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Respiratory Medicine Exam I > Pharmacology of Pulmonary Infections (Anti-fungals, HIV, Influenza) > Flashcards

Pharmacology of Pulmonary Infections (Anti-fungals, HIV, Influenza) Flashcards

1
Q

What antifungal drugs are included in the azole drug class?

A 
Ketoconazole
Itraconazole
Fluconazole
Voriconazole
Posaconazole
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2
Q

What antifungal drugs are included in the echinocandins drug class?

A

Caspofungin
Micafungin
Anidulafungin

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3
Q

MOA of amphotericin B

A

Complexes with ergosterol to disrupt fungal cell membrane

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4
Q

Spectrum of activity of amphotericin B

A

Very broad

Yeasts: Candida albicans, Cryptococcus neoformans

Organisms causing endemic mycoses: Histoplasma capsulatum, Blastomyces dermatidis, Coccidioides immitis

Pathogenic molds: Aspergillus fumigatus, agents of mucormycosis

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5
Q

Primary mechanism of resistance to amphotericin B

A

Alteration to ergosterol

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6
Q

Administration of amphotericin B

A

Mainly given by IV

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7
Q

AEs of amphotericin B

A

Immediate reactions: fever, chills, muscle spasms, vomiting, headache, hypotension

Long term: renal toxicity

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8
Q

MOA of flucytosine

A

Converted to 5-FdUMP (inhibits DNA synthesis) and FUTP (inhibits RNA synthesis)

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9
Q

Spectrum of activity of flucytosine

A

Narrow

C.neoformans

Some Candida spp.

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10
Q

Primary mechanism of resistance to flucytosine

A

Altered drug metabolism

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11
Q

Administration of flucytosine

A

Water-soluble oral formulation

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12
Q

AEs of flucytosine

A

Anemia
Leukopenia
Thrombocytopenia

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13
Q

MOA of the azole drug class of antifungals

A

Inhibition of fungal CYP450 enzymes

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14
Q

Primary mechanism of resistance to the azole drug class

A

Upregulation of fungal CYP450 enzymes

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15
Q

AEs of azoles

A

They are relatively non-toxic; may cause minor GI issues and abnormal liver enzymes

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16
Q

Which of the azoels has a greater propensity to inhibit mammalian CYP450 enzymes?

A

Ketoconazole

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17
Q

Which of the azoles has oral and IV formulation, potent antifungal activity, but poor penetration into CSF?

A

Itraconazole

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18
Q

Spectrum of activity of itraconazole

A

Dimorphic fungi: Histoplasma, Blastomyces, Sporothrix

Aspergillus spp. (Largely replaced by voriconazole as the azole of choice for aspergillosis)

Dermatophytoses and onychomycosis

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19
Q

Which of the azoles has good CSF penetration, high oral bioavailability (can be given IV as well), and has the widest therapeutic index of all azoles?

A

Fluconazole

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20
Q

Spectrum of activity of fluconazole

A

Azole of choice for cryptococcal meningitis

Most comonly used for tx of mucocutaneous candidiasis

No activity against aspergillus spp. or other filamentous fungi

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21
Q

Which of the azoles has IV and oral formations, is an inhibitor of mammalian CYP3A4, and commonly causes visual disturbances?

A

Voriconazole

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22
Q

Spectrum of activity of voriconazole

A

Similar to itraconazole

Candida spp. (Including fluconazole-resistant spp. such as Candida krusei) and the dimorphic fungi

Tx of choice for invasive aspergillosis and some environmental molds

Enhanced activity against aspergillus spp. vs. other azoles

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23
Q

Which of the azoles is available only as a liquid oral preparation?

