Spironolactone , sold under the trademark Aldactone among others, is a drug primarily used to treat fluid buildup 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, premature puberty in boys, acne and excessive hair growth in women, and as part of feminine hormone therapy in transgender women. Spironolactone is drunk.
Common side effects include electrolyte abnormalities, especially high blood potassium, nausea, vomiting, headaches, rashes, and decreased sex desire. 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 aldosterone and testosterone and has some effects like estrogen. Spironolactone is a class of drugs known as potassium-sparing diuretics.
Spironolactone was discovered in 1957 and introduced in 1959. It is a List of Essential Medicines of the World Health Organization, the most effective and safe medicines needed in the health system. It is available as a generic drug. Wholesale costs in developing countries in 2014 are between US $ 0.02 and US $ 0.12 per day. In the United States the cost is about US $ 0.50 per day.
Video Spironolactone
Medical use
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 potassium levels, secondary hyperaldosteronism (as occurs with liver cirrhosis), and Conn syndrome (primary hyperaldosteronism). On its own, spironolactone is simply a weak diuretic because it primarily targets the distal nephron (collecting tubule), where only a small amount of sodium is reabsorbed, but can be combined with other diuretics to increase effectiveness.
Spironolactone directly blocks the androgen signaling and also acts as an androgen production inhibitor. Because of the antiandrogenic effect resulting from this action, it is often used off-label to treat various 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 topical formulations) 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 dose of Spiriton is not recommended in men because of the high risk of feminization and other side effects. Similarly, it is also commonly used to treat symptoms of hyperandrogenism in polycystic ovary syndrome.
High blood pressure
About 1 in 100 people with hypertension have elevated levels of aldosterone; in these individuals, the antihypertensive effect of spironolactone may exceed a complex combination regimen of other antihypertensives because it targets the underlying cause of elevated blood pressure. However, Cochrane's review found side effects at high doses and few effects on low-dose blood pressure in most people with high blood pressure. There is no evidence of people-oriented results at any dose in this group.
Heart failure
While the diuretic loop remains the first line for most people with heart failure, spironolactone has been shown to reduce both morbidity and mortality in various studies and remains an important agent for treating fluid retention, edema, and symptoms of heart failure. The current recommendation of the American Heart Association is to use spironolactone in patients with NYHA Class II-IV heart failure who have left ventricular ejection fraction & lt; 35%.
In a randomized evaluation studying people with severe congestive heart failure, people treated with spironolactone were found to have a relative risk of death of 0.70 or a 30% overall relative risk reduction compared with the placebo group, indicating significant death benefit and morbidity of the drug. People in the study intervention group also had fewer symptoms of heart failure and were rarely hospitalized. Likewise, it has shown benefits to and is recommended in patients who have recently had a heart attack and had an ejection fraction of less than 40%, who developed symptoms consistent with heart failure, or had a history of diabetes mellitus. Spironolactone should be considered a good additional agent, especially in patients who have not yet been optimized in ACE inhibitors and beta-blockers. Of note, a recent randomized, double-blinded spironolactone study in patients with symptomatic heart failure with "preserved" ejection fraction (ie 45%) found no decreased mortality from cardiovascular events, cardiac arrest, or hospitalization when spironolactone was compared with placebo.
It is recommended that alternatives to spironolactone be considered if serum creatinine is greater than 2.5 mg/dL (221 Ã,Âμmol/L) in men or greater than 2 mg/dL (176.8 μmol/L) in women, if glomerular filtration rate below 30 mL/min or with potassium serum greater than 5.0 mEq/L given the potential side effects detailed elsewhere in this article. The dose should be adjusted according to the level of kidney function as well.
According to a systematic review, in heart failure with a preserved ejection fraction, treatment with spironolactone did not improve patient outcomes. It is based on TOPCAT Trials that examine this problem, which found that those treated with placebo had a 20.4% negative incidence of vs. 18.6% negative incidence of outcome with spironolactone. However, since the p-value of this study was 0.14, and the unadjusted hazard ratio was 0.89 with a 95% confidence interval of 0.77 to 1.04, it was determined that the findings did not have statistical significance. Hence the findings that the patient's results did not improve with the use of spironolactone. Recently, when blood samples from 366 patients in the TOPCAT study were analyzed for the presence of kanrenon (spironolactone active metabolite), 30% of blood samples from Russia did not have detectable canrenone residues. This leads to the conclusion that TOPCAT trial results in Russia do not reflect actual clinical experience with spironolactone in patients with preserved ejection fractions. The TOPCAT study results are now considered to have been canceled. Key research researchers and other leading cardiologists now advise doctors to treat heart failure with preserved ejection fractions to consider prescribing pending spironolactone from two new drug multicenter trials.
Due to its antiandrogenic properties, spironolactone can cause effects associated with low androgen levels and hypogonadism in men. For this reason, men are usually not prescribed spironolactone for longer than a short time, for example, for acute exacerbations of heart failure. The new drug, eplerenone, has been approved by the US Food and Drug Administration for the treatment of heart failure, and has no spironolactone antiandrogen effect. Thus, it is much more suitable for men for whom long-term drugs are being selected. However, eplerenone may not be as effective as spironolactone or related drugs in reducing death from heart failure.
