Exam 5 - Antifungals Stahelin Flashcards
what does amphoteric mean?
has both acidic and basic groups (can act as an acid or a base)
mycosamine on amphotericin B is important for
a. pore formation
b. binding to ergosterol
c. binding to cholesterol
b. binding to ergosterol
the OH at C35 of amphotericin B is important for
a. pore formation
b. binding to ergosterol
c. binding to cholesterol
a. pore formation
the hydroxyl on mycosamine is important for
a. pore formation
b. binding to ergosterol
c. binding to cholesterol
c. binding to cholesterol (not ergosterol)
amphotericin B drug class
polyenes
amphotericin B binds to _______, the predominant sterol in fungal cell membranes
ergosterol
which of the following is FALSE about amphotericin B pharmacokinetics?
a. poorly absorbed from GI tract
b. oral amphotericin B is only effective for GI infections
c. IV injection required for systemic infection
d. fungal meningitis has no treatment
d. fungal meningitis has no treatment
(intrathecal therapy)
amphotericin B adverse effects (3 of them; broad)
-infusion related
-renal damage
-liver abnormalities occasionally
how can we alleviate the infusion-related AE of amphotericin B? (2 ways)
-reduce rate of infusion
-premedicate with diphenhydramine and/or acetaminophen
what is the reversible and irreversible component of renal damage due to amphotericin B?
reversible: reduced renal perfusion
irreversible: renal tubular injury
renal tubular injury due to amphotericin B usually occurs after using how many grams?
> 4 g
DOC for life-threatening fungal infections
amphotericin B
which polyene drug, similar to amphotericin B, is used for superficial fungal infections?
nystatin
(too toxic for systemic administration)
which of the following is NOT a lipid formulation of amphotericin B?
a. C-AMB (fungizone)
b. ABCD (amphotec)
c. L-AMB (ambisome)
d. ABLC (abelcet)
a. C-AMB (fungizone)
in conventional amphotericin B, what is used as the solubilizing agent?
a. glycerin
b. deoxycholate
c. cyclodextrins
d. sodium lauryl sulfate
b. deoxycholate
which of the following is FALSE about lipid formulations of amphotericin?
a. they reduce nephrotoxicity
b. act as reservoir of amphotericin
c. amphotec is the only one that uses true liposomes
d. each formulation uses different lipids
c. amphotec is the only one that uses true liposomes
(ambisome not amphotec)
allylamine antifungal drugs (4; slide 16-19)
-terbinafine
-naftifine
-butenafine
-tolnaftate
MOA of terbinafine and other allylamines
a. inhibits squalene epoxidase
b. inhibits 14a-demethylase
c. inhibit synthesis of B(1-3)glucan
d. inhibits thymidylate synthase and protein synthesis
a. inhibits squalene epoxidase
MOA of azoles
a. inhibits squalene epoxidase
b. inhibits 14a-demethylase
c. inhibit synthesis of B(1-3)glucan
d. inhibits thymidylate synthase and protein synthesis
b. inhibits 14a-demethylase
MOA of echinocandins
a. inhibits squalene epoxidase
b. inhibits 14a-demethylase
c. inhibit synthesis of B(1-3)glucan
d. inhibits thymidylate synthase and protein synthesis
c. inhibit synthesis of B(1-3)glucan
MOA of flucytosine
a. inhibits squalene epoxidase
b. inhibits 14a-demethylase
c. inhibit synthesis of B(1-3)glucan
d. inhibits thymidylate synthase and protein synthesis
d. inhibits thymidylate synthase and protein synthesis
cell death due to terbinafine results from accumulation of _______, not loss of ergosterol
squalene
which is structurally DIFFERENT than terbinafine, but still inhibits squalene epoxidase?
a. naftifine
b. butenafine
c. tolnaftate
c. tolnaftate
which of the following is available oral and topical?
a. terbinafine
b. naftifine
c. butenafine
d. tolnaftate
a. terbinafine
(others are only topical)
largest class of antimycotics (aka antifungals)
a. allylamines
b. azoles
c. echinocandins
d. polyenes
b. azoles
(> 20 drugs)
are azoles fungicidal or fungistatic?
