Antiviral Agents.pptx by dr fahad.......

Abid

1. Antiviral Agents 28 th Nov. 2011

2. Cumulative Mechanism of Antiviral A gents

3. Classification Anti-herpes virus: Idoxuridine , acyclovir, valacyclovir , famciclovir , ganciclovir , forscarnet , fomivirsen Anti-retrovirus: Nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine (AZT), Didanosine , Zalcitabine , Stavudine , Lamivudine , Abacavir Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine , Efavirenz , Delaviridine Protease inhibitors Ritonavir , Indinavir , Nelfinavir , Saquinavir , Lopinavir Anti-influenza virus Amatidine , Rimantadine , Neuraminidase inhibitors ( oseltamiveer , zanamivir ) Nonselective antiviral drugs Ribavirin , Lamivudine , Interferon alpha

4. Acyclovir (ACV) Mechanism of Action Resistance Reduced activity of viral thymidine kinase Altered DNA polymerase Indications (HSV-I>HSV-II> VZV=EBV >CMV) Genital Herpes simplex (type II) Mucocutaneous H. simplex (type I) : remains localized to lips and gums H.simplex encephalitis (type I) H. simplex (type I) keratitis : because of good corneal penetration Herpes zoster Chickenpox

5. Pharmacokinetics & Adverse Effects Pharmacokinetics Available in oral, intravenous, and topical formulations. Oral bioavailability is 15-20%. Plasma protein binding is low, diffuses into most tissues and body fluids. Cleared primarily by glomerular filtration and tubular secretion. Adverse Effects Topical: stinging and burning sensation Oral: headache, nausea, malaise Intravenous: rashes, sweating, emesis and fall in BP Other toxicities: i . Renal insufficiency (normalization on discontinuation of drug) ii. Encephalopathy : tremors, lethargy, disorientation, hallucinations, convulsions and coma

6. Valacyclovir L- valyl ester of acyclovir ~ conv to ACV thru first-pass in liver/intestine Better bioavailability than ACV Indicated in recurrent genital herpes, CMV (pro in organ transplant) Well tolerated with NV, rash. confusion, hallucinations, and seizures (at higher doses)

7. Famciclovir & Peniciclovir Acyclic guanosine analog Oxidized to penciclovir ~ Mechanim similar to ACV ~ no chain termination Indicated for genital herpes, acute zooster Minor side effects like NVD & headache Peniciclovir 1 % cream used for herpes liabialis

8. Docosanol & Trifluridine Docosanol Fusion inhibitor (of CM & HSV envelope) ~ entry prevented Used topically 10% cream for orolabial herpes Trifluridine fluorinated pyrimidine nucleoside ~ inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia , and some adenoviruses 1% soln for keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 or HSV-2 + IFN- α for ACV-resistant HSV

9. Vidarabine Adenosine analog Against HSV, VZV, CMV, HBV and some RNA viruses. Phosporylated intracellular by host enzymes to form ara -ATP, incorporated into both viral and cellular DNA. → excessive toxicity Rapidly metobolized to hypoxanthine arabinoside . Instability and toxicity limited its clinical utility . Topical application for acute keratoconjunctivitis , superficial keratitis , and recurrent epithelial keratitis due to HSV-1 and HSV-2. Intravenous for treatment of HSV encephalitis, neonatal herpes, and VZV infection in immunocompromised patients.

10. Ganciclovir Initial PO 4 by virus specific protein kinase phosphotransferase UL97 in CMV-infected cells. 100 times more active against CMV. Poor oral bio i.v . GCV for CMV colitis, esophagitis , and pneumonitis Used in comb with foscarnet for CMV retinitis Most common ADR’s inc. Myelosuppression . Others inc. nausea, diarrhea, fever, rash, headache, insomnia, and peripheral neuropathy

11. Valganciclovir L- valyl ester prodrug of ganciclovir ~ hydrolyzed to ganciclovir by intestinal and hepatic esterases . Indications similar to GCV

12. Foscarnet Mechanism Inorganic pyrophosphate analog inhibits viral DNA polymerase, RNA polymerase, and HIVreverse transcriptase directly without requiring activation by phosphorylation Blocks the pyrophosphate binding site of these enzymes Inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates . Spectrum HSV, VZV, CMV, EBV, HHV-6, HHV-8, and HIV-1. Phamacokinetics i.v . only cos of poor oral bio & GI intolerance to oral

13. Indications & ADR Indications CMV retinitis ( intravitreally ), CMV colitis, CMV esophagitis , acyclovir-resistant HSV infection, and acyclovir-resistant VZV infection + GCV ~ synergistic (ADR’s too) ADR Renal impairment ~ hypo- or hypercalcemia , hypo- or hyperphosphatemia , hypokalemia , and hypomagnesemia ( Pentamidine ) CNS ~ headache, hallucinations, and seizures ( Imipenem )

