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Pharma 1- Semmelweis > Topic 5-Agents to treat Herpes simplex (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV) and respiratory syncytial virus (RSV) infection. Anti-influenza agents > Flashcards

Topic 5-Agents to treat Herpes simplex (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV) and respiratory syncytial virus (RSV) infection. Anti-influenza agents Flashcards

1
Q

What are targets of the antiviral agents?

A
  1. ) 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)
  2. )Entry inhibitors (maraviroc, enfurvirtid)
  3. ) Uncoating inhibitor (amantadin)
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2
Q

What are other targets targets of antiviral agents?

A 
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
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3
Q

What are the three important factors regarding resistance building to antiviral agents

A
  1. )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
  2. )Antiviral Potency- Low potency is not effective, middle potency builds resistance, and high potency makes for no mutation and resistance
  3. )Genetic barrier: how many generations are needed for resistance to develop
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4
Q

Antiviral agents for HSV 1, 2 and VZV? What are their names (9 agents)

A 
Acyclovir
Valacyclovir
Pencyclovir
Famcyclovir
Vidarabine
Trifluoruridine
Idoxuridine
Brivudin
Docosanol
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5
Q

How is Acyclovir and Valacyclovir administered

A

Acyclovir is given iv, orally, and locally

Valacyclovir is given orally

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6
Q

What is the mechanism of action for Acyclovir and Valacyclovir?

A

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

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7
Q

Does the Acyclovir treatment eradicate the latent viral colonization

A

No

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8
Q

Does Acyclovir or Valacyclovir have better oral availabilty? Other pharmacokinetics

A

Valacyclovir is better

Penetrates into CNS well and eliminated by kidney, has half life of 3 hours

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9
Q

Adverse Effects of Acyclovir and Valacyclovir

A

Well tolerated, not teratogenic (given to prevent vertical transmission)
high dose IV may cause headache, nausea, vomiting

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10
Q

Indications for Acyclovir and Valacyclovir

A
  • 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
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11
Q

What are the other two main agents for HSV 1,2, and VZV taken locally and per os

A

Pencyclovir (local) and Famcyclovir (per os)

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12
Q

What is the structure and mechanism of action of Pencyclovir and famcyclovir

A

Pencyclovir is an acyclovir analogue and Famciclovir is a diacethyl prodrug that function the same as Acyclovir

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13
Q

What is the oral availability of Famcyclovir

A

70%

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14
Q

Adverse effect and indications of Famcyclovir and Pencyclovir

A

Nausea, headache, and diarrhea and same indications as Acyclovir and Valacyclovir

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15
Q

Acyclovir resistance

A

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

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16
Q

Three old, not really selective agents used mainly locally as eye drops or external solutions

A

Vidarabine, Trifluoruridine, Idoxuridine

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17
Q

Pyrimidine analogue active against HSV1 and VZW

A

Brivudin

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18
Q

Membrane penetration inhibitor of HSV used as a labial herpes cream

A

Docosanol

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19
Q

Name of drugs used for CMV (6)

A 
Gancyclovir
Valgancyclovir
Cidofovir
Foscarnet
Maribavir
Letermovir
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20
Q

What is the mechanism of action of Gancyclovir and Valgancyclovir

A

Similar to Acyclovir but broader spectrum (100 times more potent then ACV and binds EBV, HHV-6, and HHV-8) with higher toxicity

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21
Q

People at highest risk of Gancyclovir resistancy

A

After transplantation and HIV patients

22
Q

Adverse effects of Gancyclovir

A

Neutropenic, anemia, thrombocytopenia, GI, and it is teratogenic!

23
Q

Is Gancyclovir or Valgancyclovir absorbed from the gut? Does it go into the CNS? Elimination?

A

Valgancyclovir
Both go into CNS
Renal elimination

24
Q

Indications for Gancyclovir and Valgancyclovir?

A 
CMV retinitis (treatment, prophylaxis, and intraopthalmic implant is available), CMV pneumonia, esophagitis, colitis treatment (combined with anti-CMV hyper-immune serum)
Mononucleosis not treated
25
Q

What is the dCMP analogue drug?

