Pharm - Antifungals part 1 Flashcards
3 types of fungi
yeast
molds
dimorphic
_____ is a major problem for diabetic patients
onychomycoses (fungal infection of the nails)
fungal infections are medically called….
Mycoses
5 general categories of fungal infections
superficial
mucus membrane
subcutaneous
systemic (inhalation, wound)
opportunistic
5 patients at high risk for fungal infections
HIV
burn patients
barrier compromise
transplant patients
blood malignancies
tinea corporis
ringworm
tinea pedis
athlete’s foot
tinea barbae
fungal infection of beard/hair
tinea unguium
fungal infection of nails
tinea cruis
jock itch
tinea capis
fungal infection of the scalp
name 3 imidazoles that are antifungals
clotrimazole
ketoconazole
terconazole
2 polyene antifungals
amphotericin B
nystatin
3 echinocandin antifungals
capsofungin
micafungin
anidulafungin
MOA griseofulvin
interferes with microtubule assembly to inhibit mitosis
5 antifungals that inhibit ergosterol (steroid) synthesis
fluconazole
itraconazole
voriconazole
caspofungin is a ______ inhibitor
cell wall synthesis
name an antifungal that interferes with nucleic acid synthesis
5-fluorocytosine
site of action of oxaboroles
aminoacyl tRNA synthase
3 enzymes in ergosterol (steroid) synthesis
squalene synthase
squalene epoxidase
14a-sterol demethylase
why is ergosterol synthesis a target of many antifungals?
bc ergosterol is a major membrane component of fungus (NOT mammalian cells - so good target)
name 4 systemic antifungals for systemic infections
amphotericin B
flucytosine
triazoles
echinocandins
briefly explain the structure of amphotericin B
amphipathic
one side is lipid soluble and has no charge
the other side has a sugar with lot of OH groups - charged and water soluble
what route of administration is amphotericin B and why
all IV EXCEPT for fungal infections in the GI tract
poor oral absorption - insoluble in water. but if infection is in the GI, doesnt need to be absorbed anyway
is amphotericin B highly protein bound? what can you conclude from this?
more than 90% protein bound
thus, has long half life of 15 days
can amphotericin B enter the CNS well
NO
it’s big and has charge on one side
EXPLAIN the mechanism of action of amphotericin B
interacts directly with ergosterol IRREVERSIBLY– it’s ampipathic
the interaction creates a PORE in the membrane of the fungus which leads to ion leakage and ultimately death of the fungus
true or false
amphotericin B is considered fungicidal
TRUE
creates pore in the membrane by irreversibly binding ergosterol
true or false
amphotericin B binds reversibly to ergosterol
FALSE
irreversibly
resistance mechanism against amphotericin B
ergosterol modification or decrease in concentraiton of ergosterol in the membrane
liposomal vs non liposomal amphotericin B
they are different formulations of amphotericin B but…
liposomal is less potent (so more expensive), but also less nephrotoxic toxic
major toxicity of amphotericin B
nephrotoxicity
rank the binding affinity of amphotericin B to:
liposomal vehicle
ergosterol
cholesterol
highest affinity to: ergosterol
liposomal vehicle
lowest affinity to cholesterol
this is good bc cholesterol is the HUMAN major membrane component - we dont want to target this
true or false
amphotericin B is a narrow spectrum antifungal
FALSE
broad spectrum
really only used for life threatening systemic infections like meningitis, that is not responding to other treatment
bc of toxicity, amphotericin B can be used initially to ___ and then be replaced with___
decrease fungal titers and then be replaced by other agents like azoles
2 toxicities of amphotericin B
NEPHROTOXICITY
hemolytic anemia
briefly explain the structure of flucytosine and what this means regarding its use
it is small and water soluble
thus, can be given orally, and also has good bioavailability on ALL body fluids including the CSF
true or false
unlike amphotericin B, flucytosine has a narrow spectrum of action
(what does this mean about its clinical use?)
TRUE
thus given in combo with other agents for synergy and to avoid resistance.
many enzymes involved in the conversion of flucytosine to its active form – easy to develop resistance
flucytosine + Amp B is used to treat……
flucytosine + itraconazole is used to treat….
cryptococcal meningitis
chromoblastomycosis
explain the MOA of flucytosine
through cytosine permease, it is able to get into the fungus
there, it’s amine is removed by CYTOSINE DEAMINASE** and through several other steps is converted to its active form – 5-FdUmp WHICH INHIBITS thymidylate synthease – enzyme responsible for convering dUMP to dTMP and thus ultimately inhibits DNA SYNTHESIS
active form of flucytosine
5-FdUmp
INHIBITS THYMIDYLATE SYNTHASE
which is responsible for converting dUMP to dTMP — thus inhibits DNA synthesis
how does flucytosine not get into human cells to inhibit the synthesis of OUR DNA?
bc we have less cytosine permease and cytosine deaminase
true or false
compared to triazole, flucytosine has a much more narrow spectrum of activity
true
true or false
flucytosine is not effective against candida
false - it is
fungi can increase the synthesis of ______ to compete with flucytosine
pyrimidines
adverse effects flucytosine
bone marrow toxicity - myelosuppression, anemia, leukopenia, thrombocytopenia
2 classes of azole antifungals
imidazoles and triazoles
3 imidazoles (the rest of the azoles are triazoles)
3 imidazoles:
ketoconazole
miconazole
clotrimazole
explain the MOA of azole antifungals
interfere with ergosterol biosynthesis
they do this by inhibiting 14a sterol demethylase**
this creates a “fake” ergosterol called toxic 14a-methyl sterols - they get incorporated into the fungal membrane. they are toxic – they cause leakage and ultimate death of the fungus
which azoles are MORE SELECTIVE for fungal enzymes rather than human:
triazole or imidazole
triazoles are more selective for fungal
what enzyme do azoles inhibit
14a sterol demethylase
3 resistance mechanisms to azoles
-ERG11 mutation (codes for 14-a-sterol demethylase) or increased production of the enzyme
-mutation c5,6 sterol reductase
-increased efflux of azole
most fungi are susceptible to azoles
WHAT ARE THE ONLY 2 RESISTANT FUNGI TO AZOLES**
mucomycosis
candida krusei
true or false
a lot of fungi are resistant to azoles
FALSE - only 2
mucomycosis and candida krusei
**important clinical concern of azoles
AZOLES ARE CYP3A4 (and other) INHIBITORS!!!!!!!! DDI CONCERN
zidovudine/efavirenz + azoles
increased plasma levels of the antivirals bc azoles are CYP inhibitors and antivirals are CYP substrates
true or false
itraconazole is a triazole
true
AE of itraconazole
hepatotoxicity (d/c)
rash - hypersensitivity/SJS
route administration itraconazole
oral or IV
abospriton increased when given w food - well absorbed in acidic pH
what drug is a fluorinated bis-triazole
fluconazole
advantage of fluconazole over other azoles
drug interactions are less common
can fluconazole penetrate into the brain
yes
what is the TI of fluconazole
WIDE
fluconazole can be used to treat ______ after 2 weeks of amphotericin B
cryptococcal meningitis
AE fluconazole
NVD
headache
rash - rare SJS
rare hepatic failure
AE voriconazole
what kind of azole is it
how administered
visual disturbances, rash
triazole
oral or IV
which particular azole is known for prolonging QTc interval
posaconazole
which triazole has NO QT PROLONGATION
isavuconazole