14. Cidofovir Mechanism Cytosine nucleotide analog~ PO 4 to active diPO 4 independent of viral enzymes. Cidofir diPO4 ~ potent inhibitor of viral DNA polymerase ~ competitive inhibition of DNA syn Indications i.v . for CMV retinitis & (Experimental) adenovirus infections ADR Nephrotoxicity ( prehydration with normal saline/ probenecid ) ~ Proteinuria , azotemia , metabolic acidosis, and Fanconi's syndrome ( int with other nephrotoxic ) Mutagenic, gonadotoxic , embryotoxic

15. Idoxuridine Competitive inhibition of thymidylic acid synthase → block DNA synthesis ~ No effect on RNA virus. Only topical application because of its greater side effects in systemic application. Treatment of ocular or dermal infections due to herpesvirus or cowpox virus, especially acute epithelial keratitis due to herpesvirus .

16. Antiretroviral Agents HAART ~ tailored combo Life cycle of Retroviruses 6 classes of antiretrovirals NRTI’s NNRTI’s PI’s Fusion inhibitors CCR5 receptor antagonists Integrase Inhibitors

17. Nucleoside Reverse Transcriptase Inhibitors Derivative s of Pyrimidine : Zidovudine (AZT), Zalcitabine ( ddC ), Stavudine (d4T), Lamivudine (3TC) Derivative s of Purine : Didanosine ( ddI ), Abacavir (ABC)

18. Mechanism of Action Competitive inhibition of HIV-1 reverse transcriptase; Incorporated into the growing viral DNA chain → cause termination Drugs requires intracytoplasmic activation--- phosphorylation → triphosphate form Most have activity against HIV-2 as well as HIV-1.

19. Zidovudine (AZT) Azidothymidine ~ Deoxythymidine analog Anti-HIV-1 and HIV-2 Pharmacokinetics Well absorbed from the gut and distributed to most body tissues and fluids, including the cerebrospinal fluid. Eliminated primarily by renal excretion following glucuronidation in the liver . Uses + Lamivudine Decrease the rate of clinical disease progression and prolong survival. Treatment of HIV-associated dementia & thrombocytopenia Reduce the rate of vertical transmission of HIV. Adverse effect Myelosuppression → anemia or neutropenia ; gastrointestinal intolerance, headachs , insomnia

20. Zalcitabine ( ddC ) Cytosine analog ~ Anti-HIV-1 High Oral bioavailablity but short t 1/2 . ADR’s Dose-dependent peripheral neuropathy. Contraindication to use with other drugs that may cause neuropathy ( stavudine , didanosine , and isoniazid ) . Oral and esophageal ulcerations Pencreatitis (with didanosine ) Not to be given with Lamivudine (interference)

21. Stavudine (4dT) Thymidne analog ( d4T)~ Anti-HIV-1 and HIV-2 High oral bioavailability (86%) that is not food-dependent. Low PPL. Good CSF penetration. Excretion is by active tubular secretion and glomerular filtration. Dose-limiting toxicity is a dose-related peripheral sensory neuropathy. Pancreatitis, arthralgias , elevation in serum aminotransferases . Lactic acidosis with hepatic steatosis or didanosine (also pencreatitis ) Not used with AZT because AZT may reduce the phosphorylation of d4T.

22. Didanosine (ddI) Synthetic analog of deoxyadenosine Adequate oral bioavailability. Low PPL & CSF penetrations. Eliminated by glomerular filtration and tubular secretion. Should be taken on an empty stomach. Given in combination with hydroxyurea ~ depletion of intracellular pools of dATP . Dose-dependent pancreatitis, painful peripheral distal neuropathy, Diarrhea, Hepatitis, Esophageal ulceration, Cardiomyopathy , Central nervous system toxicity (headache, irritability, insomnia)

23. Abacavir (ABC) Guanosine analogue High absorption after oral distribution unaffected by food ~ glucuronidation and carboxylation HS (fever, malaise, nausea, vomiting, diarrhea, and anorexia, dyspnea , pharyngitis , skin rash).

