A Short Note On Anti-Fungal Drugs Used In Dentistry

Antifungal Drugs

•          Polyene antibiotics:  Amphotericin B, nystatin

•          Antimetabolites:  5-Fluorocytosine

•          Azoles:

                Imidazoles: Ketoconazole, miconazole (topical)

                Trizoles: Itraconazole, Fluconazole  

•          Griseofulvin

•          Topical antifungal agents: imidazoles, polyenes and others.

Adverse Effects

•          Acute: Infusion-related

–        Chills, fever, dyspnea, nausea, vomiting, bronchospasm, hypotension, convulsions

•          Chronic

–        Nephrotoxicity

                azotemia, impaired concentration, impaired urinary acidification, K & Mg wasting with hypokalemia and hypomagnesemia

–        Normochromic, normocytic anemia (↓ erythropoietin)

5-Fluorocytosine
   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).