Nephron - Furosemide

Almost all diuretics exert their action at the luminal surface of the renal tubule cells. Their mechanism of action includes interaction with specific membrane transport proteins like thiazides, furosemide etc., osmotic effects which prevent the water permeable segments of the nephron from absorbing water like mannitol, and specific interaction with enzyme like carbonic anhydrase inhibitors i.e. acetazolamide, and hormone receptors in renal epithelial cells like spironolactone. 

Furosemide Loop diuretic Decreases NaCI and KCI reabsorption in thick ascending limb of the loop of Henle in the nephron (see Chapter 15) Increased excretion of salt and water reduces cardiac preload and afterload reduces pulmonary and peripheral edema Acute and chronic heart failure severe hypertension edematous conditions Oral and IV duration 2-4 h Toxicity Hypovolemia, hypokalemia, orthostatic hypotension, ototoxicity, sulfonamide allergy... 

The most potent type of diuretic, loop diuretics are named after the loop of Henle, a component of a nephron. The nephrons are the filtering units of the kidney, and are responsible for moving fluids and waste out of the bloodstream, resulting in urine formation. The loop of Henle is a branch within each nephron where sodium and potassium are reabsorbed back into the bloodstream instead of being filtered into the urine. Loop diuretics inhibit this action and promote excretion of the sodium and potassium instead, along with calcium and magnesium. Since excess sodium causes excess fluid build-up, this results in fluid loss. Furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex), and ethacryinic acid (Edecrin) are all loop diuretics. 

Pathophysiology Non-potassium-sparing diuretics are the treatment of choice to reduce fluid retention and dyspnea. Acting at specific sites of nephrons, they inhibit sodium and water reabsorption. Loop diuretics act on the loop of Henle, producing a maximal diuretic effect equivalent to 20% to 25% of the filtered sodium load and promoting the free water clearance. Currently available loop diuretics include furosemide, bumetanide, torsemide, and ethacrynic acid. Because of their potency, they are generally effective in patients with advanced renal insufficiency (glomerular filtration rates <25 ml/min) (49). 

However, resistance to loop diuretics can occur by various mechanisms (36). These include poor adherence to therapy, poor absorption, progressive worsening of heart failure, excess volume loss, renal insufficiency, secondary hyperaldosteronism, and hypertrophy of the tubular cells of the distal nephron. Resistance due to inadequate drug absorption—either its speed or extent—is common with furosemide, which is poorly absorbed (34). Once recognized, this hurdle to response can be overcome by using loop diuretics that are predictably well absorbed, such as bumetanide and torasemide or by giving intravenous furosemide (37). 

Brenner BM, Keimowitz Rl, Wright FS, Berliner RW. An inhibitory effect of furosemide on sodium reabsorption by the proximal tubule of the rat nephron. J Clin Invest 1969 48 290-300. 

Weinstein JM, Heyman S, Brezis M. Potential deleterious effect of furosemide in radiocontrast nephropathy. Nephron 1992 62 413-415. 

Diuretic resistance may occur simply because excessive sodium intake overrides the ability of the diuretics to eliminate sodium. Other reasons exist for diuretic resistance in this population. Patients with ATN have a reduced number of functioning nephrons on which the diuretic may exert its action. Other clinical states like glomerulonephritis are associated with heavy proteinuria. Intraluminal loop diuretics cannot exert their effect in the loop of Henle because they are extensively bound to the protein present in the urine. Still other patients may have reduced bioavailability of oral furosemide. Possible therapeutic options to counteract each form of diuretic resistance are presented in Table 42-7. Combination therapy of loop diuretics plus a diuretic from a different pharmacologic class can be an effective tool in the setting of ARF. Loop diuretics increase the delivery of sodium chloride to the distal convoluted tubule and collecting duct. With time, these areas of the nephron compensate for the activity of the loop diuretic and increase sodium and chloride resorption. Diuretics that work at the... 

A decrease in prostaglandin synthesis during ARF was shown in early studies . In both haemodynamic (glycerol) and nephrotoxic (mercuric chloride) rabbit models of ARF, whole kidney PGE2 levels were increased. There is also evidence for a protective effect of PGE2 in haemodynamically mediated (norepinephrine-induced) ARF ". Furosemide, which stimulates prostaglandin production has a protective effect on renal function in some models of ARF if administered prophylactically , whereas it is of no benefit in nephrotoxic models . The beneficial effect may depend upon a combination of factors, including increased solute excretion and vasodilation however, furosemide action at other nephron and vascular sites may explain this salutary effect. 

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