Introduction

As their name suggests, potassium-sparing diuretics are medicines that “spare”, or prevent, potassium loss. Here, we talk about potassium-sparing diuretics pharmacology, why they are used and how they achieve their clinical effects.

Potassium-sparing diuretics retain potassium ions where other diuretics do not. As a result, these medicines may be used to prevent and/or treat hypokalemia.

Hypokalemia is a clinical hazard. Symptoms include:

  • Fatigue
  • Leg cramps
  • Weakness
  • Constipation
  • Increased risk of arrhythmias
  • In severe cases, respiratory depression and cardiac arrest

Potassium-sparing diuretics are used, then, as part of combination therapy in the prevention / treatment of hypokalemia. Hypokalemia may be caused as a result of other diuretics – such as loop or thiazide diuretics – that promote potassium loss. Other causes of hypokalemia include vomiting, diarrhea, diabetes type 2, hyperaldosteronism and hypomagnesemia.

Drugs such as spironolactone may also be used to treat ascites / edema due to liver cirrhosis and in the treatment of primary hyperaldosteronism.

Combination medicines – with a potassium-sparing diuretic and either a loop or thiazide diuretic – have been developed and are widely used in clinical practice. Examples include:

  • Co-amilofruse – amiloride and furosemide (loop diuretic)
  • Co-amilozide – amiloride and hydrochlorothiazide (thiazide diuretic)

Combination medicines may be used, for instance, in treating congestive heart failure where the thiazide or loop diuretic tends to cause hypokalemia. The ratio of both drugs has been carefully calibrated to ensure that it minimally impacts potassium levels.

In clinical reality, though, this is not always achievable and electrolyte disturbances may manifest.

Pharmacology of Potassium-Sparing Diuretics

Here, we review the two primary drug classes with potassium-sparing effects – epithelial sodium channel blockers and aldosterone antagonists.

Epithelial sodium channel blockers

Examples: amiloride, triamterene

Mechanism of action

Amiloride is a relatively weak diuretic.

However, when amiloride is used alongside another diuretic, it enhances total diuresis and counteracts potassium loss to a greater extent than it otherwise would on its own. In the nephron, amiloride acts on the distal convoluted tubule.

By blocking epithelial sodium channels in the distal tubule, amiloride works to reduce sodium reabsorption and, by extension, facilitates water elimination. It enhances potassium reabsorption via the same means.

Side effects

Side effects with amiloride include:

  • Gastrointestinal upset – nausea, vomiting, loss of appetite
  • Dizziness
  • Headache
  • Skin rash
  • Hypotension
  • Hyperkalemia – a risk higher in patients with type 2 diabetes, kidney disorders or in older patients.

Clinical considerations

Clinical considerations with potassium-sparing diuretics include:

  • Avoid in severe renal impairment / end-stage renal disease.
  • Avoid in hyperkalemia.
  • Do not commence combination therapy in patients with established hypokalemia, as the effects of the medicine become more unpredictable.
  • Diuretics should be avoided in cases of hypovolemia.
  • Avoid with potassium-elevating supplements and/or drugs, including aldosterone antagonists (see below).
  • As a diuretic, amiloride may impair elimination of other drugs, including drugs with a narrow therapeutic index such as lithium or digoxin.
  • Diuretics should be taken in the morning to avoid nocturia.

Aldosterone antagonists

Examples: spironolactone, eplerenone

Mechanism of action

Aldosterone is a hormone produced from the adrenal cortex; a hormone responsible for acting on mineralocorticoid receptors in the distal convoluted tubule. There, aldosterone enhances sodium and water reabsorption through its activity on luminal epithelial sodium channels (ENaC) – increasing blood volume and blood pressure. Aldosterone also encourages potassium loss.

By acting as aldosterone antagonists – drugs, such as spironolactone, reverse the above effects. Clinically, this manifests as enhanced sodium and water elimination and an increase in potassium levels. Canrenone is the active metabolite of spironolactone.

Aldosterone antagonists may be used to treat ascites and edema due to cirrhosis. They may also be used to treat heart failure or in primary hyperaldosteronism. Eplerenone is mostly reserved for heart failure only.

Side effects

Side effects with spironolactone include:

  • Urinary frequency
  • Mild hypotension
  • Hyperkalemia
  • Gynecomastia
  • Sexual dysfunction – due to their antiandrogen activity
  • Electrolyte abnormalities
  • GI effects – nausea, vomiting
  • Headache, drowsiness, dizziness
  • Rash – rarely, Stevens-Johnson syndrome
  • Mood changes
  • Menstrual disturbances
  • Rarely, hepatotoxicity

Clinical considerations

Clinical considerations with aldosterone antagonists include:

  • Avoid in severe / end-stage renal disease.
  • Avoid in hyperkalemia.
  • Avoid in Addison’s disease (a disease characterised by aldosterone deficiency)
  • Avoid in pregnant / lactating women. Spironolactone crosses the placenta during pregnancy and is present in breast milk.
  • Other potassium-elevating drugs, such as ACE inhibitors and angiotensin-receptor blockers, increase the risk of hyperkalemia. However, the combination may be deemed clinically beneficial in cases of heart failure.
  • Avoid potassium supplements.
  • Bioavailability of spironolactone is significantly enhanced when taken with food.
  • Spironolactone is a weak diuretic that takes several days to take effect. For this reason, it is frequently taken alongside another diuretic – such as a loop or thiazide diuretic – to counteract potassium loss and promote overall diuresis.

The clinical pharmacology of potassium-sparing diuretics is important. Both epithelial sodium channel blockers and aldosterone antagonists are widely used in clinical practice. However, they also come with their own risks and interactions. Where appropriate, then, their use and effects should be closely monitored.

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