Pathophysiology

Generation Phase

Diuretics increase sodium excretion by inhibiting transport at different sites of the nephron (see Chapter IIIA). This enhanced sodium loss is limited in duration and is greatest after the first dose (Fig. 1). If the sodium loss is large enough, it will lead to volume depletion.

Bolus Bolus

Bolus Bolus

Time, hr

FIGURE 1. Urinary sodium excretion (UNa) after intravenous bolus or infusion of bumetanide in patients with stable chronic renal failure. The peak natriuresis following iv bolus is 25% less during the second dose. In contrast, the natriuresis slowly declines during continuous iv infusion. The continuous infusion produced a greater natriuresis than bolus. (Adapted from Rudy DW, Voelker JR, Greene PK, et al Ann Intern Med 115:360,1991 with permission).

Time, hr

FIGURE 1. Urinary sodium excretion (UNa) after intravenous bolus or infusion of bumetanide in patients with stable chronic renal failure. The peak natriuresis following iv bolus is 25% less during the second dose. In contrast, the natriuresis slowly declines during continuous iv infusion. The continuous infusion produced a greater natriuresis than bolus. (Adapted from Rudy DW, Voelker JR, Greene PK, et al Ann Intern Med 115:360,1991 with permission).

Treatment Days

FIGURE 2. Sodium balance in three nonedematous patients treated with 100 mg of hydrochlorothiazide per day. Data for each patient reflect the average balance for each 3- or 4-day period. Net sodium loss is seen for only 3 days before a new steady state is reestablished. (Adapted from Maronde RF, Milgrom M, Vlachakis ND, Chan L, J. Am. Med. Assoc. 249:237, 1983, with permission.)

Maintenance Phase

Once fluid loss and volume depletion occur, the response to further doses of diuretics will be limited by the activation of sodium retaining mechanisms. If the diuretic dose and sodium intake remain constant, a new steady state is readily established usually within 4 days in normal subjects (Fig. 2). At the new steady state, sodium intake and output are equal; however, the effective circulating volume has decreased due to the initial period of negative sodium balance during the generation phase [26]. These same effects can be observed even during constant diuretic infusions (Fig. 1).

The proposed mechanisms of diuretic resistance are discussed in Chapter IVB1 and include:

1. Neurohumoral mediated increases in tubular reabsorption at sites that are not diuretic-sensitive. Examples include the proximal tube (angiotensin II and to a lesser degree norepinephrine) and the collecting tubule (aldosterone).

2. Flow-mediated increased in tubular reabsorption distal to the site of action of the diuretic. For example, loop diuretics cause increased downstream delivery of sodium to the distal tubule and collecting tubules, producing hypertrophy and increased Na/K ATPase activity with resultant enhanced sodium reabsorption.

3. Diminished entry of the diuretic into the lumen when renal perfusion becomes impaired.

postdiuretic sodium retention

The therapeutic effect of the diuretic during a 24-hr period will be determined by the balance between the sodium loss that occurs while the diuretic inhibits sodium transport and the sodium gain that occurs while the drug concentration is low [26]. When the diuretic concentration falls below a critical threshold, positive sodium balance may develop. This phenomenon is called postdiuretic sodium retention. The magnitude of this postdiuretic sodium retention depends on four factors (see Table 1).

If sodium intake is high and the half-life of the diuretic is short, postdiuretic sodium retention will compensate for the sodium lost while the drug was active, and there will be no net sodium loss (see Fig. 3). This commonly occurs when short-acting loop diuretics such as furosemide are given one or twice a day. In contrast, if the patient is placed on a low salt diet, even one or two doses of furosemide a day will cause a negative sodium balance.

Extrarenal adaptations contributing to postdiuretic sodium retention include ECF volume-dependent increases in circulating renin, angiotensin, and aldosterone, stimulation of renal nerves, and decreases in GFR [17, 21, 22], Reductions in ECF volume can also inhibit sodium excretion due to a reduction in the filtered sodium and an increase in fractional sodium reabsorption. Therefore, sodium excretion rates decline gradually until they match the sodium intake [10, 26]. This is known as the "braking phenomenon."

However, sodium retention occurs even when these compensatory responses are blocked or when decreases in ECF volume are prevented [1, 25, 26]. This suggests that the diuretic action directly triggers some intrarenal processes that may play an important role stimulating sodium retention. For example, loop diuretics increase solute delivery to the distal tubule, chronically increasing solute transport by distal tubule cells, resulting in their hypertrophy (see Fig. 4). These structural changes are associated with functional changes that

TABLE 1 Factors Contributing to Postdiuretic Sodium Retention

Diuretic pharmacokinetics Dietary sodium content Extrarenal adaptations Intrarenal adaptations

w 50

w 50

Days

FIGURE 3. Effect of furosemide on sodium excretion in normals ingesting high sodium diet containing 270 mEq/day. Sodium excretion was measured over 6 hr intervals. The dotted line represents the mean sodium excretion, averaged over a 24-hr period. (From Wilcox et al, Kidney Int. 31:135,1987, with permission.)

include increases in thiazide-sensitive sodium chloride cotransporters in the distal convoluted tubule and Na/K ATPase activity in the cortical collecting tubule, resulting in enhanced sodium transport [5, 7, 12, 16, 20, 23]. These changes may contribute to the return to neutral sodium balance. Once the effects of the diuretic have worn off, distal nephron segments may be primed to reabsorb more sodium [6].

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