1. Antiviral agents Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)

2. วัตถุประสงค์เชิงพฤติกรรม เข้าใจและอธิบายถึงกลไกการออกฤทธิ์, การดื้อยา, เภสัชจลนศาสตร์, อาการไม่พึง ประสงค์ที่เกิดจากการใช้ยา, การนำไปใช้ ประโยชน์ทางคลินิก รวมทั้งข้อดีและข้อเสีย ของยาต้านไวรัสในกลุ่มต่างๆได้ เข้าใจและอธิบายถึงกลไกการออกฤทธิ์, การดื้อยา, เภสัชจลนศาสตร์, อาการไม่พึง ประสงค์ที่เกิดจากการใช้ยา, การนำไปใช้ ประโยชน์ทางคลินิก รวมทั้งข้อดีและข้อเสีย ของยาต้านไวรัสในกลุ่มต่างๆได้

3. Virus Intracellular parasite Nucleic acid + protein coat = Nucleocapsid Infective particle = Virion No metabolic machinery Host cells is needed for viral replication

4. ชนิดของไวรัส โรค / อาการแสดง I.DNA virus 1.Poxvirus 2.Herpesvirus 3.Adenovirus 4.Papillomavirus II. RNA virus 1.Orthomyxovirus 2.Paramyxovirus 3.Rubellavirus 4.Rhabdovirus 5.Picornavirus 6.Retrovirus 7.Arenavirus 8.Hepadenavirus 9.Arbovirus Small pox Chickenpox, Shingles, Cold sores Sore throat, conjunctivitis Warts Influenza Measles, Mumps German measles Rabies Colds, Meningitis, Poliomyelitis AIDS Meningitis, Lassa fever Serum hepatitis Arthropod-borne encephalitis

5. Viral replication Attachment receptor of NTs, cytokines, hormones receptor of NTs, cytokines, hormones HIV … CD4 RC HIV … CD4 RC Early regulatory protein = polymerase enzyme Viral DNA/ RNA synthesis Structural protein synthesis Blocked by enfuvirtide (in HIV)

6. Antiviral agents Antiherpes & Anticytomegalovirus agents Antiretroviral agents Antiinfluenza agents Antihepatitis virus agents

7. Antiherpes & Anticytomegalovirus Acyclovir a acyclic guanosine derivative H HSV-1, HSV-2, VZV C CMV, EBV, HHV M Mechanism of action ACVACV -P Viral thymidine kinase Host kinase ACV- PP ACV-PPP Active form

8. Mechanism of action o Acyclovir triphosphate o Inhibit DNA polymerase … competitive o Incorporate into DNA and Chain termination Mechanism of resistance Alteration of viral thymidine kinase *** Alteration of viral thymidine kinase *** Cross resistance with valacyclovir, famcyclovir, ganciclovir Cross resistance with valacyclovir, famcyclovir, ganciclovir No cross resistance with foscarnet, cidofovir, trifluridine No cross resistance with foscarnet, cidofovir, trifluridine Alteration of DNA polymerase Alteration of DNA polymerase

9. Clinical uses Route of administration UseRecommended Adult dosages OralGenital herpes treatment200 mg 5 times daily or 400 mg q 8 h HSV proctitis treatment400 mg q 8 h Genital herpes suppression 400 mg q 12 h or 200 mg q 8 h Varicella800 mg qid Zoster800 mg 5 times daily Anti-CMV prophylaxis in organ transplantation 200 mg q 8 h or 800 mg q 12 h IntravenousHerpes encephalitis5 mg/ kg q 8 h Varicella or zoster in an immunosuppressed host 10 mg/ kg q 8 h Topical … Primary HSV infection.. Less effective

10. Ganciclovir Acyclic guanosine analog Acyclic guanosine analog Active in triphosphate form Active in triphosphate form GAN GAN-P phosphotransferase UL 97 in CMV infected*** viral thymidine kinase in HSV infected Mechanism of action Inhibit DNA polymerase Inhibit DNA polymerase Inhibit DNA elongation Inhibit DNA elongation

