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Chemotherapy BMSC2210 > Lecture 12 Azoles > Flashcards

Lecture 12 Azoles Flashcards

1
Q

Name the 2 different types of azoles

A

Imidazoles

Triazoles

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2
Q

What is the difference between Imidazoles and Triazoles?

A

Imidazoles = older

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3
Q

Why are azoles called azoles?

A

due to their ‘azole’ ring

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4
Q

Name some examples of imidazoles

A

Clotrimazole
Econazole
Ketoconazole
Miconazole

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5
Q

Name some examples of triazoles

A 
Fluconazole
Itraconazole
Voriconazole
Posaconazole
Isavuconazole
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6
Q

Exaplain the difference in spectrum between fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole

A 
Fluconazole = narrow spectrum, widely used but no activity against Aspergillus 
Itraconazole = is active against Aspergillus 
Voriconazole = developed from fluconazole but with a larger spectrum of activity
Posaconazole = broad spectrum including mucoraceous molds, a similar structure to itraconazole therefore same adverse effects
Isavuconazole = broad spectrum including Aspergillus, candida and mucoraceous molds
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7
Q

Explain the mode of action of azoles

A

Inhibits lanosterol 14 alpha-demethylase (CYP51A1) = no conversion of lanosterol to ergosterol
Also leads to a build-up of toxic methyl steroids = inhibition of cell growth or cell death (most are only fungistatic)

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8
Q

Which 2 azoles have 1st line licenses for Aspergillus?

A

Voriconazole

Isavuconazole

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9
Q

Which 2 azoles are able to prevent and treat candidosis?

A

Fluconazole

Itraconazole

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10
Q

Explain the study that explains the licensing for fluconazole by Rex at el, 1994

A

Compared fluconazole and amphotericin B in nonneutropenic patients with candidaemia
206 patients
Successful, unsuccessful outcomes and death number were similar
Significantly less adverse effects related to fluconazole

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11
Q

Explain the study that explains the licensing for fluconazole by Goodman et al, 1992

A

Compared fluconazole for neutropenic bone marrow transplant patients vs placebo
356 patients
Significantly less invasive fungal infections and deaths with fluconazole

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12
Q

Explain the study that explains the licensing for itraconazole by Denning et al, 1994

A

Looked at itraconazole treatment for invasive aspergillosis - note no comparison drug used
76 patients - 30 responded to the drug
125 patients used itraconazole as ‘salvage therapy’ aka has already tried and failed with another drug before - 34 completely cured, 45 improved, 20 unchanged and 26 worsened

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13
Q

Explain the study that explains the licensing for itraconazole by a meta-analysis

A

Looked at itraconazole as a prophylactic treatment for neutropenic patients
a meta-analysis from 13 different trials
The itraconazole solution showed a significant reduction in the rate of invasive infections
Itraconazole capsules did not produce the same effect

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14
Q

Explain the study that explains the licensing for voriconazole by Herbrecht et al, 2002

A

Compares voriconazole with amphotericin B deoxycholate for invasive aspergillosis
277 patients
Increase in successful outcomes and decrease in adverse effects with voriconazole
Survival curve shows a significant increase with voriconazole

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15
Q

Explain the study that explains the licensing for posaconazole by Walsh et al, 2007

A

Looked at the use of posaconazole in patients with invasive aspergillosis and are intolerant or refractory (tried other treatments but failed) to other treatments
Used a control group from old patient records - poor comparative group
Increase in successful outcomes with posaconazole
Found that as the concentration of drug increases, the proportion of patients who respond increases

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16
Q

Explain the studies that explain the licensing for posaconazole as prophylaxis by Ulman et al, 2007 and Cornely et al, 2007

A

1) Posaconazole vs fluconazole for graft vs host disease
600 patients
Posaconazole similar to fluconazole at preventing fungal infections but better at preventing aspergillosis, number of deaths from invasive fungal infections was lower
2) Posaconazole vs fluconazole/itraconazole for neutropenia
Significantly fewer infections, inc. aspergillosis and survival in posaconazole patients

17
Q

Explain the studies that explain the licensing for isavuconazole by Maertens et al, 2016

A

Compared isavuconazole and voriconazole in patients with invasive mold disease
272 patients
A similar response to both drugs
Significantly reduced side effects

18
Q

How are azoles generally metabolized?

