Anti-viral drugs

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1. Anti-viral drugs Dr. Karun Kumar Senior Lecturer Dept. of Pharmacology

2. The application of antiviral drugs in dentistry is restr . to T/t of orophar . herpes simplex & herpes labialis that occur in immunocompromised pts.

3. Classification

4. Anti-viral drugs Act at any step of viral replication Viral replic . inv. fusion of virus to host cell membrane & penetration inside the cell This is foll . by uncoating & synth. of early proteins like DNAP This is foll . b y DNA & RNA synth. After that final func . prot. are synth. & processed After packaging & assembly, viral particles are rel. (with the help of neuram .) & inf. other cells

5. Anti-herpes virus drugs These are drugs active against the Herpes group of DNA viruses which include Herpes simplex virus-1 (HSV-1), Herpes simplex virus-2 (HSV-2 ), Varicella-Zoster virus (VZV), Epstein Barr virus ( EBV) and Cytomegalovirus (CMV)

6. Acyclovir Requires a virus specific enzyme for conversion to the active metabolite that inhibits DNA synthesis and viral replication. Active against HSV-1 & 2, VZV

7. Acyclovir is preferentially taken up by the virus infected cells Due to selective generation of the active inhibitor in the virus infected cell and its greater inhibitory effect on viral DNA synthesis , acyclovir has low toxicity for host cells Acyclovir is active only against herpes group of viruses; HSV-1 is most sensitive followed by HSV-2 > VZV=EBV, while CMV is practically not affected

8. Uses Genital Herpes simplex Mucocutaneous H. simplex H . simplex encephalitis H . simplex (type I) keratitis Herpes zoster Chickenpox

9. Adverse effects Topical  Stinging and burning sensation after each application Oral  The drug is well tolerated; headache, nausea , malaise and some CNS effects are reported Intravenous  Rashes , sweating, emesis and fall in BP occur only in few patients Dose-dependent decrease in g.f.r . is the most important toxicity; occurs especially in those with kidney disease; normalises on discontin . of the drug

10. Valacyclovir Ester prodrug of Acyclovir with improved oral bioavailability (55–70 %) due to active transport by peptide transporters in the intestine It is comp. conv. to Acyclovir & higher plasma levels of Acyclovir are obtained improving clinical efficacy in certain conditions (DOC in herpes zoster) Dose  O rolabial herpes 2 g BD × 1 day In immunocompromised pt.  1 g BD × 5 days For herpes zoster  1 g TDS × 7 days

11. Famciclovir Ester prodrug of Penciclovir , which has good oral bioavailability and prolonged intracellular t½ of the active triphosphate metabolite Like Acyclovir , it needs viral thymidine kinase for generation of the active DNA polymerase inhibitor Used as an alternative to acyclovir for genital or orolabial herpes and herpes zoster Side effects are headache, nausea , loose motions, itching, rashes and mental confusion

12. Anti-influenza virus drugs Amantadine  I nhibits replication of influenza A virus ( a myxovirus) Antiviral activity is strain specific; influenza B, H5N1 (avian influenza/bird flu) and H1N1 (swine flu) strains of influenza A are resistant Acts at an early step (possibly uncoating) as well as at a late step (viral assembly) in viral replication Target of action  M2 protein (ion channel)

13. Uses  Prophylaxis of influenza A 2, T/t of infl. A 2 , Parkinsonism A/E  N ausea , anorexia, insomnia, dizziness, nightmares , lack of mental conc., rarely hallucinations. Ankle edema occurs due to local vasoconstriction Rimantadine  M ore potent, longer acting, better tolerated, fewer s/e, higher oral bioavailability than Amantadine. Dose and clinical application is similar.

14. Oseltamivir Broad spectrum activity covering influenza A (amantadine sensitive as well as resistant), H5N1 (bird flu), H1N1 ( swine flu) strains and influenza B Ester prodrug conv. to Oseltamivir carboxylate which acts by inh . Viral NA enzyme S/E  N ausea and abdominal pain due to gastric irritation (reduced by taking the drug with food), headache, weakness, sadness , diarrhoea , cough and insomnia. Skin reactions have been reported

15. Zanamivir Influenza A ( including amantadine resistant, H1N1, H5N1 strains) & influenza B virus neuraminidase inhibitor Administered by inhalation as a powder (low oral bioavailability) Mechanism of action, clinical utility and efficacy  Simi lar to Oseltamivir

16. Anti-hepatitis virus drugs Hepatitis B virus (HBV)  DNA virus [integrates into host chromosomal DNA to establish permanent infection] Hepatitis C virus (HCV)  RNA virus [does not integrate into chromosomal DNA, does not establish non curable infection , but frequently causes chronic hepatitis]

