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

Pharmacology of Antivirals Dr. Lewis EXAM 4 Flashcards

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
Q

In what type of cells is the Cytomegalovirus latent?

A

-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

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26
Q

In which patient population is CMV seen the most?

A

often in immunocompromised patients

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27
Q

What is considered a CMV disease?

A

CMV viremia (systemic infection) PLUS end organ damage

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28
Q

Ganciclovir

A

-PO, IV, and intraocular
-PO and IV with wide distribution (CNS)
Renal elimination

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29
Q

Ganciclovir - Acyclovir similarites and differences

A

-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
Q

What is the purpose of Valganciclovir?

A

-L-valyl prodrug of ganciclovir increasing the BIOAVAILABILITY
-ONLY available PO
-once in the plasma it gets ester hydrolyzed to Ganciclovir

31
Q

Adverese effects of Valglanciclovir

A

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
Q

Which enzyme is responsible for the phosphorylation of Ganciclovir?

A

-Viral protein kinase (UL97), Phosphotransferase?

33
Q

How is resistance established against Ganciclovir?

A

-Alteration of the viral protein kinase UL97

(the viral DNA polymerase can develop resistance against similar antivirals)

34
Q

Foscarnet (Foscavir)

ANTI-CMV

A

-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
Q

MOA for Foscarnet (Foscavir)

A

-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
Q

Which antiviral drug is a NONCOMPETITIVE INHIBITOR?

A

Foscarnet (Foscavir)
it doesn’t compete with other nucleotides
it is an inorganic pyrophosphate analog

37
Q

Adverse effects of Foscarnet (Foscavir)

A

-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
Q

Cidofovir (Vistide®)

A

-Cytosine analog, Acyclic nucleoside phosphonate derivative
-IV only (intravitreal (eye injection) possible)
Spectrum: CMV, Foscarnet, and Ganciclovir resistant strains, and more

39
Q

How must Cidofovir (Vistide®) be administered?

A

-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
Q

MOA of Cidofovir

A

-it is already phosphorylated
-independent of viral kinases (Host enzymes convert to diphosphate (active drug))
ONLY 2 phosphorylations required

41
Q

Adverse effects of Cidofovir

A

-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
Q

Which drugs don’t require viral phosphorylation?

A

-Foscarnet (Foscavir) - doesn’t look like a NUCLEOTIDE and binds allosteric

-Cidofovir (acyclic) - already phosphorylated, 2 further phosphorylation with cellular enzymes

43
Q

Letermovir (Prevymis)

A

-highly specific for CMV
-NEW MOA!!!: First-in-class CMV DNA terminase complex inhibitor
-low side effects profile

-DISADVANTAGE: resistance may develop quickly

44
Q

Maribavir (Livtencity®)

A

-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
Q

Which drug inhibits the protein kinase UL97?

A

Maribavir (Livetencity)

46
Q

Hepatitis C

A

-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
Q

What are the drugs used to treat HCV?

A

-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
Q

Ribavirin

A

-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
Q

Guanine analogs

A

Acyclovir
Ganciclovir
Ribavirin

50
Q

Cytosine analog

A

Cidofovir

51
Q

What are the risks and toxicities of Ribavirin?

A

-Pregnancy Cat X (contraception until 6 mo after treatment) !!!!
-Hemolytic anemia (dose-related)
-Gout
-Insomnia
-needs to be renally adjusted

52
Q

What are the NS3/A4 drugs?

A

-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
Q

What are the NS5A drugs?

A

-inhibits NS5A (replication complex for viral RNA replication and assembly)

-nomenclature: -asvir

54
Q

What are the NS5B drugs?

A

-inhibit NS5B, an RNA-dependent RNA polymerase, and halts viral replication

-nomenclature: -busvir

55
Q

How does Epclusa® work?

A

-sofosbuvir/velpatasvir; NS5B and NS5A
-so it inhibits RNA-dependent RNA polymerase AND the replication complex

56
Q

What to look out for when Epclusa® is administered

A

-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
Q

How does Harvoni® and Mavyret® work?

A

-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
Q

What to look out for when Mavyret® is administered

A

-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
Q

What to look out for when Harvoni® is administered

A

-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
Q

Which regimen is recommended for 1a and 1b?

A

-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
Q

Which products should be avoided with amiodarone (anti-arrhythmic)?

A

Havoni and Epclusa
-they contain sofosbuvir

62
Q

Which drugs should be avoided with H2RAs and PPIs?

A

Havoni -> it contains ledipasvir (NS5A)
Epclusa -> it contains velpatasvir (NS5A)

63
Q

Which drugs should be avoided in patients with cirrhosis?

A

Mavyret, Zepatier, Vosevi, and simeprevir

64
Q

Coronavirus

A

-(+) 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
Q

How are COVID patients commonly treated?

A

Remdesivir, Dexmethasone, and an Immunomodulator (tocilizumab, baricitinib, tofacitinib, sarilumab)

66
Q

How does Nirmeltravir/ritonavir work?

A

-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
Q

MOA for Remdesivir

A

-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
Q

What is the purpose of Immunomodulators?

A

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
Q

When might Molnupiravir be used?

A

-When the provider doesn’t want to use Remdesivir infusion or Ritonavir

-inhibits viral RNA polymerase

70
Q

MOA for Bebtelovimab

A

-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
Q

What are the FDA-approved drugs against Ebola?

A

-Inmazeb (combination of 3 monoclonal abs) !!!
-Ebanga (1 mab) !!!
-directed against surface glycoprotein !!!
-only studied against Zaire Ebola virus, in DR Congo

72
Q

What is Tecovirimat’s (Tpoxx) indication?

A

-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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