'{{Short description|Antibiotic and antiprotozoal medication}} {{Use dmy dates|date=December 2023}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Watchedfields = changed | verifiedrevid = 699169263 | image = Metronidazole.svg | width = 160 | alt = | image2 = Metronidazole 3D 1w3r.png | width2 = 160 | alt2 = | caption = <!-- Clinical data --> | pronounce = | tradename = Flagyl | Drugs.com = {{drugs.com|monograph|metronidazole}} | MedlinePlus = a689011 | DailyMedID = Metronidazole | pregnancy_AU = B2 | pregnancy_AU_comment = <ref name="Preg2017" /> | pregnancy_category = | routes_of_administration = [[Oral administration|By mouth]], [[Topical administration|topical]], [[Rectal administration|rectal]], [[intravenous]], [[Intravaginal administration|vaginal]] | class = | ATC_prefix = A01 | ATC_suffix = AB17 | ATC_supplemental = {{ATC|D06|BX01}}, {{ATC|G01|AF01}}, {{ATC|J01|XD01}}, {{ATC|P01|AB01}}, {{ATCvet|P51|CA01}} <!-- Legal status --> | legal_AU = S4 | legal_AU_comment = <ref>https://www.tga.gov.au/resources/prescription-medicines-registrations/metronidamed-medsurge-pharma-pty-ltd</ref> | legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = | legal_DE = <!-- Anlage I, II, III or Unscheduled --> | legal_DE_comment = | legal_NZ = <!-- Class A, B, C --> | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="NIH" /><ref name="DailyMed-2023-2">{{cite web | title=Metronidazole tablet | website=DailyMed | date=30 January 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d7455566-16aa-488a-af2a-93b55a04c02f | access-date=5 July 2023 | archive-date=6 September 2023 | archive-url=https://web.archive.org/web/20230906080325/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d7455566-16aa-488a-af2a-93b55a04c02f | url-status=live }}</ref><ref name="DailyMed-2023-3">{{cite web | title=Metronidazole Vaginal Gel, 0.75%- metronidazole gel | website=DailyMed | date=17 June 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=63ed1e7e-d264-4e35-af83-ec37fa5b06d1 | access-date=5 July 2023 | archive-date=6 September 2023 | archive-url=https://web.archive.org/web/20230906080325/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=63ed1e7e-d264-4e35-af83-ec37fa5b06d1 | url-status=live }}</ref> | legal_EU = | legal_EU_comment = | legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> | legal_UN_comment = | legal_status = <!-- For countries not listed above --> <!-- Pharmacokinetic data --> | bioavailability = 80% (by mouth), 60–80% (rectal), 20–25% (vaginal)<ref name=MSR>{{cite web|title=Flagyl, Flagyl ER (metronidazole) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=3 April 2014|url=http://reference.medscape.com/drug/flagyl-metronidazole-342566#showall|url-status=live|archive-url=https://web.archive.org/web/20140407080028/http://reference.medscape.com/drug/flagyl-metronidazole-342566#showall|archive-date=7 April 2014 }}</ref><ref name = MD>{{cite web|title=Metronidazole|work=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|date=14 January 2014|access-date=3 April 2014|url=http://www.medicinescomplete.com/mc/martindale/current/ms-16893-c.htm| veditors = Brayfield A }}{{dead link|date=September 2019}}</ref><ref name="Pharmaceutical Press-2017">{{cite book | veditors = Brayfield A | title=Martindale: The Complete Drug Reference | edition=39th | year=2017 | publisher=Pharmaceutical Press | location=London | isbn= 978-0-85711-309-2 }}</ref> | protein_bound = 20%<ref name = MSR/><ref name = MD/> | metabolism = [[Liver]]<ref name = MSR/><ref name = MD/> | metabolites = [[Hydroxymetronidazole]] | onset = | elimination_half-life = 8 hours<ref name = MSR/><ref name = MD/> | duration_of_action = | excretion = Urine (77%), faeces (14%)<ref name = MSR/><ref name = MD/> <!-- Identifiers --> | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 443-48-1 | CAS_supplemental = | PubChem = 4173 | IUPHAR_ligand = | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00916 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 4029 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 140QMO216E | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00409 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 6909 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 137 | NIAID_ChemDB = 007953 | PDB_ligand = 2MN | synonyms = <!-- Chemical and physical data --> | IUPAC_name = 2-(2-Methyl-5-nitro-1''H''-imidazol-1-yl)ethanol | C=6 | H=9 | N=3 | O=3 | SMILES = OCCn1c(C)ncc1[N+](=O)[O-] | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C6H9N3O3/c1-5-7-4-6(9(11)12)8(5)2-3-10/h4,10H,2-3H2,1H3 | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = VAOCPAMSLUNLGC-UHFFFAOYSA-N | density = | density_notes = | melting_point = 159 | melting_high = 163 | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }} <!-- Definition and uses --> '''Metronidazole''', sold under the brand name '''Flagyl''' among others, is an [[antibiotic]] and [[antiprotozoal medication]].<ref name=AHFS2015/> It is used either alone or with other antibiotics to treat [[pelvic inflammatory disease]], [[endocarditis]], and [[bacterial vaginosis]].<ref name=AHFS2015/> It is effective for [[dracunculiasis]], [[giardiasis]], [[trichomoniasis]], and [[amebiasis]].<ref name=AHFS2015/> It is an option for a first episode of mild-to-moderate [[Clostridioides difficile infection|''Clostridioides difficile'' colitis]] if [[vancomycin]] or [[fidaxomicin]] is unavailable.<ref name=AHFS2015/><ref name="pmid29462280">{{cite journal | vauthors = McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Shaklee Sammons J, Sandora TJ, Wilcox MH | title = Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) | journal = Clinical Infectious Diseases | volume = 66 | issue = 7 | pages = e1–e48 | date = March 2018 | pmid = 29462280 | pmc = 6018983 | doi = 10.1093/cid/cix1085 }}</ref> Metronidazole is available [[oral administration|orally]] (by mouth), as a cream or gel, and by slow [[intravenous infusion]] (injection into a vein).<ref name="AHFS2015">{{cite web|title=Metronidazole|url=https://www.drugs.com/monograph/metronidazole.html|publisher=The American Society of Health-System Pharmacists|access-date=31 July 2015|url-status=live|archive-url=https://web.archive.org/web/20150906002140/http://www.drugs.com/monograph/metronidazole.html|archive-date=6 September 2015 }}</ref><ref name="NIH">{{cite web | title=Metronidazole injection, solution | website=DailyMed | date=16 January 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3dc5f411-3312-4add-8198-161eed98132b | access-date=5 July 2023 | archive-date=6 September 2023 | archive-url=https://web.archive.org/web/20230906075601/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3dc5f411-3312-4add-8198-161eed98132b | url-status=live }}</ref> <!