HOME

TheInfoList



OR:

Spironolactone, sold under the brand name Aldactone among others, is a
medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure, low blood potassium that does not improve with supplementation, early puberty in boys,
acne Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
and excessive hair growth in women, and as a part of transgender hormone therapy in
transfeminine A transgender (often abbreviated as trans) person is someone whose gender identity or gender expression does not correspond with their sex assigned at birth. Many transgender people experience dysphoria, which they seek to alleviate through tr ...
people. Spironolactone is taken by mouth. Common side effects include
electrolyte abnormalities Electrolyte imbalance, or water-electrolyte imbalance, is an abnormality in the concentration of electrolytes in the body. Electrolytes play a vital role in maintaining homeostasis in the body. They help to regulate heart and neurological function, ...
, particularly high blood potassium, nausea, vomiting, headache, rashes, and a decreased desire for sex. In those with liver or kidney problems, extra care should be taken. Spironolactone has not been well studied in pregnancy and should not be used to treat high blood pressure of pregnancy. It is a steroid that blocks the effects of the
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
s aldosterone and testosterone and has some
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
-like effects. Spironolactone belongs to a class of medications known as
potassium-sparing diuretic Potassium-sparing diuretics refers to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The steroidal aldosteron ...
s. Spironolactone was discovered in 1957, and was introduced in 1959. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2020, it was the 51st most commonly prescribed medication in the United States, with more than 13million prescriptions.


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. On its own, spironolactone is only a weak
diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics i ...
because it primarily targets the distal nephron ( collecting tubule), where only small amounts of
sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...
are reabsorbed, but it can be combined with other diuretics to increase efficacy. The classification of spironolactone as a "potassium-sparing diuretic" has been described as obsolete. Spironolactone is also used to treat Bartter's syndrome due to its ability to raise potassium levels. Spironolactone 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 Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
, seborrhea, hirsutism, and pattern hair loss in women. Spironolactone is the most commonly used medication in the treatment of hirsutism in the
United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., ...
. 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 Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...
, in women, dose of 50-100mg in 1 or 2 doses.


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 An ejection fraction (EF) is the volumetric fraction (or portion of the total) of fluid (usually blood) ejected from a chamber (usually the heart) with each contraction (or heartbeat). It can refer to the cardiac atrium, ventricle, gall bladder, ...
of less than 35%. In a randomized evaluation which studied people with severe
congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
, people treated with spironolactone were found to have a relative risk of death of 0.70 or an overall 30%
relative risk reduction In epidemiology, the relative risk reduction (RRR) or efficacy is the relative decrease in the risk of an adverse event in the exposed group compared to an unexposed group. It is computed as (I_u - I_e) / I_u, where I_e is the incidence in the ex ...
compared to the
placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...
group, indicating a significant
death Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...
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. Likewise, it has shown benefit for and is recommended in patients who recently had a
heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...
and have an ejection fraction less than 40%, who develop symptoms consistent with heart failure, or have a history of
diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
. Spironolactone should be considered a good add-on agent, particularly in those patients "not" yet optimized on ACE inhibitors and
beta-blockers Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack (secondary prevention). They are al ...
. 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 A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...
. It is recommended that alternatives to spironolactone be considered if serum creatinine is greater than 2.5 mg/dL (221 μmol/L) in males or greater than 2 mg/dL (176.8 μmol/L) in females, if glomerular filtration rate is below 30 mL/min or with a serum potassium of greater than 5.0 mEq/L given the potential for adverse events detailed elsewhere in this article. Doses should be adjusted according to the degree of kidney function as well. According to a systematic review, in heart failure with preserved
ejection fraction An ejection fraction (EF) is the volumetric fraction (or portion of the total) of fluid (usually blood) ejected from a chamber (usually the heart) with each contraction (or heartbeat). It can refer to the cardiac atrium, ventricle, gall bladder, ...
, 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 In frequentist statistics, a confidence interval (CI) is a range of estimates for an unknown parameter. A confidence interval is computed at a designated ''confidence level''; the 95% confidence level is most common, but other levels, such as 9 ...
of 0.77 to 1.04, it is determined the finding had no
statistical significance In statistical hypothesis testing, a result has statistical significance when it is very unlikely to have occurred given the null hypothesis (simply by chance alone). More precisely, a study's defined significance level, denoted by \alpha, is the p ...
. Hence the finding that patient outcomes are not improved with use of spironolactone. When blood samples from 366 participants in the TOPCAT study were analyzed for presence of
canrenone Canrenone, sold under the brand names Contaren, Luvion, Phanurane, and Spiroletan, is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone which is used as a diuretic in Europe, including in Italy and Belgium. ...
(an active metabolite of spironolactone), 30% of blood samples from
Russia Russia (, , ), or the Russian Federation, is a transcontinental country spanning Eastern Europe and Northern Asia. It is the largest country in the world, with its internationally recognised territory covering , and encompassing one-ei ...
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. The TOPCAT study results are now considered to have been invalidated. The study's prime investigator and other prominent research cardiologists are now advising physicians treating heart failure with preserved ejection fraction to consider prescribing spironolactone pending outcome of two multicenter trials of newer medications. Due to its 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 The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
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 Canrenone, sold under the brand names Contaren, Luvion, Phanurane, and Spiroletan, is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone which is used as a diuretic in Europe, including in Italy and Belgium. ...
in reducing mortality from heart failure. 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. 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 Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occa ...
and potentially deadly abnormal heart rhythms.


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 Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professi ...
found adverse effects at high doses and little effect on blood pressure at low doses in the majority of people with high blood pressure. There is no evidence of person-oriented outcome at any dose in this group.


