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螺内酯

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螺内酯
Skeletal formula of spironolactone
Ball-and-stick model of the spironolactone molecule
臨床資料
读音/ˌspaɪroʊnoʊˈlæktoʊn/ SPY-roh-noh-LAK-tone,[1] 聆聽i/ˌspɪəroʊnoʊˈlæktoʊn/ SPEER-oh-noh-LAK-tone[2]
商品名Aldactone及其他
其他名稱SC-9420; NSC-150339; 7α-Acetylthiospirolactone; 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
AHFS/Drugs.comMonograph
MedlinePlusa682627
核准狀況
懷孕分級
给药途径口服給藥,[4] 局部外用藥物[5]
藥物類別鹽皮質激素受體拮抗劑,抗雄激素
ATC碼
法律規範狀態
法律規範
藥物動力學數據
生物利用度60–90%[10][11][12]
血漿蛋白結合率螺內酯: 88% (與血清白蛋白及alpha-1酸性白蛋白（英语：Orosomucoid）結合)[13]
坎利酮: 99.2% (與白蛋白結合)[13]
药物代谢肝臟, 其他:
• 去乙醯化作用（經由羧酸酯酶）
• 硫氧化作用（經由含黃素單加氧酶（英语：flavin-containing monooxygenase）
• 硫甲基化（經由硫嘌呤甲基轉移酶）
• 組織蛋白乙醯化
• 羥基化（經由CYP3A4）
• 內酯 水解（經由對氧磷酶-3（英语：PON3））[10][11][16][17][18][19][20]
代謝產物7α-硫醇基螺內酯（英语：7α-Thiospironolactone）, 7α-硫甲基螺內酯（英语：7α-thiomethylspironolactone）, 6β-羥基-7α-硫甲基螺內酯（英语：6β-hydroxy-7α-thiomethylspironolactone）, 坎利酮, 及其他[10][11][14]
(三者均具活性)[15]
生物半衰期螺內酯: 1.4小時[10]
7α-硫甲基螺內酯: 13.8小時[10]
6β-羥基-7α-硫甲基螺內酯: 15.0小時[10]
坎利酮: 16.5小時[10]
排泄途徑尿液, 膽汁[11]
识别信息
  • S-[(7R,8R,9S,10R,13S,14S,17R)-10,13-Dimethyl-3,5'-dioxospiro[2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-17,2'-oxolane]-7-yl] ethanethioate
CAS号52-01-7  checkY
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.122 編輯維基數據鏈接
化学信息
化学式C24H32O4S
摩尔质量416.58 g·mol−1
3D模型（JSmol）
熔点134至135 °C（273至275 °F）
  • O=C5O[C@@]4([C@@]3([C@H]([C@@H]2[C@H](SC(=O)C)C/C1=C/C(=O)CC[C@]1(C)[C@H]2CC3)CC4)C)CC5
  • InChI=1S/C24H32O4S/c1-14(25)29-19-13-15-12-16(26)4-8-22(15,2)17-5-9-23(3)18(21(17)19)6-10-24(23)11-7-20(27)28-24/h12,17-19,21H,4-11,13H2,1-3H3/t17-,18-,19+,21+,22-,23-,24+/m0/s1 checkY
  • Key:LXMSZDCAJNLERA-ZHYRCANASA-N checkY
螺內酯25毫克片劑。

螺內酯（INN:spironolactone），以"Aldactone"等商品名稱於市場上銷售，是一種利尿劑。[21]它可用於治療因肝臟疾病或腎臟疾病引起的水腫。[4]它也用於降低某些類型心臟衰竭導致的疾病惡化、住院及死亡風險。[22][23]其他用途有治療女性的痤瘡與毛髮過度生長、補充後仍未改善的低血鉀症、難以治療的高血壓，以及男孩的性早熟。[4][24][25][26]它還可在女性化激素療法中作為阻斷睪固酮作用的藥物 。[27]

螺內酯通常以口服方式給藥，但也有外用藥物劑型。[4]

使用後常見的副作用有電解質異常，特別是高血鉀症、噁心、嘔吐、頭痛、皮疹以及性慾降低。[4]對於肝臟或腎臟有問題的患者，使用時應格外謹慎。[4]