-- Side effects --> Common side effects include [[nausea]], [[Dysgeusia|a metallic taste]], [[Anorexia (symptom)|loss of appetite]], and headaches.<ref name=AHFS2015/> Occasionally [[seizure]]s or allergies to the medication may occur.<ref name=AHFS2015/> Some state that metronidazole should not be used in early [[pregnancy]], while others state doses for trichomoniasis are safe.<ref name=Preg2017/>{{Weasel inline|date=July 2023}} Metronidazole is generally considered compatible with [[breastfeeding]].<ref name="Preg2017">{{cite web|title=Metronidazole Use During Pregnancy|url=https://www.drugs.com/pregnancy/metronidazole.html|website=www.drugs.com|access-date=1 January 2017|url-status=live|archive-url=https://web.archive.org/web/20170101163010/https://www.drugs.com/pregnancy/metronidazole.html|archive-date=1 January 2017 }}</ref><ref name="SPS - Specialist Pharmacy Service">{{cite web |title=Safety in Lactation: Metronidazole and tinidazole |url=https://www.sps.nhs.uk/articles/safety-in-lactation-metronidazole-and-tinidazole/ |website=SPS - Specialist Pharmacy Service |access-date=22 February 2020 |archive-date=21 February 2020 |archive-url=https://web.archive.org/web/20200221162641/https://www.sps.nhs.uk/articles/safety-in-lactation-metronidazole-and-tinidazole/ |url-status=live }}</ref> <!-- History, society and culture --> Metronidazole began to be commercially used in 1960 in France.<ref name="Corey-2013">{{cite book| vauthors = Corey EJ |title=Drug discovery practices, processes, and perspectives|date=2013|publisher=John Wiley & Sons|location=Hoboken, N.J.|isbn=978-1-118-35446-9|page=27|url=https://books.google.com/books?id=E6Dv5XsXU-IC&pg=PA27|url-status=live|archive-url=https://web.archive.org/web/20170908135757/https://books.google.com/books?id=E6Dv5XsXU-IC&pg=PA27|archive-date=8 September 2017 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> It is available in most areas of the world.<ref name="Trichomoniasis treatment in women-2003">{{cite web| vauthors = Schmid G |title=Trichomoniasis treatment in women|url=http://apps.who.int/rhl/rti_sti/gscom/en/|access-date=1 August 2015|date=28 July 2003|url-status=dead|archive-url=https://web.archive.org/web/20150801004047/http://apps.who.int/rhl/rti_sti/gscom/en/|archive-date=1 August 2015 }}</ref> In 2022, it was the 133rd most commonly prescribed medication in the United States, with more than 4{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Metronidazole Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Metronidazole | access-date = 30 August 2024 }}</ref> ==Medical uses== [[File:Metronidazole Aurobindo tube.jpg|left|thumb|A tube of metronidazole cream]] Metronidazole has activity against some [[protozoan]]s and most [[anaerobic bacteria]] (both [[Gram-negative bacteria|Gram-negative]] and [[Gram-positive bacteria|Gram-positive]] classes) but not the [[aerobic bacteria]].<ref name="pmid9360057">{{cite journal |vauthors=Freeman CD, Klutman NE, Lamp KC |title=Metronidazole. A therapeutic review and update |journal=Drugs |volume=54 |issue=5 |pages=679–708 |date=November 1997 |pmid=9360057 |doi=10.2165/00003495-199754050-00003}}</ref><ref name="pmid20067388">{{cite journal |vauthors=Löfmark S, Edlund C, Nord CE |title=Metronidazole is still the drug of choice for treatment of anaerobic infections |journal=Clin Infect Dis |volume=50 |issue= Suppl 1|pages=S16–23 |date=January 2010 |pmid=20067388 |doi=10.1086/647939|doi-access=free }}</ref> Metronidazole is primarily used to treat: [[bacterial vaginosis]], [[pelvic inflammatory disease]] (along with other antibacterials like [[ceftriaxone]]), [[pseudomembranous colitis]], [[aspiration pneumonia]], [[rosacea]] (topical), fungating wounds (topical), intra-abdominal infections, [[lung abscess]], [[periodontal disease]], [[amoebiasis]], oral infections, [[giardiasis]], [[trichomoniasis]], and infections caused by susceptible anaerobic organisms such as ''[[Bacteroides]], [[Fusobacterium]], [[Clostridium]], [[Peptostreptococcus]]'', and ''[[Prevotella]]'' species.<ref name = AMH/> It is also often used to eradicate ''[[Helicobacter pylori]]'' along with other drugs and to prevent infection in people recovering from surgery.<ref name = AMH/> Metronidazole is bitter and so the liquid suspension contains metronidazole benzoate. This may require [[hydrolysis]] in the gastrointestinal tract and some sources speculate that it may be unsuitable in people with diarrhea or feeding-tubes in the duodenum or jejunum.<ref name="Geoghegan-2017">{{cite web |url = https://www.pharmaceutical-journal.com/learning/cpd-article/clostridium-difficile-diagnosis-and-treatment-update/20202242.cpdarticle |title = ''Clostridium difficile'': diagnosis and treatment update |publisher = Royal Pharmaceutical Society |vauthors = Geoghegan O, Eades C, Moore LS, Gilchrist M |work = The Pharmaceutical Journal |date = 9 February 2017 |access-date = 22 January 2018 |archive-date = 7 March 2019 |archive-url = https://web.archive.org/web/20190307054301/https://www.pharmaceutical-journal.com/learning/cpd-article/clostridium-difficile-diagnosis-and-treatment-update/20202242.cpdarticle |url-status = live }}</ref><ref name="Dickman-2012">{{cite book |vauthors = Dickman A |title=Drugs in Palliative Care |date=2012 |publisher=OUP Oxford |isbn=978-0-19-163610-3 |page=355 |url=https://books.google.com/books?id=mSzs_8ijZpgC&pg=PA355 |access-date=29 August 2020 |archive-date=25 June 2022 |archive-url=https://web.archive.org/web/20220625064231/https://books.google.com/books?id=mSzs_8ijZpgC&pg=PA355 |url-status=live }}</ref> ===Bacterial vaginosis=== Drugs of choice for the treatment of bacterial vaginosis include metronidazole and [[clindamycin]].<ref name="pmid10028110">{{cite journal |vauthors = Joesoef MR, Schmid GP, Hillier SL |title = Bacterial vaginosis: review of treatment options and potential clinical indications for therapy |journal = Clinical Infectious Diseases |volume = 28 |issue = Suppl 1 |pages = S57–S65 |date = January 1999 |pmid = 10028110 |doi = 10.1086/514725 |title-link = doi |doi-access = free }}</ref> An effective treatment option for mixed infectious vaginitis is a combination of clotrimazole and metronidazole.<ref name="pmid37773671">{{cite journal |vauthors=Huang Y, Shen C, Shen Y, Cui H |title=Assessing the Efficacy of Clotrimazole and Metronidazole Combined Treatment in Vaginitis: A Meta-Analysis |journal=Altern Ther Health Med |volume=30 |issue=1 |pages=186–191 |date=January 2024 |pmid=37773671}}</ref> ===Trichomoniasis=== The [[5-nitroimidazole]] drugs (metronidazole and [[tinidazole]]) are the mainstay of treatment for infection with ''[[Trichomonas vaginalis]]''. Treatment for both the infected patient and the patient's sexual partner is recommended, even if asymptomatic. Therapy other than 5-nitroimidazole drugs is also an option, but cure rates are much lower.