Medications Known to Cause Hyponatremia
The most common drug classes that cause hyponatremia include thiazide diuretics, selective serotonin reuptake inhibitors (SSRIs), carbamazepine, and other psychotropic medications, with thiazides and SSRIs representing the highest-risk agents in clinical practice. 1, 2, 3
Major Drug Classes and Mechanisms
Diuretics
Thiazide diuretics are among the most frequent causes of drug-induced hyponatremia, particularly in elderly women 1, 3. The mechanism involves:
- Impairment of urinary dilution capacity 1
- Direct renal loss of sodium and potassium 1
- Stimulation of antidiuretic hormone (ADH) release 1
- Possible dipsogenic (thirst-inducing) effect 1
- Upregulation of aquaporin-2 (AQP2) in collecting ducts through prostaglandin E2 pathways, creating nephrogenic syndrome of inappropriate antidiuresis (NSIAD) 4
Loop diuretics can also cause hyponatremia but are generally less problematic than thiazides 5. Potassium-sparing diuretics (amiloride, triamterene, spironolactone) carry risk, especially when combined with ACE inhibitors or in patients with chronic kidney disease 5.
Psychotropic Medications
Antidepressants, particularly SSRIs and SNRIs, are established causes of hyponatremia through syndrome of inappropriate ADH secretion (SIADH) 6, 2, 3:
- SSRIs (sertraline, fluoxetine, paroxetine, citalopram, escitalopram) cause hyponatremia in 0.5-32% of patients, with higher rates in elderly populations 2, 3, 7
- SNRIs (venlafaxine, duloxetine) carry similar risk, with venlafaxine specifically noted to cause hyponatremia through SIADH 6, 2
- Tricyclic antidepressants (amitriptyline, imipramine) also induce SIADH 2, 3
The mechanism involves intrarenal AQP2 upregulation compatible with NSIAD, where plasma AVP levels are actually suppressed by negative feedback 4. Sertraline has been shown to upregulate V2 receptor mRNA and increase cAMP production in the absence of vasopressin 4.
Antipsychotics cause hyponatremia through similar mechanisms 2, 7, 4:
- Haloperidol upregulates V2 receptor mRNA and increases cAMP production without vasopressin, with resultant AQP2 upregulation blocked by tolvaptan or PKA inhibitors 4
- Risperidone, olanzapine, quetiapine, and other atypical antipsychotics are implicated 2, 7
Anticonvulsants
Carbamazepine is one of the most notorious anticonvulsants for causing hyponatremia, affecting up to 40% of patients in some series 2, 3, 7:
- Mechanism involves intrarenal AQP2 upregulation through V2R-cAMP-PKA signaling activation 4
- Carbamazepine upregulates V2R mRNA and increases cAMP production in collecting duct cells without vasopressin 4
Other anticonvulsants with significant risk include 2, 3, 7:
- Oxcarbazepine (structurally similar to carbamazepine)
- Valproic acid
- Lamotrigine
- Levetiracetam (appears safer but still carries some risk) 5
Chemotherapeutic Agents
Vincristine and ifosfamide cause SIADH with sustained plasma AVP levels 4:
Cyclophosphamide induces hyponatremia through intrarenal AQP2 upregulation (NSIAD mechanism) 4:
- Upregulates V2R mRNA in collecting duct cells 4
- Increases cAMP production without vasopressin 4
- Effect blocked by V2R antagonists or PKA inhibitors 4
Platinum-based agents (cisplatin, carboplatin) and other chemotherapeutics also carry risk 2, 7, 4.
Other Medication Classes
Proton pump inhibitors (omeprazole, lansoprazole, pantoprazole) have been infrequently but consistently reported as causes of hyponatremia 2, 3, 7.
Antibiotics occasionally implicated include 2, 3, 7:
Antihypertensive agents beyond diuretics 2, 3:
- Desmopressin (used for diabetes insipidus or nocturnal polyuria) causes hyponatremia through selective V2 receptor binding 4
- Oxytocin (used for labor induction) acts as V2R agonist 4
- Chlorpropamide (highest consensus for dose adjustment in renal impairment) 5
- Glyburide carries risk, especially in elderly 5
NSAIDs and opioids are also recognized causes 2, 7.
High-Risk Populations
Elderly patients, particularly women, are at substantially greater risk for drug-induced hyponatremia 6, 1, 3:
- Age-related decline in renal concentrating ability 3
- Polypharmacy increases risk 7
- Reduced total body water and altered pharmacokinetics 3
Patients taking diuretics or who are volume depleted face increased risk with any additional hyponatremia-inducing agent 6.
Synergistic Effects
The combination of thiazide diuretics and SSRIs creates a synergistic effect in impairing renal free water clearance 1:
- Thiazides impair urinary dilution and cause renal sodium loss 1
- SSRIs cause SIADH 1
- Combined mechanisms produce severe hyponatremia more readily than either agent alone 1
This combination should prompt careful monitoring, especially in elderly women 1.
Clinical Recognition and Management
Meticulous medication history is essential in evaluating any patient with hyponatremia 2, 7:
- Review all current medications, including over-the-counter agents 2
- Consider temporal relationship between drug initiation and hyponatremia onset 3
- Assess for polypharmacy and multiple potential culprits 7
Discontinuation of the offending agent is the primary management strategy 2, 7:
- Responsible medications should be stopped when identified 2
- "Re-challenge" should be avoided 2
- Patients and caregivers must be informed to prevent future exposure 2
Even mild hyponatremia (130-135 mmol/L) from medications carries adverse outcomes including impaired cognition, increased fall risk, fractures, and mortality 2, 8.
Common Pitfalls
Failing to recognize drug-induced hyponatremia because of confounding comorbidities and polypharmacy 7. Multiple medications may contribute simultaneously, making identification challenging 7.
Overlooking medications used in everyday practice (proton pump inhibitors, antibiotics, newer antihypertensives) as potential causes 3. These agents are less commonly recognized but still capable of inducing clinically significant hyponatremia 3.
Not monitoring high-risk patients (elderly, those on multiple hyponatremia-inducing agents) with baseline and periodic sodium levels 1, 7.