Antifungal medication

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

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.

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

Canesten (clotrimazole) antifungal cream

Triazoles

Thiazoles

Allylamines

Allylamines inhibit squalene epoxidase, another enzyme required for ergosterol synthesis:

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.[3]

Others

Adverse effects

Apart from side-effects like liver damage or affecting estrogen levels, 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.[12] Azole antifungals also are both substrates and inhibitors of the cytochrome P450 family CYP3A4,[12] 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.[13] Approximately half of suspected cases of fungal infection in nails have a non-fungal cause.[13] The side effects of oral treatment are significant and people without an infection should not take these drugs.[13]

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.

Antidandruff shampoos

Nizoral (ketoconazole) 2% shampoo

Antifungal agents (such as ketoconazole) are often found in antidandruff shampoos. The antifungal drugs inhibit the yeast Malassezia globosa, which encourages seborrhoeic dermatitis and tinea versicolor.

Agent Trade names Medical applications
Ketoconazole[14] Nizoral, Fungoral and Sebizole Preliminary findings, research and studies including the completion of a small controlled clinical trial have produced data suggesting ketoconazole shampoo is effective as a hair loss treatment in men with androgenic alopecia. Larger controlled clinical studies are still needed to evaluate the ideal dosage and formulation, and to determine the routine of treatment for this condition, thus ketoconazole shampoo is not FDA-approved for this indication.
Ciclopirox olamine Loprox The cream and lotion form of this agent is used to treat fungal infections of the skin. The lacquer form is used as part of a treatment plan to treat fungal infections of the nails. The shampoo form is used to treat and prevent dandruff or to treat seborrhoeic dermatitis.
Piroctone olamine Octopirox[15] and Nivea Complete Control[16] Piroctone olamine is sometimes used as an antifungal agent, and it often used in dandruff shampoos in lieu of zinc. Piroctone olamine is said to be less toxic than other antidandruff agents, often bypassing some of the normal FDA warnings, but still must be used with care, and only externally.
Zinc pyrithione[17] Head & Shoulders, Johnson and Johnson ZP-11, Clinic All Clear, Pantene Pro V and Sikkai Powder An antifungal and antibacterial agent first reported in the 1930s, zinc pyrithione is best known for its use in the treatment of dandruff and seborrhoeic dermatitis. It also has antibacterial properties and is effective against many pathogens from the Streptococcus and Staphylococcus genera. Its other medical applications include treatments of psoriasis, eczema, ringworm, fungus, athletes foot, dry skin, atopic dermatitis, tinea, and vitiligo.
Selenium sulfide Selsun Blue, Head & Shoulders and Vichy Dercos Anti-Dandruff Shampoo Selenium sulfide is available as a 1% and 2.5% lotion and shampoo. In some countries, the higher-strength preparations require a doctor's prescription. The shampoo is used to treat dandruff and seborrhea of the scalp, and the lotion is used to treat tinea versicolor, a fungal infection of the skin.
Tar[18] Neutrogena T-Gel Is effective as a therapeutic treatment to control scalp itching and flaking symptomatic of scalp psoriasis, eczema, seborrhoeic dermatitis, and dandruff.
Tea tree oil[19] Dr. Bronner's Castile Soap It is used topically as an ingredient in creams, ointments, lotions, soaps, and shampoos.[20]

See also

References

  1. ↑ Baginski M, Czub B. "Amphotericin B and its new derivatives." Current Drug Metabolism. 2009 Jun;10(5) : 459–69
  2. ↑ [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC88906> Sheehan D., Hitchcock C, Sibley C. Current and Emerging Azole Antifungal Agents]
  3. ↑ Echinocandins for the treatment of systemic fungal infection | Canadian Antimicrobial Resistance Alliance (CARA)
  4. ↑ 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.
  5. ↑ "antifung". Archived from the original on 17 June 2008. Retrieved 2008-07-09.
  6. ↑ "Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions". Journal of Antimicrobial Chemotherapy 46 (2): 171–9. 2000. doi:10.1093/jac/46.2.171. PMID 10933638. Retrieved 2014-04-18.
  7. ↑ "Haloprogin". DrugBank. University of Alberta. November 6, 2006. Retrieved 2007-02-17.
  8. ↑ Docampo, R.; Moreno, S.N. (1990). "The metabolism and mode of action of gentian violet". Drug Metab. Rev. 22 (2–3): 161–178. doi:10.3109/03602539009041083. PMID 2272286.
  9. ↑
  10. ↑
  11. ↑
  12. ↑ 12.0 12.1 doctorfungus > Antifungal Drug Interactions Content Director: Russell E. Lewis, Pharm.D. Retrieved on Jan 23, 2010
  13. ↑ 13.0 13.1 13.2 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., 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. doi:10.1046/j.1365-2133.2003.05242.x. PMID 12653730.
    • 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.
  14. ↑ McGrath J, Murphy GM (1991). "The control of seborrhoeic dermatitis and dandruff by antipityrosporal drugs". Drugs 41 (2): 178–84. doi:10.2165/00003495-199141020-00003. PMID 1709848.
  15. ↑ Dubini F, Bellotti MG, Frangi A, Monti D, Saccomani L (2005). "In vitro antimycotic activity and nail permeation models of a piroctone olamine (octopirox) containing transungual water soluble technology". Arzneimittel-Forschung 55 (8): 478–83. doi:10.1055/s-0031-1296892. PMID 16149717.
  16. ↑ NIVEA
  17. ↑ Warner RR, Schwartz JR, Boissy Y, Dawson TL (2001). "Dandruff has an altered stratum corneum ultrastructure that is improved with zinc pyrithione shampoo". J. Am. Acad. Dermatol. 45 (6): 897–903. doi:10.1067/mjd.2001.117849. PMID 11712036.
  18. ↑ Piérard-Franchimont C, Piérard GE, Vroome V, Lin GC, Appa Y (2000). "Comparative anti-dandruff efficacy between a tar and a non-tar shampoo". Dermatology (Basel) 200 (2): 181–4. doi:10.1159/000018362. PMID 10773717.
  19. ↑ Prensner R (2003). "Does 5% tea tree oil shampoo reduce dandruff?". The Journal of family practice 52 (4): 285–6. PMID 12681088.
  20. ↑ "Tea tree oil". Medline Plus, a service of the U.S. National Library of Medicine from the National Institutes of Health. 27 July 2012.

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