What medications can cause hyponatremia, especially in elderly patients or those with a history of heart failure or liver disease?

Medications That Cause Hyponatremia

Highest-Risk Drug Classes

Thiazide diuretics are the most common and dangerous cause of drug-induced hyponatremia, particularly in elderly patients, and should be avoided in frail elderly individuals with high water intake or those with heart failure or liver disease. 1, 2

Thiazide and Thiazide-Like Diuretics

• Hydrochlorothiazide causes hyponatremia through multiple mechanisms: impaired urinary dilution, renal sodium/potassium loss, stimulation of antidiuretic hormone (ADH), and possible dipsogenic effects 3, 2, 4
• Chlorthalidone carries similar hyponatremia risk as hydrochlorothiazide, though both remain problematic in advanced chronic kidney disease 5
• The European Society of Cardiology explicitly identifies thiazides as potentially inappropriate medications in elderly patients with hyponatremia history, causing hypovolemia, postural hypotension, falls, dehydration, and electrolyte disturbances 1
• Thiazides are often ineffective in elderly patients due to reduced glomerular filtration, making them doubly problematic 6, 1
• The greatest electrolyte shifts occur within the first 3 days of thiazide administration 5

Loop Diuretics

• Furosemide, bumetanide, and torsemide cause hyponatremia through volume depletion and secondary ADH stimulation, though less commonly than thiazides 6, 2
• Loop diuretics maintain effectiveness even with reduced renal function, though tubular secretion may be impaired below creatinine clearance <30 mL/min 1

Potassium-Sparing Diuretics

• Spironolactone, amiloride, and triamterene can contribute to hyponatremia, particularly when combined with other medications 6
• Spironolactone carries high risk of hyperkalemia in older adults, especially with concurrent ACE inhibitors or ARBs 6, 1

Psychotropic Medications

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Sertraline and other SSRIs cause hyponatremia through syndrome of inappropriate ADH release (SIADH) 7, 3, 8
• The FDA explicitly warns that SSRIs have been associated with clinically significant hyponatremia in elderly patients, who may be at greater risk 7
• The combination of thiazide diuretics and SSRIs creates a synergistic effect, dramatically increasing hyponatremia risk through dual mechanisms 3
• Sertraline may induce nephrogenic syndrome of inappropriate antidiuresis (NSIAD) by upregulating V2 receptors and increasing cAMP production without vasopressin 4

Antipsychotics

• Haloperidol upregulates V2 receptor mRNA and increases cAMP production in the absence of vasopressin, causing NSIAD 4
• Other antipsychotics induce hyponatremia through intrarenal aquaporin-2 upregulation 4

Anticonvulsants

• Carbamazepine is a well-established cause of hyponatremia through SIADH and NSIAD mechanisms 8, 4
• Carbamazepine upregulates V2 receptors and activates V2R-cAMP-PKA signaling independent of vasopressin 4

Chemotherapeutic Agents

• Vincristine causes SIADH with sustained plasma AVP levels 4
• Ifosfamide produces SIADH through sustained AVP secretion 4
• Cyclophosphamide induces hyponatremia via intrarenal AQP2 upregulation (NSIAD mechanism), with suppressed plasma AVP levels 4

Other Medications

Hormonal Agents

• Desmopressin causes hyponatremia through selective V2 receptor binding, particularly dangerous when prescribed for nocturnal polyuria in older patients 4
• Oxytocin acts as a V2 receptor agonist and produces hyponatremia when used to induce labor or abortion 4

Cardiovascular Medications

• ACE inhibitors have been infrequently implicated as causes of hyponatremia 8
• Amiodarone is an uncommon but recognized cause of drug-induced hyponatremia 8

Other Drug Classes

• Proton pump inhibitors have been infrequently associated with hyponatremia 9, 8
• Antibiotics (specific agents not detailed) can occasionally cause hyponatremia 9, 8
• Hypoglycemic agents have been reported as infrequent causes 8

High-Risk Patient Populations

Elderly Patients

• Elderly women face substantially elevated risk of hyponatremia when taking hydrochlorothiazide or SSRIs 5, 7
• Frail elderly patients with chronically high water intake should avoid thiazides entirely 2
• Greater sensitivity to drug-induced hyponatremia cannot be ruled out in older individuals 7

Patients with Heart Failure

• Heart failure patients on diuretics require careful electrolyte monitoring, as hyponatremia can worsen clinical outcomes 6
• The American College of Cardiology recommends ongoing monitoring of serum electrolytes every 3-6 months for stable patients, more frequently for high-risk patients 5

Patients with Liver Disease (Cirrhosis)

• The EASL guidelines recommend treating hyponatremia when serum sodium is lower than 130 mmol/L in cirrhotic patients 6
• Fluid restriction is the standard of care but is seldom effective in hypervolemic hyponatremia associated with cirrhosis 6
• Vaptans (tolvaptan) have been approved in the USA for management of severe hypervolemic hyponatremia (<125 mmol/L) associated with cirrhosis 6

Critical Monitoring Requirements

Initial Monitoring

• The FDA mandates periodic determination of serum electrolytes in at-risk patients, with particular attention to the first 3 days when electrolyte shifts are most significant 5
• The KDOQI guidelines recommend checking electrolyte levels and eGFR within 4 weeks of hydrochlorothiazide initiation and following dose escalation 5

Ongoing Monitoring

• Check electrolytes every 3-6 months for stable patients without risk factors 5
• More frequent monitoring required for patients with renal impairment, heart failure, or concurrent medications affecting electrolytes 6, 5

Special Circumstances

• During major surgery or ICU admission, frequent laboratory monitoring may be necessary 5
• Large gastrointestinal losses require more frequent electrolyte checks 5
• Unexplained neurological symptoms (nausea, vomiting, headache, confusion, lethargy) require immediate electrolyte measurement 5

Management Principles

Correction Rate

• Correct sodium at a rate not exceeding 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 1, 5
• Inadvertent rapid correction is common in thiazide-induced hyponatremia because diluting ability is restored when the diuretic is discontinued 2

Medication Adjustments

• Patients should hold or reduce hydrochlorothiazide doses during acute illness with vomiting, diarrhea, or decreased oral intake 5
• Responsible agents should be discontinued and "re-challenge" should be avoided 8

Alternative Treatments

• Loop diuretics maintain effectiveness even with reduced renal function and may be preferred over thiazides in elderly patients 1
• Consider chlorthalidone over hydrochlorothiazide in advanced CKD, though both carry hyponatremia risk 5

Common Pitfalls

• Combining thiazide diuretics with SSRIs creates synergistic hyponatremia risk through dual mechanisms and requires especially careful monitoring 3
• Failing to monitor electrolytes within the first 3 days of thiazide initiation misses the period of greatest risk 5
• Not recognizing that hypokalemia increases susceptibility to osmotic demyelination syndrome during correction 2
• Prescribing thiazides to frail elderly patients with high water intake or psychogenic polydipsia 2