Antiviral Drugs.pptx Drugs and their uses

Antiviral Drug , their effects and uses

1. Antiviral Drugs

2. Viruses are obligate intracellular parasites They lack both a cell wall and a cell membrane They do not carry out metabolic processes They cannot make anything on their own, they use the cell’s materials to build themselves their replication depends primarily on synthetic processes of the host cell

3. Therefore, to be effective, antiviral agents must either block viral entry into or exit from the cell or be active inside the host cell clinical symptoms appear late in the course of the disease, at a time when most of the virus particles have replicated At this late, symptomatic stage of the viral infection, administration of drugs that block viral replication has limited effectiveness

4. Nonselective inhibitors of virus replication may interfere with host cell function and result in toxicity Progress in antiviral chemotherapy began in the early 1950s

5. General Principles of Viruses Viruses are intracellular parasites, i.e. they utilize: Host metabolic enzymes Host ribosome for protein synthesis Structure of viruses Nucleic acid core: DNA or RNA (never both) Often contain crucial virus-specific enzymes Surrounded by protein: “capsid” and sometimes an outer lipid “envelope” Complete viral particle: “ virion ” Often visible by electron microscopy

6. VIRAL REPLICATION : Adsorption and penetration into susceptible host cells Uncoating of viral nucleic acid Synthesis of early regulatory proteins Synthesis of RNA or DNA Synthesis of late regulatory proteins Assembly (maturation) of viral particles Release from cells

7. Treatment of respiratory virus infection Neuraminidase inhibitors ( Oseltamivir , Zanamivir , analogs of sialic acid) Inhibitors of viral coating ( Amantidine , rimantidine ) Ribavirin

8. Neuraminidase inhibitors Orthomyxoviruses that cause influenza contain the enzyme neuraminidase, which is essential to the life cycle of the virus neuraminidase inhibitors interfere with release of new virions from infected host cells thus halt the spread of infection within the respiratory tract oseltamivir and zanamivir are effective against both Type A and Type B influenza viruses

9. Mode of action: Infuenza virus employs a specific neuraminidase that is inserted into the host cell membrane for the purpose of releasing newly formed virions . Oseltamivir and zanamivir are transition-state analogs of the sialic acid substrate and serve as inhibitors of the enzyme activity

10. Pharmacokinetics: Oseltamivir is an orally active prodrug that is rapidly hydrolyzed by the liver to its active form Zanamivir is not active orally and is either inhaled or administered intranasally Both drugs are eliminated unchanged in the urine

11. Adverse effects: gastrointestinal discomfort and nausea Zanamivir should be avoided in individuals with severe reactive asthma or chronic obstructive respiratory disease Resistance: Mutations of the neuraminidase

12. Inhibitors of viral uncoating Amantadine and rimantadine are effective against influenza A infections equally effective in both treatment and prevention both drugs reduce the duration and severity of systemic symptoms if started within the first 48 hours after exposure to the virus

13. Mode of action: block the viral membrane matrix protein, M2, which functions as a channel for hydrogen ion This channel is required for the fusion of the viral membrane with the cell membrane that ultimately forms the endosome The acidic environment of the endosome is required for viral uncoating These drugs may also interfere with the release of new virions

14. Pharmacokinetics: Both drugs are well absorbed orally Amantadine distributes throughout the body and readily penetrates into the CNS rimantadine does not cross the blood-brain barrier to the same extent Amantadine is not extensively metabolized, rimantadine is extensively metabolized by the liver both the metabolites and the parent drug are eliminated by the kidney

15. Adverse effects: side effects of amantadine are mainly associated with the CNS insomnia, dizziness, and ataxia, hallucinations and seizures Amantadine and rimantadine should be used with caution in pregnant and nursing mothers

16. Resistance: result from a change in one amino acid of the M2 matrix protein Cross-resistance occurs between the two drugs

17. Ribavirin Ribavirin is a synthetic guanosine analog It is effective against a broad spectrum of RNA and DNA viruses ribavirin is used in treating infants and young children with severe RSV infections It is not indicated for use in adults with RSV.

