Anti-Fungals Flashcards
Two ways that fungi can grow
Single Cell (Yeasts) Filamentous Multicellular Aggregates (Molds)
Yeasts typically reproduce by…
budding
Molds are made of…
hyphae
What are dimorphic fungi?
Ones that can grow as either yeasts or molds
Yeast in host
Six important dimorphic fungi
Sporotrichosis Coccidiomycosis Paracoccidiomycosis Chromoblastomycosis Blastomycosis Histoplasmosis
How do fungi reproduce?
Forming spores through mitosis or forming sexual spores
Fungi growing sexual spores are said to be in…
the perfect state
Describe the cell wall of a pathogenic fungus
Nonmotile, Rigid
Contain Chitin and Polysaccharides
What mycoses are transmissible from person to person?
Scalp ringworm
Thrush in the newborn (from mom with Candida)
Important details for dermatomycoses.
Filamentous fungi on keratinized tissue (skin, hair, nails)
Symptoms - Itching, burning, crackling of skin
Examples - Athlete’s Foot, Ringworm, Jock Itch)
Important details for onychomycoses?
Localized fungal infection of the nail or nail bed
Caused by dermatophyte
Thickening of nail (white, yellow, or brown)
Two examples of yeast-like fungi involving internal organs
Histoplasmosis
Candidiasis
Anti-fungals for Dermatomycoses?
Tolnaftate (Tinactin)
Clotrimazole (Lotrimin)
Griseofulvin
Tolnaftate mechanism of action?
Inhibition of Fungal squalene epoxidase
Results in loss ergosterol synthesis in fungi
Loss of membrane stability
Why is tolnaftalate selective for the fungus and not the host?
Humans use cholesterol, not ergosterol
Three non-tolnaftate squalene epoxidase inhibitors?
Terbenafine
Naftifine
Butenafine
Clotrimazole is administered how?
Vaginal Tablet
Topical
Clotrimazole is a member of the _____ class of antifungal agents
Azole
What do azoles do against fungi?
Inhibit Cytochrome p450 (which catalyzes 14alpha demethylation of lanosterol in ergosterol production) by inhibiting the binding/activation of molecular oxygen
Selectivity of Azoles?
Greater affinity for fungal cytochrome p450 than human
Selectivity is not absolute
Non-Clotrimazole azoles listed?
Miconazole
Ketoconazole
Griseofulvin is used for…
Systemic treatment of dermatomycoses
How does Griseofulvin work?
- It disrupts mitotic spindle binding to polymerized microtubules (inhibiting mitosis).
- Binds in newly formed keratin to prevent fungal growth
Griseofulvin is used to treat..
Onychomycosis (fungal infections of the nails)
Why does Griseofulvin take so long?
Keratin in old tissues may still support fungal growth
Dissolution rate of Griseofulvin?
Very slow (because it is water insoluble)
How to improve the dissolution rate of Griseofulvin?
Microsize and ultramicrosize particles
Taken in a high fat diet
Adverse effects of Griseofulvin?
Photosensitivity, Hypersensitivity, Headache
Antifungals used to treat systemic infections?
Amphotericin B 5-Fluorocytosince Ketoconazole Fluconazole Itraconazole Echinocandins
Amphotericin B is amphoteric…what does that mean
Acidic and a Basic Group
Specific phillicities of Amphotericin B?
Lipophillic polyene region (bottom)
Hydrophilic polyalcohol region
Absorption info for Amphotericin B?
Poor water solubility
Not absorbed well in GI
Must be administered by slow IV infusion
What is the Amphotericin B deoxycholate complex or cholesterol complex?
A bile salt complex which is reconstituted with sterile water
(you can also get it as a liposomal suspension for injection, but I don’t feel like making another card for it)
Major acute rxns to Amphotericin B?
Fever and Chills
Sometimes HA, Nausea, Vomiting, nephrotoxicity, HTN
Major limiting toxicities of Amphotericin B?
Nephrotoxicity
Hypokalemia
Name six fungal infections that Amphotericin B is the drug of choice for?
Aspergillosis Blastomycosis Coccidiomycosis Cryptococcosis Histoplasmosis Mucormycosis
Mechanism of action for Amphotericin B?
Binding to ergosterol in the membranes
Pores open in the membrane
Leakage of ions and Small organic molecules
Selectivity of Amphotericin B?
