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PT 1 > L49-50 Pulm > Flashcards

L49-50 Pulm Flashcards

1
Q

What are the systemic antifungal drugs for treatment of systemic fungal infections?

A
  1. Polyenes (Amphotericin B)
  2. Fluorinated pyrimidine (Flucytosine)
  3. Azoles
  4. Echinocandins (Caspofungin, Micafungin, Andiulafungin)
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2
Q

What are the systemic antifungal drugs for treatment of mucocutaneous infections?

A
  1. Griseofulvin

2. Allylamines (Terbinafine)

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3
Q

What are the topical antifungal drugs for treatment of cutaneous infections?

A
  1. Topical polyenes (Nystatin)
  2. Topical Allylamines (Terbinafine, Butenafine)
  3. Topical Azoles
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4
Q

What is the broadest spectrum anti-fungal drug and how is it administered?

A

Amphotericin B

IV only

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5
Q

What is the MOA of Amphotericin B?

A

Binds to ergosterol in the fungal membrane, forms a pore, which increases membrane permeability, efflux of essential molecules, fungal cell death

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6
Q

What is Amphotericin B not active against?

A

C. lusitaniae

Pseudallescheria boydii

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7
Q

Because Amphotericin B is associated with significant toxicities, it is reserved for what issues?

A

Life-threatening mycotic infections, particularly fungal infections in immunosuppresed patients, severe fungal pneumonia, severe cryptococcal meningitis, disseminated infections of endemic mycoses, and patients not responding to Azole-treatment of invasive Asperigillus

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8
Q

How is Amphotericin B used?

A

Initial induction therapy (4 weeks) to reduce fungal burden, then replaced by Azole drugs for consolidation therapy

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9
Q

Amphotericin B is the treatment of choice for ___.

A

Zygomycosis/mucormycosis

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10
Q

What is the only antifungal agent approved for use in pregnant/breastfeeding women?

A

Amphotericin B

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11
Q

What are the infusion -related AE of Amphotericin B?

A

Fever, chills, muscle spasms, vomiting, headache, hypotension

Prevent by slowing infusion rate, treat with anti-pyretic, anti-histamine, steroids

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12
Q

What are the cumulative toxicities of Amphotericin B?

A
  1. Nephrotoxicity (reversible - decreased renal perfusion vs. irreversible - renal tubular injury, tubular acidosis)
  2. Hepatotoxicity
  3. Anemia
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13
Q

Flucytosine has a narrow spectrum of activity, but is useful for what reasons?

A

Good oral absorption, wide distribution, good CSF penetration (Cryptococcal meningitis)

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14
Q

Because Flucytosine use is restricted by high incidence of primary and acquired resistance, it can be…

A

…used in combination with other anti-fungals, especially Amphotericin B or an Azole

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15
Q

What is the MOA of Flucytosine?

A

Enters the fungal cell through a cytosine permease in the membrane; acted on by a fungal-specific cytosine deaminase, becomes 5-flurouracil. This converts to 5-FUTP (inhibits RNA synthesis) or 5-FdUMP (inhibits thymidylate synthase, which inhibits DNA synthesis)

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16
Q

What drug acts synergistically with Flucytosine?

A

Amphotericin B - enhances its permeability

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17
Q

What is the spectrum of activity of Flucytosine?

A

Cryptococcus neoformans
Candida sp.
Agents of chromoblastomycosis (tropical climates)

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18
Q

What combination is used to treat Candidiasis or Cryptococcosis?

A

Flucytosine + Amphotericin B

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19
Q

What combination is used to treat Chromoblastomycosis?

A

Flucytosine + Itraconazole

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20
Q

What combination is used to treat Crytptococcal meningitis?

A

Flucytosine + Amphotericin B

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21
Q

What are the AE of Flucytosine?

A
  1. GI (nausea, vomiting, diarrhea)
  2. bone marrow toxicity (anemia, leukopenia, thrombocytopenia)
  3. Teratogenic
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22
Q

Why do AE occur with Flucytosine?

A

Gut microflora express cytosine deaminase, which converts Flucytosine to 5-flurouracil, an anti-metabolite

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23
Q

What is the MOA of the azoles?

A

Inhibition of 14-alpha-sterol demethylase, which is involved in the synthesis of ergosterol - this impairs membrane function (increased membrane permeability, decreased activity of membrane-associated proteins), impaired growth

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24
Q

Describe the spectrum of activity of azoles broadly.

A

In order from fewest to most:

  1. Ketoconazole
  2. Fluconazole
  3. Itraconazole
  4. Voriconazole
  5. Posaconazole
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25
Q

What are the common AE of azoles?