fungistatic
which antifungal drug class works by inhibiting the demethylation of lanosterol, inhibiting its conversion to ergosterol?
azoles
what is the importance of the nitrogen on the 5-membered aromatic ring of azoles?
essential for binding iron in P450 enzyme
ketoconazole IC50 for candida 14a-demethylase enzyme vs human enzyme (values)
candida: 10^-9 M
human: 10^-6 M
(more selective for fungal enzyme)
first orally active azole (slide 26)
a. fluconazole
b. itraconazole
c. isavuconazole
d. ketoconazole
d. ketoconazole
be able to look at structural features of azoles
okay
what does the added methyl group on voriconazole do?
improved binding to fungal 14a-demethylase and increase spectrum
what does the furan ring of posaconazole do?
alters and increases spectrum of activity
posaconazole is available as what two dosage forms?
-oral (as suspension)
-IV
which of the following is TRUE about isavuconazole?
a. lipid-soluble
b. prodrug
c. structurally similar to itraconazole
d. short half life
b. prodrug
(a. is water soluble; c. is voriconazole; d. is long)
which of the following is FALSE about isavuconazole?
a. prodrug is isavuconazonium
b. isavuconazonium is cleaved by plasma esterases
c. release active drug and pro-drug cleavage product
d. cleavage product has long half life
d. cleavage product has long half life (short)
T or F: oteseconazole is used for high risk of recurring fungal or yeast infections
T
newest azole drug to be approved
a. fluconazole
b. posaconazole
c. oteseconazole
d. itraconazole
c. oteseconazole (approved in 2022)
example of CYP inducer that can dec triazole levels (slide 35)
rifampin
which of the following is NOT a correct drug interaction with ketoconazole?
a. inhibits metabolism of terfenadine and cisapride
b. decrease AUC and half life of triazolam
c. increases bioavailability of cyclosporin
d. rifampin reduces ketoconazole levels
b. decrease AUC and half life of triazolam (increase)
80% of fluconazole is excreted by the ______ unchanged
kidney
ketoconazole is a potent inhibitor of
a. CYP2C9
b. CYP2C19
c. CYP3A4
d. CYP3A8
c. CYP3A4
put these CYPs in order by which metabolizes voriconazole the most in the liver: CYP3A4, CYP2C9, CYP2C19
CYP2C19 > CYP3A4 > > CYP2C9
posaconazole is metabolized in liver by _________
glucoronidation
which echinocandin is a synthetically modified glarea lozoyensis?
a. caspofungin
b. micafungin
c. anidulafungin
a. caspofungin
which echinocandin is synthetically modified coleophoma empetri
a. caspofungin
b. micafungin
c. anidulafungin
b. micafungin
which echinocandin is synthetically modified aspergillus nidulans?
a. caspofungin
b. micafungin
c. anidulafungin
c. anidulafungin
echinocandins route of admin
IV
target enzyme of echinocandins
a. dihydrofolate reductase
b. b(1-3)glucan synthase
c. chitin synthase
d. squalene monooxygenase
b. b(1-3)glucan synthase
3 structural components of yeast cell wall
chitin
glucan
mannoprotein
-Disseminated and mucocutaneous candida
-Salvage therapy in patients with aspergillosis who fail to respond to amphotericin B
a. caspofungin
b. micafungin
c. anidulafungin
a. caspofungin
-mucocutaneous candida
-Candida prophylaxis in bone marrow transplant patients
a. caspofungin
b. micafungin
c. anidulafungin
b. micafungin
-Esophogeal candidiasis
-Invasive candidiasis
a. caspofungin
b. micafungin
c. anidulafungin
c. anidulafungin
longest half life and no known drug interactions
a. caspofungin
b. micafungin
c. anidulafungin
c. anidulafungin
T or F: echinocandins are metabolized by liver CYPs
F (degraded in blood and in tissues)
rezafungin drug class
a. allylamine
b. azole
c. echinocandin
d. polyene
c. echinocandin
Novel, once-weekly echinocandin antifungal for adults with limited or no alternative treatment options (candidiasis).
