Chemistry:Chlorhexidine

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Short description: Disinfectant and antiseptic
Chlorhexidine
Chlorhexidin.svg
Chlorhexidine 3D spacefill.png
Clinical data
Pronunciationklɔː(r)ˈhɛksɪdiːn
Trade namesBetasept, ChloraPrep, Chlorostat, others
Other namesCHX, CHG, 1,6-bis(4-chloro-phenylbiguanido)hexane
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: A
Routes of
administration		Topical
ATC code
Legal status
Legal status
  • AU: S5, S6, S7
  • US: OTC / Rx-only
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC22H30Cl2N10
Molar mass505.45 g·mol−1
3D model (JSmol)
Melting point134 to 136 °C (273 to 277 °F)
Solubility in water0.8
  (verify)

Chlorhexidine[1] is a disinfectant and antiseptic with the molecular formula C22H30Cl2N10, which is used for skin disinfection before surgery and to sterilize surgical instruments.[2] It is also used for cleaning wounds, preventing dental plaque, treating yeast infections of the mouth, and to keep urinary catheters from blocking.[3] It is used as a liquid or a powder.[2][3] It is commonly used in salt form, either the gluconate[4] or the acetate.[5]

Side effects may include skin irritation, tooth discoloration, and allergic reactions,[3] although the risk appears to be the same as other topical antiseptics.[6][7] Chlorhexidine rinse is also known to have a bitter metallic aftertaste. Rinsing with water is not recommended as it is known to increase the bitterness.[8] It may cause eye problems if direct contact occurs.[9][10] Use in pregnancy appears to be safe.[11] Chlorhexidine may come mixed in alcohol,[12][13][14] water, or surfactant solution.[3] It is effective against a range of microorganisms, but does not inactivate spores.[2]

Chlorhexidine came into medical use in the 1950s.[15] Chlorhexidine is available over the counter in the United States .[9] It is on the World Health Organization's List of Essential Medicines.[16][17] In 2021, it was the 247th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[18][19]

Uses

Chlorhexidine is used in disinfectants (disinfection of the skin and hands), cosmetics (additive to creams, toothpaste, deodorants, and antiperspirants), and pharmaceutical products (preservative in eye drops, active substance in wound dressings and antiseptic mouthwashes).[20] A 2019 Cochrane review concluded that based on very low certainty evidence in those who are critically ill "it is not clear whether bathing with chlorhexidine reduces hospital-acquired infections, mortality, or length of stay in the intensive care unit (ICU), or whether the use of chlorhexidine results in more skin reactions."[21]

In endodontics, chlorhexidine has been used for root canal irrigation and as an intracanal dressing.[22][23] It has however been replaced by the use of sodium hypochlorite bleach in much of the developed world.[citation needed]

Antiseptic

Chlorhexidine is active against Gram-positive and Gram-negative organisms, facultative anaerobes, aerobes, and yeasts.[24] It is particularly effective against Gram-positive bacteria (in concentrations ≥ 1 μg/L). Significantly higher concentrations (10 to more than 73 μg/mL) are required for Gram-negative bacteria and fungi. Chlorhexidine is ineffective against polioviruses and adenoviruses. The effectiveness against herpes viruses has not yet been established unequivocally.[25]

There is strong evidence that chlorhexidine is more effective than povidone-iodine for clean surgery.[26][27] Evidence shows that it is an effective antiseptic for upper limb surgery.[6]

Meta-data spanning several decades shows that the efficacy of chlorhexidine (against organisms that cause surgical site infection) has not changed,[28] dispelling concerns over emerging resistance.

Dental use

Perichlor brand 0.12% chlorhexidine gluconate solution

Use of a chlorhexidine-based mouthwash in combination with normal tooth care can help reduce the build-up of plaque and improve mild gingivitis.[29] There is not enough evidence to determine the effect in moderate to severe gingivitis.[29] Its use as a mouthwash has a number of adverse effects including damage to the mouth lining, tooth discoloration, tartar build-up, and impaired taste.[29] Extrinsic tooth staining occurs when chlorhexidine rinse has been used for four weeks or longer.[29]

Mouthwashes containing chlorhexidine which stain teeth less than the classic solution have been developed, many of which contain chelated zinc.[30][31][32]

Chlorhexidine is a cation which interacts with anionic components of toothpaste, such as sodium lauryl sulfate and sodium monofluorophosphate, and forms salts of low solubility and reduced antibacterial activity. Hence, to enhance the antiplaque effect of chlorhexidine, "it seems best that the interval between toothbrushing and rinsing with CHX [chlorhexidine] be more than 30 minutes, cautiously close to two hours after brushing".[33]

Topical

Chlorhexidine gluconate is used as a skin cleanser for surgical scrubs, as a cleanser for skin wounds, for preoperative skin preparation, and for germicidal hand rinses.[24] Chlorhexidine eye drops have been used as a treatment for eyes affected by Acanthamoeba keratitis.[34]

