Potassium Sparing Diuretics and Aldosterone Antagonists

Potassium-sparing diuretics

Potassium-sparing diuretics (amiloride and triamterene) inhibit sodium reabsorption in the distal convoluted tubule and cause retention of potassium and magnesium. They have weak diuretic action and are mainly used in combination with thiazides or loop diuretics to conserve potassium as a more effective alternative to giving potassium supplements.

Aldosterone antagonists

• Spironolactone is also a potassium-sparing diuretic via its action blocking aldosterone's activation of the Na+/K+ pump in the distal convoluted tubule. This results in net sodium loss and potassium retention. Compared to triamterene and amiloride, spironolactone has a delayed onset of action as it works via changes in gene transcription. It is used to potentiate thiazide or loop diuretics and is particularly useful in the treatment of severe heart failure.
• Eplerenone¹ is used in stable patients with left ventricular failure (left ventricular ejection fraction of 40% or less) and heart failure following myocardial infarction,² primarily in those who cannot tolerate the side-effects of spironolactone.

Combination formulations

• Thiazide plus potassium-sparing diuretic - Co-amilozide, Navispare®, Co-triamterzide, Dyazide®, Dytide® and Kalspare®
• Loop plus potassium-sparing diuretic - Co-amilofruse, Frusene®
• Spironolactone plus thiazide diuretic- Co-flumactone
• Spironolactone plus loop diuretic - Lasilactone®

Potassium conservation

Potassium sparing diuretics are used to counteract potassium loss associated with thiazide and loop diuretics.

In addition, spironolactone's uses include:

Treatment of oedema and ascites

Used to treat oedema and ascites associated with:

• Cirrhosis:
  • Useful with the secondary hyperaldosteronism of hepatic cirrhosis.
  • Typical dose of 100-200 mg o.d.
  • Monitor response with daily weights (loss should be limited to 0.5 kg/day in patients without peripheral oedema, 1 kg/day in those with peripheral oedema).
  • Additional diuresis with low-dose loop diuretic may be required but hepatorenal syndrome may occur with overly aggressive therapy.
  • Paracentesis and transjugular intrahepatic portosystemic shunts (TIPS) are further options for refractory ascites.³
• Malignancy: spironolactone can be used to treat malignant ascites as in hepatic cirrhosis.⁴
• Nephrotic syndrome:
  • Used in conjunction with loop diuretics where there is massive oedema and low urinary sodium excretion.
  • Results can be disappointing as very high doses of spironolactone may be required (up to 600 mg daily) where side-effects (particularly nausea) usually limit treatment.^5,6

Congestive heart failure

• In low dose with loop diuretic and ACE Inhibitors (ACEI), spironolactone reduces mortality in those with advanced heart failure (NYHA class III and IV) and guidance suggests it should be used as part of routine management of these patients.⁷
• The RALES study⁸ looked at the addition of low dose spironolactone(12.5-50 mg) to ACEI, loop diuretic and digoxin. It was stopped early when interim analysis showed a 30% reduction in death in the spironolactone wing of the trial.
• The benefit of aldosterone antagonists to those with heart failure is related to the antialdosterone action as the low dose is insufficient to achieve significant diuresis.
• Increasing the dose increases the risk of of hyperkalaemia (particularly since these patients are likely to be also taking an ACEI) and, usually, a daily dose of 25 mg is recommended. 50 mg may be recommended by a specialist if heart failure is worsening and serum potassium is normal.

Post MI

• The EPHESUS study⁹ looked at the role of eplerenone post-acute myocardial infarction complicated by left ventricular dysfunction and heart failure. Where started between 3-14 days post infarct, eplerenone reduced mortality (by 15%) and morbidity.
• No evidence of spironolactone's efficacy nor comparative studies of eplerenone versus spironolactone exist for this clinical scenario, so spironolactone, despite its cheaper cost, should not be substituted.¹⁰

Primary hyperaldosteronism (Conns syndrome)

Specialist use for diagnosis, pre-surgical treatment and symptom palliation.

Low renin hypertension

• Spironolactone is recommended as a fourth-line drug for use in resistant hypertension in current BHS guidelines.¹¹ Eplerenone is not currently licensed for the treatment of hypertension in the UK.
• There is current research interest in the group of hypertensives with normal K⁺ and aldosterone but elevated aldosterone-renin ratios. This comparatively common group do not have classic primary hyperaldosteronism, but appear more likely to have 'resistant' hypertension and may benefit from more targeted antihypertensive treatment.¹²
• In the recent SALT (Spironolactone, Amiloride, Losartan and Thiazide) trial,¹³ bendroflumethiazide 5 mg was found to be as effective as spironolactone 100 mg at lowering blood pressure in this patient group. However, spironolactone was a better natriuretic agent, raising plasma renin 4-fold (compared to 2-fold on bendroflumethiazide) - suggesting that inappropriate aldosterone release or response may still contribute to the Na⁺ retention of low-renin hypertension.

Hirsutism

Note, this is an unlicensed specialist use.