The clinical benefit of spironolactone as a diuretic is usually not visible until 2-3 days after dosing begins. Likewise, the maximum antihypertensive effect may not be visible for 2-3 weeks.
In contrast to some other diuretics, potassium supplementation should be not given when taking spironolactone, as this may lead to elevated levels of potassium serum potassium which causes hyperkalemia and potentially lethal abnormal heart rhythms.
Skin and hair condition
Androgens such as testosterone and DHT play an important role in the pathogenesis of a number of dermatological conditions including acne, seborrhea, hirsutism (hair growth in the body/body overweight in women), and hair loss patterns (androgenic alopecia). In this demonstration, women with complete androgen insensitivity syndrome (CAIS) do not produce sebum or develop acne and have little or no body, pubic, or axillary hair. In addition, men with deficiency 5-defectase type II deficiency 5 Î ± -the conversion into enzymes that greatly potentiate the androgenic effects of testosterone in the skin, have little or no acne, few facial hair, less body hair, and reported no pattern incidents male hair loss. In contrast, hyperandrogenism in women, for example due to polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH), is commonly associated with acne and hirsutism as well as virilization (masculinisation) in general. In accordance with the foregoing, antiandrogens are very effective in the treatment of androgen-dependent skin and hair.
Due to the spironolactone antiandrogen activity, it can be very effective in treating acne in women, and also reduces the oil naturally produced in the skin. Although not the main goal of treatment, spironolactone's ability to help with problematic skin and acne problems is found to be one of the most beneficial side effects and has been quite successful. Often, for women who treat acne, spironolactone is prescribed and paired with birth control pills. Positive results in the installation of both drugs have been observed, although these results may not be visible for up to three months. Spironolactone is commonly used in the treatment of hirsutism in women, and is considered the first-line antiandrogen for this indication. Spironolactone can be used in the treatment of female hair loss patterns (FPHL). There is low temporary quality evidence that supports its use for these indications. Although it appears to be effective, it should be noted that not all cases of FPHL depend on androgens.
Antiandrogens such as spironolactone are male-specific teratogens that can fossil male fetuses because of their antiandrogen effects (see below). For this reason, it is recommended that antiandrogens are only used to treat women of reproductive age in conjunction with adequate contraception. Oral contraceptives, which contain estrogen and progestin, are usually used for this purpose. In addition, oral contraceptives alone are functional and independently effective antiandrogens in androgen-dependent skin and hair treatment, and therefore can significantly improve the effectiveness of antiandrogens in the treatment of the condition.
Spironolactone is not generally used in men for the treatment of dermatologically androgen-dependent conditions due to feminizing side effects, but effective for indications like in the same man. This is evidenced by the usefulness of spironolactone as an antiandrogen in transgender women.
Transgender hormone therapy
Spironolactone is often used as a component of feminine hormone therapy in transgender women, especially in the United States (where cyproterone acetate is not available), usually other than estrogen. Other clinical effects include decreased male hair pattern, induction of breast development, feminization in general, and lack of spontaneous erection.
Dosage and form
Spironolactone is usually used at low doses 25 to 50 mg/day in the treatment of heart failure, while it is used at low doses up to 25 to 200 mg/day in the treatment of essential hypertension, and at high doses of 100 to 400 mg/d for hyperaldosteronism and ascites because of cirrhosis. These drugs are usually used at high doses of 100 to 200 mg/day in skin care and hair condition in women, and at high doses of 100 to 400 mg/day in feminine hormone therapy for transgender women.
Spironolactone is available in tablet form (25 mg, 50 mg, 100 mg) for use by mouth. It has also been marketed in the form of topical 2% and 5% cream in Italy for the treatment of acne and hirsutism under the brand name Spiroderm, but the product is no longer available. 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.
Comparison
There are several options available for antiandrogen therapy. Spironolactone, cyproterone acetate, and flutamide are some of the most popular and widely used drugs. Compared with cyproterone acetate, spironolactone is less potent as a heavy antiandrogen and binding affinity. However, at the dose in which they are commonly used, spironolactone and cyproterone acetate have been found to be approximately equivalent in terms of their effectiveness for various androgenic conditions, although cyproterone acetate has shown little if not statistically significant gains. in some studies. Also, it has been suggested that cyproterone acetate can be more effective in cases where androgen levels are more pronounced, although this has not been proven.
Flutamide, another commonly used non-steroidal antiandrogen and pure androgen blocker, although less severe by weight and binding affinity than spironolactone or cyproterone acetate, has been found to be more effective than one of them as an antiandrogen when used at typical doses of treatment. Unfortunately, the use of both cyproterone acetate and flutamide has been linked to hepatotoxicity, which can be severe with flutamide and has resulted in cyproterone acetate never been approved in the United States. Bicalutamide is a stronger, safer, and more tolerant alternative to flutamide, but is relatively little studied in the treatment of androgen-dependent conditions other than prostate cancer, although it has been used to treat hirsutism successfully. Analogous gonadotropin-releasing hormone (GnRH) is another very effective option for antiandrogen therapy, but it is not yet widely used for this purpose because of its high costs and limited insurance coverage even though it is now widely available as a generic drug. Thus, spironolactone may be the only antiandrogen option that is practical, safe, available, and well supported in some cases.
