What medications can cause Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)?

Medications That Can Cause SIADH

Numerous medications can cause Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), with antidepressants, antipsychotics, chemotherapeutic agents, and antiepileptic drugs being the most common culprits.

Major Drug Classes Associated with SIADH

Psychotropic Medications

• Antidepressants

  • Selective Serotonin Reuptake Inhibitors (SSRIs): fluoxetine, sertraline, paroxetine, citalopram, escitalopram 1, 2, 3
  • Tricyclic Antidepressants (TCAs): amitriptyline, nortriptyline, imipramine 4
  • Monoamine Oxidase Inhibitors (MAOIs) 5
  • SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors) 5
  • Mirtazapine 5

• Antipsychotics

  • Typical: haloperidol 6
  • Atypical: olanzapine, clozapine 5

Chemotherapeutic Agents

• Vincristine 7
• Cyclophosphamide (both oral and IV forms) 8, 6
• Ifosfamide 6

Anticonvulsants/Antiepileptics

• Carbamazepine 9, 6
• Oxcarbazepine
• Valproate 5

Diuretics

• Thiazide diuretics 5, 6

Hormones

• Desmopressin 6
• Oxytocin 6

Other Medications

• Chlorpropamide 9
• NSAIDs 5
• Opioids 5
• Immunosuppressants (e.g., cyclosporine) 5

Mechanisms of Drug-Induced SIADH

Drug-induced SIADH occurs through two main mechanisms:

1. SIADH (Syndrome of Inappropriate ADH Secretion)

   • Characterized by uncontrolled hypersecretion of ADH
   • Seen with vincristine and ifosfamide 6

2. NSIAD (Nephrogenic Syndrome of Inappropriate Antidiuresis)

   • Characterized by intrarenal activation of water reabsorption with suppressed plasma ADH
   • Common with antipsychotics, antidepressants, anticonvulsants, cyclophosphamide, and thiazide diuretics 6
   • Involves upregulation of V2 receptors and increased cAMP production

Risk Factors for Drug-Induced SIADH

• Age: Elderly patients are at higher risk 5, 2
• Gender: Women are more susceptible 2
• Polypharmacy: Concurrent use of multiple medications that can cause SIADH 5
• Low body weight 2
• Lower baseline serum sodium 2
• Concurrent diuretic use 1, 2

Clinical Presentation and Monitoring

Symptoms of drug-induced SIADH depend on the severity of hyponatremia:

• Mild (Na 126-135 mEq/L): Often asymptomatic
• Moderate (Na 120-125 mEq/L): Nausea, headache, weakness
• Severe (Na <120 mEq/L): Confusion, seizures, coma 4

Monitoring Recommendations

• Monitor serum sodium levels within 1-2 weeks after starting medications known to cause SIADH
• For high-risk patients (elderly, female, using diuretics), consider more frequent monitoring
• Be vigilant for early symptoms like headache, nausea, and confusion

Management of Drug-Induced SIADH

1. Discontinue the offending medication if possible 4
2. Fluid restriction (1,000-1,500 mL/day) 4
3. Salt supplementation for mild cases 4
4. Pharmacologic treatment for severe or refractory cases:
   • Tolvaptan (vasopressin receptor antagonist)
   • Demeclocycline
   • Urea 4

Important Considerations

• SIADH typically develops within the first few weeks of treatment and resolves within 2 weeks after discontinuation 2
• Correction of serum sodium should not exceed 8-10 mmol/L per day to avoid osmotic demyelination syndrome 4
• When prescribing medications known to cause SIADH, consider alternatives if the patient has other risk factors
• Patients with a history of SIADH with one medication may develop it again with another medication from the same class

By recognizing medications that can cause SIADH and monitoring at-risk patients, clinicians can prevent serious complications associated with drug-induced hyponatremia.