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Flashcards in Antifungal 1 Deck (50):
1

Yeasts shape

oval or round

2

Yeasts grow via

budding

3

Molds composed of

hyphae

4

Dimporphic fungi (syndromes)

  1. Sporotrichosis
  2. Coccidiodiomycosis
  3. Paracoccidioidomycosis
  4. Blastomycosis
  5. Chromoblastomycosis
  6. Histoplasmosis

5

Cells of fungi that are pathogenic in humans are...

nonmotile and have a rigid cell wall

 

(usually containing chitin and polysaccharides)

6

Two exceptions to the "non-transmissible" rule

Ringworm of scalp

Neonatal candida

7

Dermatomycoses live on ___ tissue

keratinized

8

Antifungals to treat dermatomycoses

Tolnaftate

Clotrimazole

Griseofulvin

9

Tolnaftate MOA

Inhibits squalene epoxidase

10

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

The fungal enzye is more sensitive to the drug

11

Steps in ergosterol synthesis

  • Squalene

(squalene epoxidase) 

  • Protonated squalene
  • Lanosterol
  • Ergosterol

12

Other squalene epoxidase inhibitors

Terbenafine

Naftifine

Butenafine

13

Clotrimazole MOA

Inhibits +++Fe-CYP450

which catalyzes the 14a-demethylation of lanosterol

14

Normal intermediate between Lanosterol and Ergosterol contains______

COOH group on D ring

15

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

16

Two other examples of -azole antifungal agents

Miconazole

Ketoconazole

17

___ used for systemic treatment of dermatomycoses

Griseofulvin

18

Griseofulvin MOA

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

19

Griseofulvin is used for this (possibly long term)

Onychomycoses

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

20

Antifungals to treat systemic infections

Amphoteracin B

Flucytosine

Itraonazole

Fluconazole

Echinocandins

21

AMP B contains __ and ___

lipophilic polyene region and hydrophilic polyalcohol region

22

AMP B must be administered ____ . Why?

IV 

Poor water solubility

23

Major Amp B acute reaction

Fever and Chills

24

Major Amp limiting toxicities

Nephrotoxicity

hypokalemia

25

AmpB is ___ for treatment of ____

broad spec

deep mycoses

26

AmpB MOA

binds directly to ergosterol in fungal membranes

 

Opens pores that let out small organic molecules

27

AmpB - binding ergosterol vs cholesterol

10x more strongly

28

Fluorocytosine MOA

Susceptible fungi convert:

5FC >> 5FU >> 5 fluorodeoxyuridine monophosphate

29

5FDUMP function

inhibits thymidylate synthase

(inhibits DNA synth)

30

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

31

mechanistically, what does the 5FU do?

Elimination of F+ is impossible b/c Fluorine is the most electronegative element

 

**functions as ANTIMETABOLITE

 

32

incorported into RNA in place of uracil

5-fluorouracil

Due to vanderwall radius similarity of F & H

33

5FU is also used as a ___ in humans

Anti-cancer agent

34

5 fluorocytosine is used with ___ to treat ___ infections

AmpB 

Candida and Crypto meningitis

35

High level of ____ to 5 FC

resistance

 

**administration with AmpB can kill resistant strains when they emerge

36

Whats one of the mechanisms of synergy between AmpB and 5FC

AmpB increases permeability of fungal cells

 

enhanes uptake of 5FC

37

5FC toxicity: main concern

bone marrow suppression

leads to leukopenia and thrombocytopenia

38

Ketoconazole ROA and use

Oral

Systemic infetions (blasto, histo, coccidio, paracoc)

39

Ketoconazole vs AmpB

Keto is tolerated better but is less effective

40

Fluconazole is a ______ (as opposed to a ____)

Triazole (3N's in a 5 membered ring)

Imidizole (2N's)

41

Fluconazole penetrates well into _____

the CNS

makes it appropriate for fungal meningitis

42

Fluconazole is first line for...

prevention of relapse of crypto meningitis in AIDS patients (who recieved AmpB)

43

Fluconazole infrequently causes...

hepatotoxicity

44

Itraconazole composition

1-1-1-1 racemic mixture of 4 diastereomers

 

(its a triazole like fluconazole)

45

Itraconazole ineffective for ___

treating CNS infections - doesnt appear in CSF

 

**very heavily bound to plasma proteins and is bound in tissues

46

Itraconazole preferred over ketoconazole for ____

non-meningeal histoplasmosis

 

(also disseminated histo in AIDS patients who were given AmpB)

47

Itraconazole AE's

heart failure

hepatoxicity

DDI with other P450 drugs (contraindicated with Cisapride, pimozide, quinidine, and dofetilide)

 

48

Echinocandins MOA

inhibit 1,3-ß-glucan synthase 

Halts production of 1,3 B glucan for cell wall

49

Echinocandins spectrum

 

Synergistic with what others?

Broad spec

 

Voriconazole

AmpB

50

Echinocandins ROA and AE's

IV

hepatotoxicity and hypersensitivity reactions