In the Name of Allah, the Beneficent, the Merciful

1. In the Name of Allah, the Beneficent, the Merciful

2. ANTIVIRALS Azam Bakhtiarian Dept. of Pharmacology

3. Viruses, what are they? • Viruses are all parasites of the living • They use the cell’s materials to build themselves

4. Viruses • Unable to replicate on their own • Assemble to viruses once in host cell • DNA virus made of DNA and protein coat • RNA virus made of RNA and protein

5. Viral Life Cycle at the Cellular Level 1. Entry of genetic information 2. Replication of genetic information 3. Assembly and release of virions

6. Viruses • Steps for Viral Replication • 1) adsorption and penetration into cell • 2) uncoating of viral nucleic acid • 3) synthesis of regulatory proteins • 4) synthesis of RNA or DNA • 5) synthesis of structural proteins • 6) assembly of viral particles • 7) release from host cell

9. DRUGS FOR INFLUENZA

10. Amantadine Rimantadine • Active against influenza type A, not type B • Inhibit viral uncoating • increase lysosomal pH • Oral, long half-life; amantadine excreted renally • Can prevent influenza A • Can treat influenza A if used early

11. M2 inhibitors: Mechanism Neuraminidase Hemagglutinin RNA M2 protein (only on type A) H+ H+ H+ H+ X • M2 channel allows acidification of virus • Initiates uncoating of viral RNA • Allows viral replication • M2 inhibitors block this action M2 inhibitors

12. Amantadine Use: Flu prophylaxis , Anti – Parkinson SE: CNS (nervousness, dizziness, slurred speech, insomnia, hallucination, depression) GI (anorexia, nausea, constipation) ↓dosage with renal problems

13. NEURAMINIDASE INHIBITORSZanamivir (Relenza); Oseltamivir (Tamiflu) • Block release of new virions from infected cells. • Inhibit influenza A and B . • Zanamivir is a powder given by oral inhalation, can cause bronchospasm; Oseltamivir is given by mouth, cause N,V. • Less toxic than the older agents, but are more expensive

15. Antiviral agents for influenza:two classes of drugs Matrix protein (M2) inhibitors amantadine and rimantadine inhibit virus uncoating influenza A only Neuraminidase inhibitors oseltamivir and zanamivir inhibit release of virus from infected cells active against all known strains of influenza

16. DRUGS FOR INFLUENZA • INHIBITORS OF VIRAL UNCOATING: Amantadine and Rimantadine Active against influenza type A • NEURAMINIDASE INHIBITORSZanamivir (Relenza); Oseltamivir (Tamiflu) Active against influenza type A&B

17. DRUG FOR RSV & INFLUENZA • Ribavirin is a guanosine analog that is phosphorylated by host cell . • Inhibit the viral RNA-dependent RNA polymerase of influenza A and B, respiratory syncytial virus, and HIV-1. • Hemolytic anemia (Systemic Therapy) • Bronchospasm (Aerosol Therapy)

18. DRUGS FOR RSV • Palivizumab • is a humanized monoclonal antibody directed against the F glycoprotein on the surface of RSV. • For the prevention of RSV infection in high-risk infants and children such as premature infants . • Adverse effect : elevation in serum aminotransferase levels.

19. DRUGS FOR HSV OR VZV

21. ACYCLOVIR(Zovirax) • Spectrum: HSV-1 > HSV-2 > VZV > EBV >> CMV • Mechanism: • HSV thymidine kinase produces mono-P • Host completes phosphorylation to tri-P • Triphosphate inhibits viral DNA polymerase and acts as chain terminator • Resistance: TK (important) , VDP • Route: IV, oral (20% bioavailability), or topical • Excretion: Renal

24. Mechanism of Resistance Acyclovir • Alteration in viral thymidine kinase • Alteration in viral DNA polymerase • Cross-resistance with valacyclovir, famciclovir, and ganciclovir

25. ACYCLOVIR(Zovirax) Herpes (topical): 5% ointment reduces viral shedding/improves healing SE: burning, stinging Herpes (PO): 200mg q 4 h for 10 days shortens clinical course/ ↓pain SE: N/V, diarrhea, rash

26. Acyclovir - Clinical Use • Herpes Simplex Virus: • Genital - primary, recurrent, and suppressive • Orolabial - suppressive • HSV encephalitis - drug of choice, prevents death • Varicella-Zoster Virus: • Immunocompromised • Chickenpox • EBV:Oral hairy leukoplakia in AIDS • CMV: Protective at renal or marrow transplantation

27. Orolabial Herpes Simplex Virus

28. Chickenpox (Varicella-Zoster Virus)

29. Oral Hairy Leukoplakia in AIDS (Epstein-Barr Virus)

30. Newer Oral Anti-Herpes Drugs • Prodrugs that are converted to active agents when passing through intestinal wall or liver, to achieve higher levels than oral acyclovir • Valacyclovir (Valtrex): prodrug of acyclovir (48%) • recurrent genital herpes • genital herpes suppression • in preventing CMV after organ transplantation • SE: In AIDS patients receiving high-dosage of Val thrombotic thrombocytopenic purpura and hemolyticuremic syndrome.

31. Newer Oral Anti-Herpes Drugs Famciclovir (Famvir): prodrug of penciclovir (70%) • active against HSV-1, HSV-2, VZV, EBV, and HBV. • phosphorylation by the virus-specified thymidine kinase • inhibition of the viral DNA polymerase • Penci-3P has lower affinity for the viral DNAP than AC3P • SE: headache, diarrhea, and nausea incidence of mammary adenocarcinoma was also increased In female rats receiving famciclovir for 2 years.

