Which medications are commonly associated with hyponatremia, especially in elderly patients or those with heart failure, cirrhosis, or renal insufficiency?

Medications That Commonly Cause Hyponatremia

The most clinically significant drug classes causing hyponatremia are thiazide diuretics, selective serotonin reuptake inhibitors (SSRIs), and carbamazepine, with thiazides and SSRIs posing particularly high risk when used together, especially in elderly women. 1, 2

High-Risk Medication Classes

Diuretics

• Thiazide diuretics (hydrochlorothiazide, chlorthalidone, indapamide) are among the most common causes of drug-induced hyponatremia, typically developing within 2 weeks of initiation but can occur at any time during therapy 3
• Thiazides impair urinary dilution by blocking the Na+/Cl- cotransporter in the distal convoluted tubule, stimulate ADH secretion, cause renal sodium and potassium loss, and may increase water intake 3
• Loop diuretics (furosemide, bumetanide, torsemide) can also cause hyponatremia through excessive sodium and water loss, though less commonly than thiazides 4
• Spironolactone requires dose adjustment in chronic kidney disease and can contribute to electrolyte disturbances including hyponatremia 4

Antidepressants

• SSRIs (sertraline, escitalopram, fluoxetine, paroxetine, citalopram) cause hyponatremia through syndrome of inappropriate ADH (SIADH), with elderly patients at particularly high risk 5, 6, 2
• SNRIs (venlafaxine, duloxetine) carry similar risk to SSRIs, with venlafaxine specifically noted to cause hyponatremia that "may occur as a result of treatment" and appears to be SIADH-mediated 5
• The mechanism involves intrarenal activation of vasopressin V2 receptors and aquaporin-2 upregulation, even with suppressed plasma AVP levels (nephrogenic SIAD) 7

Anticonvulsants

• Carbamazepine is a well-established cause of SIADH and hyponatremia, acting through V2 receptor activation and cAMP-PKA signaling 2, 7
• Oxcarbazepine carries moderate to high evidence for causing SIADH 8

Antipsychotics

• Haloperidol and other antipsychotics can upregulate V2R mRNA and increase cAMP production independent of vasopressin, leading to nephrogenic SIAD 7
• These medications are particularly concerning in elderly patients with dementia 2

Chemotherapy Agents

• Vincristine and other vinca alkaloids cause sustained plasma AVP elevation consistent with classic SIADH 7
• Cyclophosphamide and ifosfamide induce hyponatremia through intrarenal AQP2 upregulation (nephrogenic SIAD mechanism) 7
• Cisplatin is associated with SIADH and can exacerbate hypokalemia in cancer patients 8

Other Medications

• NSAIDs (ibuprofen, naproxen, indomethacin) can impair free water clearance and contribute to SIADH 2
• Tramadol was added to the 2019 AGS Beers Criteria as a medication associated with hyponatremia 8
• Desmopressin acts as a selective V2 receptor agonist and can induce severe hyponatremia, especially in elderly patients treated for nocturnal polyuria 7
• Oxytocin functions as a V2R agonist and can produce hyponatremia when used for labor induction 7
• Proton pump inhibitors, antibiotics, ACE inhibitors, and amiodarone have been infrequently implicated but should be considered 2

Highest-Risk Patient Populations

Elderly Patients

• Older adults, particularly women, face substantially elevated risk for thiazide-induced hyponatremia due to age-related reduction in GFR and greater defects in water excretion after water loading 3, 8
• SSRIs and SNRIs are associated with clinically significant hyponatremia in elderly patients, who may be at greater risk than younger individuals 5, 6

Patients with Multiple Risk Factors

• Combination therapy with thiazide diuretics plus SSRIs creates synergistic impairment of renal free water clearance, dramatically increasing hyponatremia risk 1
• Patients taking multiple CNS-active agents (antidepressants, antipsychotics, benzodiazepines, antiepileptics, opioids) have compounded SIADH risk 8
• Volume-depleted patients or those on concurrent diuretics face greater risk when prescribed SSRIs/SNRIs 5

Specific Comorbidities

• Patients with heart failure, cirrhosis, or renal insufficiency have impaired compensatory mechanisms and are more vulnerable to drug-induced hyponatremia 9
• Those with malnutrition have independent risk factors for hyponatremia even after adjusting for age and comorbidities 8
• Patients with dementia have higher prevalence of hyponatremia and increased susceptibility to confusion and delirium from electrolyte disturbances 8

Mechanism: Nephrogenic SIAD vs. Classic SIADH

• Classic SIADH (sustained AVP elevation): vincristine, ifosfamide 7
• Nephrogenic SIAD (intrarenal V2R activation with suppressed AVP): antipsychotics, SSRIs, carbamazepine, cyclophosphamide, thiazide diuretics—these medications upregulate aquaporin-2 through V2R-cAMP-PKA signaling independent of vasopressin 7
• Hydrochlorothiazide can upregulate AQP2 either directly or via the prostaglandin E2 pathway 7

Critical Monitoring and Management Principles

• Electrolytes should be monitored within 4 weeks after starting thiazide therapy and after dose increases, as hyponatremia typically develops within 2 weeks but can occur anytime 8, 3
• In patients with neurological symptoms (confusion, headaches, weakness), sodium levels should be measured promptly 8
• Discontinue the offending medication immediately if symptomatic hyponatremia develops; this is the most important intervention 2
• Avoid "re-challenge" with the same medication class by informing the patient and caregivers 2
• When both thiazide and SSRI are necessary, consider closer monitoring or alternative agents 1

Common Pitfalls to Avoid

• Failing to obtain meticulous medication history when evaluating hyponatremia—drug-induced causes are frequently missed 2
• Overlooking polypharmacy as a significant risk factor, particularly combinations of diuretics with psychotropic medications 8, 1
• Not recognizing that even mild drug-induced hyponatremia is associated with impaired cognition, falls, fractures, and increased mortality 2
• Continuing the offending agent while attempting to correct sodium with fluid restriction or other measures—medication discontinuation is paramount 2
• Using tolvaptan in younger patients with preserved renal function without extreme caution, as dramatic overcorrection (>1 mEq/dL/h) can occur with standard 15 mg doses 10