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Vet Derm Review > Pharmacology - Antifungals > Flashcards

Pharmacology - Antifungals Flashcards

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1
Q

Why is antifungal drug treatment often more prolonged than antibacterial treatment?

A

fungal organisms grow more slowly; drugs used (primarily azoles) are fungistatic not fungicidal

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2
Q

Mechanism of action of azole antifungals?

A

Inhibit sterol 14alpha-demethylase, a cytochrome p450-dependent fungal enzyme involved in synthesis of ergosterol (component of fungal cell wall) from lanoesterol –> result is accumulation of 14alpha-methylsterols, which disrupt the fungal cell membrane

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3
Q

Mechanism of action: echinocandins

A

disrupt function of the (1–>3)-beta-D-glucan synthase complex; inhibit the formation of beta-1,3-D-glucans in the fungal cell wall

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4
Q

What are the components of the fungal cell wall?

A

interwoven polymers of glucans, chitins, and various proteins

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5
Q

Mechanism of action: amphotericin B

A

forms aggregates in cell membrane with ergosterol, leading to pores that cause leakage of cellular contents

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6
Q

Mechanism of action: 5-flucytosine

A

disrupts RNA (via 5-fluorouridine triphosphate) and DNA (via 5-flurodeoxyuridine monophosphate) synthesis

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7
Q

T/F: All azole antifungals are teratogenic.

A

True - should be avoided in pregnancy

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8
Q

What is the difference between imidazoles or triazoles?

A

imidazoles contain 2 nitrogen molecules in their azole ring; triazoles contain 3 nitrogen molecules in their azole ring

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9
Q

What are the imidazole antifungal drugs?

A

ketoconazole, enilconazole, clotrimazole

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10
Q

Route of adminstration: enilconazole

A

topical – poor oral bioavailability

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11
Q

Route of adminstration: clotrimazole

A

topical – poor oral bioavailability

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12
Q

Route of adminstration: ketoconazole

A

both oral and topical

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13
Q

What are the triazole antifungal drugs?

A

itraconazole, fluconazole

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14
Q

Difference in metabolism between imidazoles and triazoles?

A

triazole antifungals are more slowly metabolized and have less impact on mammalian sterol synthesis than imidazoles

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15
Q

Mechanism of resistance to azole antifungals?

A

mutations in the gene encoding the demethylase enzyme, increased production of C-14alpha demethylase, and increased azole efflux by fungal cell membrane transporters

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16
Q

T/F: Resistance to one azole implies resistance to other azole antifungal drugs.

A

FALSE

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17
Q

Primary indications for ketoconazole

A

Malassezia dermatitis, feline nasal and cutaneous cryptococcosis

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18
Q

What improves oral absorption of ketoconazole?

A

administration with food

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19
Q

What inhibits oral absorption of ketoconazole?

A

antacids

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20
Q

How is ketoconazole metabolized?

A

liver (BUT moderate hepatic dysfunction does not alter blood levels of ketoconazole)

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21
Q

How is ketoconazole excreted?

A

inactive products are excreted in bile, and to a lesser extent, the urine

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22
Q

T/F: Ketoconazole is ineffective for treatment of meningeal cryptococcosis.

A

True - poor CNS penetration

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23
Q

Tissue distribution: ketoconazole

A

skin, bone, joint, lung – poor CNS penetration

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24
Q

Spectrum of activity: ketoconazole

A

dimorphic fungi, Malassezia; ineffective for aspergillosis

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25
Q

Tissue distribution: itraconazole

A

skin, bone, lung; may enter the CNS and eye with inflammation

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26
Q

Spectrum of activity: itraconazole

A

dimorphic fungi and molds, Malassezia

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27
Q

Tissue distribution: fluconazole

A

widely distributed - skin, lung, CNS, urine, eye

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28
Q

Spectrum of activity: fluconazole

A

Some Candida spp. Malassezia spp., some dimorphic fungi; Poor activity against molds. Aspergillus spp. are intrinsically resistant

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29
Q

Spectrum of activity: voriconazole

A

Dimorphic fungi, yeasts, and molds with the exception of Sporothrix schenckii and zygomycetes

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30
Q

Tissue distribution: voriconazole

A

CNS, eye, lung, bone

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31
Q

Spectrum of activity: posaconazole

A

Dimorphic fungi, yeasts, and molds INCLUDING zygomycetes

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32
Q

Tissue distribution: posaconazole

A

Widely distributed

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33
Q

Spectrum of activity: Amphotericin B

A

Broad spectrum. Also active against Leishmania

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34
Q

Tissue distribution: Amphotericin B

A

Limited penetration of CNS and eye

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35
Q

Spectrum of activity: 5-Flucytosine

A

Cryptococcus and Candida spp.

36
Q

Tissue distribution: 5-Flucytosine

A

widely distributed - including CNS, urine, eye

37
Q

Spectrum of activity: griseofulvin

A

dermatophytes

38
Q

Tissue distribution: griseofulvin

A

concentrates in the skin

39
Q

Spectrum of activity: terbinafine

A

activity highest for dermatophytes. To a lesser extent may have activity against other dimorphic and filamentous fungi

40
Q

Tissue distribution: terbinafine

A

concentrates in the skin and hair

41
Q

Spectrum of activity: capsofungin

A

Candida and Aspergillus spp. NOT active against Cryptococcus spp. OR when given alone to treat Coccidioides

42
Q

Tissue distribution: capsofungin

A

widely distributed - poor penetration of CNS and eye

43
Q

Adverse effects: ketoconazole

A

vomiting, anorexia, lethargy, diarrhea, increases of serum transaminases; hepatitis; pruritus and cutaneous erythema; lightening of hair coat color and cataract formation

44
Q

Why are drug-drug interactions common with ketoconazole?

