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Antiviral chemotherapy


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Antiviral chemotherapy

  2. 2. <ul><li>Most clinically useful antiviral agents exert their action on viral replication, either at stage of nucleic synthesis or at stage of late protein synthesis and processing. </li></ul><ul><li>With exception of Forscanate, all of drugs are active against herpes virus and against human immuno-deficiency virus (HIV) are antimetabolites with structural similarity to naturally occurring compounds </li></ul>
  3. 3. <ul><li>In order to interfere with viral nucleic synthesis or the late synthesis of viral proteins; they must first undergo conversion to active forms, usually triphoshate derivatives. </li></ul><ul><li>For example, drug such as Zidovudine (AZT) undergo phosphorylation by host kinase to form nucleotide analog that may inhibit viral DNA polymerase. </li></ul>
  4. 4. <ul><li>Selective toxicity results because viral DNA polymerase are more sensitive to inhibition by these antimetabolites than are mammalian polymerase. </li></ul><ul><li>One of the most important recent trends in antiviral chemotherapy has been the combination therapy. </li></ul><ul><li>With the combination therapy there is increase in effectiveness and prevention or delay of emergency of resistance. </li></ul>
  5. 5. <ul><ul><li>The current approach to treatment of infection with H.I.V. is the initiation of treatment with two or three drugs if possible before symptoms appear . </li></ul></ul><ul><li>When 3 drugs are used, the combination usually includes 2 inhibitors of reverse transcriptase plus an inhibitor of H.I.V. protease. </li></ul><ul><li>Such drug combination can slow or reverse the increase in viral RNA titers that accompany progression of disease </li></ul><ul><li>They may delay the emergence of resistant strain of H.I.V. </li></ul>
  6. 6. ANTIHERPES DRUGS ACYCLOVIR ( ACYCLO-GUANOSINE) <ul><li>Is a guanosine analog active against Herpes Simplex Virus (HSV) and Zoster Virus (VZV). </li></ul><ul><li>The drug is activated to form Acyclovir triphosphate, a competitive substrate for DNA polymerase leading to chain termination following its incorporation into viral DNA. </li></ul><ul><li>Resistant strains lack thymidine kinase; the enzyme involved in initial virus specific phosphorylation of Acyclovir </li></ul>
  7. 7. PHARMACOKINETICS <ul><li>Acyclovir can be administered by the topical, oral and intravenous routes. </li></ul><ul><li>Renal excretion is the major route of elimination </li></ul>
  8. 8. CLINICAL USE $ TOXICITY <ul><li>Oral Acyclovir is used for treatment of mucoteneous and genital Herpes lesions. </li></ul><ul><li>The oral drug is well tolerated but may cause G.I.T. distress and headache </li></ul><ul><li>I/V administration is used for severe Herpes disease ( including encephalitis) and for neonatal HSV infection. </li></ul><ul><li>Toxic effects with parenteral administration include delirium, tremor, seizure, hypotension and nephrotoxicity. </li></ul>
  9. 9. ACYCLOVIR CNGENERS FAMCICLOVIR <ul><li>Is a pro-drug converted PENCICLOVIR by first pass metabolism in the liver. </li></ul><ul><li>Used orally in genital herpes and Herpes Zoster. </li></ul><ul><li>Penciclovir also undergoes activation by Viral thymidine kinase,and triphosphate form inhibits DNA polymerase but does not cause chain termination. </li></ul><ul><li>Valacyclovir is converted to Acyclovir by hepatic metabolism after oral administration and reaches plasma levels three to five times greater than those achieved by Acyclovir. </li></ul><ul><li>Valacyclovir has a longer duration of action than acyclovir but is otherwise identical. </li></ul>