11.  A A A Antiviral activity  C C C CMV, HSV, VZV, EBV, HHV-8  V V V Very good activity to CMV***  R R R Resistance  U U U UL 97 gene mutation  D D D DNA polymerase mutation  t t t thymidine kinase mutation  C C C Cross resistance with Cidofovir, Acyclovir

12. P ’ kinetics Low oral bioavailabilty … 6-9% Renal excretion Clinical uses ….CMV Route of administration UseRecommended adult dosages IVCMV retinitisInduction: 5 mg/ kg q 12 h Maintenance: 5 mg/ kg /day OralCMV retinitis treatment or prophylaxis 1 g q 8 h Intraocular implant CMV retinitis1 implant q 5-8 months Others … CMV colitis, CMV esophagitis, CMV pneumonitis

13. ADRs m myelosuppression*** esp. neutropenia CNS S/E … headache, changes in mental status, seizures Mitogenic to mammalian cells Carcinogenic & Embryotoxic in animals

14. Antiretroviral agents Human Immunodeficiency Virus (HIV) RNA virus Human Immunodeficiency Virus (HIV) RNA virus AIDS (Acquired Immune Deficiency Syndrome)

16. AIDS CD4 infected CD4 infected Immune deficiency Immune deficiency Opportunistic infection Opportunistic infection Pneumocystic carinii Pneumonia (PCP) Pneumocystic carinii Pneumonia (PCP) Toxoplasma gondii … Toxoplasmosis Toxoplasma gondii … Toxoplasmosis Mycobacterium avium complex (MAC) Mycobacterium avium complex (MAC) Mycobacterium tuberculosis Mycobacterium tuberculosis Viral infection … CMV Viral infection … CMV Fungal infection … Cyrptococcal meningitis, Oral candidiasis Fungal infection … Cyrptococcal meningitis, Oral candidiasis Tumor Tumor Organ dysfunction … Brain, CVS, Kidney Organ dysfunction … Brain, CVS, Kidney Finally … DEATH Finally … DEATH

17. Antiretroviral agents Nucleoside reverse transcriptase inhibitors (NRTIs) Non nucleoside reverse transcriptase inhibitors (NNRTIs) Protease inhibitors (PIs) Fusion inhibitors (FIs)

18. Nucleoside reverse trancriptase inhibitors Mechanism of action I Inhibit HIV reverse transcriptase ncorporate into viral DNA … Chain termination A Active in triphosphate form Zidovudine (Azidothymidine, AZT) Zidovudine (Azidothymidine, AZT) Didanosine (ddI) Didanosine (ddI) Zalcitabine (ddC) Zalcitabine (ddC) Stavudine (d4T) Stavudine (d4T) Lamivudine (3TC) Lamivudine (3TC) Abacavir (ABC) Abacavir (ABC) Emtricitabine (FTC) Emtricitabine (FTC)

19. NRTIs Thymidine Cytosine Adenosine Guanosine Thymidine Tenofovir

20. Non-nucleoside reverse transcriptase inhibitors Nevirapine Nevirapine Delavirdine Delavirdine Efavirenz Efavirenz Mechanism of action I Inhibit reverse transcriptase enzyme at different point N No DNA incorporation* o phosphorylation needed U Use in combination with other group … rapid resistance N No cross resistance with NRTIs or PIs**

21. Protease Inhibitors (PIs) Inhibit Protease Enzyme … essential for mature structural protein Easy resistance … Use in combination * *Major ADRs* Altered body fat distribution … buffalo hump, truncal obesity, facial & peripheral atrophy Insulin resistance Hyperlipidemia, Hypertriglyceridemia Spontaneous bleeding in hemophilia

22. Protease Inhibitors (PIs) Saquinavir Saquinavir Ritonavir Ritonavir Indinavir Indinavir Nelfinavir Nelfinavir Amprenavir Amprenavir Lopinavir … New agents Lopinavir … New agents Fosamprenavir Fosamprenavir Atazanavir Atazanavir

23. Fusion inhibitor Novel class of ARV use in HIV infection Enfuvirtide (Fuzeon®, T-20) Linear 36 aa synthetic peptide Inhibit HIV fusion with CD4+ cell Bind to HR1 in gp 41 at viral glycoprotein envelope Inhibit conformational change of envelope Inhibit HIV fusion No cross resistance with other class Reserve >>> last option to be used***

