依那普利

依那普利
臨床資料
商品名（英语：Drug nomenclature）	Vasotec、Renitec、Enacard及其他
AHFS/Drugs.com	Monograph
MedlinePlus	a686022
核准狀況	美 DailyMed: Enalapril;
懷孕分級	澳: D ; Contraindicated;
给药途径	口服或靜脈注射給藥
藥物類別（英语：Drug class）	血管張力素轉化酶抑制劑
ATC碼	C09AA02 (WHO) ;
法律規範狀態
法律規範	歐：Rx-only; 美：处方药（℞-only）; 处方药（℞-only）;
藥物動力學數據
生物利用度	60% (口服)
药物代谢	肝臟 (成為依那普利拉（英语：enalaprilat）)
生物半衰期	11小時 (依那普利拉)
排泄途徑	腎臟
识别信息
	IUPAC命名法 (2S)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]pyrrolidine-2-carboxylic acid; ;
CAS号	75847-73-3
PubChem CID	5388962;
IUPHAR/BPS	6322;
DrugBank	DB00584 ;
ChemSpider	4534998 ;
UNII	69PN84IO1A;
KEGG	D07892 ;
ChEBI	CHEBI:4784 ;
ChEMBL	ChEMBL578 ;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID5022982 ;
ECHA InfoCard	100.119.661
化学信息
化学式	C20H28N2O5
摩尔质量	376.45 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
熔点	143至144.5 °C（289.4至292.1 °F）
	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 ;

依那普利（英語：Enalapril）以Vasotec等商品名於市面上銷售，是一種血管張力素轉化酶抑制劑（ACE抑制劑），用於治療高血壓、糖尿病腎病和心臟衰竭。^[4]於治療心臟衰竭時，一般會與利尿劑（如呋塞米）聯合使用。^[5]此藥物經由口服或靜脈注射方式給藥。^[4]口服後通常會在一小時內開始作用，效力持續長達一天。^[4]

此藥物屬於血管張力素轉化酶 (ACE) 抑制劑家族。^[4]

使用後常見的副作用有頭痛、疲倦、姿位性低血壓和咳嗽。^[4]嚴重的副作用有血管性水腫和低血壓。^[4]據信個體於懷孕期間使用會對胎兒造成傷害。^[4]依那普利的包裝上因此被美國食品藥物管理局（FDA）要求加上對胎兒可能產生毒性的黑框警告。^[6]^[7]

依那普利於1978年取得專利，並於1984年獲准用於醫療用途。^[8]它已被納入世界衛生組織基本藥物標準清單之中。^[9]於2021年，此藥物在美國最常使用處方藥中排名第278，開立的處方箋數量超過80萬張。^[10]^[11]市面上已有其通用名藥物流通。^[12]

醫療用途

依那普利用於治療高血壓、有症狀的心臟衰竭和無症狀的左心室功能障礙。^[13]ACE抑制劑（包括依那普利）已被證明能夠減緩現有慢性腎臟病在蛋白尿/微量白蛋白尿（尿蛋白，慢性腎臟病的生物標誌物）存在情況下的病情惡化和進展。^[14]在沒有蛋白尿/微量白蛋白尿的情況下（包括糖尿病族群），則無這種腎臟保護作用。^[15]這種療效尤其在高血壓和/或糖尿病患者中得到證明，且很可能在其他群體中也能看到（需要對現有研究作進一步探索和亞組分析）^[16]^[14]^[17]依那普利廣泛用於治療慢性腎衰竭。^[18]此外它是一種治療原發性多飲症（英语：Primary polydipsia）的新興藥物。一項雙盲安慰劑對照試驗表明，當依那普利用於此目的時，可導致60%患者的水消耗量減少（由排尿量和滲透壓測量而得）。^[19]

副作用

使用依那普利最常見的副作用有血清肌酐升高（20%）、頭暈（2-8%）、低血壓（1-7%）、暈厥（2%）和乾咳（1-2%）。最嚴重的常見不良事件是血管性水腫（0.68%），通常會影響到使用者的臉部和嘴唇，危及呼吸道。血管性水腫可能在治療中的任何時間發生，但最常是在使用前幾次劑量後發生。^[2]據報導，非洲裔因此而發生的血管性水腫及死亡率更高。^[2]已觀察到使用此藥物會導致粒細胞缺乏症（英语：Agranulocytosis）。^[20]

一些證據顯示依那普利會對發育中的胎兒造成傷害和死亡。依那普利在個體懷孕期間可能會損害胎兒的腎臟並導致羊水過少（英语：oligohydramnios）。依那普利會分泌進入母乳，不建議進行母乳哺育的個體使用。^[2]

