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 Indinavir Oseltamivir Reltegravir

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. Viruses susceptible to drug therapy DNA Viruses 1.Herpes virus (HSV 1 & HSV 2) 2.Varicella Zoster (VZV) 3.Cytomegalovirus (CMV) 4.Hepatitis B virus RNA Viruses 1.Hepatitis C 2.HIV (Retro virus) 3.Respiratory syncytial virus 4.Influenza A & infl. B viruses

8. Treatment of Influenza A AMANTADINE MOA: Inhibits uncoating no 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 & restlessness Livedo reticularis  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 Foscarnet acts directly on DNA polymerase

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

13. USES of ACYCLOVIR Genital Herpes:1st episode  viral shedding,  duration of symptoms Orolabial herpes: 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 1 st episode of genital Herps to 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 1 st 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 (overlapping myelosuppression toxicities)

16. When acyclovir is effective as CMV prophylaxis why gancyclovir is used? 1.To treat lung, colon infection 2.Good in AIDS ptns 3.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 5 ̀ 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 immuno compromised C.I: Pregnancy

19. HEPATITIS B: Lamivudine (ARV drug) Inhibits HBV-DNA polymerase & HIV- reverse- transcriptase by competing with dCTP Uses: 1.Chronic Hepatitis B infection with evidence of active viral replication 2.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 liver disease 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? 1.Lamivudine 2.Ribavirin 3.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 NRTIsNon NRTIS Protease inhibitors Zidovidine NevirapineSaquinavir Didanosine DelavirdineIndinavir Stavudine EfavirenzRitonavir Lamivudine Atazanavir

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

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. NRTIs MAJOR TOXIC EFFECT Zidovudine Bone marrow suppression, myopathy & lactic acidosis (LA) LamivudineLESS TOXIC THAN ABOVE Didanosine NEUROPATHY, Hepatitis, LA, PANCREATITIS Abacavir HYPERSENSITIVITY REACTIONS, MYOPATHY Stavudine NEUROPATHY, Hepatitis, LA PANCREATITIS (no myopathy)

33. 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!

34. 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

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

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

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

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

39. 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

40. 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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