Antiviral Drugs -1

pharmacology of antiviral drugs

1. Antiviral Drugs ( Non retroviral drugs) by Dr . Alka Bansal Associate Professor, Department of Pharmacology, SMS Medical College, Jaipur

2. 11 / 18 / 1 2 D r . T . V . R a o MD 2

3. Viruses are special pathogens because they- a re obligate intracellular parasites. cannot replicate on its own. - use the host cell’s machinery to synthesize their protein , DNA, and RNA. - v irus containing envelope is antigenic in nature. - difficult to kill because they live inside the cells.

4. Contd.. - viruses multiply in nucleus and cytoplasm. - usually diagnosis is made late as symptomms appear late. - antiviral drugs do not kill, only inhibit multiplication so relapse common after stopping treatment. - current antiviral drugs do not affect non- replicating and latent infections.

5. Non –retro viruses controlled by current antiviral therapy Herpes viruses Cytomegalovirus (CMV) Hepatitis viruses Influenza viruses (the “flu”) Respiratory syncytial virus (RSV) Human immunodeficiency virus (HIV)

6. Stages of viral replication Cell entry – attachment - penetration Uncoating Transcription of viral genome Translation Assembly of virion components Release

7. Mechanism of action viruses selectively enter the cells infected with virus. - 1-interfere/inhibit early events like ability of virus to bind to cells and uncoating 2- interfere/ inhibit viral nucleic acid synthesis and/or regulation 3- inhibit viral protein synthesis. Best responses to antiviral drugs are in patients with competent immune systems

8. 11 / 18 / 1 2 8 Dr.T.V.Rao MD

9. Antiviral drugs- classification A)-Anti herpes (DNA virus) drugs- acyclovir, valacyclovir , famciclovir , ganciclovir , valganciclovir , idoxuridine , trifluridine,cidofovir , foscarnet B)-Anti influenza (RNA)virus drugs- amantadine , rimantadine , oseltamivir , zanamivir , peramivir C)-Anti-hepatitis (BOTH)virus drugs- HBV- lamivudine , entecavir , adefovir dipivoxil , tenofovir , telbivudine HCV- ribavirin etc.

10. Anti-Viral drugs Ph a r m a co l og y of acyclovir a nd congeners- All are guanosine nucleoside analogues. Valacyclovir is prodrug of acyclovir Famciclovir is prodrug of penciclovir . Penciclovir is used only topically whereas Famciclovir can be administered orally.

11. Mechanism of Action of Acyclovir 11 / 18 / 1 2 D r . T . V . R a o MD 20

12. M/A - Acyclovir Acyclovir is phosphorylated by a viral thymidine - kinase , then metabolized by host cell kinases to nucleotide analogues . The analogue inhibits viral DNA- polymerase. Acyclovir is thus selectively activated in cells infected with herpes virus. Uninfected cells do not phosphorylate acyclovir

13. Contd.. Resistance is due to altered viral thymidine kinase , DNA polymerase. Cross resistance with famciclovir , valacyclovir , ganciclovir

14. Antiviral spectrum Acyclovir: HSV-1, HSV-2, VZV, Shingles. Ganciclovir / Cidofovir : CMV Famciclovir : Herpes genitalis and shingles Foscarnet : HSV, VZV, CMV , HIV Penciclovir : Herpes labialis Trifluridine : Herpetic keratoconjunctivitis

15. Virus and Drug treatment HSV- idoxuridine , acyclovir, valacyclovir,famciclovir , penciclovir CMV- ganciclovir , valganciclovir , cidofovir , foscarnet Influenza- amantadine , rimantadine , oseltamivir , zanamvir , peramivir HBV – entecavir , tenofovir , lamivudine , adefovir , telbivudine HCV-

16. Acyclovir Pharmacokinetics of Acyclovir : Oral bioavailability ~ 20-30% Distribution in all body tissues including CNS Renal excretion: > 80% Half life: 2-5 hours Administration: Topical, Oral , IV depending on severity and recurrences.

