(Data from Cody RJ, Pickworth KK: Approaches to diuretic therapy and electrolyte imbalance in congestive heart failure. In Deedwania PC [ed]: Update in Congestive Heart Failure, vol 12. Philadelphia, Saunders, 1994, p 37.)

Figure 39-2 Blood volume, measured by ¹²⁵I albumin, is given on the x axis as a percent of normal blood volume. Four groups of heart failure patients receiving digoxin and diuretics but no angiotensin-converting enzyme inhibitors are identified: patients with contracted blood volume (n = 4; −12 ± 6% < normal); patients with a mild increase in blood volume (n = 8; 14 ± 3% > normal); patients with a moderate increase in blood volume (n = 7; 25 ± 3% > normal); and patients with a severe increase in blood volume (n = 8; 40 ± 10% > normal). Systemic vascular resistance does not differ among the groups, but cardiac index decreases with blood volume expansion. Pulmonary capillary wedge and right arterial pressures increase. The expansion of blood volume is associated with progressive reduction of renal blood flow and compensatory increase of renal filtration fraction. Urine flow rate is also decreased in patients with increased blood volume, but is not significantly reduced compared with patients with contracted blood volume. With progressive increase of blood volume, plasma renin activity (ng/mL/hr) is suppressed. Despite diuretic therapy, there may be a range of blood volume expansion, which influences cardiac and renal function. ∗P < .05 by analysis of variance.

The reduction of the glomerular filtration rate in heart failure is highly correlated with hemodynamic parameters, where the greatest reduction of cardiac output and renal blood flow are associated with the greatest reduction of the glomerular filtration rate.^1,⁶ Renal blood flow and function tend to decrease with age in normal subjects, and an age effect can be superimposed on the overall reduction in renal blood flow and function due to the heart failure process.⁶ The resultant diminished delivery of sodium to the distal nephron at the level of the macula densa becomes a potent stimulus for renin release.⁷ Aldosterone further increases sodium retention at the distal nephron at the expense of potassium excretion. Although current therapy for heart failure may improve cardiac output and renal blood flow, no current oral therapy has uniformly improved the glomerular filtration rate.

Neurohormonal factors that promote retention of sodium and water include aldosterone, vasopressin, angiotensin II, norepinephrine, and the vasoconstrictor prostaglandins; in contrast, prostacyclin, dopamine, and atrial natriuretic factor favor sodium excretion.^3,⁴ The effect of vasopressin is primarily the promotion of free water retention, rather than sodium retention, and this typically contributes to hyponatremia.

Pharmacokinetics of Diuretic Therapy

Response to Diuretic Administration for Acute Cardiac Decompensation

The sites of diuretic actions and their role in the edema of cardiac decompensation have been reviewed.^10,¹¹ In the last decade, there have not been substantial breakthroughs in new diuretic development or mechanisms. The hemodynamic response to diuretic therapy has been characterized primarily in the setting of pulmonary edema. The acute hemodynamic response revealed a vasodilator effect¹²^–¹⁴ and reduction of cardiac filling pressures.¹²^–¹⁵ During acute decompensated heart failure, changes in cardiac output varied from increased or no change to significant reduction, and changes in hemodynamics could proceed, or lag, production of diuresis. Such evaluations were conducted in diverse patient populations and must be interpreted accordingly. It has been stated that the vasodilator effect could precede the occurrence of diuresis, but the database for this effect is limited. Studies have reported either vasoconstriction,¹⁶ or initial vasodilation followed by vasoconstriction¹⁷ with acute or short-term follow-up. A review of the cited literature therefore reveals a fully divergent range of hemodynamic response to diuretics, although the majority of acute studies demonstrate a reduction of cardiac filling pressures.¹²^–¹⁵ Loop diuretics have been shown to decrease renal vasculature resistance and to increase total and cortical renal blood flow.^13,^18,¹⁹ However, this may be related to severity of heart failure.²⁰ It is difficult to isolate a single neurohormonal factor as being primarily responsible for the overall hemodynamic and regional hemodynamic response to diuretics. Acute diuretic therapy may increase renin and aldosterone.^16,^17,^20,²¹ Sympathetic nervous system activity also increases in response to diuretics.^20,²¹ The impact of neurohormonal activation is an attenuation of the otherwise favorable effects of diuretics.

Loop Diuretics

As this chapter focuses on acute cardiac decompensation, the response to parenteral diuretic therapy will be emphasized (Table 39-2), without an extensive review of pharmacology. The term loop diuretic has evolved to encompass pharmacologic compounds which exert their primary action on the thick ascending loop of Henle. To reach the intraluminal site of action, these organic acids must first be secreted into the proximal tubule via the organic acid pathway. Once in the lumen, active reabsorption of chloride is inhibited in both the medullary and cortical portions of the loop of Henle. Decreased sodium reabsorption also occurs since the chloride ion is cotransported with sodium and potassium.

Table 39–2 Pharmacokinetics of Intravenous Diuretics: Are there appreciable differences?

The three loop diuretics traditionally used in the United States to treat the edema of heart failure are furosemide, bumetanide, and torsemide. They are of equal efficacy but vary in pharmacokinetic properties.^11,²² Ethacrynic acid remains available, but has a progressively diminishing role for edema management.²³^–²⁵ Despite equal efficacy among loop diuretics, clinicians will often substitute one for the other with the hope of improved efficacy. Torsemide has a greater duration of action than its counterparts, but in general, the strategy of changing from one loop diuretic to another is typically not effective. After oral administration, furosemide has 40% bioavailability, bumetanide has 80%, and torsemide has greater than 80% bioavailability. A diminished diuresis and a prolonged renal elimination of the drug may be expected in heart failure when renal dysfunction is evident. Torsemide has two active metabolites, which probably accounts for its longer elimination half-life of 3 hours. Residual loop diuretic concentration is eliminated by nonrenal mechanisms, including hepatic degradation and excretion. Because of the differences in bioavailability and potency, equivalent doses of bumetanide, furosemide, and torsemide are 1 mg, 40 mg, and 20 mg, respectively. All three agents are extensively bound to plasma proteins and are rapidly secreted by the organic acid pathway of the proximal tubule. In chronic renal failure, competition for this pathway by exogenous and accumulated endogenous organic acids causes lower peak concentration of the drug at its site of action. Therefore, a diminished diuresis and a prolonged renal elimination of the drug may be expected in heart failure when renal dysfunction is evident. The diuretic effect is apparent within 30 minutes after oral administration and peaks in 1 to 2 hours.²⁶^–³⁰ Bumetanide has a somewhat shorter duration of action than that of furosemide or torsemide. Torsemide, like other loop diuretics, must be secreted into the urine by the organic acid secretory system in the proximal tubule to be effective.²³ It produces a maximum sodium excretion rate at approximately the same time with either intravenous or oral administration. Although the pharmacokinetics of torsemide are linear, increases in doses above 50 mg do not appear to increase the maximum sodium excretion rate but do increase the duration of the pharmacodynamic effect. One study has defined a ceiling dose of 100 mg of torsemide in patients with renal insufficiency and has recommended that repeated administration of torsemide is more effective than increasing the dose at this point.²³ It has been shown in another study that 20 mg of intravenous torsemide is approximately as effective as 40 mg of intravenous furosemide.²⁴ However, additional well-controlled trials of torsemide are necessary to determine whether it provides clinical benefit beyond current loop diuretics.