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Clinical Pharmacology II > Antiviral and Antiretroviral Therapies > Flashcards

Antiviral and Antiretroviral Therapies Flashcards

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1
Q

Goal of antiviral and antiretroviral therapy ?

A
  • Theoretical
    1) Eliminate the virus
  • Reality
    1) Reduce viral load 2) Maintain viral load
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2
Q

Definition of Induction therapy ?

A
  • Reduce the viral load (Titer) to a level that is undetectable and/or has no S&S
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3
Q

Definition of maintenance therapy?

A
  • Maintain viral load at a undetectable / lowest possible state
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4
Q

Influenza A and B ?

A
  • Negative sense ssRNA viruses
  • Single agent therapy

or

  • No Treatment
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5
Q

Herpes virus (HSV1, HSV2 and CMV)?

A
  • dsDNA viruses
  • Single agent therapy

&

  • Short treatment duration
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6
Q

Hepatitis Virus (HBV & HCV) ?

A
  • Positive sense ssRNA viruses
  • Two agent therapy

&

  • Long treatment duration
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7
Q

Retrovirus (HIV)

A
  • Three + Agents therapy

&

  • Indefinite treatment
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8
Q

Antiretro virals simply inhibit the production of new viruses

T or F

A
  • True

- Have no effect on pre existing viruses

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9
Q

T or F

Immune system is critical for clearing mature viruses ?

A
  • True
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10
Q

Viral resistance to antiretro therapies generally occurs when ?

A
  • The virus mutates and still allows the target protein to continue to work even when the drug is present
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11
Q

T or F

The viral mutation prevents the drug from binding (Resistance) but such mutations result in less virulent viruses?

A
  • True
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12
Q

How many steps can antiviral therapy target in a virus?

A
  • 9 Steps in viral replication
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13
Q

What do M2 anti influenza agents target?

A
  • M2 inhibitors block viral unpacking
  • Blocks the M2 proton pump = No unpacking
  • A lot of resistance not recommended
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14
Q

Neuraminidase inhibitors block what ?

A
  • Block viral escape from the host cell
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15
Q

MOA of Oseltamivir (Tamiflu) ?

A
  • Neuraminidase inhibitor
  • Reversibly binds and inhibits the viral Neuraminidase to block viral detachment from host cell
  • Impairs cleavage of Neuraminic acid tether
  • Impairs the enzyme Sialidase
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16
Q

T or F

Oseltamivir (Tamiflu) is given as a prodrug, activated by hepatic esterases into active metabolite

A
  • True
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17
Q

What does Oseltamivir (Tamiflu) treat?

A
  • Influenza A and B
  • Very little resistance thus far
  • Some resistance for avian flu H7N9
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18
Q

Adverse effects of Oseltamivir (Tamiflu)?

A
  • Some neuropsychiatric events have been reported
  • Self-injury
  • Delirium
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19
Q

Anti-herpesvirus agents target what ?

A
  • limit the viral replication during the lytic active phase
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20
Q

What are the Major targets for herpesvirus inhibition are vDNA synthesis?

A

1) NucleoSIDE DNA polymerase inhibitors
2) NucleoTIDE DNA polymerase inhibitors
3) Pyrophosphate analog DNA polymerase inhibitors

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21
Q

T or F

A NucleoSIDE has a phosphate group attached ?

A
  • False

- Pentose
Base + Ribose or Deoxyribose

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22
Q

T or F

A NuleoTIDE has a phosphate group attached?

A
  • True

- Pentose
Base + Ribose or Deoxyribose + Phosphate group

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23
Q

T or F

All antiherpesviruse agents mimic some part of the dNTP structure to deceive the DNA polymerase?

A
  • True
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24
Q

Valacyclovir and Valganciclovir are nucleoside analogs, what do they require?

