Anti-fungal mechanisms Flashcards
1
Q
Most important drugs to remember regarding Drug-Drug interactions via hepatic mechanisms
A
Azoles and Griseofulvin
2
Q
Mitotic spindle inhibitor
A
Griseofulvin
3
Q
Anti-metabolite
A
Flucytosine
4
Q
Examples of endemic fungi that cause disease in immunocompromised pt.’s
A
histoplasma
coccidoides
paracoccidoides
5
Q
Why are fungal infeaction increasing
A
- increases in medical technique (intravascular catheters)
- 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
6
Q
three classes of currently available anti-fungal drugs
A
- systemic drugs (oral or parenteral) for systemic infections
- oral systemic drugs for mucocutaneous infections
- topical drugs for mucocutaneous infections
7
Q
types (areas) of fungal infections
*increase in severity as you go deeper
A
- superficial (from bad hygeine)
- cutaneous (ring worm and athletes foot)
- subcutaenous (from a wound)
- systemic
- opportunistic
8
Q
Tx for aspergillosis
A
Voriconazole IV
9
Q
Tx for Blastomycosis
A
itraconazole PO
10
Q
Tx for blastomycosis
A
amphotericin B IV then Itraconazole PO
11
Q
Tx for candidiasis
A
Fluconazole PO
12
Q
Tx for coccidiomycosis
A
Fluconazole IV/PO or itraconazole PO
13
Q
Tx for cryptococcus
3
A
*amphotericin B IV + Flucystosine PO, then Fluconazole PO
14
Q
Tx for histoplasmosis
A
amphotericin B IV + itraconazole PO
15
Q
Tx for mucomycosis
A
amphotericin B
16
Q
Tx for sporotrichosis
A
amphotericine B IV and/or itraconazole PO
17
Q
Flucytosine has only one indication….
A
cryptococcal infections
18
Q
Drug class which inhibits membrane function
A
amphotericin B
19
Q
Drugs class that disrupts ergosterol synthesis
A
Azoles, terbinafine, naftiline
20
Q
Drugs that inhibit Cell Wall Synthesis
A
caspofungin (echocandins)
21
Q
Drugs that inhibit nucleic acid synthesis
A
5-flourocytosine
22
Q
MOA for terbinafine
A
blocks the conversion of squalene to squalene epoxide
23
Q
toxic byproduct that accumulates due to terbinafine
A
squalene
24
Q
Azole group MOA
A
prevents the conversion of lanosterol to ergosterol
25
Toxicity associated with amphotericin B
RENAL TOXICITY
26
amphotericin B MOA
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
27
most anti-fungal agents are
fungicidal
28
what accounts for prominent renal toxicity associated with amphotericin B
binding of human membrane sterols
29
Is Amphotericin B orally absorbed?
no
30
Amphotericin B--> means of administration
IV---> ALWAYS
31
Common adverse effects with amphotericin B: IMMEDIATE
"INFUSION-RELATED REACTIONS"
- - fever chills, muscle spasms, vomiting, headache and HYPOtension
- - premedications often given :antipyretic, antihistamines, meperidine, corticosteroids
32
Common adverse effects with amphotericin B:
| DELAYED
"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
33
will abnormalities resolve upon discontinuation of amphotericin B
Yes
34
Only drug comparable to amphotericin B
Nystatin
35
Uses for nystatin
topical application in tx of candidiasis
| *identical mechanism of action to that of apmho B
36
nystatin can only be administered
topically
37
three types of candidiasis
mucocutaneous candidiasis
oropharyngeal candidiasis (thrush)
vulvovaginal candidiasis
38
"The fungins"
echinocandins
39
echinocandins MOA
inhibit beta 1,3 glucan synthesis
| -->leads to loss of membrane integrity and cell death
40
examples of an echinocandin
caspofungin (major)
| micofungin (minor)
41
Caspofungin is used against
aspergillus
| candida
42
two classes of AZOLEs and strucutral differences
imidazoles: 2 N's in azole ring
triazole: 3 N's in azole ring
43
Imidazole drug
ketaconazole
44
triazoles
all the rest
45
MOA for Azole drugs
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
all azoles inhibit which CYP
CYP3A4
47
All azoles are substrates for CYP3A4 except
posaconazole
48
drug class with the biggest impact on hepatic metabolism
AZOLES
| also grisofulvin
49
Azoles that have low solubiulity and thus have no utility in penetration of CSF
Ketoconazole
| Itraconazole
50
substrates for P-gp in BBB
ketaconazole
| itraconazole
51
fluconazole elimination is through
urine
52
other azoles are eliminated via
hepatic mechanisms
53
azoles with the highest incidence of GI side effects
pasaconazole
| itraconazole
54
azoles contraindicated in pregnancy
fluconazole
| voriconazole
55
FDA has limited use of which AZOLE?
