Antifungal Agents Flashcards
Amphoterecin B
Mechanism: Polyene antibiotic, binds ergosterol in cell membranes. Fungicidal.
Pharmacokinetics: use only IV or topically. Rapid sequestration in organs. Excreted by kidney, major route through biliary tract
Adverse: VERY TOXIC. Nephro toxicity, anemia secondary to bone marrow depression, infusion toxicities (chills, fever, vomiting)
Role: broad spectrum including opportunistic (candida, aspergillus) and systemic (histoplasma, cryptococci, blastomuces, coccidiodes)
DRUG OF CHOICE IN LIFE THREATENING INFECTIONS
Nystatin
similar to amphotericin B, but toxicity limits use to topical treatment only
Echinocandins
Caspofungin most important
Mechanism: disrupt cell wall synthesis, inhibits synthesis of beta (1,3) D-glucan, an essential component of fungal cell walls.
Pharmacokinetics: IV infusions. Dosage reduction for pts w/ hepatic insufficiency, increase dosage if pt taking inducers of CYP450
Adverse: histamine mediated symptoms (rash, swelling, pruitus)
Use: Invasive aspergillosis in pts intolerant to ampho B or itraconazole
Azoles - Triazoles
Itraconazole
Fluconazole
Mechanism: selective inhibition of fungal CYP450 -> decrease ergosterol synthesis. Cidal or static.
Pharm: Oral bioavailability real good 90%+
Adverse: Hepatotoxicity (more w/ itraconazole vs. fluconazole.)
P. good overall, doesn’t inhibit animal steroid biosynthesis.
Inhibits CYP450 metabolism
Use: Vaginal candidiasis is topical treatment fails
Oropharyngeal + esophageal candidiasis. Serious systemic candidal infections.
Itraconazole -Agent of choice for systemic therapy is dermatophytoses on onychomycosis
Imidazoles
(Ketoconazole
Clotrimazole
Miconazole)
Mechanism: inhibits P450 dependent enzyme, resulting in decreased lvls of ergosterol. Alteration of membrane permeability.
static/cidal
Pharm: only keto used systemically (oral and IV)
Poorly absorbed, max w/ low pH (eat!)
Eliminated by hepatic metabolism. Excreted in breast milk.
Adverse: Ketaconazole has shit systemic effects: anorexia/vomiting/nausea, rash, hepatotoxicity, jaundice. Avoid in pregnancy.
Use: Chronic mucocutaneous candidiasis.
Oral and vaginal candidiasis -> clotrimazole topically as creams.
Drug-drug interaction: Drug interactions:
Antacids/Dimetidine: elevation of pH leads to decreased oral absorption
Cyclosporine/phenytoid/antocoagulasts; ketoconazole is strong inhibitor of CYP450 metabolism leading to increased drug effect
Rifampin : decreases effect of ketoconazole by inducing metabolism
Terbenafine
Mechanism: synthetic allylamine. Inferferes w/ ergosterol synthesis by inhibiting squalene oxidase, toxic effects from squaline accumulation.
Fungicidal -> accumulates in keratin.
Pharm: agent of choice in once daily oral dose for toe/finger nail infections (onychomycosis)
Available topically for athlete’s foot. (tinea cruris/corporis)
Adverse: GI upset, rash, headache. Interference w/ CYP450 metabolism
Flucytosine
Mechanism: nucleoside analog that impairs DNA synthesis. Resistance in fungi that lack cytosine deaminase.
Pharm: well absorbed after oral admin, 4 doses. Great distribution into tissues including CNS. 90% excreted unchanged in urine - renal dosing.
Adverse: nausea, vomiting, skin lesions. Prolonged high levels -> bone marrow depression, abnormal liver function, hair loss. Bacteria converts this drug to bad things.
Use: rarely given alone (usually w/ Amph B)
Serious infections of cryptococcosis, candidiasis and chromoblastomycosis
Griseofulvin
Mechanism: binds to microtubules and inhibits mytosis. Fungistatic
Pharm: not absorbed well, reduce particle size and eat fatty foods. Has affinity for diseased skin (accumulates in keratin)
Adverse: hypersensitivity rxns most common.
Use: for severe dermatophytosis (superficial) involving skin and hair or fingernails or toenails.
Replaced by shorter course of therapy w/ ireconazole or terbinafine
Pentamidine
Mechanism: inhibits protein and nucleic acid synthesis
Pharm: IM/IV -. inhalation produces higher levels and lower toxicity in treating p. jivovici pneumonia (opportunistic in AIDS pts)
Adverse: severe toxicities, hypoglycemia, nephrotoxicity, leukopenia
Use: effective against a lot of protozoa!
(bactim preferable for non-AIDS patients and for prophylaxis of ALL pts.)
