Spironolactone

Spironolactone is a mineralocorticoid receptor antagonist that is also a weak anti-androgen. It reduces death and admission in heart failure with reduced ejection fraction, treats resistant hypertension, primary aldosteronism and ascites in cirrhosis, and is used for acne and hirsutism in women. Its main danger is hyperkalaemia, especially when given with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in kidney impairment. It is cheap and widely available in East Africa.

Classification. Aldosterone antagonist; potassium sparing diuretic.

Mechanism. Competes with aldosterone at the mineralocorticoid receptor in the distal nephron, reducing sodium reabsorption and potassium and hydrogen ion loss. It also blocks androgen receptors and lowers testosterone synthesis, and it reduces myocardial fibrosis.

Pharmacodynamics. Onset of diuresis is slow: the maximum effect is reached after 3 to 5 days. Blood pressure effect builds over 2 to 4 weeks. Raises serum potassium and lowers magnesium loss.

Pharmacokinetics. Oral bioavailability about 70%; food raises absorption. Half life of the parent drug is 1.5 hours; active metabolites (canrenone, 7 alpha thiomethylspironolactone) have half lives of 14 to 16 hours. Metabolised in the liver; excreted in urine and bile.

Heart failure with reduced ejection fraction, adult.

• Start 12.5 to 25 mg once daily, only if potassium is 5.0 mmol/L or less and eGFR is above 30 mL/min.

• Increase to 25 to 50 mg once daily after 4 to 8 weeks if potassium stays under 5.0 mmol/L.

• Target 25 to 50 mg once daily; maximum 50 mg daily in heart failure.

Resistant hypertension, adult. Start 12.5 to 25 mg once daily; increase to 50 mg after 4 weeks; usual maintenance 25 to 50 mg; maximum 100 mg daily.

Primary aldosteronism, adult. 100 to 400 mg daily in 1 to 2 doses before surgery; maintenance 25 to 100 mg daily when treated medically, titrated to potassium and blood pressure.

Ascites in cirrhosis, adult. Start 100 mg once daily in the morning (with furosemide 40 mg); increase both together every 3 to 7 days in the ratio 100 mg to 40 mg, to a maximum of spironolactone 400 mg and furosemide 160 mg daily. Target weight loss 0.5 kg daily (1 kg daily with leg oedema).

Nephrotic syndrome and other oedema, adult. 100 to 200 mg daily (maximum 400 mg), reduced to the lowest effective dose.

Acne and hirsutism in women (off label, specialist). 50 to 100 mg daily, up to 200 mg daily; reliable contraception is required.

Children. Oedema and heart failure: 1 to 3 mg/kg daily in 1 or 2 divided doses (maximum 100 mg daily).

Contraindications. Hyperkalaemia (potassium above 5.5 mmol/L); Addison disease; anuria; severe kidney impairment (eGFR under 30 mL/min) in heart failure or hypertension; hypersensitivity; concurrent eplerenone.

Warnings. Hyperkalaemia, which can be fatal; hyponatraemia; kidney function decline; gynaecomastia and breast pain in men (dose related, usually reversible); menstrual irregularity. Stop in dehydrating illness (sick day rule). Give with care when an angiotensin converting enzyme inhibitor or angiotensin receptor blocker is used together. May interfere with some digoxin assays.

Adverse effects. Hyperkalaemia, gynaecomastia, breast tenderness, menstrual disturbance, erectile dysfunction, reduced libido, hyponatraemia, nausea, rash, rarely agranulocytosis.

Interactions. Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, potassium supplements, trimethoprim, ciclosporin and tacrolimus: hyperkalaemia. Non steroidal anti-inflammatory drugs: kidney injury and reduced effect. Digoxin: raised levels and assay interference. Lithium: raised levels. Salicylates reduce effect. Heparin raises potassium.

Special groups.

• Pregnancy: avoid; anti-androgen effect on a male foetus (feminisation).

• Breastfeeding: canrenone enters milk in small amounts; usually acceptable, with infant monitoring.

• Patients of African ancestry: effective in resistant hypertension and low renin states; heart failure benefit is shown in all groups.

• Older adults: start 12.5 mg daily; high risk of hyperkalaemia.

• Kidney impairment: avoid with eGFR under 30 mL/min unless specialist care; start 12.5 mg daily or on alternate days at eGFR 30 to 50 mL/min.

• Liver impairment: used in ascites; monitor sodium, potassium and creatinine closely.

Formulations. Tablets 25, 50, 100 mg; oral suspension in some markets; combinations with hydrochlorothiazide or furosemide in some markets.

Administration. Oral with food, once daily in the morning (or in 2 doses at higher doses).

Baseline. Blood pressure, potassium, sodium, creatinine and eGFR, current drugs affecting potassium, pregnancy test in women.

Monitoring. Potassium and creatinine at 1 week and 4 weeks after starting or any dose increase, then every 3 to 6 months. Halve the dose if potassium is above 5.5 mmol/L; stop and treat if potassium is above 6.0 mmol/L or creatinine rises by more than 30%. Daily weight in ascites.

Stopping. No taper. Hold on sick days with vomiting or diarrhoea.

Common prescribing errors. Starting at 50 mg or higher in heart failure; giving with potassium supplements; omitting a potassium check at 1 week; continuing when potassium is above 5.5 mmol/L; not checking eGFR first.