Loop diuretics resistance

Two types of diuretics are used for volume management in HF thiazides and loop diuretics. Thiazide diuretics such as hydrochlorothiazide, chlorthalidone, and metolazone block sodium and chloride reabsorption in the distal convoluted tubule. Thiazides are weaker than loop diuretics in terms of effecting an increase in urine output and therefore are not utilized frequently as monotherapy in HF. They are optimally suited for patients with hypertension who have mild congestion. Additionally, the action of thiazides is limited in patients with renal insufficiency (creatinine clearance less than 30 mL/minute) due to reduced secretion into their site of action. An exception is metolazone, which retains its potent action in patients with renal dysfunction. Metolazone is often used in combination with loop diuretics when patients exhibit diuretic resistance, defined as edema unresponsive to loop diuretics alone. 

There is significant controversy over the role of loop diuretics in the treatment of ARE Theoretical benefits in hastening recovery of renal function include decreased metabolic oxygen requirements of the kidney, increased resistance to ischemia, increased urine flow rates that reduce intraluminal obstruction and filtrate backleak, and renal vasodilation.6 Theoretically, these effects could lead to increased urine output, decreased need for dialysis, improved renal recovery, and ultimately, increased survival. However, there are conflicting... 

Prolonged administration of loop diuretics can lead to a second type of diuretic resistance. Enhanced delivery of sodium to the distal tubule can result in hypertrophy of distal convoluted cells.17 Subsequently, increased sodium chloride absorption occurs in the distal tubule which diminishes the effect of the loop diuretic on sodium excretion. Addition of a distal convoluted tubule diuretic, such as metolazone or hydrochlorothiazide, to a loop diuretic can result in a synergistic increase in urine output. There are no data to support the efficacy of one distal convoluted tubule diuretic over another. The common practice of administering the distal convoluted tubule diuretic 30 to 60 minutes prior to the loop diuretic has not been studied, although this practice may first inhibit sodium reabsorption at the distal convoluted tubule before it is inundated with sodium from the loop of Henle. 

Strategies are available to overcome diuretic resistance (Table 75-5), a common problem in patients with ARF. Agents from different pharmacologic classes, such as diuretics that work at the distal convoluted tubule (thiazides) or the collecting duct (amiloride, triamterene, spironolactone), may be synergistic when combined with loop diuretics. Metolazone is commonly used because, unlike other thiazides, it produces effective diuresis at GFR less than 20 mL/min. 

Therapy of congestive heart failure. By lowering peripheral resistance, diuretics aid the heart in ejecting blood (reduction in afterload, pp. 132, 306) cardiac output and exercise tolerance are increased. Due to the increased excretion of fluid, EEV and venous return decrease (reduction in preload, p. 306). Symptoms of venous congestion, such as ankle edema and hepatic enlargement, subside. The drugs principally used are thiazides (possibly combined with K+-sparing diuretics) and loop diuretics. 

Thiazide diuretics are not effective with advanced renal insufficiency (serum creatinine level of 221 omol/l) and loop diuretics are needed, often at relatively large doses. Combining a loop diuretic with a long-acting thiazide diuretic, such as meto-lazone, is effective in patients resistant to a loop-diuretic alone. Potassium-sparing diuretics should be avoided in patients with renal insufficiency. 

When ascites and edema become severe, diuretic therapy can be very useful. However, cirrhotic patients are often resistant to loop diuretics because of decreased secretion of the drug into the tubular fluid and because of high aldosterone levels. In contrast, cirrhotic edema is unusually responsive to spironolactone and eplerenone. The combination of loop diuretics and an aldosterone receptor antagonist may be useful in some patients. 

The loop diuretics act promptly, even in patients who have poor renal function or who have not responded to thiazides or other diuretics. The loop diuretics cause decreased renal vascular resistance and increased renal blood flow. [Note Loop diuretics increase the Ca++ content of urine (see p. 227), whereas thiazide diuretics decrease the Ca++ concentration of the urine.]... 

Brater DC. Resistance to loop diuretics Why it happens and what to do about it. Drugs 1985 30 427-43. 

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). 

An alternative in the diuretic-resistant patient is the use of continuous infusions of loop diuretics rather than bolus diuretic therapy. Such infusions can also be given with a small volume of hypertonic saline, with good effect (39). The reasons why continuous infusions of loop diuretics work when bolus doses have failed may relate to a more efficient time-course of diuretic delivery and/or less activation of the renin-angiotensin system (40). Furosemide and torasemide may be the safest loop diuretics to be given as infusions, in that infusion of bumetanide has been associated with severe musculoskeletal symptoms (41). 