如果個體在懷孕期間服用，部分動物研究顯示螺內酯可能會影響胎兒性器官的發育。[28]雖然在目前少數的人體研究中尚未觀察到此現象，[28][29][30]但由於有理論上的風險，懷孕或考慮懷孕的女性應在使用前與醫師討論。[29]

螺內酯是一種類固醇，能阻斷醛固酮的作用，並在較小程度上阻斷睪固酮的作用，進而產生一些類雌激素的效果。[31][32][33][4][34]螺內酯屬於一種被稱為保鉀利尿劑（英语：Potassium-sparing diuretic）的藥物類別。[4]

螺內酯於1957年被發現，並於1959年投入醫療用途。[35][36][37]它已列入世界衛生組織基本藥物標準清單之中。[38]市面上有此藥物的通用名藥物（學名藥）販售。[4]它是美國於2023年排名第52位最常用的處方藥，累計處方箋數量超過1,200萬張。[39][40]螺內酯在跨性別社群中有悠久的使用歷史。[41]雖然各種更精確、副作用更少的替代藥物（如比卡魯胺與醋酸環丙孕酮）日益普及，但此藥物仍繼續使用中。[31][32]

醫療用途

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螺内酯、醋酸环丙孕酮和氟他胺对使用外源性睾酮的去势雄性大鼠的雄激素受体拮抗效力对比（通过抑制雄激素依赖性腹侧前列腺重量来衡量）

螺內酯主要用於治療射出分率減少的心臟衰竭（英语：Heart failure with reduced ejection fraction）（HFrEF），在標準療法中加入此藥可顯著降低死亡率與住院率。[42][43][44]對於射出分率保留的心臟衰竭（HFpEF），研究顯示它能改善左心室舒張功能並減少住院，但對總死亡率無顯著影響。[45]也有證據支持其用於治療合併抗藥性高血壓的HFpEF患者。[46]

此外，螺內酯常用於治療肝硬化腹水、腎病症候群等水腫症狀，以及原发性高醛固酮症與低血鉀症 。[47]由於其作用於遠端腎單位（集尿管），僅能重吸收少量鈉離子，故單獨使用的利尿效果較弱，常會與其他利尿劑併用以提升療效。[45]它也能用於治療巴特氏症候群（患者腎臟無法正常回收鹽分，導致鹽分大量隨尿液流失，鉀離子也被過度排泄）以提升血鉀水平。[46]

螺內酯憑藉其抗雄性激素特性，在皮膚科被視為抗生素以外治療女性荷爾蒙性痤瘡的替代方案。[48][49]它也被用於管理多囊卵巢症候群引起的多毛症、脂漏性皮膚炎與女性型脫髮。[50][51][52]然而由於存在高度女性化風險，不建議男性使用高劑量螺內酯進行抗雄性激素治療。

心臟衰竭

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袢利尿劑用於治療急性症狀，[53]而螺內酯等鹽皮質激素受體拮抗劑（MRA）與之不同，可用於長期降低慢性心衰竭的死亡率與發病率。[22][54]研究證實其可使心衰竭死亡率降低30%。[22]美國心臟協會建議NYHA心功能II-IV級且射出分率小於35%的患者使用鹽皮質激素受體拮抗劑。[55]

由於螺內酯具抗雄性激素特性，男性長期使用可能會導致性腺功能低下副作用。[56]較新藥物依普拉酮已獲美國食品藥物管理局（FDA）核准，由於其缺乏抗雄性激素作用，更適合男性長期使用。[57]雖然 MRA藥物（包含有螺內酯、依普拉酮與坎利酮）對心衰竭皆有益，但其具體療效差異仍存在臨床不確定性 。[58]

高血壓

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約有1%高血壓患者因醛固酮過高而致病，螺內酯因針對病因，療效優於複雜聯合法。但考科藍合作組織發佈的綜述指出，對多數患者而言，低劑量螺內酯降壓效果有限，高劑量則會引發副作用，針對這類（非原發性醛固酮增多症的）大眾高血壓患者，目前尚無證據顯示服用任何劑量的螺內酯能有效改善以人為本的預後結果（如降低死亡率或併發症風險）。[59]

