Spironolactone, marketed under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure, low blood potassium that does not improve with supplementation, early-onset puberty, and acne and excessive hair growth in women. It is also used for hormone therapy in transgender women. Spironolactone is taken by mouth.
Common side effects include electrolyte abnormalities, particularly high blood potassium, nausea, vomiting, headache, rashes, and a decreased desire for sex. In those with liver or kidney problems, extra care should be taken. Spironolactone has not been well studied in pregnancy and should not be used to treat high blood pressure of pregnancy. It is a steroid that blocks the effects of the hormones aldosterone and testosterone and has some estrogen and progesterone-like effects. Spironolactone belongs to a class of medications known as potassium-sparing diuretics.
Spironolactone was introduced in 1959. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication. The wholesale cost in the developing world as of 2014 is between US$0.02 and US$0.12 per day. In the United States it costs about US$0.50 per day.
Medical uses
Spironolactone is used primarily to treat heart failure, edematous conditions such as nephrotic syndrome or ascites in people with liver disease, essential 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 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.
Spironolactone directly blocks androgen signaling and also acts as an inhibitor of androgen production. Due to the antiandrogenic effects that result from these actions, it is frequently used off-label to treat a variety of dermatological conditions in which androgens, such as testosterone and dihydrotestosterone (DHT), play a role. Some of these uses include androgenic alopecia in men (either at low doses or as a topical formulation) and women, and hirsutism (excessive hair growth), acne, and seborrhea in women. Spironolactone is the most commonly used drug in the treatment of hirsutism in the United States. Higher doses of spironolactone are not recommended in males due to the high risk of feminization and other side effects. Similarly, it is also commonly used to treat symptoms of hyperandrogenism in polycystic ovary syndrome.
High blood pressure
About one person in one hundred with hypertension has elevated levels of aldosterone; in these people, the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives since it targets the primary cause of the elevated blood pressure. However, a Cochrane review found adverse effects at high doses and little effect on blood pressure at low doses in the majority of people with high blood pressure. There is no evidence of person-oriented outcome at any dose in this group.
Heart failure
While loop diuretics remain first-line for most people with heart failure, spironolactone has shown to reduce both morbidity and mortality in numerous studies and remains an important agent for treating fluid retention, edema, and symptoms of heart failure. Current recommendations from the American Heart Association are to use spironolactone in patients with NYHA Class II-IV heart failure who have a left ventricular ejection fraction of <35%.
In a randomized evaluation which studied people with severe congestive heart failure, people treated with spironolactone were found to have a relative risk of death of 0.70 or an overall 30% relative risk reduction compared to the placebo group, indicating a significant death and morbidity benefit of the drug. Patients in the study's intervention arm also had fewer symptoms of heart failure and were hospitalized less frequently. Likewise, it has shown benefit for and is recommended in patients who recently suffered a heart attack and have an ejection fraction less than 40%, who develop symptoms consistent with heart failure, or have a history of diabetes mellitus. Spironolactone should be considered a good add-on agent, particularly in those patients "not" yet optimized on ACE inhibitors and beta-blockers. Of note, a recent randomized, double-blinded study of spironolactone in patients with symptomatic heart failure with "preserved" ejection fraction (i.e. >45%) found no reduction in death from cardiovascular events, aborted cardiac arrest, or hospitalizations when spironolactone was compared to placebo.
It is recommended that alternatives to spironolactone be considered if serum creatinine is >2.5 mg/dL (221µmol/L) in males or >2 mg/dL (176.8 µmol/L) in females, if glomerular filtration rate is below 30mL/min or with a serum potassium of >5.0 mEq/L given the potential for adverse events detailed elsewhere in this article. Doses should be adjusted according to the degree of renal function as well.
