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Time course of loop and thiazide diuretic-induced electrolyte complications

Time course of loop and thiazide diuretic-induced electrolyte complications
Literature review current through: Jan 2024.
This topic last updated: Apr 24, 2023.

INTRODUCTION — Therapy with a loop- or thiazide-type diuretic may be associated with a variety of fluid and electrolyte complications, including volume depletion, azotemia, hypokalemia, metabolic alkalosis, hyponatremia, hyperuricemia, and hypomagnesemia [1]. In addition, the potassium-sparing diuretics (amiloride, triamterene, mineralocorticoid receptor antagonists) can induce hyperkalemia and metabolic acidosis, while carbonic anhydrase inhibitors such as acetazolamide can cause hypokalemia and metabolic acidosis.

What is underappreciated is the time course with which these complications occur, which has been best studied with loop and thiazide diuretics. Assuming that the diuretic dose and dietary solute (eg, sodium and potassium) and water intake are relatively constant and that the patient is hemodynamically stable, most of the above problems develop during the first two to three weeks of therapy if they are going to occur (figure 1) [1-3]. The reason for this time limitation is that the initial solute and water losses lead to compensatory changes that limit further losses. Thus, after the initial period of solute and water loss, a new steady state is attained in which solute and water intake and excretion are roughly equal, as they were before diuretic therapy was initiated. This phenomenon has been called diuretic braking. (See "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'The steady state'.)

However, thiazide-induced hyponatremia is one exception to this time course. Although early studies suggested that thiazide-induced hyponatremia occurs within 14 days of drug initiation [4], later studies have suggested a much wider range. As an example, a retrospective cohort study involving 1275 individuals found that the median time to hyponatremia was 1.75 years [5]. Similarly, a systematic review found that, although the mean time to hyponatremia was 19 days, the time of onset varied from 1 day to 3650 days [6]. The wide variability of the time course for hyponatremia associated with thiazide diuretics may reflect the many mechanisms for altered water balance that occur in patients taking thiazides. (See "Diuretic-induced hyponatremia".)

SODIUM AND WATER LOSSES — The initial sodium and water losses induced by diuretic therapy lead to increases in a variety of sodium-retaining factors, such as angiotensin II, aldosterone, and norepinephrine, as well as to a possible reduction in systemic blood pressure [2,7]. These sodium-retaining forces eventually equal the sodium-wasting activity of the diuretic. When this occurs, there is a new steady state in which sodium and water intake and excretion are roughly equal. There will be no further diuresis (unless the diuretic dose or frequency is increased). With loop diuretics, the extracellular fluid volume will remain reduced by the amount of sodium lost during the first few days of therapy. With thiazide diuretics, the initial salt and water losses are typically followed by a period of positive salt and water balance, returning the extracellular fluid volume near (but not to) basal levels. The mechanisms responsible for this secondary response are not clear. (See "Use of thiazide diuretics in patients with primary (essential) hypertension", section on 'Antihypertensive mechanism'.)

In addition to the acute neurohumoral responses, structural adaptations also contribute to the compensatory sodium retention induced by chronic diuretic therapy. Studies in experimental animals show that the increase in sodium chloride delivery out of the loop of Henle that is seen with a loop diuretic leads to hypertrophy and increased sodium reabsorptive capacity in the distal and cortical collecting tubules [8,9]; with a thiazide diuretic, the increase in delivery and the subsequent hypertrophic response are limited to the connecting tubule and cortical collecting tubule [9,10]. Indirect evidence suggests that the same phenomenon occurs in humans. When compared with controls, subjects who have received a loop diuretic for one month show, after 24 hours off the diuretic, an impaired response to a loop diuretic (compatible with increased sodium reabsorption at some other site in the nephron) and an enhanced response to a thiazide diuretic (suggesting increased sodium reabsorption at a thiazide-sensitive site, presumably the distal tubule) (figure 2) [11].

Although these observations have primarily been obtained in nonedematous patients with hypertension [2,7], the same principles apply to edematous states such as heart failure [3]. However, the time to reattainment of the steady state may be delayed in those patients on the flat part (rather than the ascending limb) of the Frank-Starling curve (figure 3). In this setting, initial fluid loss will lower intracardiac filling pressures but not the cardiac output. As a result, the counterregulatory hormonal responses will not be activated, and the diuresis will continue until forward output begins to fall [12]. (See "Use of diuretics in patients with heart failure" and "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling", section on 'Pressure-volume relationships in HF'.)

