Chapter 48 Antifungal Agents

Question 1

why is it harder to make anti-fungal drugs vs. anti-bacterial drugs

Answer 1

fungi and humans are eukaryotes, so share metabolic pathways for energy, protein ,and cell division
need to isolate a unique molecular target in fungi, whereas in bacteria we have unique molecular targets

Question 2

essential steroid-like substance that’s important for fungal plasma membrane

Answer 2

ergosterol

Question 3

what does eliminating ergosterol do?

Answer 3

messes up fungal membrane integrity –> fungal cell death

Question 4

ergosterol is to fungal plasma membrane as (blank) is to human plasma membranes

Answer 4

cholesterol

Question 5

what enzyme do both imidazole and triazole work on?

Answer 5

inhibitors of 14alpha demethylase –> mediates the conversion of lanosterol to ergosterol
-2nd key step in ergosterol synthesis

Question 6

echinocandins can affect what enzyme other than 14 alpha demthylase

Answer 6

B(1,3) D-glucan synthase –> enzyme that adds glucose residues from UDP-glucose to the growing polysaccharide chain (so block this and fuck up cell wall integrity)

Question 7

how is flucytosine (5-fluorocytosine) taken up?

Answer 7

fungistatic usually; fungal cells via cytosine specific permeases expressed only in the fungal membranes; mammals don’t have this so they are protected

Question 8

what does flucytosine (5-fluorocytosine) act upon once taken up

Answer 8

cytosine deaminase converts flucytosine into 5-fluorouracil (5-FU) –> 5-FdUMP –> protein inhibitor of thymidylate synthesis –> inhibition of DNA synthesis and cell division

Question 9

What makes flucytosine similar to an anti-cancer drug?

Answer 9

its converted to 5-FU which is an antimetabolite in cancer chemotherapy –> can cause adverse effects in host cells

Question 10

three infectious agents making up the spectrum of flucytosine’s activity

Answer 10

candidiasis
cryptococcosis
chromomycosis

Question 11

MOA of griseofulvin

Answer 11

inhibits fungal mitosis by binding to tubulin and microtubule associated proteins –> disrupts assembly of mitotic spindles
fungistatic

Question 12

MOA of squalene epoxidase action

Answer 12

converts squalene to lanosterol –> 1st key step of ergosterol synthesis

Question 13

three antifungal agents that inhibit squalene expoxidase

Answer 13

terbinafine
naftifine
butenafine
stops the conversion of squalene to lanosterol –>accumulation of sqalene = toxic metabolite; no ergosterol synthesis

Question 14

don’t give terbinafine to

Answer 14

renal failure patients
hepatic failure
pregnant women

Question 15

what enzyme do -azoles work upon?

Answer 15

14alpha sterol demethylase (converts lanosterol to ergosterol –> 2nd key step)

Question 16

what has limited the use of ketoconazole

Answer 16

imidazole class

• GI absorption issue –> can’t use w/ achlorhydria, bicarb, antacids, H2 blockers, or PPIs b/c needs acidic environment to be converted into salt to be absorbed
• inhibits CYP450 enzymes 17,20
• inhibits side-chain cleavage enzymes in adrenal gland and gonads –> decreases steroid hormone synthesis –> gynecomastia and impotence

Question 17

what has ketoconazole been replaced with

Answer 17

itraconazole

Question 18

two indications for topical ketoconazole

Answer 18

common dermatophyte infections

seborrheic dermatitis

Question 19

why is fluconazole the DOC for cryptococcal meningitis

Answer 19

hydrophilic triazole –> bioavailability nearly 100%, absorption is not influenced by gastric pH, once absorbed diffuses freely into CSF, sputum, urine, and saliva
excellent CSF penetration, not many side effects

Question 20

MOA polyene

Answer 20

macrolide antifungal agent
bind to ergosterol and disrupts fungal plasma membrane stability –> produces channels/pores that allow leakage of essential cellular components out of the cell –> cell death

Question 21

what is the prototypic membrane of the group that polyene acts upon (idk how to word this)

Answer 21

Amphotericin B

Question 22

how does polyene have selectivity toxicity

Answer 22

affinity of amphotericin B for ergosterol is 500x greater than for cholesterol..so fucks with fungal shit more

Question 23

what is an immediate reaction to amphotericin B and what are four symtoms

Answer 23

cytokine storm –> TNF alpha and IL-1

symptoms –> fevers, chills, rigors, and hypotension

Question 24

three agents in the echnocandin class

Answer 24

-class of antifungals that target funal cell wall synthesis by noncomp inhibiting synthesis of B(1,3)-D-glucans
caspofungin
micafungin
anidulafungin