Viral pathology and pharmacology - Miller

Question 1

Acyclic Guamosine Analogs -mimic guanine nucleotides

Answer 1

acyclovir

valacyclovir

Question 2

DNA chain termination

Answer 2

acyclovir
valacyclovir (prodrug of acyclovir)
penciclovir
famciclovir (prodrug of pen)
ganciclovir
valganciclovir (prodrug of gan)

Question 3

ADME of acyclic analogs

Answer 3

• oral bioavailability variable, but vala and fam have better oral absorption
• widely distributed
• dosed mult times a day
• renal filt - dose adj
• topical = irritation
• oral- NVD, headache, rash, some hepatox
• high doses - IV (>25 plasma lvl) = myelosuppression (ESP in vala and gan), nephrotox, neurotox

Question 4

Cytidine monophosphate analog

CMP (cytosine), targets C nucleotides

Answer 4

Cidofivir

Question 5

bypasses need for viral thymidine kinase, already has one phosphate, only needs to add two ph

Answer 5

Cidofovir

Question 6

ADME of Cidofovir

Answer 6

• use in HSV, VSV, or CMV
  -low F
  long t1/2 - 87 hrs = ONE TIME DOSING
  -renal exc = dose adj
  nephrotox
  bone marrow suppression/myelosupression

Question 7

noncompetitive inh of pyrophosphate binding site or viral DNA polymerase
presevents conversion fo triphosphate to mono-phosphate = cannot incorporate in DNA chain

Answer 7

Foscarnet

Question 8

ADME of Foscarnet

Answer 8

• low F so given IV
• short t1/2 4-8 hrs
• > 80% exc in urine
• nephrotox
• HYPOCALCEMIA
• neurotox/CNS signs

Question 9

antisense therapy - mimic regulatory RNA mcs (siRNAs and miRNAs) to downreg viral gene expression to inh DNA replication

Answer 9

Fomivirsen

Question 10

Effective against influenza type “A” (not H1N1)

Answer 10

• Amatadine (Symadine, Symmetral)

- Rimantadine (Flumadine)

Question 11

Amatadine (Symadine, Symmetral

Rimantadine (Flumadine) MOA

Answer 11

• inh of uncoating

- inh of assembly of surface glycoproteins like hemagglutin on nascent virion

Question 12

ADME of Amantadine and Rimantadine

Answer 12

well absorbed PO
amantadine - renal
rimantidine 25% renal (dose adj if CrCl65, 75% hepatic
-nausea, nervousness
-ADR w/ CNS sedatives and psychotropics (bc of NMDA recptor antagonism and release of catecholamines

Question 13

Oseltamivir (Tamiflu) and Zanamivir (relenza)

MOA

Answer 13

analogs of sialic acid - which is a residue on the host cell that is bound to the virus. Neuraminidase (N-glycoprotein) cleaves sialic acid so that the viral particle can spread infection.
These drugs BLOCK neuraminidase, thus blocking release of progeny virus.

This only helps prevent spread of inf. Does not kill primary virus.

Question 14

peramivir

Answer 14

IV - used for H1N1 flu, request from FDA

Question 15

Zanamivir (relenza)

ADME

Answer 15

• poor oral absorption
• intranasal/ inhalation
• do not use with resp equipment
• renal exc predominates

Question 16

Oseltamivir (Tamiflu) and Zanamivir (relenza)

used for

Answer 16

inh flu A and B (including H1N1 and amantadine-resistant strains)
prevention and treatment (mostly treatment)
-best used within 48 hrs
-safe in pregnancy
-inh Flumist (live attenuated virus), avoid using when getting this vaccine

Question 17

Oseltamivir (Tamiflu) ADME

Answer 17

• well absorbed PO - nausea/emesis
• psychiatric ADR
• prodrug -phosphate salt
• renal exc predominates

Question 18

Acyclic nucleotide analog of adenosine monophosphate (AMP)

Answer 18

Adefovir

Question 19

adefovir MOA, ADME

Answer 19

-mimics adenosine. entering host cells as prodrug, phosphorylated to adefovir diphosphate.
Acyclic, serves as a competitive inhibitor of ciral DNA polymerase. terminates DNA chain elongation
-Used for Hep B

• rapidly absorbed PO
• renal elim - dose adj if CrCl <50
• well tolerated
• headache, Gi discomfort. higher doses = nephrotox

Question 20

Recombinant and natural interferons use

Answer 20

hep B and C
and Kaposi’;s sarcoma (HIV)

alpha-INF is most used

Question 21

Recombinant and natural interferon MOA

Answer 21

activation of JAK-STAT pathway which is involved in upreg of genes for 24+ proteins that affect viral life cycle:
-inh of transription/translation, processing of key viral proteins, and maturation and release of new viral proteins

Question 22

Recombinant and natural interferon ADME

Answer 22

• parental, onset at 6-8 hrs
• liver/renal exc, dose adj for end-stage renal disease
• flu symptoms- fever, chills, myalgia, headache
• myelosup
• neurotox
• autoimmune disorders like thyroiditis, inc hepatic enzymes (AST/ALT)
• INH CYP450

Question 23

Lamivudine adn Telbivudine use

Answer 23

Hep

Hep B?

Question 24

nucleoside analogs of pyrimidines of cytosine and thymine

Answer 24

Lamivudine adn Telbivudine

Question 25

Lamivudine adn Telbivudine MOA

Answer 25

-phos to triphophate form which is used by Hep B polymerase (and HIV reverse transcriptase) = DNA synth blocked bc cannot have proper 5' to 3' link Lamivudine - 3' sulfur Telbivudine - L-stereoisomer of thymidine instead of req D-form

Question 26

Lamivudine adn Telbivudine ADME

Answer 26

- well absorbed orally - tolerated, but some malaise and ab pain - liver enlargement - inc in lactic acid - inc in hapatic transaminases (AST/ALT/LFT)

Question 27

Ribavirin (Tribavirin) MOA

Answer 27

- inh replication of broad range of DNA and RNA viruses - Primary: Inh inosine-5'-phosphate dehydrogenase which dec synth of GTP - G nucleic acids - Secondary: inh post-transcriptional processing of viral mRNA (5'capping which is dependent on GTP) - lack of GTP = lack of capping

Question 28

Ribavirin (Tribavirin) ADME

Answer 28

IV, but good roal F - hepatic met w/ renal elim - dose related myelosup

Question 29

Ribavirin (Tribavirin) use

Answer 29

Hep C and Aerosol RSV