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PHRM 840 > Pharmacology of Antifungals > Flashcards

Pharmacology of Antifungals Flashcards

1
Q

Properties of cells in humans

A
  1. ribosomes 60S/40S
  2. no cell wall
  3. dietary folate
  4. differences in DNA gyrase/topoisomerase
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2
Q

Humans and fungi are what cells?

A

eukaryotic

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3
Q

Antifungal agents two basic targets?

A
  1. action on cell wall

2. block nucleic acid aynthesis

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4
Q

Which group of drops target action on cell wall? 4

A
  1. Azoles
  2. Allylamine
  3. polyenes
  4. echinocandin
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5
Q

Which group of drugs block nucleic acid synthesis?

A

pyrimidine analog

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6
Q

Azoles can be broken down into?

A

Imidazoles and triazoles

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7
Q

Imidazoles (3)

A
  1. Ketoconazole
  2. Clotrimazole
  3. Miconazole
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8
Q

Triazole (2)

A
  1. Fluconazole
  2. Posaconazole
  3. Voriconazole
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9
Q

Itraconazole

A

Sporanox

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10
Q

Fluconazole

A

Diflucan

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11
Q

Voriconazole

A

Vfend

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12
Q

Posaconazol

A

Noxafil

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13
Q

Isavuconazonium - Isavuconazole

A

Cresemba

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14
Q

Allylamines

A

Terbinafine

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15
Q

Polyenes

A

amphotericin B

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16
Q

Amphotericin B desoxycholate

A

Fungisone IV

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17
Q

Liposomal AmpB

A

AmBisome

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18
Q

Lipid complex AmpB

A

Abelcet

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19
Q

Echinocandin (3)

A
  1. Anidulafungin
  2. Caspofungin
  3. Micafungin
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20
Q

Caspofungin

A

Cancidas

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21
Q

Anidulafungin

A

Eraxis

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22
Q

Micafungin

A

Mycamine

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23
Q

Localized manifestations of fungal infections are not life

threatening and usually do not disseminate in

A

immunocompetent hosts

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24
Q

Fungi can become opportunistic, systemic pathogens in

A

normal hosts with parenteral administration

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25
Q

Opportunistic, systemic fungal infections also occur in patients
with

A

underlying medical problems or immunosuppression

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26
Q

What inhibits the enzyme that synthesizes beta-glucans called the penicillin of antifungasl?

A

enchinocandins

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27
Q

What binds ergosterol, weaken the membrane, cause pore formation, leakage of k+ and Na+, fungal cell death

A

polyenes

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28
Q

What inhibits the enzyme that synthesizes ergosterol?

A

azoles

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29
Q

What is converted to 5-FU to inhibit DNA synthesis as a pyrimidine analog

A

5-flucytosine

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30
Q

Pregnancy category for polyenes

A

category B

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31
Q

Pregnancy category for echinocandins

A

category c

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32
Q

Pregnancy category for azoles

A

category D

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33
Q

What antifungals are recommended to be avoided during the. first trimester of pregnancy?

A

azoles

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34
Q

Formulations of enchinocandins?

A

IV only slow infusion

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35
Q

Metabolism of enchinocandins

A

slow metabolism by hydrolysis/N-acetylation

36
Q

Excretion of echinocandins

A

primarily in urine

37
Q

Enchinocandins in order of increasing half life

A

Caspofungin, Micafungin, Anidulafungi

38
Q

SE of enchinocandins

A 
Histamine-mediated symptoms 
Hepatic toxicity (Monitoring: LFTs)
39
Q

Dose adjustment is required for enchinocandins in renal impairment pts

A

False, no dose adjustment needed

40
Q

Does echinocandins have CSF penetration?

A

no, do not use for meningitis

41
Q

Mutations in FKS1 or FKS2 (Candida glabrata) gene
which encode glucan synthase
(increased or decreased) sensitivity to echinocandins

A

decreased

42
Q

Mechanisms of resistance to echinocandins (3)

A
  1. Upregulation of multidrug transporters
  2. Biofilms
  3. Increased chitin synthase gene expression (chitin also a fungal cell wall component)
43
Q

Amphotericin B is selective for

A

fungal erosterol

44
Q

main sterol of mammalian cell membranes

A

cholesterol

45
Q

What Induces ROS in fungal cell - accumulation of free radicals

A

Amphotericin B

46
Q

Is there a dose adjustment needed for amphotericin B for renal impairment?

A

no dose adjustment needed

47
Q

Does amphotericin B have CSF penetration?

A

No, poor CSF penetration

48
Q

What bind ergosterol in the fungal membrane and cause leakage of intracellular contents?

A

polyenes

49
Q

What formulations of amphotericin B reduce toxicity?

