Antifungal

Not to be confused with Antifungal protein.

Antifungal
Drug class
Canesten (clotrimazole) antifungal cream
Synonyms	antimycotic medication
In Wikidata

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).

Contents

• 
  1 Classes
  
  
  
  • 
    1.1 Polyene antifungals
    
  
  
  • 
    1.2 Imidazole, triazole, and thiazole antifungals
    
    
    
    • 
      1.2.1 Imidazoles
      
    
    
    • 
      1.2.2 Triazoles
      
    
    
    • 
      1.2.3 Thiazoles
      
    
    
    
    
  
  
  • 
    1.3 Allylamines
    
  
  
  • 
    1.4 Echinocandins
    
  
  
  • 
    1.5 Others
    
  
  
  
  


• 
  2 Adverse effects
  


• 
  3 See also
  


• 
  4 References
  


• 
  5 External links
  

Classes

Polyene antifungals

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 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.

• Amphotericin B


• Candicidin


• 
  Filipin – 35 carbons, binds to cholesterol (toxic)


• Hamycin


• 
  Natamycin – 33 carbons, binds well to ergosterol


• Nystatin


• Rimocidin

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

• Bifonazole


• Butoconazole


• Clotrimazole


• Econazole


• Fenticonazole


• Isoconazole


• Ketoconazole


• Luliconazole


• Miconazole


• Omoconazole


• Oxiconazole


• Sertaconazole


• Sulconazole


• Tioconazole

Triazoles

• Albaconazole


• Efinaconazole


• Epoxiconazole


• Fluconazole


• Isavuconazole


• Itraconazole


• Posaconazole


• Propiconazole


• Ravuconazole


• Terconazole


• Voriconazole

Thiazoles

• Abafungin

Allylamines

Allylamines^[3] inhibit squalene epoxidase, another enzyme required for ergosterol synthesis. Examples include amorolfin, butenafine, naftifine, and terbinafine.^[4][5][6]

Echinocandins

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

• Anidulafungin


• Caspofungin


• Micafungin

Echinocandins are administered intravenously, particularly for the treatment of resistant Candida species.^[7][8]

Others

• 
  Aurones - have been shown to possess antifungal properties^[9]
  


• 
  Benzoic acid – has antifungal properties, such as in Whitfield's ointment, Friar's Balsam, and Balsam of Peru.^[10]
  


• 
  Ciclopirox – (ciclopirox olamine) – is a hydroxypyridone antifungal that interferes with active membrane transport, cell membrane integrity, and fungal respiratory processes. It is most useful against tinea versicolour.^[11]
  


• 
  Flucytosine or 5-fluorocytosine – an antimetabolite pyrimidine analog ^[12]
  


• 
  Griseofulvin – binds to polymerized microtubules and inhibits fungal mitosis^{[medical citation needed]}
  


• 
  Haloprogin – discontinued due to the emergence of more modern antifungals with fewer side effects ^[13]
  


• 
  Tolnaftate – a thiocarbamate antifungal, which inhibits fungal squalene epoxidase (similar mechanism to allylamines like terbinafine)^{[medical citation needed]}
  


• 
  Undecylenic acid – an unsaturated fatty acid derived from natural castor oil; fungistatic, antibacterial, antiviral, and inhibits Candida morphogenesis^{[citation needed]}
  


• 
  Triacetin - hydrolysed to acetic acid by fungal esterases.^[14]
  


• 
  Crystal violet – a triarylmethane dye, it has antibacterial, antifungal, and anthelmintic properties and was formerly important as a topical antiseptic.^[15]
  


• Castellani's paint


• 
  Orotomide (F901318) - pyrimidine synthesis inhibitor.^[16][17]
  


• 
  Miltefosine disrupts fungal cell membrane dynamics by interacting with ergosterol ^[18]
  


• 
  Potassium iodide is the preferred treatment for lymphocutaneous sporotrichosis and subcutaneous zygomycosis (basidiobolomycosis). The mode of action is obscure.^[19]
  


