Why is Fomepizole (4-methylpyrazole) given to patients with toxic alcohol poisoning?

Fomepizole in Toxic Alcohol Poisoning

Fomepizole is given in toxic alcohol poisoning because it competitively inhibits alcohol dehydrogenase, preventing the metabolism of methanol and ethylene glycol into their toxic metabolites that cause life-threatening acidosis, renal damage, and neurological complications. 1

Mechanism of Action

• Fomepizole blocks alcohol dehydrogenase, the enzyme that catalyzes the initial steps in metabolizing ethylene glycol and methanol into their toxic metabolites 1
• Ethylene glycol is metabolized to glycolate, glyoxylate, and oxalate, which cause metabolic acidosis and renal damage 1
• Methanol is metabolized to formaldehyde and formic acid, which cause metabolic acidosis and visual disturbances 1
• By inhibiting this metabolism, fomepizole prevents formation of these toxic compounds while allowing the parent alcohols to be eliminated unchanged 1, 2

Clinical Indications

• FDA-approved for ethylene glycol or methanol poisoning, or suspected ingestion of these toxic alcohols 1
• Indicated as first-line antidote for toxic alcohol poisoning, preferred over ethanol due to:
  • Simplicity of use and lack of need for compounding in pharmacy 3
  • Reduction in medication errors 3
  • Potential to avoid hemodialysis in selected cases 4, 2
  • Anticipated safety in children 3, 5

Treatment Protocol

• Treatment should be started as soon as possible based on history and initial findings, including anion gap metabolic acidosis, while awaiting measurement of alcohol concentration 2
• Standard dosing: 15 mg/kg loading dose followed by 10 mg/kg every 12 hours until alcohol concentrations are <30 mg/dL 2
• Dosage must be adjusted during extracorporeal treatment as fomepizole is dialyzable 3, 6
• Target plasma concentrations of fomepizole in humans should be in the range of 100-300 μmol/L (8.6-24.6 mg/L) to ensure effective inhibition of alcohol dehydrogenase 1

Clinical Outcomes

• When administered early, fomepizole prevents:
  • Ethylene glycol-related renal failure 2
  • Methanol-related visual and neurological injuries 2
• May obviate the need for hemodialysis when administered prior to significant acidosis or organ injury 4, 2
• In a French trial, 5 patients with ethylene glycol concentrations ranging from 46.5 to 345 mg/dL were treated with fomepizole alone without hemodialysis, and none developed signs of renal injury 1

Indications for Hemodialysis with Fomepizole

• Despite fomepizole treatment, hemodialysis is still recommended in patients with:
  • Severe metabolic acidosis (anion gap >27 mmol/L) 3, 6
  • Visual disturbances or altered mental status 4
  • Acute kidney injury 6
  • High ethylene glycol concentration (>50 mmol/L or >310 mg/dL) 3

Advantages Over Ethanol

• Fomepizole is preferred over ethanol for several reasons:
  • More predictable pharmacokinetics 2
  • No need for blood level monitoring 2
  • No central nervous system depression 2
  • No hypoglycemia risk 3
  • No need for compounding (ethanol requires compounding of 10% solution from 95% solution in the US) 3

Safety Profile

• Fomepizole is well-tolerated with fewer serious side effects than ethanol 2
• Has been used successfully in pediatric patients, including infants 5
• Contraindicated only in cases of allergy to pyrazoles 2

Treatment Monitoring

• Monitor anion gap to evaluate treatment effectiveness, with cessation of extracorporeal treatment recommended once anion gap is <18 mmol/L 3
• For ethylene glycol poisoning, extracorporeal treatment can be stopped when ethylene glycol concentration is <4 mmol/L 3
• Fomepizole blood level monitoring is not necessary 2

Fomepizole represents a significant advancement in the management of toxic alcohol poisoning, providing a safer and more effective alternative to ethanol while potentially reducing the need for hemodialysis in selected patients.