MOA of Antifungals

Question 1

What is the method by which most anti-fungal drugs work?

- what are the two outliers and what do they do?

Answer 1

• They produce alterations in the fungal membrane

Griseofulvin
- Mitotic Spindle Inhibitor

Flucytosine
- Antimetabolite (acts identical to 5 fluorouracile)

Question 2

What drugs are prescribed for the majority of fugal infections? - when is they only time you would use Flucytosine?

Answer 2

Majority:

• Amphotericin B
• Azoles

Flucytosine is only indicated in Cryptococcal Infections

Question 3

Why does Amphotericin B cause renal toxicity?

Answer 3

• It acts on Ergosterols, which are similar to human sterols
• Because it binds some human sterols it can create pores in human cells too
• Exhibits most toxicity in the Kidney

Question 4

What is the only administration method for Amphotericin B?

- what form is this drug put into to decrease toxicity

Answer 4

IV, putting it into micelles reduces toxicity

• Other forms (spheres, disks, and ribbons) have been formed but are way more expensive and only allowed for limited improvement

Question 5

What are patients treated with amphotericin B given prior to treatment to reduce adverse drug effects?

Answer 5

• Antipyretics
• Antihistamines
• Meperidine
• Corticosteroids

Question 6

Why is anemia a long term side effect of amphotericin use?

Answer 6

Anemia is secondary to renal damage.

Kidneys produce ERYTHROPOIETIN that is needed to stimulate blood cell formation.

Question 7

Azole use may result in a pro-arrthmogenic effect. Which have been indicated to produce this effect?

Answer 7

Fluconzazole, Posaconazole, and Voriconazole

Question 8

T or F: no azole should be given during pregnancy if at all possible

Answer 8

True, Voriconazole and Fuconazole should especially be avoided

Question 9

What unique affect sets ketoconazoles apart from the other azoles?

Answer 9

• Potential to cause Adrenal Insufficiency by causing adrenals to decrease corticosteriod production

Question 10

What are some important Drug-Drug interactions of Voriconazole?

Answer 10

Cyclosporine and Tacrolimus **This is due to its inhibitory effect on CYP3A4

Question 11

If a patient has fungal meningitis which drugs would you most need to use?

Answer 11

Fluconazole Voriconazole

**Both can access the CSF

Question 12

What is the best azole drug that has been made thus far, and what are the 3 reasons for this?

Answer 12

Fluconazole

1. Penetrates into CSF
2. Good oral Bioavailability
3. Large Therapeutic Window

Question 13

A patient has mucomycosis, what drug to you use to treat it?

Answer 13

Posaconazole - its the only drug with activity against this fungus

Question 14

T or F: like Flucazole, Flucytosine has a broad therapeutic window.

Answer 14

False, Flucytosine has a very narrow therapeutic window

Question 15

Which antifungals are associated with infusion reactions?

Answer 15

Amphotericin B

Echinocandins

Question 16

Antifungals associated with Bone Marrow Supression?

Answer 16

5-Flurocytosine (specifically agranulocytosis) 
Amphotericin B (decreased erythropoetin production)

Question 17

Antifungals associated with Cutaneous photosensitivity and malignancy?

Answer 17

Voriconazole

Question 18

Antifungals associated with Photopsia?

Answer 18

Voriconazole

Question 19

Antifungals associated with CNS issues?

Answer 19

Voriconazole

Question 20

Antifungals associated with Renal Toxicity?

Answer 20

Amphotericin B

Question 21

Antifungals associated with hepatic dysfunction?

Answer 21

All Azoles
Amphotericin B
5-flurocytosine
Echinocandins

Question 22

Antifungals associated with Cardiac problems?

Answer 22

Azoles, especially in the presence of other drugs

Question 23

Antifungals associated with GI issues?

Answer 23

Itraconazole
Posaconazole
5-flurocytosine

Question 24

What are some side effects that characterize infusion reactions?

Answer 24

Chills, Fever, Flushing, Headache

Question 25

Why do azoles cause drug-drug interactions?

Answer 25

They are metabolized by CYP3A4 which is a p450 that deals with a lot of different drugs

Question 26

Why does 5-flurocytosine have such unique side effects? - what is the cause of this?

Answer 26

5-flurocytosine is metabolized to 5-flurouricil in Fungi after it is pumped in.

• Humans don’t have the enzyme that converts 5-flurocytosine to 5-flurouricil, but our bacteria do
• In GI bacteria convert it so 5-flurouricil (a chemo drug)
• Because of this we see chemotherapeutic effects of the drug, such as bone marrow suppression, and GI perturbation

Question 27

By what mechanism does resistance to Nystatin and Amphotericin arise?

Answer 27

Sterol Modification

Question 28

By what mechanism does resistance to Caspofugin and micafungin arise?

Answer 28

Altered Glucan Synthase

Question 29

By what mechanism does Flucytosine resistance arise?

Answer 29

Modifying Permease or Thymidine Synthase

Question 30

What mechanism leads to resistance to Ketoconazole, Flutoconazole, and Itraconazole?

Answer 30

• Efflux
• Demthylase Alteration-
  Bypass-
  overproduction

Question 31

What drug has replaced Griseofulvin in treatment of Dermatophytosis?

Answer 31

Terbinafine

Question 32

Why does Amphotericin cause cardiac dysfunction?

Answer 32

K+ doesn’t get reabsorbed in the kidney and the heart relies a lot on K+ to contract properly

Question 33

Why are antihistamines and/or hydrocortisone often given before administration of antifungals? - which antifungals is this usually necessary for?

Answer 33

To Reduce the effects of Infusion reactions associated with Amphotericin B and Eichocandins

Question 34

What antimicrobial is notorius for giving people Red Man Syndrome?

Answer 34

Vancomycin