Med chem of antifungal agents Flashcards by Meghan Collins

Which location of fungal infections are most concerning because they may become invasive?

Subcutaneous
-Fungi are generally implanted in the skin
-Fungal growth produces a lesion

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Systemic/invasive fungal infection

-Fungi have invaded deep tissues
-Can be self-limiting or cause severe disease with high mortality rates

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Antifungal drugs and targets: mimic _____ that are mainly found in fungal infections

Enzymes

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Which drugs are considered polyenes?

Does it absorb in the gut well?

Amphotericin B

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Main features of polyenes

-Amphoteric: has both acidic and basic groups
-Contains a lipophilic polyene region (bottom) and a hydrophilic polyalcohol region (top)
-Macrolide ring
-Fungicidal

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Amphotericin B MOA

-Binds ergosterol = predominant sterol in fungal cell membranes
-Specificity: binds ergosterol with higher affinity than cholesterol
-Creates pores in cell membrane –> allows ions to leave and cells die
-Withdraws ergosterol from membrane –> instability of fungal cell membrane

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PK of amphotericin B
-______ absorbed from GI tract
-_____ form is only effective for GI infections
-_____ form for systemic infections
-______ therapy needed for fungal meningitis

-Poorly absorbed from GI tract
-Oral amphotericin B ONLY effective for GI infections
-IV injection is required for systemic infections
-Intrathecal therapy is needed for fungal meningitis

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ADR of amphotericin B
-May premedicate with _____ to help reduce ______ related ADR

-____ damage
*Reversible component: ______
*Irreversible component: _____

-_____ abnormalities occasionally observed

-Toxicity is low enough to allow use, but still very toxic
-Infusion related (fever, chills) –> may be reduced by reducing the infusion rate
***Premedicate with diphenhydramine and/or acetaminophen

-Renal damage
**Reversible component=reduced renal perfusion
**Irreversible component = renal tubular injury (permanent kidney damage) –> usually occurs after prolonged administration (> 4 grams)

-Liver abnormalities occasionally observed

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Amphotericin B in systemic infections

-Broad spectrum antimycotic
**Trying to disrupt fungal cell membrane
**Broad spectrum antimycotic
**Drug of choice for life-threatening fungal infections
-IV administration over 1-4 hours

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Amphotericin B in superficial fungal infections (what is the name of the medication?)
**Oral thrush; infection on skin

-Nystatin - polyene drug similar to amphotericin B
**Too toxic for systemic administration so cannot be used IV b/c it will damage healthy human cells

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Amphotericin formulations

-Conventional amphotericin B (Fungizone)
*Colloidal suspension
*Deoxycholate (a bile salt) used as a solubilizing agent

-Lipid formulation (Amphotec)
*Colloidal dispersion
*Encapsulated liposomal amphotericin B (ambisome)
*Amphotericin B lipid complex (Abelcet)

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Lipid formulations of amphotericin
-Lipid formulations reduce _________
-Act as a _____ of amphotericin

-______ also reduces infusion toxicity bc it uses ____

-______ has less nephrotoxicity, but potentially more fever

-Nephrotoxicity

-Reservoir (encapsulated to get to target of fungal cell membrane)

-Ambisome; true liposomes

-ABCD

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-Most fungi have _______ in their cell membranes
**Plays the same role as cholesterol in mammalian cell membranes

-Ergosterol

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Ergosterol synthesis pathway

Squalene (poisonous; disrupts fungal cell membranes) is converted to squalene epoxide via squalene epoxidase. Squalene epoxidase becomes lanosterol via CYP450 14alpha-demthylase which becomes ergosterol.

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Terbinafine MOA

-Disrupts ergosterol synthesis by inhibiting squalene epoxidase –> causes a build up of squalene which disrupts the fungal cell membrane

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Terbinafine has minimal SE because it hits the ____ enzyme at a much lower concentration (greater selectivity for the _____ enzyme compared to ____ enzyme)

Fungal

Fungal; mammalian

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Terbinafine is available for ____ & ____ administration

Oral; topical
**Because of high selectivity of fungal enzymes, it is safe

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What kinds of infections is terbinafine best used for?