  10. 10. FORSCANATE <ul><li>It is a phosphono-formate derivate that does not require phosphorylation for anti-viral activity. </li></ul><ul><li>Though not anti-metabolite,Forscarnate inhibits viral Rna polymerase,DNA polymerase and H.I.V. reverse transcriptase. </li></ul>
  11. 11. PHARMACOKINETICS <ul><li>Is given intravenously and penetrates well into tissues including CNS. </li></ul><ul><li>Up to one third of a dose may be deposited in the bone. </li></ul><ul><li>The drug undergoes renal elimination in direct proportion to Creatinine clearance. </li></ul>
  12. 12. CLINICAL USE & TOXICITY <ul><li>The drug is used for prophylate and treatment of cytomegalo-Virus[CMV] infection…including CMV retinitis. </li></ul><ul><li>Forscarnet inhibits herpes DNA polymerase in Acyclovir resistant strains that are thymidine kinase deficient and may suppress such resistant Herpetic infections in patients with AIDS. </li></ul>
  13. 13. ADVERSE EFFECTS <ul><li>Include nephrotoxicity with disturbance in electrolyte balance[especially calcium and phosphate];genito-urinary ulceration and CNS symptoms[headache,hallucinations,seizures]. </li></ul>
  14. 14. GANCICLOVIR <ul><li>A guanine derivate,is triphosphorylated to form nucleotide that inhibits DNA polymerase of CMV and HSV-infected cells. </li></ul>
  15. 15. PHARMACOKINETICS <ul><li>Is usually given I/V and penetrates well into tissues,including the eye and CNS. </li></ul><ul><li>The drug undergoes renal elimination in direct proportion to creatinine clearance. </li></ul><ul><li>Although oral bioavailability is less than 10%;an oral formulation is available for maintenance therapy. </li></ul>
  16. 16. CLINICAL USE & TOXICITY <ul><li>Used for the prophylaxis and treatment of CMV retinitis and other CMV infection in immunompromised patients. </li></ul><ul><li>Systemic toxic effects…include leucopenia;thrombocytopenia;mucositis;hepatic dysfunction and seizures. </li></ul>
  17. 17. CIDOFOVIR <ul><li>Is activated exclusively by host cell-kinases and inhibits DNA polymerase of HSV;CMV,Adenovirus and papillomavirus. </li></ul><ul><li>Resistance is due to mutation in the DNA polymerase gene. The drug has been used by I/V and topical ant by intra-vitreal injection. </li></ul><ul><li>Cidofovir undergoes renal elimination in proportion to creatinine clearance. </li></ul>
  18. 18. CLINICAL USE <ul><li>Effective in CMV retinitis; may be of value in mucocutaneous infection including those resistant to Acyclovir. </li></ul><ul><li>Nephrotoxicity is the major dose limiting toxicity. </li></ul>
  19. 19. ANTI-HIV AGENTS REVERSE TRANSCRIPTASE INHIBITORS ZIDOVUDINE <ul><li>Formerly called Azidothymidine. </li></ul><ul><li>Is an anti-metabolite that requires phosphorylation by host kinase to form nucleotide analog that inhibits reverse transcriptase and cause chain termination in viral DNA. </li></ul>
  20. 20. PHARMACOKINETICS <ul><li>Zidovudine is active orally [with 60% bioavailability], and is distributed to most tissues; including CNS. </li></ul><ul><li>Elimination of the drug involves both hepatic metabolism to glucuronides and renal excretion. </li></ul><ul><li>Dosage reduction is necessary in ureamia patients and those with cirrhosis. </li></ul><ul><li>Plasma half-life… ranges from 1 to 3 hours. </li></ul>
  21. 21. CLINICAL USE <ul><li>Zidovudine temporarily reduces mortality and morbidity in patients with AIDS and AIDS-related complex. </li></ul><ul><li>It also of value in prophylaxis against HIV infection through accidental needle sticks and against vertical transmission from mother to neonate. </li></ul>
