Potassium-sparing diuretics induce diuresis while retaining potassium. They are particularly useful in patients requiring diuresis who are at risk of hypokalaemia. 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. The following article describes the mechanism of action, indications for use, cautions and adverse effects, contraindications and clinically significant interactions for potassium-sparring diuretics. Mechanism of Action Agents such as amiloride hydrochloride and triamterene act by binding to epithelial sodium channels (ENaCs), preventing sodium reabsorption in the collecting tubules and collecting ducts of the kidney. This reduces the electrical potential across the tubular epithelium, thereby decreasing potassium secretion. 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. Used alone, potassium sparring diuretics are weak, as distal Na+/K+ exchange only accounts for about 2% of filtered sodium. However in combination with thiazide or loop diuretics they effectively reduce potassium loss, serving as an alternative to potassium supplementation and prolong survival in patients with heart failure. 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) Partly metabolised in liver Renal Variable Spironolactone Tmax 2.6 h; protein binding >90%; slow onset, prolonged effect Extensive metabolism; prodrug converted to canrenone Renal & biliary Spironolactone: 10 min; Canrenone: 16h 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 All potassium sparring diuretics are contraindicated in hyperkalaemia (specifically eplerenone and triamterene/chlortalidone are contraindicated if serum potassium level >5mmol/L at initiation), severe renal impairment and in combination with other potassium-sparing diuretics or potassium supplements. Specifically, eplerenone is contraindicated if when CrCl <30 mL/min, in severe hepatic impairment (Child-Pugh C), or with strong CYP3A4 inhibitors. Spironolactone and triamterene are contraindicated in Addison’s disease which occurs due to a mineralocorticoid and glucocorticoid deficiency. 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. Spironolactone can also cause gynaecomastia, menstrual disorders and testicular atrophy due to its action on progesterone and androgen receptors, this effect is less likely with eplerenone due to a lower affinity for these receptors but still possible. Furthermore, a raised blood urea level can occur with treatment. 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. Generally, potassium-sparring diuretics should be used carefully in elderly, diabetics, those prone to acidosis (amiloride) and patients with hepatic or renal impairment. Furthermore, gastrointestinal upset is common. Interactions Hyperkalaemia risk is increased when used 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 frequently used together for heart failure (monitoring of serum potassium levels is required). There is an additive hypotensive effect when potassium sparring are used with antihypertensives, antipsychotics: chlorpromazine and prochlorperazine, MAOIs and TCAs (postural hypotension). NSAIDs increase the risk of renal failure and reduce efficacy of potassium-sparring diuretics; aspirin and indomethacin antagonise the effects of diuretics due to inhibition of prostaglandin synthesis 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 CYP3A4 Mediated Interactions Eplerenone is 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) 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 Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019. 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 200 multiple-choice questions to reinforce learning. Learn More Rate This Article