A

GI distress, hepatotoxicity, teratogenic

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26
Q

All azoles are either ___ or ___ of a range of hepatic CYP450 enzymes.

A

Substrates; inhibitors

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27
Q

Which 2 azoles have the most drug interactions?

A

Itraconazole and Voriconazole

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28
Q

Itraconazole and Voriconazole should never be given to a patient taking ___ due to increased risk of developing fatal ___.

A

Statins; rhabdomyolysis

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29
Q

What are the unique AE of Ketoconazole?

A

Decreased cortisol and testosterone - gynecomastia, libido, impotence, menstrual irregularities, hypotension, fatigue

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30
Q

What are the unique AE of Fluconazole?

A

Minor - nausea, headache, skin rash, GI

Alopecia with long duration/high dose

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31
Q

Why is Fluconazole useful in treating fungal bladder infections?

A

80% of drug eliminated unchanged in urine

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32
Q

What drug is most commonly used to treat mucocutaneous candidiasis?

A

Fluconazole

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33
Q

What is the treatment of choice for Cryptococcal meningitis?

A

Fluconazole (excellent CSF penetration)

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34
Q

What are the unique AE of Itraconazole?

A
  1. Triad of HTN, Hypokalemia, and peripheral edema

2. Can cause CHF in patients with ventricular dysfunction

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35
Q

What are the unique AE of Voriconazole?

A
  1. Periostitis (bone pain - inflammation of the periosteum)
  2. Transient vision changes (vision blurring, flashes of light, changes in color vision)
  3. Photosensitivity/rash (SJS)
  4. Visual/auditory hallucinations
  5. Seizures
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36
Q

What is the only azole active against Zygomycosis/Mucormycosis?

A

Posaconazole

37
Q

What are the first anti-fungals to directly target the fungal cell wall?

A

Echinocandins

38
Q

What are the AE of Echinocandins?

A

Histamine-like effect (skin itching), Teratogenic

39
Q

What is the MOA of Echinocandins?

A

Competitively inhibits beta(1-3)-D-glucan synthase complex involved in biosynthesis of the principal building block of the fungal cell wall, which impairs structural integrity and increases osmotic instability and leads to cell death

40
Q

Discuss the spectrum of activity of Echinocandins.

A

NONE toward Cryptococus or dimorphics

Good against Candida and Aspergillus

41
Q

What are Griseofulvin and Terbinafine used to treat?

A

Superficial skin and nail infections with dermatophytes (Microsporum, Epidermophyton, Trichophyton)

42
Q

What are the AE of Griseofulvin?

A
  1. Nervous systems (headache, lethargy, vertigo, blurred vision)
  2. Skin (urticaria, photosensitivity, rash, skin eruptions)
  3. Hepatotoxicity
  4. Leukopenia, neutropenia, monocytosis
  5. Teratogenic
43
Q

What is the MOA of Griseofulvin?

A

Fungistatic - binds to fungal microtubules, preventing the formation of the mitotic spindle and inhibit fungal mitosis

Accumulates in newly differentiated keratin-producing precursor cells, which allows the new growth of hair, skin, and nails to be free of infections

44
Q

What is Terbinafine used for?

A

Dermatophytes and C. albicans

Treatment of various tinea + onchomycosis

45
Q

What is the MOA of Terbinafine?

A

Inhibits fungal squalene epoxidase. Squalene increases, leading to toxic products and fungal cell death

46
Q

What is the MOA of Nystatin?

A

Binds to ergosterol and forms pores in the fungal membrane

47
Q

What is Nystatin used for?

A

Treatment of oral candidiasis

48
Q

Where is the majority of iron found?

A

Hemoglobin (70%)

49
Q

Discuss the absorption of iron.

A

Fe2+ (ferrous) absorbed actively into mucosal cells and converted to Fe3+ (ferric). Then transported to bone marrow via transferrin or plasma/liver/spleen via ferritin.

50
Q

Iron is exported from the mucosal cell via ___, which is regulated by ___.

A

Ferroportin; hepcidin

51
Q

What happens to hepcidin and ferroportin in anemia of chronic disease?

A

Hepcidin is overexpressed and the ferroportin gates are decreased, trapping the iron.

52
Q

What happens to hepcidin and ferroportin in hemochromatosis?

A

Hepcidin is underexpressed and the ferroportin gates are increased, releasing iron (overload).

53
Q

Describe the iron balance in iron deficiency.

A

Decreased ferritin

Increased transferrin

54
Q

Describe the iron balance in iron overload.

A

Increased ferritin

Decreased transferrin

55
Q

What is the only indication for iron therapy?

A

Prevention or treatment of iron deficiency anemia

Increased requirements (premature infants, children, pregnan\t/lactating women)
Inadequate absorption
Blood loss

56
Q

What are the oral iron therapies?