<ref name="pmid9132982">{{cite journal |vauthors = duBouchet L, Spence MR, Rein MF, Danzig MR, McCormack WM |title = Multicenter comparison of clotrimazole vaginal tablets, oral metronidazole, and vaginal suppositories containing sulfanilamide, aminacrine hydrochloride, and allantoin in the treatment of symptomatic trichomoniasis |journal = Sexually Transmitted Diseases |volume = 24 |issue = 3 |pages = 156–160 |date = March 1997 |pmid = 9132982 |doi = 10.1097/00007435-199703000-00006 |s2cid = 6617019 |doi-access = free }}</ref> ===Giardiasis=== Oral metronidazole is a treatment option for [[giardiasis]], however, the increasing incidence of [[nitroimidazole]] resistance is leading to the increased use of other compound classes.<ref name="pmid26258002">{{cite journal |vauthors = Leitsch D |title = Drug Resistance in the Microaerophilic Parasite ''Giardia lamblia'' |journal = Current Tropical Medicine Reports |volume = 2 |issue = 3 |pages = 128–135 |date = September 2015 |pmid = 26258002 |pmc = 4523694 |doi = 10.1007/s40475-015-0051-1 }}</ref> ===Dracunculus=== In the case of ''[[Dracunculus medinensis]]'' (Guinea worm), metronidazole just eases worm extraction rather than killing the worm.<ref name=AHFS2015/> ===''C. difficile'' colitis=== Initial antibiotic therapy for less-severe ''[[Clostridioides difficile infection]]'' colitis ([[pseudomembranous colitis]]) consists of metronidazole, [[vancomycin]], or [[fidaxomicin]] by mouth.<ref name="pmid29462280"/> In 2017, the IDSA generally recommended vancomycin and fidaxomicin over metronidazole.<ref name="pmid29462280"/> Vancomycin [[Oral administration|by mouth]] has been shown to be more effective in treating people with severe ''C. difficile'' colitis.<ref name="pmid17599306">{{cite journal |vauthors = Zar FA, Bakkanagari SR, Moorthi KM, Davis MB |title = A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity |journal = Clinical Infectious Diseases |volume = 45 |issue = 3 |pages = 302–307 |date = August 2007 |pmid = 17599306 |doi = 10.1086/519265 |title-link = doi |doi-access = free }}</ref> === ''E. histolytica'' === ''[[Entamoeba histolytica]]'' invasive [[Amoebiasis|amebiasis]] is treated with metronidazole for eradication, in combination with [[diloxanide]] to prevent recurrence.<ref name="Ryan-2018">{{cite book |title=Sherris medical microbiolog |isbn=978-1-259-85981-6 |edition= Seventh |location=New York | publisher = McGraw Hill LLC |oclc=1004770160 |vauthors = Ryan KJ, Ahmad N, Alspaugh JA, Drew WL, Lagunoff M, Pottinger P, Reller LB, Reller ME, Sterling CR, Weissman S |date = 12 January 2018}}</ref> Although it is generally a standard treatment it is associated with some side effects.<ref name="pmid32356312">{{cite journal |vauthors = Rawat A, Singh P, Jyoti A, Kaushik S, Srivastava VK |title = Averting transmission: A pivotal target to manage amoebiasis |journal = Chemical Biology & Drug Design |volume = 96 |issue = 2 |pages = 731–744 |date = August 2020 |pmid = 32356312 |doi = 10.1111/cbdd.13699 |s2cid = 218475533 }}</ref> ===Preterm births=== 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). Metronidazole was ineffective in preventing preterm delivery in high-risk pregnant women (selected by history and a positive fFN test) and, conversely, the incidence of preterm delivery was found to be higher in women treated with metronidazole.<ref name="pmid16398774">{{cite journal |vauthors = Shennan A, Crawshaw S, Briley A, Hawken J, Seed P, Jones G, Poston L |title = A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study |journal = BJOG |volume = 113 |issue = 1 |pages = 65–74 |date = January 2006 |pmid = 16398774 |doi = 10.1111/j.1471-0528.2005.00788.x |s2cid = 11366650 }}</ref> ===Hypoxic radiosensitizer=== In addition to its anti-biotic properties, attempts were also made to use a possible [[Radiosensitizer|radiation-sensitizing effect]] of metronidazole in the context of radiation therapy against [[Tumor hypoxia#Radiotherapy|hypoxic tumors]].<ref name="pmid6884824">{{cite journal | vauthors = Nori D, Cain JM, Hilaris BS, Jones WB, Lewis JL | title = Metronidazole as a radiosensitizer and high-dose radiation in advanced vulvovaginal malignancies, a pilot study | journal = Gynecologic Oncology | volume = 16 | issue = 1 | pages = 117–28 | date = August 1983 | pmid = 6884824 | doi = 10.1016/0090-8258(83)90017-3 }}</ref> However, the neurotoxic side effects occurring at the required dosages have prevented the widespread use of metronidazole as an adjuvant agent in radiation therapy.<ref name="Sarna_2013">{{cite journal | vauthors = Sarna JR, Furtado S, Brownell AK | title = Neurologic complications of metronidazole | journal = The Canadian Journal of Neurological Sciences | volume = 40 | issue = 6 | pages = 768–776 | date = November 2013 | pmid = 24257215 | doi = 10.1017/s0317167100015870 }}</ref> However, other [[nitroimidazole]]s derived from metronidazole such as [[nimorazole]] with reduced electron affinity showed less serious neuronal side effects and have found their way into radio-onological practice for head and neck tumors in some countries.<ref name="Overgaard_1998">{{cite journal | vauthors = Overgaard J, Hansen HS, Overgaard M, Bastholt L, Berthelsen A, Specht L, Lindeløv B, Jørgensen K | title = A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85 | journal = Radiotherapy and Oncology | volume = 46 | issue = 2 | pages = 135–46 | date = February 1998 | pmid = 9510041 | doi = 10.1016/s0167-8140(97)00220-x }}</ref> === Perioral dermatitis === ''[[Canadian Family Physician]]'' has recommended topical metronidazole as a third-line treatment for the [[perioral dermatitis]] either along with or without oral [[tetracycline]] or oral [[erythromycin]] as first and second line treatment respectively.<ref name="pmid15856972">{{cite journal |vauthors = Cheung MJ, Taher M, Lauzon GJ |title = Acneiform facial eruptions: a problem for young women |journal = Canadian Family Physician |volume = 51 |pages = 527–533 |date = April 2005 |issue = 4 |pmid = 15856972 |pmc = 1472951 }}</ref> ==Adverse effects== Common [[adverse drug reaction]]s (≥1% of those treated with the drug) associated with systemic metronidazole therapy include: [[nausea]], [[diarrhea]], weight loss, abdominal pain, vomiting, headache, dizziness, and 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 [[paraesthesia]].<ref name="AMH">{{cite book | veditors = Rossi S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }}</ref> High doses and long-term systemic treatment with metronidazole are associated with the development of [[leucopenia]], [[neutropenia]], increased risk of [[peripheral neuropathy]], and [[central nervous system]] toxicity.<ref name=AMH/> Common adverse drug reaction associated with topical metronidazole therapy include local redness, dryness and skin irritation; and eye watering (if applied near eyes).