Spironolactone, sold under the brand name Aldactone among others, is a diuretic medication 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, and low blood potassium that does not improve with supplementation, early puberty in boys, acne and excessive hair growth in women. It can also be used to block the effects of testosterone in transgender women and nonbinary people undergoing feminizing hormone replacement therapy. Spironolactone usually available in tablets, taken by mouth, though topical forms are also available.
Potassium-sparing diuretics or antikaliuretics refer 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 aldosterone antagonists can also be used for treatment of primary hyperaldosteronism. Spironolactone, a steroidal aldosterone antagonist, is also used in management of female hirsutism and acne from PCOS or other causes.
A mineralocorticoid receptor antagonist or aldosterone antagonist, is a diuretic drug which antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is often used as adjunctive therapy, in combination with other drugs, for the management of chronic heart failure. Spironolactone, the first member of the class, is also used in the management of hyperaldosteronism and female hirsutism. Most antimineralocorticoids, including spironolactone, are steroidal spirolactones. Finerenone is a nonsteroidal antimineralocorticoid.
Eplerenone, sold under the brand name Inspra, is an aldosterone antagonist type of potassium-sparing diuretic that is used to treat chronic heart failure and high blood pressure, particularly for people with resistant hypertension due to elevated aldosterone. It is a steroidal antimineralocorticoid of the spirolactone group and a selective aldosterone receptor antagonist (SARA).
The mineralocorticoid receptor, also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the NR3C2 gene that is located on chromosome 4q31.1-31.2.
Potassium canrenoate or canrenoate potassium (USAN), also known as aldadiene kalium, the potassium salt of canrenoic acid, is an aldosterone antagonist of the spirolactone group. Like spironolactone, it is a prodrug, and is metabolized to active canrenone in the body.
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. It is also an important active metabolite of spironolactone, and partially accounts for its therapeutic effects.
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-spirolactosteroids, or simply 17α-spirolactones, which feature their spirolactone group at the C17α position. They are antimineralocorticoids, or antagonists of the mineralocorticoid receptor, and have been employed clinically as potassium-sparing diuretics. Some also possess progestogenic and/or antiandrogen properties, which have both contributed to side effects and been utilized for medical indications. The spirolactones were developed by G. D. Searle & Company in the 1950s and thereafter and were denoted as "SC" compounds.
Mexrenone is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone that was never marketed. It is the lactonic form of mexrenoic acid (mexrenoate), and mexrenoate potassium (SC-26714), the potassium salt of mexrenoic acid, also exists. In addition to the mineralocorticoid receptor, mexrenone also binds to the glucocorticoid, androgen, and progesterone receptors. Relative to spironolactone, it has markedly reduced antiandrogen activity. Eplerenone is the 9-11α-epoxy analogue of mexrenone.
SC-5233, also known as 6,7-dihydrocanrenone or 20-spirox-4-ene-3,20-dione, is a synthetic, steroidal antimineralocorticoid of the spirolactone group which was developed by G. D. Searle & Company in the 1950s but was never marketed. It was the first synthetic antagonist of the mineralocorticoid receptor to have been identified and tested in humans. The drug was found to lack appreciable oral bioavailability and to be of low potency when administered parenterally, but it nonetheless produced a mild diuretic effect in patients with congestive heart failure. SC-8109, the 19-nor (19-demethyl) analogue, was developed and found to have improved oral bioavailability and potency, but still had low potency. Spironolactone followed and had both good oral bioavailability and potency, and was the first synthetic antimineralocorticoid to be marketed. It has about 46-fold higher oral potency than SC-5233.
Mespirenone (INN), also known as Δ1-15β,16β-methylenespironolactone, is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone that was never marketed. Animal research found that it was 3.3-fold more potent as an antimineralocorticoid relative to spironolactone. In addition to its antimineralocorticoid properties, mespirenone is also a progestogen, antigonadotropin, and antiandrogen. It is 2- to 3-fold as potent as spironolactone as a progestogen and antigonadotropin but its antiandrogenic activity is markedly reduced and weak in comparison. Mespirenone is also a potent and specific enzyme inhibitor of 18-hydroxylase and thus of mineralocorticoid biosynthesis. The drug was under development by Schering and reached phase II clinical trials but was discontinued in 1989.
Spirorenone (INN) 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. The initial discovery of spirorenone was deemed a great success, as no compound with greater antimineralocorticoid activity had been developed since spironolactone in 1957. Moreover, spirorenone itself has virtually no affinity for the androgen receptor while its progestogenic activity shows species differences, being somewhat greater than that of spironolactone in rabbits but absent in mice and rats. As such, it was characterized as a highly potent antimineralocorticoid with far fewer hormonal side effects relative to spironolactone.
SC-8109 is a steroidal antimineralocorticoid of the spirolactone group which was never marketed. It is a potent antagonist of the mineralocorticoid receptor and is more potent than the related drug SC-5233. However, SC-8109 was found to have relatively low oral bioavailability and potency, though it nonetheless produced a mild diuretic effect in patients with congestive heart failure. Spironolactone, another spirolactone, followed and had both good oral bioavailability and potency, and was the first antimineralocorticoid to be marketed.
Dicirenone is a synthetic, steroidal antimineralocorticoid of the spirolactone group which was developed as a diuretic and antihypertensive agent but was never marketed. It was synthesized and assayed in 1974. Similarly to other spirolactones like spironolactone, dicirenone also possesses antiandrogen activity, albeit with relatively reduced affinity.
←
6β-Hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS) is a steroidal antimineralocorticoid of the spirolactone group and a major active metabolite of spironolactone. Other important metabolites of spironolactone include 7α-thiospironolactone, 7α-thiomethylspironolactone, and canrenone (SC-9376).
7α-Thiospironolactone is a steroidal antimineralocorticoid and antiandrogen of the spirolactone group and a minor active metabolite of spironolactone. Other important metabolites of spironolactone include 7α-thiomethylspironolactone, 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (SC-9376).
7α-Thioprogesterone is a synthetic, steroidal, and potent antimineralocorticoid (putative) and antiandrogen which was developed by G. D. Searle & Co and was described in the late 1970s and early 1980s but was never developed or introduced for medical use. It is a derivative of progesterone (pregn-4-ene-3,20-dione) with a thio (sulfur) substitution at the C7α position, and is related to the spirolactone group of drugs but lacks a γ-lactone ring.
Prorenoic acid, or prorenoate, is a synthetic steroidal antimineralocorticoid which was never marketed.
The pharmacodynamics of spironolactone, an antimineralocorticoid and antiandrogen medication, concern its mechanisms of action, including its biological targets and activities, as well as its physiological effects. The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition. In addition, spironolactone has sometimes been found to increase estradiol and cortisol levels and hence could have slight indirect estrogenic and glucocorticoid effects. The medication has also been found to interact very weakly with the estrogen and progesterone receptors, and to act as an agonist of the pregnane X receptor. Likely due to increased activation of the estrogen and/or progesterone receptors, spironolactone has very weak but significant antigonadotropic effects.
