Antifungal agents Flashcards
What are fungi
eukaryotic organisms growing as single cells (yeasts) or as filamentous multicellular aggregates (molds)
dimorphic fungi
can grow as yeasts (oval or round) in host and molds (hyphae) at room temperature in vitro
examples of dimorphic fungi
sporotrichosis coccidioidomycosis paracoccidioidomycosis chromoblastomycosis blastomycosis histoplasmosis
Cells of fungi that are pathogenic in humans are
nonmotile and have a rigid cell wall, usually containing chitin and polysaccharides
Mycoses are generally not transmissible except for
ringworm
thrush in newborn from candida albicans during childbirth
Dermatomycoses
filamentous fungi that live on keratinized tissue
itching, burning and cracking of skin
Onychomycoses
localized fungal infection of nail or nail bed
Examples of systemic infections by yeast-like fungi
histoplasmosis and candidiasis
Drugs used to treat dermatomycoses
- Tolnaftate
- Clotrimazole
- Griseofulvin
MOA of tolnaftate
inhibits fungal squalene epoxidase, resulting in decreased ergosterol biosynthesis
What is ergosterol?
the steroid present in fungal cell membranes
Why is inhibition of ergosterol biosynthesis not cytotoxic to the host?
mammalian cells contain cholesterol in the cell membranes not ergosterol and fungal squalene epoxidase is more sensitive to tolnaftate than mammalian squalene epoxidase
Other squalene epoxidase inhibitors used as antifungal agents
terbinafine
naftifine
butenafine
The azole class of antifungals inhibit
cytochrome P450
cytochrome P450 catalyzes
the 14a-demethylation of lanosterol during its conversion to ergosterol
What does clotrimazole inhibit
the binding and activation of molecular oxygen by cytochrome P450 and therefore inhibits the conversion of lanosterol to ergosterol
Describe the selectivity of clotrimazole to human cytochrome P450
azoles have a greater affinity for the fungal cytochrome P450 than the human one, but the azoles still do bind to human cytochrome P450 and can inhibit drug metabolism
Other examples of azole antifungal agents
miconazole and ketoconazole
How does Griseofulvin work?
disrupts the mitotic spindle by binding to polymerized microtubles to inhibit mitosis
What is griseofulvin used to treat?
used in the treatment of onychomycosis
deposited in newly formed keratin, where it prevents fungal growth
What kind of diet can increase the absorption of griseofulvin?
high fat diet
Adverse effects of griseofulvin?
photosensitivity, hypersensitivity and headache
Antifungals to treat systemic infections
- Amphotericin B
- 5-Fluorocystosine
- Ketoconazole
- Fluconazole
- Itraconazole
- Echinocandins
Describe the structure of Amphotericin B
amphoteric
lipophilic polyene region and a hydrophilic polyalcohol region
Side effects of amphotericin B
fever and chills
sometimes headache, nausea, vomiting, nephrotoxicity and hypotension
Major limiting toxicities of amphotericin B
nephrotoxicity and hypokalemia
drug of choice for life threatening fungal infections
Amphotericin B
Amphotericin B used to treat
deep mycoses including aspergillosis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis and mucormycosis
MOA of amphotericin B
binds to ergosterol in membranes of sensitive fungi, opening pores and allowing leakage of ions and small organic molecules
MOA of 5-fluorocytosine
susceptible fungi convert 5-fluorocytosine to 5-fluorouracil, which is converted into 5-fluorodeoxyuridine monophosphate
What does 5-fluorodeoxyuridine monophosphate inhibit
thymidylate synthase - thus inhibiting DNA biosynthesis
5-fluorouracil incorporation into RNA in place of uracil does what
leads to the inhibition of protein synthesis
5-fluorouracil functions as a
antimetabolite (analog of an essential substrate that is accepted by the metabolic pathway but cannot itself support the life of the cell)
5-fluorocytosine (flucytosine) is used to treat?
used in combination with amphotericin B to treat systemic Candida infections and Cryptococcus neoformans meningitis
Spectrum of activity for 5-fluorocytosine
limited to susceptible strains of Candida, Cryptococcus, Torulopsis glabrata, Cladosporium and Aspergillus
Toxicity of 5-fluorocytosine
depresses bone marrow funciton (leukopenia and thrombocytopenia)
monitor kidney function
nausea, vomiting, diarrhea, rash and enterocolitis
Ketoconazole used for
oral treatment of systemic infections
tolerated better than AmpB but less effective
Ketaconazole treats
blastomycosis, histoplasmosis, coccidioidomycosis and paracoccidioidomycosis
fluconazole used to treat
IV infusion to treat cryptococcal meningitis in AIDS patients
prevention of relapse of cryptococcal meningitis in AIDS patients
oral dose for treatment of vaginal candidiasis
Toxicity of fluconazole
rare cases of hepatotoxicity
Therapeutic uses of itraconazole
preferred treatment over ketoconazole for the treatment of nonmeningeal histoplasmosis (does not penetrate CSF)
AIDS patients with disseminated histoplasmosis
Serious side effects of itraconazole
heart failure
rare severe hepatotoxicity
coadministration of itraconazole is contraindicated with
cisapride, pimozide, quinidine and dofetilide
Echinocandins inhibit
1,3-beta-glucan synthesis in the fungal cell walls by noncompetitive inhibition of 1,3-beta-glucan synthase
Describe use of echinocandins
broad spectrum antifungal agents that have no cross-resistance with other antifungals and are synergistic with voriconazole and amphotericine B
Adverse reactions of echinocandins
hepatotoxicity and sensitivity/allergic reactions
