View source for Benzydamine

{{Short description|Locally acting nonsteroidal anti-inflammatory drug}}
{{Infobox drug
| verifiedrevid      = 414278352
| IUPAC_name         = 3-(1-benzyl-1''H''-indazol-3-yloxy)-''N,N''-dimethylpropan-1-amine
| image              = Benzydamine-2D-skeletal.png
| image_class = skin-invert-image
<!--Clinical data-->| tradename          = Maxtra Gargle, Difflam, Tantum verde
| Drugs.com          = {{drugs.com|international|benzydamine}}
| pregnancy_AU       = B2
| legal_BR           = C1
| legal_BR_comment   = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>
| legal_UK           = P and POM
| legal_UK_comment   = <ref>{{cite web |title=Benzydamine hydrochloride Medicinal forms |website=BNF |url=https://bnf.nice.org.uk/drugs/benzydamine-hydrochloride/medicinal-forms/ |access-date=12 April 2025}}</ref>
| legal_EU           = OTC
| legal_EU_comment   = 
| routes_of_administration = Oral, topical
<!--Pharmacokinetic data-->| bioavailability    = 
| protein_bound      = <20%
| metabolism         = 
| elimination_half-life = 13 hours
| excretion          = [[Kidney]]
<!--Identifiers-->| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 642-72-8
| ATC_prefix         = A01
| ATC_suffix         = AD02
| ATC_supplemental   = <br />{{ATC|G02|CC03}}<br />{{ATC|M01|AX07}}<br />{{ATC|M02|AA05}}<br />{{ATC|R02|AX03}}
| PubChem            = 12555
| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
| ChemSpiderID       = 12036
| ChEBI_Ref          = {{ebicite|correct|EBI}}
| ChEBI              = 94563
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = 4O21U048EF
| KEGG_Ref           = {{keggcite|correct|kegg}}
| KEGG               = D07516
| ChEMBL_Ref         = {{ebicite|correct|EBI}}
| ChEMBL             = 12610
<!--Chemical data-->| C                  = 19
| H                  = 23
| N                  = 3
| O                  = 1
| smiles             = n2c(OCCCN(C)C)c1ccccc1n2Cc3ccccc3
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| StdInChI           = 1S/C19H23N3O/c1-21(2)13-8-14-23-19-17-11-6-7-12-18(17)22(20-19)15-16-9-4-3-5-10-16/h3-7,9-12H,8,13-15H2,1-2H3
| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
| StdInChIKey        = CNBGNNVCVSKAQZ-UHFFFAOYSA-N
}}

'''Benzydamine''' (also known as '''Tantum Verde''' and branded in some countries as Maxtra Gargle, Difflam and Septabene), available as the [[hydrochloride]] salt, is a locally acting [[nonsteroidal anti-inflammatory drug]] (NSAID) with local [[anaesthetic]] and [[analgesic]] properties for [[pain management|pain relief]] and [[anti-inflammatory]] treatment of [[Inflammation#Types|inflammatory conditions]] of the [[mouth]] and [[throat]].<ref>{{cite journal | vauthors = Turnbull RS | title = Benzydamine Hydrochloride (Tantum) in the management of oral inflammatory conditions | journal = Journal | volume = 61 | issue = 2 | pages = 127–34 | date = February 1995 | pmid = 7600413 }}</ref> It falls under class of chemicals known as [[indazole]].

==History==
It was synthesized in Italy in 1964 and marketed in 1966.<ref name="flipper6989">{{cite web|url=https://flipper.diff.org/app/items/info/6989|title=DEXTROMETHORPHAN AND BENZYDAMINE'S USE AND MISUSE|website=Flipper.diff.org|access-date=25 June 2022}}</ref>

==Uses==
===Medical===
* [[odontology|Odonto]][[stomatology]]: [[gingivitis]], [[stomatitis]], [[glossitis]], [[aphthous ulcers]], [[dental surgery]] and oral [[Mouth ulcer|ulceration]] due to [[radiation therapy]].
* Otorhinolaryngology: [[glandular fever]], [[pharyngitis]], [[tonsillitis]], post-[[tonsillectomy]], [[radiation]] or [[intubation]] [[mucositis]].
It may be used alone or as an adjunct to other therapy giving the possibility of increased [[therapeutic effect]] with little risk of interaction.

