Chapter 48 Antifungal Agents Flashcards
why is it harder to make anti-fungal drugs vs. anti-bacterial drugs
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
essential steroid-like substance that’s important for fungal plasma membrane
ergosterol
what does eliminating ergosterol do?
messes up fungal membrane integrity –> fungal cell death
ergosterol is to fungal plasma membrane as (blank) is to human plasma membranes
cholesterol
what enzyme do both imidazole and triazole work on?
inhibitors of 14alpha demethylase –> mediates the conversion of lanosterol to ergosterol
-2nd key step in ergosterol synthesis
echinocandins can affect what enzyme other than 14 alpha demthylase
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)
how is flucytosine (5-fluorocytosine) taken up?
fungistatic usually; fungal cells via cytosine specific permeases expressed only in the fungal membranes; mammals don’t have this so they are protected
what does flucytosine (5-fluorocytosine) act upon once taken up
cytosine deaminase converts flucytosine into 5-fluorouracil (5-FU) –> 5-FdUMP –> protein inhibitor of thymidylate synthesis –> inhibition of DNA synthesis and cell division
What makes flucytosine similar to an anti-cancer drug?
its converted to 5-FU which is an antimetabolite in cancer chemotherapy –> can cause adverse effects in host cells
three infectious agents making up the spectrum of flucytosine’s activity
candidiasis
cryptococcosis
chromomycosis
MOA of griseofulvin
inhibits fungal mitosis by binding to tubulin and microtubule associated proteins –> disrupts assembly of mitotic spindles
fungistatic
MOA of squalene epoxidase action
converts squalene to lanosterol –> 1st key step of ergosterol synthesis
three antifungal agents that inhibit squalene expoxidase
terbinafine
naftifine
butenafine
stops the conversion of squalene to lanosterol –>accumulation of sqalene = toxic metabolite; no ergosterol synthesis
don’t give terbinafine to
renal failure patients
hepatic failure
pregnant women
what enzyme do -azoles work upon?
14alpha sterol demethylase (converts lanosterol to ergosterol –> 2nd key step)
what has limited the use of ketoconazole
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
what has ketoconazole been replaced with
itraconazole
two indications for topical ketoconazole
common dermatophyte infections
seborrheic dermatitis
why is fluconazole the DOC for cryptococcal meningitis
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
MOA polyene
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
what is the prototypic membrane of the group that polyene acts upon (idk how to word this)
Amphotericin B
how does polyene have selectivity toxicity
affinity of amphotericin B for ergosterol is 500x greater than for cholesterol..so fucks with fungal shit more
what is an immediate reaction to amphotericin B and what are four symtoms
cytokine storm –> TNF alpha and IL-1
symptoms –> fevers, chills, rigors, and hypotension
three agents in the echnocandin class
-class of antifungals that target funal cell wall synthesis by noncomp inhibiting synthesis of B(1,3)-D-glucans
caspofungin
micafungin
anidulafungin
