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Wikipedia

Spironolactone

January 13, 2023

Not to be confused with Spirolactone.

Spironolactone, sold 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.[4] It is also used in the treatment of high blood pressure, low blood potassium that does not improve with supplementation, early puberty in boys, acne and excessive hair growth in women, and as a part of transgender hormone therapy in transfeminine people.[4][17][18] Spironolactone is taken by mouth.[4]

Spironolactone
Clinical data
Pronunciation/ˌspaɪroʊnoʊˈlæktoʊn/ SPY-roh-noh-LAK-tone,[1] /ˌspɪəroʊnoʊˈlæktoʊn/ SPEER-oh-noh-LAK-tone[2]
Trade namesAldactone, Spiractin, Verospiron, many others; combinations: Aldactazide (+HCTZ), Aldactide (+HFMZ), Aldactazine (+altizide), others
Other namesSC-9420; NSC-150339; 7α-Acetylthiospirolactone; 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
AHFS/Drugs.comMonograph
MedlinePlusa682627
License data
Pregnancy
category
Routes of
administration		By mouth,[4] topical[5]
Drug classAntimineralocorticoid; Steroidal antiandrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60–90%[6][7][8]
Protein bindingSpironolactone: 88% (to albumin and AGP)[9]
Canrenone: 99.2% (to albumin)[9]
MetabolismLiver, others:
• Deacetylation via CES
• S-Oxygenation via FOM
• S-Methylation via TMT
• Dethioacetylation
• Hydroxylation via CYP3A4
• Lactone hydrolysis via PON3[6][7][12][13][14][15][16]
Metabolites7α-TS, 7α-TMS, 6β-OH-7α-TMS, canrenone, others[6][7][10]
(All three active)[11]
Elimination half-lifeSpironolactone: 1.4 hrs[6]
7α-TMS: 13.8 hours[6]
6β-OH-7α-TMS: 15.0 hrs[6]
Canrenone: 16.5 hours[6]
ExcretionUrine, bile[7]
Identifiers
  • S-[(7R,8R,9S,10R,13S,14S,17R)-10,13-Dimethyl-3,5'-dioxospiro[2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-17,2'-oxolane]-7-yl] ethanethioate
CAS Number
  • 52-01-7 Y
PubChem CID
  • 5833
IUPHAR/BPS
  • 2875
DrugBank
  • DB00421 Y
ChemSpider
  • 5628 Y
UNII
  • 27O7W4T232
KEGG
  • D00443 Y
ChEBI
  • CHEBI:9241 Y
ChEMBL
  • ChEMBL1393 Y
CompTox Dashboard (EPA)
  • DTXSID6034186
ECHA InfoCard100.000.122
Chemical and physical data
FormulaC24H32O4S
Molar mass416.58 g·mol−1
3D model (JSmol)
  • Interactive image
Melting point134 to 135 °C (273 to 275 °F)
  • O=C5O[C@@]4([C@@]3([C@H]([C@@H]2[C@H](SC(=O)C)C/C1=C/C(=O)CC[C@]1(C)[C@H]2CC3)CC4)C)CC5
  • InChI=1S/C24H32O4S/c1-14(25)29-19-13-15-12-16(26)4-8-22(15,2)17-5-9-23(3)18(21(17)19)6-10-24(23)11-7-20(27)28-24/h12,17-19,21H,4-11,13H2,1-3H3/t17-,18-,19+,21+,22-,23-,24+/m0/s1 Y
  • Key:LXMSZDCAJNLERA-ZHYRCANASA-N Y
  (verify)

Common side effects include electrolyte abnormalities, particularly high blood potassium, nausea, vomiting, headache, rashes, and a decreased desire for sex.[4] In those with liver or kidney problems, extra care should be taken.[4] Spironolactone has not been well studied in pregnancy and should not be used to treat high blood pressure of pregnancy.[3] It is a steroid that blocks the effects of the hormones aldosterone and testosterone and has some estrogen-like effects.[4][19] Spironolactone belongs to a class of medications known as potassium-sparing diuretics.[4]

Spironolactone was discovered in 1957, and was introduced in 1959.[20][21][22] It is on the World Health Organization's List of Essential Medicines.[23][24] It is available as a generic medication.[4] In 2020, it was the 51st most commonly prescribed medication in the United States, with more than 13 million prescriptions.[25][26]

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, low blood levels of potassium, 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.[27] 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.[28] Spironolactone is also used to treat Bartter's syndrome due to its ability to raise potassium levels.[29]

Spironolactone has antiandrogenic activity. For this reason, it is frequently used to treat a variety of dermatological conditions in which androgens play a role. Some of these uses include acne, seborrhea, hirsutism, and pattern hair loss in women.[30] Spironolactone is the most commonly used medication in the treatment of hirsutism in the United States.[31] 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 symptoms of hyperandrogenism, such as due to polycystic ovary syndrome.[32]

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 less than 35%.[33]

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 medication. People in the study's intervention arm also had fewer symptoms of heart failure and were hospitalized less frequently.[34] Likewise, it has shown benefit for and is recommended in patients who recently had 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.[33] 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.[35]

According to a 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.[36] When blood samples from 366 participants 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 do not reflect actual clinical experience with spironolactone in patients with preserved ejection fraction.[37] 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.[38]

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 U.S. Food and Drug Administration 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. However, eplerenone may not be as effective as spironolactone or the related medication canrenone in reducing mortality from heart failure.[39]

The clinical benefits of spironolactone as a diuretic are typically not seen until 2–3 days after dosing begins. Likewise, the maximal antihypertensive effect may not be seen for 2–3 weeks.[medical citation needed]

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.[medical citation needed]

High blood pressure

About 1 in 100 people with hypertension have 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.[40] There is no evidence of person-oriented outcome at any dose in this group.[40]

High aldosterone levels

Spironolactone is used in the treatment of hyperaldosteronism (high aldosterone levels or mineralocorticoid excess), for instance primary aldosteronism (Conn's syndrome).[41] Antimineralocorticoids like spironolactone and eplerenone are first-line treatments for hyperaldosteronism.[41] They improve blood pressure and potassium levels, as well as left ventricular hypertrophy, albuminuria, and carotid intima-media thickness, in people with primary aldosteronism.[41] In people with hyperaldosteronism due to unilateral aldosterone-producing adrenocortical adenoma, adrenalectomy should be preferred instead of antimineralocorticoids.[41] Spironolactone should not be used to treat primary aldosteronism in pregnancy due to its antiandrogen-related risk of teratogenicity in male fetuses.[42][43][44][45]

Skin and hair conditions

Androgens like testosterone and DHT play a critical role in the pathogenesis of a number of dermatological conditions including oily skin, acne, seborrhea, hirsutism (excessive facial/body hair growth in women), and male pattern hair loss (androgenic alopecia).[46][47] 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.[48][49] 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.[50][51][52][53][54] 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.[46] In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions.[55][56]

Because of the antiandrogenic activity of spironolactone, it can be quite effective in treating acne in women.[57] In addition, spironolactone reduces oil that is naturally produced in the skin and can be used to treat oily skin.[58][59][47] 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.[58][59] Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill.[58][59] Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months.[58][59] Spironolactone has been reported to produce a 50 to 100% improvement in acne at sufficiently high doses.[60] Response to treatment generally requires 1 to 3 months in the case of acne and up to 6 months in the case of hirsutism.[60] Ongoing therapy is generally required to avoid relapse of symptoms.[60] Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication.[61] Spironolactone can be used in the treatment of female-pattern hair loss (pattern scalp hair loss in women).[62] There is tentative low quality evidence supporting its use for this indication.[63] Although apparently effective, not all cases of female-pattern hair loss are dependent on androgens.[64]

Antiandrogens like spironolactone are male-specific teratogens which can feminize male fetuses due to their antiandrogenic effects.[55][65][66] For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception.[55][65][66] Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose.[55] 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.[55][67]

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.[62] As an example, spironolactone has been reported to reduce symptoms of acne in males.[68] An additional example is the usefulness of spironolactone as an antiandrogen in transgender women.[69][70][71]

Topical spironolactone has been found to be effective in the treatment of acne as well.[72] 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.[73][74] The products were discontinued in 2006 when the creams were added to the list of doping substances with a decree of the Ministry of Health that year.[74]

Comparison

Spironolactone, the 5α-reductase inhibitor finasteride, and the nonsteroidal antiandrogen flutamide all appear to have similar effectiveness in the treatment of hirsutism.[61][75][76] However, some clinical research has found that the effectiveness of spironolactone for hirsutism is greater than that of finasteride but is less than that of flutamide.[61] The combination of spironolactone with finasteride is more effective than either alone for hirsutism and the combination of spironolactone with a birth control pill is more effective than a birth control pill alone.[61] One study showed that spironolactone or the steroidal antiandrogen cyproterone acetate both in combination with a birth control pill had equivalent effectiveness for hirsutism.[61] Spironolactone is considered to be a first-line treatment for hirsutism, finasteride and the steroidal antiandrogen cyproterone acetate are considered to be second-line treatments, and flutamide is no longer recommended for hirsutism due to liver toxicity concerns.[61] The nonsteroidal antiandrogen bicalutamide is an alternative option to flutamide with improved safety.[77][78]

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.[58] However, this was based on low- to very-low-quality evidence.[58] 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.[79] In addition, some clinical research has found that flutamide is more effective than spironolactone in the treatment of acne.[58] In one study, flutamide decreased acne scores by 80% within 3 months, whereas spironolactone decreased symptoms by only 40% in the same time period.[80][81][82] However, the use of flutamide for acne is limited by its liver toxicity.[83][84][85][86] Bicalutamide is a potential alternative to flutamide for acne as well.[87][88] 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.[79][56]

