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MNI (immuno pharm) > L37- Antifungals > Flashcards

L37- Antifungals Flashcards

1
Q

(1) is the main target for anti-fungal agents

fungi have cell walls made out of (2)

A

1- ergosterol
2- chitin

-fungi resistant to anti-bacterials, bacteria resistant to anti-fungals

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2
Q

describe the classic classification of fungal infections

A

Opportunistic, immuno-compromised hosts:

  • cancer chemotherapy
  • following organ transplant
  • HIV infection

Primary, immuno-competent hosts

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3
Q

describe the classification of fungal infections based on site of infections

A

Superficial mycoses: skin, mucous membranes, hair, nails

Subcutaneous mycoses: dermis, subcutaneous tissue, adjacent bone

Systemic mycoses: affects internal organs

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4
Q

______ are the main superficial mycoses

A
  • dermatophytoses

- superficial form of candidiasis

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5
Q

(1) are the common causes of systemic mycoses and (2) is the biggest issue with these types of infections

A

1- (rarely occurs, worse than sepsis) candidiasis, cryptococcosis, aspergillosis

2- difficult to treat –> life-threatening

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6
Q

list the anti-fungals by MOA

A

1) alter cell permeability: Polyenes, Azoles, Allylamines
2) block nucleic acid synthesis: Anti-metabolites
3) disrupts microtubule function: Griseofulvin
4) disrupts fungal cell wall: Echinocandins

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7
Q

list the systemic drugs (for subcutaneous and system mycoses)

A
  • amphotericin B (polyene)
  • flucytosine (anti-metabolite)
  • azoles
  • echinocandins
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8
Q

describe the MOA of amphotericin B

A

(polyene)

  • binds to ergosterol on fungal cell membrane
  • forms pore in the cell membrane
  • pores allow leakage of intracellular ions / macromolecules => cell death
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9
Q

Amphotericin B:

  • fungi-(static/cidal)
  • (broad/narrow) spectrum
  • (3) is the main clinical use in general because of (4)
A

1- fungicidal
2- broad spectrum
3- life-threatening mycoses – including pregnancy
4- very toxic

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10
Q

Amphotericin B, describe routes of administration

A

IV mainly, poor oral F as its highly insoluble (deoxycholate colloidal suspension)

Intrathecal administration in meningeal disease (only way to reach CSF)

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11
Q

______ is used to treat severe mycoses in pregnant patients

A

amphotericin B

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12
Q

(1) is the nearly universal side-effect from amphotericin B where (2) and (3) measures can be taken to minimize (1)

A

1- Infusion-related toxicity: fever/chills, muscle spasms, vomiting, HA, hypotension

2- slow infusion rate OR dec daily dose
3- pretreat with antihistamines, glucocorticoids, antipyretics, or analgesics

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13
Q

Besides infusion related toxicity, (1) is the main mechanism of the other common side effect of amphotericin B. (2) are the three major signs of toxicity from (1) and (3) can be given to slow (1) process. (4) is the other major result of toxicity from (1).

A

1- amphotericin B binds cholesterol –> forming pores –> renal toxicity

2- azotemia (high N in blood), slight dec GFR, renal tubular acidosis = severe K+/Mg++ wasting

3- Na loading (saline infusion with amphotericin B)

4- hypochromic normocytic anemia via dec EPO

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14
Q

Amphotericin B:
-(1) should be monitored closely during therapy (include all)

-(2) is a direct toxicity from intrathecal administration

A

1- renal function, LFTs, serum electrolytes (K, Mg), CBC, Hb

2- seizures or other serious neurological damage

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15
Q

Describe the improved formulation of amphotericin B and its advantages

A

Lipid formulations – adds lipid carrier:

  • L-AMB, liposomal amphotericin B
  • ABLC, amphotericin B lipid complex
  • ABCD, amphotericin B colloidal dispersion
  • improves distribution across BBB
  • improves efficacy as fungi activate medication via lipases
  • decreases AEs: less severe nephrotoxicity
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16
Q

(1) is the main anti-metabolite for treating systemic mycoses, it is a synthetic (purine/pyrimidine).

A

1- flucytosine

2- pyrimidine

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17
Q

Flucytosine in taken into fungal cells via (1). Then it is first converted into (2) in order to block (3). It is also converted in (4) in order to inhibit (5).