24. Emtricitabine (FTC) Fluorinated analog of lamivudine Good oral bio (unaffected by food)~ elimination by GF & ATS ADR’s inc headache, diarrhea, nausea, and asthenia. Hyperpigmentation of palms/soles

25. Lamivudine (3TC) Cytosine analog High oral bio (not dep on food) Comb with zidovudine and stavudine for HIV-1 ADR’s: headache, dizziness, insomnia, fatigue, and gastrointestinal discomfort +TMP-SMX ~ ↑bio. + Zal ~ inhibits i/c phophorylation of one another

26. Tenofovir Acyclic nucleoside phosphonate analog of adenosine ~ only 2 i/c PO 4 req Low oral bio (+fatty meal) Nausea, diarrhea, vomiting, flatulence Renal failure, Fanconi’s synd , Bone marrow toxicity with demineralization (loss of Ca/PO 4 due to proximal renal tubulopathy ), fetotoxic

27. Nonnucleoside reverse transcriptase inhibitors Including delavirdine , nevirapine , efavirenz . Bind directly to a site on the viral reverse transcriptase that is near to but distinct from the binding site of the NRTIs. Neither compete with nucleoside triphosphates nor require phosphorylation to be active. The binding to the enzyme’s active site results in blockade of RNA- and DNA-dependent DNA polymerase activities.

28. Specific activity against HIV-1. Cross-resistance among this class of agents. The rapid emergence of resistance prohibits monotherapy with any of the NNRTIs. No cross-resistance between the NNRTIs and the NRTIs or the protease inhibitors. Oral bioavailability is high. Metabolized by the CYP3A P450 isoform , excreted in the urine. Adverse effects: skin rash

29. Protease inhibitors Including ritonavir , nelfinavir , saquinavir , indinavir amprenavir . Active against both HIV-1 & -2 No I/C activation needed. Combination therapy with other agents is recommended to avoid emergence of resistance, because of specific genotypic alterations. Gag and Gag- Pol gene Polyproteins , Immature budding particles translate Final structural proteins, Mature virioncore protease

30. Pharmacokinetics & Interactions Pharmacokinetics Poor oral bio. Nelfinavir & saquinavir with fatty meal ( Indinavir ~ ↓ ed bioavailability) All substrates of CYP3A4 ~ extensive metabolism ~ urinary excretion Drug Interactions Drug interactions shown. Rotinavir most potent inhibitor of CYP ( Saquinavir ; least). Interactions shown with simvastatin or lovastatin ( rhabdomyolysis ), midazolam or triazolam (Excessive sedation), fentanyl (Resp. dep ). warfarin , sildenafil and phenytoin Rifampin & St. John's wort (inducers)

31. ADRs Adverse Effects Parathesias , nausea, vomiting, and diarrhea Syndrome of altered body fat distribution (buffalo hump and truncal obesity, with facial and peripheral atrophy) with exception of atazanavir Insulin resistance Hyperlipidemia bone loss and osteoporosis

32. PI’s I Atazanavir OD ~ acidic medium for abs~ biliary exc. (not for hepatic insuf ) May cause indirect hyperbilirubinemia , ↑ ed hep enzymes (with HBV/HCV). No dyslipidemia . ECG changes. Inhibitor of CYP (3A4, 2C9)~ Interactions Duranavir + ritonavir Sulfonamide allergy Interactions Fosamprenavir prodrug of amprenavir (+ rito ) Rash (SJS) Both inducer & inhibitor of 3A4

33. PI’s II Indinavir Abs. max at acidic indirect hyperbilirubinemia and nephrolithiasis . Lopinavir + Ritonavir (Well-tolerated) diarrhea, abdominal pain, nausea, vomiting, and asthenia Nefinavir high absorption in the fed state diarrhea and flatulence ( antidiarrheals ) Ritonavir +food ~ high PPL ~ fecal ( Hep . Insuff ) GI dist., dyslipidemias Inhibitor of 3A4 (Advantage)

34. PI’s III Saquinavir hard gel capsule (+ nelfinavir )~ poor oral bioavailability ~ fecal exc GI, Rhinitis (Low dose) Tipranavir Poor oral bio (Fatty meal)~ + ritonavir ~ both inh / ind 3A4 GI, rash, hepatic, increased risk for intracranial hemorrhage

35. Entry Inhibitors V iral envelope glycoprotein complex gp160 attachement to CD4 → changes in gp120 → access to CCR5 (/CXCR4) → changes in gp120 →fusion & entry of virus Drugs in this class include Enfuvirtide , & Maraviroc .

