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Pharm Test 3 > Antifungals > Flashcards

Antifungals Flashcards

1
Q

Five main antifungal drug classes/drugs:

A

1) Polyenes
2) Azoles
3) Pneumocandins (& echinocandins)
(4) Pyrimidines)
5) Drugs used to treat dermatophytosis

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2
Q

polyenes: an important drug in this category, and some characteristics

A

1) Polyenes
* E.g., amphotericin B
* Broad spectrum, fungicidal
* High systemic toxicity

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3
Q

azoles: an important drug in this category, and some characteristics

A
  • E.g., itraconazole
  • Broad spectrum, fungistatic
  • Very low toxicity
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4
Q

pneumocandins: an important drug in this category, and some characteristics

A
  • Newest AF drugs, low toxicity, replacing polyenes for systemic therapy
  • E.g., caspofungin
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5
Q

important drug used to treat dermatophytosis

A

Terbinafine

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6
Q

difference between bacterial and fungal cell and consequence

A

Unlike bacteria, fungi are eukaryotic
>harder to attack without affecting host

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7
Q

main targets of antifungal drugs, generally

A

Plasma membrane
>Most systemic drugs (polyenes, azoles)

Cell wall
>(pneumocandins)

Protein synthesis, Nucleic acid synthesis
>(Flucytosine)

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8
Q

specific component of fungal plasma membrane that is the target of many antifungals

A

Plasma membrane contains ergosterol instead of cholesterol
> target of many antifungals

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9
Q

plyenes mechanism of action and toxicity

A

Polyenes bind ergosterol in fungal membrane
> inserted into membrane
> several molecules come together to form a pore
> pores cause fungal cell to lyse (fungicidal)

Unfortunately, it also binds cholesterol to some extent in mammalian cells somewhat > toxic to host

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10
Q

what is Amphotericin B?

A

A polyene macrolide antifungal

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11
Q

pharmacokinetics of Amphotericin B; absorption, distribution

A

Conventional amphotericin B is usually formulated with bile salts to improve solubility, however can cause adverse effects

Poor oral absorption; usually given IV
Distributes to extracellular fluid; poorly into CNS

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12
Q

pharmacokinetics of Amphotericin B; elimination

A

Most metabolized in liver
> bile; smaller amount excreted in urine

Long half-life: ~ 26 h in dogs; drug continues to be excreted for weeks after discontinuation of therapy

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13
Q

spectrum of Amphotericin B

A

Broad (greater than the azoles)
* Many serious systemic mycotic infections

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14
Q

clinical use of amphotericin B

A

Systemically, main use is in dogs & cats with life-threatening systemic mycoses, esp. in immunocompromised patients due to the fungicidal nature of the drug

Ampho B is often administered once followed by longer follow-up therapy with azole

Systemic use is sporadic in equine medicine, rare/absent in food animals

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15
Q

route of administration of amphotericin in most species

A

Topical administration in most species

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16
Q

Amphotericin B adverse effects and how to minimize

A

The most toxic antimicrobial drug in clinical use

Main adverse effect is dose-dependent nephrotoxicity seen primarily with bile salt formulations

IV admin should be slow (4-6 h)

Lipid-complex formulations are much safer

17
Q

The first relatively safe class of antifungal drugs; now the most commonly used for systemic antifungal therapy

A

Azoles

18
Q

Azoles spectrum and bioavailability

A

Broad spectrum; fungistatic

Good oral bioavailability

19
Q

which types of azoles are worse for systemic use and more toxic? which are better? which are good for topical?

A

For systemic use, older imidazoles (e.g., ketoconazole) are usually less effective and are more toxic than newer triazoles (e.g., itraconazole)

For topical use, imidazoles & triazoles are
often interchangeable (good efficacy, low toxicity)

20
Q

Azoles mechanism of action

A

Triazoles inhibit fungal P450 enzymes involved in ergosterol formation
>generally fungistatic effect

Azoles inhibit mammalian hepatic P450 enzymes
> inhibits metabolism of many concurrently administered drugs

21
Q

difference in safety profile between imidazoles and triazoles

A

Imidazoles: endocrine adverse effects are common with systemic therapy

Triazoles: generally very safe

22
Q

types of azoles?

