Metronidazole

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Metronidazole
Systematic (IUPAC) name
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol
Clinical data
Trade namesFlagyl, Filmet
AHFS/Drugs.commonograph
Pregnancy cat.B (US) B2 (Au)
Legal statusPrescription Only (S4) (AU) POM (UK) -only (US)
Routesoral, topical, rectal, IV, vaginal
Pharmacokinetic data
Bioavailability100% (oral)
59–94% (rectal)
MetabolismHepatic
Half-life6–7 hours
ExcretionRenal (60-80%), biliary (6–15%)
Identifiers
CAS number443-48-1 YesY
ATC codeA01AB17 , D06BX01, G01AF01, J01XD01, P01AB01, QP51AA01
PubChemCID 4173
DrugBankDB00916
ChemSpider4029 YesY
UNII140QMO216E N
KEGGD00409 N
ChEBICHEBI:6909 N
ChEMBLCHEMBL137 N
NIAID ChemDB007953
Chemical data
FormulaC6H9N3O3 
Mol. mass171.15 g/mol
Physical data
Melt. point159–163 °C (318–325 °F)
 N (what is this?)  (verify)
 
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Metronidazole
Systematic (IUPAC) name
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol
Clinical data
Trade namesFlagyl, Filmet
AHFS/Drugs.commonograph
Pregnancy cat.B (US) B2 (Au)
Legal statusPrescription Only (S4) (AU) POM (UK) -only (US)
Routesoral, topical, rectal, IV, vaginal
Pharmacokinetic data
Bioavailability100% (oral)
59–94% (rectal)
MetabolismHepatic
Half-life6–7 hours
ExcretionRenal (60-80%), biliary (6–15%)
Identifiers
CAS number443-48-1 YesY
ATC codeA01AB17 , D06BX01, G01AF01, J01XD01, P01AB01, QP51AA01
PubChemCID 4173
DrugBankDB00916
ChemSpider4029 YesY
UNII140QMO216E N
KEGGD00409 N
ChEBICHEBI:6909 N
ChEMBLCHEMBL137 N
NIAID ChemDB007953
Chemical data
FormulaC6H9N3O3 
Mol. mass171.15 g/mol
Physical data
Melt. point159–163 °C (318–325 °F)
 N (what is this?)  (verify)

Metronidazole (INN) /mɛtrəˈndəzl/ (Flagyl,FILMET and others) is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal.[1] It is the drug of choice for first episodes of mild-to-moderate Clostridium difficile infection.[2] It is marketed in the United States by Pfizer and globally by Sanofi under the trade name Flagyl, and is also sold under other brand names. In Bangladesh it is marketed by Beximco Pharma under the trade name of Filmet. Metronidazole was developed in 1960.

Metronidazole is used also 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).

Medical uses[edit]

Metronidazole can be indicated for the treatment of:

Bacterial[edit]

Protozoal[edit]

Nonspecific[edit]

Preterm births[edit]

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.[4]

In a study it has been found that metronidazole is not the right antibiotic to administer in these circumstances and that it was often administered too late to be of use. Clindamycin administered early in the second trimester to women who test positive for bacterial vaginosis seemed to be more effective.[5]

Veterinary use[edit]

Metronidazole is not labeled for animal use but is widely used to treat infections of Giardia in dogs, cats, and other companion animals, although it does not reliably clear infection with this organism and is being supplanted by Fenbendazole for this purpose in dogs and cats.[6] Metronidazole is also used for the management of chronic inflammatory bowel disease in cats and dogs.[7] Another common usage is the treatment of systemic and/or GI clostridial infections in horses. Metronidazole or simply "Metro" is used in the aquarium hobby to treat ornamental fish and as a wide spectrum treatment for bacterial and protozoan infections in reptiles and amphibians. It is also used to treat human enteric (gi) and systemic infections. In general, the veterinary community may use metronidazole for any potentially susceptible anaerobic infection. The U.S. Food and Drug Administration (FDA) suggests that it only be used when necessary because it has been shown to be carcinogenic in mice and rats as well as the microbes that it is prescribed to fight. The main reason that it should be used sparingly, however, is the fact that it still works, thus it shouldn't be abused lest the microbes develop a resistance.[8][9]

Adverse effects[edit]

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

Metronidazole is listed by the US National Toxicology Program (NTP) as reasonably anticipated to be a human carcinogen.[10] Although some of the testing methods have been questioned, oral exposure has been shown to cause cancer in experimental animals.[10] The relationship between exposure to metronidazole and human cancer is unclear.[10] One study (Beard et al. 1988) found an excess in lung cancer among women (even after adjusting for smoking), while other studies (IARC 1987; Thapa et al. 1998) found either no increased risk, or a statistically insignificant risk.[10] [11] Metronidazole is listed as a possible carcinogen according to the WHO International Agency for Research on Cancer (IARC).[12]

Due to its potential carcinogenic properties, metronidazole is banned in the EU and the USA for veterinary use in the feed of animals and is banned for use in any food animals in the USA.[13][14] In the USA, this type of restriction is covered under the Delaney clause.

