Dr. Stahelin Antifungals Flashcards
1
Q
Opportunistic pathogens
A
Absidia corymbifera, Aspergillus fumigatus, candida albicans, cryptococcus neoforman, pneumocycstis jiroveci, rhizomucor pusillus, rhizopus oryzar
2
Q
Dermatophytosis
A
- classic skin and hair infections (ringworm, athlete’s foot, jock itch, etc)
- Epidermophyton, Trichophyton, and microsporum are the 3 genera of mold that grown on keratin on a living host
- causes a series of conditions called tineas
3
Q
Onchomycosis
A
non-dermatophyte nail infections or any fungal nail infection caused by any fungus
4
Q
Amphotericin B
A
- Polyenes
- MOA: binds to ergosterol and withdraws ergosterol from the cell membrane in fungal cells
- reason for specificity: mammalian and bacterial cell membranes contain cholesterol
- fungicidal
- Structure: contains both acidic and basic groups in the structure. Contains a lipophilic polyene region and hydrophilic polyalcohol region (amphiphilic). Contains a macrolide ring.
- mycosamine group: required for binding to ergosterol
- hydroxyls are critical for pore formation and binding to cholesterol
5
Q
amphotericin B major toxicities
A
- infusion-related - fevers, chills, muscle spasms, vomiting, headache, and hypotensions. Premedicated with diphenhydramine and/or tylenol
- Renal damaged- reduced renal perfusion (reversible) and real tubular injury (irreversible)
6
Q
Amphotericin B SOA
A
candida albicans, cryptococcus neoformans, histoplasma capsulatum, blastomyces dermatitidis, coccidioides immitis, and aspergillu fumigatus
7
Q
Terbinafine
A
- allylamines
- MOA: disrupts ergosterol synthesis by inhibiting squalene epoxidase. Squalene imbeds into the membrane and can lead to toxicity and fungal cell death
- reason for specificity: 2500 fold selectivity for fungal enzyme compared to mammalian enzyme
- SOA: mostly effective against dermatophytes (epidermophyton, trichophyton, and microsporum), especially onychomycosis
- fiungicidal
8
Q
Azoles
A
- MOA: inhibition of 14-alpha-demethylase, that prevents the binding and activation of molecular oxygen by cytochrome P450 which prevents the conversion of lanosterol to ergosterol. The build-up of toxic sterols leads to damage to the cell membrane and the inability of fungi to continue to spread
- reason for specificity: humans use the same enzyme to make cholesterol for our cell membranes but fungal enzymes are more sensitive
- Fungistatic
- azole antifungals are metabolized by CYP450 enzymes
9
Q
Miconazole
A
- first described azole antifungals
- differ in distance of azole group from asymmetric carbon
- the alteration changes the SOA, interactions with CYP, and route of administration
10
Q
Ketoconazole
A
- first azole with sufficient oral bioavailability to be used clinically for deep tissue infections
- based on miconazole: dioxolane ring on asymmetric carbon and reduced metabolism by CYP3A4
- potent inhibitor of CYP3A4
11
Q
Itraconazole
A
- based on ketoconazole: triazole instead of imidazole, modified substituent on dioxolane ring, improved specificity for fungal P450 enzyme
- extensively metabolized by CYP3A4 in the liver
- variable absorption
- bad taste
12
Q
Itraconazole SOA
A
Similar SOA to fluconazole plus aspergillus. Not as broad as voriconazole, posaconazole, or isavuconazole
- azole of choice for Histoplasma, Blastomyces, and sporothrix
- extensively used for dermatophytoses and onychomycosis
13
Q
Fluconazole
A
- substantially modified ketoconazole: triazole in place of imidazole, F in place of Cl on benzene ring, hydroxyl and 2nd triazole on asymmetric carbon, dioxolane ring eliminated.
- 80% excreted by kidney and unchanged
- high solubility and bioavailability
- penetrates CSF
14
Q
Fluconazole SOA
A
- good activity against C. albicans and many other candida spps (most commonly used for mucocutaneous candida)
- some candida spps are naturally resistant (C. krusei, C. glabrata)
- Cryptococcus Neoformans - azole of choice for treatment and prophylaxis of cryptococcal meningitis
15
Q
Voriconazole
A
- based on fluconazole: maintains triazole, hydroxyl, and fluorine substituents. 2nd triazole replaces with fluoropyrimidine ring. Added methyl group - improved binding to fungal 14 alpha-demethylase and increased SOA.
