Antiviral Agents

• Virus entry:

  • Inhalation - via respiratory tract
  • Ingestion - via GI tract
  • Inoculation - through skin abrasions/mucous membranes/transfusions/injections/transplants
  • Congenital - from mother to foetus
• Stopping a virus:

  • Host defence mechanisms
  • Humoral
  • Cell-mediated
  • Antiviral agents
  • Inhibition of nucleic acid synthesis
  • Inhibition of viral proteins

  Antiviral agents are still underdeveloped in comparison to antibiotics.
• Balance of host defence mechanisms:

  • Role of cytokines
  • The activation of host cells such as lymphocytes
  • Lymphocytes such as T or B cells and Natural Killer cells
• Immuno-stimulation can be achieved by:

  • Administration of human immune globulin
  • Administration of immuno-stimulant drugs

  This is usually done by vaccination
• Antivirals in dental practice are nucleoside analogues - interfere with replication of viral nucleic acid - therefore more effective the earlier they are prescribed.
• Antiherpetic agents are predominantly nuceloside analogues - example: aciclovir - an analogue of the purine nucleoside guanosine. These are incorporated into DNA - why they can induce toxicity if used inappropriately.
• How acyclovir (an antiherpetic agent - aka a nucleoside analogue) works:

  • Transformed by phosphorylation into active state by viral enzymes - so the virus helps to activate the therapeutic agent
  • Greater affinity for viral than host enzymes - therefore less toxic - important; one of the problems with antiviral agents is that as well as affecting the viral DNA, they can also affect host DNA, so there's a limitation on the dose that can be used
  • Incorporates into viral DNA
  • Inhibits viral DNA synthesis
  • In the early stages, when there's more replication going on, it's going to be more effective
• Pharmacokinetics of acyclovir (antiherpetic agent - aka a nucleoside analogue):

  • Aciclovir half-life is 2.5 hours (short)
  • Crosses the blood-brain barrier - given systemically
  • Excreted by the kidneys
  • Resistance is rare
  • Administration: may be prescribed topically (ointment - by dentist) or intravenously (in hospital)
• Unwanted effects of acyclovir (antiherpetic agent - aka a nucleoside analogue):

  • Nausea and headaches
  • Transient burning sensation on application
• Idoxuridine:

  • A thymidine analogue
  • Phosphorylated in cells and is incorporated into cellular and viral DNA
  • Unlike aciclovir it doesn't block DNA synthesis
  • Mainly used against DNA viruses and is too toxic for systemic use - can be used topically though
• Zidovudine (AZT):

  • A thymidine analogue
  • Cytopathic against HIV-1
  • Mode of action:
  • Inhibits viral RNA-dependent DNA polymerase
  • Prevents further nucleotides from being incorporated into a growing strand of DNA
  • Action can be enhanced by aciclovir and interferon
  • Administration: orally or by continuous intravenous infusion
• Zidovudine (AZT):

  • Pharmacokinetics:
  • Rapidly absorbed from GIT
  • Peak plasma concentration after 30-90 minutes
  • Metabolised in the liver and excreted via kidneys
  • Unwanted effects:
  • Anaemia
  • Granulocytopaenia
  • Regular blood count every 2 weeks
  • Main use = treatment of HIV and AIDS patients who are symptomatic
• Reverse transcriptase inhibitors:

  • An RNA-dependent DNA polymerase inhibitor
  • They are nucleoside analogues - some of the newer drugs e.g. Nevirapine are non-nucleosides
• Non-nucleoside analogues are used in the treatment of AIDS - eg nevirapine and delavirdine
• Other antiviral agents:

  • Interferons - a group of cytokines
  • 3 main types: Alpha/Beta/Gamma
  • Glycoproteins produced by the body in response to a viral infection
  • Enhance the cytotoxic capacity of T-lymphocytes
• Prions:

  • Not bacteria or virus but are infective agents
  • Contain no genetic material and are pure proteins
  • Can produce configurational changes in host protein
• Prion diseases:

  • BSE - Bovine Spongiform Encephalitis (cattle)
  • Creutzfeldt-Jakob disease
  • Not possible to sterilise instruments - disposable used