Which of the following is the mechanism of action of fomepizole in the treatment of ethylene glycol and methanol poisoning?

Explanation

## Fomepizole in Toxic Alcohol Poisoning ### Mechanism of Action **Key Point:** Fomepizole (4-methylpyrazole) is a competitive inhibitor of alcohol dehydrogenase (ADH), the first enzyme in the metabolic pathway of ethylene glycol and methanol. ### Pathophysiology of Toxic Alcohol Poisoning ```mermaid flowchart TD A[Ethylene glycol or Methanol ingestion]:::outcome --> B[Alcohol dehydrogenase ADH]:::action B --> C[Toxic metabolites formed]:::urgent C --> D[Glycolaldehyde → Glycolic acid → Oxalic acid<br/>Formaldehyde → Formic acid]:::urgent D --> E[Metabolic acidosis, organ damage]:::urgent F[Fomepizole blocks ADH]:::action --> G[Prevents toxic metabolite formation]:::action G --> H[Allows unchanged alcohol excretion in urine]:::outcome ``` ### Why Fomepizole is Superior to Ethanol | Feature | Fomepizole | Ethanol | |---------|-----------|--------| | **Mechanism** | Competitive ADH inhibitor | Competitive ADH inhibitor | | **Affinity for ADH** | Higher (Km ~0.3 mM) | Lower (Km ~1 mM) | | **CNS effects** | None | Intoxication, hypoglycemia | | **Monitoring** | Simpler | Requires blood ethanol levels | | **Route** | IV | IV | | **Dosing** | Fixed protocol | Variable | **High-Yield:** Fomepizole is now the preferred antidote for ethylene glycol and methanol poisoning because: 1. It has higher affinity for ADH than ethanol 2. It does not cause intoxication or hypoglycemia 3. It allows simpler dosing without blood level monitoring 4. It prevents formation of toxic metabolites (oxalic acid from ethylene glycol causes acute kidney injury; formic acid from methanol causes blindness) ### Clinical Pearl **Warning:** Fomepizole must be given EARLY in poisoning, before significant metabolite accumulation. Once metabolic acidosis and organ damage develop, hemodialysis becomes necessary to remove both the parent compound and its toxic metabolites. ### Timing of Intervention 1. **Fomepizole alone** — if given within 8–12 hours of ingestion 2. **Fomepizole + hemodialysis** — if metabolic acidosis is severe or renal failure is present