What medications can cause hyponatremia?

Medications That Can Cause Hyponatremia

Multiple medication classes can cause hyponatremia, with thiazide diuretics being the most common culprit, followed by SSRIs, antipsychotics, and antiepileptic drugs. 1, 2

Diuretics

• Thiazide and thiazide-like diuretics are the number one cause of drug-induced hyponatremia, with highest risk in the first weeks after initiation 2
• Hydrochlorothiazide can cause rapid development of hyponatremia when added to the combination of spironolactone and furosemide 3
• Thiazide diuretics induce hyponatremia through impairment of urinary dilution, renal sodium loss, stimulation of antidiuretic hormone (ADH), and possibly through a dipsogenic effect 4
• Thiazides can upregulate aquaporin-2 (AQP2) in the collecting duct without vasopressin, either directly or via the prostaglandin E2 pathway 5
• Loop diuretics (like furosemide) can also cause hyponatremia but may actually decrease the risk compared to thiazides due to their different mechanism of action 2

Psychotropic Medications

Antidepressants

• Selective Serotonin Reuptake Inhibitors (SSRIs) commonly cause hyponatremia through syndrome of inappropriate ADH secretion (SIADH) 4, 5
• Sertraline (Zoloft) can cause hyponatremia, particularly in elderly patients and those taking diuretics 6
• Fluoxetine (Prozac) can cause hyponatremia that appears to be the result of SIADH, with cases of serum sodium lower than 110 mmol/L reported 7
• SSRIs typically cause hyponatremia shortly after initiation of treatment 2

Antipsychotics

• Antipsychotic medications can induce hyponatremia through intrarenal mechanisms for AQP2 upregulation 5
• Haloperidol has been shown to upregulate V2 receptor mRNA and increase cAMP production in the absence of vasopressin 5

Anticonvulsants

• Carbamazepine can cause hyponatremia through upregulation of V2 receptor mRNA and increased cAMP production 5
• Other antiepileptic drugs have also been associated with hyponatremia 8

Other Medications

• Proton pump inhibitors have been infrequently associated with hyponatremia 8
• Anticancer chemotherapeutic agents, particularly vincristine and ifosfamide, can cause SIADH 5
• Cyclophosphamide can upregulate V2R mRNA and increase cAMP production, leading to hyponatremia 5
• Desmopressin (used for diabetes insipidus) can induce hyponatremia when prescribed for nocturnal polyuria in older patients 5
• Oxytocin can produce hyponatremia when used to induce labor or abortion 5
• Angiotensin-converting enzyme inhibitors have been infrequently associated with hyponatremia 8
• Hypoglycemic agents have been rarely reported to cause hyponatremia 8
• Amiodarone has been infrequently linked to hyponatremia 8
• Immune checkpoint inhibitors can cause hyponatremia due to hypophysitis and adrenalitis resulting in secondary and primary cortisol deficiency 2

Risk Factors for Drug-Induced Hyponatremia

• Elderly patients are at greater risk for developing hyponatremia with SSRIs and SNRIs 6, 7
• Patients taking diuretics are at greater risk of developing hyponatremia when also taking SSRIs 6, 7
• Patients who are volume depleted are at increased risk 6, 7
• Women, particularly elderly women, appear to be at increased risk for thiazide-SSRI combination-induced hyponatremia 4
• Patients with advanced liver disease or cirrhosis are particularly susceptible to hyponatremia 3
• Patients with heart failure are at increased risk of developing hyponatremia 3

Clinical Implications and Monitoring

• Hyponatremia may present with headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness 6, 7
• More severe cases can present with hallucinations, syncope, seizures, coma, respiratory arrest, and death 6, 7
• When starting medications known to cause hyponatremia, especially in high-risk patients, monitor serum sodium levels within 2-4 weeks of initiation 3
• Consider discontinuation of the medication in patients with symptomatic hyponatremia 6, 7
• Particular caution is needed when combining medications that can cause hyponatremia through different mechanisms (e.g., thiazides and SSRIs) 4

Common Pitfalls to Avoid

• Failing to recognize drug-induced hyponatremia as a cause of falls, confusion, or seizures, especially in elderly patients 8
• Ignoring mild hyponatremia (130-135 mmol/L) as clinically insignificant, as even mild hyponatremia can cause neurocognitive problems 1
• Not monitoring electrolytes after starting medications known to cause hyponatremia 3
• "Re-challenging" patients with medications that previously caused hyponatremia 8
• Overlooking the synergistic effect of multiple medications that can cause hyponatremia through different mechanisms 4