Chlorhexidine

Chlorhexidine
Systematic (IUPAC) name
N,N′′′′1,6-Hexanediylbis[N′-(4-chlorophenyl)(imidodicarbonimidic diamide)]
Clinical data
Trade names Avagard, BactoShield CHG, Betasept, ChloraPrep, Chlorostat, Corsodyl, Dyna-Hex, Hibiclens, Hibistat, Operand Chlorhexidine Gluconate, Peridex, PerioChip, PerioGard
AHFS/Drugs.com FDA Professional Drug Information
Legal status
Legal status
Identifiers
CAS Number 55-56-1 YesY
ATC code A01AB03 (WHO) B05CA02, D08AC02, D09AA12 (dressing), R02AA05, S01AX09, S02AA09, S03AA04
PubChem CID 5353524
DrugBank DB00878 YesY
ChemSpider 2612 YesY
UNII R4KO0DY52L YesY
KEGG D07668 YesY
ChEBI CHEBI:3614 YesY
ChEMBL CHEMBL790 YesY
Synonyms 1,6-bis(4-chloro-phenylbiguanido)hexan
Chemical data
Formula C22H30Cl2N10
Molar mass 505.446 g/mol
Physical data
Solubility in water 0.0008 mg/mL (20 °C)
  (verify)

Chlorhexidine is an antibacterial used as an antiseptic and for other applications. It is a cationic polybiguanide (bisbiguanide). It is used primarily as its salts (e.g., the dihydrochloride, diacetate, and digluconate).

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[1]

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).[2]

Antiseptic

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.[3]

Chlorhexidine is active against Gram-positive and Gram-negative organisms, facultative anaerobes, aerobes, and yeasts.[3] 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.[4]

Chlorhexidine, like other cation-active compounds, remains on the skin. It is frequently combined with alcohols (ethanol and isopropyl alcohol).

Dental use

Perichlor brand 0.12% chlorhexidine gluconate solution.

Chlorhexidine is often used as an active ingredient in mouthwash designed to reduce dental plaque and oral bacteria. It has been shown to have an immediate bactericidal action and a prolonged bacteriostatic action due to adsorption onto the pellicle-coated enamel surface.[5] If it is not deactivated, chlorhexidine lasts longer in the mouth than other mouthwashes, which is partly why it is to be preferred over other treatments for gingivitis.[6] To treat periodontal pockets equal or greater than 5 mm, chlorhexidine is also available in high concentration (36%) in a gelatin chip.

There are oral pathologic conditions in which the maintenance of oral hygiene with the twice-daily use with 0.12% chlorhexidine gluconate solution (in which a salt of chlorhexidine and gluconic acid has been dissolved) is required for healing and regeneration of the oral tissues. These conditions included gingivitis, periodontitis, dental traumas[7] (such as subluxation), oral cysts,[8] and after wisdom tooth extraction. The clinical efficacy of the application of chlorhexidine as a component of oral rinses is well documented by many clinical studies summarized by review articles.[9]

Continued use of products containing chlorhexidine for long periods can cause stains on teeth, tongue, and gingiva, also on silicate and resin restorations; prolonged use can also reduce bitter and salty taste sensations – this latter symptom can be reversed by ceasing use of chlorhexidine.[10] The brownish discoloration of teeth and tongue is due to the disintegration of bacterial membranes, leading to the denaturation of bacterial proteins.[11] At the same time, disulfide functions are reduced to thiol functions[12] that form dark complexes with iron(III) ions found in saliva.[13]

Mouthwashes containing chlorhexidine which stain teeth less than the classic solution have been developed, many of which contain chelated zinc.[14][15][16]

According to the prescribing information,[17] chlorhexidine gluconate has not been proven to reduce subgingival calculus and in some studies actually increased deposits.[18] When combined with xylitol, a synergistic effect has been observed to enhance efficacy.[19]

Chlorhexidine's role in preventing tooth decay (dental caries) is controversial and "the clinical data are not convincing".[20]

Chlorhexidine is neutralized by common toothpaste additives such as sodium lauryl sulfate and sodium monofluorophosphate. Although data are limited, to maximize effectiveness, it may be best to keep more than a 30-minute interval between brushing and using the mouthwash, ″cautiously close to 2 hours after brushing".[21]

Topical

Nepal is the first country in the world to use chlorhexidine to treat the umbilical cord of newborn babies, and received a USAID Pioneers Prize for reducing the neonatal death rate.[22] 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 also neonatal mortality by 12%.[23] Chlorhexidine gluconate is used as a skin cleanser for surgical scrubs, a cleanser for skin wounds, for preoperative skin preparation and germicidal hand rinses.[3] Chlorhexidine eye drops have been used as a treatment for eyes affected by Acanthamoeba keratitis.[24]

Toxicity

Genotoxicity study in rats indicate chlorhexidine digluconate is able to induce primary DNA damage in leukocytes, in kidney cells[25] and in oral mucosal cells, but no chromosome breakage or loss in erythrocytes.[26] Chlorhexidine is highly cytotoxic in vitro being able to induce apoptotic and autophagic/necrotic cell deaths, disturbance of mitochondrial function, intracellular Ca2+ increase and oxidative stress.[27]

Chlorhexidine does not meet current 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.[4] In the U.S., 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.[28]

Non-human animals

For use in non-human animals, it is used as a topical disinfectant of wounds. It is also more beneficial to wound healing than using saline solutions alone.[29] Post-surgery respiratory problems have been associated with the use of chlorhexidine products in cats.[30] If the product is put into the ear in the presence of a ruptured eardrum, it can also lead to deafness.[31] It is commonly used to manage skin infections in dogs. In addition to this, it is an active ingredient in teat disinfectant products used within the dairy farming industry.