  22. 22. TOXICITY <ul><li>The primary toxicity is bone-marrow suppression leading to anaemia and neutropenia,which may require transfusion. </li></ul><ul><li>Others…Gastro-intestinal distress;thrombocytopenia;headache,myalgia;hepatitis;agitation and insomnia may occur. </li></ul>
  23. 23. DRUG INTERACTIONS <ul><li>Drugs undergo hepatic glucuronidation,including acetaminophen,Benzodizepines;Cimetidine and sulphonamides may increase plasma levels of zidovudine. </li></ul><ul><li>Metabolism of Zidovudine may also be inhibited by Azole antifungals and Protease inhibitors. </li></ul><ul><li>Rifampicin increases clearance of zidovudine. </li></ul>
  24. 24. DIDANOSINE <ul><li>It is an analoque of deoxyadenosine which is activated by host cell kinases to a triphosphate form that inhibits reverse transcriptase and cause chain termination. </li></ul>
  25. 25. PHARMACOKINETICS AND CLINICAL USE <ul><li>Oral bioavailability of Didanosine is reduced by food and chelating agents. </li></ul><ul><li>The drug is eliminated by glomerular filtration and active tubular secretion. </li></ul>
  26. 26. TOXICITY <ul><li>Pancreatitis is dose limiting and occurs more frequently in alcoholic patients and those with hyper-triglyceridemia. </li></ul><ul><li>Other adverse effects include peripheral neuropathy;diarrhoea;hepatic dysfunction;hyperuricaemia and CNS effects. </li></ul>
  27. 27. ZALCITABINE <ul><li>MECHANISM…Is pyrimidine nucleotide and its mechanism of action is similar to Zidovudine. </li></ul>
  28. 28. PHARMACOKINETICS & CLINICAL USE <ul><li>Its bioavailability is high following oral use. </li></ul><ul><li>Dosage adjustment is needed in patients with renal insufficiency. </li></ul><ul><li>Dosage adjustment is needed in patients with renal insufficiency. </li></ul>
  29. 29. TOXICITY <ul><li>Dose dependent peripheral neuropathy is major adverse effect. </li></ul><ul><li>Others…Pancreatitis;oesaphageal ulceration,stomatitis and arthralgias. </li></ul>
  30. 30. LAMIVUDINE <ul><li>Like other reverse transcriptase inhibitors; it requires activation by host cell kinases,and the drug is active against HIV-1 including strains resistant to Zidovudine. </li></ul><ul><li>The drug is also effective in hepatitis B. </li></ul>
  31. 31. PHARMACOKINETICS & CLINICAL USES <ul><li>Lamuvidine is used orally in combination regimes with Zidovudine. </li></ul><ul><li>Dosage adjustment is needed in patients with renal insufficiency. </li></ul>
  32. 32. TOXICITY <ul><li>Adverse effects of Lamuvidine are usually mild and include G.I.T.distress,headache,insomnia and fatique. </li></ul>
  33. 33. STAVUDINE <ul><li>MECHANISM…Is a thymidine analog, its mechanism of inhibition of reverse transcriptase are similar to those of other reverse transcriptase inhibitors. </li></ul>
  34. 34. PHARMACOKINETICS <ul><li>Stavudine has good oral bioavailability and penetrates most tissues including the CNS. </li></ul><ul><li>Dosage adjustment is needed in renal insufficiency. </li></ul>
  35. 35. TOXICITY <ul><li>Peripheral neuropathy is dose limiting. </li></ul>
  36. 36. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS:[NNRTI] <ul><li>Bind directly to a site on viral reverse transcriptase that is near but is distinct from the binding site of reverse transcriptase inhibitors. </li></ul><ul><li>NNRTIs neither compete with nucleoside triphosphate nor require phosphorylation to be active, and they usually have specific action against HIV-1. </li></ul><ul><li>The binding of NNRTIs to enzymes active site result in blockade of RNA and DNA dependent polymerase activities. </li></ul>
