Pharmacodynamics of spironolactone

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. Spironolactone has a very short biological half-life and is considered to be a prodrug; hence, its active metabolites are responsible for most of its pharmacodynamics. The major active forms of spironolactone include 7α-thiomethylspironolactone (7α-TMS) and canrenone (7α-desthioacetyl-δ6-spironolactone), while minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and a number of others. Aside from its primary mechanisms of action of antimineralocorticoid and antiandrogenic action, spironolactone has been found in preclinical research to interact very weakly with the progesterone and estrogen receptors and to have very weak mixed progestogenic and antiprogestogenic activity as well as very weak mixed estrogenic and antiestrogenic activity. The clinical significance of these actions, if any, is uncertain. However, a small clinical study found that high doses of spironolactone had neither progestogenic nor antiprogestogenic effects in women. In any case, if one or both of these actions are clinically relevant, they might contribute to the menstrual irregularities and breast side effects of spironolactone. Spironolactone is also an agonist of the pregnane X receptor, and is able to induce the expression of CYP3A4 and P-glycoprotein in the body via this action. This effect may contribute to the drug interactions of spironolactone.

Antimineralocorticoid activity Spironolactone inhibits the effects of mineralocorticoids, namely, aldosterone, by displacing them from the mineralocorticoid receptor (MR) in the cortical collecting duct of kidney nephrons. This decreases the reabsorption of sodium and water while limiting the excretion of potassium. Hence, aldosterone antagonists are potassium (K+) sparing diuretics. The medication has a slightly delayed onset of action, and so it takes several days for diuresis to occur since the MR is a nuclear receptor which works through regulating gene transcription and gene expression. Therefore, the production and expression of ENaC and ROMK electrolyte channels in the distal nephrons, which give the drug its diuretic properties, has a delayed onset of action. In addition to direct antagonism of the MRs, the antimineralocorticoid effects of spironolactone may also in part be mediated by direct inactivation of 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 antimineralocorticoid effects of spironolactone is relatively slow, with the peak effect sometimes occurring 48 hours or more after the first dose. Canrenone is an antagonist of the MR as is spironolactone, but it is slightly more potent in comparison. It has been determined that 7α-TMS accounts for around 80% of the potassium-sparing effect of spironolactone while canrenone accounts for the remaining approximately 10 to 25%. Accordingly, 7α-TMS occurs at higher circulating concentrations than does canrenone in addition to having a higher relative affinity for the MR.

Antiandrogenic activity

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