<ref name=AMH/><ref name="Drugs.com SFX">{{Drugs.com|sfx|metronidazole-topical-side-effects}}</ref> Metronidazole has been associated with cancer in animal studies.<ref name="Flagyl metronidazole tablets label">{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012623s061lbl.pdf |title=Flagyl metronidazole tablets label|access-date=5 August 2015 |url-status=live |archive-url=https://web.archive.org/web/20160122041235/http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012623s061lbl.pdf |archive-date=22 January 2016 }}</ref>{{failed verification|reason=no discussion of cancer in animal studies|date=September 2019}} In rare cases, it can also cause temporary [[hearing loss]] that reverses after cessation of the treatment.<ref name="pmid10474673">{{cite journal | vauthors = Iqbal SM, Murthy JG, Banerjee PK, Vishwanathan KA | title = Metronidazole ototoxicity--report of two cases | journal = The Journal of Laryngology and Otology | volume = 113 | issue = 4 | pages = 355–357 | date = April 1999 | pmid = 10474673 | doi = 10.1017/s0022215100143968 | s2cid = 45989669 }}</ref><ref name="pmid7986915">{{cite journal | vauthors = Lawford R, Sorrell TC | title = Amebic abscess of the spleen complicated by metronidazole-induced neurotoxicity: case report | journal = Clinical Infectious Diseases | volume = 19 | issue = 2 | pages = 346–348 | date = August 1994 | pmid = 7986915 | doi = 10.1093/clinids/19.2.346 }}</ref> Some evidence from studies in rats indicates the possibility it may contribute to [[serotonin syndrome]], although no case reports documenting this have been published to date.<ref name="pmid17963129"/><ref name="pmid18971895">{{cite journal | vauthors = Karamanakos PN | title = The possibility of serotonin syndrome brought about by the use of metronidazole | journal = Minerva Anestesiologica | volume = 74 | issue = 11 | pages = 679 | date = November 2008 | pmid = 18971895 }}</ref> ===Mutagenesis and carcinogenesis=== In 2016 metronidazole was listed by the U.S. [[National Toxicology Program]] (NTP) as reasonably anticipated to be a human [[carcinogen]].<ref name="National Toxicology Program (NTP)-2016"/> Although some of the testing methods have been questioned, oral exposure has been shown to cause cancer in experimental animals and has also demonstrated some mutagenic effects in bacterial cultures.<ref name="National Toxicology Program (NTP)-2016"/><ref name = TGA/> The relationship between exposure to metronidazole and human cancer is unclear.<ref name="National Toxicology Program (NTP)-2016"/><ref name="pmid12052431">{{cite journal | vauthors = Bendesky A, Menéndez D, Ostrosky-Wegman P | title = Is metronidazole carcinogenic? | journal = Mutation Research | volume = 511 | issue = 2 | pages = 133–144 | date = June 2002 | pmid = 12052431 | doi = 10.1016/S1383-5742(02)00007-8 | bibcode = 2002MRRMR.511..133B }}</ref> One study <ref name="pmid3339906">{{cite journal | vauthors = Beard CM, Noller KL, O'Fallon WM, Kurland LT, Dahlin DC | title = Cancer after exposure to metronidazole | journal = Mayo Clinic Proceedings | volume = 63 | issue = 2 | pages = 147–153 | date = February 1988 | pmid = 3339906 | doi = 10.1016/s0025-6196(12)64947-7 }}</ref> found an excess in lung cancer among women (even after adjusting for smoking), while other studies <ref name="INCHEM2-1998">{{cite web | title=Metronidazole (IARC Summary & Evaluation, Supplement7, 1987) | website=INCHEM2 | date=3 March 1998 | url=http://www.inchem.org/documents/iarc/suppl7/metronidazole.html | access-date=12 September 2019 | archive-date=4 August 2020 | archive-url=https://web.archive.org/web/20200804014404/http://www.inchem.org/documents/iarc/suppl7/metronidazole.html | url-status=live }}</ref><ref name="pmid9762949">{{cite journal | vauthors = Thapa PB, Whitlock JA, Brockman Worrell KG, Gideon P, Mitchel EF, Roberson P, Pais R, Ray WA | title = Prenatal exposure to metronidazole and risk of childhood cancer: a retrospective cohort study of children younger than 5 years | journal = Cancer | volume = 83 | issue = 7 | pages = 1461–1468 | date = October 1998 | pmid = 9762949 | doi = 10.1002/(sici)1097-0142(19981001)83:7<1461::aid-cncr25>3.0.co;2-1 | title-link = doi | doi-access = free }}</ref><ref name="pmid19585498">{{cite journal | vauthors = Friedman GD, Jiang SF, Udaltsova N, Quesenberry CP, Chan J, Habel LA | title = Epidemiologic evaluation of pharmaceuticals with limited evidence of carcinogenicity | journal = International Journal of Cancer | volume = 125 | issue = 9 | pages = 2173–2178 | date = November 2009 | pmid = 19585498 | pmc = 2759691 | doi = 10.1002/ijc.24545 }}</ref> found either no increased risk, or a [[Statistical significance|statistically insignificant]] risk.<ref name="National Toxicology Program (NTP)-2016">{{cite book | vauthors = ((National Toxicology Program)) | chapter-url = https://ntp.niehs.nih.gov/ntp/roc/content/profiles/metronidazole.pdf | chapter = Metronidazole | year = 2016 | title = Report on Carcinogens | edition = Fourteenth | publisher = [[National Toxicology Program]] (NTP) | url = https://ntp.niehs.nih.gov/go/roc14 | access-date = 9 February 2020 | archive-url=https://web.archive.org/web/20200209202538/https://ntp.niehs.nih.gov/ntp/roc/content/profiles/metronidazole.pdf | archive-date=9 February 2020 | url-status = live }}</ref><ref name="Pfizer-Flagyl-375">{{cite web | url = http://www.pfizer.com/pfizer/download/uspi_flagyl_375.pdf | title = Flagyl 375 U.S. Prescribing Information | publisher = Pfizer | url-status = dead | archive-url = https://web.archive.org/web/20080807175611/http://www.pfizer.com/pfizer/download/uspi_flagyl_375.pdf | archive-date = 7 August 2008 }}</ref> Metronidazole is listed as a possible carcinogen according to the [[World Health Organization]] (WHO) [[International Agency for Research on Cancer]] (IARC).<ref name="International Agency for Research on Cancer (IARC)-2019">{{cite web | url = https://monographs.iarc.fr/agents-classified-by-the-iarc/ | title = Agents Classified by the IARC Monographs, Volumes 1–124 | publisher = [[International Agency for Research on Cancer]] (IARC) | date = 8 July 2019 | access-date = 12 September 2019 | url-status = live | archive-url = https://web.archive.org/web/20190906143757/https://monographs.iarc.fr/agents-classified-by-the-iarc/ | archive-date = 6 September 2019 }}</ref> A study in those with [[Crohn's disease]] also found chromosomal abnormalities in circulating lymphocytes in people treated with metronidazole.