According to systematic review, in heart failure with preserved ejection fraction, treatment with spironolactone did not improve patient outcomes. This is based on the TOPCAT Trial examining this issue, which found that of those treated with placebo had a 20.4% incidence of negative outcome vs 18.6% incidence of negative outcome with spironolactone. However, because the p-value of the study was 0.14, and the unadjusted hazard ratio was 0.89 with a 95% confidence interval of 0.77 to 1.04, it is determined the finding had no statistical significance. Hence the finding that patient outcomes are not improved with use of spironolactone. More recently, when blood samples from 366 patients in the TOPCAT study were analyzed for presence of canrenone (an active metabolite of spironolactone), 30% of blood samples from Russia lacked detectable residues of canrenone. This led to the conclusion that the TOPCAT trial results in Russia don't reflect actual clinical experience with spironolactone in patients with preserved ejection fraction. The TOPCAT study results are now considered to have been invalidated. The study's prime investigator and other prominent research cardiologists are now advising physicians treating heart failure with preserved ejection fraction to consider prescribing spironolactone pending outcome of two multicenter trials of newer medications.
Due to its antiandrogen 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 drug, eplerenone, has been approved by the U.S. Food and Drug Administration for the treatment of heart failure, and lacks the antiandrogen effects of spironolactone. As such, it is far more suitable for men for whom long-term medication is being chosen. However, eplerenone may not be as effective as spironolactone or the related drug canrenone in reducing mortality from heart failure.
The clinical benefits of spironolactone as a diuretic are typically not seen until 2â€"3 days after dosing begins. Likewise, the maximal antihypertensive effect may not be seen for 2â€"3 weeks.
Unlike with some other diuretics, potassium supplementation should not be administered while taking spironolactone, as this may cause dangerous elevations in serum potassium levels resulting in hyperkalemia and potentially deadly abnormal heart rhythms.
Skin and hair conditions
Androgens like testosterone and DHT play a critical role in the pathogenesis of a number of dermatological conditions including acne, seborrhea, hirsutism (excessive facial/body hair growth in women), and pattern hair loss (androgenic alopecia). In demonstration of this, women with complete androgen insensitivity syndrome (CAIS) do not produce sebum or develop acne and have little to no body, pubic, or axillary hair. Moreover, men with congenital 5α-reductase type II deficiency 5α-reductase being an enzyme that greatly potentiates the androgenic effects of testosterone in the skin, have little to no acne, scanty facial hair, reduced body hair, and reportedly no incidence of male pattern hair loss. Conversely, hyperandrogenism in women, for instance due to polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH), is commonly associated with acne and hirsutism as well as virilization (masculinization) in general. In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions.
Because of the antiandrogen activity of spironolactone, it can be quite effective in treating acne in women, and also reduces oil that is naturally produced in the 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 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 (FPHL). There is tentative low quality evidence supporting its use for this indication. Although apparently effective, it should be noted that not all cases of FHPL are dependent on androgens.
Antiandrogens like spironolactone are male-specific teratogens which can feminize male fetuses due to their antiandrogen effects (see below). 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. This is evidenced by the usefulness of spironolactone as an antiandrogen in transgender women.
Transgender hormone therapy
Spironolactone is frequently used as a component of hormone replacement therapy in transgender women, especially in the United States (where cyproterone acetate is not available), usually in addition to an estrogen. 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 body hair, the induction of breast development, feminization in general, and lack of spontaneous erections.
Comparison with other antiandrogens
There are few available options for antiandrogen therapy. Spironolactone, cyproterone acetate, and flutamide are some of the most well-known and widely used drugs. Compared to cyproterone acetate, spironolactone is considerably less potent as an antiandrogen by weight and binding affinity. However, despite this, at the doses of which they are typically used, spironolactone and cyproterone acetate have been found to be generally about equivalent in terms of effectiveness for a variety of androgen-related conditions, though, cyproterone acetate has shown a slight though non-statistically-significant advantage in some 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 used antiandrogen which is nonsteroidal and a pure androgen blocker, though much less potent by weight and binding affinity than either spironolactone or cyproterone acetate, has been found to be more effective than either of them as an antiandrogen when it is used at the typical treatment doses. Unfortunately, the uses of both cyproterone acetate and flutamide have been associated with hepatotoxicity, which can be severe with flutamide and has resulted in cyproterone acetate never being approved in the United States. Bicalutamide is a more potent, safer, and more tolerable alternative to flutamide, but is relatively little-studied in the treatment of androgen-dependent conditions aside from prostate cancer, though it has been used to treat hirsutism with success. Gonadotropin-releasing hormone (GnRH) analogues are another very effective option for antiandrogen therapy, but have not been widely employed for this purpose due to their high cost and limited insurance coverage despite many now being available as generics. As such, spironolactone may be the only practical, safe, available, and well-supported antiandrogen option in some cases.
