Spironolactone, sold under the brand name Aldactone among others, is classed as a diuretic medication. It can be used to treat edema due to liver disease or kidney disease. It is also used to reduce risk of disease progression, hospitalization and death due to some types of heart failure. Other uses include acne and excessive hair growth in women, hypokalemia that does not improve with supplementation, high blood pressure that is difficult to treat and early puberty in boys.
It can also be used to block the effects of testosterone as a part of feminizing hormone therapy. Spironolactone is usually available in tablets, taken by mouth, though topical forms are also available.Common include electrolyte abnormalities, particularly hyperkalemia, nausea, vomiting, headache, rashes, and a decreased desire for sex. In those with liver or kidney problems, extra care should be taken.
If taken during pregnancy, some animal studies suggest that spironolactone may affect the development of sex organs in babies. While this has not occurred in the few human studies available, women who are pregnant or considering pregnancy should discuss spironolactone use with their doctor due to the theoretical risk.
Spironolactone is a steroid that blocks the effects of the aldosterone and, to a lesser degree, testosterone, causing some estrogen-like effects.
Spironolactone belongs to a class of medications known as potassium-sparing diuretics.Spironolactone was discovered in 1957, and was introduced in 1959.
It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2022, it was the 52nd most commonly prescribed medication in the United States, with more than 12million prescriptions. Spironolactone has a history of use in the trans community. Its use continues despite the rise of various accessible alternatives such as bicalutamide and cyproterone acetate with more precise action and less side effects.
Multiple studies show that spironolactone improves left ventricular diastolic function and reduce heart failure hospitalisations in patients with heart failure with preserved ejection fraction (HFpEF), though without benefits in all-cause death or overall hospitalisation rates. There is also evidence suggesting spironolactone may be effective in HFpEF with resistant hypertension (defined as blood pressure >130/80 mmHg) refractory to an ACE inhibitor/ARB, calcium channel blocker, and diuretic.
It is also used to treat conditions such as nephrotic syndrome or ascites in people with liver disease, essential hypertension, hypokalemia, secondary hyperaldosteronism (such as occurs with liver cirrhosis), and Conn's syndrome (primary hyperaldosteronism). The most common use of spironolactone is in the treatment of heart failure. On its own, spironolactone is only a weak diuretic because it primarily targets the distal nephron (collecting tubule), where only small amounts of sodium are reabsorbed, but it can be combined with other diuretics to increase efficacy. The classification of spironolactone as a "potassium-sparing diuretic" has been described as obsolete. Spironolactone is also used to treat Bartter's syndrome due to its ability to raise potassium levels.
Spironolactone, which has antiandrogenic effects, may help improve acne in adult women, with modest benefits demonstrated in recent clinical trials. Its use is limited by short-term outcome data and minimal reporting of side effects. It is considered a possible alternative to antibiotics for hormonal acne. It is also used to manage other androgen-related conditions such as hirsutism, seborrhoea, and female pattern hair loss Spironolactone is used for the treatment of hirsutism in the United States.
High doses of spironolactone, which are needed for considerable antiandrogenic effects, are not recommended for men due to the high risk of feminization and other side effects. Spironolactone can be used to treat of hyperandrogenism, such as due to polycystic ovary syndrome.
Spironolactone improves left ventricular diastolic function in patients with heart failure with preserved ejection fraction, however it has no effect on mortality and hospitalization.
Due to its antiandrogenic properties, spironolactone can cause effects associated with low androgen levels and hypogonadism in males. For this reason, men are typically not prescribed spironolactone for any longer than a short period of time, e.g., for an acute exacerbation of heart failure. A newer medication, eplerenone, has been approved by the US Food and Drug Administration (FDA) for the treatment of heart failure, and lacks the antiandrogenic effects of spironolactone. As such, it is far more suitable for men for whom long-term medication is being chosen. While Mineralocorticoid Receptor Antagonist (MRA) as a class (including spironolactone, eplerenone, and canrenone), is likely to be beneficial in heart failure patients, the precise comparative magnitude of effect on mortality between spironolactone and eplerenone remains subject to some clinical uncertainty, with limited comparative data available for canrenone.
