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CMOD > Anti-fungal mechanisms > Flashcards

Anti-fungal mechanisms Flashcards

1
Q

Most important drugs to remember regarding Drug-Drug interactions via hepatic mechanisms

A

Azoles and Griseofulvin

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2
Q

Mitotic spindle inhibitor

A

Griseofulvin

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3
Q

Anti-metabolite

A

Flucytosine

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4
Q

Examples of endemic fungi that cause disease in immunocompromised pt.’s

A

histoplasma
coccidoides
paracoccidoides

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5
Q

Why are fungal infeaction increasing

A
  1. increases in medical technique (intravascular catheters)
  2. greater percentage of immunocompromised pt.’s are surviving with better treatments (eg. HIV, cancer, transplants)
    * number of immunodefficient patient has grown–>therefore the rates have gone up
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6
Q

three classes of currently available anti-fungal drugs

A
  1. systemic drugs (oral or parenteral) for systemic infections
  2. oral systemic drugs for mucocutaneous infections
  3. topical drugs for mucocutaneous infections
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7
Q

types (areas) of fungal infections

*increase in severity as you go deeper

A
  1. superficial (from bad hygeine)
  2. cutaneous (ring worm and athletes foot)
  3. subcutaenous (from a wound)
  4. systemic
  5. opportunistic
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8
Q

Tx for aspergillosis

A

Voriconazole IV

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9
Q

Tx for Blastomycosis

A

itraconazole PO

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10
Q

Tx for blastomycosis

A

amphotericin B IV then Itraconazole PO

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11
Q

Tx for candidiasis

A

Fluconazole PO

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12
Q

Tx for coccidiomycosis

A

Fluconazole IV/PO or itraconazole PO

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13
Q

Tx for cryptococcus

3

A

*amphotericin B IV + Flucystosine PO, then Fluconazole PO

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14
Q

Tx for histoplasmosis

A

amphotericin B IV + itraconazole PO

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15
Q

Tx for mucomycosis

A

amphotericin B

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16
Q

Tx for sporotrichosis

A

amphotericine B IV and/or itraconazole PO

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17
Q

Flucytosine has only one indication….

A

cryptococcal infections

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18
Q

Drug class which inhibits membrane function

A

amphotericin B

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19
Q

Drugs class that disrupts ergosterol synthesis

A

Azoles, terbinafine, naftiline

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20
Q

Drugs that inhibit Cell Wall Synthesis

A

caspofungin (echocandins)

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21
Q

Drugs that inhibit nucleic acid synthesis

A

5-flourocytosine

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22
Q

MOA for terbinafine

A

blocks the conversion of squalene to squalene epoxide

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23
Q

toxic byproduct that accumulates due to terbinafine

A

squalene

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24
Q

Azole group MOA

A

prevents the conversion of lanosterol to ergosterol

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25
Q

Toxicity associated with amphotericin B

A

RENAL TOXICITY

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26
Q

amphotericin B MOA

A

amphipathic–> binds to ergosterol with its double bond side and H2O on its -OH side–> multiple drug molecules aggregate to form pores–> pores allow leakage, leading to cell death

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27
Q

most anti-fungal agents are

A

fungicidal

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28
Q

what accounts for prominent renal toxicity associated with amphotericin B

A

binding of human membrane sterols

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29
Q

Is Amphotericin B orally absorbed?

A

no

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30
Q

Amphotericin B–> means of administration

A

IV—> ALWAYS

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31
Q

Common adverse effects with amphotericin B: IMMEDIATE

A

“INFUSION-RELATED REACTIONS”

    • fever chills, muscle spasms, vomiting, headache and HYPOtension
    • premedications often given :antipyretic, antihistamines, meperidine, corticosteroids
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32
Q

Common adverse effects with amphotericin B:

DELAYED

A

“RENAL TOXICITY”
–sometimes necessitates dialysis
sodium loading to reduce pre-renal toxicity
anemia: due to loss of erythropoeitin
abnormal liver function tests
seizures: followoing intracthecal drug administration

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33
Q

will abnormalities resolve upon discontinuation of amphotericin B

A

Yes

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34
Q

Only drug comparable to amphotericin B

A

Nystatin

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35
Q

Uses for nystatin

A

topical application in tx of candidiasis

*identical mechanism of action to that of apmho B

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36
Q

nystatin can only be administered

A

topically

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37
Q

three types of candidiasis

A

mucocutaneous candidiasis
oropharyngeal candidiasis (thrush)
vulvovaginal candidiasis

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38
Q

“The fungins”

A

echinocandins

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39
Q

echinocandins MOA

A

inhibit beta 1,3 glucan synthesis

–>leads to loss of membrane integrity and cell death

40
Q

examples of an echinocandin

A

caspofungin (major)

micofungin (minor)

41
Q

Caspofungin is used against

A

aspergillus

candida

42
Q

two classes of AZOLEs and strucutral differences

A

imidazoles: 2 N’s in azole ring
triazole: 3 N’s in azole ring

43
Q

Imidazole drug

A

ketaconazole

44
Q

triazoles

A

all the rest

45
Q

MOA for Azole drugs

A

avidly combine with CYP450 enzyme and prevent the 14-aplha demethylation of lanosterol–> prevention of ergosterol–>disturbs membrane integrity–>inhibits growth
*therefore if it inhibits human CYP’s–> possible ADE’s

46
Q

all azoles inhibit which CYP

47
Q

All azoles are substrates for CYP3A4 except

A

posaconazole

48
Q

drug class with the biggest impact on hepatic metabolism

A

AZOLES

also grisofulvin

49
Q

Azoles that have low solubiulity and thus have no utility in penetration of CSF

A

Ketoconazole

Itraconazole

50
Q

substrates for P-gp in BBB

A

ketaconazole

itraconazole

51
Q

fluconazole elimination is through

52
Q

other azoles are eliminated via

A

hepatic mechanisms

53
Q

azoles with the highest incidence of GI side effects

A

pasaconazole

itraconazole

54
Q

azoles contraindicated in pregnancy

A

fluconazole

voriconazole

55
Q

FDA has limited use of which AZOLE?