In some markets, the drug is supplied as an over-the-counter cream (Lonol in Mexico from [[Boehringer Ingelheim]]) used for topical treatment of musculoskeletal system disorders: sprains, strains, bursitis, tendinitis, synovitis, myalgia, periarthritis.

===Recreational===
Benzydamine has been used recreationally. If taken in excess amounts, it acts as a [[deliriant]] and [[CNS stimulant]].<ref name=clintox /> Such use, particularly among teenagers, has been reported in Brazil,<ref>{{cite journal | vauthors = Opaleye ES, Noto AR, Sanchez Z, Moura YG, Galduróz JC, Carlini EA | title = Recreational use of benzydamine as a hallucinogen among street youth in Brazil | journal = Revista Brasileira de Psiquiatria | volume = 31 | issue = 3 | pages = 208–13 | date = September 2009 | pmid = 19784487 | doi = 10.1590/S1516-44462009000300005 | doi-access = free}}</ref><ref>{{cite journal | vauthors = Mota DM, Costa AA, Teixeira C, Bastos AA, Dias MF | title =Use abusive of benzydamine in Brazil: an overview in pharmacovigilance | language = pt | journal = Ciencia & Saude Coletiva | volume = 15 | issue = 3 | pages = 717–24 | date = May 2010 | pmid = 20464184 | doi = 10.1590/S1413-81232010000300014 | doi-access = free}}</ref> Poland,<ref name=clintox/> Romania, and Turkey.{{citation needed|date=February 2023}}

==Contraindications==
There are no contraindications to the use of benzydamine except for known [[hypersensitivity]].

==Side effects==
Benzydamine is well tolerated. Occasionally oral tissue numbness or stinging sensations may occur, as well as itching, a skin rash, skin swelling or redness, difficulty breathing and wheezing.

==Pharmacology==
It selectively binds to inflamed tissues ([[Prostaglandin#Biosynthesis|Prostaglandin synthetase inhibitor]]) and is normally free of adverse systemic effects.
Unlike other NSAIDs, it does not inhibit cyclooxygenase or lipooxygenase, and is not ulcerogenic.<ref name=clintox>{{cite journal |vauthors=Anand JS, Glebocka ML, Korolkiewicz RP |title=Recreational abuse with benzydamine hydrochloride (tantum rosa) |journal=Clinical Toxicology |volume=45 |issue=2 |pages=198–9 |year=2007 |pmid=17364645 |doi=10.1080/15563650600981210 |doi-access=free}}</ref><ref name="pmid3304305">{{cite journal |vauthors=Müller-Peddinghaus R |title=New pharmacologic and biochemical findings on the mechanism of action of the non-steroidal antiphlogistic, benzydamine. A synopsis |language=German |journal=[[Arzneimittel-Forschung]] |volume=37 |issue=5A |pages=635–45 |date=May 1987 |pmid=3304305}}</ref>