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.[32] For best effectiveness, food, drink, smoking, and mouth rinses should be avoided for at least one hour after use. Many topical skin products, cleansers, and hand sanitizers should also be avoided to prevent deactivation when chlorhexidine (a topical itself or the residue from a cleanser) is meant to remain on the skin.

Synthesis

The structure is based on two molecules of proguanil, linked with an HMDA spacer.

Chlorhexidine synthesis:[33] eidem, U.S. Patent 2,684,924 (1954 to I.C.I.).

See also

References

  1. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  2. ↑ Thomas Güthner; et al. (2007), "Guanidine and Derivatives", Ullman's Encyclopedia of Industrial Chemistry (7th ed.), Wiley, p. 13
  3. 1 2 3 Leikin, Jerrold B.; Paloucek, Frank P., eds. (2008), "Chlorhexidine Gluconate", Poisoning and Toxicology Handbook (4th ed.), Informa, pp. 183–184
  4. 1 2 Hans-P. Harke (2007), "Disinfectants", Ullman's Encyclopedia of Industrial Chemistry (7th ed.), Wiley, pp. 10–11
  5. ↑ Jenkins S, Addy M, Wade W (August 1988). "The mechanism of action of chlorhexidine. A study of plaque growth on enamel inserts in vivo". J. Clin. Periodontol. 15 (7): 415–24. doi:10.1111/j.1600-051X.1988.tb01595.x. PMID 3183067.
  6. ↑ Gaffar A, Afflitto J, Nabi N (October 1997). "Chemical agents for the control of plaque and plaque microflora: an overview". Eur. J. Oral Sci. 105 (5 Pt 2): 502–07. doi:10.1111/j.1600-0722.1997.tb00237.x. PMID 9395116.
  7. ↑ Zadik Y (December 2008). "Algorithm of first-aid management of dental trauma for medics and corpsmen". Dent Traumatol 24 (6): 698–701. doi:10.1111/j.1600-9657.2008.00649.x. PMID 19021668.
  8. ↑ Zadik Y, Yitschaky O, Neuman T, Nitzan DW (July 2011). "On the self-resolution nature of the buccal bifurcation cyst". J. Oral Maxillofac. Surg. 69 (7): e282–4. doi:10.1016/j.joms.2011.02.124. PMID 21571416.
  9. ↑ Lang N, Brecx MC (1986). "Chlorhexidine digluconate-an agent for chemical plaque control and prevention of gingival inflammation". Journal of Periodontal Research 21: 74–89. doi:10.1111/j.1600-0765.1986.tb01517.x.
  10. ↑ Helms JA, Della-Fera MA, Mott AE, Frank ME (October 1995). "Effects of chlorhexidine on human taste perception". Arch. Oral Biol. 40 (10): 913–20. doi:10.1016/0003-9969(95)00062-T. PMID 8526801.
  11. ↑ Hjeljord LG, Rolla G, Bonesvoll P (1973). "Chlorhexidine-protein interactions". J Periodontal Res Suppl 12: 11–6. doi:10.1111/j.1600-0765.1973.tb02158.x. PMID 4269593.
  12. ↑ Gilbert, Hiram F. (2006). "Molecular and Cellular Aspects of Thiol-Disulfide Exchange". Advances in Enzymology and Related Areas of Molecular Biology. pp. 69–172. doi:10.1002/9780470123096.ch2. ISBN 978-0-470-12309-6.
  13. ↑ Jocelyn, PC (1972). Biochemistry of the SH Group. London-New York: Academic Press. p. 82. ISBN 0-12-385350-8.
  14. ↑ Bernardi F, Pincelli MR, Carloni S, Gatto MR, Montebugnoli L (August 2004). "Chlorhexidine with an Anti Discoloration System. A comparative study". Int J Dent Hyg 2 (3): 122–26. doi:10.1111/j.1601-5037.2004.00083.x. PMID 16451475.
  15. ↑ Sanz, M.; Vallcorba, N.; Fabregues, S.; Muller, I.; Herkstroter, F. (1994). "The effect of a dentifrice containing chlorhexidine and zinc on plaque, gingivitis, calculus and tooth staining". Journal of Clinical Periodontology 21 (6): 431–7. doi:10.1111/j.1600-051X.1994.tb00741.x. PMID 8089246.
  16. ↑ Kumar, S; Patel, S; Tadakamadla, J; Tibdewal, H; Duraiswamy, P; Kulkarni, S (2013). "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. doi:10.1111/j.1601-5037.2012.00560.x. PMID 22672130.
  17. ↑ "Colgate Periogard Rinse (Rx only)". Colgate. Retrieved 2011-09-12.
