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BMSC2210 - Chemotherapy > L11 - Azoles > Flashcards

L11 - Azoles Flashcards

1
Q

What are the 2 types of azole antifungals?

A

Imidazoles

Triazoles

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2
Q

What Azole was introduced first?

A

Imidazoles

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3
Q

How man nitrogens in imidazole ring?

A

2

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4
Q

How many nitrogens in triazole ring?

A

3

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5
Q

What are the 5 Triazoles?

A 
Fluconazole
Itraconazole 
Posaconazole
Voriconazole
Isavuconazole
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6
Q

What is the mode of action of Azoles?

A

Inhibit ergosterol synthesis

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7
Q

How are Imidazoles used?

A

topically treat superficial infection

too toxic for sytemic use

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8
Q

What are imidazoles commonly used to treat?

A

oral/vaginal thrush

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9
Q

What are the 2 main types of structure of triazoles?

A

linkage of 3 rings

linear molecules

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10
Q

What step of ergosterol synthesis to azoles target?

A

Lanosterol conversion to Eburicol by C14a-lanosterol demethylase

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11
Q

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

A

Fecosterol conversion to Ergosterol by /.\22 Desaturase

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12
Q

How is isavuconazium sulfate made into an active drug?

A

esterases in host

—> isavuconazole

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13
Q

What are the effects of Azoles?

A

accumulated 14a methyl sterols

disrupt structure/function of membrane

fungistatic

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14
Q

Do azoles act directly on disruption of cell wall biosynthesis?

A

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

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15
Q

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

A

Itraconazole

Voriconazole

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16
Q

What are the 4 imidazoles?

A

Clotrimazole
Econazole
Miconazole
Ketoconazole

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17
Q

Spectrum of activity of fluconazole?

A
  • most yeasts
  • C.Krusei RESISTANT
  • Most moulds RESISTANT
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18
Q

Spectrum of activity of Itraconazole and Voriconazole?

A
  • most yeasts

- Mucoraceous moulds RESISTANT

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19
Q

Spectrum of activity of Posaconazole and Isavuconazole?

A
  • Most yeasts
  • Most moulds
  • SOME ACTIVITY against Murcoraceous moulds
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20
Q

Formulations and indications of IMIDAZOLES?

A

Topical

Superficial infection

21
Q

Formulations and indications of FLUCONAZOLE?

A

Capsules/solution

  • Candidosis
  • Cryp Meningitis
22
Q

Formulations and indications of ITRACONAZOLE?

A

Capsules/solution

  • 2nd aspergillosis
  • Candidosis
  • Histoplamosis
23
Q

Formulations and indications of VORICONAZOLE?

A

Tablets/solution

  • Aspergillosis
  • Candidosis
  • Fusarium/Scedosporium infection
24
Q

Formulations and indications of POSCONAZOLE?

A

Tablet/Solution/IV

  • Refractory aspergillosis
  • Fusarium infection
  • Coccidio/chromoblastomycosis
25
Q

Formulations and indications of ISAVUCONAZOLE?

A

Capsules/IV

  • Invasive apsergillosis
  • Mucormycosis (if intolerant to AmphB)
26
Q

Fluconazole vs. Amphotericin B?

A

No sig. diff.

Fluconazole less toxic

27
Q

Fluconazole prophylaxis for neutropenic BMT patients?

A

Effective compared to placebo

28
Q

Evidence for efficacy of Itraconazole?

A

Solution better than capsules

prophylaxis for neutropic patients

29
Q

Evidence of efficacy of Posaconazole?

A

GvHD = Posaconazole BETTER than fluconazole

NEUTROPENIA = survival longer if taken Posa vs. flu/itra

30
Q

Evidence of efficacy of Voriconazole?

A

treats invasive aspergillosis better than AmphB deoxycholate

31
Q

Evidences of Isavuconazole vs. Voriconazole for invasive mould?

A

no difference in success BUT FEWER ADVERSE EFFECTS IN ISAVU

32
Q

Side effects of fluconazole?

A

H, N, V, D, R

33
Q

Side effects of Itraconazole?

A

H, N, V, D, R

shortness of breath

34
Q

Side effects of Voriconazole?

A

H. N, V, D, R

visual disturbances
peripheral oedema

35
Q

Side effects of Posaconazole?

A

H, N, V, D, R

36
Q

What enzymes are azoles metabolised by?

A

CYP450 enzymes

37
Q

What enzymes do Azoles INHIBIT?

A

CYP450 enzymes

38
Q

What is the key CYP450 enzyme for azoles?

A

CYP3A4

39
Q

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

A

6

40
Q

what is therapeutic drug monitoring (TDM)?

A

getting drug conc. in the right “window”

41
Q

When is TDM important?

A

drug has unpredictable absorption

Unpredictable metabolism

drug interactions affecting conc.

42
Q

What are the ways that azole antifungal resistance can occur?

A 
Efflux pumo
Target modification
Target upregulation
Bypass pathways
Biofilm formation
43
Q

What fungus possesses Azole resistance by EFFLUX PUMPS?

A

Candida

44
Q

How does the Candida Efflux pump work?

A

efflux pumps pump Azole out

mutations in pump regulator genes so pumps expressed all the time

45
Q

What are the 2 types of efflux pumps?

A

ATP binding cassettes family (CDR)

Major facilitator family (MDR)

46
Q

What fungi possess Azole resistance by TARGET MODIFICATION?

A

Aspergillus

Candida

47
Q

How does target modification in candidas/aspergillus work?

A

Lanosterol 14-a-demethylase

mutations prevent binding to azoles

*** Aspergillus - short nucleotide 35bp duplication in promoter increases expression

L98H change too

48
Q

What is Target upregulation regarding Azole resistance?

A

upregulation - “out compete” azole

e.g. candida - upreglation of lanosterol demethylase gene through expression of UPC2 gene

49
Q

How does Azole resistance through bypass pathways occur?

A

lose function in ERG3 = accumulation of 14a methyl fecosterol

BMSC2210 - Chemotherapy (17 decks)

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