Medical Pharmacology Chapter 26:  Renal Pharmacology

• Loop Diuretic Drugs

  • Introduction

    • Agents include:

      • Furosemide (Lasix)

      • Bumetanide (Bumex)

      • Torsemide (Demadex)

      • Ethycrinic acid, no longer in use because of toxicity.

  • Mechanism of action:

    • Inhibition of NaCl reabsorption in the thick ascending limb of the loop of Henle

      • Loop diuretics inhibit the Na⁺/K⁺/2Cl^- transport system in the luminal membrane resulting in:

        1.  reduction in sodium chloride reabsorption.

        2.  a decrease in the normal lumen-positive potential (secondary to potassium recycling)

        3.  a positive lumen potential: drives divalent cationic reabsorption (calcium magnesium)

        4.  and thusly, loop diuretics increase magnesium and calcium excretion.

           • Hypomagnesemia may occur in some patients.

           • Hypocalcemia does not usually develop because calcium is reabsorbed in the distal convoluted tubule.

             • In circumstances that result in hypercalcemia, calcium excretion can be enhanced by administration of loop diuretics with saline infusion.

    • Since a significant percentage of filtered NaCl is absorbed by the thick ascending limb of loop of Henle, diuretics acting at this site are highly effective

  • Loop diuretics--Properties:  

    • Rapidly absorbed following oral administration (may be administered by IV).

    • Acts rapidly

    • Eliminated by a renal secretion and glomerular filtration (half-life -- depend on renal function)

    • Co-administration of drugs that inhibit weak acid secretion (e.g. probenecid or indomethacin) may alter loop diuretic clearance.

    • Other effects:

      • Furosemide: increases renal blood flow; blood flow redistribution within the renal cortex

      • Furosemide decreases pulmonary congestion and the left ventricular filling pressure in congestive heart failure (CHF), changes occurring prior to increasing urine output.

  • Clinical Uses:

    • Major uses:

      • Acute pulmonary edema

      • Acute hypercalcemia

      • Management of edema

    • Other uses:

      • Hyperkalemia:

        • Loop diuretics increase potassium excretion

        • This effect is increased by concurrent administration of NaCl and water.

      • Acute renal failure:

        • May increase rate of urine flow and increase potassium excretion.

        • May convert oligouric to non-oligouric failure {easier clinical management}

        • Renal failure duration -- not affected

      •  Anion overload:

        • Bromide, chloride, iodide: all reabsorbed by the thick ascending loop:

        • Systemic toxicity may be reduced by decreasing reabsorption

          • concurrent administration of sodium chloride and fluid is required to prevent volume depletion

  •  Toxicity:

    •  Hypokalemia metabolic alkalosis:

      • Increased delivery of NaCl and water to the collecting duct increases potassium and proton secretion, causing a hypokalemic metabolic alkalosis

      • Hypokalemia is managed by potassium replacement and by ensuring adequate fluid intake

    • Ototoxicity:

      • Dose-related hearing loss (in usually reversible)

      • Ototoxicity more common:

        •  With decreased renal function

        •  With concurrent administration of other ototoxic drugs such as aminoglycosides

    •  Hyperuricemia:

      • May cause gout

      • Loop diuretics cause increased uric acid reabsorption in the proximal tubule, secondary to hypovolemic states.

    •  Hypomagnesemia: loop diuretics cause:

      1. Reduction in sodium chloride reabsorption

      2. Decreases in normal lumen-positive potential (secondary to potassium recycling)

      3. Positive lumen potential: drives divalent cationic reabsorption (calcium magnesium)

      4. Therefore, loop diuretics increase magnesium and calcium excretion.

         • Hypomagnesemia may occur in some patients.

         • Reversed by oral magnesium administration

    •  Allergic reactions:

      • Furosemide: skin rash, eosinophilia, interstitial nephritis(less often)

    • Other toxicities:

      • Dehydration (may be severe)

      • Hyponatremia (less common than with thiazides thought may occur in patients who increased water intake in response to a hypovolemic thirst)

      • Hypercalcemia may occur in severe dehydration and if a hypercalcemia condition {e.g. oat cell long carcinoma} is also present.

Ives, H.E., Diuretic Agents, in: Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 242-259.