|Systematic (IUPAC) name|
17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone acetate
|Pregnancy cat.||B3 (AU) C (US)|
|Legal status||POM (UK) ℞-only (US)|
|Mol. mass||416.574 g/mol|
| (what is this?)
Spironolactone (INN, BAN, USAN) (pronounced //), commonly referred to simply as "spiro", and marketed primarily under the brand name Aldactone in most countries, is a synthetic, steroidal antimineralocorticoid agent with additional antiandrogen and weak progestogen properties, as well as some indirect estrogen and glucocorticoid effects, which is used primarily as a diuretic and antihypertensive, but also for the purpose of reducing elevated or unwanted androgen activity in the body. It acts predominantly as a competitive antagonist of the aldosterone (or mineralocorticoid) receptor, and belongs to a class of pharmaceutical drugs known as potassium-sparing diuretics.
Spironolactone is a relatively old drug, having been introduced clinically in 1959. It has been predicted that spironolactone will be superseded in cardiovascular conditions (e.g., heart failure and hypertension) by the newer agents such as the structurally related compound eplerenone, which is also an aldosterone antagonist but is selective and lacks many of the actions and side effects of spironolactone, and as such is much more tolerable in comparison. However, spironolactone is still far more widely used than eplerenone. Spironolactone nonetheless still finds frequent use as an antiandrogen.
- 1 Uses
- 2 Pharmacology
- 3 Pharmacokinetics
- 4 Adverse reactions
- 5 Spironolactone bodies
- 6 Chemical synthesis
- 7 See also
- 8 References
- 9 External links
As a diuretic/antihypertensive
Spironolactone is used primarily to treat heart failure, ascites in patients with liver disease, low-renin hypertension, hypokalemia, secondary hyperaldosteronism (such as occurs with hepatic cirrhosis), and Conn's syndrome (primary hyperaldosteronism). On its own, spironolactone is only a weak diuretic because its effects target the distal nephron (collecting tubule), where small amounts of sodium are reabsorbed; but it can be combined with other diuretics to increase efficacy. About one person in one hundred with hypertension has elevated levels of aldosterone; in these persons, the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives.
Because spironolactone reduces the body's production of testosterone and blocks the androgen receptors, in men it can cause effects associated with low testosterone levels and hypogonadism in males. For this reason, men are not typically prescribed spironolactone for any longer than a short period of time as for acute heart failure. A newer drug, eplerenone has been approved by the U.S. Food and Drug Administration for treatment of heart failure, has no similar antiandrogen effects and thus is far more suitable for men for whom long term medication is contemplated. Potassium supplementation should not be administered while taking spironolactone as this may cause hyperkalemia, a potentially deadly condition. Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone, especially during the first twelve months of use and whenever dosage is increased.
In a randomized evaluation which studied people with severe congestive heart failure, patients treated with spironolactone were found to have a relative risk of death of 0.70 or 30% relative risk reduction compared to the placebo group, indicating a significant mortality and morbidity benefit of the drug. Patients in the study arm also had fewer symptoms of heart failure and were hospitalized less frequently.
As an antiandrogen
Spironolactone is a potent antagonist of the androgen receptor as well as an inhibitor of androgen production. Due to the antiandrogenic effects that result from these actions, it is frequently used to treat a variety of cosmetic conditions in which androgen hormones such as testosterone and dihydrotestosterone (DHT) play a role, including hirsutism, androgenic alopecia, acne, and seborrhea in females, and male pattern baldness in either low doses or as a topical formulation in males; higher doses are not recommended for males due to the high risk of feminization and other side effects. In addition, it is also commonly used to treat symptoms of hyperandrogenism in polycystic ovary syndrome.
Spironolactone is frequently used as a component of hormone replacement therapy in trans women undergoing sex reassignment therapy, usually in addition to an estrogen. It is generally recommended to be prescribed at a dose of 100–200 mg per day for this purpose by the major transgender healthcare guideline bodies, though it is frequently used at doses up to 300–400 mg in cases of treatment-resistant individuals, and doses as high as 600 mg have been used in clinical studies with additional benefit. Spironolactone significantly depresses plasma testosterone levels, reducing them to female/castrate levels at sufficient doses and in combination with estrogen. The clinical response consists of, among other effects, decreased male pattern hair, the induction of breast development, feminization in general, and lack of spontaneous erections.
