antifungal drugs
DESCRIPTION
• Polyene antibiotics: Amphotericin B, nystatin • Antimetabolites: 5-Fluorocytosine • Azoles: Antifungal DrugsAntifungalDrugs Imidazoles: Ketoconazole, miconazole (topical) Trizoles: Itraconazole, Fluconazole Drug of Choice for most systemic fungal infections. Even those susceptible to others but where the disease rapidly progressive, in Immunocompromized or involves CNS.TRANSCRIPT
Antifungal DrugsAntifungal 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 Model for Amphotericin B induced Pore in Cell MembranePore in Cell Membrane
In fungi: ergosterol in membranes: higher affinity thanmammalian cholesterol for AmB
Adverse EffectsAdverse 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)
QA
SNGFRRE
RA
PGC
ΔP
PT
Kf
Influence of Amphotericin B Infusion on Influence of Amphotericin B Infusion on Determinants of Single Nephron GFRDeterminants of Single Nephron GFR
Influence of Amphotericin BInfluence of Amphotericin Bon intracellular Caon intracellular Ca++++ levels levelsin glomerular mesangial cellsin glomerular mesangial cells
Theory
Pore
↑ Na entry
Depolarization
Voltage-dep. Ca channels
Contraction
Calcium channel blockers are protective against AmB- nephrotoxicityin-vivo in rats
Salt loading is protective against nephrotoxicity in vivo in animals
f-AmBL-AmBf-AmB
L-AmB
AmB-DOC
Differential Effects of L-AmB on Mammalian Differential Effects of L-AmB on Mammalian and Fungal Cells, in Contrast to free AmBand Fungal Cells, in Contrast to free AmB
RBCFungal Cell
5-Fluorocytosine5-FluorocytosineA fluorinated pyrimidineA 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 AzolesThe AzolesImidazoles and TriazolesImidazoles 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.
KetoconazoleKetoconazole(older, more toxic, replaced by itraconazole, but less costly)(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
TriazolesTriazoles
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 AgentsOther Antifungal AgentsGriseofulvin
• 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).