There is insufficient clinical evidence to compare the effectiveness of spironolactone with other antiandrogens for female-pattern hair loss.[89] 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.[79][90][91] However, higher doses also have greater side effects, such as menstrual irregularities.[58]

Alternative Spironolactone Use

Spironolactone medication is not approved for use as an antiandrogen by the Food and Drug Administration; instead, it is used off-label for such purposes.[92]

Forms

Spironolactone is available in the form of tablets (25 mg, 50 mg, 100 mg; brand name Aldactone, others) and suspensions (25 mg/5 mL; brand name CaroSpir) for use by mouth.[93][94][95][96][97] It 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, but this product is no longer available.[5][98] The medication is also available in combination with other medications, such as hydrochlorothiazide (brand name Aldactazide, others).[97][99] Spironolactone has poor water solubility, and for this reason, only oral and topical formulations have been developed; other routes of administration such as intravenous injection are not used.[6] The only antimineralocorticoid that is available as a solution for parenteral use is the related medication potassium canrenoate.[100]

Contraindications

Contraindications of spironolactone include hyperkalemia (high potassium levels), severe and end-stage kidney disease (due to high hyperkalemia risk, except possibly in those on dialysis), Addison's disease (adrenal insufficiency and low aldosterone levels), and concomitant use of eplerenone.[101][102] It should also be used with caution in people with some neurological disorders, no urine production, acute kidney injury, or significant impairment of kidney excretory function with risk of hyperkalemia.[101]

Side effects

One of the most common side effects of spironolactone is frequent urination. Other general side effects include dehydration, hyponatremia (low sodium levels), mild hypotension (low blood pressure),[80] ataxia (muscle incoordination), drowsiness, dizziness,[80] dry skin, and rashes. Because of its antiandrogenic activity, spironolactone can, in men, cause breast tenderness, gynecomastia (breast development), feminization in general, and demasculinization, as well as sexual dysfunction including loss of libido and erectile dysfunction, although these side effects are usually confined to high doses of spironolactone.[103] At very high doses (400 mg/day), spironolactone has also been associated with testicular atrophy and reversibly reduced fertility, including semen abnormalities such as decreased sperm count and motility in men.[104][105] However, such doses of spironolactone are rarely used clinically.[105] In women, spironolactone can cause menstrual irregularities, breast tenderness, and breast enlargement.[30][58][106] Aside from these adverse effects, the side effects of spironolactone in women taking high doses are minimal, and it is well tolerated.[58][80][107]

The most important potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening.[101] Hyperkalemia in these people can present as a normal anion-gap metabolic acidosis.[101] It has been reported that the addition of spironolactone to loop diuretics in patients with heart failure was associated with a higher risk of hyperkalemia and acute kidney injury (AKI).[108] Spironolactone may put people at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis.[101][109] In addition, there has been some evidence suggesting an association between use of the medication and bleeding from the stomach and duodenum,[101] though a causal relationship between the two has not been established.[110][111] Also, spironolactone is immunosuppressive in the treatment of sarcoidosis.[112]

Most of the side effects of spironolactone are dose-dependent.[57] Low-dose spironolactone is generally very well tolerated.[57] Even higher doses of spironolactone, such as 100 mg/day, are well tolerated in most individuals.[57] Dose-dependent side effects of spironolactone include menstrual irregularities, breast tenderness and enlargement, orthostatic hypotension, and hyperkalemia.[57] The side effects of spironolactone are usually mild and rarely result in discontinuation.[57]

Side effects of spironolactone in clinical studies for acne in women
Side effect RCTs (n (ITT) = 326) Case series (n (ITT) = 663)
Number % Number %
Menstrual irregularities 38 13.4 (of 283) 216 33.4 (of 646)
Breast tenderness 8 2.5 30 4.5
Breast enlargement 7 2.1 13 2.0
Dizziness/vertigo/lightheadedness 11 3.4 ≥19a ≥2.9
Headache 5 1.5 ≥10a ≥1.5
Nausea and/or vomiting 6 1.8 24 3.6
Weight gainb 5 1.5 1 0.2
Abdominal pain 0 0 ≥11a ≥1.7
Polyuria 2 0.6 8 1.2
Fatigue/lethargy 1 0.3 ≥12a ≥1.8
Footnotes: a = Precise values unavailable due to inadequate reporting. b = Not monitored in most studies. Description: Side effects of spironolactone (25–400 mg/day) with ≥1% incidence in a 2017 hybrid systematic review of clinical studies of spironolactone for acne in women. Side effects with <1% incidence included postural hypotension, depression, diarrhea, muscle pain, increased appetite, drowsiness, rashes/drug eruptions, chloasma-like skin pigmentation, polydipsia, weakness, leg edema, libido changes, and palpitations. [...] Certain side effects, like breast enlargement, reduced premenstrual symptoms, and less oily skin/greasy hair, could be beneficial. Side effects often could not be unambiguously attributed to spironolactone due concomitant use of other medications, particularly birth control pills. Hyperkalemia was rare (14/469; 3.0%) and was "invariably mild and clinically insignificant". Risk of bias was high and quality of evidence was low to very low. Sources: See template.

High potassium levels

Spironolactone can cause hyperkalemia, or high blood potassium levels.[105] Rarely, this can be fatal.[105] Of people with heart disease prescribed typical dosages of spironolactone, 10 to 15% develop some degree of hyperkalemia, and 6% develop severe hyperkalemia.[105] At a higher dosage, a rate of hyperkalemia of 24% has been observed.[113] An abrupt and major increase in the rate of hospitalization due to hyperkalemia from 0.2% to 11% and in the rate of death due to hyperkalemia from 0.3 per 1,000 to 2.0 per 1,000 between early 1994 and late 2001 has been attributed to a parallel rise in the number of prescriptions written for spironolactone upon the publication of the Randomized Aldactone Evaluation Study (RALES) in July 1999.[105][113][114][27] However, another population-based study in Scotland failed to replicate these findings.[115][116] The risk of hyperkalemia with spironolactone is greatest in the elderly, in people with renal impairment (e.g., due to chronic kidney disease or diabetic nephropathy), in people taking certain other medications (including ACE inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs, the antibiotic trimethoprim, and potassium supplements), and at higher dosages of spironolactone.[105][27][117][118]

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.[58][59][119] 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.[58] 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.[58][59][119] However, other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors.[27] Occasional testing on a case-by-case basis in those with known risk factors may be justified.[58] 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.[58] Notably, non-use of routine potassium monitoring with spironolactone in young women would reduce costs associated with its use.[58]

Breast changes

Spironolactone frequently causes breast pain and breast enlargement in women.[120][121] This is "probably because of estrogenic effects on target tissue."[105] At low doses, breast tenderness has been reported in only 5% of women, but at high doses, it has been reported in up to 40% of women.[122][57] Breast enlargement and tenderness may occur in 26% of women at high doses.[80] Some women regard spironolactone-induced breast enlargement as a positive effect.[58]

Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men.[104][121][123][124] At low doses, the rate is only 5 to 10%,[124] but at high doses, up to or exceeding 50% of men may develop gynecomastia.[104][121][123] In the RALES, 9.1% of men taking 25 mg/day spironolactone developed gynecomastia, compared to 1.3% of controls.[125] 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.[126][127] The severity of gynecomastia with spironolactone varies considerably, but is usually mild.[104] As with breast enlargement caused by spironolactone in women, gynecomastia due to spironolactone in men is often although inconsistently accompanied by breast tenderness.[104] In the RALES, only 1.7% of men developed breast pain, relative to 0.1% of controls.[125]

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.[125] Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication.[104] 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.[128][129]

Menstrual disturbances

Spironolactone at higher doses can cause menstrual irregularities as a side effect in women.[57] These irregularities include metrorrhagia (intermenstrual bleeding), amenorrhea (absence of menstruation), and breakthrough bleeding.[57] They are common during spironolactone therapy, with 10 to 50% of women experiencing them at moderate doses and almost all experiencing them at a high doses.[80][105] For example, about 20% of women experienced menstrual irregularities with 50 to 100 mg/day spironolactone, whereas about 70% experienced menstrual irregularities at 200 mg/day.[57] Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation.[105] Spironolactone produces an irregular and anovulatory pattern of menstrual cycles.[80] It is also associated with metrorrhagia and menorrhagia (heavy menstrual bleeding) in large percentages of women,[120] as well as with polymenorrhea (short menstrual cycles).[130][131] The medication reportedly has no birth control effect.[132]

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.[80][133][134] An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels.[104] Indeed, CYP17A1 genotype is associated with polymenorrhea.[135] 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.[80][136]

Mood changes

Research is mixed on whether antimineralocorticoids like spironolactone have positive or negative effects on mood.[137][138][139] In any case, it is possible that spironolactone might have the capacity to increase the risk of depressive symptoms.[137][138][139] However, a 2017 hybrid systematic review found that the incidence of depression in women treated with spironolactone for acne was less than 1%.[58] Likewise, a 10-year observational study found that the incidence of depression in 196 transgender women taking high-dose spironolactone in combination with an estrogen was less than 1%.[140]

Rare reactions

Aside from hyperkalemia, spironolactone may rarely cause adverse reactions such as anaphylaxis, kidney failure,[141] hepatitis (two reported cases, neither serious),[142] agranulocytosis, DRESS syndrome, Stevens–Johnson syndrome or toxic epidermal necrolysis.[143][144] Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported.[105][124]

Spironolactone bodies

 
Micrograph (H&E stain) of an adrenal gland showing 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.[145]

Pregnancy and breastfeeding

In the United States, spironolactone is considered pregnancy category C meaning that it is unclear if it is safe for use during pregnancy.[3][4] It is able to cross the placenta.[120] 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 medication while nursing.[101] 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.[146]

A study found that spironolactone was not associated with teratogenicity in the offspring of rats.[147][148][149] Because it is an antiandrogen, however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses.[147][148] 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).[147][149] Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100 mg/kg per day).[149]

