What medications can cause hyponatremia?

Common Medications That Cause Hyponatremia

The most common medication classes causing hyponatremia are thiazide diuretics, selective serotonin reuptake inhibitors (SSRIs), and anticonvulsants, with particular caution needed when thiazides and SSRIs are combined due to synergistic effects. 1, 2

Major Drug Classes

Diuretics

• Thiazide diuretics are among the most frequent causes of drug-induced hyponatremia, inducing it through multiple mechanisms: impaired urinary dilution, renal sodium and potassium loss, stimulation of antidiuretic hormone (ADH), and possibly increased thirst 1
• Thiazides cause hyponatremia by upregulating aquaporin-2 (AQP2) in the collecting duct without vasopressin, either directly or via the prostaglandin E2 pathway 2
• Loop diuretics (furosemide, bumetanide, torasemide) can cause hyponatremia, particularly when combined with other diuretics 3
• The combination of hydrochlorothiazide with spironolactone and furosemide can cause rapid development of hyponatremia 4
• Patients taking diuretics are at greater risk for developing hyponatremia, especially elderly patients 5, 6

Psychotropic Medications

• SSRIs (fluoxetine, sertraline) cause hyponatremia through syndrome of inappropriate ADH secretion (SIADH), with cases of serum sodium lower than 110 mmol/L reported 5, 1
• Hyponatremia from SSRIs appears to be the result of SIADH and is reversible when the medication is discontinued 5
• Antipsychotics (haloperidol) induce hyponatremia by intrarenal mechanisms for AQP2 upregulation, compatible with nephrogenic syndrome of inappropriate antidiuresis (NSIAD) 2
• SSRIs and SNRIs are associated with clinically significant hyponatremia, particularly in elderly patients 7

Anticonvulsants

• Carbamazepine causes hyponatremia through SIADH, with the risk appearing to be dose-related 6, 2
• Signs and symptoms include headache, new or increased seizure frequency, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness leading to falls 6
• Elderly patients and those treated with diuretics are at greater risk of developing hyponatremia with carbamazepine 6

Chemotherapeutic Agents

• Vincristine causes SIADH with sustained plasma AVP levels 2
• Cyclophosphamide and ifosfamide induce hyponatremia by intrarenal mechanisms for AQP2 upregulation, with cyclophosphamide upregulating V2 receptor mRNA and increasing cAMP production in the absence of vasopressin 2

Other Medications

• Desmopressin can induce hyponatremia when prescribed for nocturnal polyuria in older patients due to selective binding to vasopressin V2 receptor 2
• Oxytocin acts as a V2R agonist and can produce hyponatremia when used to induce labor or abortion 2
• Proton pump inhibitors, antibiotics, ACE inhibitors, hypoglycemic agents, and amiodarone have been infrequently implicated as causes of hyponatremia 8

High-Risk Populations

Elderly Patients

• Elderly patients are at greater risk of developing hyponatremia with SSRIs, SNRIs, carbamazepine, and diuretics 5, 6, 7
• Elderly women appear to be at particularly increased risk when prescribed both an SSRI and a thiazide diuretic 1

Volume-Depleted Patients

• Patients taking diuretics or who are otherwise volume depleted are at greater risk for hyponatremia when treated with SSRIs or SNRIs 5

Patients with Cirrhosis

• Patients with cirrhosis and ascites are particularly vulnerable to hyponatremia and require careful monitoring 4
• ACE inhibitors can aggravate hypotension in patients with cirrhosis and have not been clinically useful in treating ascites-related hyponatremia 4

Critical Drug Combinations

• The combination of thiazide diuretics and SSRIs has a synergistic effect in impairing renal free water clearance, leading to severe hyponatremia 1
• This combination requires careful monitoring, especially in elderly women 1
• Combination of multiple diuretics (loop plus thiazide) increases risk of hyponatremia 3

Monitoring Recommendations

• Check electrolyte levels and kidney function within 4 weeks of initiating thiazide diuretics and after dose escalation 4
• Monitor serum sodium levels when initiating medications known to cause hyponatremia, especially in high-risk patients 4
• Discontinue the causative medication in patients with symptomatic hyponatremia and institute appropriate medical intervention 5, 6

Clinical Pitfalls

• Avoid rapid correction of hyponatremia to prevent osmotic demyelination syndrome 4
• Vaptans (tolvaptan, conivaptan) can cause rapid correction of sodium levels when used inappropriately and must be used cautiously 4
• Responsible agents should be discontinued and "re-challenge" should be avoided by informing the patient and involved caregivers 8
• Meticulous history taking and recording of pharmacotherapy is warranted to identify potentially culprit medications 8