Time course of loop and thiazide diuretic-induced electrolyte complications
- D Craig Brater, MD
D Craig Brater, MD
- Emeritus Dean, Indiana University School of Medicine
- Vice President for Programs, Regenstrief Foundation
- David H Ellison, MD, FASN, FAHA
David H Ellison, MD, FASN, FAHA
- Professor of Medicine and Physiology & Pharmacology
- Oregon Health & Science University
- Section Editors
- Richard H Sterns, MD
Richard H Sterns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Fluid and Electrolytes
- Professor Emeritus
- University of Rochester School of Medicine and Dentistry
- Michael Emmett, MD
Michael Emmett, MD
- Editor-in-Chief — Nephrology
- Section Editor — Fluid and Electrolytes
- Chief of Internal Medicine
- Baylor University Medical Center
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 . 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 , 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 . 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 . 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 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) .
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