How does voriconazole (antifungal medication) cause hyponatremia (low sodium levels) and what are the management strategies?

Voriconazole-Induced Hyponatremia: Mechanisms and Management

Voriconazole can cause hyponatremia through syndrome of inappropriate antidiuretic hormone secretion (SIADH), particularly in patients with elevated drug levels, and management requires therapeutic drug monitoring with dose adjustment or discontinuation based on severity. 1, 2, 3

Mechanism of Voriconazole-Induced Hyponatremia

Voriconazole-induced hyponatremia occurs through several mechanisms:

1. SIADH: Voriconazole can trigger inappropriate ADH release, leading to water retention and dilutional hyponatremia 2
2. Dose-dependent toxicity: Higher voriconazole trough concentrations (>5.0 μg/mL) are associated with increased risk of hyponatremia 1
3. Risk factors:
   • Age >47 years
   • Prolonged voriconazole use
   • Genetic polymorphisms in CYP2C19 (affecting drug metabolism)
   • Female gender (for electrolyte abnormalities generally) 1, 2

Clinical Presentation

Hyponatremia associated with voriconazole typically:

• Develops within 2-3 weeks of treatment initiation 2
• Can be severe (sodium levels <125 mEq/L)
• May present with neurological symptoms if severe (confusion, seizures)
• Often occurs alongside other adverse effects (hepatotoxicity, visual disturbances)

Management Strategy

1. Prevention and Monitoring

• Baseline assessment: Check electrolytes before initiating voriconazole
• Regular monitoring:
  • Serum sodium levels weekly for the first month, then biweekly
  • Voriconazole trough concentrations (target: >1-1.5 μg/mL for efficacy, <5-6 μg/mL to minimize toxicity) 4, 5
  • Liver function tests (as hepatotoxicity may occur concurrently)

2. Management of Established Hyponatremia

For mild-moderate hyponatremia (Na 125-134 mEq/L):

• Dose reduction: Reduce voriconazole dose to achieve trough levels <5 μg/mL 6
• Fluid restriction: Consider if SIADH is confirmed
• Continue monitoring: Check sodium levels every 1-2 days until stable

For severe hyponatremia (Na <125 mEq/L) or symptomatic patients:

• Discontinue voriconazole and switch to alternative antifungal agent 3
• Sodium correction: Follow standard hyponatremia protocols (avoid rapid correction)
• Consider nephrology consultation for management of severe or refractory cases

3. Alternative Antifungal Options

If voriconazole must be discontinued:

• Liposomal amphotericin B: For severe invasive fungal infections
• Echinocandins (caspofungin, micafungin, anidulafungin): For candidemia and some invasive aspergillosis cases
• Posaconazole: Alternative triazole with different side effect profile
• Isavuconazole: Newer triazole with potentially fewer electrolyte disturbances

Special Considerations

• Renal dysfunction: Patients with CKD are at higher risk for electrolyte abnormalities; use oral formulation for patients with creatinine clearance <50 mL/min 4, 7
• Drug interactions: Voriconazole is both a substrate and inhibitor of CYP2C19, CYP2C9, and CYP3A4, which can lead to significant interactions affecting drug levels 5
• Genetic factors: CYP2C19 polymorphisms can lead to higher voriconazole levels and increased risk of toxicity 2
• Recovery timeline: Hyponatremia typically resolves within 7-10 days after dose reduction or discontinuation 2, 3

Pitfalls to Avoid

• Failure to monitor: Not checking sodium levels regularly during voriconazole therapy
• Ignoring drug levels: Not performing therapeutic drug monitoring when available
• Delayed recognition: Attributing symptoms to underlying disease rather than drug toxicity
• Rapid correction: Correcting sodium too quickly, which can lead to osmotic demyelination syndrome
• Overlooking concurrent electrolyte abnormalities: Voriconazole can also cause hypokalemia (18% incidence) 1

By implementing proper monitoring and early intervention, the risk of severe voriconazole-induced hyponatremia can be significantly reduced while maintaining effective antifungal therapy.