Unit 09 drugs

Question 2

what are the 5 main antifungal drug classes

Answer 2

Polyenes, azoles, pyrimidines, echinocandins and terbinafine

Question 3

what are examples polyenes

Answer 3

amphotericin B, nystatin and natamycin

common fungicidal agents but they have high systemic toxicity.

Question 4

what are examples fo azoles

Answer 4

itraconazole and voriconazole

• very low toxicity and considered to have fungistatic effects

Question 5

examples of pyrimidines

Answer 5

• flucytosine
• agents that can penetrate BBB

Question 6

ex of echinocandin

Answer 6

capsofungin

• newer class of antifungal which appear to ahve low toxicity

Question 7

what classes of antifungals inhibit ergosterol synthesis

Answer 7

allylamines, benxylamines, imidazoles, and triazoles

Question 8

what antifungal targets the cell wall? what targets the PM?

Answer 8

echinocandins targets cell wall

Polyenes parget the Plasma membrane

Question 9

what antifungal targets DNA synthesis

Answer 9

flucytosine

Question 10

what antifungal targets mitotic spindle?

Answer 10

Griseofulvin

Question 11

what is amphotericin B

Answer 11

a polyene antifungal agent that attacks by binding to ergosterol and dsitrupting fungal membrane stability

• when it binds it produces channels or pores that alter fungal membrane permeability and allow for leakage of essential cellular contents ultimately leading to cell death

Question 12

what are soem drawbacks to amphotericin B and adverse effects

Answer 12

resistance is becoming more common and drug also bidns to cholesterol fairly easily so can lead to toxicity

adverse effects:

• Nephrotoxicity: patients see urine changes (protien, blood or casts) before increased levels of urea and nitrogen would be noted in blood
• also fever, vomiting, nausea, phlebitis (inflammation of veins)
• IV administration may cause thrombosis therefore infusion must be slow (over 4-6 hours)
• administration of fluids containing NaCl prior to treatment may lessen nephrotoxicity

*lipid complex formualtions are safer and preferred to reduce kdiney damage

Question 13

when is amphotericin B used?

Answer 13

mainly in patients with life treatening systemic mycoses (esp if immunocompromised) bc its fungicidal

*For immunocompetent patients, many practitioners prefer the safer azoles (such as itraconazole) even though most azoles are fungistatic

Question 14

Abelcet® , Amphotec® and AmBisome® ?

Answer 14

lipid formualtions of amphotericin B

Question 15

what are azoles

Answer 15

ex: imidazoles and triazoles

newer class of drugs compared to polyenes

broad spectrum of activity, are safer and have good oral bioavailability

Question 16

downside of azoles

Answer 16

teratogenic: interfere with embryonic retinoic acid homeostasis and should therefore be avoided in pregnant individuals.

Question 17

imidazole vs trizoles

Answer 17

older imidazoles such as ketoconazole are less effective and more toxic than newer triazoles such as itraconazole

Question 18

ex of imidazoles

Answer 18

Ketoconazole (systemic)
Clotrimazole, miconazole (topical)

Question 19

ex of triazoels

Answer 19

Fluconazole
Itraconazole (oral)
Posaconazole
Voriconazole

*top to bottom is inc spectrum

Question 20

How do Triazoles work?

Answer 20

• inhibit fungal P450 enzymes that are involved in ergosterol formation, specifically sterol-14α-demethylases

*take with caution because also inhibit mammalian hepatic P450 enzymes

Question 21

what is the major draw back of triazoles?

