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Flashcards in Antifungal Agents Deck (70):
1

MOA of Azoles

inhibit cytochrome P 450
impaired synthesis of ergosterol
impaired fungal cell membrane formation

2

MOA of polyenes

bind to ergosterol in fungal cell membrane and disrupt membrane integrity

3

MOA of Flucytosine

-is an anti-metabolite
-inhibits RNA and DNA synthesis

4

MOA of Echinocandins

inhibit synthesis of B(1,3)-D-glucan (cell wall component)

5

MOA of Griseofulvin

anti-mitotic

6

MOA of Terbinafine

-inhibit squaline epoxidase
-blocks ergosterol synthesis

7

what are the pharmacokinetics of Triazoles

-metabolized slowly
-less effect on human sterol synthesis

8

what are the Triaoles drugs

-Itraconazole
-Voriconazile
-Fluconazole
-Posaconazole

9

what are the Imidazoles

-Clotrimazole
-Miconazole
-Ketoconazole

10

MOA of Azoles

-inhibit cytochrome P 450
-impaired synthesis of ergosterol
-impaired fungal cell membrane formation

11

the selective activity of Azoles is due to what

-differences in membrane sterols:
Mammalian: Cholesterol
Fungal: Ergosterol

12

What are the adverse effects of Ketoconazole

-anorexia, nausea, vomiting, pruritus, rash, dizziness, photophobia
-reduced plasma testosterone --> gynecomastia, decreased libido and erectile dysfunction in males, menstrual irregularities in females
-inhibition of adrenal steroidogenesis, decreased cortisol, hepatic toxicity and necrosis
-teratogenecity

13

what are the drug interaction of Ketoconazole

-strong inhibitor of CYP3A4 and other enzymes
-increased serum concentrations of many other drugs
-Absorption reduced by drugs that decrease gastric acidity (antacids, PPIs, H2-receptor blockers)

14

Fluconazole is active against what

-most Candida species
-Coccidioides and Cryptococcus spp
Histoplasma capsulatum (at higher doses)

15

Fluconazole is not active against what

C. krusei
Many strains of C. glabrata
Most molds

16

what are the pharmacokinetics of Fluconazole

-lowest affinity for mammalian P450 enzymes
-good water solubility and CSF penetration

17

what are the adverse effects of Fluconazole

-headache, GI distress, facial edema, rash, pruritus
-Stevens-Johnson syndrome, anaphylaxis, hepatic toxicity , leukopenia, hypokalemia, QT prolongation, torsades de pointes reported
-Teratogenic

18

Fluconazole drug interactions

-strong inhibitor of CYP2C9 and 2C19
-moderate inhibitor of CYP3A4
-may increase serum concentrations of drugs metabolized by enzymes especially those metabolized by CYP2C9 and CYP2C19 or CYP3A4 may increase risk of QT prolongation and torsades de pointes

19

what is the spectrum of activity of Itraconazole

broader than fluconazile

20

Itraconazole is active against what

Cryptococcus neoformans
Aspergillus spp.
Coccidioides spp.
H. capsulatum
Sporothrix spp.
Dermatophytes

21

Itraconzole is not active against what

Scedosporium spp
Scopulariopsis spp.
Flusarium spp
Zygomycetes

22

what are the adverse effects of Itraconazole

-GI distress- nausea, vomiting, rash
-Stevens-Johnson syndrome, hepatic toxicity, edema, hypokalemia, hypertension, negative inotropic effects, congestive heart failure
Peripheral neuropathy, visual disturbances, hearing loss
Teratogenic

23

Itraconazole is contraindicated in what patients

patients with history of heart failure/ventricular dysfunction

24

drug interactions of Itraconazole

-strong inhibitor of CYP3A4
-increased serum levels of other drugs metabolized by this system
-absorption reduced by drugs that decrease gastric acidity (antacids, PPIs, H2 receptor blockers)

25

spectrum activity of Voriconazole

similar to itraconazole

26

Voriconazole is active against

-most species of Candida
-Blastomyces dermatitidis
-Cryptococcus neoformans
-Paracoccidioides brasiliensis
Scedosproium spp
-Aspergillus spp
-Coccidioides spp.
-H. capsulatum
-Dermatophytes
-Fusarium spp

27

Voriconazole is not active against

Zygomycetes spp
Sporothrix

28

Is Voriconazole or Amphotericin more effective for invasive aspergillosis

Voriconazole

29

what are the pharmacokinetics of Voriconazole

-serum concentrations vary - may required monitoring

30

what are the adverse effects of Voriconazole

Transient visual disturbances- blurred vision, photophobia, altered color or image perception
Rash, Stevens-Johnson syndrome, hepatic toxicity, confusion, hallucinations
Anaphylaxis
Teratogenic

31

drug interactions of Voriconazole

Metabolized by and inhibits, CYP2C19, CYP2C9, and CYP3A4 → serum levels may be influenced by drugs that affect these enzymes and serum levels of other drugs metabolized by these enzymes may be increased

32

what is the spectrum of activity of Posaconazole

-similar to Itraconazole
-activity is twice that of itraconzole

33

Posaconazole has increased activity against

Absidia spp

34

how is Posaconazole administered

oral, taken with meals

35

what are the adverse effects of Posaconazole

Headache, GI distress, rash
Hepatic toxicity, QT prolongation
Arrythmias, anaphylaxis, angioedema (rare)
Teratogenic

36

Prosaconazole drug interactions

Metabolized by UDP glucuronidation
Substrate of P-glycoprotein (permeability glycoprotein)
Strong inhibitor of CYP3A4 → increased serum levels of other drugs metabolized by this system
Used with caution with other drugs known to prolong the QT interval; contraindicated with such drugs that are metabolized by CYP3A4