High aldosterone levels

Spironolactone is used in the treatment of hyperaldosteronism (high aldosterone levels or mineralocorticoid excess), for instance primary aldosteronism (Conn's syndrome). Antimineralocorticoids like spironolactone and eplerenone are first-line treatments for hyperaldosteronism. They improve blood pressure and potassium levels, as well as left ventricular hypertrophy,
albuminuria Albuminuria is a pathological condition wherein the protein albumin is abnormally present in the urine. It is a type of proteinuria. Albumin is a major plasma protein (normally circulating in the blood); in healthy people, only trace amounts of ...
, and carotid intima-media thickness, in people with primary aldosteronism. In people with hyperaldosteronism due to unilateral aldosterone-producing
adrenocortical adenoma Adrenocortical adenoma is commonly described as a benign neoplasm emerging from the cells that comprise the adrenal cortex. Like most adenomas, the adrenocortical adenoma is considered a benign tumor since the majority of them are non-functioning ...
, adrenalectomy should be preferred instead of antimineralocorticoids. Spironolactone should not be used to treat primary aldosteronism in pregnancy due to its antiandrogen-related risk of teratogenicity in male fetuses.


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 The human skin is the outer covering of the body and is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue guarding muscles, bones, ligaments and internal organs. Human skin is similar to most ...
,
acne Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
, seborrhea, hirsutism (excessive facial/body hair growth in women), and male pattern hair loss (androgenic alopecia). In demonstration of this, women with complete androgen insensitivity syndrome (CAIS) do not produce
sebum A sebaceous gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur in the greatest nu ...
or develop acne and have little to no body,
pubic In vertebrates, the pubic region ( la, pubis) is the most forward-facing (ventral and anterior) of the three main regions making up the coxal bone. The left and right pubic regions are each made up of three sections, a superior ramus, inferior ...
, or axillary hair. Moreover, men with congenital 5α-reductase type II deficiency, 5α-reductase being an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that greatly potentiates the androgenic effects of testosterone in the skin, have little to no acne, scanty facial hair, reduced body hair, and reportedly no incidence of male-pattern hair loss. Conversely, hyperandrogenism in women, for instance due to
polycystic ovary syndrome Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...
(PCOS) or
congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex ...
(CAH), is commonly associated with acne and hirsutism as well as virilization (masculinization) in general. In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions. Because of the antiandrogenic activity of spironolactone, it can be quite effective in treating acne in women. In addition, spironolactone reduces oil that is naturally produced in the skin and can be used to treat oily skin. Though not the primary intended purpose of the medication, the ability of spironolactone to be helpful with problematic skin and acne conditions was discovered to be one of the beneficial side effects and has been quite successful. Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill. Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months. Spironolactone has been reported to produce a 50 to 100% improvement in acne at sufficiently high doses. Response to treatment generally requires 1 to 3 months in the case of acne and up to 6 months in the case of hirsutism. Ongoing therapy is generally required to avoid relapse of symptoms. Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication. Spironolactone can be used in the treatment of female-pattern hair loss (pattern scalp hair loss in women). There is tentative low quality evidence supporting its use for this indication. Although apparently effective, not all cases of female-pattern hair loss are dependent on androgens. Antiandrogens like spironolactone are male-specific teratogens which can feminize male
fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal dev ...
es due to their antiandrogenic effects. For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception. Oral contraceptives, which contain an
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
and a progestin, are typically used for this purpose. Moreover, oral contraceptives themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions, and hence can significantly augment the effectiveness of antiandrogens in the treatment of such conditions. Spironolactone is not generally used in men for the treatment of androgen-dependent dermatological conditions because of its feminizing side effects, but it is effective for such indications in men similarly. As an example, spironolactone has been reported to reduce symptoms of acne in males. An additional example is the usefulness of spironolactone as an antiandrogen in transgender women. Topical spironolactone has been found to be effective in the treatment of acne as well. As a result, topical pharmaceutical formulations containing 2% or 5% spironolactone cream became available in
Italy Italy ( it, Italia ), officially the Italian Republic, ) or the Republic of Italy, is a country in Southern Europe. It is located in the middle of the Mediterranean Sea, and its territory largely coincides with the homonymous geographical ...
for the treatment of acne and hirsutism in the early 1990s. 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.


Comparison

Spironolactone, the
5α-reductase inhibitor 5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes o ...
finasteride, and the nonsteroidal antiandrogen flutamide all appear to have similar effectiveness in the treatment of hirsutism. 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. 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. One study showed that spironolactone or the steroidal antiandrogen cyproterone acetate both in combination with a birth control pill had equivalent effectiveness for hirsutism. 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. The nonsteroidal antiandrogen bicalutamide is an alternative option to flutamide with improved
safety Safety is the state of being "safe", the condition of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings There are two slightly di ...
. The combination of spironolactone with a birth control pill in the treatment of acne appears to have similar effectiveness to a birth control pill alone and the combination of a birth control pill with cyproterone acetate, flutamide, or finasteride. However, this was based on low- to very-low-quality evidence. Spironolactone may be more effective than birth control pills in the treatment of acne, and the combination of spironolactone with a birth control pill may have greater effectiveness for acne than either alone. In addition, some clinical research has found that flutamide is more effective than spironolactone in the treatment of acne. In one study, flutamide decreased acne scores by 80% within 3 months, whereas spironolactone decreased symptoms by only 40% in the same time period. However, the use of flutamide for acne is limited by its liver toxicity. Bicalutamide is a potential alternative to flutamide for acne as well. Spironolactone can be considered as a first-line treatment for acne in those who have failed other standard treatments such as topical therapies and under certain other circumstances, although this is controversial due to the side effects of spironolactone and its teratogenicity. There is insufficient clinical evidence to compare the effectiveness of spironolactone with other antiandrogens for female-pattern hair loss. The effectiveness of spironolactone in the treatment of both acne and hirsutism appears to be dose-dependent, with higher doses being more effective than lower doses. However, higher doses also have greater side effects, such as menstrual irregularities.