Because of the antiandrogenic activity of spironolactone, it can be quite effective in treating acne in women. In addition, spironolactone reduces oil that is naturally produced in the skin and can be used to treat oily skin. Though not the primary intended purpose of the medication, the ability of spironolactone to be helpful with problematic skin and acne conditions was discovered to be one of the beneficial side effects and has been quite successful. Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill. Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months. Spironolactone has been reported to produce a 50 to 100% improvement in acne at sufficiently high doses. Response to treatment generally requires 1 to 3 months in the case of acne and up to 6 months in the case of hirsutism. Ongoing therapy is generally required to avoid relapse of symptoms. Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication. Spironolactone can be used in the treatment of female-pattern hair loss (pattern scalp hair loss in women). There is tentative low quality evidence supporting its use for this indication.
Antiandrogens like spironolactone are male-specific which can feminize male due to their antiandrogenic effects.
For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception. Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose. Moreover, oral contraceptives themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions, and hence can significantly augment the effectiveness of antiandrogens in the treatment of such conditions.Spironolactone is not generally used in men for the treatment of androgen-dependent dermatological conditions because of its feminizing side effects, but it is effective for such indications in men similarly. As an example, spironolactone has been reported to reduce symptoms of acne in males. An additional example is the usefulness of spironolactone as an antiandrogen in transgender women and nonbinary individuals.
Topical spironolactone is effective in the treatment of acne as well. As a result, topical pharmaceutical formulations containing 2% or 5% spironolactone cream became available in Italy for the treatment of acne and hirsutism in the early 1990s.
The combination of spironolactone with a birth control pill in the treatment of acne appears to have similar effectiveness to a birth control pill alone and the combination of a birth control pill with cyproterone acetate, flutamide, or finasteride. However, this was based on low- to very-low-quality evidence. Spironolactone may be more effective than birth control pills in the treatment of acne, and the combination of spironolactone with a birth control pill may have greater effectiveness for acne than either alone. In addition, some clinical research has found that flutamide is more effective than spironolactone in the treatment of acne. In one study, flutamide decreased acne scores by 80% within 3 months, whereas spironolactone decreased symptoms by only 40% in the same period.
However, the use of flutamide for acne is limited by its liver toxicity. Bicalutamide is a potential alternative to flutamide for acne as well. Spironolactone can be considered as a first-line treatment for acne in those who have failed other standard treatments such as topical therapies and under certain other circumstances, although this is controversial due to the side effects of spironolactone and its teratogenicity.There is insufficient clinical evidence to compare the effectiveness of spironolactone with other antiandrogens for female-pattern hair loss. The effectiveness of spironolactone in the treatment of both acne and hirsutism appears to be dose-dependent, with higher doses being more effective than lower doses.
A potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening. Hyperkalemia can present as a normal anion-gap metabolic acidosis. It has been reported that the addition of spironolactone to loop diuretics in people with heart failure was associated with a higher risk of hyperkalemia and acute kidney injury. Spironolactone may put people at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis. In addition, there has been some evidence suggesting an association between use of the medication and hemorrhage from the stomach and duodenum, though a causal relationship between the two has not been established. Also, spironolactone is immunosuppressive in the treatment of sarcoidosis.
Most of the side effects of spironolactone are dose-dependent. Low-dose spironolactone is generally very well tolerated. Even higher doses of spironolactone, such as 100 mg/day, are well tolerated in most individuals. Dose-dependent side effects of spironolactone include menstrual irregularities, breast tenderness, and enlargement, orthostatic hypotension, and hyperkalemia. The side effects of spironolactone are usually mild and rarely result in discontinuation.