In a study of the predictive markers for transgender women requesting breast augmentation, there was a significantly higher rate of those treated with spironolactone requesting breast augmentation compared to other antiandrogens such as cyproterone acetate or GnRH analogues, which was interpreted by the study authors as being potentially indicative that spironolactone may result in poorer breast development in comparison. This may be related to the fact that spironolactone has been regarded as a comparatively weak antiandrogen relative to other options.
Available forms
Spironolactone is usually used in the form of oral tablets. The drug has also been marketed in the form of 2% and 5% topical cream in Italy for the treatment of acne and hirsutism under the brand name Spiroderm, although this product is no longer available. Spironolactone has poor water solubility, and for this reason, only oral and topical formulations have been developed and other routes of administration such as intravenous injection are not employed.
Contraindications
Contraindications of spironolactone include renal disease and hyperkalemia (high levels of potassium), among others.
Side effects
The most common side effect of spironolactone is urinary frequency. Other general side effects include dehydration, hyponatremia (low sodium levels), mild hypotension (low blood pressure), ataxia (muscle incoordination), drowsiness, dizziness, dry skin, and rashes. Because it reduces androgen levels and directly blocks androgen signaling, spironolactone can, in men, cause breast tenderness, gynecomastia (breast development), and feminization in general, as well as testicular atrophy, reversibly reduced fertility, and sexual dysfunction including loss of libido and erectile dysfunction. In women, spironolactone can cause menstrual irregularities, breast tenderness, and breast enlargement.
The most important potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening. Hyperkalemia in these patients can present as a non anion-gap metabolic acidosis. Spironolactone may put patients 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 drug and bleeding from the stomach and duodenum, though a causal relationship between the two has not been established. Also, spironolactone has been shown to be immunosuppressive in the treatment of sarcoidosis.
Hyperkalemia
Spironolactone can cause hyperkalemia, which can, rarely, be fatal. Of those prescribed typical doses, 10% to 15% developed hyperkalemia, and in 6%, it was severe. An increase in the rates of hospitalization (from 0.2% to 11%) and death (from 0.3 per 1,000 to 2.0 per 1,000) due to hyperkalemia from 1994 to 2001 has been attributed to a parallel rise in the number of prescriptions written for spironolactone following the publication of the RALES study. The risk of hyperkalemia with spironolactone treatment is greatest in the elderly, in people with renal impairment, and in people simultaneously taking potassium supplements or ACE inhibitors.
Although spironolactone poses an important risk of hyperkalemia in the elderly, those with renal or cardiovascular disease, or those taking drugs or supplements which increase circulating potassium levels, the rate of hyperkalemia in young women without such characteristics treated with spironolactone for dermatological conditions has been found not to differ from that of controls. This suggests that hyperkalemia is not a significant risk in such patients and that routine monitoring of circulating potassium levels is unnecessary in this population.
Breast effects
In women, spironolactone is commonly associated with breast pain and breast enlargement, "probably because of [indirect] estrogenic effects on target tissue." Breast enlargement may occur in 26% of women and is described as mild, while breast tenderness is reported to occur in up to 40% of women taking high dosages of the drug. Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men. At low dosages, the rate is only 5â€"10%, but at high dosages, up to or exceeding 50% of men may develop gynecomastia. The severity of the gynecomastia varies considerably, but is usually mild. As with women, gynecomastia associated with spironolactone is commonly although inconsistently accompanied by breast tenderness. Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the drug.
Menstrual disturbances
In women, menstrual disturbances are common during spironolactone treatment, with 10 to 50% of women experiencing them at moderate doses and almost all experiencing them at a high doses. Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation. Spironolactone produces an irregular, anovulatory pattern of menstrual cycles. It is also associated with metrorrhagia and menorrhagia (or menometrorrhagia) in a large percentage of women. It has no birth control effect. 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.
The menstrual disturbances associated with spironolactone can usually be controlled well by concomitant treatment with an oral contraceptive.
Infertility
At high dosages, spironolactone has been associated with semen abnormalities such as decreased sperm count and motility in men.
