What medications can cause hyponatremia?

Medications That Cause Hyponatremia

Major Drug Classes

The most common medication classes causing hyponatremia include thiazide diuretics, selective serotonin reuptake inhibitors (SSRIs), antipsychotics, antiepileptic drugs, and proton pump inhibitors, with thiazides being the single most frequent culprit. 1

Diuretics

• Thiazide diuretics (hydrochlorothiazide, chlorthalidone) are the number one cause of drug-induced hyponatremia 1
• Thiazides cause hyponatremia through multiple mechanisms: impairment of urinary dilution, renal sodium and potassium loss, stimulation of antidiuretic hormone (ADH), and possibly a dipsogenic effect 2
• The risk is highest in the first weeks after initiation, then gradually decreases to a stable but still elevated level after approximately 3 months 1
• Loop diuretics (furosemide, bumetanide, torasemide) can cause hyponatremia, particularly when combined with other diuretics 3
• The combination of multiple diuretics (loop plus thiazide) significantly increases hyponatremia risk 3
• Adding hydrochlorothiazide to spironolactone and furosemide can cause rapid development of hyponatremia, especially in patients with cirrhosis 3

Antidepressants

• SSRIs (fluoxetine, sertraline, paroxetine, citalopram, escitalopram) cause hyponatremia through syndrome of inappropriate ADH release (SIADH) 2, 4
• Fluoxetine (Prozac) can cause hyponatremia that appears to result from SIADH, with cases of serum sodium lower than 110 mmol/L reported 5
• Sertraline has been associated with clinically significant hyponatremia, particularly in elderly patients 6
• Tricyclic antidepressants increase the risk of thiazide-associated hyponatremia when used in combination 7
• Antidepressants place patients at particularly high risk for developing hyponatremia 8

Antiepileptic Drugs

• Carbamazepine causes hyponatremia through SIADH, with the risk appearing to be dose-related 8
• Carbamazepine can upregulate V2 receptor mRNA and increase cAMP production in the absence of vasopressin, leading to aquaporin-2 (AQP2) upregulation 9
• Other antiepileptic drugs associated with hyponatremia include valproate, oxcarbazepine, and lamotrigine 1

Antipsychotics

• Antipsychotics cause hyponatremia by intrarenal mechanisms for AQP2 upregulation, compatible with nephrogenic syndrome of inappropriate antidiuresis (NSIAD) 9
• Haloperidol upregulates V2R mRNA and increases cAMP production in the absence of vasopressin 9
• Plasma AVP levels are suppressed by negative feedback in antipsychotic-induced hyponatremia 9

Chemotherapeutic Agents

• Vincristine causes SIADH with sustained plasma AVP levels 9
• Ifosfamide is associated with sustained plasma AVP levels and causes SIADH 9
• Cyclophosphamide induces hyponatremia by intrarenal mechanisms for AQP2 upregulation, compatible with NSIAD 9
• Cyclophosphamide upregulates V2R mRNA and increases cAMP production in the absence of vasopressin 9

Other Medications

• Proton pump inhibitors are associated with hyponatremia, typically occurring shortly after treatment initiation 1
• Desmopressin can induce hyponatremia when prescribed for nocturnal polyuria in older patients due to selective binding to vasopressin V2 receptor 9
• Oxytocin acts as a V2R agonist and can produce hyponatremia when used to induce labor or abortion 9
• Vaptans (tolvaptan, conivaptan) can cause rapid correction of sodium levels when used inappropriately 3
• ACE inhibitors can aggravate hypotension in patients with cirrhosis 3
• NSAIDs increase the risk of thiazide-associated hyponatremia when used in combination 7

Mechanisms of Drug-Induced Hyponatremia

• Drug-induced hyponatremia can be grouped into SIADH (characterized by uncontrolled hypersecretion of AVP) and NSIAD (produced by intrarenal activation for water reabsorption with suppressed plasma AVP levels) 9
• Nephrogenic antidiuresis (NSIAD) is the major mechanism for drug-induced hyponatremia caused by most psychotropic agents, cyclophosphamide, and thiazide diuretics 9
• Hydrochlorothiazide can upregulate AQP2 in the collecting duct without vasopressin, either directly or via the prostaglandin E2 pathway 9

High-Risk Populations

• Elderly patients are at greater risk of developing hyponatremia with SSRIs, SNRIs, and thiazide diuretics 5, 6
• Elderly women appear to be at particularly increased risk for severe hyponatremia when taking both an SSRI and a thiazide diuretic 2
• Patients taking diuretics or who are volume depleted are at greater risk 5
• Patients with cirrhosis and ascites are particularly vulnerable to hyponatremia 3
• Patients receiving large doses of thiazides, having multiple comorbidities (heart failure, liver disease, malignancy), and taking several medications are at increased risk 7

Monitoring Recommendations

• Check electrolyte levels and kidney function within 4 weeks of initiating thiazide diuretics and after dose escalation 3
• Monitor serum sodium levels when initiating medications known to cause hyponatremia, especially in high-risk patients 3
• Sodium concentration should be monitored in patients with risk factors for developing thiazide-associated hyponatremia 7
• Measure serum sodium levels promptly in patients with neurologic signs indicating reduced sodium levels 7

Clinical Significance

• The combined use of thiazide diuretics and SSRIs may have a synergistic effect in impairing renal free water clearance, highlighting the need for careful monitoring when both medications are prescribed 2
• For most drugs associated with hyponatremia, including thiazides, the cause-effect relationship is tightly linked to newly initiated treatment 1
• Medications are among the most common causes of hyponatremia, along with SIADH 4