Chlorhexidine is very effective for poor countries like Nepal and its use is growing in the world for treating the umbilical cord. A 2015 Cochrane review has yielded high-quality evidence that within the community setting, chlorhexidine skin or cord care can reduce the incidence of omphalitis (inflammation of the umbilical cord) by 50% and neonatal mortality by 12%.[35]

Side effects

Chlorhexidine is ototoxic (toxic to the inner ear). If put into a ruptured ear canal if may lead to deafness.[36]

Chlorhexidine does not meet European specifications for a hand disinfectant. Under the test conditions of the European Standard EN 1499, no significant difference in the efficacy was found between a 4% solution of chlorhexidine digluconate and soap.[25] In the US, between 2007 and 2009, Hunter Holmes McGuire Veterans Administration Medical Center conducted a cluster-randomized trial and concluded that daily bathing of patients in intensive care units with washcloths saturated with chlorhexidine gluconate reduced the risk of hospital-acquired infections.[37]

Whether prolonged exposure over many years may have carcinogenic potential is still not clear. The US Food and Drug Administration recommendation is to limit the use of a chlorhexidine gluconate mouthwash to a maximum of six months.[38]

When ingested, chlorhexidine is poorly absorbed in the gastrointestinal tract and can cause stomach irritation or nausea.[39][40] If aspirated into the lungs at high enough concentration, as reported in one case, it can be fatal due to the high risk of acute respiratory distress syndrome.[40][41]

Mechanism of action

At physiologic pH, chlorhexidine salts dissociate and release the positively charged chlorhexidine cation. The bactericidal effect is a result of the binding of this cationic molecule to negatively charged bacterial cell walls. At low concentrations of chlorhexidine, this results in a bacteriostatic effect; at high concentrations, membrane disruption results in cell death.[24]

Chemistry

It is a cationic polybiguanide (bisbiguanide).[42]

Deactivation

Chlorhexidine is deactivated by forming insoluble salts with anionic compounds, including the anionic surfactants commonly used as detergents in toothpastes and mouthwashes, anionic thickeners such as carbomer, and anionic emulsifiers such as acrylates/C10-30 alkyl acrylate crosspolymer, among many others. For this reason, chlorhexidine mouth rinses should be used at least 30 minutes after other dental products.[43]

Synthesis

The structure is based on two molecules of proguanil, linked with a hexamethylenediamine spacer.

Two routes for chlorhexidine synthesis:[44] U.S. Patent 2,684,924 (1954 to I.C.I.). The compounds designated (...)2 are substituted hexanes.

Society and culture

Brands

Chlorhexidine topical is sold as Betasept, Biopatch, Calgon Vesta, ChloraPrep One-Step, Dyna-Hex, Hibiclens, Hibistat Towelette, Scrub Care Exidine, Spectrum-4 among others.[45]

Chlorhexidine gluconate mouthwash is sold as Dentohexin, Paroex, Peridex, PerioChip, Corsodyl and Periogard, among others.[46]

Veterinary medicine

In animals, chlorhexidine is used for topical disinfection of wounds,[47] and to manage skin infections.[48] Chlorhexidine-based disinfectant products are used in the dairy farming industry.[49]

Post-surgical respiratory problems have been associated with the use of chlorhexidine products in cats.[50]

