Antifungal 1 Flashcards
Yeasts shape
oval or round
Yeasts grow via
budding
Molds composed of
hyphae
Dimporphic fungi (syndromes)
- Sporotrichosis
- Coccidiodiomycosis
- Paracoccidioidomycosis
- Blastomycosis
- Chromoblastomycosis
- Histoplasmosis
Cells of fungi that are pathogenic in humans are…
nonmotile and have a rigid cell wall
(usually containing chitin and polysaccharides)
Two exceptions to the “non-transmissible” rule
Ringworm of scalp
Neonatal candida
Dermatomycoses live on ___ tissue
keratinized
Antifungals to treat dermatomycoses
Tolnaftate
Clotrimazole
Griseofulvin
Tolnaftate MOA
Inhibits squalene epoxidase
Why doesn’t inhibition of squalene epoxidase affect mammillian cells as much as fungi?
The fungal enzye is more sensitive to the drug
Steps in ergosterol synthesis
- Squalene
(squalene epoxidase)
- Protonated squalene
- Lanosterol
- Ergosterol
Other squalene epoxidase inhibitors
Terbenafine
Naftifine
Butenafine
Clotrimazole MOA
Inhibits +++Fe-CYP450
which catalyzes the 14a-demethylation of lanosterol
Normal intermediate between Lanosterol and Ergosterol contains______
COOH group on D ring
How do azoles (like clotrimazole) block CYP450 during ergosterol synthesis
The electrons on N bind to the Fe3+ on CYP450.
This happens more readily with fungal enzyme than with humans
Two other examples of -azole antifungal agents
Miconazole
Ketoconazole
___ used for systemic treatment of dermatomycoses
Griseofulvin
Griseofulvin MOA
Disrupts the mitotic spindle by binding to polymerized MTs to inhibit mitosis
Griseofulvin is used for this (possibly long term)
Onychomycoses
Treatment lasts up to a year since keratin in old tissue may support fungal growth.
Antifungals to treat systemic infections
Amphoteracin B
Flucytosine
Itraonazole
Fluconazole
Echinocandins
AMP B contains __ and ___
lipophilic polyene region and hydrophilic polyalcohol region
AMP B must be administered ____ . Why?
IV
Poor water solubility
Major Amp B acute reaction
Fever and Chills
Major Amp limiting toxicities
Nephrotoxicity
hypokalemia
AmpB is ___ for treatment of ____
broad spec
deep mycoses
AmpB MOA
binds directly to ergosterol in fungal membranes
Opens pores that let out small organic molecules
AmpB - binding ergosterol vs cholesterol
10x more strongly
Fluorocytosine MOA
Susceptible fungi convert:
5FC >> 5FU >> 5 fluorodeoxyuridine monophosphate
5FDUMP function
inhibits thymidylate synthase
(inhibits DNA synth)
Mechanism of DUMP to DTMP conversion
- Michael addition >> enolate created
- added to iminium in methyleneTHF (thiss eliminates THF)
- Uracil derivative formed
- Delivery of hydride from THF to the uracil intermediate (via Michael reation)
- Generates enolate >> eliminates the enzyme = product
mechanistically, what does the 5FU do?
Elimination of F+ is impossible b/c Fluorine is the most electronegative element
**functions as ANTIMETABOLITE
incorported into RNA in place of uracil
5-fluorouracil
Due to vanderwall radius similarity of F & H
5FU is also used as a ___ in humans
Anti-cancer agent
5 fluorocytosine is used with ___ to treat ___ infections
AmpB
Candida and Crypto meningitis
High level of ____ to 5 FC
resistance
**administration with AmpB can kill resistant strains when they emerge
Whats one of the mechanisms of synergy between AmpB and 5FC
AmpB increases permeability of fungal cells
enhanes uptake of 5FC
5FC toxicity: main concern
bone marrow suppression
leads to leukopenia and thrombocytopenia
Ketoconazole ROA and use
Oral
Systemic infetions (blasto, histo, coccidio, paracoc)
Ketoconazole vs AmpB
Keto is tolerated better but is less effective
Fluconazole is a ______ (as opposed to a ____)
Triazole (3N’s in a 5 membered ring)
Imidizole (2N’s)
Fluconazole penetrates well into _____
the CNS
makes it appropriate for fungal meningitis
Fluconazole is first line for…
prevention of relapse of crypto meningitis in AIDS patients (who recieved AmpB)
Fluconazole infrequently causes…
hepatotoxicity
Itraconazole composition
1-1-1-1 racemic mixture of 4 diastereomers
(its a triazole like fluconazole)
Itraconazole ineffective for ___
treating CNS infections - doesnt appear in CSF
**very heavily bound to plasma proteins and is bound in tissues
Itraconazole preferred over ketoconazole for ____
non-meningeal histoplasmosis
(also disseminated histo in AIDS patients who were given AmpB)
Itraconazole AE’s
heart failure
hepatoxicity
DDI with other P450 drugs (contraindicated with Cisapride, pimozide, quinidine, and dofetilide)
Echinocandins MOA
inhibit 1,3-ß-glucan synthase
Halts production of 1,3 B glucan for cell wall
Echinocandins spectrum
Synergistic with what others?
Broad spec
Voriconazole
AmpB
Echinocandins ROA and AE’s
IV
hepatotoxicity and hypersensitivity reactions
