Antifungal 1 Flashcards by Chris Rodarte

Yeasts shape

oval or round

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Yeasts grow via

budding

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Molds composed of

hyphae

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Dimporphic fungi (syndromes)

Sporotrichosis
Coccidiodiomycosis
Paracoccidioidomycosis
Blastomycosis
Chromoblastomycosis
Histoplasmosis

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Cells of fungi that are pathogenic in humans are…

nonmotile and have a rigid cell wall

(usually containing chitin and polysaccharides)

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Two exceptions to the “non-transmissible” rule

Ringworm of scalp

Neonatal candida

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Dermatomycoses live on ___ tissue

keratinized

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Antifungals to treat dermatomycoses

Tolnaftate

Clotrimazole

Griseofulvin

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Tolnaftate MOA

Inhibits squalene epoxidase

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Why doesn’t inhibition of squalene epoxidase affect mammillian cells as much as fungi?

The fungal enzye is more sensitive to the drug

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Steps in ergosterol synthesis

Squalene

(squalene epoxidase)

Protonated squalene
Lanosterol
Ergosterol

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Other squalene epoxidase inhibitors

Terbenafine

Naftifine

Butenafine

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Clotrimazole MOA

Inhibits +++Fe-CYP450

which catalyzes the 14a-demethylation of lanosterol

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Normal intermediate between Lanosterol and Ergosterol contains______

COOH group on D ring

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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

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Two other examples of -azole antifungal agents

Miconazole

Ketoconazole

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___ used for systemic treatment of dermatomycoses

Griseofulvin

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Griseofulvin MOA

Disrupts the mitotic spindle by binding to polymerized MTs to inhibit mitosis

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Griseofulvin is used for this (possibly long term)

Onychomycoses

Treatment lasts up to a year since keratin in old tissue may support fungal growth.

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Antifungals to treat systemic infections

Amphoteracin B

Flucytosine

Itraonazole

Fluconazole

Echinocandins

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AMP B contains __ and ___

lipophilic polyene region and hydrophilic polyalcohol region

AMP B must be administered ____ . Why?

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