L49-50 Pulm Flashcards
What are the systemic antifungal drugs for treatment of systemic fungal infections?
- Polyenes (Amphotericin B)
- Fluorinated pyrimidine (Flucytosine)
- Azoles
- Echinocandins (Caspofungin, Micafungin, Andiulafungin)
What are the systemic antifungal drugs for treatment of mucocutaneous infections?
- Griseofulvin
2. Allylamines (Terbinafine)
What are the topical antifungal drugs for treatment of cutaneous infections?
- Topical polyenes (Nystatin)
- Topical Allylamines (Terbinafine, Butenafine)
- Topical Azoles
What is the broadest spectrum anti-fungal drug and how is it administered?
Amphotericin B
IV only
What is the MOA of Amphotericin B?
Binds to ergosterol in the fungal membrane, forms a pore, which increases membrane permeability, efflux of essential molecules, fungal cell death
What is Amphotericin B not active against?
C. lusitaniae
Pseudallescheria boydii
Because Amphotericin B is associated with significant toxicities, it is reserved for what issues?
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
How is Amphotericin B used?
Initial induction therapy (4 weeks) to reduce fungal burden, then replaced by Azole drugs for consolidation therapy
Amphotericin B is the treatment of choice for ___.
Zygomycosis/mucormycosis
What is the only antifungal agent approved for use in pregnant/breastfeeding women?
Amphotericin B
What are the infusion -related AE of Amphotericin B?
Fever, chills, muscle spasms, vomiting, headache, hypotension
Prevent by slowing infusion rate, treat with anti-pyretic, anti-histamine, steroids
What are the cumulative toxicities of Amphotericin B?
- Nephrotoxicity (reversible - decreased renal perfusion vs. irreversible - renal tubular injury, tubular acidosis)
- Hepatotoxicity
- Anemia
Flucytosine has a narrow spectrum of activity, but is useful for what reasons?
Good oral absorption, wide distribution, good CSF penetration (Cryptococcal meningitis)
Because Flucytosine use is restricted by high incidence of primary and acquired resistance, it can be…
…used in combination with other anti-fungals, especially Amphotericin B or an Azole
What is the MOA of Flucytosine?
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)
What drug acts synergistically with Flucytosine?
Amphotericin B - enhances its permeability
What is the spectrum of activity of Flucytosine?
Cryptococcus neoformans
Candida sp.
Agents of chromoblastomycosis (tropical climates)
What combination is used to treat Candidiasis or Cryptococcosis?
Flucytosine + Amphotericin B
What combination is used to treat Chromoblastomycosis?
Flucytosine + Itraconazole
What combination is used to treat Crytptococcal meningitis?
Flucytosine + Amphotericin B
What are the AE of Flucytosine?
- GI (nausea, vomiting, diarrhea)
- bone marrow toxicity (anemia, leukopenia, thrombocytopenia)
- Teratogenic
Why do AE occur with Flucytosine?
Gut microflora express cytosine deaminase, which converts Flucytosine to 5-flurouracil, an anti-metabolite
What is the MOA of the azoles?
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
Describe the spectrum of activity of azoles broadly.
In order from fewest to most:
- Ketoconazole
- Fluconazole
- Itraconazole
- Voriconazole
- Posaconazole
What are the common AE of azoles?
GI distress, hepatotoxicity, teratogenic
All azoles are either ___ or ___ of a range of hepatic CYP450 enzymes.
Substrates; inhibitors
Which 2 azoles have the most drug interactions?
Itraconazole and Voriconazole
Itraconazole and Voriconazole should never be given to a patient taking ___ due to increased risk of developing fatal ___.
Statins; rhabdomyolysis
What are the unique AE of Ketoconazole?
Decreased cortisol and testosterone - gynecomastia, libido, impotence, menstrual irregularities, hypotension, fatigue
What are the unique AE of Fluconazole?
Minor - nausea, headache, skin rash, GI
Alopecia with long duration/high dose
Why is Fluconazole useful in treating fungal bladder infections?
80% of drug eliminated unchanged in urine
What drug is most commonly used to treat mucocutaneous candidiasis?
Fluconazole
What is the treatment of choice for Cryptococcal meningitis?
Fluconazole (excellent CSF penetration)
What are the unique AE of Itraconazole?
- Triad of HTN, Hypokalemia, and peripheral edema
2. Can cause CHF in patients with ventricular dysfunction
What are the unique AE of Voriconazole?
- Periostitis (bone pain - inflammation of the periosteum)
- Transient vision changes (vision blurring, flashes of light, changes in color vision)
- Photosensitivity/rash (SJS)
- Visual/auditory hallucinations
- Seizures
What is the only azole active against Zygomycosis/Mucormycosis?
Posaconazole
What are the first anti-fungals to directly target the fungal cell wall?
Echinocandins
What are the AE of Echinocandins?
Histamine-like effect (skin itching), Teratogenic
What is the MOA of Echinocandins?
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
Discuss the spectrum of activity of Echinocandins.
NONE toward Cryptococus or dimorphics
Good against Candida and Aspergillus
What are Griseofulvin and Terbinafine used to treat?
Superficial skin and nail infections with dermatophytes (Microsporum, Epidermophyton, Trichophyton)
What are the AE of Griseofulvin?