References

  1. ↑ "Chlorhexidine (CHX) in dentistry: state of the art". Minerva Stomatologica 61 (9): 399–419. September 2012. PMID 22976567. https://pubmed.ncbi.nlm.nih.gov/22976567/. Retrieved 30 September 2021. 
  2. ↑ 2.0 2.1 2.2 WHO Model Formulary 2008. World Health Organization. 2009. pp. 321–22. ISBN 9789241547659. 
  3. ↑ 3.0 3.1 3.2 3.3 British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. pp. 568, 791, 839. ISBN 9780857111562. 
  4. ↑ "Chlorhexidine Gluconate". https://pubchem.ncbi.nlm.nih.gov/compound/Chlorhexidine-Gluconate. 
  5. ↑ "Chlorhexidine Acetate". https://pubchem.ncbi.nlm.nih.gov/compound/Chlorhexidine-Acetate. 
  6. ↑ 6.0 6.1 "Chlorhexidine versus povidone-iodine skin antisepsis before upper limb surgery (CIPHUR): an international multicentre prospective cohort study". BJS Open 5 (6): zrab117. November 2021. doi:10.1093/bjsopen/zrab117. PMID 34915557. 
  7. ↑ "The Comparative Efficacy of Chlorhexidine Gluconate and Povidone-iodine Antiseptics for the Prevention of Infection in Clean Surgery: A Systematic Review and Network Meta-analysis". Annals of Surgery 274 (6): e481–e488. December 2021. doi:10.1097/SLA.0000000000004076. PMID 32773627. 
  8. ↑ "Chlorhexidine (Oral Route) Precautions - Mayo Clinic". https://www.mayoclinic.org/drugs-supplements/chlorhexidine-oral-route/precautions/drg-20068551. 
  9. ↑ 9.0 9.1 "Chlorhexidine Gluconate topical". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/chlorhexidine-gluconate-topical.html. 
  10. ↑ Tabor, Edward; Bostwick, D. C.; Evans, C. C. (1989). "Corneal Damage due to Eye Contact with Chlorhexidine Gluconate". JAMA: The Journal of the American Medical Association 261 (4): 557–558. doi:10.1001/jama.1989.03420040091021. PMID 2909794. https://jamanetwork.com/journals/jama/article-abstract/376080. 
  11. ↑ Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams & Wilkins. 2011. p. 252. ISBN 9781608317080. https://books.google.com/books?id=OIgTE4aynrMC&pg=PA252. 
  12. ↑ "Prevantics Swab- chlorhexidine gluconate and isopropyl alcohol solution". 26 October 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=db61e7fd-c421-4e3c-bc88-0343230273de. 
  13. ↑ "Prevantics Swab- chlorhexidine gluconate and isopropyl alcohol solution". 26 October 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ff999b50-0b6b-404e-b4f1-c6694fe47a9b. 
  14. ↑ "Prevantics Maxi Swabstick- chlorhexidine gluconate and isopropyl alcohol solution". 26 October 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93ca3c07-40b4-3a91-e053-2995a90a0afd. 
  15. ↑ Biocompatibility of Dental Materials. Springer Science & Business Media. 2008. p. 351. ISBN 9783540777823. https://books.google.com/books?id=mrreTHuo54wC&pg=PA351. 
  16. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  17. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  18. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  19. ↑ "Chlorhexidine - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Chlorhexidine. 
  20. ↑ Thomas Güthner (2007), "Guanidine and Derivatives", Ullman's Encyclopedia of Industrial Chemistry (7th ed.), Wiley, p. 13 
  21. ↑ "Chlorhexidine bathing of the critically ill for the prevention of hospital-acquired infection". The Cochrane Database of Systematic Reviews 8 (8): CD012248. August 2019. doi:10.1002/14651858.CD012248.pub2. PMID 31476022. 
  22. ↑ "Preparation of contaminated root canal systems – the importance of antimicrobial irrigants.". Dental Inc.: 34–36. July–August 2008. 
  23. ↑ "Die Bedeutung chemischer Spülungen in der Endodontie". Endodontie Journal (2): 22–23. 2010. http://www.oemus.com/archiv/pub/sim/ej/2010/ej0210/ej0210_22_23_raab.pdf. [yes|permanent dead link|dead link}}]
  24. ↑ 24.0 24.1 24.2 "Chlorhexidine Gluconate". Poisoning and Toxicology Handbook (4th ed.). Informa. 2008. pp. 183–84. 
  25. ↑ 25.0 25.1 Ullman's Encyclopedia of Industrial Chemistry (7th ed.). Wiley. 2007. pp. 10–11. 
  26. ↑ "The Comparative Efficacy of Chlorhexidine Gluconate and Povidone-iodine Antiseptics for the Prevention of Infection in Clean Surgery: A Systematic Review and Network Meta-analysis". Annals of Surgery 274 (6): e481–e488. December 2021. doi:10.1097/SLA.0000000000004076. PMID 32773627. 
  27. ↑ "Preoperative skin antiseptics for preventing surgical wound infections after clean surgery". The Cochrane Database of Systematic Reviews 2015 (4): CD003949. April 2015. doi:10.1002/14651858.CD003949.pub4. PMID 25897764. 
  28. ↑ "Bacterial sensitivity to chlorhexidine and povidone-iodine antiseptics over time: a systematic review and meta-analysis of human-derived data". Scientific Reports 13 (1): 347. January 2023. doi:10.1038/s41598-022-26658-1. PMID 36611032. Bibcode: 2023NatSR..13..347A. 