24. HAART; Highly Active AntiRetrovirus Therapy 3 Antiretrovirus in combinations N NNRTIs based regimen NNRTIs + 2 NRTIs Efavirenz + 2 NRTIs (3TC + AZT/ Tenofovir/ d4T) P PIs based regimen PI + 2NRTIs Lopinavir/ RNV (kaletra®)+ 2NRTIs (3TC + AZT/ d4T) T Triple NRTIs regimen >>> 3 NRTIs ABC + 3TC + AZT/ d4T

25. Four drug regimen 3 NRTIs + 1 PIs or NNRTIs 3 NRTIs + 1 PIs or NNRTIs May be more effective in high viral load > 100,000 May be more effective in high viral load > 100,000 GPO vir® in Thailand S30 = d4T 30 + 3TC 150 + Nevirapine 200 mg S40 = d4T 40 + 3TC 150 + Nevirapine 200 mg

26. Factors affecting anti-retroviral regimen P ’ kinetic profile Potency ADRs Tolerability Resistance Life style Drug interaction Advantage VS Disadvantage of ARV agents AZT + Ganciclovir … bone marrow suppression ddI + dapsone … altered absorption Clarithromycin … Enzyme inhibitor Rifampin … Enzyme inducer

27. Anti-influenza agents M2 Inhibitors M2 Inhibitors Amantadine Rimantadine Neuraminidase inhibitors Neuraminidase inhibitors Zanamivir Oseltamivir

28. Amantadine and Rimantadine Cyclic amine M Mechanism of action Inhibit viral uncoating Bind at M MM M2 protein Effective to I II Influenza A only** Easy mutation of M2 protein … drug resistance

29. Neuraminidase inhibitors Zanamivir & Oseltamivir N Neuramidinase … essential for viral release & viral penetration E Effective both Influenza A & B** Zanamivir Intranasal powder for inhalation.. Low oral bioavailability Rapid renal clearance O Oseltamivir Oral … p pp prodrug … Activate in gut & liver into Oseltamivir carboxylate … active form

30. Viral hepatitis Hepatitis A Hepatitis A Hepatitis B Hepatitis B Hepatitis C Hepatitis C Hepatitis D Hepatitis D Hepatitis E Hepatitis E Interferon (IFN) Peginterferon Ribavirin Lamivudine (3TC) Adefovir

31. Anti-hepatitis agents Interferons … IFN α, IFN β, IFN γ.. Endogeneous protein IFN  use in chronic hepatitis B & hepatitis C Lamivudine >>> chronic hepatitis B Adefovir >>> chronic hepatitis B Ribavirin >>> chronic hepatitis C

32. PEG IFN Pegylated interferon  Conjugated with polyethylene glycol (PEG) Longer half-life >>> 45 hrs … Once a week Less clearance PEG IFN -2b (PEG Intron®) Chronic hepatitis C Monotherapy 1.0 g/ kg/ wk SC for 1 year Combined with ribavirin 1.5 g/ kg/ wk SC + Ribavirin 800 mg/ day PEG Intron powder for injection PEG Intron RedipenTM

33. Ribavirin (Rebetol®) Guanosine analog Activate by phosphorylation Expected mechanism of action I Inhibit guanosine triphosphate synthesis Inhibit RNA dependent RNA polymerase Hep C, Influenza A, B, Parainfluenza, RSV, Paramyxovirus

34. Adefovir dipivoxil Hepsera® Diester prodrug of adefovir Adefovir diphosphate = active Inhibit HBV DNA polymerase** Incorporate into DNA & chain termination Active for HBV including lamivudine resistance Clinical use >>> Active chronic hepatitis B infection in adults 10 mg OD for 1 year

35. Antiviral agents Antiherpes & Anti-CMV Acyclovir & derivatives Ganciclovir, Foscarnet Antiretrovirus NRTIs NNRTIs PIs FIs Antiinfluenza M2 inhibitors Neuraminidase inhibitors Antihepatitis IFN/ PEG IFN Ribavirin Adefovir