<ref name="TGA">{{cite web|title=Metrogyl Metronidazole Product Information|work=TGA eBusiness Services|publisher=Alphapharm Pty Limited|date=8 May 2013|access-date=3 April 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05077-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20160909043856/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05077-3|archive-date=9 September 2016 }}</ref> ===Stevens–Johnson syndrome=== Metronidazole alone rarely causes [[Stevens–Johnson syndrome]], but is reported to occur at high rates when combined with [[mebendazole]].<ref name="pmid12604501">{{cite journal | vauthors = Chen KT, Twu SJ, Chang HJ, Lin RS | title = Outbreak of Stevens-Johnson syndrome/toxic epidermal necrolysis associated with mebendazole and metronidazole use among Filipino laborers in Taiwan | journal = American Journal of Public Health | volume = 93 | issue = 3 | pages = 489–492 | date = March 2003 | pmid = 12604501 | pmc = 1447769 | doi = 10.2105/ajph.93.3.489 }}</ref> === Neurotoxicity === Several studies in the human<ref>{{cite journal | vauthors = Yamamoto T, Abe K, Anjiki H, Ishii T, Kuyama Y | title = Metronidazole-induced neurotoxicity developed in liver cirrhosis | journal = Journal of Clinical Medicine Research | volume = 4 | issue = 4 | pages = 295–298 | date = August 2012 | pmid = 22870180 | doi = 10.4021/jocmr893w | pmc = 3409628 }}</ref> and animal modules have recorded the [[neurotoxicity]] of metronidazole. One possible mechanism of this toxicity is that metronidazole may cause interference with postsynaptic central monoaminergic neurotransmission and immunomodulation.<ref>{{Cite journal | vauthors = Bariweni MW, Kamenebali I, Denyefa JB |date=2024-04-15 |title=Metronidazole-induced neurotoxicity: Possible central serotonergic and noradrenergic system involvement |url=https://pharmacoj.com/ojs/index.php/Medph/article/view/74 |journal=Medical and Pharmaceutical Journal |volume=3 |issue=1 |pages=22–34 |doi=10.55940/medphar202474|doi-access=free }}</ref> Other research suggests the role of [[nitric oxide]] isoforms and [[inflammatory cytokine]]s.<ref>{{cite journal | vauthors = Chaturvedi S, Malik MY, Rashid M, Singh S, Tiwari V, Gupta P, Shukla S, Singh S, Wahajuddin M | title = Mechanistic exploration of quercetin against metronidazole induced neurotoxicity in rats: Possible role of nitric oxide isoforms and inflammatory cytokines | journal = Neurotoxicology | volume = 79 | pages = 1–10 | date = July 2020 | pmid = 32151614 | doi = 10.1016/j.neuro.2020.03.002 | bibcode = 2020NeuTx..79....1C }}</ref> ==Drug interactions== ===Alcohol=== {{See also|Disulfiram-like drug}} Consuming [[ethanol|alcohol]] while taking metronidazole has been suspected in [[case reports]] to cause a [[disulfiram-like reaction]] with effects that can include [[nausea]], [[vomiting]], [[flushing (physiology)|flushing]] of the skin, [[tachycardia]], and [[shortness of breath]].<ref name="pmid8947362">{{cite journal | vauthors = Cina SJ, Russell RA, Conradi SE | title = Sudden death due to metronidazole/ethanol interaction | journal = The American Journal of Forensic Medicine and Pathology | volume = 17 | issue = 4 | pages = 343–346 | date = December 1996 | pmid = 8947362 | doi = 10.1097/00000433-199612000-00013 }}</ref> People are often advised not to drink alcohol during systemic metronidazole therapy and for at least 48 hours after completion of [https://renixcare.com/ treatment].<ref name="AMH"/> However, some studies call into question the mechanism of the interaction of alcohol and metronidazole,<ref name="pmid4320226">{{cite journal | vauthors = Gupta NK, Woodley CL, Fried R | title = Effect of metronidazole on liver alcohol dehydrogenase | journal = Biochemical Pharmacology | volume = 19 | issue = 10 | pages = 2805–2808 | date = October 1970 | pmid = 4320226 | doi = 10.1016/0006-2952(70)90108-5 }}</ref><ref name="pmid10676835"> {{cite journal | vauthors = Williams CS, Woodcock KR | title = Do ethanol and metronidazole interact to produce a disulfiram-like reaction? | journal = The Annals of Pharmacotherapy | volume = 34 | issue = 2 | pages = 255–257 | date = February 2000 | pmid = 10676835 | doi = 10.1345/aph.19118 | quote = 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 | s2cid = 21151432 }}</ref><ref name="pmid12022894">{{cite journal | vauthors = Visapää JP, Tillonen JS, Kaihovaara PS, Salaspuro MP | title = Lack of disulfiram-like reaction with metronidazole and ethanol | journal = The Annals of Pharmacotherapy | volume = 36 | issue = 6 | pages = 971–974 | date = June 2002 | pmid = 12022894 | doi = 10.1345/1542-6270(2002)036<0971:lodlrw>2.0.co;2 }}</ref> and a possible [[serotonin toxicity|central toxic serotonin reaction]] for the alcohol intolerance is suggested.<ref name="pmid17963129">{{cite journal | vauthors = Karamanakos PN, Pappas P, Boumba VA, Thomas C, Malamas M, Vougiouklakis T, Marselos M | title = Pharmaceutical agents known to produce disulfiram-like reaction: effects on hepatic ethanol metabolism and brain monoamines | journal = International Journal of Toxicology | volume = 26 | issue = 5 | pages = 423–432 | year = 2007 | pmid = 17963129 | doi = 10.1080/10915810701583010 | s2cid = 41230661 }}</ref> 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]]), thus propylene glycol may potentially have similar interaction effects with metronidazole.{{medical citation needed|date=April 2014}} ===Other drug interactions=== Metronidazole is a moderate [[CYP2C9]] inhibitor. CYP2C9 is an enzyme of [[cytochrome P450]] family. Therefore, metronidazole may interact with medications metabolized by this enzyme.<ref name="Flockhart-2007">{{cite web |vauthors=Flockhart DA |title=Drug Interactions: Cytochrome P450 Drug Interaction Table |publisher=[[Indiana University School of Medicine]] |year=2007 |url=http://medicine.iupui.edu/flockhart/table.htm |access-date=4 January 2022 |archive-date=10 October 2007 |archive-url=https://web.archive.org/web/20071010053126/http://medicine.iupui.edu/flockhart/table.htm |url-status=live }}</ref><ref name="pmid25470432">{{cite journal | vauthors = Kudo T, Endo Y, Taguchi R, Yatsu M, Ito K | title = Metronidazole reduces the expression of cytochrome P450 enzymes in HepaRG cells and cryopreserved human hepatocytes | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 45 | issue = 5 | pages = 413–419 | date = May 2015 | pmid = 25470432 | doi = 10.3109/00498254.2014.990948 | s2cid = 26910995 }}</ref><ref name="pmid20698928">{{cite journal | vauthors = Tirkkonen T, Heikkilä P, Huupponen R, Laine K | title = Potential CYP2C9-mediated drug-drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide | journal = Journal of Internal Medicine | volume = 268 | issue = 4 | pages = 359–366 | date = October 2010 | pmid = 20698928 | doi = 10.1111/j.1365-2796.2010.02257.x | s2cid = 45449460 }}</ref> Examples of such medications are [[lomitapide]], [[warfarin]], etc.