Antifungal Agents

Question 1

Amphotericin B: mechanism of action

Answer 1

• binds ergosterol in fungal cell membrane
• forms pores–> cell content leakage
• fungicidal

Question 2

Amphotericin B: pharmacokinetics

Answer 2

• IV/topical

- renal excretion

Question 3

Amphotericin B: clinical uses

Answer 3

• broad spectrum, including opportunistic and systemic

- drug of choice in all life-threatening fungal infections

Question 4

Amphotericin B: adverse reactions

Answer 4

• very toxic <–less selective toxicity b/c binds to cholesterol components in mammals
• nephrotoxicity
• infusion-related toxicity=chills, fever, vomiting, rigor, hypotension
• anemia

Question 5

Nyastatin: mechanism of action

Answer 5

-binds ergosterol in fungal cells

Question 6

Nyastatin: pharmacokinetics

Answer 6

• topical only

- no absorption from GI

Question 7

Nyastatin: clinical uses

Answer 7

-topical treatment of Candidal infections of skin, mucous, membranes

Question 8

Nyastatin: adverse reactions

Answer 8

-mild GI upset

Question 9

Types of Echinocandins

Answer 9

1. Capsofungin 2. Micafungin

Question 10

Capsofungin: mechanism of action

Answer 10

• inhibits synthesis of Beta (1,3)-D-glucan (=component of fungal cell walls)
• disrupts cell wall assembly
• high selective toxicity

Question 11

Capsofungin: pharmacokinetics

Answer 11

• IV
• hepatic metabolism
• dosage reduction w/hepatic insufficiency
• dosage increase w/co-tx w/CYP450 inducers

Question 12

Capsofungin: clinical uses

Answer 12

-invasive aspergillosis in pts intolerant to other therapies

Question 13

Capsofungin: adverse reactions

Answer 13

• histamine-mediated possible

- fever, nausea/vomiting, headache, phlebitis

Question 14

Types of Triazoles

Answer 14

• Fluconazole
• Itraconazole
• Terconazole (topical only)

Question 15

Triazoles: mechanism of action

Answer 15

• highly selective inhibitor of fungal cytochrome P450 (14alpha-demethylase)
• reduces normal sterol synthesis
• fungistatic

Question 16

Triazoles: pharmacokinetics

Answer 16

• oral
• can enter CNS
• renal excretion
• long half-life=daily dosing

Question 17

Triazoles: clinical uses

Answer 17

• fluconazole: vaginal candidiasis, oropharyngeal and esophageal candidiasis
• itraconazole: aspergillosis, histoplasmosis, sporotrichosis
• viraconazole: invasive aspergillosis

Question 18

Triazoles: adverse reactions

Answer 18

• overall well tolerated
• GI distress
• some drug interactions similar to imidazoles

Question 19

Types of Imidazoles

Answer 19

• ketoconazole (systemically and topically)
• clotrimazole (topical only)
• miconazole (topical only)

Question 20

Imidazoles: mechanism of action

Answer 20

• inhibits P450 enzyme (14alpha-demethylase) -_> decreased levels of ergosterol
• disruption of membrane synthesis –> altered membrane permeability
• fungicidal

Question 21

Imidazoles: pharmacokinetics

Answer 21

• ketconazole=oral and IV
• clotri/micon=topical only
• hepatic metabolism
• excreted in breast milk

Question 22

Imidazoles: clinical uses

Answer 22

• keto: chronic mucocuatneous candidiasis and systemic fungal infections
• oral and vaginal cadidiasis (mico/clotri)

Question 23

Imidazoles: adverse reactions

Answer 23

• ketoconazole systemically:
• nausea, vomiting, anorexia. hepatotoxicity.
• avoid in pregnancy
• can inhibit mammalian testosterone synthesis
• ketoconazole=strong inhibitor of CYP3A4 drug metabolism
• rifampin decreases ketocon effect by inducing metabolism

Question 24

Terbinafine: mechanism of action

Answer 24

• ihibits squalene oxidase –> interferes w/ergosterol synthesis
• fungicidal

Question 25

Terbinafine: pharmacokinetics

Answer 25

-oral and topical

Question 26

Terbinafine: clinical uses

Answer 26

- oral=toe/finger nail infections | - topical=athletes foot

Question 27

Terbinafine: adverse reactions

Answer 27

- GI upset | - interferes w/CYP450 metabolism

Question 28

Flucytosine: mechanism of action

Answer 28

- converted in fungal cell to 5-fluorouracil --> interferes w/DNA synthesis - high selective toxicity - fungicidal

Question 29

Flucytosine: pharmacokinetics

Answer 29

- oral | - renal excretion

Question 30

Flucytosine: clinical uses

Answer 30

- effective, but rarely given alone; usually Ampho B + Flucytosine - serious infections of cryptococcosis, candidiasis, chromoblastomycosis

Question 31

Flucytosine: adverse reactions

Answer 31

- nausea, vomiting, skin rashes | - prolonged tx=bone marrow depression, abnormal liver fxn, hair loss

Question 32

Griseofulvin: mechanism of action

Answer 32

- binds microtubules --> inhibits fungal mitosis and processing of cell wall components - fungistatic

Question 33

Griseofulvin: pharmacokinetics

Answer 33

- oral | - fecal excretion

Question 34

Griseofulvin: clinical uses

Answer 34

- severe dermatophytosis @ skin, hair, or nails | - infrequently used, often replaced by shorter course therapy

Question 35

Griseofulvin: adverse reactions

Answer 35

- hypersenstivity | - headache, GI distress

Question 36

Pentamidine: mechanism of action

Answer 36

-inhibits protein/nucleic acid synthesis

Question 37

Pentamidine: pharmacokinetics

Answer 37

- IV/IM | - inhalation for fungal pneumonia

Question 38

Pentamidine: clinical uses

Answer 38

- effective against wide variety of protozoa | - treats P. jirovici (carinii) pneumonia in AIDS patients

Question 39

Pentamidine: adverse reactions

Answer 39

- leukopenia, hypoglycemia, hypotension | - nephro/hepatotoxicity