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Chemotherapy intercalation > Lecture 13 Azoles > Flashcards

Lecture 13 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 thier ‘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 mucaracious moulds, similar structure to intraconazole therefore same adverse effects
Isavuconazole = broad spectrum including aspergillus, candida and mucaracious moulds
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7
Q

Explain the mode of action of azoles

A

Inhibits lanosterol 14 alpha demethylase (CYP51A) = no conversion of lanosterol to ergosterol
Also leads to a build up of toxic methysteriods = 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

Intraconazole

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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 non neurtropenic patients with candidaemia
206 patients
Sucessful, unsuccessful outcomes and death number 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 intraconazole by Denning et al, 1994

A

Looked at intraconazole treatment for invasive aspergillosis - note no comparison drug used
76 patients - 30 responded to the drug
125 patients used intraconazole 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 intraconazole by a meta-analysis

A

Looked at intraconazole as prophylactic treatment for neutropenic patients
meta analysis from 13 different trials
Intaconazole solution showed a significant reduction in rate of invasive infections
Intraconazole 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 deoxylate 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 explains 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 less infections, inc. aspergillosis and survival in posaconazole patients

17
Q

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

A

Compared isavuconazole and voriconazole in patients with invasive mould disease
272 patients
Similar response to both drugs
Significantly reduced side effects

18
Q

How are azoles generally metabolised?

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, diarrhoea
rash
deranged liver functions
generally safe and well tolerated
20
Q

What toxicities are associated with itraconazole?

A 
headache
nausea/vomiting, diarrhoea - with oral solution due to having to give with cytodextrin 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, diarrhoea
deranged liver functions
peripheral oedema
rash
photosensitivity - can lead to squamous cell carcinoma and hepatotoxicity
22
Q

What toxicities are associated with posaconazole?

A 
headache
nausea/vomiting, diarrhoea
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

metabolise and inhibit CYP450 enzymes - CYP3A4 mostly, also 2C19 and 2C9
Alot of other drugs are also metabolised 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 an CYP450 inhibitor is added

A

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

27
Q

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

A

If an CYP450 inducer is added, the azole concentration reduces

28
Q

Do azoles need drug monitoring and why?

A

Yes as efficacy and toxicity relate to the drug concentrations
Unpredictable absorption, metabolism and drug interactions affecting concentration
e.g. fluconazole can effect 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 ‘by pass 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 intercalation (14 decks)

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