Pharm - Antifungals part 1 Flashcards by amanda kastel

3 types of fungi

yeast
molds
dimorphic

How well did you know this?

Not at all

Perfectly

_____ is a major problem for diabetic patients

onychomycoses (fungal infection of the nails)

How well did you know this?

Not at all

Perfectly

fungal infections are medically called….

Mycoses

How well did you know this?

Not at all

Perfectly

5 general categories of fungal infections

superficial
mucus membrane
subcutaneous
systemic (inhalation, wound)
opportunistic

How well did you know this?

Not at all

Perfectly

5 patients at high risk for fungal infections

HIV
burn patients
barrier compromise
transplant patients
blood malignancies

How well did you know this?

Not at all

Perfectly

tinea corporis

ringworm

How well did you know this?

Not at all

Perfectly

tinea pedis

athlete’s foot

How well did you know this?

Not at all

Perfectly

tinea barbae

fungal infection of beard/hair

How well did you know this?

Not at all

Perfectly

tinea unguium

fungal infection of nails

How well did you know this?

Not at all

Perfectly

tinea cruis

jock itch

How well did you know this?

Not at all

Perfectly

tinea capis

fungal infection of the scalp

How well did you know this?

Not at all

Perfectly

name 3 imidazoles that are antifungals

clotrimazole
ketoconazole
terconazole

How well did you know this?

Not at all

Perfectly

2 polyene antifungals

amphotericin B
nystatin

How well did you know this?

Not at all

Perfectly

3 echinocandin antifungals

capsofungin
micafungin
anidulafungin

How well did you know this?

Not at all

Perfectly

MOA griseofulvin

interferes with microtubule assembly to inhibit mitosis

How well did you know this?

Not at all

Perfectly

5 antifungals that inhibit ergosterol (steroid) synthesis

fluconazole
itraconazole
voriconazole

How well did you know this?

Not at all

Perfectly

caspofungin is a ______ inhibitor

cell wall synthesis

How well did you know this?

Not at all

Perfectly

name an antifungal that interferes with nucleic acid synthesis

5-fluorocytosine

How well did you know this?

Not at all

Perfectly

site of action of oxaboroles

aminoacyl tRNA synthase

How well did you know this?

Not at all

Perfectly

3 enzymes in ergosterol (steroid) synthesis

squalene synthase
squalene epoxidase
14a-sterol demethylase

How well did you know this?

Not at all

Perfectly

why is ergosterol synthesis a target of many antifungals?

bc ergosterol is a major membrane component of fungus (NOT mammalian cells - so good target)

How well did you know this?

Not at all

Perfectly

name 4 systemic antifungals for systemic infections

amphotericin B
flucytosine
triazoles
echinocandins

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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