A

Posaconazole

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24
Q

Spectrum of activity of posaconazole

A

Broadest spectrum member of the azoles

Activity against most spp. of Candida and Aspergillus

Only azole with significant activity against the agents of mucormycosis

Currently licensed for: salvage therapy in invasive aspergillosis, prophylaxis of fungal infections during induction chemo for leukemia, allogeneic bone marrow transplant pts with graft vs. host disease

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25
Q

Echinocandins are large cyclic peptides linked to a long-chain fatty acid. What is their MOA

A

Inhibition of glucan synthesis

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26
Q

Spectrum of activity of the echinocandins

A

Candida
Aspergillus

Licensed for: disseminated and mucocutaneous candidal infections, empiric antifungal therapy during febrile neutropenia (replaced amphotericin B for this indication)

NOT for C.neoformans or the agents of zygomycosis and mucormycosis

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27
Q

Primary mechanism of resistance to echinocandins

A

Point mutations in glucan synthase

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28
Q

Administration of echinocandins

A

Only IV

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29
Q

T/F: echinocandins are extremely well tolerated with minimal, if any, adverse effects

A

True

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30
Q

Caspofungin has a half life of 9-11 hours. What is its specific spectrum of activity?

A

Invasive aspergillosis — only as salvage therapy in pts that don’t respond to amphotericin B

NOT a primary tx!

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31
Q

Micafungin has a half life of 11-15 hours. What is its specific spectrum of activity?

A

Mucocutaneous candidiasis

Candidemia

Prophylaxis of candidal infections in bone marrow transplant pts

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32
Q

Anidulafungin has a half-life of 24-48 hours. What is its specific spectrum of activity?

A

Esophageal candidiasis and invasive candidiasis, including candidemia

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33
Q

Resistance to antiretroviral therapies quickly develops in HIV pts, especially with monotherapy. What 3 things must be monitored to assess effectiveness of the chosen antiretroviral regimen?

A

CD4 T-cell counts

Viral load assays

Pt’s clinical status

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34
Q

What does HAART stand for?

A

Highly active antiretroviral therapy

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35
Q

MOA of nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)

A

Competitive inhibition of HIV-1 reverse transcriptase

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36
Q

Primary mechanism of resistance to NRTIs

A

Point mutations in HIV-1 reverse transcriptase

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37
Q

All NRTIs may be associated with what adverse effect?

A

Mitochondrial toxicity

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38
Q

Abacavir is an NRTI that is a _______ analog

A

Guanosine

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39
Q

AEs of abacavir

A

Hypersensitivity (8% of pts) - first 6 weeks of therapy. Leads to fever, fatigue, nausea, vomiting, diarrhea, abdominal pain, dyspnea, pharyngitis, cough, skin rash

Do NOT reintroduce abacavir if hypersensitivity is observed; reintroduction could result in severe outcomes including death

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40
Q

Didanosine is an NRTI that is a synthetic analog of ________

A

Deoxyadenosine

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41
Q

AEs of didanosine

A

Dose dependent pancreatitis (don’t give to pts with other risk factors like alcohol abuse or hypertriglyceridemia)

Retinal changes and optic neuritis (occurs in adults at high doses, or in children; mandate periodic retinal exams)

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42
Q

NRTI that is a fluorinated analog of lamivudine

A

Emtricitabine

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43
Q

AEs of Emtricitabine

A

HA, diarrhea, nausea, rash

Hyperpigmentation of palms or soles may be observed, particularly in African Americans

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44
Q

What NRTI(s) also treat HBV, so discontinuation could exacerbate HBV sx in a patient infected with both HIV and HBV?

A

Emtricitabine
Lamivudine
Tenofovir alafenamide

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45
Q

Lamivudine is an NRTI that is a _____ analog

A

Cytosine

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46
Q

T/F: Lamivudine is rarely used d/t extreme side effect profile

A

False. AEs with Lamivudine are uncommon and hypersensitivity is rare

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47
Q

NRTI that is a thymidine analog

A

Stavudine

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48
Q

Major AE associated with Stavudine

A

Dose-related peripheral sensory neuropathy — increased by concomitant neurotoxic drug use or in pts with advanced immunosuppression

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49
Q

NRTI that is an acyclic nucleoside phosphonate (i.e., nucleotide) analog of adenosine

A

Tenofovir

50
Q

Water soluble prodrug of active tenofovir recommended for use during pregnancy

A

Tenofovir disoproxil fumarate

51
Q

AEs of tenofovir disoproxil fumarate

A

GI complaints most common — nausea, diarrhea, vomiting, flatulence

52
Q

Phosphonoamidate prodrug of tenofovir, associated with less renal toxicity than Tenofovir disoproxil fumarate