Alternative Spironolactone Use

Spironolactone medication is not approved for use as an antiandrogen by the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
; instead, it is used
off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although ...
for such purposes.


Doses and forms

Spironolactone is typically used at a low dosage of 25 to 50 mg/day in the treatment of heart failure, while it is used at low to high dosages of 25 to 200 mg/day in the treatment of essential hypertension, and at high dosages of 100 to 400 mg/day for hyperaldosteronism and ascites due to
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...
. The medication is typically used at high dosages of 100 to 200 mg/day in the treatment of skin and hair conditions in women, and at high dosages of 100 to 400 mg/day in feminizing hormone therapy for transgender women. Spironolactone can be used to treat symptoms of hyperandrogenism, such as
polycystic ovary syndrome Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...
, in women, dose of 50-100mg in 1 or 2 doses. Spironolactone is available in the form of
tablet Tablet may refer to: Medicine * Tablet (pharmacy), a mixture of pharmacological substances pressed into a small cake or bar, colloquially called a "pill" Computing * Tablet computer, a mobile computer that is primarily operated by touching the ...
s (25 mg, 50 mg, 100 mg; brand name Aldactone, others) and suspensions (25 mg/5 mL; brand name CaroSpir) for use by mouth. It has also been marketed in the form of 2% and 5% topical
cream Cream is a dairy product composed of the higher-fat layer skimmed from the top of milk before homogenization. In un-homogenized milk, the fat, which is less dense, eventually rises to the top. In the industrial production of cream, this process ...
in
Italy Italy ( it, Italia ), officially the Italian Republic, ) or the Republic of Italy, is a country in Southern Europe. It is located in the middle of the Mediterranean Sea, and its territory largely coincides with the homonymous geographical ...
for the treatment of
acne Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
and hirsutism under the brand name Spiroderm, but this product is no longer available. The medication is also available in combination with other medications, such as hydrochlorothiazide (brand name Aldactazide, others). 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. The only antimineralocorticoid that is available as a
solution Solution may refer to: * Solution (chemistry), a mixture where one substance is dissolved in another * Solution (equation), in mathematics ** Numerical solution, in numerical analysis, approximate solutions within specified error bounds * Solutio ...
for
parenteral A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. ...
use is the related medication potassium canrenoate.


Contraindications

Contraindications of spironolactone include
hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occa ...
(high potassium levels), severe and end-stage kidney disease (due to high hyperkalemia risk, except possibly in those on dialysis),
Addison's disease Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adrena ...
(adrenal insufficiency and low aldosterone levels), and concomitant use of eplerenone. 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.


Side effects

One of the most common side effects of spironolactone is frequent urination. Other general side effects include
dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
, hyponatremia (low
sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...
levels), mild
hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...
(low blood pressure),
ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
(muscle incoordination), drowsiness,
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...
, dry skin, and rashes. Because of its antiandrogenic activity, spironolactone can, in men, cause breast tenderness, gynecomastia (breast development), feminization in general, and
demasculinization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...
, as well as sexual dysfunction including loss of libido and erectile dysfunction, although these side effects are usually confined to high doses of spironolactone. 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 Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...
in men. However, such doses of spironolactone are rarely used clinically. In women, spironolactone can cause menstrual irregularities, breast tenderness, and breast enlargement. Aside from these adverse effects, the side effects of spironolactone in women taking high doses are minimal, and it is well tolerated. The most important potential side effect of spironolactone is
hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occa ...
(high
potassium Potassium is the chemical element with the symbol K (from Neo-Latin '' kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmos ...
levels), which, in severe cases, can be life-threatening. Hyperkalemia in these people can present as a normal anion-gap metabolic acidosis. 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). Spironolactone may put people at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis. In addition, there has been some evidence suggesting an association between use of the medication and bleeding from the stomach and duodenum, though a causal relationship between the two has not been established. Also, spironolactone is immunosuppressive in the treatment of
sarcoidosis Sarcoidosis (also known as ''Besnier-Boeck-Schaumann disease'') is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly af ...
. Most of the side effects of spironolactone are dose-dependent. Low-dose spironolactone is generally very well tolerated. Even higher doses of spironolactone, such as 100 mg/day, are well tolerated in most individuals. Dose-dependent side effects of spironolactone include menstrual irregularities, breast tenderness and enlargement, orthostatic hypotension, and hyperkalemia. The side effects of spironolactone are usually mild and rarely result in discontinuation.


High potassium levels

Spironolactone can cause hyperkalemia, or high blood potassium levels. Rarely, this can be fatal. Of people with heart disease prescribed typical dosages of spironolactone, 10 to 15% develop some degree of hyperkalemia, and 6% develop severe hyperkalemia. At a higher dosage, a rate of hyperkalemia of 24% has been observed. 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. However, another population-based study in
Scotland Scotland (, ) is a country that is part of the United Kingdom. Covering the northern third of the island of Great Britain, mainland Scotland has a border with England to the southeast and is otherwise surrounded by the Atlantic Ocean to ...
failed to replicate these findings. 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 inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs, the antibiotic trimethoprim, and
potassium Potassium is the chemical element with the symbol K (from Neo-Latin '' kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmos ...
supplements), and at higher dosages of spironolactone. Although spironolactone poses an important risk of hyperkalemia in the elderly, in those with kidney or cardiovascular disease, and/or in those taking medications or supplements which increase circulating potassium levels, a large retrospective study found that the rate of hyperkalemia in young women without such characteristics who had been treated with high doses of spironolactone for dermatological conditions did not differ from that of controls. This was the conclusion of a 2017 hybrid systematic review of studies of spironolactone for acne in women as well, which found that hyperkalemia was rare and was invariably mild and clinically insignificant. These findings suggest that hyperkalemia may not be a significant risk in such individuals, and that routine monitoring of circulating potassium levels may be unnecessary in this population. However, other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors. Occasional testing on a case-by-case basis in those with known risk factors may be justified. Side effects of spironolactone which may be indicative of hyperkalemia and if persistent could justify serum potassium testing include nausea, fatigue, and particularly muscle weakness. Notably, non-use of routine potassium monitoring with spironolactone in young women would reduce costs associated with its use.


