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Infectous Disease > Pharmacology of Antivirals Dr. Lewis EXAM 4 > Flashcards

Pharmacology of Antivirals Dr. Lewis EXAM 4 Flashcards

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1
Q

What are the steps of viral infections drugs can interfere with?

A
  1. Binding
  2. Uncoating
  3. Nucleotide synthesis - blocked with NRTIs (fake nucleotides, nucleosides)
  4. Integration into host genome - blocked with Integrase inhibitors
  5. viral protein processing - block proteases with Protease inhibitors
  6. Budding, Release of the virus - blocked by neuraminidase inhibitor
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2
Q

Characteristics of Herpes Simplex 1 and 2

A

-virus establishes latency in neurons after infection
-mostly asymptomatic
-painful, clustered vesicles with an erythematous base
-oro-facial, genital, eye, skin, CNS, esophagus, respiratory, liver, and rectum

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3
Q

Symtoms of Herpes Simplex 1 and 2

A

Mononucleosis syndrome: pharyngitis, fever, cervical lymphadenopathy

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4
Q

What is the primary infection of the Varicella-zoster virus called?

A

Chicken Pox or Varicella
-Fever< 103°F
-malaise (feeling unwell) prior to rash
-(maculopapular, vesicles, scabs) occurring in crops

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5
Q

What is the reactivation of the Varicella-zoster virus called?

A

Shingles or Zoster
-dermatomally-based, unilateral eruption (one-sided)
-Thoracolumbar most frequent (at the back)

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6
Q

When does Varicell-zoster become concerning?

A

-with Facial/ocular involvement
-Major concern: post-herpetic neuralgia (PHN)
-> Burning pain in nerves and the skin even after the rash goes away

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7
Q

What are the oral agents used to treat Herpes Simplex and varicella zoster?

A

Cyclovirs

Acyclovir
Valacyclovir (Acyclovir with Valin side chain)
Famciclovir

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8
Q

What are the ophthalmic agents used to treat Herpes Simplex and varicella zoster?

A

-Trifluridine
-Ganciclovir

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9
Q

What are the topical agents used to treat Herpes Simplex and varicella zoster?

A

-Acyclovir
-Docosanol
-Penciclovir

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10
Q

How strong is the Bioavailability of Acyclovir?

A

-not great: oral: 15-20%
-> Development of Valacyclovir: Valin provides protection from acid degradation

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11
Q

Is Acyclovir appropriate to treat herpes Encephalitis?

A

Yes, it is distributed widely (CNS)
20-50% serum values

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12
Q

Formulation of Acyclovir?

A

IV, PO, topical

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13
Q

What is required for Acyclovir to work against its viral target?

A

-Requires viral thymidine kinase: 1st phosphorylation

-it is Guanine analog competing with deoxyguanosine triphosphate for the viral DNA polymerase
-> INHIBITION when the false Guanini is taken up

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14
Q

What is the rate-limiting step during the incorporation of Acyclovir?

A

First phosphorylation through the viral thymidine kinase !!!!

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15
Q

Why does the elongation stop when Acyclovir is incorporated?

A

Because it does NOT have a 3’ OH binding site, which is required to bind to the phosphate of the next nucleotide

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16
Q

What are Acyclovir’s adverse effects?

A

-well tolerated
-at high doses: it can sit in the kidney and crystallize -> nephrotoxicity, so it needs to be given with lots of IV fluid
-TTP (thrombocytopenic purpura)/HUS (hemolytic uremic syndrome): at high doses
-Phlebitis: inflammation causing blood clotting
-Anemia
-GI symptoms and headache
-Neurolgic: somnolence, hallucinations, confusion
coma

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17
Q

What are the DDIs of Acyclovir?

A

Probenecid: may increase levels of Acyclovir

Meperidine: may have normeperidine (toxic metabolite of Meperidine) levels increased

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18
Q

What is the role of the L-valyl ester prodrug of Acyclovir? = Valacyclovir

A

Improves Bioavailability !!!
-Valacyclovir is orally available only

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19
Q

What is Famciclovir converted to in the liver and intestines?