17. Drugs for hepatitis B Combination therapy not superior Drugs used sequentially Lamivudine, Tenofovir , Entecavir , Adefovir and Telbivudine Entacavir  Most active 1 st line option for treating chr. hepatitis B

18. Drugs for hepatitis C Aim  SVR (Undetectable HCV-RNA in blood for at least 6 mths . after therapy completion) Oral Ribavirin + Peg-INF α  Standard therapy Achieves SVR in 50-80% cases (given for 6-12 mths .) Ribavirin  Activity against influenza A, B, RSV, other DNA & RNA viruses IFNs  L ow mol. wt. glycoprotein cytokines produced by host cells in response to viral infections IFNRs  JAK-STAT tyrosine protein kinase receptors

19. Interferons Bind to specific cell surface receptors & affect viral replication at multiple steps Viral penetration Synthesis of viral mRNA Assembly of viral particles Release of viral particles Direct or indirect suppression of viral protein synthesis

20. Uses of IFN α Chronic hepatitis B and C AIDS-related Kaposi’s sarcoma Condyloma acuminata (HPV) refractory to podophyllin H . simplex, H. zoster and CMV infections in immunocompromised patients as adjuvant to acyclovir/ganciclovir

21. Adverse effects Flu-like symptoms  F atigue , aches and pains , malaise , fever, dizziness, anorexia, taste and visual disturbances (a few hours after each injection) Neurotoxicity—numbness , neuropathy, tremor Myelosuppression (dose limiting ); neutropenia, thrombocytopenia

22. New specific anti-HCV drugs Target specific NS (non str.) viral proteins Achieved SVR of 99% Shortened duration of therapy (12-24 weeks) Less toxic than Ribavirin or IFN α NS5B polymerase inh .  Sofosbuvir NS3/4A protease inh .  Simeprevir NS5A inh .  Daclatasvir , Ledipasvir , Velpatasvir

23. Anti-retrovirus drugs Drugs active against HIV Useful in prolonging and improving the QOL & postponing complications of AIDS or ARC Do not cure the infection Dentists run the risk of accidental exp. to HIV inf. 1 st line drugs  NRTIs, NNRTIs, IIs, Pis Reserve drugs  Entry inh . & CCR5 rec. inhibitor In India, t/t under NACP & implemented by NACO

24. Classification

25. Reverse transcriptase inhibitors Competitive inhibitors Nucleoside reverse transcriptase inhibitors (NRTIs ) Nucleotide reverse transcriptase inhibitors Non-competitive inhibitors Non-nucleoside reverse transcriptase inhibitors ( NNRTIs) Non-nucleotide reverse transcriptase inhibitors

26. NRTI Prodrugs activated by host cell kinases to form triphosphates Competitively inhibit reverse transcriptase & act as chain terminators by incorporation into the DNA chain Resistance to these drugs emerges rapidly if used alone

27. Zidovudine (AZT) After phosphorylation in the host cell— zidovudine triphosphate selectively inhibits viral reverse transcriptase in preference to cellular DNA polymerase

28. Zidovudine prevents infection of new cells by HIV, but has no effect on proviral DNA that has already integrated into the host chromosome It is effective only against retroviruses Zidovudine itself gets incorporated into the proviral DNA and terminates chain elongation

29. Uses In HIV infected patients only in combination with at least 2 other ARV drugs One of the 2 optional NRTIs used by NACO for its first line triple drug ARV regimen There is a sense of well-being and patients gain weight However , beneficial effects are limited from a few months to a couple of years after which progressively non-responsiveness develops

30. Adverse effects Anaemia and neutropenia are the most important and dose-related adverse effects Nausea, anorexia, abdominal pain, headache , insomnia and myalgia are common at the start of therapy, but diminish later Myopathy, pigmentation of nails, lactic acidosis, hepatomegaly , convulsions and encephalopathy are infrequent

31. Interactions Paracetamol increases toxicity , probably by competing for glucuronidation Azole antifungals also inhibit metabolism Stavudine and Zidovudine exhibit mutual antagonism by competing for the same activation pathway

32. Didanosine It is a purine nucleoside analogue which after intracellular conversion to didanosine triphosphate competes with ATP for incorporation into viral DNA, inhibits HIV reverse transcriptase and terminates proviral DNA Its use has declined due to higher toxicity than other NRTIs

33. Stavudine It is also a thymidine analogue which acts in the same way as AZT By utilizing the same thymidine kinase for activation , AZT antagonises the effect of stavudine and the two should not be used together It should also not be combined with didanosine , because both cause peripheral neuropathy R esistance to Stavudine develops as for other NRTIs

34. Lamivudine It is phosphorylated intracellularly and inhibits HIV reverse transcriptase as well as HBV DNA polymerase Its incorporation into viral DNA results in chain termination Most human DNA polymerases are not affected and systemic toxicity is low Uses  I n combination with other anti-HIV drugs, HB S/E  H eadache , fatigue, rashes, nausea, anorexia , abdominal pain

