AntiViral drug

antiviral drug including viral replication, acyclovir, oseltamivir, interferons, anti retrovirus, highly active antiretroviral therapy

1. Antiviral Dr. Sumit Senior Resident

2. Noble prize 1988: Gertrude Elion and George Hitchings

3. Viral Structure Genome: Consist of either double or single stranded DNA or RNA Capsid: protein coat Lipid envelope: derived from the infected host cell

4. Replication of virus Viral replication

5. Classification of virus DNA Virus Adenovirus Hepadnavirus (hepatitis B) Herpes viruses HSV1,2 Varicella zoster CMV EBV Papilloma virus Pox virus Parvovirus RNA Virus Picornavirus Polio Hepatitis A Orthomyxovirus Paramyxoviruses Measles Rhabdovirus Rabies Arbovirus Dengue, yellow fever Rotavirus, retrovirus

6. Classification of antiviral drug Anti-herpes virus agents: Acyclovir, ganciclovir, famciclovir , penciclovir , valaciclovir , idoxuridine , trifluridine , vidarabine , foscarnet , fomivirsen , cidofovir . 2. Anti-influenza virus agents: Amantadine , rimantadine , oseltamivir, zanamivir . 3. Anti-Hepatitis virus/Nonselective antiviral drugs Primarily for hepatitis B: Lamivudine, Adefovir dipivoxil , Tenofovir Primarily for hepatitis C: Ribavirin, Interferon α 4. Drugs for Papilloma virus: Imiquimod

7. Mechanism based antiviral classification DNA polymerase inhibitors Purine analogues: acyclovir, valacyclovir , ganciclovir, cidofovir , adefovir , vidarabine etc Pyrimidine analogues: Idoxuridine , trifluridine , Non nucleoside: Foscarnet m-RNA synthesis inhibitors : Ribavirin, fomivirsen Inhibitors of viral penetration and uncoating : Amantadine, Rimantadine Neuraminidase inhibitors: Oseltamivir, Zanamivir , peramivir Immunomodulators : Interferons, palivizumab , Imiquimod

8. Anti-Retrovirus :

9. Anti-Herpes V irus D rugs: DNA viruses HSV-1, HSV2, VZV, EBV, and CMV. Acyclovir: G uanine nucleoside analogue , Prodrug Inhibits DNA synthesis and viral replication Activity: HSV-1>HSV-2 > VZV=EBV, No affect on CMV

10. Acyclovir Resistance Acyclovir resistance in HSV has been linked to one of three mechanisms: Impaired production of viral thymidine kinase Altered thymidine kinase substrate specificity Altered viral DNA polymerase Pharmacokinetics:

11. Adverse effects:

12. Ganciclovir & Valganciclovir Guanine nucleoside analogue Mechanism of action is similar to acyclovir Administered intravenously due to poor oral bioavailability Used for vision-threatening retinitis CMV Intravitreal implant for CMV retinitis in AIDS patients Most common side effect is myelosuppression Dose dependent neutropenia, anaemia, thrombocytopenia

13. Cotton wool appearance of cmv retinitis

14. foscarnet

15. Adverse effect: Nephrotoxicity: increases serum creatinine, nephritis and necrosis Electrolyte imbalance: chelates divalent cations, hypocalcemia and hypomagnesemia are seen Hypokalemia, hypo- and hyperphosphatemia, seizures, and arrhythmias

16. fomiversen

17. ANTI-INFLUENZA AGENTS

18. Anti-influenza virus agents

19. Oseltamivir & Zanamivir :

20. Anti Hepatitis Drugs

21. Adverse effects:

22. Antiretroviral agents: A ctive against human immunodeficiency virus ( HIV), a retrovirus. Use to prolong and improve the quality of life and postpone complications of acquired immunodeficiency syndrome (AIDS) or AIDS related complex (ARC), do not cure the infection . C linical efficacy of ART is monitored by plasma HIV-RNA assays and CD4 lymphocyte count carried out at regular intervals

23. Established targets for anti-HIV drugs: HIV reverse transcriptase : Which transcripts HIV-RNA into proviral DNA. HIV protease : Which cleaves the large virus directed polyprotein into functional viral proteins. Fusion of viral envelope with plasma membrane of CD4 cells through which HIV-RNA enters the cell. Chemokine coreceptor (CCR5) on host cells which provide anchorage for the surface proteins of the virus. HIV-integrase : Viral enzyme which integrates the proviral DNA into host DNA

24. Pathogenesis of HIV and target of various drugs

25. Nucleoside reverse transcriptase (NRT) inhibitors Zidovudine is the first drug to be used in the treatment of HIV infection . Mechanism of action : NRT inhibitors competitively inhibit the enzyme reverse transcriptase and terminate DNA chain elongation in the virus Major adverse effect include bone marrow suppression leading to megaloblastic anemia, neutropenia and thrombocytopenia contra-indicated in patient with Hb < 8g %, also cause myopathy. Chronic administration is associated with lipodystrophy syndrome, nail hyperpigmentation and lipoatrophy

26. Uses: Zidovudine is used in HIV infected patients only in combination with at least 2 other ARV drugs Used for the prophylaxis of needle stick injury patients and for the prevention of vertical transmission of HIV from mother to fetus Didanosine : Causes pancreatitis , hyperuricemia, optic neuritis and also painful sensory peripheral neuropathy Stavudine : C auses dose limiting peripheral neuropathy , most strongly associated with lipodystrophy syndrome among all NRTIs and protease inhibitors

27. NNRTI These drugs inhibit reverse transcriptase by acting at a site (allosteric site) different from that of NRTIs, selective for HIV-1 Nevirapine is used in pregnant women during labor and in the newborn to prevent vertical transmission from the mother to the baby . PROTEASE INHIBITORS An aspartic protease enzyme encoded by HIV, involved in the production of structural proteins and enzymes (including reverse transcriptase and integrase) of the virus from the large viral polyprotein synthesized in the infected cell. Polyprotein is broken into various functional components by this protease enzyme helps in the maturation of infectious virions , post-translational modification.

28. Act at late step of viral cycle, hence effective in both newly as well as chronically infected cells. HIV-infected cells produce immature noninfectious viral progeny—hence prevent further rounds of infection. All are extensively metabolized mainly by CYP All PIs (especially ritonavir and lopinavir ) are potent inhibitors of CYP3A4 Adverse effects of pis are gastrointestinal intolerance, asthenia, headache, dizziness, limb and facial tingling, numbness and rashes. Lipodystrophy, dyslipidaemia, insulin resistance, diabetes may be exacerbated. Indinavir crystalises in urine and increases risk of urinary calculi.

29. Entry (fusion) inhibitor Enfuvirtide : S ynthetic peptide acts by binding to HIV-1 envelope transmembrane glycoprotein ( gp41) involved in fusion of viral and cellular membranes. Inhibit Fusion of two membranes, prevent entry of the virus into the cell, It is not active against HIV-2 Integrase inhibitor Raltegravir : HIV- proviral DNA transcripted in the cytoplasm of host cell translocates to the nucleus along with an integrase enzyme. The HIV-integrase nicks host chromosomal DNA and integrates the proviral DNA Raltegravir is an orally active drug that blocks this step by inhibiting the integrase enzyme

30. HIV TREATMENT PRINCIPLES AND GUIDELINES: The goal of therapy is to maximally and durably inhibit viral replication so that the patient can attain and maintain effective immune response towards potential microbial pathogen highly active antiretroviral therapy ’ ( HAART) with combination of 3 or more drugs is indicated.

31. Thank you