IV. ANTIFUNGAL AGENTS dr. WIWIK RAHAYU, M.Kes

Depart. Of. Pharmacology & TherapyFaculty Of Medicine Riau University

Antifungal AgentsMikosis Sistemik/ subkutaneusAmfoterisisn BFlukonazolFlusitosinItrakonazolKetokonazol

Mikosis SuperfisialisKlotrimazolEkonazolGriseofulvinMikonazolNistatin

*

A. Drugs that affect fungal membranes1. Amphotericin B (Fungizone) a. Structure and mechanism of action-is an antibiotic that binds to ergosterol (a major componenet of fungal cell membranes) and alters membrane tto allow leakage of cellular contents.

b. Pharmacologic properties-is poorly absorbed from the gastrointestinal tract and so is administered intravenously; has poor penetration into the CNS.-is eliminated predominantly through the biliary route. Blinds to tissue membranes and serum lipoproteins.- Can be detected in urine for weeks after cessation of therapy.

c. Therapeutic usesis used to treat most severe fungal infection, including those caused by candida albicants, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, Aspergillus species, and Sporothrix schenckii, especially in immunocompromised patients.Is the most effective antifungal agent and is usually the drug of choise for major systemic infections.In some cases, combination therapy with flucytosine is advantageous.

d. Adverse effectsare significant; causes chills and fever in 50% of patients and impaired renal function in 80%.Also may produce anaphylaxis.therapy index

2.Ketonazole, miconazole, clotrimazole, and fluconazolea. General propertiesare imidazole derivates that block the synthesis of ergosterol by inhibiting the cytochrome P-450-mediated sterol 14-demethylase.Are broad-spectrum antifungals; also inhibit many gram-positive bacteria and some protozoa.

*

Ketonazole (Nizoral)

-can be administered orally; elevation of gastric pH impairs absorption. It does not penetrate CSF.-Is extensively bond to plasma protein. It is metabolized in the liver by o-dealkylation and hydroxylation to inactive metabolites; t1/2 is approximately 3 hours.-Most commonly causes gastric upset (3%-20% of patients). Itching, rashes, and headaches are observed in 1% of patients.

Ketonazole (Nizoral) Rarely causes gynecomastia with breast pain in males and reversible liver dysfunction

- Is useful for treatment of mucocutaneous candidiasis, histoplasmosis, and paraccoccidioidomycosis as well as dermatophyte infections.

*

c. Fluconazole (Diflucan)

-is available for IV or oral administration.-Is useful for oropharyngeal, isopharyngeal, and systemic candidiasis. Also used for acute and maintenance therapy of cryptococcalmeningitis.- Has negligible effect on mammalian enzymes.

d. Miconazole (Monistat)

Is available for topical application, which is associated with high incidence of burning and itching. Can be used for tinea pedis, ringworm, and cutaneous and vulvovaginal

e. Clotrimazole (Lotrimin, Mycelex) and terconazole (Terazol)-are available for topical application and are useful for many dermatophyte infections. candidiasis.

3. Nystatin-is a polyene antibiotic similar in structure and mechanism of action to amphotericin B.- is too toxic for systemic administration. Is not absorbed from the gastrointestinal tract; oral preparations can be used prophylactically with tetracycline to prevent superinfection of the intestine.

B. Other antifungal agents1. Griseofulvin (Fulvicin, Grisactin)-binds to microtubules and prevents spindle formation and mitosis in fungi. Also binds filament proteins such as keratin. The drug accumulates in skin, hair, and nails.

1. Griseofulvin (Fulvicin, Grisactin)-Is adequately absorbed after oral administration and is partially metabolized by the liver and slowly excreted in feces and urine.-Is administered as oral therapy for dermatophyte infections.-Is used for long-term therapy of hair and nail infections.- hepatotoxicity.

2. Flucytosine (Ancobon)Is actively transported into fungal cells and is converted to 5-fluorouracil and subsequently to 5-fluorodeoxyyuridylic acid, which is an inhibitor of pyrimidine and nucleic acid synthesis. Human cells lack the ability to convert large amounts of flucytosine to the uracil form.Is well-absorbed afer oral administration; penetrates many tissues, including the CNS. The drug is not metabolized and is extracted by glomeral filtration.Is rarely used as a single drug, but often is used in combination with other antifungal agents.Resistance develop rapidly and limits its use. The majer adverse effect is depression of bone marrow function.

*

Vadineisha

TERIMA KASIH

*

*

*

*

*

*