作用機轉

血管張力素轉化酶 (ACE)在正常情況下會將血管張力素I轉化為血管張力素II。血管張力素II有收縮血管的作用，導致血壓升高。依那普利拉（英语：Enalaprilat）是依那普利的活性代謝物，可抑制ACE。ACE受壓制後會降低血管張力素II的水平，而減少血管收縮，血壓因而降低。^[2]

藥物代謝動力學

依那普利的藥物代謝動力學數據如下：^[2]

開始作用：約1小時
峰值效果：4-6小時
作用時間：12-24小時
吸收率：~60%
代謝：前藥（即依那普利）經生物轉化為依那普利拉^[21]

結構活動關係

依那普利的分子中有一L-脯胺酸部分，負責藥物的口服生物利用度。此藥物是一種前藥，表示它會在代謝後發揮作用。分子的"-OCH2CH3"部分在代謝過程中會分裂，碳原子處形成羧酸鹽，然後與ACE酶的Zn+2位點相互作用。此藥物需經代謝轉化成活性代謝物後，方能抑制ACE酵素。此結構特徵與代謝機制讓其作用時間較另一同類藥物卡托普利更長。作用持續時間與劑量有關聯，在建議劑量下，抗高血壓和血液動力學作用已被證明可維持至少24小時。^[22]^[23]依那普利發生作用速度比卡托普利為慢，但作用時間較長。然而此藥物與卡托普利不同 - 不含硫醇成分。

歷史

必治妥施貴寶的前身之一 - 施貴寶製藥開發出第一種ACE抑制劑 - 卡托普利，但因口服後會產生金屬味（經證明是由其中的硫醇造成）等副作用。默克製藥因而開發出依那普利與卡托普利競爭。^[24]^[25]^:12–13

默克首先開發出來的是依那普利拉，目的在克服卡托普利的前述缺點。藉由羧酸鹽部分取代卡托普利分子中的硫醇部分，並進行結構優化，而成功開發出與卡托普利效力相近的依那普利。然而依那普利拉有其自身的問題 - 它的口服利用度較差。默克研究人員經由乙醇酯化依那普利拉，製造出依那普利，而將此問題克服。^[25]

默克製藥於1981年將依那普利上市，到1988年，此藥物成為默克首個銷售額達10億美元的單一藥物。^[25]藥物專利於2000年到期，通用名藥物隨之出現。^[26]

社會與文化

法律地位

歐洲藥品管理局所屬的人用藥品委員會（英语：Committee for Medicinal Products for Human Use）（CHMP）採納正面意見，於2023年9月建議授予藥品Aqumeldi（含依那普利馬來酸鹽）兒科用藥行銷授權，用於治療心臟衰竭（年齡範圍從出生開始至18歲以下）。^[27]Aqumeldi的申請人是Proveca Pharma Limited，^[27]並於2023年11月獲准在歐盟用於前述的醫療用途。^[3]

