• Major Uses:
  • Acute pulmonary edema
  • Acute hypercalcemia
  • edema states
• Additional Uses:
  • Acute renal failure
  • Hyperkalemia
  • Anion overload

• 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.

       • Hhypocalcemia 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) -- 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.