Hyponatremia and Thiazides

Thiazide diuretics were first introduced in 1957 and soon became recognized as a cause of hyponatremia. Thiazides are very commonly used for the treatment of hypertension and are recommended by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) as first-line therapy for uncomplicated hypertension. Thiazides can be the sole cause of hyponatremia, and they may also exacerbate hyponatremia in patients with syndrome of inappropriate antidiuretic hormone hypersecretion. Although thiazides do not inhibit the ability to concentrate urine like loop diuretics, they do impair the diluting ability by (1) inhibition of Na and Cl transport at the cortical diluting sites, (2) stimulation of vasopressin release, (3) reduction of glomerular filtration rate, and (4) enhanced proximal water reabsorption, which reduces delivery to distal diluting sites. Water retention from impaired water excretion combined with cation depletion may result in severe hyponatremia. It is recommended that thiazides be avoided in elderly frail patients with chronically high water intake, in patients who have psychogenic polydipsia, and heavy beer drinkers, as these patients depend on excretion of maximally dilute urine to maintain fluid balance. Thiazide-induced hyponatremia is linked to increased morbidity and has costly implications. The prevalence of thiazide-induced hyponatremia is not well known and is based mostly on retrospective data and anecdotes. A recent study by Leung and colleagues addresses this issue. This retrospective study followed 2613 newly treated adult outpatients with hypertension for up to 10 years. Hyponatremia was classified as moderate if the serum sodium was 125 mmol ⁄ L to 130 mmol ⁄ L, severe if it was 120 mmol ⁄ L to 124 mmol ⁄ L, and very severe if <120 mmol ⁄ L. Secondary outcomes were total hospitalizations associated with hyponatremia. They compared 229 patients exposed to ongoing thiazide therapy with 2393 patients who were not exposed. In the thiazide-exposed group, 96% of patients were receiving hydrochlorothiazide, with chlorthalidone, indapamide, and metolazone making up the remaining 4%. In the thiazide treatment group, 66 (30%) patients developed hyponatremia (Na 130), which was moderate in 88% with a median time to onset of 21 months. The incidence rate was about 3-fold higher in the thiazide-treated patients. Most people responded to discontinuation of the thiazide. This study suggests that treating 15 patients over 5 years would result in one case of hyponatremia. In conclusion, thiazide-induced hyponatremia seems relatively common, and although it often occurs soon after treatment is initiated, patients continue to need monitoring since it can occur up to 10 years later. Our experience supports the current literature. We recommend avoidance of thiazides in patients with psychogenic polydipsia, heavy beer drinkers, and the frail elderly, as thiazide-induced hyponatremia is more likely to occur in people who consume a lot of water. However, thiazides are inexpensive, provide a reasonable reduction in blood pressure, and remain part of the treatment regimen in many patients with hypertension.