Antidote
Fomepizole (Antizol)
Also called Antizol, 4-MP, 4-methylpyrazole
Indications
- Ethylene glycol or methanol poisoning, known or suspected, alone or with hemodialysis (label)
- Preferred over ethanol for methanol (AACT 2002); validated efficacy, predictable kinetics, easy dosing and few adverse effects (AACT 1999)
- Started on suspicion, before a level returns, when history, an osmolar gap or acidosis point to a toxic alcohol
Mechanism of action
Fomepizole competitively inhibits alcohol dehydrogenase (label), the enzyme that starts the metabolism of methanol, ethylene glycol and ethanol; in vitro it halves enzyme activity at about 0.1 µmol/L (label). The parent alcohols do little harm: alcohol and aldehyde dehydrogenase turn methanol into formic acid, which injures the optic nerve and causes acidosis, and ethylene glycol into glycolic acid and oxalate, which cause acidosis and calcium oxalate kidney injury. With the first step blocked, the parent alcohol is excreted by the kidneys or removed by dialysis, and no new acid forms.
Pharmacology
- Metabolic: stops further acid production; acidosis already present still needs bicarbonate and often dialysis
- Renal: none of 10 ethylene glycol patients with a normal creatinine at enrollment developed kidney injury on fomepizole (Brent 1999)
- Toxic alcohol kinetics: on fomepizole methanol's half-life was 54 h (Brent 2001), which is why methanol is dialyzed more often than ethylene glycol
- Ethanol: fomepizole slows ethanol elimination by about 40%, and ethanol slows fomepizole elimination by about 50% (label)
- CNS: no intoxication, unlike ethanol therapy; headache 14%, nausea 11%, dizziness, drowsiness and metallic taste 6% each (label)
Pharmacokinetics
| Target level | 100–300 µmol/L (8.6–24.6 mg/L) for full enzyme blockade (label) |
|---|---|
| Distribution | Vd 0.6–1.02 L/kg (label) |
| Half-life | Not calculated: Michaelis-Menten elimination after a single dose (label) |
| Autoinduction | Induces its own metabolism, first-order after 30–40 h; hence 15 mg/kg every 12 h after four 10 mg/kg doses (label) |
| Metabolism | Mainly to 4-carboxypyrazole, 80–85% of the dose (label) |
| Elimination | Urine; 1–3.5% unchanged (label) |
| Dialysis | Dialyzable: dose every 4 h during hemodialysis (label) |
| Stopping | When the alcohol is undetectable or under 20 mg/dL and the patient is asymptomatic with a normal pH (label) |
Chemistry
- 4-methylpyrazole, C₄H₆N₂, MW 82.1: a small pyrazole heterocycle (label)
- 1 g/mL liquid, soluble in water and very soluble in ethanol; melting point 25°C, so a cool vial may solidify and must be liquefied before use (label)
- Each dose diluted in at least 100 mL saline or D5W and infused over 30 min (label)
Adverse effects and cautions
In the one-pagers
- Toxidromes and AntidotesReversal antidotes: Methanol, ethylene glycol: Fomepizole 15 mg/kg IV, then 10 mg/kg every 12 h: Blocks alcohol dehydrogenase
- Toxins, Stings and Anaphylaxis in the FieldCardiotoxic, delayed and interacting drugs: Disulfiram-alcohol reaction: disulfiram irreversibly blocks aldehyde dehydrogenase, so acetaldehyde builds up: flushing, throbbing headache, vomiting, chest pain and, in severe cases, shock, ST depression or infarction. Enzyme activity takes 6 or more days to recover. Treat with fluids and a vasopressor; because disulfiram also inhibits dopamine beta-hyd
Other antidote drugs
Sources
- FDA label: Fomepizole Injection (American Regent, 2020)
- AACT ethylene glycol (1999) and methanol (2002) guidelines
- Brent 1999 and 2001 (NEJM)
- EXTRIP methanol (extrip-workgroup.org) and ethylene glycol (Ghannoum 2023) recommendations
For education and exam preparation only. Follow your institution’s protocols. Typical adult values for study. Follow your local protocols and medical direction.