Although spironolactone poses an important risk of hyperkalemia in the elderly, in those with kidney or cardiovascular disease, and/or in those taking medications or supplements which increase circulating potassium levels, a large retrospective study found that the rate of hyperkalemia in young women without such characteristics who had been treated with high doses of spironolactone for dermatological conditions did not differ from that of controls. This was the conclusion of a 2017 hybrid systematic review of studies of spironolactone for acne in women as well, which found that hyperkalemia was rare and was invariably mild and clinically insignificant. These findings suggest that hyperkalemia may not be a significant risk in such individuals, and that routine monitoring of circulating potassium levels may be unnecessary in this population. However, other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors. Occasional testing on a case-by-case basis in those with known risk factors may be justified. Side effects of spironolactone which may be indicative of hyperkalemia and if persistent could justify serum potassium testing include nausea, fatigue, and particularly muscle weakness. Notably, non-use of routine potassium monitoring with spironolactone in young women would reduce costs associated with its use.
Among young gender-diverse individuals taking spironolactone, hyperkalemia is rare and (if present) transient and asymptomatic. Larger doses do not appear to increase risks in this population. A broader retrospective study found that the rate of hyperkalemia in gender-diverse individuals is correlated with age, with those above 45 years old being more at risk. The finding suggests that patients below or at 45 years old without other conditions that affect potassium handling can be spared from routine monitoring.
Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men.
At low doses, the rate is only 5 to 10%, but at high doses, up to or exceeding 50% of men may develop gynecomastia. In the RALES, 9.1% of men taking 25 mg/day spironolactone developed gynecomastia, compared to 1.3% of controls. Conversely, in studies of healthy men given high-dose spironolactone, gynecomastia occurred in 3 of 10 (30%) at 100 mg/day, in 5 of 8 (62.5%) at 200 mg/day, and in 6 of 9 (66.7%) at 400 mg/day, relative to none of 12 controls. The severity of gynecomastia with spironolactone varies considerably, but is usually mild. As with breast enlargement caused by spironolactone in women, gynecomastia due to spironolactone in men is often although inconsistently accompanied by breast tenderness. In the RALES, only 1.7% of men developed breast pain, relative to 0.1% of controls.The time to onset of spironolactone-induced gynecomastia has been found to be 27 ± 20 months at low doses and 9 ± 12 months at high doses. Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication. However, after a sufficient duration of gynecomastia being present (e.g., one year), hyalinization and fibrosis of the tissue occurs and drug-induced gynecomastia may become irreversible.
It has been suggested that the weak progestogenic activity of spironolactone is responsible for these effects, although this has not been established and spironolactone has been shown to possess insignificant progestogenic and antiprogestogenic activity even at high dosages in women. An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels. Indeed, CYP17A1 genotype is associated with polymenorrhea. Regardless of their mechanism, the menstrual disturbances associated with spironolactone can usually be controlled well by concomitant treatment with a birth control pill, due to the progestin component.
A study found that spironolactone was not associated with in the offspring of rats.
Because it is an antiandrogen, however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses. In accordance, a subsequent study found that partial feminization of the genitalia occurred in the male offspring of rats that received doses of spironolactone that were five times higher than those normally used in humans (200 mg/kg per day). Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100 mg/kg per day).In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans.
Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific . A case report described a woman who was prescribed spironolactone during pregnancy with triplets and delivered all three (one boy and two girls) healthy; there was no feminization in the boy. In addition, spironolactone has been used at high doses to treat pregnant women with Bartter's syndrome, and none of the infants (three boys, two girls) showed toxicity, including feminization in the male infants. There are similar findings, albeit also limited, for another antiandrogen, cyproterone acetate (prominent genital defects in male rats, but no human abnormalities (including feminization of male fetuses) at both a low dose of 2 mg/day or high doses of 50 to 100 mg/day). In any case, spironolactone is nonetheless not recommended during pregnancy due to theoretical concerns relating to feminization of males and also to potential alteration of fetal potassium levels.A 2019 systematic review found insufficient evidence that spironolactone causes birth defects in humans. However, there was also insufficient evidence to be certain that it does not.
