Antifungals

Question 1

Allylamines?
What do they do?

Cidal or static?

What is their problem?

Answer 1

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

1. Membrane tension, faulty membrane
2. Build up of squalene

Problem very greasy not good systemically and first pass is an issue.

Not orally available mostly topical use

Question 2

Name the Allylamines?

Answer 2

Naftifine

Terbinafine (topical and pill)- One example of one that can be used systemically

Question 3

WHat are the Non-Allylamines squalene epoxidase inhibitors?

Answer 3

• Butenafine - Broader spectrum
• Tolnaftate - Non-prescription preparations for decades.
• Topically used greasy

Question 4

Conazoles

What do they do?

Answer 4

Ergosterol biosynth inhibitors

Azole group think inhbition of CYP450s

Question 5

Antifungal coverage chart

Answer 5

Question 6

What is the general trend with conazoles in terms of spectrum?

Answer 6

Spectrum increases as you go from:

• Fluconazole (No molds)
• Itraconazole
• Voriconazole
• Isavuconazole
• Posaconazole (Broad and best)

Question 7

What are the broad spectrum conazoles?

Answer 7

Vori, Isavu, Posa

Question 8

Amphotericin spectrum?

Answer 8

Broad pretty much everything.

Question 9

Fungin Coverage?

Answer 9

• Good with yeast but variable efficacy with everything else

Question 10

Difference between Human and Fungal cells

Answer 10

Sterol they have ergosterol instead of cholesterol

Question 11

Conazole

MOA

Answer 11

• Block synthesis at a later step than Allylamines
• Blocking P450 resposible for oxidating Lanosterol
• This causes leakage

Question 12

Conazole Resistance and Main interaction with drugs and P450?

Answer 12

• Target modification and efflux - This whole thing occurs much more slowly than bacteria
• Interaction with Heme of P450 and Azole nitrogen lone pair.

Question 13

Coverage of conazoles

Yeast (Candida)

Mold (Asperigillus, Fusarium, Zygomycetes)

Answer 13

• Yeast all- Fluconazole, Itraconazole, Voriconazole, Posaconazole)
• Asperigillus- Itra, Vori, Posa
• Fusarium- Vori and Posa
• Zygo- Posa

Question 14

Conazole P450 interactions

3 points to know?

Mechanism of Human P450 interactions?

Answer 14

• All have 3A4
• Voriconazole has the most
• Isavu and Posa have the fewest

Question 15

WHat other interactions do conazoles have?

Oral bioavailability increases when?

Answer 15

• P-glycoprotein transporters - Mostly the biggers ones
• Increases with increase in acid (isaconazole and posaconazole)

Question 16

Most conazoles?

Which one doesnt?

Answer 16

• Lengthen QTc
• But Isavuconazole shortens

Question 17

Topical and Supository Conazoles?

Answer 17

• Clotrimazole
• Econazole
• Butoconazole
• Very lipophilic not good for systemic

Question 18

Echinocandins MOA?

Answer 18

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

Question 19

Echinocandins resistance?

Answer 19

• Mutation of synthase and/or upregulation of other cell wall components.

Question 20

Echinocandins

General special properties?

administration?

Metabolism and Excretion?

Answer 20

• 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

Question 21

What are the echinocandins

Answer 21

Caspofungin, Anidulafungin, Micafungin

They are all very similar dont need to know specifics within class

Question 22

Major coverage and uses of echinocandins (fungins)

Answer 22

• Narrow spectrum
• Candidal infections that are resistant to azoles
• Apergillus infections
• Less common
  
  • Esophageal candidiasis
  • Prophylactically in patients undergoing hematopoietic stem cell transplant

Question 23

Amphotericin B

Solubility?

What is it?

Preparation?

Answer 23

Polyene macrolide no bacteria effect

Amphoteric: Acidic carboxyl nd basic primary amino functional groups

Poor water solubility

Prep using emulsifying agents and liposomes

Question 24

Amphotericin B

Binding to ergosterol?

Answer 24

• Cation
• Greasy portions bind to each other

Question 25

Amphotericin B Spectrum? Cidal or static? Toxicity?

Answer 25

* Broad * Both * Very toxic * Nephrotoxic * Thrombophlebitis (vein clot causes inflammation) * Fever, shaking, chills, hypotension

Question 26

Liposomal targeting of Fungal cell wall? Selectivity Role of Liposomes Toxicities of AmBisome?

Answer 26

* 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