<ref name = MSR/> ==Pharmacology== ===Mechanism of action=== Metronidazole is of the [[nitroimidazole]] class. It inhibits nucleic acid synthesis by forming [[nitroso]] [[radical (chemistry)|radical]]s, which disrupt the DNA of microbial cells.<ref name = MSR/><ref name="AC">{{cite book|title=Austria-Codex| veditors = Haberfeld H |at=Anaerobex-Filmtabletten|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2020|language=de}}</ref> This function only occurs when metronidazole is partially reduced, and because this reduction usually happens only in anaerobic bacteria and protozoans, it has relatively little effect upon human cells or [[aerobic bacteria]].<ref name="Eisenstein-2007"> {{cite book | vauthors = Eisenstein BI, Schaechter M | chapter = DNA and Chromosome Mechanics | chapter-url = https://books.google.com/books?id=1Zl70SLDU3oC&pg=PA28 | veditors = Schaechter M, Engleberg NC, DiRita VJ, Dermody T | title = Schaechter's Mechanisms of Microbial Disease | publisher = Lippincott Williams & Wilkins | location = Hagerstown, MD | year = 2007 | page = 28 | isbn = 978-0-7817-5342-5 }}</ref> ===Pharmacokinetics=== [[File:Hydroxymetronidazole.svg|thumb|[[Hydroxymetronidazole]], the main metabolite]] Oral metronidazole is approximately 80% [[bioavailable]] via the gut and peak [[blood plasma]] concentrations occur after one to two hours. Food may slow down absorption but does not diminish it. Of the circulating substance, about 20% is bound to [[plasma protein]]s. It penetrates well into tissues, the [[cerebrospinal fluid]], the [[amniotic fluid]] and breast milk, as well as into [[abscess]] cavities.<ref name="AC" /> About 60% of the metronidazole is [[metabolize]]d by [[oxidation]] to the main metabolite [[hydroxymetronidazole]] and a [[carboxylic acid]] derivative, and by [[glucuronidation]]. The metabolites show antibiotic and antiprotozoal activity ''[[in vitro]]''.<ref name="AC" /> Metronidazole and its metabolites are mainly excreted via the kidneys (77%) and to a lesser extent via the faeces (14%).<ref name = MSR/><ref name = MD/> The [[biological half-life]] of metronidazole in healthy adults is eight hours, in infants during the first two months of their lives about 23 hours, and in [[Preterm birth|premature]] babies up to 100 hours.<ref name="AC" /> The biological activity of hydroxymetronidazole is 30% to 65%, and the elimination half-life is longer than that of the parent compound.<ref name="pmid10384859">{{cite journal | vauthors = Lamp KC, Freeman CD, Klutman NE, Lacy MK | title = Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials | journal = Clinical Pharmacokinetics | volume = 36 | issue = 5 | pages = 353–373 | date = May 1999 | pmid = 10384859 | doi = 10.2165/00003088-199936050-00004 | s2cid = 37891515 }}</ref> The serum half-life of hydroxymetronidazole after [[suppository]] was 10 hours, 19 hours after intravenous infusion, and 11 hours after a tablet.<ref name="pmid6588489">{{cite journal | vauthors = Bergan T, Leinebo O, Blom-Hagen T, Salvesen B | title = Pharmacokinetics and bioavailability of metronidazole after tablets, suppositories and intravenous administration | journal = Scandinavian Journal of Gastroenterology. Supplement | volume = 91 | pages = 45–60 | year = 1984 | pmid = 6588489 }}</ref> ==Bacterial resistance== {{see also|Antibiotic abuse|Antibiotic resistance}} Bacteria may have developed unexpectedly higher resistance to metronidazole.<ref>{{cite journal | vauthors = Krakovka S, Ribacke U, Miyamoto Y, Eckmann L, Svärd S | title = Characterization of Metronidazole-Resistant ''Giardia intestinalis'' Lines by Comparative Transcriptomics and Proteomics | journal = Frontiers in Microbiology | volume = 13 | pages = 834008 | date = 11 January 2022 | pmid = 35222342 | pmc = 8866875 | doi = 10.3389/fmicb.2022.834008 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Alauzet C, Lozniewski A, Marchandin H | title = Metronidazole resistance and nim genes in anaerobes: A review | journal = Anaerobe | volume = 55 | pages = 40–53 | date = February 2019 | pmid = 30316817 | doi = 10.1016/j.anaerobe.2018.10.004 | s2cid = 52983319 }}</ref><ref>{{cite journal | vauthors = Smith A | title = Metronidazole resistance: a hidden epidemic? | journal = British Dental Journal | volume = 224 | issue = 6 | pages = 403–404 | date = March 2018 | pmid = 29545544 | doi = 10.1038/sj.bdj.2018.221 | url = https://eprints.gla.ac.uk/159683/1/159683.pdf | access-date = 2 February 2024 | url-status = live | archive-url = https://web.archive.org/web/20231118221737/https://eprints.gla.ac.uk/159683/1/159683.pdf | archive-date = 18 November 2023 }}</ref>{{clarify|Higher than what?|date=January 2024}} == History == The drug was initially developed by [[Rhône-Poulenc]] in the 1950s<ref name="pmid25557515">{{cite journal | vauthors = Quirke V | title = Targeting the American market for medicines, ca. 1950s-1970s: ICI and Rhône-Poulenc compared | journal = Bulletin of the History of Medicine | volume = 88 | issue = 4 | pages = 654–696 | date = 29 December 2014 | pmid = 25557515 | pmc = 4335572 | doi = 10.1353/bhm.2014.0075 }}</ref> and licensed to [[G.D. Searle, LLC|G.D. Searle]].<ref name="Leagle">{{cite web|url=https://www.leagle.com/decision/198734088otc2521326|title=G.D. SEARLE & CO. v. COMM {{!}} 88 T.C. 252 (1987) {{!}} 8otc2521326 {{!}} Leagle.com|website=Leagle|access-date=18 June 2019}}</ref> Searle was acquired by Pfizer in 2003.<ref name="Pfizer-2">{{cite web|url=https://www.pfizer.com/about/history/pfizer_pharmacia|title=2003:Pfizer and Pharmacia Merger|website=Pfizer|access-date=18 June 2019|archive-date=26 June 2019|archive-url=https://web.archive.org/web/20190626122138/https://www.pfizer.com/about/history/pfizer_pharmacia|url-status=live}}</ref> The original patent expired in 1982, but [[evergreening]] reformulation occurred thereafter.<ref name="pmid30799664">{{cite journal | vauthors = Dickson S | title = Effect of Evergreened Reformulations on Medicaid Expenditures and Patient Access from 2008 to 2016 | journal = Journal of Managed Care & Specialty Pharmacy | volume = 25 | issue = 7 | pages = 780–792 | date = July 2019 | pmid = 30799664 | doi = 10.18553/jmcp.2019.18366 | title-link = doi | pmc = 10398228 | doi-access = free }}</ref> == Brand name == In India, it is sold under the brand name Metrogyl and Flagyl.<ref name="Medical Dialogues">{{cite web | url=https://medicaldialogues.in/partner/jbcpl/metrogyl-er-Metronidazole-Extended-release | title=Metrogyl ER | publisher=Medical Dialogues | access-date=1 March 2021 | archive-date=17 April 2021 | archive-url=https://web.archive.org/web/20210417230512/https://medicaldialogues.in/partner/jbcpl/metrogyl-er-Metronidazole-Extended-release | url-status=live }}</ref> In Bangladesh, it is available as Amodis, Amotrex, Dirozyl, Filmet, Flagyl, Flamyd, Metra, Metrodol, Metryl, etc.