Mechanisms of PPI-Induced Hyponatremia
Proton pump inhibitors (PPIs) can cause hyponatremia primarily through direct effects on renal water handling, leading to syndrome of inappropriate antidiuretic hormone secretion (SIADH), with the highest risk occurring during the first weeks of treatment. 1
Primary Mechanisms
PPIs directly cause hyponatremia as a side effect, particularly in the early weeks of treatment, with a nearly 7-fold increased risk in the first week that gradually declines to a lower risk with ongoing use 2
The primary mechanism involves PPI-induced SIADH, where PPIs disrupt normal water handling in the kidneys, leading to water retention with subsequent dilution of serum sodium 1, 3
The risk is highest with newly initiated PPI therapy (≤90 days) with adjusted odds ratios of 2.78 for any PPI, specifically: omeprazole 2.67, pantoprazole 2.06, and esomeprazole 2.89 4
Risk Factors and Time Course
Elderly patients (>65 years) are particularly susceptible, with studies showing 31.3% of elderly patients on long-term PPI therapy developing moderate hyponatremia compared to 9.3% in non-PPI users 5
The hyponatremia risk is most pronounced during the first week of PPI initiation (aOR 6.87) and gradually decreases over time, reaching an aOR of 1.64 by the fifth week 2
Ongoing PPI treatment beyond the initial period carries a much lower risk (aOR 1.10), suggesting adaptation to the medication over time 2, 4
The effect appears to be a class effect, as demonstrated by cases where patients developed hyponatremia with different PPIs sequentially (e.g., omeprazole followed by pantoprazole) 3
Secondary Contributing Mechanisms
PPIs increase gastric pH, which promotes intestinal microbial proliferation and dysbiosis, potentially contributing to systemic inflammation that may affect water homeostasis 1
Impaired absorption of micronutrients due to PPI use may play a secondary role in electrolyte disturbances 1
In patients with cirrhosis, PPIs can exacerbate hyponatremia, which is already a risk factor for hepatic encephalopathy, creating a dangerous cycle 1
Clinical Implications
Hyponatremia is the most common electrolyte abnormality in hospitalized patients, affecting 15-30% of children and adults 1, 6
Symptoms of hyponatremia can be nonspecific (headache, nausea, confusion, lethargy) making prompt diagnosis difficult 1
Severe hyponatremia can lead to hyponatremic encephalopathy, a medical emergency that can be fatal or cause irreversible brain injury if inadequately treated 1
When hyponatremia occurs in a patient recently started on a PPI, the PPI should be considered a potential culprit; however, if the patient has been on the medication long-term, other causes should be investigated first 2, 3
Monitoring of serum sodium is advisable when initiating PPI therapy, particularly in high-risk patients such as the elderly or those with cirrhosis 1, 5