What is the relationship between Angiotensin-Converting Enzyme (ACE) inhibitors and hyponatremia?

From the Guidelines

ACE inhibitors can cause hyponatremia, though this is an uncommon side effect, and patients with severe hyponatremia (serum sodium concentration less than 130 mmol per liter) are at higher risk of hypotension when treated with ACE inhibitors 1. The mechanism involves increased antidiuretic hormone (ADH) levels due to decreased angiotensin II production, which normally inhibits ADH. This leads to increased water reabsorption in the kidneys, diluting serum sodium. Additionally, ACE inhibitors can reduce aldosterone levels, decreasing sodium reabsorption in the distal tubule.

Key Points to Consider

• Patients at higher risk include the elderly, those on diuretics, and individuals with heart failure, liver disease, or renal impairment 1.
• Common ACE inhibitors that may cause this effect include lisinopril, enalapril, ramipril, and captopril.
• Symptoms of hyponatremia include headache, confusion, nausea, muscle cramps, and in severe cases, seizures or coma.
• Management involves monitoring serum sodium levels in high-risk patients, especially during the first few weeks of therapy.
• If mild hyponatremia occurs, fluid restriction may help. In more severe cases (sodium <125 mEq/L or symptomatic patients), the ACE inhibitor may need to be discontinued and replaced with an alternative medication such as an angiotensin receptor blocker, though these can occasionally cause similar effects 1.

Clinical Considerations

• The risk of azotemia is highest in patients who are most dependent on the renin-angiotensin system for support of renal homeostasis (i.e., class IV or hyponatremic patients) 1.
• A significant increase in serum creatinine with the use of ACEIs is observed in 15% to 30% of patients with severe HF, but in only 5% to 15% of patients with mild to moderate symptoms 1.
• Renal function usually improves after a reduction in the dose of concomitantly administered diuretics, and thus, these patients can generally be managed without the need to withdraw treatment with the ACEI 1.

From the Research

Relationship between ACE Inhibitors and Hyponatremia

• ACE inhibitors have been associated with the development of hyponatremia, although this is a rare complication 2, 3, 4.
• The mechanism of ACE inhibitor-induced hyponatremia is not fully understood, but it is thought to be related to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) 2, 3.
• Studies have reported cases of severe hyponatremia induced by ACE inhibitor therapy, with serum sodium levels decreasing significantly after initiation of treatment 2, 3, 4.
• In some cases, discontinuation of ACE inhibitor therapy has led to an increase in serum sodium levels, suggesting a causal relationship between the medication and hyponatremia 2, 3, 4.

Clinical Implications

• Clinicians should be aware of the potential for ACE inhibitors to cause hyponatremia, particularly in patients with risk factors for hyponatremia or those taking other medications that can affect serum sodium levels 2, 5.
• Monitoring of serum sodium levels is recommended in patients taking ACE inhibitors, especially after initiation of therapy or when other factors that can affect water or salt homeostasis are present 2, 5.
• ACE inhibitors may also have a beneficial effect on hyponatremia in certain patients, such as those with congestive heart failure, by increasing the urinary diluting ability of the kidney 6.

Pathophysiological Mechanisms

• The exact mechanisms by which ACE inhibitors cause hyponatremia are not fully understood, but may involve changes in antidiuretic hormone secretion, renal function, or other factors affecting water and salt balance 2, 3, 6.
• Further research is needed to fully elucidate the relationship between ACE inhibitors and hyponatremia, as well as to identify patients at highest risk for this complication 2, 3, 4.