Pharmacology of Antifungal Agents

Antifungal Drugs: Part 2

• Classification of Antifungal Drugs:
  • Inhibitors of cell membrane function
    • Polyenes (e.g., Amphotericin B, Nystatin): Affect cell membrane function.
  • Inhibitors of ergosterol synthesis
    • Azoles (Imidazoles and Triazoles).
      • Imidazoles (e.g., Clotrimazole, Miconazole, Ketoconazole)
      • Triazoles (e.g., Itraconazole, Posaconazole, Fluconazole, Voriconazole).
    • Allylamines (e.g., Terbinafine, Tolnaftate).
    • Morpholines.
  • Inhibitors of cell wall synthesis: Echinocandins (e.g., Caspofungin)
  • Inhibitors of RNA/DNA functions/mitosis inhibitors: Flucytosine, Griseofulvin.

Inhibitors of Ergosterol Synthesis

• Three enzymes in pathway:
  • Squalene epoxidase (inhibited by allylamines).
  • Lanosterol 14α-demethylase (inhibited by azoles).
  • Δ14-Reductase (inhibited by morpholines).

Mechanism of Action: Azoles (Imidazoles and Triazoles)

• Inhibition of CYP450 14α-demethylase: This enzyme is vital for ergosterol synthesis. Its inhibition leads to a lack of ergosterol, causing the fungal cell membrane to become damaged and dysfunctional.
• This results in fungal cell death.
• Reduced strength of inhibition for human cells: The drugs' ability to bind to the human equivalent enzyme is much less compared to fungal enzyme, thus minimizing effects on human cells.
• High binding affinity to Fungal enzyme: Ketoconazole demonstrates a significant increased affinity to human fungal enzyme compared to the human equivalent.

Selected Triazole Antimycotics

• Itraconazole: Structurally related to ketoconazole; more effective and better tolerated orally; broad-spectrum antifungal agent. More expensive than ketoconazole.

• Advantages over ketoconazole: Not hepatotoxic; effective against Aspergillus; longer half-life. Active hydroxy metabolite.

• Absorption issues: Requires acidic conditions for absorption; does not readily penetrate CNS and CSF.

• Drug interactions: Potent CYP3A4 inhibitor, so needs careful co-administration with other CYP3A4 substrates.

• Posaconazole: Novel itraconazole analog; designed after active 0-1 hydroxyl metabolite; mainly metabolized by phase II glucuronide conjugation; fewer drug interactions. Thus, better tolerability compared to ketoconazole or itraconazole.

• Fluconazole: Two triazole rings + hydroxy group; water-soluble; suitable for oral and IV administration. Excellent oral bioavailability; long half-life; used to treat candidiasis and cryptococcosis; penetrates CNS and CSF; highly potent drug of choice for treating cryptococcal meningitis

• Voriconazole: Fluorinated pyrimidine analog of fluconazole; broader spectrum; good oral absorption and penetration; extensive CYP450 biotransformation. Active against Aspergillus and Candida; significant drug interactions.

Inhibitors of Cell Wall Synthesis: Echinocandins

• Caspofungin: Semi-synthetic cyclic peptide; long lipophilic side chain; used in treating life-threatening infections; effective against Candida species resistant to other drugs and azole-resistant Aspergillus; not effective against Cryptococcus neoformans.
• Mode of action: Inhibits 1,3-β-glucan synthase, crucial for cell wall synthesis; no oral bioavailability.

Inhibitors of RNA/DNA Functions:

• Flucytosine: 5-fluorocytosine; inhibits RNA/DNA function thus inducing cell death; pyrimidine analog that gets misincorporated. It's orally active, and works on Candida or Cryptococcus.
• Griseofulvin: Antifungal antibiotic from Penicillium griseofulvum; incorporated in newly synthesized keratin. Mode of action involves binding to tubulin, interfering with microtubule function & inhibiting mitosis (i.e, fungistatic).

Microtubule Structure

• Microtubules are polymers of α-and β-tubulin protein heterodimers; involved in cell division, cell motility and intracellular transport.