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
SNGFR
RA RE
PGC ΔP 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 Baseline
AmB
8
Post-AmB
7.5
5.0 AmB 0.02 AmB 0.025
2.5
AmB 0.03
0.0
0
10
20
30
40
50
60
70
80
90
100
Glomerular Filtration Rate (ml/min)
Renal Blood Flow (ml/min)
10.0
Time (min)
Baseline
L- AmB
Glomerular Filtration Rate (ml/min)
Renal Blood Flow (ml/min)
7.5
5.0
0.0
0
10
20
L-AmB 0.01
L-AmB 0.08
L-AmB 0.02
L-AmB 0.25
L-AmB 0.04
L-AmB 0.5
30
40
50
Time (min)
60
70
2
6
90
100
Baseline
AmB
L-AmB 0.01 Experimental
Post-AmB L-AmB 0.08 Period
L-AmB 0.02
L-AmB 0.25
L-AmB 0.04
L-AmB 0.5
4
2
0 80
AmB 0.03
4
8
Post-L-AmB
AmB 0.02 AmB 0.025
0
10.0
2.5
6
Baseline
L-AmB
Post-AmB
Experimental Period
Fungal Cell
L-AmB
RBC f-AmB
AmB-DOC
f-AmB 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 αdemethylase (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
Fluconazole
• 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)
• Completely absorbed and better tolerated • Renal excretion • Less endocrine effects • Penetrates well into CSF • Cryptococcal, coccidial meningitis. Candidiasis. • Drug Interactions
Other Antifungal Agents Griseofulvin
Topical Antifungals
• 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.
• 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).