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Thiazide-Induced Hyponatremia: Reproducibility by Single Dose Rechallenge and an Analysis of Pathogenesis

Eitan Friedman, MD; Mordechai Shadel, MD; Hillel Halkin, MD; and Zvi Farfel, MD
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Requests for Reprints: Zvi Farfel, MD, Department of Medicine E, Sheba Medical Center, Tel Hashomer 52621, Israel.

Current Author Addresses: Dr. Friedman: Molecular Pathophysiology Branch, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.

Drs. Shadel and Halkin: Department of Medicine A; Dr. Farfel, Department of Medicine E, Sheba Medical Center, Tel Hashomer 52621, Israel.

© 1989 American College of PhysiciansAmerican College of Physicians

Ann Intern Med. 1989;110(1):24-30. doi:10.7326/0003-4819-110-1-24
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Study Objective: To determine whether a single-dose of thiazide administered to patients with previous thiazide-induced hyponatremia will cause hyponatremia and, if so, to analyze its pathogenesis.

Design: Prospective controlled study comparing patients with previous thiazide-induced hyponatremia with two control groups.

Patients and Controls: Eleven patients with thiazide-induced (Kaluril [hydrochlorothiazide, 50 mg; amiloride, 5 mg] ) hyponatremia of less than 130 mmol/L at least 1 week before the study. Two groups of controls: 10 young healthy volunteers and 11 elderly hypertensive patients previously treated uneventfully with thiazide.

Interventions: Administration of a single dose of hydrochlorothiazide, 50 mg, and amiloride, 5 mg.

Measurements: Blood pressure, pulse rate, body weight, serum urea, creatinine, sodium, potassium, magnesium, osmolality, plasma antidiuretic hormone, renin, aldosterone and also urinary sodium, potassium, osmolality, and cyclic adenosine monophosphate (cAMP) before and 6 to 8, 12, and 24 hours after drug administration.

Results: Within 6 to 8 hours serum sodium decreased in patients, young controls, and elderly controls by 5.5 ±1.1 (mean ± SE), 1.2 ± 0.4, and 1.8 ± 0.9 mmol/L, respectively (Py < 0.001 [patients versus young controls], Pe = 0.017 [patients versus elderly controls]). Serum osmolality decreased in patients, young controls, and elderly controls by 14.9 ± 2.6, 2.8 ± 1.6, and 6.6 ± 1.5 mmol/kg, respectively (Py < 0.001, Pe = 0.012). All patients and only one control subject reached osmolality of less than 280 mmol/kg. At 6 to 8 hours all patients gained weight (0.85 ± 0.13 kg) whereas young and elderly controls lost weight (0.47 ± 0.23 and 0.45 ± 0.2 kg, respectively) (Py « 0.001, Pe « 0.001). Patients' responses to the drug did not differ from both control groups regarding sodium and potassium urinary excretion, osmolar and free water clearance, and antidiuretic hormone blood levels. Water restriction in one patient attenuated serum sodium reduction.

Conclusions: Use of a single-dose of a thiazide diuretic may predict the development of hyponatremia. Increased body weight apparently due to polydipsia may play a major role in the pathogenesis of thiazide- induced hyponatremia.





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