Depression
Increased glucocorticoid activity in the body is associated with depression. As such, it is thought that there may be a risk of depression with spironolactone treatment. Some clinical research supports this notion.
Rare reactions
Spironolactone may rarely cause more severe side effects such as anaphylaxis, renal failure, hepatitis (two reported cases, neither serious), agranulocytosis, DRESS syndrome, Stevens-Johnson syndrome or toxic epidermal necrolysis. Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported. It should also be used with caution in people with some neurological disorders, anuria, acute kidney injury, or significant impairment of renal excretory function with risk of hyperkalemia.
Spironolactone bodies
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.
Pregnancy and breastfeeding
Spironolactone is considered Pregnancy Category C meaning that it is unclear if it is safe for use during pregnancy. It is able to cross the placenta. Likewise, it has been found to be present in the breast milk of lactating mothers and, while the effects of spironolactone or its metabolites have not been extensively studied in breastfeeding infants, it is generally recommended that women also not take the drug while nursing. However, only very small amounts of spironolactone and its metabolite canrenone enter breast milk, and the amount received by an infant during breastfeeding (<0.5% of the mother's dose) is considered to be insignificant.
A study found that spironolactone was not associated with teratogenicity 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 (200Â mg/kg per day). Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100Â 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 birth defects. 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 2Â mg/day or high doses of 50 to 100Â 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.
Interactions
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. Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone as a diuretic, especially during the first twelve months of use and whenever the dosage is increased. Doctors may also recommend that some patients may be advised to limit dietary consumption of potassium-rich foods. However, recent data suggests that both potassium monitoring and dietary restriction of potassium intake is unnecessary in healthy young women taking spironolactone for acne.
Research has suggested that spironolactone may be able to interfere with the effectiveness of antidepressant treatment. As the drug acts as an antimineralocorticoid, it is thought that it may reduce the effectiveness of certain antidepressants by interfering with normalization of the hypothalamicâ€"pituitaryâ€"adrenal axis and increasing glucocorticoid levels. However, other research contradicts this hypothesis and has suggested that spironolactone may actually produce antidepressant-like effects in animals.
Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications. Spironolactone together with trimethoprim/sulfamethoxazole increases the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron.
Spironolactone has been reported to induce the enzyme CYP3A4, which can result in interactions with various drugs. However, it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4.
Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found in studies 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 the drug for hyperandrogenism, and licorice may hence 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 clinically useful in reversing licorice-induced hypokalemia.
Aspirin and other nonsteroidal anti-inflammatory drugs have been found to attenuate the diuresis and natriuresis induced by spironolactone therapy but not to affect its antihypertensive effect.
Pharmacology
Spironolactone is known to possess the following biological activity:
- Mineralocorticoid receptor (MR) antagonist
- Androgen receptor (AR) antagonist/very weak partial agonist
- Estrogen receptor (ER) mixed agonist/antagonist
- Progesterone receptor (PR) agonist
- Glucocorticoid receptor (GR) antagonist
- Pregnane X receptor (PXR) agonist (and thus CYP3A4 and P-glycoprotein inducer)
- Steroid 11β-hydroxylase, aldosterone synthase, and 17α-hydroxylase/17,20-lyase inhibitor
There is also evidence that spironolactone may block voltage-dependent Ca2+ channels.
Although spironolactone is known to possess the above activities, it should be noted that the drug is a prodrug, with active metabolites such as 7α-thiomethylspironolactone (7α-TMS) and canrenone being responsible for its clinical effects. For this reason, the actual in vivo clinical profile of spironolactone may differ from the activities and effective and inhibitory concentrations described above and to the right. In any case, interaction with both the MR and AR have been observed for metabolites of spironolactone. On the other hand, spironolactone itself has only very low affinity for the ER, suggesting that its metabolites may be responsible for this activity.
Antimineralocorticoid activity
Spironolactone inhibits the effects of mineralocorticoids, namely, aldosterone, by displacing them from MR in the cortical collecting duct of renal nephrons. This decreases the reabsorption of sodium and water while limiting the excretion of potassium (A K+ sparing diuretic). The drug has a slightly delayed onset of action, and so it takes several days for diuresis to occur. This is because the MR is a nuclear receptor which works through regulating gene transcription and gene expression, in this case, to decrease the production and expression of ENaC and ROMK electrolyte channels in the distal nephrons. In addition to direct antagonism of the MRs, 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 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.