a. rezafungin
b. ibrexafungerp
c. flucytosine
d. griseofulvin
a. rezafungin
oral, small molecule inhibitor of glucan synthase enzyme in fungi; used for vulvovaginal candidiasis
a. rezafungin
b. ibrexafungerp
c. flucytosine
d. griseofulvin
b. ibrexafungerp
antimetabolite drug that inhibits thymidylate synthase
a. rezafungin
b. ibrexafungerp
c. flucytosine
d. griseofulvin
c. flucytosine
disrupts fungal microtubules
a. rezafungin
b. ibrexafungerp
c. flucytosine
d. griseofulvin
d. griseofulvin
what is the active metabolite of flucytosine that inactivates thymidylate synthase?
a. 5-FU
b. 5-FUMP
c. 5-UDP
d. 5-FdUMP
d. 5-FdUMP
(suicide inhibitor)
which of the following is TRUE about flucytosine?
a. IV only
b. removed by kidney
c. penetrates poorly into CSF
d. nearly always administered with amphotericin B and itraconazole
b. removed by kidney
(a. is oral; c. penetrates well; d. is amphotericin B and fluconazole)
is griseofulvin fungicidal or fungistatic?
fungistatic
antifungal that inhibits leucyl transfer RNA synthetase (LeuRS), thus inhibiting protein synthesis
a. tavaborole
b. griseofulvin
c. flucytosine
d. fluconazole
a. tavaborole
which chemical element is essential for tavaborole activity?
a. chlorine
b. aluminum
c. selenium
d. boron
d. boron
tavaborole is used for topical treatment of __________ (nail fungus)
onychomycosis
resistance to antifungals: intrinsically resistant to fluconazole; reduced susceptibility to flucytosine and amphotericin B
a. Candida krusei
b. Candida glabrata
c. Aspergillus terreus
a. Candida krusei
resistance to antifungals: multiazole, echinocandin, and multidrug resistance
a. Candida krusei
b. Candida glabrata
c. Aspergillus terreus
b. Candida glabrata
resistance to antifungals: intrinsically resistant to amphotericin
a. Candida krusei
b. Candida glabrata
c. Aspergillus terreus
c. Aspergillus terreus
resistance to antifungals: reduced ergosterol content
a. azoles
b. polyenes
c. echinocandins
d. flucytosine
b. polyenes
resistance to antifungals: target site mutations; rare
a. azoles
b. polyenes
c. echinocandins
d. flucytosine
c. echinocandins
resistance to antifungals: cytosine deaminase or UPRT
a. azoles
b. polyenes
c. echinocandins
d. flucytosine
d. flucytosine
antifungal tx of choice for systemic infections in PREGNANCY
amphotericin B
which of the following can be used to treat vaginal yeast infections in PREGNANT patients?
a. single dose fluconazole
b. single dose itraconazole
c. single dose posaconazole
d. single dose isavuconazole
e. BID fluconazole
a. single dose fluconazole (150 mg)
Which of the below choices is the mechanism of action of terbinafine?
A. Inhibits the glucan synthase enzyme.
B. Inhibits thymidylate synthase.
C. Inhibits the 14-alpha-demethylase CYP450.
D. Inhibits the squalene epoxidase enzyme
D. Inhibits the squalene epoxidase enzyme
Which of the following drugs is an orally available small molecule inhibitor of the fungal glucan synthase enzyme?
A. Itraconazole
B. Griseofulvin
C. Caspofungin
D. Ibrexafungerp
E. Amphotericin B
D. Ibrexafungerp
Which of the following drugs inhibits the leucyl transfer RNA synthetase?
A. Tavaborole
B. Griseofulvin
C. Flucytosine
D. Amphotericin B
E. Fluconazole
A. Tavaborole
Which of the following drugs given by IV, is a synthetically modified fungal compound, and inhibits the fungal beta-glucan synthase enzyme?
A. Ibrexafungerp
B. Tavaborole
C. Griseofulvin
D. Itraconazole
E. Caspofungin
E. Caspofungin