36. FI’s Enfuvirtide +gp41 ~ changes prevented Only active againse HIV-1~ admn by s.c . inj ~ meta by CYP Irritation at inj site, HS, pneumonia Maraviroc + CCR5 ~ blocking entry Only effective against ones showing tropism for CCR5 Rapid ( var ) abs. ~ fecal excretion mainly cough, upper respiratory tract infections, muscle and joint pain, diarrhea, sleep disturbance, and increases in hepatic transaminase levels

37. Integrase Inhibitors Raltegravir Binds to enzyme integrase needed for replication of HIV-1 & -2 Inhibits strand transfer → integration of reverse-transcribed HIV DNA into the chromosomes of host cells inhibited Oral bio not established ~ glucuronidation ADR’s inc GI, headache, CK elevation

38. Antihepatitis Agents A-E Treatment of Hepatitis C Treatment of Hepatitis B IFN & oral lamivudine , adefovir , enetecavir , or telbivudine Ribavirin

39. IFN- α Mechanism Naturally occurring, inducible glycoproteins Induction of enzymes ~ inhibition of viral RNA syn ~ degradation of viral mRNA/ tRNA . Signalling ~ inhibition of viral penetration, protein processing, maturation/release, ↑ ed expression of MHC Ag’s, ↑ ed phagocytotic activity & ↑ ed CTL proliferation & survival. Pharmacokinetics S.c ./ im /iv only ~ cellular uptake ~ GF and degradation ADR’s fever, chills, myalgias , arthralgias , and gastrointestinal disturbances. bone marrow suppression including granulocytopenia . CNS toxicity ~ somnolennce & behavioral changes Contra ind in hep decomp , Autoimmue , Arrhythmia, pregnancy

40. Adefovir Dipivoxil Pharmacokinetics Good oral bio ~ hydolyzed to parent compound by intestinal & blood esterases . Excreted by GF & ATS Pharmacodynamics Diester prodrug of adefovir ~ PO 4 by cellular kinase to active ~ competitively inhibits HBV DNA polymerase ~ chain termination. Used for HBV, HIV, and HSV. ADR’s Dose-dependent nephrotoxicity headache, diarrhea, asthenia, and abdominal pain, low serum creatine levels, embryotoxic Contraindicated in lactic acidosis and hepatic steatosis

41. Entecavir Oral Guanosine analog Inhibits base priming, reverse transcription of the negative strand, and synthesis of the positive strand of HBV DNA Oral full bio ( dep on food) Well-tolerated with headache, fatigue, dizziness, and nausea

42. Telbivudine Thymidine analog~ TriPO4~ Chain termination Orally effective (no effect of food) ~ no meta ~ renal exc. Mild ADR’s fatigue, headache, abdominal pain, upper respiratory infection, increased creatine phosphokinase levels, and nausea and vomiting, lactic acidosis. Contraindicated in steatosis

43. Ribavirin Synthetic guanosine analog Dynamics TriPO4 active~ inhibiting guanosine triphosphate formation preventing viral mRNA capping blocking RNA-dependent RNA polymerase Kinetics Oral.iv . (+fatty meal) ADR dose-dependent transient anemia Elevated bil Teratogen

44. Anti-Influenza Agents Classified by their core proteins (A,B,C) subtype HN (H1N1, H1N2, and H3N2) Neuraminidase & uncoating inhibitors

45. Neuraminidase inhibitors Oseltamivir & zanamivir Pharmacodynamics Neuraminidase help viral release from cell by cleaving sialic acid from GP transition-state analogs of the sialic acid substrate ~ inhibition Pharmacokinetics Os is orally active pro ~ hydrolyzed in liver to active. Zana inhaled/ Intranansal Both eliminated unchaged in urine ADR (OS) GI ( Zan ) RT irritation

46. Inhibitors of viral uncoating I Pharamcodynamics Amantadine & Rimantadine block M2 (viral membrane matrix protein ~ H ion channel). Important for fusion ~ formation of endosome Interfere with release of new virion Pharmacokinetics Ready oral abs. & dist throughout Am ~ CNS penetration. Little meta ~ urinary exc. (Renal failure) Rim ~ no CNS penetration. Extensive metabolism (hydroxylation, conjugation, and glucuronidation ) ~ Renal exc Indications Equally effective in treatment & prevention of Inf A (only) No effect immune response to vaccine. Protection before the humoral response

47. Inhibitors of viral uncoating II ADR’s Am ~ CNS Minor (insomnia, dizziness, and ataxia) Major (hallucinations and seizures). Contraindicated in with psychiatric problems, cerebral atherosclerosis, renal impairment, or epilepsy Rim ~ Lesser CNS effects Both cause GI disturbances

48. Anti-herpes Mechanism of Action Back

49. Anti-herpes Mechanism of Action I

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54. Nevirapine (NVP) Good oral abs. ~ lipophilic enters fetal/milk/CNS~ glu by CYP ADRs include rash( upto 20%: more in women), fever, headache, somnolence and elevated serum transaminases and fatal hepatotoxicity ↑ es metabolism of PI’s,