It is described as having powerful [[Reinforcement|reinforcing]] effects in animals and showing cross-sensitization with [[drug misuse|drugs of misuse]] such as [[heroin]] and [[cocaine]]. It is hypothesized that it has [[cannabinoid]] agonistic activity and this may account for its [[recreational drug|recreational]] and [[hallucinogen]]ic effects.<ref name="pmid28429885" /> However, it has also been theorized that, based on structural similarity to [[lysergic acid diethylamide]] (LSD) and descriptions of its visual hallucinatory effects, benzydamine might be acting as a [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] [[agonist]] and hence as a [[serotonergic psychedelic]].<ref name="ŐszJîtcăSălcudean2023">{{cite journal | vauthors = Ősz BE, Jîtcă G, Sălcudean A, Rusz CM, Vari CE | title = Benzydamine-An Affordable Over-the-Counter Drug with Psychoactive Properties-From Chemical Structure to Possible Pharmacological Properties | journal = Pharmaceuticals (Basel) | volume = 16 | issue = 4 | date = April 2023 | page = 566 | pmid = 37111323 | pmc = 10144213 | doi = 10.3390/ph16040566 | doi-access = free | url = }}</ref><ref name="ChiappiniMiuliMosca2021">{{cite journal | vauthors = Chiappini S, Miuli A, Mosca A, Pettorruso M, Guirguis A, John MC, Martinotti G, Di Giannantonio M, Schifano F | title = The Benzydamine Experience: A Systematic Review of Benzydamine Abuse | journal = Curr Neuropharmacol | volume = 19 | issue = 10 | pages = 1728–1737 | date = October 2021 | pmid = 33441070 | pmc = 8977632 | doi = 10.2174/1570159X19666210113151136 | url = }}</ref> More research is needed to determine the [[mechanism of action]] of the effects of benzydamine as a drug of misuse.<ref name="ŐszJîtcăSălcudean2023" /><ref name="ChiappiniMiuliMosca2021" />

===Pharmacokinetic===
Benzydamine is poorly absorbed through skin<ref name="pmid1932611">{{cite journal |vauthors=Baldock GA, Brodie RR, Chasseaud LF, Taylor T, Walmsley LM, Catanese B |title=Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects |journal=[[Biopharmaceutics & Drug Disposition]] |volume=12 |issue=7 |pages=481–92 |date=October 1991 |pmid=1932611 |doi=10.1002/bdd.2510120702|s2cid=42167110 }}</ref> and vagina.<ref name="pmid3610512">{{cite journal |vauthors=Maamer M, Aurousseau M, Colau JC |title=Concentration of benzydamine in vaginal mucosa following local application: an experimental and clinical study |journal=[[International Journal of Tissue Reactions]] |volume=9 |issue=2 |pages=135–45 |date=1987 |pmid=3610512}}</ref>

==Synthesis==
[[File:Benzydamine synthesis.svg|class=skin-invert-image|thumb|center|500px|Benzydamine synthesis:<ref name=Palazzo>{{cite journal | vauthors = Palazzo G, Corsi G, Baiocchi L, Silvestrini B | title = Synthesis and pharmacological properties of 1-substituted 3-dimethylaminoalkoxy-1H-indazoles | journal = Journal of Medicinal Chemistry | volume = 9 | issue = 1 | pages = 38–41 | date = January 1966 | pmid = 5958958 | doi = 10.1021/jm00319a009}}</ref><ref>{{cite patent|country=FR|number=1382855}}; Palazzo, {{US patent|3318905}} (1964, 1967 both to Angelini Francesco).</ref>]]
Synthesis starts with the reaction of the ''N''-benzyl derivative from [[methyl anthranilate]] with [[nitrous acid]] to give the ''N''-nitroso derivative. Reduction by means of [[sodium thiosulfate]] leads to the transient hydrazine ('''3'''), which undergoes spontaneous internal hydrazide formation. Treatment of the enolate of this amide with 3-chloro-1-dimethylamino propane gives benzydamine ('''5'''). Please note there is an error in this section: US3318905 states that the nitroso derivative is reduced with sodium hydrosulfite (sodium dithionite) and not with sodium hyposulfite (sodium thiosulfate), as shown in the above scheme and stated in text. 
[[File:Benzydamine synthesis 2.svg|class=skin-invert-image|thumb|center|500px|<ref name=Palazzo/><ref>{{cite journal | vauthors = Baiocchi L, Corsi G, Palazzo G | title = Ricerche nel campo degli indazoli.—Nota 1. Sulla ciclizzazione termica di azidi di acidi N-aril-N-benzil-carbamici. | journal = Annali di Chimica | date = 1965 | volume = 55 | pages = 116–25 }}</ref>]]
An interesting alternative synthesis of this substance starts by sequential reaction of ''N''-benzylaniline with [[phosgene]], and then with [[sodium azide]] to product the corresponding carbonyl azide. On heating, nitrogen is evolved and a separatable mixture of [[nitrene]] insertion product and the desired ketoindazole # results. The latter reaction appears to be a [[Curtius rearrangement]] type product to produce an N-isocyanate #, which then cyclizes. Alkylation of the enol with sodium methoxide and 3-dimethylaminopropyl chloride gives benzydamine.