A
  • Requires conversion to dNTP analogs for activity
  • Depends on
    1) Viral thymidine kinase
    2) Viral UL97 kinase
    3) Host cell kinase
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25
Cidofovir is a nucleotide analog (1 Phosphate), what does it require for activation?
- Requires conversion to dNTP analog for activity - Depends on 1) Host Kinase
26
Foscarnet is a pyrophosphate (Diphosphate) analog it requires viral and host kinase activation? t or F
- False - Mimics diphosphate product of DNA syn - Blocks DNA polymerase activity - Does not require viral or host cell kinase activation
27
Valacyclovir (Valtrex) (Improved nucleoside analog) MOA ?
- Inhibition of viral DNA polymerase
28
T or F Viral thymidine kinase able to phosphorylate any nucleoside (even though it’s not a “Thymidine)
- True
29
Treatment of activity of Valcyclovir ?
- Treats HSV 1 and HSV 2 | - Some coverage for VZV
30
Valcyclovir is a pro drug, L-valyl ester of Aacyclovir, Converted to acyclovir via first pass metabolism T or F
- True Better absorption - Less doses - Better efficacy
31
What is the most common resistance of Valcyclovir?
1) Viral Thymidine kinase mutations that prevent conversion to nucleotide analog (MOST COMMON) or 2) Viral DNA Polymerase mutations that prevent drug from binding and DNA incorporation
32
T or F Acyclovir can cause nephrotoxicity; Valacyclovir is much better tolerated
- True
33
Valcyclovir is excreted via the kidneys, taking what increases the serum concentration?
- Probenacid increases serum concentration
34
Valganciclovir (Improved nucleoside analog) mimics what?
- Mimics pentose sugar
35
What does Valganciclovir treat?
- > 100x more effective than Acyclovir against CMV - Approved for treatment of CMV in 1) Immunocompromised patients 2) HIV 3) Organ transplant
36
T or F Valganciclovir is given as a prodrug?
- True | - Take with food - Converted to Ganciclovir via first pass metabolism Valganciclovir = L-valyl ester of ganciclovir
37
Resistance to Valganciclovir is caused by what ?
- Mutations in viral UL97 | - Prevents drug from being phosphorylated
38
Valganciclovir adverse effects ?
- Myelosuppression
39
Valganciclovir is safe in pregnancy ? T or F
- False | - Teratogenic/mutagenic
40
T or F Cidofovir is a Nucleotide analog?
- True
41
MOA of Cidofovir ?
- Inhibition of viral DNA polymerase - Converted to diphosphate by host cell kinases - “looks” like a triphosphate - Activity is independent of viral kinases
42
T or F Cidofovir mimics a triphosphate?
- True | - Only needs host kinase for activity
43
Cidofovir resistance occurs when?
- Mutations in viral DNA polymerase that prevent it from binding drug
44
When is Cidofovir used?
- > 100x more effective than acyclovir against CMV - Treatment of CMV in immunocompromised patients (HIV; organ transplant) - Used for acyclovir-resistant HSV infections (no cross-resistance) (val) acyclovir-resistant HSV infections
45
T or F Cidofovir is used to treat acyclovir-resistant HSV infections (val)acyclovir-resistant HSV infections
- True | - No cross-resistance
46
T or F Cidofovir has poor absoprtion and is given IV
- True
47
Cidofovir is excreted via the Kidneys and is usually given with?
- Probenecid Protects kidneys from damage - Saline To further dilute urine
48
Cidofovir is contraindicated with other nephrotoxic agents T or F
- True
49
Adverse Effects of Cidofovir?
- Nephrotoxicity (proximal tubular nephropathy) - Fanconi syndrome Excess amounts of glucose, bicarbonate, phosphates (phosphorus salts), uric acid, potassium, and certain amino acids being excreted in the urine -Acid-base imbalances common
50
T or F Cidofovir is safe during pregnancy?
