Antifungals MedChem Flashcards
1
Q
Lower Number Antifungals Factors
A
- Evolutionarily similar to humans
- Fewer unique fungal targets
- Less incentive for drug development due to lack of prevalence
- Increasing immunocompromised populations drive antifungal development
2
Q
Membrane Permeabilizers
A
- Cell membranes of fungi have unique steroids like ergosterol
- Target this specific cholesterol not present in humans that helps regulate cell membrane fluidity
- Allow block enzymatic synthesis of these steroids
3
Q
Polyene Agents
A
- Lactones with large, polyalkene ring
- Colored since it absorbs visible light
- Increased conjugated bonds increases activity and decreases toxicity
- Typical compounds: nystatin and amphotericin B
- Highly asymmetric distribution of polarity
4
Q
Amphotericin B
A
- Similar to Nystatin but has 7 conjugated double bonds
- Lower toxicity allows IV administration
- Also has a liposomally encapsulated formula with even less toxicity
5
Q
Polyene MoA
A
- Insert themselves into plasma membrane
- Increased affinity for ergosterol containing membranes due to intermolecular foces like pi-pi stacking
- Much less affinity for cholesterol
- Cells become essentially “leaky” to small ions and organics due to disruption of membrane packing
- Oligomerization of polyene-ergosterol complexes into barrel shaped pore with polar groups inside the pore
- Unknown mechanisms of resistance are developing
6
Q
Ergosterol Selectivity
A
- 3x more double bonds than cholesterol
- More pi-pi stacking interaction than cholesterol
- Also increases selectivity as polyenes gain more double bonds
7
Q
Amphotericin B Formulations
A
- Different formulations have different properties
- Very different size/shape formulations that interact with lipoproteins and cells very differently
- Causes different PK effects and stability factors
8
Q
Major Differences in Amphotericin B Formulations
A
- All lipid formulations show lowered nephrotoxicity than the deoxycholate formulation
- Lower infusion reactions for lipid formulations, excluding amphotec
- Some lipid formulations better in aspergillosis, but not proven in head to head studies
9
Q
Azoles
A
- Inhibit 14-alpha-demethylation, mediated by a specific fungal cytochrome P450
- Enzyme involved in ergosterol synthesis
- No close human equivalent to that enzyme
- 14-a-demethylation has 3 successive aliphatic hydroxylations followed by the elimination of formate and water
10
Q
Azole Components
A
- Imidazole or triazole pharmacore (binds to P450 heme site)
- Large, generally hydrophobic R group that mimics lanosterol molecule to enhance binding to fungal site
- Terminal polarity for solubility
11
Q
Ketoconazole
A
- Cream, shampoo, lotion, or oral
- Uptake is a function of stomach acidity, don’t use with acidic lowering drugs/foods
- Oral ketoconazole strongly inhibits CYP 3A4 isoenzyme
- Can be used to inhibit cyclosporin degradation
12
Q
Triazole
A
- 3 nitrogen warhead, seen in more new azoles
- More specific for fungal P450
- Less metabolism so better PK
- EX: Voriconazole (Vfend) and Efinaconazole (Jublis)
- Still have diflurophenyl, but much smaller R group
13
Q
Vfend
A
- Voriconazole
- Low solubility except in acid
- Oral or IV use
- DDI through CYP3A4
14
Q
Jublia
A
- Efinaconazole
- Topical
- Drug/formulation optimized for nail permeation
15
Q
Cresemba
A
- Isavuconazonium Sulfate
- Polar prodrug of effective isavuconazole
- Rare example of orally active quaternary ammonium
- Low water solubulity, so prodrug makes it viable for infusion with diffusion
- Charge is delocalized on triazole to allow for oral absorption, bioequivalent no matter then route
- Extensive Vd and protein binding requires it to have a loading dosage
