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Antifungals Flashcards

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1
Q

Antifungals fall into 3 categories:

A
  1. systemic drugs for systemic infections
  2. oral drugs for mucocutaneous infections
  3. topical drugs for mucocutaneous infections
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2
Q

Amphotericin A and B are produced by _____

A

streptomyces nodosus

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3
Q

General structure of amphotericin B

A

amphoteric polyene macrolide

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4
Q

How is amphotericin B prepared for intravenous administration?

A

since it is nearly insoluble–> colloidal suspension with sodium desoxycholate, lipid-associated delivery system

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5
Q

When is oral administration of amphotericin B effective?

A

only on fungi within lumen of the GI tract. It is poorly absorbed so, orally, it cannot be used for treatment of systemic diseases.

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6
Q

Half-life of amphotericin B

A

LONG. 15 days… excreted slowly in urine

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7
Q

How is the dose of amphotericin B adjusted for hepatic or renal impairment and dialysis?

A

Its not.

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8
Q

Distribution of amphotericin B

A

total body fluid, but very little in CSF

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9
Q

What limits amphotericin B therapy?

A

toxicity– drug-induced renal impairment

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10
Q

What are the pros to using lipid delivery vehicle to administer amphotericin B?

A

serves as an amphotericin resevoir, reducing non specific binding to human cell membranes. This reduces toxicity and allows larger doses

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11
Q

Amphotericin B MOA

A

Fungicidal: binds ergosterol and alters permeability of cell forming pores (amphipathic)leakage, death

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12
Q

Resistance to Amphotericin B

A

impaired ergosterol binding by decreasing ergosterol concentration or modifying it

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13
Q

What is the spectrum of Amphotericin B?

A

It is the broadest spectrum antifunal: Yeast (candida, cryptococcus), mycoses (histoplasma, blastomyces, coccidioides) pathogenic molds (aspergillus and mucormycosis)

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14
Q

What fungal organisms display an intrincic resistance to amphotericin B?

A

candida lusitaniae and pseudallescheria bodyii

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15
Q

When is amphotericin B useful?

A

nearly all life-threatening mycotic infections. Can be used initally to reduce fungal burden. local or topical administration

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16
Q

What are the 2 categories of amphotericin B toxicity?

A

Infusion related and cumulative

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17
Q

Infusion related toxicity

A

fever, chills, spasms, vomiting, hypotension, headache. Ameliorated by slowing rate or decreasing dose. Premedication and test dose to avoid

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18
Q

What is the most significnt toxic reaction to amphotericin?

A

renal damage: renal tubular acidosis and severe potassium and magnesium wasting

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19
Q

Cumulative toxicity

A

Reversible: decreased renal perfusion, prerenal failure
Irreversible: renal tubular injury. occurs with prolonged administration
Abnormal liver function test, anemia

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20
Q

Avoiding cumulative toxicity

A

prerenal component may be due to sodium loading–> normal saline infusions

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21
Q

General chemistry of flucytosine

A

water soluble pyrimidine related to 5-FU

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22
Q

Is amphotericin highly or poorly serum protein bound?

A

Highly- 90%

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23
Q

Is flucytosine highly or poorly serum protein bound?