35. Tenofovir Only nucleotide analogue used as anti-HIV drug Also active against HBV Preferentially inhibits HBV DNA polymerase and HIV-reverse transcriptase NACO includes tenofovir in its first line 3 drug regimen as an alternative Due to its high efficacy, good tolerability and low risk of resistance, tenofovir is being preferred for HBV infection, especially lamivudine resistant cases

36. NNRTIs Inh . Rt by acting at an allosteric site diff. from NRTIs Resistance to these drugs develops very rapidly Directly inhibit HIV reverse transcriptase without the need for intracellular phosphorylation Indicated in combination regimens for HIV Either NVP or EFV is included in the first line triple drug regimen used by NACO

37. Retroviral Protease Inhibitors (PIs) An aspartic protease enzyme encoded by HIV is involved in the production of structural proteins and enzymes (including rt and integrase ) of the virus from the large viral polyprotein synthesized in the infected cell The polyprotein is broken into various functional components by this protease enzyme

38. 6 protease inhibitors— Atazanavir (ATV), Indinavir ( IDV), Nelfinavir (NFV), Saquinavir (SQV ), Ritonavir (RTV) and Lopinavir (in combination with ritonavir LPV/r) have been marketed in India for use against HIV They bind to the active site of protease molecule, interfere with its cleaving function , and are more effective viral inhibitors than AZT

39. As they act at a late step of viral cycle , they are effective in both newly as well as chr. infected cells Under their influence , HIV-infected cells produce immature noninfectious viral progeny—hence prevent further rounds of infection All PIs (especially ritonavir and lopinavir ) are potent inhibitors of CYP3A4

40. In dentistry, the drugs level ↑ in + nce of PIs are Metronidazole, Lidocaine , Midazolam & CBMZ PIs are avoided in 1st line regimens, because their use in initial regimens markedly restricts second line regimen options Most guidelines, including that of NACO, reserve them for failure cases

41. Boosted PI regimen Used nowadays A protease inhibitor taken with a low dose of ritonavir (100 mg) Ritonavir boosts levels of the PI by ↑ BA ↓ FPM ↓ CL Of companion PI Permits ↓ in no. or freq. of tablets taken

42. Integrase inhibitors Raltegravir  A ctive against both HIV-1 and HIV-2 . Component of 1 st line triple drug regimen along with two NRTIs in some countries In India, 2 nd line regimen (higher cost) 2. Dolutegravir  2 nd gen. Int. inh . Activity similar to Raltegravir Yielded sup. results than Raltegravir in triple drug Can be used in Raltegravir resistant cases

43. Entry (fusion) inhibitor Enfuvirtide  A cts by binding to HIV-1 envelope glycoprotein 'gp41' (fusion of viral and cellular membranes) Entry of the virus into the cell is blocked Not active against HIV-2 Reserve drug for multi resistant HIV

44. CCR5 receptor inhibitor Maraviroc  A nti-HIV drug which blocks the host CD4 cell receptor labelled CCR5 Chemokine receptor of host CD4 cells anchors the the HIV through its glycoprotein gp120 Entry of the viral genome into the CD4 cell is interfered with

45. Treatment of HIV infection Complex , lifelong, needs expertise, strong motivation & commitment of the patient, resources, expensive In India, ARV provided free under NACO HAART  C ombination of ≥ 3 ARV drugs belonging to at least two major classes mandatory for t/t 1 st line regimen  2 NRTIs + 1 NNRTI NRTIs  L amivudine, Abacavir , Tenofovir NNRTI  Efavirenz pref. over Nevirapine

46. Highly active antiretroviral therapy (HAART) WHO guidelines for ART (2016) When to start  All HIV + ve pts. regardless of WHO clinical stage & at any CD4 cell For pts. With TB & HIV, t/t of TB should be started 1 st foll . By ART asap within 1 st 8 weeks of t/t 2. What to start  2 NRTI + 1 NNRTI ( Tenofovir + Lamivudine[or Emtricitabine ] + Efavirenz ) 3. Post exposure prophylaxis (For 28 days; start within 72 hrs )  Tenofovir + Lamivudine + Protease inhib .

47. 1 st line regimens (NACO, 2018) ART regimens Recommended for Tenofovir + Lamivudine + Efavirenz Age > 10 yrs., Body wt. >30 kg Abacavir + Lamivudine + Efavirenz Abn . Serum creatinine or Body wt. <30 kg

48. 2 nd line regimen All 3 drugs of regimen changed  “Switch” of the entire regimen Lamivudine may be contd. (Exerts residual antiviral activity & ↓ viral fitness) Boosted PI + 2 NRTIs (Lamivudine + 1 NRTI not used earlier) OR Boosted PI + Integrase inhibitor ( Ralte ./ Dolute .)