Which of the following medications can cause hyponatremia: sertraline, Entresto (sacubitril/valsartan), or pyridostigmine bromide?

Which Medications Can Cause Hyponatremia

Both sertraline and Entresto (sacubitril/valsartan) can cause hyponatremia, while pyridostigmine bromide is not associated with this adverse effect.

Sertraline and Hyponatremia

Sertraline carries a well-established risk of hyponatremia through the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The FDA drug label explicitly warns that hyponatremia may occur with SSRIs including sertraline, with cases documented below 110 mmol/L 1. The mechanism involves euvolemic hyponatremia from inappropriate ADH secretion 2.

Key clinical features of sertraline-induced hyponatremia:

• Elderly patients face the highest risk, particularly those taking diuretics or who are volume depleted 1
• Symptoms range from headache, confusion, and weakness to seizures, coma, and death in severe cases 1
• Recent meta-analyses confirm sertraline significantly increases hyponatremia risk (OR = 4.15) 3, though it carries lower risk compared to other SSRIs like venlafaxine (OR = 5.99) or paroxetine (OR = 4.93) 3
• The risk is highest within the first weeks of treatment initiation 4

Monitoring requirements: Discontinue sertraline in patients with symptomatic hyponatremia and institute appropriate medical intervention 1. Regular electrolyte monitoring is essential, especially in high-risk populations 5.

Entresto (Sacubitril/Valsartan) and Hyponatremia

Entresto can cause hyponatremia, though the mechanism differs from sertraline. As an angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan was associated with more symptomatic hypotension than valsartan alone in clinical trials 6, and case reports document probable ARNI-induced hyponatremia 7.

Clinical considerations:

• The valsartan component (an ARB) contributes to hyponatremia risk through RAAS inhibition
• Guidelines note that patients on Entresto require blood pressure and renal function monitoring 8
• In heart failure management, if a patient stable on optimal guideline-directed medical therapy develops low sodium, look for other causes first rather than immediately discontinuing foundational HF therapies 9

Important caveat: The PARADIGM-HF trial actually showed a smaller risk of hyponatremia with sacubitril/valsartan compared to enalapril 10, suggesting the overall hyponatremia risk may be lower than with traditional ACE inhibitors despite case reports.

Pyridostigmine Bromide

Pyridostigmine does not cause hyponatremia. This cholinesterase inhibitor is used for neurogenic orthostatic hypotension and improves orthostatic tolerance through increased peripheral vascular resistance 11. Its side effects include nausea, vomiting, abdominal cramping, sweating, salivation, and urinary incontinence 11—but hyponatremia is not among them.

Clinical Algorithm for Management

When hyponatremia develops in patients on these medications:

1. Confirm true hyponatremia (not pseudohyponatremia from hemolysis)
2. Assess severity: Mild (126-135 mEq/L), moderate (120-125 mEq/L), severe (<120 mEq/L) 2
3. Determine chronicity: Acute (<48 hours) vs. chronic
4. Identify the culprit:
   • For sertraline: Consider discontinuation, especially if symptomatic or severe 1
   • For Entresto: Evaluate if patient is stable on therapy—if yes, investigate other causes first 9; if recently initiated, may need dose adjustment
5. Implement treatment:
   • Mild: Monitor and water restriction to 1,000 mL/day 2
   • Moderate to severe: Fluid restriction plus albumin infusion 2
   • Symptomatic: Discontinue offending agent and provide appropriate medical intervention 1

Critical pitfall: Do not automatically discontinue Entresto in stable heart failure patients with hyponatremia—this may reflect disease progression rather than drug effect, and stopping foundational HF therapy increases mortality risk 9, 12.