Systemic & Topical Some are fungistatic, while others are fungicidal

1. Systemic & Topical Some are fungistatic, while others are fungicidal

2. Overview • Fungal infections classification: • Superficial infections: Ringworm (tinea) → skin and mucous membrane. Incidence rate is high. • Systemic infections: Candida albicans → opportunist infections. Fatality rate is high. • Antifungal agents classification: • Antibiotics : Amphotericin B; Nystatin, Griseofulvin • Azole : Ketoconazole; • Allylamines : Terbinafine; • Pyrimidine : Flucytosine

3. Fungal Infection in Humans (Mycosis) • Major Types of Mycoses • superficial • cutaneous • subcutaneous • systemic • opportunistic • Symptoms vary from cosmetic to life threatening

4. Antifungal Agents • Polyene antibiotics • The polyene antibiotics bind with sterols in the fungal cell membrane, principally ergosterol. This causes the cell's contents to leak out and the cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. • Nystatin • Amphotericin B (may be administered liposomally) • Natamycin • Rimocidin • Filipin • Pimaricin

5. Nystatin: The first antibiotic against fungi • Like many other antimycotics and antibiotics, Nystatin is of bacterial origin. It was isolated from Streptomycesnoursei in 1950 by Elizabeth Lee Hazen and Rachel Fuller Brown, who were doing research for the Division of Laboratories and Research of the New York State Department of Health. • The soil sample where they discovered Nystatin, was from the garden of Hazen's friends called Nourses, therefore the strain was called noursei. Hazen and Brown named Nystatin after the New York StatePublic Health Department in 1954.

6. Amphotericin B • Produced by Streptomyces nodosus. Amphoteric polyene macrolide. • Pharmacological Effect: broad-spectrum • Mechanism: Binds to ergosterol in fungi (humans and Mycoplasma have cholesterol) to form pores. The pores permit leakage of intracellular contents leading to cell lysis and death.

7. Griseofulvin • Derived from a species of Penicillium called Penicillium griseofulvum. • Griseofulvin binds to polymerized microtubules and inhibits fungal mitosis. • Fungistatic drug. • Its deposited in newly forming skin where it binds to keratin, protecting the skin from new infection. • Its insoluble but administered in a microcrystalline form only. • Its used in the systemic treatment of dermatophytosis.

8. Azoles • Azoles are Synthetic compounds. • Classification is according to the number of nitrogen atoms in the five-membered azole ring • The imidazole and triazole groups of antifungal drugs inhibit the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell membrane synthesis. These drugs also block steroid synthesis in humans.

9. Mechanism of action of Azoles • Reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes. • Greater affinity for fungal than for human cytochrome P450 enzymes. • Imidazoles exhibit a lesser degree of specificity than the triazoles, accounting for their higher incidence of drug interactions and side effects. • Ketoconazole was the first oral azole introduced into clinical use

10. Antifungal Agents Imidazole and triazole • Imidazoles: • Miconazole Bifonazole Thiabendazole • Ketoconazole Butoconazole Tiaconazole • Clotrimazole Econazole Sertaconazole • Mebendazole Fenticonazole Sulconazole • Isoconazole Oxiconazole • Triazoles: are newer, and are less toxic and more effective: • Fluconazole Ravuconazole Posaconazole • Itraconazole Voriconazole

11. Antifungal Agents • Allylamines • Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis: • Allylamines are non-competitive and reversibleinhibitors of Squalene epoxidase. • Examples: Terbinafine, Amorolfine, Naftifine, Butenafine, • Terbinafine –is marketed as Lamisil • Terbinafine is synthetic, oral formulation & Fungicidaltreatment of dermatophytoses, especially onychomycosis (nail infection). Its more effective than griseofulvin or itraconazole.

12. Antifungal Agents Echinocandin • Echinocandins irreversibly inhibits β-1,3 –D glucan synthase, the enzyme complex that forms glucan polymers in the fungal cell wall. Glucan polymers are responsible for providing rigidity to the cell wall. Disruption of β-1,3-D glucan synthesis leads to reduced cell wall integrity, cell rupture, and cell death. • Examples include: Anidulafungin Caspofungin Micafungin

13. Flucytosine • Flucytosine is a Pyrimidine antimetabolite. • Flucytosine （5-FC）is a water-solublepyrimidine analog. • Its spectrum of action is much narrower than that of amphotericin B. • Mechanism of action: 5-FC (taken up by fungal cells via the enzyme cytosine permease) → 5-FU → F-dUMP and FUTP → thus inhibiting DNA and RNA synthesis, respectively. • Synergy with amphotericin B. • Spectrum of action: Cryptococcus neoformans, Aspergillus, some candida species (except C.krusei), and the dematiaceous molds that cause chromoblastomycosis.

14. Flucytosine Mechanism of Action: • Flucytosine is Converted by cytosine deaminase into 5-fluorouracil which is then converted through a series of steps to 5-fluorouridine triphosphate and incorporated into fungal RNA leading to miscoding during mRNA and protein synthesis. • Flucytosine can also be converted by a series of steps to 5-fluorodeoxyuridine monophosphate which is a noncompetitive inhibitor of thymidylate synthase, interfering with DNA synthesis.

15. Antifungal Agents • Others: • Fluocinonide • Salicylic Acid (topical) • Tinactin or Tolnaftate • Potassium Iodide

16. Sources • Mark Gladwin, Bill Trattler, 1998. Clinical Microbiology made ridiculously simple. • Lange Medical Microbiology • http://www.lamisil.com/ • http://www.tinactin.com/ • http://en.wikipedia.org/wiki/Griseofulvin • http://www.journals.uchicago.edu/CID/journal/issues/v30n4/990666/990666.text.html?erFrom=-4860378516935905751Guest • http://www.mycology.adelaide.edu.au/downloads/antifungals.pdf#search=%22antifungal%20drugs%22 • http://inventors.about.com/library/inventors/blnystatin.htm