Anti Viral

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Anti Viral

  1. 1. ANTI-VIRAL/ANTI-FUNGAL AGENTS
  2. 2. ANTI-VIRAL AGENTS <ul><li>VIRUSES : </li></ul><ul><li>Single or double stranded DNA or RNA enclosed in a protein – CAPSID </li></ul><ul><li>Obligate intracellular parasite </li></ul><ul><li>Replication depends on synthetic processes of the host cell </li></ul><ul><li>Anti-viral drugs must either block entry or exit from cell or be active inside the host cell </li></ul>
  3. 3. VIRAL REPLICATION <ul><li>Viral attachment and entry ( enfuvirtide, docosanol, palivizumab ) </li></ul><ul><li>Adsorption and penetration into susceptible host </li></ul><ul><li>cells ( G lobulins and interferon-alfa ) </li></ul><ul><li>Un-coating of viral nucleic acid ( Amantadine ) </li></ul><ul><li>Synthesis of early regulatory proteins ( Fomivirsen ) </li></ul><ul><li>Synthesis of RNA or DNA ( RT Inhibitors ) </li></ul><ul><li>Synthesis of late regulatory proteins </li></ul><ul><li>( Protease Inhibitors ) </li></ul><ul><li>Packing and Assembly (maturation) of viral </li></ul><ul><li>particles ( Rifampicin ) </li></ul><ul><li>Release from cells ( Neuraminidase Inhibitors ) </li></ul>
  4. 4. ANTI-VIRAL AGENTS <ul><li>Anti-Herpes </li></ul><ul><li>Acyclovir Famciclovir Valacyclovir </li></ul><ul><li>Ganciclovir Valganciclovir Lamivudine </li></ul><ul><li>Vidarabine Idoxuridine Trifluridine </li></ul><ul><li>Cidofovir Sorivudine Fomivirsen </li></ul><ul><li>Penciclovir </li></ul>
  5. 5. <ul><li>Anti-retroviral Agents </li></ul><ul><li>Nucleoside RT inhibitors </li></ul><ul><li>Zidovudine Zalcitabine Didanosine </li></ul><ul><li>Stavudine Lamivudine Abacavir </li></ul><ul><li>Emtricitabine </li></ul><ul><li>Non-nucleoside RT Inhibitors </li></ul><ul><li>Nevirapine Delavirdine Efavirenz </li></ul>
  6. 6. ANTI-Hepatitis B <ul><li>Lamivudine </li></ul><ul><li>Adenofovir Dipivoxil </li></ul><ul><li>Entecavir </li></ul><ul><li>Interferon alfa-2b </li></ul><ul><li>Famciclovir </li></ul><ul><li>ANTI-Hepatitis C </li></ul><ul><li>Pegylated interferon alfa-2a and 2b </li></ul><ul><li>Ribavirin, interferon alfa 2a, 2b, alfacon </li></ul>
  7. 7. Protease Inhibitors <ul><li>Saquinavir Lopinavir/Ritonavir Indinavir Nelfinavir Amprenavir Darunavir Atazanavir Tipranavir Fosamprenavir </li></ul>
  8. 8. Anti-influenza Agents <ul><li>Amantadine Rimantadine </li></ul><ul><li>Neuraminidase Inhibitors </li></ul><ul><li>Oseltamivir (Tamiflu) </li></ul><ul><li>Zanamivir </li></ul><ul><li>Ribavirin Palivizumab </li></ul><ul><li>Interferons </li></ul>
  9. 9. Miscellaneous <ul><li>Immuno-modulating Agents </li></ul><ul><li>Inosiplex Isoprinosine </li></ul><ul><li>Foscarnet </li></ul>
  10. 10. ANTI-HERPES ANTI-VARICELLA ZOSTER
  11. 11. ACYCLOVIR <ul><li>Acyclovir(9- [2-hydroxy methyl]-9-H-guanine) </li></ul><ul><li>Acyclic guanosine derivative against HSV1, HSV2, and VZV </li></ul><ul><li>Weaker activity against EBV, CMV </li></ul><ul><li>and Human Herpes Virus 6 (HHV 6) </li></ul>
  12. 12. MECHANISM OF ACTION <ul><li>REQUIRES 3 PHOSPHORYLATION STEPS: </li></ul><ul><ul><li>Converted to di and triphosphate compounds by the host’s cellular enzymes </li></ul></ul><ul><ul><li>Converted to monophosphate derivative by virus-specified thymidine kinase </li></ul></ul><ul><ul><li>Acyclovir triphosphate inhibits viral DNA synthesis </li></ul></ul>
  13. 13. <ul><li>Acts as a chain terminator because it lacks 3’ hydroxyl group </li></ul><ul><li>Competitive inhibition of deoxy-GTP for viral DNA polymerase </li></ul><ul><li>RESISTANCE </li></ul><ul><li>HSV: absence of partial production of viral thymidine kinase, altered thymidine kinase substrate specificity, and altered viral DNA polymerase </li></ul><ul><li>VZV: mutation in VZV thymidine kinase and mutations in viral DNA polymerase </li></ul>
