Spironolactone

(BAN, rINN)
Spironolactone Chemical formula
Synonyms: Espironolactona; SC-9420; Spirolactone; Spironolactonum; Spironolakton; Spironolaktonas; Spironolaktoni. 7 oxo-17 thio)-17-hydroxy-3-oxo-pregn4-ene-21-carboxylic acid tone.
Cyrillic synonym: Спиронолактон.

💊 Chemical information

Chemical formula: C24H32O4S = 416.6.
CAS — 52-01-7.
ATC — C03 DA01.
ATC Vet — QC0 3DA01.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, and US.

Ph. Eur. 6.2

(Spironolactone). A white or yellowish-white powder. Practically insoluble in water; soluble in alcohol. It exhibits polymorphism. Protect from light.

USP 31

(Spironolactone). A light cream-coloured to light tan, crystalline powder with a faint to mild mercaptan-like odour. Practically insoluble in water; soluble in alcohol and in ethyl acetate; freely soluble in chloroform and in benzene; slightly soluble in methyl alcohol and in fixed oils.

Stability.

There was no appreciable loss of spironolactone from extemporaneously prepared suspensions of spironolactone, 2.5, 5 and 10 mg/mL, in a cherry syrup after storage for 2 weeks at 5° or 30° or at ambient room temperature under intense fluorescent light. 1 Degradation was less than 5% for samples stored for 4 weeks, but was more noticeable in suspensions with a higher initial concentration. There were no changes in colour or odour. Bacterial and fungal counts were well within acceptable limits after 4 weeks at 30°. 1. Mathur LK, Wickman A. Stability of extemporaneously compounded spironolactone suspensions. Am J Hosp Pharm 1989; 46: 2040–2.

💊 Adverse Effects

Spironolactone may give rise to headache and drowsiness, and gastrointestinal disturbances, including cramp and diarrhoea. Ataxia, mental confusion, and skin rashes have been reported as adverse effects. Gynaecomastia is not uncommon and in rare cases breast enlargement may persist. Other endocrine disorders include hirsutism, deepening of the voice, menstrual irregularities, and impotence. Transient increases in blood-urea-nitrogen concentrations may occur and mild acidosis has been reported. Spironolactone has been shown to cause tumours in rats. Spironolactone may cause hyponatraemia and hyperkalaemia.

Incidence of adverse effects.

A survey found that of 788 patients given spironolactone 164 developed adverse effects.1These included hyperkalaemia in 8.6%, dehydration in 3.4%, hyponatraemia in 2.4%, gastrointestinal disorders in 2.3%, neurological disorders in 2%, rash, and gynaecomastia. Hyperkalaemia was associated with renal impairment and the use of potassium supplements: only 2.8% of nonuraemic patients not receiving potassium chloride developed hyperkalaemia, while 42.1% of those with marked uraemia and treated with potassium chloride became hyperkalaemic. In a study2 of 54 patients (53 female, 1 male) taking spironolactone 200 mg daily for hirsutism or acne adverse effects were reported in 91%.2 Menstrual disturbances occurred in 72% of patients, breast tenderness in 39%, dry skin in 39%, and breast enlargement in 24%. Other adverse effects included nausea and vomiting, dizziness, headache, drowsiness, and skin rashes. Two patients developed a chloasma-like pigmentation of the face. The gynaecological effects were reduced in patients taking oral contraceptives.
1. Greenblatt DJ, Koch-Weser J. Adverse reactions to spironolactone: a report from the Boston Collaborative Drug Surveillance Program. JAMA 1973; 225: 40–3
2. Hughes BR, Cunliffe WJ. Tolerance of spironolactone. Br J Dermatol 1988; 118: 687–91.

Carcinogenicity.

Breast cancer was reported in 5 patients taking spironolactone and hydrochlorothiazide for prolonged periods1 although it was suggested2 that the association with spironolactone therapy was unlikely to be causal. Although the rat may not be an appropriate model for determining long-term safety in man,3,4 evidence of carcinogenicity in this species prompted the UK CSM to limit the product licences of spironolactone-containing products to exclude use in essential hypertension or idiopathic oedema.5
1. Loube SD, Quirk RA. Breast cancer associated with administration of spironolactone. Lancet 1975; i: 1428–9
2. Jick H, Armstrong B. Breast cancer and spironolactone. Lancet 1975; ii: 368–9
3. Lumb G, et al. Effects in animals of chronic administration of spironolactone—a review. J Environ Pathol Toxicol 1978; i: 641–60
4. Wagner BM. Long-term toxicology studies of spironolactone in animals and comparison with potassium canrenoate. J Drug Dev 1987; 1 (suppl 2): 7–11
5. Committee on Safety of Medicines. Spironolactone. Current Problems 1988
21. Available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ FILE&dDocName=CON2024428&RevisionSelectionMethod= LatestReleased (accessed 25/07/08)

Effects on the blood.