32. Famciclovir - Clinical Use • Herpes Simplex Virus: • Genital - primary, recurrent, and suppressive • Varicella-Zoster Virus: • Immunocompromised • acute herpes zoster (shingles). • associated with a shorter duration of postherpetic neuralgia.

33. Trifluridine-Herpes Drugs Spectrum: HSV-1 , HSV-2 Mechanism: inhibits viral DNA synthesis (host) after phosphorylation by host Enz Used in: Acyclovir Resistance HSV-infection keratoconjunctivitis, Epithelial keratitis Route: Topical (1% Sol.) (No systemic use)

34. DRUGS FOR CMV

35. Approval of oral valganciclovir is a major advance Ganciclovir(Cytovene) • Useful for CMV but also covers HSV, VZV • Triphosphate inhibits viral DNA polymerase • Intravenous for therapy of disease; oral for maintenance or prophylaxis • Renal excretion • For CMV retinitis (especially); also for colitis, Pneumonitis

36. Ganciclovir(Cytovene) SE: Bone marrow depression Neutropenia Anemia Rash, fever N/V Liver dysfunction

37. Cidofovir • is a cytosine nucleotide analog with in vitro activity against CMV, HSV-1, HSV-2, VZV, EBV • Phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes. • inhibiting DNA synthesis • IV for the treatment of CMV retinitis. • Prevent nephrotoxicity : admin. + probenecid which blocks active tubular secretion SE: neutropenia and metabolic acidosis (Rare)

38. Fomivirsen • is an oligonucleotide that inhibits CMV through an antisense mechanism. • inhibiting virus replication. • No cross-resistance with ganciclovir, cidofovir, foscarnet • in patients with AIDS and patients who are intolerant of or unresponsive to alternative therapies.

39. Drugs used for Opthalmological Infections by HSV & CMV • Cidofovir: active against retinitis CMV & HSV, acyclovir-Resis Fomiversin: against retinitis CMV • Trifluridine: treatment of herpetic keratitis (topical) , acyclovir-Resis

40. Retinitis in left eye (CMV)

41. Foscarnet(Foscavir) • Analogue of pyrophosphate • Inhibits viral DNA polymerase • Intravenous route only • Renal excretion • Very toxic – Nephrotoxic, hallucination, seizures • For CMV retinitis, acyclovir-resistant HSV or VZV

42. Therapy for Herpes Viruses • Herpes simplex or zoster • Acyclovir • Foscarnet, trifluridine, Cidofovir • Cytomegalovirus • Ganciclovir • Foscarnet, Fomivirsen

43. DRUGS FOR HIV

44. Drugs for HIV Infection • Reverse Transcriptase (RT) Inhibitors • Nucleoside (or tide) RT inhibitors (NRTIs) • First there was AZT alone • Then there was AZT and ddI and ddC • Now there is AZT,ddI,ddC,d4T,3TC,ABC, FTC(and Tenofovir (TDF), a nucleotide RT inhibitor) • Non-nucleoside RT inhibitors (NNRTIs) • First there was nevirapine, Delavirdine, Efavirenz • Protease Inhibitors • There are now 8, which have revolutionized the care of people with HIV infection

45. Zidovudine(Azidothymidine, AZT, ZDV, Retrovir) • Mechanism: • Phosphorylated by host enzymes • Tri-P inhibits viral DNA polymerase • Acts as chain terminator • Resistance is common with continued use • Oral or IV, gets into CSF, short half-life • Can diminish perinatal transmission (the 26% risk drops to 8%) when given in the latter part of pregnancy and to the infant for 6 wks

46. Zidovudine(Azidothymidine, AZT, ZDV, Retrovir) Side Effects: Bone marrow depression Anemia, thrombocytopenia N/V, Liver problems Tremors, confusion, anxiety

47. Drug interactions • Increased serum levels of AZT: probenecid, phenytoin, methadone, fluconazole, valproic acid, and lamivudine, either through inhibition of first-pass metabolism or decreased clearance. • AZT decrease phenytoin levels

48. AZT causes neutropenia, anemia, myopathy • ddI causes pancreatitis • ddI, ddC, d4T cause peripheral neuropathy • Abacavir can cause a fatal hypersensitivity rxn • All can cause fatal lactic acidosis, steatosis Nucleoside Analogue RT Inhibitors • Zidovudine (AZT, ZDV, Retrovir) • Didanosine (dideoxyinosine, ddI, Videx) • Zalcitabine (dideoxycytidine, ddC, Hivid) • Stavudine (d4T, Zerit) • Lamivudine (3TC, Epivir) • Abacavir (ABC, Ziagen) • Emtricitabine (FTC, Emtriva) • Tenofovir (TDF, Viread) - Actually a nucleotide

49. Non-Nucleoside RT Inhibitors • Binds to a site on the HIV RT and blocks DNA polymerase activity. • Resistance occurs rapidly if used alone • Three are FDA-approved • Nevirapine (Viramune) ** • Delavirdine (Rescriptor) • Efavirenz (Sustiva) ** can prevent perinatal transmission

50. Protease Inhibitors • Block virion maturation • More potent than RT inhibitors • Resistance occurs rapidly if used alone • Many drug interactions via hepatic enzymes • Inhibitors of CYP3A * • 8 are FDA-approved:- Saquinavir (Fortovase)* - Ritonavir (Norvir)*- Indinavir (Crixivan)* - Nelfinavir (Viracept)* - Amprenavir (Agenerase)* - Fosamprenavir (Lexiva) - Lopinavir / Ritonavir (Kaletra)* - Atazanavir (Reyataz)