  14. 14. PHARMACOKINETICS <ul><li>Oral bioavailability ranges from 10-30% and decreases with increasing dose </li></ul><ul><li>Clearance thru GF and TS </li></ul><ul><li>Half-life: 3 hrs in normal renal function and 20 hrs in anuria </li></ul><ul><li>Distributes widely in body fluids including vesicular fluid, aqueous humor, and CSF </li></ul><ul><li>Concentrated in breast milk, amniotic fluid, and placenta </li></ul><ul><li>Percutaneous absorption is low </li></ul>
  15. 15. THERAPEUTIC USES <ul><li>First and recurrent genital herpes : </li></ul><ul><ul><li>200 mg 5x daily for 10 days – oral </li></ul></ul><ul><ul><li>5 mg/kg per 8 hrs – IV </li></ul></ul><ul><ul><li>Recurrent : </li></ul></ul><ul><ul><li>400 mg 2x daily or 200 mg 3x daily </li></ul></ul>
  16. 16. THERAPEUTIC USES <ul><li>ACUTE HERPES ZOSTER (SHINGLES) </li></ul><ul><li>SYSTEMIC ACYCLOVIR PROPHYLAXIS </li></ul><ul><li>HSV ENCEPHALITIS ( IV form) </li></ul><ul><li>VARICELLA ZOSTER VIRUS INFECTION </li></ul><ul><li>CMV PROPHYLAXIS </li></ul>
  17. 17. SIDE EFFECTS <ul><li>TOPICAL PREPARATIONS- mucosal irritation and transient burning to genital lesions </li></ul><ul><li>ORAL – nausea, diarrhea, rash, headache, renal insufficiency, and neurotoxicity </li></ul><ul><li>IV- renal insufficiency, CNS side effects </li></ul>
  18. 18. VALACYCLOVIR <ul><li>L- valyl ester of acyclovir </li></ul><ul><li>Rapidly converted to acyclovir after oral administration </li></ul><ul><li>Serum levels are 3-5x greater than acylcovir </li></ul><ul><li>Treatment of primary and recurrent genital herpes and herpes zoster infections </li></ul><ul><li>Prevents CMV disease in post-transplant patients </li></ul>
  19. 19. Pharmacokinetics <ul><li>Oral bioavailability is 54%s </li></ul><ul><li>CSF fluid levels are 50% of those in serum </li></ul><ul><li>Elimination half-life: 2.5-3.3 hours </li></ul><ul><li>Generally well-tolerated </li></ul>
  20. 20. FAMCICLOVIR <ul><li>Diacetyl ester prodrug of 6 deoxy penciclovir and rapidly converted to PENCICLOVIR by FIRST-PASS metabolism </li></ul><ul><li>Penciclovir does not cause chain termination </li></ul><ul><li>Oral form is approved for managing HSV and VZV infections </li></ul><ul><li>First episode genital herpes </li></ul><ul><li> 250 mg TID for 5-10 days </li></ul><ul><li>Recurrent genital herpes – 250 mg BID for 1 year Herpes zoster of 3 days – 500 mg TID x 10 days It is as effective as acyclovir in reducing healing time and zoster associated pain </li></ul>
  21. 21. FAMCICLOVIR <ul><li>Comparable to valacyclovir in treating zoster and reducing associated pain in older adults </li></ul><ul><li>500 mg TID x 10 days is comparable to high dose of acyclovir in treating zoster in immuno-compromised patients and in opthalmic zoster </li></ul><ul><li>Associated with dose-related reductions in Hepatitis B Virus DNA and transaminase levels in patients with chronic HBV hepatitis </li></ul>
  22. 22. Pharmacokinetics <ul><li>Oral bioavailability: 70% </li></ul><ul><li>Intracellular half-life: 10 hours in HSV-1 infected cells </li></ul><ul><li>20 hours in HSV-2 infected cells </li></ul><ul><li>7 hours in VZV infected cells in vitro. </li></ul><ul><li>Excretion: primarily in the urine </li></ul>
  23. 23. PENCICLOVIR <ul><li>Penciclovir (9- [4-hydroxy-3-hydroxymethyl but-1-yl] guanine </li></ul><ul><li>An acyclic guanine nucleoside </li></ul><ul><li>Active metabolite of famciclovir </li></ul><ul><li>Spectrum of activity and potency against HSV & VZV is similar to acyclovir </li></ul><ul><li>Inhibitory activity to HSV </li></ul>
