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. 

Finally, poor CO may contribute to diuretic resistance. In these patients, it may become necessary to add vasodilators or inotropes to enhance perfusion to the kidneys. Care must be taken, as vasodilators can decrease renal blood flow despite increasing CO through dilation of central and peripheral vascular beds. 

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. 

The answer is b. (Hardman, pp 695-697.) A significant increase in the amount of any osmotically active solute in voided urine is usually accompanied by an increase in urine volume Osmotic diuretics affect diuresis through this principle. The osmotic diuretics (such as mannitol) are nonelectrolytes that are freely filtered at the glomerulus, undergo limited re absorption by the renal tubules, retain water in the renal tubule, and promote an osmotic diuresis, generally without significant Na excretion. Ln addition, these diuretics resist alteration by metabolic processes. 

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. 

Common Causes of Diuretic Resistance in Patients with Acute Renal Failure... 

Givertz MM et al The effects of KW-3902, an adenosine Al-receptor antagonist, on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance. 3 Am Coll Cardiol 2007 50(16) 1551. [PMID 17936154]... 

Kramer BK, Schweda F, Riegger GA. Diuretic treatment and diuretic resistance in heart failure. Am J Med 1999 106(l) 90-6. 

Ellison DH. Diuretic resistance physiology and therapeutics. Semin Nephrol. 1999 19 581-597. 

Due to clinical, laboratory and therapeutic differences, it is possible to distinguish between simple and problematic ascites. The latter includes (I.) recurrent ascites, (2.) refractory ascites, (3.) diuretic resistant ascites, and 4.) diuretic intractable ascites, (s. tab. 16.8)... 

Rector, W.G. Diuretic-resistant ascites. Arch. Intern. Med. 1986 146 1597-1600... 

Peltekian, K.M., Wong, F., Liu, RR, Logan, A.G., Sherman, M., Blendis, L.M. Cardiovascular, renal and neurohumoral response to single large-volume paracentesis in patients with cirrhosis and diuretic-resistant ascites. Amer. J. Gastroenterol. 1997 92 394- 399... 

Becker BN, Greene J, Evanson J, Chidsey G, Stone WJ. Ginseng-induced diuretic resistance. JAMA 1996 276(8) 606-7. 

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). 

KIrchner KA,Voelker JR, Brater DC. Intratubular albumin blunts the response to furosemide-a mechanism for diuretic resistance in the nephrotic syndrome. Pharmacol Exp Ther 1990 252 1097-101. 

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.)...

L. K. M. De Bruyne, Mechanisms and management of diuretic resistance in congestive heart failure. Postgrad Med J 79 268-271 (2003). 

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... 

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