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Cardiopulm Exam 1 > Anti-Fungals, Anti-Influenza, Anti-TB > Flashcards

Anti-Fungals, Anti-Influenza, Anti-TB Flashcards

1
Q

MOA of Amphotericin B

A

• Forms a complex with ergosterol and disrupts the fungal plasma membrane

  • Ergosterol is a cell membrane sterol that is found in the cell membrane of fungi
  • The predominant cell membrane sterol in human cells and bacteria is cholesterol
  • Binds to ergosterol and alters the permeability of the cell
  • This happens because multiple amphotericin B molecules form pores in the fungal membrane
  • Amphotericin B binds with lipids (i.e., ergosterol) along the double bond rich side of its structure and associates with water molecules along the hydroxyl-rich side of its structure
  • Forms pore
  • Leakage of intracellular ions and macromolecules leads to cell death
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2
Q

Resistance of Amphotericin B

A

• Ergosterol binding is impaired

  • Decreased membrane concentration of ergosterol
  • Modified ergosterol that had less of an affinity for amphotericin B
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3
Q

Adverse Effects of Amphotericin B

A

• Immediate reactions related to IV infusion

  • FEVER, CHILLS, MUSCLE SPASMS, VOMITING, HEADACHE, AND HYPOTENSION
  • Can be prevented by slowing the infusion rate or decreasing the dose
  • Premedication with corticosteroids, antipyretics, antihistamines, or meperidine can be
    helpful in preventing these adverse effects

• Long term effects that occur over time:

  • RENAL DAMAGE
    • Occurs in nearly all patients given a clinically relevant dose
    • Decreased renal perfusion
      ~ Reversible
      - Renal tubular injury and subsequent dysfunction
      ~ Irreversible
    • Toxicity manifests as tubular acidosis and severe potassium and magnesium wasting
  • ANEMIA
    • Reduced erythropoietin production by damaged renal tubular cells
  • SEIZURES
    • May develop during intrathecal therapy
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4
Q

Flucytosine: MOA

A

• Taken up into the fungal cell by the enzyme cytosine permease

• Converted intracellularly to 5-FU and then to 5-fluorodeoxyuidine monophosphate (FdUMP)
and fluorouridine triphosphate (FUTP)

  • FdUMP inhibits DNA synthesis
  • FUTP inhibits RNA synthesis
  • Selective toxicity achieved because human cells are unable to convert flucytosine to its active metabolites
  • Synergy with amphotericin B
  • Enhanced penetration of flucytosine through amphotericin-damaged fungal cell membranes
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5
Q

Flucytosine: Resistance

A

• Altered metabolism of flucytosine

  • Develops rapidly in flucytosine monotherapy
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6
Q

Flucytosine: Adverse Effects

A
  • Structurally related the the chemotherapeutic agent 5-fluorouracil (5-FU)
  • Adverse effects result from the metabolism of flucytosine to 5-FU outside the fungal cell
  • Possibly conducted by intestinal flora

• Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia

  • Most common

• Derangement of liver enzymes

  • Occurs less frequently
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7
Q

Azoles: MOA

A

• Reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes

• Selective toxicity
- Greater affinity for fungal than for human cytochrome P450 enzymes

  • Ketoconazole has less selectivity versus the triazoles
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8
Q

Azoles: Resistance

A

Upregulation of fungal cytochrome P450 enzymes causes standard azole dosages to be less
efficacious

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9
Q

Azoles: Adverse Effects

A
  • Ketoconazole has less selectivity versus the triazoles, therefore ketoconazole has a greater propensity for adverse effects
  • Azoles in general are relatively nontoxic
  • Minor upset GI symptoms are possible

• All azoles can cause abnormalities in liver enzymes
- Rarely elicit clinical hepatitis

• Drug-drug interactions possible due to potential off target effects of azoles on mammalian
cytochrome P450 system

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10
Q

Ketoconazole

A

• Greater propensity to inhibit mammalian cytochrome P450 enzymes

  • Less selective for fungal P450 enzymes versus the triazoles

• Systemic ketoconazole rarely used for systemic fungal infections in the US

  • Ketoconazole and other imidazoles are more common for dermatological functions
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11
Q