  29. ↑ 29.0 29.1 29.2 29.3 "Chlorhexidine mouthrinse as an adjunctive treatment for gingival health". The Cochrane Database of Systematic Reviews 3 (3): CD008676. March 2017. doi:10.1002/14651858.CD008676.pub2. PMID 28362061. 
  30. ↑ "Chlorhexidine with an Anti Discoloration System. A comparative study". International Journal of Dental Hygiene 2 (3): 122–126. August 2004. doi:10.1111/j.1601-5037.2004.00083.x. PMID 16451475. 
  31. ↑ "The effect of a dentifrice containing chlorhexidine and zinc on plaque, gingivitis, calculus and tooth staining". Journal of Clinical Periodontology 21 (6): 431–437. July 1994. doi:10.1111/j.1600-051X.1994.tb00741.x. PMID 8089246. 
  32. ↑ "Effectiveness of a mouthrinse containing active ingredients in addition to chlorhexidine and triclosan compared with chlorhexidine and triclosan rinses on plaque, gingivitis, supragingival calculus and extrinsic staining". International Journal of Dental Hygiene 11 (1): 35–40. February 2013. doi:10.1111/j.1601-5037.2012.00560.x. PMID 22672130. 
  33. ↑ "Rinsing with chlorhexidine gluconate solution after brushing and flossing teeth: a systematic review of effectiveness". Quintessence International 37 (8): 605–612. September 2006. PMID 16922019. 
  34. ↑ "Medical interventions for acanthamoeba keratitis". The Cochrane Database of Systematic Reviews 2015 (2): CD010792. February 2015. doi:10.1002/14651858.CD010792.pub2. PMID 25710134. 
  35. ↑ "Chlorhexidine skin or cord care for prevention of mortality and infections in neonates". The Cochrane Database of Systematic Reviews 2015 (3): CD007835. March 2015. doi:10.1002/14651858.CD007835.pub2. PMID 25739381. 
  36. ↑ "Chlorhexidine ototoxicity in ear surgery, part 1: review of the literature". Journal of Otolaryngology - Head & Neck Surgery 40 (6): 437–440. December 2011. PMID 22420428. 
  37. ↑ "Daily Bathing With Antiseptic Agent Significantly Reduces Risk of Hospital-Acquired Infections in Intensive Care Unit Patients". Agency for Healthcare Research and Quality. 23 April 2014. https://innovations.ahrq.gov/profiles/daily-bathing-antiseptic-agent-significantly-reduces-risk-hospital-acquired-infections. 
  38. ↑ "Measurements of chlorhexidine, p-chloroaniline, and p-chloronitrobenzene in saliva after mouth wash before and after operation with 0.2% chlorhexidine digluconate in maxillofacial surgery: a randomised controlled trial". The British Journal of Oral & Maxillofacial Surgery 55 (2): 150–155. February 2017. doi:10.1016/j.bjoms.2016.10.007. PMID 27789177. 
  39. ↑ "Chlorhexidine Adverse Effects". https://www.poison.org/articles/chlorhexidine-adverse-effects-172. 
  40. ↑ 40.0 40.1 "Chlorhexidine". Pubchem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/chlorhexidine#section=Human-Toxicity-Excerpts. 
  41. ↑ "Chlorhexidine gluconate ingestion resulting in fatal respiratory distress syndrome". Veterinary and Human Toxicology 44 (2): 89–91. April 2002. PMID 11931511. "An 80-y-old woman with dementia accidentally ingested approximately 200 mL of Maskin (5% chlorhexidine) in a nursing home and then presumably aspirated gastric contents.". 
  42. ↑ "Structural requirements of guanide, biguanide, and bisbiguanide agents for antiplaque activity". Antimicrobial Agents and Chemotherapy 12 (6): 721–729. December 1977. doi:10.1128/aac.12.6.721. PMID 931371. 
  43. ↑ "Chlorhexidine". Disinfection, Sterilization, and Preservation (5th ed.). Lippincott Williams & Wilkins. 2000. pp. 321–36. ISBN 978-0-683-30740-5. https://books.google.com/books?id=3f-kPJ17_TYC&pg=PA321. Retrieved 10 October 2016. 
  44. ↑ "850. Bisdiguanides having antibacterial activity". Journal of the Chemical Society (Resumed): 4422–4425. 1956. doi:10.1039/JR9560004422. 
  45. ↑ "Hibiclens Uses, Side Effects & Warnings - Drugs.com". https://www.drugs.com/mtm/hibiclens.html. 
  46. ↑ "Chlorhexidine gluconate Uses, Side Effects & Warnings - Drugs.com". https://www.drugs.com/mtm/chlorhexidine-gluconate-oral-rinse.html. 
  47. ↑ "Chapter 2. Wound management: a new protocol for dogs and cats. Chlorhexidine solution". Reconstructive Surgery and Wound Management of the Dog and Cat. CRC Press. 2013. ISBN 9781482261455. 
  48. ↑ "Antimicrobial agents. Chlorhexidine". Small Animal Clinical Pharmacology. Elsevier Health Sciences. 2008. p. 552. ISBN 978-0702028588. 
  49. ↑ Mastitis Control in Dairy Herds. CABI. 2010. p. 120. ISBN 9781845937515. 
  50. ↑ "Post-Surgical Respiratory Distress in Cats Associated with Chlorhexidine Surgical Scrubs". ADDL Newsletters. Indiana Animal Disease Diagnostic Laboratory. Winter 1996. http://www.addl.purdue.edu/newsletters/1996/winter/psrd.shtml. 



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