高醛固酮水平

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螺內酯與依普拉酮是治療原發性高醛固酮症的第一線藥物。[60]它們能改善血壓與血鉀水平，並減輕左心室肥大、蛋白尿及頸動脈內膜中層厚度（英语：Intima–media thickness） 。[60]若病因為單側醛固酮分泌腎上腺腺瘤（英语：adrenocortical adenoma），則首選應為腎上腺切除術，而非藥物治療。[60]由於螺內酯具有抗雄性激素特性，可能導致男性胎兒畸形，因此禁用於治療於孕期個體的原發性高醛固酮症。[61][29][62][63]

皮膚與毛髮狀況

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雄性激素（如睪固酮與二氫睪酮）在多種皮膚問題中扮演關鍵角色，包括油性皮膚、痤瘡、脂漏性皮膚炎、多毛症及雄激素性脫髮 。[64][65]研究證實完全性雄性激素不敏感症候群（英语：Complete androgen insensitivity syndrome）的女性不會產生皮脂或痤瘡，且幾乎沒體毛。[66][67]而先天缺乏5α-還原酶（負責強化皮膚中雄性激素作用的酶）的男性，則少有痤瘡或是脫髮 。[68][69]相反地，患有多囊卵巢症候群等高雄性激素症的女性，常伴隨痤瘡、多毛與男性化特徵。[64]因此，抗雄性激素藥物在治療這類與雄性激素相關的皮膚及毛髮問題上極為有效。[70][71][72]

螺內酯憑藉其抗雄性激素活性，能有效改善女性痤瘡並減少皮脂分泌。[73][74][74]這項用途最初被視為藥物的有益副作用，現已成為皮膚科的成功療法。[74]螺內酯常與避孕藥併用以增強對痤瘡療效，通常需1至3個月見效（多毛症則需6個月），且需持續治療以防復發。[75][76]螺內酯目前被視為治療女性多毛症的第一線抗雄性激素藥物，亦有用於治療女性型脫髮的初步證據。[77][78][79]

由於螺內酯具有"男性特異性致畸胎性" ，可能導致男性胎兒女性化，因此僅建議育齡女性在採取充分避孕措施（如服用口服避孕藥）的前提下使用。[70][80][81]口服避孕藥本身亦具有抗雄性激素功能，能與螺內酯產生協同作用。[70][82]

雖然螺內酯對男性同樣有效，但因女性化副作用而較少用於男性皮膚治療。[78][83]然而它是跨性別女性與非二元性別者常用的重要藥物。[27][84]此外，外用螺內酯乳霜（2%或5%）曾於1990年代在義大利上市，但因被列入禁藥名單而於2006年停產。[85][86]

藥物比較

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螺內酯是治療多毛症的第一線藥物，其療效優於非那雄胺（二線藥物），但遜於氟他胺。[77]然而氟他胺因有肝毒性已不再受推薦，安全性較高的比卡魯胺是其替代選項。[77][87]螺內酯與非那雄胺或避孕藥聯用效果更佳。[77]

針對痤瘡，螺內酯與避孕藥聯用的療效與其他抗雄性激素藥物相當。[74]雖有研究指氟他胺見效更快，但因其肝毒性副作用而受限 。[71][88]螺內酯可作為標準療法無效時的第一線選擇，但其劑量與療效呈正相關，而使用高劑量會有月經不調等副作用，也會對胎兒有致畸的風險。[74][89][72]

跨性別激素治療

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雖然使用螺內酯可能引起矛盾反應（英语：paradoxical reactions），在臨床上仍常作仿單標示外使用，用於跨性別女性的女性化激素治療。特別是在無法取得醋酸環丙孕酮的美國，螺內酯通常作為雌激素的輔助藥物，用以抑制雄性激素。[90][27][84][91]比卡魯胺等替代方案的普及程度目前仍不及螺內酯。[92]

由於螺內酯的抗雄性激素作用需在高劑量下才顯現，因此可能產生多種副作用，這與僅專一作用於雄性激素受體的藥物不同。[31][32][33]當螺內酯與雌二醇聯用時，對跨性別女性的效果包括：減少男性型體毛、促進乳房發育及整體雌性化特徵，以及減少自發性勃起。[91]