A

potent inhibitor of mammalian cytochrome p450 enzymes and efflux transporter proteins such as P-glycoprotein; inhibits testosterone and cortisol synthesis

45
Q

What improves oral absorption of itraconazole?

A

best absorbed when given with food - because the acid secretion stimulated with feeding increases the drug solubility (necessary for dissolution and absorption)

46
Q

What is itraconazole complexed with to improve solubility?

A

cyclodextrin

47
Q

What inhibits oral absorption of itraconazole?

A

gastric acid suppressants (H2 blockers, PPI)

48
Q

What is the only triazole drug that is converted to an active metabolite? What is the metabolite?

A

itraconazole –> hydroxylitraconazole

49
Q

T/F: Advanced liver disease decreases itraconazole concentrations.

A

False - INCREASES itraconazole concentrations

50
Q

Adverse effects: itraconazole

A

vomiting and anorexia; hepatotoxicity; ulcerative skin lesions (dogs given >10 mg/kg/day)

51
Q

T/F: Both ketoconazole and itraconazole suppress adrenal and testicular function.

A

False - only ketoconazole does

52
Q

What fungi are intrinsically resistant to fluconazole?

A

Aspergillus spp. (also has poor activity against molds)

53
Q

Why does fluconazole diffuse into body fluids better than other azoles?

A

more water soluble

54
Q

How is fluconazole excreted?

A

renal excretion account for more than 90% of elimination of fluconazole

55
Q

Voriconazole is related to what other azole?

A

second-generation triazole derived from fluconazole

56
Q

Voriconazole is not active against what fungi?

A

Sporothrix spp. or zygomycetes

57
Q

What inhibits oral absorption of voriconazole?

A

food

58
Q

Adverse effects: voriconazole

A

reversible visual effects (photophobia, blurred vision), peripheral neuropathies, photosensitization

59
Q

What is the most potent inhibitor of p450 enzymes of the TRIazoles?

A

voriconazole

60
Q

Posaconazole is related to what other azole?

A

itraconazole analogue

61
Q

What azole has the broadest spectrum?

A

posaconazole – includes zygomycetes

62
Q

What improves oral absorption of posaconazole?

A

fatty food

63
Q

What inhibits oral absorption of posaconazole?

A

gastric acid suppressants (H2 blockers, PPI)

64
Q

What immunomodulatory effects does amphotericin B possess?

A

activates macrophages and enhances macrophage-killing capacity

65
Q

Route of adminstration: Amphotericin B

A

poor aqueous solubility and is not absorbed from the GI tract - formulated for IV infusion

66
Q

Adverse effects: Amphotericin B

A

nephrotoxicity**, fever, inappetance, vomiting, phlebitis at the IV infusion site

67
Q

How can nephrotoxicity with Amphotericin B be decreased?

A

loading with sodium before the infusion, slow administratioin in a large volume of fluid

68
Q

Why are lipid formulations of Amphotericin B less nephrotoxic?

A

reduced rate of transfer of AMB to mammalian cell membranes and increased drug clearance from the blood by the mononuclear phagocyte system

69
Q

Why is mammalian cell toxicity limited with 5-Flucytosine?

A

mammalian cells cannot convert flucytosine into 5-fluorouracil

70
Q

Why is 5-flucytosine given concurrently with Amphotericin B?

A

marked drug resistance can occur during treatment, flucytosine may be synergistic with AMB

71
Q

Mechanism of resistance to 5-flucytosine?

A

modifications in fungal enzymes that are required for flucytosine uptake and metabolism

72
Q

Route of adminstration: 5-flucytosine

A

oral - absorbed rapidly and well from GI tract

73
Q

How is 5-flucytosine excreted?

A

80% of the dose is excreted unchanged in the urine

74
Q

Administration of 5-flucytosine is contraindicated in what species?

A

dogs – often develop a severe drug eruption (TEN) within 2-3 weeks of starting treatment

75
Q

Adverse effects: 5-flucytosine

A

myelosuppression and GI signs

76
Q

Mechanism of action: griseofulvin

A

binds to fungal tubulin – leading to impaired microtubule function and mitotic arrest

77
Q

Is griseofulvin fungicidal or fungistatic?

A

fungistatic

78
Q

What improves oral absorption of griseofulvin?

A

fatty food or whole milk

79
Q

What effect does griseofulvin have on cytochrome p450 enzymes?

A

INDUCES cytochrome p450 enzymes – decreases efficacy of drugs that are metabolized to inactive metabolites by P450 enzymes

80
Q

Adverse effects: griseofulvin

A

drug-drug interactions (induces cytochrome p450), teratogenic, inappetance, vomiting, diarrhea; myelosuppresion in cats (esp with FIV infection)

81
Q

Mechanism of action: terbinafine

A

synthetic allylamine that inhibits fungal squalene epoxidase – blocks fungal lanosterol and ergosterol synthesis –> leads to accumulation of toxic squalene –> fungal cell lysis

82
Q

Mechanism of resistance to terbinafine?

A

altered squalene epoxidase

83
Q

What improves oral absorption of terbinafine?

A

administration with food

84
Q

Is capsofungin fungicidal or fungistatic?

A

fungicidal against Candida spp. and fungistatic against Aspergillus spp.

85
Q

Why are echinocandins ineffective against Cryptococcus?

A

because they possess little glucan synthase

86
Q

Route of adminstration: caspofungin

A

IV infusion

Vet Derm Review (44 decks)

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