The patient is in sodium balance in the new steady state, but the pattern of daily sodium excretion is altered: sodium will be lost during the period that the diuretic is acting, while sodium excretion will be very low for the remainder of the day due to increased activity of the sodium-retaining forces [7]. Although subject to some error [13], a 24-hour urine collection can be obtained to assess compliance with dietary sodium restriction (since daily sodium excretion will be roughly equal to intake if the patient's weight is stable), but measurement of the urine sodium concentration in a random urine specimen (often called a "spot" urine) will often be misleading, varying with the time since the diuretic dose. (See "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)".)

One other characteristic resulting from activation of sodium-retaining forces is that the maximal natriuretic response to an intravenous diuretic is seen with the first dose; even with continuous intravenous infusion of a loop diuretic, for example, the natriuresis usually begins to diminish within the first 12 hours (figure 4) [14]. This principle also applies to oral therapy, assuming there is no defect in drug absorption. (See "Causes and treatment of refractory edema in adults".)

The sequence is somewhat different in patients who are markedly volume expanded due to primary renal sodium retention (eg, in acute glomerulonephritis or acute or chronic kidney disease). In this setting, the renin-angiotensin system is suppressed and will not be activated by initial sodium loss, since hypervolemia persists. Thus, the second and subsequent doses may produce as large a natriuresis as the original dose until most of the excess fluid has been removed. Even in this setting, however, the first dose still represents the maximum response that will be seen.

POTASSIUM LOSSES — Considerations applicable to sodium losses also apply to other diuretic-induced losses, including that of potassium. The development of hypokalemia will limit further potassium losses (figure 1), an effect that is mediated in the aldosterone-sensitive distal nephron both by decreased potassium secretion by principal cells and increased potassium reabsorption in the intercalated cells. However, the kaliuresis may persist for several days longer than the natriuresis [15] since the inhibitory effect of hypokalemia will be counterbalanced by the hypovolemia-mediated rise in aldosterone secretion. (See "Evaluation of the adult patient with hypokalemia".)

Potassium supplementation is infrequently needed when loop or thiazide diuretics are used alone but is much more likely to be required when used in combination. Whether or not to empirically treat patients initiated on loop or thiazide diuretics is unclear. In one large cohort of approximately 650,000 patients initiated on loop diuretics, a simultaneous prescription for potassium supplementation was associated with a reduction in the eight-year relative risk of death of 7 and 16 percent among those treated with <40 and >40 mg/day of furosemide, respectively [16]. Although further study is needed, it is important to monitor for and treat hypokalemia in patients treated with diuretics.

SUMMARY AND RECOMMENDATIONS

Therapy with a diuretic may be associated with fluid and electrolyte complications. This primarily involves volume depletion, azotemia, and hypokalemia, but metabolic alkalosis, hyponatremia, hyperuricemia, and hypomagnesemia may also occur. Assuming that the diuretic dose and dietary and water intake are relatively constant and that the patient is hemodynamically stable, most of these problems, except for hyponatremia, develop during the first two to three weeks of therapy. Thiazide-associated hyponatremia may occur much later and therefore requires ongoing monitoring. (See 'Introduction' above.)

The initial sodium and water losses induced by diuretic therapy lead to increases in a variety of sodium-retaining factors, which eventually equal the sodium-wasting activity of the diuretic. When this occurs, there is a new steady state. There will be no further diuresis, but the extracellular fluid volume will be reduced by the amount of sodium lost during the first few days of therapy. This persistent volume depletion accounts for the efficacy of the diuretic in the treatment of hypertension or edema. The patient is in sodium balance in the new steady state, but the pattern of daily sodium excretion is altered: sodium will be lost during the period that the diuretic is acting, while sodium excretion will be very low for the remainder of the day due to increased activity of the sodium-retaining forces. (See 'Sodium and water losses' above.)

Similar considerations apply to other diuretic-induced losses, including that of potassium. The development of hypokalemia will limit further potassium losses. However, the kaliuresis may persist for several days longer than the natriuresis. (See 'Potassium losses' above.)

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