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Year 2 Clinical Pathology > Intro to antifungal agents > Flashcards

Intro to antifungal agents Flashcards

1
Q

Name the 2 (/3) main types of fungi?

A

1) Filamentous fungi (moulds)
2) Yeats
3) Also have dimorphic fungi which exist in both forms

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2
Q

Name the 5 main antifungal targets?

A

1) DNA synthesis
2) Mitosis
3) Cell wall: beta -1-3-glucan
4) Cell membrane: ergosterol
5) Protein synthesis

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3
Q

Why is ergosterol a good target for anti fungal agents?

A

Humans don’t have ergosterol in cell membranes (we have cholesterol) so reduces toxicity to humans

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4
Q

Why is beta-1-3-glucan that makes fungal cell walls a good target for anti fungal agents?

A

Humans don’t have cell walls so no toxicity to humans

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5
Q

What is ergosterol?

A

Found mainly in fungal cell membranes
Forms clusters within the phospholipid bilayer
Has a role in the regulation of membrane permeability
Required for normal growth and function of the fungal cell membrane, hence fungal viability

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6
Q

What are the 2 relevant steps in ergosterol biosynthesis (including enzymes)?

A

1)Squalene -> Lanosterol
Enzyme = squalene epoxidase
2) Lanosterol -> Ergosterol
Enzyme = lanosterol 14a demethylase

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7
Q

What are Beta-1-3 glucans?

A

Large polymers of UDP glucose
Make up 50-60% of dry weight of fungal cell wall
Forms a fibrous network on the inner surface of the cell wall
Synthesised by Beta-1-,30glucan synthase

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8
Q

What are the 4 main classes of antifungal agents?

A

1) Polyenes
2) Allylamines
3) Azoles
4) Echinocandins

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9
Q

What is the mode of action of polyenes?

A

Association with ergosterol in a physical way, formation of pore-like molecular aggregates
Cause loss of membrane integrity and leakage of K+
Causes cell death

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10
Q

Give 2 examples of polyenes?

A

1) Amphotericin B

2) Nystatin

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11
Q

What is the spectrum of activity of Amphotericin B?

A

Most fungi of medical importance

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12
Q

What are the 2 main adverse effects of amphotericin B?

A

1) allergic reactions

2) nephrotoxicity (pores are formed in ergosterol-free membranes)

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13
Q

Why are lipid associated Amphotericin B formulations more commonly used that simply amphotericin?

A

Minimize delivery of AmB to kidney cells
Delivery is targeted to fungal cell and/or reticulo-endothelial system (liver, spleen, lymph nodes)
This reduces nephrotoxicity

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14
Q

When is amphotericin B used clinically and how?

A

Not absorbed orally so administered parenterally
Used in serious or systemic infections (such as aspergilllosis, candidiasis, cryptococcosis)
Not used, if possible in people with existing nephrotoxicity

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15
Q

When is nystatin used clinically and how?

A

Not absorbed orally and is too toxic for systemic use

Used in superficial infections (such as oral/vaginal candidiasis)

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16
Q

What is the mode of actions of Allylamines?

A

Inhibit ergosterol synthesis (inhibit squalene epoxidase)

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17
Q

Give one example of an allylamine?

A

Terbinafine

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18
Q

What is the spectrum of activity of allylamines (terbinafine)?

A

Broad spectrum of activity in vitro but in practise only used in one type of infection

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19
Q

What is the main adverse effect of allylamines?

A

Liver toxicity - jaundice, hepatitis - rarely fatal

20
Q

What is the clinical use of allylamines?

A

Dermatophyte infections (superficial fungal infections)

1) Topical use: athletes foot (tinea pedis), tinea corporis, tinea cruris
2) Systemic (oral) use: scalp ringworm (tinea capitis), onychomycosis

21
Q

What are azoles?

A

Synthetic compounds containing a 5-membered azole ring
Imidazoles have 2 N atoms
Triazoles have 3 N atoms

22
Q

What is the mode of action of azoles?

A

Inhibit ergosterol synthesis

inhibit lanosterol 14a-demethylase leading to a build up of 14a-sterols in membrane

23
Q

What is the spectrum of activity of azoles?

