Flashcards in Anti-fungals Deck (47):
differentiate b/w fungi in the imperfect and perfect states
imperfect: only asexual spores
perfect: sexual spores (can be induced from imperfect)
describe fungi characteristics
-molds: tubular hyphae
-dimorphic: yeast in host, mold at room temp
-nonmotile, rigid cell wall (chitin, polysaccharides)
are fungal infections transmissible person to person?
no- except scalp ringworm or neonatal thrush
four disease states with fungal infections
4. mucous membranes
briefly describe dermatomycoses
live on keratinized tissue (skin, hair, nails)
sx: itching, burning, skin cracking
briefly describe onychomycoses
caused by a dermatophyte
sx: nail thickens, discolored (white/yellow/brown)
what drugs are used to treat dermatomycoses?
1. tolnaftate (tinactin)
2. clotrimazole (lotrimin)
tolnaftate (tinactin) MOA
inhibits fungal squalene epoxidase - decreases ergosterol synthesis (for cell membrane)
what are some other squalene epoxidase inhibitors?
clotrimazole (lotrimin) MOA
azole drug: inhibits cyt p450, blocking 14a-demethylation of lanosterol to ergostanol
can clotrimazole react with human cells?
yes- although it is much more selective for fungi
two other azole antifungals besides clotrimazole
what is griseofulvin used for?
systemic treatment of dermatomycoses
disrupts mitotic spindle by binding polymerized microtubules to inhibit mitosis
what does griseofulvin treat?
onychomycoses: deposited in the newly formed keratin, where it prevents fungal growth
old nail can still have persistent infection, so therapy may last for up to or more than 1y
chemical properties of griseofulvin that are limiting? how do we get around these problems?
-use microsize and ultramicrosize particles to increase dissolution rate
-taken w/ high fat diet to increase absorption
AE of griseofulvin
what are 6 systemic antifungals?
1. Amphotericin B (fungizone)
2. 5-fluorocytosine (ancoban, flucytosine)
3. Ketoconazole (Nizoral)
4. Fluconazole (Diflucan)
chemical properties of ampho B
-poor water solubility - not absorbed well from GI (so given IV slow infusion or as liposomal suspension injection)
-bile salt complex form = deoxycholate complex
-sterile lyophilized form = cholesterol complex
SE of ampho B
-major acute rxn: fever/chills
-headache, nausea, vomit, nephrotoxicity, hypotension
-limiting toxicities: nephrotoxicity + hypokalemia
what is the drug of choice for life-threatening fungal infections?
ampho B (broad spec- can do deep mycoses)
ampho B MOA
binds ergosterol in membranes, opens pores - leakage of ions and small organic molecules
why does ampho B cause some toxicity?
it also binds some cholesterol
bacteria convert 5-fluorocytosine to 5-fluorouracil to 5-fluorodeoxyuridine monophosphate - this inhibits thymidylate synthase, inhibiting DNA synthesis
alternate 5-fluorocytosine MOA
antimetabolite - 5-fluorouracil incorporated into RNA in place of uracil, inhibiting protein synthesis
why does 5-fluorocytosine not affect human cells?
humans have little or no cytosine deaminase activity
-combined w/ ampho B - systemic candida, cryptococcus, meningitis
-also for Torulopsis glabrata, Cladosporium, Aspergillus
PK of 5-fluorocytosine
-well absorbed in GI + penetrates CSF
toxicity of 5-fluorocytosine
-depress bone marrow fxn: leukopenia, thrombycytopenia
-careful w/ patients w/ impaired renal fxn
-nausea, vomit, diarrhea, rash, enterocolitis
uses of ketoconazole
-oral use for systemic infections
-tx: blastomycosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis
PK of ketoconazole vs. ampho B
better tolerated than ampho B, but less effective
what kind of drug is fluconazole?
triazole (3 N's in a 5-membered ring)
PK of fluconazole
high bioavailability + penetrates CSF
AE and DDI with fluconazole?
decreased incidence b/c more selective for fungi
-rare: hepatotoxicity (monitor if abnormal liver fxn tests)
-IV: AIDS cryptococcal meningitis
-200 mg daily for prevention of crypto meningitis relapse controlled by ampho B
-150 mg p.o.- vaginal candidiasis
what is itraconazole a mixture of?
1:1:1:1 of 4 diastereomers
also a triazole
PK of itraconazole
more than 90% bound to serum proteins
extensively bound in tissues
does NOT go to CSF
-itraconazole > ketoconazole for nonmeningeal histo
-AIDS disseminated histo w/ stabilization during ampho B therapy
at what dose is itraconazole well tolerated?
AE of itraconazole
-400 mg/d: some GI distress
-nausea, vomit, hypokalemia, rash
what patients should not receive itraconazole?
CHF patients b/c it can cause heart failure
DDI with itraconazole
DDI if given with other drugs metabolized by cyt p450, including:
inhibits 1,3-B glucan synthesis in fungal cell wall by noncompetitive inhibitin of 1,3-B glucan synthase
(selective for fungus)
uses of echinocandins
-broad spec w/ no cross resistance
-synergistic w/ voriconazole and ampho B
AE of echinocandins