參考文獻

^ ^1.0 ^1.1 Enalapril Use During Pregnancy. Drugs.com. 2020-02-28 [2020-03-13].
^ ^2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 Vasotec- enalapril maleate tablet. DailyMed. 2018-11-12 [2020-04-26].
^ ^3.0 ^3.1 Aqumeldi EPAR. European Medicines Agency. 2023-11-15 [2024-01-20]. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ ^4.0 ^4.1 ^4.2 ^4.3 ^4.4 ^4.5 ^4.6 Enalaprilat/Enalapril Maleate. The American Society of Health-System Pharmacists. [2016-12-08]. （原始内容存档于2016-12-21）.
^ World Health Organization. Stuart MC, Kouimtzi M, Hill SR , 编. WHO Model Formulary 2008. World Health Organization. 2009: 286. ISBN 9789241547659. hdl:10665/44053 .
^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 202310-22.
^ Enalapril. Sta tpearls [Internet]. [2024-08-08]. Enalapril has a boxed warning for fetal toxicity.
^ Fischer J, Ganellin CR. Analogue-based Drug Discovery. John Wiley & Sons. 2006: 467. ISBN 9783527607495. （原始内容存档于2016-12-20）（英语）.
^ World Health Organization. The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. hdl:10665/371090 . WHO/MHP/HPS/EML/2023.02.
^ The Top 300 of 2021. ClinCalc. [2024-01-14]. （原始内容存档于2024-01-15）.
^ Enalapril - Drug Usage Statistics. ClinCalc. [2024-01-14].
^ Enalapril maleate: FDA-Approved Drugs. U.S. Food and Drug Administration (FDA). [2021-09-24].
^ Enalapril. MedlinePlus. U.S. National Library of Medicine. October 2010. （原始内容存档于2015-02-08）.
^ ^14.0 ^14.1 Xie X, Liu Y, Perkovic V, Li X, Ninomiya T, Hou W, et al. Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials. American Journal of Kidney Diseases. May 2016, 67 (5): 728–741. PMID 26597926. doi:10.1053/j.ajkd.2015.10.011 .
^ Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ (Clinical Research Ed.). February 2016, 352: i438. PMC 4772784 . PMID 26868137. doi:10.1136/bmj.i438.
^ Mishima E, Haruna Y, Arima H. Renin-angiotensin system inhibitors in hypertensive adults with non-diabetic CKD with or without proteinuria: a systematic review and meta-analysis of randomized trials. Hypertension Research. April 2019, 42 (4): 469–482. PMID 30948820. S2CID 96434746. doi:10.1038/s41440-018-0116-3.
^ McMurray JJ. Clinical practice. Systolic heart failure. The New England Journal of Medicine. January 2010, 362 (3): 228–238. PMID 20089973. doi:10.1056/NEJMcp0909392. Two large trials showed that when patients with NYHA class II, III, or IV heart failure were treated with enalapril, as compared with placebo, in addition to diuretics and digoxin, the rates of admission to the hospital were reduced, and the relative risk reduction for death was 16 to 40%.
^ He YM, Feng L, Huo DM, Yang ZH, Liao YH. Enalapril versus losartan for adults with chronic kidney disease: a systematic review and meta-analysis. Nephrology. September 2013, 18 (9): 605–614. PMID 23869492. S2CID 31791094. doi:10.1111/nep.12134.
^ Greendyke RM, Bernhardt AJ, Tasbas HE, Lewandowski KS. Polydipsia in chronic psychiatric patients: therapeutic trials of clonidine and enalapril. Neuropsychopharmacology. April 1998, 18 (4): 272–281. PMID 9509495. doi:10.1016/S0893-133X(97)00159-0 .
^ Todd PA, Goa KL. Enalapril. A reappraisal of its pharmacology and therapeutic use in hypertension. Drugs. March 1992, 43 (3): 346–381. PMID 1374319. S2CID 262278681. doi:10.2165/00003495-199243030-00005.
^ Menard J and Patchett A. Angiotensin-Converting Enzyme Inhibitors. Pp 14-76 in Drug Discovery and Design. Volume 56 of Advances in Protein Chemistry. Eds Richards FM, Eisenberg DS, and Kim PS. Series Ed. Scolnick EM. Academic Press, 2001. ISBN 9780080493381. Pg 30 互联网档案馆的存檔，存档日期2017-09-10.
^ Enalapril 10mg Tablets - Summary of Product Characteristics. Section 5.1 Pharmacodynamic properties. emc (electronic medicines compendium). 2023-02-21.
^ Given BD, Taylor T, Hollenberg NK, Williams GH. Duration of action and short-term hormonal responses to enalapril (MK 421) in normal subjects. Journal of Cardiovascular Pharmacology. 1984, 6 (3): 436–441. PMID 6202969. doi:10.1097/00005344-198405000-00010 .
^ Bryan J. From snake venom to ACE inhibitor--The discovery and rise of captopril.. Pharmaceutical Journal. April 2009, 282 (7548): 455.
^ ^25.0 ^25.1 ^25.2 Li JJ. Chapter 1: History of Drug Discovery. Li JJ, Corey EJ (编). Drug Discovery: Practices, Processes, and Perspectives. John Wiley & Sons. April 2013. ISBN 9781118354469.
^ Staff, Drug Discovery Online. Patent expiry looms: 18 blockbusters expose $37 billion to generic competition by 2005 互联网档案馆的存檔，存档日期2016-05-12. Page accessed 2016-04-23
^ ^27.0 ^27.1 Aqumeldi: Pending EC decision. European Medicines Agency. 2023-09-15 [2023-09-21]. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

[Drugs.com_pregnancy-1] 1.0 ^1.1 Enalapril Use During Pregnancy. Drugs.com. 2020-02-28 [2020-03-13].

[Vasotec_FDA_label-2] 2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 Vasotec- enalapril maleate tablet. DailyMed. 2018-11-12 [2020-04-26].

[Aqumeldi_EPAR-3] 3.0 ^3.1 Aqumeldi EPAR. European Medicines Agency. 2023-11-15 [2024-01-20]. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

[AHFS2016-4] 4.0 ^4.1 ^4.2 ^4.3 ^4.4 ^4.5 ^4.6 Enalaprilat/Enalapril Maleate. The American Society of Health-System Pharmacists. [2016-12-08]. （原始内容存档于2016-12-21）.

[WHO2008-5] World Health Organization. Stuart MC, Kouimtzi M, Hill SR , 编. WHO Model Formulary 2008. World Health Organization. 2009: 286. ISBN 9789241547659. hdl:10665/44053 .

[6] "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 202310-22.

[7] Enalapril. Sta tpearls [Internet]. [2024-08-08]. Enalapril has a boxed warning for fetal toxicity.