• Coal tar


• 
  Copper(II) sulfate^[20]
  


• Selenium disulfide


• Sodium thiosulfate


• Piroctone olamine


• 
  Iodoquinol, clioquinol
  


• Acrisorcin


• Zinc pyrithione


• Sulfur

Adverse effects

Apart from side effects like altered estrogen levels and liver damage, many antifungal medicines can cause allergic reactions in people.^[21] 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.^[22] Azole antifungals also are both substrates and inhibitors of the cytochrome P450 family CYP3A4,^[22] 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.^[23] Approximately half of suspected cases of fungal infection in nails have a non-fungal cause.^[23] The side effects of oral treatment are significant and people without an infection should not take these drugs.^[23]

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

See also

• 
  Antifungals portal
  


• Antimicrobial


• Fungicide

References

1. 
   ^ 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..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"""""""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
   


2. 
   ^ Sheehan DJ, Hitchcock CA, Sibley CM (January 1999). "Current and emerging azole antifungal agents". Clinical Microbiology Reviews. 12 (1): 40–79. PMC 88906. PMID 9880474.
   


3. 
   ^ 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.
   


4. 
   ^ "As Fungal Infections Expand, so Does Market | GEN Magazine Articles | GEN". GEN. Retrieved 2015-10-17.
   


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.
   


6. 
   ^ "Tinea Cruris". nurse-practitioners-and-physician-assistants.advanceweb.com. Retrieved 2015-10-17.
   


7. 
   ^ Echinocandins for the treatment of systemic fungal infection | Canadian Antimicrobial Resistance Alliance (CARA)
   


8. 
   ^ Cappelletty D, Eiselstein-McKitrick K (March 2007). "The echinocandins". Pharmacotherapy. 27 (3): 369–88. doi:10.1592/phco.27.3.369. PMID 17316149.
   


9. 
   ^ 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.
   


10. 
    ^ 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.
    


11. 
    ^ "antifung". Archived from the original on 17 June 2008. Retrieved 2008-07-09.
    


12. 
    ^ Vermes A, Guchelaar HJ, Dankert J (August 2000). "Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions". The Journal of Antimicrobial Chemotherapy. 46 (2): 171–9. doi:10.1093/jac/46.2.171. PMID 10933638.
    


13. 
    ^ "Haloprogin". DrugBank. University of Alberta. November 6, 2006. Retrieved 2007-02-17.
    


14. 
    ^ "Dermatotherapeutic Agents". Ullmann's Encyclopedia of Industrial Chemistry (7th ed.). 2007. doi:10.1002/14356007.a08_301.pub2.
    


15. 
    ^ 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.
    


16. 
    ^ 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.
    


17. 
    ^ 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.
    


18. 
    ^ 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.
    


19. 
    ^ "Systemic Therapy". Rook's Textbook of Dermatology. 4 (8th ed.). 2010. p. 74.48.
    


20. 
    ^ 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.
    


21. 
    ^ 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.
    


22. 
    ^ ^ab doctorfungus > Antifungal Drug Interactions Archived June 19, 2010, at the Wayback Machine. Content Director: Russell E. Lewis, Pharm. D. Retrieved on Jan 23, 2010
    


23. 
    ^ ^abc 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.
      
    
    
    
    

