Balancing Diuretic Therapy in Heart Failure: Loop Diuretics, Thiazides, and Aldosterone Antagonists

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1 BALANCING DIURETIC THERAPY IN HEART FAILURE CHF NOVEMBER/DECEMBER Balancing Diuretic Therapy in Heart Failure: Loop Diuretics, Thiazides, and Aldosterone Antagonists In heart failure, sodium is retained by the kidneys despite increases in extracellular volume. There is activation of renin secretion, which culminates in the production of angiotensin II, causing vasoconstriction and aldosterone secretion. These synergistically produce an increase in tubular reabsorption of sodium and water. Diuretics are the mainstay of symptomatic treatment to remove excess extracellular fluid in heart failure. Diuretics that affect the ascending loop of Henle are most commonly used. Thiazide diuretics promote a much greater natriuretic effect when combined with a loop diuretic in patients with refractory edema. Recently, spironolactone, an aldosterone receptor blocking agent, has been recommended to attenuate some of the neurohormonal effects of heart failure. Regardless of the diuretic, patients need to be counseled on the importance of avoiding sodium in their diet (CHF. 2002;8: ) 2002 CHF, Inc. Sara Paul, RN, MSN, FNP From the Heart Failure Clinic, Medical University of South Carolina, Charleston, SC Address for correspondence: Sara Paul RN, MSN, FNP, th Street Drive NW, Hickory, NC smcpaul@earthlink.net Manuscript received February 12, 2001; accepted April 25, 2001 Sodium Retention and Edema in Heart Failure Some fundamental features of extracellular volume overload in heart failure have been known and well documented in medical literature for decades. At the turn of the century, Starling 1 noted that blood volume was more than likely to be increased in patients with edema. Over 50 years ago, Starr et al. 2,3 showed that edema occurs only when venous pressure is elevated, and Warren and Stead 4 made the observation that an increase in weight precedes an increase in venous pressure. In 1946, Merrill 5,6 noted that weight gain in patients with congestive heart failure (CHF) was the result of salt and water retention by the kidney due to low renal blood flow. The physiology behind these observations remains the same today. In normal subjects, intravascular volume (plasma volume) and interstitial space, which together constitute the extracellular volume (ECV), remain constant, despite altered sodium and water intake. Since sodium constitutes more than 90% of the total cations of the extracellular fluid, the body content of sodium is the primary determinant of ECV. Control of ECV is dependent upon sodium balance, which is controlled by the kidneys. If ECV is increased in a normal person, the kidneys excrete extra salt and water. In CHF, however, sodium is retained by the kidneys despite increases in ECV. Sodium and water retention is not necessarily due to decreased cardiac output, since there are high output states that also cause edema, such as severe anemia, thyrotoxicosis, chronic arteriovenous fistula, Paget s disease, and beriberi. 7 Furthermore, sodium retention is not caused by decreased blood volume, since blood volume is increased with CHF, not decreased. It is clear, however, that salt and water retention in CHF is at least in part due to the body s attempt to maintain a normal arterial blood pressure. Data from a group of patients with untreated severe left ventricular dysfunction gave insight into the physiology of edema in CHF. As would be expected, these patients had resting tachycardia and increased rightand left-sided filling pressures. 8 Despite a 50% reduction in cardiac output, arterial blood pressure was

2 308 BALANCING DIURETIC THERAPY IN HEART FAILURE CHF NOVEMBER/DECEMBER 2002 normal due to increased systemic vascular resistance. Total body water was increased 16% above normal, almost all of which was in the extracellular space. Plasma volume increased by 34% and total body exchangeable sodium increased 37%. Effective renal plasma flow was severely decreased to 30% of normal due to severe renal vasoconstriction. Glomerular filtration rate was reduced to a lesser extent, suggesting greater efferent than afferent arteriolar vasoconstriction. Plasma norepinephrine was increased more than six times above normal and plasma renin activity was nine times normal. Aldosterone was increased six times above normal and plasma atrial natriuretic peptide was increased to 15 times normal. It appears, therefore, that the sodium-retaining effects of the catecholamines and the renin-angiotensin system prevail over the natriuretic effects of atrial natriuretic peptide in advanced CHF. It is noteworthy that the marked increase in plasma volume did not mitigate the ongoing activation of neurohormonal sodium-retaining mechanisms. Diminished renal blood flow is thought to be the stimulus for activation of renin secretion in heart failure, which culminates in the production of angiotensin II, causing vasoconstriction and aldosterone secretion. Angiotensin II and aldosterone synergistically