A

poorly

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24
Q

Flucytosine absorption

A

over 90%

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25
Distribution of flucytosine
total body fluid including CSF
26
Elimination of flucytosin
via glomerular filtration or dialysis
27
Does renal impairment affect flucytosine?
yes, levels rise rapidly and can cause toxicity
28
Flucytosine MOA
taken up by cytosine permease--> converted to 5-FU--> 5-flurodeoxyuridine monophosphate (Fdump inhibits DNA synthesis) and flurouridine triphosphate (inhibits RNA synthesis)
29
Flucytosine resistance
altered metabolism of flucytosine which develops rapidly in course of flucytosine monotherapy
30
Flucytosine spectrum
C neoformans and some Candida and demateaceous molds that cause chromoblastomycosis
31
Fluctyosine clinical use
confined to combination therapy because of its demonstrated synergy and avoiding resistance. With amphotericin B or cryptococcal meningitis or with itraconazole for chromoblastomycosis
32
Adverse effects of flucytosine
metabolism by flora to toxic 5-FU--> bone marrow toxicity with anemia, leukopenia, thrombocytopenia, derangement of liver enzymes. Enterocolitis......GI, bone marrow suppression, hepatic
33
Flucytosine therapeutic window
small--> increased risk of toxicity at higher levels and development of resistance at lower levels
34
Method of administration of flucytosine
oral only
35
How is flucytosine selective for funal cells?
human cells are not able to convert parent drug
36
How is flucytosine synergistic with amphotericin B?
can enter through pores
37
Flucytosine is used in combination therapy with _____
amphotericin B or azoles
38
General chemistry/structure of azoles
synthetic compounds that can be classified as either imidazoles or triazoles according to the number or nitrogen atoms in the 5 membered azole ring
39
The imidazoles consist of :
ketoconazole, miconazole, clotrimazole
40
The triazoles consist of:
itraconazole, posaconazole, fluconazole, voriconazole,
41
The antifungal activity of azoles result from ____.
reduction of ergosterol synthesis by inhibition of fungal cytochrome p450 enzyme
42
The selective toxicity of azole drugs result from :
greater affinity for fungal p450s than human.
43
Which has a higher incidence of drug interactions and adverse effects imidazoles or triazoles?
Imidazole, due to lesser degree of selectivity
44
Resistance to azoles
increasing use of these agents for prophylaxis and therapy may be selecting for clinical drug resistance
45
Azole spectrum of action
broad. Includes Candida, C. neoformans, endemic mycosis (blastomycosis, coccidiodomycosis, histoplasmosis), dermatophytes, Aspergillus(itraconazole and voriconazole). P boydii (resistant to amphotericin)
46
Azole adverse effects
GI upset, liver enzyme abnormalities, clinical hepatitis. Prone to drug interactions due to P450
47
____ was the first oral azole introduced into clinical use
ketoconazole
48
Why has ketoconazole fallen out of clinical use?
it is less selective for fungal P450 (over human) than newer azoles
49
Itraconazole administration
oral and intravenous
50
Itraconazole absorption
increased by food and low gastric pH
51
Itraconazole drug interactions
reduced bioavailability when taken with rifamycins. Its effects on the metabolism of other hepatically cleared medications are much less than those of ketoconazoles
52
what limits the effectiveness of Itraconazole
reduced bioavailability
53
Distribution of Itraconazole
poorly into CSF
54
Itraconazole spectrum
dimorphic fungi, histoplasma, blastomyces, sporothrix, dermatophytsoses, oncychomycosis, asperbillus (but not used)
55
Fluconazole distribution
high degree of water solubility, good CSF penetration
56
Fluconazole bioavailability
high
57
Fluconazole drug interactions
less common, least effect of all the azoles on hepatic microsomal enzymes
58
Fluconazole therapeutic index
widest of azoles, permitting more aggressive therapy
59
Fluconazole is the azole of choice for treatment of ______
cryptococcal meningitis (and secondary prophylaxis)
60
Fluconazole clinical use
1. IV equivalent to amphotericin in rx of candidemia 2. agent most commonly used for mucocutaneous candidiases 3. dimoprhic fungi limited to coccidiodal 4. no activity against aspergillus
61
voriconazole administration and F
Admin: oral or intravenous. well absorbed orally with 90% F.
62
voriconazole metabolism
hepatic. Inhibitor of CYP3A4 (drug interactions)
63
voriconazole toxicities
rash, elevated hepatic enzymes, visual disturbances, photosensitivity
64
The treatment of choice for invasive aspergillosis is ____.
voriconazole
65
_____ is the newwest triazole.
posaconazole
66
Absorption, administration of posaconazole
Admin: oral only. Abs: improved with high fat meals
67
_____ is the broadest spectum member of the azole family.
posaconazole
68
Echinocandins chemistry and PK
large cyclic peptides linked to a long fatty acid. Active against Candida, aspergillus, but NOT C neoformans or agents of zygomycosis and mucormycosis. IV only.
69
Echinocandins MOA
act at the level of the fungal cell wall by inhibiting synthesis of B (1-3) glucan that results in disruption of fungal cell wall and death
70
What are the 3 echinocandins?
anidulafungin, caspofungin, micafungin
71
Griseofulvin clinical use
systemic treatment of dermatophytosis
72
Griseofulvin administration
microcrystallin form, improves with fatty foods
73
Griseofulvin MOA
binds keratin to protect new skin/hair from infection. Fungostatic
74
Griseofulvin adverse effects
allergic syndrome, hepatitis, drug interactions with warfarin and phenobarbital
75
terbinafine use
dermatophytoses, esp onychomycosis
76
terbinafine Moa
fungicidal: interferes with ergosterol biosynthesis by inhibiting squalene epoxidase which leads to accumulation of sterol squalene which is toxic to the cell.
77
Nystatin
polyene macrolide, topical use only, little toxicity but bad taste, active against Candida, good for local infections
78
Topical azoles
Clotrimazole and miconazole godo for dermatophytic infections including tinea corporis, tinea pedia, and tinea cruris
79
Topical allylamines
terinafine and naftifine tinea cruris and tinea corporis
80
which 2 antifungals are closest in their spectrum?
azoles and flucytosine
81
Which antifungals function at the cell membrane?
azoles, polyenes (amb), allylamines (terbinafine)
82
Which antifungals work at the cell wall?
echinocandins
83
which antifunals work at the intracellular level?
flucytosine and griseofulvin
84
What are the types of echinocandins?
anidulafungin, caspofungin, micafungin
85
Antifungals that have hepatic toxicities
all azoles, Amb, 5-FC, echniocandins
86
antifungals that have renal toxicity
AMB, voriconazole
87
Antifungals with CNS toxicities
voriconazole
88
Antifungals with photopsia toxicity (possible malignancy)
voriconazole
89
Antifungals with cutaneous toxicities
all
90
Antifungals with GI toxicity
itraconazole, posaconazole, 5-FC
91
Antifungals with cardiac toxicity
itraconazole
92
Antifungals with QT prolongation
all azoles
93
Antifungals with infustion reactions
amb, echinocandins
94
Antifungals with bone marrow suppression
AMB, 5-FC,
95
How do azoles interact with CYPS?
they inhibit ergosterol synthesis by blocking 14-alpha demethylase, a CYP enzyme needed to convert lanosterol and ergosterol
96
What is the significance of CYP2c19 polymorphisms?
significant interpatient variability for voriconazole serum levels
97
ketoconazole inhibits what synthesis?
steroid (androsterone)

Pharmacology (4 decks)

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