Breast changes

Spironolactone frequently causes
breast pain Breast pain is the symptom of discomfort in either one or both breasts. Pain in both breasts is often described as ''breast tenderness'', is usually associated with the menstrual period and is not serious. Pain that involves only one part of a br ...
and breast enlargement in women. This is "probably because of estrogenic effects on target tissue." 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. Breast enlargement and tenderness may occur in 26% of women at high doses. Some women regard spironolactone-induced breast enlargement as a positive effect. Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men. At low doses, the rate is only 5 to 10%, but at high doses, up to or exceeding 50% of men may develop gynecomastia. In the RALES, 9.1% of men taking 25 mg/day spironolactone developed gynecomastia, compared to 1.3% of controls. Conversely, in studies of healthy men given high-dose spironolactone, gynecomastia occurred in 3 of 10 (30%) at 100 mg/day, in 5 of 8 (62.5%) at 200 mg/day, and in 6 of 9 (66.7%) at 400 mg/day, relative to none of 12 controls. The severity of gynecomastia with spironolactone varies considerably, but is usually mild. As with breast enlargement caused by spironolactone in women, gynecomastia due to spironolactone in men is often although inconsistently accompanied by breast tenderness. In the RALES, only 1.7% of men developed breast pain, relative to 0.1% of controls. The time to onset of spironolactone-induced gynecomastia has been found to be 27 ± 20 months at low doses and 9 ± 12 months at high doses. Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication. However, after a sufficient duration of gynecomastia being present (e.g., one year), hyalinization and fibrosis of the tissue occurs and drug-induced gynecomastia may become irreversible.


Menstrual disturbances

Spironolactone at higher doses can cause menstrual irregularities as a side effect in women. These irregularities include
metrorrhagia Intermenstrual bleeding, previously known as metrorrhagia, is uterine bleeding at irregular intervals, particularly between the expected menstrual periods. It is a cause of vaginal bleeding. In some women, menstrual spotting between periods occur ...
(intermenstrual bleeding), amenorrhea (absence of menstruation), and
breakthrough bleeding Intermenstrual bleeding, previously known as metrorrhagia, is uterine bleeding at irregular intervals, particularly between the expected menstrual periods. It is a cause of vaginal bleeding. In some women, menstrual spotting between periods occur ...
. 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. 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. Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation. Spironolactone produces an irregular and
anovulatory Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulat ...
pattern of menstrual cycles. It is also associated with metrorrhagia and menorrhagia (heavy menstrual bleeding) in large percentages of women, as well as with
polymenorrhea Polymenorrhea, also known as frequent periods, frequent menstruation, or frequent menstrual bleeding, is a menstrual disorder in which menstrual cycles are shorter than 21days in length and hence where menstruation occurs more frequently than usu ...
(short menstrual cycles). The medication reportedly has no birth control effect. It has been suggested that the weak progestogenic activity of spironolactone is responsible for these effects, although this has not been established and spironolactone has been shown to possess insignificant progestogenic and antiprogestogenic activity even at high dosages in women. An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...
by spironolactone and consequent changes in sex hormone levels. Indeed, CYP17A1 genotype is associated with polymenorrhea. Regardless of their mechanism, the menstrual disturbances associated with spironolactone can usually be controlled well by concomitant treatment with a birth control pill, due to the progestin component.


Mood changes

Research is mixed on whether antimineralocorticoids like spironolactone have positive or negative effects on mood. In any case, it is possible that spironolactone might have the capacity to increase the risk of depressive symptoms. However, a 2017 hybrid systematic review found that the incidence of depression in women treated with spironolactone for acne was less than 1%. 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%.


Rare reactions

Aside from hyperkalemia, spironolactone may rarely cause adverse reactions such as
anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follo ...
,
kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
,
hepatitis Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes ( jaundice), poor appetite, vomiting, tiredness, abdominal ...
(two reported cases, neither serious), agranulocytosis, DRESS syndrome, Stevens–Johnson syndrome or toxic epidermal necrolysis. Five cases of
breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
in patients who took spironolactone for prolonged periods of time have been reported.


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
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
ic inclusions surrounded by clear halos in preparations stained with
hematoxylin Haematoxylin or hematoxylin (), also called natural black 1 or C.I. 75290, is a compound extracted from heartwood of the logwood tree ('' Haematoxylum campechianum'') with a chemical formula of . This naturally derived dye has been used as ...
and eosin.


