Animal species show great variability in mean lethal doses of methanol. The special susceptibility of humans to methanol toxicity is due to metabolism to formate and formaldehyde, not due to methanol itself. Since the conversion of methanol to its toxic metabolites is relatively slow, there is often a delay of 6–30 hours before the appearance of severe toxicity.
Physical findings in early methanol poisoning are generally nonspecific, such as inebriation and gastritis, and possibly an elevated osmolar gap (see Chapter 58). In severe cases, the odor of formaldehyde may be present on the breath or in the urine. After a delay, the most characteristic symptom in methanol poisoning— visual disturbance—occurs along with anion gap metabolic acidosis. The visual disturbance is frequently described as “like being in a snowstorm” and can progress to blindness. Changes in the retina
FIGURE 23–3 Methanol is converted to the toxic metabolites formaldehyde and formate by alcohol dehydrogenase and aldehyde dehydrogenase. By inhibiting alcohol dehydrogenase, fomepizole and ethanol reduce the formation of toxic metabolites.
CHAPTER 23 The Alcohols 405 may sometimes be detected on examination, but these are usually late. The development of bradycardia, prolonged coma, seizures, and resistant acidosis all imply a poor prognosis. The cause of death in fatal cases is sudden cessation of respiration. A serum methanol concentration higher than 20 mg/dL warrants treatment, and a concentration higher than 50 mg/dL is considered serious enough to require hemodialysis. Serum formate levels are a better indication of clinical pathology but are not widely available.
The first treatment for methanol poisoning, as in all critical poisoning situations, is support of respiration. There are three specific modalities of treatment for severe methanol poisoning: suppression of metabolism by alcohol dehydrogenase to toxic products, hemodialysis to enhance removal of methanol and its toxic products, and alkalinization to counteract metabolic acidosis.
The enzyme chiefly responsible for methanol oxidation in the liver is alcohol dehydrogenase (Figure 23–3). Fomepizole, an alcohol dehydrogenase inhibitor, is approved for the treatment of methanol and ethylene glycol poisoning. It is administered intravenously in a loading dose of 15 mg/kg followed by 10 mg/kg every 12 hours for 48 hours and then 15 mg/kg every 12 hours thereafter until the serum methanol level falls below 20–30 mg/dL. The dosage increase after 48 hours is based on evidence that fomepizole rapidly induces its own metabolism by the cytochrome P450 system. Patients undergoing hemodialysis are given fomepizole more frequently (6 hours after the loading dose and every 4 hours thereafter). Fomepizole appears to be safe during the short time it is administered for treatment of methanol or ethylene glycol poisoning. The most common adverse effects are burning at the infusion site, headache, nausea, and dizziness. Intravenous ethanol is an alternative to fomepizole. It has a higher affinity than methanol for alcohol dehydrogenase; thus, saturation of the enzyme with ethanol reduces formate production. Ethanol is used intravenously as treatment for methanol and ethylene glycol poisoning. The dose-dependent characteristics of ethanol metabolism and the variability of ethanol metabolism require frequent monitoring of blood ethanol levels to ensure appropriate alcohol concentration.