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
2
Q
What antifungal drugs are included in the echinocandins drug class?
A
Caspofungin
Micafungin
Anidulafungin
3
Q
MOA of amphotericin B
A
Complexes with ergosterol to disrupt fungal cell membrane
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
5
Q
Primary mechanism of resistance to amphotericin B
A
Alteration to ergosterol
6
Q
Administration of amphotericin B
A
Mainly given by IV
7
Q
AEs of amphotericin B
A
Immediate reactions: fever, chills, muscle spasms, vomiting, headache, hypotension
Long term: renal toxicity
8
Q
MOA of flucytosine
A
Converted to 5-FdUMP (inhibits DNA synthesis) and FUTP (inhibits RNA synthesis)
9
Q
Spectrum of activity of flucytosine
A
Narrow
C.neoformans
Some Candida spp.
10
Q
Primary mechanism of resistance to flucytosine
A
Altered drug metabolism
11
Q
Administration of flucytosine
A
Water-soluble oral formulation
12
Q
AEs of flucytosine
A
Anemia
Leukopenia
Thrombocytopenia
13
Q
MOA of the azole drug class of antifungals
A
Inhibition of fungal CYP450 enzymes
14
Q
Primary mechanism of resistance to the azole drug class
A
Upregulation of fungal CYP450 enzymes
15
Q
AEs of azoles
A
They are relatively non-toxic; may cause minor GI issues and abnormal liver enzymes
16
Q
Which of the azoels has a greater propensity to inhibit mammalian CYP450 enzymes?
A
Ketoconazole
17
Q
Which of the azoles has oral and IV formulation, potent antifungal activity, but poor penetration into CSF?
A
Itraconazole
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
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
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
21
Q
Which of the azoles has IV and oral formations, is an inhibitor of mammalian CYP3A4, and commonly causes visual disturbances?
A
Voriconazole
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
23
Q
Which of the azoles is available only as a liquid oral preparation?
A
Posaconazole
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
25
Echinocandins are large cyclic peptides linked to a long-chain fatty acid. What is their MOA
Inhibition of glucan synthesis
26
Spectrum of activity of the echinocandins
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
27
Primary mechanism of resistance to echinocandins
Point mutations in glucan synthase
28
Administration of echinocandins
Only IV
29
T/F: echinocandins are extremely well tolerated with minimal, if any, adverse effects
True
30
Caspofungin has a half life of 9-11 hours. What is its specific spectrum of activity?
Invasive aspergillosis — only as salvage therapy in pts that don’t respond to amphotericin B
NOT a primary tx!
31
Micafungin has a half life of 11-15 hours. What is its specific spectrum of activity?
Mucocutaneous candidiasis
Candidemia
Prophylaxis of candidal infections in bone marrow transplant pts
32
Anidulafungin has a half-life of 24-48 hours. What is its specific spectrum of activity?
Esophageal candidiasis and invasive candidiasis, including candidemia
33
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?
CD4 T-cell counts
Viral load assays
Pt’s clinical status
34
What does HAART stand for?
Highly active antiretroviral therapy
35
MOA of nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
Competitive inhibition of HIV-1 reverse transcriptase
36
Primary mechanism of resistance to NRTIs
Point mutations in HIV-1 reverse transcriptase
37
All NRTIs may be associated with what adverse effect?
Mitochondrial toxicity
38
Abacavir is an NRTI that is a _______ analog
Guanosine
39
AEs of abacavir
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
40
Didanosine is an NRTI that is a synthetic analog of ________
Deoxyadenosine
41
AEs of didanosine
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)
42
NRTI that is a fluorinated analog of lamivudine
Emtricitabine
43
AEs of Emtricitabine
HA, diarrhea, nausea, rash
Hyperpigmentation of palms or soles may be observed, particularly in African Americans
44
What NRTI(s) also treat HBV, so discontinuation could exacerbate HBV sx in a patient infected with both HIV and HBV?
