Antifungals Flashcards
Allylamines?
What do they do?
Cidal or static?
What is their problem?
Inhibit the conversion of squalene to squalene epoxide
Step in Sterol biosynthesis
Effectively block downstream conversion of lanosterol and ergosterol–> Malfunction
Static or cidal depends on the species
Causes build up of squalene
- Membrane tension, faulty membrane
- Build up of squalene
Problem very greasy not good systemically and first pass is an issue.
Not orally available mostly topical use
Name the Allylamines?
Naftifine
Terbinafine (topical and pill)- One example of one that can be used systemically
WHat are the Non-Allylamines squalene epoxidase inhibitors?
- Butenafine - Broader spectrum
- Tolnaftate - Non-prescription preparations for decades.
- Topically used greasy
Conazoles
What do they do?
Ergosterol biosynth inhibitors
Azole group think inhbition of CYP450s
Antifungal coverage chart
What is the general trend with conazoles in terms of spectrum?
Spectrum increases as you go from:
- Fluconazole (No molds)
- Itraconazole
- Voriconazole
- Isavuconazole
- Posaconazole (Broad and best)
What are the broad spectrum conazoles?
Vori, Isavu, Posa
Amphotericin spectrum?
Broad pretty much everything.
Fungin Coverage?
- Good with yeast but variable efficacy with everything else
Difference between Human and Fungal cells
Sterol they have ergosterol instead of cholesterol
Conazole
MOA
- Block synthesis at a later step than Allylamines
- Blocking P450 resposible for oxidating Lanosterol
- This causes leakage
Conazole Resistance and Main interaction with drugs and P450?
- Target modification and efflux - This whole thing occurs much more slowly than bacteria
- Interaction with Heme of P450 and Azole nitrogen lone pair.
Coverage of conazoles
Yeast (Candida)
Mold (Asperigillus, Fusarium, Zygomycetes)
- Yeast all- Fluconazole, Itraconazole, Voriconazole, Posaconazole)
- Asperigillus- Itra, Vori, Posa
- Fusarium- Vori and Posa
- Zygo- Posa
Conazole P450 interactions
3 points to know?
Mechanism of Human P450 interactions?
- All have 3A4
- Voriconazole has the most
- Isavu and Posa have the fewest
WHat other interactions do conazoles have?
Oral bioavailability increases when?
- P-glycoprotein transporters - Mostly the biggers ones
- Increases with increase in acid (isaconazole and posaconazole)
Most conazoles?
Which one doesnt?
- Lengthen QTc
- But Isavuconazole shortens
Topical and Supository Conazoles?
- Clotrimazole
- Econazole
- Butoconazole
- Very lipophilic not good for systemic
Echinocandins MOA?
Interferes with the synthesis of the fungal cell wall
blocks 1,3-B-glucan synthase that converts UDP-glucose to B-D glucan
Ruptures the cell wall
Echinocandins resistance?
- Mutation of synthase and/or upregulation of other cell wall components.
Echinocandins
General special properties?
administration?
Metabolism and Excretion?
- The target is so unique that you dont see toxicity with these drugs
- Peptide makes it poorly bioavailable
- Target mutations are common –>relapse is common
- There are no drug interactions
INJECTION
- Slow metabolism
What are the echinocandins
Caspofungin, Anidulafungin, Micafungin
They are all very similar dont need to know specifics within class
Major coverage and uses of echinocandins (fungins)
- Narrow spectrum
- Candidal infections that are resistant to azoles
- Apergillus infections
- Less common
- Esophageal candidiasis
- Prophylactically in patients undergoing hematopoietic stem cell transplant
Amphotericin B
Solubility?
What is it?
Preparation?
Polyene macrolide no bacteria effect
Amphoteric: Acidic carboxyl nd basic primary amino functional groups
Poor water solubility
Prep using emulsifying agents and liposomes
Amphotericin B
Binding to ergosterol?
- Cation
- Greasy portions bind to each other
Amphotericin B
Spectrum?
Cidal or static?
Toxicity?
- Broad
- Both
- Very toxic
- Nephrotoxic
- Thrombophlebitis (vein clot causes inflammation)
- Fever, shaking, chills, hypotension
Liposomal targeting of Fungal cell wall?
Selectivity
Role of Liposomes
Toxicities of AmBisome?
- Mammalian have no cell wall
- Attracts to the fungal cell wall - targeting agent
- This makes the drug less nephrotoxic because there is less interaction, renal toxicity can still be seen