A

Ferrous sulfate
Ferrout gluconate
Ferrous fumarate

57
Q

What are the AE of oral iron therapy?

A

Nausea, vomiting, black stools

58
Q

What are the parenteral iron therapies?

A

Iron dextran
Iron sucrose
Iron gluconate

59
Q

When is parenteral iron therapy indicated?

A

When oral iron is not tolerated, post-GI resection, malabsorption syndromes

60
Q

What are the AE of parenteral iron therapy?

A

Pain, tissue staining (IM), headache, fever, nausea, vomiting, back/joint pain, allergic reactions, anaphylaxis

61
Q

What can happen in acute and chronic iron toxicity?

A

Acute: fatal in children, necrotizing gastroenteritis

Chronic: seen in hemochromatosis, multiple red cell transfusions, leads to organ failure

62
Q

How is acute iron toxicity treated?

A

Gastric aspiration
Gastric lavage-phosphate or carbonate solutions
Iron chelation

63
Q

How is chronic toxicity treated?

A

Intermittent phlebotomy if no anemia

Iron chelation

64
Q

What are the pro-drug forms of B12?

A

Cyanocobalamin

Hydroxycobalamin

65
Q

What are the active forms of B12?

A

Deoxyadenosylcobalamin

Methylcobalamin

66
Q

What form of folic acid is absorbed into the blood stream? Where is folate stored?

A

Monoglutamate

Liver

67
Q

How is B12 deficiency treated?

A

Parenteral injections of cyanocobalamin or hydroxycobalamin

68
Q

How is folic acid deficiency treated?

A

Oral folic acid

69
Q

What is unique about oral B12 therapy?

A

Works even with IF deficiency at high levels

70
Q

What stimulates proliferation and differentiation of erythroid cells and stimulates release of reticulocytes from BM?

A

EPO

71
Q

What produces EPO?

A

Kidney

72
Q

What is the relationship between EPO and Hgb normally? In chronic renal failure?

A

Inverse; both low in chronic renal failure

73
Q

What are the indications for EPO therapy?

A
  1. Chronic renal failure
  2. Patients with aplastic anemia, leukemias, HIV/AIDS, associated anemias, cancer
  3. Anemia of prematurity
  4. Post phlebotomy
74
Q

What are the AE of EPO therapy?

A

HTN, thrombotic complications, allergic reactions

Black box warning: increased mortality, serious cardiovascular and thromboembolic events, increased risk of tumor progression/recurrence

75
Q

What are the growth factors that stimulate proliferation and differentiation of myeloid cells?

A

G-CSF and GM-CSF

76
Q

What else does GM-CSF do?

A

Stimualtes proliferation and differentiation of erythroid and megakaryocytic cells

77
Q

What else does G-CSF do?

A

Promotes release of HSCs from the BM into the peripheral circulation

78
Q

What recombinant proteins are used to give G-CSF and GM-CSF?

A
  1. Filgrastim: recombinant human G-CSF
  2. Pegfilgrastim: filgrastim conjugated to polyethylene glycol (longer half-life)
  3. Sargramostim: recombinant human GM-CSF
79
Q

What are the indications for G-CSF/GM-CSF?

A
  1. After intensive chemotherapy (including for acute myeloid leukemia)
  2. Treatment of neutropenia
  3. High dose chemo with autologous stem cell rescue
  4. Mobilization of peripheral blood stem cells for autologous transplant (G-CSF)
80
Q

What are the AE of G-CSF?

A

Bone pain, rarely splenic rupture, allergic reactions

Preferred

81
Q

What are the AE of GM-CSF?

A

Fever, arthralgia, myalgia, peripheral edema, pleural/pericardial effusion, allergic reactions

82
Q

What promotes proliferation of megakaryocytic progenitors?

A

IL-11

83
Q

Where is IL-11 produced?

A

BM stromal cells

84
Q

What is recombinant human IL-11?

A

Oprelvekin

85
Q

What are the indications for IL-11?

A
  1. Patients with thrombocytopenia after chemo
86
Q

What are the AE for IL-11?

A

Fatigue, headache, dizziness, dyspnea, arrhythmias, hypokalemia

87
Q

What is Romiplostim?

A

Novel protein (peptibody) with two domains - a peptide domain that binds the TPO receptor and an Ab Fc domain that increases half-life; used for thrombocytopenia, especially ITP

88
Q

What is Eltrombopag?

A

Small-molecule thrombopoietin-receptor agonist; used for thrombocytopenia, especially ITP

Also seems to increase Hgb and white cell counts

89
Q

What are the AE of Romiplostim and Eltrombopag?

A

Headache, myalgia, BM fibrosis

PT 1 (34 decks)

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