Binds 10 times more strongly to vesicles containing ergosterol than those with cholesterol
BUT some cholesterol binding still occurs, resulting in toxicity
Mechanism of 5-Fluorocytosine action?
Susceptible fungi convert 5-Fluorocytosine to 5-Fluorouracil, which is conversed to 5-fluorodeoxyuridine monophosphate
5-fluorodeoxyuridine monophosphate inhibits…
Thymidylate synthase
An enzyme required for DNA synthesis
Steps of Biosynthetic conversion of deoxyuridine monophosphate
- Michael addition to Uracil to make an enolate
- Added to iminium ion in methelene-THF
- Intermediate eliminates THF, forming uracil derivative
- In Michael addition, enolate is generated
- Enzyme is eliminated to generate final product
How does the presence of 5-fluorouracil influence the deoxyuridine monophosphate mechanism?
Elimination of F+ is impossible
Nothing around to be more electronegative
Leaves a big-ole unbreakable chain
Aside from problems with the generation of thymidylate synthase, what else does 5-fluorouracil do to prevent fungi?
It incorporates into RNA in place of uracil
Inhibited protein synthesis
5-fluorouracil = antimetabolite
What is an anti-metabolite?
The analog o an essential substrate that is accepted by the metabolic pathway, but cannot itself support life in the cell
5-Fluorocytosine selectivity?
Human cells have little or no cytosine deaminase activity
Therapeutic use of 5-Fluorocytosine?
Used w/ Amp. B on systemic Candida+Cryptococcus meningitis.
Sometimes torpulopsis glabrata, cladosporidium, and aspergillis
Resistance to 5-Fluorocytosine?
With with Amp. B to kill resistant strains
How does 5-Fluorocytosine function change with Amph. B added?
Amph. B fucks up the fungal cell permeability
Makes it easier for 5-Fluorocytosine to get up in there
Toxicity associated with 5-Fluorocytosine?
Depressed Bone Marrow Fxn - Leukopenia, thrombocytopenia
Nausea, Vomiting, Diarrhea
Rash, Entercolitis
5-Fluorocytosine should be administered with extreme caution to which patients?
Bone marrow depression
Diminished renal function
How might 5-Fluorocytosine nausea be diminished?
Capsules administered a few at a time over a 15 minute period
Important details on Ketoconazole?
Oral treatment of systemic infection
Better tolerated than AmpB, but less effective
What is Ketoconazole used to treat?
Bastomycosis
Histoplasmosis
Coccidiomycosis
Paracoccioiomycosis
Describe the structure of Fluconazole?
A triazole (3 Ns in a 5 membered ring) Not an Imidazole (2Ns)
Bioavailability of Fluconazole?
High bioavailability
Penetrates into the CSF
Selectivity of Fluconazole?
Selective for Fluconazole cytochrome p450
Therapeutic use of Fluconazole?
IV infusion – Cryptococcal memingitis in AIDS patients whose infection has been controlled by AB
Single dose – Vaginal candidiasis
Toxicity assocaited with Fluconazole?
Rare cases of hepatotoxicity (including fatalities)
Itraconazole is a mix of…
Four Diastereomers
Itraconazole availability….
90% bound to serum proteins, extensively bound in tissues
Can Itraconazole be used to treat CSF infections?
Nope
No detectable drug in the CSF
Therapeutic use of Itraconazole?
Preferred over keto for non-meningeal histoplasmosis.
AIDS pateints w/ disseminated Histo (stabilized by AB)
Untoward effects of Itraconazole?
GI distress (at 400mg/day or more), Nausea, Vomiting
Hypokalemia, Rash
Heart Failure
Hepatotoxicity
Itraconazole cannot be coadministered with…
drugs metabolized by Cytochrome p450
ex. cisapride, pimozide, quinidine, dofetilide
Functional activity of Echinocandins?
Inhibit 1,3 beta glucan synthesis in the fungal cell walls by non-competitive inhibition of 1,3 beta-glucan synthase
Selectivity of Echinocandins?
Good because mammalisn cells lack 1,3 beta-glucan synthase
Cross resistance of Echinocandins?
None
Echinocandins are synergistic with…
Voriconazole and Amph. B
Mode of administration for Echinocandins?
IV
Adverse reactions to Echinocandins?
Hepatotoxicity
Sensitivity/Allergic Reactions
