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Pharmacology > Antifungals agents > Flashcards

Antifungals agents Flashcards

1
Q

two funguses transmitted from person to person

A

1.)ringworm of the scalp
2.) thrush in the newborn, resulting from infection
transmitted from the mother with Candida albicans during childbirth.

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2
Q

Dermatomycoses

A

Tolnaftate (Tinactin®).
Clotrimazole (Lotrimin®)
Griseofulvin

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3
Q

Tolnaftate MOA

A

inhibits fungal squalene epoxidase, resulting in decreased ergosterol biosynthesis in susceptible fungi
-inhibition of ergosterol biosynthesis results in selective cytotoxicity for the parasite and not the host

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4
Q

what is the selective toxicity for squalene epoxidase in fungi than humans?

A

fungal enzyme is more sensitive to the drug than the mammalian enzyme

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5
Q

Other squalene epoxidase inhibitors

A

terbinafine
naftifine
butenafine

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6
Q

Clotrimazole MOA

A

-azole class of antifungal agents
-azoles inhibit cytochrome P450, which catalyzes the 14α-demethylation of lanosterol during its conversion to
ergosterol
-in presence of azoles: inhibits the binding and activation of molecular oxygen by cytochrome P450 and therefore inhibits the conversion of lanosterol to ergosterol

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7
Q

selectivity of azoles

A

Azoles have greater affinity for the fungal cytochrome P450 than human cytochrome P450. However, selectivity is not absolute
-azoles can bind to human cytochrome P450 and inhibit drug metabolism

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8
Q

other azole drugs

A

Miconazole

Ketoconazole

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9
Q

Griseofulvin MOA

A

disrupts the mitotic spindle by binding to polymerized microtubules to inhibit mitosis

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10
Q

Griseofulvin used to treat

A

onychomycosis (fungal infection of nails)

-It is deposited in newly formed keratin, where it prevents fungal growth

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11
Q

characteristics of Griseofulvin

A

water insoluble, and the dissolution rate is very slow in water. Microsize and ultramicrosize particles are used to increase the dissolution rate. It is also taken with a high fat
diet to increase absorption.

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12
Q

side effects of Griseofulvin

A

photosensitivity, hypersensitivity, and headache

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13
Q

Antifungals to Treat Systemic Infections

A 
Amphotericin B (Fungizone®)
5-Fluorocytosine (Ancobon®, Flucytosine)
Ketoconazole (Nizoral®).
Fluconazole (Diflucan®)
Itraconazole
Echinocandins
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14
Q

Amphotericin B MOA

A

involves binding to ergosterol in the membranes of sensitive fungi.
-Pores open in the membrane, allowing leakage of ions and small organic molecules

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15
Q

Amphotericin selectivity

A

binds 10 times more strongly to vesicles containing ergosterol than to those containing cholesterol.
-some does bind resulting in toxicity

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16
Q

Amphotericin characteristics

A
  • amphoteric - it has both an acidic and a basic group.
  • lipophilic polyene region (bottom) and a hydrophilic polyalcohol region
  • poor water solubility
  • not absorbed well from the GI tract
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17
Q

how should Amphotericin be administered?

A

slowly by IV infusion

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18
Q

how else is Amphotericin available

A
  • bile salt complex called the deoxycholate complex
  • cholesterol complex as a sterile lyophilized form-> reconstitutes in sterile water
  • liposomal Amphotericin B suspension for injection
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19
Q

side effects of Amphotericin

A
  • fever and chills.
  • headache, N&V,
  • nephrotoxicity, and hypotension
  • major limiting toxicities are nephrotoxicity and hypokalemia
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20
Q

therapeutic use of Amphotericin

A

-life-threatening fungal infections
-broad spectrum antimycotic used in the treatment of deep mycoses including aspergillosis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, and
mucormycosis

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21
Q

5-Fluorocytosine MOA

A

-in presence of 5-fluorouracil
Susceptible fungi convert 5-fluorocytosine to 5-fluorouracil, which is converted into 5-fluorodeoxyuridine monophosphate (5-fluoro-2’-deoxyuridylic acid)
-5-Fluorodeoxyuridine monophosphate inhibits thymidylate synthase, thus inhibiting DNA biosynthesis.

22
Q

in the presence of 5-fluorouracil

A

elimination of F+ is impossible because fluorine is the most electronegative element.

