Pharmacology of Antifungals Flashcards
1
Q
Properties of cells in humans
A
- ribosomes 60S/40S
- no cell wall
- dietary folate
- differences in DNA gyrase/topoisomerase
2
Q
Humans and fungi are what cells?
A
eukaryotic
3
Q
Antifungal agents two basic targets?
A
- action on cell wall
2. block nucleic acid aynthesis
4
Q
Which group of drops target action on cell wall? 4
A
- Azoles
- Allylamine
- polyenes
- echinocandin
5
Q
Which group of drugs block nucleic acid synthesis?
A
pyrimidine analog
6
Q
Azoles can be broken down into?
A
Imidazoles and triazoles
7
Q
Imidazoles (3)
A
- Ketoconazole
- Clotrimazole
- Miconazole
8
Q
Triazole (2)
A
- Fluconazole
- Posaconazole
- Voriconazole
9
Q
Itraconazole
A
Sporanox
10
Q
Fluconazole
A
Diflucan
11
Q
Voriconazole
A
Vfend
12
Q
Posaconazol
A
Noxafil
13
Q
Isavuconazonium - Isavuconazole
A
Cresemba
14
Q
Allylamines
A
Terbinafine
15
Q
Polyenes
A
amphotericin B
16
Q
Amphotericin B desoxycholate
A
Fungisone IV
17
Q
Liposomal AmpB
A
AmBisome
18
Q
Lipid complex AmpB
A
Abelcet
19
Q
Echinocandin (3)
A
- Anidulafungin
- Caspofungin
- Micafungin
20
Q
Caspofungin
A
Cancidas
21
Q
Anidulafungin
A
Eraxis
22
Q
Micafungin
A
Mycamine
23
Q
Localized manifestations of fungal infections are not life
threatening and usually do not disseminate in
A
immunocompetent hosts
24
Q
Fungi can become opportunistic, systemic pathogens in
A
normal hosts with parenteral administration
25
Opportunistic, systemic fungal infections also occur in patients
with
underlying medical problems or immunosuppression
26
What inhibits the enzyme that synthesizes beta-glucans called the penicillin of antifungasl?
enchinocandins
27
What binds ergosterol, weaken the membrane, cause pore formation, leakage of k+ and Na+, fungal cell death
polyenes
28
What inhibits the enzyme that synthesizes ergosterol?
azoles
29
What is converted to 5-FU to inhibit DNA synthesis as a pyrimidine analog
5-flucytosine
30
Pregnancy category for polyenes
category B
31
Pregnancy category for echinocandins
category c
32
Pregnancy category for azoles
category D
33
What antifungals are recommended to be avoided during the. first trimester of pregnancy?
azoles
34
Formulations of enchinocandins?
IV only slow infusion
35
Metabolism of enchinocandins
slow metabolism by hydrolysis/N-acetylation
36
Excretion of echinocandins
primarily in urine
37
Enchinocandins in order of increasing half life
Caspofungin, Micafungin, Anidulafungi
38
SE of enchinocandins
```
Histamine-mediated symptoms
Hepatic toxicity (Monitoring: LFTs)
```
39
Dose adjustment is required for enchinocandins in renal impairment pts
False, no dose adjustment needed
40
Does echinocandins have CSF penetration?
no, do not use for meningitis
41
Mutations in FKS1 or FKS2 (Candida glabrata) gene
which encode glucan synthase
(increased or decreased) sensitivity to echinocandins
decreased
42
Mechanisms of resistance to echinocandins (3)
1. Upregulation of multidrug transporters
2. Biofilms
3. Increased chitin synthase gene expression (chitin also a fungal cell wall component)
43
Amphotericin B is selective for
fungal erosterol
44
main sterol of mammalian cell membranes
cholesterol
45
What Induces ROS in fungal cell - accumulation of free radicals
Amphotericin B
46
Is there a dose adjustment needed for amphotericin B for renal impairment?
no dose adjustment needed
47
Does amphotericin B have CSF penetration?