• Spironolactone in high dose acts as an anti-androgen, competitively inhibiting testosterone binding to the androgen receptor.
• It reduces scores of hirsutism by 15-40% within 6 months of treatment, with maximal effect seen between 9 and 12 months.¹⁴
• It appears more effective than finasteride and low dose cyproterone acetate in treating hirsutism even up to 12 months following the end of treatment.¹⁵
• The combined oral contraceptive pill should be used simultaneously to prevent pregnancy and to complement anti-androgen action.

Include:

• Hyperkalaemia
• Concurrent use of other potassium-sparing products¹⁶
• Hyponatraemia
• Renal failure, anuria, diabetic nephropathy¹⁶
• Addison's disease (spironolactone)
• Pregnancy and breastfeeding (spironolactone)

Include:

• Co-administration of an ACEI or angiotensin 2 receptor antagonist
• Diabetes mellitus
• Renal impairment
• Hepatic impairment (aldosterone antagonists)
• Pregnancy and breastfeeding (potassium-sparing diuretics)
• The elderly
• Porphyria (spironolactone)¹⁷
• Patients undergoing anaesthesia (spironolactone reduces vascular responsiveness to noradrenaline)

Include:

• Gastro-intestinal disturbances (nausea, abdominal pain, flatulence) and GI bleeding¹⁸
• Rashes
• Postural hypotension
• Electrolyte disturbances (hyperkalaemia, hyponatraemia)
• Blue fluorescence of urine (amiloride)
• Gynaecomastia (10% incidence in RALES⁸), menstrual irregularities, impotence (spironolactone)
• Triamterene inhibits dihydrofolate reductase and can cause folate deficiency - avoid in those trying to conceive or already pregnant

Include:

• Potassium supplements should not be prescribed with potassium-sparing diuretics as this will lead to hyperkalaemia.
• Increased risk of hyperkalaemia with co-prescription of ACEI and angiotensin 2 receptor antagonists (this can be severe), ciclosporin and tacrolimus, NSAIDs (particularly indomethacin), trimethoprim (use another suitable antibiotic).
• Increased risk of nephrotoxicity when NSAIDs given with potassium sparing diuretics or aldosterone antagonists.
• Spironolactone increases plasma concentrations of digoxin.
• Aldosterone antagonists increase plasma concentrations of lithium (due to decreased excretion) and raises the risk of toxicity.
• CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, amiodarone) increase eplerenone plasma concentrations whilst CYP3A4 inducers (e.g. St Johns Wort or rifampicin) decrease its concentration.

Potassium sparing diuretics

• When potassium sparing diuretics are used to address hypokalaemia:¹⁹
  • Measure fluid and electrolyte status prior to starting treatment and usually on a weekly basis until potassium concentration is stable.
  • Thereafter regular monitoring may be required, particularly in the elderly and those with renal or hepatic impairment. This may be 1-2 times a year up to every 1-2 months depending on the degree of risk.
  • Stop if serum potassium is over 6 mmol/l or if renal impairment develops (serum creatinine>130 μmol/l).

Spironolactone^7,20

• Start at 25 mg once daily. Check blood chemistry at 1,4, 8 and 12 weeks; 6, 9 and 12 months and 6 monthly thereafter (unless there is any change in therapy, intercurrent illness or worsening renal impairment).
• If hyperkalaemia (5.5-5.9 mmol/l) or creatinine rises to 200 μmol/l, reduce the dose to 25 mg on alternate days and monitor blood chemistry intensively
• If serum potassium is 6.0 mmol/l or greater or creatinine more than 200 μmol/l, stop spironolactone and seek specialist help.
• Hyperkalaemia is a major concern in the combination of ACEI and spironolactone but significant hyperkalaemia (≥6.0 mmol/l) was uncommon in the RALES study⁸ with the low doses of spironolactone used. However, RALES excluded patients with an initial serum creatinine of greater than 221 μmol/l or potassium greater than 5 mmol/l.
• A US study,²¹ however, suggested that many patients receiving spironolactone for congestive heart failure are inadequately followed-up and are at risk of developing hyperkalaemia (15% developed hyperkalaemia and 6% developed severe hyperkalaemia within 3 months of starting treatment). Elevated baseline serum creatinine predicts those at highest risk. Another study has linked the increased prescription of spironolactone post-RALES to increased admissions for hyperkalaemia.²²

Eplerenone²

• Eplerenone is usually started on day 3-14 following an MI.
• Check serum potassium at outset of therapy - do not commence where >5.0 mmol/l.
• Usual initial dose is 25 mg o.d., increasing to maintenance dose of 50 mg o.d. over 4 weeks according to regular serum potassium checks.
• Where serum potassium is between 5.5-6 mmol/l, reduce dose and maintain vigilance and if over 6 mmol/l stop the drug.

With spironolactone:²⁰

• Symptom improvement occurs within a few weeks to months of starting treatment (i.e. not immediately).
• Avoid NSAIDs not prescribed by a doctor.
• Temporarily stop spironolactone if diarrhoea and/or vomiting and contact your doctor.