毕索洛尔

畢索洛爾（INN：bisoprolol）以Zebeta、Concor（康肯）等商品名於市面上販售，是一種β受體阻滯劑，對β1腎上腺素受體（英语：beta-1 adrenergic receptor）具選擇性，用於治療心血管疾病（包括心跳過速、高血壓、心絞痛和心臟衰竭 ）。此藥物係透過口服方式給藥。 使用後常見的副作用有頭痛、疲倦、腹瀉和腿部腫脹。較嚴重的副作用有氣喘惡化、遮蔽辨識低血糖的能力以及心臟衰竭惡化。 尚有個體於懷孕期間使用可能會對胎兒有害的疑慮。 畢索洛爾於1976年取得專利，並於1986年獲得瑞典批准用於醫療用途。於1992年獲得美國食品藥物管理局（FDA）批准用作醫療用途。 此藥物已列入世界衛生組織基本藥物標準清單之中。市面上有通用名藥物販售。美國於2020年中最常使用的處方藥中，此藥物排名第267，開立的處方箋數量超過100萬張。 畢索洛爾可用於預防心臟病發作後，有疾病惡化風險的患者再度發生心血管事件、用於治療鬱血性心臟衰竭導致的射血分數降低以及作為治療高血壓的二線藥物。 畢索洛爾可能有治療高血壓的功效，但不建議作為一線藥物。對於伴有合併症（例如鬱血性心臟衰竭）的患者，它可作為一線抗高血壓藥物的輔助藥物，對於已服用適當劑量的血管張力素轉化酶抑制劑，但仍存在輕度至中度症狀的患者，可添加此種β受體阻滯劑以促進療效。 該藥物在心臟缺血（英语：Coronary ischemia）時可減少心肌的活動，而減少對氧氣和營養的需求，並在血液供應較少的情況之下仍能輸送足夠量的氧氣和營養以滿足心臟的需求。 過量使用可導致疲勞、低血壓、低血糖、支氣管痙攣和心跳過緩。發生支氣管痙攣和低血糖是因為體內有高濃度藥物時，可成為位於肺部和肝臟的β2腎上腺素受體（英语：β2 adrenergic receptor）的拮抗劑。支氣管痙攣是由於肺部β2受體受到阻滯而發生。低血糖是由於肝臟中透過β2受體對肝糖分解和糖質新生的刺激減少而發生。 目前尚無此藥物造成相關臨床明顯藥物性肝損傷的病例報告。 罹患氣喘或支氣管痙攣的個體應避免使用非選擇性β受體阻滯劑，因為它們可能會引發惡化和症狀加劇。選擇性β1腎上腺素受體阻斷劑（如畢索洛爾）尚未顯示會導致氣喘惡化，對於患有心臟合併症的輕至中度氣喘，而已得到控制的患者可謹慎使用。 於2014年所做的一項統合分析發現，β1腎上腺受體選擇性阻滯劑（畢索洛爾）對肺功能影響很小（與非選擇性β受體阻滯劑比較），患者仍對沙丁胺醇（β2腎上腺素受體激動藥）救援治療產生反應，並贊同於選定有氣喘，但已受控制的患者使用畢索洛爾。 於2020年所做的一項臨床試驗支持前述觀點，使用畢索洛爾對個體在沙丁胺醇給藥後，不會對支氣管擴張發生顯著影響。 畢索洛爾具有心臟保護作用，因為它能選擇性、競爭性阻斷兒茶酚胺（腎上腺素）對β1受體（腎上腺素受體）的刺激，β1受體主要存於心肌細胞和心臟電傳導系統（心臟特有）中，但也存於腎臟的鄰腎小球細胞中。通常腎上腺素和正腎上腺素對β1受體的刺激會活化訊息傳遞級聯，最終分別導致心肌收縮力（英语：Myocardial contractility）增加以及心肌和心臟起搏功能增強。畢索洛爾會競爭性地阻斷該級聯反應的活化，因此降低心肌和心臟起搏細胞的腎上腺素活性/刺激。降低的腎上腺素活性表現為心肌收缩力减弱和心率降低。 畢索洛爾的β1腎上腺素受體選擇性在與其他非選擇性β腎上腺素受體阻滯劑相比時尤為重要。此藥物的作用僅限於含有β1腎上腺素受體的區域，主要是心臟和部分的腎臟。雖然β1腎上腺素受體選擇性藥物（如畢索洛爾）可幫助患者避免某些與非選擇性β受體阻滯劑活性相關的副作用（作用於其他額外的腎上腺素受體，例如α1和β2），但並不表示它在治療β受體阻滯劑適用心臟疾病（例如心臟衰竭）方面更具優勢，但對於患有特定合併症的患者可能會有益處。 畢索洛爾比阿替洛爾、美托洛爾和倍他洛爾（英语：betaxolol）具有更高程度的β1腎上腺素受體選擇性。此藥物對β1受體的選擇性比對β2受體的高出11至15倍。另一種β受體阻滯劑奈必洛爾（英语：nebivolol）的β1受體選擇性則約為高出3.5倍。 畢索洛爾可抑制腎素（也稱血管收縮素原酶）分泌約達65%，可抑制心搏過速約達30%。 進入人體的畢索洛爾，其生物利用度高達約90%，生物半衰期為10-12小時。循環中的畢索洛爾一半由肝臟代謝，其餘的以原有形式經腎臟排出，約少於2%可能經由糞便排出。 畢索洛爾可溶於脂質和水。它被歸類為具有中等親脂性的β受體阻滯劑，因此具有中等穿越血腦屏障的潛力。因而畢索洛爾與高親脂性β受體阻滯劑如普萘洛爾相比，可能會對中樞神經系統產生較小的的影響，且產生神經精神（英语：Neuropsychiatry）副作用的風險較低，相對而言，畢索洛爾比低親脂性β受體阻滯劑如阿替洛爾所產生的影響會較較大。 畢索洛爾與血漿蛋白結合率約為35%，分佈容積為3.5升/公斤，總清除率約15升/小時 。畢索洛爾經兩種方式從人體排除 - 50%在肝臟中轉化為無活性的代謝物，然後經腎臟排泄。其餘50%則經由腎臟以藥物原形排除。由於肝臟和腎臟的消除相同，因此肝或是腎功能不全的患者無需調整劑量。 此藥物的藥物代謝動力學呈線性，且與年齡無關。 在各項研究中，發現慢性心臟衰竭患者血漿中畢索洛爾的濃度高於健康受試者，生物半衰期也較長。目前尚缺乏此藥物於健康受試者和慢性心臟衰竭受試者之間的藥物代謝動力學直接比較證據。 此藥物在印度以Bisotab品牌銷售。於市面上的其他品牌尚有Cardicor, Congescor及Bisoprolol-ratiopharm等。 Monocor Product information. Health Canada. 2009-07-31 [2024-04-19].  Zebeta (Bisoprolol Fumarate) Tablets. DailyMed. [2024-04-19].  Bisoprolol fumarate tablet, film coated. DailyMed. 2024-03-06 [2024-04-19]. （原始内容存档于2024-04-19）.  Bühring KU, Sailer H, Faro HP, Leopold G, Pabst J, Garbe A. Pharmacokinetics and metabolism of bisoprolol-14C in three animal species and in humans. Journal of Cardiovascular Pharmacology. 