  24. 24. MECHANISM OF ACTION <ul><li>Inhibitor of viral DNA synthesis </li></ul><ul><li>Initially phosphorylated by viral thymidine kinase </li></ul><ul><li>Penciclovir triphosphate has a lower affinity in competitive inhibition of viral DNA polymerase thus can not cause chain termination </li></ul><ul><li>100 fold less potent in inhibiting DNA polymerase than acyclovir but present in higher concentration and prolonged period in infected cells </li></ul>
  25. 25. THERAPEUTIC USES <ul><li>Intravenous form- 5 mg/kg per 8-12 hrs for 7 days is comparable to acyclovir in treatment of mucocutaneous HSV infection </li></ul><ul><li>Topical 1% penciclovir cream applied every 2 hrs while awake for 4 days shortens healing time and symptoms by about 1 day in recurrent labial HS. </li></ul><ul><li>(reserved usage) </li></ul>
  26. 26. SIDE EFFECTS <ul><li>Mutagenic at high concentrations </li></ul><ul><li>(IV form is not usually given) </li></ul><ul><li>No clinically important drug interactions have identified </li></ul>
  27. 27. TRIFLURIDINE <ul><li>Fluorinated pyrimidine nucleoside that has an in vitro inhibitory activity against HSV 1 & 2 , CMV, vaccinia and certain adenoviruses </li></ul><ul><li>Inhibits viral DNA synthesis </li></ul><ul><li>Phosphorylated intracellularly into its active form by cellular enzymes </li></ul><ul><li>Incorporation into both viral and cellular DNA prevents its systemic use </li></ul>
  28. 28. MECHANISM OF ACTION <ul><li>Trifluridine monophosphate irreversibly inhibits thymidylate synthetase </li></ul><ul><li>Trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate incorporation into DNA by DNA polymerases </li></ul>
  29. 29. CLINICAL USES <ul><li>Primary keratoconjunctivitis and recurrent epithelial keratitis due to HSV 1 and 2 </li></ul><ul><li>Topical trifluridine is more active than idoxuridine and comparable to vidarabine in HSV ocular infections </li></ul>
  30. 30. ADVERSE EFFECTS <ul><li>Discomfort upon instillation </li></ul><ul><li>Palpebral edema </li></ul><ul><li>Hypersensensitivity reaction, irritations and superficial punctate or epithelial keratopathy </li></ul>
  31. 31. VIDARABINE <ul><li>Adenosine analog with an in vitro activity against HSV, VZV, and CMV </li></ul><ul><li>Phosphorylated intracellularly by host enzymes to form ara-ATP and then inhibits viral DNA polymerase </li></ul><ul><li>Vidarabine triphosphate is incorporated into both viral and cellular DNA </li></ul><ul><li>Rapidly metabolized in vivo to hypoxanthine arabinoside through removal of 6-amino group by adenosine deaminase – decrease viral activity </li></ul>
  32. 32. Therapeutic Usage <ul><li>3% ointment – acute keratoconjunctivitis, superficial keratitis, recurrent epithelial keratitis (HSV1 and 2) </li></ul><ul><li>IV vidarabine – HSV encephalitis, neonatal herpes, VZV infection </li></ul>
  33. 33. DOCOSANOL <ul><li>Saturated 22-carbon aliphatic alcohol. </li></ul><ul><li>Inhibits FUSION between plasma membrane and HSV envelope resulting in prevention of viral entry into cells and subsequent viral replication. </li></ul><ul><li>Only for orolabial HERPES </li></ul>
  34. 34. ANTI-CMV AGENTS
  35. 35. GANCICLOVIR <ul><li>(9- [1,3-dihydroxy-2-prepoxymethyl]guanine) </li></ul><ul><li>Cyclic guanosine analog that requires triphosphorylation for activation prior to inhibiting viral DNA polymerase </li></ul><ul><li>Similar structure to acyclovir except in having additional hydroxymethyl group on the acyclic side chain </li></ul>
