螺内酯的药效学

Wikipedia contributors. (2021, January 11). Pharmacodynamics of spironolactone. In Wikipedia, The Free Encyclopedia. Retrieved 06:05, April 11, 2021, from https://en.wikipedia.org/w/index.php?title=Pharmacodynamics_of_spironolactone&oldid=999597573

以这个版本为准,开始翻译。

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The pharmacodynamics of spironolactone, an antimineralocorticoid and antiandrogen medication, concern its mechanisms of action, including its biological targets and activities, as well as its physiological effects. The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition. In addition, spironolactone has sometimes been found to increase estradiol and cortisol levels and hence could have slight indirect estrogenic and glucocorticoid effects. The medication has also been found to interact very weakly with the estrogen and progesterone receptors, and to act as an agonist of the pregnane X receptor. Likely due to increased activation of the estrogen and/or progesterone receptors, spironolactone has very weak but significant antigonadotropic effects.

螺内酯是一种抗盐皮质激素和抗雄激素药物,其药效学涉及其作用机制,包括其生物学靶点和生物活性,以及其生理效应。螺内酯的药效学特点是高抗盐皮质激素活性,中等抗雄激素活性,弱的类固醇生成抑制作用。此外,有时发现螺内酯可以增加雌二醇和皮质醇水平,因此可能有轻微的间接雌激素和糖皮质激素作用。这种药物还被发现与雌激素和孕激素受体的相互作用非常弱,并作为孕烷X受体的激动剂。可能是由于能增加雌激素和/或黄体酮受体的激活,螺内酯有非常微弱但显著的抗性腺激素作用。

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注释:

盐皮质激素

这是一张让人好奇心害死猫的图片。
盐皮质激素的结构在上图的紫色部分。

盐皮质激素的排钾保钠作用


促进ENaC和Na+/K+ ATPase表达。ENaC有排钾保钠的作用,促进肾小管的重吸收。

螺内酯是抗盐皮质激素

螺内酯,是一种人工合成的甾体化合物,一种低效利尿剂,其结构与醛固酮相似,为醛固酮的竞争性抑制剂。由于其仅作用于远曲小管和集合管,对肾小管其他各段无作用,故利尿作用较弱。另外,螺内酯对肾小管以外的醛固酮靶器官也有作用。

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Spironolactone has a very short biological half-life and is considered to be a prodrug; hence, its active metabolites are responsible for most of its pharmacodynamics. The major active forms of spironolactone include 7α-thiomethylspironolactone (7α-TMS) and canrenone (7α-desthioacetyl-δ6-spironolactone), while more minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and a number of others.
螺内酯的生物半衰期非常短,被认为是一种前药;因此,其活性代谢物是其大部分药效学的来源。螺内酯的主要活性形式有7α-硫甲基螺内酯(7α-TM)和坎利酮(7α-去硫代乙酰-δ6-螺内酯),而螺内酯的次要代谢物有7α-硫代螺内酯(7α-TS)、6β-羟基-7α-硫甲基螺内酯(6β-OH-7α-TM)等。

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注释:

image
螺内酯
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7α-硫甲基螺内酯,螺内酯的主要活性形式。它约占螺内酯保钾作用的80%。
image

Canrenone,螺内酯的第二种主要活性形式。它约占螺内酯保钾效果的10%到25%。

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Spironolactone is an antagonist of the AR, the biological target of androgens like testosterone and DHT.[27][28] Its affinity for the AR has been found to vary widely between different studies, with a range of 2.7 to 67% of that of DHT.[29][30][31][32] One study found affinities for the AR of 3.0% for spironolactone, 4.2% for 7α-TMS, and 3.1% for 7α-TS.[30] Conversely, the affinity of canrenone for the AR was found to be 0.84% of that of DHT in another study, relative to 67% for spironolactone.[32] However, another study found the affinity of canrenone for the AR to be 2.5 to 14%, relative to 4.1 to 31% in the case of spironolactone.[33] Another study that directly compared the affinities of spironolactone and canrenone reported that spironolactone had 5-fold higher affinity for the AR than canrenone (5% and 1% of that of DHT, respectively).[27] A comparative study of binding inhibition to the AR in rat prostate cytosol AR found IC50 values of 3 nM for DHT, 24 nM for cyproterone acetate, and 67 nM for spironolactone.[34] Spironolactone antagonizes the effects of exogenous testosterone administered to castrated animals.[29] It works by binding to the AR and displacing androgens like testosterone and DHT from the receptor, thereby reducing its activation by these hormones.[27] A study found that oral spironolactone had “about 10 to 20% of the feminizing effect of cyproterone acetate” on sexual differentiation in male rat fetuses, with 40 mg/day spironolactone having an equal effect to 1 to 3 mg/day cyproterone acetate.[35][36]