In a study of predictive markers for transgender women requesting breast augmentation, there was a significantly higher rate of those treated with spironolactone who requested breast enlargement compared with other antiandrogens such as cyproterone acetate or GnRH analogue, interpreted by the study authors as potentially suggesting that Spironolactone can lead to worse breast development compared. This may be related to the fact that spironolactone has been considered relatively relative to antiandrogens relative to other options.
Maps Spironolactone
Contraindications
Contraindications to spironolactone include end-stage renal disease and hyperkalemia (high levels of potassium), among others.
Side effects
The most common side effect of spironolactone is the frequency of urine. Other common side effects include dehydration, hyponatremia (low sodium levels), mild hypotension (low blood pressure), ataxia (muscle connectivity), drowsiness, dizziness, dry skin, and rash. Because it reduces androgen levels and directly blocks androgen signaling, spironolactone can, in men, cause breast pain, gynecomastia (male breast development), and generalized feminization, as well as testicular atrophy, reversible diminished sterility, 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 individuals may present as non-anion-gap metabolic acidosis. Spironolactone can put people at high risk for gastrointestinal problems such as nausea, vomiting, diarrhea, cramps, and gastritis. In addition, there is some evidence to suggest a link between drug use and bleeding from the stomach and duodenum, although 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, or high blood potassium levels. Rarely, this can be fatal. Of the people prescribed the typical dose of spironolactone, 10 to 15% have been found to develop some degree of hyperkalemia, and 6% have been found to develop severe hyperkalemia. At higher doses, a 24% hyperkalemia rate has been observed. A sudden increase in hospitalization rates from 0.2% to 11% and in mortality rates from 0.3 per 1,000 to 2.0 per 1,000 because hyperkalemia between early 1994 and late 2001 has been associated with a parallel increase in the number of prescriptions written for spironolactone after the publication of the Randomized Aldactone Evaluation Study (RALES) in July 1999. The risk of hyperkalemia with spironolactone was highest in the elderly, in people with chronic kidney disease, and in people who also took potassium supplements or ACE .
Although spironolactone poses an important risk of hyperkalemia in the elderly, those with kidney or cardiovascular disease, or those taking a drug or supplement that increases potassium levels in circulation, the level of hyperkalemia in young women without characteristics as has been treated with spironolactone for dermatological conditions. has been found to be no different from the control. This suggests that hyperkalemia is not a significant risk in these patients, and regular monitoring of circulating potassium levels is not required in this population.
Breast Effects
In women, spironolactone is commonly associated with breast tenderness and breast enlargement, "probably due to an indirect estrogenic effect on the target tissue." Breast enlargement can occur in 26% of women and is described as mild, while breast tenderness is reported in up to 40% of women taking high doses of the drug. Spironolactone is also common and dose-dependent producing gynecomastia (breast development) as a side effect in men. At low doses, levels are only 5-10%, but at high doses, up to or exceeding 50% of men can develop gynecomastia. The severity of the gynecomastics varies greatly, but is usually mild. Like women, gynecomastia associated with spironolactone usually occurs inconsistently with breast tenderness. Spironolactone-induced gynecomastia usually regress after several weeks after discontinuation of the drug.
Menstrual disorders
In women, menstrual disorders are common during the treatment of spironolactone, with 10 to 50% of women experience it in moderate doses and almost all at high doses. Most women who take moderate doses of spironolactone have amenorrhea, and normal menstruation usually returns within two months of discontinuation. Spironolactone produces irregular anovulation menstrual cycle patterns. It is also associated with metrorrhagia and menorrhagia (or menometrorrhagia) in a large percentage of women. It has no birth control effect. It has been argued that progestogenic activity of spironolactone is weakly responsible for this effect, although this has not been established and spironolactone has been shown to have an insignificant progestogenic and antiprogestogenic activity even at high doses in women. Another proposed cause is the inhibition of 17-hydroxylase and hence the metabolism of sex steroids by spironolactone and consequent changes in sex hormone levels.
Menstrual disorders associated with spironolactone can usually be well controlled by treatment along with oral contraceptives.
Infertility
At high doses, spironolactone has been associated with sperm abnormalities such as decreased sperm count and motility in men.
Depression
Increased glucocorticoid activity in the body is associated with depression. Thus, it is estimated that there may be a risk of depression with the treatment of spironolactone. A small number of clinical studies support this notion.
Rare reaction
Spironolactone rarely can cause more severe side effects such as anaphylaxis, renal failure, hepatitis (two reported cases, not serious), agranulocytosis, DRESS syndrome, Stevens-Johnson syndrome or toxic epidermal necrolysis. Five cases of breast cancer in patients who used spironolactone for a long time have been reported. It should also be used with caution in people with some neurological disorders, no urine production, acute kidney injury, or significant excretory renal dysfunction with a risk of hyperkalemia.
