What medications are known to cause hyponatremia?

Drugs Causing Hyponatremia

Thiazide diuretics are the most common culprit of drug-induced hyponatremia, with highest risk in the first weeks after initiation, followed by selective serotonin reuptake inhibitors (SSRIs), antipsychotics, and antiepileptic drugs (particularly carbamazepine and oxcarbazepine). 1

Major Drug Classes Associated with Hyponatremia

Diuretics

• Thiazide diuretics represent the number one cause of drug-induced hyponatremia, with risk peaking in the first weeks after initiation and then gradually decreasing to a stable but still elevated level after approximately 3 months 1
• Loop diuretics, in contrast, appear to decrease the risk for hyponatremia by promoting negative water balance 1

Psychotropic Medications

• Antidepressants (particularly SSRIs) typically cause hyponatremia shortly after treatment initiation 1
• Antipsychotics (including haloperidol) induce hyponatremia through intrarenal mechanisms involving aquaporin-2 (AQP2) upregulation, compatible with nephrogenic syndrome of inappropriate antidiuresis (NSIAD) 2
• These agents upregulate V2 receptor mRNA and increase cAMP production even in the absence of vasopressin 2

Antiepileptic Drugs

• Carbamazepine, oxcarbazepine, and valproic acid carry the highest risk among antiseizure medications 3
• Carbamazepine causes hyponatremia through intrarenal AQP2 upregulation via V2R-cAMP-PKA signaling activation 2
• These medications typically cause hyponatremia shortly after initiation 1

Chemotherapeutic Agents

• Vincristine and ifosfamide are associated with sustained plasma AVP levels and cause true SIADH 2
• Cyclophosphamide induces hyponatremia through intrarenal mechanisms for AQP2 upregulation (NSIAD pattern) with suppressed plasma AVP levels 2
• Immune checkpoint inhibitors increase risk of hypophysitis and adrenalitis, resulting in hyponatremia due to secondary and primary cortisol deficiency 1

Other Common Medications

• Proton pump inhibitors have been infrequently implicated but are recognized as potential causes 4, 5
• Desmopressin (used for diabetes insipidus) can induce hyponatremia when prescribed for nocturnal polyuria, particularly in older patients, due to selective V2 receptor binding 2
• Oxytocin acts as a V2 receptor agonist and can produce hyponatremia when used to induce labor or abortion 2

Mechanistic Considerations

SIADH vs. NSIAD

• Traditional SIADH involves uncontrolled hypersecretion of arginine vasopressin (AVP), seen with vincristine and ifosfamide 2
• Nephrogenic SIAD (NSIAD) is the major mechanism for most drug-induced hyponatremia, characterized by intrarenal activation of water reabsorption with suppressed plasma AVP levels 2
• Drugs causing NSIAD include antipsychotics, antidepressants, anticonvulsants, cyclophosphamide, and thiazide diuretics 2

Protective Medications

• Sodium-glucose cotransporter-2 (SGLT-2) inhibitors and lithium appear to decrease the risk for hyponatremia by promoting negative water balance 1

Clinical Pitfalls

• For most drugs associated with hyponatremia, the cause-effect relationship is tightly linked to newly initiated treatment, making medication history timing critical 1
• Meticulous history taking and recording of pharmacotherapy is essential to identify potentially culprit medications 4
• Responsible agents should be discontinued and "re-challenge" should be avoided by informing the patient and involved caregivers 4
• Hyponatremia is associated with adverse outcomes including impaired cognition, falls, fractures, and mortality, even when mild 4