Antifungal Agents
Polyenes – Amphotericin B, Nystatin
Amphothericin B
- Mechanism
Ø Binds to ergosterol in fungal membranes better than to cholesterol in mamallian cells – selective toxicity
Ø Alters fungal cell permeability and transport properties
Ø No activity in bacteria, some in mycoplasma
- Structure
Ø polyene antibiotic
Ø insoluble in H2O
Ø restricted activity between pH 6 and 7
- Absorption
Ø poor from the GI tract – useful in oral, esophageal, and GI infection
Ø has to be given IV for systemic mycoses
Ø poor CNS penetration but is effective against fungal meningitis
- Circulating drug is bound to plasma lipoporteins
- Accumulates in the RE system and tissues
- Metabolized in the Liver
- Adverse Effects:
1) Nephrotoxicity (80%) irreversible or partially reversible
2) Anemia
3) Hypokalemia
4) Fever during infusion
5) Shaking chills during infusion – give meperidine and acetominophen before
- Use: treatment of severe systemic fungal infections
- Resistance – none, some are just naturally less sensitive or resistance
Nystatin
- polyene antifungal
- actins are primarily upon yeasts (weak against dermatophytes)
- Limited to topical use (oral, vaginal, skin)
Azoles – Miconazole, Clotrimazole, Ketoconazole, Fluconazole, Itraconazole
- Mechanism
Ø inhibit C-14 demethylase enzyme (cytP450 necessary for synthesis of fungal ergosterol)
Ø fungistatic
Ø very slow – don’t use for severe or life threatening infections
- Absorption
Ø considerable variance
Ø Fluconazole – well absorbed
Ø Ketoconazole and Itraconazole – dependent on stomach pH for absorption
Ø Fluconazole is ONLY ONE that penetrates well into the CSF
- All metabolized in the liver
Clotrimazole
- only used topically
- troches – lozenges
- yeast infections – Gyne-lotrimin
Miconazole
- used maily for topical infections
- IV for systemic infections also; rare
- Poor GI absorption
- Ex. OTC Micatin for Athelete’s foot
Ketoconazole
- poor CNS penetration
- dependent on stomach acid for absorption
- DO NOT USE IN PREGNANCY
- High doses: interferes with androgen and glucocorticoid synthesis
Ø can be used to correct Hirsutism
- Many drug interactions
1) antacids and H2 blockers block absorption
2) rifampin decreases ketoconazole levels by inducing hepatic metabolism
3) raises syslosporine levels due to enzyme competition
4) interferes with the clearance of terfenadine and astemizole
- Used for
1) oral thrush and esophageal Candida
2) mild to moderate Histoplasmosis
3) mild to moderate Blastomycosis
4) Onychomycosis
Itraconazole
- similar in structure and properties to Ketoconazole
- wider spectrum – Aspergillus and Sprorthrix schenckii
Fluconazole
- achieves antifungal levels in the CSF
- easily absorbed orally
- less vomiting than keto or itra and hepatitis is less common
- extremely expensive (7-12 per pill)
Flucytosine
- Mechanism
Ø Flucytosine is actively transported into the fungal cell.
Ø Converted to 5-fluorouracil (5-FU) by fungal cytosine deaminase
Ø 5-FU is converted to 5-fluorodeoxyuridylic acid, which inhibits thymidylate synthetase
Ø inhibits pyrimidine and RNA synthesis
Ø Fungistatic
- Resistance
Ø develops rapidly
- Uses: fungal UTIs, combo therapy
- Absorption – good, orally
- Penetrated CSF
- No metabolism in humans
- Excreted 1o by kidney – high levels in urine
- Adverse effects
Ø Depresses bone marrow function (like the chemo drug 5-FU)
Ø Nausea and skin rashes
Griseofulvin
- Mechanism
Ø binds and depolymerizes microtubules and prevents spindle formation during mitosis
Ø taken up exclusively by fungi
Ø also binds to intermediate filament type proteins (keratin) – accumulated in keratinized layer of epithelium, hair, and nails
- Absorption
Ø orally in suspension is adequately absorbed
Ø slowly excreted in feces and urine
- well tolerated – low toxicity
- Used for – topical fungal infections
Ø especially hair and nails – long term
Tags: Amphothericin B, anemia, Blastomycosis, Clotrimazole, Fluconazole, Histoplasmosis, Hypokalemia, Ketoconazole, Miconazole, Mycoplasma, Nephrotoxicity, Nystatin, oral thrush
