Antifungal

An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others. Such drugs are usually obtained by a doctor's prescription, but a few are available OTC (over-the-counter).

Not to be confused with Antifungal protein.
Antifungal
Drug class
Canesten (clotrimazole) antifungal cream
Synonymsantimycotic medication
In Wikidata

Types

There are two types of antifungals: local and systemic. Local antifungals are usually administered topically or vaginally, depending on the condition being treated. Systemic antifungals are administered orally or intravenously.

Of the clinically employed azole antifungals, only a handful are used systemically.[1] These include ketoconazole, itraconazole, fluconazole, fosfluconazole, voriconazole, posaconazole, and isavuconazole.[1][2] Examples of non-azole systemic antifungals include griseofulvin and terbinafine.

Classes

Polyenes
Main article: Polyene antimycotic

A polyene is a molecule with multiple conjugated double bonds. A polyene antifungal is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungals amphiphilic. The polyene antimycotics bind with sterols in the fungal cell membrane, principally ergosterol. This changes the transition temperature (Tg) of the cell membrane, thereby placing the membrane in a less fluid, more crystalline state. (In ordinary circumstances membrane sterols increase the packing of the phospholipid bilayer making the plasma membrane more dense.) As a result, the cell's contents including monovalent ions (K+, Na+, H+, and Cl−), small organic molecules leak and this is regarded one of the primary ways a cell dies.[3] Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. However, at therapeutic doses, some amphotericin B may bind to animal membrane cholesterol, increasing the risk of human toxicity. Amphotericin B is nephrotoxic when given intravenously. As a polyene's hydrophobic chain is shortened, its sterol binding activity is increased. Therefore, further reduction of the hydrophobic chain may result in it binding to cholesterol, making it toxic to animals.

Azoles

Azoles inhibit conversion of lanosterol to ergosterol by inhibition of lanosterol 14α-demethylase.[4]

Imidazoles

Triazoles

Thiazoles

Allylamines

Allylamines[5] inhibit squalene epoxidase, another enzyme required for ergosterol synthesis. Examples include amorolfin, butenafine, naftifine, and terbinafine.[6][7][8]

Echinocandins

Echinocandins inhibit the creation of glucan in the fungal cell wall by inhibiting 1,3-Beta-glucan synthase:

Echinocandins are administered intravenously, particularly for the treatment of resistant Candida species.[9][10]

Others

Side effects

Apart from side effects like altered estrogen levels and liver damage, many antifungal medicines can cause allergic reactions in people.[23] For example, the azole group of drugs is known to have caused anaphylaxis.

There are also many drug interactions. Patients must read in detail the enclosed data sheet(s) of any medicine. For example, the azole antifungals such as ketoconazole or itraconazole can be both substrates and inhibitors of the P-glycoprotein, which (among other functions) excretes toxins and drugs into the intestines.[24] Azole antifungals also are both substrates and inhibitors of the cytochrome P450 family CYP3A4,[24] causing increased concentration when administering, for example, calcium channel blockers, immunosuppressants, chemotherapeutic drugs, benzodiazepines, tricyclic antidepressants, macrolides and SSRIs.

Before oral antifungal therapies are used to treat nail disease, a confirmation of the fungal infection should be made.[25] Approximately half of suspected cases of fungal infection in nails have a non-fungal cause.[25] The side effects of oral treatment are significant and people without an infection should not take these drugs.[25]

Azoles are the group of antifungals which act on the cell membrane of fungi. They inhibit the enzyme 14-alpha-sterol demethylase, a microsomal CYP, which is required for biosynthesis of ergosterol for the cytoplasmic membrane. This leads to the accumulation of 14-alpha-methylsterols resulting in impairment of function of certain membrane-bound enzymes and disruption of close packing of acyl chains of phospholipids, thus inhibiting growth of the fungi. Some azoles directly increase permeability of the fungal cell membrane.

