Pharmacodynamics 7α-Thiomethylspironolactone, the major active form of<unk> . It accounts for about 80% of the potassium-sparing effect of<unk> . Canrenone, the second major active form of<unk> . It accounts for around 10 to 25% of the potassium-sparing effect of<unk> . The pharmacodynamics of<unk>  are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition, among other more minor activities.<unk>  is a prodrug, so most of its actions are actually mediated by its various active metabolites. The major active forms of<unk>  are 7α-thiomethylspironolactone (7α-TMS) and canrenone (7α-desthioacetyl-δ6-spironolactone).<unk>  is a potent antimineralocorticoid. That is, it is an antagonist of the mineralocorticoid receptor (MR), the biological target of mineralocorticoids like aldosterone and 11-deoxycorticosterone. By blocking the MR,<unk>  inhibits the effects of mineralocorticoids in the body. The antimineralocorticoid activity of<unk>  is responsible for its therapeutic efficacy in the treatment of edema, high blood pressure, heart failure, hyperaldosteronism, and ascites due to cirrhosis. It is also responsible for many of the side effects of<unk> , such as urinary frequency, dehydration, hyponatremia, low blood pressure, fatigue, dizziness, metabolic acidosis, decreased kidney function, and its risk of hyperkalemia. Due to the antimineralocorticoid activity of<unk> , levels of aldosterone are significantly increased by the medication, probably reflecting an attempt of the body to maintain homeostasis.<unk>  is a moderate antiandrogen. That is, it is an antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). By blocking the AR,<unk>  inhibits the effects of androgens in the body. The antiandrogenic activity of<unk>  is mainly responsible for its therapeutic efficacy in the treatment of androgen-dependent skin and hair conditions like acne, seborrhea, hirsutism, and pattern hair loss and hyperandrogenism in women, precocious puberty in boys with testotoxicosis, and as a component of feminizing hormone therapy for transgender women. It is also primarily responsible for some of its side effects, like breast tenderness, gynecomastia, feminization, and demasculinization in men. Blockade of androgen signaling in the breast disinhibits the actions of estrogens in this tissue. Although useful as an antiandrogen in women, who have low testosterone levels compared to men,<unk>  is described as having relatively weak antiandrogenic activity.<unk>  is a weak steroidogenesis inhibitor. That is, it inhibits steroidogenic enzymes, or enzymes involved in the production of steroid hormones.<unk>  and/or its metabolites have been found in vitro to weakly inhibit a broad array of steroidogenic enzymes including cholesterol side-chain cleavage enzyme, 17α-hydroxylase, 17,20-lyase, 5α-reductase, 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, 21-hydroxylase, and aldosterone synthase (18-hydroxylase). However, although very high doses of<unk>  can considerably decrease steroid hormone levels in animals,<unk>  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<unk>  in humans, which may in part be related to compensatory upregulation of their synthesis. The weak steroidogenesis inhibition of<unk>  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.<unk>  has been found in some studies to increase levels of estradiol, an estrogen, although many other studies have found no changes in estradiol levels. The mechanism of how<unk>  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<unk>  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<unk>  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<unk> , and in an attempt to maintain homeostasis, 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<unk> , and those that have found increases often have observed only small changes. In accordance,<unk>  has not been associated with conventional glucocorticoid medication effects or side effects. Other activities of<unk>  may include very weak interactions with the estrogen and progesterone receptors and agonism of the pregnane X receptor. These activities could contribute to the menstrual irregularities and breast side effects of<unk>  and to its drug interactions, respectively. Pharmacokinetics The pharmacokinetics of<unk>  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<unk>  over the decades. Absorption Levels of<unk>  and its major active metabolites after a single oral dose of 100 mg<unk>  in humans. The bioavailability of<unk>  when taken by mouth is 60 to 90%. The bioavailability of<unk>  and its metabolites increases significantly (+22–95% increases in levels) when<unk>  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 of<unk> , as well as due to a decrease of the first-pass metabolism. The relationship between a single dose of<unk>  and plasma levels of canrenone, a major active metabolite of<unk> , has been found to be linear across a dose range of 25 to 200 mg<unk> . Steady-state concentrations of<unk>  are achieved within 8 to 10 days of treatment initiation. Little or no systemic absorption has been observed with topical<unk> . Distribution<unk>  and its metabolite canrenone are highly plasma protein bound, with percentages of 88.0% and 99.2%, respectively.<unk>  is bound equivalently to albumin and α1-acid glycoprotein, while canrenone is bound only to albumin.<unk>  and its metabolite 7α-thiospironolactone show very low or negligible affinity for sex hormone-binding globulin (SHBG). In accordance, a study of high-dosage<unk>  treatment found no change in steroid binding capacity related to SHBG or to corticosteroid-binding globulin (CBG), suggesting that<unk>  does not displace steroid hormones from their carrier proteins. This is in contradiction with widespread statements that<unk>  increases free estradiol levels by displacing estradiol from SHBG.<unk>  appears to cross the blood–brain barrier. Metabolism<unk>  metabolism in humans. Canrenone may be further reduced (into di-, tetra-, and hexahydrogenated metabolites), hydroxylated, and conjugated (e.g., glucuronidated).<unk>  is rapidly and extensively metabolized in the liver upon oral administration and has a very short terminal half-life of 1.4 hours. The major metabolites of<unk>  are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (7α-desthioacetyl-δ6-spironolactone). These metabolites have much longer elimination half-lives than<unk>  of 13.8 hours, 15.0 hours, and 16.5 hours, respectively, and are responsible for the therapeutic effects of the medication. As such,<unk>  is a prodrug. The 7α-thiomethylated metabolites of<unk>  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<unk>  include 7α-thiospironolactone (7α-TS), which is an important intermediate to the major metabolites of<unk> , as well as the 7α-methyl ethyl ester of<unk>  and the 6β-hydroxy-7α-methyl ethyl ester of<unk> .<unk>  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<unk> , and also binds covalently to other proteins. 7α-TS is also S-methylated into 7α-TMS, a transformation catalyzed by thiol S-methyltransferase. Unlike the related medication eplerenone,<unk>  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 hydroxylated at the C3α and C3β positions.<unk>  is dethioacetylated into canrenone. Finally, the C17 γ-lactone ring of<unk>  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<unk>  is eliminated by the kidneys, while minimal amounts are handled by biliary excretion.
Spironolactone
Chlorothiazide
Cyclothiazide
Amiloride
Hydrochlorothiazide
Furosemide
Torasemide
Bumetanide