  37. 37. NEVIRAPINE <ul><li>Oral bioavailability is excellent > 90% and is not food dependent. The drug is highly lipophilic,approximately 60% protein bound, and achieves CSF levels which are 45% of those in plasma. </li></ul><ul><li>It is extensively metabolized by CYP3A P 450 isoform to hydroxylated metabolites and then excreted, primarily in the urine. </li></ul><ul><li>Single dose of Nevirapine [200 Mg] has recently been shown to be effective in the prevention of transmission of HIV from mother to newborn when administration to women at the onset of labour and followed by a 2 Mg/Kg oral dose given to neonates within 3 days. </li></ul><ul><li>Severe and life threatening skin rashes have occurred with or without rashes. </li></ul><ul><li>It induces CYP3A drug metabolism of itself co-administration result in a decrease in Indinivar,Ritinovair and Saquinavir levels as well as oral contraceptives. </li></ul><ul><li>Nevirapine levels may increase during co-administration with inhibitors CYP3A metabolism such as Cimetidine and macrolide agents. </li></ul>
  38. 38. ADVERSE EFFECTS <ul><li>Severe and life-threatening skin rashes have occurred during Nevirapine therapy including Stevens-Johnson syndrome and toxic epidermal necrolysis…It occurs in 18 % of patients receiving the drug during the 1st month of therapy </li></ul><ul><li>Other adverse effects include headache, fatique, nausea, diarrhoea and increased serum amino transferase levels. </li></ul>
  39. 39. DELAVIRIDINE <ul><li>Oral bioavailability is good ( 85 % ) but is reduced by antacids. </li></ul><ul><li>Extensive bound to plasma proteins ( 98 % ). </li></ul><ul><li>CSF concentration average only 0.4 % of those in plasma. </li></ul><ul><li>Extensively metabolized to inactive metabolites by the CYP3A and CYP2D6 P 450 enzymes. It also inhibits CYP3A and thus inhibits its own metabolism. </li></ul>
  40. 40. ADVERSE EFFECTS <ul><li>Skin rashes ( 18 % ) </li></ul><ul><li>Headache; fatique, nausea; diarrhoea and increased serum amino transferase levels. </li></ul>
  41. 41. DRUG INTERACTIONS <ul><li>Delaviridine plasma concentrations are reduced in presence of antacids, Didanosine, Phenytoin, Phenorbarbitone, Carbamazepine, Rifampicin, Nelfinavir and Saquinavir. </li></ul><ul><li>Concentrations are increased during co-administration with Clarithromycin; Indinavir; Nelfinavir; Saquinavir; Dapsone; Alprazolam; Midazolam; Triazolam; Nifedipine; Cispride; Quinidine; Warfarin and Ergot derivatives. </li></ul><ul><li>Co-administration of Delaviridine with Phenytoin; Phenorbarbitone; Carbamazepine and Rifampicinn is specifically not recommended. </li></ul><ul><li>Co-administration with antacids or Didanosine should be separated at least one hour. </li></ul><ul><li>Delaviridine has shown to be teratogenic in rats thus pregnancy should be avoided when taking Delaviridine. </li></ul>
  42. 42. EFAVIRENZ <ul><li>It is given orally; once daily because of its plasma half-life ..approx 50 hours. </li></ul><ul><li>It is 99 % bound to plasma albumin and its CSF concentration is ~ 1 % of that in the plasma. </li></ul><ul><li>It is inactivated in the liver. </li></ul>
  43. 43. ADVERSE EFFECTS <ul><li>The unwanted effects are relatively mild and consists mainly of CNS ( dizziness; confusion, dysphoria ), which resolve as therapy is continued. </li></ul><ul><li>Skin rashes occur in about 25 % of patients and gastro-intestinal disorders are experienced in 2 %.. </li></ul><ul><li>Drug interactions could be a hazard and animal studies indicate that foetal abnormalities could occur. </li></ul>