Emtricitabine
Lamivudine
Tenofovir alafenamide
45
Lamivudine is an NRTI that is a _____ analog
Cytosine
46
T/F: Lamivudine is rarely used d/t extreme side effect profile
False. AEs with Lamivudine are uncommon and hypersensitivity is rare
47
NRTI that is a thymidine analog
Stavudine
48
Major AE associated with Stavudine
Dose-related peripheral sensory neuropathy — increased by concomitant neurotoxic drug use or in pts with advanced immunosuppression
49
NRTI that is an acyclic nucleoside phosphonate (i.e., nucleotide) analog of adenosine
Tenofovir
50
Water soluble prodrug of active tenofovir recommended for use during pregnancy
Tenofovir disoproxil fumarate
51
AEs of tenofovir disoproxil fumarate
GI complaints most common — nausea, diarrhea, vomiting, flatulence
52
Phosphonoamidate prodrug of tenofovir, associated with less renal toxicity than Tenofovir disoproxil fumarate
Tenofovir alafenamide
53
AEs of tenofovir alafenamide
AEs are uncommon but may include GI sx or headache
54
NRTI that is a deoxythymidine analog and is safe to use in pregnant women
Zidovudine
55
AEs of Zidovudine
Macrocytic anemia
Neutropenia
GI intolerance, HA, insomnia
56
MOA of non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Bind directly to HIV-1 reverse transcriptase, resulting in allosteric inhibition of RNA and DNA-dependent DNA polymerase activity
57
What are the first generation NNRTIs?
Delavirdine
Efavirenz
Nevirapine
58
What are the second generation NNRTIs?
Etravirine
| Rilpivirine
59
What type of testing is recommended prior to intiating therapy with NNRTIs?
Baseline genotypic testing to screen for resistant HIV-1 reverse transcriptase mutants (point mutations that alter NNRTI binding)
60
AEs of NNRTIs as a class
GI intolerance
| Skin rash
61
Why are NNRTIs associated with many drug-drug interactions?
They are metabolized by the CYP450 system
62
________ 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 ______
Skin rash; pregnancy; CYP3A; CYP2D6
63
Efavirenz is combined with _____ and ______ as a once/daily combination pill
Tenofovir; emtricitabine
64
Efavirenz is metabolized by ____ and _____
CYP3A4; CYP2B6
65
AEs of Efavirenz
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
Can efavirenz be used in pregnancy?
Yes, but only after 8 weeks due to birth defects observed in a primate study
67
Etravirine is a diarylpyrimidine that acts as a substrate as well as an inducer of ________ and an inhibitor of _____ and ______
CYP3A4; CYP2C9 and CYP2C19
68
Most common AEs with etravirine
Rash
Nausea
Diarrhea
69
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
Nevirapine
70
AEs of nevirapine
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
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?
Yes, it is recommended for use in pregnancy
AEs = rash, depression, HA, insomnia, increased serum aminotransferases
72
MOA of protease inhibitors used in tx of HIV
Block the HIV protease and prevent maturation of the final structural proteins that make up the mature virion core
73
AEs of protease inhibitors as a class
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
Protease inhibitors are metabolized by _______.
______ has the most pronounced inhibitory effect, and ______ the least
CYP3A4
Ritonavir; saquinavir
75
Boosted _____ or ______ are recommended protease inhibitors for use in pregnant women
Atazanavir; darunavir
76
AEs of atazanavir
Most common = diarrhea and nausea
Skin rash in 20%
Indirect hyperbilirubinemia with overt jaundice (10%)
77
Darunavir is a protease inhibitor that must be co-administered with _____ or ______
Ritonavir; cobicistat
78
AEs of darunavir
Rash (occasionally severe)
Darunavir contains sulfonamide moiety — may cause hypersensitivity reaction in a pt with a sulfa allergy
79
Prodrug of amprenavir that is rapidly hydrolyzed by enzymes in the intestinal epithelium
Fosamprenavir
80
AEs of Fosamprenavir
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
AEs of indinavir
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
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
Ritonavir
83
_______ 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
Lopinavir
84
AEs of nelfinavir
Diarrhea and flatulence
[diarrhea may be dose limiting]
85
_______ 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
Ritonavir
86
A minimal amount of Saquinavir is absorbed when taken orally. .What are some AEs?
