Lecture 12 Azoles Flashcards
Name the 2 different types of azoles
Imidazoles
Triazoles
What is the difference between Imidazoles and Triazoles?
Imidazoles = older
Why are azoles called azoles?
due to their ‘azole’ ring
Name some examples of imidazoles
Clotrimazole
Econazole
Ketoconazole
Miconazole
Name some examples of triazoles
Fluconazole Itraconazole Voriconazole Posaconazole Isavuconazole
Exaplain the difference in spectrum between fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole
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
Explain the mode of action of azoles
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)
Which 2 azoles have 1st line licenses for Aspergillus?
Voriconazole
Isavuconazole
Which 2 azoles are able to prevent and treat candidosis?
Fluconazole
Itraconazole
Explain the study that explains the licensing for fluconazole by Rex at el, 1994
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
Explain the study that explains the licensing for fluconazole by Goodman et al, 1992
Compared fluconazole for neutropenic bone marrow transplant patients vs placebo
356 patients
Significantly less invasive fungal infections and deaths with fluconazole
Explain the study that explains the licensing for itraconazole by Denning et al, 1994
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
Explain the study that explains the licensing for itraconazole by a meta-analysis
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
Explain the study that explains the licensing for voriconazole by Herbrecht et al, 2002
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
Explain the study that explains the licensing for posaconazole by Walsh et al, 2007
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
Explain the studies that explain the licensing for posaconazole as prophylaxis by Ulman et al, 2007 and Cornely et al, 2007
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
Explain the studies that explain the licensing for isavuconazole by Maertens et al, 2016
Compared isavuconazole and voriconazole in patients with invasive mold disease
272 patients
A similar response to both drugs
Significantly reduced side effects
How are azoles generally metabolized?
By CYP450 enzymes in the liver
CYP3A4 mostly, also 2C19 and 2C9
What toxicities are associated with fluconazole?
headache nausea/vomiting, diarrhea rash deranged liver functions generally safe and well tolerated
What toxicities are associated with itraconazole?
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
What toxicities are associated with voriconazole?
headache visual disturbances nausea/vomiting, diarrhea deranged liver functions peripheral edema rash photosensitivity - can lead to squamous cell carcinoma and hepatotoxicity
What toxicities are associated with posaconazole?
headache nausea/vomiting, diarrhea deranged liver functions rash Toxicity is a rare issue
What toxicities are associated with isavuconazole?
limited so far
GI disturbances
some cutaneous effects e.g. rash, itching
some liver dysfunction
Explain why azoles have many drug interactions
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
