Lecture 2 - Antiviral Agent 1 Flashcards
Neuraminidase inhibitors
Oseltamivir
Zanamivir
Peramivir
Cap dependent endonuclease inhibitor
Baloxavir
Neuraminidase Inhibitors MOA
Block neuraminidase interfering with the release of replicated influenza virus from infected host cells
Best efficacy if admin w/in 12hrs of symptoms
What does Neuraminidase enzyme do
Cleaves cellular-receptor silica acid allowing replicated virus to exit
cleaves silica acid on the mucin in airway epithelium facilitating upper airway invasion
Oseltamivir Dosing & Dose adjustment
5 days = treatment
10 days = Prophylaxis
Req renal dose adjustment due to renal clearing
Route of admin for Neuraminidase inhibitors
Oseltamivir = PO Zanamivir = INH Peramivir = IV
CI Oseltamivir
Severe renal and hepatic impairment
** can use in Pregnancy **
DI Oseltamivir
Probenecid inhibit renal elim = inc conc
Oseltamivir ADE
Mostly GI, take with food
Zanamivir Dosing
Treatment = 5 days Prophylaxis = 10 days
DI + Dose adjustment Zanamivir
None, v little renal clearance ~ 10%
Also class C greg = can use
CI Zanamivir
Asthma, COPD (give albuterol before giving drug)
Zanamivir ADE
Cough
Btonchospasm
Peramivir dosing
5 days = treatment only
no prophylaxis dose
Peramivir Dose adjustment
Yes, renal cleared
DI Peramivir
none
Peramivir ADE
D,N,V
some CNS
Baloxavir (cap endonuclease inhibitor) MOA
inhibition of Cap-dependent endonuclease lends to interruption of viral RNA transcription
Baloxavir Dosing & Adjustment
1 tab both treatment & Prophylaxis, give within 48hrs of symptom
no adjustment, just for weight
Baloxavir DI
Dont co-admin with polyvalent cations = chelate
Baloxavir ADE
D,N,V
Remdesivir MOA
Binds nd inhibits viral RNA-dependent RNA polymerase activity
Its an adenosine analog thats FDA approved
Remdesivir Dosing adjustment
no renal or hepatic
given IV
Remdesivir CI
Hepatic insufficiency
renal dysfunction
Remdesivir ADE
Rash
Nephrotoxicity
hepatic toxicity
Remdesivir DI
Hepatic enzyme + P-GP inducers not recommended due to potential decrease in remdesivir drug conc
ie. Rifamycins, Carbamazepine, Phenobarbital, Efavirenz, Nevirapine, Rilpivirine
Dexamethasone MOA
Binding to Pro/3CLpro (viral protease), inhibition of neutrophil apoptosis/demargination, promotion of anti-inflammatory genes (IL-10)
Dexamethasone dose adjustment
Nah
Dexamethasone CI
Current MTB, HSV
Dexamethasone DI
moderate CYP450, 3A4 inducer
Dexamethasone ADE
Reactivation of HBV, HSV, TB, dysglycemias, CNS changes
Tocilizumab MOA
Monoclonal antibody to IL-6 receptor, treats cytokine release syndrome
Tocilizumab Dosing adjustments
None
IV only, given once
Tocilizumab CI & DI
Dont give in ppl with low BC
Dont give with immunosuppressants
Tocilizumab ADE
HSV/VZV reactivation Opportunistic infections** TB Thrombosis** GI perforation Hypersensitivity
Baracitinib MOA
inhibit clatkhrin-mediated endocytosis and thereby inhibit viral entry, modulates hematopoiesis and immune cell function
JAK1 inhib
Baracitinib Dose adjustments + clearance
50% w/ renal dysfunction = 2mg
75% renal clearance
Baracitinib DI
Probenecid dec clearance
Azathiorine and cyclosporine inc cytopenias
Baracitinib ADE
Cytopenias** Opportunistic infections** Thrombosis** Hepatotoxicity Dyslipidemia Malignancy HSV,VSV reactivation
Nirmatrelvir w/ ritonavir (Paxlovid)
Protease inhibitor w/ booster
Nirmatrelvir: 3CLpro or nsp5 protease inhibitor
Ritonavir: CYP450 enzyme inhibitor (acts as booster)
Paxlovid renal dose adjustment
50% with renal dysfunction
Paxlovid CI
Severe renal dysfunction
Paxlovid DI
Potent CYP3A4 inhib
Paxlovid ADE
Mostly GI
Dysguesia = impaired taste
Rebound phenomena
Enzyme inducers that reduce lvls of Paxlovid
Rifampin Rifabutin Phenytoin Phenobarbital Carbamazepine
Enzyme inhibitors that increase lvls of Paxlovid
Itraconazole Voriconazole Fluconazole Posaconazole Isavuconazonium Clarithromycin
Molnupiravir MOA
Active metabolite works via viral error catastrophe, also referred to as viral lethal mutagenesis.
