Antiviral

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Antiviral

  1. 1. ANTIVIRAL DRUGSANTIVIRAL DRUGS Faraza JavedFaraza Javed Mphil PharmacologyMphil Pharmacology
  2. 2. WHAT IS VIRUS?WHAT IS VIRUS? An obligate intracellular microorganism which multiply in the nucleus or cytoplasm of host cell and use metabolic machinery of host cell is called virus. The drugs used against the replication of virus in host cell is known as antiviral drugs.
  3. 3. CLASSIFICATION OF VIRUSCLASSIFICATION OF VIRUS Viruses are not usually classified into conventional taxonomic groups but are usually grouped according to such properties as size, the type of nucleic acid they contain, the structure of the capsid and the number of protein subunits in it, host species, and immunological characteristics.
  4. 4. Two classification systems exist:Two classification systems exist:  The Hierarchical virus classification system  The Baltimore Classification System
  5. 5. The Hierarchical virus classificationThe Hierarchical virus classification systemsystem In 1962 Lwoff, R. W. Horne, and P. Tournier advanced a comprehensive scheme for the classification of all viruses consisting of phylum - class - order - family - subfamily - genus - species - strain/type. Four main characteristics are used:  Nature of the nucleic acid: RNA or DNA  Symmetry of the capsid
  6. 6.  Presence or absence of an envelopePresence or absence of an envelope  Dimensions of the virion and capsidDimensions of the virion and capsid All Families have the suffix -viridae e.g. Caliciviridae, Picornaviridae, Reoviridae. Genera have the suffix -virus. Within the Picornaviridae there are 5 genera: enterovirus, cardiovirus, rhinovirus, apthovirus and hepatovirus.
  7. 7. The Baltimore ClassificationThe Baltimore Classification The Baltimore system of virus classification provides a useful guide with regard to the various mechanisms of viral genome replication. These various types of virus genomes can be broken down into seven fundamentally different groups, which obviously require different basic strategies for their replication..
  8. 8. David Baltimore, who originated the scheme, has given his name to the so-called "Baltimore Classification" of virus genomes. The replication strategy of the virus depends on the nature of its genome. Viruses can be classified into seven (arbitrary) groups::
  9. 9. I: Double-stranded DNAI: Double-stranded DNA Some replicate in the nucleus e.g. adenoviruses using cellular proteins. Poxviruses replicate in the cytoplasm and make their own enzymes for nucleic acid replication. (Adenoviruses; Herpesviruses; Poxviruses, etc) II: Single-stranded (+)sense DNAII: Single-stranded (+)sense DNA Replication occurs in the nucleus
  10. 10. involving the formation of a (-)sense strand, which serves as a template for (+)strand RNA and DNA synthesis. e.g. (Parvoviruses). III: Double-stranded RNAIII: Double-stranded RNA These viruses have segmented genomes. Each genome segment is transcribed separately to produce monocistronic mRNAs. (Reoviruses, Birnaviruses).
  11. 11. IIV: Single-stranded (+)sense RNAV: Single-stranded (+)sense RNA Naked RNA is infectious, no involvement of virion particle associated polymerase. e.g. (Picornaviruses, Togaviruses). V: Single-stranded (-)sense RNAV: Single-stranded (-)sense RNA Must have a virion particle RNA directed RNA polymerase. e.g. (Orthomyxoviruses, Rhabdoviruses etc).
  12. 12. VI: Single-stranded (+)sense RNA with DNAVI: Single-stranded (+)sense RNA with DNA intermediate in life-cycleintermediate in life-cycle (RT-RNA-virus)(RT-RNA-virus) Genome is (+)sense but unique among viruses in that it is DIPLOID, and does not serve as mRNA, but as a template for reverse transcription. e.g. (Retroviruses) VII: Double-stranded DNA with RNAVII: Double-stranded DNA with RNA intermediateintermediate (RT-DNA-virus)(RT-DNA-virus) This group of viruses also relies on reverse
  13. 13. but unlike the Retroviruses, this occurs inside the virus particle on maturation. On infection of a new cell, the first event to occur is repair of the gapped genome, followed by transcription. e.g. (Hepadnaviruses).
