Antiviral Therapy Dr. Cluck EXAM 4 Flashcards
How is Influenza A further categorized?
-hemagglutinin (H) and neuraminidase (N)
-strains affecting humans: H1N1, H1N2 and H3N2
When should the drug therapy for Influenza be started?
Within 48 hours of symptoms
Duration: 5 days (no benefit beyond 5 days)
Prophylaxis duration: 10 days (up to 6 weeks when in a community outbreak)
MOA of Adamantanes and which subtype to treat?
-blocks M2 ion-channel protein -> stops uncoating
-only active against Influenza type A
-low barrier to resistance (not recommended by FDA) !!!
-> WOULD NOT be the best choice to treat Influenza
What are the indications of Amatadine?
-Influenza
-Parkinson’s disease
-must be renally adjusted
-CNS effects (especially in the elderly)
PK Profile of Rimantadine
-Renal and Hepatic metabolism; must be adjusted if there is SEVERE dysfunction in either
-Side effects less than with Amantadine
Neuraminidase Inhibitors
-inhibit cleavage of viral progeny thus limiting
infectivity
-the earlier the better -it limits replication to one round and may prevent the disease if early enough
- shorten disease duration by 3 days
-Oseltamivir, Zanamivir, Peramivir
Side effects of Oseltamivir
-N/V
-Labeling Update in 2006: Neuropsychiatric events based on reports of self-injury (only in adolescents of asian descent)
What is the dose of Oseltamivir?
75mg BID or 75mg DAILY for prophylaxis
must be renally adjusted -> 30 mg
Zanamivir
-dry-powder inhaler only (CAUTION in patients with
pre-existing lung disease)
-bronchodilator prior to dose is recommended
-no renal or hepatic adjustment
Peramivir
-shares characteristics of both oseltamivir and zanamivir, thought to be more potent (but not sure)
-IV only
-possible cross-resistance
-expensive (1000$ per dose)
-requires renal adjustment !!!
Baloxavir
-polymerase acidic (PA) endonuclease inhibitor
-for acute uncomplicated influenza
-Interactions with live/attenuated vaccines and polyvalent cation (ion, calcium supplements)
-Warning: 50 cases of anaphylaxis (7 fatal)
Treatment of Herpes simplex 1, 2, and Varicella-zoster
-with the “-ovirs”: acyclovir, valacyclovir, famciclovir,
penciclovir
-Rate limiting step is their requirement of bioactivation (VTK)
-Acyclic Nucleoside (Guanosine) Analogues
-MOA: competitive inhibition of viral DNA polymerase - inserting false nucleoside
Acyclovir
-when given IV, pt needs to be on maintenance fluid to prevent nephrotoxicity
-must be adjusted in renal insufficiency
-orally: less nephrotoxicity, more N/V issues
-poor oral bioavailability (10-20%) -> has to be given several times per day orally
Valacyclovir
-prodrug of Acyclovir
-more commonly used bc of improved bioavailability (55%)
-renal adjustment when renal insufficient
Famciclovir
-Prodrug of Penciclovir -> conversion via aldehyde oxidase
-Penciclovir topical ONLY (f.e. cancer sores) !!!
-Excellent oral bioavailability (75%)
-side effects: headache, GI
Which antiviral drug may be used for cancer sores?
-Topical agent: Penciclovir
Which antiviral drug is approved for Herpes simplex on the eye?
-Trifluridine (Viroptic)
-Nucleoside analog active against HSV
A systemic agent will probably be added
-Approved for HSV keratoconjunctivitis and recurrent epithelial keratitis
-also active against Vaccinia virus
Which antiviral drug is used specifically for Herpes simplex 1?
Abreva (N-docosanol)
-Must be used at the first symptom of cold sore (eg tingling) -> shortened by 1 day
-lacks clinical data supporting its use
-in vitro activity against many viruses including HIV
Mechanism of resistance against antivirals
-modified viral thymidine kinase (VTK)
-Altered DNA polymerase
Cytomegalovirus Drug Therapy
-the kinase (UL97) phosphorylated the drug
-ganciclovir, valganciclovir, cidofovir,
foscarnet
-foscarnet and cidofovir do NOT require bioactivation by the kinase
Ganciclovir
-Predominant use is in CMV
-activated by phosphotransferase UL97 (in CMV-infected cells)
-Can also be activated by viral kinases in HSV/VZV
-> Hence can be used to treat herpes simplex or VZV
PK of Ganciclovir
-needs to be renally adjusted
-poor oral bioavailability -> not given orally (Valganciclovir is the PO option)
-dose-limiting side effect is myelosuppression
Valganciclovir
-prodrug of parent drug ganciclovir
-Increased bioavailability (~60% with food)
-Must be adjusted in renal insufficiency
When to use Foscarnet?
-resistant herpes virus -> resistance is often due to altered kinase enzymes -> effective bc it doesn’t require bioactivation via kinases
-MOA: non-competitive inhibitor of the viral DNA polymerase -> it doesn’t look like a nucleotide, it is a pyrophosphate and binds allosteric at a different site
-renal TOXICITY!!!, electrolyte abnormalities (Ca++)
When to use Cidofovir?
-nucleotide analong
-mostly CMV, also in herpes-resistant strains
-toxicity limits its use
-does not require bioactivation
-must be given with probenecid (increases systemic levels) and fluid boluses
Summary of Activity Profiles
Acyclovir and congeners:
HSV-1 > HSV-2 > VZV > EBV > CMV (least activity in EBV and CMV)
Ganciclovir/Valganciclovir
HSV-1 = HSV-2 = VZV = EBV = CMV (bc Ganciclovir is activated by either TK or UL97 - its indication is CMV though)
Foscarnet and cidofovir will likely cover all herpesviruses
-> not first line ->only in case of resistance
->TOXICITY
Drugs used for HepB
-Peginterferon alfa-2a (alfa-2b?) - not first line bc of TOXICITY
-Entecavir
-Tenofovir disoproxil and alafenamide/Adefovir
-Lamivudine/Emtricitabine (may develop resistance)
What is the drug therapy for HepC?
-used to be Interferons
-Combination therapy
-The newest agents are: Protease inhibitors, NS5A, and NS5B inhibitors
Which drug is used as an adjunct to Interferon therapy
Ribavirin
- increases SVR (sustained virologic response) rate -> hepC not detected for 12 weeks
How do Interferons work?
promotes an antiviral state within the cell via a cascade of cell signaling
-flu-like side effects, anemia, depression during therapy
-last resort
What is the purpose of pegylated Interferons?
prolongs the half-life of Interferons
-peginterferon alpha-2a (Pegasys)
-peginterferon alpha-2b (PegIntron)
What are the side effects associated with Ribavirin?
-hemolytic anemia (pt feel out of breath)
-CAUTION in renal dysfunction (<CrCl 50)
-MOA: disrupts guanine metabolism (via dehydrogenase inhibition)
Which drug is considered Pangenotypic and is found in many HepC Combi-products?
Sofosbuvir (Sovaldi) - NS5B polymerase inhibitor
-should not be given with rifampin (Sofosbuvir is a substrate for P-glycoprotein -> rifampin induces P-gp which would decrease Sofosbuvir?)
-high barrier to resistance
-NO CYP interaction
NS5A Replication Complex Inhibitors
Elbasvir
Ledipasvir
Ombitasvir
Daclatasvir
Velpatasvir