Earlier studies suggested a relation between metronidazole and various birth defects. Those studies are now considered flawed and more recent studies "do not support a significant increased risk for birth defects or other adverse effects on the fetus."[15]

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]

Central nervous system[edit]

Metronidazole toxicity is rare (though the actual incidence is not known with certainty). Toxic levels of metronidazole can cause symmetrical lesions in the brain in the corpus callosum and dentate nuclei. Patients present with nausea, vomiting, dysarthria, vertigo, and confusion. Other side effects of the metronidazole can include dry mouth, diarrhea, headache, dizziness, or peripheral neuropathy. An examination of a patient reveals that the patient is confused and has dysarthria (difficult or unclear articulation of speech that is otherwise linguistically normal), ataxia (loss of full control of bodily movements), abnormal eye movements including nystagmus and ophthalmoparesis.

Magnetic resonance imaging (MRI) most often shows bilateral symmetric hyperintense lesions of the dentate nuclei in FLAIR (fluid-attenuated inversion recovery) sequences, as well as symmetric lesions of the corpus callosum and basal ganglia. Most reports have been seen in patients who receive approximately one gram a day of metronidazole for over 30 days.[16][17][18]

Interaction with alcohol[edit]

Consuming ethanol (alcohol) while taking 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.[19] Typically a 2006 Medicines Handbook warns that consumption of alcohol should be avoided by patients during systemic metronidazole therapy and for at least 48 hours after completion of treatment.[3] However there are studies calling into question the mechanism of the interaction of alcohol and metronidazole,[20] ,[21][22] and a possible central toxic serotonin reaction for the alcohol intolerance suggested.[23] Metronidazole is also generally thought to inhibit the liver metabolism of propylene glycol (found in some foods, medicines and in many electronic cigarette e-liquids), and thus propylene glycol may potentially have similar interaction effects with metronidazole.

Stevens–Johnson syndrome[edit]

Metronidazole alone rarely causes Stevens–Johnson syndrome but is reported to occur at high rates when combined with mebendazole.[24]

Serotonin syndrome[edit]

Serotonin syndrome has been reported with metronidazole. Symptoms may appear within minutes of oral dosage, and/or days to months. Signs and symptoms may include: increased heart rate, shivering, sweating, dilated pupils, twitching, over-responsive reflexes, hyperthermia, fever, confusion, hyper-vigilance, agitation, muscle rigidity, headache, elevated blood pressure, and changes in blood chemistry. The only direct treatment is to discontinue the offending drugs.[23][25]

Mechanism of action[edit]

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 oxido-reductase. Many of the reduced nitroso intermediates will form sulfinamides and thioether linkages with cysteine-bearing enzymes, thereby deactivating these critical enzymes. As many as 150 separate enzymes are affected.

In addition or alternatively, 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.[26]

Synthesis[edit]

2-Methylimidazole (1) may be prepared via the Debus-Radziszewski imidazole synthesis, or from ethylenediamine and acetic acid, followed by treatment with lime, then Raney nickel. 2-Methylimidazole nitrated to give 2-methyl-4(5)-nitroimidazole (2), which is in turn alkylated with ethylene oxide or 2-chloroethanol to give metronidazole (3):[27][28][29]

Synthesis of metronidazole.png

References[edit]

