anti fungal drugs Flashcards
Why do ppl get fungi infections?
Immune system declining
Large application of antibiotic??
Fungal infections fall into 2 distinct categories
Superficial mycoses (skin, mucous )
-contagious
Deep seated mycoses (systemic, lung, CNS)
-non-contagious
allylamine and benzylamine antifungal drugs
inhibit ergosterol biosynthesis at the level of squalene epoxidase
naftifine
terbinafine
butenafine
azole antifungal drugs
inhibit cytochrom P450 dependent enzymes C14 a-demethylase involved in the biosynthesis of ergosterol
Imidazoles (less potent)
-miconazole
-clotrimazole
-ketoconazole
Triazoles(potent)
- fluconazole
-itraonazole
-voriconazole
-posaconazole
polyene antifungal drugs
interact with sterols in the cell membrane to form channels through which small molecules leak from the inside of the fungal cell to the outside and kill the fungal
nystatin
pimaricin (natamycin)
amphoteticin B
echinocandins
concentrated-dependent,
noncompetitive inhibitors of b-1,3 gluten synthase
caspofugngin
micafungin
anidula fungin
anti metabolit and other antifungal drugs
5-fluorytosine acts as an inhibitor of both DNA and RNA synthesis via the intracytoplasmic conversion of 5-flurocytosine to 5-fluorouracil
polyene structure
alternating conjugated double bonds that constitute a part of there macrolide ring structure
is polyenes are fungicidal or fungistatic
fungicidal
what is polyene toxicity due to ?
polyenes bind to cholesterol, although they have a 500x affinity for ergosterol over cholesterol
what was the first broad spectrum anti fungi
nystatin
what forms are nystatin available in
topical cream
oral suspension
pill
not available IV for humans
what bacteria was natamycin isolated from
streptomycin natalensis from South africa
this medication is not absorbed systemically, used for the treatment of fungal keratitis and used as a natural antifungal food additive
natamycin
amphotericin B dosage form
injection as well as pill
why is the use of amphotericin B limited
toxicity in the liver and kidneys
don’t give with other nephrotoxic drugs
foliation with liposomes has been approved
amphotericin B characteristics
insoluble in water
must be formulated as a suspension that is not absorbed in GI
systemic= IV administration
highly protein bound
half life >18 hrs
does not close BBB
toxicities of amphotericin B
simulate host immune cells –> release of inflammatory cytokine
nephrotoxicity
hypokalemia
hypomagnesemia
bone marrow suppression
what was the first antifungal allyamine
naftifine
what drug was synthesized as a potential serotonin reuptake inhibitor
naftifine
naftifine is only used for
topical indications
terbinafine (lamisil) characteristics
readily absorbed in the GI
40% ora biovailability
high level of metabolism by multiple CYP
high protein binding
plasma half-life of 36 hrs
accumulates in nails with a half life of 300hrs
Terbinafine is active against
a broad spectrum of fungal strains
this is a benzylamine instead of a allylamine
butenafine
tolnaftate
-thiocarbamate that can be made very expensive
-athletes foot, ringworm, jock itch
-only topical
-no candida
amorolfine
-onychomycosis treatment
-ony used topically
-can be combined with terbinafine to improve efficacy
Azole
-five membered nitrogen heterocyclic ring
-containing at least one other non carbon atom ( n, s, o)
what are imidazole agents usually used for
external fungal infections
what are triazole agents more commonly used for
systemic infections
clotrimazole
-first discovered
-a stable carbocation, imidazole ring
-not well absorbed
-cream, aerosolized spray, solution (ear inf)
Miconazole
-2nd member of azoles
-imidazole ring
-most widely used
-superficial and internal use
-neonatal thrush
-absorbed when taken internally –> DDI
-racemic compound , only R
- active enantiomer not used due to cost
what azoles are substituted with a chlorine
isoconazole
econazole
what azoles are substituted with a sulfur
feniconazole ( more rapid clearance)
sulconazole
tioconazole (in the rink instead of linker)
sertaconazole ( cyclic sulfur atom)
butoconazole ( linker atom on other ring)
omoconazole
- has designed simple pH sensitivity onto limited half-life of the active ingredient
-external use only
-accidental ingestive is safe bc will not survive stomach acid
oxiconazole
acid sensitive functional group the helps render the compound safer for accidental ingestion
Bifonazole
-structually unique azole
-target two different processes in the sterol biosynthesis pathway
-reason why azoles should be limited by ppl who are taking statin to control cholesterol
ketoconazole
- first azole to be used for systemic candida
-poor PK ( moderate absorption, high protein binding, short half life)
Itraconazole
-better pharmacokinetic than ketoconazole
-readily metabolized by CYP3A4
-99.8% protein bound, protects it from rapid metabolism and clearance
posconazole
- the most active triazole for systemic infections
-excellent PK profile
-no significant adverse event up to 1600 mg/day
fluconazole
- two triazole units
-does not have a chiral center
-less expensive
-less likely ti have undesired side effect by a spector isomer
-broad spectrum
-excellent PK (90% bioavailability ) - not highly metabolized
-inhibit 2c9, 3A4
terconazole
a simplified and cheaper triazole
voriconazole
-available as tablet and IV
-DOC for aspergillosis
- ADR: hepatotoxicity, visual disturbances, hallucinations, rash, QT prolongation
- many DDI (immunosuppressants)
abafungin
- not an azole
-ihibits 14a-sterol demethylase
-limited antibacterial activity
-suggesting more than one MOA
what is the penicillins of antifunal
echinocandins
echinocandins and pneumocandin moa
herbal compounds able to block cell wall synthesis
capsofungin
used to treat aspergillosis
are echinocandins fungicidal or static
fungicidal agents candida spp
fungistatic against aspergillus
echinocandins AE
hepatitis
rash
caspofungin
-the first to be approved by FDA 27 years after echinocandins
-broad spectrum antifungal activity
-new class
-IV only
-half life = 10 hrs , 1 single injectable is suitable
-used for patients that don’t respond to other
micafungin
-injectable
-similar PK to caspofungin
-no DDI
-decreased toxicity
-useful for the Treatment of severely immunocompromised patients
anidulafungin
-newest antifugual
-longer half life = 27 hours
-lower protein bouncing =84%
-metabolism through hydrolysis**
-no CYP**
-no DDI
-excellent therapeutic index
all of the echinocandins represent the
last line defense
griseofulvin
-ringworm
-oral suspension (insoluble)
-poor oral biovailabity
-half life 9 hours *
-metabolized by bioconjugation **
flucytosine
-a nucleic acid analog
-water soluble
-well absorbed after oral Administration
-used with other antifungal
-flucytosine+ amp B to treat cryptococcosis and disseminated candidiasis
-flucytosine + azoles treat cryptococcal meningitis
ciclopirox
-mechanism unknown
-used in combination with azole or allylamine
