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Year 2 Clinical Pathology > 1. Antifungal agents > Flashcards

1. Antifungal agents Flashcards

1
Q

What are fungi?

A

A group of spore-producing organisms feeding on organic matter.
-includes moulds, yeasts, mushrooms.

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2
Q

How do fungi differ in size from bacteria and viruses?

A

Fungi are generally larger

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3
Q

What are the 2 main pathogenic classifications of pathogenic fungi?

A

Yeasts
Filamentous fungi

NB. some are dimorphic (exist in both forms)

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4
Q

How do filamentous fungi divide?

A

Spore-production

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5
Q

How do yeasts divide?

A

Budding

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6
Q

What is the difference in the structures of filamentous fungi and yeasts?

A

FILAMENTOUS FUNGI = hair-like structures

YEASTS = large, oval structures

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7
Q

Give 3 examples of dimorphic fungi.

A

Histoplasma spp (»Endemic mycoses)
Candida albicans
Malasezzia spp.

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8
Q

Give an example of a condition caused by filamentous fungi.

A

Athlete’s foot

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9
Q

Give an example of a condition caused by yeasts.

A

Thrush (candida albicans)

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10
Q

What is an important feature for antifungal targets?

A

Selective toxicity - don’t cause harm to humans.

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11
Q

What is ‘Pneumocystis jirovecii’?

A

Yeast&raquo_space; pneumonia

especially in immunosupressed

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12
Q

What types of cells do fungi contain? What problem does this cause for antifungal targets?

A

Eukaryotic

-more similar to human cells, so makes selective toxicity harder

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13
Q

What are the main targets for antifungals, and why?

A
  • CELL WALL (humans don’t have one)
  • CELL MEMBRANE (different composition to humans)
  • DNA/PROTEIN SYNTHESIS
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14
Q

What is a fungal cell wall composed of?

A

B-1,3-glucans

not peptidoglycan like bacteria

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15
Q

What do fungal cell membranes contain instead of cholesterol?

A

Ergosterol

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16
Q

What is the function of ergosterol in fungal cell membranes?

A

Forms clusters in phospholipid bilayer
»regulates membrane permeability
»required for normal growth & function of cell wall

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17
Q

What is the process of ergosterol biosynthesis?

A

SQUALENE &raquo_space; LANOSTEROL &raquo_space; ERGOSTEROL

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18
Q

What are the enzymes involved in ergosterol synthesis? (2)

A

Squalene epoxidase

Lanosterol 14a demethylase

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19
Q

How do antifungal agents act on ergosterol synthesis?

A

Inhibit the enzymes involved

squalene epoxidase & lanosterol 14a demethylase

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20
Q

What is B-1,3-glucans?

A

Large polymer of UDP-glucose&raquo_space; fibrous nerwork of fungal cell wall

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21
Q

What is B-1,3-glucans synthesised by?

A

B-1,3-glucan synthase

antifungal target

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22
Q

What are the 4 classes of antifungals?

A
  • Polyenes
  • Allylamines
  • Azoles
  • Echinocandins
  • (Other; 5-fluorocytosine, griseofulvin)
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23
Q

What is the mode of action of polyenes?

A

Association with ergosterol
» forms pore-like aggregates
» loss of membrane integrity & K+ leakage
» cell death

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24
Q

Give 2 examples of polyenes.

A

Amphotericin B

Nystatin

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25
Q

What is nystatin used for?

A

Superficial infections (eg. thrush)

  • too toxic for systemic use
  • not orally absorbed
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26
Q

What is the spectrum of Amphotericin B?

A

Broad spectrum - most fungi

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27
Q

What are the adverse effects of Amphotericin B?

A
  • Allergic reactions

- Nephrotoxicity (»pores in human membranes)

28
Q

What type of Amphotericin B is now used and why?

A

Lipid-associated AmB

eg. liposomal AmB
- reduced nephrotoxicity

29
Q

How is Amphotericin B clinically used?

A

Administered parenterally for serious/systemic infections (eg. pulmonary aspergillosis).
-not absorbed orally

30
Q

When should Amphotericin B be avoided?

A

With patients with existing nephrotoxicity

31
Q

What is the mode of action of allylamines?

A

Inhibit ergosterol synthesis

-squalene epoxidase

32
Q

Give an example of an allylamine.

A

Terbinafine

33
Q

What is the spectrum of activity of Terbinafine (allylamine)?

A

Broad spectrum in vitro

34
Q

What are possible adverse effects of Terbinafine?

A

Liver toxicity

|&raquo_space;jaundice, hepatitis

35
Q

What are allylamines used to treat?