Spironolactone bodies
Long-term spironolactone gives the histologic characteristics of spironolactone bodies in the adrenal cortex. Spironolactone bodies are eosinophilic, spherical, concentric cytoplasmic enclosures coated surrounded by a clear circle of light in preparation stained with hematoxylin and eosin.
Pregnancy and breastfeeding
Spironolactone is considered the Category of Pregnancy C which means it is unclear whether it is safe to use during pregnancy. He is able to cross the placenta. Likewise, it has been found to be present in breastfeeding breastmilk and, while the effects of spironolactone or its metabolites have not been studied extensively in breastfed infants, it is generally recommended that women also not take medication while breastfeeding. However, only a few spironolactone and canrenone metabolites enter breast milk, and the amount received by infants during breastfeeding (0.5% of the mother's dose) is considered insignificant.
One study found that spironolactone was not associated with teratogenicity in mouse offspring. Because it is antiandrogen, however, spironolactone theoretically has the potential to cause feminization of the male fetus at sufficient doses. Accordingly, subsequent research found that partial feminization of the genitalia occurred in boys from rats who received a dose of spironolactone five times higher than that typically used in humans (200 mg/kg per day). Another study found abnormalities of the reproductive tract associated with the dose of both sex rats at low doses (50 to 100 mg/kg per day).
But in practice, despite limited experience, spironolactone has never been reported to cause observed feminization or other congenital defects in humans. Among 31 newborns exposed to spironolactone in the first trimester, there are no signs of birth defects. A case report describes a woman who was prescribed spironolactone during pregnancy with triplets and gave birth to a third (one male and two female) healthy; there is no feminization in the boy. In addition, spironolactone has been used at high doses to treat pregnant women with Bartter syndrome, and no infants (three boys, two girls) showed toxicity, including feminization in boys. There are similar, though limited, findings for other antiandrogens, cyproterone acetate (a prominent genital defect in male rats, but no human abnormalities (including feminization of the male fetus) at low doses of 2 mg/day or high doses of 50 to 100 mg/day). However, spironolactone is still not recommended during pregnancy because of the theoretical problems associated with male feminization as well as potential changes in fetal potassium levels.
Interactions
Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people taking this drug avoid potassium supplements and substitutes for potassium-containing salts. Doctors should be careful to monitor potassium levels in men and women taking spironolactone as a diuretic, especially during the first twelve months of use and whenever the dose is increased. Doctors may also recommend that some patients may be advised to limit consumption of potassium-rich foods. However, recent data suggest that both potassium monitoring and dietary restriction of potassium intake are not needed in healthy young women taking spironolactone for acne.
Studies have shown that spironolactone may interfere with the effectiveness of antidepressant treatment. As the drug acts as an antimineralocorticoid, it is thought that it can reduce the effectiveness of certain antidepressants by disrupting the normalization of the hypothalamus-pituitary-adrenal axis and increasing glucocorticoid levels. However, other studies contradict this hypothesis and suggest that spironolactone can actually produce antidepressant effects in animals.
Spironolactone can also have many other interactions, most commonly with heart medications and other blood pressure. Spironolactone along with trimethoprim/sulfamethoxazole increases the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent excretion of potassium in the distal tubule of the nephron.
Spironolactone has been reported to induce the CYP3A4 enzyme, which can produce interactions with various drugs. However, it has also been reported that spironolactone metabolites irreversibly inhibit CYP3A4.
Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found in studies to inhibit the antimineralocorticoid effect of spironolactone. In addition, the addition of licorice to spironolactone has been found to reduce the antimineralocorticoid side effects of spironolactone in women treated with drugs for hyperandrogenism, and licorice can therefore be used to reduce the side effects in women treated with spironolactone as an impaired antiandrogen. by them. At the other end of the spectrum, spironolactone is clinically useful in reversing licorice-induced hypokalemia.
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to weaken diuresis and natriuresis caused by spironolactone therapy but do not affect the antihypertensive effect.
Pharmacology
Pharmacodynamics
Spironolactone is known to have the following biological activity:
- Mineralocorticoid receptor antagonist (MR)
- Androgen receptor (AR) antagonist/partial agonist is very weak
- Estrogen receptor (ER) mixture of agonist/antagonist
- Agonist progesterone (PR) agonist
- Glucocorticoid receptor antagonist (GR)
- The pregnant X receptor (PXR) agonist (and thus CYP3A4 and P-glycoprotein inducer)
- Steroid 11? -hydroxylase, aldosterone synthase, and 17? -hydroxylase/17,20-lyase inhibitor
There is also evidence that spironolactone can block channels that depend on the Ca 2 voltage.
