A fluorinated pyrimidine
• Converted to 5 fluorouracil by a deaminase then to 5-fdUMP, which inhibits thymidylate synthase and DNA synthesis
• Selective toxicity to fungal cells (no deaminase in mammalian cells)
• Resistance is common. Do not use alone, but in combination with AmB cryptococcal meningitis
• Bone marrow toxicity – pancytopenia -reversible
The Azoles
Imidazoles and Triazoles
• Triazoles newer with fewer side effects
• Impair synthesis of ergosterol; inhibit sterol 14 α-demethylase (of cyt. P450). Acumulation of precursors which inhibit growth.
• Mammalian cells can incorporate already formed cholesterol; fungi have to synthesize
• Adverse effects due to inhibition of mammalian steroid synthesis
• Drug interactions due to inbibition of cyt. P450 enzymes.
Ketoconazole
(older, more toxic, replaced by itraconazole, but less costly)
• Absorption variable (better in acidic medium)
• Poor concentration in CSF
• Metabolized by Cyt. P450 enzymes
• Adverse effects:
– Nausea, anorexia, vomiting
– Endocrine: menstrual abnormalities, gynecomastia, azoospermia, decreased libido and potency
– Hypertension and fluid retention
– Hepatitis (rare-fatal)
– Drug Interactions (inhibition of cyt. P450)
• Therapeutic Use: coccidiomycosis, histoplasmosis if not severely ill or immunocompromized. Oral, esophageal, mucocutaneous candidiasis
Triazoles
Itraconazole
• Varied absorption. Metabolized by cyt P450
• Has less endocrine effects but occur at high doses
• Less hepatitis
• Histoplasmosis and blastomycosis
• Many drug interactions (due to inhibition of cyt P4503A4) Fluconazole
• Completely absorbed and better tolerated
• Renal excretion
• Less endocrine effects
• Penetrates well into CSF
• Cryptococcal, coccidial meningitis. Candidiasis.
• Drug Interactions
• Other Antifungal Agents
Griseofulvin
• Binds to microtubules/ disrupts mitosis
• Deposits in keratin layers
• Dermatophytes actively concentrate it
• Infections of skin, hair, nails; Prolonged therapy.
• Toxicity: headache, neuro & hepatotoxicity, photo-sensitivity, carcinogenic.
Topical Antifungals
• For stratum corneum, mucosa, cornea by dermatophytes & Candida.
• Not for subcutaneous, nail or hair infections.
• Many azoles; Tolnaftate; nystatin (Candida only); naftifine; terbinafine; Whitfield’s ointment (Benzoic+Salicylic Acid).
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