There are very few available options for androgen receptor antagonist drug therapy. Spironolactone, cyproterone acetate, and flutamide are the most well-known and widely used agents. Compared to cyproterone acetate, spironolactone is considerably less potent as an antiandrogen by weight and binding affinity to the androgen receptor. However, despite this, at the doses in which they are typically used, spironolactone and cyproterone acetate have been found to be generally equivalent in terms of effectiveness for a variety of androgen-related conditions; though, cyproterone acetate has frequently shown a slight but non-statistically significant advantage in many studies. Also, it has been suggested that cyproterone acetate could be more effective in cases where androgen levels are more pronounced, though this has not been proven. Flutamide, another frequently employed antiandrogen which is a pure, selective androgen receptor antagonist, is much less potent by weight and binding affinity than either spironolactone or cyproterone acetate, but at the doses used, has usually been found to be more effective than either of them as an antiandrogen. Unfortunately, both cyproterone acetate and flutamide have been associated with hepatotoxicity, severely so in the case of the latter, and cyproterone acetate is not available in certain countries such as the United States. Gonadotropin-releasing hormone (GnRH) analogues are another option for antiandrogen therapy, and are the most effective of any other by far, but on account of their limited use and peptide nature, despite the fact that many are now available as generics, they tend to be very expensive, and are not always covered by insurance. Thus, spironolactone may be the only practical, available, and safe option in many cases.
- Mineralocorticoid receptor (IC50 = 24 nM)
- Androgen receptor (IC50 = 77 nM)
- Progesterone receptor (EC50 = 740 nM)
- Glucocorticoid receptor (IC50 = 2,410 nM)
It does not significantly bind to either of the two estrogen receptors (ERα, ERβ), nor is its very weak activity at the glucocorticoid receptor listed above considered to be significant at clinically relevant concentrations.
Spironolactone inhibits the effects of mineralocorticoids including aldosterone and corticosterone by competing for intracellular mineralocorticoid receptors in the cortical collecting duct. This decreases the reabsorption of sodium and water, while decreasing the secretion of potassium. The drug has a fairly slow onset of action, and so, it takes several days to develop. This is because steroid receptors are nuclear receptors which work via regulating gene transcription (in this case the ENaC and ROMK channels will be decreased), and it takes time for gene expression to change. In addition to direct antagonism of the mineralocorticoid receptors, the antimineralocorticoid effects of spironolactone may also in part be mediated by direct inactivation of steroid 11β-hydroxylase and aldosterone synthase (18-hydroxylase), enzymes involved in the biosynthesis of the mineralocorticoids.
Spironolactone inhibits steroid 11β-hydroxylase, and notably, this enzyme is essential for the production of the glucocorticoid hormone cortisol. Thus, in theory, glucocorticoids would be lowered in addition to mineralocorticoids (indicating that spironolactone should also produce some degree of antiglucocorticoid effects). However, in practice this has been found not to be the case, and spironolactone has actually been shown to increase cortisol levels, both with acute and chronic administration. This has been elucidated to be due to its antagonism of the mineralocorticoid receptor, which suppresses negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis positively regulates the secretion of adrenocorticotropic hormone (ACTH), which in turn signals the adrenal glands, the major source of corticosteroid biosynthesis in the body, to increase production of glucocorticoids, and so by disinhibiting it, spironolactone raises their circulating levels. Thus, any antiglucocorticoid activity of spironolactone via suppression of glucocorticoid synthesis appears to be more than fully offset by its concurrent stimulatory effects on glucocorticoid production.
Spironolactone mediates its antiandrogenic effects via a variety of actions, which include the following:
- Direct blockade of androgens from interacting with the androgen receptor. It should be noted though that spironolactone, similarly to other steroidal antiandrogens such as cyproterone acetate, is not a pure, or silent, antagonist of the androgen receptor, but is actually a weak partial agonist with the capacity for both agonist and antagonist effects. However, in the presence of significant levels of high-efficacy full agonists like testosterone and DHT, which is usually the case, even in regards to the relatively low female ranges for androgens, it behaves, for all intents and purposes, purely as an antagonist, at least under normal circumstances and at typically used doses. Nonetheless, there may still be a potential for spironolactone to produce androgenic effects in the body at sufficiently high doses and/or in those with low enough endogenous androgen concentrations. As an example, one condition in which spironolactone is contraindicated is prostate cancer, as the drug has been shown in vitro to significantly accelerate carcinoma growth in the absence of any other androgens, and was found to do so at the relatively high rate of approximately 32%, which was about 35% that of DHT (indicating that its potential intrinsic activity at the androgen receptor may be somewhere around one-third that of endogenous full agonists).
- Inhibition of 17α-hydroxylase and 17,20-desmolase, enzymes in the androgen biosynthesis pathway, which in turn results in decreased testosterone and dihydrotestosterone (DHT) levels. Though, its inhibition of these enzymes is said to be relatively weak.
