Antifungals Flashcards
Antifungal drugs mimic what?
many mimic enzymes homologous in fungi to mammals
What antifungal drugs are polyenes?
amphotericin B
What are the main features of amphotericin B?
amphoteric: has both acidic and basic groups
contains a liphophilic polyene region and a hydrophilic polyalcohol region - amphiphilic
is it a macrolide ring
fungicidal: perturbs membrane –> cell lysis
What is special about the structure of amphotericin B?
contains mycosamine: required for binding to ergosterol, but also binds to cholesterol (not good because we’re trying to target fungal cells, not human cells, so get a lot of toxicity)
hydroxyl group may complement pore formation in fungal cell membrane: ions + water can move across pores –> destabilizes and kills fungal cells
What is the MOA of amphotericin B?
binds to ergosterol - predominant sterol in fungal cell membranes
reason for specificity: mammalian cell membranes contain cholesterol
binding to ergosterol leads to intercalation of cell membrane –> membrane disrupted, ions leak, fungal cell dies because it’s destabilized
can also withdraw ergosterol from membrane: forms cage like structures to pull it out of membrane –> destabilization
What are the pharmacokinetics of amphotericin B?
poorly absorbed from GI tract because it’s so big: given IV!
oral amphotericin B only effective for GI infections; IV required for systemic infection
What are the adverse effects of amphotericin B?
pretty toxic
infusion-related: fever, chills, muscle spasms, vomiting, headache, hypotension - can be helped by reducing rate of infusion; premedicate with diphenhydramine and/or acetaminophen
renal damage: reversible component - reduced renal perfusion; irreversible component - renal tubular injury (usually after >4g administered)
What are the therapeutic applications of amphotericin B?
systemic infections - broad spectrum antimyotic
DOC for life-threatening fungal infections
superficial fungal infections: nystatin (polyene drug similar to amphotericin B)
Why do we use different amphotericin formulations?
use lipid formulations to decrease toxic side effects - nephrotoxicity
act as reservoir of amphotericin: lipids have intermediate affinity for amphotericin, higher than cholesterol, lower then ergosterol
amphotericin B colloidal dispersion, liposomal amphotericin B, amphotericin B lipid complex
ambisome also reduces infusion toxicity (uses true liposomes)
What antifungal drugs are allylamines?
terbinafine
What is the MOA of terbinafine?
disrupts ergosterol synthesis by inhibiting squalene epoxidase enzyme
death of fungal cells results from accumulation of squalene (toxic) - fungicidal
What are the main features of terbinafine?
high selectivity for fungal enzyme compared to mammalian enzyme (low SEs)
What is terbinafine used for?
mainly effective against dermatophytes - skin + nail fungal infections
available for oral and topical administration
What antifungal drugs are azoles?
ketoconazole, itraconazole, fluconazole, voriconazole, isavuconazole, oteseconazole
What is the key feature of azoles?
5-membered aromatic ring
the nitrogen on the ring is essential for binding iron in CYP450 enzyme
What is the MOA of azoles?
inhibition of 14-alpha demethylase
fungistatic - stall + reduce growth of fungal cells
inhibits demethylase step and binds the iron; in CYP450, preventing the conversion of lanosterol to ergosterol
build up of toxic sterols over time
What is the selectivity of azoles?
much more selective than amphotericin B
humans use same enzyme to make cholesterol for our cell membranes
fungal enzyme more sensitive, however azoles inhibit other mammalian CYP450s
What is the metabolism of azoles?
metabolized extensively by liver CYP450s - all metabolites are inactive
only those azoles with reduced metabolism are used for systemic infection
Ketoconazole
1st azole with sufficient oral bioavailability to be used clinically for deep tissue infections
based on miconazole but this one has a dioxolane ring on asymmetric carbon, reduced metabolism by CYP3A
Itraconazole
based on ketoconazole, but this one has a triazole instead of imidazole (3 nitrogens), modified substituent on diozolane ring; improved specificity for fungal P450 enzyme
Fluconazole
substantially modified from ketoconazole, this one has triazole in place of imidazole, F in place of Cl on benzene ring, hydroxyl and 2nd triazole on asymmetric carbon, dioxolane ring is eliminated
Voriconazole
based on fluconazole, maintains triazole, hydroxyl, and flourine substituents; 2nd triazole replaced with fluoropyrimidine ring
added methyl group - improves binding to fungal 14-alpha demethylase and increased spectrum
Posaconazole
derived from itraconazole, this one has a furan ring - alters and increases spectrum of activity, F replaces Cl
broad spectrum activity
available for oral and IV
Isavuconazole
this is a water soluble pro-drug - cyclodextrin not required for solubility; reduced nephrotoxicity relative to voriconazole
structurally similar to voriconazole
broad spectrum activity
long half-life
What is the prodrug of isavuconazole?
isavuconazonium - cleaved by plasma esterases, releases active drug and pro-drug cleavage product
pro-drug cleavage product has a short half-life, this allows the active metabolite to have a longer half-life
Oteseconazole
used for high risk of fungal or yeast infections (reoccurring)
selective inhibition of the fungal enzyme CYP51 (a 14-alpha demethylase)
low # of adverse events because it has such good selectivity to fungal enzymes
Azole antifungals are metabolized by what?
metabolized by and inhibit liver CYP450 enzymes
concentration of drugs metabolized by CYP enzymes can be increased
inducers of CYPs can decrease triazole levels (rifampin is a potent inducer)
Ketoconazole is a potent inhibitor of what?