Although spironolactone is known to have the above activity, it should be noted that the drug is prodrug, with active metabolites such as 7? -thiomethylspironolactone (7-TMS) and canrenone are responsible for their clinical effects. For this reason, the actual clinical profile of spironolactone may differ from the activity and the effective concentration and inhibition described above and on the right. However, interactions with MR and AR have been observed for spironolactone metabolites. On the other hand, spironolacton alone has only a very low affinity for ER, indicating that its metabolites may be responsible for this activity.
antimineralocorticoid activity
Spironolactone inhibits the effects of mineralocorticoids, ie aldosterone, by removing them from MR in the cortical collecting tract of renal nephrons. This reduces reabsorption of sodium and water while limiting potassium excretion (A K sparingly diuretics). The drug has a slightly delayed onset of action, so it takes several days for diuresis. This is because MR is a nuclear receptor that works through gene transcription settings and gene expression, in this case, to reduce the production and expression of the ENAC and ROMK electrolyte channels in the distal nephron. In addition to the direct antagonism of MRs, the antimineralocorticoid effect of spironolactone may also be partially mediated by direct inactivation of 11-hydroxylase steroids and aldosterone synthase (18-hydroxylase), enzymes involved in mineralocorticoid biosynthesis. If the mineralocorticoid content decreases then there is a lower circulation rate to compete with spironolactone to affect gene expression as mentioned above. The onset of action of antimineralocorticoid spironolactone effects is relatively slow, with peak effects occurring occasionally 48 hours or more after the first dose.
Canrenone is an MR antagonist similar to spironolactone, but slightly more powerful than. Has it been determined that 7? -TMS accounts for about 80% of potassium-spironolactone effects while a canrenone account for estimated residuals of 10 to 25%. Corresponding, 7? -TMS occurs at higher circulating concentrations than does canrenone in addition to having a higher relative affinity for MR.
Antiandrogenic Activities
Spironolactone is a potent and direct antagonist of AR, blocking androgens such as testosterone from binding and activating receptors. The antagonism of spironolactone AR largely underlies the antiandrogen activity and is responsible for therapeutic benefits in the treatment of androgen-dependent conditions such as acne, hirsutism, and hair loss patterns and their usefulness in hormone therapy for transgender women. In addition, AR antagonism of spironolactone is involved in feminine side effects such as gynecomastia in men.
Spironolactone, like other steroidal antiandrogens such as cyproterone acetate, is not pure, or silent, antagonist AR, but rather a weak partial agonist with capacity for antagonistic and agonistic effects. However, given the high level of agonist that is high enough such as testosterone and DHT (cases where spironolactone is usually used even with relative "low" levels in women), spironolactone behaves more like a pure antagonist.. Nevertheless, there may still be potential for spironolactone to produce androgenic effects in the body at fairly high doses and/or in those with very low endogenous androgen concentrations. For example, a condition in which spironolactone is contraindicated is prostate cancer in men treated with androgen deprivation therapy, since spironolactone has shown in vitro to significantly accelerate carcinoma growth in the absence of other androgens. Accordingly, two case reports have illustrated the worsening of prostate cancer with the treatment of spironolactone in patients with disease, leading the authors to conclude that spironolactone has the potential for androgenic effects in some contexts and may have to be considered as selective androgens. receptor modulator (SARM), although with most antagonistic effects.
In vitro , canrenone binds and blocks AR. However, relative to spironolactone, canrenone is described as having a very weak affinity for AR. Accordingly, replacement of spironolactone with canrenone in male patients has been found to reverse spironolactone-induced gynecomastia, suggesting that canrenone is relatively less potent in vivo as antiandrogen. Thus, based on the above, the antiandrogen effect of spironolactone is thought to be largely due to other metabolites rather than to canrenone. Corresponding, 7? -TS and 7? -TMS has been found to have an equivalent affinity for AR prostate mice relative to spironolactone, thus possibly accounting for retention of the antiandrogenic activity of spironolactone.
Estrogenic activity
Spironolactone has been found to interact directly with ER. One study found that spironolactone did not interact with human ER in the specific concentration ranges tested. However, subsequent research found that the drug interacted with human ER at higher concentrations, albeit with a very low affinity (K i = 20Ã,ÂμM). In the same study, spironolactone was given to mice and was found to produce estrogen-estrogen and antiestrogenic effects or selective estrogen receptor modulators (SERMs) described as very similar to tamoxifen. Despite the fact that tamoxifen has two orders of magnitude higher affinity for ER than spironolactone, the two drugs show the same potential in vivo . The likelihood of spironolactone interacting with ER itself is distant due to its very low affinity for in vitro receptors . However, spironolactone metabolism can produce metabolites with greater ER affinity, which may explain the activity.
The authors of the study concluded that the direct interactions of spironolactone (and/or its metabolites) with ER may be involved in gynecomastia, feminization, and effects on drug-associated gonadotropin levels. Furthermore, it has also been suggested that, as a SERM-like drug, ER agonistic activity of spironolactone in the pituitary gland can be responsible for its antigonadotropic effect while ER antagonist spironolactone activity in the endometrium can be responsible for the menstrual disorders associated with it. Such an action might explain the effect of this spironolactone considering the finding that it is not progestogenic or antiprogestogenic in women even at high doses.
