LOOP DIURETICS Mechanisms. The loop diuretics inhibit sodium reabsorption in the ascend- i

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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. (PgDn key for more text) * 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. (PgDn key for more text) * 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. (PgDn key for more text) * 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. (PgDn key for more text) 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. (PgDn key for more text) 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. (Home key to return to top of file)

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