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Antivirals Flashcards

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1
Q

Classes of Antivirals

A

– Hepatitis inhibitors
– Non‐nucleoside reverse transcriptase inhibitors
– HIV protease inhibitors
– Fusion/Entry
– Integration inhibitors.

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2
Q

Antiherpes/CMV Drug list

A
  • Acyclovir
  • Ganciclovir
  • Foscarnet
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3
Q

Antihepatitis Drug List

A
  • Interferons
  • Ribavirin
  • Simepravir
  • Sofosbuvir
  • Ledipasvir/Sofosbuvir
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4
Q

Anti-influenza

A

• Amantidine, Oseltamivir, Zanamivir

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5
Q

Inhibition of Viral DNA polymerase

A
  1. acyclovir
  2. vidarabine
  3. foscarent
  4. ganciclovir
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6
Q

DNA structure

A

base + sugar = nucleoside
base + sugar + phosphate = nucleotide

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7
Q

Herpes simplex virus agens

A

Acyclovir
*guanosine look alike

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8
Q

Antiherpes MOA

A

Hase to undergo 3 phosphorylations . . .
inhibits polymerization and causes chain termination.

Competes with deoxyGTP and competitively inhibits viral DNA polymerase, therefore no DNA synthesis.

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9
Q

What is the first step for the MOA of Acyclovir?

A

Metabolically activated via 3 phosphorylations. Initial
phosphorylation occurs by viral thymidine kinase

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10
Q

Acyclovir ADME

A

– May be administered topically and via i.v.
(unique to acyclovir)
– Diffuses into most tissues/body fluids including CSF

The earlier in the infection that you take it, the better.

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11
Q

Acyclovir is a first-line agent against:

A

Herpes simplex encephalitis

neonatal HSV

severe HSV or

VZV infections

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12
Q

Main acyclovir TOXICITIES

A

neuro and renal toxicity

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13
Q

Acyclovir mechanism of resistance

A

Alteration (mutation) in viral thymidine kinase or viral _DNA
polymerase_ (Primary mechanism)
– Cross resistant to valacyclovir, famciclovir, ganciclovir

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14
Q

Acyclovir resistance can be treated with:

A

Foscarnet (doesn’t require viral phosphorylation)

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15
Q

Anti CMV agents

A
  • Ganciclovir
  • Foscarnet
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16
Q

Ganciclovir MOA

A

Acyclic guanosine analog (requires tri‐phosphorylation similar to acyclovir), first phosphorylation cataylzed by CMV kinase

Active against: CMV (100x > acyclovir)

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17
Q

What is the main toxicity of Ganciclovir?

A

Myelosuppression

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18
Q

When is the treatment of CMV related to transplant?

A

Used as treatment/prophylaxis for CMV post‐transplantation

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19
Q

Foscarnet MOA

A

Inhibits Viral DNA polymerase, RNA polymerase, HIV RT. No activation required!!!!

Looks like phosphate

Useful in strains resistant to acyclovir

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20
Q

Foscarnet Administration

A

IV only!!!!

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21
Q

Foscarnet TOXICITIES

A
  • Renal toxicity
  • Hyperphosphatemia, hypokalemia/calcemia/magnesemia
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22
Q

AntiHepatitis Agents

A
  • *Ribavarin**
  • *Pegylated (Peg) Interferon**

HCV Protease Inhibitors **not HIV*

Simeprevir (Olysio)

HCV Polymerase Inhibitors
Sofosbuvir (Solvadi)
Sofosbuvir/Ledipasvir (Harvoni)

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23
Q

How do the interferons work?

A

Pegylated forms = LONG half lives! (once per week injection)
antiviral

immunomodulatory (boosts immunity)

antiproliferative actions

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24
Q

How does INterferon work?

A

Interferon alpha

_ Induces_ intracellular signals leading to _inhibition of viral
penetration/translation/transcription/protein
processing/maturation_, and release
↑ major histocompatibility complex antigens

↑ phagocytic activity of macrophages
↑ the proliferation and survival of cytotoxic T cells.
Has direct effect on virus as well