Agranulocytosis has been reported1,2 in association with the use of spironolactone.
1. Stricker BHC, Oei TT. Agranulocytosis caused by spironolactone. BMJ 1984; 289: 731
2. Whitling AM, et al. Spironolactone-induced agranulocytosis. Ann Pharmacother 1997; 31: 582–5.

Effects on electrolyte balance.

CALCIUM. A report1 suggested that spironolactone may have a calcium-sparing effect, in addition to its well known potassium-sparing properties.
1. Puig JG, et al. Hydrochlorothiazide versus spironolactone: longterm metabolic modifications in patients with essential hypertension. J Clin Pharmacol 1991; 31: 455–61.
POTASSIUM. There have been reports1-3 of severe hyperkalaemia in patients taking spironolactone, including patients with renal impairment and those with a high potassium intake from either dietary sources or potassium supplements. In the Boston Collaborative Drug Surveillance Program4 hyperkalaemia was reported in 42.1% of patients with uraemia taking spironolactone and receiving potassium supplements compared with 2.8% of those without uraemia and not receiving potassium supplements. Two deaths were attributed to hyperkalaemia in patients taking spironolactone and potassium chloride. Potassium supplements should be avoided in patients receiving spironolactone, and plasma-potassium concentrations should be carefully monitored in those with renal impairment.
1. Pongpaew C, et al. Hyperkalemic cardiac arrhythmia secondary to spironolactone. Chest 1973; 63: 1023–5
2. Udezue EO, Harrold BP. Hyperkalaemic paralysis due to spironolactone. Postgrad Med J 1980; 56: 254–5
3. O’Reilly PH, et al. Life-threatening hyperkalaemia after bladder decompression for high pressure chronic retention. Lancet 1987; ii: 859
4. Greenblatt DJ, Koch-Weser J. Adverse reactions to spironolactone: a report from the Boston Collaborative Drug Surveillance Program. JAMA 1973; 225: 40–3.

Effects on endocrine function.

Spironolactone has been associated with disturbances of endocrine function. The most prominent in men is gynaecomastia which appears to be related to both dose and duration of treatment. Incidences of 62%1 and 100%2 have been reported. Gynaecomastia has also been accompanied by impotence.3,4 The effects are generally reversible on stopping treatment. Reversal of male-pattern baldness has also been reported.5 In women symptoms include breast enlargement and tenderness.6 The incidence of menstrual abnormalities may be high: unspecified disturbances have been reported in 33 of 53 women,6secondary amenorrhoea in 6 of 9,7 and secondary and primary amenorrhoea in 1 and 2 patients, respectively.8 The incidence of gynaecological disturbances has been found to be lower in women taking oral contraceptives.6 The mechanism of the effects of spironolactone on the endocrine system is unclear. Some workers9 suggested that although spironolactone affects testosterone synthesis, the more likely explanation was its anti-androgenic action, and reduction in 17-hydroxylase activity. Others10 found an alteration in the testosterone/oestrogen ratio due to an increase in testosterone clearance and increased peripheral conversion to estradiol. In addition, spironolactone is reported to inhibit binding of dihydrotestosterone to receptors.
1. Huffman DH, et al. Gynecomastia induced in normal males by spironolactone. Clin Pharmacol Ther 1978; 24: 465–73
2. Bellati G, Idéo G. Gynaecomastia after spironolactone and potassium canrenoate. Lancet 1986; i: 626
3. Greenblatt DJ, Koch-Weser J. Gynecomastia and impotence complications of spironolactone therapy. JAMA 1973; 223: 82
4. Greenlaw C. Spironolactone induced gynecomastia: a case report. Drug Intell Clin Pharm 1977; 11: 70–3
5. Thomas PS. Hair: wanted and unwanted. BMJ 1986; 293: 698
6. Hughes BR, Cunliffe WJ. Tolerance of spironolactone. Br J Dermatol 1988; 118: 687–91
7. Levitt JI. Spironolactone therapy and amenorrhea. JAMA 1970; 211: 2014–15
8. Potter C, et al. Primary and secondary amenorrhea associated with spironolactone therapy in chronic liver disease. J Pediatr 1992; 121: 141–3
9. Loriaux DL, et al. Spironolactone and endocrine dysfunction. Ann Intern Med 1976; 85: 630–6
10. Rose LI, et al. Pathophysiology of spironolactone-induced gynecomastia. Ann Intern Med 1977; 87: 398–403.