In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans.[147][148][150][151] Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific birth defects.[151] 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.[151] 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.[146][147] 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).[151] 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.[147][152]

A 2019 systematic review found insufficient evidence that spironolactone causes birth defects in humans.[153] However, there was also insufficient evidence to be certain that it does not.[153]

Overdose

Spironolactone is relatively safe in acute overdose.[101] Symptoms following an acute overdose of spironolactone may include drowsiness, confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, and diarrhea.[101] In rare cases, hyponatremia, hyperkalemia, or hepatic coma may occur in individuals with severe liver disease.[101] However, these adverse reactions are unlikely in the event of an acute overdose.[101] Hyperkalemia can occur following an overdose of spironolactone, and this is especially so in people with decreased kidney function.[101] Spironolactone has been studied at extremely high oral doses of up to 2,400 mg per day in clinical trials.[100][154] Its oral median lethal dose (LD50) is more than 1,000 mg/kg in mice, rats, and rabbits.[101]

There is no specific antidote for overdose of spironolactone.[101] Treatment may consist of induction of vomiting or stomach evacuation by gastric lavage.[101] The treatment of spironolactone overdose is supportive, with the purpose of maintaining hydration, electrolyte balance, and vital functions.[101] Spironolactone should be discontinued in people with impaired kidney function or hyperkalemia.[101]

Interactions

Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this medication avoid potassium supplements and salt substitutes containing potassium.[155] 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.[119] 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.[156]

Spironolactone has been reported to induce the enzymes CYP3A4 and certain UDP-glucuronosyltransferases (UGTs), which can result in interactions with various medications.[12][157][158] However, it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4.[159] 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.[160] Spironolactone has also been found to inhibit UGT2B7.[161] Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications, for instance digoxin.[101]

Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found to inhibit the antimineralocorticoid effects of spironolactone.[162][163][164] 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.[162][163] On the opposite end of the spectrum, spironolactone is useful in reversing licorice-induced hypokalemia.[165][166] 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.[29][167]

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 glucocorticoids such as cortisol.[168][169] However, other research contradicts this hypothesis and has suggested that spironolactone might actually produce antidepressant effects, for instance studies showing antidepressant-like effects of spironolactone in animals.[170]

Pharmacology

Pharmacodynamics

Main article: Pharmacodynamics of spironolactone
 
7α-Thiomethylspironolactone, the major active form of spironolactone. It accounts for about 80% of the potassium-sparing effect of spironolactone.[6][171][172]
 
Canrenone, the second major active form of spironolactone. It accounts for around 10 to 25% of the potassium-sparing effect of spironolactone.[173]

The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition, among other more minor activities.[100][103][126] Spironolactone is a prodrug, so most of its actions are actually mediated by its various active metabolites.[100] The major active forms of spironolactone are 7α-thiomethylspironolactone (7α-TMS) and canrenone (7α-desthioacetyl-δ6-spironolactone).[6][100]

Spironolactone is a potent antimineralocorticoid.[6] That is, it is an antagonist of the mineralocorticoid receptor (MR), the biological target of mineralocorticoids like aldosterone and 11-deoxycorticosterone.[6] By blocking the MR, spironolactone inhibits the effects of mineralocorticoids in the body.[6] 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.[174][175] 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.[176] 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.[55][80]

Spironolactone is a moderate antiandrogen.[103][133][158] That is, it is an antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT).[103][133][158] By blocking the AR, spironolactone inhibits the effects of androgens in the body.[103][133][158] 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.[133][160][177] It is also primarily responsible for some of its side effects, like breast tenderness, gynecomastia, feminization, and demasculinization in men.[104][177] Blockade of androgen signaling in the breast disinhibits the actions of estrogens in this tissue.[178] Although useful as an antiandrogen in women, who have low testosterone levels compared to men,[179][180] spironolactone is described as having relatively weak antiandrogenic activity.[181][177][182][183]

Spironolactone is a weak steroidogenesis inhibitor.[103][126][133][184] That is, it inhibits steroidogenic enzymes, or enzymes involved in the production of steroid hormones.[103][126][133][184] Spironolactone and/or its metabolites have been found in vitro to weakly inhibit 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).[133][184][185][186] 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.[58][103][126][133][158] 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.[103][126][187] 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.[103][104] However, its androgen synthesis inhibition is probably clinically insignificant.[60]

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.[103][126] 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.[188][189] 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.[190][191] 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.[188][192][193]

In response to the antimineralocorticoid activity spironolactone, and in an attempt to maintain homeostasis, the body increases aldosterone production in the adrenal cortex.[194][195][196] Some studies have found that levels of cortisol, a glucocorticoid hormone that is also produced in the adrenal cortex, are increased as well.[195][196][197] However, other clinical studies have found no change in cortisol levels with spironolactone,[133][198][91][199] and those that have found increases often have observed only small changes.[200] In accordance, spironolactone has not been associated with conventional glucocorticoid medication effects or side effects.[201][202]

Other activities of spironolactone may include very weak interactions with the estrogen and progesterone receptors and agonism of the pregnane X receptor.[91][203] These activities could contribute to the menstrual irregularities and breast side effects of spironolactone and to its drug interactions, respectively.[204][205][206]

Pharmacokinetics

The pharmacokinetics of spironolactone have not been studied well, which is in part because it is an old medication that was developed in the 1950s.[127] Nonetheless, much has been elucidated about the pharmacokinetics of spironolactone over the decades.[207][208][209][6][210][211][212][213]

Absorption

 
Levels of spironolactone and its major active metabolites after a single oral dose of 100 mg spironolactone in humans.[214]

The bioavailability of spironolactone when taken by mouth is 60 to 90%.[6][7][8] The bioavailability of spironolactone and its metabolites increases significantly (+22–95% increases in levels) when spironolactone is taken with food, although it is uncertain whether this further increases the therapeutic effects of the medication.[215][216][217] The increase in bioavailability is thought to be due to promotion of the gastric dissolution and absorption of spironolactone, as well as due to a decrease of the first-pass metabolism.[215][218][219] The relationship between a single dose of spironolactone and plasma levels of canrenone, a major active metabolite of spironolactone, has been found to be linear across a dose range of 25 to 200 mg spironolactone.[181] Steady-state concentrations of spironolactone are achieved within 8 to 10 days of treatment initiation.[172][220]

Little or no systemic absorption has been observed with topical spironolactone.[221]

Distribution

Spironolactone and its metabolite canrenone are highly plasma protein bound, with percentages of 88.0% and 99.2%, respectively.[6][9] Spironolactone is bound equivalently to albumin and α1-acid glycoprotein, while canrenone is bound only to albumin.[6][9] Spironolactone and its metabolite 7α-thiospironolactone show very low or negligible affinity for sex hormone-binding globulin (SHBG).[222][223] 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.[224] This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG.[91][225]

Spironolactone appears to cross the blood–brain barrier.[226][227]

Metabolism

 
Spironolactone metabolism in humans.[228] Canrenone may be further reduced (into di-, tetra-, and hexahydrogenated metabolites), hydroxylated, and conjugated (e.g., glucuronidated).[228]

Spironolactone is rapidly and extensively metabolized in the liver upon oral administration and has a very short terminal half-life of 1.4 hours.[6][7] The major metabolites of spironolactone are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (7α-desthioacetyl-δ6-spironolactone).[6][7][171] These metabolites have much longer elimination half-lives than spironolactone of 13.8 hours, 15.0 hours, and 16.5 hours, respectively, and are responsible for the therapeutic effects of the medication.[6][7] As such, spironolactone is a prodrug.[229] The 7α-thiomethylated metabolites of spironolactone were not known for many years and it was originally thought that canrenone was the major active metabolite of the medication, but subsequent research identified 7α-TMS as the major metabolite.[6][171][172] Other known but more minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), which is an important intermediate to the major metabolites of spironolactone,[12] as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone.[10]

Spironolactone is hydrolyzed or deacetylated at the thioester of the C7α position into 7α-TS by carboxylesterases.[12][230] Following formation of 7α-TS, it is S-oxygenated by flavin-containing monooxygenases to form an electrophilic sulfenic acid metabolite.[12] This metabolite is involved in the CYP450 inhibition of spironolactone, and also binds covalently to other proteins.[12] 7α-TS is also S-methylated into 7α-TMS, a transformation catalyzed by thiol S-methyltransferase.[12] Unlike the related medication eplerenone, spironolactone is said to not be metabolized by CYP3A4.[231] However, hepatic CYP3A4 is likely responsible for the 6β-hydroxylation of 7α-TMS into 6β-OH-7α-TMS.[13][232] 7α-TMS may also be hydroxylated at the C3α and C3β positions.[14] Spironolactone is dethioacetylated into canrenone.[15] Finally, the C17 γ-lactone ring of spironolactone is hydrolyzed by the paraoxonase PON3.[16][233] It was originally thought to be hydrolyzed by PON1, but this was due to contamination with PON3.[16]

Pharmacokinetics of 100 mg/day spironolactone and its metabolites
Compound Cmax (day 1) Cmax (day 15) AUC (day 15) t1/2
Spironolactone 72 ng/mL (173 nmol/L) 80 ng/mL (192 nmol/L) 231 ng•hour/mL (555 nmol•hour/L) 1.4 hours
Canrenone 155 ng/mL (455 nmol/L) 181 ng/mL (532 nmol/L) 2,173 ng•hour/mL (6,382 nmol•hour/L) 16.5 hours
7α-TMS 359 ng/mL (924 nmol/L) 391 ng/mL (1,006 nmol/L) 2,804 ng•hour/mL (7,216 nmol•hour/L) 13.8 hours
6β-OH-7α-TMS 101 ng/mL (250 nmol/L) 125 ng/mL (309 nmol/L) 1,727 ng•hour/mL (4,269 nmol•hour/L) 15.0 hours
Sources: See template.

