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Metronidazole

Systematic (IUPAC) name
2-(2- methyl- 5-nitro- 1H- imidazol- 1-yl) ethanol
Identifiers
CAS number	443-48-1
ATC code	A01AB17 , D06BX01, G01AF01, J01XD01, P01AB01, QP51AA01
PubChem	4173
DrugBank	APRD00631
ChemSpider	4029
Chemical data
Formula	C6H9N3O3
Mol. mass	171.15 g/mol
Physical data
Melt. point	159–163 °C (318–325 °F)
Pharmacokinetic data
Bioavailability	100% (oral) 59–94% (rectal)
Metabolism	Hepatic
Half life	6–7 hours
Excretion	Renal (60-80%), biliary (6–15%)
Therapeutic considerations
Pregnancy cat.	B(US) B2 (Au)
Legal status	Prescription Only (S4)(AU) POM(UK) ℞-only(US)
Routes	oral, topical, rectal, IV, vaginal
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Metronidazole (INN) (pronounced /mɛtrəˈnaɪdəzoʊl/) is a nitroimidazole anti-infective medication used mainly in the treatment of infections caused by susceptible organisms, particularly anaerobic bacteria and protozoa. It is marketed by Pfizer under the trade name Flagyl in the US, by Sanofi-Aventis globally under the same tradename, Flagyl, and by various generic manufacturers.

Metronidazole is also used 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).

[edit] Treatment

Metronidazole, taken up by diffusion, is selectively absorbed by anaerobic bacteria and sensitive protozoa. Once taken up by anaerobes, it is non-enzymatically reduced because of lowered ferredoxin, which is produced by the action of pyruvate:ferredoxin oxido-reductase. This reduction causes the production of toxic products to anaerobic cells, and allows for selective accumulation in anaerobes.

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.^[1]

[edit] Indications

Systemic metronidazole is indicated for the treatment of:

[edit] Bacterial

• Bacterial vaginosis, commonly associated with overgrowth of Gardnerella species and coinfective anaerobes (Mobiluncus, Bacteroides), in symptomatic patients
• Pelvic inflammatory disease in conjunction with other antibiotics such as ofloxacin, levofloxacin, or ceftriaxone
• Anaerobic bacterial infections such as Bacteroides fragilis, spp, Fusobacterium spp, Clostridium spp, Peptococcus spp, Peptostreptococcus spp, Prevotella spp, or any other anaerobes in intra-abdominal abscess, peritonitis, empyema, pneumonia, aspiration pneumonia, lung abscess, diabetic foot ulcer, meningitis and brain abscess, bone and joint infections, septicemia, endometritis, tubo-ovarian abscess, or endocarditis
• Pseudomembranous colitis due to Clostridium difficile
• Helicobacter pylori eradication therapy, as part of a multi-drug regimen in peptic ulcer disease

[edit] Protozoal

• Vaginitis due to Trichomonas vaginalis infection^[2] in both symptomatic patients as well as their asymptomatic sexual contacts - always consult the GP and contact all previous partners
• Protozoal infections due to Entamoeba histolytica (Amoebic dysentery or Hepatic abscesses), and Giardia lamblia (Giardiasis) should be treated alone or in conjunction with iodoquinol or diloxanide furoate
• With amphotericin B and certain other drugs, it is used as an adjunct in the attempted treatment of primary amoebic meningoencephalitis caused by Naegleria fowleri infection of the bowels

[edit] Nonspecific

• Prophylaxis for those undergoing potentially contaminated colorectal surgery or appendectomies and may be combined with neomycin
• Acute gingivitis and other dental infections (TGA approved, non-U.S. Food and Drug Administration (FDA) approved)
• Crohn's disease with colonic or perianal involvement (non-FDA approved) - believed to be more effective in combination with ciprofloxacin
• Topical metronidazole is indicated for the treatment of rosacea, and in the treatment of malodorous fungating wounds.^[3]

[edit] Prevention of preterm births

Latest^[when?] paper studying Metronidazole found "Metronidazole therapy before 32 weeks was associated with an increased risk of preterm birth", possibly as a result of "changes in the vaginal flora... seen with vaginal clindamycin or oral metronidazole therapy."^[4]

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.^[5]

Lamont has argued that Metronidazole is not the right antibiotic to administer in these circumstances and was often administered too late to be of use. Clindamycin administered early in the second trimester to women who test positive for bacterial vaginosis seems to be more effective.^[6]

[edit] Adverse effects

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 black hairy tongue, leukopenia, neutropenia, increased risk of peripheral neuropathy and/or CNS toxicity.^[3]

Metronidazole is listed by the International Agency for Research on Cancer (IARC) as a potential human carcinogen. Although some of the testing methods have been questioned, it has been shown to cause cancer in experimental animals.^[7] Yet, metronidazole was shown to be safe in humans.^[7][8] It appears to have a fairly low potential for cancer risk and under most circumstances the benefits of treatment outweigh the risk. Metronidazole is banned in the EU for veterinary use in the feed of animals.^[9]

Earlier studies suggested a relation between metronidazole and various birth defects. Those studies are nowadays considered flawed and more recent studies "do not support a significant increased risk for birth defects or other adverse effects on the fetus."^[10]

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]

[edit] Interaction with alcohol

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,^[11] however there are studies calling that notion into question.^[12] 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,^[13][14] and a possible central toxic serotonin reaction for the alcohol intolerance suggested.^[15]

[edit] Stevens-Johnson Syndrome with Mebendazole

Metronidazole alone rarely causes Stevens-Johnson syndrome but is reported to occur at high rates when combined with Mebendazole.^[16]

[edit] References

[edit] External links

• Metronidazole monograph
• Merck manuals
• [1]