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25
What are the toxicities of alpha interferon?
"flu-like symptoms" = biggest downfall **_abortifacent_**
26
Ribavirin (HCV)
**_Guanosine analog_** that is *phosphorylated intracellularly* . *Blocks capping of viral mRNA* _**inhibits viral RNA‐dependent polymerase**_ \**Can be used in combination with interferon*
27
Ribavarin (HCV) Toxicities
Hemolytic anemia ## Footnote **_teratogenic_**
28
How is Simeprevir used?
``` Oral use in **_combination w/peginterferon alfa and ribavirin to treat HCV_** genotype 1 (Standard of care, 24‐48 weeks) ```
29
Simeprevir MOA
Protease inhibitor: **_Targets NS3/4A protease_**
30
Simeprevir toxicities
P‐glycoprotein transporter/**_CYP3A4_** inhibitors/substrates = Rx‐Rx interactions (**_rosuvastatin/atorvastatin_**)
31
What is the most effective drug for HCV?
Sofosbuvir
32
Sofosbuvir MOA
RNA‐dependent **_NS5B_ RNA Polymerase inhibito**r.
33
What's special about Sofosbuvir?
Activity against **_all HCV genotypes_** (1‐6) AND those resistant to PIs. Use in **combo with w/peginterferon alfa and ribavirin**
34
What are Sofosbuvir Toxicities?
**_P‐glycoprotein transporter substrate_**, contraindicated with P‐gp inducers (**rifampin**). $1,000 per pill!!!!!!
35
Ledipsavir/Sofosbuvir
Inhibits **_NS5A_** protein which impacts replication (interacts with NS5B), assembly, release and host cell function
36
Ledipsavir/Sofosbuvir Effectiveness
Activity against **_all HCV genotypes_** (1‐6) AND those resistant to PIs. 99% SVR!! FDA approved combo without peg or ribavarin.
37
When do you give anti-influenza agents?
Quicly, withing 48 hrs of onset of symptoms
38
How do Tamiflu and Relenza work?
Oseltamivir (Tamiflu,oral) and zanamivir (Relenza, inhalation) – **Neuraminidase inhibitors:** Analogs of **_sialic acid_** = inhibit release
39
Tamiflu and Relenza Targets
Activity against **_influenza A and B_**. *Zanamivir* is useful against **oseltamivir‐resistant strains**
40
**_Anti-retroviral_** Non-Nucleoside/Nucleotide RTI
1. Abacavir 2. Tenofovir 3. Lamivudine/Emtricitibine 4. Efavirenz Don't wanna b LATE!!
41
**_Antiretroviral_** HIV protease inhibitors
1. Ritonavir 2. Darunavir 3. Atazanavir
42
**_Antiretroviral_** Fusion, entry, and integration inhibitors
1. Enfuvirtide 2. Maraviroc 3. Dolutegravir
43
How do proviruses enter a cell?
1. **_Bind_** to **CD4/Chemokine **receptors 2. **_Fuse_** with cell, uncoating 3. **_Synthesize dsDNA_** copy of ssRNA genome by RT 4. Translocate to nucleus 5. **_Integrate i_**nto DNA 6. Transcribe/Translate viral proteins (by cell) 7. Assemble new virions = **_Proteolytically "mature" virus_**
44
Why are retroviruses prone to resistance?
Retroviral replication ERROR PRONE = **_Increased_** mutation frequency
45
What is Cobicistat used for?
**CYP3A4 inhibitor** therefore increases **_bioavailability of other_** drugs
46
Combo THERAPY
Standard of care. Drugs are selected based on patient’s strain resistance: **Genotype strain for mutations in RT and protease genes.**
47
Nucleoside reverse transcriptase inhibitors | (NRTIs)
**Competitive inhibition** of RT – Incorporation into viral DNA. **_Activated by cellular phosphorylation to triphosphate_**
48
Why is there usually resistance to NRTIS?
Mutations in viral RT
49
What is an example of NRTIs?
Zidovudine/AZT
50
NRTI Toxicity
**_ Lactic acidosis w/hepatic steatosis_** – life‐ threatening – **Due to NRTI‐mediated inhibition of mitochondrial function ***Build‐up of triglycerides* = hepatic steatosis
51
Abacavir Toxicities
**_Myocardial infarction_** **_Hypersensitivity reactions _**
52
Who should not receive Abacavir?
_**Individuals with HLA‐B\*5701**_ or a **_reaction_** should NEVER receive abacavir!!!!
53
Lamivudine & Emtricitabine
**_Used in HBV treatment_** (inhibits HBV RT) Emtricitabine = fluorinated analog of lamivudine = long t½ = **_once‐daily dosing_**
54
Tenofovir
nucleotide analog of **adenosine. Competitively inhibits HIV RT = chain termination after incorporation into DNA**
55
How is Tenofivir Administered?
Tenofovir is co‐administered **_with emtricitabine_** as a first‐line RTI backbone therapy
56
Tenofivir Toxicity
**_Renal Accumulation:_** Tubular necrosis, Renal failure, Fanconi’s Syndrome
57
Non‐nucleoside Reverse Transcriptase Inhibitors | (NNRTIs)
Efavirenz Bind directly to **HIV‐1 reverse transcriptase** and inhibit RNA‐ and DNA‐dependent DNA polymerase activity *• Binding site of NNRTIs is distinct from that of **NRTIs (allosteric)***
58
DDIs with NNRTs!
Extensive metabolism/induction **_via P450_** (CYP3A4) pathway = drug‐drug interactions (limits use in HAART)
59
Efavirenz
Half life is DAYS!!! Toxicity: **_Nightmares/Psychiatric disturbances_** (at start of therapy, then resolve)
60
HIV protease inhibitors
Pepitdomimetics. Metabolized by, inhibitors of CYP3A4 (drug interactions)
61
HIV protease inhibitors TOXICITIES
– Lipodystrophy – ↑ triglycerides/LDL
62
PI: Ritonavir
Inhibitor of CYP3A4 = **used with other PIs to ↑ their serum levels**= less frequent dosing, more tolerability (“BOOSTING”) ↑ triglycerides/LDL, elevated serum aminotransferase levels
63
Atazanavir
Concurrent use with a**_ntacids_** block absorption
64
Darunavir
**Don't give with sulfa allergy!!!**
65
Lopinavir
Only available as a **_fixed dose combo w/ritonavir_** ## Footnote *ritonavir Inhibits CYP3A4 = ↑ lopinavir blood levels*
66
Entry Inhibitors
Maraviroc: **Binds selectively to CCR5**
67
When is Maraviroc used?
Used in HIV‐1 strains resistant to other drugs
68
Enfuvirtide
**Binds to gp41 s** – Sub‐cutaneous injection (peptide) Only for treatment experienced HIV patients **_w/ongoing HIV replication_**
69
Integrase Strand TransferInhibitors (INSTIs) ## Footnote **_"gravir"_**
Dolutegravir: Inhibits viral DNA strand integration in host genome \*effective in INSTI resistance
70
Treatment Targets

Pharmacology (9 decks)

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