Fomepizole
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 Chemical structure of fomepizole | |
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| Pronunciation | /ˌfoʊˈmɛpɪzoʊl/ |
| Trade names | Antizol, others |
| Other names | 4-Methylpyrazole |
| AHFS/Drugs.com | Monograph |
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Intravenous | |
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JSmol) | |
| Density | 0.99 g/cm3 |
| Boiling point | 204 to 207 °C (399 to 405 °F) (at 97,3 kPa) |
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Fomepizole, also known as 4-methylpyrazole, is a medication used to treat
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 use
Fomepizole is used to treat ethylene glycol and methanol poisoning. It acts to inhibit the breakdown of these toxins into their active toxic metabolites. Fomepizole is a competitive inhibitor of the enzyme alcohol dehydrogenase,[6] found in the liver. This enzyme plays a key role in the metabolism of ethylene glycol, and of methanol.
- Ethylene glycol is first metabolized to 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.
- Methanol is first metabolized to formaldehyde by alcohol dehydrogenase. Formaldehyde then undergoes further oxidation, via formaldehyde dehydrogenase, to become formic acid.[7] Formic acid is the primary toxin responsible for the metabolic acidosis, and for the visual disturbances, associated with methanol poisoning.
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.[8]
Fomepizole is most effective when given soon after ingestion of ethylene glycol or methanol. Delaying its administration allows for the generation of harmful metabolites.[8]
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).
In a chronic alcoholic who has built up a tolerance to ethanol, this removes some of the disincentives to ethanol consumption ("
It is, in essence, the antithesis of a
Adverse effects
Common side effects associated with fomepizole use include headache and nausea.[9]
Kinetics
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.
Metabolism and elimination
Following multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system.
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.
Fomepizole is dialyzable.
Other uses
Apart from medical uses, the role of 4-methylpyrazole in
References
- FDA. Retrieved 22 October 2023.
- ^ "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
- ^ "Antizol- fomepizole injection". DailyMed. U.S. National Library of Medicine. Retrieved 24 December 2020.
- ^ a b c d e f g "Fomepizole". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
- hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
- PMID 11134450.
- ^ "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.
- ^ PMID 19458366.
- PMID 18639955.
- S2CID 93580021.
