Lecture 21: Antivirals II Flashcards
1
Q
What are herpes viruses?
A
- LARGE, Double stranded DNA
- Latent infections
- Enveloped
2
Q
What does it mean when it says that Herpes viruses are latent or lytic?
A
- Lytic: ACTIVELY makes new virions [HSV-1]
- Latent: Dormant
HSV-1 can enter latent state when it infects neurons
3
Q
What are the two Human Herpes Simplex Virues?
A
- HSV-1: Oral Herps; ~60% of adults, face/lips
- HSV-2: Genital Herps; ~16% of adults, unpredictable
4
Q
What is Varicella Zoster Virus?
A
- “Chickpox” –reactiveates–> Shingles
- Can cause Rash/Blisters that scab [VERY PAINFUL]
5
Q
What is the prevention for the Varicella Zoster Virus?
A
- 2 doses of shingrix, separeated by 2-6 months
- For all immunocompetent adults +50yo
6
Q
What are some of the other Human Herpes Virues?
A
- Epstein-Barr: targets lymphs; NO TREATMENT
- Kaposi Sarcome Associated Herpesvirues
7
Q
What are a few of the Anti-herpesvirus agents that are used/
A
- Acyclovir
- Valacyclovir
- Cidofovir
- Foscarnet
- Penciclovir
- Ganciclovir
- Valganciclovir
8
Q
What are some of the important to note about the sturcture of acyclovir and what it affects?
A
- It is a Acyclic guanosine derivative
- Lack 3’ hydroyl
- Prodrug
9
Q
How does Acycolvir requires to become active?
A
- uses VIRAL kinases for 1 Phos, and Cellular Kinases for the 2 Phos
WONT leave the cell because of the Phos’s
10
Q
What is the mechanism of action for Acyclovir?
A
- Competitive Inhibitor for viral DNA polymerase
- Competes with dGTP
- Chain Terminator
11
Q
What is the spectrum of activity for Acyclovir?
A
- HSV-1, HSV-2, VZV
- Lower activity against EBV, CMV, HSV-6
12
Q
What is important to know about the the Pharmacokinetics of Acyclovir
A
- Ok Bioavailabilty [15-30%]
- NOT affected by food
13
Q
What are some fo the adverse effects of Acyclovir?
A
- Very well tolerated
- Maybe Nausea, Diarrhea, rash, or headache
14
Q
What are some of the resistance for acyclovir?
A
- Mutations toward Thymidine kinase [wont make active form]
- More so in frequently in immunocompromised people
14
Q
When talking about the structure of Valacycovir, what is important to know about it?
A
- L-Valyl Ester of acyclovir; so Prodrug
- Converted into Acyclovir by esterases in the intestine and liver
15
Q
Breifly describe the pathway of Valacyclovir in the Body?
A
- 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
16
Q
What is important to know about Famciclovir and Penciclovir?
What is Fam? Metabolism?
A
- Famciclovir is a PRODRUG of Penciclovir
- Converted by First Pass Metabolism
17
Q
What is the Mechanism of Action for Famciclovir and Penciclovir?
A
- Triphosphorylated by viral and cellular kinases
- Competitive Inhibitor for Viral DNA Poly
- NO chain termination [because of 3’ hydroxyl]
18
Q
How does Penciclovir differ from Acycolvir?
A
- 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
19
Q
What are some of the clinical uses for Famicilovir and Penciclovir?
Oral? Topical?
A
- Oral: Gential Herps, Acute Zoster
- Topical: recurrent Herps
20
Q
What are some of the important things to know about Genciclovir?
MOA? What is it good for? Toxic?
A
- Structurally and Mechanisitcally similar to Pencicloivr
- Better for CMV [Retinitis: IV, PO, Implants]
- MORE TOXIC THAN Acyclovir
21
Q
What is the resistance for Ganciclovir?
A
- Mutations in CMV kinase or CMV DNA pol
- Mutation in DNA = resistance for Cidofovir or foscarnet
22
Q
What is Valganciclovir?
A
- Monovalyl Ester of Ganciclovir
- Gets Repidly hydrolyized to genciclovir by Esterases in the intestine and liver
Similar to Acycloivr and Valacyclovir
23
Q
What are some of the things that Foscarnet inhibits?
Does is need phophorylation?
A
- Inhibits viral DNA poly, RNA Poly, And HIV RT; Blocks the binding site of Viral DNA poly; Inhibits Cleavage
- NO phosphorylation
24
# W
What is the mechanism of action for Foscarnet?
- Carboxyl overlaps the binding site of b-phosphate = DNA unable to translocate
24
25
What are the Pharmacokinetics or Toxicity of Foscarnet?
- Poor orally; because of Polarity
- May cause Renal issues, Phophatemia or Calcemia
## Footnote
HYPO OR HYPER
26
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
27
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
## Footnote
VERY BROAD SPEC
28
What is the Clinicl use for Cidofovir?
- CMV Retinitis IV
29
What is Letermovir?
- Newest herps drug
- Use for prophyaxis of CMV during stem cell
- Well tolerated
30
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]
31
What is important to know about the Influeza Virus?
- **Negative** strand RNA virus
- Enveloped
- New Strains can be made by "Reassortment"
32
What are the 3 types of Influenza viruses?
- **A, B, C**
- A: Infects humans & animals
- B: Mainly Humans
- C: Dont worry about
33
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**
34
What is the life cycle of Influenza viral?
- Virus enters cell --> mRNA moves **into Nucleus** --> leaves nucleus where it then leaves the cell
35
What anti-fluenza drug is going to have an affect on Flu A?
| MOA? Target?
- **Amantadine**
- Blocks uncoating; inhibits penetration into host
## Footnote
**Targets M2 [how viruses move through] on Flu A**
36
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]
37
What is Oseltamivir?
- **Prodrug**: converted by liver
- Effective Inhibitor of NA
- Active against Flu A & B [but less so for B]
38
What are some of the pharmacokinetics and toxicities for Oseltamivir?
- Readily absorbed orally; 75% reaches circulation as active drug
- Nausea and Vomiting; **Well tolerated**
39
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
## Footnote
**Oseltamivir gets resisted more easliy**
Arg292Lys; Asn294Ser; His274Tyr = Resistance?
40
What is Zanamivir?
- Same MOA as Oseltamivir
- Good toward Flu A & B
- **Oral Inhaler**; -COOH group makes it poor orally
41
What is the Pharmacokinetics and the toxicities for zanamavir?
- Unchaged in the kidenys because of inhaled
- **Bronchospams**; NOT for those with asthman or COPD
42
What is Peramivir?
- NEWEST; good against Flu A & B
- IV or Injectable
- **Really for those that are NOT responding to other Flu therapy**
43
What is Baloxavir Marboxil?
## Footnote
MOA? Indication? Adverse Effects?
- MOA: Inhibits viral "cap-snatching" = Blocking transcription
- Indication: Same as Tamiflu [<48h]
- AE: Diarrhea, Bronchitis
44
What is important to know about Hepatitis C Virus [HCV]?
## Footnote
What is it? what can it cause? Transmittion?
- Small, + Stranded RNA Virus
- Causes Chronic Liver Infections
- **Transmitted by contamined blood - IV drug users**
45
What are some of the major causes from Hepatitis C?
- Chronic Hepatitis, Liver Cirrhosis, Hepatocellular Carcinma
46
What is the way that Interferons is used toward viral infections?
- Induces syntheis of cellular proteins
- should be given with Ribavirin
47
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**
48
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...
49
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
50
What do the HCV Protease Inhibitors do?>
- Target HCV Protease NS
