Why thiazide diuretics cause hypokalaemia
Thiazide diuretics (for example bendroflumethiazide) cause hypokalaemia (low blood potassium) indirectly, because extra sodium reaches the collecting duct (the final drainage channel) and potassium is lost in the urine.
Remember
Thiazides do not act on potassium directly: by blocking sodium reabsorption early on, they send more sodium to the collecting duct, and its uptake there pulls potassium into the urine.
A thiazide diuretic blocks the sodium-chloride cotransporter (NCC, a protein that carries sodium and chloride from the urine into the cell) in the early distal convoluted tubule, a section of the nephron. More sodium and water then flow on to the late distal tubule and the collecting duct.
Two things then push potassium into the urine. The principal cells (the cells that reabsorb sodium and secrete potassium) take up the extra sodium. Removing positively charged sodium from the urine leaves the lumen electrically negative, which favours potassium leaving through potassium channels on the urine-facing surface of the cell. The faster flow also washes secreted potassium away, so its concentration in the lumen stays low and secretion carries on. Fluid loss from the diuretic also tends to raise aldosterone (the adrenal hormone that tells the kidney to hold on to sodium and release potassium), which adds to the potassium loss.
The result can be hypokalaemia. It is an indirect effect: thiazides do not act on potassium transport directly, and the potassium loss occurs downstream of the thiazide target. Loop diuretics (a different class, such as furosemide) carry the same risk by the same route.
Thiazides also tend to produce a mild metabolic alkalosis. Extra sodium delivery also drives hydrogen ion secretion by intercalated cells (the acid-secreting cells of the collecting duct), and this extra acid loss gives the mild alkalosis, meaning the blood is too alkaline because bicarbonate rises.
Serum potassium is checked in patients taking a thiazide, particularly when other potassium-lowering factors are present.
Key facts
- Site of action
- thiazides block the sodium-chloride cotransporter in the early distal convoluted tubule.
- Where potassium is lost
- downstream of the thiazide target, in the late distal tubule and collecting duct.
- Electrical effect
- sodium reabsorbed by principal cells makes the lumen more negative, which favours potassium secretion.
- Flow effect
- faster flow washes secreted potassium away, keeping the gradient for secretion favourable.
- Acid-base change
- thiazides tend to produce a hypokalaemic metabolic alkalosis.
- Opposite effect
- spironolactone and amiloride raise potassium instead.
Exam traps
- Thiazides do not directly inhibit potassium reabsorption in the proximal convoluted tubule (the segment nearest the glomerulus), because they act in the early distal convoluted tubule and the potassium loss arises further downstream.
- Thiazides do not waste potassium by lowering aldosterone (the adrenal hormone that tells the kidney to hold on to sodium and release potassium), because lower aldosterone would reduce potassium loss, and fluid loss from diuretics tends to raise aldosterone instead.
- Thiazides do not work by inhibiting the sodium-potassium pump on the side of the tubular cell facing the blood, because that pump keeps working and builds up the potassium inside the cell that drives secretion; digoxin is a drug that inhibits this pump.
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