<ref name="Medex">{{cite web | url=https://medex.com.bd/generics/751/metronidazole/brand-names | title=Metronidazole Brands | publisher=Medex | access-date=24 November 2021 | archive-date=24 November 2021 | archive-url=https://web.archive.org/web/20211124002208/https://medex.com.bd/generics/751/metronidazole/brand-names | url-status=live }}</ref> In Pakistan, it is sold under the brand name of Flagyl and Metrozine.{{citation needed|date=December 2022}} In the United States it is sold under the brand name Noritate.<ref name="RxList">{{cite news |title=Noritate (Metronidazole): Uses, Dosage, Side Effects, Interactions, Warning |url=https://www.rxlist.com/noritate-drug.htm |access-date=8 December 2023 |website=RxList |language=en |archive-date=8 December 2023 |archive-url=https://web.archive.org/web/20231208121650/https://www.rxlist.com/noritate-drug.htm |url-status=live }}</ref> ==Synthesis== [[2-Methylimidazole]] ('''1''') may be prepared via the [[Debus-Radziszewski imidazole synthesis]], or from [[ethylenediamine]] and [[acetic acid]], followed by treatment with [[calcium oxide|lime]], then [[Raney nickel]]. 2-Methylimidazole is nitrated to give 2-methyl-4(5)-nitroimidazole ('''2'''), which is in turn [[alkylation|alkylated]] with [[ethylene oxide]] or [[2-chloroethanol]] to give metronidazole ('''3'''):<ref name="Ebel">{{Ullmann | vauthors = Ebel K, Koehler H, Gamer AO, Jäckh R | title = Imidazole and Derivatives | doi = 10.1002/14356007.a13_661 }}</ref><ref name="Actor">{{Ullmann | vauthors = Actor P, Chow AW, Dutko FJ, McKinlay MA | title = Chemotherapeutics | doi = 10.1002/14356007.a06_173 }}</ref><ref name="Kraft-1989">{{cite journal | vauthors = Kraft MY, Kochergin PM, Tsyganova AM, Shlikhunova VS | title = Synthesis of metronidazole from ethylenediamine | journal = Pharmaceutical Chemistry Journal | year = 1989 | volume = 23 | issue = 10 | pages = 861–863 | doi = 10.1007/BF00764821 | s2cid = 38187002 }}</ref> :[[File:Synthesis of metronidazole.png|600px]] ==Research== Metronidazole is researched for its anti-inflammatory and immunomodulatory properties. Studies have shown that metronidazole can decrease the production of [[reactive oxygen species]] (ROS) and [[nitric oxide]] by activated immune cells, such as [[macrophage]]s and [[neutrophil]]s. Metronidazole's [[Immunity (medical)|immunomodulatory]] properties are thought to be related to its ability to decrease the activation of [[nuclear factor-kappa B]] (NF-κB), a [[transcription factor]] that regulates the expression of [[Inflammatory cytokine|pro-inflammatory]] [[cytokine]]s, including [[chemokine]]s, and [[Cell adhesion molecule|adhesion molecules]]. Cytokines are small proteins that are secreted by immune cells and play a key role in the immune response.<ref name="pmid10767254">{{cite journal |vauthors=Opal SM, DePalo VA |title=Anti-inflammatory cytokines |journal=Chest |volume=117 |issue=4 |pages=1162–72 |date=April 2000 |pmid=10767254 |doi=10.1378/chest.117.4.1162 |s2cid=2267250 |url=}}</ref> Chemokines are a type of cytokines that act as chemoattractants, meaning they attract and guide immune cells to specific sites in the body where they are needed.<ref name="pmid26490276">{{cite journal |vauthors=van der Vorst EP, Döring Y, Weber C |title=Chemokines |journal=Arterioscler Thromb Vasc Biol |volume=35 |issue=11 |pages=e52–6 |date=November 2015 |pmid=26490276 |doi=10.1161/ATVBAHA.115.306359 |url=|doi-access=free }}</ref> Cell adhesion molecules play an important role in the immune response by facilitating the interaction between immune cells and other cells in the body, such as endothelial cells, which form the lining of blood vessels.<ref name="pmid9150551">{{cite journal |vauthors=Elangbam CS, Qualls CW, Dahlgren RR |title=Cell adhesion molecules--update |journal=Vet Pathol |volume=34 |issue=1 |pages=61–73 |date=January 1997 |pmid=9150551 |doi=10.1177/030098589703400113 |s2cid=46474241 |url=}}</ref> By inhibiting NF-κB activation, metronidazole can reduce the production of pro-inflammatory cytokines, such as [[Tumor necrosis factor-alpha|TNF-alpha]], [[Interleukin 6|IL-6]], and [[Interleukin 1 beta|IL-1β]].<ref name="pmid20399284">{{cite journal |vauthors=Rizzo A, Paolillo R, Guida L, Annunziata M, Bevilacqua N, Tufano MA |title=Effect of metronidazole and modulation of cytokine production on human periodontal ligament cells |journal=Int Immunopharmacol |volume=10 |issue=7 |pages=744–50 |date=July 2010 |pmid=20399284 |doi=10.1016/j.intimp.2010.04.004 |url=}}</ref> Metronidazole has been studied in various immunological disorders, including [[inflammatory bowel disease]], [[Periodontal disease|periodontitis]], and [[rosacea]]. In these conditions, metronidazole has been suspected to have anti-inflammatory and immunomodulatory effects that could be beneficial in the treatment of these conditions.<ref name="pmid37295025">{{cite journal |vauthors=Gonçalves-Santos E, Caldas I, Fernandes V, Franco L, Pelozo M, Feltrim F, Maciel J, Machado J, Gonçalves R, Novaes R |title=Pharmacological potential of new metronidazole/eugenol/dihydroeugenol hybrids against Trypanosoma cruzi in vitro and in vivo |journal=Int Immunopharmacol |volume=121 |issue= |pages=110416 |date=August 2023 |pmid=37295025 |doi=10.1016/j.intimp.2023.110416 |s2cid=259126738 |url=}}</ref> Despite the success in treating rosacea with metronidazole,<ref name="pmid37550898">{{cite journal |vauthors=King S, Campbell J, Rowe R, Daly ML, Moncrieff G, Maybury C |title=A systematic review to evaluate the efficacy of azelaic acid in the management of acne, rosacea, melasma and skin aging |journal=J Cosmet Dermatol |volume=22 |issue=10 |pages=2650–2662 |date=October 2023 |pmid=37550898 |doi=10.1111/jocd.15923 |s2cid=260701677 |url=|doi-access=free }}</ref><ref name="pmid37591279">{{cite journal |vauthors=Kazemi S, Hawkes JE |title=Ocular rosacea associated with transient monocular vision loss: resolution with oral metronidazole |journal=Dermatol Online J |volume=29 |issue=3 |pages= |date=June 2023 |pmid=37591279 |doi=10.5070/D329361439 |s2cid=263745257 |url=https://escholarship.org/content/qt9zz9v05q/qt9zz9v05q.pdf?t=rxxvc4 |doi-access=free |access-date=2 February 2024 |archive-date=2 February 2024 |archive-url=https://web.archive.org/web/20240202143841/https://escholarship.org/content/qt9zz9v05q/qt9zz9v05q.pdf?t=rxxvc4 |url-status=live }}</ref><ref name="pmid36478427">{{cite journal |vauthors=Kim JS, Seo BH, Cha DR, Suh HS, Choi YS |title=Maintenance of Remission after Oral Metronidazole Add-on Therapy in Rosacea Treatment: A Retrospective, Comparative Study |journal=Ann Dermatol |volume=34 |issue=6 |pages=451–460 |date=December 2022 |pmid=36478427 |pmc=9763916 |doi=10.5021/ad.22.093 |url=}}</ref><ref name="pmid36177741">{{cite journal |vauthors=Yamasaki K, Miyachi Y |title=Perspectives on rosacea patient characteristics and quality of life using baseline data from a phase 3 clinical study conducted in Japan |journal=J Dermatol |volume=49 |issue=12 |pages=1221–1227 |date=December 2022 |pmid=36177741 |pmc=10092295 |doi=10.1111/1346-8138.16596 |url=}}</ref><ref name="pmid36330970">{{cite journal |vauthors=Dall'Oglio F, Nasca MR, Gerbino C, Micali G |title=Advances in pharmacotherapy for rosacea: what is the current state of the art? |journal=Expert Opin Pharmacother |volume=23 |issue=16 |pages=1845–1854 |date=November 2022 |pmid=36330970 |doi=10.1080/14656566.2022.2142907 |s2cid=253301872 |url=}}</ref> the exact mechanism of why metronidazole in rosacea is efficient is not precisely known, i.e., which properties of metronidazole help treat rosacea: antibacterial or immunomodulatory or both, or other mechanism is involved.