Diuretic Therapy

Loop and distal tubular diuretics are necessary adjuncts in the medical therapy for HF when symptoms are the result of sodium and water retention. Diuretics reduce congestive symptoms and signs and can be titrated as needed to restore euvolemia and to reach an estimated "dry" weight goal for the patient.

Relief of signs and symptoms must be achieved without causing side effects, particularly symptomatic hypotension or worsening renal function. Underutilization of diuretic therapy is common, but excessive diuresis is also problematic, limiting ventricular preload and producing excessive lowering of blood pressure, especially in conjunction with antihypertensive drugs such as ACE inhibitors, ARBs, and beta blockers. Diuretic administration should be accompanied by a recommendation for dietary sodium restriction to between 2000 and 3000 mg daily for the typical patient with HF (see Section 6). Fluid restriction is best reserved for the patient refractory to diuretics with a high oral fluid intake or symptomatic hyponatremia.

Although some retrospective analyses have generated concern about the long-term safety of diuretics,83,84 this concern is not supported by any controlled data. There are few controlled studies of diuretics because few symptomatic patients can be managed without them. Still, there are data to support the safety and efficacy of diuretics.85 A trial in which patients with stable and relatively mild HF without evidence of significant volume overload were randomized to substitution of an ACE inhibitor or continued diuretic showed that the large majority of patients required reinstatement of diuretic therapy.86 Very small trials suggest that in patients with reduced LVEF with or without HF, ACE inhibitor therapy may prevent remodeling more than diuretics, but that diuretics may be superior for symptom improvement.87,88 However, there are no controlled clinical trial data prospectively evaluating the overall impact of diuretic therapy on mortality in patients with HF. Diuretics may cause activation of the RAAS, potentiate hypotensive effects of ACE inhibitors,89,90 and may decrease cardiac output, especially in patients with diastolic LV dysfunction. Diuretics also may induce hypokalemia and hypomagnesemia.

Loop Diuretics. Loop diuretics, which act on the ascending limb of the renal medullary loop of Henle, are considered the diuretic class of choice for the treatment of HF. These drugs produce a greater fractional excretion of filtered sodium than is induced by thiazide-type diuretics. The onset of action with intravenous administration is within minutes, making this route of administration preferable for the acutely symptomatic or hospitalized patient (see Section 12).

Thiazide Diuretics. Thiazide diuretics, which inhibit sodium reabsorption in the distal renal tubule, may be effective as monotherapy in HF patients with mild volume overload and preserved renal function. They are generally superior to loop diuretics as antihypertensive agents. They are delivered to their site of action by filtration and are ineffective when the glomerular filtration rate falls below 30 mL/min.

Potassium-Sparing Diuretics. Potassium-sparing diuretics, other than aldosterone antagonists, have no direct diuretic activity. Several are formulated in combination with thiazides for the treatment of hypertension, but are not generally useful in HF. For patients with excessive potassium losses on loop diuretics, coincident administration of these agents can be helpful. However, because of their beneficial effects on prognosis and ability to facilitate diuresis, aldosterone antagonists are preferred for this purpose. The use of these agents for purposes other than as a diuretic is discussed earlier in this section. Table 7.3 and Table 7.4 provide dosage and other information about loop diuretics, thiazides, and potassium-sparing diuretics.6,91,92

HF can adversely affect the pharmacokinetics of diuretics in a number of ways. Delayed absorption, resulting from gut edema from high central venous pressure, can reduce peak serum concentration. The volume of distribution is variable in the setting of chronic HF. Relative hypotension or reduced cardiac output producing a limitation in renal blood flow reduces the delivery of diuretic to the kidney. In general, these limitations can be overcome by successively increasing the dose administered.

Thiazide-type diuretics can be used in combination with loop diuretics to augment natriuresis when high doses of loop diuretic are ineffective at restoring euvolemia. Improved natriuresis from the combination of these 2 classes of diuretics is expected as they act at different sites in the kidney to produce sodium loss. In addition, resistance to loop diuretics can occur, partially due to progressive hypertrophy of distal renal tubular endothelial cells. This results in greater distal tubular reabsorption of sodium, which in turn reduces the net natriuretic effect of loop diuretics. Combining a thiazide-type diuretic with a loop diuretic typically will overcome this compensatory hypertrophy and result in a significantly greater diuretic effect. Metolazone is a thiazide-like diuretic with better oral availability than loop diuretics. It has a half-life of approximately 14 hours. The diuretic effects of metolazone are preserved even in patients with reduced GFR (<20 ml/min) because it does not decrease GFR or renal plasma flow; in contrast, thiazide diuretics can decrease GFR which contribute to their lower efficacy in patients with renal impairment.

