L11 - Azoles

Question 1

What are the 2 types of azole antifungals?

Answer 1

Imidazoles

Triazoles

Question 2

What Azole was introduced first?

Answer 2

Imidazoles

Question 3

How man nitrogens in imidazole ring?

Answer 3

2

Question 4

How many nitrogens in triazole ring?

Answer 4

3

Question 5

What are the 5 Triazoles?

Answer 5

Fluconazole
Itraconazole 
Posaconazole
Voriconazole
Isavuconazole

Question 6

What is the mode of action of Azoles?

Answer 6

Inhibit ergosterol synthesis

Question 7

How are Imidazoles used?

Answer 7

topically treat superficial infection

too toxic for sytemic use

Question 8

What are imidazoles commonly used to treat?

Answer 8

oral/vaginal thrush

Question 9

What are the 2 main types of structure of triazoles?

Answer 9

linkage of 3 rings

linear molecules

Question 10

What step of ergosterol synthesis to azoles target?

Answer 10

Lanosterol conversion to Eburicol by C14a-lanosterol demethylase

Question 11

What is another step of ergosterol synthesis that azoles MAY effect?

Answer 11

Fecosterol conversion to Ergosterol by /.\22 Desaturase

Question 12

How is isavuconazium sulfate made into an active drug?

Answer 12

esterases in host

—> isavuconazole

Question 13

What are the effects of Azoles?

Answer 13

accumulated 14a methyl sterols

disrupt structure/function of membrane

fungistatic

Question 14

Do azoles act directly on disruption of cell wall biosynthesis?

Answer 14

NO - affect on membrane LEADS to disruption of cell wall biosynthesis

Question 15

What Azoles may be fungicidal when fungus exposed to high conc.?

Answer 15

Itraconazole

Voriconazole

Question 16

What are the 4 imidazoles?

Answer 16

Clotrimazole
Econazole
Miconazole
Ketoconazole

Question 17

Spectrum of activity of fluconazole?

Answer 17

• most yeasts
• C.Krusei RESISTANT
• Most moulds RESISTANT

Question 18

Spectrum of activity of Itraconazole and Voriconazole?

Answer 18

• most yeasts

- Mucoraceous moulds RESISTANT

Question 19

Spectrum of activity of Posaconazole and Isavuconazole?

Answer 19

• Most yeasts
• Most moulds
• SOME ACTIVITY against Murcoraceous moulds

Question 20

Formulations and indications of IMIDAZOLES?

Answer 20

Topical

Superficial infection

Question 21

Formulations and indications of FLUCONAZOLE?

Answer 21

Capsules/solution

• Candidosis
• Cryp Meningitis

Question 22

Formulations and indications of ITRACONAZOLE?

Answer 22

Capsules/solution

• 2nd aspergillosis
• Candidosis
• Histoplamosis

Question 23

Formulations and indications of VORICONAZOLE?

Answer 23

Tablets/solution

• Aspergillosis
• Candidosis
• Fusarium/Scedosporium infection

Question 24

Formulations and indications of POSCONAZOLE?

Answer 24

Tablet/Solution/IV

• Refractory aspergillosis
• Fusarium infection
• Coccidio/chromoblastomycosis

Question 25

Formulations and indications of ISAVUCONAZOLE?

Answer 25

Capsules/IV - Invasive apsergillosis - Mucormycosis (if intolerant to AmphB)

Question 26

Fluconazole vs. Amphotericin B?

Answer 26

No sig. diff. Fluconazole less toxic

Question 27

Fluconazole prophylaxis for neutropenic BMT patients?

Answer 27

Effective compared to placebo

Question 28

Evidence for efficacy of Itraconazole?

Answer 28

Solution better than capsules prophylaxis for neutropic patients

Question 29

Evidence of efficacy of Posaconazole?

Answer 29

GvHD = Posaconazole BETTER than fluconazole NEUTROPENIA = survival longer if taken Posa vs. flu/itra

Question 30

Evidence of efficacy of Voriconazole?

Answer 30

treats invasive aspergillosis better than AmphB deoxycholate

Question 31

Evidences of Isavuconazole vs. Voriconazole for invasive mould?

Answer 31

no difference in success BUT FEWER ADVERSE EFFECTS IN ISAVU

Question 32

Side effects of fluconazole?

Answer 32

H, N, V, D, R

Question 33

Side effects of Itraconazole?

Answer 33

H, N, V, D, R shortness of breath

Question 34

Side effects of Voriconazole?

Answer 34

H. N, V, D, R visual disturbances peripheral oedema

Question 35

Side effects of Posaconazole?

Answer 35

H, N, V, D, R

Question 36

What enzymes are azoles metabolised by?

Answer 36

CYP450 enzymes

Question 37

What enzymes do Azoles INHIBIT?

Answer 37

CYP450 enzymes

Question 38

What is the key CYP450 enzyme for azoles?

Answer 38

CYP3A4

Question 39

95% of all drug oxidation occurs through the action of how many CYP enzymes?

Answer 39

6

Question 40

what is therapeutic drug monitoring (TDM)?

Answer 40

getting drug conc. in the right "window"

Question 41

When is TDM important?

Answer 41

drug has unpredictable absorption Unpredictable metabolism drug interactions affecting conc.

Question 42

What are the ways that azole antifungal resistance can occur?

Answer 42

``` Efflux pumo Target modification Target upregulation Bypass pathways Biofilm formation ```

Question 43

What fungus possesses Azole resistance by EFFLUX PUMPS?

Answer 43

Candida

Question 44

How does the Candida Efflux pump work?

Answer 44

efflux pumps pump Azole out mutations in pump regulator genes so pumps expressed all the time

Question 45

What are the 2 types of efflux pumps?

Answer 45

ATP binding cassettes family (CDR) Major facilitator family (MDR)

Question 46

What fungi possess Azole resistance by TARGET MODIFICATION?

Answer 46

Aspergillus | Candida

Question 47

How does target modification in candidas/aspergillus work?

Answer 47

Lanosterol 14-a-demethylase mutations prevent binding to azoles *** Aspergillus - short nucleotide 35bp duplication in promoter increases expression L98H change too

Question 48

What is Target upregulation regarding Azole resistance?

Answer 48

upregulation - "out compete" azole e.g. candida - upreglation of lanosterol demethylase gene through expression of UPC2 gene

Question 49

How does Azole resistance through bypass pathways occur?

Answer 49

lose function in ERG3 = accumulation of 14a methyl fecosterol