Accordingly, one study found that in women treated with GnRH analogues, spironolacton therapy almost completely prevented bone loss associated with these drugs, whereas treatment with selective flutamide AR antagonists did not have such effects. Other studies have also found an inverse relationship between spironolactone and decreased bone mineral density and fractures in men. Estrogens are notorious for maintaining and have a positive effect on bone, and it has been suggested that estrogenic activity of spironolactone may be involved in its positive effect on bone mineral density. However, it should also be noted that high levels of aldosterone have been associated with adverse bone changes, and therefore antimineralocorticoid spironolactone activity may be partially or completely responsible for this effect as a potential alternative explanation.
In addition to direct interaction with ER, spironolactone also has some indirect estrogenic activity, mediating through several actions, including:
- By acting as an antiandrogen, because androgens can suppress estrogen production and signal (eg, in the breast).
- In estradiol conversion inhibition becomes estrone, resulting in an increase in the circulation ratio of estradiol to estrone. Estradiol is much stronger than estrone as estrogen, which is relatively inactive. Increased peripheral conversion rate of testosterone to estradiol, thereby lowering the circulation ratio of testosterone to estradiol.
Spironolactone has been found to act as a reversible inhibitor of human 17-hydroxisteroid dehydrogenase 2 (17? -HSD2), albeit with a weak potential (K i = 0.25-2.4 Ã,? M; IC 50 = 0.27-1,1Ã,? M). C7? thioalkyl derivatives of spironolactone such as 7? analog-thiethyl is found to inhibit enzymes with greater potential, suggesting that actual active metabolites of spironolactone such as 7? -TMS may be more potential inhibitor. 17? -HSD2 is the key enzyme responsible for inactivation of estradiol to estrone in various tissues, and inhibition of 17? -HSD2 by spironolactone may be involved in gynecomastia and alter the ratio of testosterone in circulation to drug-related estradiol. Spironolactone has also been associated with positive effects on bone, and it should be noted that 17? -HSD2 inhibitors are being investigated as potential new treatments for osteoporosis because of their ability to prevent inactivation of estradiol in this tissue.
Progestogenic activity
Spironolactone has a weak progestogenic activity in bioassays. His action in this case is the result of direct agonist activity in PR, albeit with very low maximal potential. Progestogenic activity of spironolactone has been suggested to be involved in some of its side effects, including menstrual irregularities seen in women and unwanted lipid profile changes seen at higher doses. It has also been suggested to increase gynecomastia caused by the estrogenic effect of spironolactone, as progesterone is known to be involved in the development of the mammary glands.
Although it has been widely suggested that menstrual irregularities associated with spironolactone are due to their progestogenic activity, and although animal studies (involving both rhesus rabbits and monkeys) have demonstrated a clear progestogenic effect, the dose of spironolactone used in animals to produce a progestogenic effect is highly high, and no evidence of progestogenic or antiprogestogenic effects (as judged by endometrial changes) has been observed in women even with high clinical doses of spironolactone treatment. Thus, it has been stated that the progestogenic potential of spironolactone is below the level of clinical significance in humans and that medication-related abnormalities should have different causes. Other possible mechanisms of menstrual disorders associated with suggested spironolactone include disorders with the hypothalamus-pituitary-gonad axis, inhibition of enzymatic steroidogenesis, and mixed estrogenic and antestrogenic activity.
Antigonadotropic Effects
Pure AR antagonists such as flutamide and bicalutamide are potent progonadotropins with indirect estrogenic activity in men. This is because they block AR in the pituitary and hypothalamus glands and thus inhibit negative androgen feedback in the hypothalamus-pituitary-gonadal axis. This, in turn, results in increased secretion of gonadotropins, activation of gonadal steroidogenesis, and a 2-fold increase in testosterone levels and a 2.5-fold increase in estradiol levels. In contrast, progestogen AR antagonists, such as cyproterone acetate, are not progonadotropic, because PR activation is antigonadotropic, and, indeed, cyproterone acetate is potentially antigonadotropic in clinical practice.
Although spironolactone is a potent AR antagonist without a significant progestogenic effect in women even at high doses and is therefore a pure AR antagonist, many interesting studies do not find progonadotropic in men, or to increase testosterone or estradiol levels. In addition, spironolactone is also said to have very little or no antigonadotropic activity (in terms of lowering normal gonadotropin levels) even at high doses, although multiple conflicting reports exist. However, since spironolactone generally does not increase the level of gonadotropin regardless of the inhibition of the potential of androgen signaling, it must have some level of antigonadotropic activity sufficient to at least keep the gonadotropin level elevated. Since estrogens are antigonadotropic in progestogens, and as SERM-like activity has been described for spironolactone, the antigonadotropic effect of spironolactone may be due to estrogenic activity.
Steroidogenesis inhibition
Spironolactone is capable of significantly lowering testosterone levels at high doses despite not acting as antigonadotropin, and this is thought to be due to the inhibition of 17-hydroxylase and 17,20-lyase direct enzymes, the enzymes necessary for testosterone biosynthesis.. Although spironolactone is said to be a relatively weak inhibitor of 17-hydroxylase and 17,20-lyase, at least compared with stronger steroidogenesis inhibitors such as ketoconazole and abiraterone acetate (which can reduce testosterone concentrations to castrate levels), this action is considered to contribute most antiandrogenic effects of spironolactone, such as lowering testosterone levels in women with hyperandrogenism and in transgender women. Canrenone inhibits steroidogenic enzymes such as 17? -hydroxylase, 17,20-lyase, 11-hydroxylase, cholesterol side cleavage enzyme, and 21-hydroxylase equal to spironolactone, but more potent in comparison.