18. also effective in chronic hepatitis C infections when used in combination with interferon- α -2b reduce the mortality and viremia of Lassa fever

19. Mode of action Drug is first converted to 5 phosphate derivatives, the major product being compound ribavirin triphosphate Which interfere with the synthesis of guanosine triphosphate, thus, inhibits capping of viral messenger RNA, Also inhibits the viral RNA-dependent polymerase of certain viruses

20. Ribavirin triphosphate inhibits the replication of a wide range of DNA and RNA viruses, including influenza A and B, parainfluenza, respiratory syncytial virus, paramyxoviruses, HCV, and HIV-1

21. Pharmacokinetics: effective orally and intravenously Absorption is increased if the drug is taken with a fatty meal drug and its metabolites are eliminated in the urine

22. Adverse effects: dose-dependent transient anemia Elevated bilirubin contraindicated in pregnancy

23. Treatment of hepatic viral infection

24. Hepatitis Hepatitis is an inflammation of the liver that is caused by a variety of infectious viruses  and noninfectious agents leading to a range of health problems, some of which can be fatal. There are five main strains of the hepatitis virus, referred to as types A, B, C, D and E

25.  In particular, types B and C lead to chronic disease in hundreds of millions of people and together are the most common cause of liver cirrhosis, liver cancer and viral hepatitis-related deaths and are the only hepatic viral infection for which therapy is currently available.

26. Treatment of hepatic viral infection Several agents effective against HBV and HCV are now available. Hepatitis B is may be treated with peg interferon α -2a which is injected SC once weekly. Interferon α -2b injected IM or SC three times weekly is also useful treatment for hepatitis B but interferon α -2a has better efficacy. oral therapy includes Lamivudine, adefovir , telbivudine,tenofovir .

27. Combination therapy of interferon with Lamivudine is no more effective then monotherapy with lamivudine. Patients with AIDS who are co-infected with hepatitis B are usually poor respondents to interferon therapy. Treatment for chronic hepatitis C includes combination of peg interferon α -2a or peg interferon α -2B plus ribavirin.

28. INTERFERON ALFA Interferons are host cytokines that exert complex antiviral, immunomodulatory, and antiproliferative actions is a family of naturally occurring, inducible glycoproteins that interfere with the ability of viruses to infect cells

29. interferons are synthesized by recombinant DNA technology At least three types of interferon exist (alpha, beta,gamma ) Mode of action: antiviral mechanism is incompletely understood Induction of host cell enzymes that inhibit viral RNA translation, ultimately leading to the degradation of viral mRNA and tRNA

30. Pharmacokinetics: Interferon is not active orally administered intralesionally, subcutaneously, or intravenously Adverse effects: flu-like symptoms on injection Fatigue and mental depression are common bone marrow suppression including granulocytopenia , neurotoxicity characterized by somnolence and behavioral disturbances

31. Lamivudine (3TC) Lamivudine is a cytosine analog (nucleotide analog) It is an inhibitor of both HBV DNA polymerase and HIV reverse transcriptase competitively inhibits HBV DNA polymerase at concentrations that have negligible effects on host DNA polymerase

32. Chronic treatment is associated with decreased plasma HBV DNA levels, improved biochemical markers, and reduced hepatic inflammation Pharmacokinetics: well absorbed orally and is widely distributed plasma half-life is about 9 hours Seventy percent is excreted unchanged in the urine

33. Adefovir dipivoxil It is a nucleotide analog phosphorylated to adefovir diphosphate , which is then incorporated into viral DNA This leads to termination of further DNA synthesis and prevents viral replication Both decreased viral load and improved liver function have occurred in patients treated with adefovir

34. Pharmacokinetics: administered once a day and is excreted in the urine drug should be used cautiously in patients with existing renal dysfunction

35. Entecavir is a guanosine analog approved for the treatment of HBV infections it competes with the natural substrate, deoxyguanosine triphosphate, for viral reverse transcriptase effective against lamivudine -resistant strains of HBV Liver inflammation and scarring are improved

36. It is given once a day Patients should be monitored closely for several months after discontinuation of therapy because of the possibility of severe hepatitis

37. Telbivudine is a thymidine analog that can be used in the treatment of HBV Unlike lamivudine and adefovir , telbivudine is not effective against HIV or other viruses drug is administered orally, once a day, with or without food eliminated by glomerular filtration as the unchanged drug, and no metabolites have been detected

38. Treatment of Herpesvirus Infections Herpesviridae  are a large family of DNA viruses that cause diseases in animals, including humans The members of this family are also known as  herpesviruses At least five species of Herpesviridae --  HSV-1 , which causes facial cold-sores, HSV-2 (genital herpes),  Varicella zoster virus , which causes chicken-pox and shingles,  Epstein-Barr virus , which causes mononucleosis (glandular fever) and  Cytomegaloviru s -- are extremely widespread among humans

39. Acyclovir It is the prototypic antiherpetic therapeutic agent Herpes simplex virus (HSV) Types 1 and 2, varicella -zoster virus (VZV), and some Epstein-Barr virus mediated infections are sensitive to acyclovir It is the treatment of choice in HSV encephalitis More effective then vidarabine .

