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ANTI VIRAL Agents

ANTI VIRAL Agents. Kaukab Azim, MBBS, PhD Modified by: iSRAA. Viruses. Features of Antiviral Drugs Purine or pyrimidine analogs Prodrugs must be phosphorylated Antivirals have a narrow spectrum of action

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ANTI VIRAL Agents

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  1. ANTI VIRAL Agents Kaukab Azim, MBBS, PhD Modified by: iSRAA

  2. Viruses

  3. Features of Antiviral Drugs • Purine or pyrimidine analogs • Prodrugs must be phosphorylated • Antivirals have a narrow spectrum of action • Inhibit active replication; do not kill latent viruses, need host immune response • Resistance is common • Synergistic effects when given together • Efficacy relates to con. in infected cells • Start therapy early for optimal efficacy

  4. A good antiviral drug will Interfere with a viral specific function Only kill virus-infected cells Prevent viral replication

  5. Sites Of Anti Viral Drug Action Enfuvirtide, maraviroc Reltegravir Oseltamivir Indinavir

  6. Classes • Class I Antinfluenza agents • Class II Antiherpetic agents • Class III Antiviral for HBV & HCV • Class IV Antiretroviral therapy (ART) • Class V Agents against human Papiloma virus and RSV

  7. DNA Viruses Herpes virus (HSV 1 & HSV 2) Varicella Zoster (VZV) Cytomegalovirus (CMV) Hepatitis B virus RNA Viruses Hepatitis C HIV (Retro virus) Respiratory syncytial virus Influenza A & infl. B viruses Viruses susceptible to drug therapy

  8. Treatment of Influenza AAMANTADINE • MOA: Inhibits uncoatingno penetration • Uses: Prophylaxis & treatment, influenza A • It used to be active against influenza A, but not influenza B. As in recent past seasons, there is a high prevalence (>99%) of influenza A resistant to amantadine. Therefore it is no longer recommended for Influenza A • S/E: CNS: insomnia & restlessnessLivedoreticularis •  dose in renal dysfunction • Good alternative to a vaccine in the elderly or in immuno compromised patients

  9. OSELTAMIVIR: Tamiflu • Prophylaxis and treatment of Influenza A and B • Neuraminidase inhibitor • Flu virus attaches to host cell membrane – hemagglutinin on viral envelope binds to sialic acid moiety in glycoprotein of cell membranes • Neuraminidase enzyme cleaves viral attachment • Neuraminidase inhibitor keep the virus tethered to the host cell membrane; prevent it from being released and thus spreading to other cells

  10. OSELTAMIVIR: Tamiflu

  11. Treatment of HSV, VZV and CMV • Acyclovir • Ganciclovir • Foscarnet • 1st two are purine analogs • Acyclovir and Ganciclovir are prodrugs • Compete with dGTP for viral DNA- polymerase & inhibit viral DNA synthesis • Foscarnetacts directly on DNA polymerase

  12. ACYCLOVIR:guanine analog MOA: Inhibits HSV replication Acyclovir Acyclo-MP Acyclo-DP Acyclo-TP (ACTIVE DRUG) Stops viral replication Viral thymidine kinase Competes with dGTP for viral polymerase Cell kinase Chain termination Cell kinase Incorporated into growing DNA strand

  13. USES of ACYCLOVIR • Genital Herpes: 1st episodeviral shedding, duration of symptoms • Orolabialherpes: Topical/ oral acyclovir (penciclovir) • Herpes encephalitis: Acyclovir I/V • Varicella zoster: Oral, till all lesions encrusted I/V in disseminated CNS or Visceral infection • Cytomegalovirus: Prophylaxis only (prevent CMV infection in transplant ptns)

  14. Use in pregnancy: • For 1st episode of genital Herpsto prevent neonatal herpes (H.pneumonia) • Side effects: • Nephrotoxic(reversible crystalline nephropathy) • Encephalopathy (rare) • Resistance: • Mutations occur in the thymidine kinase gene causing an enzyme that does not phosphorylate acyclovir • Occurs more in HIV+ive people

  15. GANCICLOVIR • 1st drug effective against CMV • Uses: Cytomegalovirus (CMV): • Acute infection (retinitis, pneumonia in AIDS) • Prophylactic (in transplant patients, AIDS) • S/E: • Bone marrow toxicity (granulocytopenia & thrombocytopenia) • Drug Interactions: • DO NOT give with ZIDOVUDINE (overlappingmyelosuppressiontoxicities)

  16. When acyclovir is effective as CMV prophylaxis why gancyclovir is used? • To treat lung, colon infection • Good in AIDS ptns • Has less teratogenicity

  17. FOSCARNET(alternate to Ganciclovir for CMV) • Not a prodrug! • Uses; CMV infections, Acyclovir-resistant HSV encephalitis • MOA; Directly inhibits DNA polymerase • Side Effect: • Renal function, hypocalcaemia, teratogenic, mutagenic & carcinogenic drug • Drug Interactions: • Cyclosporine (renal toxicity), • Pentamidine(hypocalcaemia), • Imipenem(seizures)