There is no specific antidote for overdose of spironolactone. Treatment may consist of induction of vomiting or stomach evacuation by gastric lavage. The treatment of spironolactone overdose is supportive, with the purpose of maintaining tissue hydration, electrolyte balance, and . Spironolactone should be discontinued in people with impaired kidney function or hyperkalemia.
Spironolactone has been reported to induce the CYP3A4 and certain UDP-glucuronosyltransferases (UGTs), which can result in drug interaction with various medications.
However, it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4. In any case, spironolactone has been found to reduce the bioavailability of oral estradiol, which could be due to induction of estradiol metabolism via CYP3A4. Spironolactone has also been found to enzyme inhibitor UGT2B7.Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found to inhibit the antimineralocorticoid effects of spironolactone. Moreover, the addition of licorice to spironolactone has been found to reduce the antimineralocorticoid side effects of spironolactone in women treated with it for hyperandrogenism, and licorice hence may be used to reduce these side effects in women treated with spironolactone as an antiandrogen who are bothered by them. On the opposite end of the spectrum, spironolactone is useful in reversing licorice-induced hypokalemia. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to attenuate the diuresis and natriuresis induced by spironolactone, but, not to affect its antihypertensive effect.
Some research has suggested that spironolactone might be able to interfere with the effectiveness of antidepressant treatment. As the medication acts as an antimineralocorticoid, it is thought that it might be able to reduce the effectiveness of certain antidepressants by interfering with normalization of the hypothalamic–pituitary–adrenal axis and by increasing levels of such as cortisol.Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999). However, other research contradicts this hypothesis and has suggested that spironolactone might produce antidepressant effects. For instance, studies showing antidepressant-like effects of spironolactone in animals.
Spironolactone is a potent antimineralocorticoid. That is, it is an antagonist of the mineralocorticoid receptor (MR), the biological target of mineralocorticoids like aldosterone and 11-deoxycorticosterone. By blocking the MR, spironolactone inhibits the effects of mineralocorticoids in the body. The antimineralocorticoid activity of spironolactone is responsible for its therapeutic efficacy in the treatment of edema, high blood pressure, heart failure, hyperaldosteronism, and ascites due to cirrhosis.
It is also responsible for many of the side effects of spironolactone, such as urinary frequency, dehydration, hyponatremia, low blood pressure, fatigue, dizziness, metabolic acidosis, decreased kidney function, and its risk of hyperkalemia. Due to the antimineralocorticoid activity of spironolactone, levels of aldosterone are significantly increased by the medication, probably reflecting an attempt of the body to maintain homeostasis.Spironolactone is a moderate antiandrogen. That is, it is an antagonist of the androgen receptor (AR), the biological target of like testosterone and dihydrotestosterone (DHT). By blocking the AR, spironolactone inhibits the effects of androgens in the body. The antiandrogenic activity of spironolactone is mainly responsible for its therapeutic efficacy in the treatment of androgen-dependent skin and hair conditions like acne, seborrhea, hirsutism, and pattern hair loss and hyperandrogenism in women, precocious puberty in boys with testotoxicosis, and as a component of feminizing hormone therapy for transgender women. It is also primarily responsible for some of its side effects, like breast tenderness, gynecomastia, feminization, and demasculinization in men. Blockade of androgen signaling in the breast disinhibits the actions of in this tissue.
Although useful as an antiandrogen in women, who have low testosterone levels compared to men, spironolactone is described as having relatively weak antiandrogenic activity.Spironolactone is a weak steroidogenesis inhibitor. That is, it inhibits steroidogenic enzymes, or involved in the steroidogenesis. Spironolactone and/or its metabolites have been found in vitro to weakly enzyme inhibitor a broad array of steroidogenic enzymes including cholesterol side-chain cleavage enzyme, 17α-hydroxylase, 17,20-lyase, 5α-reductase, 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, 21-hydroxylase, and aldosterone synthase (18-hydroxylase). However, although very high doses of spironolactone can considerably decrease steroid hormone levels in animals, spironolactone has shown mixed and inconsistent effects on steroid hormone levels in clinical studies, even at high clinical doses. In any case, the levels of most steroid hormones, including testosterone and cortisol, are usually unchanged by spironolactone in humans, which may in part be related to compensatory upregulation of their synthesis.