40. The most common use of acyclovir is in therapy for genital herpes infections given prophylactically to seropositive patients before bone marrow and after heart transplants

41. Mode of action: It is a guanosine analog that lacks a sugar moiety. It is monophosphorylated in the cell by the herpes virus - encoded enzyme, thymidine kinase The monophosphate analog is converted to the di- and triphosphate forms by the host cells Acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase and is itself incorpotaed into viral DNA and cause premature DNA chain termination.

42. Pharmacokinetics: Administration of acyclovir can be by an intravenous, oral, or topical route The drug distributes well throughout the body, including the CSF Excretion into the urine occurs both by glomerular filtration and by tubular secretion The valyl ester, valacyclovir has greater oral bioavailability than acyclovir

43. Adverse effects: local irritation may occur from topical application headache, diarrhea, nausea, and vomiting may result after oral administration High-dose valacyclovir can cause GIT problems and thrombotic thrombocytopenia purpura in patients with AIDS Transient renal dysfunction may accoyr at high doses

44. Resistance: Altered or deficient thymidine kinase and DNA polymerases Cross-resistance to the other cyclovirs occurs

45. Cidofovir approved for treatment of CMV-induced retinitis in patients with AIDS it is a nucleotide analog of cytosine, the phosphorylation of which is not dependent on viral enzymes inhibits viral DNA synthesis available for intravenous, intravitreal (injection into the eye's vitreous humor between the lens and the retina), and topical administration

46. produces significant toxicity to the kidney and it is C/I in patients with preexisting renal impairment and in those who are taking nephrotoxic drugs (NSIDS) Probenecid must be coadministered with cidofovir to reduce the risk of nephrotoxicity.

47. Foscarnet Unlike most of the antiviral agents, foscarnet is not a purine or pyrimidine analog It is an inorganic pyrophosphate analog inhibits herpesvirus DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly without requiring activation by phosphorylation Foscarnet blocks the pyrophosphate binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates

48. It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV-1, and HIV-2 It is approved for CMV retinitis in immunocompromised hosts and for acyclovir-resistant HSV and herpes zoster infections Pharmacokinetics: Foscarnet is available in an intravenous formulation only It must also be given frequently to avoid relapse when plasma levels fall enters the bone matrix, from which it slowly leaves

49. Adverse effects: nephrotoxicity , anemia, nausea, and fever hypocalcemia and hypomagnesemia

50. Ganciclovir Ganciclovir is an analog of acyclovir that has 8- to 20-times greater activity against CMV - the only viral infection for which it is approved Mode of action: Like acyclovir, ganciclovir is activated through conversion to the nucleoside triphosphate by viral and cellular enzymes The nucleotide competitively inhibits viral DNA polymerase and can be incorporated into the DNA The combination of ganciclovir and foscarnet is synergistic in vitro against CMV

51. Pharmacokinetics: administered intravenously and distributes throughout the body, including the CSF Like valacyclovir , valganciclovir has high oral bioavailability Adverse effects: dose-dependent neutropenia Ganciclovir is carcinogenic as well as embryotoxic and teratogenic in experimental animals

52. Penciclovir and famciclovir Penciclovir is an acyclic guanosine nucleoside derivative that is active against HSV-I, HSV-2, and VZV It is only administered topically Penciclovir triphosphate has an intracellular half-life 20- to 30-fold longer than does acyclovir triphosphate

53. Famciclovir , another acyclic analog of 2'-deoxyguanosine, is metabolized to the active penciclovir The antiviral spectrum is similar to that of ganciclovir , but it is presently approved only for treatment of acute herpes zoster drug is effective orally

54. Vidarabine ( ara -A) Vidarabine ( arabinofuranosyl adenine, ara -A) is one of the most effective of the nucleoside analogs active against HSV-1, HSV-2, and VZV, but use is limited to treatment of immunocompromised patients with HSV keratoconjunctivitis Vidarabine is only available as an ophthalmic ointment

55. Trifluridine Trifluridine is a fluorinated pyrimidine nucleoside analog structurally very similar to thymidine competitively inhibit the incorporation of thymidine triphosphate into viral DNA Trifluridine monophosphate is an irreversible inhibitor of viral thymidine synthase It is active against HSV-1, HSV-2, and vaccinia virus