Antiandrogenic activity
Spironolactone is a potent and direct antagonist of the AR, blocking androgens like testosterone from binding to and activating the receptor. The AR antagonism of spironolactone mostly underlies its antiandrogen activity and is 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 like gynecomastia in men.
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. In accordance, two 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.
Estrogenic activity
Spironolactone has been found to directly interact with the ER. Although a study found that spironolactone did not interact with the human ER at the concentration range tested, a subsequent study found that the drug did interact with the human ER at higher concentrations, albeit with very low (micromolar) affinity (inhibition constant = 2 × 10âˆ'5). In the same study, spironolactone was administered to rats and found to produce mixed estrogenic and antiestrogenic or selective estrogen receptor modulator (SERM)-like effects that were described as very similar to those of tamoxifen. In spite of the fact that tamoxifen had three orders of magnitude higher affinity for the ER than did spironolactone, the two drugs showed similar potency in vivo. It has been said that the likelihood of spironolactone interacting with the ER itself is remote in consideration of its very low affinity for the receptor in vitro. However, metabolism of spironolactone may result in metabolites with greater ER affinity, which could thus account for the activity.
The authors of the study concluded that direct interaction of spironolactone (and/or its metabolites) with the ER could be involved in the gynecomastia, feminization, and effects on gonadotropin levels that the drug is associated with. Subsequently, it has also been suggested that, as a SERM-like drug, ER agonistic activity of spironolactone in the pituitary gland could be responsible for its antigonadotropic effects while ER antagonstic activity of spironolactone in the endometrium could be responsible for the menstrual disturbances that are associated with it. Such actions might explain these effects of spironolactone in light of the finding that it is not significantly progestogenic or antiprogestogenic in women even at high dosages.
In accordance, a study found that in women treated with a GnRH analogue, spironolactone therapy almost completely prevented the bone loss that is associated with these drugs, whereas treatment with the selective AR antagonist flutamide had no such effect. Other studies have also found an inverse relationship between spironolactone and decreased bone mineral density and bone fractures in men. Estrogens are well known for maintaining and having positive effects on bone, and it has been suggested that the estrogenic activity of spironolactone may be involved in its positive effects on bone mineral density. However, it should also be noted that high levels of aldosterone have been associated with adverse bone changes, and so the antimineralocorticoid activity of spironolactone might partially or fully be responsible for these effects as a potential alternative explanation.
In addition to direct interaction with the ER, spironolactone also has some indirect estrogenic activity, which it mediates via several actions, including:
- By acting as an antiandrogen, as androgens can suppress both estrogen production and signaling (e.g., in the breasts).
- Inhibition of the conversion of estradiol to estrone, resulting in an increase in the ratio of circulating estradiol to estrone. Estradiol is far more potent than estrone as an estrogen, which is comparatively almost inactive.
- Enhancement of the rate of peripheral conversion of testosterone into estradiol, thus decreasing the ratio of circulating testosterone to estradiol.
Spironolactone has been found to act as a reversible inhibitor of human 17β-hydroxysteroid dehydrogenase 2 (17β-HSD2), albeit with weak potency (Ki = 0.25â€"2.4 μM; IC50 = 0.27â€"1.1 μM). C7α thioalkyl derivatives of spironolactone like the 7α-thioethyl analogue were found to inhibit the enzyme with greater potency, suggesting that the actual active metabolites of spironolactone like 7α-TMS might be more potent inhibitors. 17β-HSD2 is a key enzyme responsible for inactivation of estradiol into estrone in various tissues, and inhibition of 17β-HSD2 by spironolactone may be involved in the gynecomastia and altered ratio of circulating testosterone to estradiol that the drug is associated with. Spironolactone has also been associated with positive effects on bone, and it is notable that 17β-HSD2 inhibitors are under investigation as potential novel treatments for osteoporosis due to their ability to prevent estradiol inactivation in this tissue.
