Pharmacology of Antifungals (Hall) Flashcards
MoA of Echinocandins
- Inhibits the enzyme that synthesizes Beta glucans
- “Penicillin of antifungals”
MoA of Polyenes
- Binds to ergosterol weakens the fungal cell membrane
- Causes the cells to be leaky
- Leads to fungal cell death
MoA of Azoles
-Inhibits the synthesis of ergosterol in fungal cells
5-Flucytosine (5-FC)
- Is converted into 5FU to inhibit DNA synthesis
- Pyrimidine analog
Mechanism of resistance to echinocandins
1) Mutations in FKS1 or FKS2 which encode glucan synthase
- Decreased sensitivity to echinocandins
2) Upregulation of multidrug transporters
3) Biofilms
4) Increased chitin synthase gene expression
How can you reduce toxicity of Amphotericin B
- Use the lipid formulation
- Amphotericin B Deoxycholate
- Ambisome, Abelcet
Mechanisms of resistance to Amphotericin B
- Reduced ergosterol content (defective ERG2 or ERG3 genes)
- Alterations in sterol content to those with reduced affinity
- Alterations in sterol to phospholipid ratio
- Reorientation or masking of ergosterol
How do Azoles work
-By decreasing ergosterol synthesis and cell membrane formation by inhibiting lanosterol 14-a-demethylase
Why are Azoles toxic
- Largely due to potential inhibition of mammalian CYP450s
- Imidazoles are more toxic than triazoles
- All of possible hepatic toxicities
Sporonox (Itraconzole)
- Should not be used in pts with a history of CHF
- QT interval prolongation
- Poor CSF Penetration
Diflucan (Fluconazole)
- Has the widest therapeutic index of all the azoles
- Good CSF penetration
- Can be used in UTIs
Vfend (Voriconazole)
- Toxicities may include; rash, elevated hepatic enzymes and visual disturbances
- Good tissue penetration
Noxafil (Posaconazole)
- When co-administered with statins it can prolong QT intervals
- If it is the oral suspension take with a high fat meal
Cresemba (Isavuconazonium)
- Prodrug of isavuconazole
- Can prolong QT interval too
Mechanism of resistance of Azoles
- Point mutation of ERG11 gene
- Overexpression of ERG11 gene
- Alteration in ERG3 gene lead
- Increase in mRNA levels for efflux pump genes (decreases the accumulation of the azole in fungal cells