1986, 8 (Suppl 11): S21–S28. PMID 2439794. S2CID 38147937. doi:10.1097/00005344-198511001-00004.  Leopold G. Balanced pharmacokinetics and metabolism of bisoprolol. Journal of Cardiovascular Pharmacology. 1986, 8 (Suppl 11): S16–S20. PMID 2439789. S2CID 25731558. doi:10.1097/00005344-198511001-00003.  Horikiri Y, Suzuki T, Mizobe M. Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. Journal of Pharmaceutical Sciences. March 1998, 87 (3): 289–294. PMID 9523980. doi:10.1021/js970316d.  Bisoprolol Fumarate. The American Society of Health-System Pharmacists. [2016-12-08]. （原始内容存档于2016-12-21）.  Bisoprolol 2.5mg/5mg/10mg film coated tablet - Summary of Product Characteristics (SPC) - (eMC). medicines.org.uk. 2014-02-18 [2016-12-14]. （原始内容存档于2016-12-20）.  Bisoprolol - FDA prescribing information, side effects and uses. drugs.com. [2016-12-14]. （原始内容存档于2016-12-21）.  Bisoprolol (Zebeta) Use During Pregnancy. drugs.com. [2016-12-14]. （原始内容存档于2016-12-21）.  Fischer J, Ganellin CR. Analogue-based Drug Discovery. John Wiley & Sons. 2006: 461. ISBN 9783527607495. （原始内容存档于2017-09-08）.  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.  Drugs@FDA: FDA Approved Drug Products. [2013-11-13]. （原始内容存档于2015-02-25）.  The Top 300 of 2020. ClinCalc. [2022-10-07]. （原始内容存档于2021-02-12）.  Bisoprolol - Drug Usage Statistics. ClinCalc. [2022-10-07]. （原始内容存档于2022-09-28）.  Bangalore S, Makani H, Radford M, Thakur K, Toklu B, Katz SD, et al. Clinical outcomes with β-blockers for myocardial infarction: a meta-analysis of randomized trials. The American Journal of Medicine. October 2014, 127 (10): 939–953. PMID 24927909. doi:10.1016/j.amjmed.2014.05.032 .  CIBIS-II Investigators. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial.. The Lancet. January 1999, 353 (9146): 9–13. S2CID 10083527. doi:10.1016/S0140-6736(98)11181-9. > Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta-blockers for hypertension. The Cochrane Database of Systematic Reviews. January 2017, 1 (1): CD002003. PMC 5369873 . PMID 28107561. doi:10.1002/14651858.CD002003.pub5.  Clinical information for Hypertension I Heart Foundation. heartfoundation-prod.azurewebsites.net. [2023-05-13]. （原始内容存档于2022-09-13）.  CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS).. Circulation. October 1994, 90 (4): 1765–1773. PMID 7923660. doi:10.1161/01.cir.90.4.1765 .  Konishi M, Haraguchi G, Kimura S, Inagaki H, Kawabata M, Hachiya H, et al. Comparative effects of carvedilol vs bisoprolol for severe congestive heart failure. Circulation Journal. June 2010, 74 (6): 1127–1134. PMID 20354334. doi:10.1253/circj.cj-09-0989 .  