  18. RIBAVIRIN: • Respiratory Syncytial Virus (given by aerosol only) • Hepatitis C • MOA: • Synthetic analogue of nucleoside; • Inhibits GTP synthesis • Inhibits 5̀ capping of viral mRNA, • Inhibits RNA- dependent RNA polymerase • S/ E: Headache, insomnia, anemia, teratogenesis • Uses:Severe RSV infection with serious underlying respiratory, CV problems or immunocompromised • C.I: Pregnancy

  19. HEPATITIS B: Lamivudine (ARV drug) • Inhibits HBV-DNA polymerase & HIV- reverse-transcriptase by competing with dCTP • Uses: • Chronic Hepatitis B infection with evidence of active viral replication • HIV infection • SE: N/V, headache, insomnia, fatigue

  20. HEPATITIS B: INTERFERONs • Interferon -2b & INF- :Cytokine • Broad spectrum antivirals, Immuno modulator activity, Antiproliferative actions; • Reduces progression of liverdisease in HBV • S/E: Many, Flu-like syndrome, Bone marrow suppression

  21. A 10-days old baby girl/ an AIDS ptn with low CD+4/ or bone marrow transplant pt. is suffering from RSV pneumonitis, what is the treatment of choice? • Lamivudine • Ribavirin • Oseltamivir

  22. HEPATITIS C:Peg-interferon  Ribavirin • PAPILLOMAVIRUS: • Imiquimod • For topical treatment of perianal & external genital warts

  23. Stages in Retrovirus development

  24. Why Body Defenses Disappear

  25. Anti retroviral agents • 4-5 big classes 1) Protease Inhibitors 2) Nucleoside reverse transcriptase Inhibitors 3) Non-nucleoside reverse transcriptase inhibitors 4) Fusion Inhibitors 5) Integrase inhibitors

  26. Retrovirus & Anti retroviral agents

  27. Drugs in different classes

  28. ART • Antiretroviral therapy (ART) is begun when: • Symptomatic disease is present, regardless of CD+4 count and viral load OR • Patient has CD+4 < 350 cells/mm3 with any value of RNA copies per milliliter OR • Plasma HIV RNA viral load>10,000-20,000/ml • HIV infection associated with lots of symptoms. Malaise, fever, blood disorders, neurological, opportunistic infections etc. difficult to separate these effects from the side effects of the drugs

  29. Zidovudine (NRTIS) • Inhibit reverse transcriptase – prevent conversion of viral RNA to DNA • All NRTIs nucleoside analogs e.g. Zidovudine (azidothymidine- AZT) a thymidine analog • NRTIs: narrow therapeutic window, dose limiting toxicities (mainly due to mitochondrial toxicity and inhibition of cellular DNA polymerases) • In toxicity– withdraw drug until symptoms clear or become tolerable OR the drug has to be discontinued

  30. No viral DNA formed AZT AZTmonophosphate AZT diphosphate AZT triphosphate Thymidine kinase (host) Chain elongation is terminated at thymidine residues (lack of 3’-OH group) Thymidylate kinase Cell Kinase Incorporated into Viral DNA strand

  31. Resistance • Major cause of treatment failure •  Likelihood of resistance: -duration of therapy - Advancing disease • Due to point mutations in reverse transcriptase enzyme • 33% patients on monotherapy with AZT become resistant within a year

  32. NON NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs) • Nevirapine • Delavirdine • Efavirenz • MOA: • Bind directly to reverse transcriptase • Allosteric inhibition of enzyme function • Blocks transcription of viral RNA to DNA • Note: They are NOT pro drugs!

  33. Pharmacokinetics Of NNRTIs • Well absorbed orally • Enter CNS (nevirapine more than the others) • Metabolized in the liver by cytochrome P450 enzymes • Excreted by the kidney • Lot of potential (cyp450) for drug interactions • Toxicity: • Relatively low toxicity, also affect lipid profile. Toxicities do not overlap with NRTIs • Major toxicity: Skin rashes

  34. Protease Inhibitors (Do not need to be prodrugs) • Saquinavir • Indinavir • Ritonavir • MOA: • Blocks the protease enzyme •  HIV protease cleaves newly synthesizedpolyproteins at the appropriate places to create the mature protein components of an infectious HIV virion.  • Can inhibit cell to cell spread of the virus

  35. Toxicity • Saquinavir: • GIT disturbances • Indinavir: • “trunkal obesity”(Cushing-like syndrome) • Nephrolithiasis (kidney stones) • Hemolytic anemia • Ritonavir: • Paresthesias

  36. FUSION INHIBITORS • Enfuvirtide, Maraviroc • MOA: • Prevents the fusion of HIV with the host cell membrane • Uses: • To treat AIDS which is progressing despite HAART

  37. INTEGRASE INHIBITOR • Integration of viral DNA into host DNA • First approved HIV-integraseinhibitor. • Raltegravir- integrase inhibitor • Use: Detectable viremia & treatment failure in ptn with triple class experience • Short term efficacy

  38. Adherence • It is currently recommended that antiretroviral therapy be initiated with 2 NRTIs in combination with an NNRTI, PI, or integrase inhibitor. • A major determinant of degree and duration of viral suppression • Poor adherence associated with virologic failure • Optimal suppression requires 90-95% adherence • Suboptimal adherence is common

  39. CONCLUSIONS ART: Delays disease progression Prolongs survival Reduces maternal to child transmission. BUT: Therapy is still suboptimal Complete suppression of viral replication has not been achieved. Drugs are toxic Resistance is a major problem

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