Antiviral Agents

Question 1

Antiherpes drugs

Answer 1

• Acyclovir
• Ganciclovir
• Cidofovir
• Foscarnet

Question 2

Acyclovir

Answer 2

• Active aganist HSV-1/2 and VZV
• Activated to acyclovir triphosphate, a competitive substrate for DNA polymerase –> cause chain termination and incorporation into viral DNA
• Oral: used for treatment of mucocutaneous and genital herpes lesions. Also for prophylaxis in immunocompromised patients
• IV: used for severe herpes disease, including encephalitis and neonatal HSV infection

Question 3

Ganciclovir

Answer 3

• Active against HSV and CMV
• Triphosphorylated to form a nucleotide that inhibits DNA polymerase, do not cause chain termination
• Used for prophylaxis and treatment of CMV retinitis and other CMV infections in immunocompromised patients

Question 4

Cidofovir

Answer 4

• Inhibits DNA polymerase of HSV, CMV, adenovirus and papillomavirus
• Its phosphorylation does not require viral kinase
• Used in CMV retinits, mucocutaneous HSV infections, and in genitaø warts

Question 5

Foscarnet

Answer 5

• Does not require phosphorylation for activity
• Inhibits viral RNA polymerase, DNA polymerase, and HIV reverse transcriptase
• Alternative drug for prophylaxis and treatment of CMV infections

Question 6

Nucleoside reverse transcriptase inhibitors

Answer 6

• Zidovudine (ZDV)
• Didanosine (ddI)
• Zalcitabine (ddC)
• Lamivudine (3TC)
• Stavudine (d4T)
• Abacavir

Question 7

Nucleoside reverse transcriptase inhibitors: Mechanism of action

Answer 7

• Prodrugs converted by host cell kinases to triphosphates
• Competitively inhibit binding of natural nucleotides to the dNTP-binding site of reverse transcriptase
• Act as chain terminators

Question 8

Zidovudine (ZDV)

Answer 8

• Frequently used in combination drug regimens (HAART)
• Used in prophylaxis against HIV infection
• Azole antifungals and protease inhibitors may increase plasma levels of zidovudine

Question 9

Nonnucleoside reverse transcriptase inhibitors

Answer 9

• Nevirapine
• Delaviridine
• Efavirenz
• Tenofovir

Question 10

Nonnucleoside reverse transcriptase inhibitors: Mechanism of action

Answer 10

• Do not require phosphorylation to be active
• Do not compete with nucleoside triphosphate
• Bind to a site on reverse transcriptase different form NRTIs
• No cross-resistance with NRTIs
• Resistance caused by pol gene mutation

Question 11

Nevirapine

Answer 11

• Currently used in alternative combination regimens
• Effective i preventing HIV vertical transmission when given to mother at the onset of labor and to the neonate
• Can cause Steven-Johnson syndrome
• Blood levels increased by cimetidine and macrolides, decreased by rifampin

Question 12

Delaviridine

Answer 12

• Drug reaction major problem with this drug

- Metabolized by both CYP3A4 and CYP2D6

Question 13

Efavirenz

Answer 13

• Effective in HIV treatment when used in combination with 2 NRTIs
• Metabolized by P450 - involved in drug interactions

Question 14

Tenofovir

Answer 14

• Do not require bioactivation via host cell kinases
• Completly inhibits reverse transcriptase and cause chain termination
• Used in HAART regimens

Question 15

Protease inhibitors

Answer 15

• Indinavir
• Ritonavir
• Saquinavir
• Nelfinavir
• Amprenavir
• Lopinavir

Question 16

• Protease inhibitors: Mechanism of action

Answer 16

• Inhibit the active site in the viral enzyme, aspartate protease (HIV-1 protease)
• This enzyme is coded by the pol gene, and cleaves precursor polyproteins to form the final structural proteins of the mature virion core
• Caused disorders in carbohydrate and lipid metabolism - hyperglycemia and insulin resistance, or hyperlipidemia

Question 17

Indinavir

Answer 17

• Bioavailability inhibited in the presence of food

- Serum levels are increased by azole antifungals and decreased by rifamycins

Question 18

Ritonavir

Answer 18

• Should be taken with meals

- Most common adverse effect: GI irritation and bitter taste

Question 19

Fusion inhibitors

Answer 19

• Enfuviritide

- Maraviroc

Question 20

Enfuviritde

Answer 20

• Binds to th gp41 subunit of the viral envelope glycoprotein
• Prevent the conformational changes required for the fusion of the viral and cellular membranes
• Resistance: mutation in env gene
• Administered subcutaneously

Question 21

Anti-influenza agents

Answer 21

• Amantadine
• Rimantadine
• Oseltamivir
• Zanamivir

Question 22

Amantadine, Rimantadine

Answer 22

• Inhibit an early step in replication of the influenza A virus
• Prevent “uncoating” by binding to a protein M2 = protein that function as a proton ion channel required at the onset of infection to permit acidification of the virus core, which in turn activates viral RNA transcriptase
• Used as prophylaxis against influenza A virus with 80% efficacy

Question 23

Oseltamivir, Zanamivir

Answer 23

• Inhibits neuraminidases (NA) produced by influenza A and B viruses.
• NA cleaves sialic acid residues from viral proteins and surface proteins of infected cells. Its function is to promote virion release and to prevent clumping of newly released virions
• Used to impede viral spread

Question 24

Anti-hepatitis agents

Answer 24

• Interferon-α (INF-α)
• Lamivudine
• Ribavirin
• Adefovir

Question 25

Interferon-α: Mechanism of action

Answer 25

- Increase the activity of Janus kinases (JAKS) - JAKS phosphorylate signal transducers and activators of transcription (STATS) to increase the formation of antiviral proteins - Activate host cell ribonuclease that preferentially degrades viral mRNA - Also promote formation of natural killer cells that destroy infected liver cells

Question 26

Interferon-α: Clinical

Answer 26

- Used in chronic HBV as an individual agent or in combination with Lamivudine - Used in combination with Ribavirin to reduce progression of acute HCV to chronic HCV infection - Used in treatment of Kaposi's sarcoma, papillomatosis, and topically for genital warts

Question 27

Adefovir

Answer 27

- Competitively inhibit HBV DNA polymerase - Incorporate into viral DNA --> chain termination - Used to suppress HBV replication and improves liver histology and fibrosis

Question 28

Lamivudine

Answer 28

- NRTI - Active in chronic HBV - Can be used in lower doses for hepatitis than for HIV infection - longer intracellular half-life in HBV - Suppresses HBV replication and is remarkably nontoxic

Question 29

Ribavirin

Answer 29

- Inhibits guanosine triphosphate formation - Prevents capping of viral mRNA - Block RNA-dependent RNA polymerase - Inhibit replication in influenza A and B, parainfluenza, RSV, paramyxoviruses, HCV, and HIV - Used in combination with INF-α in chronic HCV infection in patients with compensated liver disease