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Alcohols and Aldehydes
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
Fomepizole and ethanol are specific antidotes for methanol intoxication. Fomepizole is an ADH inhibitor that effectively blocks the metabolism of methanol and reduces the conversion of the alcohol to formaldehyde and formic acid. In addition, the administration of ethanol also forces the competition of the alcohols for ADH, thus diverting the metabolism away from methanol. As such, fomepizole should be given intravenously (I.V.)* to all patients with methanol intoxication. Caution is in order for ethanol administration, since it may cause CNS depression and hypoglycemia, as the dose is not easily manipulated.† However, fomepizole has great efficacy and fewer side effects than ethanol; hence, it is the favored antidote in the treatment of methanol intoxication.
Case 86: Unconscious Outside a Club
Published in Layne Kerry, Janice Rymer, 100 Diagnostic Dilemmas in Clinical Medicine, 2017
Fomepizole is a competitive inhibitor of alcohol dehydrogenase and its administration will slow the metabolism of methanol and thus the rate of formaldehyde/formic acid production. Intravenous folinic acid may be given to enhance formic acid degradation. Care is otherwise supportive. Patients may develop permanent visual damage following methanol-induced retinal/optic nerve oedema and subsequent optic nerve demyelination, as well as damage to the basal ganglia.
Fomepizole dosing during continuous renal replacement therapy – an observational study
Published in Clinical Toxicology, 2022
Yvonne E. Lao, Trond Vartdal, Sten Froeyshov, Brian Latimer, Christiane Kvaerner, Marija Mataric, Peter Holm, Siri Foreid, Dag Jacobsen, Kenneth McMartin, Knut Erik Hovda
Methanol and ethylene glycol are toxic alcohols with a potential fatal outcome when poisoned. Large outbreaks of methanol poisoning with high mortality are regularly reported [1,2], as are case reports of intentional or accidental ingestion of ethylene glycol [3,4]. Early treatment with the antidotes ethanol or fomepizole is effective and lifesaving [5]. Both substances act by inhibiting the alcohol dehydrogenase enzyme, and thus preventing the formation of the toxic metabolites (formic acid from methanol and glycolic acid from ethylene glycol). Although ethanol can cause a pronounced central nervous system (CNS) depression, it also requires frequent monitoring of plasma ethanol. Fomepizole, on the other hand, has limited side effects (e.g., headache and dizziness), and does not require monitoring of plasma concentration. Treatment guidelines therefore recommend fomepizole as the antidote of choice [5]. Plasma concentrations of fomepizole above 10 µmol/L are considered effective and will prevent formation of the toxic metabolites, based on studies done in non-human primates [6,7].
Recent developments in predicting CYP-independent metabolism
Published in Drug Metabolism Reviews, 2021
Nikhilesh V. Dhuria, Bianka Haro, Amit Kapadia, Khadjia A. Lobo, Bernice Matusow, Mary A. Schleiff, Christina Tantoy, Jasleen K. Sodhi
The family of alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) are found abundantly in human liver cytosol and are primarily involved in the conversion of primary alcohols to aldehydes and aldehydes to carboxylic acids via NADP + reduction (Singh et al. 2013; Bhatt et al. 2017; Di et al. 2021). These enzymes are best recognized for their role in the metabolism of ethanol but are also involved in the metabolism of endogenous and exogenous aldehydes to mitigate oxidative stress (Singh et al. 2013), endogenous substrates such as retinol (Napoli 1999), and xenobiotic compounds such as abacavir, hydroxyzine, ethambutol, and felbamate (Foti and Dalvie 2016; Di et al. 2021). Additionally, the in vivo inhibition of ADHs and ALDHs by drugs such as fomepizole, cimetidine, and disulfiram have been demonstrated to result in decreased ethanol metabolism. Thus fomepizole, a nonspecific ADH inhibitor, is commonly used as an antidote for methanol or ethylene glycol (anti-freeze) poisoning (Brent 2009). Meanwhile, the ALDH inhibitor disulfiram is clinically utilized as a deterrent for ethanol consumption, as it prevents ethanol metabolism and results in increased acetaldehyde levels that are associated with myriad unpleasant side effects (Petersen 1992; Chen et al. 2014).
A review of methanol poisoning: a crisis beyond ocular toxicology
Published in Cutaneous and Ocular Toxicology, 2020
Peter Pressman, Roger Clemens, Saura Sahu, A. Wallace Hayes
Fomepizole/4-methylpyrazole (Antizol) acts similarly to ethanol. It is a stronger competitive inhibitor of alcohol dehydrogenase (ADH) and, in addition, does not cause hypoglycaemia or sedation. Fomepizole is relatively easier to administer than ethanol, and it does not require monitoring of serum concentrations. It is tempting to speculate that in the developing world where fomepizole may not be readily available, ethanol becomes the agent of choice. However, due to competition for ADH, the therapeutic ethanol concentration depends on the concentration of the other two alcohols, but a therapeutic ethanol concentration around 22 mmol/L (100 mg/dl) is generally recommended. This in itself is an obstacle since quantitative measurement in a resource poor setting is unlikely.