Antifungal Drugs

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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.

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Drug of Choice for most systemic fungal
infections. Even those susceptible to others
but where the disease rapidly progressive, in
Immunocompromized or involves CNS.
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Model for Amphotericin B induced Pore in Cell
Membrane
In fungi ergosterol in membranes higher
affinity than mammalian cholesterol for AmB
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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)

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Influence of Amphotericin B Infusion on
Determinants of Single Nephron GFR
QA
RA
RE
SNGFR
PGC
?P
Kf
PT
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Influence of Amphotericin B on intracellular Ca
levels in glomerular mesangial cells
Theory
Pore
? Na entry
Depolarization
Voltage-dep. Ca channels
Contraction
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Calcium channel blockers are protective against
AmB- nephrotoxicity in-vivo in rats
Salt loading is protective against
nephrotoxicity in vivo in animals
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Salt loading or Supplements Protect Against
AmB- Nephrotoxicity In Humans
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Alternative Formulations to Decrease Toxicity
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Lipid formulations 20-50 times more expensive
than AmB-deoxycholate
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Renal Effects of AmB-DOC Liposomal AmB
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RBC
Fungal Cell
f-AmB
AmB-DOC
L-AmB
f-AmB
L-AmB
Differential Effects of L-AmB on Mammalian and
Fungal Cells, in Contrast to free AmB
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5-FluorocytosineA 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

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The AzolesImidazoles and Triazoles

• Triazoles newer with fewer side effects
• Impair synthesis of ergosterol inhibit sterol 14
  a-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.

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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

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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

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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 Whitfields ointment
  (BenzoicSalicylic Acid).