- False | - Teratogen/mutagen, incorporated into human DNA should be avoided in pregnancy
51
Foscarnet (Pyrophosphate (Diphsophate) analog) MOA ?
- Inhibition of viral DNA polymerase - Competitive inhibitor - Mimics Pyrophosphate (Diphosphate) - Competitively inhibits binding of new dNTP
52
Foscarnet is used to treat?
- CMV-induced retinitis in immunocompromised | patients (HIV; organ transplant; etc.)
53
Foscarnet resistance occurs via mutations in viral DNA polymerase? T or F
- True | - Prevent it from binding drug
54
T or F Foscarnet cleared primarily by the kidneys, Dosage must be carefully calculated based on Cr clearance!
- True
55
Foscarnet and Cidofovir have the same adverse effects? T or F
- True - Nephrotoxicity (proximal tubular nephropathy) - Fanconi syndrome Excess amounts of glucose, bicarbonate, phosphates (phosphorus salts), uric acid, potassium, and certain amino acids being excreted in the urine -Acid-base imbalances common
56
Goal treatment of HepB?
- Suppression of disease to slow progression of cirrhosis | - Reduce risk of liver cancer
57
Goal treatment of HepC?
- Eradication of virus - Absence of detectable virus 24 weeks after completion of therapy - Recommended for those at increased risk for progression to cirrhosis
58
T or F About 15-30% of patients clear HepC virus without treatment?
- True
59
PEGinterferon alfa (PEGylated interferon alpha) is used to treat?
- HepB and HepC (IV; SQ) | - Coadministered with a broad-spectrum antiviral such as Ribavirin
60
PEGinterferon alfa (PEGylated interferon alpha) MOA in treating HepB and HepC ?
- Binds to interferon receptors on host cells to - “prime” them to resist infection - Inhibits viral 1) Penetration 2) Translation 3) Transcription 4) Protein processing 5) Maturation 6) Release - Increases expression of viral antigens
61
PEGinterferon alfa (PEGylated interferon alpha) is contraindicated in pts with?
1) Hepatic decompensation 2) Autoimmune disease 3) Cardiac arrhythmia
62
PEGinterferon alfa (PEGylated interferon alpha) adverse side effects?
- Flu-like symptoms (30% of pts) resolve on their own - Neurologic symptoms - Autoantibodies - Arrhythmias
63
T or F Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide are both prodrugs of Tenofovir
- True
64
Where is the prodrug Tenofovir Disoproxil Fumarate (TDF) converted to Tenofovir?
- Plasma
65
Where is the prodrug Tenofovir Alafenamide converted to Tenofovir?
- Intracellularly
66
3 Benefits of the prodrug Tenofovir Alafenamide (TA) converting to Tenofovir intracellularly?
1) Lower dosing 2) Improved antiviral activity 3) Better distribution into lymphoid tissues
67
T or F Tenofovir is an Adenine nucleotide analog ?
- True
68
Tenofovir MOA?
- Developed as an Antiretroviral nucleotide 1) Inhibits DNA polymerase 2) Causes DNA chain termination
69
Tenofovir clinical use?
- HBV and HIV-1 - Included in regimens for pts coinfected with both viruses HepB/HIV - Because its Anti-HIV activity
70
Tenofovir is given PO and distribution is improved when given with fatty meals. T or F
- True
71
Tenofovir as a AntiRetroViral for HIV MOA
- Inhibits Reverse Transcriptase (rather than DNA polymerase) - Considered a Nucleotide RTI
72
Tenofovir adverse effects ?
- GI complaints
73
Anti-HCV agents distribute broadly into three categories based on their target, what are the targets?
1) NS3 (Protease) 2) NS5A 3) NS5B (RNA polymerase)
74
Ribavirin (guanosine nucleoside analog) has one exception when treating HepC, what is the exception?
Acts both nonspecifically on 1) mRNA 2) Viral RNA polymerase
75
Ribavirin (guanosine nucleoside analog) MOA?
- Broad-spectrum antiviral - Inhibits guanine capping of viral mRNA - Takes the place of 7-Methylguanosine Cap - Inhibits RNA-dependent RNA polymerase in RNA viruses - Preventing translation of viral mRNAs