螺内酯是雄激素受体的拮抗剂,雄激素受体是睾酮和二氢睾酮等雄激素的生物靶标。

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7α-TS
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7α-TMS

螺内酯对雄激素受体的亲和力在不同的研究之间差别很大,为二氢睾酮的2.7%到67%。
一项研究发现,螺内酯对雄激素受体的亲和力为3.0%,7α-TMS的亲和力为4.2%,7α-TS的亲和力为3.1%。

AR = 雄激素受体
DHT = 二氢睾酮

相反,在另一项研究中,坎利酮对AR的亲和力是DHT的0.84%,而对螺内酯的亲和力是67%。
然而,另一项研究发现,坎利酮对AR的亲和力为2.5%至14%,相对于螺内酯的亲和力为4.1%至31%。
另一项直接比较螺内酯和坎利酮亲和力的研究报告称,螺内酯对AR的亲和力是坎利酮的5倍(分别是DHT的5%和1%)。

对大鼠前列腺胞浆AR结合抑制的比较研究发现,DHT的IC50值为3 nM,醋酸环丙孕酮为24 nM,螺内酯为67 nM。

螺内酯拮抗外源性睾酮对去势动物的影响。它的工作原理是与AR结合,并将睾酮和DHT等雄激素从受体上移除,从而减少这些激素的激活。一项研究发现,口服螺内酯对雄性大鼠胎鼠性分化的女性化作用约为醋酸环丙孕酮的10%至20%,每天40毫克的螺内酯与每天1至3毫克的醋酸环丙孕酮的效果相当。

The AR antagonism of spironolactone mostly underlies its antiandrogenic activity and is the major mechanism responsible for its therapeutic benefits in the treatment of androgen-dependent conditions like acne, hirsutism, and pattern hair loss and its usefulness in hormone therapy for transgender women.[27][16] In addition, the AR antagonism of spironolactone is involved in its feminizing side effects in men like gynecomastia.[27] Spironolactone has been found to produce gynecomastia without changes in testosterone or estradiol levels, implicating AR antagonism in this side effect.[29] Gynecomastia is a major known side effect of AR antagonists.[37]

螺内酯的AR拮抗作用主要是其抗雄激素活性的基础,也是其在治疗雄激素依赖疾病(如痤疮、多毛症和脱发)以及对跨性别女性进行激素治疗的有效性的主要机制。 此外,螺内酯的AR拮抗作用也参与了其女性化副作用,例如男性乳房发育症。 螺内酯已被发现在没有睾酮或雌二醇水平变化的情况下产生女性乳房发育的副作用,这种副作用中牵涉到AR拮抗作用。 男性乳房发育是AR拮抗剂的主要已知副作用。

Spironolactone, similarly to other steroidal antiandrogens such as cyproterone acetate, is actually not a pure, or silent, antagonist of the AR, but rather is a weak partial agonist with the capacity for both antagonistic and agonistic effects.[38][39][40][41] However, in the presence of sufficiently high levels of potent full agonists like testosterone and DHT (the cases in which spironolactone is usually used even with regards to the “lower” relative levels present in females),[41] spironolactone will behave more similarly to a pure antagonist. Nonetheless, there may still be a potential for spironolactone to produce androgenic effects in the body at sufficiently high dosages and/or in those with very low endogenous androgen concentrations. As an example, one condition in which spironolactone is contraindicated is prostate cancer in men being treated with androgen deprivation therapy,[42] as spironolactone has been shown in vitro to significantly accelerate carcinoma growth in the absence of any other androgens.[39] In accordance, three case reports have described significant worsening of prostate cancer with spironolactone treatment in patients with the disease, leading the authors to conclude that spironolactone has the potential for androgenic effects in some contexts and that it should perhaps be considered to be a selective androgen receptor modulator (SARM), albeit with mostly antagonistic effects.[43][44][45] However, in another case report, spironolactone was effective in normalizing prostate-specific antigen in a man with prostate cancer.[46] In addition, spironolactone has been studied limitedly in the treatment of prostate cancer.[47][48]