市售劑型

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螺內酯有口服片劑（25、50、100毫克，商品名稱"Aldactone"等）與懸浮液（25毫克/5毫升，商品名 稱"Carospir"） 。[93][94][95][96][97]此外，亦有與氫氯噻嗪組成的複方製劑（如商品名稱"Aldactazide"）。[97][98]

在義大利曾曾上市商品名成為"Spiroderm"的2%或5%外用乳膏，用於治療痤瘡，但目前已停產。[5][99]由於螺內酯的水溶性極差，僅開發出口服與外用劑型，而無供靜脈注射等給藥途徑。[10]唯一可供注射使用的相關礦物皮質酮受體拮抗劑為坎利酮鉀（potassium canrenoate）。[100]

禁忌症

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使用螺內酯的禁忌症有高血鉀症、嚴重及末期腎臟病（因高血鉀風險極高，但接受腎透析者或可除外）、愛迪生氏病（腎上腺功能不全及低醛固酮水平），以及併用依普拉酮。[7][101]對於患有特定神經系統疾病、有無尿症病史、急性腎損傷，或腎臟排泄功能顯著受損且具高血鉀風險的患者，亦應謹慎使用。[7]

副作用

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使用螺內酯最常見的副作用是頻尿症，其他一般反應包括脫水、低血鈉症、輕度低血壓、共濟失調、嗜睡、頭暈、皮膚乾燥及皮疹。[71]因其抗雄性激素活性，高劑量下可能導致男性乳房脹痛、男性乳腺發育及性功能障礙。在極高劑量（每日400毫克）下，可能引發睪丸萎縮（英语：Testicular atrophy）與可逆性生育力下降，但臨床罕見使用此劑量。[102][103][104]女性則可能出現月經不調、乳房脹痛或增大，但整體而言人體對其耐受性良好。[50][74][105]

最嚴重的潛在風險為高血鉀症，嚴重時可危及生命，並可能表現為正常陰離子間隙的代謝性酸中毒。[7]將螺內酯加入袢利尿劑治療心衰竭時，可能增加急性腎損傷風險。[7]對腸胃道的副作用有噁心、嘔吐、胃炎，甚至可能與胃出血有關。[7][106] 多數副作用具有劑量依賴性。[73] 人體對低劑量螺內酯通常耐受性極佳，每日100毫克對多數人亦屬安全。[73] 劑量相關的副作用如直立性低血壓、月經異常與高血鉀通常程度輕微，鮮少會導致停藥。[73]

高血鉀水平

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螺內酯可能導致高血鉀，嚴重時具致命性。[104]在心臟病患者中，約10%至15%會出現血鉀升高，且風險隨劑量與RALES研究（全稱為Randomized Aldactone Evaluation Study，隨機對照安達通評估研究）發表後的處方增長而上升。[104][107][108]高齡、腎功能不全及併用血管張力素轉化酶抑制劑（ACEI）或 非類固醇抗發炎藥（NSAIDs）等藥物者風險最高。[109][110]

然而研究顯示在無風險因素的年輕女性或跨性別群體（特別是45歲以下）中，高血鉀極為罕見，且多為輕微無症狀。[74][111][74]對於這類健康族群，常規血鉀監測可能非必要，有助於降低醫療成本。僅在出現肌肉無力或疲勞等症狀時，才需進行個別檢測。[74]

乳房變化

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螺內酯可能引發乳房疼痛與增大，在女性中高劑量使用後的發生率可達40%。[112][73]在男性中，它常導致劑量依賴性的乳房發育，低劑量發生率約5%至10%，高劑量則可能超過50% 。[103][113]

此副作用通常程度輕微，低劑量平均於27個月後出現，高劑量則縮短至9個月。[103]雖然停藥後數週通常會消退，但若症狀持續超過一年，組織可能因纖維化而變得不可逆。[114][115]

