Medications That Cause Hypokalemia
Loop diuretics (furosemide, bumetanide, torsemide) and thiazide diuretics (hydrochlorothiazide) are the most common drug-related causes of hypokalemia, with thiazides causing hypokalemia in 7-56% of patients and loop diuretics producing dose-dependent potassium depletion. 1, 2, 3
Loop Diuretics
Loop diuretics cause hypokalemia by inhibiting the NKCC transporter in the loop of Henle, resulting in natriuresis and increased potassium excretion. 1
- Furosemide specifically causes hypokalemia through increased sodium delivery to the cortical collecting duct with consequent increased potassium excretion via the ROMK2 channel to maintain electrical neutrality 1
- Hypokalemia may develop especially with brisk diuresis, inadequate oral electrolyte intake, when cirrhosis is present, or during concomitant use of corticosteroids, ACTH, licorice in large amounts, or prolonged use of laxatives 4
- Potassium supplements and/or dietary measures may be needed to control or avoid hypokalemia in patients taking furosemide 4
Thiazide Diuretics
Thiazide diuretics inhibit the sodium-chloride transporter in the distal tubule, causing hypokalemia through increased sodium delivery to the cortical collecting duct and upregulation of the aldosterone-sensitive ENaC channel. 1
- Hydrochlorothiazide causes hypokalemia in 12.6% of users, equivalent to approximately 2.0 million US adults 3
- Women have 2.22 times higher risk, non-Hispanic blacks have 1.65 times higher risk, and underweight patients have 4.33 times higher risk of developing hypokalemia with hydrochlorothiazide 3
- Long-term therapy (≥5 years) increases risk by 1.47 times compared to shorter duration 3
- The hypokalaemic effect can counter-balance the potassium-raising effects of ACE inhibitors/ARBs and potassium-sparing diuretics 1
Corticosteroids
Corticosteroids cause hypokalemia through mineralocorticoid effects, with hydrocortisone causing more hypokalemia than methylprednisolone at equivalent doses. 5
- Concomitant use of corticosteroids with diuretics increases the risk of hypokalemia 4
High-Risk Clinical Scenarios
The following factors increase the incidence or severity of diuretic-induced hypokalemia: 6
- High salt diets 6
- Large urine volumes 6
- Metabolic alkalosis 6
- Increased aldosterone production 6
- Simultaneous use of two diuretics acting on different tubular sites 6
- Higher doses of diuretics (prevalence 2-11% with low-to-moderate doses) 7
Additional Contributing Medications
- ACTH increases hypokalemia risk when combined with diuretics 4
- Laxatives with prolonged use contribute to potassium depletion 4
- Large amounts of licorice can exacerbate diuretic-induced hypokalemia 4
- Beta-agonists can worsen hypokalemia through transcellular potassium shifts 5
- Insulin causes transcellular shifts leading to hypokalemia 5
Prevention Strategies
Fixed-dose combination therapy with potassium-sparing diuretics reduces hypokalemia risk by 68% compared to monotherapy (adjusted OR 0.32). 3
- Low-salt diet rich in potassium, magnesium, and chloride prevents diuretic-induced hypokalemia 8
- Use of low doses of short-acting diuretics in mild-to-moderate hypertension reduces risk 8
- Combining with ACE inhibitors or low-dose spironolactone prevents hypokalemia in heart failure patients on high-dose diuretics 7
- Regular monitoring of serum potassium is essential, particularly during the first few months of therapy 4
Important Caveats
Even among patients taking potassium supplements, 27.2% on monotherapy and 17.9% on polytherapy still develop hypokalemia, indicating that supplementation alone is often insufficient. 3
- Digitalis therapy may exaggerate metabolic effects of hypokalemia, especially myocardial effects 4
- The extent of potassium deficiency usually does not exceed 200-300 mEq, but even modest deficiency may have important consequences including cardiac arrhythmias, muscle weakness, rhabdomyolysis, and glucose intolerance 6