What is the role of Fomepizole in treating methanol and ethylene glycol poisoning?

Role of Fomepizole in Treating Methanol and Ethylene Glycol Poisoning

Fomepizole is the first-line antidote for both methanol and ethylene glycol poisoning, acting as a competitive inhibitor of alcohol dehydrogenase to prevent the formation of toxic metabolites that cause metabolic acidosis, renal failure, and neurological damage. 1

Mechanism of Action

Fomepizole works by:

• Competitively inhibiting alcohol dehydrogenase (ADH), the enzyme that catalyzes the initial metabolism of methanol and ethylene glycol into their toxic metabolites 2
• Preventing formation of:
  • Glycolate and oxalate (from ethylene glycol), which cause metabolic acidosis and renal damage
  • Formate (from methanol), which causes metabolic acidosis and visual disturbances

Treatment Protocol

Indications for Treatment

Treatment should be initiated when there is:

• History of ingestion
• Elevated anion gap metabolic acidosis
• Increased osmolal gap
• Visual disturbances (methanol)
• Oxalate crystals in urine (ethylene glycol)
• Documented serum concentration >20 mg/dL 1

Dosing Regimen

• Loading dose: 15 mg/kg IV over 30 minutes
• Maintenance dose:
  • 10 mg/kg IV every 12 hours for 4 doses
  • Then 15 mg/kg every 12 hours until alcohol levels <20 mg/dL or patient is asymptomatic with normal pH 1
• During hemodialysis: Dosing must be adjusted as fomepizole is dialyzable, requiring continuous infusion at 1 mg/kg/h during dialysis 3, 4

Fomepizole vs. Ethanol

Fomepizole offers several advantages over ethanol:

• More predictable pharmacokinetics
• No sedation or inebriation
• No need for blood level monitoring
• Fewer medication errors
• Reduced need for intensive care monitoring
• May obviate the need for hemodialysis in selected patients 3, 4

The 2023 EXTRIP guidelines and expert consensus recommend fomepizole as the preferred first-line antidote for its simplicity of use, lack of need for compounding, reduction in medication errors, and potential for avoiding hemodialysis in selected patients 3.

Indications for Hemodialysis

Hemodialysis should be initiated based on the following criteria when using fomepizole:

• Ethylene glycol/methanol concentration >50 mmol/L (>310 mg/dL)
• Osmol gap >50
• Glycolate concentration >12 mmol/L
• Anion gap >27 mmol/L
• Clinical indications: coma, seizures, or acute kidney injury 3, 1

Safety Profile

Fomepizole has an excellent safety profile:

• Adverse reactions occur in only about 7% of patients
• Most common side effects are mild and transient:
  • Injection site pain/burning
  • Nausea/vomiting
  • Vessel puncture site inflammation
  • Drowsiness/confusion
  • Serum aminotransferase elevation 5

Clinical Outcomes

When administered early in the course of poisoning, fomepizole:

• Prevents renal injury in ethylene glycol poisoning by inhibiting formation of toxic metabolites 6
• Prevents visual and neurological injuries in methanol poisoning 7
• Normalizes acid-base status within hours of initiation 6

Treatment Algorithm

1. Immediate assessment:

   • Measure anion gap, osmolal gap, and acid-base status
   • Obtain toxic alcohol levels if available (but don't delay treatment)

2. Initiate fomepizole:

   • Administer loading dose immediately when poisoning is suspected
   • Continue maintenance dosing as outlined above

3. Determine need for hemodialysis based on:

   • Alcohol concentration >50 mmol/L
   • Severe metabolic acidosis (anion gap >27 mmol/L)
   • Renal failure
   • Significant clinical symptoms (coma, seizures)

4. Continue treatment until:

   • Alcohol concentration <4 mmol/L (<25 mg/dL)
   • Anion gap <18 mmol/L
   • Resolution of acid-base abnormalities 3, 1

Common Pitfalls and Caveats

• Don't delay treatment while waiting for toxic alcohol levels; initiate fomepizole based on clinical suspicion
• Adjust fomepizole dosing during hemodialysis to compensate for its elimination
• Monitor for alcohol withdrawal in patients with concomitant alcohol use disorder, especially if hemodialysis is performed 3
• Don't rely on osmolal gap alone for diagnosis as it can be normal in late presentations when alcohols have been metabolized
• Fomepizole is preferred over ethanol but is more expensive; however, the overall cost may be lower due to reduced need for ICU care and potential avoidance of hemodialysis 4

Fomepizole has revolutionized the management of toxic alcohol poisonings by providing a safer, more predictable alternative to ethanol with fewer complications and potentially reducing the need for hemodialysis in selected cases.