Spironolactone

Medical uses

Spironolactone is used primarily to treat heart failure, edematous conditions such as nephrotic syndrome or ascites in people with liver disease, essential hypertension, hypokalemia, secondary hyperaldosteronism (such as occurs with hepatic cirrhosis), and Conn's syndrome (primary hyperaldosteronism). On its own, spironolactone is only a weak diuretic because it primarily targets the distal nephron (collecting tubule), where only small amounts of sodium are reabsorbed, but it can be combined with other diuretics to increase efficacy.

Spironolactone is an antagonist of the androgen receptor (AR) as well as an inhibitor of androgen production. Due to the antiandrogenic effects that result from these actions, it is frequently used off-label to treat a variety of dermatological conditions in which androgens, such as testosterone and dihydrotestosterone (DHT), play a role. Some of these uses include androgenic alopecia in men (either at low doses or as a topical formulation) and women, and hirsutism (excessive hair growth), acne, and seborrhea in women. Spironolactone is the most commonly used drug in the treatment of hirsutism in the United States. Higher doses of spironolactone are not recommended in males due to the high risk of feminization and other side effects. Similarly, it is also commonly used to treat symptoms of hyperandrogenism in polycystic ovary syndrome.

There is tentative low quality evidence supporting its use in female pattern hair loss.

High blood pressure

About one person in one hundred with hypertension has elevated levels of aldosterone; in these people, the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives since it targets the primary cause of the elevated blood pressure. However, a Cochrane review found adverse effects at high doses and little effect on blood pressure at low doses in the majority of people with high blood pressure. There is no evidence of person-oriented outcome at any dose in this group.

Heart failure

While loop diuretics remain first-line for most people with heart failure, spironolactone has shown to reduce both morbidity and mortality in numerous studies and remains an important agent for treating fluid retention, edema, and symptoms of heart failure. Current recommendations from the American Heart Association are to use spironolactone in patients with NYHA Class II-IV heart failure who have a left ventricular ejection fraction of <35%.

In a randomized evaluation which studied people with severe congestive heart failure, people treated with spironolactone were found to have a relative risk of death of 0.70 or an overall 30% relative risk reduction compared to the placebo group, indicating a significant death and morbidity benefit of the drug. Patients in the study's intervention arm also had fewer symptoms of heart failure and were hospitalized less frequently. Likewise, it has shown benefit for and is recommended in patients who recently suffered a heart attack and have an ejection fraction less than 40%, who develop symptoms consistent with heart failure, or have a history of diabetes mellitus. Spironolactone should be considered a good add-on agent, particularly in those patients "not" yet optimized on ACE inhibitors and beta-blockers. Of note, a recent randomized, double-blinded study of spironolactone in patients with symptomatic heart failure with "preserved" ejection fraction (i.e. >45%) found no reduction in death from cardiovascular events, aborted cardiac arrest, or hospitalizations when spironolactone was compared to placebo.

It is recommended that alternatives to spironolactone be considered if serum creatinine is >2.5 mg/dL (221µmol/L) in males or >2 mg/dL (176.8 µmol/L) in females, if glomerular filtration rate is below 30mL/min or with a serum potassium of >5.0 mEq/L given the potential for adverse events detailed elsewhere in this article. Doses should be adjusted according to the degree of renal function as well.

According to systematic review, in heart failure with preserved ejection fraction, treatment with spironolactone did not improve patient outcomes. This is based on the TOPCAT Trial examining this issue, which found that of those treated with placebo had a 20.4% incidence of negative outcome vs 18.6% incidence of negative outcome with spironolactone. However, because the p-value of the study was 0.14, and the unadjusted hazard ratio was 0.89 with a 95% confidence interval of 0.77 to 1.04, it is determined the finding had no statistical significance. Hence the finding that patient outcomes are not improved with use of spironolactone.

Due to its antiandrogen properties, spironolactone can cause effects associated with low androgen levels and hypogonadism in males. For this reason, men are typically not prescribed spironolactone for any longer than a short period of time, e.g., for an acute exacerbation of heart failure. A newer drug, eplerenone, has been approved by the U.S. Food and Drug Administration for the treatment of heart failure, and lacks the antiandrogen effects of spironolactone. As such, it is far more suitable for men for whom long-term medication is being chosen. However, eplerenone may not be as effective as spironolactone or the related drug canrenone in reducing mortality from heart failure.

The clinical benefits of spironolactone as a diuretic are typically not seen until 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 and potentially deadly abnormal heart rhythms.

