Chemical formula: C₆H₉N₃O₃ Molecular mass: 171.154 g/mol PubChem compound: 4173
Metronidazole belongs to the group of nitroimidazoles. It is reduced in sensitive protozoa and strictly anaerobic bacteria with formation of acetamide and N-(2-hydroxyethyl)-oxamid acid. Interaction with DNA leads to inhibition of the nucleic acid synthesis of the micro-organisms concerned, which results in the death of these agents.
There is no parallel resistance to other antibacterial substances.
When applied topically metronidazole is active against the inflammatory aspect of rosacea.
Metronidazole is an anti-infectious drug belonging to the pharmacotherapeutic group of nitroimidazole derivatives, which have effect mainly on strict anaerobes. This effect is probably caused by interaction with DNS and different metabolites.
Metronidazole has antibacterial and antiprotozoal actions and is effective against anaerobic bacteria and against Trichomonas vaginalis and other protozoa including Entamoeba histolytica, Gardia lamblia and anaerobic bacteria.
The MIC breakpoints separating susceptible from intermediately susceptible and intermediately susceptible from resistant organisms are as following:
S≤4 mg/l and R>4 mg/l
The prevalence of acquired resistance may vary geographically and with time for selected species and local information is desirable, particularly when treating severe infections. This information gives only approximate guidance on probabilities whether microorganisms will be susceptible to Metronidazole or not.
Suscetible:
Gram negative aerobes:
Helicobacter pylori
Anaerobes:
Bacteroides fragilis
Bifidobacterium>>resistant (70%)
Bilophila
Clostridium
Clostridium difficile
Clostridium perfringens
Eubacterium
Fusobacterium
Peptostreptococcus
Prevotella
Porphyromonas
Veillonella
Resistant:
Gram positive aerobes:
Actinomyces
Anaerobes:
Mobiluncus
Propionibacterium acnes
Antiparasitic activity:
Entamoeba histolytica
Giardia intestinalis
Trichomonas vaginalis
Cross–resistance with tindazol occurs.
Metronidazole is readily absorbed following administration by mouth and bioavailability is 90-100%. Peak plasma concentrations of approximately 5µg/ml and 10µg/ml are achieved an average of 1-2 hours after single doses of 250mg and 500mg respectively. Some accumulation and consequently higher concentrations occur when multiple doses are given. Absorption may be delayed, but is not reduced overall, by administration with food.
Metronidazole is widely distributed. It appears in most body tissues and fluids. It also crosses the placenta and rapidly enters foetal circulation. No more than 20% is bound to plasma proteins.
After administration of a single 500 mg dose, mean Metronidazole peak plasma concentrations of ca. 14–18 μg/ml are reached at the end of a 20 minute infusion. 2-hydroxy-metabolite peak plasma concentrations of ca. 3 μg/ml are obtained after a 1 g single i.v. dose. Steady state Metronidazole plasma concentrations of about 17 and 13 μg/ml are reached after administration of Metronidazole every 8 or 12 hours, respectively.
Plasma protein binding is less than 10%, and the volume of distribution 1.1 ± 0.4 l/kg.
Metronidazole is metabolised in the liver by side-chain oxidation and glucuronide formation.
The plasma elimination half-life of metronidazole is about 6-9 hours; that of the hydroxy metabolite is slightly longer. The half-life of metronidazole is reported to be longer in neonates and in patients with severe liver disease.
More than 50% of the administered dose is excreted in the urine, as unchanged metronidazole (ca. 20% of the dose) and its metabolites. About 20% of the dose is excreted with faeces. Clearance is 1.3 ± 0.3 ml/min/kg, while renal clearance is about 0.15 ml/min/kg. The plasma elimination half-life of Metronidazole is ca. 8 hours, and of the 2-hydroxy-metabolite ca. 10 hours.
The plasma elimination half-life of metronidazole is not influenced by renal impairment, however this may be increased for 2-hydroxy- and an acetic acid metabolite. In the case of haemodialysis, metronidazole is rapidly excreted and the plasma elimination half-life is decreased to ca. 2.5 h. Peritoneal dialysis does not appear to affect the elimination of Metronidazole or its metabolites compared to patients with renal impairment.