Itraconazole

A
  • Oral and IV formulations
  • Reduced bioavailability when taken with rifamycins
  • Poor penetration into cerebral spinal fluid
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12
Q

Fluconazole

A

• High oral bioavailability

  • Can also be given by IV
  • Good cerebral spinal fluid penetration
  • Drug interactions less common
  • Least effect of all azoles on hepatic enzymes

• Widest therapeutic index of all azoles

  • Allows for more aggressive dosing

• Spectrum

  • Azole of choice for treatment and secondary prophylaxis of cryptococcal meningitis
  • Most commonly used for the treatment of mucocutaneous candidiasis
  • No activity against Aspergillus spp. or other filamentous fungi
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13
Q

Voriconazole

A
  • Oral and IV formulations
  • Well absorbed orally with a high bioavailability
  • Inhibits mammalian CYP3A4 ***
  • Dose reduction in medications normally metabolized by CYP3A4 required when
    voriconazole initiated~ Examples: cyclosporine, tacrolimus, statins
• Specific toxicities
- Rash
- Elevated hepatic enzymes
- Visual disturbances
     ~Common (30% of patients)
      ~ Blurring, changes in color vision or brightness        
      ~ Occur immediately and resolve within about 30 minutes
- Photosensitivity dermatitis
   ~ Common with chronic oral therapy

• Treatment of choice for invasive aspergillosis and some environmental molds

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14
Q

Posaconazole

A
  • Rapidly distributes to tissues with a low dosage level in the circulation
  • Inhibits mammalian CYP3A4
  • Dose reduction in medications normally metabolized by CYP3A4 required when
    posaconazole initiated
  • Only azole with significant activity against mucormycosis
  • Activity against most species of Candida and Aspergillus
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15
Q

Echinocandins: MOA

A
  • Inhibit synthesis of beta(1-3)-glucan at the fungal cell wall by inhibiting glucan synthase
  • This disrupts the fungal cell wall and leads to fungal cell death
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16
Q

Caspofungin

A

• Disseminated and mucocutaneous candidal infections

• Empiric anti-fungal therapy during febrile neutropenia
- Replaced amphotericin B in this indication

• Invasive aspergillosis

  • Only as salvage therapy in amphotericin B non-responders
  • Not primary therapy
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17
Q

Micafungin

A
  • Mucocutaneous candidiasis
  • Candidemia
  • Prophylaxis of candidal infections in bone marrow transplant patients
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18
Q

Anidulafungin

A

Esophageal candidiasis and invasive candidiasis, including candidemia

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19
Q

Echinocandins: Resistance

A

Point mutations in glucan synthase

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20
Q

Echinocandins: Adverse Effects

A
  • Well tolerated

* Minor GI side effects and flushing reported infrequently

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21
Q

Neuraminidase inhibitors: MOA

A

• Competitive inhibitors of viral neuraminidase
- Bind to enzyme’s active site

• Inhibition of viral neuraminidase results in bunching of newly released influenza virions to each other and clumping of virions to the membrane of the infected host cell

• This halts the spread of the infection within the respiratory tract due to a reduction in the
released influenza A and B virus progeny from infected host cells

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22
Q

Neuraminidase inhibitors: Resistance

A

Can develop but is rare

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23
Q

Neuraminidase inhibitors: Adverse Effects

A

Increased risk of hallucinations, delirium, and abnormal behavior

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24
Q

Oseltamivir

A
  • Oral administration
  • Prodrug activated by hepatic esterases
  • Adverse effects
  • Nausea, vomiting, and headache
  • Fatigue and diarrhea more common with prophylactic use
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25
Q

Zanamivir

A
  • Administered directly to respiratory tract by inhalation
  • Adverse effects
  • Cough, bronchospasm (occasionally severe), reversible decrease in pulmonary
    function, and transient nasal and throat discomfort
  • Administration not recommended for patients with underlying airway disease
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26
Q