- Nervous systems (headache, lethargy, vertigo, blurred vision)
- Skin (urticaria, photosensitivity, rash, skin eruptions)
- Hepatotoxicity
- Leukopenia, neutropenia, monocytosis
- Teratogenic
What is the MOA of Griseofulvin?
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
What is Terbinafine used for?
Dermatophytes and C. albicans
Treatment of various tinea + onchomycosis
What is the MOA of Terbinafine?
Inhibits fungal squalene epoxidase. Squalene increases, leading to toxic products and fungal cell death
What is the MOA of Nystatin?
Binds to ergosterol and forms pores in the fungal membrane
What is Nystatin used for?
Treatment of oral candidiasis
Where is the majority of iron found?
Hemoglobin (70%)
Discuss the absorption of iron.
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.
Iron is exported from the mucosal cell via ___, which is regulated by ___.
Ferroportin; hepcidin
What happens to hepcidin and ferroportin in anemia of chronic disease?
Hepcidin is overexpressed and the ferroportin gates are decreased, trapping the iron.
What happens to hepcidin and ferroportin in hemochromatosis?
Hepcidin is underexpressed and the ferroportin gates are increased, releasing iron (overload).
Describe the iron balance in iron deficiency.
Decreased ferritin
Increased transferrin
Describe the iron balance in iron overload.
Increased ferritin
Decreased transferrin
What is the only indication for iron therapy?
Prevention or treatment of iron deficiency anemia
Increased requirements (premature infants, children, pregnan\t/lactating women)
Inadequate absorption
Blood loss
What are the oral iron therapies?
Ferrous sulfate
Ferrout gluconate
Ferrous fumarate
What are the AE of oral iron therapy?
Nausea, vomiting, black stools
What are the parenteral iron therapies?
Iron dextran
Iron sucrose
Iron gluconate
When is parenteral iron therapy indicated?
When oral iron is not tolerated, post-GI resection, malabsorption syndromes
What are the AE of parenteral iron therapy?
Pain, tissue staining (IM), headache, fever, nausea, vomiting, back/joint pain, allergic reactions, anaphylaxis
What can happen in acute and chronic iron toxicity?
Acute: fatal in children, necrotizing gastroenteritis
Chronic: seen in hemochromatosis, multiple red cell transfusions, leads to organ failure
How is acute iron toxicity treated?
Gastric aspiration
Gastric lavage-phosphate or carbonate solutions
Iron chelation
How is chronic toxicity treated?
Intermittent phlebotomy if no anemia
Iron chelation
What are the pro-drug forms of B12?
Cyanocobalamin
Hydroxycobalamin
What are the active forms of B12?
Deoxyadenosylcobalamin
Methylcobalamin
What form of folic acid is absorbed into the blood stream? Where is folate stored?
Monoglutamate
Liver
How is B12 deficiency treated?
Parenteral injections of cyanocobalamin or hydroxycobalamin
How is folic acid deficiency treated?
Oral folic acid
What is unique about oral B12 therapy?
Works even with IF deficiency at high levels
What stimulates proliferation and differentiation of erythroid cells and stimulates release of reticulocytes from BM?
EPO
What produces EPO?
Kidney
What is the relationship between EPO and Hgb normally? In chronic renal failure?
Inverse; both low in chronic renal failure
What are the indications for EPO therapy?
- Chronic renal failure
- Patients with aplastic anemia, leukemias, HIV/AIDS, associated anemias, cancer
- Anemia of prematurity
- Post phlebotomy
What are the AE of EPO therapy?
HTN, thrombotic complications, allergic reactions
Black box warning: increased mortality, serious cardiovascular and thromboembolic events, increased risk of tumor progression/recurrence
What are the growth factors that stimulate proliferation and differentiation of myeloid cells?
G-CSF and GM-CSF
What else does GM-CSF do?
Stimualtes proliferation and differentiation of erythroid and megakaryocytic cells
What else does G-CSF do?
Promotes release of HSCs from the BM into the peripheral circulation
What recombinant proteins are used to give G-CSF and GM-CSF?
- Filgrastim: recombinant human G-CSF
- Pegfilgrastim: filgrastim conjugated to polyethylene glycol (longer half-life)
- Sargramostim: recombinant human GM-CSF
What are the indications for G-CSF/GM-CSF?
- After intensive chemotherapy (including for acute myeloid leukemia)
- Treatment of neutropenia
- High dose chemo with autologous stem cell rescue
- Mobilization of peripheral blood stem cells for autologous transplant (G-CSF)
What are the AE of G-CSF?
Bone pain, rarely splenic rupture, allergic reactions
Preferred
What are the AE of GM-CSF?
Fever, arthralgia, myalgia, peripheral edema, pleural/pericardial effusion, allergic reactions
What promotes proliferation of megakaryocytic progenitors?
IL-11
Where is IL-11 produced?
BM stromal cells
What is recombinant human IL-11?
Oprelvekin
What are the indications for IL-11?
- Patients with thrombocytopenia after chemo
What are the AE for IL-11?
Fatigue, headache, dizziness, dyspnea, arrhythmias, hypokalemia
What is Romiplostim?
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
What is Eltrombopag?
Small-molecule thrombopoietin-receptor agonist; used for thrombocytopenia, especially ITP
Also seems to increase Hgb and white cell counts
What are the AE of Romiplostim and Eltrombopag?
Headache, myalgia, BM fibrosis
