Pharmacology of Antifungals Flashcards
1
Q
Fungi Drug Targets
A
- Also eukaryotic (like humans)
- Need to target the differences in our cells
- EX: Cell wall (B1,3/B1,6/glucans), ergosterol, DNA synthesis
2
Q
Fungi includes…
A
- Yeast
- Mold
- Dimorphic Fungi
3
Q
Yeast Examples
A
- Candida
- Cryptococcus
- *C. name**
4
Q
Mold Examples
A
- Aspergillus
- Zygomycetes
5
Q
Dimorphics Examples
A
- Histoplasma
- Blastomyces
- Coccidioides (C. immitis**)
6
Q
Dimorphics + Temperature
A
- Different forms depending on temperature
- Cold = Mold
- Yeast = Heat
7
Q
Are fungi harmful?
A
- Most are harmless if healthy
- Local manifestations don’t usuallythreaten life/disseminate into immunocompetent hosts
- Opportunistic, systemic pathogens that take advantage of immunocompromised or parenteral administration
- Systemic = life-threatening
8
Q
Antifungal Agents
A
- Echinocandins
- Polyenes
- Azoles
- 5-flucytosine
9
Q
Echinocandins MoA/Examples
A
- Target cell wall components
- Inhibit enzyme that synthesizes B-glucans
- “Penicillin of antifungals”
- EX: caspofungin, anidulafungin, micafungin
10
Q
Polyenes MoA/Examples
A
- Bind ergosterol
- Weaken membrane and causes pore formation
- Leakage of K+ and Na+ causes cell death but can also cause mammalian toxicity
- EX: amphotericin B, Nystop
11
Q
Azoles MoA/Examples
A
- Inhibit the enzyme that synthesizes ergosterol
- EX: fluconazole, ketoconazole, itraconazole
12
Q
5-flucytosine (5-FC) MoA/Examples
A
- Converted to 5-FU to inhibit DNA synthesis as a pyrimidine analog
- Side effect: myelosuppression
13
Q
Echinocandins
A
- Inhibit B-glucan synthase
- Not present in mammalian cells
- Fungal cell lyses if cell wall isn’t intact
- Fungicidal
- IV only (slow infusion)
- Slow metabolism by hydrolysis/N-acetylation
- Excretion: primarily in urine
14
Q
Echinocandins SE
A
- Histamine-mediated symptoms
- Hepatic toxicity (Monitor LFTs)
15
Q
Resistance + Echinocandins
A
- Mutations in FKS1 or FKS2 (Candida glabrata) gene which encodes the catalytic subunit of glucan synthase
- Upregulation of multidrug transporters
- Biofilms
- Increased chitin synthase gene expression (cell wall component)
16
Q
Sterols
A
- Ergosterol is main sterol for fungi, while cholesterol is mean sterol for mammalian cell membranes
- Provides a selectivity for drugs like amphotericin B
- Induces ROS in fungal cell (accumulation of free radicals)
17
Q
Lipid Amphotericin B
A
- Cause less nephrotoxicity and infusion-related reactions
- Give IV for life threatening systemic infections, poor GI absorption
- Rapid toxicity with non-lipid formulations (infusion related), delayed nephrotoxicity
18
Q
Polyene Monitoring
A
- Serum creatinine**
- BUN**
- Renal function
- Electrolytes
- LFTs
- PTT
- CBC
19
Q
Amphotericin B Resistance
A
- Decreased ergosterol content (defective genes)
- Alterations in sterol content to those with reduced affinity (fecosterol, episterol)
20
Q
P450s
A
- Azoles have increased affinity for fungal P450s
- Fungistatic
- Enzyme used to synthesize ergosterol targeted (lanosterol 14-alpha-demethylase)
21
Q
Azole Classifications
A
- Imidazoles (2 nitrogen in azole ring)
- Triazoles (3 nitrogen in ring)
- Triazoles MOSTLY PO/IV while Imidazoles are typically topical
- Exception: Jublia (topical triazole)
22
Q
Azole Toxicity
A
- Due to inhibition of mammalian P450s
- Inhibit CYP3A4, 2C9, and 2C19 as well as P-glycoproteins
- Imidazole > Triazoles
- ALL have risk of GI upset/hepatotoxicity
23
Q
Azole Resistance
A
- Overexpression or alteration of the drug target
- Production of low affinity sterols (14alpha-methylfecosterol)
- Up-regulation of drug transporters
- Cellular changes that reduce toxicity or increase tolerance of drug-induced stress
24
Q
Itraconazole CI
A
- History of CHF
- Extensively metabolized by CYP3A4 which can potentially cause cardiac arrhythmias/death if used with drugs that prolong QT interval
25
Q
Fluconazole Therapeutic Index
A
- Widest of all the azoles
- Oral and IV
- Good bioavailability and CSF penetration (60-80%)
- Only antifungal to reach [therapeutic] in urinary tract
26
Q
Voriconazole
A
- Causes rash, elevated hepatic enzymes, and visual disturbances
- Prolonged therapy: fluorosis and periostitis
27
Q
Posaconazole
A
- Co-administer with statins that DON’T prolong QT interval
- Take with high-fat meal for adequate absorption
28
Q
Isavuconazonium
A
- Good oral bioavailability
- Can shorten QT interval (preferred use)
29
Q
Terbinafine/Butenafine
A
- Non-azole inhibitors of ergosterol synthesis
- Topicals
- Inhibit squalene epoxidase (further upstream)
- More sensitive to fungal squalene and causes toxic build-up of squalene in the fungal cell
30
Q
5-FC
A
- Water soluble pyrimidine analog
- Human cells can’t convert the 5-FC
- Inhibits DNA/RNA synthesis and therefore protein synthesis as well
- Active metabolites: 5-FU, F-dUMP (inhibits DNA), FUTP (incorporated into RNA and inhibits proteins)
31
Q
5-FC Resistance
A
- Loss of permease activity
- Loss of deaminase activity
- Synergize with amphotericin (resistance develops quickly)
- Renally eliminated
32
Q
5-FC SE
A
- Reversible bone marrow toxicity from FU metabolite
- Hepatotoxicity
- Monitor: hematologic, renal, and hepatic status
