Systematic (IUPAC) name | |
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2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol | |
Clinical data | |
Trade names | Flagyl |
AHFS/Drugs.com | monograph |
Pregnancy cat. | B(US) B2 (Au) |
Legal status | Prescription Only (S4) (AU) POM (UK) ℞-only (US) |
Routes | oral, topical, rectal, IV, vaginal |
Pharmacokinetic data | |
Bioavailability | 100% (oral) 59–94% (rectal) |
Metabolism | Hepatic |
Half-life | 6–7 hours |
Excretion | Renal (60-80%), biliary (6–15%) |
Identifiers | |
CAS number | 443-48-1 |
ATC code | A01AB17 , D06BX01, G01AF01, J01XD01, P01AB01, QP51AA01 |
PubChem | CID 4173 |
DrugBank | DB00916 |
ChemSpider | 4029 |
UNII | 140QMO216E |
KEGG | D00409 |
ChEBI | CHEBI:6909 |
ChEMBL | CHEMBL137 |
Chemical data | |
Formula | C6H9N3O3 |
Mol. mass | 171.15 g/mol |
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Physical data | |
Melt. point | 159–163 °C (318–325 °F) |
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Metronidazole (INN) ( /mɛtrəˈnaɪdəzoʊl/) is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal.[1] It is the drug of choice for first episodes of mild-to-moderate Clostridium difficile infection.[2] It is marketed by Pfizer under the trade name Flagyl in the US, by Sanofi-Aventis globally under the same tradename Flagyl, in Pakistan and Bangladesh it is also available with the brand name of Nidagyl manufactured and marketed by Star Laboratories. In Thailand it is marketed as Mepagyl by Thai Nakhorn Patana. They are also marketed in UK by Milpharm Limited and Almus Pharmaceuticals. Metronidazole was developed in 1960.
Metronidazole is used also as a gel preparation in the treatment of the dermatological conditions such as rosacea (Rozex and MetroGel by Galderma) and fungating tumours (Anabact, Cambridge Healthcare Supplies).
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Metronidazole is indicated for the treatment of:
Metronidazole has also been used in women to prevent preterm birth associated with bacterial vaginosis, amongst other risk factors including the presence of cervicovaginal fetal fibronectin (fFN). A randomised controlled trial demonstrated that metronidazole was ineffective in preventing preterm delivery in high-risk pregnant women and, conversely, the incidence of preterm delivery was actually higher in women treated with metronidazole.[4]
In a study it has been found that metronidazole is not the right antibiotic to administer in these circumstances and that it was often administered too late to be of use. Clindamycin administered early in the second trimester to women who test positive for bacterial vaginosis seemed to be more effective.[5]
Metronidazole is not labeled for animal use but is widely used to treat infections of Giardia in dogs, cats, and other companion animals, although it does not reliably clear infection with this organism and is being supplanted by fenbendazole for this purpose in dogs and cats.[6] Metronidazole or simply "Metro" is used in the aquarium hobby to treat ornamental fish as a wide spectrum treatment for bacterial and protozoan infections. It is also used to treat human enteric (gi) and systemic infections. The U.S. Food and Drug Administration (FDA) prohibits the use of metronidazole in food animals.[7]
Common adverse drug reactions (≥1% of patients) associated with systemic metronidazole therapy include: nausea, diarrhea, and/or metallic taste in the mouth. Intravenous administration is commonly associated with thrombophlebitis. Infrequent adverse effects include: hypersensitivity reactions (rash, itch, flushing, fever), headache, dizziness, vomiting, glossitis, stomatitis, dark urine, and/or paraesthesia.[3]
High doses and/or long-term systemic treatment with metronidazole is associated with the development of leukopenia, neutropenia, increased risk of peripheral neuropathy and/or CNS toxicity.[3]
Metronidazole is listed by the US National Toxicology Program (NTP) as reasonably anticipated to be a human carcinogen. Although some of the testing methods have been questioned[citation needed], oral exposure has been shown to cause cancer in experimental animals.[8] The relationship between exposure to metronidazole and human cancer is unclear.[8] One study (Beard et al. 1988) found an excess in lung cancer among women (even after adjusting for smoking), while other studies (IARC 1987; Thapa et al. 1998) found either no increased risk, or a statistically insignificant risk.[8] [9] It appears to have a fairly low potential for cancer risk and under most circumstances the benefits of treatment outweigh the risk. Metronidazole is listed as a possible carcinogen according to the WHO International Agency for Research on Cancer (IARC).[10]
Due to its potential carcinogenic properties, metronidazole is banned in the EU and the USA for veterinary use in the feed of animals and is banned for use in any food animals in the USA.[11][12] In the USA, this type of restriction is covered under the Delaney clause.
