Antidotes for Toxic-alcohol Poisoning

The use of ethanol or, preferably, fomepizole for alcohol dehydrogenase (ADH) inhibition is a mainstay in the management of toxicity due to ingestion of methanol, ethylene glycol, or diethylene glycol.[6–8]

The toxicity of methanol and of ethylene glycol is well described, and each year in the United States there are about 5000 exposures that require treatment and 20–30 associated deaths reported to poison centers.[2,9,10] Methanol and ethylene glycol, as parent compounds, are relatively nontoxic. However, they are metabolized by ADH to toxic metabolites that can cause end-organ damage and death. Methanol is metabolized via ADH to formic acid, which results in anion-gap metabolic acidosis and ocular toxicity. Retinal toxicity secondary to methanol poisoning is usually irreversible.[6,11] Ethylene glycol is metabolized via ADH to glycolic acid, which results in anion-gap metabolic acidosis, and oxalic acid, which results primarily in renal toxicity due to the formation of calcium oxalate crystals.[7,12] Both can produce irreversible CNS toxicity.

Poisoning by diethylene glycol (historically and tragically used as a glycerin substitute and also in household products such as wallpaper stripper and Sterno brand heating fuel[13,14]) is less common but associated with very high morbidity and mortality.[15,16] Diethylene glycol is metabolized via ADH to hydroxy-ethoxyacetic acid and diglycolic acid and causes anion-gap metabolic acidosis, bilateral cortical necrosis, and sensorimotor polyneuropathy.[16–20]

Ethanol

For many years, ethanol has been used to inhibit ADH and limit the metabolism of methanol and ethylene glycol to their respective metabolites.[21] The dose of ethanol needed to competitively inhibit ADH depends on the comparative affinity of the specific toxic alcohol for ADH. Most authorities recommend using a dose of ethanol sufficient to achieve and maintain a serum ethanol concentration of 100–150 mg/dL. In the presence of ethanol, the half-lives of ethylene glycol (in patients with normal renal function) and methanol are approximately 17.5 and 45 hours, respectively.[6,7]

Ethanol can be administered intravenously or orally. However, a commercial i.v. preparation of ethanol is no longer available, and extemporaneous preparation is too time-consuming to be considered satisfactory. A loading dose is necessary to quickly achieve the desired serum concentration of 100–150 mg/dL; then a maintenance dose is administered, using serum ethanol concentrations to maintain the desired target. Repeat evaluations of the serum ethanol concentration are required to ensure that the target level is achieved and maintained. Individual differences in ethanol metabolism occur due to pharmacogenetics and whether the patient is induced or becomes induced secondary to chronic ethanol exposure.[6,7]

The risks associated with ethanol administration include central nervous system (CNS) depression, hypoglycemia (due to decreased gluconeogenesis), nausea, and vomiting. Intravenous administration of ethanol poses an additional risk of phlebitis and hypertonicity with hyponatremia. Frequent assessment of the serum ethanol concentration and monitoring of venous blood glucose are required.

Fomepizole

Fomepizole competitively inhibits ADH and is an effective and safe antidote for both ethylene glycol and methanol toxicity.[6,7] In the presence of fomepizole, the half-lives of ethylene glycol (in patients with normal renal function) and methanol are 14.5 and 40 hours, respectively.[22]

The Food and Drug Administration (FDA)-approved regimen of fomepizole is an i.v. loading dose of 15 mg/kg over 30 minutes followed by a dose of 10 mg/kg every 12 hours, with the frequency of dosing increased to every 4 hours during hemodialysis.[23] Fomepizole induces its own metabolism, presumably through the cytochrome P-450 2E1 isoenzyme; therefore, after 48 hours of drug administration, the fomepizole dose should be increased to 15 mg/kg every 12 hours.

Fomepizole is generally well tolerated. Adverse events reported with the use of fomepizole include mild irritation at the i.v. infusion site, headache, nausea, dizziness, drowsiness, and a bad or metallic taste in the mouth.

Although there are no head-to-head comparisons of fomepizole versus ethanol for the management of toxic-alcohol poisoning, the former's ease of administration and relative lack of serious adverse effects have elevated it to preferred status. The clinical advantages of fomepizole over ethanol are a much higher potency of ADH inhibition (K i = 0.1μmol/L, a 1000-fold higher affinity than that of ethanol), better maintenance of therapeutic blood concentrations, and fewer adverse effects; moreover, the administration of fomepizole is less labor-intensive.[12]

Additional and Supportive Therapy

In addition to antidote administration, hemodialysis should be considered in all toxic-alcohol exposures in which toxic metabolites have already formed, as evidenced by anion-gap metabolic acidosis or end-organ damage, and for patients with toxic serum methanol or ethylene glycol concentrations whose elimination of parent or toxic metabolites is expected to be inordinately prolonged (e.g., cases involving significant methanol exposure or ethylene glycol ingestion by a patient with renal impairment). Empiric hemodialysis is recommended if the serum methanol concentration is >25 mg/dL and if the serum ethylene glycol concentration is >50 mg/dL with renal insufficiency.[6,7] Hemodialysis also should be considered in cases of severe isopropyl alcohol poisoning in patients with hemodynamic instability.

Intravenous administration of 50 mg of folic acid every six hours enhances methanol elimination and has been shown to prevent retinal toxicity in animal models.[8,24,25] Also, urinary alkalinization (i.e., a urine pH of >8) with i.v. sodium bicarbonate enhances formate elimination and may reduce the distribution of formic acid to the eye.

Theoretically, the use of i.v. thiamine hydrochloride 100 mg and i.v. pyridoxine hydrochloride 50 mg every six hours should shunt the metabolism of ethylene glycol away from production of oxalic acid to production of less toxic metabolites'[26,27] though there are no data from studies of humans to support this practice, these agents are well tolerated and the potential benefits outweigh any risks.

Implications for the Pharmacist Methanol or ethylene glycol toxicity should be suspected in a patient with anion-gap metabolic acidosis in whom laboratory testing reveals a low (or no) ethanol concentration, no ketones, and a normal lactic acid concentration (clinicians need to be aware that some test results can be skewed by glycolic acid, the toxic metabolite of ethylene glycol). Fomepizole and adjuvants that act as cofactors should be used as soon as toxic alcohols are included in the differential diagnosis. Fomepizole should be continued until the patient is no longer acidemic and the toxic-alcohol serum concentration is presumed or confirmed to be <25 mg/dL. The availability of testing for toxic alcohols is limited.