No, poor CSF penetration
48
What bind ergosterol in the fungal membrane and cause leakage of intracellular contents?
polyenes
49
What formulations of amphotericin B reduce toxicity?
lipid formulations
50
Dosage forms for amphotericin B
IV and oral
51
When to use IV formulatinn of amphotericin B
life threatening systemic
| infections
52
When to use oral formulation of amphotericin B
for GI infections
53
Adverse effects of amp-B
rapid toxicity and delayed toxicity
54
Rapid toxicity w/ non-lipid formulations
nfusion-related fever, chills, malaise,
rigors (pre-medication -NSAIDs,
diphenhydramine, acetaminophen,
meperidine, hydrocortisone)
55
Delayed toxicity:
Nephrotoxicity (may
add to nephrotoxicity of other drugs)
(dose adjustment for conventional form
only)
56
The risk of severe kidney damage during amphotericin B therapy depends on
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
What to monitor for kidney damage during ampB therapy
Serum creatinine
BUN
Renal Function - Electrolytes LFTs PTT CBC
58
Mechanisms of resistance to Amphotericin B (2)
1. Decreased ergosterol content (defective ERG2 or ERG3 genes)
2. Alterations in sterol content to those with reduced affinity
(fecosterol, episterol)
59
Which antifungals decrease ergosterol synthesis and cell membrane formation by inhibiting cytochrome P450 activity (lanosterol 14-α-demethylase)?
azoles
60
Azoles are classified as Imidazoles or Triazoles based on
number of nitrogen atoms in the five-membered azole ring (Imidazoles = 2; triazoles = 3)
61
What dosage forms are available for azoles?
PO and IV
62
Azoles toxicity is largely due to
potential inhibition of mammalian CYP 450s
63
Azoles are substrates/ inhibitors of which CYP 450
CYP 3A4, 2C9 and 2C19
64
ADE of azoles
risk of GI upset and possible
hepatic toxicities!
drug interactions
65
Mechanisms of resistance to Azoles (4)
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
What formulation of azoles can help limit toxicity
topical azoles
67
Topical azoles may cause what ADE
hypersensitivity reactions
68
Systemic azoles differ in their
water solubility, absorption, half-life, etc.
69
Itraconazole (Sporanox®) should not be used in patients with
history of CHF
70
Itraconazole (Sporanox®)
- GI upset
- poor CSF penetration
- absorption increased by food
71
widest therapeutic index of all the azoles
fluconazole
72
Fluconazole (Diflucan)
- oral/IV
- GI upset
- 60-80% CSF penetration
73
Only antifungal that achieves therapeutic concentrations in urinary tract
fluconazole
74
Voriconazole (Vfend®) toxicities may include
rash, elevated hepatic enzymes and visual disturbances
75
Voriconazole (Vfend®)
- oral/IV
| - good tissue penetration
76
What co-administration with statins that prolong the QT interval should be avoided
Posaconazole (Noxafil®)
77
Posaconazole (Noxafil®)
- oral suspension, tablets, IV
| - rash, GI upset, elevated ALT,
78
Posaconazole Oral suspension: Must be taken with
high fat meal
79
Isavuconazonium (Cresemba®)
- Oral/IV
- GI upset
- shorten QT interval
80
Non-Azole inhibitors of ergosterol synthesis
Terbinafine (Lamisil AT®) and Butenafine (Lotrimin Ultra®)
81
Terbinafine (Lamisil AT®) and Butenafine (Lotrimin Ultra®) inhibit
ergosterol biosynthesis by
inhibiting the squalene epoxidase -
an earlier step in ergosterol biosynthesis
82
taken up by fungal cytosine permease and converted to active metabolites intracellularly
5-flucytosine (Ancobon®)
83
5-flucytosine (Ancobon®)
- active only against yeast
- oral
- penetrates CSF
84
5-flucytosine (Ancobon®) moa
- 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
5-flucytosine (Ancobon®) toxicity is due to
metabolism to fluorouracil (possibly by intestinal flora)
86
Fluorouracil metabolite can cause
- reversible bone marrow toxicity
| - hepatotoxicity
