Potassium-sparing diuretics induce diuresis while retaining potassium. They are particularly useful in patients requiring diuresis who are at risk of hypokalaemia. Agents such as amiloride hydrochloride and triamterene act by binding to epithelial sodium channels (ENaCs), preventing sodium reabsorption in the collecting tubule of the kidney. This reduces the electrical potential across the tubular epithelium, thereby decreasing potassium secretion. Used alone, they are weak diuretics, but in combination with thiazide or loop diuretics they effectively reduce potassium loss, serving as an alternative to potassium supplementation. In the UK, there are no licensed formulations of triamterene as monotherapy, but it is available in a combination product with chlortalidone, a thiazide-like diuretic. Spironolactone and eplerenone (mineralocorticoid receptor antagonists) are also potassium-sparing diuretics, though their mechanism differs. They competitively antagonise aldosterone binding to its receptor at the aldosterone-dependent sodium-potassium exchange site in the distal tubule, promoting sodium excretion while reducing potassium loss. Eplerenone is more selective for mineralocorticoid receptors, whereas spironolactone also binds androgen receptors, which can lead to endocrine effects such as gynecomastia or altered PSA levels in prostate cancer patients treated with abiraterone. Indications Spironolactone: oedema and ascites in liver cirrhosis, adjunct in heart failure, resistant hypertension, nephrotic syndrome, and diagnosis/treatment of primary hyperaldosteronism (Conn’s syndrome). Eplerenone: adjunct in left ventricular dysfunction post-myocardial infarction and in chronic mild heart failure with systolic dysfunction. Adobe stock images Fig 1: Diuretics and the kidney Pharmacokinetics The following table describes the pharmacokinetics of potassium-sparring diuretics: Drug (oral) Absorption/Distribution Metabolism Excretion Half-life Amiloride F ≈ 50%; Tmax 3–4 h; not protein bound Not metabolised Renal (proximal tubule) ~6 h Triamterene Rapid, incomplete absorption; Tmax 1 h; 55% protein bound (91% for metabolite) Extensive metabolism → active metabolite Renal Variable Spironolactone Tmax 2.6 h; protein binding >90%; slow onset, prolonged effect Extensive → active metabolites Renal & biliary Parent: 1.3 h; metabolites: 2.8–11.2 h Eplerenone F ≈ 69%; Tmax 1.5–2 h; absorption not affected by food; protein binding 50% CYP3A4 metabolism, no active metabolites 67% renal, 32% faecal 3–6 h Contraindications General: hyperkalaemia (specifically eplerenone and triamterene/chlortalidone are contraindicated if serum potassium level >5mmol/L at initiation), severe renal impairment, combination with other potassium-sparing diuretics or potassium supplements. Eplerenone: contraindicated if CrCl <30 mL/min, severe hepatic impairment (Child-Pugh C), or with strong CYP3A4 inhibitors. Spironolactone & Triamterene: contraindicated in Addison’s disease (occurs due to a mineralocorticoid and glucocorticoid deficiency) Amiloride: contraindicated in severe renal impairment. Adverse Effects and Cautions For Use The most significant adverse effect for potassium-sparing diuretics is hyperkalaemia. This is more likely to occur in elderly/poor renal function and ongoing monitoring of serum potassium levels is required. Mineralocorticoid receptor antagonists can also cause gynaecomastia and a raised blood urea level. Both effects are usually reversible upon discontinuation of treatment. Furthermore, eplerenone can also cause metabolism and nutrition disorders such as hypercholesterolaemia, hyponatraemia and hypothyroidism. Triamterene can also cause blue fluorescence of urine. General cautions: use carefully in elderly, diabetics, those prone to acidosis (amiloride) and patients with hepatic or renal impairment. Interactions Hyperkalaemia risk ↑: with ACE inhibitors, ARBs, co-trimoxazole, ciclosporin, tacrolimus, potassium supplements. Mineralocorticoid antagonists and ACE-inhibitors both block effects of aldosterone and when used together increase the risk of hyperkalemia, however are used together for heart failure (monitoring of serum potassium levels is required). Additive hypotensive effect with antihypertensives, antipsychotics: chlorpromazine and prochlorperazine, MAOIs and TCAs (postural hypotension)). NSAIDs: ↑ renal failure risk and reduce efficacy; aspirin and indomethacin antagonise the effects of diuretics due to inhibition of prostaglandin synthesis Eplerenone: metabolised by CYP3A4 Contraindicated with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, nefazadone) Dose reduction required with mild to moderate inhibitors of CYP3A4 (e.g., eythromycin, amiodarone, diltiazem, verapamil, fluconazole) Not recommended with strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s wort) Other specific interactions that are significant for potassium-sparing diuretics include the following: Amiloride: stop ≥3 days before glucose tolerance test. Carbamazepine: increased risk of hyponatraemia Digoxin level increased by spironolactone and eplerenone, spironolactone can also interfere with certain serum digoxin assays Lithium: toxicity risk when combined with diuretics or ACE inhibitors due to reduced renal clearance of lithium. If concomitant administration is required, lithium monitoring should take place Created using AIFig 2: Hyperkalaemia causing medications References Spironolactone 12.5 mg Film-coated Tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 3/3/25 Eplerenone 25 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 3/3/2025 Eplerenone | Drugs | BNF | NICE accessed 3/3/2025 Diuretics | Treatment summaries | BNF | NICE accessed 3/3/2025 ALDACTONE® (spironolactone) Clinical Pharmacology | Pfizer Medical Information – US Accessed 6/3/2025 Amiloride 5mg Tablets – Summary of Product Characteristics (SmPC) – (emc) accessed 6/3/2025 Triamterene/Chlortalidone 50mg/50mg film-coated tablets SPC. available from MHRA. Accessed 11.3.25 https://bnf.nice.org.uk/drugs/triamterene/ accessed 11.3.25 Knauf H, Möhrke W, Mutschler E. Delayed elimination of triamterene and its active metabolite in chronic renal failure. Eur J Clin Pharmacol. 1983;24(4):453-6. doi: 10.1007/BF00609885. PMID: 6861860. Recommendations | Chronic heart failure in adults: diagnosis and management | Guidance | NICE accessed 12/3/25 Do you think you’re ready? Take the quiz below Pro Feature - Quiz Potassium-Sparring Diuretics Question 1 of 3 Submitting... Skip Next Rate question: You scored 0% Skipped: 0/3 More Questions Available Upgrade to TeachMePharmacy Pro Challenge yourself with over 2100 multiple-choice questions to reinforce learning Learn More Rate This Article