Toxic Alcohols & Poisoning Management

• Core Concept All toxic alcohols share two hallmark toxicities:
• Central nervous system (CNS) depression
• High-anion-gap metabolic acidosis
• Mechanism CNS depression driven by GABA_A receptor potentiation
• Mimics the effect of endogenous inhibitory neurotransmission
• Potency varies with lipid solubility and molecular size
• Metabolic acidosis arises from organic acid byproducts
• Formic acid (methanol) → inhibits cytochrome c oxidase
• Glycolic + oxalic acid (ethylene glycol) → direct tissue injury
• Primary alcohols discussed:
• Ethanol — beverage alcohol; also a therapeutic agent
• Methanol — industrial solvent, antifreeze, fuel
• Ethylene glycol — antifreeze, de-icing fluid

• Pathophysiology
• Metabolized by alcohol dehydrogenase (ADH) → acetaldehyde → acetate
• Acetate enters the TCA cycle → minimal acidosis in pure ethanol intoxication
• CNS depression proportional to blood ethanol concentration (BEC)
• Clinical Presentation
• Mild (BEC 100–200 mg/dL): euphoria, ataxia, slurred speech
• Moderate (200–300): confusion, vomiting, stupor
• Severe (>300): respiratory depression, coma, hypothermia
• Hypoglycemia — especially in children and malnourished patients
• Diagnostic Clues
• Osmolar gap elevation (ethanol is osmotically active)
• Anion gap typically normal (unless comorbid ketoacidosis)
• Management
• Supportive care: airway protection, IV fluids, glucose
• Thiamine supplementation to prevent Wernicke encephalopathy
• Hemodialysis rarely needed (reserved for extremely high BEC > 400–500)

• Pathophysiology
• ADH → formaldehyde → formic acid (toxic metabolite)
• Formic acid inhibits cytochrome c oxidase (mitochondrial complex IV)
• Histotoxic hypoxia — tissues unable to use oxygen
• Clinical Features
• Latent period: 6–24 hours (ADH saturation delay)
• Visual disturbances: blurred vision, scotomas, photophobia
• Severe: blindness (optic nerve toxicity), fixed dilated pupils
• CNS depression, seizures, coma
• Metabolic acidosis with high anion gap
• Laboratory Findings
• Elevated osmolar gap (early)
• Elevated anion gap (late, as formic acid accumulates)
• Serum methanol level > 20 mg/dL is concerning
• Treatment
• Fomepizole or ethanol (ADH competitive inhibition)
• Folate supplementation (enhances formic acid metabolism)
• Hemodialysis for high levels (> 50 mg/dL) or severe acidosis

• Pathophysiology
• ADH → glycolaldehyde → glycolic acid (primary toxic acid)
• Glycolic acid → glyoxylic acid → oxalic acid
• Oxalic acid precipitates with calcium → calcium oxalate crystals
• Clinical Features
• Stage 1 (first 12 h): inebriation, nausea, vomiting (CNS depression)
• Stage 2 (12–24 h): cardiopulmonary — tachycardia, hypertension, CHF
• Stage 3 (24–72 h): nephrotoxicity — flank pain, oliguria, renal failure
• Cranial nerve palsies (especially facial nerve) may occur
• Laboratory Findings
• Elevated osmolar gap (early)
• Elevated anion gap with severe metabolic acidosis
• Calcium oxalate crystals in urine (envelope or dumbbell shape)
• Hypocalcemia (due to calcium binding)
• Treatment
• Fomepizole or ethanol (ADH inhibition)
• Thiamine + pyridoxine (cofactors for glyoxylic acid metabolism)
• Hemodialysis for severe acidosis or high levels (> 50 mg/dL)

• Key Distinction Both methanol and ethylene glycol cause osmolar + anion gap acidosis; ethanol causes only osmolar gap
• Visual symptoms → methanol
• Renal failure + crystals → ethylene glycol

Fomepizole (4-Methylpyrazole)

• Mechanism Competitive, reversible inhibitor of alcohol dehydrogenase
• Binds the active site of ADH with high affinity
• Prevents conversion of methanol → formic acid and ethylene glycol → glycolic acid
• Advantages
• Long half-life (~10–12 h) — dosing every 12 hours
• Predictable pharmacokinetics, no CNS depression
• No hypoglycemia risk (unlike ethanol infusion)
• Dosing
• Loading: 15 mg/kg IV
• Maintenance: 10 mg/kg IV q12h (increased to 15 mg/kg after 48 h due to autoinduction)
• Indications
• Methanol or ethylene glycol poisoning with confirmed ingestion
• Elevated serum levels or high clinical suspicion

Ethanol as Antidote

• Mechanism Competitive substrate for ADH — higher affinity than methanol or ethylene glycol
• Saturates ADH, preventing toxic alcohol metabolism
• Drawbacks
• Requires continuous IV infusion to maintain therapeutic level (100–150 mg/dL)
• CNS depression, hypoglycemia, phlebitis
• Monitoring: frequent serum ethanol levels required
• When to use Fomepizole unavailable; resource-limited settings

• Definition Adverse reaction when certain drugs are combined with ethanol
• Inhibits aldehyde dehydrogenase (ALDH) → acetaldehyde accumulation
• Acetaldehyde causes flushing, nausea, palpitations, hypotension
• Key Drugs Associated
• Metronidazole — antibiotic, common culprit
• Griseofulvin — antifungal
• Others: cefoperazone, cefotetan, chloramphenicol, procarbazine, sulfonylureas
• Mechanism Aldehyde dehydrogenase inhibition leads to:
• Acetaldehyde buildup → histamine release → vasodilation
• Symptoms: facial flushing, headache, tachycardia, nausea, vomiting
• Clinical Relevance
• Always inquire about recent alcohol consumption before prescribing these drugs
• Reaction can be severe (hypotension, arrhythmias)

• Osmolar Gap
• Calculated: measured osmolality − (2 × Na + glucose/18 + BUN/2.8)
• Normal gap < 10. Elevated gap suggests toxic alcohol or ethanol
• Anion Gap
• Calculated: Na − (Cl + HCO₃)
• Normal gap: 8–12. Elevated in methanol and ethylene glycol poisoning
• Hemodialysis Indications
• Severe metabolic acidosis (pH < 7.2)
• End-organ damage (visual loss, renal failure)
• Serum toxic alcohol level > 50 mg/dL (methanol or ethylene glycol)
• Osmolar gap > 20–30 with clinical suspicion
• Cofactor Therapy
• Methanol: folate (leucovorin) to enhance formic acid metabolism
• Ethylene glycol: thiamine + pyridoxine to shunt glyoxylic acid away from oxalate
• Key Distinction Mnemonic (Original)
• Methanol → M = Macular (visual) damage
• Ethylene glycol → E = Elimination (renal) damage