• Introduction

• Mechanism of Action

• Properties of Loop Diuretics

• Clinical Uses:

  • Major Uses:

    • acute pulmonary edema

    • acute hypercalcemia

    • edema states

  • Additional Uses:

    • acute renal failure

    • hyperkalemia

    • anion overload

• Toxicity:

  • hypokalemia metabolic alkalosis

  • ototoxicity

  • hyperuricemia

  • hypomagnesemia

  • allergic reactions

  • severe dehydration

  • hyponatremia

• 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

    •  Inhibit the Na^+/K^+//2Cl^- transport system in the luminal membrane

      1. Reduction in sodium chloride reabsorption

      2. Decreases 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.

         • 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)

  • Do-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) -- prior to an increase in urine output.

• Clinical Uses:

  • Major uses:

    •  Acute pulmonary edema

    •  Acute hypercalcemia

    •  Management of edema

  • Other uses:

    •  Reduction of Intracranial Pressure

    •  Hyperkalemia:

      • Loop diuretics increase potassium excretion

      • Effect 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

    • In 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 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.