A

imidazoles and triazoles

23
Q

what is ketoconazole? what is it used for?

A

Systemic imidazole
* The first azole to be marketed
* No longer used as an antifungal (eclipsed by the triazoles)
because it inhibits mammalian sterol synthesis

  • Sometimes used in the management of hyperadrenocorticism because of its ability to inhibit cortisol synthesis (a use unrelated to its antifungal properties)
24
Q

what is ketoconazole? what is it used for?

A

Systemic imidazole
* The first azole to be marketed
* No longer used as an antifungal (eclipsed by the triazoles)
because it inhibits mammalian sterol synthesis

  • Sometimes used in the management of hyperadrenocorticism because of its ability to inhibit cortisol synthesis (a use unrelated to its antifungal properties)
25
Q

Some topical imidazoles? why are they not used systemically?

A

Miconazole
Clotrimazole
Enilconazole

(Drugs too toxic for systemic use)

26
Q

what type of drug is itraconazole? what is its spectrum, absorption, safety?

A

Fairly broad spectrum triazole
>used in cats, dogs

Good oral absorption

No adverse effects on mammalian steroid synthesis

Contraindicated in pregnancy > teratogenic effects

27
Q

what are echinocandins? what is the main example? what is the mechanism?

A

A new class of antifungal drugs
Caspofungin is the main example
* Mechanism: Inhibits fungal cell wall synthesis

28
Q

what are the uses of echinocandins?

A
  • Fungistatic activity against Aspergillus spp., fungicidal activity against most Candida spp.
  • In humans, all agents are well tolerated, with similar
    adverse effect profiles and few drug-drug interactions
  • No animal data; experimental; expensive

spectrum is narrower than polyenes

29
Q

what is the mechanism of terbafine?

A

inhibits ergosterol synthesis in virtually all dermatophytes (and several other types of fungi)
* Toxic metabolites accumulate > fungicidal

30
Q

uses of terbinafine

A

fungicidal
* Originally more effective than itraconazole or griseofulvin for dermatophytosis, but resistance is a moving target and it depends on the strain
* Works synergistically with azoles
- Novartis
* Cats: Administered topically & orally; clipping may be important Dogs: Topical treatment alone is acceptable for localized infections but generalized infections respond better to topical + oral
* In severe cases, combination of oral & topical treatment of clipped animals gives fastest resolution (whether using terbinafine or azoles or a combination of drugs)
* Distributes to skin, nails, fat (& milk)
* Available over-the-counter

31
Q

time of treatment for terbafine

A

Enters newly forming keratin > therapy typically requires 1-3 months for mycological cure

(much longer for nails)

32
Q

main adverse effects of terbinafine

A
  • Low incidence of adverse effects in dogs & cats
    > well tolerated even for prolonged therapy (60 days)
  • May see GI upset; nausea & vomiting may indicate hepatic injury; rare but severe skin problems
  • Inhibits some hepatic P450 enzymes > consider in animals receiving other drugs metabolized in the liver
33
Q

Tolnaftate is useful against?

A

Effective against dermatophytes

34
Q

how can we treat candida albicans?

A
  • Mucocutaneous infections in many species
  • Usually secondary to prolonged antibacterial treatment or immunosuppression

Treatment:
-Manage predisposing factors
-Depending on location, severity:
>Topical azole or polyene if lesions accessible
>Systemic azole or polyene +/- other

35
Q

how can we treat Aspergillus fumigatus?

A
  • Mucous membranes in dogs
  • Air sacs in poultry
  • Guttural pouch in horses
  • Mastitis & abortion in cattle

Treatment:
-Usually preventable via management
-Depending on location, severity:
>Topical azole or polyene if lesions accessible
>Polyene or azole +/- other

36
Q

how can we treat Blastomyces dermatitidis?

A
  • Disseminated disease often starting in lungs, esp. in dogs

Treatment:
-May require combined amphotericin B + azole
-Often requires prolonged treatment if established
-Often combine with anti- inflammatory therapy for tx of fungal pneumonia, otherwise dead fungal cells trigger pulmonary inflammatory reaction that can be fatal

Pharm Test 3 (16 decks)

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