LEC 29 Antivirals Flashcards
How does Acyclovir work?
What does it treat?
- Guanosine derivative that inhibits DNA synthesis
- Activated only in infected cells, bc it requires a viral kinase for the first of three phosporylation steps
Tx of HSV. Reduces symptoms and transmission d/t reduced viral shedding
What other HSV/CMV drugs have the same MOA as Acyclovir?
- Valacyclovir
- Penciclovir
- Famciclovir
What DNA synthesis drugs work better for CMV?
- Gancyclovir, Valganiclovir, Cidofovir - Slightly diff MOA; more active against CMV DNA Polymerase
- Foscarnet - different; works when resistance to gancyclovir is seen
How do nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) work?
- They inhibit reverse transcription
- NRTIs lack a 3’ OH group so the attachment of the next nucleotide is impossible
What do you know about Abacavir?
- NRTI
- Good oral F
- 12-24 h half life
- Resistance requires several mutations
What do you know about Didanosine?
- NRTI
- Good oral F
- Cellular metabolism and renal clearance
- Pancreatitis can be a problem - limit use in alcoholics
What do you know about Emtricitabine?
- NRTI
- Good oral F
- AE: hyperpigmentation of palms and soles
What do you know about Lamivudine?
- NRTI
- 80% F
- Well tolerated and possibly safer than didanosine
What do you know about Stavudine (d4T)?
- NRTI
- Good CNS penetration
What do you know about Tenofovir?
- NRTI
- Works well for HBV also
- Often co-administered with emtricitabine
What do we know about Zalcitabine?
- NRTI
- Can cause dose-dependent neuropathy (slowly reversible)
What do we know about Zidovudine (AZT)?
- NRTI
- First anti-retroviral
- Often co-administered with lamivudine
- Admin to preg women in late stage preg and neonates has been shown to reduce vertical transmission of HIV by 23%
What are the general adverse effects of NRTIs?
- Lactic acidosis
- Hepatomegaly, steatosis
- Not generally metabolized by CYP450 in liver
Which two NRTIs should NOT be co-administered?
Stavudine and Didanosine
How do NNRTIs work?
- Bind to a different site on the viral reverse transcriptase
- Result is the same – blocking RNA to DNA
- Highly susceptible to resistance through mutations in the pol gene - combine with other therapies
What do you know about Efavirenz?
- NNRTI
- can be given once daily d/t long half life
- has shown teratogenicity - avoid giving to preg pts in first trimester
What do you know about Nevirapine?
- NNRTI
- A single dose is effective in prevention of transmission of HIV from mother and child
- Given during labor and to the neonate
What are the adverse effects of NNRTIs?
- Multiple drug interactions
- Metabolized by liver
- Some induce and some inhibit CYP450
- Must know what meds the pt is taking
How do protease inhibitors work?
- In late stage of the life cycle
- Precursors of coat proteins Gag-Pol are made
- Must be cleaved at specific points by proteases to assemble correctly
- Specific protease inhibitors target this process
HIV/AIDS Tx
Protease inhibitors are usually combined with what other antiretroviral drug class as a part of HAART?
Reverse Transcriptase Inhibitors
All PIs are substrates and inhibitors of what?
CYP3A4
What do you know about Ritonavir?
- PI
- Good oral F
- Metabolized by CYP3A4
- Strong inhibitor of CYP3A4
- Subtherapeutic levels of ritonavir can inhibit the CYP3A4-mediated metabolism of other PIs
What do you know about Atazanavir?
- PI
- 12 h half life - QD dosing
- Less effect on pt’s lipid profile than other PIs
- Potent inhibitor of CYP3A4 CYP2C9
What are the adverse effects of protease inhibitors?
- Use in HAART has led to carb and lipid metabolism disorders
- Cross inhibits endogenous lipid-regulating proteins
- Leads to “buffalo hump” and gynecomastia
- Hyperglycemia and Insulin resistance
How do entry inhibitors work?
- Attachment of many HIV strains requires to receptors on human cells
- Drugs bind to this receptor or the proteins that can block attachment and entry of HIV into the cell
What do you know about Maraviroc?
- Entry Inhibitor
- Good oral F
- Good tissue penetration
- Binds specifically to CCR5
- No x-reactivity with other entry inhibitor (enfuvirtide)
- Substrate of CYP3A4 - watch use with PIs and other 3A4 inhibitors
What do you know about Enfuvirtide?
- Entry Inhibitor
- Synthetic 36-aa peptide
- Binds to the gp41 subunit of the virus and inhibits conformational changes required for entry
- Is not a P450 substrate
How do Oseltamivir and Zanamivir work?
- Anti flu drugs
- Inhibit neuraminidase A and B
- Reduce viral spreading
How is Oseltamivir administered?
- Orally
- Prodrug that is activated in the gut
Can cause GI upset
How is Zanamivir delivered?
Intranasally
can cause bronchospasms
When must Tamiflu and Relenza be administered in order to be effective?
- EARLY - replication of the virus peaks 24-72 hours after infxn
- Can shorten duration of symptoms by 1-2 days
- Once daily prophylaxis is 70-90% effective
How does Baloxavir maboxil (Xofluza) work?
- Targets virus polymerase complex
- enzyme inhibitor
- targeting of cap-dependent endonuclease activity
- reduces ability to make viral RNA needed for replication
When must Xofluza be administered?
- w/i first 48 hrs of symptoms
- can reduce length and severity of symptoms and viral shedding
- One dose orally
- Really long half life - >80 hrs
How does INF-α work?
- HBV and HCV tx
- Host cytokine that exerts complex antiviral, immunomodulatory, and antiproliferative actions
- Enhances phagocytic activity of macrophages
- Augmentation of the proliferation and survival of cytotoxic T cells
- Must be delivered parenterally
How does PEGylating INF-α make it a better drug?
Dramaticallly increases half life - from QD dosing to once weekly dosing
What is the main route of clearance of INF-α and what are its adverse effects?
- Proteolytic degradation in the kidney
- AE: GI irritation, flu-like syndrome, fatigue, severe depression, alopecia, thyroid dysfunction, mental confusion
What do you know about Ribavirin?
- Prodrug - when active, represents RNA nucleotide
- Used in combo with INF-α for HCV
- Exact MOA unknown - inhibits GTP formation, mRNA capping, and blocks RNA-dep polymerases
- Inhibits many DNA and RNA viruses including: HCV, Flu A and B, RSV, HIV
- Monotherapy not effective - must combine with other antivirals