Alternatively, use of [[chloroacetamide]] in the alkylation step followed by acid hydrolysis produces [[bendazac]] instead.

==Research==
Studies indicate that benzydamine has notable [[in vitro]] [[antibacterial]] activity and also shows synergism in combination with other antibiotics, especially tetracyclines, against antibiotic-resistant strains of [[Staphylococcus aureus]] and [[Pseudomonas aeruginosa]].<ref>{{cite journal | vauthors = Fanaki NH, el-Nakeeb MA | title = Antimicrobial activity of benzydamine, a non-steroid anti-inflammatory agent | journal = Journal of Chemotherapy | volume = 4 | issue = 6 | pages = 347–52 | date = December 1992 | pmid = 1287137 | doi = 10.1080/1120009X.1992.11739190 }}</ref><ref>{{cite journal | vauthors = Fanaki NH, El-Nakeeb MA | title = Antibacterial activity of benzydamine and antibiotic-benzydamine combinations against multifold resistant clinical isolates | journal = Arzneimittel-Forschung | volume = 46 | issue = 3 | pages = 320–3 | date = March 1996 | pmid = 8901158 }}</ref>

It also has some [[Cannabinoid receptor|cannabinoid]] activity in rats but has not been tested in humans.<ref name="pmid28429885">{{cite journal |vauthors=Avvisati R, Meringolo M, Stendardo E, Malavasi E, Marinelli S, Badiani A |title=Intravenous self-administration of benzydamine, a non-steroidal anti-inflammatory drug with a central cannabinoidergic mechanism of action |journal=[[Addiction Biology]] |volume=23 |issue=2 |pages=610–619 |date=March 2018 |pmid=28429885 |doi=10.1111/adb.12516 |s2cid=206970991 |url=http://sro.sussex.ac.uk/id/eprint/67500/1/__smbhome.uscs.susx.ac.uk_ellenaj_Desktop_SRO_Avvisati_BZY_R2.pdf}}</ref> It is also hypothesized to act on [[5-HT2A receptor|5-HT2A]] receptors due to its structural similarity with [[serotonin]].<ref name="flipper6989" />

== See also ==
* [[AB-FUBINACA]]
* [[Pravadoline]]
* [[GW-405,833]]
* [[Bendazac]]

== References ==
{{Reflist}}

== External links ==
* {{ cite web 
| url = http://www.medicinenet.com/benzydamine-oral_rinse/article.htm
| title = Benzydamine oral rinse
| publisher = Medicinenet
}}
* {{ cite web
| url = http://www.netdoctor.co.uk/medicines/100003456.html
| title = Difflam spray (benzydamine)
| date = 8 March 2020
| publisher = Net Doctor, UK
}}
* {{cite web
 |url=http://tantumverde.ie/ 
 |title=Tantum Verde (benzydamine) 
 |publisher=Carysfort Healthcare Limited, Ireland 
 |url-status=dead 
 |archive-url=https://web.archive.org/web/20151125211741/http://tantumverde.ie/ 
 |archive-date=2015-11-25 
}}

{{Stomatological preparations}}
{{Anti-inflammatory and antirheumatic products}}
{{Topical products for joint and muscular pain}}
{{Stimulants}}
{{Prolactin inhibitors and anti-inflammatory products for vaginal administration}}
{{Hallucinogens}}
{{Muscarinic acetylcholine receptor modulators}}
{{Authority control}}

[[Category:Nonsteroidal anti-inflammatory drugs]]
[[Category:Indazoles]]
[[Category:Dimethylamino compounds]]
[[Category:Dental drugs]]
[[Category:Benzyl compounds]]
[[Category:Muscarinic antagonists]]
[[Category:Aromatic ethers]]