56. It is generally considered to be the drug of choice for treatment of HSV keratoconconjunctivitis and recurrent epithelial keratitis the use of trifluridine is restricted to topical application as a solution to the eye half-life is approximately 12 minutes Side effects include a transient irritation of the eye and palpebral (eyelid) edema

57. HIV Treatment Human immunodeficiency virus (HIV) is a  lentivirus  (slowly replicating retrovirus) that causes acquired immunodeficiency syndrome (AIDS) AIDS is a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, or breast milk In these body fluids, HIV is present as both free virus particles and virus within infected immune cells

58. HIV infects vital cells in the human immune system such as helper T cells (specifically CD4 +  T cells), macrophages, and dendritic cells When CD4 +  T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections

59. Selection of the appropriate combination is based on 1) avoiding the use of two agents of the same nucleoside analog, 2) avoiding overlapping toxicities and genotypic and phenotypic characteristics of the virus, 3) patient factors such as disease symptoms and concurrent illnesses, 4) impact of drug interactions, and 5) ease of adherence to a frequently complex administration regimen

60. NRTIs Mechanism of action: NRTIs act by competitive inhibition of HIV-1 reverse transcriptase These drugs are analogs of native ribosides which all lack a 3'-hydroxyl group Once they enter cells, they are phosphorylated by cellular enzymes to the corresponding triphosphate analog Because the 3'-hydroxyl group is not present, a 3'-5'-phosphodiester bond between an incoming nucleoside triphosphate and the growing DNA chain cannot be formed, and DNA chain elongation is terminated

61. Affinities of the drugs for many host cell DNA polymerases are lower than they are for HIV reverse transcriptase ABACAVIR: a guanosine analog that is well absorbed following oral administration (83%) and is unaffected by food Abacavir is often co-administered with lamivudine , and a once daily, fixed-dose combination formulation is available

62. DIDANOSINE : a synthetic analog of deoxyadenosine and is administered orally EMTRICITABINE : a fluorinated analog of lamivudine with a long intracellular half-life (> 24 hours), allowing for once-daily dosing

63. STAVUDINE : thymidine analog stavudine has high oral bioavailability (86%) that is not food-dependent TENOFOVIR: Tenofovir is an acyclic nucleoside phosphonate ( ie , nucleotide) analog of adenosine Like the nucleoside analogs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA

64. However, only two intracellular phosphorylations are required for active inhibition of DNA synthesis it is also approved for the treatment of patients with HBV infection Tenofovir is often co-administered with emtricitabine , and a once-daily, fixed-dose combination formulation is available, either alone or in combination with efavirenz

65. ZALCITABINE: Zalcitabine ( ddC ) is a cytosine analog with high oral bioavailability (87%) and a serum half-life of 1–2 hours Zalcitabine therapy is associated with a dose-dependent peripheral neuropathy that can be treatment-limiting in 10–20%

66. ZIDOVUDINE ( azidothymidine ; AZT ): It is a deoxythymidine analog that is well absorbed (63%) and distributed to most body tissues and fluids, including the CSF Zidovudine is available in a fixed-dose combination formulation with lamivudine , either alone or in combination with abacavir

67. Zidovudine was the first antiretroviral agent to be approved and has been well studied The drug has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals Also effective in the treatment of HIV-associated dementia and thrombocytopenia

68. The NRTIs are primarily renally excreted, and all require dosage adjustment in renal insufficiency except abacavir Adverse effects of NRTIs: toxicities of the NRTIs are believed to be due to inhibition of the mitochondrial DNA polymerase in certain tissues the dideoxynucleosides , such as zalcitabine , didanosine , and stavudine , have a greater affinity for the mitochondrial DNA polymerase

69. peripheral neuropathy, pancreatitis, and lipoatrophy All the NRTIs have been associated with a potentially fatal liver toxicity characterized by lactic acidosis and hepatomegaly with steatosis Drug Interaction: concomitant use of agents in the same class is contraindicated (for example, zidovudine plus stavudine

70. NNRTIs Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are highly selective, noncompetitive inhibitors of HIV-1 reverse transcriptase They bind to HIV reverse transcriptase at adjacent site to the active site, inducing a conformational change resulting in enzyme inhibition They do not require activation by cellular enzymes

