Can hydrochlorothiazide (HCTZ) cause hyponatremia?

Hydrochlorothiazide and Hyponatremia

Yes, hydrochlorothiazide can definitely cause hyponatremia (low sodium), and this is a well-documented adverse effect that can lead to significant morbidity and mortality in susceptible individuals.

Mechanism and Risk

Hydrochlorothiazide (HCTZ) causes hyponatremia through several mechanisms:

1. Direct effect on sodium handling: HCTZ blocks sodium reabsorption in the distal tubule, leading to increased sodium excretion 1
2. Impaired free water excretion: Despite low antidiuretic hormone (ADH) levels, HCTZ impairs the kidney's ability to excrete free water 2
3. Increased water intake: Patients susceptible to HCTZ-induced hyponatremia often demonstrate increased thirst and water consumption 2, 3
4. Reduced urea-mediated water excretion: Lower urea excretion in susceptible individuals impairs water excretion capacity 2

Risk Factors

Patients at highest risk for developing HCTZ-induced hyponatremia include:

• Elderly patients
• Female sex
• Low body mass/weight
• Possible genetic susceptibility
• Excessive fluid intake (especially beer consumption) 4
• Reduced dietary salt intake 4

Clinical Presentation

Hyponatremia from HCTZ can present with:

• Mild symptoms: weakness, fatigue, headache
• Severe symptoms: confusion, seizures, coma 5, 6
• Can develop within days of starting therapy or after months/years of use 6

Management Recommendations

When hyponatremia occurs with HCTZ:

1. Discontinue the thiazide diuretic immediately 1
2. Consider alternative antihypertensive therapy:
   • Loop diuretics if a diuretic is still required 1
   • ACE inhibitors, ARBs, or beta blockers as alternatives
3. Correct hyponatremia:
   • Fluid restriction for mild-moderate cases
   • Sodium replacement for severe cases
   • Avoid overly rapid correction to prevent osmotic demyelination syndrome 6

Prevention Strategies

To prevent HCTZ-induced hyponatremia:

• Use the lowest effective dose (12.5-25 mg) 1
• Monitor serum sodium levels regularly, especially in high-risk patients
• Consider alternative antihypertensive agents in patients with prior hyponatremia
• Educate patients about appropriate fluid intake

Special Considerations

The 2017 ACC/AHA hypertension guidelines specifically state: "If hyponatremia is present, it would be important to avoid or stop thiazide diuretic therapy. In this case, a loop diuretic should be used if a diuretic is required" 1.

The risk of hyponatremia is particularly high when HCTZ is combined with other factors that can lower sodium levels, such as excessive beer consumption or reduced salt intake 4.

Human Pharmacology Research Perspective: A single dose rechallenge study demonstrated that patients with prior HCTZ-induced hyponatremia showed significant sodium drops within 6-8 hours of re-exposure, confirming individual susceptibility to this adverse effect 3.

In cirrhotic patients, hydrochlorothiazide can cause "rapid development of hyponatremia" when added to spironolactone and furosemide 1, highlighting the need for caution in this population.