A

1- cytosine permease

2/3- 5-FU –> 5-FdUMP –> inhibits Thymidylate synthetase –> blocks dTMP synthesis

4/5- 5-FUTP –> inhibits protein synthesis

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18
Q

Flucytosine:

  • fungi-(static/cidal)
  • (narrow/broad) spetrum
  • works best when used with (3), specifically for (4) disease
  • used in combination because (5)
A 
1- fungistatic
2- narrow spectrum
3- amphotericin B
4- systemic candidiasis or cryptococcosis
5- to avoid resistance
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19
Q

list the AEs for Flucytosine

A
  • -> metabolized into 5-FU => bone marrow toxicity:

- pancytopenia: anemia, leukopenia, thrombocytopenia

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20
Q

list all the azoles

A

Imidazoles: *ketoconazole, miconazole, clotrimazole

Triazoles: itraconazole, flucanazole, vorionazole, posaconizole

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21
Q

describe the MOA of Azoles

A
  • inhibition of cytochrome P450 enzyme 14-α-sterol demethylase leading to inhibition of lanosterol —> ergosterol
  • reduction in overall ergosterol synthesis
  • membrane function is disrupted and permeability is increased => cell death
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22
Q

describe the AEs of Azoles in general

A
  • relatively non-toxic

- minor GI upset is most common AE

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23
Q

describe the additional effects Ketoconazole has in addition to its main MOA (hint- 3)

A

1) dec plasma testosterone:
- Men: gynecomastia, dec libido, dec potency
- Women: menstrual irregularities

2) high doses inhibits adrenal steroid synthesis and dec plasma cortisol (addison’s)
3) strong CYP3A4 inhibitor –> inc toxicity of drugs (warfarin, cyclosporin)

24
Q

Ketoconazole:

  • (1) describe absorption and distribution
  • (2) is the main clinical use
A

1:

  • best absorbed at low gastric pH –> therefore use of antacids, H2 blockers, PPIs => dec absorption
  • poor CSF penetration

2: topically for superficial mycoses due to narrow spectrum and high toxicity

25
Q

Fluconazole:

  • (1) route of administration, include F
  • (2) describe distribution
  • (3) are the main AEs
A

1- IV, oral (high oral F)

2- good CSF penetration

3: drug interactions
- moderate CYP3A4 inhibitor
- strong CYP2C9 inhibitor

26
Q

describe the many clinical uses for fluconazole

A

1) Candidiasis (esophageal, oropharyngeal, vulvovaginal, urinary) and Candidemia
2) coccidiodiomycosis

3) maintenance therapy for cryptococcal meningitis (after amphotericin B, flucytosine
4) alternative to amphotericin B in non-severe cryptococcal meningitis
5) initial and secondary prophylaxis for cryptococcal meningitis

27
Q

fluconazole is notably ineffective against ______

A

Aspergillus and other filamentous fungi

28
Q

Itraconazole:

  • (1) describe absorption and what effects it
  • (2) describe distribution
  • metabolized by (3) and strong inhibitor of (3) and may lead to (4) if co-administered with (5)
A

1- poor F: reduced by antacids, H2 blockers, PPIs

2- poor CSF penetration

3- CYP3A4
4- fatal arrhythmias
5- cisapride, quinidine

29
Q

Itraconazole:

  • preferred drug for mycoses due to (1)
  • effective against (2) superficial mycoses
  • effective against (3), but has been replaced by (4) which is more effective
A

1- Dimorphic Fungi: blastomyces, Sporothrix, Histoplasma

2- onychomycosis, dematophytoses

3- Aspergillus
4- voriconazole

30
Q

Voriconazole:

  • similar spectrum to (1) azole
  • DOC for (2)
A

1- itraconazole

2- invasive aspergillosis

31
Q

describe the AEs for voriconazole

A

-transient visual disturbances, 30% Pts

Drug interactions:
-metabolized and inhibits CYP2C19, CYP2C9, CYP3A4

32
Q

Posaconazole:

  • similar spectrum to (1) azole with additional (2) activity
  • 2nd line / alternative to (3) drug for (4) mycoses
  • AE –> inhibits (5)
A

1- itraconazole
2- Zygomycetes (like Mucor)

3- amphotericin B
4- mucoid mycoses

5- inhibits CYP3A4

33
Q

(1) is the main echinocandins. It functions by inhibiting (2) synthesis, resulting in (3). It is administered in (4) fashion.