A

Tenofovir alafenamide

53
Q

AEs of tenofovir alafenamide

A

AEs are uncommon but may include GI sx or headache

54
Q

NRTI that is a deoxythymidine analog and is safe to use in pregnant women

A

Zidovudine

55
Q

AEs of Zidovudine

A

Macrocytic anemia
Neutropenia
GI intolerance, HA, insomnia

56
Q

MOA of non-nucleoside reverse transcriptase inhibitors (NNRTIs)

A

Bind directly to HIV-1 reverse transcriptase, resulting in allosteric inhibition of RNA and DNA-dependent DNA polymerase activity

57
Q

What are the first generation NNRTIs?

A

Delavirdine
Efavirenz
Nevirapine

58
Q

What are the second generation NNRTIs?

A

Etravirine

Rilpivirine

59
Q

What type of testing is recommended prior to intiating therapy with NNRTIs?

A

Baseline genotypic testing to screen for resistant HIV-1 reverse transcriptase mutants (point mutations that alter NNRTI binding)

60
Q

AEs of NNRTIs as a class

A

GI intolerance

Skin rash

61
Q

Why are NNRTIs associated with many drug-drug interactions?

A

They are metabolized by the CYP450 system

62
Q

________ is an adverse effect that occurs in up to 38% of patients taking Delavirdine. It is a drug that must be avoided in ________. It is extensively metabolized by ______ and ______

A

Skin rash; pregnancy; CYP3A; CYP2D6

63
Q

Efavirenz is combined with _____ and ______ as a once/daily combination pill

A

Tenofovir; emtricitabine

64
Q

Efavirenz is metabolized by ____ and _____

A

CYP3A4; CYP2B6

65
Q

AEs of Efavirenz

A

Mainly involve CNS — dizziness, drowsiness, insomnia, nightmares, HA, depression, mania, psychosis

Others include skin rash, nausea, vomiting, diarrhea, crystalluria, elevated liver enzymes, increases in total serum cholesterol by 10-20%

66
Q

Can efavirenz be used in pregnancy?

A

Yes, but only after 8 weeks due to birth defects observed in a primate study

67
Q

Etravirine is a diarylpyrimidine that acts as a substrate as well as an inducer of ________ and an inhibitor of _____ and ______

A

CYP3A4; CYP2C9 and CYP2C19

68
Q

Most common AEs with etravirine

A

Rash
Nausea
Diarrhea

69
Q

A single dose of this drug is administered at the onset of labor, followed by another dose to the neonate within 3 days of delivery and is effective at preventing transmission of HIV from mother to newborn

A

Nevirapine

70
Q

AEs of nevirapine

A

Rash — maculopapular eruption that spares palms and soles; occurs in first 4-8 weeks of therapy and can be a dose-limiting toxicity

Liver toxicity — more frequent with higher CD4 counts, in women, and in those with HBV or HCV co-infection

71
Q

Rilpivirine is co-formulated with emtricitabine and tenofovir into a single once daily tablet to increase compliance. It is a diarylpyrimidine like etravirine. Can it be used in pregnancy? What are the most common AEs?

A

Yes, it is recommended for use in pregnancy

AEs = rash, depression, HA, insomnia, increased serum aminotransferases

72
Q

MOA of protease inhibitors used in tx of HIV

A

Block the HIV protease and prevent maturation of the final structural proteins that make up the mature virion core

73
Q

AEs of protease inhibitors as a class

A

GI intolerance (may be dose limiting)

Lipodystrophy — metabolic: hyperglycemia, hyperlipidemia; morphologic: lipoatrophy, fat deposition

Redistribution and accumulation of body fat — central obesity, dorsocervical fat enlargement (buffalo hump), peripheral and facial wasting, breast enlargement, cushingoid appearance

74
Q

Protease inhibitors are metabolized by _______.