In patients with impaired liver function, the metabolism of metronidazole is expected to decrease, leading to an increase in the plasma elimination half-life. In patients with severe liver impairment, clearance may be decreased up to ca. 65%, resulting in an accumulation of metronidazole in the body.
The systemic concentration of metronidazole following topical administration of metronidazole cream to 18 healthy volunteers ranged from 19 ng/ml to 107 ng/ml with a mean Cmax of 49 ng/ml i.e. 600 times lower than after 2 g oral administration.
The tmax for the topical formulation was 8.9 hours. The absorption rate-limited half life for metronidazole is 33 hours. The oral half life of metronidazole is approximately 8 hours.
Following oral administration, metronidazole is absorbed speedily and almost completely with maximum serum levels after 1-2 hours. If administered rectally, approximately 80% of the substance is available systematically and the serum maximum is reached after approximately 4 hours. Following vaginal administration only approximately 20% are found in the serum; in this case the maximum is reached later, after 8–24 hours. The serum half life is about 8 (6 to 10) hours. Several metabolites are formed in the human organism; the hydroxymetabolite (1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole) and the “acidic” metabolite (2-methyl-5-nitroimidazole-1-yl-acetic acid) are the main metabolites.
Approximately 80% of the substance is excreted renally, the not metabolised share being less than 10%. Small amounts (ca.6%) are also excreted via the liver. Renal insufficiency prolongs excretion only insignificantly. In the case of severe hepatic insufficiency a delayed elimination must be expected. In patients with highly reduces liver function the half-life can be prolonged to up to 30 hours. Protein binding is less than 20%. The apparent volume of distribution is ca. 36 l.
Acute toxicity was tested in mice in two different routes of administration. If administered orally, the LD50 values were 3 800 mg/kg body weight and if administered intraperitoneally they were 3 950 mg/kg body weight. Thus, acute toxicity is very low.
No cases of acute toxicity in humans were known. The toxic blood level is stated to be 200 µg/ml, which is 10-fold higher than taken according to the intended oral use.
In chronic toxicity studies no side effects could be observed in rats after administration of metronidazole for 26 to 80 weeks. Only at doses of 300 to 600 mg/kg body weight and day did testis dystrophy and prostate atrophy occur. Toxic effects in dogs receiving 75 mg/kg body weight and day were expressed as ataxia and tremor. Investigations in monkeys showed a dose-dependent increase in hepatic cell degeneration after administration of 45, 100 and/or 225 mg/kg body weight and day for one year.
18 mg/kg/day were stated as being the lowest toxic dose at 8 weeks continuous oral administration to humans. Cholestatic hepatosis and peripheral neuropathy are generally rare side effects.
Following nitroreduction, metronidazole acts mutagenic in bacteria. Methodologically valid investigation yielded non indication of a mutagenic effect in mammalian cells in vitro and in vivo. Investigation in lymphocytes of patients treated with metronidazole yielded no relevant indications of DNA-damaging effects.
There are indications that metronidazole has tumorigenic effects in rats and mice. The increase rate of lung tumours after oral administration to mice is especially worth mentioning. There does not appear to be a connection with genotoxic mechanism of action since no increased mutation rates were observed in various organs including the lung of transgenic mice after administration of high doses of metronidazole.
After intra peritoneal administration of metronidazole (15 µg/g body weight) to hairless mice for 4 weeks an increase in UV-induced skin tumours was observed.
The significance of these carcinogenicity findings for cutaneous treatment of rosacea with metronidazole cream in humans remains unclear, especially as decades of systemic use of metronidazole in humans have yielded no indications of an increase risk of cancer. Nevertheless, patients should be advised to avoid direct exposure of the treated skin areas to sun light if possible.
Animal experiments did not show any teratogenic or other embryotoxic effects in rats at doses of up to 200 mg/kg body weight and in rabbits up to 150 mg/kg body weight per day.
In a local tolerance study metronidazole cream was considered slightly irritant, without any systemic toxicity. Skin sensitisation power of metronidazole cream has been found to be very low, and no phototoxicity or photosensitization has been observed.
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