Elimination

The majority of spironolactone is eliminated by the kidneys, while minimal amounts are handled by biliary excretion.[234]

Chemistry

See also: Spirolactone and List of steroidal antiandrogens § Spirolactone derivatives

Spironolactone, also known as 7α-acetylthiospirolactone, is a steroidal 17α-spirolactone, or more simply a spirolactone.[100] It can most appropriately be conceptualized as a derivative of progesterone,[125][235][220] 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 in at the C7α position.[236][237][238] These structural modifications of progesterone confer increased oral bioavailability and potency,[239] potent antiandrogenic activity, and strongly reduced progestogenic activity.[240] The C7α substitution is likely responsible for or involved in the antiandrogenic activity of spironolactone, as 7α-thioprogesterone (SC-8365), unlike progesterone,[241] is an antiandrogen with similar affinity to the AR as that of spironolactone.[242] In addition, the C7α substitution appears to be responsible for the loss of progestogenic activity and good oral bioavailability of spironolactone, as SC-5233, the analogue of spironolactone without a C7α substitution, has potent progestogenic activity but very poor oral bioavailability similarly to progesterone.[241][243][244]

Names

Spironolactone is also known by the following equivalent chemical names:[236][237][238]

  • 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

Chemical structures of spirolactones
 
Chemical structures of progesterone and spirolactones (steroid-17α-spirolactones).

Spironolactone is closely related structurally 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).[100]

Synthesis

Chemical syntheses of spironolactone and its analogues and derivatives have been described and reviewed.[245]

History

The natriuretic effects of progesterone were demonstrated in 1955, and the development of spironolactone as a synthetic antimineralocorticoid analogue of progesterone shortly followed this.[125][235][246][247] Spironolactone was first synthesized in 1957,[20][246][247] was patented between 1958 and 1961,[248][249] and was first marketed, as an antimineralocorticoid, in 1959.[250][251] Gynecomastia was first reported with spironolactone in 1962,[100][252] and the antiandrogenic activity of the medication was first described in 1969.[253] This shortly followed the discovery in 1967 that gynecomastia is an important and major side effect of AR antagonists.[254][255] Spironolactone was first studied in the treatment of hirsutism in women in 1978.[256][162][257][258][259] It has since become the most widely used antiandrogen for dermatological indications in women in the United States.[96][260][261][262] Spironolactone was first studied as an antiandrogen in transgender women in 1986, and has since become widely adopted for this purpose as well, particularly in the United States where cyproterone acetate is not available.[263][264][265]

Early oral spironolactone tablets showed poor absorption.[266] The formulation was eventually changed to a micronized formulation with particle sizes of less than 50 μg, which resulted in approximately 4-fold increased potency.[266][267]

Society and culture

Generic names

The English, French, and generic name of the medication is spironolactone and this is its INN, USAN, USP, BAN, DCF, and JAN.[98][99][236][268] Its name is spironolactonum in Latin, spironolacton in German, espironolactona in Spanish and Portuguese, and spironolattone in Italian (which is also its DCIT).[98][99][268]

Spironolactone is also known by its developmental code names SC-9420 and NSC-150339.[98][99][236]

Brand names

Spironolactone is marketed under a large number of brand names throughout the world.[98][99] The major brand name of spironolactone is Aldactone.[98][99] Other important brand names include Aldactone-A, Berlactone, CaroSpir, Espironolactona, Espironolactona Genfar, Novo-Spiroton, Prilactone (veterinary), Spiractin, Spiridon, Spirix, Spiroctan, Spiroderm (discontinued),[5] Spirogamma, Spirohexal, Spirolon, Spirolone, Spiron, Spironolactone Actavis, Spironolactone Orion, Spironolactone Teva, Spirotone, Tempora (veterinary), Uractone, Uractonum, Verospiron, and Vivitar.[98][99]

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.[99]

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.[98][99]

Usage

There was a total of 17.2 million prescriptions for spironolactone in the United States between the beginning of 2003 and the end of 2005.[269] There was a total of 12.0 million prescriptions for spironolactone in the United States in 2016 alone.[270] It was the 66th top prescribed medication in the United States in 2016.[270]

Research

Prostate conditions

Spironolactone has been studied at a high dosage in the treatment of benign prostatic hyperplasia (BPH; enlarged prostate).[271][272][273] It was found to be better than placebo in terms of symptom relief following three months of treatment.[271][272] However, this was not maintained after six months of treatment, by which point the improvements had largely disappeared.[271][272][273] Moreover, no difference was observed between spironolactone and placebo with regard to volume of residual urine or prostate size.[271][272] Gynecomastia was observed in about 5% of people.[272] On the basis of these results, it has been said that spironolactone has no place in the treatment of BPH.[272]

Spironolactone has been studied and used limitedly in the treatment of prostate cancer.[274][275][29]

Epstein–Barr virus

Spironolactone has been found to block Epstein–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.[276] This effect of spironolactone was determined to be independent of its antimineralocorticoid actions.[276] Thus, spironolactone or compounds based on it have the potential to yield novel antiviral medications with a distinct mechanism of action and limited toxicity.[276]

Other conditions

Spironolactone has been studied in the treatment of rosacea in both males and females.[277][278][279][68][280]

Spironolactone has been studied in fibromyalgia in women.[281][282] It has also been studied in bulimia nervosa in women, but was not found to be effective.[283]

