Exam #4: Antifungal Agents- Part 2 (Moniri)

Question 1

______ is an inhibitor of the enzyme SQUALENE EPOXIDASE

Answer 1

lamisil (terbenafine)

Question 2

What happens when you inhibit squalene epoxidase?

Answer 2

• NO formation of squalene epoxide, so NO formation of ERGOSTEROL in the end
• BUILD UP of squalene precursor

Question 3

T/F The cell wall of fungi purpose is to provide rigidity and structural support

Answer 3

FALSE: only really for the attachment of the glycoproteins

Question 4

T/F SQUALENE is toxic to fungal cells

Answer 4

TRUE

Question 5

inhibition of ________ is the target of -AZOLE antifungals

Answer 5

CYP 450 14-alpha demethylase

Question 6

What happens when you inhibit CYP 450 14-alpha demethylase?

Answer 6

• NO formation of ergosterol

- Build up of precursor lanosterol (much more fluid vs. ergosterol)

Question 7

What happens when there is no ERGOSTEROL in the fungi cell wall?

Answer 7

the cell wall is susceptible to leaking–> lead to bursting

Question 8

Describe the structure Amphoteracin B

Answer 8

• POLYENE (double bonds)
• has HYDROPHILIC (top) and LIPOPHILIC (bottom) regions
• Amphoteric: acidic AND basic groups

Question 9

T/F Conjugation is directly related to antifungal activity and human toxicity

Answer 9

TRUE

7 C=C is optimal
If you remove double bond–> LOSE antifungal activity AND cause MORE toxicity

Question 10

POLYENE MEMBRANE DISRUPTER:

Where does AMPHOTEROCIN B bind? What does this cause to happen?

Answer 10

directly to the ergosterol (lipophilic region

hydrophilic regions come together and form a PORE–> leading to leaking of K and H20

Question 11

POLYENE MEMBRANE DISRUPTER:

How can toxicity (LIVER and KIDNEY) occur from Amphoterocin B?

Answer 11

can SEQUESTER CHOLESTEROL from human membranes

Question 12

POLYENE MEMBRANE DISRUPTER:

Amphoteracin B has an _____ spectrum of activity. What does it cover?

Answer 12

excellent

yeast
mold
thermally dimorphic fungi

Question 13

POLYENE MEMBRANE DISRUPTER:

Describe the structure of Nystain

Answer 13

-sim to Ampho except ONE less double bond= less antifungal activity–> more TOXIC (highly toxic if systemically administer)

Question 14

POLYENE MEMBRANE DISRUPTER:

Nystatin is ONLY effective against

Answer 14

candida sp (Candidiasis)

Question 15

POLYENE MEMBRANE DISRUPTER:

Why can Nystatin used for oral thrush be swish AND swallowed?

Answer 15

because its too large to cross into systemic circulation

Question 16

POLYENE MEMBRANE DISRUPTER:

If _________ is in magic mouth rinse NEED to expectorant b/c it will make you sleepy

Answer 16

diphenhydramine

Question 17

All -AZOLES contain either: (2)

Answer 17

imidazole OR triazone

Question 18

CYP 450 14 alpha demethylase is _____ dependent. What attaches to this part of the enzyme?

Answer 18

heme

the imidiazole OR triazone

Question 19

When the imidiazole OR triazone binds to the heme in CYP 450 14-alpha demethylase this causes what to happen?

Answer 19

• 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

Question 20

T/F Mammals DO NOT express CYP 450 14 alpha demethylase found in fungal cells

Answer 20

FALSE: THEY DO and its used for cholesterol biosynthesis

Question 21

Why don’t -AZOLES inhibit mammalian CYP 450 14 alpha demethylase and lead to the accumulation of 14-sterols in mammal cells?

Answer 21

b/c the affinity of the drugs for the fungal enzyme is MUCH better than the human enzyme

Question 22

AZOLES also have good affinity for other human CYP enzymes such as_______. They are EXTENSIVELY and RAPIDLY DEGRADED BY 1st pass metabolism

Answer 22

CYP 3A4

Question 23

-AZOLES have a drug interaction with _____ and _____ due to the competition for CYP 3A4

Answer 23

• statin

- BZ

Question 24

AZOLES:

_______ is a metabolized ALOT by CYP 450. Describe an example

Answer 24

ketoconazole

ketoconazole + triazolam (sedative)= 22x increase in AUC—> patient is still drowsy !!