Effects on lipid metabolism.

Unlike thiazide diuretics, spironolactone appeared not to increase serum-cholesterol concentrations in a study of 23 patients.1
1. Ames RP, Peacock PB. Serum cholesterol during treatment of hypertension with diuretic drugs. Arch Intern Med 1984; 144: 710–14.

Effects on the liver.

Hepatotoxicity characterised by cholestatic lesions has been reported in a patient receiving spironolactone.1 Only one other published case of spironolactone-associated hepatotoxicity was known to the authors.
1. Renkes P, et al. Spironolactone and hepatic toxicity. JAMA 1995; 273: 376–7.

Effects on the skin.

Lichen-planus-like skin eruptions developed in a 62-year-old woman who was taking digoxin, propranolol, diazepam, spironolactone, and iron tablets.1 Flares of the lichen-planus-like eruption seemed to be associated with use of spironolactone and there was evidence of resolution when spironolactone was withdrawn. Cutaneous vasculitis was associated with spironolactone on 3 occasions in an 80-year-old man.2A chloasma-like pigmentation of the face was reported in 2 patients receiving spironolactone for hirsutism or acne.3
1. Downham TF. Spironolactone-induced lichen planus. JAMA 1978; 240: 1138
2. Phillips GWL, Williams AJ. Spironolactone induced vasculitis. BMJ 1984; 288: 368
3. Hughes BR, Cunliffe WJ. Tolerance of spironolactone. Br J Dermatol 1988; 118: 687–91.

Hypersensitivity.

Eosinophilia and a rash developed in 2 patients with alcoholic cirrhosis while taking spironolactone.1
1. Wathen CG, et al. Eosinophilia associated with spironolactone. Lancet 1986; i: 919–20.

💊 Precautions

Spironolactone should not be used in patients with hyperkalaemia or severe renal impairment. It should be used with care in patients who are at increased risk of developing hyperkalaemia; such patients include the elderly, those with diabetes mellitus, and those with some degree of renal or hepatic impairment. It should also be given with care to patients likely to develop acidosis. Serum electrolytes and blood-urea-nitrogen should be measured periodically.

Breast feeding.

The concentration of canrenone was measured1 in the serum and milk of a breast-feeding woman taking 25 mg of spironolactone four times daily. The milk to serum concentration ratios of canrenone at 2 and 14.5 hours after a dose of spironolactone were 0.72 and 0.51 respectively, and it was estimated that the amount of canrenone ingested by the infant would be 0.2% of the mother’s daily dose of spironolactone. The serum potassium and sodium levels of the infant were in the normal range. The American Academy of Pediatrics2 considers that spironolactone is therefore usually compatible with breast feeding.
1. Phelps DL, Karim A. Spironolactone: relationship between concentrations of dethioacetylated metabolite in human serum and milk. J Pharm Sci 1977; 66: 1203
2. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 06/07/04)

Diabetes mellitus.

Severe hyperkalaemia was reported in a type 1 diabetic woman with hyporeninaemic hypoaldosteronism given spironolactone.1
1. Large DM, et al. Hyperkalaemia in diabetes mellitus—potential hazards of coexisting hyporeninaemic hypoaldosteronism. Postgrad Med J 1984; 60: 370–3.

Interference with la

boratory estimations. Spironolactone and canrenoate can interfere with some assays for plasma-digoxin concentrations.1-3 However, spironolactone may also produce actual changes in digoxin concentrations and results of assays should be interpreted with caution.
1. Yosselson-Superstine S. Drug interferences with plasma assays in therapeutic drug monitoring. Clin Pharmacokinet 1984; 9: 67–87
2. Foukaridis GN. Influence of spironolactone and its metabolite canrenone on serum digoxin assays. Ther Drug Monit 1990; 12: 82–4
3. Steimer W, et al. Intoxication due to negative canrenone interference in digoxin drug monitoring. Lancet 1999; 354: 1176–7.