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January 13, 2023
spironolactone, confused, with, spirolactone, sold, under, brand, name, aldactone, among, others, medication, that, primarily, used, treat, fluid, build, heart, failure, liver, scarring, kidney, disease, also, used, treatment, high, blood, pressure, blood, pot. Not to be confused with Spirolactone Spironolactone sold 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 4 It is also used in the treatment of high blood pressure low blood potassium that does not improve with supplementation early puberty in boys acne and excessive hair growth in women and as a part of transgender hormone therapy in transfeminine people 4 17 18 Spironolactone is taken by mouth 4 SpironolactoneClinical dataPronunciation ˌ s p aɪ r oʊ n oʊ ˈ l ae k t oʊ n SPY roh noh LAK tone 1 ˌ s p ɪer oʊ n oʊ ˈ l ae k t oʊ n SPEER oh noh LAK tone 2 Trade namesAldactone Spiractin Verospiron many others combinations Aldactazide HCTZ Aldactide HFMZ Aldactazine altizide othersOther namesSC 9420 NSC 150339 7a Acetylthiospirolactone 7a Acetylthio 17a hydroxy 3 oxopregn 4 ene 21 carboxylic acid g lactoneAHFS Drugs comMonographMedlinePlusa682627License dataUS DailyMed SpironolactonePregnancycategoryAU B3 3 Routes ofadministrationBy mouth 4 topical 5 Drug classAntimineralocorticoid Steroidal antiandrogenATC codeC03DA01 WHO Legal statusLegal statusUK POM Prescription only US onlyPharmacokinetic dataBioavailability60 90 6 7 8 Protein bindingSpironolactone 88 to albumin and AGP 9 Canrenone 99 2 to albumin 9 MetabolismLiver others Deacetylation via CES S Oxygenation via FOM S Methylation via TMT Dethioacetylation Hydroxylation via CYP3A4 Lactone hydrolysis via PON3 6 7 12 13 14 15 16 Metabolites7a TS 7a TMS 6b OH 7a TMS canrenone others 6 7 10 All three active 11 Elimination half lifeSpironolactone 1 4 hrs 6 7a TMS 13 8 hours 6 6b OH 7a TMS 15 0 hrs 6 Canrenone 16 5 hours 6 ExcretionUrine bile 7 IdentifiersIUPAC name S 7R 8R 9S 10R 13S 14S 17R 10 13 Dimethyl 3 5 dioxospiro 2 6 7 8 9 11 12 14 15 16 decahydro 1H cyclopenta a phenanthrene 17 2 oxolane 7 yl ethanethioateCAS Number52 01 7 YPubChem CID5833IUPHAR BPS2875DrugBankDB00421 YChemSpider5628 YUNII27O7W4T232KEGGD00443 YChEBICHEBI 9241 YChEMBLChEMBL1393 YCompTox Dashboard EPA DTXSID6034186ECHA InfoCard100 000 122Chemical and physical dataFormulaC 24H 32O 4SMolar mass416 58 g mol 13D model JSmol Interactive imageMelting point134 to 135 C 273 to 275 F SMILES O C5O C 4 C 3 C H C H 2 C H SC O C C C1 C C O CC C 1 C C H 2CC3 CC4 C CC5InChI InChI 1S C24H32O4S c1 14 25 29 19 13 15 12 16 26 4 8 22 15 2 17 5 9 23 3 18 21 17 19 6 10 24 23 11 7 20 27 28 24 h12 17 19 21H 4 11 13H2 1 3H3 t17 18 19 21 22 23 24 m0 s1 YKey LXMSZDCAJNLERA ZHYRCANASA N Y verify Common side effects include electrolyte abnormalities particularly high blood potassium nausea vomiting headache rashes and a decreased desire for sex 4 In those with liver or kidney problems extra care should be taken 4 Spironolactone has not been well studied in pregnancy and should not be used to treat high blood pressure of pregnancy 3 It is a steroid that blocks the effects of the hormones aldosterone and testosterone and has some estrogen like effects 4 19 Spironolactone belongs to a class of medications known as potassium sparing diuretics 4 Spironolactone was discovered in 1957 and was introduced in 1959 20 21 22 It is on the World Health Organization s List of Essential Medicines 23 24 It is available as a generic medication 4 In 2020 it was the 51st most commonly prescribed medication in the United States with more than 13 million prescriptions 25 26 Contents 1 Medical uses 1 1 Heart failure 1 2 High blood pressure 1 3 High aldosterone levels 1 4 Skin and hair conditions 1 4 1 Comparison 1 5 Alternative Spironolactone Use 1 6 Forms 2 Contraindications 3 Side effects 3 1 High potassium levels 3 2 Breast changes 3 3 Menstrual disturbances 3 4 Mood changes 3 5 Rare reactions 3 6 Spironolactone bodies 3 7 Pregnancy and breastfeeding 4 Overdose 5 Interactions 6 Pharmacology 6 1 Pharmacodynamics 6 2 Pharmacokinetics 6 2 1 Absorption 6 2 2 Distribution 6 2 3 Metabolism 6 2 4 Elimination 7 Chemistry 7 1 Names 7 2 Analogues 7 3 Synthesis 8 History 9 Society and culture 9 1 Generic names 9 2 Brand names 9 3 Availability 9 4 Usage 10 Research 10 1 Prostate conditions 10 2 Epstein Barr virus 10 3 Other conditions 11 References 12 External linksMedical uses EditSpironolactone is used primarily to treat heart failure edematous conditions such as nephrotic syndrome or ascites in people with liver disease essential hypertension low blood levels of potassium 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 27 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 28 Spironolactone is also used to treat Bartter s syndrome due to its ability to raise potassium levels 29 Spironolactone has antiandrogenic activity For this reason it is frequently used to treat a variety of dermatological conditions in which androgens play a role Some of these uses include acne seborrhea hirsutism and pattern hair loss in women 30 Spironolactone is the most commonly used medication in the treatment of hirsutism in the United States 31 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 symptoms of hyperandrogenism such as due to polycystic ovary syndrome 32 Heart failure Edit 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 less than 35 33 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 medication People in the study s intervention arm also had fewer symptoms of heart failure and were hospitalized less frequently 34 Likewise it has shown benefit for and is recommended in patients who recently had 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 33 Of note a recent randomized double blinded study of spironolactone in patients with symptomatic heart failure with preserved ejection fraction i e gt 45 found no reduction in death from cardiovascular events aborted cardiac arrest or hospitalizations when spironolactone was compared to placebo 35 According to a 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 36 When blood samples from 366 participants 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 do not reflect actual clinical experience with spironolactone in patients with preserved ejection fraction 37 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 38 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 U S Food and Drug Administration 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 However eplerenone may not be as effective as spironolactone or the related medication canrenone in reducing mortality from heart failure 39 The clinical benefits of spironolactone as a diuretic are typically not seen until 2 3 days after dosing begins Likewise the maximal antihypertensive effect may not be seen for 2 3 weeks medical citation needed 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 medical citation needed High blood pressure Edit About 1 in 100 people with hypertension have 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 40 There is no evidence of person oriented outcome at any dose in this group 40 High aldosterone levels Edit Spironolactone is used in the treatment of hyperaldosteronism high aldosterone levels or mineralocorticoid excess for instance primary aldosteronism Conn s syndrome 41 Antimineralocorticoids like spironolactone and eplerenone are first line treatments for hyperaldosteronism 41 They improve blood pressure and potassium levels as well as left ventricular hypertrophy albuminuria and carotid intima media thickness in people with primary aldosteronism 41 In people with hyperaldosteronism due to unilateral aldosterone producing adrenocortical adenoma adrenalectomy should be preferred instead of antimineralocorticoids 41 Spironolactone should not be used to treat primary aldosteronism in pregnancy due to its antiandrogen related risk of teratogenicity in male fetuses 42 43 44 45 Skin and hair conditions Edit Androgens like testosterone and DHT play a critical role in the pathogenesis of a number of dermatological conditions including oily skin acne seborrhea hirsutism excessive facial body hair growth in women and male pattern hair loss androgenic alopecia 46 47 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 48 49 Moreover men with congenital 5a reductase type II deficiency 5a 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 50 51 52 53 54 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 46 In accordance with the preceding antiandrogens are highly effective in the treatment of the aforementioned androgen dependent skin and hair conditions 55 56 Because of the antiandrogenic activity of spironolactone it can be quite effective in treating acne in women 57 In addition spironolactone reduces oil that is naturally produced in the skin and can be used to treat oily skin 58 59 47 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 58 59 Oftentimes for women treating acne spironolactone is prescribed and paired with a birth control pill 58 59 Positive results in the pairing of these two medications have been observed although these results may not be seen for up to three months 58 59 Spironolactone has been reported to produce a 50 to 100 improvement in acne at sufficiently high doses 60 Response to treatment generally requires 1 to 3 months in the case of acne and up to 6 months in the case of hirsutism 60 Ongoing therapy is generally required to avoid relapse of symptoms 60 Spironolactone is commonly used in the treatment of hirsutism in women and is considered to be a first line antiandrogen for this indication 61 Spironolactone can be used in the treatment of female pattern hair loss pattern scalp hair loss in women 62 There is tentative low quality evidence supporting its use for this indication 63 Although apparently effective not all cases of female pattern hair loss are dependent on androgens 64 Antiandrogens like spironolactone are male specific teratogens which can feminize male fetuses due to their antiandrogenic effects 55 65 66 For this reason it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception 55 65 66 Oral contraceptives which contain an estrogen and a progestin are typically used for this purpose 55 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 55 67 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 62 As an example spironolactone has been reported to reduce symptoms of acne in males 68 An additional example is the usefulness of spironolactone as an antiandrogen in transgender women 69 70 71 Topical spironolactone has been found to be effective in the treatment of acne as well 72 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 73 74 The products were discontinued in 2006 when the creams were added to the list of doping substances with a decree of the Ministry of Health that year 74 Comparison Edit Spironolactone the 5a reductase inhibitor finasteride and the nonsteroidal antiandrogen flutamide all appear to have similar effectiveness in the treatment of hirsutism 61 75 76 However some clinical research has found that the effectiveness of spironolactone for hirsutism is greater than that of finasteride but is less than that of flutamide 61 The combination of spironolactone with finasteride is more effective than either alone for hirsutism and the combination of spironolactone with a birth control pill is more effective than a birth control pill alone 61 One study showed that spironolactone or the steroidal antiandrogen cyproterone acetate both in combination with a birth control pill had equivalent effectiveness for hirsutism 61 Spironolactone is considered to be a first line treatment for hirsutism finasteride and the steroidal antiandrogen cyproterone acetate are considered to be second line treatments and flutamide is no longer recommended for hirsutism due to liver toxicity concerns 61 The nonsteroidal antiandrogen bicalutamide is an alternative option to flutamide with improved safety 77 78 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 58 However this was based on low to very low quality evidence 58 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 79 In addition some clinical research has found that flutamide is more effective than spironolactone in the treatment of acne 58 In one study flutamide decreased acne scores by 80 within 3 months whereas spironolactone decreased symptoms by only 40 in the same time period 80 81 82 However the use of flutamide for acne is limited by its liver toxicity 83 84 85 86 Bicalutamide