A

Cidofovir

26
Q

What is the mechanism of action of Cidofovir

A

Its active metabolite, cidofovir diphosphate, inhibits viral replication by selectively inhibiting viral DNA polymerases. Does not need thymidine kinase

27
Q

What are the indications of Cidofovir

A

Herpes viruses, adeno-, polioma-,pox-, and papilloma viruses.
Also ACV GCV resistant mutants
CMV retinitis of HIV patients, also resistant HSV or CMV infections

28
Q

Kinetics of Cidofovir

A

IV, weak penetration into CNS, excreted by kidneys

29
Q

Adverse effects of Cidofovir

A

nephrotoxic, neutropenia, teratogenic!!

30
Q

Foscarnet mechanism of action

A

Pyrophosphate analogue, non competitive inhibitor of DNA polymerase enzymes –blocks the cleavage of
diphosphates during incorporation. Active against human herpes viruses and little bit against HBV and HIV. Synergistic with gancyclovir

31
Q

Foscarnet kinetics

A

iv. administered, penetrates well into CNS, accumulates in bone, excreted through kidney

32
Q

Adverse effects of Foscarnet

A

nephrotoxicity (interferes with calcium and phosphate excretion), decrease of haemoglobin level (neutropenia is not typical), bone alterations, CNS

33
Q

Indications of Foscarnet

A

Used for gancyclovir resistance or intolerance (CMV) –2nd choice, active against ACV resistant HSV

34
Q

Maribavir mechanism and kinetics

A

(Used only in special cases)
-Selective inhibitor of the nucleoside kinase
-Low toxicity (tasting disturbances are reported)
-After successful phase I and II trial phase III trial was unsuccessful (low dose for prophylaxis was
tested)
-Higher doses were used for therapy against multi-resistant CMV

35
Q

Letermovir

A

-Blocks the terminase complex of CMV (this
cleaves multiple DNA chain after duplication)
-CMV specific
-No cross-resistance
-Atoxic (headache, fatigue and mild CV side effects are possible)
-Indicated for prophylaxis in case of bone marrow transplantation

36
Q

What two treatments are used for respiratory syncytial virus

A

Ribavirin and Palivisumab

37
Q

What is the mechanism of action of Ribavirin?

A

It is a guanosine (ribonucleic) analog used to stop viral RNA synthesis and viral mRNA capping, thus, it is a nucleoside inhibitor

38
Q

Ribavirin is effective against

A

HSV, VZ,influenza A,B, RSV, HCVm hemorrhagic fever viruses (Lassa fever and krim-longo fever)
Used in immunosuppressed infants and young children with severe RSV and chronic hep C in combination with interferon alpha

39
Q

Administration and treatment length of Ribavirin

A

Oral, aerosol
HCV (12-48 weeks orally)
RSV (3-7 days inhaled)

40
Q

Adverse effects of Ribavirin

A

hemolytic anemia, teratogenic, carcinogenic, CNS (fatigue, insomnia, asthenia), skin problems, coughing, inhaled form can cause conjunctivitis

41
Q

Contraindications of Ribavirin

A

Anemia, kidney failure, ischemic vascular disease, pregnancy,

42
Q

What is Palivisumab and how and when is it given

A

Monoclonal antibody give as prophylactic agent in RSV, given intramuscularly for compromised children

43
Q

What are the Adamantins used for and what are the two drugs

A

Amantadin and rimantadin both are agents for influenza

44
Q

Amantadin and Rimantadin mechanism of action

A

They bind to the M2 protein on the viral membrane and block the uncoating. They are effect only against influenza A, but resistance is possible

45
Q

What are the Neuraminidase inhibitors used in treatment of Influenza

A

Oseltamivir
Zanamivir
Peramirvir
Lanimamivir

46
Q

What is the mechansim of action of the neuraminidase inhibitors

A

To cleave a sialic acid bridge and relase the ready virion from the cell so the agents inhibit the virus to infect new cells

47
Q

During H1N1 pandemia which drug was the flu resistant to

A

Oseltamivir.

Zanamivir was unchanged

48
Q

How are the Neuraminidase inhibitors administrated

A

Oseltamivir is a oral (IV is possible too) prodrug excreted renally
Zanamivir is available as an inhaled dust
Peramivir is an IV drug
Lanimamivir is a long acting parenteral drug, used as once therapy

49
Q

What are the adverse effects of Neuraminidase inhibitors

A

Oseltamivir: GI issues, headache
Zanamivir: bronchospasm, unpleasant sensation in pharynx and nose

50
Q

When are Neuraminidase inhibitors effective

A

first days of infection

51
Q

What is the blocker of cap-dependent endonuclease in the flue

A

baloxavir,

Fast effect, atoxic, given orally

Pharma 1- Semmelweis (16 decks)

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