Question 25

-AZOLES can be used as pharmacologic booster for ______

Answer 25

cyclosporine

Question 26

What is the primary MOA of AZOLE resistance?

Answer 26

mutation in the gene encoding for CYP 450 14 alpha methylase

Question 27

AZOLE Resistance | You can select for mutations by changing the dose. Would this mutation inhibit lanosterol?

Answer 27

NO

Question 28

__________ is IMIDAZOLE based -covers Candida sp., Tinea, Thermally Dimorphic Agents, and __________. Poor efficacy in (2)

Answer 28

Ketoconazole Pityrosporum ovale (dandruff) immunosuppressed pts; meningitis

Question 29

Itraconazole effects CYP 450 metabolism to a less degree than Ketoconazole b/c

Answer 29

the imidazole is replaced by A TRIAZOLE

Question 30

What are the DOC for Itraconazole in pts w/ NON-MENINGEAL infections

Answer 30

Oral Capsules

Question 31

Itraconazole capsules COVER: _______ | Solution COVER:_______

Answer 31

capsules (require normal stomach acidity): TDM, aspergillus, tinea solution:candidiasis

Question 32

Gastric Acid suppression will ______ the plasma concentration of itraconazole CAPSULES

Answer 32

decrease

Question 33

Posaconazole is similar to Itraconazole except.... (3)

Answer 33

- stomach acidity does not matter - covers Aspergillus and CA in IMMUNOCOMPROMISED - effective for mucormycosis

Question 34

What is the main difference between Fluconazole vs. other -azoles? (3)

Answer 34

- rapid and almost complete absorption from GI - readily crosses the BBB - metabolized by CYP 450 2C9 and 2C19

Question 35

Fluconazole is a major cause of _______ resistance

Answer 35

CANDIDA (C. parapsilosis and C.glabrata) 3-day monistat is better than oral fluconazole in the long run

Question 36

Fluconazole does NOT have coverage against?

Answer 36

Aspergillus sp

Question 37

Difference between Voriconazole?

Answer 37

has activity against Aspergillosis | covers esophageal candidiasis, can cross BBB, same metabolism

Question 38

Isacuonazonium sulfate (Cresemba); parent is a prodrug of _______. What is this drug approved for?

Answer 38

isavuconazole invasive aspergillosis and murcormycosis

Question 39

Topical AZOLEs are NOT approved for systemic use. But they have excellent coverage against?

Answer 39

tinea cutaneous candida (i.e. vagina)

Question 40

T/F A Troche (tablet that is sucked on) is absorbed systemically

Answer 40

FALSE: this drug is a topical GI agent | covers mouth, pharynx, esophagus

Question 41

The squalene Epoxidase inhibitors (i.e. Terbinafine) are used ONLY for? WHich is the only one available for ORAL USE

Answer 41

tinea terbinafine

Question 42

How is uracil converted to thymine with (cancer anti-metabolite). Why can't this occur with 5-FluroUracil?

Answer 42

via thymidylate synthetase because there is a fluro group and it can't be removed

Question 43

T/F thymine is critical to DNA synthesis

Answer 43

TRUE cell undergoes apoptosis when its not there

Question 44

When is Flucytosine useful?

Answer 44

when "things" become resistant

Question 45

What enzyme converts Flucytosine to 5-FU?

Answer 45

fungal cytosine-deaminase

Question 46

What occurs to 5-FU? (2)

Answer 46

- ribosylation (add ribose sugar) | - triphosphorylation (add phosphate)--> leads it being stuck in DNA chain

Question 47

MOA of Griseofulvin

Answer 47

inhibition of fungal spindles

Question 48

_______ ABSOLUTELY decreases the effectiveness of OCs

Answer 48

Griseofulvin

Question 49

What is the MOA of Echinocandins?

Answer 49

inhibitors or fungal cell wall synthesis by inhibiting BETA-GLUCANS SYNTHASE