Peramivir

A
  • Administered as a single IV dose for treatment of acute uncomplicated influenza in adults
  • Adverse effects
  • Diarrhea (most common)
  • Skin or hypersensitivity reactions (less common)
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27
Q

Adamantanes

A

• Block the M2 proton ion channel of the virus particle and inhibit uncoating of the viral RNA within infected host cells, thus preventing replication

  • Interfering with the function of the M2 proton ion channel:
    • Inhibits acid-mediated dissociation of the ribonucleoprotein complex early in
      replication
    • Potentiates acidic pH-induced conformational changes in hemagglutinin during its
      intracellular transport later in replication~ Hemagglutinin is a antigenic surface glycoprotein partially responsible for helping
      influenza virions bind to and infect new host cells
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28
Q

Neuraminidase inhibitors: Resistance

A
  • High rates in H1N1 and H3N2

* Not commonly used in the treatment or prevention of influenza

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29
Q

Neuraminidase inhibitors: Adverse Effects

A
  • Nausea, anorexia, nervousness, difficulty in concentrating, insomnia, and light-headedness
  • Birth defects have been reported after exposure during pregnancy
30
Q

Isoniazid: MOA

A

The most active drug for the treatment of tuberculosis caused by susceptible strains.

• Inhibits mycolic acid synthesis

  • Mycolic acids are essential components of mycobacterial cell walls

• Prodrug that is activated by KatG

  • KatG is the mycobacterial catalase-peroxidase

• The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis

31
Q

Isoniazid: Resistance

A
  • Overexpression of inhA
  • Mutation or deletion of the katG gene
  • Promoter mutations resulting in overexpression of ahpC
  • Mutations in kasA
  • Resistance develops quickly if used as monotherapy
32
Q

Isoniazid: Adverse Effects

A
  • Related to dosage and duration of administration
  • Isoniazid-induced hepatitis is the most major toxic effect
  • Peripheral neuropathy (10-20% of patients on a high dose)
33
Q

Rifampin: MOA

A

• Inhibits RNA synthesis by binding to the beta subunit of bacterial DNA-dependent RNA
polymerase

• Bactericidal

• Very good penetration and can kill intracellular organisms and those sequestered in
abscesses and lung cavities

• Strong inducer of cytochrome P450 isoforms, which increases the metabolism of many other
drugs

34
Q

Rifampin: Resistance

A

• Point mutations in rpoB, the gene for the beta subunit of RNA polymerase

  • These mutations prevent rifampin from binding to RNA polymerase and prevents
    inhibition of RNA synthesis
  • Resistance develops quickly if used as monotherapy
  • Cross resistance to other rifamycin derivatives (i.e., rifabutin and rifapentine)
35
Q

Rifampin: Adverse Effect

A

• Harmless orange color to urine, sweat, and tears

  • May permanently stain soft contact lenses

• Occasional adverse effects include rashes, thrombocytopenia, and nephritis

36
Q

Ethambutol: MOA

A

• Inhibition of mycobacterial arabinosyl transferases

  • These are encoded by the embCAB operon
  • Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall
37
Q

Ethambutol: Resistance

A

• Mutations resulting in overexpression of emb gene products or within the embB structural
gene

  • Overexpression overwhelms the action of ethambutol and mutations within the structure
    prevent ethambutol binding

• Ethambutol resistance emerges rapidly if used as a monotherapy

38
Q

Ethambutol: Adverse Effects

A

• Most common adverse effect is retrobulbar neuritis

  • Results in loss of visual acuity and red-green color blindness
  • Recommended to establish a baseline visual acuity and color discrimination and to re-
    test monthly after beginning ethambutol
  • Ethambutol is contraindicated in children too young to permit assessment of visual acuity
    and red-green color discrimination
39
Q

Pyrazinamide: MOA

A

• Converted to pyrazinoic acid (active form) by mycobacterial pyrazinamidase

  • Pyrazinamidase is encoded by pncA

• Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport functions

40
Q

Pyrazinamide: Resistance

A

• Impaired uptake of pyrazinamide

  • Results in not a high enough concentration in the cell to be efficacious

• Mutations in pncA that impair conversion of pyrazinamide to its active form

  • Results in not enough of the active form of pyrazinamide within the cell which leads to lower efficacy
41
Q