Skin and nail fungal infections
-Ringworm, pityriasis versicolor

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Naftifine (Lotrimin) and butenafine (Lotrimin Ultra) are chemically similar to _____ and have the same MOA
**Available OTC

Tolnaftate has a different structure than terbinafine, but also inhibits _______

**Only available in ____ preparations

Terbinafine

Squalene epoxidase

Topical

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Key feature of azoles

5-membered aromatic ring

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Azoles MOA

Inhibits 14 alpha-demethylase (inhibits demethylation reaction)

Fungistatic (inhibit fungal growth w/o killing the cell)

***Leads to cell death due to lack of ergosterol which is essential in the fungal cell membrane

**Azoles bind the iron in the catalytic site of Cytochrome P450 to prevent lanosterol binding –> get a build up of lanosterol and starving the cell of ergosterol –> accumulation of toxic sterols in cell membrane

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Azoles selectivity

-Humans use the same enzyme to make cholesterol for our cell membranes
-Fungal enzymes are thousand fold more selective than human enzymes
-Azoles inhibit other mammalian CYP450s, so must monitor drug-drug interactions

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Azoles metabolism

-Extensively metabolized by CYP450s
-All metabolites are inactive
-Only those azoles with reduced metabolism are used for systemic infections

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Ketoconazole
-First azole with sufficient ____ bioavailability to be used clinically for _________________
-Based on ______

Oral; deep tissue infections

Miconazole
-Dioxolane ring on asymmetric carbon
-Reduced metabolism by CYP3A4

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Itraconazole -Based on _____ -_____ instead of imidazole -Modified substituent on dioxolane ring -Improved specificity for fungal ____ enzyme

Ketoconazole Triazole P450

Fluconazole -Substantially modified from ketoconazole *____ in place of imidazole *___ in place of Cl on benzene ring *____ and 2nd triazole on asymmetric carbon *Dioxolane ring eliminated

Triazole F Hydroxyl

Voriconazole -Based on _____ *Maintains triazole, hydroxyl, and ___ substituents *2nd triazole replaced with ______ *Added ____ group improves binding to fungal 14 alpha - demethylase and increases the spectrum

Fluconazole Fluorine Fluoropyrimidine ring Methyl

Posaconazole -Derived from _____ *Has_____ ring *_____ replaces Cl *_____ spectrum of activity * Available for ___ (as suspension) and ___ admin

Itraconazole Furan F Broad oral; IV

Isavuconazole -Structurally similar to ____ -_____ spectrum activity (similar to voriconazole, but also zygomycetes) -____ soluble prodrug **______ not required for solubility **______ nephrotoxicity relative to voriconazole **___ half life **Prodrug is _______ **Cleaved by _____ -Very fast -Release active drug and pro-drug cleavage product -Cleavage product has ______ half-life

Voriconazole Broad Water Cyclodextrin Reduced Long Isavuconazonium Plasma esterases short

Oteseconazole -Used for ____ fungal/yeast infections (reoccurring) -_____ tx outcomes compared to fluconazole -Selective inhibition of the fungal enzyme ____ (a 14-alpha demethylase) -Lower number of ADR

High risk Improved CYP51 **More worried about drug-drug interactions

-In general, azole antifungals are metabolized and inhibit liver _______ enzymes *Triazole concentrations can be increased by other drugs metabolized by this pathway *Concentration of drugs metabolized by CYP enzymes can be increased *Inducers of CYPs can _____ triazole levels ~_____ is a potent inducer

CYP450 Decrease Rifampin

Ketoconazole and CYP450 -Ketoconazole is a potent ____ of CYP3A4 -Drug interactions *Inhibited metabolism of terfenadine & cisapride (off market) *_______ bioavailability of cyclosporin *CYP3A4 inducers (rifampin) _______ ketoconazole levels

Inhibitor Increases reduce

Azole metabolism -Itraconazole is extensively metabolized by ____ in liver -Fluconazole is 80% _____ by the kidney unchanged -Voriconazole is metabolized extensively in the liver by _____ > CYP3A4 >> CYP2C9 -Posaconazole is metabolized in the liver by ______

