Exam #4: Antifungal Agents- Part 2 (Moniri) Flashcards
______ is an inhibitor of the enzyme SQUALENE EPOXIDASE
lamisil (terbenafine)
What happens when you inhibit squalene epoxidase?
- NO formation of squalene epoxide, so NO formation of ERGOSTEROL in the end
- BUILD UP of squalene precursor
T/F The cell wall of fungi purpose is to provide rigidity and structural support
FALSE: only really for the attachment of the glycoproteins
T/F SQUALENE is toxic to fungal cells
TRUE
inhibition of ________ is the target of -AZOLE antifungals
CYP 450 14-alpha demethylase
What happens when you inhibit CYP 450 14-alpha demethylase?
- NO formation of ergosterol
- Build up of precursor lanosterol (much more fluid vs. ergosterol)
What happens when there is no ERGOSTEROL in the fungi cell wall?
the cell wall is susceptible to leaking–> lead to bursting
Describe the structure Amphoteracin B
- POLYENE (double bonds)
- has HYDROPHILIC (top) and LIPOPHILIC (bottom) regions
- Amphoteric: acidic AND basic groups
T/F Conjugation is directly related to antifungal activity and human toxicity
TRUE
7 C=C is optimal
If you remove double bond–> LOSE antifungal activity AND cause MORE toxicity
POLYENE MEMBRANE DISRUPTER:
Where does AMPHOTEROCIN B bind? What does this cause to happen?
directly to the ergosterol (lipophilic region
hydrophilic regions come together and form a PORE–> leading to leaking of K and H20
POLYENE MEMBRANE DISRUPTER:
How can toxicity (LIVER and KIDNEY) occur from Amphoterocin B?
can SEQUESTER CHOLESTEROL from human membranes
POLYENE MEMBRANE DISRUPTER:
Amphoteracin B has an _____ spectrum of activity. What does it cover?
excellent
yeast
mold
thermally dimorphic fungi
POLYENE MEMBRANE DISRUPTER:
Describe the structure of Nystain
-sim to Ampho except ONE less double bond= less antifungal activity–> more TOXIC (highly toxic if systemically administer)
POLYENE MEMBRANE DISRUPTER:
Nystatin is ONLY effective against
candida sp (Candidiasis)
POLYENE MEMBRANE DISRUPTER:
Why can Nystatin used for oral thrush be swish AND swallowed?
because its too large to cross into systemic circulation
POLYENE MEMBRANE DISRUPTER:
If _________ is in magic mouth rinse NEED to expectorant b/c it will make you sleepy
diphenhydramine
All -AZOLES contain either: (2)
imidazole OR triazone
CYP 450 14 alpha demethylase is _____ dependent. What attaches to this part of the enzyme?
heme
the imidiazole OR triazone
When the imidiazole OR triazone binds to the heme in CYP 450 14-alpha demethylase this causes what to happen?
- the active site is sterically blocked by the AZOLE so lanesterol CAN NOT bind
- the heme is “tied up” which the enzyme is dependent on
T/F Mammals DO NOT express CYP 450 14 alpha demethylase found in fungal cells
FALSE: THEY DO and its used for cholesterol biosynthesis
Why don’t -AZOLES inhibit mammalian CYP 450 14 alpha demethylase and lead to the accumulation of 14-sterols in mammal cells?
b/c the affinity of the drugs for the fungal enzyme is MUCH better than the human enzyme
AZOLES also have good affinity for other human CYP enzymes such as_______. They are EXTENSIVELY and RAPIDLY DEGRADED BY 1st pass metabolism
CYP 3A4
-AZOLES have a drug interaction with _____ and _____ due to the competition for CYP 3A4
- statin
- BZ
AZOLES:
_______ is a metabolized ALOT by CYP 450. Describe an example
ketoconazole
ketoconazole + triazolam (sedative)= 22x increase in AUC—> patient is still drowsy !!
-AZOLES can be used as pharmacologic booster for ______
cyclosporine
What is the primary MOA of AZOLE resistance?
mutation in the gene encoding for CYP 450 14 alpha methylase
AZOLE Resistance
You can select for mutations by changing the dose. Would this mutation inhibit lanosterol?
NO
__________ is IMIDAZOLE based
-covers Candida sp., Tinea, Thermally Dimorphic Agents, and __________.
Poor efficacy in (2)
Ketoconazole
Pityrosporum ovale (dandruff)
immunosuppressed pts; meningitis
Itraconazole effects CYP 450 metabolism to a less degree than Ketoconazole b/c
the imidazole is replaced by A TRIAZOLE
What are the DOC for Itraconazole in pts w/ NON-MENINGEAL infections
Oral Capsules
Itraconazole capsules COVER: _______
Solution COVER:_______
capsules (require normal stomach acidity): TDM, aspergillus, tinea
solution:candidiasis
Gastric Acid suppression will ______ the plasma concentration of itraconazole CAPSULES
decrease
Posaconazole is similar to Itraconazole except…. (3)
- stomach acidity does not matter
- covers Aspergillus and CA in IMMUNOCOMPROMISED
- effective for mucormycosis
What is the main difference between Fluconazole vs. other -azoles? (3)
- rapid and almost complete absorption from GI
- readily crosses the BBB
- metabolized by CYP 450 2C9 and 2C19
Fluconazole is a major cause of _______ resistance
CANDIDA
(C. parapsilosis and C.glabrata)
3-day monistat is better than oral fluconazole in the long run
Fluconazole does NOT have coverage against?
Aspergillus sp
Difference between Voriconazole?
has activity against Aspergillosis
covers esophageal candidiasis, can cross BBB, same metabolism
Isacuonazonium sulfate (Cresemba); parent is a prodrug of _______. What is this drug approved for?
isavuconazole
invasive aspergillosis and murcormycosis
Topical AZOLEs are NOT approved for systemic use. But they have excellent coverage against?
tinea
cutaneous candida (i.e. vagina)
T/F A Troche (tablet that is sucked on) is absorbed systemically
FALSE: this drug is a topical GI agent
covers mouth, pharynx, esophagus
The squalene Epoxidase inhibitors (i.e. Terbinafine) are used ONLY for? WHich is the only one available for ORAL USE
tinea
terbinafine
How is uracil converted to thymine with (cancer anti-metabolite). Why can’t this occur with 5-FluroUracil?
via thymidylate synthetase
because there is a fluro group and it can’t be removed
T/F thymine is critical to DNA synthesis
TRUE
cell undergoes apoptosis when its not there
When is Flucytosine useful?
when “things” become resistant
What enzyme converts Flucytosine to 5-FU?
fungal cytosine-deaminase
What occurs to 5-FU? (2)
- ribosylation (add ribose sugar)
- triphosphorylation (add phosphate)–> leads it being stuck in DNA chain
MOA of Griseofulvin
inhibition of fungal spindles
_______ ABSOLUTELY decreases the effectiveness of OCs
Griseofulvin
What is the MOA of Echinocandins?
inhibitors or fungal cell wall synthesis by inhibiting BETA-GLUCANS SYNTHASE