17. Adverse effects of Acyclovir/ Ganciclovir Nausea, vomiting and diarrhea Nephrotoxicity - crystalluria , haematuria , renal insufficiency Myelosuppression – Neutropenia and thrombocytopenia – Ganciclovir

18. Therapeutic uses Acyclovir is the drug of choice for HSV Genital , mucocutaneous infections HSV encephalitis, keratitis Herpes zoster, chicken pox HSV infections in immunocompromised persons. Ganciclovir is the drug of choice for : CMV retinitis in immunocompromised patient Prevention of CMV disease in transplant patients

19. Cidofovir - It is approved for the treatment of CMV retinitis in immunocompromised patients( ganciclovir failure ) It is a nucleotide analog of cytosine – no phosphorylation required. It inhibits viral DNA synthesis Available for IV, Intravitreal inj , topical on anogenital warts. weekly given. Nephrotoxicity is a major disadvantage. Given with pre and post dose oral probeneacid which inhibits its tubular secretion increasing availability and decreases nephrotoxicity .

20. Vidarabine Vidarabine is a nucleoside (adenosine) analogue The drug is converted to its triphosphate analog which inhibits viral DNA- polymerase. Antiviral spectrum of Vidarabine : HSV-1, HSV-2 and VZV. Oral bioavailability ~ 2% Administration: Ophthalmic ointment Its use is limited to HSV keratoconjunctivitis in immunocompromised patient only . Anemia and SIADH are adverse effects .

21. Trifluridine Trifluridine is a Pyrimidine nucleoside analogue - inhibits viral DNA synthesis. Antiviral spectrum : HSV-1, HSV-2 and VZV. Use is limited to Topical - Ocular HSV Keratitis

22. Foscarnet an inorganic pyrophosphate analog unrelated to any nucleic acid precursor . It directly inhibits viral DNA and RNA-polymerase and viral inverse transcriptase(it does not require phosphorylation for antiviral activity) HSV-1, HSV-2, VZV, CMV and HIV. Oral bioavailability ~ 10-20% so given I.V. Distributed to all tissues including CNS Adverse effects Hypocalcemia and hypomagnesemia (due to chelation of the drug with divalent cations ) are common,neurotoxic , nephrotoxic , renal diabetes, anaemia .

23. Contd.. Therapeutic uses of Foscarnet It is an alternative drug for HSV infections (acyclovir resistant / immunocompromised patient ) CMV retinitis ( ganciclovir resistant / immunocompromised patient

24. Anti-influenza virus Infuenza virus is a RNA virus which causes respiratory infections Segmented genome and core proteins define its type A, B, C. A produces pandemics ,epidemics and B produces sporadic infections H5N1 ( bird flu) and H1N1 (swine flu) are prevalent now.

25. Anti-influenza drugs - Amantadine / Rimantadine ( prevent uncoating by inhibiting M2 proteins) Oseltamivir / Zanamavir / Peramivir ( viral neuraminidase inhibitors) RSV bronchiolitis–Ribavirin

26. Amantadine and Rimantadine (methyl derivative) - Tricyclic amine unrelated to any nucleic acid precursor Prevention & Treatment of influenza A (not B) Inhibition of viral uncoating by inhibiting the viral membrane protein M2 Oral bioavailability ~ 50-90% Amantadine cross extensively BBB whereas Rimantadine does not cross extensively Dose P-100mgOD; T/t 100mg BD for 5 days Not preferred now Amantadine has anti- parkinsonian effects also .

27. Ne ur a m i n i d a s e i n h i b i t o r s : - Prevent the release of new virions and their spread from cell to cell . Broad spectrum so against type A and B both. Oseltamivir requires activation to oselamivir carboxylate by liver esterases so may not be effective in infants . More useful if given in initial 48hrs.

