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Antifungal Drugs

Antifungal Drugs
Polyene antibiotics: Amphotericin B, nystatin
Antimetabolites: 5-Fluorocytosine
Azoles:
Imidazoles: Ketoconazole, miconazole (topical)
Trizoles: Itraconazole, Fluconazole
Echinocandins
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
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 AmB-
Nephrotoxicity
In Humans
Alternative Formulations to Decrease Toxicity
Lipid formulations:
20-50 times more
expensive than
AmB-deoxycholate
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). Accumulation 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 inhibition 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 Azoles
Topical use: Miconazole, Clotrimazole
- effective vs dermatophytes
Voriconazole invasive aspergillosis
Posaconazole broader spectrum
Echinocandins
Caspofungin, Anidulafungin, Micafungin
Effective against Candida, Aspergillus
Inhibits beta glucan synthesis
Lack oral bAv, extensively protein bound,
does not penetrate into CSF
Minimal adverse effects

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
(Benzoic+Salicylic Acid).