Other actions
Progestogenic activity
Spironolactone has weak progestogenic activity in bioassays. Its actions in this regard are a result of direct agonist activity at the PR, though with a very low half-maximal potency. Spironolactone's progestogenic activity has been suggested to be involved in some of its side effects, including the menstrual irregularities seen in women and the undesirable serum lipid profile changes that are seen at higher doses. It has also been suggested to augment the gynecomastia caused by the estrogenic effects of spironolactone, as progesterone is known to be involved in mammary gland development.
Although it has been widely stated that the menstrual irregularities associated with spironolactone are due to its progestogenic activity, and although animal studies (involving both rabbits and rhesus monkeys) have shown clear progestogenic effects, the dosages of spironolactone used in animals to produce progestogenic effects were very high, and no evidence of progestogenic nor antiprogestogenic effects (as assessed by endometrial changes) have been observed in women even with high clinical dosages of spironolactone treatment. As such, it has been stated that the progestogenic potency of spironolactone is below the level of clinical significance in humans and that the menstrual abnormalities associated with the drug must have a different cause. Other possible mechanisms of the menstrual disturbances associated with spironolactone that have been suggested include interference with the hypothalamicâ€"pituitaryâ€"gonadal axis, inhibition of enzymatic steroidogenesis, and mixed estrogenic and antiestrogenic activity.
Antigonadotropic activity
Pure AR antagonists like flutamide and bicalutamide are potent progonadotropins with indirect estrogenic activity in males. This is because they block the AR in the pituitary gland and hypothalamus and thereby inhibit the negative feedback of androgens on the hypothalamicâ€"pituitaryâ€"gonadal axis. This, in turn, results in increased gonadotropin secretion, activation of gonadal steroidogenesis, and an up to 2-fold increase in testosterone levels and 2.5-fold increase in estradiol levels. Conversely, AR antagonists that are also progestogens, like cyproterone acetate, are not progonadotropic, as activation of the PR is antigonadotropic, and, indeed, cyproterone acetate is potently antigonadotropic in clinical practice.
Although spironolactone is a potent AR antagonist with no significant progestogenic effects in women even at high dosages and hence is a pure-like AR antagonist, many studies have interestingly not found it to be progonadotropic in men, nor to increase testosterone or estradiol levels. Moreover, spironolactone is also said to possess very little or no antigonadotropic activity (in terms of lowering gonadotropin levels to below normal) even at high dosages, although some conflicting reports exist. Nonetheless, since spironolactone does not generally increase gonadotropin levels in spite of potent inhibition of androgen signaling, it must have some degree of antigonadotropic activity sufficient to at least keep gonadotropin levels from increasing. As estrogens are antigonadotropic similarly to progestogens, and as SERM-like activity has been described for spironolactone, the antigonadotropic effects of spironolactone may be due to estrogenic activity.
Steroidogenesis inhibition
Spironolactone is able to significantly lower testosterone levels at high dosages in spite of not acting as an antigonadotropin, and this is thought to be due to direct enzymatic inhibition of 17α-hydroxylase and 17,20-lyase, enzymes necessary for the biosynthesis of testosterone. Although spironolactone is said to be a relatively weak inhibitor of 17α-hydroxylase and 17,20-lyase, at least compared to more potent steroidogenesis inhibitors like ketoconazole and abiraterone acetate (which are able to reduce testosterone concentrations to castrate levels), this action is considered to contribute a significant portion of the antiandrogen effects of spironolactone, for instance lowering testosterone levels in women with hyperandrogenism and in transgender women.
There is also mixed/conflicting evidence that spironolactone may inhibit 5α-reductase, and thus the synthesis of the potent androgen DHT from testosterone, to some extent. However, the combination of spironolactone and the potent 5α-reductase inhibitor finasteride has been found to have significant improved effectiveness in the treatment of hirsutism relative to spironolactone therapy alone, suggesting that any inhibition of 5α-reductase by spironolactone is only weak or at best incomplete.
Spironolactone has been found not to have activity as an aromatase inhibitor.
