Exam 4 - Med Chem: Fungal Flashcards
Fungi Overview:
Diverse Group of _________
_____ cell wall
eukaryotes
rigid
what are the two groups of fungi
yeast and mold…
Yeast or Mold?
grow as single cell
yeast
Yeast or Mold?
Divide asexually
yeast
Yeast or Mold?
Divide by budding/fission
yeast (aka asexually)
Yeast or Mold?
Filamentous multicellular aggregates (hyphae)
mold
Yeast or Mold?
Grow by elongation at their tips
mold
Yeast or Mold?
usually separated into cell like units by crosswalls called septa
mold
4 characteristics of pathogenic fungi?
can grow at high temperatures
able to reach target tissues…
able to digest and absorb components of human tissues
able to withstand/evade the immune system
3 types of fungal infections?
superficial/cutaneous
subcutaneous
systemic/invasive
what are examples of superficial/cutaneous fungal infections?
dermatophytosis (ringworm, jock itch, athletes foot)
onchomycosis (nail fungus)
what is a dimorphic fungi?
at room temperature it is hyphae (mold)
in humans or media that is 37 celsius it is yeast
Histoplasmosis:
is caused by a _______ fungi
comes from what thing in nature?
Spore or non spore forming?
dimorphic endemic
bat/bird droppings
spore
Blastomycosis:
caused by a ______ fungi
comes what thing in nature?
dimorphic endemic
rotting wood/soil
Candidiasis:
Yeast or mold?
Part of ______ flora
Can be invasive but typically is localized where??
yeast
normal human flora
mucous membrane
Risk Factors for Opportunistic fungal infections?
immunosuppression... burn wounds/trauma central venous catheters broad spec abx diabetes renal insufficiency requiring dialysis
Candida causes what diseases typically?
Cutaneous candidiasis (diaper rash, athletes foot, jock itch) Esophagitis Onchomycosis (nail) Oropharyngeal (thrush) Vulvovaginitis
what women are at risk for vulvovaginitis?
diabetics
pregnant women
women treated with broad spec abx
3 disease states of Aspergillosis
opportunistic infections
allergic states..
Toxicoses
What drug is apart of the polyene antifungal class?
Amphotericin B
Features of Amphotericin B: Hydro, Lipo, or Amphi -philic? \_\_\_\_\_ ring structure Fungi - cidal or static? Good or poor bioavailability?
Amphi!
Macrolide structure
cidal
POOR bioavail (use PO only if GI infection, use IV for systemic!)
MOA of Amphotericin B
it binds to ergosterol – leads to leakage of intracellular contents
what is egosterol
the main sterol in fungal cell membranes
ADEs of Amphotericin B?
V toxic..
Infusion Related rxn – reduce rate of infusion if issues: fever, chills, muscle spasms, vomiting, headahces and hypotension
Renal damage!!
________ is a polyene drug that is similar to amphotericin B but is too toxic for systemic administration/only used for superficial fungal infections
Nystatin
what is a way to reduce nephrotoxicity of amphotericin?
put it in a lipid formulation
Egosterol Synthesis Pathway:
________ –> ________ –> Egosterol
Squalene –> Lanosterol –> Egosterol
what two drugs/classes inhibit egosterol synthesis?
-Azoles and Terbinafine
terbinafine inhibits what enzyme?
squalene epoxidase (inhibits egosterol synthesis)
Terbinafine:
Fungi -cidal or -static
cidal
happens bc too much squalene bulidup!
Terbinafine is best for what disease states?
cutaneous/superficial fungal infections:
dermatophytes and onchomycoses
Key structure part of -Azoles
5 membered aromatic ring
-Azoles:
Fungi -cidal or -static
static
-Azoles:
inhibit ergosterol synthesis by inhibiting what enzyme?