  44. 44. PROTEASE INHIBITOR <ul><li>In HIV, the mRNA transcribed from the provirus is translated into two biochemically inert polyproteins. </li></ul><ul><li>A virus-specific protease then converts the polyproteins into various structural and functional proteins by cleavage at appropriate positions. </li></ul><ul><li>Since this protease does not occur in the host, it is a good target for chemotherapeutic intervention. </li></ul><ul><li>HIV- specific protease inhibitors bind to the site where cleavage occurs , and their use, in combination with reverse transcriptase inhibitors, has transformed the therapy of AIDS. Examples are Saquinavir (SQV ), Nelfinavir (NFV ); Indinavir (IDV ); Ritonavir ( RTV ) and Amprenavir ( AMP ). </li></ul>
  45. 45. INDINAVIR <ul><li>MECHANISM….Inhibits HIV-1 protease, an enzyme that cleavases viral precursor proteins and is critical to the production of mature infectious virions. </li></ul><ul><li>Resistance to Indinavir is mediated by multiple point mutations. </li></ul>
  46. 46. PHARMACOKINETICS <ul><li>Oral biovailability is good except in presence of food. </li></ul><ul><li>Clearance is mainly via the liver, with about 10 % renal excretion. </li></ul>
  47. 47. TOXICITY <ul><li>Nausea; diarrhoea; thrombocytopenia; hyper-bilirubinemia and nephro-lithiasis occur. </li></ul><ul><li>To reduce renal damage, it is important to maintain good hydration. </li></ul><ul><li>It is a substrate for and inhibitor of the cytochrome P 450 isoenzyme CYP3A4 and is implicated in drug interactions. </li></ul><ul><li>Serum levels of Indinavir are increased By Azole antifungals and decreased by Rifampicin. </li></ul>
  48. 48. RITONAVIR <ul><li>MECHANISMS..of action and resistance are quite similar to those of Indinavir. </li></ul>
  49. 49. PHARMACOKINETICS <ul><li>Oral biovailability is good, and the drug should be taken with meals. </li></ul><ul><li>Clearance is mainly via the liver and dosage reduction is necessary in patients with hepatic impairment. </li></ul>
  50. 50. TOXICITY <ul><li>Most common G.I.T. irritation and bitter taste. </li></ul><ul><li>Paraesthesias and elevation of hepatic amino- transferases and triglycerides in plasma also occur. </li></ul><ul><li>DRUG INTERACTIONS:…Are of major concern. </li></ul><ul><li>Drugs that inhibit the activity of cytochrome P 450 e.g. Erythromycin; Azole anti-fungals; Cimetidine etc..elevate serum levels of antiviral drugs. </li></ul><ul><li>Ritonavir inhibits the metabolism of a wide range of drugs including Dronabinol; Erythromycin; Ketoconazolee; Prednisolone; Rifampicin and Saquinavir. </li></ul>
  51. 51. SAQUINAVIR <ul><li>Must be taken with meals to avoid gastro-intestinal distress and has only 4 % oral bioavailability. </li></ul><ul><li>The drug has additive or synergistic effects against HIV-1 when used in combination with Reverse transcriptase. </li></ul>
  52. 52. TOXICITY <ul><li>Marked gastro-intestinal effects; also cause headache and neutropenia…Serum levels may be increased by ingestion of Ketoconazole; Ritonavir or grape-fruits. </li></ul>
  53. 53. NELFINAVIR <ul><li>Has a higher absorption in fed state; is extensively protein bound (> 98 % ). </li></ul><ul><li>Undergoes metabolism by CYP3A and is excreted primarily in the faeces. </li></ul><ul><li>Plasma half-life is 3 to 5 hours, </li></ul>
  54. 54. ADVERSE EFFECTS <ul><li>Diarrhoea and flatulence </li></ul>
