LOOP DIURETICS

   Mechanisms. The loop diuretics inhibit sodium reabsorption in the ascend-
      ing portion of the loop of Henle. Because this portion of the nephron
      is responsible for reclaiming 30-40% of the filtered sodium, inhibition
      at this site can result in a very large diuresis. The loop agents are
      therefore the most efficacious of all the diuretics. As with the
      thiazides, the increase in the sodium appearing downstream in the col-
      lecting duct results in an increase in the excretion of potassium and
      hydrogen ion, and a hypokalemic metabolic alkalosis may result. The
      loop agents also increase calcium excretion.

   Indications
   * Edema associated with congestive heart failure, cirrhosis, or renal dis-
      ease such as nephrotic syndrome. Parenteral furosemide and ethacrynic
      acid are labeled for use in pulmonary edema and other situations in
      which prompt onset of diuresis is indicated, and when oral therapy is
      impractical.   
   * Hypertension: furosemide is labeled for use in hypertensive patients who
      do not respond adequately to thiazides. It should be used together with
      other hypotensive drugs.

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 * Ethacrynic acid is labeled for use in patients with ascites caused by
      malignancy, in idiopathic edema and lymphedema, and in short-term
      treatment of edema due to congenital heart disease in pediatric
      patients other than infants.
   * Hypercalcemia (unlabeled): furosemide can lower serum calcium (and other
      electrolytes) when given in sufficient dosage. Appropriate replacement
      electrolytes must be infused simultaneously to avoid serious
      deficiency. This method is not suitable for lithium overdosage.

   * Acute renal failure (unlabeled): in oliguria (but not anuria), and in
      situations in which heavy pigment loads are expected, eg, transfusion
      reactions, brisk diuresis may sometimes be induced with these agents.
      Unfortunately, there is very little evidence that the outcome is favor-
      ably influenced by these maneuvers.

   Pharmacokinetics (see also Table 6-3)
   * Absorption: The loop agents are well absorbed after oral administration.
      Their onset of action, even when given orally, is faster than that of
      the thiazides.



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   * Elimination: These drugs have relatively short half-lives. They are
      rapidly excreted into the urine and have their therapeutic action from
      the luminal side of the nephron.

   Contraindications and Warnings
   * Hypersensitivity: to individual agents and to sulfonamides in the case
      of furosemide and bumetanide. (Note: ethacrynic acid is chemically dis-
      tinct and may be an appropriate choice in a patient with sulfonamide
      sensitivity.)
   * Anuria.
   * Hepatic coma or precoma.
   * Hypovolemia.
   * Electrolyte deficiency: correct before giving the diuretic.
   * Do not use ethacrynic acid in pregnant women or infants.

   Adverse Reactions
   * CV: Hypovolemia and hypotension: rapid diuresis, especially in the
      patients receiving other hypotensive agents, may result in severe
      orthostatic hypotension, syncope, and other manifestations of
      hypovolemia.


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   * Electrolyte deficiency: potassium and magnesium deficiencies may occur.
      In patients receiving digitalis, arrhythmias may be induced.
   * CNS: Ototoxicity: especially in patients receiving other ototoxic drugs
      such as aminoglycoside antibiotics. It is usually reversible (see also
      Chapter 23). Vertigo, headache, and blurred vision may also occur with
      any of the loop agents. Furosemide is associated with paresthesias and
      xanthopsia. Bumetanide has been associated with asterixis and en-
      cephalopathy in patients with liver disease.
   * GI: Furosemide and bumetanide are associated with occasional gastric up-
      set, nausea and vomiting. Ethacrynic acid may occasionally induce
      severe watery diarrhea.
   * Hematologic (rare): thrombocytopenia, agranulocytosis.   
   * Metabolic: hyperuricemia (but uricosuria may be induced by ethacrynic
      acid), hyperglycemia, azotemia. Elevation of all serum constituents may
      occur if hemoconcentration results from excessive diuresis.  Muscle
      pain may occur.



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   Toxicity and Overdosage
   * Severe hypovolemia, hypotension, and electrolyte deficiency. CNS ab-
      normalities, including coma, may result. Treatment requires prompt re-
      placement of volume and electrolytes.
   Interactions
   * Hypotensive agents: loop diuretics potentiate the effects of all
      hypotensive drugs.
   * Lithium: loop diuretics, like the thiazides, decrease the clearance of
      lithium.
   * Ototoxic antibiotics: additive or synergistic action.
   * Thiazides, especially metolazone: marked increase in diuresis, "high
      ceiling" effect.

   * Miscellaneous pharmacokinetic interactions: ethacrynic acid displaces
      warfarin from serum proteins; probenecid and NSAIDs may interfere with
      the action of loop diuretics by reducing their secretion into the
      tubule; loop diuretics may interfere with the excretion of salicylates.




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   Drugs of Special Importance
   * Furosemide is the loop agent with the longest record of use and it is
      available in generic form.

   Related Drugs:
   * Ticrynafen is an ethacrynic acid analog that was marketed briefly as a
      uricosuric diuretic. It was withdrawn because of toxicity but other
      analogs are under study.














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