FUROSEMIDClass: Loop DiureticsPharmacokineticsThe loop diuretics are rapidly absorbed.

They are eliminated by the kidney by glomerular filtration and tubular secretion.

Absorption of oral furosemide: 2-3 hours and is nearly as complete as with intravenous administration.

The duration of effect for furosemide is usually 2-3 hours

Half-life depends on renal function. Since loop agents act on the luminal side of the tubule, their diuretic activity correlates with their secretion 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.

PharmacodynamicsLoop diuretic inhibit the activity of the Na+K+2Cl symporter in the thick ascending limb of the loop of Henle (selectively inhibit NaCl reabsorption) and also diminish the lumen-positive potential that comes from K+ recycling.

This positive potential normally drives divalent cation reabsorption in the loop, and by reducing this potential, loop diuretics cause an increase in Mg2+ and Ca2+ excretion.

Prolonged use can cause significant hypomagnesemia in some patients. Since vitamin D-induced intestinal absorption of Ca2+ can be increased and Ca2+ is actively reabsorbed in the DCT, loop diuretics do not generally cause hypocalcemia.

Loop diuretics induce synthesis of renal prostaglandins, which participate in the renal actions of these diuretics. NSAIDs (eg, indomethacin) can interfere with the actions of the 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.

In addition to their diuretic activity, loop agents have direct effects on blood flow through several vascular beds. Furosemide increases renal blood flow. Both furosemide and ethacrynic acid have also been shown to reduce pulmonary congestion and left ventricular filling pressures in heart failure before a measurable increase in urinary output occurs, and in anephric patients.

Clinical Indications & DosageThe most important indications for the use of the loop diuretics include acute pulmonary edema, other edematous conditions, and acute hypercalcemia. Other indications for loop diuretics include hyperkalemia, acute renal failure, and anion overdose.A. HYPERKALEMIAB. ACUTE RENAL FAILURELoop agents can increase the rate of urine flow and enhance K+ excretion in acute renal failure. However, they do not 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 theoretically worsen cast formation in myeloma and light chain nephropathy.C. ANION OVERDOSEToxicityA. HYPOKALEMIC METABOLIC ALKALOSISBy inhibiting salt reabsorption in the TAL, loop diuretics increase delivery to the collecting duct. Increased delivery leads to increased secretion of K+ and H+ by the duct, causing hypokalemic metabolic alkalosis. This toxicity can be reversed by K+ replacement and correction of hypovolemia.B. OTOTOXICITYLoop diuretics occasionally cause dose-related hearing loss that is usually reversible. It is most common in patients who have diminished renal function or who are also receiving other ototoxic agents such as aminoglycoside antibiotics.C. HYPERURICEMIALoop 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. HYPOMAGNESEMIAE. ALLERGIC & OTHER REACTIONS

Because Henle's loop is normally responsible for so much salt and water reabsorption, loop diuretics can cause severe dehydration. Hyponatremia is less common than with the thiazides (see below), but patients who increase water intake in response to hypovolemia-induced thirst can become severely hyponatremic with loop agents. Loop agents are sometimes used for their calciuric effect, but hypercalcemia can occur in volume-depleted patients who have anotherpreviously occultcause for hypercalcemia, such as metastatic breast or squamous cell lung carcinoma.

ContraindicationsFurosemide 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.

SPIRONOLACTONEClass: Potassium-sparing diureticsSpironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone. Onset and duration of its action are determined by the kinetics of the aldosterone response in the target tissue. Substantial inactivation of spironolactone occurs in the liver. Overall, spironolactone has a rather slow onset of action, requiring several days before full therapeutic effect is achieved. Eplerenone is a spironolactone analog with greater selectivity for the aldosterone receptor.PharmacodynamicsSpironolactone binds to aldosterone receptors and may also reduce the intracellular formation of active metabolites of aldosterone.Clinical Indications & DosagePotassium-sparing diuretics are most useful in states of mineralocorticoid excess or hyperaldosteronism (also called aldosteronism), due either to primary hypersecretion (Conn's syndrome, ectopic adrenocorticotropic hormone production) or to secondary hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic syndrome, or other conditions associated with diminished effective intravascular volume). Use of diuretics such as thiazides or loop agents can cause or exacerbate volume contraction and may cause secondary hyperaldosteronism. In the setting of enhanced mineralocorticoid secretion and excessive delivery of Na+ to distal nephron sites, renal K+ wasting occurs. Potassium-sparing diuretics of either type may be used in this setting to blunt the K+ secretory response.ToxicityA. HYPERKALEMIAThe risk of this complication is greatly increased by renal disease (in which maximal K+ excretion may be reduced) or by the use of other drugs that reduce renin (b blockers, NSAIDs) or angiotensin II activity (angiotensin-converting enzyme inhibitors, angiotensin receptor inhibitors). Since most other diuretic agents lead to K+ losses, hyperkalemia is more common when K+-sparing diuretics are used as the sole diuretic agent, especially in patients with renal insufficiency. B. HYPERCHLOREMIC METABOLIC ACIDOSISBy inhibiting H+ secretion in parallel with K+ secretion, the K+-sparing diuretics can cause acidosis similar to that seen with type IV renal tubular acidosis.C. GYNECOMASTIASynthetic steroids may cause endocrine abnormalities by actions on other steroid receptors. Gynecomastia, impotence, and benign prostatic hyperplasia have all been reported with spironolactone. Such effects have not been reported with eplerenone.D. ACUTE RENAL FAILUREThe combination of triamterene with indomethacin has been reported to cause acute renal failure. This has not been reported with other K+-sparing diuretics.E. KIDNEY STONESTriamterene is only slightly soluble and may precipitate in the urine, causing kidney stones.ContraindicationsThese agents can cause severe, even fatal hyperkalemia in susceptible patients. Oral K+ administration should be discontinued if K+-sparing diuretics are administered. Patients with chronic renal insufficiency are especially vulnerable and should rarely be treated with these diuretics.. Patients with liver disease may have impaired metabolism of triamterene and spironolactone, so dosing must be carefully adjusted.