CYP3A4 excreted CYP2C19 Glucuronidation

Echinocandins: lipopeptides -Synthetically modified fungal compounds -Examples (3) -All must be administered ____

Caspofungin, Micafungin, Anidulafungin IV

Structure of echinocandins

-Cyclic hexapeptides with long, modified fatty acid side chains

MOA of echinocandins -Inhibit the synthesis of ____ (cell wall component) ***Makes _____ for cell wall to be stable -Reason for selectivity: _____ -Fungicidal: _____ -_____ spectrum of activity -Cross resistance with other antifungals???

-Beta (1-3) glucan = target enzyme ***Crosslink Mammalian cells lack beta (1-3) glucan Destabilizes the membrane and causes leaky cells to die Broad (synergistic with voriconazole and amphotericin B) NOPE!

_______ is required for chitin production

Beta (1,3) glucan; when these are depleted, it weakens the membrane --> good because structure is not similar in humans so it targets the fungal cell

Beta (1,3) glucan is normally located at the tip of the ____; echinocandins cause those to ____

Hyphae Burst/break

Caspofungin use

-Disseminated & mucocutaneous candida -Salvage tx in pts with aspergillosis who fail to respond to amphotericin B

Micafungin use

-Mucocutaneous candida -Candida prophylaxis in bone marrow transplant pts

Anidulafungin use

-Esophageal candidiasis -Invasive candidiasis -Has longest half-life & no known drug interactions ****NOT disrupting/inhibiting human enzymes

Which fungins are associated with fewer ADR

Micafungin Anidulafungin

Metabolism of echinocandins -Degraded in _____ & _____

-NOT metabolized by liver CYPs (not stable bc they have a lot of ring opening by proteases) -Blood & tissues *Ring opening *Peptide hydrolysis

Rezafungin -Novel, ____ (frequency) echinocandin antifungal for adults with ______. -____ administrations, semisynthetic molecule that inhibits the beta-glucan synthase enzyme. -Much _____ half-life than other echinocandins, which allowed for _____ dosing instead of continuous IV.

Once weekly; limited or no alternative tx options (candidiasis) IV Longer; once weekly

Ibrexafungerp (own class); targets the same thing as echinocandins, but has a different structure -____(route of admin), small molecular inhibitor of _____ enzyme in fungi -Triterpenoid antifungal that inhibits glucan synthase, depleting ____ and acting as a fungicidal.

Oral; glucan synthase (similar to glucocandins, but these are smaller so they can be given PO) -1,3 -beta-D-glucan

Ibrexafungerp is mostly active against candida and used for________ It is metabolized by hydroxylation via ____ and then via ______ & ____ Well-tolerated due to the selective activity against the glucan synthase enzyme

Vulvovaginal candidiasis Hydroxylation; glucuronidation & sulfation

Flucytosine MOA

Antimetabolite (pyrimidine analog) -Inhibits thymidylate synthase -Interferes with protein synthesis **Prodrug in fungal infection

Reasons for flucytosine specificity

Mammalian cells are unable to convert flucytosine to active metabolite, so it only targets fungal cells

Flucytosine synergizes with _______

Amphotericin B

Flucytosine must go through the ______ to enter the cytoplasm It ultimately becomes _____ which is an active compound that inhibits dTMP which would have become _____ to extend the DNA chain ***prevents ____ from being created

Cytosine permease transporter 5-FdUMP Triphosphate Nucleic Acids

Flucytosine is first converted by cytosine deaminase to _____ *Phosphorylated to form 5-FdUMP *5-FdUMP mimics ______ *5-FdUMP is a substrate, a competitive inhibitor, and a suicide inhibitor of ________ *In 5-FdUMP, there is a F in place of H found in dUMO *F is the most electronegative atom, so it cannot be _____ *Thymidylate synthase gets trapped in an ______ form and cannot react with ______ *No dTMP can be produced --> inhibits ________

