E5 antifungals - stahelin

Question 1

i think i will use chatGPT to do all of these so im sorry if it looks stupid

Answer 1

no problem cole, it’s a dense lecture! (study the structures on physical flashcards or make a quizlet or sum)

Question 2

fungal cells use _______ as their primary membrane sterol while human cells use ____________ instead

Answer 2

ergosterol, cholesterol

Question 3

given what you know about fungal cell membranes, what is important to note regarding targets?

Answer 3

many antifungal drugs target ergosterol or its synthesis which allows for selective toxicity toward fungal cells without harming human cells

Question 4

T or F:
ergosterol is found in humans

Answer 4

false

Question 5

which of the following does not bind directly to ergosterol to disrupt membrane integrity?
A. Nystatin
B. Fluconazole
C. amphotericin B

Answer 5

B, azoles inhibit enzymes in the synthesis pathway

Question 6

allylamines (terbinafine) inhibit (enzyme?), blocking the first committed step toward ergosterol in the synthesis pathway

Answer 6

squalene epoxidase

Question 7

what enzyme do the -azoles inhibit

Answer 7

14a-demethylase, a CYP450 enzyme that converts lanosterol to ergosterol

Question 8

inhibition of enzymes during ergosterol synthesis causes _______ ________ to accumulate in fungal membranes?

Answer 8

toxic sterols

Question 9

what are the 2 polyenes

Answer 9

amphoB and nystatin

Question 10

mechanism of amphoB and nystatin, cidal or static

Answer 10

bind ergosterol -> disrupt membrane, cidal

Question 11

basis for selectivity of fungi, polyenes:

Answer 11

binds ergo over cholesterol

Question 12

what is the 1 allylamine?

Answer 12

terbinafine

Question 13

Mechanism of terbinafine

Answer 13

inhibit squalene epoxidase -> causes toxic squalene accumulation in fungal cells

Question 14

terbinafine cidal or static

Answer 14

cidal, 2500x selectivity for fungal enzyme

Question 15

unique structure thing for azoles

Answer 15

contains 5-membered aromatic ring (imidazole or triazole)

Question 16

Mechanism of -azoles

Answer 16

inhibit 14a-demethylase (CYp450) -> blocks conversion of lanosterol to ergosterol

Question 17

-azoles cidal or static

Answer 17

static

Question 18

which -azole has selective inhibition of CYP51 instead?

Answer 18

oteseconazole

Question 19

what else is niche about oteseconazole?

Answer 19

low number of adverse events

Question 20

which 4 drugs are echinocandins?

Answer 20

caspofungin, micafungin, anidulafungin, rezafungin

Question 21

Are lipopeptides that are derived from fungi and synthetically modified.
A. polyenes
B. -azoles
C. allylamines
D. echinocandins

Answer 21

D

Question 22

mechanism of echinocandins (-fungins)

Answer 22

inhibit B(1,3)-glucan synthase, essential for fungal cell wall

Question 23

echinocandins cidal or static

Answer 23

cidal

Question 24

T or F:
echinocandins have no cross resistance w/ other antifungals

Answer 24

true

Question 25

Flucytosine is a _______ analog, antifungal antimetabolite

Answer 25

pyrimidine

Question 26

mechanism of flucytosine

Answer 26

converted to 5-FU -> then to 5-FdUMP -> inhibits thymidylate synthase -> blocks DNA synthesis

Question 27

selectivity for flucytosine (weird answer)

Answer 27

mammals cant activate it bc we dont have cytosine deaminase

Question 28

what drug is a triterpenoid?

Answer 28

ibrexafungerp

Question 29

mechanism of ibrexafungerp

Answer 29

inhibits glucan synthase, depleting 1,3-B-D-glucan

Question 30

ibrexafungerp cidal or static

Answer 30

cidal

Question 31

ibrexafungerp is mostly active against _______ and used for ___________ candidiasis

Answer 31

candida (duh), vulvovaginal

Question 32

how is ibrexafungerp metabolized?

Answer 32

hydroxylation by CYP3A4 and then via glucuronidation and sulfation

Question 33

Tavaborole class

Answer 33

doesnt list it, maybe its too new to have one?

Question 34

tavaborole mechanism

Answer 34

inhibits leucyl transfer RNA synthetase (LeuRS)

Question 35

tavaborole: _____ is essential for activity

Answer 35

boron, dont overthink that

Question 36

what is the toxicity of amphoB thought to be caused by?

Answer 36

binding to human cholesterol (oops)

Question 37

what is the MAIN toxicity that is concerning w/ amphoB

Answer 37

renal damage, occurs in nearly all patients

Question 38

Renal damage in amphoB: reversible: irreversible:

Answer 38

- reduced renal perfusion - renal tubular injury

Question 39

what other toxicity (not renal) does amphoB cause

Answer 39

infusion-related things like fever, chills, spasms, vomiting, hypotension

Question 40

how to mitigate infusion-related toxicities with amphoB

Answer 40

premedicate with benadryl and/or tylenol

Question 41

LO: how do the toxicities associated with amphoB relate to flucytosine therapy?

Answer 41

amphoB enhances uptake of flucytosine and allows dose reduction, mitigating amphoB toxicity *****

Question 42

synergy with amphoB and flucytosine (why combo)?

Answer 42

- amphoB damages membrane -> boost flucytosine entry - improved efficacy for meningitis

Question 43

T or F: all azoles inhibit cyp3a4

Answer 43

true

Question 44

what one other drug should you think of when you think of a 3a4 inducer that will decrease azole levels

Answer 44

rifampin

Question 45

significance of azole functional group(s) related to MOA

Answer 45

they contain either imidazole or triazole rings, these bind heme iron in fungal CYP450 -> inhibit 14a-demethylase, stopping ergosterol production

Question 46

explain how the metabolism of flucytosine in fungal cells differs from that in animal cells (direct LO)

Answer 46

fungi: Flucytosine -> 5-FU -> 5-FdUMP -> inhibits thymidylate synthase humans: Lack cytosine deaminase -> can't convert to active form

Question 47

what acts as a suicide inhibitor of thymidylate synthase?

Answer 47

flucytosine

Question 48

explain the reaction that is catalyzed by thymidylate synthase and how flucytosine inhibits the reaction

Answer 48

normally, thymidylate synthase catalyzes dUMP -> dTMP BUT with flucytosine converting it to 5-FdUMP, it becomes a suicide inhibitor which causes the enzyme to be irreversibly trapped, halting DNA synthesis

Question 49

what prevents the enzyme turnover in the thymidylate synthase reaction that gets altered by flucytosine

Answer 49

F-substitution on the dUMP that gets converted to 5-FdUMP instead