月經干擾

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高劑量螺內酯常導致女性月經不調，包括月經間期出血（英语：Intermenstrual bleeding）、閉經及突破性出血。[73]在中等劑量下發生率約10%至50%，高劑量（如每日200毫克）則幾乎所有使用者會受影響，使其呈現排卵異常且不規律的週期 。[71][104]此現象通常在停藥後兩個月內恢復，螺內酯並不具備避孕效果。[104][116]其機制可能與螺內酯影響17α-羥化酶（17α-hydroxylase）進而干擾性類固醇代謝有關。[103]不論機制為何，這類月經干擾通常可藉由併用含有黃體素成分的口服避孕藥得到有效控制。[71][117]

情緒變化

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關於螺內酯等礦物皮質酮受體拮抗劑對情緒產生正面或負面影響，研究結果不一。[118][119][120]無論如何，螺內酯可能具備增加憂鬱症狀風險的潛力。[118][119][120]然而於2017年發表的一項混合系統綜述提出因痤瘡而接受螺內酯治療的女性，其憂鬱症發生率低於1% 。[74]同樣地，一項為期10年的觀察性研究發現在196名併用高劑量螺內酯與雌激素的跨性別女性中，抑鬱症發生率亦低於1%。[121]

血脂變化

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研究發現多囊卵巢症候群女性使用高劑量螺內酯時，可能增加低密度脂蛋白（LDL,"壞"膽固醇）並降低 高密度脂蛋白（"好"膽固醇），產生不利的血脂影響。[122][123]由於LDL升高是心血管疾病的潛在風險因素，螺內酯可能不宜用於血脂異常患者。[122][123][124]類似的不利變化也見於使用醋酸環丙孕酮與比卡魯胺等其他抗雄性激素藥物的後的結果。[125][126]

罕見反應

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螺內酯除導致高血鉀外，在極少數情況下可能引發過敏性休克、腎衰竭、[127]肝炎（已有兩例報告，均不嚴重）、[128]顆粒球缺乏症（英语：Agranulocytosis）、藥物超敏反應症候群、史蒂芬斯－強森症候群或毒性表皮壞死溶解症（TEN） 。[129][130]此外，曾有五例關於長期服用螺內酯患者罹患乳癌的報告。[104][113]

螺內酯小體

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顯微照片（蘇木精-伊紅染色）：腎上腺檢體顯示出螺內酯小體。

長期服用螺內酯會在腎上腺皮質產生組織學特徵，即所謂的"螺內酯小體"。在蘇木精-伊紅染色（H&E stain）的切片中，這些小體呈現出被透明暈環繞、嗜伊紅性（英语：Eosinophilic）、圓形且具向心分層結構的細胞質包涵體。[131]

懷孕與哺乳

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螺內酯可穿過胎盤，但進入母乳的量極微（低於母親劑量0.5%），通常被認為對嬰兒無害 。[112][132]動物實驗顯示高劑量螺內酯可能導致男性胎兒生殖器部分女性化。[133][134]

雖然臨床上尚未有螺內酯導致人類男性胎兒女性化或先天缺陷的案例報告，且在巴氏症候群等案例中表現安全，但目前證據仍不足以完全排除風險。[133][135][28]基於女性化特徵與胎兒血鉀水平改變的理論性疑慮，臨床上仍不建議在孕期使用。[133][136]

藥物過量

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螺內酯在急性過量時相對安全。[7]常見症狀包括嗜睡、意識混亂、斑丘疹、噁心、嘔吐及腹瀉。[7]雖然在急性過量中較罕見，但嚴重肝病患者可能出現低鈉血症、高血鉀或肝昏迷。腎功能不全者則有更高的高血鉀風險。[7]臨床試驗曾研究每日達2,400毫克的極高劑量，其動物口服半數致死量（LD50）超過1,000毫克/公斤。[7][100][137] 目前尚無特定解毒劑。[7]處置方式有催吐或洗胃，並採取支持性治療以維持水分、電解質平衡及生命徵象。[7]若患者出現腎功能受損或高血鉀，應立即停用螺內酯。[7]

藥物相互作用

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螺內酯常引發高血鉀，使用時應避免補充鉀鹽或含鉀代鹽。[138]雖然健康年輕女性或跨性別者在特定治療下可能無需嚴格限鉀，但老年人併用複方新諾明，因其阻礙遠端腎小管排鉀，會顯著增加風險。[111][139][140]