A

Penciclovir, which is also the topical version of Famciclovir

-Famciclovir is only given ORALLY !!!

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20
Q

Why is Famciclovir sometimes preferred over Acyclovir or Valacyclovir?

A

-resistance (TK alteration) over time when Acyclovir is used in chronically ill patients

-Because it has activity against Thymidine kinase-altered viral strains

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21
Q

How is Orolabial herpes treated?

A

-Topicals
-Penciclovir (Denavir® 1% cream)
-Docosanol (Abreva® OTC)

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22
Q

How is Peniclovir different from Docasonal?
!!!

A

different MOA: Docasonal interferes with viral fusion to host cell !!!!
-prevents entry & replication

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23
Q

How is Herpes Simplex Keratoconjuctivitis treated?

A

-Trifluridine ophthalmic drops (Viroptic® 1%) - probably given with a systemic drug
->also active against acyclovir-resistant strains

-Ganciclovir ophthalmic gel (Zirgan® 0.15%)

Trifluridine is the better option

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24
Q

What is special about the spectrum of Anti Cytomegalovirus agents

A

They also treat Herpes Simplex and Varicella zoster infections
-except Letermovir !!

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25
In what type of cells is the Cytomegalovirus latent?
-life-long latency in kidneys and glands after primary infection -transmitted: sexually or by close contact, blood or tissue exposure, perinatally -lungs, liver, kidneys, esophagus, GI tract, CNS, heart, pancreas, and eyes
26
In which patient population is CMV seen the most?
often in immunocompromised patients
27
What is considered a CMV disease?
CMV viremia (systemic infection) PLUS end organ damage
28
Ganciclovir
-PO, IV, and intraocular -PO and IV with wide distribution (CNS) Renal elimination
29
Ganciclovir - Acyclovir similarites and differences
-Both are Guanine analogs BUT -Ganciclovir is phosphorylated (1st phosphorylation) via the CMV phosphotransferase (rather than a viral TK) -Ganciclovir contains a 3' OH group allowing for DNA elongation (with being a false nucleotide though)
30
What is the purpose of Valganciclovir?
-L-valyl prodrug of ganciclovir increasing the BIOAVAILABILITY -ONLY available PO -once in the plasma it gets ester hydrolyzed to Ganciclovir
31
Adverese effects of Valglanciclovir
if not renally adjusted -reversible pancytopenia (decrease in all blood cell types - toxicity against bone marrow) !!!! dangerous for patients who have bone marrow or organ transplant -fever, rash, Phlebitis, confusion, seizure
32
Which enzyme is responsible for the phosphorylation of Ganciclovir?
-Viral protein kinase (UL97), Phosphotransferase?
33
How is resistance established against Ganciclovir?
-Alteration of the viral protein kinase UL97 (the viral DNA polymerase can develop resistance against similar antivirals)
34
Foscarnet (Foscavir) ANTI-CMV
-IV only -spectrum: CMV, Acyclovir resistant HSV and VSZ -EBV, Influenza A and B, HepB, and HIV -> but not used for those -very nephrotoxic: to reduce the risk of renal failure --> given with Saline loading -> renal adjust -> Avoid other nephrotoxic meds
35
MOA for Foscarnet (Foscavir)
-doesn't look like a NUCLEOTIDE, it works allosteric site (not on the binding site) -Inorganic pyrophosphate analog -used for strains that have developed resistance to agents binding to the binding pocket -DOES NOT require thymidine kinase !!! -NON-competitive inhibitor !!!!
36
Which antiviral drug is a NONCOMPETITIVE INHIBITOR?
Foscarnet (Foscavir) it doesn't compete with other nucleotides it is an inorganic pyrophosphate analog
37
