Antiviral Agents DEPARTEMEN FARMAKOLOGI & TERAPEUTIK FK USU. 06 August

Transcription

1 Antiviral Agents Dr. Yunita Sari Pane, MS DEPARTEMEN FARMAKOLOGI & TERAPEUTIK FK USU 06 August

2 VIRUSES Obligate intracellular parasites Consist of a core genome in a protein shell and some are surrounded by a lipoprotein lack a cell wall and cell membrane do not carry out metabolic processes Replication depends on the host cell machinery 2

3 VIRUSES Steps for Viral Replication 1) adsorption and penetration into cell 2) uncoating of viral nucleic acid 3) synthesis of regulatory proteins 4) synthesis of RNA or DNA 5) synthesis of structural proteins 6) assembly of viral particles 7) release from host cell 3

4 ANTIVIRAL AGENTS Block viral entry into the cell or must work inside the cell Most agents are pyrimidine or purine nucleoside analogs 4

5 SITES OF DRUG ACTION 5

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7 Sites of Drug Action 7

8 AntiHerpesAgents Acyclovir - prototype Valacyclovir Famciclovir Penciclovir Trifluridine Vidarabine 8

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10 AntiHerpes Agents Mechanism of Action Acyclovir An acyclic guanosine derivative Phosphorylated by viral thymidine kinase Di-and tri-phosphorylated by host cellular enzymes Inhibits viral DNA synthesis by: 1) competing with dgtp for viral DNA polymerase 2) chain termination 10

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12 AntiHerpes Agents Mechanism of Resistance Acyclovir Alteration in viral thymidine kinase Alteration in viral DNA polymerase Cross-resistance with valacyclovir, famciclovir, and ganciclovir 12

13 AntiHerpes Agents Clinical Uses Acyclovir Oral, IV, and Topical formulations Cleared by glomerular filtration and tubular secretion Uses: Herpes Simplex Virus 1 and 2 (HSV) Varicella-zoster virus (VZV) Side Effects: nausea, diarrhea, headache, tremors, and delirium 13

14 AntiHerpes Agents Valacyclovir L-valyl ester of acyclovir Converted to acyclovir when ingested M.O.A.: same as acyclovir Uses: 1) recurrent genital herpes 2) herpes zoster infections Side Effects: nausea, diarrhea, and headache 14

15 AntiHerpes Agents Famciclovir Prodrug of Penciclovir(a guanosine analog) M.O.A.: same as acyclovir does not cause chain termination Uses: HSV-1, HSV-2, VZV, EBV, and hepatitis B Side Effects: nausea, diarrhea, and headache 15

16 AntiHerpes Agents Trifluridine Trifluridine- fluorinated pyrimidine Inhibits viral DNA synthesis same as acyclovir Incorporates into viral and cellular DNA Uses: HSV-1 and HSV-2 (topically) 16

17 AntiHerpes Agents Vidarabine An adenosine analog inhibits viral DNA polymerase incorporated into viral and cellular DNA metabolized to hypoxanthine arabinoside Side Effects: GI intolerance and myelosuppression 17

18 Anti-Cytomegalovirus Agents Gancyclovir Valgancyclovir Cidofovir Foscarnet Fomivirsen 18

19 Anti-Cytomegalovirus Agents Ganciclovir An acyclic guanosine analog requires triphosphorylation for activation monophosphorylationis catalyzed by a phosphotransferasein CMV and by thymidinekinasein HSV cells M.O.A.: same as acyclovir Uses: CMV*, HSV, VZV,and EBV Side Effect: myelosuppression 19

20 Anti-Cytomegalovirus Agents Valgancyclovir Monovalyl ester prodrug of gancyclovir Metabolized by intestinal and hepatic esteraseswhen administered orally M.O.A.: same as Gancyclovir Uses: CMV* Side Effect: myelosuppression 20

