Antivirals Flashcards
6 Steps in viral infection and replication
- Adsorption
- Penetration
- Viral Genome Replication
- Assembly
- Maturation
- Release
What do the guanine nucleoside analogs do and what are they?
Anti-HSV and Anti VZV
Acyclovir (Zovirax)
Valacyclovir (Valtrex)
Guanine nucleoside analog MOA
Drugs phosphorylated by viral thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs
The analog inhibits viral DNA-polymerase
Only actively replicating viruses are inhibited
Acyclovir (Zovirax) Indications and ROA
Topical, oral, IV HSV1 and 2 VZV Maybe EBV DOC for HSV lesions, HSV encephalitis, HSV infx in immunocompromised or pregnant
Acyclovir (Zovirax) PK, Saftey, and monitoring
20-30% oral bioavailability Wide distribution including CNS Renal excretion > 80% Half-life: 2-5 hrs Preg Cat B Lactation Safe IV: CrCl 20-25 give q12h, CrCl <25 q24hr Hepatic: no change needed
Acyclovir (Zovirax) MOA
Inhibits viral synthesis of DNA
Phosphorylated to acyclovir monophosphate
Cellular enzymes convert to acyclovir triphosphate
Competes with viral deoxyguanosine triphosphate for viral DNA polymerases
Lacks 3’ hydroxyl group to prevent further nucleoside attachment - chain termination
Inactivates viral DNA polymerase
Acyclovir (Zovirax) Dose
Varies with infection and severity 200, 400, 800 mg tablets, 200/5mL liquid, IV VZV: 800 mg PO 4-5/day x 7-10 days HSV: 1st: 400 mg PO 3-4/day x 7-10 days Recurrence: 400 mg PO TID x 5 days Suppression: 400 mg PO BID
Acyclovir (Zovirax) Adverse Effects
Reversible renal toxicity - crystallization in tubules
Neuro Sx: encephalopathic somnolence, halluc, confus, coma
TTP/HUS in immunocompromised
GI, HA, rash, photosensitivity, Anemia
Acyclovir (Zovirax) Resistance
Defined as MIC >2-3 mcg/mL Mostly occurs in immunocompromised Reduced or absent thymidine kinase Altered TK substrate specificity Alterations in DNA polymerase Cross resistance to famciclovir and valacyclovir
Famciclovir (Famvir) MOA
Converted to penciclovir triphosphate in liver and intestines, which has a lower affinity for viral DNA polymerase, but a longer intracellular half-life
Famciclovir (Famvir) Use and Spectrum
PO only
HSV 1 & 2, VZV, lesser EBV, invitro HBV
Famciclovir (Famvir) PK
77% oral bioavailability
1st pass = conversion to penciclovir
renal excretion > 80%
Half-life 2-3 hours
Famciclovir (Famvir) Saftey and Monitoring
Preg Cat B
Lactation: safety unknown
Renal: adjust if CrCl < 40
Hepatic: no adjustment needed
Famciclovir (Famvir) Dose
125, 250, 500 mg tablets Zoster: 500 mg TID x 7 days HSV: 1st: 250 mg PO TID x 7-10 days Recurrence: 1000 mg PO bid x 1 day w/in 6 hrs of Sx Suppression: 250 mg PO bid
Famciclovir (Famvir) Adverse Effects
Neutropenia, thrombocytopenia
Neuro Sx: somnolence, halluc, delirium
GI, HA, fatigue
elevated LFTs
Famciclovir (Famvir) Resistance
Mutations in TK or DNA polymerase
Cross resistance with acyclovir in TK negative strains - may still have activity
Resistance to HBV due to L528M point mutation in viral DNA polymerase
Valcyclovir (Valtrex)
Prodrug of Acyclovir
rapidly and almost completely converted to acyclovir via 1st pass metabolism
Same MOA, SOA, and mech of resistance as acyclovir
Valcyclovir (Valtrex) Advantage
better oral bioavailabiltiy = 55%
Valcyclovir (Valtrex) PK
55% oral bioavailability 1st pass metabolism to acyclovir Food does not affect absorption > 50% renal excretion Half-life 2-3 hours ORAL
Valcyclovir (Valtrex) Safety and Monitoring
Preg Cat B
Lactation Safe
Renal: adjust if CrCl < 30
Hepatic: none
Valcyclovir (Valtrex) Dose
500, 1000 mg tabs Zoster: 1000 mg PO tid x 7-10 days HSV: 1st: 1000 mg PO bid x 7-10 days Recurrence: 500 mg PO bid x 3-5 days Suppression: 1000 mg PO qday
Valcyclovir (Valtrex) AE
Reversible renal toxicity - crystallization in tubules
Neuro Sx: encephalopathic somnolence, halluc, confus, coma
TTP/HUS in immunocompromised
GI, HA, rash, photosensitivity, Anemia
Topicals for HSV
Penciclovir (Denavir 1% cream) - HSV1
Docosanol (Abreva OTC) - HSV1
Trifluridine (Viroptic) - HSV keratoconjunctivitis
Penciclovir (Denavir 1% cream)
For orolabial HSV
topical guanine analog similar to acyclovir
apply every 2 hrs while awake
Docosanol (Abreva OTC)
For orolabial HSV
Active against broad range of lipid-envelop viruses