  • In addition, 5-fluorouracil is incorporated into RNA in place of uracil, since the van der Waals radius of fluorine (1.35 Å) is very close to that of hydrogen (1.20 Å). This leads to inhibition of protein synthesis. In this sense, 5-fluorouracil is functioning as an antimetabolite (the analog of an essential substrate that is accepted by the metabolic pathway but cannot itself support the life of the cell).
  • Binds adenosine
23
Q

5-Fluorouracil is in itself

A

anticancer agent in humans

24
Q

selectivity of 5-Fluorouracil

A

Human cells have little or no cytosine deaminase activity

25
Q

therapeutic use of 5-Fluorocytosine

A

-used in combination with
amphotericin B to treat systemic Candida infections and Cryptococcus neoformans meningitis.
It is well absorbed through the GI tract, has a low incidence of toxicity, and can penetrate into
the cerebrospinal fluid (CSF)
-Candida, Cryptococcus, Torulopsis glabrata (now called Candida glabrata), Cladosporium, and Aspergillus

26
Q

resistance of 5-Flurorcytosine

A

can develop during therapy

27
Q

why is 5-Flurorocystosine used with amphotericin B

A

used in combination with amphotericin B to kill resistant strains when they emerge
-also, amphotericin B increases permeability of fungal cells to enhance the uptake of 5-fluorocytosine

28
Q

toxicity of 5-Fluorocystosine

A
  • nausea, vomiting, diarrhea, rash, and enterocolitis
29
Q

why should 5-Fluorocystosine be monitored in people with bone marrow depression?

A

depress bone marrow function, leading to leukopenia

and thrombocytopenia

30
Q

why should those with renal impairment be monitored with 5-Flurorcytosine

A

eliminated by the kidneys

31
Q

how can N&V be avoided with 5-Fluorocystosine

A

capsules are administered a few at a time over a 15 min period.

32
Q

Ketoconazole

A

-effective in treatment of blastomycosis, histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis

33
Q

what is tolerated better than amphotericin B

A

Ketoconazole

34
Q

Fluconazole

A
  • triazole

- high bioavailability and penetrates well into the CSF

35
Q

use for Fluconazole

A

meningitis caused by susceptible fungi

36
Q

Fluconazole selectivity

A

increased selectivity for fungal vs. human cytochrome P450.

This diminishes the incidence of adverse effects and drug interactions

37
Q

therapeutic use of Fluconazole

A

-administered by IV infusion to treat cryptococcal
meningitis in AIDS patients
- first drug of choice for prevention of relapse of cryptococcal meningitis in AIDS patients whose infection has been controlled by amphotericin B
-administered as a single oral dose (150 mg) for treatment of vaginal candidiasis.

38
Q

toxicity with Fluconazole

A

Rare cases of hepatotoxicity, including fatalities, have been reported
-Patients with abnormal liver function tests should be monitored for symptoms of hepatotoxicity

39
Q

Itraconazole characteristics

A
  • racemic mixture of four diastereomers.
  • triazole.
  • more than 90% bound to serum proteins and is extensively bound in tissues
40
Q

what is Itraxonazole not effective in treating

A

infections of CNS

41
Q

therapeutic use of Itraxonazole

A

-nonmeningeal histoplasmosis
-treatment of AIDS patients with disseminated
histoplasmosis whose disease has stabilized during amphotericin B therapy

42
Q

side effects of Itraxonazole

A
  • well tolerated at 200 mg/day
  • GI distress occasionally prevents use of 400 mg/day
  • nausea and vomiting (10%), hypokalemia (9%), and rash (2%)
  • Rare cases of severe hepatotoxicity have occurred, including liver failure and death.
43
Q

what patients should not be give Itraxonazole

A

congestive heart failure patients

44
Q

what is contraindicated with Itraxonazole

A

cisapride, pimozide, quinidine, and dofetilide

45
Q

what can increase interactions with itraxonazole

A

Coadministration of itraconazole with drugs that are metabolized by cytochrome P450

46
Q

Echinocandins MOA

A

echinocandins inhibit 1,3-β-glucan synthesis in the fungal cell walls by noncompetitive inhibition of 1,3-β-glucan synthase

47
Q

echinocandin selectivity

A

for the fungus and not the host is that

mammalian cells lack 1,3-β-glucan synthase

48
Q

therapeutic use of echinocandins

A

broad spectrum antifungal

-agents that have no cross-resistance with other antifungals and are synergistic with voriconazole and amphotericin B.

49
Q

penicillins of antifungal world

A

echinocandins

50
Q

administration of echinocandin

A

IV

51
Q

adverse reactions of echinocandins

A

hepatotoxicity and sensitivity/allergic reactions

52
Q

echinocandins

A

Caspofungin(Cancidas®)
Anidulafungin(Erixis®)
Micafungin(Mycamine®)

Pharmacology (14 decks)

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