produce an increase in tubular reabsorption of sodium and water. Angiotensin II and aldosterone exert direct myocardial effects, leading to ventricular hypertrophy and cardiac fibrosis. Diuretic Therapy in CHF Loop Diuretics. Over time, the retention of sodium leads to crackles, peripheral edema, hepatomegaly with ascites, increased blood volume, and increased cardiac filling pressures. Although diuretics do not directly treat the pathologic changes that occur with heart failure, they are the mainstay of symptomatic treatment to remove excess extracellular fluid, thus alleviating pulmonary and peripheral edema. Diuretics that exert their primary action on the thick ascending loop of Henle are most commonly used. Most of the filtered sodium is reabsorbed in the proximal tubule (60% 65%) and the loop of Henle (20%). At maximum dose, loop diuretics can lead to excretion of up to 20% 25% of filtered sodium. 9,10 The main loop diuretics used in the United States are furosemide, bumetanide, and torsemide. Thiazide diuretics, such as metolazone, are less potent than loop diuretics and are therefore less useful when used alone in CHF patients. A short-acting diuretic such as furosemide produces significant natriuresis during the 6-hour period following drug administration. However, sodium excretion falls to very low levels during the remaining 18 hours of the day because the volume depletion from the furosemide leads to activation of sodium-retaining mechanisms, such as the renin-angiotensin-aldosterone system and the sympathetic nervous system. The activated neurohormones angiotensin II, aldosterone, and norepinephrine promote tubular sodium reabsorption, thus contributing to rebound sodium retention. Consequently, if a patient consumes a highsodium diet, there is no net loss of sodium, despite diuretic therapy. Solutions to this problem include eating a low-sodium diet, taking the diuretic twice a day, or increasing the dose of diuretic. Maximum diuresis will occur with the first daily dose of diuretic, but activation of sodium-retaining mechanisms can limit the response to the second dose. Concomitant use of an angiotensin-converting enzyme (ACE) inhibitor will decrease the response and activation of the renin-angiotensin system, which may increase the diuretic effect of a second daily dose. It is important to note that diuretic therapy alone is not sufficient to control sodium and fluid retention in patients with CHF. Dietary reduction in sodium is imperative to promote diuresis and prevent accumulation of extracellular fluid. Patients must be educated about the effects of sodium in heart failure and they must learn to calculate their intake of sodium, keeping the total intake below 4000 mg per day. If they have moderate to severe heart failure with pulmonary or peripheral edema, they may need to reduce their sodium intake even further to mg per day. The reduction in intracardiac pressures that is induced by diuretics lowers intravascular pressure, thereby permitting mobilization of edema fluid from the interstitium. Edema fluid is mobilized diffusely from tissues and maintains the intravascular volume, thus supporting hemodynamics, even with rapid diuresis. However, once edema has resolved, this defense against intravascular volume depletion is not available. Lowering of the pulmonary capillary wedge pressure to the optimal range (15 18 mm Hg) produces very little, if any, decrease in cardiac index (Figure: Starling curve, point B to point C), but an excessive decrease in preload will lower the cardiac index (Figure: point C to point A). This diuretic-induced reduction in cardiac filling pressures can lead to a decline in cardiac output and activation of the renin-angiotensin system. Again, in this situation, the use of an ACE inhibitor will decrease activation of the renin-angiotensin system, but does not primarily increase the cardiac output if over-diuresis is induced. In pulmonary edema due to acute myocardial infarction, intravenous furosemide causes transient venodilation resulting in a fall in cardiac filling pressures and decreased pulmonary congestion prior to

3 BALANCING DIURETIC THERAPY IN HEART FAILURE CHF NOVEMBER/DECEMBER Figure. Diuretic effects on cardiac index and pulmonary capillary wedge pressure in the presence of left ventricular dysfunction. Modified with permission of the McGraw-Hill Co. DiPiro JT, Talbert RL, Hayes PE, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 2nd ed. Norwalk, CT: Appleton & Lange; 1993:169. the onset of diuresis. 14 Loop diuretics increase the production of vasodilator prostaglandins; thus, the venodilator response can be blocked in the presence of nonsteroidal anti-inflammatory drugs (NSAIDs) Prostaglandins protect the glomerular microcirculation by promoting vasodilation in the afferent arterioles, thereby promoting sodium excretion. 19,20 Consequently, it is important to counsel diuretic-treated patients to avoid the use of NSAIDs for pain relief. 