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See also

References
  1. Benitez, Lydia L.; Carver, Peggy L. (2019). "Adverse Effects Associated with Long-Term Administration of Azole Antifungal Agents". Drugs. 79 (8): 833–853. doi:10.1007/s40265-019-01127-8. ISSN 0012-6667.
  2. Chang, Chia-Hsuin; Young-Xu, Yinong; Kurth, Tobias; Orav, John E.; Chan, Arnold K. (2007). "The Safety of Oral Antifungal Treatments for Superficial Dermatophytosis and Onychomycosis: A Meta-analysis". The American Journal of Medicine. 120 (9): 791–798.e3. doi:10.1016/j.amjmed.2007.03.021. ISSN 0002-9343.
  3. Baginski M, Czub J (June 2009). "Amphotericin B and its new derivatives - mode of action". Current Drug Metabolism. 10 (5): 459–69. doi:10.2174/138920009788898019. PMID 19689243.
  4. Sheehan DJ, Hitchcock CA, Sibley CM (January 1999). "Current and emerging azole antifungal agents". Clinical Microbiology Reviews. 12 (1): 40–79. doi:10.1128/cmr.12.1.40. PMC 88906. PMID 9880474.
  5. Ameen M (March 2010). "Epidemiology of superficial fungal infections". Clinics in Dermatology. Elsevier Inc. 28 (2): 197–201. doi:10.1016/j.clindermatol.2009.12.005. PMID 20347663.
  6. "As Fungal Infections Expand, so Does Market | GEN Magazine Articles | GEN". GEN. Retrieved 2015-10-17.
  7. "Research and Markets: Global Antifungal Therapeutics (Polyenes, Azoles, Echinocandins, Allylamines) Market:Trends and Opportunities (2014-2019) | Business Wire". www.businesswire.com. Retrieved 2015-10-17.
  8. "Tinea Cruris". nurse-practitioners-and-physician-assistants.advanceweb.com. Archived from the original on 2017-09-01. Retrieved 2015-10-17.
  9. Echinocandins for the treatment of systemic fungal infection | Canadian Antimicrobial Resistance Alliance (CARA)
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  11. Sutton CL, Taylor ZE, Farone MB, Handy ST (February 2017). "Antifungal activity of substituted aurones". Bioorganic & Medicinal Chemistry Letters. 27 (4): 901–903. doi:10.1016/j.bmcl.2017.01.012. PMID 28094180.
  12. Wilson G, Block B (2004). Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry. Philadelphia, Pa.: Lippincott Williams & Wilkins. ISBN 0-7817-3481-9.
  13. "antifung". Archived from the original on 17 June 2008. Retrieved 2008-07-09.
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  15. "Haloprogin". DrugBank. University of Alberta. November 6, 2006. Retrieved 2007-02-17.
  16. "Dermatotherapeutic Agents". Ullmann's Encyclopedia of Industrial Chemistry (7th ed.). 2007. doi:10.1002/14356007.a08_301.pub2.
  17. Docampo R, Moreno SN (1990). "The metabolism and mode of action of gentian violet". Drug Metabolism Reviews. 22 (2–3): 161–78. doi:10.3109/03602539009041083. PMID 2272286.
  18. Oliver JD, Sibley GE, Beckmann N, Dobb KS, Slater MJ, McEntee L, du Pré S, Livermore J, Bromley MJ, Wiederhold NP, Hope WW, Kennedy AJ, Law D, Birch M (November 2016). "F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase". Proceedings of the National Academy of Sciences of the United States of America. 113 (45): 12809–12814. doi:10.1073/pnas.1608304113. PMC 5111691. PMID 27791100.
  19. Hope WW, McEntee L, Livermore J, Whalley S, Johnson A, Farrington N, Kolamunnage-Dona R, Schwartz J, Kennedy A, Law D, Birch M, Rex JH (August 2017). "Aspergillus fumigatus: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease". mBio. 8 (4): e01157-17. doi:10.1128/mBio.01157-17. PMC 5565967. PMID 28830945.
  20. Brilhante RS, Caetano EP, Lima RA, Castelo Branco DS, Serpa R, Oliveira JS, Monteiro AJ, Rocha MF, Cordeiro RA, Sidrim JJ (October 2015). "In vitro antifungal activity of miltefosine and levamisole: their impact on ergosterol biosynthesis and cell permeability of dimorphic fungi". Journal of Applied Microbiology. 119 (4): 962–9. doi:10.1111/jam.12891. PMID 26178247.
  21. "Systemic Therapy". Rook's Textbook of Dermatology. 4 (8th ed.). 2010. p. 74.48.
  22. Borkow G (August 2014). "Using Copper to Improve the Well-Being of the Skin". Current Chemical Biology. 8 (2): 89–102. doi:10.2174/2212796809666150227223857. PMC 4556990. PMID 26361585.
  23. Kyriakidis I, Tragiannidis A, Munchen S, Groll AH (February 2017). "Clinical hepatotoxicity associated with antifungal agents". Expert Opinion on Drug Safety. 16 (2): 149–165. doi:10.1080/14740338.2017.1270264. PMID 27927037.
  24. doctorfungus > Antifungal Drug Interactions Archived June 19, 2010, at the Wayback Machine Content Director: Russell E. Lewis, Pharm. D. Retrieved on Jan 23, 2010
  25. American Academy of Dermatology (February 2013). "Five Things Physicians and Patients Should Question". Choosing Wisely: an initiative of the ABIM Foundation. American Academy of Dermatology. Retrieved 2013-12-05., which cites
    • Roberts DT, Taylor WD, Boyle J (March 2003). "Guidelines for treatment of onychomycosis". The British Journal of Dermatology. 148 (3): 402–10. doi:10.1046/j.1365-2133.2003.05242.x. PMID 12653730.
    • Mehregan DR, Gee SL (December 1999). "The cost effectiveness of testing for onychomycosis versus empiric treatment of onychodystrophies with oral antifungal agents". Cutis. 64 (6): 407–10. PMID 10626104.
  • Antifungal Drugs – Detailed information on antifungals from the Fungal Guide written by R. Thomas and K. Barber
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