EM Toxicology 18: Methanol & Ethylene Glycol Flashcards
Most contemporary methanol exposures in the US occur from?
unintentional ingestion of windshield washer fluid and other automotive cleaning products
sources of ethylene glycol
M/C: automotive coolant (antifreeze)
preservative
component of hydraulic brake fluid
Remarks on ethylene glycol
Virtually all ethylene glycol toxicity results from ingestion, because it has a low vapor pressure and does not penetrate skin well.
minimum lethal dose without treatment for methanol and ethylene glycol
1 g/kg or about 100 mL in an adult
metabolism of methanol
methanol –> formaldehyde –> formic acid
At higher methanol concentrations, metabolism switchees to zero-order kinetics, and blood methanol decreases at a fixed rate, roughly 8.5 mg/dL/hour
metabolism of ethylene glycol
ethylene glycol –> glycoaldehyde –> glycolic acid –> glycoxylic acid –> oxalic acid
MOA of methanol toxicity
Formic acid is the metabolite responsible for the toxicity and metabolic acidosis that occur with methanol poisoning
Formic acid’s MOA:
- binds to cytochrome oxidase and blocks oxidative phosphorylation, leading to anaerobic metabolism and lactic acidosis
- metabolism of methanol increases the NADH/NAD+ ratio, favoring pyruvate -> lactate
remarks on methanol and metabolic acidosis
1.) Formic acid’s inhibition of cytochrome oxidase increases with decreasing pH, so acidemia worsens the blockade of aerobic metabolism
2.) At lower pH, more formic acid can enter the brain and ocular tissues, worsening CNS depression and retinal and optic nerve injury
3.) Lower pH may also prolong formic acid elimination by increasing tubular reabsorption
MOA of ethylene glycol toxicity
Glycolic acid is the toxic metabolite, and its buildup is responsible for most of the metabolic acidosis.
Glycolic acid can be metabolized to oxalic acid.
- oxalic acid can complex with calcium, which leads to hypocalcemia and precipitation of calcium oxalate crystals in tissues and urine.
End-organ damage is though to be due to
a.) direct cytotoxicity of glycolic acid (mechanism is unclear)
b.) tissue damage from precipitation of calcium oxalate crystals
Methanol poisoning is characterized by
CNS depresssion, metabolic acidosis, and visual changes
Severity of poisoning correlates more with the level of acidosis than with the methanol level
Clinical signs and symptoms may be signifianctly delayed after exposure, often by 12-24 hours, because metabolism to formic acid is required for tissue damage
Because ethanol competes for alcohol dehydrogenase, formation of the toxic metabolites from methanol will be delayed if ethanol has also been ingested
methanol is only a mild inebriant
Ocular toxicity in methanol poisoning
Retinal and optic nerve tissue seems to be especially sensitive to the toxic effects of formic acid.
photophobia or blurred or “snow field” vision
with papilledema, nystagus (rare), and nonreactive mydriasis once permanent damage has occurred
Ethylene glycol poisoning is characterized by
CNS depression, metabolic acidosis, and renal failure
First stage of ethylene glycol poisoning
“neurologic stage”
30 mins to 12 hours after ingestion
due to intoxicating effects of the ethylene glycol parent compound
may range from mild depression to seizure and coma
the generation of toxic metabolites takes 4-12 hours, or more if ethanol was co-ingested
* hypocalcemia may contribute to seizures
* metabolic acidosis appears as toxic metabolites are generated
CNS tissue effects in ethylene glycol poisoning
CNS tissue effects are from glycolic acid and calcium oxalate crystals
include cerebral edema, basal ganglia hemorrhagic infarction, and meningoencephalitis
second stage of ethylene glycol poisoning
“cardiopulmonary stage”
begins 12-24 hours after ingestion
ch’zd by tachycardia and possibly hypertension
glycolate and oxalate cyrstal deposition in tissues leads to multiorgan system failure, including heart failure, acute lung injury, and myositis
‼️ Most deaths occur during this stage ‼️