71. do not have effect on the host blood-forming elements As a class, NNRTI agents are associated with GIT intolerance and skin rash Do not have cross-resistance with NRTIs However, cross-resistance exists within the NNRTI class DELAVIRDINE it has oral bioavailability of about 85%, but this is reduced by antacids or H 2 –blockers Serum half-life is approximately 6 hours

72. extensively metabolized by liver enzymes and is an inhibitor of cytochrome P450 Rash is the most common side effect of delavirdine EFAVIRENZ: Efavirenz can be given once daily because of its long half-life (40–55 hours) treatment results in increases in CD4+ cell counts and a decrease in viral load comparable to that achieved by protease inhibitors when used in combination with NRTIs

73. therefore, it is the preferred NNRTI on the DHHS ( The United States Department of Health and Human Services) guidelines Following oral administration, efavirenz is well distributed, including to the CNS Bioavailability is enhanced when taken with a high-fat meal it is a potent inducer of cytochrome P450 enzymes

74. adverse effects include dizziness, headache, vivid dreams, and loss of concentration Rash is the other most common side effect Efavirenz should be avoided in pregnant women NEVIRAPINE: It is used in combination with other antiretroviral drugs for the treatment of HIV-1 infections in adults and children

75. oral bioavailability of nevirapine is excellent (> 90%) and is not food-dependent The drug is highly lipophilic and achieves CSF levels Serum half-life is 25–30 hours Nevirapine is an inducer of the CYP3A4 family of cytochrome P450 Common side effects are rash, fever, headache, and elevated serum transaminases and fatal hepatotoxicity

76. serious epidermal reactions i.e. Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) Toxic epidermal necrolysis (TEN ) is a potentially life-threatening condition characterized by extensive exfoliation of the epidermis and mucous membrane, which may result in sepsis and death

77. ETRAVIRINE effective against strains of HIV that have developed resistance to first-generation NNRTIs most common adverse effects of etravirine are rash, nausea, and diarrhea it has many therapeutically significant drug-drug interactions

78. HIV Protease Inhibitors Introduced in 1995 Mechanism of action: All the drugs of this class are the reversible inhibitors of HIV aspartyl protease which is a viral enzyme responsible for cleavage of viral polyproteins into number of essential enzymes( reverse transcriptase, protease, integrase).

79. The protease inhibitors exhibit at least a thousand-fold greater affinity for HIV-1 and HIV-2 enzymes than they have for human proteases The inhibition prevents maturation of the viral particles and results in the production of non-infectious virions Treatment with protease inhibitor and two NRTIs results in a decrease in the plasma viral load to undetectable levels in 60 to 95 percent of patients

80. Pharmacokinetics: Most protease inhibitors have poor oral bioavailability High-fat meals substantially increase the bioavailability of some, such as nelfinavir and saquinavir Metabolism is extensive, and very little of the protease inhibitors are excreted unchanged in the urine

81. The HIV protease inhibitors are all substantially bound to plasma proteins Adverse effects: parathesias , nausea, vomiting, and diarrhea Chronic administration results in fat redistribution, including loss of fat from the extremities and its accumulation in the abdomen and the base of the neck, and breast enlargement

82. Drug interactions: Drug interactions are a common problem for all protease inhibitors because these drugs are potent inhibitors of CYP isozymes Resistance: mutations of the protease gene

83. Entry Inhibitors Enfuvirtide : Enfuvirtide is a fusion inhibitor For HIV to gain entry into the host cell, it must fuse its membrane with that of the host cell Enfuvirtide is a 36-amino-acid peptide that binds to gp41, preventing the conformational change in viral transmembrane glycoprotein

84. As a peptide, it must be given subcutaneously Most of the adverse effects are related to the injection, including pain, erythema , induration , and nodules, which occur in almost all patients It is an expensive medication

85. Maraviroc : second entry inhibitor Because it is well absorbed orally, it is formulated as an oral tablet Maraviroc blocks the CCR5 coreceptor that works together with gp41 to facilitate HIV entry through the membrane into the cell

86. HIV may express either the CCR5 coreceptor or the CXCR4 coreceptor , or both Only the CCR5-expressing virus can be treated with maraviroc Maraviroc is metabolized by cytochromeP450 liver enzymes Maraviroc is generally well tolerated

87. Integrase Inhibitors Raltegravir (RAL) specifically inhibits the final step in integration of stand transfer of the viral DNA into our own host cell DNA has a half-life of approximately 9 hours and is therefore dosed twice daily well-tolerated with nausea, headache and diarrhea as the most common side effects