Transcript Slide 1
Antiviral agents Pawitra Pulbutr M.Sc. In Pharm (Pharmacology) วัตถุประสงค์เชิงพฤติกรรม เข้าใจและอธิบายถึงกลไกการออกฤทธิ์, การดื้อยา, เภสัชจลนศาสตร์, อาการไม่ พึงประสงค์ท่เี กิดจากการใช้ยา, การนาไปใช้ประโยชน์ทางคลินิก รวมทัง้ ข้อดี และข้อเสียของยาต้านไวรัสในกลุม่ ต่างๆได้ Virus • Intracellular parasite • Nucleic acid + protein coat = Nucleocapsid • Infective particle = Virion • No metabolic machinery • Host cells is needed for viral replication ชนิ ดของไวรัส 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 โรค/ อาการแสดง 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 Blocked by enfuvirtide Viral replication (in HIV) Attachment • receptor of NTs, cytokines, hormones • HIV … CD4 RC Early regulatory protein = polymerase enzyme Viral DNA/ RNA synthesis Structural protein synthesis Antiviral agents Antiherpes & Anticytomegalovirus agents Antiretroviral agents Antiinfluenza agents Antihepatitis virus agents Antiherpes & Anticytomegalovirus Acyclovir • acyclic guanosine derivative • HSV-1, HSV-2, VZV • CMV, EBV, HHV • Mechanism of action ACV ACV -P Viral thymidine kinase ACVPP Host kinase ACV-PPP Active form 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 *** • Cross resistance with valacyclovir, famcyclovir, ganciclovir • No cross resistance with foscarnet, cidofovir, trifluridine • Alteration of DNA polymerase Clinical uses Route of administration Oral Intravenous Use Recommended Adult dosages Genital herpes treatment 200 mg 5 times daily or 400 mg q 8 h HSV proctitis treatment 400 mg q 8 h Genital herpes suppression 400 mg q 12 h or 200 mg q 8 h Varicella 800 mg qid Zoster 800 mg 5 times daily Anti-CMV prophylaxis in organ transplantation 200 mg q 8 h or 800 mg q 12 h Herpes encephalitis 5 mg/ kg q 8 h Varicella or zoster in an immunosuppressed host 10 mg/ kg q 8 h Topical … Primary HSV infection .. Less effective Ganciclovir • Acyclic guanosine analog • Active in triphosphate form GAN • phosphotransferase UL 97 in CMV infected*** • viral thymidine kinase in HSV infected Mechanism of action • Inhibit DNA polymerase • Inhibit DNA elongation GAN-P Antiviral activity CMV, HSV, VZV, EBV, HHV-8 Very good activity to CMV*** Resistance UL 97 gene mutation DNA polymerase mutation thymidine kinase mutation Cross resistance with Cidofovir, Acyclovir P’kinetics • Low oral bioavailabilty … 6-9% • Renal excretion Route of administration Clinical uses….CMV Use Recommended adult dosages IV CMV retinitis Induction: 5 mg/ kg q 12 h Maintenance: 5 mg/ kg /day Oral CMV retinitis treatment or prophylaxis 1 g q 8 h Intraocular implant CMV retinitis 1 implant q 5-8 months Others… CMV colitis, CMV esophagitis, CMV pneumonitis ADRs • myelosuppression*** esp. neutropenia • CNS S/E… headache, changes in mental status, seizures • Mitogenic to mammalian cells • Carcinogenic & Embryotoxic in animals Antiretroviral agents Human Immunodeficiency Virus (HIV) RNA virus AIDS (Acquired Immune Deficiency Syndrome) • CD4 infected • Immune deficiency AIDS • Opportunistic infection • Pneumocystic carinii Pneumonia (PCP) • Toxoplasma gondii … Toxoplasmosis • Mycobacterium avium complex (MAC) • Mycobacterium tuberculosis • Viral infection … CMV • Fungal infection … Cyrptococcal meningitis, Oral candidiasis • Tumor • Organ dysfunction … Brain, CVS, Kidney • Finally … DEATH Antiretroviral agents Nucleoside reverse transcriptase inhibitors (NRTIs) Non nucleoside reverse transcriptase inhibitors (NNRTIs) Protease inhibitors (PIs) Fusion inhibitors (FIs) Nucleoside reverse trancriptase inhibitors Mechanism of action • Inhibit HIV reverse transcriptase • Incorporate into viral DNA … Chain termination • Active in triphosphate form • Zidovudine (Azidothymidine, AZT) • Didanosine (ddI) • Zalcitabine (ddC) • Stavudine (d4T) • Lamivudine (3TC) • Abacavir (ABC) • Emtricitabine (FTC) Thymidine Adenosine Thymidine Cytosine NRTIs Cytosine Guanosine Tenofovir Non-nucleoside reverse transcriptase inhibitors • Nevirapine • Delavirdine • Efavirenz Mechanism of action • Inhibit reverse transcriptase enzyme at different point • No DNA incorporation* • No phosphorylation needed • Use in combination with other group … rapid resistance • No cross resistance with NRTIs or PIs** 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 Protease Inhibitors (PIs) • Saquinavir • Ritonavir • Indinavir • Nelfinavir • Amprenavir • Lopinavir … New agents • Fosamprenavir • Atazanavir 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*** HAART; Highly Active AntiRetrovirus Therapy • 3 Antiretrovirus in combinations • NNRTIs based regimen • NNRTIs + 2 NRTIs • Efavirenz + 2 NRTIs (3TC + AZT/ Tenofovir/ d4T) • PIs based regimen • PI + 2NRTIs • Lopinavir/ RNV (kaletra®)+ 2NRTIs (3TC + AZT/ d4T) • Triple NRTIs regimen >>> 3 NRTIs • ABC + 3TC + AZT/ d4T Four drug regimen • 3 NRTIs + 1 PIs or NNRTIs • 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 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 Anti-influenza agents • M2 Inhibitors • Amantadine • Rimantadine • Neuraminidase inhibitors • Zanamivir • Oseltamivir Amantadine and Rimantadine • Cyclic amine • Mechanism of action • Inhibit viral uncoating • Bind at M2 protein • Effective to Influenza A only** • Easy mutation of M2 protein… drug resistance Neuraminidase inhibitors • Zanamivir & Oseltamivir • Neuramidinase … essential for viral release & viral penetration • Effective both Influenza A & B** • Zanamivir • Intranasal powder for inhalation.. Low oral bioavailability • Rapid renal clearance • Oseltamivir • Oral … prodrug … Activate in gut & liver into Oseltamivir carboxylate … active form Viral hepatitis Hepatitis Hepatitis Hepatitis Hepatitis Hepatitis A B C D E Interferon (IFN) Peginterferon Ribavirin Lamivudine (3TC) Adefovir 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 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 Combined with ribavirin 1.0 g/ kg/ wk SC for 1 year 1.5 g/ kg/ wk SC + Ribavirin 800 mg/ day PEG Intron powder for injection PEG Intron RedipenTM Ribavirin (Rebetol®) • Guanosine analog • Activate by phosphorylation • Expected mechanism of action • Inhibit guanosine triphosphate synthesis • Inhibit RNA dependent RNA polymerase • Hep C, Influenza A, B, Parainfluenza, RSV, Paramyxovirus 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 Antiviral agents Antiherpes & Anti-CMV Antiretrovirus NRTIs NNRTIs PIs FIs Antiinfluenza Acyclovir & derivatives Ganciclovir, Foscarnet M2 inhibitors Neuraminidase inhibitors Antihepatitis IFN/ PEG IFN Ribavirin Adefovir