在代謝方面，螺內酯對CYP3A4具有誘導與不可逆抑制的雙重報告，可能降低口服雌二醇的生物利用度。[141][142]此外，它與地高辛等心血管藥物存在交互作用。[7]甘草會拮抗螺內酯的抗礦物皮質酮作用，但也能減輕其副作用，且螺內酯可用於逆轉甘草引發的低血鉀。[143][144]乙醯柳酸（阿斯匹靈）等 NSAIDs則會削弱其利尿與排鈉效果。[46]

關於情緒影響，部分研究認為螺內酯可能干擾下視丘—垂體—腎上腺軸的正常化，進而削弱抗憂鬱藥療效，但另有動物實驗顯示其具備抗憂鬱潛力，目前研究結論尚不一致 。[145][146]

藥理學

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藥效學

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7α-硫甲基螺內酯為螺內酯最主要的活性代謝物，其對螺內酯整體保鉀利尿藥效的貢獻度約達80%。[10][147][148]
坎利酮為螺內酯的第二大主要活性代謝物，其對螺內酯整體保鉀利尿藥效的貢獻度約介於10%至25%之間。[149]

螺內酯是一種前體藥物，主要經由活性代謝物7α-硫甲基螺內酯與坎利酮（英语：7α-Thiomethylspironolactone）來發揮作用。[10][100]其藥效特徵為強效抗礦物皮質酮、中度抗雄性激素及微弱的類固醇合成抑制活性 。[100][102]

它作為一種礦物皮質酮受體拮抗劑，能阻斷醛固酮，臨床用於治療水腫、高血壓及心臟衰竭，但也導致頻尿、低血壓與高血鉀風險。[150][151]其抗雄性激素活性則能抑制雄性激素受體，有效治療痤瘡、多毛症及作為跨性別女性激素治療的成分，但也會引發男性乳房發育。[152][153]

此外，螺內酯在體外雖能微弱抑制17α-羥化酶等多種合成酶，但在臨床劑量下對人體睪固酮或皮質醇水平通常無顯著影響，這可能與身體的代償機制有關。[102][154][155]部分研究觀察到雌二醇升高，可能源於其抑制雌二醇失活或促進周邊轉化，進而引發乳房脹痛並有助於維持骨密度 。[156][157]

藥代動力學

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關於螺內酯的藥代動力學尚未有十分深入的研究，部分原因在於它是1950年代開發的早期藥物。[158]但在過去數十年間已釐清關於螺內酯藥代動力學的許多細節。[159][160][161][10][162][163][164][165]

吸收

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個體單次口服100毫克螺內酯後，螺內酯及其主要活性代謝產物在其體內的濃度水平。[166]

口服螺內酯的生物利用度為60%至90%。[10][11][12]隨餐服用可促進藥物溶解並減少首渡效應，使生物利用度顯著提升22%至95%。[167][168]主要活性代謝物坎利酮的血漿濃度在25至200毫克劑量範圍內呈線性關係。[169]連續用藥約8至10天可達穩態濃度。[148]外用劑型則幾乎觀察不到全身性吸收。[170]

分佈

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螺內酯及其代謝物坎利酮與血漿蛋白高度結合（分別為88.0%與99.2%）。[10][13]螺內酯對性激素結合球蛋白（SHBG）的親和力極低，研究證實它不會從載體蛋白中置換出類固醇激素，而反駁關於其藉由置換SHBG結合位點來增加游離雌二醇水平的說法。[171][172][173]此外，螺內酯似乎能通過血腦屏障。[174][175]

代謝

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螺內酯在人體內代謝流程。[176]坎利酮被進一步轉化（成為二氫、四氫及六氫化代謝產物）、羥基化以及結合（例如：葡萄糖醛酸化）。[176]