The weak steroidogenesis inhibition of spironolactone might contribute to its antiandrogenic efficacy to some degree and may explain its side effect of menstrual irregularities in women. However, its androgen synthesis inhibition is probably clinically insignificant.Spironolactone has been found in some studies to increase levels of estradiol, an estrogen, although many other studies have found no changes in estradiol levels. The mechanism of how spironolactone increases estradiol levels is unclear, but it may involve inhibition of the inactivation of estradiol into estrone and enhancement of the peripheral conversion of testosterone into estradiol. It is notable that spironolactone has been found in vitro to act as a weak inhibitor of 17β-hydroxysteroid dehydrogenase 2, an enzyme that is involved in the conversion of estradiol into estrone. Increased levels of estradiol with spironolactone may be involved in its preservation of bone density and in its side effects such as breast tenderness, breast enlargement, and gynecomastia in women and men.
In response to the antimineralocorticoid activity spironolactone, and in an attempt to maintain homeostasis, the body increases aldosterone production in the adrenal cortex.
Some studies have found that levels of cortisol, a glucocorticoid hormone that is also produced in the adrenal cortex, are increased as well. Spironolactone "acts at the basolateral side of the upper-distal tubule as well as in the collecting tubule," and does not have glucocorticoid-like effects at these specific sites; it can sometimes be prescribed as an alternative to glucocorticoids for patients with Glucocorticoid-Remediable Aldosteronism characterized by aldosterone excess, In patients "receiving spironolactone, there was a significant positive correlation between the change in cortisol and the change in HbA1c (r = 0.489, P = .003)." Patients taking spironolactone must be monitored for side effects including dizziness, headache, fatigue, diarrhea, hypertriglyceridemia and elevated liver enzymes.Other activities of spironolactone may include very weak interactions with the estrogen and progesterone receptors and agonist of the pregnane X receptor. These activities could contribute to the menstrual irregularities and breast side effects of spironolactone and to its , respectively.
Little or no systemic absorption has been observed with topical spironolactone.
Spironolactone appears to cross the blood–brain barrier.
Spironolactone is hydrolysis or acetylation at the thioester of the C7α position into 7α-TS by .
Following formation of 7α-TS, it is S-oxidation by flavin-containing monooxygenases to form an electrophilic sulfenic acid metabolite. This metabolite is involved in the CYP450 inhibition of spironolactone, and also binds covalent bond to other . 7α-TS is also S-methylation into 7α-TMS, a transformation catalyzed by thiol S-methyltransferase. Unlike the related medication eplerenone, spironolactone is said to not be metabolized by CYP3A4. However, hepatic CYP3A4 is likely responsible for the 6β-hydroxylation of 7α-TMS into 6β-OH-7α-TMS. 7α-TMS may also be at the C3α and C3β positions. Spironolactone is dethioacetylated into canrenone. Finally, the C17 γ-lactone ring of spironolactone is hydrolyzed by the paraoxonase PON3. It was originally thought to be hydrolyzed by PON1, but this was due to contamination with PON3.
Spironolactone is also known by its developmental code names SC-9420 and NSC-150339.
Spironolactone is also formulated in combination with a variety of other medications, including with hydrochlorothiazide as Aldactazide, with hydroflumethiazide as Aldactide, Lasilacton, Lasilactone, and Spiromide, with altizide as Aldactacine and Aldactazine, with furosemide as Fruselac, with benazepril as Cardalis (veterinary), with metolazone as Metolactone, with bendroflumethiazide as Sali-Aldopur, and with torasemide as Dytor Plus, Torlactone, and Zator Plus.
Spironolactone has been studied and used limitedly in the treatment of prostate cancer.
Spironolactone has been studied in fibromyalgia in women. It has also been studied in bulimia nervosa in women, but was not found to be effective.
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