Finally, loop diuretics reduce the metabolic demand of tubular cells, reducing oxygen requirements and thereby, in theory, increasing resistance to ischemic insults and perhaps other toxic circumstances. This property has been advanced as the basis for using diuretics in acute renal insufficiency. Although an attractive hypothesis to date, there is no compelling evidence to suggest any... 

Four children with the nephrotic syndrome developed transient hypercalciuria and intraluminal calcification in renal histopathological specimens without radiological evidence of renal calcification. These children were resistant to corticosteroids and were receiving furosemide plus albumin for the management of edema (10). This result stresses the pervasive effect of furosemide, and probably all loop diuretics, in increasing urinary calcium excretion, with resultant nephrocalcinosis. Whenever possible, steps should be taken to limit the hypercalciuric effect of loop diuretics. Such maneuvers could include limiting the sodium content of the diet and/or combining the loop diuretic with a thiazide diuretic. 

The use of thiazide and loop diuretics in combination to treat resistant hypertension often causes severe deterioration in renal function (50,51). It is not clear whether this is the result of excess diuresis or excessive blood pressure reduction. 

Figure 10.1 Sites and mechanisms of action of diuretics. The location of each cell type along the nephron is indicated by the shading patterns. Spironoiactone (not shown) is a competitive aldosterone antagonist and acts primarily in the collecting duct. PT, proximal tubule LH, loop of Henie TAL, thick ascending limb DT, distal tubule DCT, distal convoluted tubule CD, collecting duct PC, principal cell CA, carbonic anhydrase CAI, carbonic anhydrase inhibitors , primary active transport. (Adapted with permission from Ellison D H 1991 The physiologic basis of diuretic synergism its role in treating diuretic resistance. Annals of Internal Medicine 114 886-894.)...

I Thiazide Diuretics. Thiazide diuretics such as hydrochlorothiazide block sodium and chloride reabsorption in the distal convoluted tubule (approximately 5% to 8% of filtered sodium). The thiazides therefore are relatively weak diuretics and infrequently are used alone in heart failure. However, as is reviewed in detail in the section Treatment Advanced/Decompensated Heart Failure under Diuretic Resistance, thiazides or the thiazide-like diuretic metolazone can be used in combination with loop diuretics to promote a very effective diuresis. 

Despite normal pharmacokinetics following intravenous administration, diuretic resistance is also observed with this route, suggesting an important pharmacodynamic component to diuretic resistance. The decreased responsiveness in heart failure patients is explained in part by the high concentrations of sodium reaching the distal tubule as a result of the blockade of sodium reabsorption in the loop of Henle. As a consequence, the distal tubule hypertrophies, increasing its ability to reabsorb sodium. In addition, low cardiac output, reduced renal perfusion, and subsequent decreased delivery of drug to the kidney also may contribute to resistance. 

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... 

Patients with nephrotic syndrome commonly develop diuretic resistance. It is suggested that the impaired natriuretic response may be overcome by using higher doses to increase the delivery of free drug to the secretory site in the proximal nephron. Another approach is to use the combination of a loop diuretic with a distal diuretic. 

Patients with cirrhosis should initially be treated with spironolactone in the absence of impaired glomerular filtration rate and hyperkalemia. Thiazides may then be added for patients with a creatinine clearance >50 mL/min. For those patients who remain diuretic resistant, a loop diuretic may replace the thiazide. 

Secondary hyperaldosteronism plays a major role in the pathogenesis of edema in patients with cirrhosis. Therefore these patients should initially be treated with spironolactone in the absence of impaired GFR and hyperkalemia. Thiazides may then be added for patients with a creatinine clearance >50 mL/min. For those patients who remain diuretic resistant, a loop diuretic may replace the thiazide. Patients with impaired GFR (creatinine clearance of <30 mL/min) generally will require a loop diuretic, with addition of a thiazide in those who do not achieve adequate diuresis. Care should be taken to avoid hypokalemia, which may precipitate hepatic encephalopathy by increasing ammoniagenesis (Fig. 49-8). ... 

Both thiazides and loop diuretics also produce vasodilation, which reduces peripheral vascular resistance and helps reduce blood pressure. Thiazide diuretics are recommended as an alternative to calcium channel blockers (see below) as first choice drugs in hypertensive patients over the age of 55 years and in those of African origin of any age. 

Etacrynic acid, especially in combination with spironolactone and xipamide, markedly enhances natriuresis and diuresis. The dosage is increased as required (e.g. 1 X 25 mg or 50 mg to 2 x 50 mg per day). With a low-dose application in the form of a combined diuretic therapy, there is usually no risk of hepatic encephalopathy developing. The effect of etacrynic acid sets in at the ascending branch of the loop of Henle (active chloride transport). Renovascular resistance is lowered due to enzymatic activity, presumably as a result of a rise in the release of prostaglandin. 

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