A

DERMATOPHYTE (superficial fungal) infections

  • topcial (eg. Athletes foot)
  • systemic (eg. scalp ringworm)
36
Q

What are azoles?

A

Synthetic compounds containing a 5-membered azole ring.

37
Q

What are the 2 types of azoles, and how do they differ?

A

IMIDAZOLES - 2 nitrogen atoms

TRIAZOLES - 3 nitrogen atoms

38
Q

What is the mode of action of azoles?

A

Inhibit ergosterol synthesis (lanosterol 14a-demethylase)

|&raquo_space; build up of non-ergosterol 14a-sterols in membrane

39
Q

What is the spectrum of activity in azoles?

A

Complex/variable.

  • mainly broad
  • exceptions; fluconazole&raquo_space; Aspergillus spp.
40
Q

Which azoles are less toxic, and commonly used systemically?

A

Triazoles

not imidazoles

41
Q

Give an example of an imidazole.

A

Clotrimazole

42
Q

Give 3 examples of triazoles.

A

Fluconazole
Itraconazole
Voriconazole

43
Q

What are possible adverse effects of azoles?

A

HEPATOTOXICITY

  • mild liver enzyme abnormalities (fluconazole)
  • life-threatening hepatitis (ketoconazole - rare)
44
Q

What drug interactions do azoles have?

A

Inhibition of cytochrome P-450 enzymes.

-increases concentration of drug metabolised by it

45
Q

Rank the following in order of their antifungal spectrum:

  • Itraconazole/voriconazole
  • Fluconazole
  • Posaconazole/ isavuconazole
A

NARROW&raquo_space; BROAD:

  • Fluconazole
  • Itraconazole/voriconazole
  • Posaconazole/ isavuconazole
46
Q

What are imidazoles used for clinically?

A

Superficial infections (topical)

  • candidiasis
  • dermatophyte infections
47
Q

What are triazoles used for clinically?

A

Systemic infections (oral/parenteral)

  • Aspergillosis
  • Candidiasis
48
Q

What is the mode of action of echinocandins?

A

Inhibit B-1,3-glucan synthase

|&raquo_space;abnormal cell wall

49
Q

Give 3 examples of echinocandins.

A
  • Anidulafungin
  • Caspofungin
  • Micafungin
50
Q

What is the spectrum of activity of echinocandins?

A

Aspergillus & Candida spp.

-Not Cryptococcus spp

51
Q

What are possible adverse effects of ecinocandins?

A

Minimal

-eg. skin rash, nausea, headache

52
Q

What are ecinocandins used for clinically?

A

Systemic infections

-parenteral only

53
Q

What is 5-fluorocytosine (5-FC)?

A

Synthetic analogue of cytosine

-pyrimidine nucleoside

54
Q

What was 5-fluorocytosine developed as, and what is it now used as?

A

Developed as an anti-cancer drug

-now used as an antifungal

55
Q

What is the mode of action of 5-fluorocytosine?

A

Enters cell with fungal cytosine permease (selective toxicity)
» converted to 5-fluorouracil & 5-fluorodeoxyuridine monophosphate
» inhibits RNA/protein synthesis & DNA synthesis

56
Q

What is the spectrum of activity of 5-fluorocytosine?

A

Yeasts only

-Candida & Cryptococcus spp.

57
Q

What are the possible adverse effects of 5-fluorocytosine?

A

Bone marrow suppression

-selective toxicity is incomplete

58
Q

What is 5-fluorocytosine used for clinically?

A

Cryptococcal meningitis

in combination with AmB

59
Q

What is the mode of action of Griseofulvin?

A

Inhibits fungal mitosis.

60
Q

What is the spectrum of activity of Griseofulvin?

A

Dermatophytes

61
Q

What are the possible adverse effects of Griseofulvin?

62
Q

What is Griseofulvin used for clinically?

A

Dermatophyte infections in children

  • eg. kerion
  • NB. only agent licensed for scalp infection in children
63
Q

What is therapeutic drug monitoring?

A

Measuring drug concentrations in blood.

64
Q

What is the purpose of therapeutic drug monitoring?

A
  • Minimise toxicity

- Maximise efficacy

65
Q

Which antifungal drugs require therapeutic drug monitoring? (3)

A
  • ITRACONAZOLE (make sure it doesn’t decrease too much)
  • 5-FLUOROCYTOSINE (bone marrow toxicity if too high)
  • VORICONAZOLE (liver toxicity when too high)

Year 2 Clinical Pathology (13 decks)

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