<ref name="pmid32362310">{{cite journal |vauthors=Seidler Stangova P, Dusek O, Klimova A, Heissigerova J, Kucera T, Svozilkova P |title=Metronidazole Attenuates the Intensity of Inflammation in Experimental Autoimmune Uveitis |journal=Folia Biol (Praha) |volume=65 |issue=5–6 |pages=265–274 |date=2019 |pmid=32362310 |doi= 10.14712/fb2019065050265|s2cid=218491876 |url=|doi-access=free }}</ref><ref name="pmid18182250">{{cite journal |vauthors=Fararjeh M, Mohammad MK, Bustanji Y, Alkhatib H, Abdalla S |title=Evaluation of immunosuppression induced by metronidazole in Balb/c mice and human peripheral blood lymphocytes |journal=Int Immunopharmacol |volume=8 |issue=2 |pages=341–50 |date=February 2008 |pmid=18182250 |doi=10.1016/j.intimp.2007.10.018 |url=}}</ref> Increased [[Reactive oxygen species|ROS]] production in rosacea is thought to contribute to the inflammatory process and skin damage, so metronidazole's ability to decrease ROS may explain the mechanism of action in this disease, but this remains speculation.<ref name="pmid15499754">{{cite journal |vauthors=Jones D |title=Reactive oxygen species and rosacea |journal=Cutis |volume=74 |issue=3 Suppl |pages=17–20, 32–4 |date=September 2004 |pmid=15499754 |doi= |url=}}</ref><ref name="pmid17725855">{{cite journal |vauthors=Narayanan S, Hünerbein A, Getie M, Jäckel A, Neubert RH |title=Scavenging properties of metronidazole on free oxygen radicals in a skin lipid model system |journal=J Pharm Pharmacol |volume=59 |issue=8 |pages=1125–30 |date=August 2007 |pmid=17725855 |doi=10.1211/jpp.59.8.0010 |s2cid=19772010 |url=|doi-access=free }}</ref> Metronidazole is also researched as a potential anti-inflammatory agent in [[periodontitis]] treatment.<ref name="pmid38613247">{{cite journal |vauthors=Suárez LJ, Arce RM, Gonçalves C, Furquim CP, Santos NC, Retamal-Valdes B, Feres M |title=Metronidazole may display anti-inflammatory features in periodontitis treatment: A scoping review |journal=Mol Oral Microbiol |volume= 39|issue= 4|pages= 240–259|date=April 2024 |pmid=38613247 |doi=10.1111/omi.12459}}</ref> ==Veterinary use== Metronidazole is used to treat infections of ''[[Giardia]]'' in dogs, cats, and other companion animals, but it does not reliably clear infection with this organism and is being supplanted by [[fenbendazole]] for this purpose in dogs and cats.<ref name="pmid7978640">{{cite journal | vauthors = Barr SC, Bowman DD, Heller RL | title = Efficacy of fenbendazole against giardiasis in dogs | journal = American Journal of Veterinary Research | volume = 55 | issue = 7 | pages = 988–990 | date = July 1994 | doi = 10.2460/ajvr.1994.55.07.988 | pmid = 7978640 }}</ref> It is also used for the management of chronic inflammatory bowel disease, gastrointestinal infections, periodontal disease, and systemic infections in cats and dogs.<ref name="Hoskins-2001">{{cite news | vauthors = Hoskins JD | title = Advances in managing inflammatory bowel disease | date = 1 October 2001 | url = http://veterinarynews.dvm360.com/dvm/Gastroenterology/Advances-in-managing-inflammatory-bowel-disease/ArticleStandard/Article/detail/3000 | newspaper = DVM Newsmagazine | access-date = 28 December 2013 | url-status = live | archive-url = https://web.archive.org/web/20131231000212/http://veterinarynews.dvm360.com/dvm/Gastroenterology/Advances-in-managing-inflammatory-bowel-disease/ArticleStandard/Article/detail/3000 | archive-date = 31 December 2013 }}</ref><ref>{{Cite web |title=METRONIDAZOLE (Veterinary—Systemic) |url=https://cdn.ymaws.com/www.aavpt.org/resource/resmgr/imported/metronidazole.pdf |access-date=4 July 2024}}</ref> Another common usage is the treatment of systemic and/or gastrointestinal [[clostridia]]l infections in horses. Metronidazole is used in the aquarium hobby to treat ornamental fish and as a broad-spectrum treatment for bacterial and protozoan infections in reptiles and amphibians. In general, the veterinary community may use metronidazole for any potentially susceptible anaerobic infection. The U.S. [[Food and Drug Administration]] (FDA) suggests it only be used when necessary because it has been shown to be carcinogenic in mice and rats, as well as to prevent antimicrobial resistance.<ref name="Plumb-2008">{{cite book | vauthors = Plumb DC | title = Veterinary Drug Handbook | edition = 6th | publisher = Wiley | year = 2008 | isbn = 978-0-8138-2056-9 }}</ref><ref name="Drugs.com">{{cite web | title = Metronidazole | publisher = Drugs.com | url = https://www.drugs.com/pro/metronidazole.html | url-status = live | archive-url = https://web.archive.org/web/20130624052834/http://www.drugs.com/pro/metronidazole.html | archive-date = 24 June 2013 }}</ref> The appropriate dosage of metronidazole varies based on the animal species, the condition being treated and the specific formulation of the product.<ref>{{Cite web |title=Metronidazole For Dogs: Safe Dosages And Uses |url=https://www.forbes.com/advisor/pet-insurance/pet-care/metronidazole-for-dogs/ |access-date=2024-07-04 |website=Forbes }}</ref> == References == {{Reflist}} == External links == * {{cite web| url = https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/metronidazole-and-tinidazole | work = Merck manuals| title = Metronidazole and Tinidazole }} {{Stomatological preparations}} {{Antibiotics and chemotherapeutics for dermatological use}} {{Gynecological anti-infectives and antiseptics}} {{Other antibacterials}} {{Agents against amoebiasis and other protozoal diseases}} {{Excavata antiparasitics}} {{Agents against amoebozoa}} {{Portal bar|Medicine}} [[Category:Drugs developed by AbbVie]] [[Category:Antiprotozoal agents]] [[Category:Disulfiram-like drugs]] [[Category:Fishkeeping]] [[Category:French inventions]] [[Category:IARC Group 2B carcinogens]] [[Category:Nitroimidazole antibiotics]] [[Category:Drugs developed by Pfizer]] [[Category:Wikipedia medicine articles ready to translate]] [[Category:Sanofi]] [[Category:World Health Organization essential medicines]]'