Lecture 21: Antivirals II Flashcards
What are herpes viruses?
- LARGE, Double stranded DNA
- Latent infections
- Enveloped
What does it mean when it says that Herpes viruses are latent or lytic?
- Lytic: ACTIVELY makes new virions [HSV-1]
- Latent: Dormant
HSV-1 can enter latent state when it infects neurons
What are the two Human Herpes Simplex Virues?
- HSV-1: Oral Herps; ~60% of adults, face/lips
- HSV-2: Genital Herps; ~16% of adults, unpredictable
What is Varicella Zoster Virus?
- “Chickpox” –reactiveates–> Shingles
- Can cause Rash/Blisters that scab [VERY PAINFUL]
What is the prevention for the Varicella Zoster Virus?
- 2 doses of shingrix, separeated by 2-6 months
- For all immunocompetent adults +50yo
What are some of the other Human Herpes Virues?
- Epstein-Barr: targets lymphs; NO TREATMENT
- Kaposi Sarcome Associated Herpesvirues
What are a few of the Anti-herpesvirus agents that are used/
- Acyclovir
- Valacyclovir
- Cidofovir
- Foscarnet
- Penciclovir
- Ganciclovir
- Valganciclovir
What are some of the important to note about the sturcture of acyclovir and what it affects?
- It is a Acyclic guanosine derivative
- Lack 3’ hydroyl
- Prodrug
How does Acycolvir requires to become active?
- uses VIRAL kinases for 1 Phos, and Cellular Kinases for the 2 Phos
WONT leave the cell because of the Phos’s
What is the mechanism of action for Acyclovir?
- Competitive Inhibitor for viral DNA polymerase
- Competes with dGTP
- Chain Terminator
What is the spectrum of activity for Acyclovir?
- HSV-1, HSV-2, VZV
- Lower activity against EBV, CMV, HSV-6
What is important to know about the the Pharmacokinetics of Acyclovir
- Ok Bioavailabilty [15-30%]
- NOT affected by food
What are some fo the adverse effects of Acyclovir?
- Very well tolerated
- Maybe Nausea, Diarrhea, rash, or headache
What are some of the resistance for acyclovir?
- Mutations toward Thymidine kinase [wont make active form]
- More so in frequently in immunocompromised people
When talking about the structure of Valacycovir, what is important to know about it?
- L-Valyl Ester of acyclovir; so Prodrug
- Converted into Acyclovir by esterases in the intestine and liver
Breifly describe the pathway of Valacyclovir in the Body?
- In gut lumen –> into intestinal wall by dipeptide transporter –> portal –> ACV
- OR –> Val-ACV goes into Liver –> ACV
GUT: luminal esterases –> Val to ACV
INTESTINAL: Intestinal Esterases –> Val to ACV
LIVER: Hepatic Esterases –> Val to ACV
What is important to know about Famciclovir and Penciclovir?
What is Fam? Metabolism?
- Famciclovir is a PRODRUG of Penciclovir
- Converted by First Pass Metabolism
What is the Mechanism of Action for Famciclovir and Penciclovir?
- Triphosphorylated by viral and cellular kinases
- Competitive Inhibitor for Viral DNA Poly
- NO chain termination [because of 3’ hydroxyl]
How does Penciclovir differ from Acycolvir?
- Pen has higher affintiy for HSV TK [Phos easily]
- Pen Triphos is more stable
- HSV DNA is better toward Acyc Triphos
- Acyc Triphos is a Chain Terminator
What are some of the clinical uses for Famicilovir and Penciclovir?
Oral? Topical?
- Oral: Gential Herps, Acute Zoster
- Topical: recurrent Herps
What are some of the important things to know about Genciclovir?
MOA? What is it good for? Toxic?
- Structurally and Mechanisitcally similar to Pencicloivr
- Better for CMV [Retinitis: IV, PO, Implants]
- MORE TOXIC THAN Acyclovir
What is the resistance for Ganciclovir?
- Mutations in CMV kinase or CMV DNA pol
- Mutation in DNA = resistance for Cidofovir or foscarnet
What is Valganciclovir?
- Monovalyl Ester of Ganciclovir
- Gets Repidly hydrolyized to genciclovir by Esterases in the intestine and liver
Similar to Acycloivr and Valacyclovir
What are some of the things that Foscarnet inhibits?
Does is need phophorylation?
- Inhibits viral DNA poly, RNA Poly, And HIV RT; Blocks the binding site of Viral DNA poly; Inhibits Cleavage
- NO phosphorylation
W
What is the mechanism of action for Foscarnet?