28. Contd.. Do not interfere with immune response to influenza A vaccine. Can be used for both prophylaxis and acute treatment. Dose : P-75mg OD; T/t-75mgBD A/E- nausea ,weakness, abdominal pain, diarrhoea , cough, sadness , skin reactions

29. Contd … Zanamavir is given intranasally , useful in oseltamivir resistant cases also. Dose :P- 10mg through inhaler, rotacap OD, T/t- 10mg BD for 5-7 days Risk of bronchospasm with zanamavir . Laninamivir -long acting inhaled neuraminidase inhibitor against oseltamivir resistant virus. Peramivir - drug given i.v ., single dose 600 mg treatment.

30. Hepatic viral infections Hepatic Viral infections: AIM : HBV- suppression of replication HCV-eradication HBV is DNA virus which integrates into host Dna like HIV virus and can cause permanent, latent infection. HCV is RNA virus which donot integrate so can be eradicated. Interferons and ribavirin are non specific antiviral agents.

31. Ribavirin Ribavirin is a guanosine analog. Inhibition of RNA polymerase Antiviral spectrum: DNA and RNA viruses are susceptible, including influenza, parainfluenza viruses,RSV , Lassa virus Distribution in all body tissues, except CNS Administration : Oral, IV, Inhalational in RSV. Anemia and jaundice are adverse effects Not advised in pregnancy.

32. Contd.. Therapeutic uses Ribavirin Drug of choice for: RSV bronchiolitis and pneumonia in hospitalized children (given by aerosol) Lassa fever An alternative drug for: Influenza, parainfluenza , measles virus infection in immunocompromised patients

33. Interferons - are natural proteins produced by the cells of the host immune systems in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. Antiviral, immune modulating and anti-proliferative actions Three classes of interferons – α,β,γ

34. Contd.. α and β interferons are produced by all the cells in response to viral infections γ interferons are produced only by T lymphocyte and NK cells in response to cytokines – immune regulating effects γ has less anti-viral activity compared to α and β interferons

35. Mechanism of action of Interferons act by JAK –STAT pathway to increase antiviral proteins, and promote formation of natural killer cells. Act at multiple steps like viral penetration, synthesis of viral RNA/ DNA, viral assembly and release. Used in chronic HBV and with ribavirin in acute HCV. Induction of:????? a protein kinase which inhibits protein synthesis an oligo-adenylate synthase which leads to degradation of viral mRNA a phosphodiesterase which inhibit t-RNA The action of these enzymes leads to an inhibition of translation

36. Anti-viral drugs A n t i vi r a l s p e c tr u m : Interferon α Includes HBV, HCV and HPV. Anti-proliferative actions may inhibit the growth of certain cancers - like Kaposi sarcoma and hairy cell leukemia.

37. Anti-viral drugs P h a r m a c o k i n e t ic s : Interferons • • • Oral bioavailability: < 1% Administered Intralesionally, S.C, and I.V Distribution in all body tissues, except CNS and eye. Half lives: 1-4 hours

38. Therapeutic uses Interferons Chronic hepatitis B and C (complete disappearance is seen in 30%). HZV infection in cancer patients (to prevent the dissemination of the infection) CMV infections in renal transplant patients Condylomata acuminata (given by intralesional injection). Complete clearance is seen ~ 50%. Hairy cell leukemia (in combination with zidovudine ) AIDS related Kaposi’s sarcoma

39. Adverse effects of Interferons Acute flu-like syndrome (fever, headache) Bone marrow suppression (granulocytopenia, thrombocytopenia) Neurotoxicity (confusion, seizures) Cardiotoxicity – arrhythmia , hypotension Impairment of fertility Thyroid dysfunction, alopecia, hepatic dysfunction.