  36. 36. MECHANISM OF ACTION <ul><li>Monophosphorylated intracellularly by a virus-induced enzyme </li></ul><ul><li>Phosphorylation is catalyzed by a viral thymidine kinase during HSV, phosphotransferase UL97 encoded gene during CMV infection </li></ul><ul><li>Ganciclovir di & triphosphate formed by cellular enzymes </li></ul><ul><li>Triphosphate is a competitive inhibitor of deoxyguanosine triphosphate incorporation into DNA inhibiting viral rather than cellular DNA polymerase </li></ul><ul><li>Viral DNA incorporation causes cessation of DNA chain elongation </li></ul>
  37. 37. PHARMACOKINETICS <ul><li>Oral bioavailability is 6-9% following ingestion with food and less in the fasting state </li></ul><ul><li>CSF concentration are approximately 50 % of those in serum </li></ul>
  38. 38. CLINICAL USES <ul><li>Delay progression of CMV retinitis in AIDS </li></ul><ul><li>CMV colitis & esophagitis </li></ul><ul><li>CMV infection in transplant patient </li></ul><ul><li>CMV pneumonitis </li></ul><ul><li>CMV retinitis </li></ul><ul><li>CMV, HSV1, HSV2, EBV & HHV-8 </li></ul>
  39. 39. ADVERSE REACTIONS <ul><li>Myelosuppression </li></ul><ul><li>CNS toxicity </li></ul><ul><li>Vitreous hemorrhage, retinal detachment </li></ul><ul><li>Neutropenia (2 nd wk) </li></ul><ul><li>CNS (headache, behavioral changes, convulsions, coma) </li></ul><ul><li>Infusion related phlebitis, azotemia, anemia, rash, fever, liver function test abnormalities </li></ul>
  40. 40. VALGANCICLOVIR <ul><li>L- valyl ester prodrug of ganciclovir </li></ul><ul><li>Hydrolyzed to active compound ganciclovir by intestinal and hepatic enzymes </li></ul><ul><li>Well absorbed (60%) & rapidly metabolized in intestinal walls & liver to ganciclovir </li></ul><ul><li>Renal excretion thru GN and TS </li></ul><ul><li>Usage:CMV retinitis in AIDS and for prevention of CMV in high risk kidney, heart transplant. </li></ul>
  41. 41. CIDOFOVIR <ul><li>(1- [(S)-3-hydroxy-2-(phosphonomethoxy)-propyl]cytosine dihydrate) </li></ul><ul><li>Cytidine nucleoside analog with inhibitory activity against human herpes, papilloma, polyoma, pox, and adenoviruses </li></ul><ul><li>Phosphorylation to active disphosphate is independent of viral enzymes </li></ul><ul><li>After phosphorylation; it acts as potent inhibitor to viral DNA polymerase </li></ul>
  42. 42. PHARMACOKINETICS <ul><li>Penetration into the CNS or eye have not been well characterized </li></ul><ul><li>Terminal half-life is 2.6 hrs, cidofovir diphosphate half-life is 17- 65 hrs </li></ul><ul><li>IV administration must be administered with probenecid to block active tubular secretion and decrease nephrotoxicity </li></ul>
  43. 43. CLINICAL USES <ul><li>CMV, HSV 1, HSV 2, VZV, EBV, HHV-6,HHV8, adenovirus, poxvirus, poliomyxovirus, Human papilloma virus </li></ul><ul><li>CMV retinitis </li></ul><ul><li>Polyoma virus associated progressive multifocal leukoencephalopathy syndrome associated with AIDS </li></ul><ul><li>Topical – recurrent genital herpes, anogenital warts </li></ul>
  44. 44. FOSCARNET <ul><li>Phosphonoformic Acid Inorganic Pyrophosphate analog that inhibits viral DNA polymerase, RNA polymerase and HIV transcriptase directly without requiring activation by phosphorylation </li></ul><ul><li>Taken up slowly by cells and does not undergo significant intracellular metabolism </li></ul><ul><li>Reversibly blocks the pyrophosphate binding site of the viral polymerase </li></ul><ul><li>Inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates </li></ul>
