What is the relationship between Hydrochlorothiazide (HCTZ) and hyponatremia?

From the Guidelines

Hydrochlorothiazide (HCTZ) can cause hyponatremia, particularly in the elderly, as a result of its diuretic effect and potential for electrolyte level abnormalities.

Relationship between HCTZ and Hyponatremia

• HCTZ is a thiazide diuretic that inhibits the sodium–chloride transporter in the distal tubule, leading to increased sodium delivery to the cortical collecting duct and potential for hyponatremia 1.
• The risk of hyponatremia may be heightened in patients with heart failure, particularly those with refractory edema or those requiring high doses of diuretics 1.
• Studies have shown that thiazide diuretics, including HCTZ, can cause significant electrolyte shifts within the first 3 days of administration, leading to hypokalaemia, hyponatraemia, and compensatory mechanisms for sodium retention 1.
• The American Journal of Kidney Diseases recommends checking electrolyte levels and eGFRs within 4 weeks of initiation of treatment with a thiazide, such as HCTZ, and following thiazide dose escalation to minimize the risk of hyponatremia and other electrolyte level abnormalities 1.

Clinical Considerations

• Clinicians should be aware of the potential for HCTZ to cause hyponatremia, particularly in vulnerable populations such as the elderly, and monitor electrolyte levels and renal function accordingly 1.
• The use of HCTZ should be carefully considered in patients with heart failure, and the benefits and risks of treatment should be weighed on an individual basis 1.

From the FDA Drug Label

CLINICAL PHARMACOLOGY Hydrochlorothiazide blocks the reabsorption of sodium and chloride ions, and it thereby increases the quantity of sodium traversing the distal tubule and the volume of water excreted. Metabolic toxicities associated with excessive electrolyte changes caused by hydrochlorothiazide have been shown to be dose-related.

The relationship between Hydrochlorothiazide (HCTZ) and hyponatremia is that hyponatremia is a potential metabolic toxicity associated with the use of HCTZ, particularly with excessive electrolyte changes caused by the drug, which can be dose-related 2.

From the Research

Relationship between Hydrochlorothiazide (HCTZ) and Hyponatremia

The relationship between Hydrochlorothiazide (HCTZ) and hyponatremia is complex and not fully understood. However, several studies have investigated this relationship:

• HCTZ can cause hyponatremia, a potentially life-threatening condition, especially in elderly patients and those with certain risk factors such as low body mass and concurrent use of other medications that impair water excretion 3, 4, 5.
• The pathophysiology of thiazide-induced hyponatremia is thought to involve a combination of factors, including excessive fluid intake, cation depletion, osmotic inactivation of sodium, and reduced ability to excrete free water 4, 5.
• Studies have shown that patients with thiazide-induced hyponatremia have higher water intake and lower urea excretion compared to controls, suggesting an important role for polydipsia and urea-mediated water excretion in the pathogenesis of thiazide-induced hyponatremia 3.
• The cumulative incidence of thiazide-induced hyponatremia is estimated to be around 3-4% over a 2-year period, with a higher risk in older adults and those with higher comorbidity burden 6.
• Genetic predisposition is considered a potential risk factor for thiazide-induced hyponatremia, and several studies are attempting to clarify this in order to identify patients at risk 7.

Risk Factors and Pathophysiology

Some of the key risk factors and pathophysiological mechanisms involved in HCTZ-induced hyponatremia include:

• Age: older adults are at higher risk of developing hyponatremia 4, 5, 6.
• Low body mass: patients with low body mass are at higher risk of developing hyponatremia 4, 5.
• Concurrent use of other medications: certain medications can impair water excretion and increase the risk of hyponatremia 4.
• Excessive fluid intake: high water intake can contribute to the development of hyponatremia 3, 4.
• Cation depletion: depletion of sodium and potassium can contribute to the development of hyponatremia 4, 5.
• Reduced ability to excrete free water: thiazide diuretics can impair the ability to excrete free water, leading to hyponatremia 4, 5.