Pharmacology USMLE Questions: Diuretics – Thiazides, Ethacrynic Acid and Spironolactone

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Diuretics are tested on USMLE Step 1 through their site of action, their electrolyte effects and their side effects. If you know where each one acts in the nephron, most questions become easy. Pick your answer first, then open the explanation.

Question 1: A diuretic that raises calcium and glucose

A 60-year-old woman with hypertension starts a new once-daily diuretic. Three months later, laboratory studies show serum sodium 132 mEq/L, potassium 3.2 mEq/L, bicarbonate 31 mEq/L, calcium 10.6 mg/dL, uric acid 8.4 mg/dL and fasting glucose 118 mg/dL. Her calcium, glucose and uric acid were normal before treatment. This drug most likely acts at which of the following sites?

A. Na⁺-K⁺-2Cl⁻ cotransporter in the thick ascending limb
B. Na⁺-Cl⁻ cotransporter in the distal convoluted tubule
C. Carbonic anhydrase in the proximal convoluted tubule
D. Epithelial sodium channels (ENaC) in the collecting duct
E. Aldosterone receptors in the collecting duct

Correct answer: B. Na⁺-Cl⁻ cotransporter in the distal convoluted tubule

These findings fit a thiazide diuretic such as hydrochlorothiazide. Thiazides block the Na⁺-Cl⁻ cotransporter in the distal convoluted tubule. Their side effects follow the mnemonic “hyper-GLUC“: hyperGlycemia, hyperLipidemia, hyperUricemia and hyperCalcemia, plus hyponatremia, hypokalemia and metabolic alkalosis. Because they reduce urinary calcium, thiazides are useful in calcium kidney stones.

Why the other options are wrong:

  • Loop diuretics (thick ascending limb) cause hypocalcemia, because they increase calcium excretion.
  • Carbonic anhydrase inhibitors (acetazolamide) cause metabolic acidosis, not alkalosis.
  • ENaC blockers (amiloride, triamterene) are potassium-sparing and cause hyperkalemia.
  • Aldosterone antagonists (spironolactone) are potassium-sparing and cause hyperkalemia.

Question 2: A loop diuretic for a patient with a sulfa allergy

A 68-year-old man with heart failure has worsening leg edema and crackles in both lungs. He needs a loop diuretic. He has a documented history of a severe allergic reaction to sulfonamide drugs. Which of the following diuretics is the most appropriate choice?

A. Furosemide
B. Bumetanide
C. Ethacrynic acid
D. Hydrochlorothiazide
E. Acetazolamide

Correct answer: C. Ethacrynic acid

Ethacrynic acid is a loop diuretic that is not a sulfonamide, so it is used in patients with sulfa allergy. Like other loop diuretics, it inhibits the Na⁺-K⁺-2Cl⁻ cotransporter in the thick ascending limb. It is the most ototoxic of the loop diuretics and can also cause hyperuricemia.

Why the other options are wrong:

  • Furosemide is a sulfonamide loop diuretic.
  • Bumetanide is also a sulfonamide loop diuretic.
  • Hydrochlorothiazide is a sulfonamide and is not a loop diuretic.
  • Acetazolamide is a sulfonamide carbonic anhydrase inhibitor with weak diuretic effect.

Question 3: A new heart failure drug added to an ACE inhibitor

A 55-year-old woman with heart failure with reduced ejection fraction has been stable on lisinopril and carvedilol. Spironolactone is added to her regimen. Which of the following laboratory abnormalities is the most important to monitor for?

A. Hypokalemia
B. Hypercalcemia
C. Hyperglycemia
D. Metabolic alkalosis
E. Hyperkalemia

Correct answer: E. Hyperkalemia

Spironolactone is an aldosterone receptor antagonist that acts on the collecting duct. It reduces mortality in heart failure with reduced ejection fraction, but it is potassium-sparing. Combined with an ACE inhibitor (which also lowers aldosterone), the risk of hyperkalemia is significant, especially if kidney function is reduced. Monitor potassium and creatinine. Spironolactone also has antiandrogen effects, such as gynecomastia in men; eplerenone causes fewer of these effects.

Why the other options are wrong:

  • Hypokalemia is caused by loop and thiazide diuretics.
  • Hypercalcemia is a side effect of thiazides.
  • Hyperglycemia is a side effect of thiazides.
  • Metabolic alkalosis is caused by loop and thiazide diuretics; potassium-sparing diuretics tend to cause acidosis.

Key takeaways

  • Thiazides: DCT; hyperglycemia, hyperlipidemia, hyperuricemia, hypercalcemia.
  • Loop diuretics lose calcium; ethacrynic acid is the loop diuretic for sulfa allergy.
  • Spironolactone + ACE inhibitor: watch for hyperkalemia.

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Written and reviewed by Dr. Ray Makar, MD, dermatologist with 20 years of clinical practice. Last reviewed: October 2026. For exam preparation only, not medical advice.

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