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.
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 minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and a number of others.
Aside from its primary mechanisms of action of antimineralocorticoid and antiandrogenic action, spironolactone has been found in preclinical research to interact very weakly with the progesterone and estrogen receptors and to have very weak mixed progestogenic and antiprogestogenic activity as well as very weak mixed estrogenic and antiestrogenic activity. The clinical significance of these actions, if any, is uncertain. However, a small clinical study found that high doses of spironolactone had neither progestogenic nor antiprogestogenic effects in women. In any case, if one or both of these actions are clinically relevant, they might contribute to the menstrual irregularities and breast side effects of spironolactone. Spironolactone is also an agonist of the pregnane X receptor, and is able to induce the expression of CYP3A4 and P-glycoprotein in the body via this action. This effect may contribute to the drug interactions of spironolactone.
Antimineralocorticoid activity Spironolactone inhibits the effects of mineralocorticoids, namely, aldosterone, by displacing them from the mineralocorticoid receptor (MR) in the cortical collecting duct of kidney nephrons. This decreases the reabsorption of sodium and water while limiting the excretion of potassium. Hence, aldosterone antagonists are potassium (K+) sparing diuretics. The medication has a slightly delayed onset of action, and so it takes several days for diuresis to occur since the MR is a nuclear receptor which works through regulating gene transcription and gene expression. Therefore, the production and expression of ENaC and ROMK electrolyte channels in the distal nephrons, which give the drug its diuretic properties, has a delayed onset of action. In addition to direct antagonism of the MRs, the antimineralocorticoid effects of spironolactone may also in part be mediated by direct inactivation of 11β-hydroxylase and aldosterone synthase (18-hydroxylase), enzymes involved in the biosynthesis of mineralocorticoids. If levels of mineralocorticoids are decreased, then there are lower circulating levels to compete with spironolactone to influence gene expression as mentioned above. The onset of action of the antimineralocorticoid effects of spironolactone is relatively slow, with the peak effect sometimes occurring 48 hours or more after the first dose.
Canrenone is an antagonist of the MR as is spironolactone, but it is slightly more potent in comparison. It has been determined that 7α-TMS accounts for around 80% of the potassium-sparing effect of spironolactone while canrenone accounts for the remaining approximately 10 to 25%. Accordingly, 7α-TMS occurs at higher circulating concentrations than does canrenone in addition to having a higher relative affinity for the MR.
Antiandrogenic activity
Spironolactone is an antagonist of the AR, the biological target of androgens like testosterone and DHT. Its affinity for the AR has been found to vary widely depending on the report consulted, with a range of 2.7 to 67% that of DHT. One study found AR affinities of 3.0% for spironolactone, 4.2% for 7α-TMS, and 3.1% for 7α-TS. In contrast, the affinity of canrenone for the AR was found to be 0.84% that of DHT in another study, relative to 67% for spironolactone. 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. 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). 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.
Spironolactone antagonizes the effects of exogenous testosterone administered to castrated animals. It works by binding to the AR and displacing androgens like testosterone and DHT from the receptor, thereby reducing its activation by these hormones. 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 a dose of 40 mg/day spironolactone having an effect equal to 1–3 mg/day cyproterone acetate.
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. In addition, the AR antagonism of spironolactone is involved in its feminizing side effects, such as gynecomastia in men. Spironolactone has been found to produce gynecomastia without changes in testosterone or estradiol levels, implicating AR antagonism in this side effect. Gynecomastia is a major known side effect of AR antagonists.
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. 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), 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, as spironolactone has been shown in vitro to significantly accelerate carcinoma growth in the absence of any other androgens. 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. However, in another case report, spironolactone was effective in normalizing prostate-specific antigen in a man with prostate cancer. In addition, spironolactone has been studied in the treatment of prostate cancer.
Canrenone binds to and blocks the AR in vitro. However, relative to spironolactone, canrenone is described as having very weak affinity for the AR. 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. The antiandrogenic effects of spironolactone are considered in large part to result from other metabolites rather than canrenone. 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.
Spironolactone is described as having relatively weak antiandrogenic activity. Nonetheless, it is useful as an antiandrogen in women, who have low androgen levels compared to men. In addition, instances of gynecomastia, decreased libido, and erectile dysfunction have been reported in men taking very high doses of spironolactone (200 to 400 mg/day).
Affinities of selected ligands at the androgen receptor Compound (%) Ki (nM) 100 1.18 136 0.87 117 1.01 67.0 1.76 14.8 8.0 13.6 8.7 12.5 9.5 6.6 18 4.9 24 2.0 58 0.84 140 0.079 1200 0.00084 140,000 Notes: (1) Human skin fibroblasts used for assays. (2) Situation in vivo is different for flutamide and spironolactone due biotransformation. (3) Conflicting findings for spironolactone. Sources: Main: Related:
Spironolactone has been found to be effective in the treatment of hirsutism in women at a dosage of as low as 50 mg/day. At dosages of 100 mg/day and 200 mg/day, observed reductions in hair shaft diameter were 19% ± 8% and 30% ± 3%, respectively (p = 0.07). Levels of free testosterone were unchanged, however, suggesting that the antiandrogenic efficacy of spironolactone was due exclusively to direct AR blockade. 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. 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. 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.
Studies have found that spironolactone is associated with a significantly lower risk of prostate cancer in men ( = 0.69). This was apparent for high-dose spironolactone, using doses of 75 mg/day and above ( = 0.74). Conversely, lower doses of spironolactone (<75 mg/day) were not associated with a decreased risk of prostate cancer ( = 0.99). Levels of prostate-specific antigen (PSA) were assessed and were found to be significantly lower in spironolactone-treated men. The decreased incidence of prostate cancer with spironolactone was hypothesized to be due to its known antiandrogenic activity.
Steroidogenesis inhibition