CP4 - Introduction to Antifungal agents

Question 1

what are the 3 classes of pathogenic fungi?

Answer 1

1. filamentous fungi
2. moulds/yeasts
3. dimorphic - can exist in both forms depending on the conditions that they are exposed to

Question 2

which type of fungi can cause disease?

Answer 2

microfungi

Question 3

name some targets of antifungals

Answer 3

1. DNA synthesis
2. mitosis
3. cell membrane
4. protein synthesis
5. cell wall

Question 4

what is the main component of the cell membrane in humans and fungi?

Answer 4

humans - cholesterol

fungi - ergosterol

Question 5

what is the main component of a fungal cell wall?

Answer 5

B-1,3-glucan

Question 6

what is the function of ergosterol in fungal PM?

Answer 6

1. regulates membrane permeability

2. important for the normal growth and function of the fungal cell wall

Question 7

which 2 stages of ergosterol synthesis are attacked by drugs?

Answer 7

squalene –> lanosterole via squalene epoxidase

lanosterol –> ergosterol via lanosterol 14alpha demethylase

Question 8

what are beta-1,3-glucans?

Answer 8

1. large polymers of UDP-glucose
2. form a large component of the fungus and its cell wall
3. synthesised by B-1,3-glucan synthase

Question 9

what are the classes of antifungals?

Answer 9

1. polyenes
2. Allylamines
3. azaleas
4. echinocandins
5. others

Question 10

name some examples of polyenes

Answer 10

amphotericin B

Nystatin

Question 11

what is the mode of action of polyenes?

Answer 11

1. associated with ergosterol
2. form pore-like aggregations in the PM
3. membrane loses its integrity and K+ leaks out of the cell, causing it to die

Question 12

what is the spectrum of activity of amphotericin B?

Answer 12

most fungi of medical importance

Question 13

what is the clinical use of amphotericin B?

Answer 13

Aspergillus candida
Cryptococcus
used for serious or systemic infections
parenteral administration

Question 14

what are the adverse effects of polyenes?

Answer 14

1. allergic reactions
2. nephrotoxicity, due to a potential spillover effect on human membranes, usually to a lesser extent and reversible, but not used in patients with existing nephrotoxicity

Question 15

what is the clinical use of nystatin?

Answer 15

only used for superficial infections, because it is not absorbed orally and is too toxic for systemic use.
oral.vaginal candidiasis
no systemic side effects

Question 16

name an example of Allylamines

Answer 16

terbinafine

Question 17

what is the mode of action of allylamines?

Answer 17

they stop ergosterol synthesis by inhibiting squalene epoxidase, therefore PM cannot form properly.

Question 18

what is the spectrum of activity go allylamines?

Answer 18

broad spectrum in vitro

Question 19

what is the clinical use of allylamines?

Answer 19

dermatophyte infections (superficial/topical use)
1. athlete's foot
2. tinea corporis
3. cruris
systemic
1. scalp ringworm
2. onychomycosis

Question 20

what are the adverse effects of allylamines?

Answer 20

liver toxicity, jaundice, hepatits, but this is rarely fatal

Question 21

what are azoles?

Answer 21

synthetic compounds containing a 5 membered azalea ring

Question 22

what are the 2 types of azoles?

Answer 22

1. imidazole - 2 N atoms

2. triazoles - 3 N atoms

Question 23

gives examples of imidazoles and triazoles

Answer 23

1. imidazoles- clotrimazole, ketoconazole

2. triazoles - fluconazole, itraconzole, voriconazole

Question 24

what is the mode of action of azoles?

Answer 24

inhibit ergosterol synthesis, leading to a build-up of monomers. fungus loses its viability because the PM cannot function

Question 25

what is the spectrum of activity azoles?

Answer 25

together, azaleas cover all fungi. fluconazole is the only azole that is ineffective against aspergillus

Question 26

what is the clinical use of imidazoles?

Answer 26

superficial infections -clotrimazole for candidiasis

Question 27

what are the adverse effects of imidazoles?

Answer 27

toxic, rarely used systemically, they can cause life threatening hepatitis

Question 28

what is the clinical use of triazoles?

Answer 28

systemic infections - aspergillosis, candidiasis (fluconazole), serous fungal infections

Question 29

what are the adverse effects of triazoles?

Answer 29

less toxic, therefore systemic use is more common. can cause mild liver enzyme abnormalities

Question 30

name some examples of echinocandins

Answer 30

anidulafungin caspofungin micafungin

Question 31

what is the mode of action of echinocandins

Answer 31

inhibit B-1,3-glucan synthase, which is the main structural component of the cell wall. leads to a severely abnormal cell wall

Question 32

what is the spectrum of actions of echinocandins?

Answer 32

aspergillus and candida, misses certain moulds and cryptococcus

Question 33

what is the clinical use of echinocandins?

Answer 33

systemic infections, only available as IV

Question 34

what are the adverse effects of echinocandins?

Answer 34

``` minimal. skin rash nausea vomiting headache this is due to a lack of B-1,3-glucan analogue in humans ```

Question 35

what is 5-flurocytosine (5-FC)

Answer 35

a synthetic analogue of cytosine, a pyrimidine nucleoside

Question 36

what is the mode of action of 5-fluorocytosine?

Answer 36

inhibits RNA/protein synthesis and DNA synthesis. it is selectively toxic because entry into the cell required fungal cytosine permease

Question 37

what is the spectrum of activity of 5-fluorocytosine?

Answer 37

yeasts only, candida and cryptococcus

Question 38

what is the clinical use of 5-fluorocytosine?

Answer 38

cryptococcal meningitis, in combination with Amphotericin B (only indication)

Question 39

what is an adverse effect of 5-fluorocytosine?

Answer 39

can penetrate into human cells, but to a smaller extent. could cause bone marrow suppression

Question 40

what is the mode of action of griseofulvin?

Answer 40

inhibits fungal mitosis

Question 41

what is the spectrum of activity of griseofulvin?

Answer 41

dermatophytes

Question 42

what is the clinical use of griseofulvin?

Answer 42

infections in children requiring systemic treatment, eg. scale infections

Question 43

what are the adverse effects of griseofulvin?

Answer 43

minimal

Question 44

what is a general adverse effect of azoles?

Answer 44

hepatotoxicity

Question 45

what are the drug interactions of azoles?

Answer 45

inhibit cytochrome p450 enzyme, as a result,the concentration of all drugs metabolised by this enzyme increases

Question 46

which fungi are fluconazole, itra/voriconazole and posa/isavuconazole effective against?

Answer 46

1. yeasts only 2. yeasts and aspergillus 3. yeasts, aspergillus and mucoraceous moulds

Question 47

why is therapeutic monitoring of drugs necessary?

Answer 47

1. to minimise toxicity | 2. to maximise efficacy

Question 48

which antifungals require TDM?

Answer 48

1. intraconazole 2. 5-flurocytosine 3. voriconazole