40. Specific Anti- hepatitis drugs for HBV -DOC for treating chronic HBV is Entecavir Entecavir-guanosine analogue-viral DNA polymerase inhibitor, for lamivudine resistant HBV strains and chronic HBV. PK- taken empty stomach T1/2- 128-148 hrs. Dose :0.5 mgOD , for lamivudine resistant: 1mg OD,A/E- lactic acidosis. Tenofovir - another first line drug for chronic hepatitis, few GIT related adverse effects, 300mg OD, given as disoproxil prodrug

41. CONTD.. Lamivudine - cytosine analogue for chronic HBV, HIV. High resistance(upto70%), 100mg OD. A/E less .NO any hepatic, hematological,pancreatic , neurological toxicity. Lamivudine resistant cases respond well to adefovir , tenofovir . Adefovir - antimetabolite , slow acting , least active so not first line A/E- nephrotoxicity , lactic acidosis, hepatomegaly and steatosis , flu like syndrome. Telbivudine -more resistance, myalgia , cough, git , 600mg OD.

42. Anti-hepatitis drugs- HCV For acute and chronic HCV DOC is pegylated IFN α with ribavirin . Ribavirin -wide spectrum, orally, chronic HCV A/E- dose dependent hemolytic anaemia

43. New drugs for HCV Target specific non structural viral proteins which play important role in viral replication All are given orally and in combination with ribavirin + PegIFN α or amongst themselves . Show drug drug interactions with CYP3A4 and Pgp inducers and inhibitors. Duration of therapy- 12-24 weeks.

44. Classification of anti HCV drugs 1- Pr otease inhibitors(NS3A/4)- Telo pr evir , boceprevir , simeprevir , grazoprevir , paritaprevir , glecaprevir , volixaprevir .( functional RNA is not formed and no replication ). 2-RNA polymerase NS5 A inhibitors- Elb as vir , orbitasvir , dactalasvir,ledipasvir , velpatasvir ( affect replication and assembly;not given with PPI/ H2 blockers) 3- NS5 B polymerase inhibitors- sofus b uvir , dasabuvir ( chain terminator )

45. Important points Sofusbuvir - prodrug , chain terminator, against all (1-6) genotypes,resistance donot develop easily, used in decompensated liver disease also, taken with fatty meal.400mg OD. A/e- - abdominal pain, fatigue, joint pain, anaemia . Simepravir -blocks cleavage of HCV polyprotein complex so functional RNA is not formed and no replication. Against genotype 1,4.

46. Contd.. Dactalasvir - can be given in patients with concommitant HIV and advanced liver disease, all genotypes. Ledipasvir -FDC (LDV/SOF)OD, genotypes 1,4,5,6, used in HIV coinfection . Velpatasvir - FDC(VEL/SOF) OD, all genotypes.

47. S ummary Antiviral spectrum : Acyclovir: HSV-1, HSV-2, VZV, Shingles. Ganciclovir / Cidofovir : CMV Famciclovir : Herpes genitalis and shingles Foscarnet : HSV, VZV, CMV, HIV Penciclovir : Herpes labialis Trifluridine : Herpetic keratoconjunctivitis

48. Vi rus Diseases Drug ( s) of choice Alternative drugs FLU Influenza Oseltamivir , zanamivir amantadine Rimantadine RSV Pneumonia, bronchiolitis Ribavirin (aerosol) HSV Genital herpes Acyclovir Foscarnet Keratitis Conjunctivitis Trifluridine Idoxuridine Vidarabine Encephalitis Acyclovir Neonatal HSV infection Acyclovir Vidarabine Herpes infections in immuno- compromised host . Acyclovi r Foscarnet 1 51

49. VZV In normal host No therapy In immunocompro- mised host, or during pregnancy Acyclovir Foscarnet CMV Retinitis Ganciclovir Foscarnet HIV AIDS HIV antibody positive with CD4 count < 500/mm 3 Zidovudine ± protease inhibitors Didanosine, Stavudine HBV HCV Hepatitis B, C Interfero n

50. Thanks