Methanol Poisoning

Overview

Methanol (CH₃OH), also called methyl alcohol or wood alcohol, is found in paint removers, shellac, antifreeze, and industrial solvents. It is also added to industrial ethanol to make it unfit for drinking. Ingestion of as little as 8 g (10 mL) can cause toxicity ranging from blindness to death.

Goodman & Gilman's Pharmacological Basis of Therapeutics, p. 540

Pathophysiology & Metabolism

The key to understanding methanol toxicity is its metabolic pathway:

Metabolism of ethanol and methanol showing how fomepizole blocks alcohol dehydrogenase

Figure: Metabolism of methanol (red). Fomepizole blocks alcohol dehydrogenase (ADH), preventing conversion to toxic metabolites.

Methanol → Formaldehyde (via ADH)
Formaldehyde → Formic acid (via ALDH)
Formic acid is the main toxic agent -- it injures the optic nerve and retinal ganglion cells, and accumulates to cause severe anion gap metabolic acidosis

Methanol itself is only mildly toxic; the metabolites cause the damage. This explains the characteristic latent period of 12+ hours between ingestion and symptom onset.

Goodman & Gilman's, p. 540

Clinical Presentation (Time Course)

Time	Symptoms
0-12 hours	Inebriation (like ethanol intoxication), asymptomatic period
12-24 hours	Headache, nausea, vomiting, abdominal pain (pancreatitis)
24-36 hours	Visual disturbances (blurred vision, "snowfield" vision), retinal edema progressing to blindness; seizures; severe metabolic acidosis
>48 hours	Putamen and white matter hemorrhage, Parkinson-like state, coma, death

Comprehensive Clinical Nephrology, 7th Ed., Box 13.6

Key features:

Optic toxicity: Formic acid injures retinal ganglion cells and the optic nerve -- can cause permanent bilateral blindness
Pancreatitis: GI pain is partially due to pancreatic necrosis
Respiratory depression: Severe metabolic acidosis can lead to coma or death

Diagnosis

Two-gap approach -- the hallmark of methanol (and ethylene glycol) poisoning:

Early: Elevated Osmolar Gap

Osmolar gap = Measured osmolality - Calculated osmolality (2[Na] + BUN/2.8 + glucose/18)
Methanol is osmotically active before it is metabolized
Osmolar gap >10 mOsm/kg is an important early clue
As methanol is metabolized, the osmolar gap falls but the anion gap rises

Later: Elevated Anion Gap Metabolic Acidosis

Formic acid accumulation drives a high anion gap
Anion gap = Na - (Cl + HCO₃) ; normal ~12 mEq/L
High anion gap + high osmolar gap simultaneously = strong indicator of toxic alcohol ingestion

Methanol level

Methanol level >20 mg/dL (>6 mmol/L) is diagnostic and an indication for treatment
Washington Manual of Medical Therapeutics, p. 1100; Goldman-Cecil Medicine

Treatment

1. Fomepizole (First-Line - Drug of Choice)

Fomepizole (4-methylpyrazole) is an ADH inhibitor -- it competitively blocks the enzyme that converts methanol to formaldehyde, halting toxic metabolite production.

Dosing:

Loading dose: 15 mg/kg IV
Maintenance: 10 mg/kg IV every 12 hours for 48 hours
After 48 hours: increase to 15 mg/kg every 12 hours (fomepizole auto-induces its own metabolism)
Increase frequency to every 4 hours during hemodialysis
Continue until methanol level <20 mg/dL

Important: Fomepizole does NOT reverse existing acidosis or end-organ damage -- it only prevents further toxic metabolite formation.

2. Ethanol (Second-Line - Only if Fomepizole Unavailable)

Ethanol has >10-fold greater affinity for ADH than methanol, competitively displacing it. Target blood ethanol level of 100-200 mg/dL.

IV loading dose: 0.6 g/kg, then 66 mg/kg/hour maintenance
Significantly harder to dose and titrate; adverse effects include CNS depression and hypoglycemia
Not indicated if fomepizole is available

3. Hemodialysis

Indications (any of the following):

pH ≤ 7.15
Coma or seizures
Shock
Visual deficits / blindness
Significant renal impairment
Methanol level markedly elevated

Hemodialysis directly removes methanol and formic acid, and corrects acidosis. It is frequently required in methanol poisoning because fomepizole alone results in a very prolonged methanol half-life.

4. Sodium Bicarbonate

Temporizing measure for severe acidosis
Does not treat or reverse the underlying toxicity
Also used in dialysate during hemodialysis

5. Folate / Leucovorin

Folinic acid (leucovorin) or folic acid 1 mg/kg IV (max 50 mg) every 4-6 hours
Promotes the folate-dependent pathway that metabolizes formic acid to CO₂ + H₂O (non-toxic)
Should be given in all methanol poisonings
Washington Manual of Medical Therapeutics, pp. 1099-1101; Comprehensive Clinical Nephrology, 7th Ed.

Treatment Summary Table

Intervention	Role	Dose
Fomepizole	ADH inhibitor (blocks toxic metabolism)	15 mg/kg IV load → 10 mg/kg q12h
Ethanol	ADH competitor (if fomepizole unavailable)	0.6 g/kg load → 66 mg/kg/h
Hemodialysis	Removes methanol + formic acid, corrects acidosis	Indications: pH ≤7.15, coma, seizures, vision loss
NaHCO₃	Treat severe acidosis	Per clinical severity
Folate/Leucovorin	Accelerates formic acid detoxification	1 mg/kg IV (max 50 mg) q4-6h

Key Points to Remember

The latent period (12+ hours) is due to slow accumulation of formic acid
Formic acid, not methanol itself, causes blindness and acidosis
Early diagnosis relies on osmolar gap; late diagnosis relies on anion gap metabolic acidosis
Fomepizole has replaced ethanol as first-line therapy
Hemodialysis is often required because fomepizole alone prolongs methanol's half-life dramatically
Folate is always co-administered to help detoxify formic acid via the folate pathway

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