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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 C 6H9N3O3  
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).

Contents

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 by reacting with reduced ferredoxin, which is generated by 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]

Indications

Systemic metronidazole is indicated for the treatment of:

Bacterial

Protozoal

Nonspecific

Prevention of preterm births

Latest 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]

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]

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]

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]

References

  1. ^ Cary Engleberg, N.; Schaechter, Moselio; Dermody, Terry; Dermody, Terence; DiRita, Victor (2007). Schaechter's mechanisms of microbial disease. Philadelphia: Lippincott Williams Wilkins. p. 28. ISBN 0-7817-5342-2.  
  2. ^ Cudmore SL, Delgaty KL, Hayward-McClelland SF, Petrin DP, Garber GE (October 2004). [cmr.asm.org/cgi/content/full/17/4/783 "Treatment of infections caused by metronidazole-resistant Trichomonas vaginalis"]. Clin. Microbiol. Rev. 17 (4): 783–93, table of contents. doi:10.1128/CMR.17.4.783-793.2004. PMID 15489348. PMC 523556. cmr.asm.org/cgi/content/full/17/4/783.  
  3. ^ a b c d e Rossi, Simone(ed). (2006). Rossi S. ed. Australian Medicines Handbook 2006. Australian Medicines Handbook Pty Ltd, Adelaide. ISBN 0-9757919-2-3. OCLC 224831213.  
  4. ^ Carey JC, Klebanoff MA. (April 2005). "Is a change in the vaginal flora associated with an increased risk of preterm birth?". Am J Obstet Gynecol. 192 (4): 1341–6. doi:10.1016/j.ajog.2004.12.069.  
  5. ^ Shennan A, Crawshaw S, Briley A, Hawken J, Seed P, Jones G, et al. (2006). "A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study". BJOG 113 (1): 65–74. doi:10.1111/j.1471-0528.2005.00788.x. PMID 16398774.  
  6. ^ Lamont RF (2005). "Can antibiotics prevent preterm birth—the pro and con debate". BJOG 112(suppl): 67–73. doi:10.1111/j.1471-0528.2005.00589.x. PMID 15715599.  
  7. ^ a b "Metronidazole CAS No. 443-48-1" (PDF). Report on Carcinogens, Eleventh Edition. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s112metr.pdf. Retrieved 2009-12-11.  
  8. ^ Flagyl 375 U.S. Prescribing Information Pfizer (PDF)
  9. ^ "Metronidazole Summary Report EMEA/MRL/173/96-FINAL" (PDF). Committee for Medicinal Products for Veterinary Use (CVMP). European Medicines Agency. July 1997. http://www.emea.europa.eu/pdfs/vet/mrls/017396en.pdf. Retrieved 2009-12-11.  
  10. ^ OTIS: Metronidazole (Flagyl®) and Pregnancy. http://www.otispregnancy.org/pdf/Flagyl.pdf
  11. ^ Stephen J Cina, Roger A Russell, Sandra E Conradi (1996). "Sudden death due to metronidazole/ethanol interaction". American Journal of Forensic Medical Pathology 17 (4): 343–346. doi:10.1097/00000433-199612000-00013.  
  12. ^ Gupta NK, Woodley CL, Fried R (October 1970). "Effect of metronidazole on liver alcohol dehydrogenase". Biochem. Pharmacol. 19 (10): 2805–8. PMID 4320226.  
  13. ^ Williams CS, Woodcock KR (2000). "Do ethanol and metronidazole interact to produce a disulfiram-like reaction?". Ann Pharmacother 34 (2): 255–7. doi:10.1345/aph.19118. PMID 10676835.  "the authors of all the reports presumed the metronidazole-ethanol reaction to be an established pharmacologic fact. None provided evidence that could justify their conclusions"
  14. ^ Visapaa JP, Tillonen JS, Kaihovaara PS, Salaspuro MP (2002). "Lack of disulfiram-like reaction with metronidazole and ethanol". Ann Pharmacother 36 (6): 971–4. doi:10.1345/aph.1A066. PMID 12022894.  
  15. ^ Karamanakos PN, Pappas P, Boumba VA, et al. (2007). "Pharmaceutical agents known to produce disulfiram-like reaction: effects on hepatic ethanol metabolism and brain monoamines". Int. J. Toxicol. 26 (5): 423–32. doi:10.1080/10915810701583010. PMID 17963129.  
  16. ^ Chen KT, Twu SJ, Chang HJ, Lin RS. (2003). "Outbreak of Stevens-Johnson syndrome/toxic epidermal necrolysis associated with mebendazole and metronidazole use among Filipino laborers in Taiwan." Am J Public Health 93(3): 489-492, PMID 12604501, Full text at PMC: 1447769.

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