14-alpha demethylase
aka what makes lanosterol into ergosterol
in general: what is the relationship between Azole antifungals and CYP450 enzymes
they are metabolized by the enzymes and they inhibit them
Voriconazole:
metabolized by CYP_______ extensively
(genetic polymorphisms will alter levels)
CYP 2 C 19
Ketoconazole:
potent ______ of CYP3A4
inhibitor
Ketoconazole:
Will increase levels of _______ and _______
CYP3A4 _______ (ex: _______) will reduce ketoconazole levels
triazolam and cyclosporin levels increase
CYP3A4: inducers; ex rifampin
Fluconazole:
poor or good bioavailability?
CSF penetration?
good bioavail
and yes CSF
which Azole causes visual disturbances in 30% of patients (flickering lights/zigzag lines) AND is teratogenic in animals
Voriconazole
Another antifungal drug class is called the Echinocandins: they are what type of molecule?
lipopeptide/ cyclic hexapeptide with fatty side chains
what drugs are antifungal lipopeptides/echinocandins
caspofungin
micafungin
anidulafungin
MOA of Echinocandins?
inhibit B(1/3) glucan aka a cell wall component by inhibiting Beta(1/3) glucan synthase
Echinocandins:
Fungi -cidal or -static
cidal
CYP interactions with Echinocandins?
none!!
_______ is an antifungal drug that is a pyrimidine analog/antimetabolite
Flucytosine (5-FC)
MOA of Flucytosine?
antimetabolite: inhibits thymidylate synthase / interferes with protein synthesis
Flucytosine –> _____ –> ______ (which mimics ______)
5-FC –> 5-FU –> F-FdUMP (mimics dUMP)
Flucytosine:
Oral or IV?
CSF?
Metabolism?
oral ONLY
good CSF
renally eliminated (renal impairment = toxicity)
Griseofulvin:
From a strain of ______
Fungi - cidal or -static
Oral or IV?
penicillium
static
oral ONLY
MOA of Griseofulvin?
disrupts fungal microtubules
Tavaborole:
MOA?
inhibits leucyl transfer RNA synthetase (LeuRS) aka stops protein synthesis
Tavaborole:
what element is essential for its activity
Boron
Antifungal drug resistance:
typically transferred between strains - yes or no?
NO!
Antifungal drug resistance:
main acquired resistance seen to polyenes?
reduced egosterol content in membrane
Antifungal drug resistance:
main acquired resistance to Flucytosine
cytosine deaminase or UPRT (cytosine permease)
Antifungal drug resistance:
Common Azole acquired resistance mechanisms?
target site alteration
Efflux pumps
target enzyme upregulation
Development of bypass pathways
Antifungal Toxicities: what drug(s) cause photopsia
voricaonzole
Antifungal Toxicities: what drug(s) cause renal toxicity
amphotericin B
Cyclodextrins (IV voriconazole)
Antifungal Toxicities: what drug(s) cause bone marrow suppresion
5-FC Amphotericin B (anemia bc decrease EPO production)
Antifungal Toxicities: what drug(s) cause GI toxicity?
Itraconazole
Posaconazole
5-FC
Antifungal Toxicities: what drug(s) cause QT prolongation
all Azoles
Antifungal Toxicities: what drug(s) case cardiomyopathy
intraconzaole
Antifungal Toxicities: what drug(s) cause infusion reactions
amphotericin B
Echinocandins
Antifungal Toxicities: what drug(s) cause hepatic toxicity
all azoles
Amphotericin B
5-FC
Echinocandins
Antifungal Toxicities: what drug(s) cause CNS issues
Voriconazle
Antifungal Toxicities: what drug(s) can cause a rash
all antifungal rxns
Antifungal Toxicities: what drug(s) can cause photosensitivity/malignancy
voriconazole
Antifungals and Pregnancy:
what antifungals are full on contraindicated?
voriconazole
flucytosine
griesofulvin
Antifungals and Pregnancy:
what antifungals should be avoided in pregnant women - ESPECIALLY in 1st trimester bc birth defects/miscarriage risk
Fluconazole (except single 150 mg dose not a problem tho)
Itraconazole
Posaconazole
Isavuconazole
