Metolazone Causes Low Potassium (Hypokalemia)
Metolazone causes hypokalemia (low potassium levels), not hyperkalemia. This is a well-established adverse effect of this thiazide-like diuretic that requires careful monitoring and often necessitates potassium supplementation or addition of potassium-sparing agents 1.
Mechanism and Incidence
- Metolazone is a thiazide-like diuretic that increases urinary excretion of potassium, leading to hypokalemia 2, 1
- The FDA drug label explicitly warns that "the risk of hypokalemia is increased when larger doses are used, when diuresis is rapid, when severe liver disease is present, when corticosteroids are given concomitantly, when oral intake is inadequate or when excess potassium is being lost extrarenally" 1
- In patients with liver disease, hypokalemia occurred in 80% of patients treated with metolazone alone, representing a major disadvantage that indicates this drug should be used with caution 3
- Even at low doses (2.5 mg/day), metolazone causes a mean decrease in serum potassium of 0.5-0.6 mEq/L 4
Clinical Significance and Risk Factors
- Metolazone is strongly associated with hypokalemia (P<0.0001) in acute decompensated heart failure patients, with this association persisting even after propensity adjustment 5
- The combination of metolazone with loop diuretics produces particularly severe potassium depletion, with clinically important hypokalemia (<2.5 mM) observed in 10% of treatment episodes 6
- Diuretic-induced hypokalemia can increase myocardial sensitivity to digitalis, potentially causing serious arrhythmias 1
- The risk is amplified when metolazone is combined with corticosteroids, ACTH, or when patients have inadequate oral potassium intake 1
Monitoring and Prevention Strategy
- Check serum potassium and creatinine within 5-7 days after initiating metolazone, then continue monitoring every 5-7 days until values stabilize 7
- Subsequently monitor at 3 months and then at 6-month intervals 8
- Target serum potassium levels of 4.0-5.0 mEq/L, as both hypokalemia and hyperkalemia increase mortality risk in heart failure patients 8
Management Approach
- Hypokalaemia can usually be prevented by simultaneous administration of amiloride or spironolactone when using metolazone 3
- For persistent hypokalemia despite supplementation, add potassium-sparing diuretics such as spironolactone (25-100 mg daily), amiloride (5-10 mg daily), or triamterene (50-100 mg daily) 8, 7
- Oral potassium chloride supplementation of 20-60 mEq/day may be required to maintain adequate levels 8
- Always check and correct concurrent hypomagnesemia, as this makes hypokalemia resistant to correction 8
Critical Warnings
- The European Heart Journal recommends that thiazide diuretics (including metolazone) should be questioned in patients with severe hypokalemia until the electrolyte abnormality is corrected 8
- Never administer digoxin before correcting hypokalemia, as this significantly increases the risk of life-threatening arrhythmias 8
- In acute decompensated heart failure, metolazone was independently associated with increased mortality after controlling for baseline characteristics (hazard ratio=1.20, P=0.01), suggesting that uptitration of loop diuretics may be preferred over routine early addition of metolazone 5