The parent alcohol is a decoy — the metabolite kills
"In toxic alcohol poisoning the poison is not what was drunk but what it becomes. The whole of treatment follows from one idea: stop the parent alcohol being metabolised, and remove what is already made."
Summarised from Marino's The ICU Book and Irwin & Rippe's Intensive Care Medicine; with Goldfrank's Toxicologic Emergencies.Methanol and ethylene glycol are themselves only mildly intoxicating (like ethanol). The danger is their conversion by alcohol dehydrogenase (ADH) into toxic acids that cause a severe high-anion-gap metabolic acidosis and end-organ injury. Every treatment lever targets this pathway.
Where they come from and what they become
| Alcohol | Sources | Toxic metabolite → target |
|---|---|---|
| Methanol | Windscreen wash, illicit/adulterated liquor, solvents, antifreeze | Formic acid → optic nerve/retina & basal ganglia (putamen) |
| Ethylene glycol | Antifreeze, coolants, de-icers | Glycolic acid (acidosis) & oxalic acid → renal tubules, hypocalcaemia |
| Isopropyl alcohol | Rubbing alcohol, disinfectants | Acetone — osmolar gap & ketosis but no anion-gap acidosis (a useful contrast) |
ADH is the enzyme, and the target
Parent alcohol
Methanol / ethylene glycol ingested — early, only mild inebriation and a rising osmolar gap.
Toxic acids form
Methanol → formaldehyde → formic acid. Ethylene glycol → glycoaldehyde → glycolic acid → oxalic acid. The anion gap now climbs as the osmolar gap falls.
End-organ injury
Formic acid inhibits cytochrome oxidase → optic injury/putaminal necrosis. Oxalate binds calcium → calcium-oxalate crystals in the renal tubules + hypocalcaemia.
ADH has a far higher affinity for ethanol/fomepizole than for the toxic alcohols. Block ADH and the parent alcohol is excreted unchanged (or dialysed) before it can be turned into acid.
Three stages, two signature toxidromes
| Methanol | Ethylene glycol | |
|---|---|---|
| Early (0–12 h) | Inebriation, nausea (looks like drunkenness) | Inebriation, nausea; osmolar gap |
| Intermediate | Severe anion-gap acidosis, abdominal pain | Anion-gap acidosis, tachycardia, hypertension |
| Signature injury | Visual — blurring, "snowfield", blindness; putaminal necrosis | Renal — oxalate nephropathy, AKI; hypocalcaemia, tetany |
| Late | Coma, seizures, parkinsonism | Cardiopulmonary then renal failure |
Urine clue for ethylene glycol: calcium-oxalate crystals; fluorescence under Wood's lamp if the antifreeze contained fluorescein (unreliable — do not rely on it).
Osmolar gap early, anion gap late
Timing determines which gap you see — a crucial and heavily examined concept.
| Phase | Osmolar gap | Anion gap |
|---|---|---|
| Early (parent alcohol present) | High (unmetabolised alcohol) | Normal/low |
| Late (metabolised to acid) | Falling/normal | High (acid anions) |
Osmolar gap = measured − calculated osmolality (2Na + glucose + urea + ethanol); >10 is significant. A normalising osmolar gap with a rising anion gap is ominous — the poison is being converted to acid, not clearing. A normal osmolar gap does not exclude late presentation.
Do not wait for the level
- High-anion-gap metabolic acidosis + osmolar gap + a compatible history/exposure.
- Serum methanol/ethylene glycol levels are confirmatory but often slow/unavailable — treat empirically on clinical suspicion.
- Send lactate (may be spuriously high with glycolate on some analysers), calcium, renal function, venous/arterial gas, ethanol level.
- Examine for the signature injuries (visual acuity/fundi for methanol; urine crystals, calcium for ethylene glycol).
Block, buffer, remove
Block ADH — antidote
Fomepizole (preferred) inhibits alcohol dehydrogenase; ethanol is the alternative if fomepizole is unavailable (titrate a blood level, more monitoring). Start on suspicion — do not wait for levels.
Cofactors — speed safe metabolism
Folinic/folic acid for methanol (helps clear formate); thiamine and pyridoxine for ethylene glycol (shunt toward non-toxic metabolites).
Buffer
Sodium bicarbonate for severe acidaemia — correcting pH also reduces the tissue penetration of formate.
Remove — haemodialysis
Indicated for severe acidosis, end-organ injury (visual deficit, renal failure), high levels, or clinical deterioration. Dialysis removes both the parent alcohol and its acid metabolites.
Here ethanol is a therapy (competes for ADH). Continue the antidote and cofactors until the toxic alcohol is cleared and the acidosis resolved.
Where it goes wrong
- Waiting for confirmatory levels before starting fomepizole/ethanol — treat on suspicion.
- Reassurance from a normal osmolar gap in a late presenter (already converted to acid).
- Missing the diagnosis by attributing the acidosis to "just alcohol" or lactate.
- Forgetting the cofactors (folinic acid / thiamine + pyridoxine).
- Delaying haemodialysis in a patient with visual loss, renal failure or refractory acidosis.
High-yield one-liners
Q: Toxic metabolite of methanol & its target?
Formic acid → optic nerve/retina (visual loss) + putaminal necrosis.
Q: Toxic metabolites of ethylene glycol?
Glycolic acid (acidosis) and oxalic acid (renal oxalate crystals, hypocalcaemia).
Q: Antidote of choice?
Fomepizole (ADH inhibitor); ethanol if unavailable.
Q: Osmolar vs anion gap over time?
Osmolar gap early (parent alcohol) → anion gap late (acid metabolites).
Q: Cofactors?
Methanol → folinic acid; ethylene glycol → thiamine + pyridoxine.
Side-by-side comparisons
The classic distinctions: the two toxic alcohols, and fomepizole versus ethanol as the ADH blocker.
Methanol vs Ethylene Glycol
| Feature | Methanol | Ethylene glycol |
|---|---|---|
| Toxic metabolite | Formic acid | Glycolic + oxalic acid |
| Signature injury | Visual loss, putaminal necrosis | Oxalate AKI, hypocalcaemia |
| Urine crystals | No | Calcium oxalate |
| Cofactor | Folinic acid | Thiamine + pyridoxine |
Fomepizole vs Ethanol
| Feature | Fomepizole | Ethanol |
|---|---|---|
| Action | Direct ADH inhibitor | Competes with the toxin for ADH |
| Dosing/monitoring | Fixed dosing, easy | Titrate to blood level; labour-intensive |
| Sedation/hypoglycaemia | Minimal | Yes (esp. children) |
| Availability/cost | Costly, may be limited | Cheap, widely available |
References
- Marino PL. Marino's The ICU Book. 5th ed. Wolters Kluwer; 2025.
- Irwin RS, Lilly CM, Mayo PH, Rippe JM (eds). Irwin & Rippe's Intensive Care Medicine. 9th ed. Wolters Kluwer; 2023.
- Nelson LS, Howland MA, Lewin NA, et al. Goldfrank's Toxicologic Emergencies. 11th ed. McGraw-Hill; 2019.
- Kollef MH, Isakow W, Burks AC, Despotovic VN (eds). The Washington Manual of Critical Care. 4th ed. Wolters Kluwer; 2024.
- Brent J. Fomepizole for the Treatment of Methanol/Ethylene Glycol Poisoning (META/EGA studies). N Engl J Med. 1999;340:832–838; 2001;344:424–429.