Duncan Antifungals Flashcards
Polyene Drugs
Amphotericin B
Amphotericin B Structural Features
Structure similar to membrane phospholipid w/ 7 conjugated double bonds
- Hydrophilic “rod”
- Hydrophobic “rod”
- Polar, negative charged portion (COOH)
- Polar, positive charged sugar
Amphotericin B Formulations
Deoxycholate
Lipid Formulations - Abelcet, Ambisome
Amphotericin B Lipid Formulations
Decreases nephrotoxicity and allows for higher dosing
Abelcet = ring-like structure
Ambisome = lipsome formulation
Amphotericin B MOA
Membrane targeting agent (like associates with like) - similar MOA to polymyxin
Initially interacts with LPS, is recruited to fungal membrane, and then is able to interact with lipid bilayer
Hydrophilic, ionic head associates with hydrophilic heads of phopholipids
Hydrophobic rod can insert into nonpolar interior of membrane
Unfavorable insertion of hydrophilic rod into nonpolar interior
What interaction provides major binding energy for Amphotericin B?
Binding interaction between ergosterol and hydrophobic rod of Amphotericin B
Details of MOA of Amphotericin B
Forms pores in membrane
However, modified Amphotericin B that cannot form pores in the membrane still has full antifungal activity
What part of the Amphotericin B molecule plays an important role in stabilizing the pore?
C35 OH
Removing C35 OH abolishes pore formation and only slightly reduces activity
Removing _____ abolishes activity of Amphotericin B
mycosamine (AmdeB)
Structural modifications made to Amphotericin B molecule to reduce nephrotoxicity
Adding urea-based side chains reduce nephrotoxicity and maintain antifungal activity
Why doesn’t Amphotericin B affect bacteria?
Bacterial membranes don’t contain sterols, such as ergosterol
Ways to minimize nephrotoxicity of Amphotericin B
Administer with CCB, such as diltiazem
Salt loading
Flucytosine
Prodrug - metabolized into 5-fluorouracil (anti-cancer agent)
Should NOT be used as monotherapy - resistance develops quickly
Frequently used in combination with Amphotericin B for synergy - pore formation from Amphotericin B enhances penetration of flucytosine
Flucytosine MOA
Metabolic antagonist - inhibition of DNA and RNA synthesis
Enzyme that converts flucytosine → 5-FU
Cytosine deaminase (high activity in fungi, low activity in humans)
Imidazole Structure
2 nitrogens in 5 atom ring
More toxic than triazoles
Mostly used topically due to systemic toxicities
Imidazole Drugs
Miconazole
Clotrimazole
Econazole
Ketoconazole (newer, less toxic imidazole)
Triazole Structure
3 nitrogens in 5 aton ring
Less toxic than imidazoles
Can be used systemically
Triazole Drugs
Fluconazole
Itraconazole
Voriconazole
Posaconazole
Isavuconazole
Isavuconazole
Significantly higher aqueous solubility than other triazoles because of prodrug (isavuconium) form side chain (aminocarboxyl portion) - isavuconium side chain is rapidly removed in plasma by plasma esterases
Cyclodextrin-free solution
Azoles MOA
Metabolic antagonists
Block biosynthesis of ergosterol
Primarily fungistatic
Imidazole MOA
Directly interacts with cell membrane → contributes to its toxicity
Triazole MOA
Inhibit lanosterol demethylase (CYP450) → instead of making ergosterol, pathway makes 14alpha-methyl ergosterol, which packs more loosely in membranes → leaky and unstable membranes
Azoles DDIs
CYP3A4 - Ketoconazole and Itraconazole
CYP2C9 (Warfarin) - Fluconazole
Systemic imidazoles interact with H2RAs, PPIs, and. antacids
Efinaconazole
First approved azole for topical treatment of onychomycosis
Has improved activity due to reduced keratin binding (nail-binding), which allows greater penetration to sites of fungi
Allylamines Drugs
Terbinafine (PO)
Naftiline (topical)
Allylamine and Thiocarbamate MOA
Block epoxidase step in ergosterol synthesis
Griseofulvin MOA
Affects microtubules → affects cell division
Can bind to keratin in skin and nails
Pentamidine Structure
Central sting of 5 CH2s sandwiched between two para-modified phenols
Each phenol has identical amino side chain
Pentamidine MOA/Use
Alters nucleic acid function
Used for PCP pneumonia as an alternative to Bactrim
Polyoxins and Nikkomycins Structure
Pyrimidine linked to a peptide
Structural analogue of UDP-N-Acetyl-Glucosamine
Polyoxins and Nikkomycins MOA
Target cell wall biosynthesis by blocking biosynthesis of chitin
Papulacandins and Echinocandins/Pneumocandins MOA
Noncompetitive inhibitor of glucan synthase
Work synergistically with Amphotericin B, polyoxins, and nikkomycins
Fungicidal
Echinocandin/Pneumocandin Structure
Lipopeptide
Cyclic hexapeptide nucleus
Glucan Synthase
Enzyme made up of multiple subunits: FKS1, FKS2, and Rho1
What do echinocandins/pneumocandins bind to?
FKS1
Echinocandin/Pneumocandin Sensitivity and Resistance
Fungi are uniquely sensitive due to the unique use of glucan ploysaccharide in cell wall
Fungi with little to no glucan in cell wall are resistant
Mutations in FKS1 gene cause resistance
Limitations of Echinocandins/Pneumocandins
Limited oral absorption - IV only
Increasing resistance
Ibrexafungerp
Newest glucan synthase inhibitor - FDA approved in June 2021 for candidiasis
Ibrexafungerp Structure
Triterpenoid core
Ibrexafungerp Advantages
Oral bioavailability
Activity/stability in serum environment
Ibrexafungerp MOA
Binds to and inhibits FKS1p at a similar site to echinocandins/pneumocandins → fungal cell wall loses structural integrity → fragile cell wall subject to lysis (osmotic pressure)
Sufficiently different from echinocandins/pneumocandins to not be affects by mutations leading to echinocandin/pneumocandin resistance