Porphyria.

Spironolactone has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

💊 Interactions

There is an increased risk of hyperkalaemia if spironolactone is given with potassium supplements or with other potassium-sparing diuretics. Hyperkalaemia may occur as well in patients also given ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, ciclosporin, or trilostane. In patients given spironolactone with NSAIDs or ciclosporin the risk of nephrotoxicity may also be increased. Diuretics may reduce the excretion of lithium and increase the risk of lithium toxicity. Hyponatraemia may occur in patients taking a potassium-sparing diuretic with a thiazide; this risk may be increased in patients given chlorpropamide. Spironolactone may reduce the ulcer-healing properties of carbenoxolone. See also Interference with Laboratory Estimations, under Precautions, above.

Mitotane.

For a report of the inhibition of the action of mitotane by spironolactone.

Warfarin.

For reference to the interaction between warfarin and spironolactone.

💊 Pharmacokinetics

Spironolactone is well absorbed from the gastrointestinal tract, with a bioavailability of about 90%. It is about 90% bound to plasma proteins. Spironolactone is metabolised extensively to a number of metabolites including canrenone and 7 α-thiomethylspirolactone, both of which are pharmacologically active. The major metabolite may be 7 α-thiomethylspirolactone, although it is uncertain to what extent the actions of spironolactone are dependent on the parent compound or its metabolites. Spironolactone is excreted mainly in the urine and also in the faeces, in the form of metabolites. Spironolactone or its metabolites may cross the placental barrier, and canrenone is distributed into breast milk.
1. Overdiek HWPM, Merkus FWHM. The metabolism and biopharmaceutics of spironolactone in man. Rev Drug Metab Drug Interact 1987; 5: 273–302
2. Gardiner P, et al. Spironolactone metabolism: steady-state serum levels of the sulfur-containing metabolites. J Clin Pharmacol 1989; 29: 342–7
3. Sungaila I, et al. Spironolactone pharmacokinetics and pharmacodynamics in patients with cirrhotic ascites. Gastroenterology 1992; 102: 1680–5.

💊 Uses and Administration

Spironolactone, a steroid with a structure resembling that of the natural adrenocortical hormone aldosterone, acts on the distal portion of the renal tubule as a competitive antagonist of aldosterone. It acts as a potassium-sparing diuretic, increasing sodium and water excretion and reducing potassium excretion. Spironolactone is reported to have a relatively slow onset of action, requiring 2 or 3 days for maximum effect, and a similarly slow diminishment of action over 2 or 3 days on stopping. Spironolactone is used in the management of heart failure, both to treat refractory oedema and in lower doses as an adjunct to standard therapy (see below). It is also used for refractory oedema associated with cirrhosis of the liver, or the nephrotic syndrome, and in ascites associated with malignancy. It is frequently given with the thiazides, furosemide, or similar diuretics, where it adds to their natriuretic but diminishes their kaliuretic effects, hence conserving potassium in those at risk from hypokalaemia. Diuretic-induced hypokalaemia and its management, including the role of potassium-sparing diuretics, is discussed under Effects on the Electrolyte Balance in the Adverse Effects of Hydrochlorothiazide. It has been used in the treatment of essential hypertension (in lower doses than for oedema), but in the UK is no longer recommended for use in either essential hypertension or idiopathic oedema; doubts have been expressed over its safety during longterm administration. Spironolactone is also used in the diagnosis and treatment of primary hyperaldosteronism (below). Other conditions in which spironolactone has been tried on the basis of its anti-androgenic properties include hirsutism, particularly in the polycystic ovary syndrome. In the treatment of oedema, spironolactone is usually given in an initial oral dose of 100 mg daily, subsequently adjusted as necessary; some patients may require doses of up to 400 mg daily. In hepatic cirrhosis with ascites and oedema, patients with a urinary sodium/potassium ratio greater than 1 may be given an initial dose of spironolactone 100 mg daily while patients with a ratio of less than 1 may be given initial doses of 200 to 400 mg daily. Spironolactone is given in doses of 400 mg daily in the presumptive diagnosis of primary hyperaldosteronism; in doses of 100 to 400 mg daily for the preoperative management of hyperaldosteronism; and in the lowest effective dosage for long-term maintenance therapy in the absence of surgery. Suggested doses of spironolactone for children range from 1 to 3 mg/kg daily, in divided doses. Potassium supplements should not be given with spironolactone.
1. Skluth HA, Gums JG. Spironolactone: a re-examination. DICP Ann Pharmacother 1990; 24: 52–9
2. Doggrell SA, Brown L. The spironolactone renaissance. Expert Opin Invest Drugs 2001; 10: 943–54
3. Buck ML. Clinical experience with spironolactone in pediatrics. Ann Pharmacother 2005; 39: 823–8.