  14. 14. CLASSIFICATIONCLASSIFICATION Anti HIV drugsAnti HIV drugs  Nucleoside reverse transcriptase inhibitors  Non-nucleoside reverse transcriptase inhibitors  Protease inhibitors  Entry inhibitors  Integrase inhibitors
  15. 15. Other viral drugsOther viral drugs  Viral DNA polymerase inhibitors  Inhibitor of viral uncoating and viral assembly  Neuraminidase inhibitors  immunomodulators
  16. 16. Nucleoside Reverse trancriptaseNucleoside Reverse trancriptase inhibitorsinhibitors This include group of drugs which are nucleoside analogue e.g. analogue of thymidine, adenosine,cytosine,guanosine. All are phosphorylated by host cell enzymes to give the 5-triphosphate. This compete with host nucleosides which are essential substrate for the formation of proviral DNA by viral reversetrancriptase. So, incorporation of analogues of nucleosides into growing viral
  17. 17. DNA chain thus terminating the chain.  Zidovudine and stavudine(analogue of thymidine)  Didanosine(analogue of deoxyadenosinea)  Lamvidine(analogue of cytosine)  Abacavir(analogue of guanosine)
  18. 18. Non nucleoside reversetranscriptaseNon nucleoside reversetranscriptase inhibitorsinhibitors These are chemically diverse compounds that are not nucleosideanalogue but blocks reverse transcriptase by binding near the catalytic site and denature it. Drug examples are  Efavirenz  nevirapine
  19. 19. Protease inhibitorsProtease inhibitors Protease is an enzyme present in HIV virus that converts the polyprotiens into various structural and functionalprotins by cleavage at the appropriate positions. The drug target this enzyme and viral replication stops.  Squinavir  Nelfinavir  Indinavir  ritonavir
  20. 20. Entry inhibitorsEntry inhibitors It inhibits entry of virus into the host cell by inhibiting the conformational change in glycoproteins of virus that is necessary for attachment to the receptors on host cell.  Enfurvirtide Integrase inhibitorsIntegrase inhibitors Inhibits the integration of viral DNA into the host cell DNA  Raltegravir
  21. 21. Viral DNA polymerase inhibitorsViral DNA polymerase inhibitors Viral DNA polymerase inhibitors prevent the replication by blocking DNA polymerase either by nucleoside or non-nucleoside analogue.  Nucleoside analogueNucleoside analogue aciclovir, cidofovir, famciclovir, ganciclovir, idoxuridine, penciclovir, ribavarin, valaciclovir, valganciclovir  Non nucleoside analogueNon nucleoside analogue foscarnet
  22. 22. Inhibitor of viral uncoating and viralInhibitor of viral uncoating and viral assemblyassembly A viral membrane protien M2 functions as an H+ ion channel in two steps of replication  When fusion of viral membrane and endosome membrane  Assembly and release of virion Inhibition of this protein inhibits viral uncoating and assembly. Amantadine and rimantadine
  23. 23. Neuraminidase inhibitorsNeuraminidase inhibitors Neuraminidase is an enzyme present in virus that helps in budding of new virus from infected cell. Neuraminidase inhibitors inhibits this enzyme.  Oseltamivir  Zanamivir
  24. 24. Biologics and immunomodulatorsBiologics and immunomodulators  Immunomodulators enhance the host defence. Pooled immunoglobulin contains antibodies against various viruses which are directed against virus envelop and can neutralize some viruses and prevent their attachment to host cells. e.g. interferon-α, pegylated interferon-α, inosine pranobex, palivizumab.
  25. 25. RibavirinRibavirin •It is effective against a broad spectrum of DNA and RNA viruses for example severe RSV infection in children. • It is used in combination with interfero-a-2b to eliminate chronic hepatitis C infection.
  26. 26. Mechanism of actionMechanism of action • MOA of ribavirin is studied on influenza virus. • The drug is first converted to ribivirin- triphosphate (5 phosphate derivative), which exerts its antiviral action  By inhibiting the guanosine-triphosphate formation  Preventing viral mRNA capping  Blocking RNA-dependent RNA polymerase
  27. 27. PharmacokineticsPharmacokinetics • Ribavirin is effective orally and intravenously • Absotion is increased if drug is taken with fatty meal • Aerosol is used in certain respiratory viral infections e.g in the treatmen of RSV infection. • The drug is retained in all tissues except brain • Drug and its metabolite are eliminated in the urine.
