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Pharmacology of Anti-viral drugs
Viruses are obligate intracellular parasites that rely on host cell synthetic processes for replication. Effective antiviral agents must block viral entry/exit from cells or be active inside host cells. They inhibit virus-specific replication events or preferentially inhibit virus-directed nucleic acid or protein synthesis over host-directed synthesis. Targets include viral DNA/RNA synthesis and structural/enzymatic proteins. Common antiviral drug classes inhibit viral entry, reverse transcription, protease activity, and more. Side effects depend on drug class but can include liver toxicity, hematological abnormalities, and more.
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Pharmacology of Anti-viral drugs
- 2. Viruses areobligate intracellular parasites; their replication depends primarily on synthetic processes of the host cell. Therefore, to be effective, antiviral agents must either block viral entry into or exit from the cell or be active inside the host cell. Effective antiviral agents inhibit virus-specific replicative events or preferentially inhibit virus-directed rather than host cell– directed nucleic acid or protein synthesis. Host cell molecules that are essential to viral replication also offer targets for intervention.
- 3. Viral DNAenters the host cell nucleus, where transcription into mRNA occurs catalysed by the host cell RNA polymerase. Translation of the mRNA into virus-specific proteins then takes place.
- 4. Enzymes withinthe virion synthesise its mRNA from the viral RNA template, or sometimes the viral RNA serves as its own mRNA. This is translated by the host cell into various enzymes, including RNA polymerase (which directs the synthesis of more viral RNA), and also into structural proteins of the virion.
- 5. Cell entry Uncoating Transcription of viral genome Translation ofviral proteins Assembly of virion components Release
- 7.
- 8. These aredrugs active against the Herpes group of DNA viruses which include Herpes simplex virus-1 (HSV-1), Herpes simplex virus-2(HSV2), Varicella-Zoster virus (VZV), Epstein-Barr virus (EBV), and Cytomegalovirus (CMV). Idoxuridine Trifluridine Valacyclovir Famciclovir Cidofovir Foscarnet Fomivirsen Acyclovir Ganciclovir Valganciclovir
- 9. Chemically, itis a unique tricyclic amine unrelated to any nucleic acid precursor, but inhibits replication of influenza A virus. It appears to act at an early step (possibly uncoating) as well as at a late step (viral assembly) in viral replication. This class consist following drugs - Amantadine Oseltamivir Zanamivir Rimantadine,
- 10. Several antiviraldrugs are relatively virus nonselective and inhibit viruses belonging to different classes; even cover both DNA and RNA viruses Lamivudine, • Adefovir, Ribavirin, • Interferonα Tenofovir • dipivoxil
- 11. These aredrugs active against human immunodeficiency virus (HIV) which is a retrovirus. They are useful in prolonging and improving the quality of life and postponing complications of acquired immunodeficiency syndrome (AIDS) or AIDS related complex (ARC), but do not cure the infection. The clinical efficacy of anti retrovirus drugs is monitored primarily by plasma HIV-RNA assays and CD4 lymphocyte count carried out at regular intervals. The two established targets for anti-HIV attack are: (a) HIV reverse transcriptase: Which transcripts HIV-RNA into proviral DNA. (b) HIV protease: Which cleaves the large virus directed polyprotein into functional viral proteins.
- 12. In addition, somenewer targets being exploited are: • Fusion of viral envelope with plasma membrane of CD4 cells through which HIVRNA 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. The aim of anti-HIV therapy is to cause maximal suppression of viral replication for the maximal period of time that is possible. For this, ARV drugs are always used in combination of at least 3 drugs and regimens have to be changed over time due to development of resistance. Life long therapy is required.
- 13. (a) Nucleoside reversetranscriptase inhibitors (NRTIs): Zidovudine (AZT), Didanosine, Stavudine, Lamivudine, Abacavir, Emtricitabine, Tenofovir (Nt RTI) (b) Nonnucleoside reverse transcriptase inhibitors (NNRTIs): Nevirapine, Efavirenz, Delavirdine (c) Protease inhibitors: Ritonavir, Atazanavir, Indinavir, Nelfinavir, Saquinavir, Amprenavir, Lopinavir (d) Entry (Fusion) inhibitor: Enfuvirtide (e) CCR5 receptor inhibitor: Maraviroc (f) Integrase inhibitor: Raltegravir
- 15. IDOXURIDINE –It is 5-iodo2-deoxyuridine , act as thymidine analogue. It is a water-soluble iodinated derivative of deoxyuridine It competes with thymidine, gets incorporated in DNA so that faulty DNA is formed which breaks down easily. It is effective only against DNA viruses
- 17. The majorityare nucleoside analogues, typified by zidovudine, all of which are phosphorylated by host cell enzymes to give the 5′-trisphosphate derivative. In retroviral replication this moiety competes with the equivalent host cellular trisphosphate substrates for proviral DNA synthesis by viral reverse transcriptase (viral RNA-dependent DNA polymerase). Eventually, the incorporation of the 5′- trisphosphate moiety into the growing viral DNA chain results in chain termination.
- 18. Non-nucleoside reversetranscriptase inhibitors are chemically diverse compounds that bind to the reverse transcriptase enzyme near the catalytic site and inactivate it. Most non-nucleoside reverse transcriptase inhibitors are also inducers, substrates or inhibitors, to varying degrees, of the liver cytochrome P450 enzymes
- 19. In HIVand many other viral infections, the mRNA transcribed from the provirus is translated into two biochemically inert polyproteins. A virus-specific protease then converts the polyproteins into various structural and functional proteins by cleavage at the appropriate positions . HIV-specific protease inhibitors bind to the site where cleavage occurs, and their use, in combination with reverse transcriptase inhibitors, has transformed the therapy of AIDS.
- 20. Biopharmaceuticals thathave been recruited in the fight against virus infections include immunoglobulin preparations, interferons (IFNs) and monoclonal antibodies.
- 21. Immunoglobulin Pooled immunoglobulincontains antibodies against various viruses present in the population. The antibodies are directed against the virus envelope and can ‘neutralize’ some viruses and prevent their attachment to host cells Palivisumab Related in terms of its mechanism of action to immunoglobulin is palivisumab, a monoclonal antibody directed against a glycoprotein on the surface of respiratory syncytial virus. It is used as an intramuscular injection, under specialist supervision, in children at high risk to prevent infection by this organism.
- 22. Interferon IFNs area family of inducible proteins synthesised by mammalian cells and now generally produced commercially by recombinant DNA technology. There are at least three types, α, β and γ, constituting a family of hormones involved in cell growth and regulation and the modulation of immune reactions. IFN-γ, termed immune interferon, is produced mainly by T lymphocytes as part of an immunological response to both viral and non-viral antigens
- 23. The IFNsbind to specific ganglioside receptors on host cell membranes. They induce, in host cell ribosomes, the production of enzymes that inhibit the translation of viral mRNA into viral proteins, thus halting viral replication. They have a broad spectrum of action and inhibit the replication of most viruses in vitro. Given intravenously, IFNs have a half-life of 2–4 h. They do not cross the blood– brain barrier.
- 24. Summery of anti-viraldrugs Use & Adverse effect
- 26. 1. Thepharmacological basis of therapeutics – Goodman & Gillman’s 12th edition page no. 1593-1640 2. Basic and clinical pharmacology by katzung B. G 12th edition page no. 861-889 3. K.D Tripathi , Essential of medical pharmacology 7th edition page no. 799 4. Lippincott’s Illustrated review , Pharmacology 4th edition page no. 596-613. 5. RANG and DALE pharmacology 8th edition page no. 649-652