A

1- caspofungin
2- β(1-3)-D-glucans
3- disruption of cell wall –> cell death
4- IV

34
Q

Caspofungin:

  • active against (1) fungi
  • although not active against (2)
A

1- candida, aspergillus

2- cryptococcus neoformans

35
Q

list the systemic drugs used to treat superficial mycoses

A
  • griseofulvin
  • allylamines / terbinafine

-ketoconazole, fluconazole, itraconazole

36
Q

Griseofulvin:

  • (1) MOA, simply
  • absorption of food improves with (2)
  • (3) is the main AE
A

1- disrupts mitotic spindle –> inhibit mitosis

2- fatty foods

3- drug interactions: inhibits CYP450 enzymes

37
Q

Griseofulvin:

1) is its only clinical use, although it has largely been replaced by (2

A

1- dermatophytoses of skin, hair, nails

2- itraconazole (azole), terbinafine (allylamine)

38
Q

(1) is the main allylamine, and is administered in (2) fashion. It functions to inhibit (3) in order to raise (4) levels (include effect) and decrease (5) levels (include effect).

A

1- terbinafine
2- oral, topical
3- squalene epoxidase (squalene –> squalene 2,3 oxide)
4- squalene => toxicity
5- ergosterol => loss of cell membrane integrity

39
Q

Terbinafine is effective against…..

A

dermatophytes: tinea cruris, tinea corporis

onychomycosis

40
Q

Terbinafine AEs:

  • (1) common Sxs
  • (2) metabolism effects
A

1- GI upset, rash, HA, taste disturbances

2- elevates serum liver transaminases — inhibits CYP2D6

41
Q

______ are the common topical polyenes

A

nystatin

amphotericin B

42
Q

topical amphotericin B is used for ______

A

cutaneous candidiasis

43
Q

describe the MOA of Nystatin

A

(polyene macrolide)

  • binds to ergosterol on fungal cell membrane
  • forms pore in the cell membrane
  • pores allow leakage of intracellular ions / macromolecules => cell death
44
Q

Nystatin:

  • not administered in (1) fashion because of (2), so typically administered in (3) fashion (include advantage)
  • only used to treat (4)
A

1- IV
2- extremely nephrotoxicity

3- cutaneous, vaginal, oral preparations => not absorbed via GIT, skin, vagina, so little toxicity

4- candidiasis (thrush, esophageal, vulvovaginal, etc)

45
Q

______ are the most commonly used topical azoles, found OTC

A
  • miconazole

- clotrimazole

46
Q

list the topical antifungals used to treat superficial mycoses

A
  • nystatin
  • amphotericin B
  • miconazole, clotrimazole, ketoconazole
  • terbinafine
47
Q

______ is primary therapy for esophageal candidiasis

______ is primary therapy for oropharyngeal candidiasis

A

1- IV, oral fluconazole

2:
mild: topical clotrimazole or nystatin
moderate to severe: oral fluconazole
AIDS pts: oral fluconazole

48
Q

______ is primary therapy for urinary candidiasis

A

IV, oral fluconazole

49
Q

______ is primary therapy for cutaneous candidiasis

A

topical amphotericin B
topical azole
topical nystatin

50
Q

______ is primary therapy for vulvovaginal candidiasis

______ is primary therapy for recurrent vulvovaginal candidiasis

A

1:

  • topical azoles
  • oral fluconazole

2: oral fluconazole

51
Q

______ is primary therapy for candidemia

A 
IV fluconazole
IV echinocandin (caspofungin)
52
Q

______ is primary therapy for cryptococcosis

A

amphotericin B + oral flucytosine —> followed by fluconazole maintenance

53
Q

______ is primary therapy for invasive aspergillosis

A

IV voriconazole —> followed by oral voriconazole (+ amphotericin B)

54
Q

______ is primary therapy for mucormycosis + second line treatment

A

1) amphotericin B

2) posaconazole

55
Q

______ is primary therapy for fusariosis

A

amphotericin B

56
Q

______ is primary therapy for onychomycosis

A

oral terbinafine
oral itraconazole
oral fluconazole

57
Q

PCP:

  • (1) is the unique fungal feature
  • (2) Sxs
  • (3) primary therapy
  • (4) alternatives
  • (5) adjunct in moderate to severe cases
A

(pneumocystis jirovecii pneumonia)
1- cholesterol over ergosterol

2- fever, dyspnea, dry cough

3- co-trimoxazole (trimethoprim + sulfamoxazole – folate synthesis inhibitors)

4- clindamycin + primaquine // dapsone + trimethoprim // atovaquone // pentamindine

5- prednisone

MNI (immuno pharm) (15 decks)

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