Source: Υπουργείο Υγείας (CY) Revision Year: 2017 Publisher: Medochemie Ltd, 1-10 Constantinoupoleos Street 3011, Cyprus
Pharmacotherapeutic group: Antibacterials for systemic use, Imidazole derivatives
ATC code: J01XD01
Metronidazole is a 5-nitroimidazole derivative with activity against anaerobic bacteria and protozoa. It is active against several protozoa, including Balantidium coli, Blastocystis hominis, Entamoeba histolytica, Giardia intestinalis (previously G. lamblia), and Trichomonas vaginalis.
Most obligate anaerobic bacteria are sensitive to metronidazole in vitro as are some facultative anaerobes, the action is bactericidal. It has activity against Bacteroides sp., Fusobacterium sp., Veillonella sp., Clostridium sp., Eubacterium sp., Peptococcus sp., and Peptostreptococcus sp. It has activity against the facultative anaerobes Gardnerella vaginalis, some strains of Campylobacter sp., including Campylobacter fetus jejuni, and Helicobacter pylori. Strains of Actinomyces sp. and Propionibacterium sp. are often resistant. Minimum inhibitory concentrations for susceptible anaerobic organisms are usually in the range 0.1g/ml–8.0 g/ml. The oxidative metabolites of metronidazole also have antibacterial action, with the hydroxy metabolite usually having MIC values within one dilution of the parent compound, the acid metabolite is much less active.
The mode of action of metronidazole has not been fully elucidated; it is thought that bacterial nitroreductase reduces it to an unstable intermediate, with the nitro group of metronidazole acting as an electron acceptor, which then interacts with bacterial DNA, preventing further replication, due to loss of helical structure and consequent inhibition of synthesis. It is known that anaerobic conditions are important for optimal activity.
There has been some development of resistance to metronidazole in susceptible species, but it is generally only an occasional problem.
Following intravenous administration, peak steady state plasma levels of approximately 25 g/ml, with trough levels of approximately 18 g/ml, are reported following a loading dose of 15 mg/kg bodyweight followed by 7.5 mg/kg every six hours. Following oral administration it is readily and almost completely absorbed from the gastrointestinal tract, with peak plasma concentrations occurring after about one hour. Metronidazole is widely distributed, appearing in most body tissues and fluids, including bile, bone, breast milk, cerebral abscesses, the cerebrospinal fluid, liver, including hepatic abscesses, saliva, seminal and vaginal fluid, at levels similar to plasma levels. It crosses the placental barrier and rapidly enters the foetal circulation.
It is not more than 20% plasma protein bound.
Metronidazole undergoes oxidative hepatic metabolism, by side chain oxidation and glucuronide formation. The major oxidative metabolites are the hydroxy metabolite (1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole) with significant antimicrobial activity and found in plasma and urine, and the acid metabolite (2-methyl-5-nitroimidazole-1-acetic acid) detected in urine and with much less antibacterial activity. Small quantities of reduced metabolites, probably produced by the gastrointestinal flora, are detected in urine, these include acetamide and N-(2-hydroxyethyl)oxamic acid.
The elimination half life of metronidazole is approximately 8 hours, the hydroxy metabolite has a slightly longer half life.
Metronidazole is principally excreted in the urine, mainly as metabolites, a small proportion of the dose appears in the faeces.
Metronidazole has been shown to be carcinogenic in the mouse and in the rat following chronic oral administration however similar studies in the hamster have given negative results. Epidemiological studies have provided no clear evidence of an increased carcinogenic risk in humans.
Metronidazole has been shown to be mutagenic in bacteria in vitro. In studies conducted in mammalian cells in vitro as well as in rodent or humans in vivo, there was inadequate evidence of a mutagenic effect of metronidazole, with some studies reporting mutagenic effects, while others studies were negative.
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