A

Complex, varies between drugs
Essentially broad spectrum - treat both yeasts and filamentous fungi
With the exceptions of fluconazole and aspergillus spp.

24
Q

What is the toxicity and systemic use of imidazole and triazoles?

A

Imidazoles:
Toxic and rarely used systemically (ketoconazole)
Triazoles:
Less toxic, systemic use more common

25
Q

Name the main imidazole in use?

A

Clotrimazole

26
Q

Name the 3 main triazoles in use?

A

1) Fluconazole
2) Itraconazole
3) Voriconazole

27
Q

What are the adverse effects of azoles? 2

A

1) Hepatotoxicity
- Mild liver enzyme abnormalities
- Life-threatening hepatitis
2) Drug interactions
- Inhibition of cytochrome P450 enzymes (increases concentration of all drugs metabolised by CP450 enzymes)

28
Q

What is the spectrum of fluconazole (yeasts/aspergillus spp./mucoraceous moulds)?

A

Effective against yeasts

Not effective against Aspergillus spp. or mucoraceous moulds

29
Q

What is the spectrum of Itraconazole/ voriconazole (yeasts/aspergillus spp./mucoraceous moulds)?

A

Effective against yeasts and aspergillus spp.

Not effective against mucoraceous moulds

30
Q

What is the spectrum of posaconazole/ isavuconazole (yeasts/aspergilus spp./mucoraceous moulds)?

A

Effective against yeasts, aspergillus spp. and mucoraceous moulds

31
Q

What is the clinical use of imidazoles (a type of azole)?

A

Superficial infections (topical administration)
Cadidiasis (canestan)
Dermatophyte infections

32
Q

What is the clinical use of triazoles?

A

Systemic infections (oral/parenteral administration)
Aspergillosis (used in treatment and occasionally prophylaxis)
Candidiasis (fluconazole)

33
Q

What is the mode of action of Echinocandins?

A

Inhibition of beta-1,3-glucan (used to make fungal cell walls)
Leads to construction of severely abnormal cell wall

34
Q

Give 3 examples of Echinocandins?

A

1) Anidulafungin
2) Caspofungin
3) Micafungin

35
Q

What is the spectrum of activity of echinocandins?

A

Apergillus spp and candida spp

Misses certain moulds and cryptococcus spp.

36
Q

What are the adverse effects of echinocandins?

A

Minimal: eg. skin rash, nausea, vomiting, headache, diarrhoea in common with any other drug

37
Q

What is the clinical use of echinocandins?

A

Systemic infections

Parenteral formulations only

38
Q

What is 5-fluorocytosine (5-FC)?

A

Synthetic analogue of cytosine (a pyrimidine nucleoside)
Developed as an anti-cancer drug, has no anti-cancer properties but incidentally was found to have anti-fungal properties

39
Q

What is the mode of action of 5-fluorocytosine, how does it show selective toxicity?

A

Entry into cell requires fungal cytosine permease (not found in humans so cant get into our cells - selective toxicity)
Converted to 5-fluorouracil and 5-fluorodeoxyuridine monophosphate, inhibit RNA/protein synthesis and DNA synthesis

40
Q

What is the spectrum of activity of 5-fluorocytosine?

A

Yeasts only - candida and cryptococcus spp.

41
Q

What are the adverse effects of 5-fluorocytosine?

A

Bone marrow suppression - selective toxicity is incomplete

42
Q

When is 5-fluorocytosine used clinically?

A

To treat cryptococcal meningitis (in combination with AmB)

43
Q

What are the 2 reasons for therapeutic drug monitoring?

A

1) To minimize toxicity - level should remain below a threshold value
2) To maximize efficacy - level should exceed threshold value

44
Q

Why does itraconazole require therapeutic drug monitoring?

A

To maximize efficacy - has few side effects but their is a minimum level below which it doesnt work

45
Q

Why does 5-fluorocytosine require therapeutic drug monitoring?

A

To minimize toxicity

46
Q

Why does voriconazole require therapeutic drug monitoring?

A

To minimize toxicity AND to maximize efficacy

Year 2 Clinical Pathology (64 decks)

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