______ has the most pronounced inhibitory effect, and ______ the least

A

CYP3A4

Ritonavir; saquinavir

75
Q

Boosted _____ or ______ are recommended protease inhibitors for use in pregnant women

A

Atazanavir; darunavir

76
Q

AEs of atazanavir

A

Most common = diarrhea and nausea

Skin rash in 20%

Indirect hyperbilirubinemia with overt jaundice (10%)

77
Q

Darunavir is a protease inhibitor that must be co-administered with _____ or ______

A

Ritonavir; cobicistat

78
Q

AEs of darunavir

A

Rash (occasionally severe)

Darunavir contains sulfonamide moiety — may cause hypersensitivity reaction in a pt with a sulfa allergy

79
Q

Prodrug of amprenavir that is rapidly hydrolyzed by enzymes in the intestinal epithelium

A

Fosamprenavir

80
Q

AEs of Fosamprenavir

A

Most common = HA, nausea, diarrhea, perioral paresthesias, depression

Fosamprenavir contains sulfa moiety which may cause hypersensitivity reaction in pts with sulfa allergy

Rash in 19%

81
Q

AEs of indinavir

A

Most common = unconjugated hyperbilirubinemia and nephrolithiasis due to urinary crystallization of the drug — consumption of 48 oz of water daily is important to prevent formation of kidney stones

82
Q

Boosting indinavir with ____ allows for 2x/daily dosing (as opposed to 3x/day) but this increases the chance for kidney stones, so even more fluid intake is required

A

Ritonavir

83
Q

_______ is available only in combination with low-dose ritonavir as a “booster”; it is the preferred tx in pregnant women and is generally very well tolerated with minimal adverse effects

A

Lopinavir

84
Q

AEs of nelfinavir

A

Diarrhea and flatulence

[diarrhea may be dose limiting]

85
Q

_______ is no longer used as a sole PI agent due to its high rate of GI side effecs at standard doses; a lower dose used for inhibition of CYP3A4

A

Ritonavir

86
Q

A minimal amount of Saquinavir is absorbed when taken orally. .What are some AEs?

A

GI discomfort — nausea, diarrhea, abdominal discomfort, dyspepsia

When boosted by ritonavir, less dyslipidemia or GI toxicity than with other boosted regimens

Hypersensitivity is rare

87
Q

Which PI is indicated for use in treatment-experienced patients who harbor strains resistant to other PI-agents?

A

Tipranavir - often used in combo with ritonavir

88
Q

AEs of tipranavir

A

Contains sulfonamide moiety and should not be used in pt with sulfa allergy

Most common AEs — diarrhea, neausea, vomiting, abdominal pain

Urticarial or maculopapular rash

89
Q

Describe HIV’s viral attachment to host cells

A

Viral envelope glycoprotein complex gp160 (gp120+gp41) binds to its cellular receptor CD4

This binding changes the structure of gp120 which enables access to the chemokine receptors CCR5 or CXCR4

Binding to chemokine receptors again leads to structural changes and exposes gp41

gp41 leads to the fusion of viral envelope with the host cell membrane and entry of the viral core into the host cell

90
Q

Enfuvirtide is a synthetic 36-amino acid peptide. What is its MOA in the tx of HIV?

A

Binds gp41 preventing the conformational and structural changes needed to allow fusion of the viral envelope with the host cell membrane

91
Q

Administration of enfuvirtide

A

Must be administered with subcutaneous injection 2x/day

92
Q

Primary mechanism of resistance to enfuvirtide

A

Mutations in gp41

93
Q

AEs of enfuvirtide

A

Local injection site reactions

No clinically relevant drug-drug interactions

94
Q

MOA of maraviroc in tx of HIV

A

Binds specifically and selectively to CCR5 to prevent viral entry into host cell

95
Q

Adminitration of maraviroc

A

Oral administration

96
Q

Primary mechanism of resistance of maraviroc

A

Mutations in V3 loop of gp120

97
Q

AEs of maraviroc

A

Generally well tolerated; systemic allergic reaction followed by hepatotoxicity has been reported

98
Q

MOA of the integrase strand transfer inhibitors (INSTIs) in tx of HIV

A

Inhibit strand transfer and prevent integration of reverse-transcribed HIV DNA into the chromosomes of the host cell

99
Q

AEs of INSTIs as a class

A

In general they are well tolerated

HA and GI effects most common

100
Q

Dolutegravir is the preferred agent for tx of treatment-naive pts when given in combination with what other drugs?

