Introduction

Spironolactone, a synthetic 17-lactone steroid, is a potassium-sparing diuretic that also displays antagonistic effects on the androgen and progesterone receptors.It is approved by the US Food and Drug Administration (FDA) for the treatment of heart failure, edema and ascites, hypertension, and primary hyperaldosteronism. In addition, spironolactone is often used as an off-label treatment for acne, hidradenitis, androgenetic alopecia, and hirsutism owing to its antiandrogenic properties.Particularly for women with acne, spironolactone has shown promise as an effective option that can reduce reliance on oral antibiotics. The 3D structural formula of spironolactone is shown in Figure.1.

Spironolactone is also frequently used as part of gender affirming care, and it is included in the Endocrine Society guidelines as a part of hormone regimens for transgender women (male transitioning to female). For transgender women seeking feminine physical characteristics, antiandrogens such as spironolactone can reduce muscle hypertrophy and male body hair growth, induce skin softening, change body fat distribution, and cause testicular shrinkage. For transgender men, spironolactone can treat hormonal acne and androgenic hair loss.[1]

Pharmacology

Spironolactone and two metabolites (7α-thiomethyl-spironolactone and canrenone) bind to cytoplasmic miner-alocorticoid receptors and function as aldosterone antagonists. This results in a potassium-sparing diuretic effect in the distal tubules of the kidney.

A diuretic-induced reduction in plasma volume can activate several neurohumoral systems, e.g. the renin-aldosterone-angiotensin system, sympathetic nervous system, and ADH secretion, resulting in impaired renalperfusion and increased Na⁺ and water resorption. These changes contribute towards a reduced effect of the diuretic ('diuretic resistance') and also renal impairment.

In patients with cirrhosis receiving spironolactone±furosemide, improved renal function and diuresis is seen with co-administration of octreotide 300microgram SC bid or clonidine 75microgram PO bid due to inhibition of the renin-aldosterone-angiotensin (octreotide and clonidine) and sympathetic nervous (clonidine) systems. Patients in the clonidine study were considered to have an overactive sympathetic nervous system based on a higher than normal serum norepinephrine level.[2]

Caution is required when using spironolactone in patients with prostate cancer. Sundar S etal. had reported the case of an 80-year-old man who had heavily pretreated castration refractory carcinoma of the prostate and heart failure. Following the introduction of spironolactone to manage his heart failure, the patient experienced clinical and biochemical progression of his prostate cancer. Within 2 weeks of withdrawing spironolactone the patient's prostate-specifi cantigen returned its previous level. This is the first reported case of clinical and biochemical progression of prostate cancer following the introduction of spironolactone. [3]

Aldosterone binds to the mineralocorticoid receptor and activates pro-inflammatory and other cell pathways.Thus, by preventing the binding of aldosterone, spironolactone has anti-inflammatory and other effects. Although the full therapeutic potential of this remains to be determined, benefit is seen with spironolactone in various experimental and clinical settings, with reductions in cancer growth, cancer cachexia and insulin resistance.[4-6]

Ascites: Hyperaldosteronism is a concomitant of ascites associated with portal hypertension (a transudate with a relatively low albumin concentration, best indicated by a serum-ascites albumin difference of ≥11g/L) asseen in cirrhosis, hepatocellular cancer, extensive hepatic metastases. Most evidence comes from cirrhosis,but spironolactone in a median daily dose of 200-300mg may benefit most patients with these conditions (90% in cirrhosis).[2]

Chronic heart failure (CHF): Spironolactone improves morbidity and mortality in patients with CHF and a reduced left ventricular ejection fraction. It is added in low dose (e.g. 12.5mg-25mg) to standard treatment. Its aldosterone antagonist action helps reduce vascular and myocardial fibrosis, sympathetic nervous system activation, baroreceptor dysfunction and K⁺ and Mg²⁺ depletion.

Hypertension: Aldosterone antagonists are used as a fourth-line add-on therapy in patients with hypertension failing to respond to more usual antihypertensive drugs.

Spironolactone is extensively metabolized. The 7α-thiomethyl-spironolactone and canrenone metabolites have long half-lives and are excreted in the urine. Consequently, because of their accumulation and increased risk of hyperkalemia, the use of spironolactone requires caution in milde-moderate renal impairment, and is generally contra-indicated in severe renal impairment.

Drug interactions[2]

Serious additive pharmacodynamic interactions with other drugs, notably hyperkalemia with potassium supplements (avoid concurrent use), table salt substitutes (contain both potassium and sodium chlorides), potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, certain antimicrobials (trimethoprim, nitrofurantoin), ciclosporin, LMWH and tacrolimus, particularly if other risk factors also present, e.g. elderly, renal impairment, diabetes.

Spironolactone may induce hyponatremia, particularly if used with other diuretics. This natriuretic effect is reduced by aspirin, indomethacin and possibly other NSAIDs.

Spironolactone increases the plasma concentration of digoxin by up to 25% and can interfere with digoxin plasma concentration assays.

Undesirable effects

Very common (>10%): CNS disturbances (drowsiness, lethargy, confusion, headache, fever, ataxia, fatigue), GI disturbances (anorexia, dyspepsia, nausea, vomiting, peptic ulceration, colic).

Common (<10%, >1%): gastritis, hyperkalemia, gynecomastia, breast pain.

References

[1] Bommareddy K, Hamade H, Lopez-Olivo MA, Wehner M, Tosh T, Barbieri JS. Association of Spironolactone Use With Risk of Cancer: A Systematic Review and Meta-analysis. JAMA Dermatol. 2022;158(3):275-282.

[2] Carone L, Oxberry SG, Twycross R, Charlesworth S, Mihalyo M, Wilcock A. Spironolactone. J Pain Symptom Manage. 2017;53(2):288-292.

[3] Sundar S, Dickinson PD. Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate. BMJ Case Rep.2012;bcr1120115238.

[4] King S,et al. Evidence for aldosterone-dependent growth of renal cell carcinoma. Int J Exp Pathol 2014;95:244-250.

[5] Springer J,et al. Prevention of liver cancer cachexia-induced cardiac wasting and heart failure. Eur Heart 2014;35:932-941.

[6] Ogino K, et al. Spironolactone, not furosemide improved insulin resistance in patients with chronic heart failure. Int J Cardiol 2014;171:398-403.