External links

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

v t e Antifungals (D01 and J02)
Wall/ membrane	Ergosterol inhibitors Azoles (lanosterol 14α- demethylase inhibitors) Imidazoles Topical: bifonazole‡ butoconazole chlormidazole‡ clotrimazole# croconazole‡ eberconazole econazole fenticonazole‡ flutrimazole isoconazole ketoconazole luliconazole miconazole# neticonazole‡ omoconazole‡ oxiconazole sertaconazole sulconazole tioconazole Systemic: ketoconazole Triazoles Topical: efinaconazole fluconazole# fosfluconazole terconazole Systemic: fluconazole# hexaconazole‡ isavuconazole itraconazole posaconazole voriconazole Unknown: albaconazole‡ ravuconazole† Thiazoles Topical: abafungin‡ Polyene antimycotics (ergosterol binding) Topical: hamycin‡ natamycin nystatin# Systemic: amphotericin B#, hamycin‡ Squalene monooxygenase inhibitors Allylamines Topical: naftifine terbinafine Systemic: terbinafine Benzylamines Topical: butenafine Others Topical: amorolfine β-glucan synthase inhibitors echinocandins (anidulafungin biafungin caspofungin cilofungin micafungin)
Intracellular	Pyrimidine analogues/ thymidylate synthase inhibitors flucytosine# Mitotic inhibitors griseofulvin# Aminoacyl tRNA synthetase inhibitors tavaborole
Others	bromochlorosalicylanilide chlorophetanol chlorphenesin ciclopirox crystal violet dimazole ethylparaben haloprogin‡ polynoxylin potassium iodide# salicylic acid selenium disulfide# sodium thiosulfate# sulbentine taurolidine ticlatone tolciclate tolnaftate tribromometacresol undecylenic acid Whitfield's ointment# citronella oil lemon grass lemon myrtle orange oil patchouli tea tree oil PCP: atovaquone dapsone pentamidine
#WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III

v t e Pharmacology: major drug groups
Gastrointestinal tract/ metabolism (A)	stomach acid Antacids H2 antagonists Proton pump inhibitors Antiemetics Laxatives Antidiarrhoeals/Antipropulsives Anti-obesity drugs Anti-diabetics Vitamins Dietary minerals
Blood and blood forming organs (B)	Antithrombotics Antiplatelets Anticoagulants Thrombolytics/fibrinolytics Antihemorrhagics Platelets Coagulants Antifibrinolytics
Cardiovascular system (C)	cardiac therapy/antianginals Cardiac glycosides Antiarrhythmics Cardiac stimulants Antihypertensives Diuretics Vasodilators Beta blockers Calcium channel blockers renin–angiotensin system ACE inhibitors Angiotensin II receptor antagonists Renin inhibitors Antihyperlipidemics Statins Fibrates Bile acid sequestrants
Skin (D)	Emollients Cicatrizants Antipruritics Antipsoriatics Medicated dressings
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Endocrine system (H)	Hypothalamic–pituitary hormones Corticosteroids Glucocorticoids Mineralocorticoids Sex hormones Thyroid hormones/Antithyroid agents
Infections and infestations (J, P, QI)	Antimicrobials: Antibacterials (Antimycobacterials) Antifungals Antivirals Antiparasitics Antiprotozoals Anthelmintics Ectoparasiticides IVIG Vaccines
Malignant disease (L01–L02)	Anticancer agents Antimetabolites Alkylating Spindle poisons Antineoplastic Topoisomerase inhibitors
Immune disease (L03–L04)	Immunomodulators Immunostimulants Immunosuppressants
Muscles, bones, and joints (M)	Anabolic steroids Anti-inflammatories NSAIDs Antirheumatics Corticosteroids Muscle relaxants Bisphosphonates
Brain and nervous system (N)	Analgesics Anesthetics General Local Anorectics Anti-ADHD agents Antiaddictives Anticonvulsants Antidementia agents Antidepressants Antimigraine agents Antiparkinson agents Antipsychotics Anxiolytics Depressants Entactogens Entheogens Euphoriants Hallucinogens Psychedelics Dissociatives Deliriants Hypnotics/Sedatives Mood Stabilizers Neuroprotectives Nootropics Neurotoxins Orexigenics Serenics Stimulants Wakefulness-promoting agents
Respiratory system (R)	Decongestants Bronchodilators Cough medicines H1 antagonists
Sensory organs (S)	Ophthalmologicals Otologicals
Other ATC (V)	Antidotes Contrast media Radiopharmaceuticals Dressings Senotherapeutics

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