Download Metronidazole

Metronidazole
Mechanism of action
Metronidazole has nitroimidazole structure.
It is a pro-drug: the nitro group has to be reduced to be activated.
PFOR-dependent
activation
Nitroreductasedependent activation
Pyruvate
Ferredoxin
Reduced
metronidazole
(active)
Acetyl-CoA
Reduced
ferredoxin
Metronidazole
(inactive)
Pyruvate-ferredoxin
oxidoreductase (PFOR)
NADP+
Nitroreductase
NADPH
Alcohol
dehydrogenase E
(ADHE)
Ethanol
Acetate
Pyruvate-ferredoxin oxidoreductase (PFOR), ferredoxin and nitroreductase are present in anaerobic
microbes:
Anaerobic bacteria
Luminal protozoa
Nitroreductase is specific to metronidazole.
Sensitivity to metronidazole is related to PFOR activity of microorganisms.
Selective toxicity of metronidazole is based on the lack of these compounds in mammalian cells.
Reduced derivatives of metronidazole are extremely reactive. They damage DNA, proteins and
membranes of microbae. Metronidazole is bactericidal.
Antimicrobial spectrum
Anaerobic bacteria
Bacteroides fragilis, Clostridia
Protozoa
Entamoeba hystolytica, Giardia lamblia, Trychomonas vaginalis, Gardnerella vaginalis
Resistance
Helicobacter pylori
May have a mutated oxygen-insensitive NADPH nitroreductase.
Trichomonas vaginalis
Decreased expression of ferredoxins.
Giardia lamblia
Decreased permeability to metronidazole and decreased PFOR activity.
Entamoeba hystolytica
Increased expression of superoxide dismutase
Luminal parasites
No resistance.
They are diploid, a single mutation does not render them resistant.
They lack alternative metabolic pathways to PFOR.
P-glycoprotein pumps hydrophobic drugs from their cells, but metronidazole is
hydrophilic.
Pharmacokinetics
Metronidazole enters cells by passive diffusion. It is well absorbed after oral administration.
It may be given i.v., rectally or topically to the vagina.
It is distributed widely including the CNS and abscesses throughout the body.
Metronidazole is metabolized in the liver. It may accumulate in hepatic failure.
Metronidazole inhibits cytochrome enzymes. It enhances the effects of warfarin and phenytoin.
Lithium toxicity may occur when applied together with metronidazole.
Its metabolites are excreted mostly in the urine and partly in the faeces. No dose reduction is
necessary in renal failure.
Clinical application
It is usually used in combination.
Anaerobic and mixed intra-abdominal infections
Aspiration pneumonia
C difficile colitis
Peritonitis
Brain abscess
Bacterial or trichomonal vaginitis
Gardnerella vaginalis infection
Giardiasis
Liver abscess caused by E hystolytica
Metronidazole is active against tissue trophozoites, but not against luminal amoeba.
This may be due to extensive absorption of the drug in the upper GIT and low luminal
concentrations in the colon.
Invasive amoebiasis is treated first with metronidazole followed by drugs active against
intraluminal protozoa (iodoquinol, paramomycin).
Adverse effects
Headache, dizziness, nausea, seizures
Gastrointestinal discomfort, metallic taste, stomatitis, pancreatitis
Peripheral neuropathy
Disulfiram-like effect
Metabolism of ethanol is inhibited.
Dysuria, dark urine
Metronidazole is mutagenic in bacteria and tumorigenic in rodents. It is best avoided during
pregnancy.