Earlier studies suggested a relation between metronidazole and various birth defects. Those studies are now considered flawed and more recent studies "do not support a significant increased risk for birth defects or other adverse effects on the fetus."[13]
Common adverse drug reactions associated with topical metronidazole therapy include local redness, dryness, and/or skin irritation; and eye watering (if applied near eyes).[3]
Toxic levels of metronidazole can cause symmetrical lesions in the brain in the corpus callosum and dentate nuclei. Metronidazole toxicity is rare (though the actual incidence is not known with certainty). Patients present with nausea, vomiting, dysarthria, vertigo, and confusion. Other side effects of the metronidazole can include dry mouth, diarrhea, headache, dizziness, or peripheral neuropathy. An examination of a patient reveals that the patient is confused and has dysarthria (difficult or unclear articulation of speech that is otherwise linguistically normal), ataxia (loss of full control of bodily movements), abnormal eye movements including nystagmus and ophthalmoparesis. Magnetic resonance imaging (MRI) most often shows bilateral symmetric fluid-attenuated inversion recovery (FLAIR) hyperintense lesions of the dentate nuclei (which is one of the deep cerebellar nuclei), as well as symmetric lesions of the corpus callosum and basal ganglia. The brain lesions seen on the MRI rarely enhance and may be Diffusion-Weighted Imaging (DWI) hyperintense. It has a subacute to acute course. Most reports have been seen in patients who receive approximately one gram a day of metronidazole for over 30 days.[14]
Metronidazole can rarely cause central nervous system toxicity; it does not seem to be a dose- or duration-related phenomenon. Most patients will have MRI abnormalities. Prognosis is excellent with metronidazole cessation.[15][16]
Consuming ethanol (alcohol) while using metronidazole has long been thought to have a disulfiram-like reaction with effects that can include nausea, vomiting, flushing of the skin, tachycardia (accelerated heart rate), and shortness of breath,[17] however there are studies calling that notion into question.[18] Consumption of alcohol should be avoided by patients during systemic metronidazole therapy and for at least 48 hours after completion of treatment.[3] However, the mechanism of this reaction in the clinical setting has recently been questioned by some authors,[19][20] and a possible central toxic serotonin reaction for the alcohol intolerance suggested.[21]
Metronidazole alone rarely causes Stevens–Johnson syndrome but is reported to occur at high rates when combined with mebendazole.[22]
It is important to note that serotonin syndrome is not fully understood. The complex drug interaction can happen after a couple days or take up to months. The exact mechanism is not known, a theory of serotonin dysfunction helps explain how the syndrome presents and how it is to be treated. Signs and symptoms are muscle rigidity, headache, elevated blood pressure, and changes in blood chemistry. The only direct treatment is to discontinue the offending drugs. Recently, there have been reported cases of SSRI/SNRI antidepressant drugs and metronidazole induced serotonin syndrome,[21][23] this information is not included on the metronidazole patient information leaflet. SSRI and SNRI antidepressants include Prozac, Lexapro, Celexa, Zoloft, Effexor, Cymbalta, etc.
Metronidazole is available with a prescription under the brand names Flagyl and Protostat. Other brand or generic formulations may also be available.[24]
Metronidazole, taken up by diffusion, is selectively absorbed by anaerobic bacteria and sensitive protozoa. Once taken up by anaerobes, it is non-enzymatically reduced by reacting with reduced ferredoxin, which is generated by pyruvate oxido-reductase. Many of the reduced nitroso intermediates will form sulfinamides and thioether linkages with cystein bearing enzymes deactivating these critical enzymes. As many as 150 separate enzymes are affected.
In addition or alternatively, the metronidazole metabolites are taken up into bacterial DNA, and form unstable molecules. This function only occurs when metronidazole is partially reduced, and because this reduction usually happens only in anaerobic cells, it has relatively little effect upon human cells or aerobic bacteria.[25]
2-Methylimidazole (1) may be prepared via the Debus-Radziszewski imidazole synthesis, or from ethylenediamine and acetic acid, followed by treatment with lime, then Raney nickel. 2-Methylimidazole nitrated to give 2-methyl-4(5)-nitroimidazole (2), which is in turn alkylated with ethylene oxide or 2-chloroethanol to give metronidazole (3):[26][27][28]
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