Toxic Alcohol Ingestion
A small volume of antifreeze or windshield fluid can be lethal.
- ~1.4 mL/kg: Minimum lethal EG dose (undiluted ethylene glycol)
- ~1 mL/kg: Minimum lethal methanol (unmetabolized alcohol is low-toxicity)
- 1–4 hr: Peak absorption time (oral, empty stomach)
- <4 hr: Osmolar gap window (before metabolism narrows gap)
Two common toxic alcohols
Ethylene glycol (antifreeze) and methanol (windshield fluid, solvents) are both low-toxicity until metabolized.
Why the parent compound is not the problem
Ethylene glycol and methanol themselves cause mild inebriation, not organ damage.
The osmolar gap clue
Unmetabolized alcohol raises serum osmolality, an early diagnostic clue.
Alcohol Dehydrogenase Metabolism
Hepatic ADH oxidizes the parent alcohol into reactive intermediates.
- ADH: Primary enzyme (alcohol dehydrogenase, liver cytosol)
- ~100×: ADH affinity, ethanol vs EG (ethanol preferred substrate)
- 4 steps: EG metabolite chain (to glycolic/oxalic acid)
- formaldehyde→formate: Methanol metabolite (via ADH then ALDH)
ADH as the gatekeeper enzyme
ADH converts ethylene glycol to glycolaldehyde, methanol to formaldehyde.
Downstream aldehyde dehydrogenase
ALDH rapidly oxidizes aldehydes into acids, the truly toxic species.
Why blocking ADH is the treatment target
Stopping the first enzymatic step prevents all downstream toxic products.
Toxic Metabolite Accumulation
Glycolic and oxalic acid, or formic acid, drive organ injury.
- Glycolic/oxalic acid: EG metabolite (causes AKI, calcium oxalate crystals)
- Formic acid: Methanol metabolite (causes optic nerve toxicity)
- 4–12 hr: Anion gap acidosis onset (post-ingestion)
- high: Untreated mortality (without antidote and dialysis)
Ethylene glycol toxicity pathway
Oxalic acid binds calcium, forming crystals that damage renal tubules.
Methanol toxicity pathway
Formic acid inhibits mitochondrial respiration, injuring the optic nerve.
Metabolic acidosis and the clinical clock
Delay to treatment directly worsens acidosis and organ damage.
Fomepizole Administration
Fomepizole competitively blocks alcohol dehydrogenase.
- 15 mg/kg: Loading dose (IV over 30 min)
- 10 mg/kg: Maintenance dose (q12h × 4 doses)
- ~8000×: ADH affinity vs ethanol (far stronger competitive inhibitor)
- ~1 hr: Time to near-complete blockade (after loading dose)
Competitive inhibition mechanism
Fomepizole occupies the ADH active site, blocking alcohol binding.
Dosing regimen
A loading dose saturates ADH, then maintenance doses sustain blockade.
Timing determines outcome
Earlier dosing prevents more toxic metabolite from ever forming.
Metabolite Formation Halted
Unmetabolized parent alcohol is cleared renally, often with dialysis.
- ~17 hr: Renal clearance half-life (EG, ADH blocked)
- ~3 hr: Hemodialysis half-life (removes alcohol and metabolites)
- severe acidosis: Dialysis indication (or high toxic alcohol level)
- q4h dosing: Fomepizole during dialysis (cleared faster by dialysis)
Renal elimination takes over
With ADH blocked, kidneys slowly excrete the unchanged parent alcohol.
Hemodialysis for severe cases
Dialysis clears both alcohol and metabolites far faster than kidneys alone.
Recovery and monitoring
Serial labs confirm acidosis resolves and organ function stabilizes.