What is the mechanism of Fomepizole (4-methylpyrazole) in treating ethylene glycol poisoning?

From the Guidelines

Fomepizole is the primary antidote for ethylene glycol poisoning, working by competitively inhibiting alcohol dehydrogenase (ADH), the enzyme that metabolizes ethylene glycol into toxic metabolites. When ethylene glycol is ingested, ADH converts it to glycoaldehyde, which is further metabolized to glycolic acid, glyoxylic acid, and oxalic acid. These metabolites cause metabolic acidosis, calcium oxalate crystal formation, and subsequent organ damage, particularly to the kidneys, heart, and brain. Fomepizole prevents this toxic conversion by binding to ADH with approximately 500-1000 times greater affinity than ethylene glycol, effectively blocking the metabolism of ethylene glycol and allowing it to be excreted unchanged in urine.

The mechanism of action of fomepizole is supported by the most recent study 1, which highlights the importance of early intervention in preventing the formation of toxic metabolites and improving outcomes significantly. The standard dosing regimen for fomepizole is a loading dose of 15 mg/kg intravenously, followed by 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours until ethylene glycol levels are below 20 mg/dL. During hemodialysis, the frequency should be increased to every 4 hours due to fomepizole's dialyzability, as noted in the study 1.

Some key points to consider when using fomepizole include:

• The dosage of fomepizole needs to be adjusted during extracorporeal treatment (ECTR) 1
• Fomepizole is preferred over ethanol due to its simplicity of use, lack of need for compounding in pharmacy, reduction in medication errors, potential for avoiding hemodialysis in selected patients, and anticipated safety in children 1
• Treatment should be initiated as soon as ethylene glycol poisoning is suspected, without waiting for laboratory confirmation, as early intervention prevents the formation of toxic metabolites and improves outcomes significantly.

Overall, fomepizole is a critical antidote in the treatment of ethylene glycol poisoning, and its use should be guided by the most recent and highest quality evidence 1.

From the FDA Drug Label

The results of these two studies provide evidence that fomepizole blocks ethylene glycol and methanol metabolism mediated by alcohol dehydrogenase in the clinical setting. In both studies, plasma concentrations of toxic metabolites of ethylene glycol and methanol failed to rise in the initial phases of treatment The administration of fomepizole alone blocked any rise in glycolate or formate concentrations, respectively.

The mechanism of Fomepizole (4-methylpyrazole) in treating ethylene glycol poisoning is by inhibiting alcohol dehydrogenase, an enzyme that mediates the metabolism of ethylene glycol to its toxic metabolites, such as glycolate 2.

From the Research

Mechanism of Fomepizole in Treating Ethylene Glycol Poisoning

The mechanism of fomepizole (4-methylpyrazole) in treating ethylene glycol poisoning involves the inhibition of alcohol dehydrogenase, an enzyme that converts ethylene glycol into toxic metabolites 3, 4, 5, 6, 7.

• Fomepizole works by competitively inhibiting alcohol dehydrogenase, thereby preventing the formation of toxic metabolites such as glycolate and oxalate 3, 4.
• This inhibition prevents the development of metabolic acidosis and renal failure, which are common complications of ethylene glycol poisoning 3, 5, 6.
• The use of fomepizole has been shown to be effective in preventing renal injury and improving outcomes in patients with ethylene glycol poisoning, especially when administered early in the course of treatment 3, 5, 6.

Key Findings

• Studies have demonstrated that fomepizole is a potent inhibitor of alcohol dehydrogenase, with a high affinity for the enzyme 4, 7.
• The use of fomepizole has been associated with improved outcomes, including reduced mortality and morbidity, in patients with ethylene glycol poisoning 3, 5, 6.
• Fomepizole has been shown to be well-tolerated, with few adverse effects reported 3, 7.
• The effectiveness of fomepizole in treating ethylene glycol poisoning has been demonstrated in several studies, including a systematic review of 115 publications 6.

Comparison with Ethanol

• Fomepizole has been compared to ethanol, a traditional treatment for ethylene glycol poisoning, and has been shown to have several advantages, including predictable pharmacokinetics and ease of administration 4, 6.
• However, ethanol has been shown to have some advantages over fomepizole, including lower cost and longer clinical experience 4.