76
Clinical use of Ribavirin?
- Only approved for HCV But effective against - HCV - IVA (Influenza A) - IVB (Influenza B) - HIV
77
Ribavirin contraindications include?
- Hemolytic Anemia - Renal Disease - Extremely Teratogenic, Mutagenic & Embryotoxic
78
Ribavirin is contraindicated in males and females trying to get pregnant T or F
- True - For six months prior to conception - Contraception during Tx and 6 months after
79
Grazoprevir (NS3/4A inhibitor) MOA ?
- Blocks NS3 viral protease activity that cleaves the polyprotein - Preventing the release of functional individual viral proteins
80
Grazoprevir and Ribavirin are Co formulated T or F
- True
81
T or F Grazoprevir has a long half life?
- True | - Extensively protein bound
82
Grazoprevir prevents cleavage of HepC polyproteins? T or F
- True
83
Why is Grazoprevir contraindicated in hepatic insufficiency?
- Metabolized heavily by CYP3A4 | - Contraindicated with many CYP3A4 inhibitors
84
Ledipasavir (NS5A inhibitor) is often co formulated with ?
- Grazoprevir NS5B (polymerase)/4A or - Ribavirin NS5B inhibitors
85
Ledipasavir has few drug drug interactions and well tolerated T or F
- True
86
Ledipasavir (NS5A inhibitor) treats ?
- HepC
87
Sofosbuvir (NS5B/RNA-dependent RNA polymerase inhibitor) MOA?
- Highly effective inhibitor of viral RNA polymerase - Yielding high cure rates - Prodrug nucleotide analog commonly coformulated with other anti-HCV agents
88
Sofosbuvir (NS5B/RNA-dependent RNA polymerase inhibitor) requires what?
- Requires prodrug conversion to nucleoside triphosphate (NTP) by HOST cellular kinases - Incorporated into elongating RNA strand and terminates chain
89
T or F Sofosbuvir (NS5B/RNA-dependent RNA polymerase inhibitor) is the newest most expensive drug
- True - Very high cure rates up to 97% - Extremely expensive $84,000 (12-week course)
90
Side effects of Sofosbuvir (NS5B/RNA-dependent RNA polymerase inhibitor) ?
- HA | - Fatigue
91
T or F Sofosbuvir (NS5B/RNA-dependent RNA polymerase inhibitor) is a P Glycoprotein substrate ?
- True | - Contraindicated with p Glycoprotein inducers
92
What are the two receptors on the host cell membrane where Retroviruses attach?
- CCR5 or CXCR4
93
What are the three most targeted pathways for Antiretroviral drugs?
1) Nucleoside RT inhibitors (NRTI's) 2) Necleotide RT inhibitors (Nucleotides) 3) Non-Nucleoside RT inhibitors (NNRTI's)
94
What do Proteases inhibitors (PI's) Target on retroviruses?
- Interfere with viral protein production
95
What do Integrase inhibitors target on retroviruses?
- Block vDNA into host genome | - Preventing trascription
96
T or F Antiretroviral (ART) therapy in indicated for ALL HIV infected pts?
- True - Limits disease progression - Limits transmission
97
T or F Most current therapies for HIV consist of 3+ drugs from different families?
- True - 2 NRTI's + - 1 PI or - 1 NNRTI or - 1 INSTI
98
T or F 25% of pt's with HIV also have HepC ?
- True - A lot of serous DD interactions with HepC meds - HepC compromises the liver & many ART drugs have hepatotoxicity
99
Nucleoside RT inhibitors (NRTI's) bind where?
- RT enzyme active site
100
Non-Nucleoside RT inhibitors (NNRTI's) bind where ?
- Adjacent to RT's active site | - Alters is shape
101
Non-Nucleoside RT inhibitors (NNRTI's) interferes with the binding of nucleotides or NRTI's on the RT enzyme? T or F
- False - Does not prevent from others binding - But does prevent OTHER NNRTI's from binding (Competitive inhibition) - Only 1 NNRTI at a time
102
Zidovudine AZT MOA ?
- NRTI - Competitive inhibitor of RT - Dock into enzyme active site - Preventing vDNA synthesis
103
Zidovudine is a Thymidine analog antimetabolite ? T or F