Castagno D, Jhund PS, McMurray JJ, Lewsey JD, Erdmann E, Zannad F, et al. Improved survival with bisoprolol in patients with heart failure and renal impairment: an analysis of the cardiac insufficiency bisoprolol study II (CIBIS-II) trial. European Journal of Heart Failure. June 2010, 12 (6): 607–616. PMID 20354032. S2CID 205048092. doi:10.1093/eurjhf/hfq038 . hdl:2318/134969 .  Leopold G, Pabst J, Ungethüm W, Bühring KU. Basic pharmacokinetics of bisoprolol, a new highly beta 1-selective adrenoceptor antagonist. Journal of Clinical Pharmacology. 1986, 26 (8): 616–621. PMID 2878941. S2CID 42159046. doi:10.1002/j.1552-4604.1986.tb02959.x.  Leopold G, Ungethüm W, Pabst J, Simane Z, Bühring KU, Wiemann H. Pharmacodynamic profile of bisoprolol, a new beta 1-selective adrenoceptor antagonist. British Journal of Clinical Pharmacology. September 1986, 22 (3): 293–300. PMC 1401121 . PMID 2876722. doi:10.1111/j.1365-2125.1986.tb02890.x.  Hauck RW, Schulz C, Emslander HP, Böhm M. Pharmacological actions of the selective and non-selective beta-adrenoceptor antagonists celiprolol, bisoprolol and propranolol on human bronchi. British Journal of Pharmacology. November 1994, 113 (3): 1043–1049. PMC 1510470 . PMID 7858847. doi:10.1111/j.1476-5381.1994.tb17098.x.  Bisoprolol. 2012. PMID 31643790.  Morales DR, Jackson C, Lipworth BJ, Donnan PT, Guthrie B. Adverse respiratory effect of acute β-blocker exposure in asthma: a systematic review and meta-analysis of randomized controlled trials. Chest. April 2014, 145 (4): 779–786. PMID 24202435. doi:10.1378/chest.13-1235.  Morales DR, Lipworth BJ, Donnan PT, Jackson C, Guthrie B. Respiratory effect of beta-blockers in people with asthma and cardiovascular disease: population-based nested case control study. BMC Medicine. January 2017, 15 (1): 18. PMC 5270217 . PMID 28126029. doi:10.1186/s12916-017-0781-0 .  Bennett M, Chang CL, Tatley M, Savage R, Hancox RJ. The safety of cardioselective β1-blockers in asthma: literature review and search of global pharmacovigilance safety reports. ERJ Open Research. January 2021, 7 (1). PMC 7917232 . PMID 33681344. doi:10.1183/23120541.00801-2020.  Loth DW, Brusselle GG, Lahousse L, Hofman A, Leufkens HG, Stricker BH. β-Adrenoceptor blockers and pulmonary function in the general population: the Rotterdam Study. British Journal of Clinical Pharmacology. January 2014, 77 (1): 190–200. PMC 3895360 . PMID 23772842. doi:10.1111/bcp.12181.  Bennett MR, Chang CL, Tuffery C, Hopping S, Hancox RJ. The impact of regular bisoprolol on the response to salbutamol in asthma: A double-blind randomized placebo-controlled crossover trial. Respirology. March 2021, 26 (3): 225–232. PMID 33043552. S2CID 222301890. doi:10.1111/resp.13955.  