37

Absorption of Posaconazole is reduced by

drugs that decrease gastric acidity (antacids, PPIs, H2-receptor blockers)

38

what is the solubility of Polyenes: Amohotericin B

-insole in water
-solubility increased by formation of complex with deoxycholate (bile salt)

39

what are the Lipid Amphotericin B products

Ampho B lipid complex - Ribbon- like sheets
Ampho B cholesteryl complex - disk-shaped colloidal dispersion
Liposomal amphotericin B - Unilamellar vesicle

40

MOA of ampotericin B

binds to ergosterol in fungal cell membrane, disrupts membrane integrity

41

selectivity of Amphotericin B is based on

-differences in membrane sterols:
Mammalian: Cholesterol
Fungal: Ergosterol

42

Spectrum of Amphotericin B

broad-spectrum fungicidal
*initial therapeutic agent, treatment continued with less toxic antigunal

43

Amphotericin B is the DOC for

life-threatening, fungal infections
-Aspergillus, cryptococcus, histoplasmosis, invasive candidiasis, blastomycosis, mucor, neuropenic fever

44

what are the pharmacokinetics of Amphotericin B

No oral bioavailability
Metabolism not understood-
Hepatic or renal impairment does not affect levels
Extensive tissue binding →
Long T1/2 (~15 days)\
Concentrates in liver & spleen

45

what are the adverse effects of Amphotericin B deoxycholate

-infusion rxns; related to cytokine release; premdedicate with acetaminophen, diphenhydramine, hydrocortisone, and meperidine
-nephrotoxicity: dose-limited toxicity; sodium loading with normal saline may provide protection
-hypokalemia, hypomagnesemia common due to a mild renal tubular acidosis
-anemia, weight loss, thrombocytopenia, mild leukopenia

46

what are the adverse effects of Amphotericin B lipid formuations

Infusion reactions least severe with liposomal amphotericin B
Nephrotoxicity less common and less severe than with amphotericin B deoxycholate
Hepatotoxicity (rare)

47

what is MOA of Flucytosine

-converted in fungal cytosol to 5-fluoruracil
-5-fluorouracil inhibits DNA and RNA synthesis

48

Flucytosine seletive activity based on

-cellular uptake by specific enzyme, cytosine pernease
-conversion to 5-fluorouracil by another specific fungal enzyme, cytosine deaminase

49

Flucytosine active against

Cryptococcus neoformans
Candida spp
Chromoblastomycosis

50

Flucytosine used in combination with

amphotericin B afor cryptococcal meningitis or systemic candidiasis

51

what are the pharmacokinetics of Flucytosine

Good oral bioavailability- administered orally
Volume of distribution equals total body water
Penetrates the blood brain barrier
Renal excretion

52

what are the adverse effects of Flucytosine

dose-related bone marrow toxicity

53

what are the Echinocandins

Caspofungin
Anidulafungin
Micafungin

54

what is the MAO of Echinocandins

inhibit synthesis of B(1,3)-D-glucan (fungal cell wall component) --> cell wall becomes permeable

55

Echinocandins selective activity based on

absence of cell wall in mammalian cells

56

Echinocandins active against

most species of Candida, Aspergiullus spa

57

what are the Pharmacokinetics of Echinocandins

No oral bioavailability
T1/2 ~ 10 hours after IV infusion
Extensively bound to albumin
Hepatic metabolism, does not significantly involve cytochrome P450 enzymes
No clinically significant drug interactions
No dose adjustment required in renal dysfunction

58

what are the adverse effects of Echinocandins

Generally well tolerated
Occasional rash, fever, nausea, vomiting, headache, hypokalemia and mild hepatic toxicity
Stevens-Johnson syndrome, exfoliative dermatitis, anaphylaxis - rare
Teratogenic

59

hat is Griseofulvin used for

-mucocutaneous infections
-fungal skin, nail, hair infections

60

what is the MAO of Griseofulvin

antimitotic-interacts with polymerized microtubules leading to disruption of the mitotic spindle

61

what is the activity of Griseofulvin

Fungistatic for various species of the dermatophytes
Microsporum, Epidermophyton, and Trichophyton

62

what are the pharmacokinetics of Griseofulvin

Blood levels quite variable
Best absorption when taken with a fatty meal
T1/2 = 24 hours
Keratophilic- binds to keratin, protects skin and nails from further infection

63

what are the adverse effects of Griseofulvin

Generally well tolerated- incidence of adverse effects is very low
Headache, nausea, vomiting
Teratogenic

64

Griseofulvin interactions

induces hepatic cytochrome P450 isoforms

65

what is Terbinafine used for

mucococutaneous infections

66

what is the MAO of Terbinafine

inhibit squaline epoxidase
-blocks ergosterol synthesis
-impaired fungal cell membrane synthesis
FUNGICIDAL

67

selective activity of Terbinafine is due to

1000 to 10,000 times higher binding affinity for the fungal enzyme

68

what are the pharmacokinetics of Terbinafine

Well absorbed but significant first pass metabolism to inactive metabolites
Highly lipophilic
Accumulates in skin and nails
T1/2 = 200 to 400 hours at steady state
Keratophilic

69

what are the adverse effects of Terbinafine

Well tolerated- incidence of adverse effects is very low
Nausea, diarrhea, headache, rash
Hepatotoxicity, neutropenia, Stevens-Johnson syndrome (rare)
Teratogenic

70

Drug Interactions of Terbinafine

none
does not affect cytochrome P450 isoforms