螺內酯屬前體藥物，經由肝臟迅速代謝，生物半衰期僅1.4小時。[10][177]主要活性代謝物為7α-TMS、6β-OH-7α-TMS與坎利酮，其半衰期較長（13.8至16.5小時），是發揮療效的主體。[10][11]螺內酯經羧基酯酶水解為 7α-TS中間產物，隨後轉化為7α-TMS。[16]雖然該藥物的代謝與CYP3A4無關，但仍會參與6β羥化（6β-hydroxylation）過程；此外，其內酯環則由對氧磷酶-3（PON3）負責水解。[17][20]

排泄

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絕大部分的螺內酯經由腎臟排出，僅有極少量透過膽汁（最終為糞便）排泄。[178]

化學

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螺內酯是一種甾體7α-螺內酯，可視為孕酮衍生物。[100][179]其結構在C17位形成螺環γ-內酯（Spiro-γ-lactone），並在C7α位取代乙酰硫基。[180][181]這些修飾提升口服生物利用度與藥效，並賦予其抗雄性激素活性，同時大幅降低孕酮樣活性。[182][183]研究指出，Cα位取代是其具備抗雄性激素特性且能有效口服的關鍵 。[184][185]

名稱

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螺內酯（Spironolactone）亦可由下列等效化學名稱標示:[180][181][186]

  • 7α-乙酰硫基-17alpha-羥基-3-氧代孕甾-4-烯-21-羧酸γ-內酯
  • 7α-乙酰硫基-3-氧代-17α-孕甾-4-烯-21,17β-碳酸內酯
  • 3-(3-氧代-7α-乙酰硫基-17β-羥基雄甾-4-烯-1α-基)丙酸內酯
  • 7α-乙酰硫基-17α-(2-羧乙基)雄甾-4-烯-17β-醇-3-酮γ-內酯
  • 7α-乙酰硫基-17α-(2-羧乙基)睪酮γ-內酯

類似物

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螺內酯在結構上與其他臨床使用的螺內酯類藥物密切相關，例如坎利酮、坎利酸鉀（英语：Potassium canrenoate）、屈螺酮（英语：Drospirenone）及依普拉酮。此外，也包含從未上市的螺內酯類，如SC-5233（英语：SC-5233）（6,7-二氫坎利酮；7α-脫硫乙醯基螺內酯）、SC-8109（英语：SC-8109）（19-去甲-6,7-二氫坎利酮）、Spiroxasone（英语：Spiroxasone）、Prorenone（英语：Prorenone）（SC-23133）、Mexrenone（英语：Mexrenone）（SC-25152, ZK-32055）、Dicirenone（英语：Dicirenone）（SC-26304）、Spirorenone（英语：Spirorenone）（ZK-35973）以及Mespirenone（英语：Mespirenone）（ZK-94679） 。[100]

合成

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關於螺內酯及其類似物與衍生物的化學合成方法，已有相關文獻進行過描述與回顧。[187]

歷史

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孕酮的排鈉效果於1955年獲得證實，隨後促成螺內酯這一合成抗礦物皮質酮類似物的研發。[179][188]螺內酯於1957年首次合成，1958年至1961年間取得專利，並於1959年作為鹽皮質激素受體拮抗劑藥物上市[35][189][190]

其男性乳房發育副作用於1962年首次出現報導，抗雄性激素活性則於1969年被描述。[100][191]螺內酯於1978年開始應用於治療女性多毛症，現已成為美國治療女性皮膚病徵最廣泛使用的抗雄性激素藥物。[143][192]此外，它自1986年起也被應用於跨性別女性的激素治療，特別是在缺乏醋酸環丙孕酮的美國地區 。[193][194]早期螺內酯錠劑吸收較差，後改為微粒化配方（粒徑小於50微克），使藥效提升約4倍。[195][196]

社會與文化

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通用名稱

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獸醫用螺內酯通用名藥物。

此藥物的英文、法文及通用名稱均為spironolactone（螺內酯），這也是其國際非專有藥名（INN）、美國採用名稱（USAN）、美國藥典名稱（USP）、英国核准名称（BAN）、法國核准名稱|Dénomination Commune Française}}（DCF）及日本通用名稱（英语：Japanese Accepted Name）（JAN） 。[99][98][180][197]其拉丁文名稱為spironolactonum，德文為Spironolacton，西班牙文與葡萄牙文為espironolactona，義大利文則為spironolattone（亦為其義大利通用名稱（英语：Dénomination Commune Italienne）（DCIT）[99][98][197]