Acne.

Spironolactone has been used for its anti-androgenic properties in some cases of acne where standard therapy is unsuccessful. Beneficial responses to oral therapy have been reported in patients with acne from both open1 and placebocontrolled2,3 studies. Topical application has been tried4,5 but response has been variable. It is possible that the vehicle may affect the response. In women, spironolactone may be useful when treatment with an oestrogen is contra-indicated.
1. Burke BM, Cunliffe WJ. Oral spironolactone therapy for female patients with acne, hirsutism or androgenic alopecia. Br J Dermatol 1985; 112: 124–5
2. Goodfellow A, et al. Oral spironolactone improves acne vulgaris and reduces sebum excretion. Br J Dermatol 1984; 111: 209–14
3. Muhlemann MF, et al. Oral spironolactone: an effective treatment for acne vulgaris in women. Br J Dermatol 1986; 115: 227–32
4. Messina M, et al. A new therapeutic approach to acne: an antiandrogen percutaneous treatment with spironolactone. Curr Ther Res 1983; 34: 319–24
5. Walton S, et al. Lack of effect of topical spironolactone on sebum excretion. Br J Dermatol 1986; 114: 261–4.

Alopecia.

Anti-androgens have a role in the treatment of hirsutism (see below) but have also been used in patients with androgenetic alopecia, and there is some evidence that spironolactone may be effective.1
1. Sinclair R, et al. Treatment of female pattern hair loss with oral antiandrogens. Br J Dermatol 2005; 152: 466–73.

Bartter’s syndrome.

Spironolactone may be used to reduce potassium wasting in patients with Bartter’s syndrome.

Bronchopulmonary dysplasia.

Bronchopulmonary dysplasia is a major cause of chronic lung disease in infants. Treatment often involves the use of corticosteroids. Additional supportive therapy has included the use of diuretics such as furosemide; results with hydrochlorothiazide or spironolactone have been more ambiguous.

Heart failure.

Drug therapy of heart failure is based on the use of diuretics, ACE inhibitors, cardiac glycosides, beta blockers, and vasodilators. Spironolactone has been used as a diuretic for refractory oedema, but it also has an additional role as an aldosterone antagonist.1,2 Although the precise neurohormonal mechanisms leading to the development of heart failure are still not clear, there is evidence that raised levels of aldosterone may contribute to the pathophysiology.3,4 ACE inhibitor therapy suppresses aldosterone production but this effect is not complete and the use of spironolactone with ACE inhibitors has therefore been studied. In the Randomized Aldactone Evaluation Study (RALES)5 in patients with severe heart failure, addition of spironolactone in a dose of 25 to 50 mg daily to therapy with ACE inhibitors and loop diuretics reduced the risk of death or hospitalisation,5 and the use of spironolactone should therefore be considered in such patients.6-8 A small study9 has also shown benefit in patients with less severe heart failure. However, use of spironolactone with ACE inhibitors may lead to hyperkalaemia and careful monitoring of potassium concentrations is required10,11 (see Interactions, above). A retrospective analysis12of heart failure patients found that over 10% had to stop spironolactone because of hyperkalaemia, and a further 10% stopped because of worsening renal function. Risk factors were advanced age and higher baseline plasma-potassium concentrations.
1. Tang WHW, et al. Aldosterone receptor antagonists in the medical management of chronic heart failure. Mayo Clin Proc 2005; 80: 1623–30
2. Marcy TR, Ripley TL. Aldosterone antagonists in the treatment of heart failure. Am J Health-Syst Pharm 2006; 63: 49–58
3. Struthers AD. Why does spironolactone improve mortality over and above an ACE inhibitor in chronic heart failure? Br J Clin Pharmacol 1999; 47: 479–82
4. Rocha R, Williams GH. Rationale for the use of aldosterone antagonists in congestive heart failure. Drugs 2002; 62: 723–31
5. Pitt B, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709–17
6. Hunt SA, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). Summary article: J Am Coll Cardiol 2005; 46: 1116–43. Also available at: http://circ.ahajournals.org/ cgi/reprint/112/12/e154 (accessed 07/05/08
7. The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure (update 2005). Executive summary: Eur Heart J 2005; 26: 1115–40. Full text: http://www.escardio.org/NR/ rdonlyres/8A2848B4-5DEB-41B9-9A0A-5B5A90494B64/0/ CHFFullTextehi205FVFW170505.pdf (accessed 07/05/08
8. Scottish Intercollegiate Guidelines Network. Management of chronic heart failure (February 2007). Available at: http:// www.sign.ac.uk/pdf/sign95.pdf (accessed 07/05/08)
9. Macdonald JE, et al. Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment. Heart 2004; 90: 765–70
10. Georges B, et al. Spironolactone and congestive heart-failure. Lancet 2000; 355: 1369–70
11. Juurlink DN, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351: 543–51
12. Witham MD, et al. Tolerability of spironolactone in patients with chronic heart failure—a cautionary message. Br J Clin Pharmacol 2004; 58: 554–7.