NHC-TP incorporation into viral RNA by viral RNA-dependent RNA polymerase, results in accumulation of errors in viral genome leading to inhibitor of replication
** Mutagen + toxic metabolite **
Molnupiravir Dose adjustments
none
Molnupiravir DI
none significant
Molnupirvir CI
Pregnancy
Child bearing age not on barrier contraception
Molnupirvir ADE
Teratogenicity
Cartilage + bone growth abnormalities < 18yrs old
D + N
Drugs of choice for mild-moderate ovid
Remdesivir
Paxlovid
Bebtelovimab
Drug used for PrEP?
Evusheld (Tixagevimab & Cilgavimab)
Bebtelovimab Dosing + adjustment
Slow IV push - once
No dose adjustment
Evusheld Dosing + adjustment
Q6 months, IM
No dose adjustment
Bebtelovimab DI + ADE
no many ADE
No DI
Evusheld ADE + DI
Injection side reactions
Higher rate of Cardiac events
No DI
(Val) Acyclovir prodrug of
Acyclovir
Famciclovir is prodrug of
penciclovir
(Val)Acyclovir MOA
** Requires Thymidine Kinase to activate drug **
Inhibits Viral DNA synthesis:
Inactivation of viral DNA polymerase -> competitive inhibitor of viral DNA polymerase -> incorporation not termination of Viral DNA
Acyclovir Dosing adjustments
Renal dosed
Acyclovir IV ADE
Phlebitis
Nephrotoxicty = slow infusion, hydrate to reduce
Acyclovir-resistance
- Thymidine Kinase Alterations = Primary mechanism
2. DNA polymerase mutation = < 5% HSV resistance , uncommon
Treatment for Acyclovir Resistant HSV
- HSV infection fails to respond after 4-5 days
- Switch to Foscarnet
- Foscarnet failure = switch to Cidofovir
- Therapy completed, rever to Acyclovir or valacyclovir PPX
Cidofovir MOA
Nucleotide analogue of cytosine
Inhibits viral DNA synthesis:
Competitive inhibition of viral DNA polymerase -> incorporates into growing viral DNA chain, acts as chain terminator
Cidofovir Active against….
Resistant HSV CMV HHV6 BKV Adenovirus Ebola Anthrax Monekypox
Cidofovir ADE
Nephrotoxicity = give with probenecid to decrease
Hematologic = Neutropenia ~ 20%
Cardiac arrest, Torsades de pointes, Vent tachycardia
Cidofovir dose adjustment
100% renal elim, so req dose adjustment
CMV is dependent on Viral kinase that include….
UL97
UL54
UL56
(Val)Ganciclovir MOA
Nucleoside analogue of guanosine
Inhibits Viral DNA synthesis
Inactivation of viral DNA polymerase -> competitive inhibitor of viral DNA polymerase -> incorporation into and termination of viral DNA
** 10X more active against CMV than Acyclovir **
Dosage forms of CMV treatments
Ganciclovir = IV/PO Valganciclovir = PO = prodrug = UL97 dependent
Valganciclovir is dependent on….
UL97
Valganciclovir dose adjustment
Renal clearance so have to dose adjust
Valganciclovir activity
CMV
Acyclovir resistant HSV
Ganciclovir ADE
Neutropenia ~20% Thrombocytopenia ~21% Metabolic acidosis N,V ~ 48% rash
Letermovir MOA
Inhibits CMV DNA terminase
Responsible for DNA cleavage
Letermovir depends on…
UL56
Letermovir limited to….
prophylaxis not treatment currently
CMV only also
Letermovir CI
Not recommended in severe hepatic impairment
Letermovir ADE
mostly GI
Letermovir DI
Induces 2C9 = Warfarin + Phenytoin dec lvls
** dont use w/ Rifampin **
Inhibits 3A4, Amiodarone, Atorvastatin, Glyburide + rosiglitazone = inc lvls
CMV Drug resistance
UL97 mutation
UL54 mutation
UL97 mutations, which drugs can you use
Cidofovir
Foscarnet
Letermovir
UL54 Mutation, which drugs can you use
Letermovir
Foscarnet maybe active
Maribavir indication
used for refractory CMV
works at UL97
Maribavir MOA
Multimodal inhibition of….
CMV DNA replication
Encapsidation
Nuclear egress of viral capsids
Maribavir ADE
Mostly GI
some taste disorders**
some bone marrow toxicity
Maribavir Dose adjustment
dont need for renal or hepatic impairment
Maribavir DI
CYP3A4 inducers = dec serum conc of Maribavir
increase dose when suing w/ Carbamazepine, Phenobarbital, phenytoin primidone
