Antifungal main drug classes (4)
Give examples and some properties
1) Polyenes (plasma m)
- amphotericin B (systemic); nystatin, natamycin (topical) - very toxic
- extremely effective; fungicidal
2) Azoles (plasma m)
- low toxicity
- almost as effective as amphotericin B, but fungistatic
- e.g. ketoconazole, itraconazole
Polyenes
class of antifungals that disrupt cell membrane integrity. Bind to ergosterol e.g. amphotericin and nystatin; also natamycin (topical).
Azoles
class of antifungal cell membrane synthesis inhibitors. Target ergosterol synthesis via 14-aemethylase
Echinocandins
Inhibits fungal cell wall production by inhibiting beta-glucan synthesis. Less toxic but not widely used in vet med.
Effective against Candida (cidal) and Aspergillus (static)
Not effective against zygomycetes or Cryptococcus
Terbinafine
Inhibits ergosterol synthesis. Use: dermatophytes.
Amphotericin B
Antifungal: polyene drug of choice for most systemic mycoses; binds to ergosterol to disrupt fungal cell membrane permeability. Tox: chills and fever, hypokalemia, hypotension, nephrotoxicity (dose?limiting, possibly less with liposomal forms)
Amphotericin B mechanism
Binds ergosterol in fungal membrane->inserts itself into membrane->forms pores->lyses fungal cell (fungicidal)
Spectrum for Amphotericin B
Broad (greater than the azoles)
- many serious systemic mycotic infections, e.g. Candida, Cryptococcus, Coccidioides, Histoplasma, Blastomyces, Aspergillus, etc.
ketoconazole
Antifungal azole prototype: active systemically; inhibits the synthesis of ergosterol. Used for C albicans, dermatophytes and for non?life?threatening systemic mycoses. Tox: hepatic dysfunction, inhibits steroid synthesis and P450?dependent drug metabolis
hyperadrenocorticism - what is it? Treatment?
Cushings Disease. May be due to: Tumor of the adrenal gland (primary); tumor of the pituitary gland (secondary); Iatrogenic.
Treatment: ketoconazole
Drawbacks of Triazoles
usually fungistatis (although at high label doses itraconazole may be fungicidal
4 main targets for antifungal drugs
1. Nucleic acid synthesis
- flucytosine
2. Cell wall
Misc drugs (nikkomycins, echinocandins)
3. Plasma membrane
Most systemic drugs (polyenes, azoles)
4. Protein synthesis
What triazoles regularly enter the CNS?
Fluconazole
Eliminations of triazoles
mainly hepatic except fluconazole (renal)
Treatment of systemic mycosis - yeast
1. Topical azole or polyene if lesions are accessible
2. Systemic azole or polyene +/- other if life threatening
3. Less life threatening but systemic - use an azole
Aspergillis fumigatus - treatment
1. Prevent using management
2. Topical azole or polyene if lesions are accessible (e.g. clotrimazole or enilconazole)
3. Polyene or azole +/- other if systemic
Blastomyces dermatitidis treatment
1. Identify early before it can go to the brain
2. Amphotericin B + azole with prolonged treatment
3. Combine with anti-inflammatory therapy for fungal pneumonia
(lungs - killing them with a significant number of fungal cells can cause sudden death due to
What does Griseofulvin work against?
Inhibits mitosis in virtually all dermatophytes but only dermatogphytes (tinea, or ringworm)
How is Griseofulvin used?
Orally, especially in dogs because to cats they can have bone marrow depression.
What antifungals are teratogenic?
of or relating to substances or agents that can interfere with normal embryonic development
(e.g. griseofluvin, azoles/triazoles)
Terbinafine - mechanism
Inhibits ergosterol synthesis in virtually all dermatophytes (and several other fungi - but not used in systemic mycoses)
Flucytosine - what is it? How does it work?
A fluorinated pyrimidine
Susceptible fungi metabolize to 5- fluorouracil (5-FU), which is incorporated into messenger RNA-> inhibits protein synthesis; 5-FU is further metabolized to a compound that inhibits DNA synthesis; fungicidal
(mammalian cells do n
pyrimidine
a heterocyclic organic compound with a penetrating odour
Tolnaftate -
effective against dermatophytes
- over the counter
- good for basic accessible locations
What makes fungal plasma membrane different from others?
Plasma membrane contains ergosterol instead of cholesterol
4 main targets for antifungal drugs and examples
1. Cell wall synthesis - Nikkomycins, echinocandins
2. Plasma membrane - polyenes, azoles
3. DNA synthesis - Flucytosine
4. Protein synthesis - Flucytosine