螺内酯与其他甾体类抗雄激素(如醋酸环丙孕酮)相似,实际上不是AR的完全拮抗剂或静默拮抗剂,而是弱的部分激动剂,具有拮抗和激动作用。

但是,如果强效全效激动剂(例如睾酮和DHT)的水平足够高(即使在女性中其水平相对较低,通常也使用螺内酯),螺内酯的行为与纯拮抗剂相似 。 尽管如此,螺内酯在足够高的剂量下和/或内源性雄激素浓度非常低的剂量下仍可能在体内产生雄激素作用。

举个例子,螺内酯被禁忌的一种情况是接受雄激素剥夺治疗的男性的前列腺癌,因为体外研究表明,在没有任何其他雄激素的情况下,螺内酯可以显著加速癌症的生长。

相应地,有三个病例报告描述了螺内酯治疗前列腺癌患者前列腺癌的显著恶化,这使得作者得出结论,螺内酯在某些情况下具有潜在的促雄激素作用,也许应该被认为是一种选择性雄激素受体调节剂(SARM),尽管它具有主要的拮抗作用。然而,在另一个病例报告中,螺内酯在前列腺癌男性患者的前列腺特异性抗原正常化方面是有效的。此外,螺内酯治疗前列腺癌的研究有限。

Canrenone binds to and blocks the AR in vitro.[28] However, relative to spironolactone, canrenone is described as having very weak affinity for the AR.[49] In accordance, replacement of spironolactone with canrenone in male patients has been found to reverse spironolactone-induced gynecomastia, suggesting that canrenone is comparatively much less potent in vivo as an antiandrogen.[28] As such, based on the above, the antiandrogenic effects of spironolactone are considered to be largely due to other metabolites rather than due to canrenone.[28][50][51] In accordance, 7α-TS and 7α-TMS have been found to possess approximately equivalent affinity for the rat prostate AR relative to that of spironolactone, thus likely accounting for the retention of the antiandrogenic activity of spironolactone.[30]

Spironolactone is described as having relatively weak antiandrogenic activity.[52][49][53][54] Nonetheless, it is useful as an antiandrogen in women, who have low androgen levels compared to men.[55][56] In addition, considerable incidences of gynecomastia, decreased libido, and erectile dysfunction have been reported in men taking very high doses of spironolactone (200 to 400 mg/day).[55]

Spironolactone has been found to have effectiveness in the treatment of hirsutism in women at a dosage of as low as 50 mg/day.[60] The effectiveness of spironolactone in the treatment of hirsutism in women has been found to be near-significantly greater at a dosage of 100 mg/day relative to a dosage of 200 mg/day (19% ± 8% and 30% ± 3% reduction in hair shaft diameter, respectively; p = 0.07).[61][62][35] Levels of free testosterone were unchanged, suggesting that the antiandrogenic efficacy of spironolactone was due exclusively to direct AR blockade.[61][62] In addition, other studies have found that 100 mg/day spironolactone is significantly or near-significantly inferior to 500 mg/day flutamide in improving symptoms of acne and hirsutism.[63][64][65] One study compared placebo and dosages of spironolactone of 50, 100, 150, and 200 mg/day in the treatment of acne in women and observed progressive increases in response rates up to the 200 mg/day dosage.[35][66] These findings suggest that the antiandrogenic effectiveness of spironolactone is not maximal below a dosage of 200 mg/day, and are in accordance with the typical dosage range of spironolactone of 50 to 200 mg/day in women.[63][52][67][66]

Studies have found that spironolactone is associated with a significantly lower risk of prostate cancer in men (HR = 0.69).[68][69] This was apparent for high-dose spironolactone, using doses of 75 mg/day and above (HR = 0.74).[68] Conversely, lower doses of spironolactone (<75 mg/day) were not associated with a decreased risk of prostate cancer (HR = 0.99).[68] Levels of prostate-specific antigen (PSA) were assessed and were found to be significantly lower in spironolactone-treated men.[68] The decreased incidence of prostate cancer with spironolactone was hypothesized to be due to its known antiandrogenic activity.[68]

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甾体合成抑制剂(类固醇合成酶抑制剂)