Pyrazinamide: Adverse Effects

A

Hepatotoxicity (1-5%), nausea, vomiting, drug fever, photosensitivity, and hyperuricemia

42
Q

Streptomycin: MOA

A
  • Streptomycin is an aminoglycoside antibiotic

* Aminoglycosides are protein synthesis inhibitors

43
Q

Streptomycin: Resistance

A

Streptomycin penetrates into cells poorly and is active mainly against extracellular tubercle
bacilli

44
Q

Streptomycin: Adverse Effects

A
  • Ototoxic and nephrotoxic
  • Vertigo and hearing loss are the most common adverse effects
  • Hearing loss can be permanent

• Toxicity reduced by limiting therapy to no more than 6 months

45
Q

Ethionamide: MOA

A
  • Chemically related to isoniazid

* Blocks the synthesis of mycolic acids in a similar fashion to isoniazid

46
Q

Ethionamide: Resistance

A
  • Same as isoniazid
  • Resistance develops rapidly if used as a single agent
  • Low cross-resistance between isoniazid and ethionamide
47
Q

Ethionamide: Adverse Effects

A

• Dose limiting toxicities include gastric irritation and neurologic symptoms

  • Neurologic symptoms can be relieved by pyridoxine (vitamin B6)
48
Q

Capreomycin: MOA

A

Peptide protein synthesis inhibitor

49
Q

Capreomycin: Resistance

A
  • Stains of M. tuberculosis that are resistant to streptomycin are usually susceptible to capreomycin
  • Cross resistance to strains resistant to amikacin and kanamycin
50
Q

Capreomycin: Adverse Effects

A
  • Nephrotoxic and ototoxic

* Tinnitus, deafness, and vestibular disturbances can occur

51
Q

Cycloserine: MOA

A

• Structural analog of D-alanine

• Inhibits cell wall synthesis by inhibiting the incorporation of D-alanine into the peptidoglycan
pentapeptide by inhibiting alanine racemase and D-alanyl-D-alanine ligase

  • Alanine racemase converts L-alanine to D-alanine
52
Q

Cycloserine: Adverse Effect

A

• Peripheral neuropathy and central nervous system dysfunction, including depression and psychosis

  • Also headaches, tremors, and convulsions
  • Pyridoxine (vitamin B6) should be given with cycloserine to ameliorate the neurologic toxicity
  • Adverse effects are most common in the first two weeks of therapy

• Adverse effects occur in 25% of patients
psychoses

53
Q

Aminosalicylic acid: MOA

A

• Folate synthesis inhibitor active exclusively against M. tuberculosis

• Has a similar structure to p-amino-benzoic acid (PABA) and has a similar mechanism of
action as the sulfonamides (i.e., sulfamethoxazole)

54
Q

Aminosalicylic acid: Adverse Effects

A
  • GI adverse effects, peptic ulceration, and hemorrhage
  • Hypersensitivity reactions can occur 3-8 weeks after aminosalicylic acid treatment
  • Symptoms include fever, joint pains, skin rashes, hapatosplenomegaly, hepatitis, adenopathy, and granulocytopenia
55
Q

Kanamycin / amikacin : MOA

A
  • Kanamycin and amikacin are aminoglycoside antibiotics

* Aminoglycosides are protein synthesis inhibitors

56
Q

Kanamycin / amikacin : Resistance

A
  • Amikacin has no cross resistance with streptomycin

* Amikacin has cross resistance with kanamycin

57
Q

Kanamycin / amikacin : Adverse Effect

A
  • Ototoxic and nephrotoxic
  • Vertigo and hearing loss are the most common adverse effects
  • Hearing loss can be permanent