5-fluorouracil dUMP thymidylate synthase eliminated inactive; dUMP DNA synthesis

Flucytosine PK -Available only in _____ form -Penetrates well into all fluid compartments including CSF -Removed by _____ -_______ impairment can lead to toxicity

Oral Kidney Renal

Flucytosine ADR

-Intestinal flora can metabolize to 5-FU (anti-cancer drug) -Monitor levels when combined with amphotericin bc both can cause kidney toxicity

Clinical uses of flucytosine

-Limited spectrum of activity *Cryptococcus neoformans (combined with amphotericin B for cryptococcal meningitis) *Some Candida spp *Aspergillus *Most filamentous fungi are not susceptible

Flucytosine has a ____ therapeutic window

Narrow *Concentration too high = toxicity *Concentration too low = resistance (can come from deamidase or protease)

Flucytosine is nearly always administered with ____ or ____

Amphotericin B or fluconazole

Griseofulvin MOA

-Disrupts fungal microtubules -Fungistatic (by slowing down growth & division of cells) -Must be given PO (becomes incorporated in keratin precursor cells)

Griseofulvin is used for ______ It is inactive against ______

Dermatophytes (skin, hair, nails) --> more toxic than azoles, so it is not used topically Inactive against yeast, mold & dimorphic fungi -- not absorbed

Tavaborole MOA -___ is essential for activity -Topical tx for _______

Inhibits leucyl transfer RNA synthetase (LeuRS) --> inhibits protein synthesis in fungal cells Boron Onychomycosis (nail fungus)

Resistance from candida krusei

INTRINSIC resistant to fluconazole reduced susceptibility to flucytosine & amphotericin B

Resistance from candida glabrata

Multiazole Echinocandin Multidrug resistance **Mutations in enzymes that can arise which may lead to 'R'

Resistance from aspergillus terreus

Intrinsically resistant to amphotericin

Antifungal tx has altered the types of fungi associated with infection --> ______ used to not commonly be isolated, but is very common today

C. glabrata

Resistance to antifungal agents: acquired resistance _____ transferred between strains in bacteria

is not **No plasmid-based sharing

Resistance to azoles

-Target site alteration -Reduced drug concentration via efflux pumps -Target enzyme upregulation -Development of bypass pathways -Increasingly common. esp Aspergillus

Resistance to Polyenes

Reduced ergosterol content

Resistance to Echinocandins

-Beta (1,3) glucan mutations (RARE)

Resistance to flucytosine

Cytosine deaminase or UPRT (cytosine permease)

Antifungal toxicities: hepatic

All azoles (DDI-CYP3A4) Amphotericin B 5-FC Echinocandins

Antifungal toxicities: renal

Amphotericin B (greater than 4 g) IV voriconazole (bc combined with cyclodextrins)

Antifungal toxicities: CNS

Voriconazole

Antifungal toxicities: photopsia

Voriconazole

Antifungal toxicities: cutaneous

Rash (all antifungal agents) Photosensitivity/malignancy (voriconazole)

Antifungal toxicities: GI

Itraconazole Posaconazole 5-FC **b/c can metabolize drugs to anti-cancer

Antifungal toxicities: cardiac

Cardiomyopathy (itraconazole) QTc prolongation (all azoles, esp with DDI)

Antifungal toxicities: infusion rxn

Amphotericin B Echinocandins

Antifungal toxicities: bone marrow suppression

5-FC Amphotericin B (anemia associated with decreased epoetin production)

Antifungals during pregnancy -_______ tx are OK -____ is treatment of choice for systemic infections bc it does not cross the placenta well

Topical Amphotericin B

Fluconazole, itraconazole, posaconazole, and isaconazole use in pregnancy

AVOID in pregnant women, esp 1st trimester -Possibility of birth defects & spontaneous abortion -Single dose of fluconazole 150 mg to tx vaginal yeast infection does not appear to be associated with the birth defects

Voriconazole, flucytosine, and griseofulvin use in pregnancy

CONTRAINDICATED --> fetal abnormalities observed in animals

Echinocandins used in pregnancy

Not enough data -- use is cautioned