螺内酯有时即使不充当抗促性腺激素也能在高剂量下显着降低睾丸激素水平,这被认为是由于17α-羟化酶和17,20-裂合酶的直接酶促抑制,17α-羟化酶和17,20-裂合酶是睾丸激素生物合成所必需的酶。尽管螺内酯是17α-羟化酶和17,20-裂合酶的相对较弱的抑制剂,至少与更有效的类固醇生成抑制剂(如酮康唑和醋酸阿比特龙)相比(可以将睾丸激素的浓度降低至去势水平) ,这种作用可能会促进螺内酯的抗雄激素活性,例如降低患有高雄激素症的女性和变性女性的睾丸激素水平。

坎利酮与螺内酯相似地抑制类固醇生成酶,如17α-羟化酶、17,20-裂解酶、11β-羟化酶、胆固醇侧链裂解酶和21-羟化酶,但相比之下,其作用更强。尽管有螺内酯和坎利酮对这些类固醇生成酶的影响的发现,但在临床研究中,螺内酯对类固醇激素水平表现出混合且高度不一致的影响。已有研究表明,螺内酯可能对17α-羟化酶有微弱的部分抑制作用,这反过来会导致HPG轴上调,使类固醇激素水平保持正常。相反,抑制卵巢中的17α-羟化酶可能会扰乱月经周期,从而导致月经紊乱。

动物研究发现,螺内酯在1-100 mg/kg的剂量范围内可抑制睾丸CYP450介导的5%-75%的类固醇合成,其中40 mg/kg的剂量可抑制50%。在40~200 mg/kg剂量范围内,由于对17α羟化酶等类固醇合成酶的抑制,能使睾酮和17α羟孕酮的生成减少。相比之下,螺内酯在人体内的临床剂量范围通常在4至8毫克/公斤左右。

也有混合/相互矛盾的证据表明,螺内酯可能在一定程度上抑制5-α-还原酶,从而在一定程度上抑制睾酮合成强效的雄激素DHT。但是,与单独使用螺内酯相比,螺内酯和5-α-还原酶抑制剂非那雄胺联合治疗多毛症,其效果显著提高这表明螺内酯对5α还原酶的抑制作用很弱,或者充其量是不完全的。螺内酯被发现没有芳香化酶抑制剂的活性。

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孕激素活性

螺内酯在生物测定中的孕激素活性较弱。它在这方面的作用是PR上直接激动剂活性的结果,尽管其半最大效价非常低。螺内酯的孕激素活性已被认为与它的某些副作用有关,包括女性出现的月经不调和较高剂量时出现的不良血脂变化。也有人建议增加由螺内酯的雌激素作用引起的女性乳房发育,因为已知孕激素参与乳腺发育。螺内酯的一种主要活性代谢物,肾上腺素被发现与人子宫PR相互作用,Ki为300 nM。这是相对较弱的,大约比孕酮少100倍。无论如何,在某些研究中,使用100至200 mg剂量的螺内酯,可观察到高达1200 nM的坎利酮水平。

人们普遍认为,与螺内酯有关的月经不调是由于其孕激素的作用引起的,在兔子和恒河猴中进行的动物研究均显示螺内酯具有明显的孕激素作用。[然而,在动物中产生孕激素作用的螺内酯的剂量很高(兔子为50-200 mg / kg /天,恒河猴为400 mg /天)。在一项研究中,兔子的子宫内膜转化皮下注射的阈值剂量为:醋酸环丙孕酮为0.003–0.01 mg,屈螺酮为0.1–0.3 mg,孕酮为0.5 mg,螺内酯为10–20 mg。雄性食蟹猴口服螺内酯40 mg / kg / day不能表现出促性腺激素的作用或降低睾丸激素的水平,而口服drospirenone每天4 mg / kg则有效并强烈抑制了睾酮的水平。此外,即使使用高剂量的螺内酯,也没有观察到对于妇女有孕激素作用或抗孕激素作用(通过子宫内膜变化评估)。因此,螺内酯的孕激素效应似乎低于人类的临床意义水平。此外,与螺内酯有关的月经异常必须有不同的原因。对螺内酯月经紊乱的其他可能机制的建议包括干扰下丘脑-垂体-性腺轴,抑制酶促类固醇生成,以及雌激素和抗雌激素混合活性。

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