Bristow MR, Hershberger RE, Port JD, Minobe W, Rasmussen R. Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Molecular Pharmacology. March 1989, 35 (3): 295–303. PMID 2564629.  Haeusler G, Schliep HJ, Schelling P, Becker KH, Klockow M, Minck KO, et al. High beta 1-selectivity and favourable pharmacokinetics as the outstanding properties of bisoprolol. Journal of Cardiovascular Pharmacology. 1986, 8 (Suppl 11): S2–15. PMID 2439793. S2CID 24617470. doi:10.1097/00005344-198511001-00002.  Taniguchi T, Ohtani T, Mizote I, Kanzaki M, Ichibori Y, Minamiguchi H, et al. Switching from carvedilol to bisoprolol ameliorates adverse effects in heart failure patients with dizziness or hypotension. Journal of Cardiology. June 2013, 61 (6): 417–422. PMID 23548374. doi:10.1016/j.jjcc.2013.01.009 .  Düngen HD, Apostolovic S, Inkrot S, Tahirovic E, Töpper A, Mehrhof F, et al. Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS-ELD trial. European Journal of Heart Failure. June 2011, 13 (6): 670–680. PMC 3101867 . PMID 21429992. doi:10.1093/eurjhf/hfr020.  Muresan L, Cismaru G, Muresan C, Rosu R, Gusetu G, Puiu M, et al. Beta-blockers for the treatment of arrhythmias: Bisoprolol - a systematic review (PDF). Annales Pharmaceutiques Françaises. September 2022, 80 (5): 617–634 [2023-10-26]. PMID 35093388. S2CID 246428722. doi:10.1016/j.pharma.2022.01.007. （原始内容存档 (PDF)于2024-04-19）.  Harting J, Becker KH, Bergmann R, Bourgois R, Enenkel HJ, Fuchs A, et al. Pharmacodynamic profile of the selective beta 1-adrenoceptor antagonist bisoprolol. Arzneimittel-Forschung. February 1986, 36 (2): 200–208. PMID 2870720.  Kaumann AJ, Lemoine H. Direct labelling of myocardial beta 1-adrenoceptors. Comparison of binding affinity of 3H-(-)-bisoprolol with its blocking potency. Naunyn-Schmiedeberg's Archives of Pharmacology. October 1985, 331 (1): 27–39. PMID 2866449. S2CID 22328991. doi:10.1007/bf00498849.  Klockow M, Greiner HE, Haase A, Schmitges CJ, Seyfried C. Studies on the receptor profile of bisoprolol. Arzneimittel-Forschung. February 1986, 36 (2): 197–200. PMID 2870719.  Manalan AS, Besch HR, Watanabe AM. Characterization of [3H](+/-)carazolol binding to beta-adrenergic receptors. Application to study of beta-adrenergic receptor subtypes in canine ventricular myocardium and lung. Circulation Research. August 1981, 49 (2): 326–336. PMID 6113900. doi:10.1161/01.res.49.2.326 .  Schliep HJ, Schulze E, Harting J, Haeusler G. Antagonistic effects of bisoprolol on several beta-adrenoceptor-mediated actions in anaesthetized cats. European Journal of Pharmacology. April 1986, 123 (2): 253–261. PMID 3011461. doi:10.1016/0014-2999(86)90666-7.  