Glucocorticoid activity
Spironolactone has been shown to inhibit steroid 11β-hydroxylase, an enzyme that is essential for the production of the glucocorticoid hormone cortisol. Because of this, glucocorticoid levels might be expected to be lowered, and hence, spironolactone might have some antiglucocorticoidic effects. In clinical practice, however, this has not been found to be the case; spironolactone has actually been found to increase cortisol levels, both with acute and chronic administration. Research has shown that this is due to antagonism of the MR, which suppresses negative feedback on the hypothalamicâ€"pituitaryâ€"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 both mineralocorticoids and glucocorticoids. Therefore, by antagonizing the MR, spironolactone causes an increase in ACTH secretion and by extension an indirect rise in cortisol levels. As such, any anti-glucocorticoid activity of spironolactone via direct suppression of glucocorticoid synthesis (at the level of the adrenals) appears to be more than fully offset by its concurrent indirect stimulatory effects on glucocorticoid production.
At the same time, spironolactone weakly binds to and acts as an antagonist of the GR, showing antiglucocorticoid properties, but to a significant degree only at very high concentrations that are probably not clinically relevant.
Pharmacokinetics
Absorption
The bioavailability when taken by mouth of spironolactone is 60 to 90%. The bioavailability of the drug improves significantly when it is taken with food. Steady-state concentrations of spironolactone are achieved within 8Â days of treatment initiation.
Distribution
Spironolactone and its metabolite canrenone are highly plasma protein bound, with percentages of 88.0% and 99.2%, respectively. Spironolactone is bound equivalently to albumin and α1-acid glycoprotein, while canrenone is bound only to albumin. Spironolactone and its metabolite 7α-thiospironolactone show very low or negligible affinity for sex hormone-binding globulin (SHBG). In accordance, a study of high-dosage spironolactone treatment found no change in steroid binding capacity related to SHBG or to corticosteroid-binding globulin (CBG), suggesting that spironolactone does not displace steroid hormones from their carrier proteins. This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG.
Metabolism
Spironolactone is rapidly and extensively metabolized in the liver upon oral administration and has a short terminal half-life of 1.4 hours. The major metabolites of spironolactone are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (7α-desthioacetyl-δ6-spironolactone), and these metabolites have much longer half-lives in comparison (13.8 hours, 15.0 hours, and 16.5 hours, respectively). These metabolites are responsible for the therapeutic effects of spironolactone, and for this reason, spironolactone is a prodrug. Until fairly recently, the 7α-thiomethylated metabolites of spironolactone had not been identified and it was thought that canrenone was the major active metabolite. However, they have since been characterized and 7α-TMS has been identified as the major metabolite of spironolactone.
It has been determined that 7α-TMS accounts for around 80% of the potassium-sparing effect of spironolactone while canrenone only accounts for the remaining approximate 10 to 25%. In accordance, 7α-TMS occurs at higher circulating concentrations than does canrenone and has a higher relative affinity for the MR. Other known but more minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone. In addition to the MR, 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.
Canrenone is an antagonist of the MR similarly to spironolactone, but is slightly more potent in comparison. In addition, canrenone inhibits steroidogenic enzymes such as 11β-hydroxylase, cholesterol side-chain cleavage enzyme, 17α-hydroxylase, and 21-hydroxylase similarly to spironolactone, but once again is more potent in doing so in comparison. In vitro, canrenone binds to and blocks the AR. However, relative to spironolactone, canrenone is described as having very weak affinity to 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. As such, based on the above, the antiandrogen effects of spironolactone are considered to be largely due to other metabolites rather than due to canrenone.
Spironolactone is not metabolized by CYP3A4, unlike the related drug eplerenone.
Elimination
The majority of spironolactone is eliminated by the kidneys, while minimal amounts are handled by biliary excretion.
Chemistry
Spironolactone, also known as 7α-acetylthiospirolactone, is a steroidal 17α-spirolactone, or more simply a spirolactone. It can most appropriately be conceptualized as a derivative of progesterone (itself also a potent antimineralocorticoid) in which a hydroxyl group has been substituted at the C17α position (as in 17α-hydroxyprogesterone), the acetyl group at the C17β position has been cyclized with the C17α hydroxyl group to form a spiro 21-carboxylic acid γ-lactone ring, and an acetylthio group has been substituted at the C7α position. These structural modifications of progesterone confer increased oral bioavailability and potency, potent antiandrogenic activity, and greatly reduced progestogenic activity. The C7α substitution is likely responsible for or involved in the antiandrogenic activity of spironolactone, as 7α-thioprogesterone (SC-8365) is a potent antiandrogen with similar affinity to the AR as that of spironolactone.