螺內酯亦因其研發代號SC-9420而為人所知。[99][98][180]

商品名稱

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螺內酯在全球以多種商品名銷售，其原廠藥名為Aldactone.[99][98]其他常見名稱有Spiractin、Spirolon、Verospiron等，另有Prilactone與Tempora等獸醫用劑型。[99][98]

此外，螺內酯常與其他藥物製成複方製劑，例如：與氫氯噻嗪聯合為商品名稱Aldactazide製劑、與氫氟噻嗪（英语：Hydroflumethiazide）聯合為商品名稱Aldactide製劑、與呋塞米（Furosemide）聯合為商品名稱Frusela製劑及與托拉塞米聯合為商品名稱Dytor Plus製劑。[198] [98]這些複方藥多用於強化利尿效果或管理心血管疾病。

市場供應

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螺內酯在全球各地均有銷售。[99][98]

研究

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前列腺疾病

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螺內酯曾被研究用於治療良性前列腺增生症（BPH） 。[199][200]雖然在治療三個月時症狀緩解優於對照組，但六個月後改善效果基本上消失，且在縮小前列腺體積或殘尿量方面與對照組無異，約5%受試者出現男性乳房發育 。[199][200][201]基於上述結果，學界認為螺內酯並不適於治療BPH。[200]

此外，螺內酯在治療前列腺癌方面的研究與應用亦十分有限。[202][203][46]

EB病毒

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研究發現螺內酯能抑制人類疱疹病毒第四型（EB病毒）及其他人類皰疹病毒的產生。其機制是藉由抑制EB病毒的海星狀微管相關蛋白質功能，該蛋白對於具感染性的病毒生成非常重要。[204]螺內酯的這項作用已被證實與其抗礦物皮質酮作用無關。[204]

其他病症

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螺內酯曾被研究用於治療男性與女性的玫瑰斑（酒糟鼻） 。[205][206][207][83] [208]

此外，螺內酯曾針對女性的纖維肌痛症進行過研究 。[209][210]它也曾被研究用於治療女性的心因性暴食症，但結果顯示並無療效。[211]

參考文獻

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  1. ^ Loughlin KR, Generali JA. The Guide to Off-label Prescription Drugs: New Uses for FDA-approved Prescription Drugs. Simon and Schuster. 2006: 131– [2016-11-06]. ISBN 978-0-7432-8667-1. （原始内容存档于2022-10-07）. 
  2. ^ Clark MA, Harvey RA, Finkel R, Rey JA, Whalen K. Pharmacology. Lippincott Williams & Wilkins. 2011-12-15: 286, 337 [2016-11-06]. ISBN 978-1-4511-1314-3. （原始内容存档于2022-10-07）. 
  3. ^ Spironolactone Pregnancy and Breastfeeding Warnings. The American Society of Health-System Pharmacists. [2015-11-29]. （原始内容存档于2015-12-02）. 
  4. ^ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Spironolactone. The American Society of Health-System Pharmacists. [2015-10-24]. （原始内容存档于2015-11-16）. 
  5. ^ 5.0 5.1 Farid NR, Diamanti-Kandarakis E. Diagnosis and Management of Polycystic Ovary Syndrome. Springer Science & Business Media. 2009-02-27: 235– [2016-11-06]. ISBN 978-0-387-09718-3. （原始内容存档于2022-10-07）. 
  6. ^ Aldactone 25 mg Film-Coated TabletsSummary of Product Characteristics (SmPC). (emc). 2022-02-03 [2023-08-02]. （原始内容存档于2022-10-06）. 
  7. ^ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 Aldactone- spironolactone tablet, film coated. DailyMed. 2018-11-29 [2020-01-01]. （原始内容存档于2015-09-10）. 
  8. ^ Qaialdo EPAR. European Medicines Agency (EMA). 2023-07-25 [2023-08-02]. （原始内容存档于2023-07-27）. 
  9. ^ Qaialdo. Union Register of medicinal products. 32023-05-31 [2023-06-06]. （原始内容存档于2023-06-06）. 
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