antiviral drugs

Question 1

targets of the antiviral agents:

Answer 1

Targets of the antiviral agents
1. DNA/RNA synthesis inhibition
A. Nucleoside / nucleotide analogs:
** Need activation (2 or 3 phosphorilations) –triphosphate derivatives blocks DNA / RNA polymerase and / or cause chain termination after incorporation
B. Non competitive inhibitors (NNRTI, foscarnet, HCV)

2. Entry inhibitors (maraviroc, enfuvirtid)
3. Uncoating inhibitor (amantadin),

Targets of the 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

Question 2

Agents against herpes viruses I.
Agents for HSV 1, 2 and VZV

Aciclovir and Valaciclovir:
Which analogues are they? who is a prodrug?
Mechanism- 2
Kinetics 
Aciclovir taken?  3
Valacyclovir taken? 1
CNS? 
Eliminated by?
Adverse effects:

Answer 2

-Guanosine analogs (nucleosides).
valacyclovir prodrug of aciclovir

• The ACV treatment not eradicates the latent viral colonization

Mechanism:
They need triple phosphorylation, which the first step is done by the virus enzme of infected cells (thymidilate kinase)-> inhibits viral DNA polymerase.
An intermediate ACV-TP is also selective for viral DNA polymerase.

Kinetics:
Aciclovir:
A. iv. B. po (low bioavailability- 15%) C. local),
B. Valaciclovir (po. high bioavailability).

It penetrates into secretes and into CNS well.

Indications:

1) VZV.
2) HSV.

It is eliminated by the kidney (by filtration and secretion).

Adverse effects: well tolerated with oral form (might cause vomit and nausea).
If high Dose IV-> treatment hydration is important to prevent crystaluria).
Not teratogenic: it is given in case of active herpes to prevent vertical transmission.

Question 3

Agents against herpes viruses III.
Agents for HSV 1, 2 and VZV:

Penciclovir

Answer 3

Penciclovir is an ACV analogue but it not causes DNA chain termination.

guanosine analogue
admin: (local) for such as local herpes.

Adverse effects: headache, diarrhea, nausea

HSV and VZV

Question 4

cmv drugs:
gangiclovir (guanosine analogue)
valganciclovir (another guanosine analogue)

Answer 4

mechanism: similar to acyclovir.

Acivity against:
CMV
VZV
HSV

Mostly used in CMV prophylaxis of MV infection including retinits, in aids and transplant patients.

Given IV for ganciclovir.
Given oral for valganciclovir.

Side effects:
Hematotoxicity (leukopenia and thrombocytopenia),
mucositis, fever rash and crystalluria.

Can Cause seizures in high doses.

Question 5

CMV drug

Cidofovir (cytosine analog)

Answer 5

a deoxy-cytosine mono phosphate.
mechanism: phosphorylation does not depend on the viral thymidine kinase.

Kinetics:
excreted by tubular secretion.
admin: IV

Spectrum: Herpes viruses and other viruses such as
adeno, polio,pox and papilloma virus.

IT is a good antiviral drug against ACV and GCV resistant viruses.

Question 6

CMV drug
Foscarnet

Method of admin

Answer 6

A pyrophosphate (so not a metabolite) derivative which non-competitive inhibitts the RNA polymerase enzyme (blocks cleavage of diphosphates during incorporation into the DNA).

Kinetics:
Given IV
Penetrates to CNS.
secretion via kidneys

Spectrum:
HSV (acyclovir resistant), 
VZ 
CMV (retinitis)
Also used in HIV with ganciclovir combo.

adverse effects:.

1) Nephrotoxic-> ATN +electrolyte imbalance.
2) bone alterations (due to bone accumulation of drug).
3) CNS effects.

Question 7

RSV drugs

Ribavirin

Answer 7

Guanosine analogue

Mechanism:

1) monophosphorylated form inhibits IMP dehydrogenase.
2) Triphosphate inhibits VIRAL RNA polymerase and end capping of viral RNA.

Broad spectrum… (both RNA and DNA viruses)
HSV, VZV, influenza (a and B), RSV and more..

Mainly used in
adjunct to alpha interferons in hep C.
RSV
Lassa and Hantavirus.

Kinetics:
Oral and aerosol admin

Side effectsL
hemolytic anemia, bone marrow suprression in high doses.
teratogenic.
upper airway irritation

Question 8

RSV

Palivisumab

Answer 8

prophylatic agent
monoclonal antibody against RSV
given IM for compromised children.

Question 9

Influenza drugs:
Amantadine
Rimatadine

Answer 9

Mechanism: Blocks attachment, penetration and uncoating of influenza AAAAAAA.

Clinical use: Prophylaxis mainly, but may reduce duration of flue symptoms by 1-2 days.

TAken orally

Side effects:
CNS: Nervousness, insomnia, seizures in OD!
Causes atropine like peripheral effects and livedo reticularis.

Question 10

Influenza drugs

Oseltamivir and zanamivir

Answer 10

Neuraminidase inhibitors

Mechanism: Inhibit neuraminidase of influenza A and BBBBB. This decreases the likelihood that the virus will penetrate uninfected cells.

Clinical uses: Prophylaxis mainly, but may decrease duration of flu symptoms by 2-3 days.

Oseltamivir: ORal
Zanamivir: Inhalation

Adverse:
Oseltamivir (orally taken): GI discomfor and nausea.
Zanamivir: Irritation of the respiratory tract and bronchospasm (careful with COPD patients).