  28. 28. Adverse effectsAdverse effects • When given orally and intravenously:  Dose dependent transient anemia  Elevated bilirubin • When given through aerosol it is safer but can  Deteriorate the respiratory function of infants. Therefore monitoring is essential. • Teratogenic effects so contraindicated in pregnancy
  29. 29. Interferon:Interferon:  Naturally occurring inducible glycoprotein  Interfere with ability of viruses to infect cells  Synthetically prepared by Recombinant DNA technology  Three types Exist ▪ Alpha ▪ Beta ▪ Gamma  Interferon alpha-2b has been approver for the treatment of Hepatitis B & C, Condylomata acuminata and Cancer  Interferon Beta has some effectiveness in treatment of Multiple sclerosis
  30. 30. Mode of Action  Induction of host cell enzymes  Inhibit Viral RNA translation leading to degradation of Viral mRNA & tRNA  The Exact mechanism is incompletely understood
  31. 31. Pharmacokinetics:  Not active orally, but can be administered  Intralesionally ▪ Subcutaneously ▪Intravenously  Little active form is found in plasma  Metabolized in Liver  Cellular uptake and metabolism by Liver and Kidney cause disappearance from plasma  Negligible Renal elimination
  32. 32. Adverse Effects:  Flu-like symptoms (Fever, Chills, Myalgias, Arthralgias, Gastrointestinal disturbances)  Fatigue  Mental Depression  Bone marrow suppression including  Granulocytopenia ,Neurotoxicity  Hypersensitivity reaction and Hepatic failure are rare
  33. 33. AcyclovirAcyclovir  It has greater specificity than Vidarabine against herpes viruses.  Use in the treatment of choice in HSV encephalitis and increase rate of survival.  It is given prophylactically to sero +ve patients before bone marrow & after heart transplants.
  34. 34. Mechanism of actionMechanism of action  Acyclovir, is a guanosine analog that lacks a true sugar moiety.  It is monophosphorylated in the cell by herpes virus encoded enzyme thymidine kinase.  Monophosphorylated analog is converted to di & triphosphate forms by the host cells.  Acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase & is itself incorporated into the viral DNA
  35. 35. cont.….cont.….  It cause premature DNA chain termination.  Irreversible binding of acyclovir containing template primer to viral DNA polymerase inactivate the enzyme.  The drug is less effective against the most enzyme.
  36. 36. PharmacokineticsPharmacokinetics  It is administered by intravenous, oral, tropical route.  It distributes well throughout the body including CSF.  It is partially metabolize to an inactive product.  Excretion into the urine occurs both by glomerular filtration & by tubular secretion.
  37. 37.  It is accumulates in patients with renal failure.  The valyl ester,valacyclovir has greater oral bioavailability than acyclovir.  This easter is rapidly hydrolyzed to acyclovir & achieves levels of the later comparable to those from i.v acyclovir administration..
  38. 38. Adverse EffectsAdverse Effects  Adverse effects depends upon route of administration.  Local irritation may occur from topical application i.e. head,diarrhea,nausia,&vomiting may result after oral administration.  Transient renal dysfunction may occur at high doses or in dehydrated patient receiving the drug i.v.
  39. 39.  High dose of Valacyclovir can cause gastrointestinal problems &thrombotic thrombocytopenia purpura in patients with AIDS.. ResistanceResistance  Altered or deficient thymidine kinase &DNA polymerases have been found in some resistant viral stains..
  40. 40.  It is most commonly isolated from immunocompromised patients.  Cross resistance to other cyclovirs occurs.
  41. 41. EnfuviritideEnfuviritide It is an HIV infusion inhibitor,the first of the novel class of antiretroviral drugs used in the combination therapy for the treatment of HIV-1 infection.
  42. 42. Mechanism of actionMechanism of action  It works by disrupting HIV-1 molecular machinery at the final stage of infusion with the target cell,preventing uninfected cells from being infected..
  43. 43.  HIV binds to the host CD4+ cell via a viral transmembrane protein, then undergoes a conformational change that assists in the fusion of viral membrane to the host cell membrane. Enfuviritide binds to the viral transmembrane protein preventing the creation of an entry pore for the capsid of the virus, keeping it out of the cell.
  44. 44. Clinical useClinical use  The drug is generally given by subcutaneous injection in combination with others to treat HIV infection when resistance become a problem or when the patient is intolerant of other antiretrovirals.
  45. 45. PharmacokineticsPharmacokinetics  Enfuvirtide is a synthetic peptide and is thus not bioavailable orally. Following a twice- daily subcutaneous injection of 30 to 90 mg, its bioavailability is approximately 84.3%. Comparable absorption of the 90-mg dose has been reported in different injection sites of the abdomen, thigh, and arm. The volume of distribution is 5.5 liters, and the clearance rate is 1.4 liters/hour.
  46. 46. Adverse effectsAdverse effects  Flu-like symptoms Central effects such as  Headache  Dizziness  Alterations in mood  Gastrointestinal effects  Hypersensitivity reactions
  47. 47. Drug drug interactionsDrug drug interactions  Clinical studies involving enfuvirtide are limited. No clinically significant drug interaction was reported when this medication was used in combination with the other antiretroviral drugs. In cell culture media assays, enfuvirtide exhibited additive-to- synergistic effects when it was combined with individual members of various antiretroviral agents, such as zidovudine AZT, Retrovir drug, lamivudine.

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