Acne in women

Because of spironolactone's antiandrogen effects, it can be quite effective in clearing severe acne conditions, such as cystic acne, caused by slightly elevated or elevated levels of testosterone in women. In reducing the levels of testosterone, excess oil that is naturally produced in the skin is also reduced. Though not the primary intended purpose of the medication, its ability 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. A significant number of patients have reported that they have seen positive results in the pairing of these two medications, although these results may not be seen for up to three months.

Transgender hormone therapy

Spironolactone is frequently used as a component of hormone replacement therapy in transgender women, especially in the United States (where cyproterone acetate is not available), usually in addition to an estrogen. Spironolactone significantly depresses plasma testosterone levels, reducing them to female/castrate levels at sufficient doses and in combination with estrogen. The clinical response consists of, among other effects, decreased male pattern body hair, the induction of breast development, feminization in general, and lack of spontaneous erections.

Comparison with other antiandrogens

There are few available options for antiandrogen therapy. Spironolactone, cyproterone acetate, and flutamide are some of the most well-known and widely used drugs. Compared to cyproterone acetate, spironolactone is considerably less potent as an antiandrogen by weight and binding affinity to the androgen receptor. However, despite this, at the doses of which they are typically used, spironolactone and cyproterone acetate have been found to be generally about equivalent in terms of effectiveness for a variety of androgen-related conditions, though, cyproterone acetate has shown a slight though non-statistically-significant advantage in some studies. Also, it has been suggested that cyproterone acetate could be more effective in cases where androgen levels are more pronounced, though this has not been proven.

Flutamide, another frequently used antiandrogen which is non-steroidal and a pure androgen receptor antagonist, though much less potent by weight and binding affinity than either spironolactone or cyproterone acetate, has been found to be more effective than either of them as an antiandrogen when it is used at the typical treatment doses. Unfortunately, the uses of both cyproterone acetate and flutamide have been associated with hepatotoxicity, which can be severe with flutamide and has resulted in cyproterone acetate never being approved in the United States. Bicalutamide is a more potent, safer, and more tolerable alternative to flutamide, but is relatively little-studied in the treatment of androgen-dependent conditions aside from prostate cancer, though it has been used to treat hirsutism with success. Gonadotropin-releasing hormone (GnRH) analogues are another very effective option for antiandrogen therapy, but have not been widely employed for this purpose due to their high cost and limited insurance coverage despite many now being available as generics. As such, spironolactone may be the only practical, safe, available, and well-supported antiandrogen option in some cases.

In a study of the predictive markers for transgender women requesting breast augmentation, there was a significantly higher rate of those treated with spironolactone requesting breast augmentation compared to other antiandrogens such as cyproterone acetate or GnRH analogues, which was interpreted by the study authors as being potentially indicative that spironolactone may result in poorer breast development in comparison. This may be related to the fact that spironolactone has been regarded as a comparatively weak antiandrogen relative to other options.

Available forms

Spironolactone is usually used in the form of oral tablets. The drug has also been marketed in the form of 2% and 5% topical cream in Italy for the treatment of acne and hirsutism under the brand name Spiroderm, although this product is no longer available. Spironolactone has poor water solubility, and for this reason, only oral and topical formulations have been developed and other routes of administration such as intravenous injection are not employed.

Contraindications

Contraindications of spironolactone include hyperkalemia (high levels of potassium) among others.

Side effects

The most common side effect of spironolactone is urinary frequency. Other general side effects include dehydration, hyponatremia (low sodium levels), mild hypotension (low blood pressure), ataxia (muscle incoordination), drowsiness, dizziness, dry skin, and rashes. Because it reduces androgen levels and blocks androgen receptors, spironolactone can, in men, cause breast tenderness, gynecomastia (breast development), and feminization in general, as well as testicular atrophy, reversibly reduced fertility, and sexual dysfunction including loss of libido and erectile dysfunction. In women, spironolactone can cause menstrual irregularities, breast tenderness, and breast enlargement.

The most important potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening. Hyperkalemia in these patients can present as a non anion-gap metabolic acidosis. Spironolactone may put patients at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis. In addition, there has been some evidence suggesting an association between use of the drug and bleeding from the stomach and duodenum, though a causal relationship between the two has not been established. Also, spironolactone has been shown to be immunosuppressive in the treatment of sarcoidosis.