A

ketaconzaole PO,

  • -> severe liver injury and
  • ->CYP drug interactions
  • -> pro-arrhythmogenic
  • ->andrenal gland problems (stops production of corticosteroids like aldosterone, cortisol and testosterone
56
Q

Azole with good oral bioavailability, high CSF penetration, best tolerance and WIDEST THERAPEUTIC INDEX

A

FLUCONAZOLE

57
Q

Voriconazole ADVERSE EFFECTS

A

photosentsitive dermatitis, elevated liver enzymes, temporary visual disturbances upon IV administration, NEUROLOGICAL SYMPTOMS (HALLUCINATIONS)

58
Q

only azole with acitivyt against mucomycosis

A

posaconazole

59
Q

posaconazole side effects

A

CYP mediated drug-drug interactions

60
Q

TOPICAL AZOLES

A

clotrimazole
miconazole
*absorption is negligible and ADE’s are rare

61
Q

topical azoles used to treat…

A

candidiasis

62
Q

Pyrimidine analog with NARROW THERAPEUIC WINDOW

A

FLUCYTOSINE (5-FC)

63
Q

Flucytosine MOA

A
  1. enters cell via cytosine permease
  2. converted to 5-flourouracil (this conversion is not possible in mammals but is carried out by intestinal microflora)
  3. becomes incorporated into intermediary metabolism
  4. inhibits DNA and RNA sythesis
64
Q

antifungal that is an anti-metabolite (cell-cycle inhibitior)

A

flucytosine

65
Q

side effects of flucytosine

A

“typical side effects of cell-cycle inhibition”

  1. anemia
  2. leukopenia
  3. thrombocytopenia (low platelet count)
  4. elevated liver enzymes
66
Q

AF drugs linked to hepatic ADE’s

A

all azoles
amphotericin B
5-FC
echinocandins

67
Q

AF drugs linked to renal toxicity

A

amphotericin B

68
Q

AF drugs linked to CNS ADE’s

A

voriconazole

69
Q

AF drugs causing photopsia

A

variconazole

70
Q

AF drugs causing GI symptoms

A

itraconazole
posaconazole
5-FC

71
Q

AF drugs with cardiac ADE’s

A

all azoles especially with drug nteractions

72
Q

AF drugs causing infusion reactions

A

amphotericin B

echinocandins

73
Q

AF drugs causing bone marrow suppression

A 
5-FC
Amphotericin B (anemia associated with decreased epoetin productions)
74
Q

AF drugs with cutaneous dermatological side effects

A

Rash–> all antifungals

photosensitivity/malignancy–> variconazole

75
Q

Drugs that cause cytoplasmic membrane pores

A

Nystatin

ampho B

76
Q

Drugs that interrupt ergosterol synthesis (demethylase)

77
Q

drugs that interrupt ergosterol synthesis (qualene oxidase)

A

terbinafine, naftifine

78
Q

drugs interruptind DNA/RNA synthesis

A

flucytosine

79
Q

Gucan synthesis inhibition

A

Caspofungin, micafungin

80
Q

Microtubule disruption

A

griseofulvin

81
Q

Mitotic spindle inhibitor

A

Griseofulvin

82
Q

Griseofulvin reduces the clinical activity of

A

Warfarin
oral contraceptives
cyclosporin
aprepitant

83
Q

drug with no effect on CYP

A

terbinafine

84
Q

drug requireing routine CBC’s

A

terbinafine

*transient lymphopenia and neutropenia with oral administration

85
Q

MOA for terbinafine

A

inhibits ergosterol synthesis at the level of squaline oxidase

86
Q

AF’s that cannot be given during pregnancy

A

fluconazole

voriconazole

87
Q

Pro-arrythmogenic azoles

A

fluconazole
posaonazole
voriconazole

88
Q

only azole that is not a substrate for cyp3a4

A

pasoconzole

89
Q

azole drugs useless in csf

90
Q

low solubility azoles

A

keto
itra
posa (but posa has high absorption)

91
Q

End result of ketoconazole

A

inhibition of steroid synthesis and adrenal insufficiency

92
Q

only drug wtih activity against mucormycosis

A

pasoconazole

93
Q

mucocutaneous candida can be treated with

A

nystatin
clotrimazole
miconazole

94
Q

systemic candidiasis can be treated with

*aspergillus with the IV here too

A

caspofungin IV

fluconazole PO

95
Q

pyrimidine analog that enters cell via cytidine permease

96
Q

5FC is converted to 5 FU by

A

intestinal microflora

97
Q

side effects of 5FC

A 
GI upset
anemia
leukopenia
thrombocytopenia
renal toxicity
elevated hepatic enzymes

CMOD (19 decks)

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