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PHRM 865: Theraputics V > Lecture 21: Antivirals II > Flashcards

Lecture 21: Antivirals II Flashcards

1
Q

What are herpes viruses?

A
  • LARGE, Double stranded DNA
  • Latent infections
  • Enveloped
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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

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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
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4
Q

What is Varicella Zoster Virus?

A
  • “Chickpox” –reactiveates–> Shingles
  • Can cause Rash/Blisters that scab [VERY PAINFUL]
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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
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6
Q

What are some of the other Human Herpes Virues?

A
  • Epstein-Barr: targets lymphs; NO TREATMENT
  • Kaposi Sarcome Associated Herpesvirues
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7
Q

What are a few of the Anti-herpesvirus agents that are used/

A
  • Acyclovir
  • Valacyclovir
  • Cidofovir
  • Foscarnet
  • Penciclovir
  • Ganciclovir
  • Valganciclovir
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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
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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

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10
Q

What is the mechanism of action for Acyclovir?

A
  • Competitive Inhibitor for viral DNA polymerase
  • Competes with dGTP
  • Chain Terminator
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11
Q

What is the spectrum of activity for Acyclovir?

A
  • HSV-1, HSV-2, VZV
  • Lower activity against EBV, CMV, HSV-6
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12
Q

What is important to know about the the Pharmacokinetics of Acyclovir

A
  • Ok Bioavailabilty [15-30%]
  • NOT affected by food
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13
Q

What are some fo the adverse effects of Acyclovir?

A
  • Very well tolerated
  • Maybe Nausea, Diarrhea, rash, or headache
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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
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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
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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

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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
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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]
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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
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19
Q

What are some of the clinical uses for Famicilovir and Penciclovir?

Oral? Topical?

A
  • Oral: Gential Herps, Acute Zoster
  • Topical: recurrent Herps
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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
Q

W

What is the mechanism of action for Foscarnet?

A
  • Carboxyl overlaps the binding site of b-phosphate = DNA unable to translocate
24
Q
A
25
Q

What are the Pharmacokinetics or Toxicity of Foscarnet?

A
  • Poor orally; because of Polarity
  • May cause Renal issues, Phophatemia or Calcemia

HYPO OR HYPER

26
Q

What is Cidofovir?

A
  • Analog of Cytosine; Phosphonate cannot be cleaved my cellular esterases [phosphorylated by cellular Kinases]
  • Half-life = 17-65h
  • Poor substrate for humans
27
Q

What is the MOA, Spectrum and and Adverse for Cidofovir?

A
  • Spectrum: CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8…
  • MOA: Competitive inhibitor and Chain Terminator
  • AE: Nephrotoxicitiy

VERY BROAD SPEC

28
Q

What is the Clinicl use for Cidofovir?

A
  • CMV Retinitis IV
29
Q

What is Letermovir?

A
  • Newest herps drug
  • Use for prophyaxis of CMV during stem cell
  • Well tolerated
30
Q

What is the mechanism of action for Letermovir?

A
  • Herps virus DNA replication is a rolling circle; Leter binds to pUL56 = inhibits terminase complex [stops replication]
31
Q

What is important to know about the Influeza Virus?

A
  • Negative strand RNA virus
  • Enveloped
  • New Strains can be made by “Reassortment”
32
Q

What are the 3 types of Influenza viruses?

A
  • A, B, C
  • A: Infects humans & animals
  • B: Mainly Humans
  • C: Dont worry about
33
Q

What are the different subtypes for Flu A?

A
  • Hemaggultinin [H] & Neruamindiase [N]
  • There are 16 Hs and 9 Ns
  • Each virus has 1 H and 1 N
34
Q

What is the life cycle of Influenza viral?

A
  • Virus enters cell –> mRNA moves into Nucleus –> leaves nucleus where it then leaves the cell
35
Q

What anti-fluenza drug is going to have an affect on Flu A?

MOA? Target?

A
  • Amantadine
  • Blocks uncoating; inhibits penetration into host

Targets M2 [how viruses move through] on Flu A

36
Q

What does Neuraminidase do, and what is the importance of the Neuraminidase Inhibitors?

A
  • 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
Q

What is Oseltamivir?

A
  • Prodrug: converted by liver
  • Effective Inhibitor of NA
  • Active against Flu A & B [but less so for B]
38
Q

What are some of the pharmacokinetics and toxicities for Oseltamivir?

A
  • Readily absorbed orally; 75% reaches circulation as active drug
  • Nausea and Vomiting; Well tolerated
39
Q

What is the main therapeutic use for Oseltamivir and some of the resistance?

A
  • 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?

40
Q

What is Zanamivir?

A
  • Same MOA as Oseltamivir
  • Good toward Flu A & B
  • Oral Inhaler; -COOH group makes it poor orally
41
Q

What is the Pharmacokinetics and the toxicities for zanamavir?

A
  • Unchaged in the kidenys because of inhaled
  • Bronchospams; NOT for those with asthman or COPD
42
Q

What is Peramivir?

A
  • NEWEST; good against Flu A & B
  • IV or Injectable
  • Really for those that are NOT responding to other Flu therapy
43
Q

What is Baloxavir Marboxil?

MOA? Indication? Adverse Effects?

A
  • MOA: Inhibits viral “cap-snatching” = Blocking transcription
  • Indication: Same as Tamiflu [<48h]
  • AE: Diarrhea, Bronchitis
44
Q

What is important to know about Hepatitis C Virus [HCV]?

What is it? what can it cause? Transmittion?

A
  • Small, + Stranded RNA Virus
  • Causes Chronic Liver Infections
  • Transmitted by contamined blood - IV drug users
45
Q

What are some of the major causes from Hepatitis C?

A
  • Chronic Hepatitis, Liver Cirrhosis, Hepatocellular Carcinma
46
Q

What is the way that Interferons is used toward viral infections?

A
  • Induces syntheis of cellular proteins
  • should be given with Ribavirin
47
Q

What are some of the clinical uses and toxicities of Interferon Alpha as antiviral drug?

A
  • HCV, HBV, HHV-8, Papillomavirus
  • May cause Fatal or life-threatening neuropsychiatric, autoimmune uschemic, and infectious disorders
48
Q

What is Ribavirin and what is its spectrum of activity?

A
  • A ganosine analog with incimplete pruine riung; Prodrug
  • Spectrum: Flu A & B; Hepatitis A, B , & C; Gential Herps, Herps Z, Measles, Hantavirus…
49
Q

What is the mechanism of action for Ribavirin?

A
  • NOT known but; Inhibition of inosine monophosphate dehydrogenase = reduce GTP levels
  • Good in Combo for Hep C
50
Q

What do the HCV Protease Inhibitors do?>

A
  • Target HCV Protease NS

PHRM 865: Theraputics V (42 decks)

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