Robert A. Star

University of Texas, Southwestern Medical Center, Dallas, Texas 75235-8856

Diuretics, especially thiazide diuretics, are a frequent cause of hyponatremia. Paradoxically, loop diuretics can be important adjuncts in the treatment of acute symptomatic hyponatremia, the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and diabetes insipidus.


Hyponatremia is caused by water retention due to a continued water intake more than the ability of the kidneys to excrete electrolyte-free water. The resulting hypo tonicity causes water movement into cells, with cell swelling. Swelling of brain cells causes cerebral edema, which results in the neurologic symptoms of hyponatremia. Since brain cells regulate their volume, patients are symptomatic only if the hyponatremia is acute or very severe.

What is the cause of the water retention? Normally, hyponatremia should suppress the secretion of antidiuretic hormone (arginine vasopressin or AVP), decreasing the water permeability of the collecting duct system, allowing the excess water to be excreted. However, AVP release is controlled by both osmotic and nonosmotic stimuli. In the latter case, AVP is released in response to non-osmotic stimuli such as reductions in effective arterial volume, irrespective

Diuretic Agents: Clinical Physiology and Pharmacology

Copyright © 1997 by Academic Press. All rights of reproduction in any form reserved.

TABLE 1 Etiology of Hyponatremia

Volume depletion

GI losses

Vomiting, diarrhea

Renal losses Diuretics, hypoaldosteronism, salt-wasting

Skin losses burns, cystic fibrosis

Abdominal sequestration; peritonitis; arsenic or mercury poisoning; pancreatitis, etc.

Potassium depletion


Primary polydipsia Hypothyroidism Glucocorticoid deficiency Drugs (see Table 2) Nausea, pain SIADH

Beer potomania

Volume excess

Congestive heart failure

Hepatic cirrhosis with ascites

Nephrotic syndrome with severe hypoalbuminemia

Renal failure of whether total extracellular volume (ECF) is reduced as in vomiting or expanded as in heart failure or cirrhosis with ascites, or normal as in pain, nausea or drugs. Indeed, except for patients with psychogenic polydipsia, all patients with sustained hyponatremia have elevated AVP levels. Therefore, it is helpful to categorize the conditions associated with hyponatremia by the volume status of the patients (decreased, normal, or increased; see Table 1). Hyponatremia occurs in beer potomania because the ability to excrete free water is decreased because of poor dietary intake [ 10]. Beer drinkers may ingest only 250 mOsmol/day or less of sodium, potassium, or protein. Hyponatremia will occur if they ingest more than 5 liters of water a day (since the minimum achievable urine osmolality is 50 mOsm).

Mild hyponatremia is a relatively common complication of diuretic therapy [ 16]. However, if patients drink large volumes of water, as occurs for unknown reasons in elderly women [6], severe hyponatremia may result. Three mechanisms contribute to the hyponatremia: (i) volume depletion causes increased AVP as discussed above, (ii) potassium depletion causes an intracellular shift of sodium for potassium, and (iii) impaired renal free water formation as a result of diminished delivery of filtrate (increased proximal reabsorption) or inhibition of sodium reabsorption in the diluting segments (loop of Henle and distal tubule). As described in Chapter VC1, most cases of hyponatremia are caused by thiazides, not loop diuretics. This occurs because they act at different sites along the nephron. Thiazides act primarily in the distal convoluted tubule and initial collecting duct to promote hypertonic salt loss. The loss of salt causes volume retention, and AVP induced water retention. The urine sodium + po tassium concentrations average about 150 mM, while plasma levels were below 110 mM. In contrast, loop diuretics act at the medullary thick ascending limb, causing hypotonic or isotonic fluid loss, in part, because they decrease medullary hypertonicity. Thus, hyponatremia is distinctly uncommon.

Hyponatremia generally occurs within the first 2 or 3 weeks of diuretic therapy. After this time, a new steady state is established in which water and solute intake is balanced by excretion. However, hyponatremia can become worse if vomiting, diarrhea, increased water intake, or a new drug is added.

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