is a potential alternative to flutamide for acne as well 87 88 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 79 56 There is insufficient clinical evidence to compare the effectiveness of spironolactone with other antiandrogens for female pattern hair loss 89 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 79 90 91 However higher doses also have greater side effects such as menstrual irregularities 58 Alternative Spironolactone Use Edit Spironolactone medication is not approved for use as an antiandrogen by the Food and Drug Administration instead it is used off label for such purposes 92 Forms Edit Spironolactone is available in the form of tablets 25 mg 50 mg 100 mg brand name Aldactone others and suspensions 25 mg 5 mL brand name CaroSpir for use by mouth 93 94 95 96 97 It 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 but this product is no longer available 5 98 The medication is also available in combination with other medications such as hydrochlorothiazide brand name Aldactazide others 97 99 Spironolactone has poor water solubility and for this reason only oral and topical formulations have been developed other routes of administration such as intravenous injection are not used 6 The only antimineralocorticoid that is available as a solution for parenteral use is the related medication potassium canrenoate 100 Contraindications EditContraindications of spironolactone include hyperkalemia high potassium levels severe and end stage kidney disease due to high hyperkalemia risk except possibly in those on dialysis Addison s disease adrenal insufficiency and low aldosterone levels and concomitant use of eplerenone 101 102 It should also be used with caution in people with some neurological disorders no urine production acute kidney injury or significant impairment of kidney excretory function with risk of hyperkalemia 101 Side effects EditOne of the most common side effects of spironolactone is frequent urination Other general side effects include dehydration hyponatremia low sodium levels mild hypotension low blood pressure 80 ataxia muscle incoordination drowsiness dizziness 80 dry skin and rashes Because of its antiandrogenic activity spironolactone can in men cause breast tenderness gynecomastia breast development feminization in general and demasculinization as well as sexual dysfunction including loss of libido and erectile dysfunction although these side effects are usually confined to high doses of spironolactone 103 At very high doses 400 mg day spironolactone has also been associated with testicular atrophy and reversibly reduced fertility including semen abnormalities such as decreased sperm count and motility in men 104 105 However such doses of spironolactone are rarely used clinically 105 In women spironolactone can cause menstrual irregularities breast tenderness and breast enlargement 30 58 106 Aside from these adverse effects the side effects of spironolactone in women taking high doses are minimal and it is well tolerated 58 80 107 The most important potential side effect of spironolactone is hyperkalemia high potassium levels which in severe cases can be life threatening 101 Hyperkalemia in these people can present as a normal anion gap metabolic acidosis 101 It has been reported that the addition of spironolactone to loop diuretics in patients with heart failure was associated with a higher risk of hyperkalemia and acute kidney injury AKI 108 Spironolactone may put people at a heightened risk for gastrointestinal issues like nausea vomiting diarrhea cramping and gastritis 101 109 In addition there has been some evidence suggesting an association between use of the medication and bleeding from the stomach and duodenum 101 though a causal relationship between the two has not been established 110 111 Also spironolactone is immunosuppressive in the treatment of sarcoidosis 112 Most of the side effects of spironolactone are dose dependent 57 Low dose spironolactone is generally very well tolerated 57 Even higher doses of spironolactone such as 100 mg day are well tolerated in most individuals 57 Dose dependent side effects of spironolactone include menstrual irregularities breast tenderness and enlargement orthostatic hypotension and hyperkalemia 57 The side effects of spironolactone are usually mild and rarely result in discontinuation 57 vte Side effects of spironolactone in clinical studies for acne in women Side effect RCTs n ITT 326 Case series n ITT 663 Number Number Menstrual irregularities 38 13 4 of 283 216 33 4 of 646 Breast tenderness 8 2 5 30 4 5Breast enlargement 7 2 1 13 2 0Dizziness vertigo lightheadedness 11 3 4 19a 2 9Headache 5 1 5 10a 1 5Nausea and or vomiting 6 1 8 24 3 6Weight gainb 5 1 5 1 0 2Abdominal pain 0 0 11a 1 7Polyuria 2 0 6 8 1 2Fatigue lethargy 1 0 3 12a 1 8Footnotes a Precise values unavailable due to inadequate reporting b Not monitored in most studies Description Side effects of spironolactone 25 400 mg day with 1 incidence in a 2017 hybrid systematic review of clinical studies of spironolactone for acne in women Side effects with lt 1 incidence included postural hypotension depression diarrhea muscle pain increased appetite drowsiness rashes drug eruptions chloasma like skin pigmentation polydipsia weakness leg edema libido changes and palpitations Certain side effects like breast enlargement reduced premenstrual symptoms and less oily skin greasy hair could be beneficial Side effects often could not be unambiguously attributed to spironolactone due concomitant use of other medications particularly birth control pills Hyperkalemia was rare 14 469 3 0 and was invariably mild and clinically insignificant Risk of bias was high and quality of evidence was low to very low Sources See template High potassium levels Edit Spironolactone can cause hyperkalemia or high blood potassium levels 105 Rarely this can be fatal 105 Of people with heart disease prescribed typical dosages of spironolactone 10 to 15 develop some degree of hyperkalemia and 6 develop severe hyperkalemia 105 At a higher dosage a rate of hyperkalemia of 24 has been observed 113 An abrupt and major increase in the rate of hospitalization due to hyperkalemia from 0 2 to 11 and in the rate of death due to hyperkalemia from 0 3 per 1 000 to 2 0 per 1 000 between early 1994 and late 2001 has been attributed to a parallel rise in the number of prescriptions written for spironolactone upon the publication of the Randomized Aldactone Evaluation Study RALES in July 1999 105 113 114 27 However another population based study in Scotland failed to replicate these findings 115 116 The risk of hyperkalemia with spironolactone is greatest in the elderly in people with renal impairment e g due to chronic kidney disease or diabetic nephropathy in people taking certain other medications including ACE inhibitors angiotensin II receptor blockers nonsteroidal anti inflammatory drugs the antibiotic trimethoprim and potassium supplements and at higher dosages of spironolactone 105 27 117 118 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 58 59 119 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 58 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 58 59 119 However other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors 27 Occasional testing on a case by case basis in those with known risk factors may be justified 58 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 58 Notably non use of routine potassium monitoring with spironolactone in young women would reduce costs associated with its use 58 Breast changes Edit Spironolactone frequently causes breast pain and breast enlargement in women 120 121 This is probably because of estrogenic effects on target tissue 105 At low doses breast tenderness has been reported in only 5 of women but at high doses it has been reported in up to 40 of women 122 57 Breast enlargement and tenderness may occur in 26 of women at high doses 80 Some women regard spironolactone induced breast enlargement as a positive effect 58 Spironolactone also commonly and dose dependently produces gynecomastia breast development as a side effect in men 104 121 123 124 At low doses the rate is only 5 to 10 124 but at high doses up to or exceeding 50 of men may develop gynecomastia 104 121 123 In the RALES 9 1 of men taking 25 mg day spironolactone developed gynecomastia compared to 1 3 of controls 125 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 126 127 The severity of gynecomastia with spironolactone varies considerably but is usually mild 104 As with breast enlargement caused by spironolactone in women gynecomastia due to spironolactone in men is often although inconsistently accompanied by breast tenderness 104 In the RALES only 1 7 of men developed breast pain relative to 0 1 of controls 125 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 125 Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication 104 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 128 129 Menstrual disturbances Edit Spironolactone at higher doses can cause menstrual irregularities as a side effect in women 57 These irregularities include metrorrhagia intermenstrual bleeding amenorrhea absence of menstruation and breakthrough bleeding 57 They are common during spironolactone therapy with 10 to 50 of women experiencing them at moderate doses and almost all experiencing them at a high doses 80 105 For example about 20 of women experienced menstrual irregularities with 50 to 100 mg day spironolactone whereas about 70 experienced menstrual irregularities at 200 mg day 57 Most women taking moderate doses of spironolactone develop amenorrhea and normal menstruation usually returns within two months of discontinuation 105 Spironolactone produces an irregular and anovulatory pattern of menstrual cycles 80 It is also associated with metrorrhagia and menorrhagia heavy menstrual bleeding in large percentages of women 120 as well as with polymenorrhea short menstrual cycles 130 131 The medication reportedly has no birth control effect 132 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 80 133 134 An alternative proposed cause is inhibition of 17a hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels 104 Indeed CYP17A1 genotype is associated with polymenorrhea 135 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 80 136 Mood changes Edit Research is mixed on whether antimineralocorticoids like spironolactone have positive or negative effects on mood 137 138 139 In any case it is possible that spironolactone might have the capacity to increase the risk of depressive symptoms 137 138 139 However a 2017 hybrid systematic review found that the incidence of depression in women treated with spironolactone for acne was less than 1 58 Likewise a 10 year observational study found that the incidence of depression in 196 transgender women taking high dose spironolactone in combination with an estrogen was less than 1 140 Rare reactions Edit Aside from hyperkalemia spironolactone may rarely cause adverse reactions such as anaphylaxis kidney failure 141 hepatitis two reported cases neither serious 142 agranulocytosis DRESS syndrome Stevens Johnson syndrome or toxic epidermal necrolysis 143 144 Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported 105 124 Spironolactone bodies Edit Micrograph H amp E stain of an adrenal gland showing 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 145 Pregnancy and breastfeeding Edit In the United States spironolactone is considered pregnancy category C meaning that it is unclear if it is safe for use during pregnancy 3 4 It is able to cross the placenta 120 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 medication while nursing 101 However only very small amounts of spironolactone and its metabolite canrenone enter breast milk and the amount received by an infant during breastfeeding lt 0 5 of the mother s dose is considered to be insignificant 146 A study found that spironolactone was not associated with teratogenicity in the offspring of rats 147 148 149 Because it is an antiandrogen however spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses 147 148 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 147 149 Another study found permanent dose related reproductive tract abnormalities rat offspring of both sexes at lower doses 50 to 100 mg kg per day 149 In practice however although experience is limited spironolactone has never been reported to cause observable feminization or any other congenital defects in humans 147 148 150 151 Among 