What are the medications that can cause Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)-induced hyponatremia?

Medications That Cause SIADH-Induced Hyponatremia

Multiple drug classes can induce SIADH, with chemotherapeutic agents, antidepressants, and antiepileptic drugs being the most common culprits. 1

Major Drug Categories Causing SIADH

Chemotherapeutic Agents

• Cisplatin is a well-documented cause of SIADH-induced hyponatremia 1
• Vinca alkaloids, including vincristine and vinblastine, commonly cause SIADH 1
• Vincristine specifically can cause rare occurrences of SIADH characterized by high urinary sodium excretion in the presence of hyponatremia, with renal or adrenal disease, hypotension, dehydration, azotemia, and clinical edema being absent 2
• Cyclophosphamide is recognized as a SIADH-inducing agent 3

Antidepressants (SSRIs and SNRIs)

• Selective serotonin reuptake inhibitors (SSRIs) are among the most frequent medication-related causes of SIADH 1, 4, 5
• Sertraline can cause hyponatremia that appears to result from SIADH, with cases of serum sodium lower than 110 mmol/L reported 4
• Fluoxetine (Prozac) causes hyponatremia through SIADH, with cases of serum sodium lower than 110 mmol/L documented and appearing reversible when discontinued 5
• These medications stimulate inappropriate ADH release despite low serum osmolality, leading to water retention and subsequent physiologic natriuresis 1

Antiepileptic Drugs

• Carbamazepine is a well-established cause of SIADH 1, 3, 6
• Carbamazepine should be discontinued immediately if symptomatic hyponatremia develops 1

NSAIDs and Analgesics

• Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce SIADH 1
• Opioids are recognized as SIADH-inducing medications 1

Other Medications

• Chlorpropamide (sulfonylurea) causes SIADH 3, 6
• Diuretics, particularly thiazides, can cause SIADH-like hyponatremia 6

High-Risk Patient Populations

Elderly Patients

• Elderly patients are at significantly greater risk of developing hyponatremia with SSRIs and SNRIs 4, 5
• Age-related physiologic changes increase susceptibility to medication-induced SIADH 1

Volume-Depleted Patients

• Patients taking diuretics or who are otherwise volume depleted face greater risk of SIADH-induced hyponatremia when exposed to these medications 4, 5
• The combination of diuretics with SSRIs or other SIADH-inducing drugs creates particularly high risk 1

Clinical Recognition and Management Approach

Diagnostic Features

• SIADH from medications presents with euvolemic hyponatremia (no edema, no orthostatic hypotension, normal skin turgor) 1
• Laboratory findings include inappropriately concentrated urine (>500 mosm/kg) and elevated urine sodium (>20 mEq/L) despite hyponatremia 1
• Serum osmolality is low (<275 mosm/kg) with serum sodium <134 mEq/L 1

Immediate Management Steps

• Discontinue the offending medication immediately if symptomatic hyponatremia is present 1, 3
• For severe symptomatic hyponatremia (sodium <120 mEq/L with neurological symptoms), administer 3% hypertonic saline with target correction of 6 mmol/L over 6 hours 1
• Maximum correction must not exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 1, 3

Chronic Management

• Fluid restriction to 1 L/day is the cornerstone of treatment for mild to moderate SIADH-induced hyponatremia 1
• If fluid restriction fails, consider demeclocycline as second-line treatment 1
• Vasopressin receptor antagonists (tolvaptan) may be considered for refractory cases 3

Critical Safety Considerations

Monitoring Requirements

• Check serum sodium every 2 hours initially during active correction of severe symptomatic hyponatremia 1
• Monitor for signs of osmotic demyelination syndrome (dysarthria, dysphagia, oculomotor dysfunction, quadriparesis) typically occurring 2-7 days after rapid correction 3

Common Pitfalls to Avoid

• Never use fluid restriction as monotherapy in cerebral salt wasting (CSW), which can mimic SIADH but requires opposite treatment with volume and sodium replacement 1, 3
• Avoid overly rapid correction exceeding 8 mmol/L in 24 hours, which causes osmotic demyelination syndrome 1, 3
• Do not ignore mild hyponatremia (130-135 mmol/L) in patients on these medications, as it increases fall risk and can progress 3

Drug-Specific Warnings

• Trazodone and other antidepressants place patients at particularly high risk and warrant close sodium monitoring, especially when combined with other SIADH-inducing medications 3
• In neurosurgical patients or those with subarachnoid hemorrhage, distinguish SIADH from cerebral salt wasting before initiating fluid restriction 1, 3