Antifungal Drugs

[REVIEW] Fungal Structure

List the drug targets antifungals target

DRUG TARGETS

• bind ergosterol 

•  block ergosterol synthesis

•  inhibit β-glucan cell wall Synthesis

  • Echinocandins 

• interferes with DNA/RNA synthesis.

  • Flucytosine 

• disrupts microtubules/ Mitotic spindle

  • Griseofulvin

Describe POLYENES

• Types

• MOA

POLYENES

• Types:

  • Ampho-tericin B (systemic)

  • Ny-statin (topical)

• MOA:

  • bind ergosterol -> pores -> leakage

    • fungicidal

Describe AMPHOTERICIN B

• Clinical Usage

• Adverse Effects?

AMPHOTERICIN B

• Clinical Usage:

  • severe systemic fungal infections

  • Classic induction therapy

    • cryptococcal meningitis

  • invasive aspergillosis and mucormycosis

  • serious endemic mycoses

• ADVERSE EFFECTS

  • Infusion toxicity

    • w/ fever and Chills

  • Renal Toxicity:

  • Electrolyte loss

    • Renal injury -> hypokalemia/hypomagnesemia

  • Hematologic effect:

    • Reduced erythropoietin -> Anemia

Describe AZOLES

• MOA

• Subgroups

• Adverse Effects

AZOLES

• MOA:

  • inhibit fungal 14-alpha-demethylase -> blocks ergosterol synthesis

    • NOTE: most imp. Antifungals in practice

• SUBGROUPS

  • Imid-azoles: 

    • Often topical antifungals

      • Skin and mucosal infections

  • Tri-azoles: 

    • Common systemic azoles

      • Deeper or invasive mycoses

• Adverse Effects

  • hepatotoxicity

  • CYP inhibition 

  • QT effects 

  • GI: Nausea and intolerance

List the drug names in the drug classes: IMIDAZOLES vs. TRIAZOLES

Describe These Azoles:

• FLUCONAZOLE

  • Targets

  • Pros

• ITRACONAZOLE

  • Targets

  • Adverse Effects

• VORICONAZOLE

  • Targets

  • Adverse Effects

• BROAD-SPECTRUM TRIAZOLES

  • Types

  • Usages

FLUCONAZOLE

• Targets:

  • Candida species + Cryptococcus

    • Common use in mucosal candidiasis

• Pros:

  • Good oral bioavailability 

  • CSF penetration

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ITRACONAZOLE

Targets:

• Dimorphic fungi

• Onychomycosis

Adverse effect: 

• Negative inotrope

  • Avoid in heart Failure 

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VORICONAZOLE

• Targets:

  • invasive aspergillosis

  • Broad activity against molds 

• Adverse effects

  • Visual disturbances

  • Hepatotoxicity

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BROAD-SPECTRUM TRIAZOLES

• Types:

  • Posaconazole

  • Isavuco azole

    • Unique QT pearl

• Usage:

  • serious invasive fungal disease

  • Important in mold coverage

Describe ENCHINOCANDINS

• Types

• MOA

• Clinical Uses

• Strength/Limitations

ENCHINOCANDINS

• Types:

  • Caspo-fungin,

  • Mica-fungin,

  • Anidula-fungin

• MOA:

  • Targets Fungal cell wall

• CLINICAL USES

  • Invasive candidiasis

  • Candidemia

  • Aspergillus salvage/adjunct role

  • Often used in hospitalized patients

• STRENGTH & LIMITATION

  • Strengths:

    • well tolerated

    • Good for Candida

  • Limitations

    • Not useful for Cryptococcus

    • Poor CNS penetration

    • Poor ocular penetration

NOTE: NOTE: Major IV antifungal group

Describe FLUCYTOSINE

• MOA

• Targets

• Combo

• Adverse Effects

FLUCYTOSINE

• MOA:

  • Converts to  5-FU in fungi -> blocks DNA/RNA synthesis

• Targets:

  • Cryptococcal meningitis

• Combo:

  • Paired w/ amphotericin B

• ADVERSE EFFECTS

  • Bone marrow suppression

  • Hepatotoxicity

  • Resistance (if by itself)

Describe GRISEOFULVIN

• MOA

• Targets

• Distribution

• Adverse effects

GRISEOFULVIN

• MOA:

  • Disrupts microtubules and mitosis

• Targets:

  • Dermatophyte infections

    • Hair, skin, and nails

• Distribution:

  • Deposits in keratin precursors

• ADVERSE EFFECTS

  • Hepatotoxicity

  • Teratogenic

  • CYP interactive

  • Prolong therapy course

    • weeks-months

Describe TERBINAFINE

• MOA

• Targets

• Adverse Effects

TERBINAFINE

• MOA:

  • Inhibits squalene epoxidase -> blocks ergosterol synthesis

• Targets:

  • Dermatophytes

  • Onychomycosis 

• ADVERSE EFFECTS

  • Hepatotoxicity 

  • GI: Upset 

  • Taste Disturbance

List the TOPICAL ANTIFUNGAL AGENTS

How do fungi develop resistance

Resistance

• Altered Ergosterol Pathway

• Decrease drug uptake

• Active drug export

• Altered cell wall composition