Schliep HJ, Harting J. Beta 1-selectivity of bisoprolol, a new beta-adrenoceptor antagonist, in anesthetized dogs and guinea pigs. Journal of Cardiovascular Pharmacology. 1984, 6 (6): 1156–1160. PMID 6084774. doi:10.1097/00005344-198406060-00024 .  Schnabel P, Maack C, Mies F, Tyroller S, Scheer A, Böhm M. Binding properties of beta-blockers at recombinant beta1-, beta2-, and beta3-adrenoceptors. Journal of Cardiovascular Pharmacology. October 2000, 36 (4): 466–471. PMID 11026647. doi:10.1097/00005344-200010000-00008 .  Smith C, Teitler M. Beta-blocker selectivity at cloned human beta 1- and beta 2-adrenergic receptors. Cardiovascular Drugs and Therapy. April 1999, 13 (2): 123–126. PMID 10372227. S2CID 12639448. doi:10.1023/A:1007784109255.  Wellstein A, Palm D, Belz GG. Affinity and selectivity of beta-adrenoceptor antagonists in vitro. Journal of Cardiovascular Pharmacology. 1986, 8 (Suppl 11): S36–S40. PMID 2439796. S2CID 30987576. doi:10.1097/00005344-198511001-00006.  Bundkirchen A, Brixius K, Bölck B, Nguyen Q, Schwinger RH. Beta 1-adrenoceptor selectivity of nebivolol and bisoprolol. A comparison of [3H]CGP 12.177 and [125I]iodocyanopindolol binding studies. European Journal of Pharmacology. January 2003, 460 (1): 19–26. PMID 12535855. doi:10.1016/S0014-2999(02)02875-3.  Nuttall SL, Routledge HC, Kendall MJ. A comparison of the beta1-selectivity of three beta1-selective beta-blockers. Journal of Clinical Pharmacy and Therapeutics. June 2003, 28 (3): 179–186. PMID 12795776. S2CID 58760796. doi:10.1046/j.1365-2710.2003.00477.x.  Cojocariu SA, Maștaleru A, Sascău RA, Stătescu C, Mitu F, Leon-Constantin MM. Neuropsychiatric Consequences of Lipophilic Beta-Blockers. Medicina (Kaunas). February 2021, 57 (2): 155. PMC 7914867 . PMID 33572109. doi:10.3390/medicina57020155 .  Bisoprolol. go.drugbank.com. [2022-08-17]. （原始内容存档于2022-08-17）.  Kirch W, Rose I, Demers HG, Leopold G, Pabst J, Ohnhaus EE. Pharmacokinetics of bisoprolol during repeated oral administration to healthy volunteers and patients with kidney or liver disease. Clinical Pharmacokinetics. August 1987, 13 (2): 110–117. PMID 2887325. S2CID 25105692. doi:10.2165/00003088-198713020-00003.  Cvan Trobec K, Grabnar I, Kerec Kos M, Vovk T, Trontelj J, Anker SD, et al. Bisoprolol pharmacokinetics and body composition in patients with chronic heart failure: a longitudinal study. European Journal of Clinical Pharmacology. July 2016, 72 (7): 813–822. PMID 26996442. S2CID 14146663. doi:10.1007/s00228-016-2041-1.  Bisotab-Physician Information Page. Medical Dialogues. 2020-08-22 [2020-08-22]. （原始内容存档于2020-08-09）.  Bisoprolol. NHS. [2024-05-21].  Bisoprolol-ratiopharm. ratiopharm. [2024-05-21]. （原始内容存档于2024-06-03）.  Template:Merck Serono Medicine主題