21,22 In patients with advanced, chronic CHF and chronic renin hypersecretion, intravenous loop diuretics may cause an acute increase in plasma renin and norepinephrine levels, leading to arteriolar vasoconstriction and a rise in systemic blood pressure. This increase in afterload can transiently decrease cardiac output and increase pulmonary capillary wedge pressure, with possible worsening of dyspnea. These changes are usually reversed within 1 hour once diuresis begins and the release of vasoconstrictors decreases. 23 Electrolyte imbalance, particularly hypokalemia, is the most common adverse effect of loop diuretics. Through this mechanism, diuretics may increase mortality (especially arrhythmic deaths). In the Studies of Left Ventricular Dysfunction (SOLVD), 24 diuretic use was associated with a higher incidence of overall mortality, cardiovascular deaths, and arrhythmic or sudden deaths as compared with non-use of diuretics at baseline. Hypokalemia was thought to be the mechanism of arrhythmia mortality. Other adverse effects include hyperuricemia, which could precipitate an acute episode of gout. Ototoxicity and glucose intolerance are rare side effects. The bioavailability of oral furosemide is only about 50%, but there is wide variability among patients. 25 The dose should be governed by diuretic response. Generally, the oral dose of furosemide is twice that of the intravenous dose because of incomplete absorption. Decreased intestinal perfusion and mucosal edema may markedly slow the rate of drug absorption and rate of drug delivery to the kidney This is usually reversed when some edema fluid is removed. 27 Bumetanide and torsemide have better oral bioavailability than furosemide, and therefore there is a more predictable relationship between intravenous and oral doses with these agents. Patients with advanced heart failure become less responsive to conventional oral doses of loop diuretics due to decreased renal perfusion (decreased tubular secretion of the diuretic and reduced filtered load of sodium) and increases in sodium-retaining hormones (angiotensin II and aldosterone). 25 Resistance to diuretics may occur after chronic use. Patients are considered diuretic-resistant if they have progressive edema despite increased oral or intravenous diuretic doses. This occurs in 20% 30% of patients with severe left ventricular dysfunction. Persistent fluid retention can be caused by a number of factors (Table I). 10,21,22 Suggestions to overcome diuretic resistance include giving the diuretic via the intravenous route (bolus or infusion), optimizing the dosage, or using combination therapy with a thiazide diuretic to block sodium reabsorption at multiple sites. Alleviating factors that contribute to fluid retention, such as a high-sodium diet and use of NSAIDs, may promote a diuretic response. Bolus intravenous administration of furosemide has a short-acting effect similar to that of oral furosemide and is associated with initially high and then low rates of diuretic excretion. A continuous infusion of furosemide may have a greater net sodium excretion compared to intermittent bolus administration because a constant infusion maintains an optimal rate of drug excretion. 25,30,31 Doses of Table I. Causes of Persistent Fluid Retention in Heart Failure Inadequate diuretic dose Excess sodium intake Delayed intestinal absorption of oral diuretics Decreased diuretic excretion into the urine Increased sodium reabsorption at diuretic-insensitive sites in the nephron

4 310 BALANCING DIURETIC THERAPY IN HEART FAILURE CHF NOVEMBER/DECEMBER 2002 Table II. Adverse Effects of Potassium-Sparing Diuretics Arrhythmia Nervousness Dizziness Fatigue Headache Rash Breast tenderness Enlargement of breasts in males Inability to achieve or maintain erection Increased hair growth in females Decreased sexual ability Gastrointestinal irritation Possible decrease in effects of anticoagulants mg per hour of furosemide, 1 2 mg per hour bumetanide or mg per hour torsemide may provide better diuresis than individual bolus doses. 25 Posture can affect the patient s response to a diuretic. Patients with CHF have enhanced renal perfusion when supine, and therefore better diuretic delivery to the kidneys. Hence, supine positioning can increase the diuretic response as much as two-fold. 32 As a last resort, hemofiltration can be utilized in refractory patients who do not respond to diuretic therapy. Excess fluid can be removed by ultrafiltration of the blood through a semipermeable dialysis membrane. Occasionally, ultrafiltration can restore diuretic responsiveness in previously refractory patients. Thiazides. When a patient requires 240 mg per day of furosemide, it is better to add a thiazide diuretic, such as metolazone, than to continue to increase the patient s furosemide dose. Thiazide diuretics inhibit sodium transport in the distal tubule, although some agents, such as metolazone, may exert some proximal tubule activity as well, perhaps by blocking carbonic anhydrase. These segments normally reabsorb less of the filtered load than the loop of Henle; therefore, thiazides alone are less potent than loop diuretics. One theory suggests that by blocking the proximal tubule