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.

Drug of Choice for most systemic fungal infections. Even those susceptible to others but where the disease rapidly progressive, in Immunocompromized or involves CNS.

Model for Amphotericin B induced Pore in Cell Membrane

In fungi: ergosterol in membranes: higher affinity than mammalian cholesterol for AmB

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)

Influence of Amphotericin B Infusion on Determinants of Single Nephron GFR

QA RA

RE
SNGFR

PGC P PT Kf

Influence of Amphotericin B on intracellular Ca++ levels in glomerular mesangial cells

Theory Pore Na entry Depolarization Voltage-dep. Ca channels Contraction

Calcium channel blockers are protective against AmB- nephrotoxicity in-vivo in rats

Salt loading is protective against nephrotoxicity in vivo in animals

Salt loading or Supplements Protect Against AmBNephrotoxicity In Humans

Alternative Formulations to Decrease Toxicity

Lipid formulations: 20-50 times more expensive than AmB-deoxycholate

Renal Effects of AmB-DOC & Liposomal AmB

Fungal Cell

RBC

L-AmB

f-AmB f-AmB

AmB-DOC

L-AmB

Differential Effects of L-AmB on Mammalian and Fungal Cells, in Contrast to free AmB

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 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, photosensitivity, 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; Whitfields ointment (Benzoic+Salicylic Acid).