Hyperkalemia

Spironolactone can cause hyperkalemia, which can, rarely, be fatal. Of those prescribed typical doses, 10% to 15% developed hyperkalemia, and in 6%, it was severe. An increase in the rates of hospitalization (from 0.2% to 11%) and death (from 0.3 per 1,000 to 2.0 per 1,000) due to hyperkalemia from 1994 to 2001 has been attributed to a parallel rise in the number of prescriptions written for spironolactone following the publication of the RALES study. The risk of hyperkalemia with spironolactone treatment is greatest in the elderly, in people with renal impairment, and in people simultaneously taking potassium supplements or ACE inhibitors.

Breast events

In women, spironolactone is commonly associated with breast pain and breast enlargement, "probably because of [indirect] estrogenic effects on target tissue." Breast enlargement may occur in 26% of women and is described as mild, while breast tenderness is reported to occur in up to 40% of women taking high dosages of the drug. Spironolactone also commonly and dose-dependently produces gynecomastia (woman-like breasts) as a side effect in men. At low dosages, the rate is only 5–10%, but at high dosages, up to or exceeding 50% of men may develop gynecomastia. The severity of the gynecomastia varies considerably, but is usually mild. As with women, gynecomastia associated with spironolactone is commonly although inconsistently accompanied by breast tenderness. Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the drug.

Menstrual disturbances

In women, menstrual disturbances are common during spironolactone treatment, with 10 to 50% of women experiencing them at moderate doses and almost all experiencing them at a high doses. Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation. Spironolactone produces an irregular, anovulatory pattern of menstrual cycles. It is also associated with metrorrhagia and menorrhagia (or menometrorrhagia) in a large percentage of women. It has no birth control effect. It is thought that the weak progestogenic activity of spironolactnoe is responsible for these effects, although this has not been adequately evaluated nor firmly established. An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels.

The menstrual disturbances associated with spironolactone can usually be controlled well by concomitant treatment with an oral contraceptive.

Infertility

At high dosages, spironolactone has been associated with semen abnormalities such as decreased sperm count and motility in men.

Depression

Increased glucocorticoid activity in the body is associated with depression. As such, it is thought that there may be a risk of depression with spironolactone treatment. Some clinical research supports this notion.

Rare reactions

Spironolactone may rarely cause more severe side effects such as anaphylaxis, renal failure, hepatitis (two reported cases, neither serious), agranulocytosis, DRESS syndrome, Stevens-Johnson Syndrome or toxic epidermal necrolysis. Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported. It should also be used with caution in people with some neurological disorders, anuria, acute kidney injury, or significant impairment of renal excretory function with risk of hyperkalemia.

Spironolactone bodies

Long-term administration of spironolactone gives the histologic characteristic of spironolactone bodies in the adrenal cortex. Spironolactone bodies are eosinophilic, round, concentrically laminated cytoplasmic inclusions surrounded by clear halos in preparations stained with hematoxylin and eosin.

Pregnancy and breastfeeding

Spironolactone is considered Pregnancy Category C meaning that it is unclear if it is safe for use during pregnancy. Likewise, it has been found to be present in the breast milk of lactating mothers and, while the effects of spironolactone or its metabolites have not been extensively studied in breastfeeding infants, it is generally recommended that women also not take the drug while nursing.

Spironolactone is able to cross the placenta. 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 experienced is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans. Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific birth defects. A case report described a woman who was prescribed spironolactone during pregnancy with triplets and delivered all three (one boy and two girls) healthy; there was no feminization in the boy. In addition, spironolactone has been used at high doses to treat pregnant women with Bartter's syndrome, and none of the infants (three boys, two girls) showed toxicity, including feminization in the male infants. There are similar findings, albeit also limited, for another antiandrogen, cyproterone acetate (prominent genital defects in male rats, but no human abnormalities (including feminization of male fetuses) at both a low dose of 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.

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.

Interactions

Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this drug avoid potassium supplements and salt substitutes containing potassium. Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone as a diuretic, especially during the first twelve months of use and whenever the dosage is increased. Doctors may also recommend that some patients may be advised to limit dietary consumption of potassium-rich foods. However, recent data suggests that both potassium monitoring and dietary restriction of potassium intake is unnecessary in healthy young women taking spironolactone for acne.

Research has suggested that spironolactone may be able to interfere with the effectiveness of antidepressant treatment. As the drug acts as an antagonist of the mineralocorticoid receptor, it is thought that it may reduce the effectiveness of certain antidepressants by interfering with normalization of the hypothalamic-pituitary-adrenal axis and increasing glucocorticoid levels. However, other research contradicts this hypothesis and has suggested that spironolactone may actually produce antidepressant-like effects in animals.

Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications. Spironolactone together with trimethoprim/sulfamethoxazole increases the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron.

Spironolactone induces the enzyme CYP3A4, which can result in interactions with various drugs.

Pharmacology

Spironolactone is known to possess the following pharmacological activity:

There is also evidence that spironolactone may block voltage-dependent Ca²⁺ channels.

It should be noted however that these activities apply to the spironolactone molecule itself, but spironolactone is a prodrug, and for this reason, the actual in vivo clinical profile of spironolactone may differ from the activities and effective and inhibitory concentrations described above and to the right.

Antimineralocorticoid activity

Spironolactone inhibits the effects of mineralocorticoids, namely, aldosterone, by displacing them from mineralocorticoid receptors (MR) in the cortical collecting duct of renal nephrons. This decreases the reabsorption of sodium and water while limiting the excretion of potassium (A K+ sparing diuretic). The drug has a slightly delayed onset of action, and so it takes several days for diuresis to occur. This is because the MR is a nuclear receptor which works through regulating gene transcription and gene expression, in this case, to decrease the production and expression of ENaC and ROMK electrolyte channels in the distal nephrons. In addition to direct antagonism of the MRs, the antimineralocorticoid effects of spironolactone may also in part be mediated by direct inactivation of steroid 11β-hydroxylase and aldosterone synthase (18-hydroxylase), enzymes involved in the biosynthesis of mineralocorticoids. If levels of mineralocorticoids are decreased then there are lower circulating levels to compete with spironolactone to influence gene expression as mentioned above. The onset of action of the anti-mineralocorticoid effects of spironolactone is relatively slow, with the peak effect sometimes occurring 48 hours or more after the first dose.

Antiandrogenic activity

Spironolactone mediates its antiandrogenic effects via multiple actions, including the following:

Progestogenic activity

Spironolactone has weak progestogenic activity. Its actions in this regard are a result of direct agonist activity at the progesterone receptor, but with a half-maximal potency approximately one-tenth that of its inhibition of the androgen receptor. Spironolactone's progestogenic activity may be responsible for some of its side effects, including the menstrual irregularities seen in women and the undesirable serum lipid profile changes that are seen at higher doses. They may also serve to augment the gynecomastia caused by the estrogenic effects of spironolactone, as progesterone is known to be involved in breast development.

Estrogenic activity

Spironolactone does not bind to the estrogen receptor but has some indirect estrogenic effects which it mediates via several actions, including the following:

Inhibition of steroidogenesis

Spironolactone is said to possess very little or no antigonadotropic activity, even at high dosages. (Though conflicting reports exist.) In fact, the drug can actually increase gonadotropin levels by inhibiting androgen negative feedback on the hypothalamic-pituitary-gonadal axis via blockade of the AR. However, spironolactone is effective in lowering testosterone levels at high dosages in spite of not acting as an antigonadotropin, and this is thought to be due to direct enzymatic inhibition of 17α-hydroxylase and 17,20-lyase.

Glucocorticoid activity

Spironolactone has been shown to inhibit steroid 11β-hydroxylase, an enzyme that is essential for the production of the glucocorticoid hormone cortisol. Because of this, glucocorticoid levels might be expected to be lowered, and hence, spironolactone might have some antiglucocorticoidic effects. In clinical practice, however, this has not been found to be the case; spironolactone has actually been found to increase cortisol levels, both with acute and chronic administration. Research has shown that this is due to antagonism of the MR, which suppresses negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis positively regulates the secretion of adrenocorticotropic hormone (ACTH), which in turn signals the adrenal glands, the major source of corticosteroid biosynthesis in the body, to increase production of both mineralocorticoids and glucocorticoids. Therefore, by antagonizing the MR, spironolactone causes an increase in ACTH secretion and by extension an indirect rise in cortisol levels. As such, any anti-glucocorticoid activity of spironolactone via direct suppression of glucocorticoid synthesis (at the level of the adrenals) appears to be more than fully offset by its concurrent indirect stimulatory effects on glucocorticoid production.

At the same time, spironolactone weakly binds to and acts as an antagonist of the GR, showing antiglucocorticoid properties, but to a significant degree only at very high concentrations.

Absorption

The oral bioavailability of spironolactone is 80 to 90%. The bioavailability of the drug improves significantly when it is taken with food. Steady-state concentrations of spironolactone are achieved within 8 days of treatment initiation.

