Makindo Medical Notes

Related Subjects: | Metabolic Acidosis | Aspirin or Salicylate Toxicity | Ethylene Glycol Toxicity | Renal Tubular Acidosis | Lactic Acidosis

⚠️ FDA guidance: Fomepizole is indicated if methanol or ethylene glycol levels ≥20 mg/dL or ingestion is suspected with a compatible high anion gap metabolic acidosis. If ethylene glycol ≥50 mg/dL, or the patient has renal failure or worsening acidosis, haemodialysis should also be initiated. 💡 Remember: haemodialysis removes fomepizole — doses must therefore be given more frequently during dialysis.

📖 About

• Fomepizole (4-methylpyrazole, 4-MP) is a potent competitive inhibitor of alcohol dehydrogenase.
• It prevents the metabolism of methanol and ethylene glycol into their toxic organic acid metabolites (formic acid and glycolic/oxalic acids).
• Used in place of ethanol, which acts by the same mechanism but is harder to titrate, more toxic, and less predictable.
• Management advice should be sought from the National Poisons Information Service (NPIS) or TOXBASE.

⚗️ Mode of Action

• Both methanol and ethylene glycol themselves are relatively non-toxic.
• Toxicity occurs after hepatic alcohol dehydrogenase converts them to formic acid (causing optic and CNS injury) or glycolic/oxalic acids (causing renal failure).
• Fomepizole acts as a competitive substrate for alcohol dehydrogenase, blocking this first metabolic step and allowing the parent alcohol to be excreted unchanged.
• Inhibition is rapid, sustained, and predictable; fomepizole is renally excreted.

🎯 Indications

• Suspected or confirmed methanol or ethylene glycol poisoning with any of the following:
  • Plasma level ≥20 mg/dL (3.2 mmol/L)
  • High anion gap metabolic acidosis (anion gap >16 mmol/L) unexplained by other causes
  • Osmolar gap >10–15 mOsm/kg with history of ingestion
  • Visual disturbance (methanol) or renal impairment (ethylene glycol)

💉 Dose (for both Methanol and Ethylene Glycol Poisoning)

• Loading dose: Fomepizole 15 mg/kg IV diluted in ≥100 mL of 0.9% NaCl or 5% dextrose, infused over 30 min.
• Maintenance:
  • 10 mg/kg IV every 12 h for 4 doses, then
  • Increase to 15 mg/kg IV every 12 h thereafter.
• Continue until:
  • Serum methanol or ethylene glycol <20 mg/dL
  • pH normalised
  • Patient clinically recovered
• ⚠️ During haemodialysis: Fomepizole is dialysable. Give the same dose every 4 h during dialysis, then revert to 12-hourly once dialysis stops.

🧠 Pathophysiological Rationale

• Methanol: Metabolised → formaldehyde → formic acid → inhibits mitochondrial cytochrome oxidase → severe lactic acidosis + optic nerve injury → blindness.
• Ethylene glycol: Metabolised → glycolic → oxalic acid → binds calcium → renal tubular deposition of calcium oxalate crystals → renal failure + hypocalcaemia.
• Fomepizole halts this chain reaction early — the sooner it’s given, the less organ injury occurs.

🧩 Adjunctive and Supportive Management

• Correct metabolic acidosis with IV bicarbonate as indicated.
• Consider folinic acid (leucovorin) 50 mg IV 4-hourly for methanol toxicity (enhances formate metabolism).
• Consider thiamine (100 mg IV) and pyridoxine (50 mg IV) for ethylene glycol toxicity (enhance non-toxic metabolism).
• Initiate haemodialysis if:
  • pH <7.25 or severe acidosis refractory to bicarbonate
  • Renal failure (oliguria/anuria, creatinine rising)
  • Visual impairment or coma
  • Serum methanol/ethylene glycol >50 mg/dL

💊 Interactions

• No major pharmacological interactions, but avoid concurrent ethanol therapy — both act on alcohol dehydrogenase and may compete unpredictably.
• Monitor liver enzymes if combined with hepatotoxic drugs.

🚫 Contraindications

• Known hypersensitivity to fomepizole or pyrazoles.
• Use with caution in pregnancy — risk–benefit should favour maternal survival.

⚠️ Side Effects

• Injection-site venous irritation if undiluted (use ≥100 mL diluent).
• Headache, dizziness, nausea, mild drowsiness.
• Transient rash or eosinophilia.
• Occasional transient ↑ transaminases.

🧮 Differential: Fomepizole vs Ethanol

📚 References

• BNF: Poisoning Emergency Treatment
• TOXBASE: Ethylene Glycol and Methanol Poisoning
• FDA Label: Antizol (fomepizole) Prescribing Information (2023)
• Brent J. “Fomepizole for Ethylene Glycol and Methanol Poisoning.” N Engl J Med 2009;360:2216–2223.