21 Anti-Cytomegalovirus Agents Cidofovir A cytosine analog phosphorylation not dependent on viral enzymes Uses: CMV*, HSV-1, HSV-2, VZV, EBV, HHV-6, adenovirus, and human papillomavirus Side Effects: nephrotoxicity(prevented by admin. of probenecid) Resistance: mutation in DNA polymerase gene 21

22 Anti-Cytomegalovirus Agents Foscarnet An inorganic pyrophosphate inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase does not have to be phosphorylated Uses: HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV Resistance due to mutations in DNA polymerase gene Side Effects: hypo- or hypercalcemia and phosphotemia 22

23 Anti-Cytomegalovirus Agents Fomivirsen An oligonucleotide M.O.A.:binds to mrna and inhibits protein synthesis and viral replication Uses: CMV retinitis Side effects: iritis and increased intraocular pressure 23

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27 AntiRetroviralAgents 1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 2) NonnucleosideReverse Transcriptase Inhibitors (NNRTIs) 3) Protease inhibitors 27

28 o Reverse Transcriptase Inhibitors AntiRetroviral Agents Zidovudine(AZT) Didanosine- causes pancreatitis* Lamivudine- causes pancreatitis Zalcitabine- causes peripheral neuropathy* Stavudine- causes peripheral neuropathy* Abacavir 28

29 Mechanism of Action Zidovudine(AZT) AntiRetroviral Agents Reverse Transcriptase Inhibitors A deoxythymidine analog enters the cell via passive diffusion must be converted to the triphosphateform by mammalian thymidine kinase competitively inhibits deoxythymidinetriphosphatefor the reverse transcriptase enzyme causes chain termination 29

30 Mechanism of Resistance Zidovudine(AZT) AntiRetroviral Agents Reverse Transcriptase Inhibitors Due to mutations in the reverse transcriptase gene More frequent after prolong therapy and in persons with hiv 30

31 Clinical Uses Zidovudine AntiRetroviral Agents Reverse Transcriptase Inhibitors Available in IV and oral formulations activity against HIV-1, HIV-2, and human T cell lymphotropic viruses mainly used for treatment of HIV, decreases rate of progression and prolongs survival prevents mother to newborn transmission of HIV 31

32 AntiRetroviral Agents Reverse Transcriptase Inhibitors Side Effects Zidovudine Myelosuppression, including anemia and neutropenia GI intolerance, headaches, and insomnia 32

33 AntiRetroviral Agents o Other NRTIs Didanosine-synthetic deoxy-adenosineanalog; causes pancreatitis* Lamivudine- cytosine analog Zalcitabine- cytosine analog; causes peripheral neuropathy* Stavudine- thymidine analog;causes peripheral neuropathy* Abacavir-guanosineanalog; more effective than the other agents; fatal hypersensitivity reactions can occur 33

34 AntiRetroviral Agents o Nucleotide Inhibitors Tenofovir Adefovir 34

35 Tenofovir AntiRetroviral Agents Nucleotide Inhibitors An acyclic nucleoside phosphonateanalog of adenosine M.O.A.-competivelyinhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA Uses in combination with other antiretroviralsfor HIV-1 suppression 35

36 Adefovir An analog of adenosine monophosphate Phosphorylated by cellular kinases AntiRetroviral Agents Nucleotide Inhibitors M.O.A.-Competitively inhibits HBV DNA polymerase and results in chain termination after incorporation into viral DNA Uses- Hepatitis B Side effects- nephrotoxicity 36

37 o NonnucleosideReverse Transcriptase Inhibitors (NNRTIs) Nevirapine Delavirdine Efavirenz AntiRetroviral Agents 37

38 Mechanism of Action NNRTIs AntiRetroviral Agents Bind to site on viral reverse transcriptase, different from NRTIs results in blockade of RNA and DNA dependent DNA polymerase activity do not compete with nucleoside triphosphates do not require phosphorylation these drugs can notbe given alone substrates and inhibitors of CYP3A4 38

