Pharmacology of Antivirals Dr. Lewis EXAM 4 Flashcards
What are the steps of viral infections drugs can interfere with?
- Binding
- Uncoating
- Nucleotide synthesis - blocked with NRTIs (fake nucleotides, nucleosides)
- Integration into host genome - blocked with Integrase inhibitors
- viral protein processing - block proteases with Protease inhibitors
- Budding, Release of the virus - blocked by neuraminidase inhibitor
Characteristics of Herpes Simplex 1 and 2
-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
Symtoms of Herpes Simplex 1 and 2
Mononucleosis syndrome: pharyngitis, fever, cervical lymphadenopathy
What is the primary infection of the Varicella-zoster virus called?
Chicken Pox or Varicella
-Fever< 103°F
-malaise (feeling unwell) prior to rash
-(maculopapular, vesicles, scabs) occurring in crops
What is the reactivation of the Varicella-zoster virus called?
Shingles or Zoster
-dermatomally-based, unilateral eruption (one-sided)
-Thoracolumbar most frequent (at the back)
When does Varicell-zoster become concerning?
-with Facial/ocular involvement
-Major concern: post-herpetic neuralgia (PHN)
-> Burning pain in nerves and the skin even after the rash goes away
What are the oral agents used to treat Herpes Simplex and varicella zoster?
Cyclovirs
Acyclovir
Valacyclovir (Acyclovir with Valin side chain)
Famciclovir
What are the ophthalmic agents used to treat Herpes Simplex and varicella zoster?
-Trifluridine
-Ganciclovir
What are the topical agents used to treat Herpes Simplex and varicella zoster?
-Acyclovir
-Docosanol
-Penciclovir
How strong is the Bioavailability of Acyclovir?
-not great: oral: 15-20%
-> Development of Valacyclovir: Valin provides protection from acid degradation
Is Acyclovir appropriate to treat herpes Encephalitis?
Yes, it is distributed widely (CNS)
20-50% serum values
Formulation of Acyclovir?
IV, PO, topical
What is required for Acyclovir to work against its viral target?
-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
What is the rate-limiting step during the incorporation of Acyclovir?
First phosphorylation through the viral thymidine kinase !!!!
Why does the elongation stop when Acyclovir is incorporated?
Because it does NOT have a 3’ OH binding site, which is required to bind to the phosphate of the next nucleotide
What are Acyclovir’s adverse effects?
-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
What are the DDIs of Acyclovir?
Probenecid: may increase levels of Acyclovir
Meperidine: may have normeperidine (toxic metabolite of Meperidine) levels increased
What is the role of the L-valyl ester prodrug of Acyclovir? = Valacyclovir
Improves Bioavailability !!!
-Valacyclovir is orally available only
What is Famciclovir converted to in the liver and intestines?
Penciclovir, which is also the topical version of Famciclovir
-Famciclovir is only given ORALLY !!!
Why is Famciclovir sometimes preferred over Acyclovir or Valacyclovir?
-resistance (TK alteration) over time when Acyclovir is used in chronically ill patients
-Because it has activity against Thymidine kinase-altered viral strains
How is Orolabial herpes treated?
-Topicals
-Penciclovir (Denavir® 1% cream)
-Docosanol (Abreva® OTC)
How is Peniclovir different from Docasonal?
!!!
different MOA: Docasonal interferes with viral fusion to host cell !!!!
-prevents entry & replication
How is Herpes Simplex Keratoconjuctivitis treated?
-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
What is special about the spectrum of Anti Cytomegalovirus agents
They also treat Herpes Simplex and Varicella zoster infections
-except Letermovir !!
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
In which patient population is CMV seen the most?
often in immunocompromised patients
What is considered a CMV disease?
CMV viremia (systemic infection) PLUS end organ damage
Ganciclovir
-PO, IV, and intraocular
-PO and IV with wide distribution (CNS)
Renal elimination
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)
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
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
Which enzyme is responsible for the phosphorylation of Ganciclovir?
-Viral protein kinase (UL97), Phosphotransferase?
How is resistance established against Ganciclovir?
-Alteration of the viral protein kinase UL97
(the viral DNA polymerase can develop resistance against similar antivirals)
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
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 !!!!
Which antiviral drug is a NONCOMPETITIVE INHIBITOR?
Foscarnet (Foscavir)
it doesn’t compete with other nucleotides
it is an inorganic pyrophosphate analog
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
Cidofovir (Vistide®)
-Cytosine analog, Acyclic nucleoside phosphonate derivative
-IV only (intravitreal (eye injection) possible)
Spectrum: CMV, Foscarnet, and Ganciclovir resistant strains, and more
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)
MOA of Cidofovir
-it is already phosphorylated
-independent of viral kinases (Host enzymes convert to diphosphate (active drug))
ONLY 2 phosphorylations required
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
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
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
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
Which drug inhibits the protein kinase UL97?
Maribavir (Livetencity)
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
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
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
Guanine analogs
Acyclovir
Ganciclovir
Ribavirin
Cytosine analog
Cidofovir
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
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)
What are the NS5A drugs?
-inhibits NS5A (replication complex for viral RNA replication and assembly)
-nomenclature: -asvir
What are the NS5B drugs?
-inhibit NS5B, an RNA-dependent RNA polymerase, and halts viral replication
-nomenclature: -busvir
How does Epclusa® work?
-sofosbuvir/velpatasvir; NS5B and NS5A
-so it inhibits RNA-dependent RNA polymerase AND the replication complex
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
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
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 !!!
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
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)
Which products should be avoided with amiodarone (anti-arrhythmic)?
Havoni and Epclusa
-they contain sofosbuvir
Which drugs should be avoided with H2RAs and PPIs?
Havoni -> it contains ledipasvir (NS5A)
Epclusa -> it contains velpatasvir (NS5A)
Which drugs should be avoided in patients with cirrhosis?
Mavyret, Zepatier, Vosevi, and simeprevir
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
How are COVID patients commonly treated?
Remdesivir, Dexmethasone, and an Immunomodulator (tocilizumab, baricitinib, tofacitinib, sarilumab)
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 !!!!
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
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
When might Molnupiravir be used?
-When the provider doesn’t want to use Remdesivir infusion or Ritonavir
-inhibits viral RNA polymerase
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
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
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)
