Pharmacology - Antifungal Agents

Question 1

Why is it difficult to develop antifungal drugs?

Answer 1

Fungi and humans are both eukaryotes

Question 2

What is the important fungal steroid for plasma membranes? What does eliminating it do?

Answer 2

Ergosterol - fungal version of cholesterol

Elimination compromises fungal membrane integrity –> fungal cell death

Question 3

What do imidazole and triazole work on?

Answer 3

14a-sterol demethylase
Inhibit lanosterol to ergosterol
Inhibit synthesis of ergosterol

Question 4

What does echinocandins act on and what is its effect?

Answer 4

β-(1,3)-D-glucan synthase - inhibits cell wall synthesis

Question 5

How is flucytosine taken up?

Answer 5

Taken up my cysteine specific permeases expressed only in fungal membrane

Question 6

What does flucytosine act on?

Answer 6

Cystosine deaminase converts flucytosine to 5-FU

5-FU –> 5-FdUMP - inhibitor of thymidylate synthase (DNA synthesis and cell division)

Question 7

What three agents is flucytosine used against?

Answer 7

Candidiasis
Cryptococcosis
Chromomycosis

Question 8

What is the mechanism of griseofulvin?

Answer 8

Inhibits fungal mitosis by binding to tubulin & microtubule-associated proteins → disrupts assembly of mitotic spindles

Question 9

What is the mechanism of squalene epoxidase?

Answer 9

Converts squalene to lanosterol → 1st key step of ergosterol synthesis

Question 10

What three agents inhibit squalene epoxidase?

Answer 10

Terbinafine
Naftifine
Butenafine

Question 11

Who is terbinafine contraindicated in?

Answer 11

Renal failure
Hepatic failure
Pregnancy

Question 12

What enzyme do the -azoles work on?

Answer 12

14α-sterol demethylase → cytochrome P450 enzyme that converts lanosterol to ergosterol

Question 13

Why is ketoconazole limited in use?

Answer 13

GI absorption issue
Adverse effects on metabolism of other drugs
Decreases steroid hormone synthesis

Question 14

What has ketoconazole been replaced with?

Answer 14

Itraconazole

Question 15

What are the two indications for topical ketoconazole?

Answer 15

Common dermatophyte infections

Seborrheic dermatitis

Question 16

Why is fluconazole is the drug of choice for cryptococcal meningitis?

Answer 16

100% bioavailability
Absorption not influenced by gastric pH
Diffuses freely in CSF
Low adverse effects

Question 17

What is the mechanism of action of polyene?

Answer 17

Binds to ergosterol ad produces channels/pores that allow leakage of essential cellular contents out of the cell → leads to cell death

Question 18

What is the prototypic member of the polyene group and why is it selectively toxic?

Answer 18

Amphotericin B

Selective toxicity → affinity of amphotericin B for ergosterol is 500 times greater than its affinity for cholesterol

Question 19

What is the immediate reaction to amphotericin B?

What are the four symptoms?

Answer 19

Cytokine storm → elicits release of TNF-α & IL-1

Symptoms → fever, chills, rigors, & hypotension

Question 20

What are the three agents in the echnocandin class?

Answer 20

Caspofungin
Micafungin
Anidulafungin