31 human newborns exposed to spironolactone in the first trimester there were no signs of any specific birth defects 151 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 151 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 146 147 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 151 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 147 152 A 2019 systematic review found insufficient evidence that spironolactone causes birth defects in humans 153 However there was also insufficient evidence to be certain that it does not 153 Overdose EditSpironolactone is relatively safe in acute overdose 101 Symptoms following an acute overdose of spironolactone may include drowsiness confusion maculopapular or erythematous rash nausea vomiting dizziness and diarrhea 101 In rare cases hyponatremia hyperkalemia or hepatic coma may occur in individuals with severe liver disease 101 However these adverse reactions are unlikely in the event of an acute overdose 101 Hyperkalemia can occur following an overdose of spironolactone and this is especially so in people with decreased kidney function 101 Spironolactone has been studied at extremely high oral doses of up to 2 400 mg per day in clinical trials 100 154 Its oral median lethal dose LD50 is more than 1 000 mg kg in mice rats and rabbits 101 There is no specific antidote for overdose of spironolactone 101 Treatment may consist of induction of vomiting or stomach evacuation by gastric lavage 101 The treatment of spironolactone overdose is supportive with the purpose of maintaining hydration electrolyte balance and vital functions 101 Spironolactone should be discontinued in people with impaired kidney function or hyperkalemia 101 Interactions EditSpironolactone often increases serum potassium levels and can cause hyperkalemia a very serious condition Therefore it is recommended that people using this medication avoid potassium supplements and salt substitutes containing potassium 155 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 119 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 156 Spironolactone has been reported to induce the enzymes CYP3A4 and certain UDP glucuronosyltransferases UGTs which can result in interactions with various medications 12 157 158 However it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4 159 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 160 Spironolactone has also been found to inhibit UGT2B7 161 Spironolactone can also have numerous other interactions most commonly with other cardiac and blood pressure medications for instance digoxin 101 Licorice which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism has been found to inhibit the antimineralocorticoid effects of spironolactone 162 163 164 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 162 163 On the opposite end of the spectrum spironolactone is useful in reversing licorice induced hypokalemia 165 166 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 29 167 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 glucocorticoids such as cortisol 168 169 However other research contradicts this hypothesis and has suggested that spironolactone might actually produce antidepressant effects for instance studies showing antidepressant like effects of spironolactone in animals 170 Pharmacology EditPharmacodynamics Edit Main article Pharmacodynamics of spironolactone 7a Thiomethylspironolactone the major active form of spironolactone It accounts for about 80 of the potassium sparing effect of spironolactone 6 171 172 Canrenone the second major active form of spironolactone It accounts for around 10 to 25 of the potassium sparing effect of spironolactone 173 The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity moderate antiandrogenic activity and weak steroidogenesis inhibition among other more minor activities 100 103 126 Spironolactone is a prodrug so most of its actions are actually mediated by its various active metabolites 100 The major active forms of spironolactone are 7a thiomethylspironolactone 7a TMS and canrenone 7a desthioacetyl d6 spironolactone 6 100 Spironolactone is a potent antimineralocorticoid 6 That is it is an antagonist of the mineralocorticoid receptor MR the biological target of mineralocorticoids like aldosterone and 11 deoxycorticosterone 6 By blocking the MR spironolactone inhibits the effects of mineralocorticoids in the body 6 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 174 175 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 176 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 55 80 Spironolactone is a moderate antiandrogen 103 133 158 That is it is an antagonist of the androgen receptor AR the biological target of androgens like testosterone and dihydrotestosterone DHT 103 133 158 By blocking the AR spironolactone inhibits the effects of androgens in the body 103 133 158 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 133 160 177 It is also primarily responsible for some of its side effects like breast tenderness gynecomastia feminization and demasculinization in men 104 177 Blockade of androgen signaling in the breast disinhibits the actions of estrogens in this tissue 178 Although useful as an antiandrogen in women who have low testosterone levels compared to men 179 180 spironolactone is described as having relatively weak antiandrogenic activity 181 177 182 183 Spironolactone is a weak steroidogenesis inhibitor 103 126 133 184 That is it inhibits steroidogenic enzymes or enzymes involved in the production of steroid hormones 103 126 133 184 Spironolactone and or its metabolites have been found in vitro to weakly inhibit a broad array of steroidogenic enzymes including cholesterol side chain cleavage enzyme 17a hydroxylase 17 20 lyase 5a reductase 3b hydroxysteroid dehydrogenase 11b hydroxylase 21 hydroxylase and aldosterone synthase 18 hydroxylase 133 184 185 186 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 58 103 126 133 158 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 103 126 187 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 103 104 However its androgen synthesis inhibition is probably clinically insignificant 60 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 103 126 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 188 189 It is notable that spironolactone has been found in vitro to act as a weak inhibitor of 17b hydroxysteroid dehydrogenase 2 an enzyme that is involved in the conversion of estradiol into estrone 190 191 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 188 192 193 In response to the antimineralocorticoid activity spironolactone and in an attempt to maintain homeostasis the body increases aldosterone production in the adrenal cortex 194 195 196 Some studies have found that levels of cortisol a glucocorticoid hormone that is also produced in the adrenal cortex are increased as well 195 196 197 However other clinical studies have found no change in cortisol levels with spironolactone 133 198 91 199 and those that have found increases often have observed only small changes 200 In accordance spironolactone has not been associated with conventional glucocorticoid medication effects or side effects 201 202 Other activities of spironolactone may include very weak interactions with the estrogen and progesterone receptors and agonism of the pregnane X receptor 91 203 These activities could contribute to the menstrual irregularities and breast side effects of spironolactone and to its drug interactions respectively 204 205 206 Pharmacokinetics Edit The pharmacokinetics of spironolactone have not been studied well which is in part because it is an old medication that was developed in the 1950s 127 Nonetheless much has been elucidated about the pharmacokinetics of spironolactone over the decades 207 208 209 6 210 211 212 213 Absorption Edit Levels of spironolactone and its major active metabolites after a single oral dose of 100 mg spironolactone in humans 214 The bioavailability of spironolactone when taken by mouth is 60 to 90 6 7 8 The bioavailability of spironolactone and its metabolites increases significantly 22 95 increases in levels when spironolactone is taken with food although it is uncertain whether this further increases the therapeutic effects of the medication 215 216 217 The increase in bioavailability is thought to be due to promotion of the gastric dissolution and absorption of spironolactone as well as due to a decrease of the first pass metabolism 215 218 219 The relationship between a single dose of spironolactone and plasma levels of canrenone a major active metabolite of spironolactone has been found to be linear across a dose range of 25 to 200 mg spironolactone 181 Steady state concentrations of spironolactone are achieved within 8 to 10 days of treatment initiation 172 220 Little or no systemic absorption has been observed with topical spironolactone 221 Distribution Edit Spironolactone and its metabolite canrenone are highly plasma protein bound with percentages of 88 0 and 99 2 respectively 6 9 Spironolactone is bound equivalently to albumin and a1 acid glycoprotein while canrenone is bound only to albumin 6 9 Spironolactone and its metabolite 7a thiospironolactone show very low or negligible affinity for sex hormone binding globulin SHBG 222 223 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 224 This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG 91 225 Spironolactone appears to cross the blood brain barrier 226 227 Metabolism Edit Spironolactone metabolism in humans 228 Canrenone may be further reduced into di tetra and hexahydrogenated metabolites hydroxylated and conjugated e g glucuronidated 228 Spironolactone is rapidly and extensively metabolized in the liver upon oral administration and has a very short terminal half life of 1 4 hours 6 7 The major metabolites of spironolactone are 7a thiomethylspironolactone 7a TMS 6b hydroxy 7a thiomethylspironolactone 6b OH 7a TMS and canrenone 7a desthioacetyl d6 spironolactone 6 7 171 These metabolites have much longer elimination half lives than spironolactone of 13 8 hours 15 0 hours and 16 5 hours respectively and are responsible for the therapeutic effects of the medication 6 7 As such spironolactone is a prodrug 229 The 7a thiomethylated metabolites of spironolactone were not known for many years and it was originally thought that canrenone was the major active metabolite of the medication but subsequent research identified 7a TMS as the major metabolite 6 171 172 Other known but more minor metabolites of spironolactone include 7a thiospironolactone 7a TS which is an important intermediate to the major metabolites of spironolactone 12 as well as the 7a methyl ethyl ester of spironolactone and the 6b hydroxy 7a methyl ethyl ester of spironolactone 10 Spironolactone is hydrolyzed or deacetylated at the thioester of the C7a position into 7a TS by carboxylesterases 12 230 Following formation of 7a TS it is S oxygenated by flavin containing monooxygenases to form an electrophilic sulfenic acid metabolite 12 This metabolite is involved in the CYP450 inhibition of spironolactone and also binds covalently to other proteins 12 7a TS is also S methylated into 7a TMS a transformation catalyzed by thiol S methyltransferase 12 Unlike the related medication eplerenone spironolactone is said to not be metabolized by CYP3A4 231 However hepatic CYP3A4 is likely responsible for the 6b hydroxylation of 7a TMS into 6b OH 7a TMS 13 232 7a TMS may also be hydroxylated at the C3a and C3b positions 14 Spironolactone is dethioacetylated into canrenone 15 Finally the C17 g lactone ring of spironolactone is hydrolyzed by the paraoxonase PON3 16 233 It was originally thought to be hydrolyzed by PON1 but this was due to contamination with PON3 16 vte Pharmacokinetics of 100 mg day spironolactone and its metabolites Compound Cmax day 1 Cmax day 15 AUC day 15 t1 2Spironolactone 72 ng mL 173 nmol L 80 ng mL 192 nmol L 231 ng hour mL 555 nmol hour L 1 4 hoursCanrenone 155 ng mL 455 nmol L 181 ng mL 532 nmol L 2 173 ng hour mL 6 382 nmol hour L 16 5 hours7a TMS 359 ng mL 924 nmol L 391 ng mL 1 006 nmol L 2 804 ng hour mL 7 216 nmol hour L 13 8 hours6b OH 7a TMS 101 ng mL 250 nmol L 125 ng mL 309 nmol L 1 727 ng hour mL 4 269 nmol hour L 15 0 hoursSources See template Elimination Edit The majority of spironolactone is eliminated by the kidneys while minimal amounts are handled by biliary excretion 234 Chemistry EditSee also Spirolactone and List of steroidal antiandrogens Spirolactone derivatives