[Fis2006-8] Fischer J, Ganellin CR. Analogue-based Drug Discovery. John Wiley & Sons. 2006: 467. ISBN 9783527607495. （原始内容存档于2016-12-20）（英语）.

[WHO23rd-9] World Health Organization. The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. hdl:10665/371090 . WHO/MHP/HPS/EML/2023.02.

[10] The Top 300 of 2021. ClinCalc. [2024-01-14]. （原始内容存档于2024-01-15）.

[11] Enalapril - Drug Usage Statistics. ClinCalc. [2024-01-14].

[12] Enalapril maleate: FDA-Approved Drugs. U.S. Food and Drug Administration (FDA). [2021-09-24].

[MedlinePlus-13] Enalapril. MedlinePlus. U.S. National Library of Medicine. October 2010. （原始内容存档于2015-02-08）.

[pmid26597926-14] 14.0 ^14.1 Xie X, Liu Y, Perkovic V, Li X, Ninomiya T, Hou W, et al. Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials. American Journal of Kidney Diseases. May 2016, 67 (5): 728–741. PMID 26597926. doi:10.1053/j.ajkd.2015.10.011 .

[pmid26868137-15] Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ (Clinical Research Ed.). February 2016, 352: i438. PMC 4772784 . PMID 26868137. doi:10.1136/bmj.i438.

[pmid30948820-16] Mishima E, Haruna Y, Arima H. Renin-angiotensin system inhibitors in hypertensive adults with non-diabetic CKD with or without proteinuria: a systematic review and meta-analysis of randomized trials. Hypertension Research. April 2019, 42 (4): 469–482. PMID 30948820. S2CID 96434746. doi:10.1038/s41440-018-0116-3.

[McMurray-17] McMurray JJ. Clinical practice. Systolic heart failure. The New England Journal of Medicine. January 2010, 362 (3): 228–238. PMID 20089973. doi:10.1056/NEJMcp0909392. Two large trials showed that when patients with NYHA class II, III, or IV heart failure were treated with enalapril, as compared with placebo, in addition to diuretics and digoxin, the rates of admission to the hospital were reduced, and the relative risk reduction for death was 16 to 40%.

[pmid23869492-18] He YM, Feng L, Huo DM, Yang ZH, Liao YH. Enalapril versus losartan for adults with chronic kidney disease: a systematic review and meta-analysis. Nephrology. September 2013, 18 (9): 605–614. PMID 23869492. S2CID 31791094. doi:10.1111/nep.12134.

[19] Greendyke RM, Bernhardt AJ, Tasbas HE, Lewandowski KS. Polydipsia in chronic psychiatric patients: therapeutic trials of clonidine and enalapril. Neuropsychopharmacology. April 1998, 18 (4): 272–281. PMID 9509495. doi:10.1016/S0893-133X(97)00159-0 .

[20] Todd PA, Goa KL. Enalapril. A reappraisal of its pharmacology and therapeutic use in hypertension. Drugs. March 1992, 43 (3): 346–381. PMID 1374319. S2CID 262278681. doi:10.2165/00003495-199243030-00005.

[21] Menard J and Patchett A. Angiotensin-Converting Enzyme Inhibitors. Pp 14-76 in Drug Discovery and Design. Volume 56 of Advances in Protein Chemistry. Eds Richards FM, Eisenberg DS, and Kim PS. Series Ed. Scolnick EM. Academic Press, 2001. ISBN 9780080493381. Pg 30 互联网档案馆的存檔，存档日期2017-09-10.

[22] Enalapril 10mg Tablets - Summary of Product Characteristics. Section 5.1 Pharmacodynamic properties. emc (electronic medicines compendium). 2023-02-21.

[23] Given BD, Taylor T, Hollenberg NK, Williams GH. Duration of action and short-term hormonal responses to enalapril (MK 421) in normal subjects. Journal of Cardiovascular Pharmacology. 1984, 6 (3): 436–441. PMID 6202969. doi:10.1097/00005344-198405000-00010 .

[24] Bryan J. From snake venom to ACE inhibitor--The discovery and rise of captopril.. Pharmaceutical Journal. April 2009, 282 (7548): 455.

[HistDD-25] 25.0 ^25.1 ^25.2 Li JJ. Chapter 1: History of Drug Discovery. Li JJ, Corey EJ (编). Drug Discovery: Practices, Processes, and Perspectives. John Wiley & Sons. April 2013. ISBN 9781118354469.

[26] Staff, Drug Discovery Online. Patent expiry looms: 18 blockbusters expose $37 billion to generic competition by 2005 互联网档案馆的存檔，存档日期2016-05-12. Page accessed 2016-04-23

[Aqumeldi:_Pending_EC_decision-27] 27.0 ^27.1 Aqumeldi: Pending EC decision. European Medicines Agency. 2023-09-15 [2023-09-21]. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

[1]

[3]

[2]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]