Antifungal

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Canesten (clotrimazole) antifungal cream

An antifungal medication is a pharmaceutical fungicide used to treat and prevent mycoses 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).

Classes

Polyene antifungals

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 cell dies.[1] 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.

Imidazole, triazole, and thiazole antifungals

Azole antifungal drugs (except for abafungin) inhibit the enzyme lanosterol 14 α-demethylase; the enzyme necessary to convert lanosterol to ergosterol. Depletion of ergosterol in fungal membrane disrupts the structure and many functions of fungal membrane leading to inhibition of fungal growth.[2]

Imidazoles

Triazoles

Thiazoles

Allylamines

Allylamines[3] inhibit squalene epoxidase, another enzyme required for ergosterol synthesis. Examples include Amorolfin, Butenafine, Naftifine, and Terbinafine.[4][5][6]

Echinocandins

Echinocandins may be used for systemic fungal infections in immunocompromised patients, they inhibit the synthesis of glucan in the cell wall via the enzyme 1,3-β-glucan synthase:

Echinocandins are poorly absorbed when administered orally. When administered by injection they will reach most tissues and organs with concentrations sufficient to treat localized and systemic fungal infections.[7]

Others

Adverse effects

Apart from side-effects like liver damage or affecting estrogen levels,[medical citation needed] many antifungal medicines can cause allergic reactions in people. 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 the 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.[16] Azole antifungals also are both substrates and inhibitors of the cytochrome P450 family CYP3A4,[16] 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.[17] Approximately half of suspected cases of fungal infection in nails have a non-fungal cause.[17] The side effects of oral treatment are significant and people without an infection should not take these drugs.[17]

Mechanism of action

Antifungals work by exploiting differences between mammalian and fungal cells to kill the fungal organism with fewer adverse effects to the host. Unlike bacteria, both fungi and humans are eukaryotes. Thus, fungal and human cells are similar at the biological level. This makes it more difficult to discover drugs that target fungi without affecting human cells. As a consequence, many antifungal drugs cause side-effects. Some of these side-effects can be life-threatening if the drugs are not used properly.

See also

References

  1. Baginski M, Czub B (Jun 2009). "Amphotericin B and its new derivatives". Current Drug Metabolism. 10 (5): 459–69.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  2. > Sheehan D., Hitchcock C, Sibley C. Current and Emerging Azole Antifungal Agents
  3. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  4. "As Fungal Infections Expand, so Does Market | GEN Magazine Articles | GEN". GEN. Retrieved 2015-10-17.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  5. "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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  6. "Tinea Cruris". nurse-practitioners-and-physician-assistants.advanceweb.com. Retrieved 2015-10-17.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  7. Echinocandins for the treatment of systemic fungal infection | Canadian Antimicrobial Resistance Alliance (CARA)
  8. Wilson, Gisvold, Block, Beale (2004). Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry. Philadelphia, Pa.: Lippincott Williams & Wilkins. ISBN 0-7817-3481-9. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  9. "antifung". Archived from the original on 17 June 2008. Retrieved 2008-07-09.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  10. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  11. "Haloprogin". DrugBank. University of Alberta. November 6, 2006. Retrieved 2007-02-17.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  12. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  13. [1]
  14. [2]
  15. [3]
  16. 16.0 16.1 doctorfungus > Antifungal Drug Interactions Content Director: Russell E. Lewis, Pharm.D. Retrieved on Jan 23, 2010
  17. 17.0 17.1 17.2 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 5 December 2013.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>, which cites
    • Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
    • Mehregan, D. R.; Gee, S. L. (1999). "The cost effectiveness of testing for onychomycosis versus empiric treatment of onychodystrophies with oral antifungal agents". Cutis. 64 (6): 407–410. PMID 10626104.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>

External links

  • Antifungal Drugs – Detailed information on antifungals from the Fungal Guide written by R. Thomas and K. Barber