CYP3A4
drug interactions: increases area under curve and half-life of triazolam; increases bioavailability of cyclosporin; CYP3A4 inducers (rifampin) reduce ketoconazole levels
Itrazonazole is extensively metabolized by what?
CYP3A4 in the liver
Voriconazole is metabolized by what?
metabolized extensively in liver by CYP2C19 > CYP3A4»_space; CYP2C9
CYP2C19 polymorphisms can alter levels
Posaconazole is metabolized by what?
metabolized in liver by glucuronidation
What drug is excreted by the kidney unchanged?
fluconazole
What drugs are echinocandins?
lipopeptides
What drugs are echinocandins?
lipopeptides: synthetically modified fungal compounds - caspofungin, micafungin, anidulafungin
all must be administered IV!
broad spectrum activity; no cross resistance with other antifungals
What is the structure of echinocandins?
cyclic hexapeptides with long, modified fatty acid side chains
because they’re so big, they are not orally available
What is the MOA of echinocandins?
inhibit synthesis of beta(1-3) glucan (cell wall component; beta (1-3) glucan synthase is the target enzyme; prevents crosslinking, no stabilizing the cell wall
fungicidal - destabilizes the membrane
What is the selectivity of echinocandins?
selective for fungal cells because mammalian cells lack this activity (no comparable enzymes in mammals)
What are the clinical uses of echinocandins?
caspofungin: salvage therapy in pts with aspergillosis who fail to respond to amphotericin B in disseminated and mucocutaneous candida
micafungin: candida prophylaxis in bone marrow transplant patients, treats mucocutaneous candida
anidulafungin: esophageal and invasive candidiasis
What is the metabolism of echinocandins?
NOT metabolized by liver CYPs
degraded in blood + tissues - ring opening, peptide hydrolysis
Rezafungin
once-weekly echinocandin antifungal for adults with limited or no alternative treatment options (candidiasis)
IV administration
inhibits the beta-glucan synthase enzyme
Ibrexafungerp
oral drug! small molecule inhibitor of glucan synthase enzyme in fungi
triterpenoid antifungal that inhibits glucan synthase, depleting 1,3-beta-D-glucan and acting as a fungicidal
metabolized by hydroxylation by CYP3A4 and then via glucuronidation and sulfation
selectivity against glucan synthase enzyme, so well tolerated
What is the MOA of flucytosine?
antimetabolite (pyrimidine analog)
inhibits thymidylate synthase (prevents the formation of thymidine triphosphate to extend and grow DNA, so stops DNA synthesis) and interferes with protein synthesis
flucytosine converted to 5-FU by cytosine deaminase –> 5-FU converted to 5-FUMP by PRT –> 5-FUMP phosphorylated and converted to 5-FdUMP by ribonucleotide reductase –> 5-FdUMP inhibits thymidylate synthase preventing the formation of dTMP
What is the specificity of flucytosine?
mammalian cells are unable to convert flucytosine to active metabolite
so it is selective for fungal cells because it is metabolized in fungal cells, but not human cells
What is flucytosine synergized with?
amphotericin B
Why does 5-FdUMP permanently bind to thymidylate synthase?
F is the most electronegative atom –> cannot be eliminated
thymidylate synthase trapped in inactive form and cannot react with dUMP
do dTMP produced, DNA synthesis is inhibited
What is the PK of flucytosine?
available only in oral form
penetrates well into all fluid compartments including CSF
removed by kidney
renal impairment can lead to toxicity
What are the adverse effects of flucytosine?
intestinal flora can metabolize to 5-FU (anti-cancer drug)
monitor levels when combined with amphotericin B because both can cause kidney toxicity
Griseofulvin
disrupts fungal microtubules
fungistatic - slows down growth and division of fungal cells
must be given orally
used for dermatyophytes (skin, hair, and nails)
inactive against yeast, mold, dimorphic fungi
What is the MOA of Tavaborole?
inhibits leucyl transfer RNA synthetase (LeuRS) - inhibits protein synthesis
boron is essential for activity
What is candida krusei resistant to?
intrinsically resistant to fluconazole
reduced susceptibility to flucytosine and amphotericin B
What is candida glabrata resistant to?
multiazole, echinocandin, multidrug resistance
What is aspergillus terreus resistant to?
intrinsically resistant to amphotericin
Is acquired resistance transferred between strains of bacteria?
no
Resistance to azoles
target site alteration - accounts for most resistant strains
reduced drug concentration via efflux pumps
target enzyme upregulation
development of bypass pathways
Resistance to polyenes
reduced ergosterol content
Resistance to echinocandins
target site mutations
Resistance to flucytosine
cytosine deaminase or UPRT
What antifungals are ok during pregnancy?
topical treatment are OK
amphotericin B is treatment of choice for systemic infections
What to avoid in pregnancy?
fluconazole, itraconazole, posaconazole, isavuconazole
possibility of birth defects and spontaneous abortion
What is contraindicated in pregnancy?
voriconazole, flucytosine, griseofulvun
fetal abnormalities
Which drugs are associated with hepatic toxicity?
all azoles
amphotericin B
echinocandins
Which drugs are associated with renal toxicity?
amphotericin B
IV voriconazole
Which drugs are associated with CNS and photopsia?
voriconazole
Which drugs are associated with cutaneous toxicity?
rash - all antifungals
photosensitivity - voriconazole
Which drugs are associated with GI toxicity?
itraconazole
posaconazole
Which drugs are associated with cardiac toxicity?
itraconazole - cardiomyopathy
all azoles - QTc prolongation
Which drugs are associated with infusion reactions?
amphotericin B
echinocandins
Which drugs are associated with bone marrow suppression?
amphotericin B
