• 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)
  • 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.

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