- True | - Prodrug requires host kinase for activation
104
What are the common adverse effects for ALL NRTI's ?
1) Hepatosteatitis (Fatty Liver) 2) Hepatotoxicicty 3) Lactic acidosis
105
Where does AZT target?
- T Cells
106
What resistance can AZT have ?
- Mutations of RT that prevent drug binding
107
T or F AZT Zidovudine is the First-line treatment in pregnant women due to excellent prevention of vertical transmission (mother to child)
- True
108
What medications can alter the metabolism of AZT Zidovudine causing an increase in the prodrug levels (CYP450) and impacting its clearance?
- Probenecid - Valproic acid - Fluconazole - Atovaquone
109
AZT Zidovudine toxicities include ?
- Hematologic toxicity is increased upon coadministeration of other myelosuppressive agents - (val)ganciclovir - Ribavirin - Conventional cytotoxic chemotherapeutics
110
Nevirapine (non-nucleoside reverse transcriptase inhibitor; NNRTI) MOA ?
- Binds to RT and allosterically inhibits DNA synthesis - Binds to a hydrophobic pocket adjacent to the NTP-binding site in RT - Changes the shape of RT enough that it cannot synthesize DNA.
111
Nevirapine (non-nucleoside reverse transcriptase inhibitor; NNRTI) is metabolized in the liver by CYP3A4, thus can act as an inducer or inhibitor depending on the drug T or F
- True - Often alters CYP3A4 function - Leading to DDI issues
112
Nevirapine crosses the placenta and thus ?
- Used to prevent vertical transmission during birth
113
Nevirapine can cause Hepatotoxicity, severe hepatitis that can be life-threatening (Sudden onset) T or F
- True
114
Nevirapine can cause a macropapular rash T or F
- True | - Dose dependent
115
Atazanavir (protease inhibitor) MOA?
- Docks into the substrate-binding site (Basket) between the monomers of the retroviral protease - Competitively inhibits the cleavage of the polyprotein - Prevents production of mature viral particles
116
Atazanavir (protease inhibitor) is associated with ?
- Buffalo hump - Gynecomastia - Cushing appearance - Central obesity
117
Atazanavir (protease inhibitor) can be coadministered with PPIs, H2-blockers, or other acid-reducing agents? T or F
- False - Requires low pH to function - Absorption impaired by divalent cations (antacids, Fe/Ca supplements)
118
T or F All PIs are extensively metabolized by CYP3A4 and many inhibit CYP3A4 and other CYP450s, Sometimes exploited clinically to “boost” the levels of other antiretroviral agents
- True - Glucouronidation by UGT1A1 - Strong inhibitor of CYP3A4 and CYP2C9
119
Atazanavir (protease inhibitor) mimics a polypeptide T or F
- True
120
Atazanavir (protease inhibitor) can cause hyperbilirubinemia due to UGT1A1 inhibition T or F
- True
121
Dolutegravir (integrase inhibitor) MOA ?
- Bind to integrase enzyme - Prevents it from integrating the vDNA into the host genome - The third and final step of provirus integration
122
Dolutegravir (integrase inhibitor) is imparied by divalent cations (antacids, Fe/Ca supplements, etc.) T or F
- True
123
Dolutegravir (integrase inhibitor) toxicities include?
- Hypersensitivity - Occasional liver dysfunction - Discontinue immediately and do not restart!
124
Dolutegravir (integrase inhibitor) Integrase inhibitors are generally devoid of serious side effects and thus are extremely commonly included in modern antiretroviral cocktails T or F
- True
125
Herpes medications
VVCF 1) Valacyclovir 2) Valganciclovir 3) Cidofovir 4) Foscarnet
126
HepC Medications
RGLS (riggles!) 1) Ribavirin 2 Grazoprevir 3) Ledipasavir 4) Sofosbuvir)
127
HIV medications
DANZ (dance!) 1) Dolutegravir 2) Atazanazvir 3) Nevirapine 4) Zidovudin

Clinical Pharmacology II (5 decks)

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