Pregnancy and breastfeeding

In the United States, spironolactone is considered
pregnancy category The pregnancy category of a medication is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does ''not'' include any risks conferred by pharmaceutical agents or their ...
C meaning that it is unclear if it is safe for use during pregnancy. It is able to cross the
placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
. 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 Nursing is a profession within the health care sector focused on the care of individuals, families, and communities so they may attain, maintain, or recover optimal health and quality of life. Nurses may be differentiated from other health ...
. However, only very small amounts of spironolactone and its metabolite canrenone enter breast milk, and the amount received by an infant during breastfeeding (<0.5% of the mother's dose) is considered to be insignificant. A study found that spironolactone was not associated with teratogenicity in the offspring of rats. Because it is an antiandrogen, however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses. In accordance, a subsequent study found that partial feminization of the genitalia occurred in the male offspring of rats that received doses of spironolactone that were five times higher than those normally used in humans (200 mg/kg per day). Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100 mg/kg per day). In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans. Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific
birth defect A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities ca ...
s. A case report described a woman who was prescribed spironolactone during pregnancy with triplets and delivered all three (one boy and two girls) healthy; there was no feminization in the boy. In addition, spironolactone has been used at high doses to treat pregnant women with Bartter's syndrome, and none of the infants (three boys, two girls) showed toxicity, including feminization in the male infants. There are similar findings, albeit also limited, for another antiandrogen, cyproterone acetate (prominent genital defects in male rats, but no human abnormalities (including feminization of male fetuses) at both a low dose of 2 mg/day or high doses of 50 to 100 mg/day). In any case, spironolactone is nonetheless not recommended during pregnancy due to theoretical concerns relating to feminization of males and also to potential alteration of fetal potassium levels. A 2019 systematic review found insufficient evidence that spironolactone causes birth defects in humans. However, there was also insufficient evidence to be certain that it does not.


Overdose

Spironolactone is relatively safe in acute overdose. Symptoms following an acute overdose of spironolactone may include drowsiness, confusion, maculopapular or
erythematous rash Erythema (from the Greek , meaning red) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not asso ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...
,
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenter ...
,
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...
, and
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
. In rare cases, hyponatremia,
hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occa ...
, or hepatic coma may occur in individuals with severe liver disease. However, these adverse reactions are unlikely in the event of an acute overdose. Hyperkalemia can occur following an overdose of spironolactone, and this is especially so in people with decreased kidney function. Spironolactone has been studied at extremely high oral doses of up to 2,400 mg per day in
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
s. Its oral median lethal dose (LD50) is more than 1,000 mg/kg in mice, rats, and rabbits. There is no specific antidote for overdose of spironolactone. Treatment may consist of induction of
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenter ...
or stomach evacuation by
gastric lavage Gastric lavage, also commonly called stomach pumping or gastric irrigation, is the process of cleaning out the contents of the stomach. Since its first recorded use in early 19th century, it has become one of the most routine means of eliminating p ...
. The treatment of spironolactone overdose is supportive, with the purpose of maintaining
hydration Hydration may refer to: * Hydrate, a substance that contains water * Hydration enthalpy, energy released through hydrating a substance * Hydration reaction, a chemical addition reaction where a hydroxyl group and proton are added to a compound * ...
, electrolyte balance, and vital functions. Spironolactone should be discontinued in people with impaired kidney function or hyperkalemia.


Interactions

Spironolactone often increases serum
potassium Potassium is the chemical element with the symbol K (from Neo-Latin '' kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmos ...
levels and can cause
hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occa ...
, a very serious condition. Therefore, it is recommended that people using this medication avoid potassium supplements and salt substitutes containing potassium. Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone as a diuretic, especially during the first twelve months of use and whenever the dosage is increased. Doctors may also recommend that some patients may be advised to limit dietary consumption of potassium-rich foods. However, recent data suggests that both potassium monitoring and dietary restriction of potassium intake is unnecessary in healthy young women taking spironolactone for acne. Spironolactone together with trimethoprim/sulfamethoxazole increases the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron. Spironolactone has been reported to induce the
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s CYP3A4 and certain
UDP-glucuronosyltransferase Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is ...
s (UGTs), which can result in
interaction Interaction is action that occurs between two or more objects, with broad use in philosophy and the sciences. It may refer to: Science * Interaction hypothesis, a theory of second language acquisition * Interaction (statistics) * Interaction ...
s with various medications. However, it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4. In any case, spironolactone has been found to reduce the bioavailability of oral estradiol, which could be due to induction of estradiol metabolism via CYP3A4. Spironolactone has also been found to inhibit UGT2B7. Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications, for instance digoxin.
Licorice Liquorice (British English) or licorice ( American English) ( ; also ) is the common name of ''Glycyrrhiza glabra'', a flowering plant of the bean family Fabaceae, from the root of which a sweet, aromatic flavouring can be extracted. The l ...
, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found to inhibit the antimineralocorticoid effects of spironolactone. Moreover, the addition of licorice to spironolactone has been found to reduce the antimineralocorticoid side effects of spironolactone in women treated with it for hyperandrogenism, and licorice hence may be used to reduce these side effects in women treated with spironolactone as an antiandrogen who are bothered by them. On the opposite end of the spectrum, spironolactone is useful in reversing licorice-induced hypokalemia.
Aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to attenuate the
diuresis Diuresis () is increased urination (polyuria) or, in the related word senses more often intended, the physiological process that produces such an increase or the administration of medications to encourage that process. It involves extra urine pr ...
and natriuresis induced by spironolactone, but, not to affect its antihypertensive effect. Some research has suggested that spironolactone might be able to interfere with the effectiveness of antidepressant treatment. As the medication acts as an antimineralocorticoid, it is thought that it might be able to reduce the effectiveness of certain antidepressants by interfering with normalization of the hypothalamic–pituitary–adrenal axis and by increasing levels of glucocorticoids such as cortisol.Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999). However, other research contradicts this hypothesis and has suggested that spironolactone might actually produce antidepressant effects, for instance studies showing antidepressant-like effects of spironolactone in animals.


