Aldosterone antagonists: mechanism and hyperkalaemia
Aldosterone antagonists such as spironolactone block aldosterone (a salt-retaining hormone), so less potassium is pulled into the urine and hyperkalaemia (a high blood potassium) can follow.
Remember
Blocking aldosterone means less sodium reabsorption and less potassium secretion, so potassium is spared and hyperkalaemia is the characteristic risk.
Aldosterone is a steroid hormone released by the adrenal cortex (the outer layer of the adrenal gland). In the kidney it acts on the principal cells of the late distal convoluted tubule and collecting duct, the last stretches of each nephron. These cells reabsorb sodium and secrete potassium, which means they pass it out into the urine.
Aldosterone increases the number of epithelial sodium channels (ENaC, the pores through which sodium enters from the urine) and the activity of the sodium-potassium pump. Sodium moving in leaves the lumen (the space inside the tubule) electrically negative, and that pulls potassium out into the urine.
An aldosterone antagonist such as spironolactone blocks the hormone's effect at its receptor, so ENaC activity falls and less sodium is reabsorbed. Sodium and water are lost, giving a mild diuresis (extra urine). The lumen becomes less negative, the cells lose the stimulus to secrete potassium, and potassium can build up in the blood. Potassium is spared, which is why these drugs are called potassium-sparing diuretics, and hyperkalaemia can follow.
Loop diuretics (such as furosemide, which blocks sodium-potassium-chloride transport in the thick ascending limb, the thick-walled rising part of the loop of Henle) and thiazides (such as bendroflumethiazide) have the opposite effect on potassium. They send extra sodium and fluid to the distal nephron, so they usually cause hypokalaemia (a low blood potassium). That is why a potassium-sparing drug is usually combined with a potassium-losing one.
Key facts
- Site
- the principal cells of the late distal convoluted tubule and collecting duct.
- Mechanism
- blocking aldosterone lowers ENaC activity, so less sodium is reabsorbed.
- Main example
- spironolactone is the main aldosterone antagonist, and eplerenone is another.
- Key adverse effect
- hyperkalaemia, because potassium secretion falls.
- Warning signs
- muscle weakness, tiredness, numbness and an irregular heartbeat can signal hyperkalaemia.
- Extra potassium
- potassium-rich foods and salt substitutes such as Lo-Salt can raise potassium further in someone taking spironolactone.
- Some uses
- heart failure, hypertension (when other medicines have not worked) and oedema.
Exam traps
- Increased ENaC activity does not retain potassium. It is what aldosterone itself causes, and it increases potassium secretion, so an antagonist lowers it.
- Blocking sodium-chloride transport in the early distal convoluted tubule borrows the right outcome (less potassium secreted) but gives the wrong mechanism. That is the thiazide mechanism, and thiazides increase potassium loss, while aldosterone antagonists block the hormone's effects.
- Furosemide usually causes hypokalaemia, not hyperkalaemia. It sends more sodium to the collecting duct, which increases potassium loss.
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