- Metabolized extensively in liver by CYP2C19 > CYP3A4 > CYP2C9 (CYP2C19 polymorphisms can alter levels)
- highly soluble and high oral bioavailability
- CSF levels ~1/2 of plasma levels
- teratogenic in animals and is contraindicated in pregnancy (category D)
- side effects: visual disturbances
16
Q
Voriconazole SOA
A
- active against cadida spps including some fluconazole-resistant strains
- extended SOA against yeasts, cryptococcus, and molds including aspergillus
- may be more effective against aspergillus than amphotericin B
17
Q
Posaconazole
A
- derived from itraconazole: has a furan ring that alters and increases the spectrum of activity. Fluorine replaces carbon.
- broad spectrum of activity: similar to voriconazole but with better activity against filamentous fungi such as zygomycetes
- oral suspension and IV administration
- metabolized in the liver by glucuronidation
18
Q
Isavuconazole
A
- structurally similar to voriconazole
- broad spectrum of activity: similar to voriconazole but also zygomycetes
- water-soluble pro-drug: cyclodextrin not required for solubility, reduced nephrotoxicity relative to voriconazole.
- long half-life
- prodrug is isavuconazonium
- cleaved by plasma esterases
- fewer adverse effects and drug-drug interactions than voriconazole
- SOA: similar to voriconazole and approved for tx of invasive aspergillosis and mucormycosis
19
Q
Echinocandins
A
- lipopeptides
- all must be administered by IV due to poor bioavailability
- cyclic hexapeptides with long modified fatty acid chains
- MOA: inhibit the synthesis of beta(1,3)-glucan cell wall component. Beta(1,3)-glucan synthase is the target enzyme.
- mammalian cells lack this activity
- fungicidal
- broad spectrum of activity: synergistic with voriconazole and amphotericin B.
- No cross-resistance with other antifungals and not metabolized by liver CYPs
- degraded in blood and tissues
20
Q
Caspofungin
A
- echinocandins
- disseminated and mucocutaneous candida
- salvage therapy in patients with aspergillosis who fail to respond to amphotericin B
21
Q
Micafungin
A
- echinocandins
- mucocutaneous candida
- candida prophylaxis in bone marrow transplant patients
22
Q
anidulafungin
A
- echinocandins
- esophageal candidiasis, invasive candidiasis
- has the longest half-life and no known drug interactions
23
Q
Flucytosine
A
- antimetabolite (pyrimidine analog)
- MOA: inhibits thymidylate synthase and interferes with proteins synthesis. Flucytosine is first converted by cytosine deaminase to 5-FU. 5-FU is phosphorylated to form 5-FdUMP and 5FdUMP mimics dUMP. 5FdUMP is a substrate, a competitive inhibitor, and a suicide inhibitor of thymidylate synthase. no dTMP can be produced and thus inhibits viral DNA synthesis.
- mammalian cells are unable to convert flucytosine to active metabolite.
- Synergizes with amphotericin B
- penetrates well into all fluid compartments including CSF
24
Q
flucytosine ADR
A
- removed by kidney so renal impairment can lead to toxicity
- intestinal flora can metabolize to 5-FU anti-cancer drug and monitoring of levels is necessary when combined with amphotericin B
25
flucytosine SOA
cytptococcus neoformans (combined with amphotericin B for cryptococcal meningitis), some candida species, aspergillus, most filamentous fungi are not susceptible
26
Griseofulvin
- produced by a strain of penicillium
- disrupts fungal microtubules
- fungistatic
- must be given orally - becomes incorporated in keratin precursor cells
- used for dermatophytes
- inactive against yeast, mold, and dimorphic fungi
27
Tavaborole
- inhibits leucyl transfer RNA synthetase (LeuRS) in thus inhibiting protein synthesis
- boron is essential for activity
- topical treatment if onychomycosis