39 o NNRTIs Nevirapine AntiRetroviral Agents prevents transmission of HIV from mother to newborn when given at onset of labor and to the neonate at delivery Delavirdine teratogenic, therefore can not be given during pregnancy Efavirenz teratogenic, therefore can not be given during pregnancy 39

40 AntiRetroviral Agents 3. Protease Inhibitors Indinavir Ritonavir Saquinavir Nelfinavir Amprenavir 40

41 AntiRetroviral Agents o Protease Inhibitors The protease enzyme cleaves precursor molecules to produce mature, infectious virions these agents inhibit protease and prevent the spread of infection These agents cause a syndrome of altered body fat distribution, insulin resistance, and hyperlipidemia 41

42 AntiRetroviral Agents Protease Inhibitors Indinavir and Ritonavir M.O.A.: Specific inhibitors of the HIV-1 protease enzyme M.O.R.: mediated by expression of multiple and variable protease amino acid substitutions Side Effects:hyperbilirubinemia Contraindications:inhibitor/substrate for CPY3A4, do not give with antifungal azoles 42

43 AntiRetroviral Agents Protease Inhibitors Saquinavir A synthetic peptide-like substrate analog inhibits HIV-1 protease prevents cleavage of viral polyproteins 43

44 Nelfinavir and Amprenavir AntiRetroviral Agents Protease Inhibitors M.O.A.: Specific inhibitors of the HIV-1 protease enzyme M.O.R.: mediated by expression of multiple and variable protease amino acid substitutions Less cross-resistance with Amprenavir Side Effects: diarrhea and flatulence Amprenavir can cause Stevens-Johnson syndrome Contraindications:inhibitor/substrate for CPY3A4 44

45 AntiRetroviral Agents Protease Inhibitors Fusion Inhibitors Enfuvirtide(T-20)-binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for fusion of the viral and cellular membranes By blocking fusion (entry into cell), FUZEON prevents HIV from infecting CD4 cells 45

46 Nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) classes prevent the replication of HIV by working inside CD4 cells after they have been infected with HIV. The drugs in these three classes then target specific steps in the replication process to prevent the creation of new HIV particles. Fusion inhibitors differ from these drugs because they work on the outside of the cell to prevent HIV from fusing with, and infecting the CD4 cells in the first place. from 46 Fuzeon.com

47 Anti-Hepatitis Agents Lamivudine-Nucleoside Reverse Transcriptase Inhibitor (NRTI) Adefovir-Nucleotide Inhibitor Interferon Alfa Pegylated Interferon Alfa Ribavirin 47

48 Interferons Anti-Hepatitis Agents Interferon Alfa Endogenous proteins induce host cell enzymes that inhibit viral RNA translation and cause degradation of viral mrna and trna Bind to membrane receptors on cell surface May also inhibit viral penetration, uncoating, mrna synthesis, and translation, and virionassembly and release 48

49 Anti-Hepatitis Agents Interferons Pegylated Interferon Alfa A linear or brancedpolyethylene gylcol(peg) moiety is attached to covalently to interferon Increased half-life and steady drug concentrations Less frequent dosing Tx chronic hepatitis C in combination with ribavirin 49

50 Anti-Hepatitis Agents Ribavirin A guanosine analog phosphorylated intracellularly by host enzymes inhibits capping of viral messenger RNA inhibits the viral RNA-dependent RNA polymerase inhibits replication of DNA and RNA viruses 50

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52 Anti-Influenza Agents Amantadine Rimantadine Zanamivir Oseltamivir 52

53 Anti-Influenza Agents Amantadine and Rimantadine Cyclic amines Inhibit the uncoatingof viral RNA therefore inhibiting replication Resistance due to mutations in the RNA sequence coding for the structural M2 protein Used in the prevention and treatment of influenza A 53

54 Anti-Influenza Agents Zanamivir and Oseltamivir Inhibits the enzyme neuraminidase inhibit the replication of influenza A and Influenza B treats uncomplicated influenza infections administered intranasally 54

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