  18. ↑ Fabrício Batistin Zanatta; Raquel Pippi Antoniazzi; Cassiano Kuchenbecker Rösing (October 2010). "Staining and calculus formation after 0.12% chlorhexidine rinses in plaque-free and plaque covered surfaces: a randomized trial". J. Appl. Oral Sci. 18 (5): 515–521. doi:10.1590/S1678-77572010000500015.
  19. ↑ Decker EM, Maier G, Axmann D, Brecx M, von Ohle C (January 2008). "Effect of xylitol/chlorhexidine versus xylitol or chlorhexidine as single rinses on initial biofilm formation of cariogenic streptococci". Quintessence Int 39 (1): 17–22. PMID 18551212.
  20. ↑ Autio-Gold J (2008). "The role of chlorhexidine in caries prevention". Oper Dent 33 (6): 710–6. doi:10.2341/08-3. PMID 19051866.
  21. ↑ Kolahi J, Soolari A (September 2006). "Rinsing with chlorhexidine gluconate solution after brushing and flossing teeth: a systematic review of effectiveness". Quintessence Int 37 (8): 605–12. PMID 16922019.
  22. ↑ "USAID Recognizes the Government of Nepal for their Leadership in Saving Newborn Lives". Embassy of the United States, Kathmandu - Nepal. February 26, 2014.
  23. ↑ Sinha A, Sazawal S, Pradhan A, Ramji S, Opiyo N .; Sazawal; Pradhan; Ramji; Opiyo (2015). "Chlorhexidine skin or cord care for prevention of mortality and infections in neonates". Cochrane Database Syst Rev 3 (3): CD007835. doi:10.1002/14651858.CD007835.pub2. PMID 25739381.
  24. ↑ Alkharashi M, Lindsley K, Law HA, Sikder S (2015). "Medical interventions for acanthamoeba keratitis". Cochrane Database Syst Rev 2: CD0010792. doi:10.1002/14651858.CD010792.pub2. PMID 25710134.
  25. ↑ Grassi TF1, Camargo EA, Salvadori DM, Marques ME, Ribeiro DA. (7 March 2007). "DNA damage in multiple organs after exposure to chlorhexidine in Wistar rats.". Journal of periodontal research 210 (2): 163–167. doi:10.1016/j.ijheh.2006.09.001. PMID 17084670.
  26. ↑ Ribeiro DA1, Bazo AP, da Silva Franchi CA, Marques ME, Salvadori DM. (October 2004). "Chlorhexidine induces DNA damage in rat peripheral leukocytes and oral mucosal cells". Journal of periodontal research 39 (5): 358–361. doi:10.1111/j.1600-0765.2004.00759.x. PMID 15324357.
  27. ↑ M. Giannelli, F. Chellini, M. Margheri, P. Tonelli, A. Tani (March 2008). "Effect of chlorhexidine digluconate on different cell types: A molecular and ultrastructural investigation". Toxicology in vitro 22 (2): 308–317. doi:10.1016/j.tiv.2007.09.012. PMID 17981006.
  28. ↑ "Daily Bathing With Antiseptic Agent Significantly Reduces Risk of Hospital-Acquired Infections in Intensive Care Unit Patients". Agency for Healthcare Research and Quality. 2014-04-23. Retrieved 2014-04-29.
  29. ↑ Sanchez IR, Swaim SF, Nusbaum KE, Hale AS, Henderson RA, McGuire JA; Swaim; Nusbaum; Hale; Henderson; McGuire (1988). "Effects of chlorhexidine diacetate and povidone-iodine on wound healing in dogs". Vet Surg 17 (6): 291–5. doi:10.1111/j.1532-950X.1988.tb01019.x. PMID 3232321.
  30. ↑ Zeman, D; Mosley, J; Leslie-Steen, P (Winter 1996). "Post-Surgical Respiratory Distress in Cats Associated with Chlorhexidine Surgical Scrubs". ADDL Newsletters. Indiana Animal Disease Diagnostic Laboratory. Retrieved 2011-09-11.
  31. ↑ McDonnell, J. "Deafness in Cats". PetPlace.com. Retrieved 2011-09-11.
  32. ↑ Denton, Graham W (2000). "Chlorhexidine". In Block, Seymour S. Disinfection, Sterilization, and Preservation (5th ed.). Lippincott Williams & Wilkins. pp. 321–36. ISBN 978-0-683-30740-5.
  33. ↑ Rose, F. L.; Swain, G. (1956). "850. Bisdiguanides having antibacterial activity". Journal of the Chemical Society (Resumed): 4422. doi:10.1039/JR9560004422.

Further reading

External links

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