Not to be confused with Antifungal protein.
Canesten (clotrimazole) antifungal cream
An antifungal medication is a pharmaceutical fungicide or fungistatic 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).
Contents
- 1 Classes
- 1.1 Polyene anti fungals
- 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 Mechanism of action
- 4 See also
- 5 References
- 6 External links
Classes
Polyene anti fungals
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
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-Beta-glucan synthase:
- Anidulafungin
- Caspofungin
- Micafungin
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
- Aurones - have been shown to possess antifungal properties[8]
- Benzoic acid – has antifungal properties, but must be combined with a keratolytic agent such as in Whitfield's ointment[9]
- 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.[10]
- Flucytosine or 5-fluorocytosine – an antimetabolite pyrimidine analog [11]
- 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 [12]
- 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]
- Crystal violet – a triarylmethane dye, it has antibacterial, antifungal, and anthelmintic properties and was formerly important as a topical antiseptic.[13]
- Balsam of Peru has antifungal properties.[14][15][16]
Adverse effects
Apart from side-effects like liver damage or affecting estrogen levels,[17] 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.[18] Azole antifungals also are both substrates and inhibitors of the cytochrome P450 family CYP3A4,[18] 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.[19] Approximately half of suspected cases of fungal infection in nails have a non-fungal cause.[19] The side effects of oral treatment are significant and people without an infection should not take these drugs.[19]
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
- ^ Baginski M, Czub B (Jun 2009). "Amphotericin B and its new derivatives". Current Drug Metabolism. 10 (5): 459–69. PMID 19689243.
- ^ Sheehan D., Hitchcock C, Sibley C. "Current and Emerging Azole Antifungal Agents". ncbi.nlm.nih.gov. Retrieved 2017-03-03.
- ^ Ameen, Mahreen (4 March 2010). "Epidemiology of superficial fungal infections". Clinics in Dermatology. Elsevier Inc. 28: 197–201. PMID 20347663. doi:10.1016/j.clindermatol.2009.12.005.
- ^ "As Fungal Infections Expand, so Does Market | GEN Magazine Articles | GEN". GEN. Retrieved 2015-10-17.
- ^ "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.
- ^ "Tinea Cruris". nurse-practitioners-and-physician-assistants.advanceweb.com. Retrieved 2015-10-17.
- ^ Echinocandins for the treatment of systemic fungal infection | Canadian Antimicrobial Resistance Alliance (CARA)
- ^ Sutton, Caleb L.; Taylor, Zachary E.; Farone, Mary B.; Handy, Scott T. (2017-02-15). "Antifungal activity of substituted aurones". Bioorganic & Medicinal Chemistry Letters. 27 (4): 901–903. doi:10.1016/j.bmcl.2017.01.012.
- ^ 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.
- ^ "antifung". Archived from the original on 17 June 2008. Retrieved 2008-07-09.
- ^ Vermes A, Guchelaar HJ, Dankert J (2000). "Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions". Journal of Antimicrobial Chemotherapy. 46 (2): 171–9. PMID 10933638. doi:10.1093/jac/46.2.171. Retrieved 2014-04-18.
- ^ "Haloprogin". DrugBank. University of Alberta. November 6, 2006. Retrieved 2007-02-17.
- ^ Docampo, R.; Moreno, S.N. (1990). "The metabolism and mode of action of gentian violet". Drug Metab. Rev. 22 (2–3): 161–178. PMID 2272286. doi:10.3109/03602539009041083.
- ^ Chew, A.L.; Maibach, H.I. (2006). Irritant Dermatitis. Springer Berlin Heidelberg. p. 289. ISBN 9783540312949. Retrieved 2017-03-03.
- ^ Marks, J.G.; Elsner, P.; DeLeo, V.A. (2002). Contact & Occupational Dermatology. Mosby. ISBN 9780323014731. Retrieved 2017-03-03.
- ^ Guin, J.D. (1995). Practical Contact Dermatitis: A Handbook for the Practitioner. McGraw-Hill, Health Professions Division. ISBN 9780070251694. Retrieved 2017-03-03.
- ^ Kyriakidis I, Tragiannidis A, München S, Groll AH (2016). "Clinical hepatotoxicity associated with antifungal agents". Expert Opin Drug Saf. 16 (2): 149–165. PMID 27927037. doi:10.1080/14740338.2017.1270264.
- ^ a b doctorfungus > Antifungal Drug Interactions Archived June 19, 2010, at the Wayback Machine. Content Director: Russell E. Lewis, Pharm. D. Retrieved on Jan 23, 2010
- ^ a b c 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, D. T.; Taylor, W. D.; Boyle, J.; British Association of Dermatologists (2003). "Guidelines for treatment of onychomycosis". The British journal of dermatology. 148 (3): 402–410. PMID 12653730. doi:10.1046/j.1365-2133.2003.05242.x.
- 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.
External links
- Antifungal Drugs – Detailed information on antifungals from the Fungal Guide written by R. Thomas and K. Barber
|
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
|
| Triazoles |
- Topical: efinaconazole
- fluconazole#
- fosfluconazole
- terconazole
- Systemic: fluconazole#
- hexaconazole‡
- isavuconazole
- itraconazole
- posaconazole
- voriconazole
- Unknown: albaconazole‡
- ravuconazole†
|
| Thiazoles |
|
|
Polyene antimycotics
(ergosterol binding) |
- Topical: hamycin‡
- natamycin
- nystatin#
Systemic: amphotericin B#, hamycin‡
|
Squalene monooxygenase
inhibitors |
| Allylamines |
- Topical: naftifine
- terbinafine
Systemic: terbinafine
|
| Benzylamines |
|
|
| Others |
|
|
β-glucan synthase
inhibitors |
- echinocandins (anidulafungin
- biafungin
- caspofungin
- cilofungin
- micafungin)
|
|
| Intracellular |
Pyrimidine analogues/
thymidylate synthase inhibitors |
|
| Mitotic inhibitors |
|
| Aminoacyl tRNA synthetase inhibitors |
|
|
| 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
|