  55. 55. DRUG INTERACTIONS <ul><li>Nelfinavir is both an inducer and inhibitor of the CYP3A system…Multiple drug interactions . </li></ul><ul><li>Nelfinavir’s AUC is increased by …Indinavir; Ritonavir; Saquinavir, Delaviridine; Efavirenz; Ketoconazole…etc </li></ul><ul><li>Nelfinazir’s AUC is decreased by Rifampicin; Cabamazepine; Phenytoin ; Pheno barbitone …etc. </li></ul><ul><li>Nelfinavir increases the levels of Lamuvidine; Indinavir; Saquinavir; Amprenavir and Rifabutin. </li></ul><ul><li>Nelfinavir decreases the AUC of Zidovudine, Delaviridine and Ethinyl-oestradiol. </li></ul>
  56. 56. AMPRENAVIR <ul><li>Rapidly absorbed from the gut. </li></ul><ul><li>Can be taken with food or without food. </li></ul><ul><li>High-fat meal may decrease absorption. </li></ul><ul><li>Plasma half-life range from 7 to 10.6 hours. </li></ul>
  57. 57. ADVERSE EFFECTS <ul><li>Nausea, vomiting; diarhoea; peri-oral paraesthesia…rash. </li></ul>
  58. 58. DRUG INTERACTIONS <ul><li>It inhibits CYP3A4 enzyme activity. </li></ul><ul><li>It can increase the serum levels of midazolam; Triazolam; Ergotamine, Cisapride, Amiodarone; Warfarin; Tricyclic antidepressants; Lovastatin; Simstatavin and Sildenafil. </li></ul><ul><li>It serum concentration could be decreased by Rifampicin and Efavirenz. </li></ul><ul><li>Its serum concentration could be increased by Ritonavir </li></ul>
  59. 59. NEW PROTEASE INHIBITORS:(PI ) <ul><li>FOS-AMPRENAVIR: …Calcium phosphate ester of Amprenavir with better solubility and resorption than the parent compound. </li></ul><ul><li>ATAZANAVIR …Is a once-daily Pi with favourable lipid profile and anti-viral potency which seems comparable to that of Nelfinavir. </li></ul><ul><li>TIPRANAVIR ..First non- peptide PI and shows good efficacy against PI-resistant viruses..Oral bioavailability is not very good and it always require Ritonavir boosting. </li></ul><ul><li>MOZENAZIR ….A cyclic PI with good solubility but with a short half-life ..3 daily doses required. </li></ul>
  60. 60. ENTRY INHIBITORS <ul><li>There are 3 crucial steps for entry of HIV into CD4+ T cells-: </li></ul><ul><li>Binding of HIV to the CD4 receptor ( ‘attachment ‘- target for attachment inhibitors ). </li></ul><ul><li>Binding to co-receptors ( target of co-receptor antagonists) </li></ul><ul><li>Fusion of virus and cell ( target of fusion inhibitors ) </li></ul>
  61. 61. ATTACHMENT INHIBITORS <ul><li>Various compounds have been developed. </li></ul><ul><li>BMS- 806 –‘ An early’ attachment inhibitor binds to HIV gp 120 specifically and reversibly and so prevents the attachment of HIV to CD4+ T –lymphocyte . </li></ul>
  62. 62. CO-RECEPTOR ANTAGONISTS <ul><li>SCH-C and SCH-D…are ccR5 receptor antagonists with oral bioavailability and potent in vitro activity against numerous HIV isolates. </li></ul>
  63. 63. FUSION INHIBITORS <ul><li>T-20 ( Enfuvirtide, Fuzeon®…Large peptide, comprised of 36 AA and must therefore be given by S/C injection like Insulin. </li></ul><ul><li>It binds to an intermediate structure of HIV gp 41 protein; which appears during entry of HIV into the target cell i.e. during fusion. </li></ul>
  64. 64. RECOMMENDED ARV DRUGS IN TANZANIA: <ul><li>1ST Line ARV combination regimen: </li></ul><ul><li>(1) Zidovudine ( ZDV ) 300 Mg twice daily </li></ul><ul><li>(NRTI ) </li></ul><ul><li>(2) Lamuvidine ( 3TC ) 150 Mg twice daily </li></ul><ul><li>(NRTI ) </li></ul><ul><li>(3) Efavirenz ( EFV ) 600 Mg once daily. </li></ul><ul><li>(NNRTI ) </li></ul><ul><li>There is a combined Zidovudine + Lamivudine Tablet= Combivir </li></ul><ul><li>[ 300 Mg ZDV + 150 Mg 3TC ] </li></ul>