- Carboxyl overlaps the binding site of b-phosphate = DNA unable to translocate
What are the Pharmacokinetics or Toxicity of Foscarnet?
- Poor orally; because of Polarity
- May cause Renal issues, Phophatemia or Calcemia
HYPO OR HYPER
What is Cidofovir?
- Analog of Cytosine; Phosphonate cannot be cleaved my cellular esterases [phosphorylated by cellular Kinases]
- Half-life = 17-65h
- Poor substrate for humans
What is the MOA, Spectrum and and Adverse for Cidofovir?
- Spectrum: CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8…
- MOA: Competitive inhibitor and Chain Terminator
- AE: Nephrotoxicitiy
VERY BROAD SPEC
What is the Clinicl use for Cidofovir?
- CMV Retinitis IV
What is Letermovir?
- Newest herps drug
- Use for prophyaxis of CMV during stem cell
- Well tolerated
What is the mechanism of action for Letermovir?
- Herps virus DNA replication is a rolling circle; Leter binds to pUL56 = inhibits terminase complex [stops replication]
What is important to know about the Influeza Virus?
- Negative strand RNA virus
- Enveloped
- New Strains can be made by “Reassortment”
What are the 3 types of Influenza viruses?
- A, B, C
- A: Infects humans & animals
- B: Mainly Humans
- C: Dont worry about
What are the different subtypes for Flu A?
- Hemaggultinin [H] & Neruamindiase [N]
- There are 16 Hs and 9 Ns
- Each virus has 1 H and 1 N
What is the life cycle of Influenza viral?
- Virus enters cell –> mRNA moves into Nucleus –> leaves nucleus where it then leaves the cell
What anti-fluenza drug is going to have an affect on Flu A?
MOA? Target?
- Amantadine
- Blocks uncoating; inhibits penetration into host
Targets M2 [how viruses move through] on Flu A
What does Neuraminidase do, and what is the importance of the Neuraminidase Inhibitors?
- The ONLY way that viruses will become replicated; SO inhibits replication
- Causes virus dessemination [Hemaglutinin binds to terminal sialc residues & cleavage by NA releases virus]
What is Oseltamivir?
- Prodrug: converted by liver
- Effective Inhibitor of NA
- Active against Flu A & B [but less so for B]
What are some of the pharmacokinetics and toxicities for Oseltamivir?
- Readily absorbed orally; 75% reaches circulation as active drug
- Nausea and Vomiting; Well tolerated
What is the main therapeutic use for Oseltamivir and some of the resistance?
- ONLY 1-day reduction of Flu; Need to start 48h of first symptoms tho
- Resistance: Mutations of neuramidiase site, decreased susceptibility
Oseltamivir gets resisted more easliy
Arg292Lys; Asn294Ser; His274Tyr = Resistance?
What is Zanamivir?
- Same MOA as Oseltamivir
- Good toward Flu A & B
- Oral Inhaler; -COOH group makes it poor orally
What is the Pharmacokinetics and the toxicities for zanamavir?
- Unchaged in the kidenys because of inhaled
- Bronchospams; NOT for those with asthman or COPD
What is Peramivir?
- NEWEST; good against Flu A & B
- IV or Injectable
- Really for those that are NOT responding to other Flu therapy
What is Baloxavir Marboxil?
MOA? Indication? Adverse Effects?
- MOA: Inhibits viral “cap-snatching” = Blocking transcription
- Indication: Same as Tamiflu [<48h]
- AE: Diarrhea, Bronchitis
What is important to know about Hepatitis C Virus [HCV]?
What is it? what can it cause? Transmittion?
- Small, + Stranded RNA Virus
- Causes Chronic Liver Infections
- Transmitted by contamined blood - IV drug users
What are some of the major causes from Hepatitis C?
- Chronic Hepatitis, Liver Cirrhosis, Hepatocellular Carcinma
What is the way that Interferons is used toward viral infections?
- Induces syntheis of cellular proteins
- should be given with Ribavirin
What are some of the clinical uses and toxicities of Interferon Alpha as antiviral drug?
- HCV, HBV, HHV-8, Papillomavirus
- May cause Fatal or life-threatening neuropsychiatric, autoimmune uschemic, and infectious disorders
What is Ribavirin and what is its spectrum of activity?
- A ganosine analog with incimplete pruine riung; Prodrug
- Spectrum: Flu A & B; Hepatitis A, B , & C; Gential Herps, Herps Z, Measles, Hantavirus…
What is the mechanism of action for Ribavirin?
- NOT known but; Inhibition of inosine monophosphate dehydrogenase = reduce GTP levels
- Good in Combo for Hep C
What do the HCV Protease Inhibitors do?>
- Target HCV Protease NS