High-altitude disorders.

Acetazolamide is generally the drug of choice for prophylaxis of high-altitude disorders. Anecdotal reports1-4 and a small-scale double-blind study5 suggested that spironolactone could be useful in preventing acute mountain sickness, although a deterioration in pulmonary function despite spironolactone prophylaxis has been noted in a patient.6
1. Currie TT, et al. Spironolactone and acute mountain sickness. Med J Aust 1976; 2: 168–70
2. Snell JA, Cordner EP. Spironolactone and acute mountain sickness. Med J Aust 1977; 1: 828
3. Turnbull G. Spironolactone prophylaxis in mountain sickness. BMJ 1980; 280: 1453
4. Rutter LD. Spironolactone prophylaxis in mountain sickness. BMJ 1980; 281: 618
5. Brown GV, et al. Spironolactone in acute mountain sickness. Lancet 1977; i: 855
6. Meyers DH. Spironolactone prophylaxis of mountain sickness. BMJ 1980; 281: 1569.

Hirsutism.

Hirsutism is frequently treated with antiandrogens, usually cyproterone or spironolactone. Spironolactone in doses of 50 to 200 mg daily has produced both subjective and objective improvement in hirsutism in patients with idiopathic hirsutism or polycystic ovary syndrome,1-4 and its use has been reviewed.5 It is preferably used with oral contraceptives,6,7to improve efficacy and menstrual irregularity and to avoid the risk of feminisation to a male fetus. Most studies have involved premenopausal women and it has been suggested4,8 that spironolactone would be useful in women in whom cyproterone is contra-indicated or not tolerated. A randomised study (not placebo-controlled) found spironolactone 100 mg daily and cyproterone 100 mg daily to be equally effective,9 while a systematic review10 of the use of spironolactone in hirsutism concluded that it was significantly more effective than both cyproterone and finasteride for up to 12 months after treatment. For reference to the use of spironolactone in alopecia, see above.
1. Cumming DC, et al. Treatment of hirsutism with spironolactone. JAMA 1982; 247: 1295–8
2. Burke BM, Cunliffe WJ. Oral spironolactone therapy for female patients with acne, hirsutism or androgenic alopecia. Br J Dermatol 1985; 112: 124–5
3. Evans DJ, Burke CW. Spironolactone in the treatment of idiopathic hirsutism and the polycystic ovary syndrome. J R Soc Med 1986; 79: 451–3
4. Barth JH, et al. Spironolactone therapy for hirsute women. Br J Dermatol 1988; 119 (suppl 33): 17
5. Christy NA, et al. Spironolactone for hirsutism in polycystic ovary syndrome. Ann Pharmacother 2005; 39: 1517–21. Correction. ibid.; 1765
6. Chapman MG, et al. Spironolactone in combination with an oral contraceptive: an alternative treatment for hirsutism. Br J Obstet Gynaecol 1985; 92: 983–5
7. Rittmaster RS. Hirsutism. Lancet 1997; 349: 191–5
8. West TET. Does spironolactone have a place in treating facial hirsutism in women? BMJ 1988; 296: 1456
9. O’Brien RC, et al. Comparison of sequential cyproterone acetate/estrogen versus spironolactone/oral contraceptive in the treatment of hirsutism. J Clin Endocrinol Metab 1991; 72: 1008–13
10. Farquhar C, et al. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Available in The Cochrane Database of Systematic Reviews; Issu
4. Chichester: John Wiley; 2003 (accessed 24/06/05).