Pharmacology


Pharmacodynamics

The
pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ...
of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition, among other more minor activities. Spironolactone is a prodrug, so most of its actions are actually mediated by its various
active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...
s. The major active forms of spironolactone are 7α-thiomethylspironolactone (7α-TMS) and
canrenone Canrenone, sold under the brand names Contaren, Luvion, Phanurane, and Spiroletan, is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone which is used as a diuretic in Europe, including in Italy and Belgium. ...
(7α-desthioacetyl-δ6-spironolactone). Spironolactone is a potent antimineralocorticoid. That is, it is an antagonist of the mineralocorticoid receptor (MR), the biological target of
mineralocorticoid Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances ( electrolyte balance and fluid balance). The primary ...
s like aldosterone and
11-deoxycorticosterone 11-Deoxycorticosterone (DOC), or simply deoxycorticosterone, also known as 21-hydroxyprogesterone, as well as desoxycortone (INN), deoxycortone, and cortexone, is a steroid hormone produced by the adrenal gland that possesses mineralocorticoid ...
. By blocking the MR, spironolactone inhibits the effects of mineralocorticoids in the body. The antimineralocorticoid activity of spironolactone is responsible for its therapeutic efficacy in the treatment of edema, high blood pressure, heart failure, hyperaldosteronism, and ascites due to
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...
. It is also responsible for many of the side effects of spironolactone, such as urinary frequency,
dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
, hyponatremia, low blood pressure, fatigue,
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...
,
metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
, decreased kidney function, and its risk of
hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occa ...
. 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 In biology, homeostasis ( British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
. Spironolactone is a moderate antiandrogen. That is, it is an antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and
dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...
(DHT). By blocking the AR, spironolactone inhibits the effects of androgens in the body. The antiandrogenic activity of spironolactone is mainly responsible for its therapeutic efficacy in the treatment of androgen-dependent skin and hair conditions like
acne Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
, 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 A trans woman or a transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity, may experience gender dysphoria, and may transition; this process commonly includes hormone replacement therapy and so ...
. It is also primarily responsible for some of its side effects, like breast tenderness, gynecomastia, feminization, and
demasculinization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...
in men. Blockade of androgen signaling in the
breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and sec ...
disinhibits the actions of
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
s in this tissue. Although useful as an antiandrogen in women, who have low testosterone levels compared to men, spironolactone is described as having relatively weak antiandrogenic activity. Spironolactone is a weak steroidogenesis inhibitor. That is, it inhibits steroidogenic enzymes, or
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s involved in the production of steroid hormones. Spironolactone and/or its metabolites have been found ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
'' 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). However, although very high doses of spironolactone can considerably decrease steroid hormone levels in animals, spironolactone has shown mixed and inconsistent effects on steroid hormone levels in clinical studies, even at high clinical doses. In any case, the levels of most steroid hormones, including testosterone and cortisol, are usually unchanged by spironolactone in humans, which may in part be related to compensatory upregulation of their synthesis. The weak steroidogenesis inhibition of spironolactone might contribute to its antiandrogenic efficacy to some degree and may explain its side effect of menstrual irregularities in women. However, its androgen synthesis inhibition is probably clinically insignificant. Spironolactone has been found in some studies to increase levels of estradiol, an
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
, although many other studies have found no changes in estradiol levels. The mechanism of how spironolactone increases estradiol levels is unclear, but it may involve inhibition of the inactivation of estradiol into estrone and enhancement of the peripheral conversion of testosterone into estradiol. It is notable that spironolactone has been found ''in vitro'' to act as a weak inhibitor of 17β-hydroxysteroid dehydrogenase 2, an enzyme that is involved in the conversion of estradiol into estrone. Increased levels of estradiol with spironolactone may be involved in its preservation of bone density and in its side effects such as breast tenderness, breast enlargement, and gynecomastia in women and men. In response to the antimineralocorticoid activity spironolactone, and in an attempt to maintain
homeostasis In biology, homeostasis ( British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
, the body increases aldosterone production in the adrenal cortex. Some studies have found that levels of cortisol, a glucocorticoid hormone that is also produced in the adrenal cortex, are increased as well. However, other clinical studies have found no change in cortisol levels with spironolactone, and those that have found increases often have observed only small changes. In accordance, spironolactone has not been associated with conventional glucocorticoid medication effects or side effects. Other activities of spironolactone may include very weak interactions with the
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
and progesterone receptors and agonism of the
pregnane X receptor In the field of molecular biology, the pregnane X receptor (PXR), also known as the steroid and xenobiotic sensing nuclear receptor (SXR) or nuclear receptor subfamily 1, group I, member 2 (NR1I2) is a protein that in humans is encoded by the ' ...
. These activities could contribute to the menstrual irregularities and
breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and sec ...
side effects of spironolactone and to its drug interactions, respectively.


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. Nonetheless, much has been elucidated about the pharmacokinetics of spironolactone over the decades.


Absorption

The bioavailability of spironolactone when taken by mouth is 60 to 90%. 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. The increase in bioavailability is thought to be due to promotion of the gastric dissolution and
absorption Absorption may refer to: Chemistry and biology *Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which s ...
of spironolactone, as well as due to a decrease of the first-pass metabolism. The relationship between a single dose of spironolactone and plasma levels of
canrenone Canrenone, sold under the brand names Contaren, Luvion, Phanurane, and Spiroletan, is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone which is used as a diuretic in Europe, including in Italy and Belgium. ...
, a major
active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...
of spironolactone, has been found to be linear across a dose range of 25 to 200 mg spironolactone. Steady-state concentrations of spironolactone are achieved within 8 to 10 days of treatment initiation. Little or no systemic
absorption Absorption may refer to: Chemistry and biology *Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which s ...
has been observed with topical spironolactone.