There is also conflicting evidence that spironolactone can inhibit 5-ductuctase, and thus the synthesis of potent DHT androgen from testosterone, to some extent. However, a potent combination of spironolactone and 5 -reductase inhibitor finasteride has been found to have a significant increase in efficacy in relative hirsutism treatment against spironolactone alone, indicating that any inhibition of 5? -reductase by spironolactone is only weak or incomplete at best. Spironolactone has been found to have no activity as an aromatase inhibitor.
Glucocorticoid effect
Spironolactone has been shown to inhibit 11-hydroxylase steroids, an enzyme important for the production of glucocorticoid cortisol hormone. Therefore, glucocorticoid levels may be expected to be lowered, and therefore, spironolactone may have some anticocorticoid effects. However, in clinical practice, 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 MR antagonism, which suppresses negative feedback on the hypothalamus-pituitary-adrenal (HPA) axis. The HPA axis positively regulates the secretion of the adrenocorticotropic hormone (ACTH), which in turn signifies the adrenal glands, the main source of corticosteroid biosynthesis in the body, to increase the production of mineralocorticoids and glucocorticoids. Therefore, by antagonizing MR, spironolactone causes increased ACTH secretion and with an expansion of indirect increases in cortisol levels. Thus, any antiglucocorticoid activity of spironolactone through direct suppression of glucocorticoid synthesis (at the adrenal level) appears to be more than fully offset by the indirect, simultaneous effects of glucocorticoid production.
At the same time, spironolactone is weakly binding and acting as a GR antagonist, indicating antigultocorticoid properties, but at a significant level only at very high concentrations that may not be clinically relevant.
Pharmacokinetics
Ingestion
Spironolactone bioavailability when taken is 60 to 90%. Drug bioavailability increases significantly when taken with food. The relationship between a single dose of spironolactone and plasma levels of canrenone, the main active metabolite of spironolactone, has been found to be linear in the dose range of 25 to 200 mg of spironolactone. A stable concentration of spironolactone is achieved within 8 days of starting treatment.
Little or no systemic absorption has been observed with topical spironolactone.
Distribution
Spironolactone and canrenone metabolites are bound to high plasma proteins, with a percentage of 88.0% and 99.2%, respectively. Spironolactone is tied to albumin and? 1 -acid glycoprotein, while canrenone is bound only to albumin. Spironolactone and its metabolites 7? -thiospironolactone shows a very low or negligible affinity for sex hormone-binding globulin (SHBG). Accordingly, research on the treatment of high-dose spironolactone found no change in the steroid-binding capacity associated with SHBG or to corticosteroid-binding globulin (CBG), suggesting that spironolactone does not replace steroid hormones from their carrier proteins. This is contrary to the widespread claim that spironolactone increases free estradiol levels by removing estradiol from SHBG.
Metabolism
Spironolactone is rapidly and extensively metabolized in the liver by oral administration and has a very short half-life of 1,4 hours. Unlike eplerenone-related drugs, spironolactone is not metabolized by CYP3A4. The main metabolite of spironolactone is 7? -thiomethylspironolactone (7? -TMS), 6? -hydroxy-7? -thiomethylspironolactone (6? -OH-7? -TMS), and canrenone (7? -destioacetyl -? 6 -spironolactone). This metabolite has a elimination half-life longer than the spironolactone of 13.8 hours, 15.0 hours, and 16.5 hours, respectively, and is responsible for the therapeutic effect of the drug. Thus, spironolactone is a prodrug. The 7? metabolic metabolically spironolactone unknown for years and initially thought that canrenone is the main active metabolite of the drug, but further research identified 7? -TMS as the main metabolite. Other known but more minor spironolacton metabolites include 7? -thosospironolactone (7? -TS) and 7? -methyl ethyl ester of spironolactone and 6? -hydroxy-7? -methyl ethyl ester of spironolactone.
Elimination
The majority of spironolactone is removed by the kidney, while the minimal amount is treated by biliary excretion.
Chemistry
Spironolactone, also known as 7? -acetylthiospirolactone , is a steroid 17? -spirolactone, or more simply spirolactone. This can be most aptly conceptualized as a progesterone derivative, itself also a potent antimineralocorticoid, in which the hydroxyl group has been replaced in C17? position (as in 17? -hydroxyprogesterone), acetyl group in C17? position has been cyclized with C17? the hydroxyl group to form the spiro-lactone 21-carboxylic ring, and the acetylthio group has been replaced in C7? position. Structural modification of progesterone provides increased bioavailability and oral potency, strong antiandrogenic activity, and greatly reduces progestogenic activity. C7? substitution is likely to be responsible for or involved in the antiandrogenic activity of spironolactone, such as 7? -thioprogesterone (SC-8365), unlike progesterone, is a potent antiandrogen with an AR-like affinity similar to that in spironolactone. Besides, C7? substitution appears to be responsible for loss of progestogenic activity and oral bioavailability of either spironolactone, as SC-5233, an analogue of spironolactone without C7? substitution, has a strong progestogenic activity but very poor oral bioavailability equals progesterone.