- Inhibition of 5α-reductase, the enzyme responsible for converting testosterone into the 3- to 10-fold more potent androgen dihydrotestosterone (DHT). However, there is conflicting data on the ability of spironolactone to affect this enzyme. An in vitro study of the effect of spironolactone on prostate tissue 5α-reductase activity found no change even with very high concentrations of the drug. In contrast, another study, after one month of treatment of spironolactone at a dose of 100 mg per day via the oral route, found a significant in vivo inhibitory effect of spironolactone on genital skin 5α-reductase activity in hirsute women as well as an inhibitory effect of the drug on 5α-reductase activity in normal genital skin in vitro, and concluded that spironolactone directly inhibits the 5α-reductase enzyme and that the property could play a role of the beneficial effects of the drug on hirsutism. However, another study of spironolactone in hirsute women, after 6 months of treatment at the same dose (100 mg/d orally), found no significant effects of the drug on the serum ratios of testosterone to DHT and its metabolites—a reliable marker of 5α-reductase activity—whereas significant changes were found with 5 mg per day oral finasteride, a well-established 5α-reductase inhibitor. Finally, yet another study of spironolactone in hirsute women, after 3 months of treatment at a higher dose of 200 mg per day orally, did find significant changes, in the same metabolic markers of 5α-reductase activity. In conclusion, whether, and how if it does, spironolactone inhibits 5α-reductase, is still not entirely clear. In any case, it can be assumed with reasonable certainty that if spironolactone truly does have any direct inhibitory effects on 5α-reductase, it is not nearly as potent as clinically employed, selective 5α-reductase inhibitors like finasteride, and the property only plays a small role in its antiandrogen effects. Supporting this deduction is a trial in which the combination of 100 mg/d spironolactone and 5 mg/d finasteride was found to be significantly more effective than spironolactone alone in the treatment of hirsutism in women.
- Acceleration of the metabolic clearance rate of testosterone by an enhancement of the rate of peripheral conversion of testosterone to estradiol.
Spironolactone has weak progestogenic properties. These are due to it acting as a direct agonist of the progesterone receptor, at which it has a half-maximal potency of approximately one tenth of that of at the androgen receptor. Spironolactone's progestogenic actions are thought to be responsible for some of its side effects, including the menstrual irregularities seen in women and the undesirable serum lipid profile changes (which are both seen with other progestins as well) that are seen at higher doses. They may also play a role in augmenting the gynecomastia and breast tenderness caused by the antiandrogenic/estrogenic effects of spironolactone, as progesterone is known to play a role in breast development.
Spironolactone has some estrogenic effects which it mediates via several indirect actions, including the following:
- By acting as an antiandrogen, since androgens suppress both estrogen production and activity.
- Displacement of estrogens from sex hormone-binding globulin (SHBG). This occurs because spironolactone binds to SHBG at a high rate, as do endogenous estrogens and androgens, but estrogens like estradiol and estrone are more easily displaced than are androgens like testosterone, and so spironolactone blocks relatively more estrogens from interacting with SHBG than it does androgens, resulting in a higher ratio of free estrogens to free androgens.
- Inhibition of the conversion of estradiol to estrone, resulting in an increase in the ratio of estradiol to estrone. This is important because estradiol is approximately 10 times as potent as estrone as an estrogen.
- Enhancement of the rate of peripheral conversion of testosterone to estradiol, resulting in lower testosterone and higher estradiol levels.
Spironolactone has a half-life of about 1–2 hours. Due to its relatively short half-life, it is thought that spironolactone may behave mainly as a prodrug to an array of active metabolites with much longer half-lives (e.g., 12–20 hours in the case of canrenone) including canrenone, 7α-methylthiospironolactone, and 6β-hydroxy-7α-methylthiospironolactone, among many others. The drug is highly plasma protein bound. It is metabolized by the liver, and is eliminated mostly renally, with only minimal biliary excretion.
The most common side effect of spironolactone is urinary frequency. Other general side effects include ataxia, drowsiness, dry skin, and rashes. Because it also affects the androgen receptors, spironolactone can cause gynecomastia and feminization in general, testicular atrophy, and sexual dysfunction consisting of loss of libido and erectile dysfunction, and in females it can cause menstrual irregularities and breast tenderness and enlargement.
Spironolactone may put patients at a heightened risk for bleeding from the stomach and duodenum, though a causal relationship between the two has not been established. Also, it has been shown to be immunosuppressive in the treatment of sarcoidosis.
Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this drug avoid potassium supplements and salt substitutes containing potassium. Doctors usually recommend periodic screening of serum potassium levels and some patients may be advised to limit dietary consumption of potassium.
Research has also shown spironolactone can interfere with the effectiveness of antidepressant treatment. The drug is actually (among its other receptor interactions) a mineralocorticoid (MR) antagonist, and has been found to reduce the effectiveness of antidepressant drugs in the treatment of major depression, it is presumed, by interfering with normalization of the hypothalamic-pituitary-adrenal axis in patients receiving antidepressant therapy.
It is also not taken under anuria, acute renal insufficiency, significant impairment of renal excretory function,or hyperkalemia.
Long-term administration of spironolactone gives the histologic characteristic of spironolactone bodies in the adrenal cortex. Spironolactone bodies are eosinophilic, round, concentrically laminated cytoplasmic inclusions surrounded by clear halos in preparations stained with hematoxylin and eosin.
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