Distribution

Spironolactone and its metabolite canrenone are highly
plasma protein bound Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse t ...
, with percentages of 88.0% and 99.2%, respectively. Spironolactone is bound equivalently to
albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Album ...
and α1-acid glycoprotein, while canrenone is bound only to albumin. Spironolactone and its metabolite
7α-thiospironolactone 7α-Thiospironolactone (7α-TS; developmental code name SC-24813; also known as deacetylspironolactone) is a steroidal antimineralocorticoid and antiandrogen of the spirolactone group and a minor active metabolite of spironolactone. Other importa ...
show very low or negligible affinity for sex hormone-binding globulin (SHBG). In accordance, a study of high-dosage spironolactone treatment found no change in steroid binding capacity related to SHBG or to corticosteroid-binding globulin (CBG), suggesting that spironolactone does not displace steroid hormones from their carrier proteins. This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG. Spironolactone appears to cross the blood–brain barrier.


Metabolism

Spironolactone is rapidly and extensively
metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
in the
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
upon
oral administration Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are ...
and has a very short
terminal half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the b ...
of 1.4 hours. The major metabolites of spironolactone are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and
canrenone Canrenone, sold under the brand names Contaren, Luvion, Phanurane, and Spiroletan, is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone which is used as a diuretic in Europe, including in Italy and Belgium. ...
(7α-desthioacetyl-δ6-spironolactone). 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. As such, spironolactone is a prodrug. 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. Other known but more minor metabolites of spironolactone include
7α-thiospironolactone 7α-Thiospironolactone (7α-TS; developmental code name SC-24813; also known as deacetylspironolactone) is a steroidal antimineralocorticoid and antiandrogen of the spirolactone group and a minor active metabolite of spironolactone. Other importa ...
(7α-TS), which is an important intermediate to the major metabolites of spironolactone, as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone. Spironolactone is hydrolyzed or deacetylated at the thioester of the C7α position into 7α-TS by carboxylesterases. Following formation of 7α-TS, it is ''S''- oxygenated by flavin-containing monooxygenases to form an electrophilic sulfenic acid metabolite. This metabolite is involved in the CYP450 inhibition of spironolactone, and also binds covalently to other
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s. 7α-TS is also ''S''- methylated into 7α-TMS, a transformation catalyzed by thiol ''S''-methyltransferase. Unlike the related medication eplerenone, spironolactone is said to not be metabolized by CYP3A4. However, hepatic CYP3A4 is likely responsible for the 6β- hydroxylation of 7α-TMS into 6β-OH-7α-TMS. 7α-TMS may also be
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...
ated at the C3α and C3β positions. Spironolactone is dethioacetylated into canrenone. Finally, the C17 γ- lactone ring of spironolactone is hydrolyzed by the paraoxonase PON3. It was originally thought to be hydrolyzed by PON1, but this was due to contamination with PON3.


Elimination

The majority of spironolactone is eliminated by the
kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
s, while minimal amounts are handled by
biliary A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates. Bile is required for the digestion of food and is secreted by the liver into passages that carry bile toward the hepatic duct. It ...
excretion.


Chemistry

Spironolactone, also known as ''7α-acetylthiospirolactone'', is a steroidal
17α-spirolactone Spirolactones are a class of functional group in organic chemistry featuring a cyclic ester attached spiro to another ring system. The name is also used to refer to a class of synthetic steroids, called steroid-17α-spirolactones, 17α-spirol ...
, or more simply a spirolactone. It can most appropriately be conceptualized as a
derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...
of progesterone, itself also a potent antimineralocorticoid, in which a hydroxyl group has been
substituted A substitution reaction (also known as single displacement reaction or single substitution reaction) is a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. Substitution reactions ar ...
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 acetyl thio group has been substituted in at the C7α position. These structural modifications of progesterone confer increased
oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid ** Oral administration of medicines ** Oral examination (also known as an oral exam or or ...
bioavailability and
potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of how ...
, potent antiandrogenic activity, and strongly reduced progestogenic activity. The C7α substitution is likely responsible for or involved in the antiandrogenic activity of spironolactone, as 7α-thioprogesterone (SC-8365), unlike progesterone, is an antiandrogen with similar affinity to the AR as that of spironolactone. 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.


Names

Spironolactone is also known by the following equivalent chemical names: * 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone * 7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone * 3-(3-Oxo-7α-acetylthio-17β-hydroxyandrost-4-en-17α-yl)propionic acid lactone * 7α-Acetylthio-17α-(2-carboxyethyl)androst-4-en-17β-ol-3-one γ-lactone * 7α-Acetylthio-17α-(2-carboxyethyl)testosterone γ-lactone


Analogues

Spironolactone is closely related structurally to other clinically used spirolactones such as
canrenone Canrenone, sold under the brand names Contaren, Luvion, Phanurane, and Spiroletan, is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone which is used as a diuretic in Europe, including in Italy and Belgium. ...
, 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 Spirorenone (INN) (developmental code name ZK-35973) is a steroidal antimineralocorticoid of the spirolactone group that was never marketed. Spirorenone possesses 5–8 times the antimineralocorticoid activity of spironolactone in animal studies. ...
(ZK-35973), and mespirenone (ZK-94679).


Synthesis

Chemical syntheses of spironolactone and its analogues and
derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...
s have been described and reviewed.


History

The natriuretic effects of progesterone were demonstrated in 1955, and the development of spironolactone as a
synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to: Science * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic ...
antimineralocorticoid analogue of progesterone shortly followed this. Spironolactone was first synthesized in 1957, was
patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A ...
ed between 1958 and 1961, and was first marketed, as an antimineralocorticoid, in 1959. Gynecomastia was first reported with spironolactone in 1962, and the antiandrogenic activity of the medication was first described in 1969. This shortly followed the discovery in 1967 that gynecomastia is an important and major side effect of AR antagonists. Spironolactone was first studied in the treatment of hirsutism in women in 1978. It has since become the most widely used antiandrogen for dermatological indications in women in the United States. 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. Early oral spironolactone tablets showed poor absorption. 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.