Hyperaldosteronism.

Hyperaldosteronism (aldosteronism) is a disorder characterised by mineralocorticoid excess due to high circulating levels of aldosterone.1-4 Mineralocorticoid excess due to other mineralocorticoids is rare. Primary hyperaldosteronism is usually caused by an aldosterone-producing adenoma (Conn’s syndrome) or primary adrenal hyperplasia. Other causes include aldosterone-producing adrenal carcinoma, and glucocorticoidsuppressible hyperaldosteronism. Secondary hyperaldosteronism is more common and results from conditions in which there is activation of the renin-angiotensin-aldosterone system, including diuretic therapy, and oedematous conditions such as heart failure, hepatic cirrhosis, and nephrotic syndrome. Bartter’s syndrome also results in hyperaldosteronism. Most patients with primary hyperaldosteronism are asymptomatic, although they may present with signs or symptoms of mineralocorticoid excess. Diagnosis often follows the incidental discovery of hypokalaemia. Symptomatic hypokalaemia may develop in some patients, particularly those taking diuretics. Diagnosis is confirmed by the presence of raised plasma and urinary aldosterone concentrations. However, the concentrations may be affected by serum-potassium concentration, posture, and time of day, and interpretation may be difficult. The plasma aldosterone:renin ratio may also be measured. In primary hyperaldosteronism the aldosterone concentration is raised but renin is suppressed, although this does not necessarily prove the diagnosis; in secondary hyperaldosteronism both are raised. Radiological and nuclear imaging are useful for further differentiating between adenoma and hyperplasia. Hyperaldosteronism due to an aldosterone-producing adenoma is usually treated surgically. The aldosterone antagonist spironolactone may be given pre-operatively to lower the blood pressure and normalise the serum potassium. In patients who are not suitable for surgery, long-term medical management involves spironolactone, initially in high doses but reduced to the lowest dose for maintenance. If spironolactone is not tolerated, amiloride may be used as an alternative, but high doses are required. There has also been a report5 of the successful use of eplerenone, another aldosterone antagonist; gynaecomastia had developed with spironolactone but resolved when treatment was changed to eplerenone. Trilostane, an adrenal suppressant, has been used to inhibit aldosterone synthesis. In primary adrenal hyperplasia surgery is not usually effective and medical management with spironolactone or amiloride is required. Additional antihypertensive therapy may also be needed. Glucocorticoid-suppressible hyperaldosteronism, also known as familial hyperaldosteronism type I (FH-I), is a rare autosomal dominant form and may be treated with dexamethasone. However, this may not control the blood pressure and spironolactone or amiloride may be required in addition. In secondary hyperaldosteronism the underlying condition should be treated, but spironolactone may be of benefit as part of the therapy.
1. Ganguly A. Primary aldosteronism. N Engl J Med 1998; 339: 1828–34
2. Stewart PM. Mineralocorticoid hypertension. Lancet 1999; 353: 1341–7
3. Kaplan NM. Cautions over the current epidemic of primary aldosteronism. Lancet 2001; 357: 953–4
4. Fraser R, et al. Cautions over idiopathic aldosteronism. Lancet 2001; 358: 332
5. Karagiannis A, et al. Eplerenone relieves spironolactone-induced painful gynaecomastia in a patient with primary aldosteronism. Nephrol Dial Transplant 2007; 22: 293.

Precocious puberty.

Spironolactone (as an anti-androgen) and testolactone were given to boys with familial precocious puberty for periods of up to 18 months. Rates of growth and bone maturation were restored to normal during combination therapy but not with either drug given alone.1 However, after further treatment for 2 to 4.2 years there was a diminishing response manifested by the recurrence of clinical features of puberty and an increase in the bone maturation rate.2 Addition of deslorelin appeared to restore the control of puberty,2 and in a long-term study3 growth rate remained normal for 6 years.
1. Laue L, et al. Treatment of familial male precocious puberty with spironolactone and testolactone. N Engl J Med 1989; 320: 496–502
2. Laue L, et al. Treatment of familial male precocious puberty with spironolactone, testolactone, and deslorelin. J Clin Endocrinol Metab 1993; 76: 151–5
3. Leschek EW, et al. Six-year results of spironolactone and testolactone treatment of familial male-limited precocious puberty with addition of deslorelin after central puberty onset. J Clin Endocrinol Metab 1999; 84: 175–8.