Adverse effects of Foscarnet (Foscavir)
-Renal dysfunction (common, can require dialysis) -Electrolyte abnormalities (low Ca, PO4, Mg, K) - monitored regularly -Bone marrow toxicity (like Ganciclovir) -elevated LFTs -Paresthesia and seizures DDIs: nephrotoxic agents, Imipenem
38
Cidofovir (Vistide®)
-Cytosine analog, Acyclic nucleoside phosphonate derivative -IV only (intravitreal (eye injection) possible) Spectrum: CMV, Foscarnet, and Ganciclovir resistant strains, and more
39
How must Cidofovir (Vistide®) be administered?
-very nephrotoxic: if SCr is over 1.5 the pt can't even take the drug -Renally adjusted !!! -With Probenecid and lots of hydration (increases systemic levels and decreases the rate in which it gets to the kidney)
40
MOA of Cidofovir
-it is already phosphorylated -independent of viral kinases (Host enzymes convert to diphosphate (active drug)) ONLY 2 phosphorylations required
41
Adverse effects of Cidofovir
-very nephrotoxic -in ~25% (proteinuria, azotemia, and proximal tubular dysfunction) -Metabolic acidosis with Fanconi’s syndrome -Neutropenia DDIs: -Nephrotoxic agents -Probenicid will interact with other meds
42
Which drugs don't require viral phosphorylation?
-Foscarnet (Foscavir) - doesn't look like a NUCLEOTIDE and binds allosteric -Cidofovir (acyclic) - already phosphorylated, 2 further phosphorylation with cellular enzymes
43
Letermovir (Prevymis)
-highly specific for CMV -NEW MOA!!!: First-in-class CMV DNA terminase complex inhibitor -low side effects profile -DISADVANTAGE: resistance may develop quickly
44
Maribavir (Livtencity®)
-for post-transplant CMV infection when the other drugs do not work (last line; Ganciclovir -> Foscarnet -> Cidofovir -> Maribavir) -MOA: competes with viral protein kinase and prevents the phosphorylation of the substrates -DDIs: -antagonize Ganciclovir bc it blocks the kinase and prevents phosphorylation (Why is Ganciclovir used w/ Maribavir???) -weak inhibitor of CYP3A4
45
Which drug inhibits the protein kinase UL97?
Maribavir (Livetencity)
46
Hepatitis C
-flavivirus, enveloped, positive sense, ss RNA (herpes is ds RNA) -agents are genotype-specific Genotype 1: 70-75% in the US Genotype 2 and 3: 15-20% in the US Genotype 4-7: other parts of the world
47
What are the drugs used to treat HCV?
-Ribavirin still used with some regimens -NS3/4A Protease inhibitors (-previr) -NS5A replication complex inhibitors (-asvir) !!! -NS5B polymerase inhibitors (-buvir) !!! (NS = nonstructural protein) -Pegylated interferon is no longer recommended
48
Ribavirin
-Guanine analog PK: oral (higher with fat meal), IV, nebulizer (RSV); Renal elimination MOA: not fully understood: inhibits guanosine triphosphate formation – Inhibits viral RNA-dependent RNA polymerase – Inhibits viral mRNA capping -Broad spectrum
49
Guanine analogs
Acyclovir Ganciclovir Ribavirin
50
Cytosine analog
Cidofovir
51
What are the risks and toxicities of Ribavirin?
-Pregnancy Cat X (contraception until 6 mo after treatment) !!!! -Hemolytic anemia (dose-related) -Gout -Insomnia -needs to be renally adjusted
52
What are the NS3/A4 drugs?
-inhibits NS3A/4 -> Protease inhibitors RECOGNIZE -previr as protease inhibitor !!! -it prevents viral maturation -should not be used Child-pugh over 6 (impaired kidney -> increased blood levels)
53
What are the NS5A drugs?
-inhibits NS5A (replication complex for viral RNA replication and assembly) -nomenclature: -asvir
54
What are the NS5B drugs?
-inhibit NS5B, an RNA-dependent RNA polymerase, and halts viral replication -nomenclature: -busvir
55
How does Epclusa® work?
-sofosbuvir/velpatasvir; NS5B and NS5A -so it inhibits RNA-dependent RNA polymerase AND the replication complex
56
What to look out for when Epclusa® is administered