A

lipid formulations

50
Q

Dosage forms for amphotericin B

A

IV and oral

51
Q

When to use IV formulatinn of amphotericin B

A

life threatening systemic

infections

52
Q

When to use oral formulation of amphotericin B

A

for GI infections

53
Q

Adverse effects of amp-B

A

rapid toxicity and delayed toxicity

54
Q

Rapid toxicity w/ non-lipid formulations

A

nfusion-related fever, chills, malaise,
rigors (pre-medication -NSAIDs,
diphenhydramine, acetaminophen,
meperidine, hydrocortisone)

55
Q

Delayed toxicity:

A

Nephrotoxicity (may
add to nephrotoxicity of other drugs)
(dose adjustment for conventional form
only)

56
Q

The risk of severe kidney damage during amphotericin B therapy depends on

A

dose and duration of treatment, underlying health and fluid status of the patient, previous or underlying kidney disease, and the receipt of other potentially nephrotoxic drugs

57
Q

What to monitor for kidney damage during ampB therapy

A

Serum creatinine
BUN
Renal Function - Electrolytes LFTs PTT CBC

58
Q

Mechanisms of resistance to Amphotericin B (2)

A
  1. Decreased ergosterol content (defective ERG2 or ERG3 genes)
  2. Alterations in sterol content to those with reduced affinity
    (fecosterol, episterol)
59
Q

Which antifungals decrease ergosterol synthesis and cell membrane formation by inhibiting cytochrome P450 activity (lanosterol 14-α-demethylase)?

A

azoles

60
Q

Azoles are classified as Imidazoles or Triazoles based on

A

number of nitrogen atoms in the five-membered azole ring (Imidazoles = 2; triazoles = 3)

61
Q

What dosage forms are available for azoles?

A

PO and IV

62
Q

Azoles toxicity is largely due to

A

potential inhibition of mammalian CYP 450s

63
Q

Azoles are substrates/ inhibitors of which CYP 450

A

CYP 3A4, 2C9 and 2C19

64
Q

ADE of azoles

A

risk of GI upset and possible
hepatic toxicities!
drug interactions

65
Q

Mechanisms of resistance to Azoles (4)

A
  1. overexpression or alteration of the drug target
  2. production of low affinity sterols (14α-methylfecosterol)
  3. up-regulation of drug transporters
  4. cellular changes that reduce drug toxicity or enable tolerance of
    drug-induced stress
66
Q

What formulation of azoles can help limit toxicity

A

topical azoles

67
Q

Topical azoles may cause what ADE

A

hypersensitivity reactions

68
Q

Systemic azoles differ in their

A

water solubility, absorption, half-life, etc.

69
Q

Itraconazole (Sporanox®) should not be used in patients with

A

history of CHF

70
Q

Itraconazole (Sporanox®)

A
  • GI upset
  • poor CSF penetration
  • absorption increased by food
71
Q

widest therapeutic index of all the azoles

A

fluconazole

72
Q

Fluconazole (Diflucan)

A
  • oral/IV
  • GI upset
  • 60-80% CSF penetration
73
Q

Only antifungal that achieves therapeutic concentrations in urinary tract

A

fluconazole

74
Q

Voriconazole (Vfend®) toxicities may include

A

rash, elevated hepatic enzymes and visual disturbances

75
Q

Voriconazole (Vfend®)

A
  • oral/IV

- good tissue penetration

76
Q

What co-administration with statins that prolong the QT interval should be avoided

A

Posaconazole (Noxafil®)

77
Q

Posaconazole (Noxafil®)

A
  • oral suspension, tablets, IV

- rash, GI upset, elevated ALT,

78
Q

Posaconazole Oral suspension: Must be taken with

A

high fat meal

79
Q

Isavuconazonium (Cresemba®)

A
  • Oral/IV
  • GI upset
  • shorten QT interval
80
Q

Non-Azole inhibitors of ergosterol synthesis

A

Terbinafine (Lamisil AT®) and Butenafine (Lotrimin Ultra®)

81
Q

Terbinafine (Lamisil AT®) and Butenafine (Lotrimin Ultra®) inhibit

A

ergosterol biosynthesis by
inhibiting the squalene epoxidase -
an earlier step in ergosterol biosynthesis

82
Q

taken up by fungal cytosine permease and converted to active metabolites intracellularly

A

5-flucytosine (Ancobon®)

83
Q

5-flucytosine (Ancobon®)

A
  • active only against yeast
  • oral
  • penetrates CSF
84
Q

5-flucytosine (Ancobon®) moa

A
  • Flucytosine enters cells by cytosine permease
  • Converted to 5-fluorouracil by cytosine deamination, and further
    metabolized to FdUMP and FUTP
  • FdUMP inhibits Thymidylate synthase = inhibits DNA synthesis.
  • FUTP incorporates into RNA and inhibits protein synthesis
85
Q

5-flucytosine (Ancobon®) toxicity is due to

A

metabolism to fluorouracil (possibly by intestinal flora)

86
Q

Fluorouracil metabolite can cause

A
  • reversible bone marrow toxicity

- hepatotoxicity

PHRM 840 (9 decks)

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