Name
Spironolactone juga dikenal dengan nama kimia setara berikut:
- 7? -Acetylthio-17? -hydroxy-3-oxopregn-4-ene-21-carboxylic acid? -lakton
- 7? -Acetylthio-3-oxo-17? -pregn-4-ene-21,17? -carbolactone
- 3- (3-Oxo-7? -acetylthio-17? -hydroxyandrost-4-en-17? -yl) asam propionat lakton
- 7? -Acetylthio-17? - (2-carboxyethyl) androst-4-en-17? -ol-3-one? -lakton
- 7? -Acetylthio-17? - (2-carboxyethyl) testosteron? -lakton
Analoginya
Spironolactone is closely related structurally to other spirolactones clinically used such as canrenone, potassium canrenoate, drospirenone, and eplerenone, and SC-5233 never marketed spirolactones (6,7-dihydrocanrenone; 7 -desthioacetylspironolactone), SC-8109 (19-or-6 , 7-dihydrocanrenone), spiroxasone, prorenone (SC-23,133), mexrenone (SC-25,152, ZK-32055), dicirenone (SC-26,304), spirorenone (ZK-35.973), and mespirenone (ZK -94.679).
Synthesis
Chemical synthesis of spironolactone and its analogues and derivatives has been described and reviewed.
History
The progesterone natriuretic effect was demonstrated in 1955, and the development of spironolactone as a progesterone synthetic antimineralocorticoid analogue soon followed this. Spironolactone was first synthesized in 1957, patented between 1958 and 1961, and first marketed, as antimineralocorticoid, in 1959. The ant arthritis (ie antiandrogen) activity of spironolactone was first discovered and reported in 1969, which immediately followed this discovery. in 1968 that gynecomastia, often and at that time the side-effect of steady-state spironolactone, was an important and major adverse effect of AR antagonists. Drugs began to be used as antiandrogens, for example in the treatment of hirsutism in women, in the late 1970s and early 1980s, and have since become the most widely used antiandrogens for dermatological indications in the United States.
Society and culture
Common names
The name of the drug in English, French, and general is spironolactone and this is INN , USAN , USP , BAN , DCF , and JAN . Its name is spironolactonum in Latin, spironolacton in German, espironolactona in Spanish and Portuguese, and spironolattone in Italian (which is also DCIT ).
Spironolactone is also known under the development code name SC-9420 and NSC-150339 .
Brand name
Spironolactone is marketed under a large number of brand names worldwide. The main brand name of spironolactone is Aldactone. Other important brand names include Aldactone-A, Berlactone, Espironolactona, Espironolactona Genfar, Novo-Spiroton, Prilactone (animal), Spiractin, Spiridon, Spirix, Spiroctan, Spiroderm (discontinued), Spirogamma, Spirohexal, Spirolon, Spirolone, Spiron, Spironolactone Actavis , Spironolactone Orion, Spironolactone Teva, Spirotone, Tempora (animal), Uretone, Uractonum, Verospiron, and Vivitar.
Spironolactone is also formulated in combination with various 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 (animal), with metolazone as Metolactone, with bendroflumethiazide as Sali-Aldopur, and with torasemide as Dytor Plus, Torlactone, and Zator Plus.
Availability
Spironolactone is widely marketed worldwide and available in almost every country, including in the United States, Canada, Britain, other European countries, Australia, New Zealand, South Africa, Central and South America, and East and Southeast Asia.
Research
Benign prostatic hyperplasia
Spironolactone has been studied at high doses in the treatment of benign prostatic hyperplasia. It was found to be better than placebo in terms of relieving symptoms after three months of treatment. However, this was not maintained after six months of treatment, where improvement has largely disappeared. In addition, no differences were observed between spironolactone and placebo with respect to residual volume of urine or prostate size. Gynecomastia is observed in about 5% of people. On the basis of this result, it has been said that spironolactone has no place in the treatment of benign prostatic hyperplasia.
Epstein.E2.80.93Barr_virus "> Epstein-Barr virus
Spironolactone has been found to block production of Epstein-Barr virus (EBV) and other human herpes viruses by inhibiting the function of EBV BC protein, which is essential for the production of infectious viruses. This spironolactone effect is determined not to depend on its antimineralocorticoid action. Thus, the spironolactone or compound based on it has the potential to produce new antiviral drugs with different mechanisms of action and limited toxicity.
Other conditions
Spironolactone has been studied in fibromyalgia in women. It has also been studied in bulimia nervosa in women, but not found to be effective.
References
External links
- Spironolactone - MedlinePlus - National US Medical Library
- Aldactone (spironolactone) patient information leaflet - PDR
Source of the article : Wikipedia
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