Chemical names
Spironolactone is also known by the following equivalent chemical names:
- 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
- 7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone
- 3-(3-Oxo-7α-acetylthio-17β-hydroxyandrost-4-en-17α-yl)propionic acid lactone
- 7α-Acetylthio-17α-(2-carboxyethyl)androst-4-en-17β-ol-3-one γ-lactone
- 7α-Acetylthio-17α-(2-carboxyethyl)testosterone γ-lactone
Analogues
Spironolactone is closely structurally related to other clinically used spirolactones such as canrenone, potassium canrenoate, drospirenone, and eplerenone, as well as to the never-marketed spirolactones SC-5233 (6,7-dihydrocanrenone; 7α-desthioacetylspironolactone), SC-8109 (19-nor-6,7-dihydrocanrenone), spiroxasone, prorenone (SC-23133), mexrenone (SC-25152, ZK-32055), dicirenone (SC-26304), spirorenone (ZK-35973), and mespirenone (ZK-94679).
History
Spironolactone was first synthesized in 1957, was patented between 1958 and 1961, and was first marketed, as an antimineralocorticoid, in 1959. The AR antagonistic (i.e., antiandrogen) activity of spironolactone was first discovered and reported in 1969, which shortly followed the discovery in 1968 that gynecomastia, a frequent and by that time well-established side effect of spironolactone, is an important and major side effect of AR antagonists. The drug started to be used as an antiandrogen, for instance in the treatment of hirsutism in women, by the late 1970s and early 1980s, and has since become the most widely used antiandrogen for dermatological indications in the United States.
Society and culture
Generic name
The English, French, and generic name of spironolactone is spironolactone (pronounced as SPYE-rÉ™-noh-LAK-tohn or as SPEER-É™-noh-LAK-tohn according to different sources) and this is its INN, USAN, USP, BAN, DCF, and JAN. Its name is spironolactonum in Latin, spironolacton in German, espironolactona in Spanish and Portuguese, and spironolattone in Italian (which is also its DCIT).
Spironolactone is also known by its developmental code names SC-9420 and NSC-150339.
Brand names
Spironolactone is marketed under a large number of brand names throughout the world. The major brand name of spironolactone is Aldactone. Other important brand names include Aldactone-A, Berlactone, Espironolactona, Espironolactona Genfar, Novo-Spiroton, Prilactone (veterinary), Spiractin, Spiridon, Spirix, Spiroctan, Spiroderm (discontinued), Spirogamma, Spirohexal, Spirolon, Spirolone, Spiron, Spironolactone Actavis, Spironolactone Orion, Spironolactone Teva, Spirotone, Tempora (veterinary), Uractone, Uractonum, Verospiron, and Vivitar.
Spironolactone is also formulated in combination with a variety of other drugs, 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.
Availability
Spironolactone is marketed widely throughout the world and is available in almost every country, including in the United States, Canada, the United Kingdom, other European countries, Australia, New Zealand, South Africa, Central and South America, and East and Southeast Asia.
Research
Benign prostatic hyperplasia
Spironolactone has been studied at a high dosage in the treatment of benign prostatic hyperplasia. It was found to be better than placebo in terms of symptom relief following three months of treatment. However, this was not maintained after six months of treatment, by which point the improvements had largely disappeared. Moreover, no difference was observed between spironolactone and placebo with regard to volume of residual urine or prostate size. Gynecomastia was observed in about 5% of people. On the basis of these results, it has been said that spironolactone has no place in the treatment of benign prostatic hyperplasia.
Fibromyalgia
Spironolactone has been assessed in a study for the treatment of fibromyalgia in women.
Epsteinâ€"Barr virus
Spironolactone has been found to block Epsteinâ€"Barr virus (EBV) production and that of other human herpesviruses by inhibiting the function of an EBV protein SM, which is essential for infectious virus production. This effect of spironolactone was determined to be independent of its antimineralocorticoid actions. Thus, spironolactone or compounds based on it have the potential to yield novel antiviral drugs with a distinct mechanism of action and limited toxicity.
References
External links
- Spironolactone - MedlinePlus - U.S. National Library of Medicine
- Aldactone (spironolactone) patient information leaflet - PDR+