  45. 45. SIDE EFFECTS <ul><li>Nephrotoxicity </li></ul><ul><li>Symptomatic hypocalcemia </li></ul><ul><li>Saline loading may reduce the risk of nephrotoxicity </li></ul><ul><li>Concurrent administration with pentamidine exacerbates both nephrotoxicity and hypocalcemia </li></ul>
  46. 46. CLINICAL USES <ul><li>CMV retinitis, colitis, esophagitis </li></ul><ul><li>Acyclovir- resistant HSV infection and VZV infection </li></ul><ul><li>HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV </li></ul>
  47. 47. FOMIVIRSEN <ul><li>21 mer-phosphorothioate oligonucleotide </li></ul><ul><li>First FDA approved anti-sense therapy. Binding to target mRNA results in inhibition of immediate early region 2 protein synthesis – inhibiting viral replication </li></ul><ul><li>Injected intravitreally in CMV retinitis in AIDS </li></ul>
  48. 48. ANTIRETROVIRAL AGENTS
  49. 49. NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS(NRTIs) <ul><li>Competitive inhibition of HIV 1 reverse transcriptase and can be incorporated into the growing viral DNA chain to cause termination </li></ul><ul><li>Requires intracytoplasmic activation as a result of phosphorylation by cellular enzymes to the triphosphate form </li></ul><ul><li>Activity against HIV 1, HIV 2 </li></ul><ul><li>Lactic acidosis & severe hepatomegaly with steatosis </li></ul>
  50. 50. ZIDOVUDINE (Azithymidine, AZT) <ul><li>Deoxythymidine analog </li></ul><ul><li>Decrease rate of clinical disease progression and prolong survival of HIV infected individuals </li></ul><ul><li>Well absorbed from the gut and distributed </li></ul><ul><li>to most body tissues & fluids </li></ul><ul><li>Eliminated by renal excretion following glucorinadation in the liver </li></ul><ul><li>Combination therapy with other anti-retroviral agents enhance potency and delay resistance </li></ul>
  51. 51. CLINICAL USES <ul><li>HIV – associated dementia & thrombocytopenia </li></ul><ul><li>Reduce rate of vertical transmission (mother-newborn) by 23% </li></ul>
  52. 52. ADVERSE EFFECTS <ul><li>Myelosuppression – most common </li></ul><ul><li>Thrombocytopenia, hyperpigmentation of nails, myopathy, anxiety, confusion and tremulousness </li></ul><ul><li>Fatal lactic acidosis & severe hepatomegaly w/ steatosis </li></ul>
  53. 53. DIDANOSINE (ddl) <ul><li>Synthetic analog of deoxyadenosine </li></ul><ul><li>Activity is potentiated by hydroxyurea due to depletion of intraocular pools of d-ATP </li></ul><ul><li>Chewable, dispersable tablet, enteric coated </li></ul><ul><li>Contains phenylalanine and Na </li></ul><ul><li>Should be taken on an empty stomach </li></ul><ul><li>Food, fluroquinolones and tetracycline </li></ul><ul><li>should be given 2 hrs before didanosine </li></ul>
  54. 54. ADVERSE EFFECTS <ul><li>Most major clinical toxocity: Dose –dependent pancreatitis </li></ul><ul><li>Painful peripheral distal neuropathy </li></ul><ul><li>Diarrhea, hepatitis, esophageal ulceration, cardiomyopathy </li></ul><ul><li>CNS toxicity </li></ul><ul><li>Precipitate gouty attacks </li></ul><ul><li>Optic neuritis </li></ul>
  55. 55. EMTRICITABINE <ul><li>Formerly called FTC </li></ul><ul><li>Fluorinated analogue of LAMIVUDINE with a long intracellular half-life(>39 hrs) </li></ul><ul><li>Oral bioavailability: 93% </li></ul><ul><li>CSF level is LOW </li></ul><ul><li>Mean plasma half-line: 8-9 hours </li></ul><ul><li>Renal excretion thru GF and TS </li></ul><ul><li>Contraindicated in children, pregnant women, and patients with renal and hepatic failure (propylene glycol) </li></ul><ul><li>Most common side effects-HA, diarrhea, hyper-pigmentation in palms and soles </li></ul><ul><li>Can not combine with LAMIVUDINE </li></ul>
