Pharmacology of Antifungals

Question 1

Fungi Drug Targets

Answer 1

• Also eukaryotic (like humans)
• Need to target the differences in our cells
• EX: Cell wall (B1,3/B1,6/glucans), ergosterol, DNA synthesis

Question 2

Fungi includes…

Answer 2

• Yeast
• Mold
• Dimorphic Fungi

Question 3

Yeast Examples

Answer 3

• Candida
• Cryptococcus
• *C. name**

Question 4

Mold Examples

Answer 4

• Aspergillus

- Zygomycetes

Question 5

Dimorphics Examples

Answer 5

• Histoplasma
• Blastomyces
• Coccidioides (C. immitis**)

Question 6

Dimorphics + Temperature

Answer 6

• Different forms depending on temperature
• Cold = Mold
• Yeast = Heat

Question 7

Are fungi harmful?

Answer 7

• 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

Question 8

Antifungal Agents

Answer 8

• Echinocandins
• Polyenes
• Azoles
• 5-flucytosine

Question 9

Echinocandins MoA/Examples

Answer 9

• Target cell wall components
• Inhibit enzyme that synthesizes B-glucans
• “Penicillin of antifungals”
• EX: caspofungin, anidulafungin, micafungin

Question 10

Polyenes MoA/Examples

Answer 10

• 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

Question 11

Azoles MoA/Examples

Answer 11

• Inhibit the enzyme that synthesizes ergosterol

- EX: fluconazole, ketoconazole, itraconazole

Question 12

5-flucytosine (5-FC) MoA/Examples

Answer 12

• Converted to 5-FU to inhibit DNA synthesis as a pyrimidine analog
• Side effect: myelosuppression

Question 13

Echinocandins

Answer 13

• 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

Question 14

Echinocandins SE

Answer 14

• Histamine-mediated symptoms

- Hepatic toxicity (Monitor LFTs)

Question 15

Resistance + Echinocandins

Answer 15

• 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)

Question 16

Sterols

Answer 16

• 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)

Question 17

Lipid Amphotericin B

Answer 17

• 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

Question 18

Polyene Monitoring

Answer 18

• Serum creatinine**
• BUN**
• Renal function
• Electrolytes
• LFTs
• PTT
• CBC

Question 19

Amphotericin B Resistance

Answer 19

• Decreased ergosterol content (defective genes)

- Alterations in sterol content to those with reduced affinity (fecosterol, episterol)

Question 20

P450s

Answer 20

• Azoles have increased affinity for fungal P450s
• Fungistatic
• Enzyme used to synthesize ergosterol targeted (lanosterol 14-alpha-demethylase)

Question 21

Azole Classifications

Answer 21

• Imidazoles (2 nitrogen in azole ring)
• Triazoles (3 nitrogen in ring)
• Triazoles MOSTLY PO/IV while Imidazoles are typically topical
• Exception: Jublia (topical triazole)

Question 22

Azole Toxicity

Answer 22

• 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

Question 23

Azole Resistance

Answer 23

• 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

Question 24

Itraconazole CI

Answer 24

• History of CHF
• Extensively metabolized by CYP3A4 which can potentially cause cardiac arrhythmias/death if used with drugs that prolong QT interval

Question 25

Fluconazole Therapeutic Index

Answer 25

- Widest of all the azoles - Oral and IV - Good bioavailability and CSF penetration (60-80%) - Only antifungal to reach [therapeutic] in urinary tract

Question 26

Voriconazole

Answer 26

- Causes rash, elevated hepatic enzymes, and visual disturbances - Prolonged therapy: fluorosis and periostitis

Question 27

Posaconazole

Answer 27

- Co-administer with statins that DON'T prolong QT interval | - Take with high-fat meal for adequate absorption

Question 28

Isavuconazonium

Answer 28

- Good oral bioavailability | - Can shorten QT interval (preferred use)

Question 29

Terbinafine/Butenafine

Answer 29

- 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

Question 30

5-FC

Answer 30

- 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)

Question 31

5-FC Resistance

Answer 31

- Loss of permease activity - Loss of deaminase activity - Synergize with amphotericin (resistance develops quickly) - Renally eliminated

Question 32

5-FC SE

Answer 32

- Reversible bone marrow toxicity from FU metabolite - Hepatotoxicity - Monitor: hematologic, renal, and hepatic status