Don’t Be Thrown for a Loop: Know Your Diuretics!

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August 10, 2017 by Casey Carr

By: Ben Iredell, PharmD

Commonly used in the ED setting, loop diuretics are versatile medications, and are used for a variety of conditions.

Loop diuretics inhibit the Na-K-2Cl symporter that transports these ions from the tubular lumen into the tubular cells in the loop of Henle. Subsequently, these ions, and consequently, water, are excreted. The loop diuretics are known as ‘high ceiling’ diuretics because they may cause a substantial diuresis – up to 20% of filtered salt and water load. Loop diuretics can cause both hyponatremia and hypokalemia, as well as metabolic alkalosis. At very high intravenous doses, loop diuretics can cause ototoxicity. Furosemide, bumetanide, and torsemide all contain a sulfa moiety, and can therefore cause hypersensitivity reactions (very rare). In this case, ethacrynic acid is used instead.

Metolazone is a thiazide-like diuretic, which inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal convoluted tubule. When patients are refractory to loop diuretic therapy, thiazide-like diuretics may be added. Metolazone is only available in oral dosage forms, and has been found to be noninferior to intravenous chlorothiazide in multiple recent studies (Shulenberger, et al and Michaud, et al).

When a loop diuretic and thiazide are used concomitantly, metolazone should be administered at least 30 minutes prior to the loop diuretic. Thiazide-like diuretics must be administered first to inhibit the Na+/Cl transporter in the distal convoluted tubule before the administration of a loop diuretic which inhibits the Na+/K+/2Clcotransporter in the loop of Henle. If the medications are not administered in this order, the cotransporter in the loop of Henle will be inhibited, but water will then be reabsorbed in the distal convoluted tubule.

This can be applied clinically in a patient with an inadequate response to IV furosemide, you can consider administering metolazone 5 mg orally 30 minutes before their next IV furosemide dose.

Class Drug Dosage Forms on Formulary Equipotent Oral Dose Bio-availability Notes
Loop Diuretics Furosemide Tablet, Oral solution, Intravenous 40 mg 50% ·  Sulfa moiety



Bumetanide Tablet 1 mg 80% ·  Sulfa moiety
Torsemide Tablet 20 mg 80% ·  Sulfa moiety

·  Tablets only on JHH Formulary

Ethacrynic acid Oral liquid, Intravenous (restricted) 50 mg 100% ·  IV restricted to patients with sulfa allergy, consultation from Allergy & Immunology, and inability to take oral medications
Thiazide-related Metolazone Tablet, suspension N/A N/A Used for refractory edema



  1. Jentzer, J. (2010). “Combination of loop diuretics with thiazide-type diuretics in health failure.” Journal of the American College of Cardiology. 56(19): 1527-34.
  2. Lexicomp Online®, Lexi-Drugs® , Hudson, Ohio: Lexi-Comp, Inc.; June 16, 2017.
  3. Molnar, J. (2009). “The clinical pharmacology of ethacrynic acid.” American Journal of Therapeutics. 16(1): 86-92.
  4. Wile, D (Sep 2012). “Diuretics: a review.”. Annals of Clinical Biochemistry. 49(Pt 5): 419–31.

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