Antidotes for poisoning by alcohols that form toxic metabolites

Abstract

The alcohols, methanol, ethylene glycol and diethylene glycol, have many features in common, the most important of which is the fact that the compounds themselves are relatively non-toxic but are metabolized, initially by alcohol dehydrogenase, to various toxic intermediates. These compounds are readily available worldwide in commercial products as well as in homemade alcoholic beverages, both of which lead to most of the poisoning cases, from either unintentional or intentional ingestion. Although relatively infrequent in overall occurrence, poisonings by metabolically-toxic alcohols do unfortunately occur in outbreaks and can result in severe morbidity and mortality. These poisonings have traditionally been treated with ethanol since it competes for the active site of alcohol dehydrogenase and decreases the formation of toxic metabolites. Although ethanol can be effective in these poisonings, there are substantial practical problems with its use and so fomepizole, a potent competitive inhibitor of alcohol dehydrogenase, was developed for a hopefully better treatment for metabolically-toxic alcohol poisonings. Fomepizole has few side effects and is easy to use in practice and it may obviate the need for haemodialysis in some, but not all, patients. Hence, fomepizole has largely replaced ethanol as the toxic alcohol antidote in many countries. Nevertheless, ethanol remains an important alternative because access to fomepizole can be limited, the cost may appear excessive, or the physician may prefer ethanol due to experience.

Alcohol, its absorption, distribution, metabolism, and excretion in the body and pharmacokinetic calculations

“…Accordingly, at elevated BAC oxidation of methanol is blocked and formation of its toxic metabolites prevented. The first‐aid treatment of patients poisoned with methanol is to administer ethanol solutions intravenously to reach BAC of 100–120 mg% (McMartin, Jacobsen, & Hovda, ). After blocking the oxidation by competitive enzyme inhibition, methanol and its toxic metabolites can be removed from the bloodstream by dialysis.…”

“…The first-aid treatment of patients poisoned with methanol is to administer ethanol solutions intravenously to reach F I G U R E 3 Comparison of the metabolism of ethanol and methanol in the liver by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzymes into more toxic metabolites, acetaldehyde and formaldehyde. Also shown are the chemical structures of the enzyme inhibitors 4-methyl pyrazole (ADH) and disulfiram (ALDH) BAC of 100-120 mg% (McMartin, Jacobsen, & Hovda, 2016). After blocking the oxidation by competitive enzyme inhibition, methanol and its toxic metabolites can be removed from the bloodstream by dialysis.…”

Intermittent versus continuous renal replacement therapy in acute methanol poisoning: comparison of clinical effectiveness in mass poisoning outbreaks

“…Treatment consists of a buffer to correct acidemia, antidote (ethanol or fomepizole) to block the metabolism of methanol, folate substitution to enhance the endogenous metabolism of formate, and dialysis to eliminate methanol and its toxic metabolite [5–7]. Formic acid/formate anions have a strong cytotoxic effect through inhibition of the mitochondrial respiration [8, 9].…”

Assessment and Management of Toxidromes in the Critical Care Unit

“…[81][82][83] Over-the-counter products containing acetaminophen, nonsteroidal anti-inflammatory drugs, and aspirin frequently land purposeful overdose patients in the ICU. [84][85][86] Carbon monoxide exposure causes CNS injury that can lead to delayed neuropsychiatric impairment long after recovery from critical illness.…”