  56. 56. LAMIVUDINE (3TC) <ul><li>Cytosine analog ,synergistic with other antiretroviral nucleoside – Stavudine, Zidovudine </li></ul><ul><li>Oral bioavailability exceeds 80% and it is not food dependent </li></ul><ul><li>Elimination in urine is UNCHANGED </li></ul><ul><li>Used in combination therapy </li></ul><ul><li>NOTE: no combination with zalcitabine-may inhibit intracellular phosphorylation of one another thus decreasing potency. </li></ul><ul><li>Approved for the treatment of chronic Hepatitis B infection </li></ul>
  57. 57. ZALCITABINE (ddC) <ul><li>Cytosine analog with synergistic anti-HIV1 activity with a variety of antiretrovirals against both zidovudine sensitive and resistant strains </li></ul><ul><li>Associated with dose-dependent peripheral neuropathy </li></ul><ul><li>Oral and esophageal ulcerations </li></ul><ul><li>Increase bioavailability in combination with probenecid or cimetidine </li></ul><ul><li>Decrease bioavailability in combination with antacids and metoclopramide </li></ul>
  58. 58. STAVUDINE (d4T) <ul><li>Thymidine analog </li></ul><ul><li>High oral bioavailability, not food dependent </li></ul><ul><li>Renal excretion thru GF and TS </li></ul><ul><li>Major dose-limiting toxicity: </li></ul><ul><li>Dose-related peripheral sensory neuropathy </li></ul><ul><li>Pancreatitis, arthralgias, elevation of serum aminotransferases </li></ul><ul><li>Phosphorylation is reduced by zidovudine </li></ul>
  59. 59. ABACAVIR <ul><li>Guanosine analog </li></ul><ul><li>Well absorbed during oral administration </li></ul><ul><li>Metabolized by alcohol dehydrogenase and glucuronosyl-transferase to inactive metabolites </li></ul><ul><li>Fatal hypersensitivity reactions </li></ul><ul><li>Nausea, vomiting, diarrhea, headache, fatigue </li></ul><ul><li>Hyperglycemia, hypertriglyceridemia and lactic acidosis </li></ul>
  60. 60. NUCLEOTIDE INHIBITOR
  61. 61. TENOFOVIR <ul><li>Acyclic nucleoside phosphonate competitively inhibits HIV reverse transcriptase and cause chain termination after incorporation to DNA </li></ul><ul><li>Indicated for use in combination with other antiretroviral agents </li></ul>
  62. 62. Pharmacokinetics <ul><li>Oral bioavailability: 25% without food </li></ul><ul><li>39-40% after a high-fat meal </li></ul><ul><li>Serum half life: 17 hours and intracellular half-line is prolonged at more than 60 hours </li></ul><ul><li>Renal elimination thru GF and TS </li></ul><ul><li>Common Side Effects: GIT complaints </li></ul>
  63. 63. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS(NNRTIs) <ul><li>Bind directly to a site on the HIV –1 reverse transcriptase </li></ul><ul><li>Blockade of RNA and DNA dependent DNA polymerase activities </li></ul><ul><li>Binding site is near but distinct from that of the NRTI’s </li></ul><ul><li>Neither compete with nucleoside triphosphate nor require phosphorylation to be active </li></ul>
  64. 64. NEVIRAPINE <ul><li>Oral bioavailability is > 90% </li></ul><ul><li>Not food dependent </li></ul><ul><li>Used as a component of a combination antiretroviral regimen </li></ul><ul><li>Effective in the prevention of transmission of HIV from mother to newborn </li></ul><ul><li>Causes severe life threatening rashes </li></ul>
  65. 65. DELAVIRDINE <ul><li>Oral bioavailability of about 85 % </li></ul><ul><li>Metabolized to inactive metabolites by the CYP3A & CYP2D6 P450 enzymes </li></ul><ul><li>Plasma concentrations are reduced by antacids, didanosine, phenytoin, phenobarbital, carbamazepine, rifabutin, rifampin, nelfinavir & saquinavir </li></ul><ul><li>Concentrations increased by clarithromycin, fluoxetine, & ketoconazole </li></ul>
