Antiviral agents

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

วัตถุประสงค์เชิงพฤติกรรมวัตถุประสงค์เชิงพฤติกรรม • เข้าใจและอธิบายถึงกลไกการออกฤทธิ์, การดื้อยา, เภสัชจลนศาสตร์, อาการไม่พึงประสงค์ที่เกิดจากการใช้ยา, การนำไปใช้ประโยชน์ทางคลินิก รวมทั้งข้อดีและข้อเสียของยาต้านไวรัสในกลุ่มต่างๆได้

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

Viral replication Blocked by enfuvirtide (in HIV) Early regulatory protein = polymerase enzyme Attachment • receptor of NTs, cytokines, hormones • HIV … CD4 RC 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 ACV-PP ACV-PPP Active form Viral thymidine kinase Host kinase

Mechanism of action • Acyclovir triphosphate • Inhibit DNA polymerase… competitive • 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 Topical … Primary HSV infection .. Less effective

Ganciclovir • Acyclic guanosine analog • 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 elongation

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 Clinical uses….CMV 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 • 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 AIDS

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 triphosphateform • Zidovudine (Azidothymidine, AZT) • Didanosine (ddI) • Zalcitabine (ddC) • Stavudine (d4T) • Lamivudine (3TC) • Abacavir (ABC) • Emtricitabine (FTC)

Cytosine Adenosine Thymidine Cytosine Guanosine Tenofovir Thymidine NRTIs

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

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

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 • 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

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 • Acyclovir & derivatives • Ganciclovir, Foscarnet • Antiretrovirus • NRTIs • NNRTIs • PIs • FIs • Antiinfluenza • M2 inhibitors • Neuraminidase inhibitors • Antihepatitis • IFN/ PEG IFN • Ribavirin • Adefovir

THE END

Antiviral agents