Fomepizole (4-Methylpyrazole)

Mechanism

Pharmacological Group and Molecular Target

High affinity competitive inhibitor of the cytosolic enzyme alcohol dehydrogenase (ADH).

Detailed Mechanism of Action

Methanol and ethylene glycol are non-toxic alcohols by themselves, but they undergo a lethal biotransformation in the body catalyzed mainly by the enzyme alcohol dehydrogenase (ADH):

Fomepizole is a competitive inhibitor of ADH with an affinity constant for the enzyme approximately 8,000 times higher than that of ethanol. By completely blocking the active site of ADH, it absolutely prevents the oxidation of methanol or ethylene glycol to their highly toxic acid metabolites. This allows the original alcohol to remain unchanged in the bloodstream, with a slow but safe rate of passive renal or pulmonary excretion.

Pharmacokinetics

Pharmacokinetic and Toxicokinetic Profile

• Distribution: It is rapidly distributed in total body water. It does not bind significantly to proteins.
• Metabolism: Hepatic; induces its own microsomal metabolism through cytochrome pathways after repeated administrations (more than 48 hours). Its main metabolite is 4-carboxypyrazole.
• Excretion: Renal; Less than 5% is excreted unchanged in the urine.
• Elimination half-life: Varies depending on the dose due to saturation of its own enzymatic clearance; ranges between 3 and 5 hours at optimal therapeutic doses.

Fomepizole (Antizole)

• Predictable and consistent enzymatic inhibition of ADH without induction of CNS depression.
• Does not require continuous monitoring of serum levels of the antidote.
• Does not cause hypoglycemia or added systemic hyperosmolarity.
• Disadvantage: Extremely high economic cost.

Ethanol (Alternative Treatment)

• Requires keeping the patient in a state of constant clinical intoxication (target concentration of 100-150 mg/dL).
• Severe CNS depressant effect, increases the risk of bronchoaspiration.
• Frequent induction of hypoglycemia and severe electrolyte imbalances.
• Requires constant monitoring of ethanol levels every 2 hours.

Indicators and dose

Specific Clinical Indications

• Confirmed or suspected intoxication by methanol or ethylene glycol, indicated when the plasma concentration of alcohol is greater than 20 mg/dL, or in the presence of metabolic acidosis with a high anion gap (anion gap) and unexplained osmolar gap.

Dosage Scheme and Infusion Protocols

• Initial Loading Dose: 15 mg/kg IV infused slowly over a period of 30 minutes diluted strictly in 100 mL of saline.
• Maintenance Dose: Administer 10 mg/kg IV every 12 hours for a total of 4 consecutive doses. Subsequently, increase the dose to 15 mg/kg every 12 hours due to self-doubling of hepatic clearance of the drug.
• Adjustment during Hemodialysis: Since fomepizole is actively cleared by extracorporeal dialyzers, the frequency of administration should be increased to every 4 hours during the hemodialysis session on a continuous basis.