EXAM 1- KHAN

BASED OFF STUDY GUIDE!!!!!!!!!!!!!!

Brand name for the following:

• Acyclovir

• Valacyclovir

• Docosanol

• Acyclovir (Zovirax)

• Valacyclovir (Valtrex)

• Docosanol (Abreva)

Brand name for the following:

• Valganciclovir

• Foscarnet

• Letermovir

• Valganciclovir (Valcite)

• Foscarnet (Foscavir)

• Letermovir (Prevymis)

Brand name for the following:

• Oseltamivir

• Zanamivir

• Baloxavir

• Nirmatrelvir/ritonavir

• Oseltamivir (Tamiflu)

• Zanamivir (Relenza)

• Baloxavir (Xofluza)

• Nirmatrelvir/ritonavir (Paxlovid)

Where are HSV-1 and HSV-2 infections in the body?

• HSV-1: mouth, skin, face, esophagus

• HSV-2: genitals, rectum, skin, hands, or meninges

What is a nucleotide? Be able to identify by picture.

• nucleotide= base+ sugar+ phosphate

  

What is a nucleoside? Be able to identify by picture.

• nucleoside= base + sugar

• 

What is a nitrogenous base? Be able to identify by picture.

• base= A,T, G, C, U

• 

What are the names of the drugs used to treat HSV?

• Acyclovir

• Valacyclovir

• Famciclovir

• Docosanol

What are the names of the drugs used to treat CMV?

• Ganciclovir

• Valganciclovir

• Cidofovir

• Foscarnet

• Letermovir

How is Acyclovir activated?

What is the name of its active form?

STEPS:

• 1st phosphorylation by HSV Thymidine Kinase (TK)

• 2nd and 3rd phosphorylation by host cell

Active form= acyclovir triphosphate (bc of 3 phosphorylations necessary)

Difference between acyclovir and deoxyguanosine:

• acyclovir= guanine + artificial acyclic sugar

  • NO 3’ HYDROXYL GROUP

• deoxyguanosine= guanine + deoxyribose sugar

What is the MOA of Acyclovir?

2 MECHANISMS:

• competitive inhibition—> inhibits DNA polymerase

• incorporated into viral DNA= inhibits elongation= chain termination

  • (bc no 3’ hydroxyl)

What does it mean when acyclovir is “selectively toxic”?

affinity to HSV TK> human TK

What is the resistance mechanisms with acyclovir?

• absence or partial production of viral TK

• mutations to DNA polymerase

Which medication is used in Acyclovir-resistant case?

Foscarnet

What adverse effects are seen with IV admin of Acyclovir?

• crystal nephropathy, decreased CrCl

• CNS—> seizures

What is the advantage of using Valacyclovir> Acyclovir?

Valacyclovir has increased oral bioavailability=increased efficacy

• Acyclovir has POOR oral bioavailability

How is Valacyclovir structurally different Acyclovir?

• Valacyclovir has a L-valyl ESTER GROUP!!!!!!!!!!

• 

What is the active form of Famciclovir?

Penciclovir

How is Famciclovir converted to Penciclovir?

oxidation and deacetylation

How is the MOA of Famciclovir compared to Acyclovir?

• Acyclovir has 2 MOA

• Famciclovir ONLY inhibits DNA polymerase (no chain termination)

MOA of Docosanol?

inhibits fusion of host cell plasma membrane and HSV envelope—> INHIBITS VIRAL ENTRY

What are the tx options for Shingles?

start within 3 days:

• Acyclovir

• Valacyclovir

• Famciclovir

What are the tx options for pain associated with Shingles?

• lidocaine

• gabapentin, pregabalin

• duloxetine, amitriptyline

What is the MOA of Ganciclovir?

• (same as acyclovir)

• 2 mechanisms

• inhibits viral DNA polymerase

• inhibits elongation, chain termination

What is the resistance with Ganciclovir?

• UL97 mutations

• DNA polymerase mutations

What are the BBW with Ganciclovir?

• myelosuppression

• carcinogenic/teratogenic

• inhibits spermatogenesis

Compare Acyclovir with Ganciclovir:

• differences/similarities in phosphorylation?

• side effects?

• concentration in cells?

• MOA?

• BOTH REQUIRE PHOSPHORYLATION, BUT

  • For acyclovir—> 1st phosphorylation done by TK

  • For ganciclovir—> 1st phosphorylation done by UL97

  • 2nd and 3rd phosphorylation for both done by host cell

• Ganciclovir has MORE severe side effects (compared to acyclovir)

• Ganciclovir is more concentrated in the cells

What are the DOC for CMV?