MOA: interferes with viral fusion to host cell
Apply 5 times/day until healed (10 days)
Shortens healing by 0.7 days
Trifluridine (Viroptic)
For HSV keratoconjunctivitis
1 drop q2h (max 9 drops/day)
Active against acyclovir resistant strains
Active against vaccinia virus and smallpox
Anti-CMV Agents
Ganciclovir (Cytovene)
Ganciclovir (Cytovene) - ROA and Spectrum
ROA: oral, IV, intraocular Spectrum: CMV/EBV - 10x potency of acyclovir HSV/VZV - equal to acyclovir Human Herpes Virus 6
Ganciclovir (Cytovene) DOC
DOC for CMV retinitis in immunocompromised
Prevention of CMV disease in transplant pts
Ganciclovir (Cytovene) PK
50% oral bioavailability
Excreted unmodified in the urine
Renal excretion >90%
Half-life: 2-4 hrs
Ganciclovir (Cytovene) Safety and Monitoring
Preg Cat C
Lactation unsafe
Renal: adjust if CrCl < 50
Hepatic: not defined
Ganciclovir (Cytovene) MOA
Competes with deoxyguanosine triphosphate
In CMV, viral phosphotransferase converts to ganciclovir triphosphate
Contains 3’-hydroxyl group allowing for DNA to continue
Ganciclovir (Cytovene) Adverse Effects
Reversible pancytopenia Fever Rash Phlebitis (IV) Confusion Renaly Dysfxn Psych disturbances Seizures
Influenza Agents
Oseltamivir (Tamiflu)
Zanamivir (Relenza)
Amantadine
Rimantadine
Neuraminidase Inhibitors
Oseltamivir and Zanamivir
Neuraminidase - flu enzyme essential for viral replication
Neuraminidase inhibitors prevent release of new virions and their spread from cell to cell
Effective against flu A and B
Do not interfere with flu A vaccine
For prophylaxis and treatment
Oseltamivir (Tamiflu) - Class and MOA
Oral neuraminidase inhibitor
Cleaves terminal sialic acid residue on glycoconjugates and destroys receptors
newly formed virions adhere to cell surface and limit spread
Oseltamivir (Tamiflu) Spectrum and AE
Flu A and B in adults and peds
Avian influenza
H5N1 disease
AE: N/V, HA
Oseltamivir (Tamiflu) Dosing
A&B Tx: 75 mg PO bid x 5 days w/in 48 hrs of Sx onset
Prophylaxis: 75 mg PO bid x 5 days w/in 48 hrs of exposure
Zanamivir (Relenza)
Neuraminidase inhibitor
Given via inhalation: 2 puffs bid x 5 days
Spectrum: uncomplicated flu A&B, some avian flu
AE: nasal and throat discomfort, bronchospasm
Not recommended in pts with severe flu, asthma or COPD
Amantadine (Symmetrel) & Rimantadine (Flumadine)
MOA, Spectrum, AE
MOA: prevents release of viral nucleic acid into host cell
Spectrum: Flu A (resistance is frequent)
AE: seizures, anticholinergic, CNS, edema, blurry vision
Much resistance - not recommended in US
Amantadine PK and off-label
50-90% bioavailability
Crosses BBB (Rimantadine does not)
Oral administration
Used for extrapyramidal Sx and Parkinsonism
Ribavirin Class and MOA
Purine nucleoside analog
MOA: inhibits RNA polymerase - not well understood
Ribavirin Spectrum
DNA and RNA viruses: flu, HCV, parainfluenza, RSV, lassa virus
Ribavirin Uses
DOC: RSV bronchiolitis and pneumonia in hospitalized children via aerosol
Alternative for: flu, parainfluenza, measles in immunocompromised pts
Used in combo with interferons or sovaldi for HCV
Ribavirin ROA and Special Pops
IV through CDC Oral and inhalation Preg Cat X Lactation unsafe BBW: hemolytic anemia
Ribavirin AE
Resp. deterioration
Depression, suicidal ideation, psych effects, anxiety
Bacterial Infxs
Fatigue, dizziness
Causes of Hepatitis
Refers to swelling of liver in response to: Drugs Toxins Excessive alcohol Infx from bacteria or viruses
Hep A
typically spreads when infected individuals improperly handle food or water
Hep B
transmitted via sexual intercourse, needle sharing, or contact with contaminated blood
Vaccine since 1980’s
Chronic Tx: interferon, NRTI, liver transplant
Hep C
More likely to cause permanent liver damage
Genes mutate fast
New genotypes make vaccine impossible
Tx: interferon plus ribavirin
NRTI
Nucleoside Reverse Transcriptase Inhibitors
Emtricitabine
Tenofovir
Entecavir - guanosine analog - lamivudine resistant strains
Lamivudine - cytosine analog HBV
Hepatitis Anti-viral Drugs
Interferons Lamviudine - cytosine analog HBV Entecavir - guanosine analog - lamivudine resistant strains Ribavirin - Hep C with interferons Sofosbuvir (Sovaldi) - Hep C Simeprivir (Olysio) - Hep C Ledipasvir-Sofosbuvir (Harvoni) - Hep C