with metolazone, more sodium is delivered to the loop of Henle, resulting in a much greater natriuretic effect than when a loop diuretic is given alone More importantly, thiazides can block compensatory responses by the distal convoluted tubule to increased sodium delivery from the loop of Henle. Thiazide diuretics can be given at the same time as a loop diuretic when the two drugs are given by the oral route. Unfortunately, intravenous metolazone is not available. When a thiazide is given orally and a loop diuretic is given intravenously, the thiazide should be given minutes in advance. Patients should be closely monitored when given combination diuretic therapy, since it can induce a profound diuresis, with electrolyte and volume depletion. Aldosterone Receptor Blockers. In the presence of neurohormonal activation, angiotensin II causes aldosterone production in the adrenal cortex, which acts on the cortical collecting tubules to conserve sodium. Aldosterone may induce perivascular and interstitial cardiac fibrosis that may reduce systolic function, increase cardiac stiffness, and thereby impair diastolic function, generating heterogeneous intracardiac conduction defects with potential for serious re-entrant arrhythmias. Aldosterone may also increase vulnerability to serious arrhythmias by inhibiting cardiac noradrenaline reuptake, impairing baroreflex-mediated heart rate variability, augmenting sympathetic activity, inhibiting parasympathetic flow, and impairing arterial compliance. Aldosterone also promotes potassium and magnesium depletion, which is potentially proarrhythmic. Aldosterone was originally thought to be blocked by ACE inhibitors. However, it is now known that usual doses of ACE inhibitors do not completely suppress aldosterone production. Furthermore, there may be an escape of aldosterone, even when ACE activity is inhibited. Up to 40% of patients on ACE inhibitors have elevated serum concentrations of aldosterone. 36 Spironolactone (Aldactone, an aldosterone receptor blocker, can be used in the presence of heart failure to diminish the degree of potassium loss or to increase net diuresis in patients with refractory edema. By competing with aldosterone for receptor sites in distal renal tubules, spironolactone increases sodium chloride and water excretion while conserving potassium and hydrogen ions. The inhibition of sodium reabsorption leads to reduced potassium excretion. Potassium-sparing diuretics have a relatively weak natriuretic effect. Recently, spironolactone has been recommended to attenuate some of the neurohormonal effects of heart failure. The Randomized Aldactone Evaluation Study (RALES) was designed to determine the effect of lowdose Aldactone (mean dose, 26 mg daily) on survival in severely symptomatic (New York Heart Association class IV) heart failure patients taking an ACE inhibitor, loop diuretic, and digoxin. 37 A total of 1663 heart failure patients were enrolled. The ejection fraction in these patients was less than 35% and the etiology of heart failure was from ischemic and nonischemic causes. All-cause mortality was the primary end point. There were 386 deaths in the placebo group vs. 284

5 BALANCING DIURETIC THERAPY IN HEART FAILURE CHF NOVEMBER/DECEMBER deaths in the treatment group. Frequency of hospitalization for heart failure was 35% lower in the treatment group and greater improvement was noted in New York Heart Association class during follow-up. The potential benefit of aldosterone antagonists in patients with milder heart failure cannot be determined from this study. Furthermore, patients with serum potassium greater than 5.0 were excluded, as well as patients with renal insufficiency. Relatively few patients in either group (about 10%) were treated with β blockers. Current recommendations state that Aldactone should be given at a low dose ( mg daily) and should be considered for patients receiving standard therapy who have severe heart failure caused by left ventricular systolic dysfunction. 38 Potassium-sparing diuretics are contraindicated in the presence of hyperkalemia and renal failure. Patients should not take potassium supplements. Aldactone should be used with caution in patients with hyponatremia, renal insufficiency, or hepatic disease. Adverse effects are listed in Table II. In summary, loop diuretics are the mainstay of diuretic therapy in CHF. One must consider the physiologic effects, both positive and negative, when administering these drugs. If loop diuretics lose effectiveness or the patient develops refractory edema, adding a thiazide diuretic may help overcome diuretic resistance through a different mechanism of action. In recent years, aldosterone antagonists have been found to improve outcomes in patients with moderate to severe heart failure who are already on an appropriate medication regimen. Regardless of the diuretic, patients need to be counseled on the importance of avoiding sodium in their diet. Medication alone cannot overcome the neurohormonal activation associated with heart failure. 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