Society and culture


Generic names

The English,
French French (french: français(e), link=no) may refer to: * Something of, from, or related to France ** French language, which originated in France, and its various dialects and accents ** French people, a nation and ethnic group identified with Franc ...
, and generic name of the medication is ''spironolactone'' and this is its , , , , , and . Its name is ''spironolactonum'' in
Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through ...
, ''spironolacton'' in
German German(s) may refer to: * Germany (of or related to) **Germania (historical use) * Germans, citizens of Germany, people of German ancestry, or native speakers of the German language ** For citizens of Germany, see also German nationality law **Ge ...
, ''espironolactona'' in Spanish and Portuguese, and ''spironolattone'' in Italian (which is also its ). Spironolactone is also known by its developmental code names ''SC-9420'' and ''NSC-150339''.


Brand names

Spironolactone is marketed under a large number of brand names throughout the world. The major brand name of spironolactone is Aldactone. Other important brand names include Aldactone-A, Berlactone, CaroSpir, Espironolactona, Espironolactona Genfar, Novo-Spiroton, Prilactone ( veterinary), Spiractin, Spiridon, Spirix, Spiroctan, Spiroderm (discontinued), Spirogamma, Spirohexal, Spirolon, Spirolone, Spiron, Spironolactone Actavis, Spironolactone Orion, Spironolactone Teva, Spirotone, Tempora (veterinary), Uractone, Uractonum, Verospiron, and Vivitar. Spironolactone is also formulated in combination with a variety of other medications, including with hydrochlorothiazide as Aldactazide, with hydroflumethiazide as Aldactide, Lasilacton, Lasilactone, and Spiromide, with altizide as Aldactacine and Aldactazine, with
furosemide Furosemide is a loop diuretic medication used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It may also be used for the treatment of high blood pressure. It can be taken by injection into a vein or by mo ...
as Fruselac, with benazepril as Cardalis (veterinary), with
metolazone Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water rea ...
as Metolactone, with bendroflumethiazide as Sali-Aldopur, and with
torasemide Torasemide, also known as torsemide, is a diuretic medication used to treat fluid overload due to heart failure, kidney disease, and liver disease and high blood pressure. It is a less preferred treatment for high blood pressure. It is taken by ...
as Dytor Plus, Torlactone, and Zator Plus.


Availability

Spironolactone is marketed widely throughout the world and is available in almost every country, including in the
United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., ...
,
Canada Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by to ...
, the
United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the continental mainland. It comprises England, Scotland, Wales and ...
, other
Europe Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...
an countries,
Australia Australia, officially the Commonwealth of Australia, is a sovereign country comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands. With an area of , Australia is the largest country by ...
,
New Zealand New Zealand ( mi, Aotearoa ) is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and over 700 smaller islands. It is the sixth-largest island coun ...
,
South Africa South Africa, officially the Republic of South Africa (RSA), is the southernmost country in Africa. It is bounded to the south by of coastline that stretch along the South Atlantic and Indian Oceans; to the north by the neighbouring coun ...
,
Central Central is an adjective usually referring to being in the center of some place or (mathematical) object. Central may also refer to: Directions and generalised locations * Central Africa, a region in the centre of Africa continent, also known a ...
and
South America South America is a continent entirely in the Western Hemisphere and mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere at the northern tip of the continent. It can also be described as the sou ...
, and East and
Southeast Asia Southeast Asia, also spelled South East Asia and South-East Asia, and also known as Southeastern Asia, South-eastern Asia or SEA, is the geographical south-eastern region of Asia, consisting of the regions that are situated south of mainland ...
.


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. There was a total of 12.0 million prescriptions for spironolactone in the United States in 2016 alone. It was the 66th top prescribed medication in the United States in 2016.


Research


Prostate conditions

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


Epstein–Barr virus

Spironolactone has been found to block
Epstein–Barr virus The Epstein–Barr virus (EBV), formally called ''Human gammaherpesvirus 4'', is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus. It is ...
(EBV) production and that of other human herpesviruses by inhibiting the function of an EBV protein SM, which is essential for infectious virus production. This effect of spironolactone was determined to be independent of its antimineralocorticoid actions. Thus, spironolactone or compounds based on it have the potential to yield novel antiviral medications with a distinct mechanism of action and limited toxicity.


Other conditions

Spironolactone has been studied in the treatment of
rosacea Rosacea is a long-term skin condition that typically affects the face. It results in redness, pimples, swelling, and small and superficial dilated blood vessels. Often, the nose, cheeks, forehead, and chin are most involved. A red, enlarg ...
in both males and females. Spironolactone has been studied in fibromyalgia in women. It has also been studied in
bulimia nervosa Bulimia nervosa, also known as simply bulimia, is an eating disorder characterized by binge eating followed by purging or fasting, and excessive concern with body shape and weight. The aim of this activity is to expel the body of calories eaten ...
in women, but was not found to be effective.


References


External links

* {{Portal bar, Medicine 3β-Hydroxysteroid dehydrogenase inhibitors 5α-Reductase inhibitors 11β-Hydroxylase inhibitors 17β-Hydroxysteroid dehydrogenase inhibitors 21-Hydroxylase inhibitors Acetate esters Aldosterone synthase inhibitors Anti-acne preparations Antimineralocorticoids Cholesterol side-chain cleavage enzyme inhibitors CYP17A1 inhibitors Hair loss medications Hair removal Lactones Pregnane X receptor agonists Pregnanes Prodrugs Progestogens Wikipedia medicine articles ready to translate Selective estrogen receptor modulators Spiro compounds Spirolactones Steroidal antiandrogens Thioesters World Anti-Doping Agency prohibited substances World Health Organization essential medicines