ketaconzaole PO,
- -> severe liver injury and
- ->CYP drug interactions
- -> pro-arrhythmogenic
- ->andrenal gland problems (stops production of corticosteroids like aldosterone, cortisol and testosterone
56
Azole with good oral bioavailability, high CSF penetration, best tolerance and WIDEST THERAPEUTIC INDEX
FLUCONAZOLE
57
Voriconazole ADVERSE EFFECTS
photosentsitive dermatitis, elevated liver enzymes, temporary visual disturbances upon IV administration, NEUROLOGICAL SYMPTOMS (HALLUCINATIONS)
58
only azole with acitivyt against mucomycosis
posaconazole
59
posaconazole side effects
CYP mediated drug-drug interactions
60
TOPICAL AZOLES
clotrimazole
miconazole
*absorption is negligible and ADE's are rare
61
topical azoles used to treat...
candidiasis
62
Pyrimidine analog with NARROW THERAPEUIC WINDOW
FLUCYTOSINE (5-FC)
63
Flucytosine MOA
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
antifungal that is an anti-metabolite (cell-cycle inhibitior)
flucytosine
65
side effects of flucytosine
"typical side effects of cell-cycle inhibition"
1. anemia
2. leukopenia
3. thrombocytopenia (low platelet count)
4. elevated liver enzymes
66
AF drugs linked to hepatic ADE's
all azoles
amphotericin B
5-FC
echinocandins
67
AF drugs linked to renal toxicity
amphotericin B
68
AF drugs linked to CNS ADE's
voriconazole
69
AF drugs causing photopsia
variconazole
70
AF drugs causing GI symptoms
itraconazole
posaconazole
5-FC
71
AF drugs with cardiac ADE's
all azoles especially with drug nteractions
72
AF drugs causing infusion reactions
amphotericin B
| echinocandins
73
AF drugs causing bone marrow suppression
```
5-FC
Amphotericin B (anemia associated with decreased epoetin productions)
```
74
AF drugs with cutaneous dermatological side effects
Rash--> all antifungals
| photosensitivity/malignancy--> variconazole
75
Drugs that cause cytoplasmic membrane pores
Nystatin
| ampho B
76
Drugs that interrupt ergosterol synthesis (demethylase)
AZOLES
77
drugs that interrupt ergosterol synthesis (qualene oxidase)
terbinafine, naftifine
78
drugs interruptind DNA/RNA synthesis
flucytosine
79
Gucan synthesis inhibition
Caspofungin, micafungin
80
Microtubule disruption
griseofulvin
81
Mitotic spindle inhibitor
Griseofulvin
82
Griseofulvin reduces the clinical activity of
Warfarin
oral contraceptives
cyclosporin
aprepitant
83
drug with no effect on CYP
terbinafine
84
drug requireing routine CBC's
terbinafine
| *transient lymphopenia and neutropenia with oral administration
85
MOA for terbinafine
inhibits ergosterol synthesis at the level of squaline oxidase
86
AF's that cannot be given during pregnancy
fluconazole
| voriconazole
87
Pro-arrythmogenic azoles
fluconazole
posaonazole
voriconazole
88
only azole that is not a substrate for cyp3a4
pasoconzole
89
azole drugs useless in csf
keto
| itra
90
low solubility azoles
keto
itra
posa (but posa has high absorption)
91
End result of ketoconazole
inhibition of steroid synthesis and adrenal insufficiency
92
only drug wtih activity against mucormycosis
pasoconazole
93
mucocutaneous candida can be treated with
nystatin
clotrimazole
miconazole
94
systemic candidiasis can be treated with
| *aspergillus with the IV here too
caspofungin IV
| fluconazole PO
95
pyrimidine analog that enters cell via cytidine permease
5-FC
96
5FC is converted to 5 FU by
intestinal microflora
97
side effects of 5FC
```
GI upset
anemia
leukopenia
thrombocytopenia
renal toxicity
elevated hepatic enzymes
```