A

By CYP450 enzymes in the liver

CYP3A4 mostly, also 2C19 and 2C9

19
Q

What toxicities are associated with fluconazole?

A 
headache
nausea/vomiting, diarrhea
rash
deranged liver functions
generally safe and well tolerated
20
Q

What toxicities are associated with itraconazole?

A 
headache
nausea/vomiting, diarrhea - with the oral solution due to having to give with cyclodextrin solution pulling water into the gut (this side effect is associated with reduced compliance)
rash
deranged liver function
shortness of breath
21
Q

What toxicities are associated with voriconazole?

A 
headache
visual disturbances
nausea/vomiting, diarrhea
deranged liver functions
peripheral edema
rash
photosensitivity - can lead to squamous cell carcinoma and hepatotoxicity
22
Q

What toxicities are associated with posaconazole?

A 
headache
nausea/vomiting, diarrhea
deranged liver functions 
rash 
Toxicity is a rare issue
23
Q

What toxicities are associated with isavuconazole?

A

limited so far
GI disturbances
some cutaneous effects e.g. rash, itching
some liver dysfunction

24
Q

Explain why azoles have many drug interactions

A

metabolize and inhibit CYP450 enzymes - CYP3A4 mostly, also 2C19 and 2C9
A lot of other drugs are also metabolized by these enzymes
Drugs like cyclosporin and vincristine likely to be used by at-risk patients but interact with azoles

25
Q

Explain what happens to the drug concentrations of another CYP450 drug when an azole is added

A

If already on the CYP450 drug and then azole added, inhibition = reduced metabolism of other drug and therefore an increase in concentration

26
Q

Explain what happens to the drug concentrations of azoles when a CYP450 inhibitor is added

A

If on an azole and then a CYP450 inhibitor is added the azole concentration increases

27
Q

Explain what happens to the drug concentrations of azoles when a CYP450 inducer is added

A

If a CYP450 inducer is added, the azole concentration reduces

28
Q

Do azoles need drug monitoring and why?

A

Yes as efficacy and toxicity are related to the drug concentrations
Unpredictable absorption, metabolism and drug interactions affecting concentration
e.g. fluconazole can affect renal function, voriconazole can be affected by genetic polymorphisms, posaconazole is affected by absorptions and genetic polymorphisms

29
Q

What are the 4 proposed mechanisms by which azole resistance is said to occur?

A

Efflux pumps
Target modification
Target up-regulation
Bypass pathways

30
Q

What are the 2 families of efflux pumps that are associated with azoles?

A 
ATP binding cassette (ABC) family
Major facilitator (MSF) family
31
Q

When does upregulation of efflux pumps occur?

A

Constitutive i.e. all the time

Or on exposure to other drugs inc azoles

32
Q

The Major facilitator (MSF) family confers up-regulation resistance to which azoles?

A

fluconazole

voriconazole

33
Q

Explain which site has target alterations in C. albicans to ensure azole resistance

A

Mutations in lanosterol 14 alpha-demethylase

= reduced affinity for azoles

34
Q

Explain which site has target alterations in A. fumigatus to ensure azole resistance

A

Some have resistance to a single azole or multiple

‘hot spot’ mutations i.e. common in G54, L98, and M220

35
Q

Which species are resistant to azoles via target upregulation?

A

C. glanrata and C. albicans
Due to upregulation of ERG11
Though dosing studies have shown that this mechanism does not have the biggest effect

36
Q

Explain what is meant by the ‘bypass pathways’ of resistance

A

bacteria are capable of evolving new targets that accomplish similar biochemical functions of the original target but are not inhibited by the antimicrobial molecule

instead of going from A to B, B is made via A to C to B

Chemotherapy BMSC2210 (14 decks)

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