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Fomepizole, also known as 4-methylpyrazole, is a medication used to treat
methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...
and ethylene glycol poisoning. It may be used alone or together with
hemodialysis Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
. It is given by
injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
. Common side effects include headache, nausea, sleepiness, and unsteadiness. It is unclear if use during
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...
is safe for the baby. Fomepizole works by blocking the
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that converts
methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...
and
ethylene glycol Ethylene glycol ( IUPAC name: ethane-1,2-diol) is an organic compound (a vicinal diol) with the formula . It is mainly used for two purposes, as a raw material in the manufacture of polyester fibers and for antifreeze formulations. It is an o ...
to their toxic breakdown products. Fomepizole was approved for medical use in the United States in 1997. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
.


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 Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected b ...
of the enzyme
alcohol dehydrogenase Alcohol dehydrogenases (ADH) () are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to NA ...
, 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
glycolaldehyde Glycolaldehyde is the organic compound with the formula . It is the smallest possible molecule that contains both an aldehyde group () and a hydroxyl group (). It is a highly reactive molecule that occurs both in the biosphere and in the inter ...
by alcohol dehydrogenase. Glycolaldehyde then undergoes further oxidation to glycolate,
glyoxylate Glyoxylic acid or oxoacetic acid is an organic compound. Together with acetic acid, glycolic acid, and oxalic acid, glyoxylic acid is one of the C2 carboxylic acids. It is a colourless solid that occurs naturally and is useful industrially. Str ...
, and
oxalate Oxalate (IUPAC: ethanedioate) is an anion with the formula C2O42−. This dianion is colorless. It occurs naturally, including in some foods. It forms a variety of salts, for example sodium oxalate (Na2C2O4), and several esters such as dimethyl ...
. Glycolate and oxalate are the primary toxins responsible for the
metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
, and for the renal damage, seen in ethylene glycol poisoning. * Methanol is first metabolized to
formaldehyde Formaldehyde ( , ) ( systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section ...
by alcohol dehydrogenase. Formaldehyde then undergoes further oxidation, via formaldehyde dehydrogenase, to become
formic acid Formic acid (), systematically named methanoic acid, is the simplest carboxylic acid, and has the chemical formula HCOOH and structure . It is an important intermediate in chemical synthesis and occurs naturally, most notably in some ants. Est ...
. 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. Fomepizole is most effective when given soon after ingestion of ethylene glycol or methanol. Delaying its administration allows for the generation of harmful metabolites.


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 Acetaldehyde (IUPAC systematic name ethanal) is an organic chemical compound with the formula CH3 CHO, sometimes abbreviated by chemists as MeCHO (Me = methyl). It is a colorless liquid or gas, boiling near room temperature. It is one of the ...
by inhibiting alcohol dehydrogenase, which in turn allows more time to further convert acetaldehyde into acetic acid by
acetaldehyde dehydrogenase Acetaldehyde dehydrogenases () are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetic acid. The oxidation of acetaldehyde to acetate can be summarized as follows: Acetaldehyde + NAD+ + Coenzyme A ↔ Acetyl-CoA + NA ...
. 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 ("
negative reinforcement In behavioral psychology, reinforcement is a consequence applied that will strengthen an organism's future behavior whenever that behavior is preceded by a specific antecedent stimulus. This strengthening effect may be measured as a higher freq ...
") while allowing them to become intoxicated with a lower dose of ethanol. The danger is that the alcoholic will then overdose on ethanol (possibly fatally). If alcoholics instead very carefully reduce their doses to reflect the now slower metabolism, they may get the "rewarding" stimulus of intoxication at lower doses with less adverse "hangover" effects - leading potentially to increased psychological dependency. However, these lower doses may therefore produce less chronic toxicity and provide a harm minimization approach to chronic alcoholism. It is, in essence, the antithesis of a
disulfiram Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects o ...
approach which tries to increase the buildup of acetaldehyde resulting in positive punishment for the patient.
Compliance Compliance can mean: Healthcare * Compliance (medicine), a patient's (or doctor's) adherence to a recommended course of treatment * Compliance (physiology), the tendency of a hollow organ to resist recoil toward its original dimensions (this is a ...
, and adherence, is a substantial problem in disulfiram-based approaches. Disulfiram also has a considerably longer half-life than that of fomepizole, requiring the person to not drink ethanol in order to avoid severe effects. If the person is not adequately managed on a
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
,
barbiturate Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential a ...
,
acamprosate Acamprosate, sold under the brand name Campral, is a medication used along with counselling to treat alcohol use disorder. For label updates seFDA index page for NDA 021431/ref> Acamprosate is thought to stabilize chemical signaling in the brai ...
, or another GABAA receptor agonist, the alcohol withdrawal syndrome, and its attendant, life-threatening risk of
delirium tremens Delirium tremens (DTs) is a rapid onset of confusion usually caused by withdrawal from alcohol. When it occurs, it is often three days into the withdrawal symptoms and lasts for two to three days. Physical effects may include shaking, shiver ...
"DT", may occur. Disulfiram treatment should never be initiated until the risk of DT has been evaluated, and mitigated appropriately. Fomepizole treatment may be initiated while the DT de-titration sequence is still being calibrated based upon the person's withdrawal symptoms and psychological health.


Adverse effects

Common side effects associated with fomepizole use include headache and nausea.


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

Hepatic; the primary metabolite is 4-carboxypyrazole (about 80 to 85% of an administered dose). Other metabolites include the
pyrazoles Pyrazole is an organic compound with the formula C3H3N2H. It is a heterocycle characterized by a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, which are in ortho-substitution. Pyrazole is a weak base, with p''K''b 11.5 ...
4-hydroxymethylpyrazole and the N -glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole. 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
coordination chemistry A coordination complex consists of a central atom or ion, which is usually metallic and is called the ''coordination centre'', and a surrounding array of bound molecules or ions, that are in turn known as ''ligands'' or complexing agents. Man ...
has been studied.


See also

* Alcohol (medicine) *
Disulfiram-like drug A disulfiram-like drug is a drug that causes an adverse reaction to alcohol leading to nausea, vomiting, flushing, dizziness, throbbing headache, chest and abdominal discomfort, and general hangover-like symptoms among others. These effects ...


References


External links

* {{Portal bar , Medicine Alcohol dehydrogenase inhibitors Antidotes Pyrazoles World Health Organization essential medicines Wikipedia medicine articles ready to translate