-Pangenotypic with or without cirrhosis -Can be given with Ribanivir in decompensated cirrhosis (Liver damage) DDI: amiodarone; CYP inducer: carbamazepine, oxacarbazine, phenobarbital, phenytoin, rifampin !!! -separate from antacids by 4h !!! and don't exceed famotidine of 40mg/day; take 4h before PPI
57
How does Harvoni® and Mavyret® work?
-Harvoni®: sofosbuvir/ledipasvir -> NS5B and NS5A -Mavyret®: glecaprevir/pibrentasvir -> NS3/A4 (protease inhibitor) and NS5A CAUTION: protease inhibitor can't be given in case of liver impairment
58
What to look out for when Mavyret® is administered
-it is Pangenotypic -Contains a protease inhibitor (NS3/4A) -DDI: CYP inducer: carbamazepine, rifampin, efavirenzestradiol contraceptives, St. John's wort, atazanavir, darunavir, lopinavir, ritonavir, atorvastatin, lovastatin, simvastatin !!!! -No issues with hemodialysis !!!
59
What to look out for when Harvoni® is administered
-works for Genotypes 1, 4, 5, and 6 -with cirrhosis, compensated cirrhosis (Child-pugh A) and decompensated cirrhosis (Child-pugh B and C) DDI: CYP-inducer: carbamazepine, oxcarbazine, phenobarbital, phenytoin, rifamycins; rosuvastatin, simeprevir, tipranavir, PPI’s -seperate from antacids by 4 hours -12 hours apart from H2RAs
60
Which regimen is recommended for 1a and 1b?
-Mavyret (Glecaprevir/pibrentasvir) (NS3/4A and (NS5A) -> Pangenotypic -Epclusa ( Sofosbuvir/velpatasvir) (NS5B and NS5A) -> Pangenotypic -Harvoni (Ledipasvir/sofosbuvir) (NS3/4A and NS5B) -> for Genotype 1, 4, 5, and 6 Zepatier (Elbasvir/grazoprevir) (NS5A and NS3/4A)
61
Which products should be avoided with amiodarone (anti-arrhythmic)?
Havoni and Epclusa -they contain sofosbuvir
62
Which drugs should be avoided with H2RAs and PPIs?
Havoni -> it contains ledipasvir (NS5A) Epclusa -> it contains velpatasvir (NS5A)
63
Which drugs should be avoided in patients with cirrhosis?
Mavyret, Zepatier, Vosevi, and simeprevir
64
Coronavirus
-(+) sense, ss RNA -Structural proteins: spike (S), envelop (E), membrane (M), and nucleocapsid (N) --> Spike is the target, rapid mutations though 7 viruses infecting humans: 229E, NL63, OC43 and HKU1- common cold SARS, MERS, SARS-CoV-2
65
How are COVID patients commonly treated?
Remdesivir, Dexmethasone, and an Immunomodulator (tocilizumab, baricitinib, tofacitinib, sarilumab)
66
How does Nirmeltravir/ritonavir work?
-used for high risk of progression -Proteas inhibitor -> inhibits the protease of the SARS-CoV protease -because of Ritonavir (CYP-inducer): check for DDIs !!!!
67
MOA for Remdesivir
-it is an adenosine nucleotide that will be incorporated instead of ATP into the nascent RNA chain by the RNA polymerase -may cause renal and liver dysfunction
68
What is the purpose of Immunomodulators?
To slow down the Hyperimmuno response if the patient needs supplemental oxygen: start with Dexamethasone -> if it doesn't work give IL-6 inhibitor or JAK-inhibitor
69
When might Molnupiravir be used?
-When the provider doesn't want to use Remdesivir infusion or Ritonavir -inhibits viral RNA polymerase
70
MOA for Bebtelovimab
-it is a neutralizing monoclonal antibody -it covers up the spike protein and prevents the virus from binding to its target cells -works like the vaccine
71
What are the FDA-approved drugs against Ebola?
-Inmazeb (combination of 3 monoclonal abs) !!! -Ebanga (1 mab) !!! -directed against surface glycoprotein !!! -only studied against Zaire Ebola virus, in DR Congo
72
What is Tecovirimat's (Tpoxx) indication?
-indicated for smallpox, has activity against M-pox !!! MOA: inhibits orthopoxvirus VP37 envelope-wrapping protein (for cell-cell and long-range dissemination)

Infectous Disease (29 decks)

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