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
Which PI is indicated for use in treatment-experienced patients who harbor strains resistant to other PI-agents?
Tipranavir - often used in combo with ritonavir
88
AEs of tipranavir
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
Describe HIV’s viral attachment to host cells
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
Enfuvirtide is a synthetic 36-amino acid peptide. What is its MOA in the tx of HIV?
Binds gp41 preventing the conformational and structural changes needed to allow fusion of the viral envelope with the host cell membrane
91
Administration of enfuvirtide
Must be administered with subcutaneous injection 2x/day
92
Primary mechanism of resistance to enfuvirtide
Mutations in gp41
93
AEs of enfuvirtide
Local injection site reactions
No clinically relevant drug-drug interactions
94
MOA of maraviroc in tx of HIV
Binds specifically and selectively to CCR5 to prevent viral entry into host cell
95
Adminitration of maraviroc
Oral administration
96
Primary mechanism of resistance of maraviroc
Mutations in V3 loop of gp120
97
AEs of maraviroc
Generally well tolerated; systemic allergic reaction followed by hepatotoxicity has been reported
98
MOA of the integrase strand transfer inhibitors (INSTIs) in tx of HIV
Inhibit strand transfer and prevent integration of reverse-transcribed HIV DNA into the chromosomes of the host cell
99
AEs of INSTIs as a class
In general they are well tolerated
HA and GI effects most common
100
Dolutegravir is the preferred agent for tx of treatment-naive pts when given in combination with what other drugs?
Tenofovir/emtricitabine
Abacavir/lamivudine
101
The half life of dolutegravir is 14 hours. What are some AEs?
AEs not common
Hypersensitivity has been reported (rash and systemic sx)
102
Elvitegravir is an INSTI that is only available in combination with what other drugs?
Cobicistat
Emtricitabine
Tenofovir
103
Elvitegravir requires boosting with _____, an ______ of CYP3A4, to be efficacious. It is associated with few adverse effects
Cobicistat; Inhibitor
104
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
Raltegravir
105
List the nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) used to tx HIV
```
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine
```
106
List the non-nucleoside reverse transcriptase inhibitors (NNRTIs) used to tx HIV
```
Delavirdine
Efavirenz
Etravirine
Nevirapine
Rilpivirine
```
107
List the protease inhibitors (PIs) used to tx HIV
```
Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir
```
108
Fusion inhibitor used to tx HIV
Enfuvirtide
109
Entry inhibitor used to tx HIV
Maraviroc
110
What are the 3 integrase strand transfer inhibitors (INSTIs) used to tx HIV?
Dolutegravir
Elvitegravir
Raltegravir
111
CYP3A4 inhibitor (boosting agent) used in tx of HIV
Cobicistat
112
Key drugs used in tx of influenza
```
Oseltamivir
Zanamivir
Peramivir
Amantadine
Rimantadine
```
113
MOA of oseltamivir, zanamivir
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
Spectrum of activity of oseltamivir, zanamivir
Active against influenza A and B
Currently active against both H3N2 and H1N1
115
Mechanisms of viral resistance to the neuraminidase inhibitors
Mutations in neuraminidase (but worldwide resistance remains rare)
116
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?
Oseltamivir is a prodrug used orally, activated in the gut and the liver
Zanamivir is administered intranasally or by oral inhaler
117
AEs of oseltamivir and zanamivir
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
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
Peramivir
119
2 influenza drugs no longer used unless absolutely necessary d/t increased resistance
Amantadine
| Rimantadine
120
MOA of amantadine, rimantadine
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
Toxic effects of amantadine, rimantadine
GI irritation, dizziness, ataxia, slurred speech
122
Pharmacokinetic differences between amantadine and rimantadine
Rimantadine has longer half-life and requires no dose adjustments in pts with renal failure