How to treat refractory cases of CMV?

Which agent is used for prophylaxis?

DOC: Ganciclovir, Valganciclovir

Refractory: Cidofovir, Foscarnet

Prophylaxis: Letermovir

What are the advantages to using Valganciclovir> Ganciclovir?

oral bioavailability is increased by 61% with Val

What is the MOA of Letermovir?

• inhibits CMV DNA terminase

  • (DNA terminase is an enzyme required for viral DNA packaging and replication)

What is the MOA of Foscarnet?

• inhibits DNA polymerase

  • by directly blocking its pyrophosphate binding site

  • inhibits cleavage of pyrophosphate from dNTP

What is the MOA of Cidofovir?

• inhibits DNA polymerase

• inhibits elongation= chain termination

Compare Cidofovir to Foscarnet:

• phosphorylation?

• structure?

• MOA?

• Phosphorylation

  • Foscarnet—> NO phosphorylation

  • Cidofovir—> needs dephosphorylated

• Structure

  • Foscarnet—> NO BASE OR SUGAR

  • Cidofovir—> based off cytidine base

• MOA

  • Foscarnet—> just inhibits DNA polymerase

  • Cidofovir—> inhibits DNA polymerase and inhibits elongation and causes chain termination

ADRs of Foscarnet?

ADRs of Cidofovir?

• Foscarnet

  • BBW—> renal impairment

  • electrolyte disturbances

• Cidofovir

  • nephrotoxicity

What is the location of each of the following?

• HA

• Neuraminidase (NA)

• M2

• PA

• Sialic Acid

• HA: surface of virus

• NA: surface of virus

• M2: surface of virus

• PA: part of the RNA polymerase complex inside virus

• Sialic Acid: surface of host cell membrane

What is the function of each of the following?

• HA

• NA

• M2

• PA

• Sialic Acid

• HA- attaches to host cell and allows virus to enter

• NA- cleaves sialic acid, allows release of virus particles into host cell

• M2- ion channel

• PA- enzyme required for viral gene transcription

• Sialic Acid- what HA binds to on the host cell, cleaved by NA

What is the MOA of Oseltamivir, Zanamivir, and Peramivir?

• NEURAMINIDASE INHIBITORS!!

• inhibits viral (influenza A and B) release

• Oseltamivir—> also inhibits amantadine/rimantadine resistant influenza A

What Neuraminidase inhibitors are mainly excreted in the kidneys?

• Oseltamivir

• Zanamivir

ADRs of Oseltamivir:

• HA, n/v

• Rare: self-injury, delirium, neuropsychiatric behavior

ADRs of Zanamivir:

• bronchospasm

• acute deterioration in pts. with asthma or COPD

ADRs of Peramivir:

• serious skin rxns/ hypersensitivity

• neuropsychiatric events

How is Oseltamivir activated?

• BY ESTERASE ENZYME

• converts oseltamivir phosphate (ester prodrug)—> oseltamivir carboxylate (active form)

What is the MOA of Baloxavir?

• inhibits endonuclease activity of polymerase acidic (PA) protein—> a specific enzyme in RNA polymerase complex required for viral gene transcription

What is an ADR with Baloxavir? Drug interactions?

• ADR—> diarrhea

• Drug Interactions:

  • DAIRY

  • MULTIVALENT CATION CONTAINING DRUGS (antacids)

What antivirals are used to treat COVID-19?

• Nirmatrelvir/Ritonavir

• Molnupiravir

• Remdesevir

What is the MOA of Nirmatrelvir/Ritonavir?

• Nirmatrelvir: inhibitor of protease M^PRO (essential in viral replication)

• Ritonavir: HIV-1 protease inhibitor and CYP3A4 inhibitor

What is the MOA of Molnupiravir?

• causes viral mutations

  • oral prodrug of cytidine—> converted to N4 hydroxycytidine

  • uptake in triphosphate form by viral RNA-dependent RNA polymerase= viral mutations

What is the MOA of Remdesevir?

• chain terminator

  • adenosine nucleotide prodrug—> phosphorylated into triphosphate

  • incorporated into nascent RNA—> chain termination

What is the BBW of Paxlovid?

significant drug-drug interactions (bc of Ritonavir)