  66. 66. EFAVIRENZ <ul><li>Principally metabolized by CYP3A4 & CYP2B6 to inactive hydroxylated metabolites </li></ul><ul><li>Principal adverse effects: CNS (dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria) </li></ul><ul><li>Pyschiatric symptoms </li></ul><ul><li>rashes </li></ul>
  67. 67. PROTEASE INHIBITORS <ul><li>Protease--responsible for cleaving precursor molecules (immature budding particles) </li></ul><ul><li>PI---result in the production of immature, non-infectious viral particles </li></ul><ul><li>Associated w/ spontaneous bleeding in hemophilia A & B </li></ul><ul><li>Do not undergo process of phosphorylation </li></ul>
  68. 68. SAQUINAVIR <ul><li>Saquinavir H- hard gel capsule – poor bioavailability, should be taken within 2 hrs after a fatty meal </li></ul><ul><li>Saquinavir S – soft gel capsule – improved absorption 3x than hard gel capsule </li></ul><ul><li>Subject to first pass-metabolism by CYP3A4 </li></ul><ul><li>Levels are increased by ritonavir, nelfinavir, delavirdine, indinavir, ketoconazole, clarithromycin, & grapefruit juice </li></ul>
  69. 69. RITONAVIR <ul><li>An inhibitor of HIV 1 & HIV 2 proteases </li></ul><ul><li>High bioavailability that is increased with food </li></ul><ul><li>Common adverse effects: GIT disturbances, paresthesias, increase aminotransferase level, altered taste, hypertriglyceridemia </li></ul>
  70. 70. INDINAVIR <ul><li>Specific inhibitor of HIV- 1 & HIV-2 proteases </li></ul><ul><li>Higher CSF penetration </li></ul><ul><li>Must be consumed in empty stomach for maximal absorption </li></ul><ul><li>Most common adverse effects are indirect hyperbilirubinemia & nephrolithiasis due to crystalization </li></ul>
  71. 71. NELFINAVIR <ul><li>Higher absorption in the fed state </li></ul><ul><li>Common adverse effects: diarrhea & flatulence </li></ul>
  72. 72. AMPRENAVIR <ul><li>Rapidly absorbed from the GIT and </li></ul><ul><li>can be taken with or without food </li></ul><ul><li>High fat meals decrease absorption </li></ul><ul><li>Common adverse effects: nausea, vomiting, diarrhea, peri-oral paresthesias, rash </li></ul><ul><li>Steven Johnson’s syndrome </li></ul><ul><li>Inhibits CYP3A4 activity </li></ul>
  73. 73. FUSION INHIBITOR
  74. 74. ENFUVIRTIDE (T-20) <ul><li>Newly approved antiretroviral agent </li></ul><ul><li>Blocks entry into the cell </li></ul><ul><li>A synthetic 36-amino acid peptide binds to the gp41 subunit of the viral envelope glycoprotein thus preventing the conformational changes required for the fusion of the viral and cellular membranes </li></ul><ul><li>Administered subcutaneously in combination with other retroviral agents </li></ul>
  75. 75. ANTI-HEPATITIS AGENTS
  76. 76. ADEFOVIR <ul><li>Phosphorylated by cellular kinases to the active diphosphate metabolite </li></ul><ul><li>Competitively inhibits HBV DNA polymerase </li></ul><ul><li>Chain termination after incorporation into viral replication </li></ul>
  77. 77. ENTECAVIR <ul><li>Oral guanosine nucleoside analog </li></ul><ul><li>Competitively inhibits all 3 functions of HBV DNA polymerase—base priming, reverse transcription of negative strand and synthesis of positive strand of HBV DNA. </li></ul><ul><li>Taken by empty stomach half life 15 hours </li></ul><ul><li>Significantly HIGHER rates of HBV DNA viral suppression than lamivudine. </li></ul>
  78. 78. INTERFERON ALFA <ul><li>Endogenous proteins that exert complex antiviral immunomodulatory & antiproliferative activities through cellular metabolic process </li></ul><ul><li>Enzyme induction, suppression of cell proliferation, immunomodulatory activities & inhibition of viral replication </li></ul><ul><li>Inhibition of viral penetration & uncoating </li></ul><ul><li>Treatment of both HBV & HCV </li></ul>
