Fomepizole

Fomepizole

Chemical structure of fomepizole
Clinical data
Pronunciation	/ˌfoʊˈmɛpɪzoʊl/
Trade names	Antizol, others
Other names	4-Methylpyrazole
AHFS/Drugs.com	Monograph
License data	US  DailyMed:  Fomepizole
Routes of administration	Intravenous
Drug class	Alcohol dehydrogenase inhibitor
ATC code	V03AB34 ( WHO )
Legal status
Legal status	AU: S4 (Prescription only) [1] US: WARNING [2] Rx-only [3]
Identifiers
IUPAC name 4-Methyl-1H-pyrazole
CAS Number	7554-65-6  Y
PubChem CID	3406
DrugBank	DB01213
ChemSpider	3289
UNII	83LCM6L2BY
KEGG	D00707
ChEBI	CHEBI:5141
ChEMBL	ChEMBL1308
CompTox Dashboard (EPA)	DTXSID3040649
ECHA InfoCard	100.028.587
Chemical and physical data
Formula	C4H6N2
Molar mass	82.106 g·mol−1
3D model (JSmol)	Interactive image
Density	0.99 g/cm3
Boiling point	204 to 207 °C (399 to 405 °F) (at 97,3 kPa)
SMILES CC1=CNN=C1
InChI InChI=1S/C4H6N2/c1-4-2-5-6-3-4/h2-3H,1H3,(H,5,6) Y Key:RIKMMFOAQPJVMX-UHFFFAOYSA-N

Fomepizole, also known as 4-methylpyrazole, is a medication used to treat methanol and ethylene glycol poisoning. ^[4] It may be used alone or together with hemodialysis. ^[4] It is given by injection into a vein. ^[4]

Common side effects include headache, nausea, sleepiness, and unsteadiness. ^[4] It is unclear if use during pregnancy causes risk to a fetus. ^[4] Fomepizole works by blocking the enzyme that converts methanol and ethylene glycol to their toxic breakdown products. ^[4]

Fomepizole was approved for medical use in the United States in 1997. ^[4] It is on the World Health Organization's List of Essential Medicines. ^[5]

Medical uses

Fomepizole is used to treat ethylene glycol and methanol poisoning. It acts to inhibit the breakdown of these toxins into their active toxic metabolites.^{[ citation needed ]}

Fomepizole is most effective when given soon after ingestion of ethylene glycol or methanol. Delaying its administration allows for the generation of harmful metabolites. ^[6]

Adverse effects

Common side effects associated with fomepizole use include headache and nausea. ^[7]

Interactions

Interaction with alcohol

Concurrent use with ethanol is contraindicated because fomepizole is known to prolong the half-life of ethanol via inhibiting its metabolism. Extending the half-life of ethanol may increase and extend the intoxicating effects of ethanol, allowing for greater (potentially dangerous) levels of intoxication at lower doses. Fomepizole slows the production of acetaldehyde by inhibiting alcohol dehydrogenase, which in turn allows more time to further convert acetaldehyde into acetic acid by acetaldehyde dehydrogenase. The result is a patient with a prolonged and deeper level of intoxication for any given dose of ethanol, and reduced hangover symptoms (since these adverse symptoms are largely mediated by acetaldehyde build up).^{[ citation needed ]}

Fomepizole’s interaction with ethanol removes some of the disincentives to ethanol consumption while allowing users to become intoxicated with a lower dose of ethanol, which creates a much higher risk for overdose.^{[ citation needed ]}

Pharmacology

Mechanism of action

Fomepizole is a competitive inhibitor of the enzyme alcohol dehydrogenase, ^[8] found in the liver. This enzyme plays a key role in the metabolism of ethylene glycol, and of methanol. ^[8]

• Ethylene glycol is first metabolized to glycolaldehyde by alcohol dehydrogenase. Glycolaldehyde then undergoes further oxidation to glycolate, glyoxylate, and oxalate. Glycolate and oxalate are the primary toxins responsible for the metabolic acidosis, and for the renal damage, seen in ethylene glycol poisoning.^{[ citation needed ]}
• Methanol is first metabolized to formaldehyde by alcohol dehydrogenase. Formaldehyde then undergoes further oxidation, via formaldehyde dehydrogenase, to become formic acid. ^[9] Formic acid is the primary toxin responsible for the metabolic acidosis, and for the visual disturbances, associated with methanol poisoning. ^[9]

By competitively inhibiting the first enzyme, alcohol dehydrogenase, in the metabolism of ethylene glycol and methanol, fomepizole slows the production of the toxic metabolites. The slower rate of metabolite production allows the liver to process and excrete the metabolites as they are produced, limiting the accumulation in tissues such as the kidney and eye. As a result, much of the organ damage is avoided. ^[6]

Pharmacokinetics

Absorption and distribution

Fomepizole distributes rapidly into total body water. The volume of distribution is between 0.6 and 1.02 L/kg. The therapeutic concentration is from 8.2 to 24.6 mg (100 to 300 micromoles) per liter. Peak concentration following single oral doses of 7 to 50 mg/kg of body weight occurred in 1 to 2 hours. The half-life varies with dose, so has not been calculated.^{[ citation needed ]}

Metabolism and elimination

Hepatic – the primary metabolite is 4-carboxypyrazole (about 80 to 85% of an administered dose). Other metabolites include the pyrazoles 4-hydroxymethylpyrazole and the N -glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole.^{[ citation needed ]}

Following multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system.^{[ citation needed ]}

In healthy volunteers, 1.0 to 3.5% of an administered dose was excreted unchanged in the urine. The metabolites also are excreted unchanged in the urine.^{[ citation needed ]}

Fomepizole is dialyzable.^{[ citation needed ]}

Research

Apart from medical uses, the role of 4-methylpyrazole in coordination chemistry has been studied. ^[10]

References

1. "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
2. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
3. "Antizol- fomepizole injection". DailyMed. U.S. National Library of Medicine. Retrieved 24 December 2020.
4. "Fomepizole". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
5. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
6. Brent J (May 2009). "Fomepizole for ethylene glycol and methanol poisoning". The New England Journal of Medicine. 360 (21): 2216–2223. doi:10.1056/NEJMct0806112. PMID   19458366.
7. Lepik KJ, Levy AR, Sobolev BG, Purssell RA, DeWitt CR, Erhardt GD, et al. (April 2009). "Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole". Annals of Emergency Medicine. 53 (4): 439–450.e10. doi:10.1016/j.annemergmed.2008.05.008. PMID   18639955.
8. Casavant MJ (January 2001). "Fomepizole in the treatment of poisoning". Pediatrics. 107 (1): 170. doi:10.1542/peds.107.1.170. PMID   11134450.
9. "Methanol poisoning". Forensic Pathology. The Internet Pathology Laboratory for Medical Education, The University of Utah Eccles Health Sciences Library. Archived from the original on 17 September 2008.
10. Vos JG, Groeneveld WL (1979). "Pyrazolato and related anions. Part V. Transition metal salts of 4-methylpyrazole". Transition Metal Chemistry. 4 (3): 137–141. doi:10.1007/BF00619054. S2CID   93580021.