Answer 21

• usually a fungistatic
• at high label tose itraconazole may have fungicidal activity as well though
• also resistance is becoming more common especially with itraconazole and fluconazole (narrowest spectrum of activtiy)

Question 22

adverse effects of triazoles

Answer 22

• not very common bc triazoles interfere with host hepatic enzymes much less than imidazoles
• hepatic and GI effects are common with ketoconzaole
• may also cause liver problems at higher doses and contraindicted in pregnancy due to at least two diff teratogenic mechanisms

Question 23

what it Itraconzole

Answer 23

• oral administration
• treat non life treatening fungal infections, fairly good spec of activity
• not effective against aspergillus or candida as the polyenes or the newer triazole coriconazole
• sometimes itraconzole can be used in palce of amphotericin B to treat life threatening infections

Question 24

what is fluconazole

Answer 24

• a triazole
• unlike other azoles it distributes will to CNS
• oral bioavailability of 100% and can be given via IV
• half lifke is 20-40 hours so a singel roal dose may be effective in some cases
• may be as effective as emphotericin B for cryptococcal meningitis and its effective against dermatophytes

Question 25

what is voriconazole

Answer 25

- type of triazole - derivative of fluconazole - also has excellent bioavilaablity and distirbution including into the CSF - broadest spectrum of activity of all triazoles

Question 26

what is Posaconaozle

Answer 26

type of triazole - its a derivative or itraconazole - oral bioavailability is good but not as good as fluconazole or voriconazole - in terms of spec of activity it is as broad as or potentialy even better than voriconazole

Question 27

what is Flucytosine and how deos it work

Answer 27

- fluorinated pyrimidine that is susceptible to fungi (mainly Cadida and cryptococcosis) - acts by metabolizing **5-fluorouracil** which is incorperated into mRNA and inhibits protein synthesis - 5-FU is futher metabolized to compounds that inhibits DNA synthesis \*Note that mammalian cells are not affected as they do not convert flucytosine to 5-FU.

Question 28

when would you prescribe flucytosine

Answer 28

- bc it readily enters the CNS it is mainly used in fungal cryptococcal meningitis in combination with toehr drugs - Fungal meningitis often requires aggressive therapy and may be fatal despite treatment

Question 29

drawbacks of flucytosine

Answer 29

- narrow spectrum on its own and resistance is common, so never prescribe alone \*hapatotoxicity and bone marrow suppression may occur following use

Question 30

what is the MOA of flucytosine?

Answer 30

- enters the fingal cell ia a transmembrae cytosine permease - inside the cell cytsine deaminase converts flucytosine to 5-fluorouracil which is subsequently converted to 5- 5-fluorodeoxyuridylic acid monophosphate (5-FdUMP) - 5-FdUMP inhibts thymidylate synthase and therby blocks the conversion of deoxyuridylate (dUMP) to deoxythymidylate (dTMP) - in absense of dTMP, DNA synthesis is inhibited

Question 32

what are examples of Echinocandins

Answer 32

caspofungin, micafungin and anidulafungin,

Question 33

MOA of echinocandins

Answer 33

unique mechanism of action where they inhibit beta-(1,3)-D-glucan synthase - an enzyme necessary for the synthesis of an essential component of the cell wall of several fungi.

Question 34

when woudl you prescribe Echinocandins?

Answer 34

- to treat esophageal candidiasis, candidemia and invasive candidiasis \* caspofungin has demonstrated efficacy as salvage therapy for the treatment of invasive aspergillosis and it is the only echinocandin approved for use in pediatric patients.

Question 35

what is Terbinafine

Answer 35

inhibits ergosterol synthesis in virtually all dermatophytes. Dermatophytes, such as ringworm, causes dermatophytosis, which is a clinical condition resulting from a fungal infection that infects the skin, hair or nails

Question 36

when u give terbinafine and details on the therapy ## Footnote rbinafine is more effective than itraconazole, and is given orally for serious infections. The drug’s half-life is extremely long, about two weeks. Therapy usually lasts for approximately three months and much longer for nail infections (onychomycosis). The main adverse effects include gastrointestinal upset, headache and rash.

Answer 36

more effective than itraconazole given orally for serious infections -half-life is extremely long, about two weeks. Therapy usually lasts for approximately three months and much longer for nail infections (onychomycosis). The main adverse effects include gastrointestinal upset, headache and rash.