  1. ^ a b c d "Metronidazole monograph". drugs.com. 
  2. ^ Cohen, S. H.; Gerding, D. N.; Johnson, S.; Kelly, C. P.; Loo, V. G.; McDonald, L.  C.; Pepin, J.; Wilcox, M. H.; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America (2010). "Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA)". Infection Control and Hospital Epidemiology 31 (5): 431–455. doi:10.1086/651706. PMID 20307191.  edit
  3. ^ a b c d e Rossi, Simone, ed. (2006). Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook Pty. ISBN 978-0-9757919-2-9. OCLC 224831213. [page needed]
  4. ^ Shennan, A.; Crawshaw, S.; Briley, A.; Hawken, J.; Seed, P.; Jones, G.; Poston, L. (2005). "General obstetrics: A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: The PREMET Study". BJOG: An International Journal of Obstetrics and Gynaecology 113 (1): 65–74. doi:10.1111/j.1471-0528.2005.00788.x. PMID 16398774.  edit
  5. ^ Lamont, R. F. (2005). "Can antibiotics prevent preterm birth-the pro and con debate". BJOG: An International Journal of Obstetrics and Gynaecology 112 (Suppl 1): 67–73. doi:10.1111/j.1471-0528.2005.00589.x. PMID 15715599.  edit
  6. ^ Barr, S. C.; Bowman, D. D.; Heller, R. L. (1994). "Efficacy of fenbendazole against giardiasis in dogs". American Journal of Veterinary Research 55 (7): 988–990. PMID 7978640.  edit
  7. ^ Hoskins, J. D. (Oct 1, 2001). "Advances in managing inflammatory bowel disease". DVM Newsmagazine. Retrieved 2013-12-28. 
  8. ^ Plumb, D. C. (2008). Veterinary Drug Handbook (6th ed.). Wiley. ISBN 0-8138-2056-1. 
  9. ^ "Metronidazole". Drugs.com. 
  10. ^ a b c d "Metronidazole CAS No. 443-48-1" (pdf). Report on Carcinogens, Twelfth Edition (2011). U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Retrieved 2011-10-28. 
  11. ^ "Flagyl 375 U.S. Prescribing Information" (pdf). Pfizer. 
  12. ^ International Agency for Research on Cancer (IARC) (May 2010). "Agents Classified by the IARC Monographs, Volumes 1–100" (PHP). World Health Organization. Retrieved 2010-06-06. 
  13. ^ Committee for Medicinal Products for Veterinary Use (CVMP) (July 1997). "Metronidazole Summary Report EMEA/MRL/173/96-FINAL" (pdf). European Medicines Agency. Retrieved 2009-12-11. 
  14. ^ "Restricted and Prohibited Drugs in Food Animals". Food Animal Residue Avoidance Databank. U.S. Food and Drug Administration. 2013. Retrieved 2013-12-28. 
  15. ^ "Metronidazole (Flagyl) and Pregnancy" (pdf). OTIS pregnancy. 
  16. ^ Aaron Lord. Department of Neurology, Columbia University. Case Report.
  17. ^ Kuriyama, A.; Jackson, J. L.; Doi, A.; Kamiya, T. (2011). "Metronidazole-Induced Central Nervous System Toxicity". Clinical Neuropharmacology 34 (6): 1. doi:10.1097/WNF.0b013e3182334b35. PMID 21996645.  edit
  18. ^ Sinha, S.; Pramod, A.; Sinha, P. S.; Saini, A. B.; Mahadevan, J.; Bharath, K.; Bindu, J.; Yasha, R. D.; Taly, T. C. (2011). "Clinical, neuroimaging and pathological features of 5-nitroimidazole-induced encephalo-neuropathy in two patients: Insights into possible pathogenesis". Neurology India 59 (5): 743–747. doi:10.4103/0028-3886.86552. PMID 22019662.  edit
  19. ^ Cina, S. J.; Russell, R. A.; Conradi, S. E. (1996). "Sudden death due to metronidazole/ethanol interaction". The American Journal of Forensic Medicine and Pathology 17 (4): 343–346. PMID 8947362.  edit
  20. ^ Gupta, N. K.; Woodley, C. L.; Fried, R. (1970). "Effect of metronidazole on liver alcohol dehydrogenase". Biochemical Pharmacology 19 (10): 2805–2808. doi:10.1016/0006-2952(70)90108-5. PMID 4320226.  edit
  21. ^ Williams, C. S.; Woodcock, K. R. (2000). "Do ethanol and metronidazole interact to produce a disulfiram-like reaction?". The Annals of Pharmacotherapy 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" 
  22. ^ Visapää, J. P.; Tillonen, J. S.; Kaihovaara, P. S.; Salaspuro, M. P. (2002). "Lack of disulfiram-like reaction with metronidazole and ethanol". The Annals of Pharmacotherapy 36 (6): 971–974. PMID 12022894.  edit
  23. ^ a b Karamanakos, P.; Pappas, P.; Boumba, V.; Thomas, C.; Malamas, M.; Vougiouklakis, T.; Marselos, M. (2007). "Pharmaceutical Agents Known to Produce Disulfiram-Like Reaction: Effects on Hepatic Ethanol Metabolism and Brain Monoamines". International Journal of Toxicology 26 (5): 423–432. doi:10.1080/10915810701583010. PMID 17963129.  edit
  24. ^ Chen, K. T.; Twu, S. J.; Chang, H. J.; Lin, R. S. (2003). "Outbreak of Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis Associated with Mebendazole and Metronidazole Use Among Filipino Laborers in Taiwan". American Journal of Public Health 93 (3): 489–492. PMC 1447769. PMID 12604501.  edit
  25. ^ Karamanakos, P. N. (2008). "The possibility of serotonin syndrome brought about by the use of metronidazole". Minerva Anestesiologica 74 (11): 679. PMID 18971895.  edit
  26. ^ Eisenstein, B. I.; Schaechter, M. (2007). "DNA and Chromosome Mechanics". In Schaechter, M.; Engleberg, N. C.; DiRita, V. J. et al. Schaechter's Mechanisms of Microbial Disease. Hagerstown, MD: Lippincott Williams & Wilkins. p. 28. ISBN 978-0-7817-5342-5. 
  27. ^ Ebel, K.; Koehler, H.; Gamer, A. O.; Jäckh, R. (2005), "Imidazole and Derivatives", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a13_661 
  28. ^ Actor, P.; Chow, A. W.; Dutko, F. J.; McKinlay, M. A. (2005), "Chemotherapeutics", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a06_173 
  29. ^ Kraft, M. Ya.; Kochergin, P. M.; Tsyganova, A. M.; Shlikhunova, V. S. (1989). "Synthesis of metronidazole from ethylenediamine". Pharmaceutical Chemistry Journal 23 (10): 861–863. doi:10.1007/BF00764821. 

External links[edit]