Distribution

Spironolactone and its metabolite canrenone are highly plasma protein bound, with percentages of 88.0% and 99.2%, respectively. Spironolactone is bound equivalently to albumin and α₁-acid glycoprotein, while canrenone is bound only to albumin. The plasma protein binding of the other metabolites of spironolactone, namely 7α-TMS and 6β-OH-7α-TMS, has not been assessed.

Metabolism

Spironolactone is rapidly and extensively metabolized in the liver upon oral administration and has a short terminal half-life of 1.4 hours. The major metabolites of spironolactone are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone, and these metabolites have much longer half-lives in comparison (13.8 hours, 15.0 hours, and 16.5 hours, respectively). These metabolites are responsible for the therapeutic effects of spironolactone. As such, spironolactone is a prodrug. Until recently, the 7α-thiomethylated metabolites of spironolactone had not been identified and it was thought that canrenone was the major active metabolite. However, they have since been characterized, 7α-TMS has been identified as the predominant metabolite of spironolactone, and it has been determined that 7α-TMS accounts for around 80% of the potassium-sparing effect of the drug while canrenone accounts for 10–25%. In accordance, 7α-TMS occurs at higher circulating concentrations than does canrenone and has a higher relative affinity for the MR. Other known metabolites of spironolactone include 7α-thiospironolactone, the 7α-methyl ethyl ester of spironolactone, and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone. Spironolactone is not metabolized by CYP3A4, unlike the related drug eplerenone.

Active metabolites

Canrenone is an antagonist of the MR similarly to spironolactone, but is slightly more potent in comparison. In addition, canrenone inhibits steroidogenic enzymes such as 11β-hydroxylase, cholesterol side-chain cleavage enzyme, 17α-hydroxylase, and 21-hydroxylase similarly to spironolactone, but once again is more potent in doing so in comparison.

In vitro, canrenone binds to and blocks the AR. However, relative to spironolactone, canrenone is described as having very weak affinity to the AR. In accordance, replacement of spironolactone with canrenone in male patients has been found to reverse spironolactone-induced gynecomastia, suggesting that canrenone is comparatively much less potent in vivo as an antiandrogen. As such, based on the above, the antiandrogen effects of spironolactone are considered to be largely due to other metabolites rather than due to canrenone.

Elimination

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

Chemistry

Spironolactone is a steroidal 17α-spirolactone, or more simply a spirolactone, and is structurally related to other clinically used spirolactones such as canrenone, potassium canrenoate, drospirenone, and eplerenone, as well as the never marketed spirolactones SC-5233, prorenone, mexrenone, mespirenone, and spirorenone.

Chemical names

Spironolactone is also known by the following equivalent chemical names:

History

Spironolactone was first synthesized in 1957, was patented between 1958 and 1961, and was first marketed in 1959. The AR antagonistic (i.e., antiandrogen) activity of spironolactone was first discovered and reported in 1969, which shortly followed the discovery in 1968 that gynecomastia, a frequent and by that time well-established side effect of spironolactone, is an important and major side effect of AR antagonists.

Generic name

The English, French, and generic name of spironolactone is spironolactone (pronounced as spy-ROW-no-LAK-tone or as speer-OH-no-LAK-tone according to difference sources) and this is its INN, USAN, BAN, DCF, and JAN. Its name is spironolactonum in Latin, spironolacton in German, espironolactona in Spanish and Portuguese, and spironolattone in Italian (which is also its DCIT).

Spironolactone is also known by its developmental code name SC-9420.

Brand names

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

Spironolactone is also formulated in combination with a variety of other drugs, including with hydrochlorothiazide as Aldactazide, with hydroflumethiazide as Aldactide, Lasilacton, Lasilactone, and Spiromide, with altizide as Aldactacine and Aldactazine, with furosemide as Fruselac, with benazepril as Cardalis (veterinary), with metolazone as Metolactone, with bendroflumethiazide as Sali-Aldopur, and with torasemide as Dytor Plus, Torlactone, and Zator Plus.

Availability

Spironolactone is marketed widely throughout the world and is available in almost every country, including in the United States, Canada, the United Kingdom, other European countries, Australia, New Zealand, South Africa, Central and South America, and East and Southeast Asia.

Epstein–Barr virus

Spironolactone has been found to block Epstein–Barr virus (EBV) production and that of other human herpesviruses by inhibiting the function of an EBV protein SM, which is essential for infectious virus production. This effect of spironolactone was determined to be independent of its antimineralocorticoid actions. Thus, spironolactone or compounds based on it have the potential to yield novel antiviral drugs with a distinct mechanism of action and limited toxicity.