A

Tenofovir/emtricitabine

Abacavir/lamivudine

101
Q

The half life of dolutegravir is 14 hours. What are some AEs?

A

AEs not common

Hypersensitivity has been reported (rash and systemic sx)

102
Q

Elvitegravir is an INSTI that is only available in combination with what other drugs?

A

Cobicistat
Emtricitabine
Tenofovir

103
Q

Elvitegravir requires boosting with _____, an ______ of CYP3A4, to be efficacious. It is associated with few adverse effects

A

Cobicistat; Inhibitor

104
Q

INSTI Pyrimidinone analog with 9 hours half-life that is the preferred option for treatment-naive persons beginning HAART, also recommended for use during pregnancy; adverse effects uncommon

A

Raltegravir

105
Q

List the nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) used to tx HIV

A 
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine
106
Q

List the non-nucleoside reverse transcriptase inhibitors (NNRTIs) used to tx HIV

A 
Delavirdine
Efavirenz
Etravirine
Nevirapine
Rilpivirine
107
Q

List the protease inhibitors (PIs) used to tx HIV

A 
Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir
108
Q

Fusion inhibitor used to tx HIV

A

Enfuvirtide

109
Q

Entry inhibitor used to tx HIV

A

Maraviroc

110
Q

What are the 3 integrase strand transfer inhibitors (INSTIs) used to tx HIV?

A

Dolutegravir
Elvitegravir
Raltegravir

111
Q

CYP3A4 inhibitor (boosting agent) used in tx of HIV

A

Cobicistat

112
Q

Key drugs used in tx of influenza

A 
Oseltamivir
Zanamivir
Peramivir
Amantadine
Rimantadine
113
Q

MOA of oseltamivir, zanamivir

A

Inhibitors of neuraminidases produced by influenza A and B

[neuraminidases cleave sialic acid residues from viral proteins and surface proteins of infected cells; function to promote virion release and to prevent clumping of newly released virions. By interfering with these actions, neuraminidase inhibitors impede viral spread]

114
Q

Spectrum of activity of oseltamivir, zanamivir

A

Active against influenza A and B

Currently active against both H3N2 and H1N1

115
Q

Mechanisms of viral resistance to the neuraminidase inhibitors

A

Mutations in neuraminidase (but worldwide resistance remains rare)

116
Q

Both oseltamivir and zanamivir decrease the time to alleviation of influenza symptoms and are more effective if used within 24 hours after symptom onset. What are some pharmacokinetic differences between the two?

A

Oseltamivir is a prodrug used orally, activated in the gut and the liver

Zanamivir is administered intranasally or by oral inhaler

117
Q

AEs of oseltamivir and zanamivir

A

Oseltamivir: GI sx, dizziness, HA, fatigue, insomnia, vertigo

Zanamivir: epistaxis, cough, throat discomfort, may induce bronchospasm (avoid in pts with severe COPD or asthma)

118
Q

Newer neuraminidase inhibitor that is the only IV anti-influenza agent available, indicated for pts unable to tolerate oral meds, or critically ill pts not responding to oral regimens

A

Peramivir

119
Q

2 influenza drugs no longer used unless absolutely necessary d/t increased resistance

A

Amantadine

Rimantadine

120
Q

MOA of amantadine, rimantadine

A

Inhibit early step in replication of influenza A; prevent uncoating by binding to a proton ion channel required at the onset of infection to permit acidification of the virus core, which in turn activates viral RNA transcriptase

Used for prophylaxis against influenza A virus; can reduce duration of sx if given within 48 hours after contact

121
Q

Toxic effects of amantadine, rimantadine

A

GI irritation, dizziness, ataxia, slurred speech

122
Q

Pharmacokinetic differences between amantadine and rimantadine

A

Rimantadine has longer half-life and requires no dose adjustments in pts with renal failure

Respiratory Medicine Exam I (9 decks)

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