• Toxicity reduced by limiting therapy to no more than 6 months

58
Q

Ciprofloxacin / levofloxacin / gatifloxacin / moxifloxacin: MOA

A
  • Ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin are fluoroquinolone antibiotics
  • Fluoroquinolones inhibit topoisomerase II (DNA gyrase) and topoisomerase IV
59
Q

Ciprofloxacin / levofloxacin / gatifloxacin / moxifloxacin: Resistance

A

• Point mutations in DNA gyrase

  • Develops rapidly if a fluoroquinolone is used as a single agent
60
Q

Ciprofloxacin / levofloxacin / gatifloxacin / moxifloxacin: Adverse Effects

A

• GI side effects
- Abdominal discomfort, nausea, vomiting, C. difficile colitis

• CNS effects
- Mild headache, dizziness

• Achiles tendon rupture

• QT prolongation and torsades de pointes
- Mainly moxifloxacin

61
Q

Linezolid: MOA

A
  • Linezolid is an oxazolidinone antibiotic

* Oxazolidinones are protein synthesis inhibitors

62
Q

Linezolid: Resistance

A

• Typical of oxazolidinone drug class

  • Point mutations at the oxazolidinone binding site
  • Methyltransferases altering oxazolidinone binding to the ribosome
63
Q

Linezolid: Adverse Effects

A

• Typical of oxazolidinone drug class

  • Myelosuppression
  • Mitochondrial toxicity
  • Drug-drug interactions

• Specific to linezolid’s use in TB treatment (prolonged use)

  • Bone marrow suppression and irreversible peripheral and optic neuropathy have been
    reported
  • Limiting the dose prevents the emergence of these side effect
64
Q

Rifabutin: MOA

A

• Bacterial RNA polymerase inhibitor

• Same as rifampin
- Inhibits RNA synthesis by binding to the beta subunit of bacterial DNA-dependent RNA
polymerase

  • Bactericidal
  • Very good penetration and can kill intracellular organisms and those sequestered in
    abscesses and lung cavities
  • Strong inducer of cytochrome P450 isoforms, which increases the metabolism of many
    other drugs
65
Q

Rifabutin: Resistance

A

• Rifabutin is cross resistant with rifampin and rifapentine

  • They all have similar mechanisms of resistance
  • Point mutations in rpoB, the gene for the beta subunit of RNA polymerase~ These mutations prevent rifampin from binding to RNA polymerase and prevents
    inhibition of RNA synthesis
66
Q

Rifabutin: Adverse Effects

A
  • Similar to rifampin (hepatotoxicity and rash)

* Can also cause leukopenia, thrombocytopenia, and optic neuritis

67
Q

Rifapentine: MOA

A
  • Bacterial RNA polymerase inhibitor
  • Same as rifampin
  • Inhibits RNA synthesis by binding to the beta subunit of bacterial DNA-dependent RNA polymerase
  • Bactericidal
  • Very good penetration and can kill intracellular organisms and those sequestered in
    abscesses and lung cavities
  • Strong inducer of cytochrome P450 isoforms, which increases the metabolism of many
    other drugs
68
Q

Rifapentine: Resistance

A

• Rifapentine is cross resistant with rifampin and rifabutin

  • Point mutations in rpoB, the gene for the beta subunit of RNA polymerase~ These mutations prevent rifampin from binding to RNA polymerase and prevents
    inhibition of RNA synthesis
69
Q

Rifapentine: Adverse Effect

A

Similar to rifampin (hepatotoxicity and rash)

70
Q

Bedaquiline: MOA

A
  • Inhibits ATP synthase in mycobacteria
  • Highly protein bound (> 99%) with a terminal half-life of 5.5 months
  • Includes bedaquiline and its active metabolite
71
Q

Bedaquiline: Resistance

A

Upregulation of a multi-substrate efflux pump

72
Q

Bedaquiline: Adverse Effects

A

• Nausea, arthralgia, and headache

  • > 25% of patients
  • Associated with both hepatotoxicity and cardiac toxicity
  • Black box warning related to the risk of QT prolongation and associated mortality
  • Used with caution in patients with other risk factors for cardiac conduction abnormalities

Cardiopulm Exam 1 (13 decks)

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