antifungals

Question 1

Polyenes

Answer 1

• natural, from streptomyces

- for systemic fungal infection

Question 2

what do polyenes target

Answer 2

the fungal membrane esp Ergosterol (fungal equivalent of cholesterol) , forms pores leading to cell death. hydrophobic and hydrophilic allow it to form pores

Question 3

membrane sterols

Answer 3

stabilise phospholipid layer- without the membrane would be static . Leakage causes lack of cations (Na and sodium loss)

Question 4

clinical use of polyenes

Answer 4

wide spectrum

Question 5

polyene used to treat systemic infection (serious)

Answer 5

Amphotericin B

Question 6

Nystatin is an

Answer 6

polyene used to treat superficial infection

Question 7

problems with polyenes

Answer 7

only available via IV (expensive); nephrotoxicity

Question 8

when were Azoles found

Answer 8

1960

Question 9

azoles are

Answer 9

the largest group of antifungals

Question 10

examples of azoles

Answer 10

imidazole, fluconazole

Question 11

imidazole

Answer 11

2 nitrogen- rarely used due to toxicity and specificity problems

Question 12

fluconazoles

Answer 12

made a lost of money- pobrlems with specificity, doesn’t work again aspergillus

Question 13

Mode of azole action

Answer 13

-inhibit ergosterol synthesis- inhibiting 14 alpha sterol demethylase. Blocks heme iron in enzyme active site. Alters membrane fluidity

mainly FUNGISTATIC- just stop growth

Question 14

problems with azoles

Answer 14

drug interaction (can stop other drugs from metabolizing- causing overdose and resistance

Question 15

allyamines

Answer 15

inhibit ergosterol biosynthesis- fungicidal, due to accumulation of squalene

Question 16

allyamines are used against

Answer 16

dermatophytes

Question 17

allyamines have a poor activity against

Answer 17

candida and aspergillus

Question 18

5-Flucytosine (5FC)

Answer 18

synthetic analogue of cytosine

Question 19

flu cytosine was originally developed as an

Answer 19

anti-cancer drug

Question 20

how does Flucytosine work

Answer 20

the drug enters the cell via cytosine permeate, where it is converted to 5- fluorouracil and inhibits preotin synthesis and DNA synthesis

Question 21

prodrug of flucytosine

Answer 21

fluorouracil

Question 22

flucytosine spectrum of acitvity

Answer 22

only works on yeast (candida and C.neoformans)

Question 23

problems with flucytosine

Answer 23

resistance is very common

Question 24

echinocandons found

Answer 24

in 70s

Question 25

echinocandons

Answer 25

semi-synthetics, first new class of antifungals in 20 years

Question 26

which anti-fungal was the first to be found in 20 years

Answer 26

echinocandins

Question 27

how do echinocandins work

Answer 27

inhibit B1, 3 gluten syntheses - cells lose shape and lyse

Question 28

echinocandins structure

Answer 28

very complicated- various layers: structural polysaccharides, chitin and gluten B1,6 and B1,3

Question 29

why do echinocandins not lyse filamentous fungi

Answer 29

due to them having other elements in their cell walls

Question 30

clinical use of echinocandins

Answer 30

candida, aspergillus | - low toxicity and not problem of cross resistance

Question 31

echinocandins have no activity against

Answer 31

Cryptococcus neoformans

Question 32

problems with echinocandins

Answer 32

not amiable orally, expensive

Question 33

superficial mycoses: dermatophytes

Answer 33

allyamines

Question 34

superficial mycosis: candidiasis

Answer 34

azoles

Question 35

systemic mycosis

Answer 35

azoles, amphotericin B, echinocandins

Question 36

amphoteicin B is used for

Answer 36

serious systemic infection

Question 37

mechanisms of resistance can be

Answer 37

natural and acquired

Question 38

acquired is

Answer 38

much more worrying

Question 39

acquired resistance is through

Answer 39

horizontal gene transfer in fungi

Question 40

main problems with antifungals

Answer 40

1) drug- drug interactions 2) toxic 3) new to market 4) IV only 5) expensive

Question 41

market worth

Answer 41

10.4 bill $

Question 42

clinically important drug interactions with amphotericin B can cause

Answer 42

nephrotoxicity, hypokalaemia and blood dyscrasias

Question 43

allyamines mode of action

Answer 43

inhibit the enzyme squalene epoxidase- preventing squalene from being converted to oxide-squalene