What medications can cause hyponatremia?

Medications That Cause Hyponatremia

Multiple medication classes can cause hyponatremia, with thiazide diuretics, SSRIs, and certain antiepileptic drugs being the most common culprits. Understanding these medications and their mechanisms is essential for preventing and managing this potentially serious electrolyte disturbance.

Common Medication Classes Associated with Hyponatremia

Diuretics

• Thiazide and thiazide-like diuretics are the number one cause of drug-induced hyponatremia, with highest risk in the first few weeks after initiation 1
• Hydrochlorothiazide can upregulate aquaporin-2 in the collecting duct without vasopressin, either directly or via prostaglandin E2 pathway 2
• Risk factors for thiazide-induced hyponatremia include advanced age, female gender, reduced body mass, and concurrent use of other medications that impair water excretion 3
• The addition of hydrochlorothiazide to spironolactone and furosemide can cause rapid development of hyponatremia 4

Psychotropic Medications

• Selective Serotonin Reuptake Inhibitors (SSRIs):

  • Fluoxetine can cause hyponatremia as a result of syndrome of inappropriate antidiuretic hormone secretion (SIADH) 5
  • Sertraline is associated with clinically significant hyponatremia, especially in elderly patients 6
  • SSRIs typically cause hyponatremia shortly after treatment initiation 1

• Antipsychotics:

  • Haloperidol and other antipsychotics can upregulate V2 receptor mRNA and increase cAMP production in the absence of vasopressin 2
  • This leads to aquaporin-2 upregulation and water retention 2

Antiepileptic Drugs

• Carbamazepine can cause hyponatremia through SIADH 7
• Signs and symptoms include headache, new or increased seizure frequency, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness 7
• Carbamazepine upregulates V2 receptor mRNA and increases cAMP production in the collecting duct cells 2

Other Medications

• Vaptans (V2-receptor antagonists):

  • While normally used to treat hyponatremia, inappropriate use can cause rapid correction of sodium levels 4
  • Tolvaptan and conivaptan must be used cautiously in cirrhosis 4

• Proton pump inhibitors are associated with hyponatremia shortly after initiation 1

• Cyclophosphamide can cause hyponatremia through intrarenal mechanisms 2

• Oxytocin can produce hyponatremia when used to induce labor or abortion 2

• Immune checkpoint inhibitors can cause hyponatremia through hypophysitis and adrenalitis 1

Synergistic Effects and High-Risk Combinations

• Combined use of thiazide diuretics and SSRIs can have a synergistic effect in impairing renal free water clearance, leading to severe hyponatremia 8
• This combination requires careful monitoring, especially in elderly women who are at increased risk 8
• Angiotensin-converting enzyme inhibitors can aggravate hypotension in patients with cirrhosis and have not been clinically useful in treating ascites-related hyponatremia 4

Pathophysiological Mechanisms

• Drug-induced hyponatremia is primarily caused by two mechanisms:

  1. Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) - characterized by uncontrolled hypersecretion of arginine vasopressin 2
  2. Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) - produced by intrarenal activation for water reabsorption with suppressed plasma AVP levels 2

• Most drug-induced hyponatremia cases involve NSIAD rather than SIADH, with drugs activating the V2R-cAMP-PKA signaling pathway in the absence of vasopressin 2

Monitoring and Management

• Consider discontinuing medications in patients with symptomatic hyponatremia 5
• Monitor serum sodium levels when initiating medications known to cause hyponatremia, especially in high-risk patients 4
• For thiazide diuretics, check electrolyte levels and kidney function within 4 weeks of initiation and after dose escalation 4
• Avoid rapid correction of hyponatremia to prevent osmotic demyelination syndrome 4
• In patients with cirrhosis, fluid restriction is generally recommended when serum sodium is <120-125 mmol/L 4

High-Risk Patient Groups

• Elderly patients are at greater risk of developing medication-induced hyponatremia 5, 6
• Women appear to be more susceptible than men to thiazide-induced hyponatremia 3
• Patients with reduced body mass are at higher risk 3
• Patients with cirrhosis and ascites are particularly vulnerable to hyponatremia 4
• Patients taking multiple medications that affect water homeostasis have compounded risk 8

Understanding these medication-related causes of hyponatremia is crucial for prevention, early recognition, and appropriate management of this potentially serious electrolyte disorder.