Topic 5-Agents to treat Herpes simplex (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV) and respiratory syncytial virus (RSV) infection. Anti-influenza agents Flashcards
(51 cards)
What are targets of the antiviral agents?
- ) DNA/RNA synthesis inhibition
- Nucleoside/nucleotide analogs (Needs activation via 2 to 3 phosphorylations to block DNA/RNA polymerase
- Non-competitive inhibitors (NNRTI, foscarnet, HCV)
- NSA5 complex inhbitors (HCV) - )Entry inhibitors (maraviroc, enfurvirtid)
- ) Uncoating inhibitor (amantadin)
What are other targets targets of antiviral agents?
1.)Other viral enzyme inhibitors Kinase inhibitor (CMV) Terminase inhibitor (CMV) Protease inhibitors (HIV, HCV) Integrase inhibitors (HIV) Neuraminidase inhibitor (Influenza) 2.)Immunological agents Interferon α Imiquimod Palivizumab
What are the three important factors regarding resistance building to antiviral agents
- )Viral fitness- How well can a virus adapt to it’s environment
- Mutant virus replicate slower than wildtype viruses and the antiviral agents select for the mutants. But with a second mutation the viral fitness is restored - )Antiviral Potency- Low potency is not effective, middle potency builds resistance, and high potency makes for no mutation and resistance
- )Genetic barrier: how many generations are needed for resistance to develop
Antiviral agents for HSV 1, 2 and VZV? What are their names (9 agents)
Acyclovir Valacyclovir Pencyclovir Famcyclovir Vidarabine Trifluoruridine Idoxuridine Brivudin Docosanol
How is Acyclovir and Valacyclovir administered
Acyclovir is given iv, orally, and locally
Valacyclovir is given orally
What is the mechanism of action for Acyclovir and Valacyclovir?
Acyclovir is a guanosine analog and valacyclovir is a valyl-ester prodrug that gets turned into acyclovir in active form
They both need triple phosphorylation to become active and the initial phosphorylation is done by thymidylate kinase in infected cells.
Then they block the viral DNA polymerase
Does the Acyclovir treatment eradicate the latent viral colonization
No
Does Acyclovir or Valacyclovir have better oral availabilty? Other pharmacokinetics
Valacyclovir is better
Penetrates into CNS well and eliminated by kidney, has half life of 3 hours
Adverse Effects of Acyclovir and Valacyclovir
Well tolerated, not teratogenic (given to prevent vertical transmission)
high dose IV may cause headache, nausea, vomiting
Indications for Acyclovir and Valacyclovir
- HSV and VZV infection in immune suppressed patient, herpes encephalitis, neonatal herpes (iv.), disseminated and ophthalmic zoster, severe primary genital herpes, recurrent genital herpes (po.), labial herpes (local)
- During immune suppression val(ACV) prophylaxis indicated in case of HSV or VZV immune positivity, high dose valacyclovir for CMV prophylaxis
What are the other two main agents for HSV 1,2, and VZV taken locally and per os
Pencyclovir (local) and Famcyclovir (per os)
What is the structure and mechanism of action of Pencyclovir and famcyclovir
Pencyclovir is an acyclovir analogue and Famciclovir is a diacethyl prodrug that function the same as Acyclovir
What is the oral availability of Famcyclovir
70%
Adverse effect and indications of Famcyclovir and Pencyclovir
Nausea, headache, and diarrhea and same indications as Acyclovir and Valacyclovir
Acyclovir resistance
Higher is immune compromised patients and allogenic bone marrow recipients
Mutant viruses can present in latent sensory ganglia
-Cross resistance with pencyclovir and sometime foscarnet (no cross resistance with cidofovir)
Means of resistance
Thymidylate kinase mutation
1.) altered affinity for acyclovir
2.) total deletion
3.) partial deletion
DNA polymerase mutation
Three old, not really selective agents used mainly locally as eye drops or external solutions
Vidarabine, Trifluoruridine, Idoxuridine
Pyrimidine analogue active against HSV1 and VZW
Brivudin
Membrane penetration inhibitor of HSV used as a labial herpes cream
Docosanol
Name of drugs used for CMV (6)
Gancyclovir Valgancyclovir Cidofovir Foscarnet Maribavir Letermovir
What is the mechanism of action of Gancyclovir and Valgancyclovir
Similar to Acyclovir but broader spectrum (100 times more potent then ACV and binds EBV, HHV-6, and HHV-8) with higher toxicity
People at highest risk of Gancyclovir resistancy
After transplantation and HIV patients
Adverse effects of Gancyclovir
Neutropenic, anemia, thrombocytopenia, GI, and it is teratogenic!
Is Gancyclovir or Valgancyclovir absorbed from the gut? Does it go into the CNS? Elimination?
Valgancyclovir
Both go into CNS
Renal elimination
Indications for Gancyclovir and Valgancyclovir?
CMV retinitis (treatment, prophylaxis, and intraopthalmic implant is available), CMV pneumonia, esophagitis, colitis treatment (combined with anti-CMV hyper-immune serum) Mononucleosis not treated
