg	1日	1回
カプトプリル	カプトリル	12.5,25	錠,細粒	1日	37.5～75mg	1日	3回
キナプリル	コナン	5,10,20	錠	1日	5～20mg	1日	1回
シラザプリル	インヒベース	0.25,0.5,1	錠	1日	0.25～2mg	1日	1回	○
テモカプリル	エースコール	1,2,4	錠	1日	1～4mg	1日	1回
デラプリル	アデカット	7.5,15,30	錠	1日	15～120mg	1日	1-2回分服
トランドラプリル	オドリック	0.5,1	錠	1日	0.5～2mg	1日	1回	○
トランドラプリル	プレラン	0.5,1	錠	1日	0.5～2mg	1日	1回	○
ベナゼプリル	チバセン	2.5,5,10	錠	1日	2.5～10mg	1日	1回
ペリンドプリル	コバシル	2,4	錠	1日	2～8mg	1日	1回	○
リシノプリル	ロンゲス	5,10,20	錠	1日	2.5～20mg	1日	1回	○
リシノプリル	ゼストリル	5,10,20	錠	1日	2.5～20mg	1日	1回	○

副作用

咳嗽：ACEはブラジキニンを分解するキニナーゼIIと同一の酵素である。ACE阻害薬はこの酵素を阻害するが、ブラジキニンは血管拡張、血漿滲出、発痛作用に関わっている。このため咳を誘発することがある。
高カリウム血症：間接的に血漿中のレニン濃度が低下するためにナトリウム取り込みとカリウム排泄が低下して高カリウム血症を来す
低血圧
腎不全

空咳の頻度

添付文書に基づき、咳が出る頻度について考察。

商品名	一般名	咳嗽の報告頻度
商品名	一般名	臨床試験	使用成績調査
タナトリル	イミダプリル	2.68%	4.76%
レニベース	エナラプリル	0.99%	2.13%
コバシル	ペリンドプリル	7.1%	8.3%
ロンゲス	リシノプリル	4.76%(高血圧症患者) 7.24%(慢性心不全患者)
エースコール	テモカプリル	不詳	不詳