Hypokalemia from excessive potassium wasting is common during loop diuretic therapy, especially during the reversal of significant volume overload. Thiazide-type diuretics also contribute to potassium wasting. Serum potassium concentration should be monitored when diuretics are used, particularly during initiation and uptitration of therapy, with supplements given as needed. Other electrolyte disturbances associated with chronic diuretic use include hypomagnesemia and hypocalcemia.

Excessive diuresis may lead to volume depletion during treatment. Symptoms may include fatigue and shortness of breath, rather than the more predictable symptoms of lightheadedness. Hyperkalemia may accompany mild volume depletion and is more likely to occur in patients receiving ACE inhibitors, ARBs, and/or aldosterone blockers, especially in patients with diabetes or those taking potassium supplements or ingesting foods with high potassium content.

Use of loop and distal tubular diuretics in combination may be necessary to relieve symptoms, but may result in excessive volume loss and electrolyte disturbance. Distal tubular diuretics should be introduced cautiously when they are combined with loop diuretics, and patients should be monitored closely for side effects. Initially, only single low doses (eg, metolazone 2.5 mg) should be administered to determine the magnitude of response. If necessary, higher doses may be used subsequently, but this should be done cautiously with close monitoring of electrolytes and volume status. Twice-daily dosing of distal agents is generally not helpful because they have a long duration of action. In most cases, the frequency of use can be cut back to every other day, once or twice weekly, or as needed based on a weight threshold.

Worsening renal function is common with excessive diuresis, especially when patients are receiving ACE inhibitors or ARBs. Fortunately, reduction in diuretic dose and restoration of euvolemia will return renal function to baseline levels in almost all cases unless hypovolemia has been prolonged or worsening renal function is due to another cause (eg, nephrotoxic drugs, post-obstructive uropathy). Intensification of diuretic therapy in these patients may be accompanied by a worsening of renal function reflected by modest elevations in blood urea nitrogen and serum creatinine concentration. Some reduction in renal function may be a necessary tradeoff for symptom relief in this setting. While there is an association between worsening renal function and adverse outcomes in HF, causality remains unproven.

The occurrence of reduced renal function should prompt a review of the patient's current medications to avoid concomitant administration of nephrotoxic drugs or drugs that reversibly affect renal function (eg, nonsteroidal anti-inflammatory drugs, antibiotics) and to determine if dose reduction in medications dependent on renal clearance (eg, digoxin) is warranted. It is essential to recognize progressive renal insufficiency from decreasing renal perfusion that will require adjustment of diuretic therapy. Worsening renal function can also result from inadequate diuresis and volume overload leading to renal venous or intraabdominal hypertension.

Loop diuretics may be associated with a variety of other side effects that may require additional treatment to correct. Rapid intravenous administration of high-dose loop diuretics should be avoided whenever possible, because hearing loss to the point of deafness can result from middle ear toxicity. Skin reactions from photosensitivity to rashes are not uncommon, and other hypersensitivity reactions including interstitial nephritis may occur. High doses of loop diuretics can worsen glucose tolerance and may result in hyperuricemia and symptoms of gout, prompted by increased uric acid reabsorption. Thiazide diuretics share most of the side effects seen with loop diuretics, although an association with pancreatitis appears be unique to loop diuretics.

Reduced diuretic requirement is not uncommon during the course of HF treatment. The initiation of more effective therapies, such as ACE inhibitors and beta blockers, may result in substantial improvement in underlying LV dysfunction and in neurohormonal abnormalities that result in sodium and water retention. Improvement in adherence to dietary sodium restrictions is not unusual during chronic therapy for HF and may substantially reduce the need for diuretic therapy. Reevaluation of diuretic dose and frequency should occur over the course of initiation and titration of therapy.

Episodic increases in sodium intake over weeks and months of follow-up are expected, given the natural variation in diet common in the daily lives of patients with HF. If untreated, this excessive dietary sodium intake may result in development or recurrence of congestive symptoms. The ability to recognize early signs and symptoms of volume overload is an important aspect of self-care for these patients. Intervention early in the development of fluid overload may allow restoration of volume status without hospitalization.

A strategy effective in many patients involves adjustment of the diuretic dose according to increases in daily weight. Some patients find it effective to increase diuretic empirically when dietary sodium indiscretion occurs. In some patients with advanced HF, monitoring of renal function and potassium is necessary before or during these periods.