  65. 65. Second line combination in Tanzania <ul><li>Didanosine (ddI ) 200 Mg bd for bodt weight greater >60Kg </li></ul><ul><li>125 Mg bd for body weight < 60 Kg </li></ul><ul><li>Stavudine ( d4T ) 40 Mg bd for bw > 60 Kg </li></ul><ul><li>30 Mg bd for bw < 60 Kg </li></ul><ul><li>Saqinavir 800 Mg tds ( to be taken with fatty meal) </li></ul><ul><li>Lopinavir 400 Mg bd ( where Saquinavir is not indicated ) </li></ul><ul><li>Abacavir (NRTI) 300 Mg bd ( where listed NRTI listed are not indicated ). </li></ul>
  66. 66. ARV THEPAPY IN HIV PREGNANT WOMEN <ul><li>Zidovudine 300 Mg bd </li></ul><ul><li>Lamuvidine 150 Mg bd. </li></ul><ul><li>Nevirapine 200 Mg od for the first two weeks then 200 Mg twice daily. </li></ul>
  67. 67. RECOMMENDED PAEDIATRIC HAARTCOMBINATIONREGIMENS IN TANZANIA <ul><li>FIRST LINE; </li></ul><ul><li>Nevirapine 200 Mg / M2 ( not more than 400 Mg/ day ) given bd. </li></ul><ul><li>Zidovudine 180 Mg/ M2 bd </li></ul><ul><li>Lamuvidine 4 Mg/Kg bd. </li></ul><ul><li>For children who can swallow capsules replaca Nevirapine with Efavirenz capsules…14 Mg/Kg od. </li></ul>
  68. 68. SECOND LINE <ul><li>Didanosine 30 Mg ( 90 to 150 mg/ M2) bd. </li></ul><ul><li>Stavudine 1 Mg/Kg bd. </li></ul><ul><li>Nelfinavir 20 to 30 / Kg tds. </li></ul>
  69. 69. MISCELLANEOUS ANTIVIRAL AGENTS <ul><li>AMANTADINE & RIMANTIDINE: </li></ul><ul><li>Inhibits the 1st steps in the replication of the Influenza A and rubella viruses. </li></ul><ul><li>These steps involve viral adsorption of the host membrane, penetration into the cell via endocytosis and virus particle uncoating. </li></ul><ul><li>Also binds to a specific protein in the surface coat of the influenza virus to prevent fusion. </li></ul>
  70. 70. CLINICAL USES & TOXICITY <ul><li>Drugs are prophylactic with 80 % efficacy against Influenza A virus infection. </li></ul><ul><li>They can reduce the duration of symptoms if given within 48 hours after contact. </li></ul>
  71. 71. TOXIC EFFECTS <ul><li>Include G.I.T. irritation; dizziness; ataxia and slurred speech . </li></ul><ul><li>Rimantadine has activity equal to Amantadine but it has a longer half-life and require no dosage adjustment in renal failure. </li></ul>
  72. 72. INTERFERONS <ul><li>Are glcoproteins produced in human leucocytes; fibroblasts and immune cells. </li></ul><ul><li>They exert multiple actions that affect viral RNA and DNA synthesis. </li></ul><ul><li>Interferons induce the formation of enzymes, including a protein-kinase that phosphorylates a factor that blocks peptide chain initiation, a phosphodiestrase that degrades terminal nucleotides of tRNA. </li></ul>
  73. 73. CLINICAL USES & TOXICITY <ul><li>Approved for use in chronic hepatitis A and B infections; Kaposi’s sarcoma, papillomatosis and topically for genital warts. </li></ul><ul><li>Also to prevent Herpes Zoster virus dissemination in cancer patients. </li></ul>
  74. 74. TOXIC EFFECTS <ul><li>Dose limiting neutropenia, G.I.T. irritation; fatique, mylagia, mental confusion and a reversible cardiomyopathy. </li></ul>
  75. 75. RIBAVIRIN <ul><li>Precise antiviral mechanism is not known. </li></ul><ul><li>The drug inhibits Guanosine triphosphate formation prevents capping of viral mRNA and can block RNA dependent RNA polymerase. </li></ul>
  76. 76. CLINICAL USE & TOXICITY <ul><li>Used in aerosol form for respiratory syncytical virus infections and may shorten the symptoms of Influenzae A and B infections. </li></ul><ul><li>Early I/V administration decrease mortality in lass fever and other viral haemorrhagic fevers… </li></ul>
  77. 77. Side effects according to route of administration <ul><li>Aerosol route..conjunctival & bronchial irritation. </li></ul><ul><li>Systemic use…..Myelosuppression. </li></ul>