  79. 79. INTERFERON ALPHA 2a <ul><li>Approved for the treatment of chronic Hepatitis C, AIDS associated Kaposi’s sarcoma, hairy cell leukemia, </li></ul><ul><li>chronic myelogenous leukemia </li></ul>
  80. 80. ADEFOVIR <ul><li>Phosphorylated by cellular kinases to the active diphosphate metabolite </li></ul><ul><li>Competitively inhibits HBV DNA polymerase </li></ul><ul><li>Chain termination after incorporation into viral replication </li></ul>
  81. 81. ENTECAVIR <ul><li>Oral guanosine nucleoside analog </li></ul><ul><li>Competitively inhibits all 3 functions of HBV DNA polymerase—base priming, reverse transcription of negative strand and synthesis of positive strand of HBV DNA. </li></ul><ul><li>Taken by empty stomach half life 15 hours </li></ul><ul><li>Significantly HIGHER rates of HBV DNA viral suppression than lamivudine. </li></ul>
  82. 82. INTERFERON ALFA <ul><li>Endogenous proteins that exert complex antiviral immunomodulatory & antiproliferative activities through cellular metabolic process </li></ul><ul><li>Enzyme induction, suppression of cell proliferation, immunomodulatory activities & inhibition of viral replication </li></ul><ul><li>Inhibition of viral penetration & uncoating </li></ul><ul><li>Treatment of both HBV & HCV </li></ul>
  83. 83. INTERFERON ALPHA 2a <ul><li>Approved for the treatment of chronic Hepatitis C, AIDS associated Kaposi’s sarcoma, hairy cell leukemia, </li></ul><ul><li>chronic myelogenous leukemia </li></ul>
  84. 84. INTERFERON ALPHA 2b <ul><li>Only preparation licensed for treatment of HBV & acute HCV </li></ul><ul><li>Leads to loss of HbeAg, normalization of aminotransferases </li></ul><ul><li>Administered subcutaneously or intramuscularly </li></ul><ul><li>Hairy cell leukemia, malignant melanoma, follicular non-Hodgkin’s lymphoma, AIDS related kaposi’s sarcoma, & chronic Hepatitis C </li></ul>
  85. 85. PEGYLATED INTERFERON ALFA <ul><li>Recently introduced for treatment of chronic hepatitis C </li></ul><ul><li>Longer duration with slower clearance </li></ul>
  86. 86. RIBAVIRIN <ul><li>Guanosine analog that is phosphorylated intracellularly by host cell enzymes </li></ul><ul><li>Interferes w/ the synthesis of guanosine triphosphate </li></ul><ul><li>Inhibit capping of viral messenger RNA </li></ul><ul><li>Inhibit viral RNA dependent RNA polymerase of certain viruses </li></ul><ul><li>Influenza A, parainfluenza, RSV, paramyxoviruses, HCV & HIV 1 </li></ul>
  87. 87. ANTI-INFLUENZA AGENTS
  88. 88. AMANTADINE/RIMANTADINE <ul><li>(1-aminoadamantane hydrochloride) </li></ul><ul><li> -methyl derivative - rimantadine </li></ul><ul><li>Inhibits uncoating of viral RNA influenza A within infected cell thus preventing replication </li></ul><ul><li>Effectively reduce the duration of symptoms of influenza when administered within 48 hrs of onset </li></ul><ul><li>Primary target is M2 proteins </li></ul>
  89. 89. OSELTAMIVIR/Zanamivir <ul><li>Neuroaminidase inhibitors </li></ul><ul><li>Inhibits replication of </li></ul><ul><li>both influenza A & B </li></ul><ul><li>5 day course regimen for </li></ul><ul><li>both influenza A & B </li></ul><ul><li>NOTE: Treatment for Bird Flu </li></ul>
  90. 90. UNCLASSIFIED
  91. 91. PALIVIZUMAB <ul><li>Prevention of RSV in high risk infants—premature and those with broncho dysplasia and congenital heart disease. </li></ul><ul><li>Humanized monoclonal antibody </li></ul>IMQUIMOD <ul><li>Immune response modifier effective in topical treatment of external genitalia & perianal warts </li></ul>

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