Loop Diuretics

LOOP DIURETICS

Loop diuretics selectively inhibit NaCl reabsorption in the TAL. Because of the large NaCl absorptive capacity of this segment and the fact that the diuretic action of these drugs is not limited by development of acidosis, as is the case with the carbonic anhydrase inhibitors, loop diuretics are the most efficacious diuretic agents currently available.

Chemistry

The two prototypical drugs of this group are furosemide and ethacrynic acid. The structures of these diuretics are shown inFigure 15–7. In addition to furosemide, bumetanide and torsemide are sulfonamide loop diuretics.

Ethacrynic acid—not a sulfonamide derivative—is a phenoxy-acetic acid derivative containing an adjacent ketone and methyl-ene group (Figure 15–7). The methylene group (shaded in figure) forms an adduct with the free sulfhydryl group of cysteine. The cysteine adduct appears to be an active form of the drug.

Organic mercurial diuretics also inhibit salt transport in the TAL but are no longer used because of their toxicity.

Pharmacokinetics

The loop diuretics are rapidly absorbed. They are eliminated by the kidney by glomerular filtration and tubular secretion. Absorption of oral torsemide is more rapid (1 hour) than that of furosemide (2–3 hours) and is nearly as complete as with intrave-nous administration. The duration of effect for furosemide is usu-ally 2–3 hours. The effect of torsemide lasts 4–6 hours. Half-life depends on renal function.

Since loop agents act on the luminal side of the tubule, their diuretic activity correlates with their secre-tion by the proximal tubule. Reduction in the secretion of loop diuretics may result from simultaneous administration of agents such as NSAIDs or probenecid, which compete for weak acid secretion in the proximal tubule. Metabolites of ethacrynic acid and furosemide have been identified, but it is not known if they have any diuretic activity. Torsemide has at least one active metab-olite with a half-life considerably longer than that of the parent compound.

Pharmacodynamics

Loop diuretics inhibit NKCC2, the luminal Na⁺/K⁺/2Cl⁻ trans-porter in the TAL of Henle’s loop. By inhibiting this transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that comes from K⁺ recy-cling (Figure 15–3). This positive potential normally drives divalent cation reabsorption in the TAL (Figure 15–3), and by reducing this potential, loop diuretics cause an increase in Mg²⁺ and Ca²⁺ excretion. Prolonged use can cause significant hypomag-nesemia in some patients. Since vitamin D–induced intestinal absorption and parathyroid hormone-induced renal reabsorption of Ca²⁺ can be increased, loop diuretics do not generally cause hypocalcemia. However, in disorders that cause hypercalcemia,Ca²⁺ excretion can be usefully enhanced by treatment with loop diuretics combined with saline infusions.

Loop diuretics have also been shown to induce expression of one of the cyclooxygenases (COX-2), which participates in the synthesis of prostaglandins from arachidonic acid. At least one of these prostaglandins, PGE₂, inhibits salt transport in the TAL and thus participates in the renal actions of loop diuretics. NSAIDs (eg, indomethacin), which blunt cyclooxygenase activity, can interfere with the actions of loop diuretics by reducing prostaglandin synthesis in the kidney. This interference is minimal in otherwise normal subjects but may be significant in patients with nephrotic syndrome or hepatic cirrhosis.

Loop agents have direct effects on blood flow through several vascular beds. Furosemide increases renal blood flow via prosta-glandin actions on kidney vasculature. Both furosemide and ethacrynic acid have also been shown to reduce pulmonary con-gestion and left ventricular filling pressures in heart failure before a measurable increase in urinary output occurs. These effects on peripheral vascular tone are also due to release of renal prostaglan-dins that were induced by the diuretics.

Clinical Indications & Dosage (Table 15–4)

The most important indications for the use of the loop diuretics include acute pulmonary edema, other edematous conditions, and acute hypercalcemia. The use of loop diuretics in these con-ditions is discussed below in Clinical Pharmacology. Other indica-tions for loop diuretics include hyperkalemia, acute renal failure, and anion overdose.

A. Hyperkalemia

In mild hyperkalemia—or after acute management of severe hyperkalemia by other measures—loop diuretics can significantly enhance urinary excretion of K⁺. This response is enhanced by simultaneous NaCl and water administration.

B. Acute Renal Failure

Loop agents can increase the rate of urine flow and enhance K⁺ excretion in acute renal failure. However, they cannot prevent or shorten the duration of renal failure. If a large pigment load has precipitated acute renal failure (or threatens to), loop agents may help flush out intratubular casts and ameliorate intratubular obstruction. On the other hand, loop agents can actually worsen cast formation in myeloma and light chain nephropathy because increased distal Cl⁻ concentration enhances secretion of Tamm-Horsfall protein, which then aggregates with myeloma Bence Jones proteins.

C. Anion Overdose

Loop diuretics are useful in treating toxic ingestions of bromide, fluoride, and iodide, which are reabsorbed in the TAL. Saline solu-tion must be administered to replace urinary losses of Na⁺ and to provide Cl⁻, so as to avoid extracellular fluid volume depletion.

Toxicity

A. Hypokalemic Metabolic Alkalosis

By inhibiting salt reabsorption in the TAL, loop diuretics increase Na⁺ delivery to the collecting duct. Increased delivery leads to increased secretion of K⁺ and H⁺ by the duct, causing hypokalemic metabolic alkalosis (Table 15–2). This toxicity is a function of the magnitude of the diuresis and can be reversed by K⁺ replacement and correction of hypovolemia.

B. Ototoxicity

Loop diuretics occasionally cause dose-related hearing loss that is usually reversible. It is most common in patients who have dimin-ished renal function or who are also receiving other ototoxic agents such as aminoglycoside antibiotics.

C. Hyperuricemia

Loop diuretics can cause hyperuricemia and precipitate attacks of gout. This is caused by hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule. It may be prevented by using lower doses to avoid development of hypovolemia.

D. Hypomagnesemia

Magnesium depletion is a predictable consequence of the chronic use of loop agents and occurs most often in patients with dietary magnesium deficiency. It can be reversed by administration of oral magnesium preparations.

E. Allergic and Other Reactions

All loop diuretics, with the exception of ethacrynic acid, are sulfonamides. Therefore, skin rash, eosinophilia, and less often, interstitial nephritis are occasional adverse effects of these drugs. This toxicity usually resolves rapidly after drug withdrawal. Allergic reactions are much less common with ethacrynic acid.

Because Henle’s loop is indirectly responsible for water reabsorption by the downstream collecting duct, loop diuretics can cause severe dehydration. Hyponatremia is less common than with the thiazides , but patients who increase water intake in response to hypovolemia-induced thirst can become severely hyponatremic with loop agents. Loop agents can cause hypercalciuria, which can lead to mild hypocalcemia and secondary hyperparathyroidism. On the other hand, loop agents can have the opposite effect (hypercalcemia) in volume-depleted patients who have another—previously occult—cause for hypercalcemia, such as metastatic breast or squamous cell lung carcinoma.

Contraindications

Furosemide, bumetanide, and torsemide may exhibit allergic cross-reactivity in patients who are sensitive to other sulfonamides, but this appears to be very rare. Overzealous use of any diuretic is dangerous in hepatic cirrhosis, borderline renal failure, or heart failure.