antivirals

Question 1

what is the aim, how, effectiveness and objectives?

Answer 1

Aim : Treat infection/diseases caused by viruses
How : Target steps in viral replication with minimal effect on host cell function
Effectiveness: Only small number of viruses respond (only a small number of targets on virus)
Objectives:
At the end of this section, you should be able to describe
1. Mechanisms of action
2. Pharmacokinetics
3. Clinicaluses
4. Resistance
5. Adverseeffects
of specific examples of antiviral drugs used clinically

Question 2

what is a virus?

Answer 2

• Latin word meaning toxin or poison
• Definition: sub-microscopic infectious agent that cannot grow or reproduce outside a host cell - need to have host cell environment to replicate
  ~100 X smaller bacteria
• Structure: RNA or DNA, protein coat (capsid), lipid-rich envelope (some viruses)

Question 3

how does viral replication happen?

Answer 3

1. Adsorption/entry
2. Uncoating
3. Transcription/mRNA synthesis
4. DNA/RNA replication
5. Protein synthesis
6. Assembly
7. Release

• antiviral drugs target these steps

Question 4

what is the classification of viruses

Answer 4

Question 5

how are viruses transmitted and treated? what are examples of types of viral infection?

Answer 5

• Viruses are transmitted to host via Imany routes (bodily fluid contact, skin-skin contact, airborne etc.)
• not all viruses cause disease
  Prevention/treatment = ↓ exposure risk, healthy immune system, vaccines, antiviral drugs
  Examples of types of infection
  Acute: Smallpox, Influenza, Rhinovirus, Ebola, SARS
  Chronic: Hepatitis B & C
  Latent: Herpesviruses → remain dormant/latent for prolonged periods of time and then cause symptoms at a random time
  Progressive: HIV → progresses to AIDS
  Cancer: HPV, Epstein-Barr

Question 6

what is SARS-CoV-2 and what is it caused by?

Answer 6

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
• Coronavirus disease caused by SARS-CoV-2 first identified in 2019 (COVID-19)

Question 7

SARS-CoV-2 believed origin and route of transmission

Answer 7

believed to have zoonotic origins (bats)
- human-human transmission confirmed January 2020
- main routes of transmission: respiratory droplets and aerosols

Question 8

how do covid-19 treatments work?

Answer 8

Antivirals:
- virus particles multiply inside the body
- antiviral drug prevents virus from multiplying
Anti-inflammatories:
- immune system dangerously overreacts to virus
- anti-inflammatory drug calms immune response
Antibody treatments:
- antibody specific to coronavirus binds to it and makes it harmless

Question 9

What do antiviral drugs target and how are they administered?

Answer 9

• Specifically target viral entry or replication with limited effects on host cells.
• Limited number of drug targets.
• Viruses highly adaptive; mutations could result in increased infectivity or development of resistance to previously effective drugs or vaccines. (ex. flu vaccine on virus mutations)
• Remdesivir: First approved antiviral for COVID-19 July 2020: authorized with conditions in Canada.
• Administered IV within 7 days of infection: patients hospitalized with severe COVID-19 or non-hospitalized patients at risk of severe COVID-19

Question 10

how is Remdesivir metabolized and how does it work as a drug?

Answer 10

• metabolized to nucleoside
  monophosphate
• triple phosphorylated
• adenosine triphosphate (ATP) analog is incorporation into the newly synthesized RNA strand
• premature termination of the RNA product

Question 11

what is Paxlovid?

Answer 11

• combo of two drugs
• Ritonavir-boosted nirmatrelvir

Question 12

how do Ritonavir and Nirmatrelvir work to treat COVID-19?

Answer 12

• Approved for patients with mild-moderate symptoms at risk of severe COVID-19; FDA – December 2021;
  Canada – January 2022.
• Ritonavir = proteas inhibitor (high dose) or booster (low dose)
• Nirmatrelvir = inhibitor of M^PRO a viral proteases in all coronaviruses known to affect humans

Question 13

adverse effects of Remdesivir and Nirmatrelvir/ritonavir

Answer 13

Remdesivir: infusion site reactions, low blood pressure, nausea, vomiting, chest tightness → someone on ventilator should not use this drug, respiratory failure, altered liver enzymes, back impairment
- also bad for people with pre-existing cardio and renal diseases
Nirmatrelvir/ritonavir: change in taste, muscle aches, swollen joints, headache, blurred vision, changes in heart-rate

Question 14

Remdesivir and Nirmatrelvir resistance

Answer 14

Remdesivir: mutations in viral RNA-dependent RNA polymerase (RdRP) → drug cant bind as readily anymore once triple phosphorylated
- ATP analogue not incorporated into RNA
Nirmatrelavir: multiple mutations identified in SARS-CoV-2 MPRO near nirmatrelavir binding site therefore drug cant bind

Question 15

overview of covid 19 phases

Answer 15