Anti-Fungal Pharmacology

Question 1

Amphotericin - Mechanism

Answer 1

Binds to ergosterol in fungal cell membranes, creating pores that result in cell lysis; fungicidal

Low selective toxicity - binds to cholesterol in mammalian cells

Question 2

Amphotericin - Pharmacokinetics

Answer 2

Topical
IV
Intrathecal

Question 3

Amphotericin - Toxicity

Answer 3

Nephrotoxocity - major limiting factor; occurs in nearly all patients but can be attenuated by pre-treatment with saline

Infusion-related toxicity: chills, fever, vomiting, hypotension; pre-medicate with acetaminophen / diphenhydramine, or administer concurrently with hydrocortisone

Question 4

Nystatin - Clinical Use

Answer 4

Topical treatment of candida infections of skin, mucous membrane, and GI tract

Question 5

Amphotericin B - Clinical Use

Answer 5

Broad spectrum treatment for life-threatening systemic fungal infections:

Candidiasis
Cocciodiodomycosis
Histoplasmosis
Cryptococcicosis 
Blastomycosis 
Aspergillosis 
Mucormycosis

Question 6

Triazoles - Agents

Answer 6

Itraconazole
Fluconazole
Voriconazole

Question 7

Imidazole - Agents

Answer 7

Ketoconazole

Question 8

Azole drugs - Mechanism

Answer 8

Inhibit 14-alpha-demethylase which synthesizes ergosterol from lanosterol

Selective toxicity due to the requirement for fungi to synthesize sterol (ergosterol) vs. obstaining it from dietary sources

Fungistatic / fungicidal depending on concentration

Question 9

Which -azole reaches therapeutic concentrations in the CSF?

Answer 9

Fluconazole

Used for treatment of cryptococcal meningitis in conjunction with amphotericin B

Question 10

Which -azoles are renally eliminated?

Answer 10

Fluconazole

Question 11

Which -azoles are hepatically eliminated?

Answer 11

Voriconazole

Itraconazole

Question 12

-Azole drugs - General toxicities

Answer 12

GI upset
Hypersensitivity
Hepatototoxicity (Voriconazole, Itraconazole) 
Teratogenic 
DDIs due to CYP inhibition

Question 13

Ketoconazole - Toxicity

Answer 13

Reversible endocrine abnormalities due to inhibition of steroid biosynthesis:

Feminization, gynecomastia, decreased libido, menstrual irregularity

HTN / fluid retention due to increased synthesis of 11-deoxy-cortisol (mineralocorticoid)

Question 14

-Azole drugs - Spectrum of use

Answer 14

Oral / esophageal candidiasis (Fluconazole)

Cryptococcal meningitis (Fluconazole)

Local Blastomycosis, Coccidiodomycosis, Histoplasmosis (Itraconazole)

Topical fungal infections (Clotrimazole, Miconazole)

Question 15

Echinocandins - Mechanism

Answer 15

Inhibits FKS1 enzyme, which prevents the synthesis of B-(1,3)-D-glucan, an essential component of fungal cell walls

Question 16

Echinocandins - Pharmacokinetics

Answer 16

IV administration only

Extensive plasma-protein binding; does not reach CSF

Question 17

Echinocandins - Agents

Answer 17

Capsofungin
Micafungin
Anidulafungin

Question 18

Echinocandins - When is dosage reduction required?

Answer 18

Capsofungin - hepatic impairment only

Micafungin and Anidulafungin - renal and hepatic impairment

Question 19

Echinocandins - Toxicity

Answer 19

Hisamine-mediated sx: rash, swelling, pruritis
Fever
Nausea / vomiting
Headache

Contraindicated in pregnancy

Question 20

Echinocandins - Uses

Answer 20

Deep invasive candidiasis

Second-line treatment of invasive aspergillosis (following Amphotericin B, Itraconazole)

Question 21

Flucytosine - Mechanism

Answer 21

Converted to 5-FU by fungal cytosine deaminase; inhibits thymidylate synthetase and blocks DNA synthesis

Selective toxicity due to the fact that humans have no / low cytosine deaminase activity

Question 22

Flucytosine - Pharmacokinetics

Answer 22

Good oral absorption with excellent distribution to tissues including CNS

Renal elimination - requires renal dosing

Question 23

Flucytosine - Toxicity

Answer 23

Reversible hepatotoxicity
Nausea / vomiting
Skin rash

At prolonged, high levels: bone marrow depression, hepatotoxicity, hair loss

Question 24

Flucytosine - Uses

Answer 24

Used in combination with Amphotericin for treatment of cryptococcal meningitis

Question 25

Terbinafine - Mechanism

Answer 25

Interferes with ergosterol synthesis by inhibiting squalene oxidase; fungicidal

Question 26

Terbinafine - Pharmacokinetics

Answer 26

Oral administration with therapeutic accumulation in keratin-based tissue (skin and nails)

Hepatic elimination

Question 27

Terbinafine - Toxicity

Answer 27

GI upset
Rash
Headache
Taste disturbances

Contraindicated in pregnancy

Question 28

Terbinafine - Uses

Answer 28

Systemic treatment of superficial skin, hair, and nail mycoses

Available topically for athlete’s foot, tinea cruris, and tinea corporis

Question 29

Griseofulvin - Mechanism

Answer 29

Binds to tubulin in microtubules inhibiting mitosis

Question 30

Griseofulvin - Pharmacokinetics

Answer 30

Poor oral absorption but improved by administration with fatty foods

Therapeutic accumulation in keratinized tissues

Excreted in feces

Question 31

Griseofulvin - Uses

Answer 31

Systemic treatment of superficial and severe mycoses of skin and nails; inhibits growth of dermatophytes

Question 32

Griseofulvin - Toxicity

Answer 32

GI upset
Reversible leukopenia
Headache

Question 33

Topical azoles

Answer 33

Clotrimazole (Lotrimin)

Miconazole (Monistat)

Question 34

Systemic treatment of dermatophytes

Answer 34

Terbinafine

Griseofulvin