Spironolactone

Spironolactone (like eplerenone) is an orally administrable, synthetic aldosterone analogue (canrenone is the active metabolite of spironolactone), a competitiveantagonist of the aldosterone receptor(aldosterone antagonist). By binding and blocking the receptor, spironolactone prevents aldosterone from interacting with its receptor. This prevents the aldosterone effects, i.e. Na+ reabsorption and K+ and H+ excretion in the collecting tube of the nephron are reduced. Spironolactone thus has a natriuretic (and diuretic) effect with simultaneous K+ retention and thus belongs to the potassium-sparing diuretics. The consequence of the diuretic effect is an antihypertensive effect. Therapeutically, however, the natriuretic effect is in the background, and the cardioprotective effect in heart failure is in the foreground. Spironolactone also has antiarrhythmic effects (K+ currents in cardiomyocytes are blocked) Only at extremely high doses does spironolactone inhibit the biosynthesis of aldosterone. The mean half-life of spironolactone is approximately 1.3h.

Spironolactone undergoes a marked first-pass effect when administered or ally and is metabolized primarily in the liver and kidneys to 7-α-thiospirolactone, canrenone or canrenoate, 7-α-thiomethylspirolactone, and 6-β-hydroxy-7-α-thiomethylspirolactone, respectively.

Maximal plasma concentrations of spironolactone are reached 1-2 hours after oral administration.

Excretion of spironolactone is predominantly renal and to a lesser extent via bile. The amount of unchanged spironolactone is low. Only metabolites are found in the urine, primarily canrenone and its glucoronide ester and 6-β-hydroxysulfoxide.

The elimination half-life for spironolactone after oral administration is 1-2 hours, whereas the metabolites are excreted more slowly. Terminal elimination half-lives are about 20 hours for canrenone, about 3 hours for 7-α-thiomethylspirolactone, and about 10 hours for 6-β-hydroxy7-α-thiomethylspirolactone.

Competitive (non-selective) inhibition of the aldosterone receptor, antiandrogenic effect by degradation of the cytochrome P450 enzymes 17α-, 11β- and 21-hydroxylase, which play a role in the synthesis of testosterone, and competitive inhibition of the 5α-dihydrotestosterone receptor.

Other effects of spironolactone include:

• Increase in sodium and chloride excretion and, to a lesser extent, calcium excretion.
• Unlike eplerenone, spironolactone is not a selective AR antagonist. In therapeutic doses, the substance also acts as an antagonist of progesterone and androgen receptors. This explains some side effects such as gynecomastia, impotence and menstrual disorders.
• reduction of potassium and ammonium excretion
• Reduction of renal magnesium excretion
• Reduction of glomerular filtration rate
• Increase in serum urea concentrations

The active substance spironolactone is used in:

primary hyperaldosteronism unless surgery is indicated

oedema and/or ascites in conditions associated with secondary hyperaldosteronism

Hypertension

Nephrotic syndrome

Experimental use in dermatological indications. These therapeutic indications primarily relate to the antigestagenic and antiandrogenic effects of spironolctone (Vargas-Mora P et al 2020):

• Acne vulgaris (Layton AM et al 2017).
• Hidradenitis suppurativa (Golbari NM et al 2019).
• Hirsutism (Tremblay RR 1986).
• Androgenetic alopecia in women (Vargas-Mora P et al 2020)
• Rosacea (Spoendlin J et al 2013)

Spironolactone must not be used during pregnancy and lactation and is contraindicated here. Animal studies have shown feminization of the genitalia of male offspring and evidence of endocrine disruption in female and male offspring. In humans, antiandrogenic effects have been demonstrated.

The pharmacologically active metabolite canrenoate passes into breast milk (milk-to-plasma concentration ratio 0.7). Therefore, spironolactone is also contraindicated during lactation. If treatment is necessary, breast-feeding must be carried out.

For adults, an initial dose of 100-200 mg of spironolactone per day is recommended. In case of insufficient efficacy, the daily dose may be increased to a maximum of 400 mg spironolactone per day.

As a maintenance dose, 50-100 mg spironolactone to a maximum of 100-200 mg spironolactone is usually sufficient.

The maintenance dose may be administered daily, every 2nd day, or every 3rd day as needed.

The clinical onset of action is achieved after 2 to 3 days or later with continuous administration; if necessary, the maximum diuretic effect may not occur until after 2 weeks.

Common side effects with spironolactone therapy include:

Life-threatening hyperkalemia (especially if renal function is impaired) ► hyperkalemic paralysis (muscle paralysis) and cardiac arrhythmias are possible

Hyperuricemia (may lead to gout attacks in predisposed patients).

In rare cases of DRESS, acute liver failure, eosinophilia, and pancreatitis have been diagnosed.

Dermatologic UAW:

• DRESS syndrome(Ghislain PD et al 2004).
• Lupus erythematosus-like exanthema (Uddin MS et al. 1979)
• Grinspan syndrome (?)
• Lichenoid and non-lichenoid exanthema (Clark C et al. 1998)
• Lichen planus (Downham TF 3rd. 1978)
• Mostly reversible gynecomastia (depending on dose level and duration of treatment)
• Increased sensitivity to touch of the nipples and breast tenderness (mastodynia)

Spironolactone must not be used in case of:

• hypersensitivity to the active substance
• anuria
• acute renal failure
• severe renal insufficiency with oliguria or anuria (creatinine clearance below 30 ml/min per 1.73 m2 of body surface area and/or serum creatinine above 1.8 mg/dl)
• Hyperkalemia
• Addison's disease or other conditions associated with hyperkalemia
• concomitant use of eplerenone or other potassium-sparing diuretics
• Hyponatremia
• Hypovolemia or dehydration

Aldactone®

1. Clark C et al (1998) Lichenoid drug eruption induced by spironolactone. Clin Exp Dermatol 23:43-44.
2. Downham TF 3rd. (1978) Spironolactone-induced lichen planus. JAMA 240:1138.
3. Ghislain PD et al (2004) Drug-induced eosinophilia and multisystemic failure with positive patch-test reaction to spironolactone: DRESS syndrome. Acta Derm Venereol 84:65-68.
4. Golbari NM et al (2019) Antiandrogen therapy with spironolactone for the treatment of hidradenitis suppurativa. J Am Acad Dermatol 80: 114-119.
5. Greenberger PA et al (1986) Readministration of spironolactone in the spironolactone-intolerant patient. N Engl Reg Allergy Proc 7:343-345.
6. Layton AM et al (2017) Oral spironolactone for acne vulgaris in adult females: A Hybrid Systematic Review. Am J Clin Dermatol 18:169-191.
7. Lee A et al. (2015) A case series of 20 women with hidradenitis suppurativa treated with spironolactone. Australas J Dermatol 56:192-196.
8. Spoendlin J et al (2013) Spironolactone may reduce the risk of incident rosacea. J Invest Dermatol 133:2480-2483.
9. Tremblay RR (1986) Treatment of hirsutism with spironolactone. Clin Endocrinol Metab 15:363-371.
10. Uddin MS et al (1979) Cutaneous reaction to spironolactone resembling lupus erythematosus. Cutis 24:198-200.
11. Vargas-Mora P et al. (2020) Spironolactone in Dermatology: Uses in Acne, Hidradenitis Suppurativa, Female Pattern Baldness, and Hirsutism. Actas Dermosifiliogr 111:639-649.

Significant interactions of spironolactone