Spironolactone also known as 7a acetylthiospirolactone is a steroidal 17a spirolactone or more simply a spirolactone 100 It can most appropriately be conceptualized as a derivative of progesterone 125 235 220 itself also a potent antimineralocorticoid in which a hydroxyl group has been substituted at the C17a position as in 17a hydroxyprogesterone the acetyl group at the C17b position has been cyclized with the C17a hydroxyl group to form a spiro 21 carboxylic acid g lactone ring and an acetylthio group has been substituted in at the C7a position 236 237 238 These structural modifications of progesterone confer increased oral bioavailability and potency 239 potent antiandrogenic activity and strongly reduced progestogenic activity 240 The C7a substitution is likely responsible for or involved in the antiandrogenic activity of spironolactone as 7a thioprogesterone SC 8365 unlike progesterone 241 is an antiandrogen with similar affinity to the AR as that of spironolactone 242 In addition the C7a substitution appears to be responsible for the loss of progestogenic activity and good oral bioavailability of spironolactone as SC 5233 the analogue of spironolactone without a C7a substitution has potent progestogenic activity but very poor oral bioavailability similarly to progesterone 241 243 244 Names Edit Spironolactone is also known by the following equivalent chemical names 236 237 238 7a Acetylthio 17a hydroxy 3 oxopregn 4 ene 21 carboxylic acid g lactone 7a Acetylthio 3 oxo 17a pregn 4 ene 21 17b carbolactone 3 3 Oxo 7a acetylthio 17b hydroxyandrost 4 en 17a yl propionic acid lactone 7a Acetylthio 17a 2 carboxyethyl androst 4 en 17b ol 3 one g lactone 7a Acetylthio 17a 2 carboxyethyl testosterone g lactoneAnalogues Edit vte Chemical structures of spirolactones Progesterone Spirolactone Canrenone Spironolactone Drospirenone Spirorenone Chemical structures of progesterone and spirolactones steroid 17a spirolactones Spironolactone is closely related structurally 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 7a 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 100 Synthesis Edit Chemical syntheses of spironolactone and its analogues and derivatives have been described and reviewed 245 History EditThe natriuretic effects of progesterone were demonstrated in 1955 and the development of spironolactone as a synthetic antimineralocorticoid analogue of progesterone shortly followed this 125 235 246 247 Spironolactone was first synthesized in 1957 20 246 247 was patented between 1958 and 1961 248 249 and was first marketed as an antimineralocorticoid in 1959 250 251 Gynecomastia was first reported with spironolactone in 1962 100 252 and the antiandrogenic activity of the medication was first described in 1969 253 This shortly followed the discovery in 1967 that gynecomastia is an important and major side effect of AR antagonists 254 255 Spironolactone was first studied in the treatment of hirsutism in women in 1978 256 162 257 258 259 It has since become the most widely used antiandrogen for dermatological indications in women in the United States 96 260 261 262 Spironolactone was first studied as an antiandrogen in transgender women in 1986 and has since become widely adopted for this purpose as well particularly in the United States where cyproterone acetate is not available 263 264 265 Early oral spironolactone tablets showed poor absorption 266 The formulation was eventually changed to a micronized formulation with particle sizes of less than 50 mg which resulted in approximately 4 fold increased potency 266 267 Society and culture EditGeneric names Edit The English French and generic name of the medication is spironolactone and this is its INN USAN USP BAN DCF and JAN 98 99 236 268 Its name is spironolactonum in Latin spironolacton in German espironolactona in Spanish and Portuguese and spironolattone in Italian which is also its DCIT 98 99 268 Spironolactone is also known by its developmental code names SC 9420 and NSC 150339 98 99 236 Brand names Edit Spironolactone is marketed under a large number of brand names throughout the world 98 99 The major brand name of spironolactone is Aldactone 98 99 Other important brand names include Aldactone A Berlactone CaroSpir Espironolactona Espironolactona Genfar Novo Spiroton Prilactone veterinary Spiractin Spiridon Spirix Spiroctan Spiroderm discontinued 5 Spirogamma Spirohexal Spirolon Spirolone Spiron Spironolactone Actavis Spironolactone Orion Spironolactone Teva Spirotone Tempora veterinary Uractone Uractonum Verospiron and Vivitar 98 99 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 99 Availability Edit 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 98 99 Usage Edit There was a total of 17 2 million prescriptions for spironolactone in the United States between the beginning of 2003 and the end of 2005 269 There was a total of 12 0 million prescriptions for spironolactone in the United States in 2016 alone 270 It was the 66th top prescribed medication in the United States in 2016 270 Research EditProstate conditions Edit Spironolactone has been studied at a high dosage in the treatment of benign prostatic hyperplasia BPH enlarged prostate 271 272 273 It was found to be better than placebo in terms of symptom relief following three months of treatment 271 272 However this was not maintained after six months of treatment by which point the improvements had largely disappeared 271 272 273 Moreover no difference was observed between spironolactone and placebo with regard to volume of residual urine or prostate size 271 272 Gynecomastia was observed in about 5 of people 272 On the basis of these results it has been said that spironolactone has no place in the treatment of BPH 272 Spironolactone has been studied and used limitedly in the treatment of prostate cancer 274 275 29 Epstein Barr virus Edit Spironolactone has been found to block Epstein 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 276 This effect of spironolactone was determined to be independent of its antimineralocorticoid actions 276 Thus spironolactone or compounds based on it have the potential to yield novel antiviral medications with a distinct mechanism of action and limited toxicity 276 Other conditions Edit Spironolactone has been studied in the treatment of 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causes mild symptoms Associated breast tenderness is common but an inconsistent feature a b c d e f g h i j k Aronson JK 2 March 2009 Meyler s Side Effects of Cardiovascular Drugs Elsevier pp 253 258 ISBN 978 0 08 093289 7 Archived from the original on 7 October 2022 Retrieved 16 October 2016 Spironolactone causes breast tenderness and enlargement mastodynia infertility cholasma altered vaginal lubrica tion and reduced libido in women probably because of estrogenic effects on target tissue Carrell DT Peterson CM 23 March 2010 Reproductive Endocrinology and Infertility Integrating Modern Clinical and Laboratory Practice Springer Science amp Business Media pp 162 ISBN 978 1 4419 1436 1 Archived from the original on 7 October 2022 Retrieved 6 October 2016 A modest improvement in hirsutism can be anticipated in 70 80 of women using even the minimum of 100 mg of spironolactone per day for 6 months 157 The most common dosage is 100 200 mg per day in a divided dosage Women treated with 200 mg day show a greater reduction in hair shaft diameter than women receiving 100 mg day 159 Menstrual irregularity usually metrorrhagia is the most common side effect of spironolactone and occurs in over 50 of patients with a dosage of 200 mg day 159 Patients must be counseled to use contraception while taking spironolactone because it theoretically can feminize a male fetus Pescovitz OH Eugster EA 2004 Pediatric Endocrinology Mechanisms Manifestations and Management Lippincott Williams amp Wilkins pp 368 ISBN 978 0 7817 4059 3 Secora AM Shin JI Qiao Y Alexander GC Chang AR Inker LA et al November 2020 Hyperkalemia and Acute Kidney Injury with Spironolactone Use Among Patients with Heart Failure Mayo Clinic Proceedings 95 11 2408 2419 doi 10 1016 j mayocp 2020 03 035 PMC 8005315 PMID 33153631 U S National Library of Medicine 2019 Spironolactone MedlinePlus Archived from the original on 5 July 2016 Retrieved 31 October 2019 Verhamme K Mosis G Dieleman J Stricker B Sturkenboom M August 2006 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Juurlink DN March 2015 Trimethoprim sulfamethoxazole and risk of sudden death among patients taking spironolactone CMAJ 187 4 E138 E143 doi 10 1503 cmaj 140816 PMC 4347789 PMID 25646289 a b c Plovanich M Weng QY Mostaghimi A September 2015 Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne JAMA Dermatology 151 9 941 4 doi 10 1001 jamadermatol 2015 34 PMID 25796182 a b c Becker KL 2001 Principles and Practice of Endocrinology and Metabolism Lippincott Williams amp Wilkins pp 708 777 1087 1196 ISBN 978 0 7817 1750 2 Archived from the original on 6 October 2022 Retrieved 6 May 2018 Spironolactone has been used successfully in dosages of 100 to 200 mg daily for the treatment of idiopathic hirsutism and hirsutism associated with polycystic ovarian disease see Chaps 96 and 101 184 Spironolactone also is both an antiandrogen and a progestagen and this explains many of its distressing side effects decreased libido mastodynia and gynecomastia may occur in 50 or more of men and menometrorrhagia and breast pain may occur in an equally large number of women taking the drug 27 a b c Tsioufis C Schmieder R Mancia G 15 August 2016 Interventional Therapies for Secondary and Essential Hypertension Springer p 44 ISBN 978 3 319 34141 5 Archived from the original on 7 October 2022 Retrieved 16 October 2016 Gynecomastia is dose related and reaches almost 50 with high spironolactone doses gt 150 mg daily while it is much less common 5 10 with low doses 25 50 mg spironolactone daily 135 Conn JJ Jacobs HS July 1998 Managing hirsutism in gynaecological practice British Journal of Obstetrics and Gynaecology 105 7 687 96 doi 10 1111 j 1471 0528 1998 tb10197 x PMID 9692407 S2CID 34751086 Breast tenderness is not uncommon and is recorded in up to 40 of women taking higher doses63 a b Side Effects of Drugs Annual A worldwide yearly survey of new data in adverse drug reactions Elsevier Science 1 December 2014 p 293 ISBN 978 0 444 63391 0 It is well known that gynecomastia is a side effect of spironolactone in men and occurs in a dose dependent manner in 7 of cases with doses of lt 50 mg per day and up to 50 of cases with doses of gt 150 mg per day 40 41 a b c McInnes GT 2008 Clinical Pharmacology and Therapeutics of Hypertension Elsevier p 125 ISBN 978 0 444 51757 9 Archived from the original on 7 October 2022 Retrieved 6 October 2016 Spironolactone lacks specificty for mineralocorticoid receptors and binds to both progesterone and dihydrotestosterone receptors This can lead to various endocrine side effects that can limit the use of spironolactone In females spironolactone can induce menstrual disturbances breast enlargement and breast tenderness 78 In men spironolactone can induce gynecomastia and impotence In RALES gynaecomastia or breast pain was reported by 10 of the men in the spironolactone group and 1 of the men in the placebo group p lt 0 001 causing more patients in the spironolactone group than in the placebo group to 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10 1038 sj npp 1301217 PMID 17035932 S2CID 10624783 Hinkelmann K Hellmann Regen J Wingenfeld K Kuehl LK Mews M Fleischer J et al November 2016 Mineralocorticoid receptor function in depressed patients and healthy individuals Progress in Neuro Psychopharmacology amp Biological Psychiatry 71 183 8 doi 10 1016 j pnpbp 2016 08 003 PMID 27519144 S2CID 4775178 Falcone T Hurd WW 1 January 2007 Clinical Reproductive Medicine and Surgery Elsevier Health Sciences pp 271 ISBN 978 0 323 03309 1 Archived from the original on 7 October 2022 Retrieved 13 August 2018 Abshagen U Sporl S L age M February 1978 Non interaction of spironolactone medication and cortisol metabolism in man Klinische Wochenschrift 56 3 135 8 doi 10 1007 BF01478568 PMID 628197 S2CID 30885047 Yamaji M Tsutamoto T Kawahara C Nishiyama K Yamamoto T Fujii M Horie M November 2010 Effect of eplerenone versus spironolactone on cortisol and hemoglobin A1 c levels in patients with chronic heart failure American Heart Journal 160 5 915 21 doi 10 1016 j ahj 2010 04 024 PMID 21095280 span, wikipedia, wiki, book, books, library,

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