Premenstrual syndrome.

Spironolactone has been used for its diuretic and anti-androgenic properties in premenstrual syndrome.

💊 Preparations

BP 2008: Spironolactone Tablets; USP 31: Spironolactone and Hydrochlorothiazide Tablets; Spironolactone Ta b l e t s .

Proprietary Preparations

Arg.: Aldactone; Drimux A; Espimax; Expal; Lanx; Modulactone; Normital; Osiren†; Rediun-E; Austral.: Aldactone; Spiractin; Austria: Aldactone; Spirobene; Spirohexal; Spirono; Belg.: Aldactone; Docspirono; Spirotop; Braz.: Aldactone; Aldosterin†; Espirolona; Spiroctan; Canad.: Aldactone; Novo-Spiroton; Chile: Alizar; Cardactona; Cz.: Spirolone†; Uractone†; Verospiron; Xenalon†; Denm.: Hexalacton; Spirix; Spiron; Fin.: Aldactone; Spiresis; Spirix; Fr.: Aldactone; Flumach; Practon; Spiroctan; Spironone; Ger.: Aldactone; Aquareduct†; duraspiron†; Jenaspiron; Osyrol; Spiro; Spirobeta; Spirogamma; Spirono; Verospiron; Gr.: Aldactone; Uridactone†; Hong Kong: Aldactone; Hung.: Huma-Spiroton; Spirolone†; Spiron; Verospiron; India: Aldactone; Indon.: Aldactone; Carpiaton; Letonal; Spirola; Irl.: Aldactone; Israel: Aldactone; Aldospirone; Spironol; Ital.: Aldactone; Spiroderm†; Spirolang; Uractone; Mex.: Aldactone; Biolactona; Quimolactona†; Vivitar; Neth.: Aldactone; Norw.: Aldactone; Spirix; NZ: Aldactone†; Spirotone; Philipp.: Aldactone; Pol.: Spironol; Verospiron; Port.: Aldactone; Aldonar; Nefrolactona†; Rus.: Aldactone (Альдактон)†; Verospiron (Верошпирон); S.Afr.: Aldactone; Spiractin; Singapore: Aldactone; Uractonum; Spain: Aldactone; Swed.: Aldactone; Spirix; Spiroscand†; Switz.: Aldactone; Primacton; Xenalon; Thai.: Aldactone; Altone; Berlactone†; Hyles; Pondactone; Spironex†; Turk.: Aldacton; UK: Aldactone; Spirospare†; USA: Aldactone; Venez.: Aldactone; Spiroctan†. Multi-ingredient: Arg.: Aldactone-D; Aldazida; Lasilacton; Austria: Aldactone Saltucin; Buti-Spirobene; Deverol mit Thiazid; Digi-Aldopur; FuroAldopur; Furo-Spirobene; Furolacton; Lasilacton; Sali-Aldopur; Spirono comp; Supracid; Belg.: Aldactazine; Docspirochlor; Braz.: Aldazida; Lasilactona; Canad.: Aldactazide; Novo-Spirozine; Cz.: Spiro Compositum†; Fr.: Aldactazine; Aldalix; Practazin; Spiroctazine; Ger.: Aldactone Saltucin†; duraspiron-comp†; Furo-Aldopur; Furorese Comp; Osyrol Lasix; Risicordin†; Sali-Aldopur†; Spiro comp; Spiro-D; Spironolacton Plus†; Spironothiazid; Spirostada comp†; India: Lasilactone; Spiromide; Indon.: Aldazide; Irl.: Aldactide; Ital.: Aldactazide; Lasitone; Spiridazide; Spirofur; Mex.: Aldazida; Lasilacton; Philipp.: Aldazide; Port.: Aldactazine; Ondolen; S.Afr.: Aldazide; Spain: Aldactacine; Aldoleo; Miscidon†; Spirometon; Switz.: Aldozone; Furocombin; Furospir; Lasilactone; Turk.: Aldactazide; UK: Aldactide; Lasilactone; USA: Aldactazide; Venez.: Aldactazida; Teradal†.
Published May 08, 2019.